Summary

Symptoms and signs of septic arthritis are an important medical emergency, with high morbidity and mortality. We review the changing epidemiology of septic arthritis of native joints in adults, encompassing the increasing frequency of the disorder and its evolving antibiotic resistance. We discuss various risk factors for development of septic arthritis and examine host factors (tumour necrosis factor α, interleukins 1 and 10) and bacterial proteins, toxins, and enzymes reported to be important determinants of pathogenesis in mouse models. Diagnosis of disease is largely clinical, guided by investigations and the opinion of skilled clinicians. We emphasise the need for timely medical and surgical intervention—most importantly, through diagnostic aspiration of relevant joints, choice of suitable antibiotic, and appropriate supportive measures. Management is growing in complexity with the advent of novel and antibiotic-resistant causative microorganisms and within the current climate of increased immunosuppression. Findings from animal models and patients are shedding light on disease pathogenesis and the possibility of novel adjunctive treatments, including systemic corticosteroids, cytokines and anticytokines, and bisphosphonates.

Introduction

The presentation of a patient with one or more hot swollen joints is a common medical emergency. Such symptoms have a broad differential diagnosis, and, although not the most typical, the most serious cause is septic arthritis. This disease has substantial morbidity and mortality.

Diagnosis of septic arthritis can be challenging even for doctors skilled in the management of musculoskeletal disease. Usually, patients present in the primary-care or emergency-room setting, and doctors working in these areas could have had little training in rheumatic disease. Delayed or inadequate treatment can lead to irreversible joint destruction and, even in expert hands, case-fatality is generally around 11%. This frequency is raised in polyarticular disease, with estimates as high as 50%.1 Moreover, resistance to conventional antibiotics is a growing difficulty.

Epidemiology

Accurate information about the epidemiology of septic arthritis is limited by several factors. First, data are mainly from retrospective cohorts, because the uncommon nature of the disorder makes prospective studies logistically difficult. Second, case-definitions generally restrict cases to those that are proven bacteriologically. Although this approach has nosological advantages, there are practical limitations. In patients in whom septic arthritis is strongly suspected clinically, the subsequent diagnosis might or might not be established microbiologically, and, historically, this situation has led to difficulties with disease categorisation.

Usual case-definition relies on modified criteria used by Newman 2 and requires one of four points to be met: (1) isolation of a pathogenic organism from an affected joint; (2) isolation of a pathogenic organism from another source (eg, blood) in the context of a hot red joint suspicious of sepsis; (3) typical clinical features and turbid joint fluid in the presence of previous antibiotic treatment; and (4) postmortem or pathological features suspicious of septic arthritis. However, case-series differ in their exclusion criteria. These typically include orthopaedic, gonococcal, tuberculous, and paediatric infections. Despite these considerations, several conclusions about epidemiology can be drawn.

The incidence of proven and probable septic arthritis in western Europe is 4—10 per 100 000 patient-years per year.3—6 This rate is amplified in disadvantaged groups from northern Europe1 and in Australia, where prevalence is 29 cases per 100 000 of the aboriginal Australian population, with a relative risk of 6·6 compared with the white Northern Territory Australian population.3 The incidence of septic arthritis seems to be rising, and this increase is linked to augmented orthopaedic-related infection6 and an ageing population, more invasive procedures being undertaken, and enhanced use of immunosuppressive treatment.

Although all ages can be affected, septic arthritis is a disease that usually arises in elderly people and very young children. Previous joint pathology (eg, rheumatoid arthritis, osteoarthritis, crystal arthropathy, and other forms of inflammatory arthritis) predisposes individuals to development of sepsis. Quantification of this increased risk is hard to establish, but it seems likely that rheumatoid arthritis presents a greater risk than osteoarthritis. A prospective study from Amsterdam, in which more than 7000 patients were followed up for 3 years with 37 incident cases of sepsis, showed that risk factors for development of septic arthritis included age older than 80 years, diabetes, rheumatoid arthritis, and recent joint surgery.7 Raised prevalence in patients on haemodialysis has also been reported and could be around 500 cases per 100 000 patients.8 Rheumatological risk factors remain important, however, even in this group.

Skin infection is an important risk factor for septic arthritis.7 Joint injection with corticosteroids has been suggested as an important cause of septic arthritis, but is rare. The precise risk is difficult to quantify, but it is probably about four cases per 10 000 injections.6 Postarthroscopic septic arthritis has a prevalence of around 14 per 10 000 procedures (0·14%).6 Moreover, disease-modifying drug treatment can predispose some patients with rheumatoid arthritis to septic arthritis,9 but to date, antagonists of tumour necrosis factor α for rheumatoid arthritis do not seem to have altered the frequency of septic arthritis. The panel summarises typical risk factors for development of septic arthritis.

Panel
Risk factors for development of septic arthritis

*
Rheumatoid arthritis or osteoarthritis
*
Joint prosthesis
*
Low socioeconomic status
*
Intravenous drug abuse
*
Alcoholism
*
Diabetes
*
Previous intra-articular corticosteroid injection
*
Cutaneous ulcers

In all age and risk groups, the most frequent causative organisms identified are Staphylococcus aureus followed by other gram-positive bacteria, including streptococci.4, 5, 10 Different microbes increase in importance in specific risk groups, but even in these populations, the most typical organisms remain S aureus and streptococci. Findings of studies have noted consistently a worrying increase in meticillin-resistant S aureus (MRSA) infection in several health-care systems, and particularly in intravenous drug abusers,1 elderly people, and individuals with infections related to orthopaedic procedures.10 The constant evolution of microorganisms has also led to emergence of new resistant strains of MRSA. These strains have been isolated from community-associated infections and have become a major problem in the USA and are starting to be seen in Europe and the UK.11, 12 They have a different antibiotic sensitivity from hospital-acquired MRSA and from isolates from intravenous drug abusers in Europe.12, 13

Intravenous drug abusers are especially susceptible to mixed bacterial infections, fungal infections, and unusual organisms. Immunosuppression has been suggested as an important risk factor for development of septic arthritis but the precise extent of this risk is unclear. Researchers studying patients with HIV infection conclude that the risk of septic arthritis relates to intravenous drug abuse rather than HIV status.14, 15
The frequency of gram-negative organisms is amplified in the older population, presumably because of an increased prevalence of comorbidities such as urinary-tract infections and cutaneous ulceration.5, 7 A slight rise in invasive Haemophilus infection in adults has also been suspected.10

Traditionally, gonococcal infection has been emphasised as a cause of septic arthritis, particularly in young adults. Several studies, however, have established that this organism is a rare cause of so-called dermatitis-arthritis syndrome in Europe and North America.1, 4, 5, 10, 16 In fact, in detailed studies with PCR techniques, Neisseria meningitidis is by far the most typical cause of dermatitis-arthritis. Neisseria gonorrhoeae is still prevalent in other parts of the world, such as aboriginal communities in Australia3 and Rwanda.17 This change needs to be considered when contact tracing and in development of prophylactic regimens.

Pathogenesis

Infection can be introduced into a joint either as a result of haematogenous spread or by direct inoculation, occurring with trauma or iatrogenically. Bacteraemia is more likely to arise in immunosuppressed individuals and patients admitted to hospital, particularly those who have invasive procedures, intravascular devices, or urinary catheters. Infection will most probably become established if the patient is immunosuppressed or the joint is damaged.4

Beyond traditional risk factors for sepsis, key advances in our understanding of the pathogenesis of septic arthritis have come from work in animals. Tarkowski and colleagues have developed an experimental mouse model of septic arthritis mediated by S aureus.18 This model parallels pathogenesis of human disease closely in that the pathogen is introduced haematogenously by intravenous injection. More than 90% of mice develop septic arthritis within 24 h of inoculation and their joints have a severe degree of bone erosion similar to changes seen in the human septic joint. This model has been used to study both host and bacterial virulence factors implicated in the establishment of joint infection. Figure 1 shows a representation of the pathogenesis of staphylococcal septic arthritis.

Pathogenesis of staphylococcal septic arthritis
TNFα=tumour necrosis factor α. IL=interleukin. Adapted from ref 30, with permission of Future Medicine.

Host factors

By genetic manipulation of animal models to induce disease, host factors affecting the response to S aureus can be studied. Genetic deletion of macrophage-derived cytokines (including lymphotoxin α, tumour necrosis factor [TNF] α, and interleukin 1 receptor) reduces host protection in S aureus sepsis, causing increased morbidity and mortality.19, 20 Similarly, absence of the anti-inflammatory cytokine interleukin 10 in knockout mice seems to amplify the frequency and severity of staphylococcal joint disease secondary to reduced clearance of pathogens.21 By contrast, the interleukin 4 knockout mouse is associated with diminished incidence and mortality, which could be attributable to the role of interleukin 4 in enhancement of bacterial growth or reduction of bacterial clearance from the joint space.22

The role of these cytokines has yet to be fully investigated in human septic arthritis. However, data from these murine studies suggest that similar work in patients would prove useful to show not only that the cytokines TNFα and interleukins 1 and 10 could be vital to mount an effective immune response to S aureus infection but also that genetic variation in expression of these cytokines might play a part in differential susceptibility to, and severity of, septic arthritis. Similarly, genetic variation leading to high expression of interleukin 4 might lead to increased susceptibility to septic arthritis.

Bacterial factors

S aureus produces many virulence factors, including diverse extracellular toxins, enzymes, and other cell-associated components. These factors have been studied in Tarkowski’s murine model by genetic deletion or mutation,18 and results indicate that certain extracellular virulence factors have a crucial role in promotion of erosive joint damage in septic arthritis.23 Components of the bacterial cell wall also modulate bacterial virulence. For example, studies of S aureus strains deficient in staphylococcal protein A have resulted in less severe disease in mice.24 Specific oligonucleotide sequences within bacterial DNA also contribute to inflammatory processes in septic joints, and synthetic analogues of these sequences trigger joint inflammation and might play a part in both aseptic and septic arthritis.25

The virulence of bacterial molecules can be studied by immunisation of animals with purified concentrates of bacterial components. By this approach, specific bacterial adhesins that facilitate S aureus infection have been well characterised.26 For example, inactivation of adhesins through vaccination with either recombinant collagen adhesin or fibrinogen-binding adhesin-clumping factor A results in a protective effect in mice subsequently challenged intravenously with S aureus.27, 28 Similarly, in an alternative murine model developed by Tissi and colleagues,29 factors implicated in pathogenesis of group B streptococcal infection have been evaluated.30 These data from animal models show that, in addition to variable host-susceptibility factors, considerable bacterial variability exists that could account for why some infections are mild and self-limiting and others are severe or fatal.

Some strains of S aureus are positive for the virulence factor Panton-Valentine leucocidin (PVL) cytotoxin, which enables them to survive in neutrophils. Such strains have been associated with fulminant infections, including joint infections in previously healthy patients, and a higher rate of complications than PVL-negative strains.31, 32 The rise in PVL-positive MRSA strains has accounted for an increase in the frequency of joint infections in some areas of the USA.11

Diagnosis

Clinical features

Ideally, septic arthritis is confirmed by detection of bacteria in synovial fluid, but predominantly, diagnosis is clinical, depending on informed integration of history, examination, and results of investigations.2 Most studies are hospital-based and include individuals in whom synovial fluid culture fails to grow bacteria but in whom clinical suspicion is high. This situation often arises when patients present with acute arthritis and evidence of infection elsewhere.5, 33, 34

Individuals with septic arthritis typically present with a 1—2 week history of a red, painful, and restricted joint.1, 16, 33 Some factors, including low virulence causative organisms and fungal and mycobacterial infections, can delay presentation.1, 35 In the context of pre-existing arthritis, the affected joint or joints will show signs that are out of proportion to disease activity detected in other joints. Generally, large joints (typically in the leg) are affected,5, 33 but in most studies up to 20% of patients have more than one joint affected.

Symptoms related to systemic infection are less common than might be expected. In a prospective analysis of patients in whom bacteria were cultured from synovial fluid, a history of fever was recorded in 34%, sweats in 15%, and rigors in only 6%.1 Similarly, a fever (>37·5°C) at presentation is detected in only about 60% of cases,1, 16, 34, 35 indicating that (contrary to popular medical opinion) raised temperature is not a prerequisite for diagnosis of septic arthritis.

Laboratory investigations

Blood should always be cultured before starting antibiotic treatment to boost the chances of obtaining causative organisms.36 In one study, blood cultures were positive in 24% of cases in whom organisms were identified in the synovial fluid, and in a further 9% of patients, blood cultures were the only source of a positive microbiological diagnosis.5 In blood samples of individuals with septic arthritis, erythrocyte sedimentation rate, C-reactive protein concentration, and white-cell count are usually raised. However, normal values for these variables at presentation have been reported; thus absence of an acute-phase response does not exclude septic arthritis.1, 37, 38

White-cell count, erythrocyte sedimentation rate, and serum C-reactive protein concentration might not distinguish septic arthritis from other forms of acute arthritis,39 but amounts of procalcitonin in serum could be useful for differentiation.40 This variable is the latest in a series of potential serological and synovial markers to be studied over the years in the search for a means to discriminate between infective and non-infective joint inflammation. To date, none has had sufficient sensitivity, specificity, or predictive value to be taken into routine clinical practice.39

Nevertheless, white-cell count, erythrocyte sedimentation rate, and C-reactive protein concentration should be measured, because when raised they are useful to monitor response to treatment. Moreover, because renal and liver abnormalities are poor prognostic factors in septic arthritis, and abnormal function could affect antibiotic choice, both should be assessed at presentation.36, 41 When indicated by a patient’s history, skin ulcer, urine, throat, and genitourinary cultures might be appropriate to aid accurate diagnosis before antibiotic treatment.36

Many researchers have attempted to identify ways in which analysis of synovial fluid can help to differentiate the various forms of acute arthritis. Synovial fluid aspiration, if it yields positive results, can be the key to diagnosis of septic arthritis, with gram stain and culture guiding choice of antibiotic treatment. In one study, gram staining of synovial fluid identified the causative organism in 50% of cases, rising to 67% after culture.5 Specimens should always be taken before antibiotic treatment is started and sent fresh for appropriate microbiology culture.42—44 Debate is ongoing about whether inoculation of synovial fluid directly into blood-culture bottles increases diagnostic yield over conventional agar culture. Our own conclusion is that no evidence supports this strategy: the laboratory should process all specimens.36

Historically, the skill of joint aspiration has been undervalued compared with other general internal medical techniques, and traditionally, junior medical staff are reluctant to aspirate joints in the emergency room. However, aspiration is a vital step for assessment of a hot swollen joint (just as lumbar puncture is for suspected meningitis), and a competent clinician needs to be found urgently to aspirate any acutely hot swollen joint when sepsis is a possibility. The only exception to this rule is suspected sepsis of a prosthetic joint, which should always be aspirated with full aseptic precautions in an operating theatre.
To diagnose crystal arthritis, samples of synovial fluid should be examined by polarising microscopy (ideally, compensated polarising-light microscopy), preferably in laboratories with adequate standardisation and quality control.45, 46 However, because artificial crystals can form on refrigeration, samples should be processed immediately or stored at room temperature before analysis.36

Whether quantification of the synovial white-cell count is helpful for diagnosis is controversial. Some researchers have suggested that this variable is a useful discriminator of septic arthritis, citing a level greater than 50 000 cells per μL as a threshold,47, 48 but others have reported that this measure cannot distinguish between crystal and septic arthritis.49—51 Concentrations of procalcitonin in synovial fluid are raised in septic arthritis,52 but whether this marker can accurately discriminate septic arthritis from other forms of acute arthritis remains to be established.

Imaging

In several studies of septic arthritis, radiographs, technetium bone scans, CT, and MRI have been examined in the hope of identifying an investigation that will discriminate septic from other forms of acute arthritis. Although these techniques can be used to assess the presence and extent of inflammation, destruction, and tissue response, they cannot accurately distinguish between infective and other causes of acute inflammatory arthritis. However, MRI can help to assess both coexistent osteomyelitis, which might indicate a need for orthopaedic intervention,36 and deep joints (such as the hip or sacroiliac joint) in patients with septicaemia with localised musculoskeletal pain. Furthermore, MRI will also indicate any tracking of purulent material into surrounding soft tissues from a primary joint infection (figure 2).

MRI of staphylococcal septic arthritis of left hip, with fluid collections between planes of gluteal muscles
Arrows indicate fluid collections.

Proven versus suspected disease

Diagnosis of septic arthritis is straightforward when bacteria are isolated from synovial fluid. However, absence of organisms on gram stain, or a subsequently negative synovial fluid culture, does not exclude the diagnosis, although it does make it less likely, and expert rheumatological advice should be sought.41 Such advice might be needed because false-negative gram stains and cultures of synovial fluid can occur, for example, with fastidious organisms or if antibiotic treatment was started before culture was done.

How do patients with septic arthritis from whom bacteria are isolated from synovial fluid compare with individuals from whom microorganisms are not cultured? One study showed that patients’ history, joint distribution, clinical examination, and acute-phase response did not differ significantly.35 Furthermore, predisposing causes, underlying diagnoses, complication rate, need for additional supportive treatment (such as dialysis or admission to intensive care), and acute and long-term mortality between groups were also closely similar (table 1). Importantly, in patients in whom bacteria were not isolated from the joint, microorganisms were detected in blood culture in 11% and from other sources in 7%, reinforcing the importance of appropriate cultures.

Comparison of clinical variables and outcomes between proven (synovial fluid culture-positive) and suspected (culture-negative) septic arthritis
Data are median (IQR) or number (%). Data taken from reference 35; mortality data provided by M Gupta.

Prognosis

Mortality for septic arthritis varies in different studies, but seems to be around 11% for monoarticular sepsis.36 In one study, a poor functional outcome was recorded in 24% and osteomyelitis in a further 8%, emphasising the need for both early diagnosis and improvements in current management strategies.5

Management

In view of the 11% mortality rate for septic arthritis, patients should be admitted to hospital for prompt assessment, supportive care, and intravenous antibiotic treatment, along with measures to aspirate pus from the joint. If evidence indicates septic shock or organ failure, patients should be treated in appropriate critical-care facilities.

Antibiotic treatment

Evidence on which to base choice or duration of antibiotic treatment for septic arthritis is scarce, and to the best of our knowledge, no randomised trials have been done. A large meta-analysis of antibiotic treatment for joint sepsis failed to show an advantage of any one therapeutic regimen over another for native joint infection.53 Consensus suggests the mainstay of treatment should be prompt removal of any purulent material and appropriate antibiotic treatment.36

Table 2 summarises UK guidelines on initial antibiotic choice; this guidance is appropriate for the UK only because, in other settings, suitable antibiotic treatment must account for geographic variation in organisms and resistance patterns. In principle, however, the antibiotic regimen should be based on likelihood of the organisms involved and current local sensitivity patterns, modified subsequently by results of gram stain and culture. Because probable pathogens in all risk groups are S aureus and streptococci, initial antibiotic treatment before organism identification should have bactericidal activity against these bacteria. Suitable choices include β-lactamase-stable penicillins, such as flucloxacillin or cloxacillin, or the cephalosporins.36

Summary of UK recommendations for initial antibiotic choice in suspected septic arthritis
Antibiotic choice will need to be modified after results of gram stain and culture, and should be reviewed locally by microbiology departments. MRSA=meticillin-resistant Staphylococcus aureus.

Modification of choice of empirical treatment could be appropriate to include activity against MRSA in patients at risk, such as nursing-home residents or recent hospital inpatients, or where the local incidence of community-associated MRSA is greater than 10%.54 Glycopeptides (eg, vancomycin) are active against most MRSA strains. For difficult infections, such as those affecting prosthetic joints, glycopeptides are used in combination with rifampicin or fusidic acid, because glycopeptides infiltrate poorly into joint and bone tissue. Clindamycin penetrates well into bone and joint tissue, and can be used as an alternative in macrolide-sensitive strains.54

Novel antibiotics

Resistance to glycopeptides has emerged as a problem in some MRSA strains, particularly in patients with deep-seated chronic infections treated with long-term glycopeptides alone. The organism usually has low-level intermediate resistance and is known as glycopeptide-intermediate S aureus (GISA). Emergence of GISA and intolerance to glycopeptides in some patients has led to use of new agents for gram-positive osteoarticular infections, because they have extended activity to include these multidrug-resistant strains.

Daptomycin and linezolid are gram-positive antibiotics from two new classes of antimicrobials, which have been licensed on the basis of results of studies in skin and soft-tissue infections. As far as we know, no randomised trials have been done to compare effectiveness and safety of these new antibiotics with traditional treatments for osteoarticular infections.55—57 Linezolid is an oxazolidinone antibiotic with bacteriostatic activity against gram-positive organisms, and it can be administered orally because it has 100% bioavailability. With treatment for longer than 2 weeks, linezolid has been associated with significant risk of reversible bone-marrow suppression and peripheral neuropathy, and a small but more worrying risk of optic neuropathy.56 Daptomycin is a lipopeptide antibiotic with bactericidal activity against gram-positive organisms, including those in the stationary phase of growth, and is licensed for complicated skin and soft-tissue infections and right-sided endocarditis. It must be given intravenously and is associated with toxic effects in muscle in about 0·4—2·5% of cases. No formal studies have been done in osteoarticular infections, and emergence of resistance has been described in prolonged courses of treatment.55

Gram-negative enterobacteriaceae are most usually seen as a cause of septic arthritis in elderly people or immunosuppressed patients. Unfortunately, multidrug resistance is a major problem, particularly in Escherichia coli, which is the most common cause of community and health-care-associated infection.58 Resistance is associated with extended-spectrum β-lactamases, which expand resistance to third-generation cephalosporins (eg, ceftriaxone) and are usually associated with resistance mechanisms to other classes of antibiotics that are often used to treat gram-negative infections. International prevalence of multiresistant enterobacteriaceae positive for extended-spectrum β-lactamases has risen greatly over the past decade. These organisms are now a major cause of both community and healthcare-associated bacteraemia and urosepsis, and are starting to be seen in joint sepsis. Multiresistant bacteria make the choice of empirical treatment difficult and increase the need to use carbapenems, such as meropenem.58—62

The need for empirical treatment of N gonorrhoeae or Haemophilus influenzae type b will depend on local epidemiology. Routine cover for these microorganisms is not indicated in western Europe in the absence of specific clinical markers because these bacteria are currently uncommon causes of septic arthritis in this region. With national and international variation in possible causative organisms and sensitivity rates, empirical antibiotic treatment and guidelines for septic arthritis should be developed locally in accordance with sensitivity patterns and probable causative organisms, and these should be reviewed and updated regularly.36 The safest option in view of the complexity of causative organisms and resistance patterns is to treat cases of suspected or proven septic arthritis with close involvement of microbiolologists.

Duration of antibiotic treatment

High-quality data are scarce that show the best duration of antibiotic treatment for septic arthritis, with the exception of treatment for N gonorrhoeae (a 1-week course of a third-generation cephalosporin is indicated). Treatment is usually given for up to 6 weeks, with the first 2 weeks administered intravenously followed by a switch to oral treatment if an oral option exists and clinical signs, symptoms, and inflammatory markers are settling.36 Use of OPAT (outpatient parenteral antimicrobial treatment) with antibiotics with a long half-life—eg, ceftriaxone and teicoplanin—has risen over the past decade. OPAT enables early discharge and follow-up if the patient is otherwise well, but parenteral treatment is still needed. This technique is especially useful when a suitable oral option is missing, and it has been used successfully for difficult infections, including septic arthritis. OPAT needs to be delivered by dedicated teams with adequate supervision and follow-up of patients.63

Needle aspiration and surgical interventions

In addition to antimicrobial treatment, successful management of acute septic arthritis requires removal of intra-articular pus. Evidence for the mode of drainage that should be used is scarce. Options include closed-needle aspiration and surgical aspiration via arthroscopy. Only one study identified by our search strategy compared needle aspiration with surgical intervention directly, and no evidence was available to enable us to recommend one treatment strategy over another.64 Both arthroscopy and needle aspiration, however, seem to have a favourable outcome, and expert opinion is that these techniques should be repeated until pus no longer accumulates. Figure 3 presents an algorithm of current UK guidelines for diagnosis and management of septic arthritis.

Diagnostic and treatment algorithms for management of the hot swollen joint
Adapted from ref 36, with permission of Oxford University Press.

Future developments

Even when antimicrobial treatment for septic arthritis is timely and appropriate, it is not always sufficient to prevent permanent joint damage and overwhelming sepsis. Therefore, novel therapeutic options are warranted. Development of experimental models of bacterial arthritis has led to important progress in understanding of disease pathogenesis. These animal models have not only shed light on the pathogenic mechanisms underlying disease development but also presented potential targets for immunotherapy of septic arthritis.
An experimental S aureus model has already been described (see Pathogenesis).18 It shows that much of the morbidity in mice (after the initial bacterial insult) is attributable to the host T-cell-mediated immune system. Perhaps counterintuitively, a growing body of evidence suggests that the immune system in septic arthritis, while essential to survival, also causes some joint destruction.65

Corticosteroids

Suppression of an excessive immune response with corticosteroids could be a more effective treatment regimen for S aureus septic arthritis than use of antibiotics alone. Tarkowski and colleagues 65 showed that, in mice treated with intraperitoneal cloxacillin together with intraperitoneal corticosteroid, prevalence, severity, and mortality associated with septic arthritis induced by S aureus inoculation was significantly reduced compared with mice treated with intraperitoneal cloxacillin alone.

123 children were enrolled into a double-blind, randomised, placebo-controlled trial assessing dexamethasone treatment for haematogenous septic arthritis. A short course of low-dose dexamethasone (0·2 mg/kg intravenously every 8 h for 12 consecutive doses), given in conjunction with antibiotic treatment, reduced duration of disease course and extent of residual joint damage and dysfunction compared with antibiotics alone.66 An equivalent study has not yet been done in adults, but such work would be useful and would need to consider also the possibility of adverse outcomes from use of steroids, such as impaired effectiveness of antibiotics.

Cytokines and bisphosphonates

Work on the Tarkowski mouse model has shown other potential immunotherapeutic targets in septic arthritis. For example, deletion of bacterial virulence factors can reduce severity of disease. Similarly, identification of host-response cytokines has indicated that TNF α antagonists and recombinant interleukin 10 could both be used as adjuncts to antibiotic treatment.19—21

Addition of bisphosphonates to an intraperitoneal treatment regimen of corticosteroids and antibiotics seems to add further clinical benefit in the animal model. This finding could be due to a decrease in osteoclast activity and a consequent reduction in skeletal destruction.67

The animal model developed by Tissi and colleagues has also been used to show that other potential immunotherapies, such as adjunctive interleukin 1068, 69 or interleukin 12,69 could enhance disease prognosis. However, none of these cytokine, anticytokine, or bisphophonate therapeutic approaches has yet been studied in patients, and we would not advocate their use outside of a randomised clinical trial.

Search strategy and selection criteria

We did a systematic search of work published in English in the following databases: Cochrane Library, Medline (1951 to Aug 31, 2008), Embase (1974 to Aug 31, 2008), and the National Electronic Library for Health. Selection of papers for full-text review depended on adherence to defined inclusion and exclusion criteria (outlined in detail in reference 41, search updated to Aug 31, 2008). In brief, we used search terms including: “infectious arthritis”, “meta-analysis”, “randomised controlled trial”, “controlled clinical trial”, “evaluation studies”, “therapy”, “diagnosis”, “epidemiology”, “microbiology”, “radiography”, and the names of the main causative bacteria in septic arthritis. The reference lists of retrieved articles and of review articles from key authors and journals were hand-searched to confirm the sensitivity of the defined search strategy. Authors were invited to contribute additional references. We excluded papers in which children younger than age 16 years were assessed; studies on reactive arthritis, chronic sepsis, osteomyelitis, spinal infection, and prosthetic joint infection; and reviews and case reports. We evaluated the methodological quality of selected papers with criteria set out by the clinical effectiveness and evaluation unit of the UK Royal College of Physicians.

Contributors

CJM did the literature search, informed by discussion with all authors. All authors were involved in writing sections of the report, and all edited, checked, and approved the final version.

Conflicts of interest

We declare that we have no conflicts of interest.

Acknowledgments

We thank the British Society for Rheumatology (BSR) for convening our working party for the BSR Hot Swollen Joint guideline; Daniel J Sexton (Duke University) for comments on an earlier draft of this Seminar; and Monica Gupta for provision of mortality data for table 1.

References

1 Gupta MN, Sturrock RD, Field M. A prospective 2-year study of 75 patients with adult-onset septic arthritis. Rheumatology (Oxford) 2001; 40: 24-30. CrossRef | PubMed

2 Newman JH. Review of septic arthritis throughout the antibiotic era. Ann Rheum Dis 1976; 35: 198-205. CrossRef | PubMed

3 Morgan DS, Fisher D, Merianos A, Currie BJ. An 18 year clinical review of septic arthritis from tropical Australia. Epidemiol Infect 1996; 117: 423-428. CrossRef | PubMed

4 Kaandorp CJ, Dinant HJ, van de Laar MA, Moens HJ, Prins AP, Dijkmans BA. Incidence and sources of native and prosthetic joint infection: a community based prospective survey. Ann Rheum Dis 1997; 56: 470-475. CrossRef | PubMed

5 Weston VC, Jones AC, Bradbury N, Fawthrop F, Doherty M. Clinical features and outcome of septic arthritis in a single UK health district 1982—1991. Ann Rheum Dis 1999; 58: 214-219. CrossRef | PubMed

6 Geirsson AJ, Statkevicius S, Vikingsson A. Septic arthritis in Iceland 1990—2002: increasing incidence due to iatrogenic infections. Ann Rheum Dis 2008; 67: 638-643. CrossRef | PubMed

7 Kaandorp CJ, van Schaardenburg D, Krijnen P, Habbema JD, van de Laar MA. Risk factors for septic arthritis in patients with joint disease: a prospective study. Arthritis Rheum 1995; 38: 1819-1825. CrossRef | PubMed

8 Al Nammari SS, Gulati V, Patel R, Bejjanki N, Wright M. Septic arthritis in haemodialysis patients: a seven-year multi-centre review. J Orthop Surg (Hong Kong) 2008; 16: 54-57. PubMed

9 Edwards CJ, Cooper C, Fisher D, Field M, van Staa TP, Arden NK. The importance of the disease process and disease-modifying antirheumatic drug treatment in the development of septic arthritis in patients with rheumatoid arthritis. Arthritis Rheum 2007; 57: 1151-1157. CrossRef | PubMed

10 Dubost JJ, Soubrier M, De Champs C, Ristori JM, Bussiere JL, Sauvezie B. No changes in the distribution of organisms responsible for septic arthritis over a 20 year period. Ann Rheum Dis 2002; 61: 267-269. CrossRef | PubMed

11 Arnold SR, Elias D, Buckingham SC, et al. Changing patterns of acute hematogenous osteomyelitis and septic arthritis: emergence of community-associated methicillin-resistant Staphylococcus aureus. J Pediatr Orthop 2006; 26: 703-708. PubMed

12 Millar BC, Loughrey A, Elborn JS, Moore JE. Proposed definitions of community-associated meticillin-resistant Staphylococcus aureus (CA-MRSA). J Hosp Infect 2007; 67: 109-113. CrossRef | PubMed

13 Fleisch F, Zbinden R, Vanoli C, Ruef C. Epidemic spread of a single clone of methicillin-resistant Staphylococcus aureus among injection drug users in Zurich, Switzerland. Clin Infect Dis 2001; 32: 581-586. CrossRef | PubMed

14 Ventura G, Gasparini G, Lucia MB, et al. Osteoarticular bacterial infections are rare in HIV-infected patients: 14 cases found among 4,023 HIV-infected patients. Acta Orthop Scand 1997; 68: 554-558. PubMed

15 Belzunegui J, Gonzalez C, Lopez L, Plazaola I, Maiz O, Figueroa M. Osteoarticular and muscle infectious lesions in patients with the human immunodeficiency virus. Clin Rheumatol 1997; 16: 450-453. CrossRef | PubMed

16 Ispahani P, Weston VC, Turner DP, Donald FE. Septic arthritis due to Streptococcus pneumoniae in Nottingham, United Kingdom, 1985—1998. Clin Infect Dis 1999; 29: 1450-1454. CrossRef | PubMed

17 Saraux A, Taelman H, Blanche P, et al. HIV infection as a risk factor for septic arthritis. Br J Rheumatol 1997; 36: 333-337. PubMed

18 Tarkowski A, Collins LV, Gjertsson I, et al. Model systems: modeling human staphylococcal arthritis and sepsis in the mouse. Trends Microbiol 2001; 9: 321-326. CrossRef | PubMed

19 Hultgren O, Eugster HP, Sedgwick JD, Korner H, Tarkowski A. TNF/lymphotoxin-alpha double-mutant mice resist septic arthritis but display increased mortality in response to Staphylococcus aureus. J Immunol 1998; 161: 5937-5942. PubMed

20 Hultgren OH, Svensson L, Tarkowski A. Critical role of signaling through IL-1 receptor for development of arthritis and sepsis during Staphylococcus aureus infection. J Immunol 2002; 168: 5207-5212. PubMed

21 Gjertsson I, Hultgren OH, Tarkowski A. Interleukin-10 ameliorates the outcome of Staphylococcus aureus arthritis by promoting bacterial clearance. Clin Exp Immunol 2002; 130: 409-414. CrossRef | PubMed

22 Hultgren O, Kopf M, Tarkowski A. Outcome of Staphylococcus aureus-triggered sepsis and arthritis in IL-4-deficient mice depends on the genetic background of the host. Eur J Immunol 1999; 29: 2400-2405. CrossRef | PubMed

23 Abdelnour A, Arvidson S, Bremell T, Ryden C, Tarkowski A. The accessory gene regulator (agr) controls Staphylococcus aureus virulence in a murine arthritis model. Infect Immun 1993; 61: 3879-3885. PubMed

24 Palmqvist N, Foster T, Tarkowski A, Josefsson E. Protein A is a virulence factor in Staphylococcus aureus arthritis and septic death. Microb Pathog 2002; 33: 239-249. CrossRef | PubMed

25 Deng GM, Tarkowski A. The features of arthritis induced by CpG motifs in bacterial DNA. Arthritis Rheum 2000; 43: 356-364. CrossRef | PubMed
26 Foster TJ, Hook M. Surface protein adhesins of Staphylococcus aureus. Trends Microbiol 1998; 6: 484-488. CrossRef | PubMed

27 Nilsson IM, Patti JM, Bremell T, Hook M, Tarkowski A. Vaccination with a recombinant fragment of collagen adhesin provides protection against Staphylococcus aureus-mediated septic death. J Clin Invest 1998; 101: 2640-2649. CrossRef | PubMed

28 Josefsson E, Hartford O, O’Brien L, Patti JM, Foster T. Protection against experimental Staphylococcus aureus arthritis by vaccination with clumping factor A, a novel virulence determinant. J Infect Dis 2001; 184: 1572-1580. CrossRef | PubMed

29 Tissi L, Marconi P, Mosci P, et al. Experimental model of type IV Streptococcus agalactiae (group B streptococcus) infection in mice with early development of septic arthritis. Infect Immun 1990; 58: 3093-3100. PubMed

30 Mathews CJ, Weston VC, Kingsley GH, Coakley G. Future management of septic arthritis. Future Rheumatol 2008; 3: 43-50. PubMed

31 Swaminathan A, Massasso D, Gotis-Graham I, Gosbell I. Fulminant methicillin-sensitive Staphylococcus aureus infection in a healthy adolescent, highlighting ‘Panton-Valentine leucocidin syndrome’. Intern Med J 2006; 36: 744-747. CrossRef | PubMed

32 Martinez-Aguilar G, Avalos-Mishaan A, Hulten K, Hammerman W, Mason EO, Kaplan SL. Community-acquired, methicillin-resistant and methicillin-susceptible Staphylococcus aureus musculoskeletal infections in children. Pediatr Infect Dis J 2004; 23: 701-706. CrossRef | PubMed

33 Goldenberg DL, Cohen AS. Acute infectious arthritis: a review of patients with nongonococcal joint infections (with emphasis on therapy and prognosis). Am J Med 1976; 60: 369-377. CrossRef | PubMed

34 Eder L, Zisman D, Rozenbaum M, Rosner I. Clinical features and aetiology of septic arthritis in northern Israel. Rheumatology (Oxford) 2005; 44: 1559-1563. CrossRef | PubMed

35 Gupta MN, Sturrock RD, Field M. Prospective comparative study of patients with culture proven and high suspicion of adult onset septic arthritis. Ann Rheum Dis 2003; 62: 327-331. CrossRef | PubMed

36 Coakley G, Mathews C, Field M, et alon behalf of the British Society for Rheumatology Standards, Guidelines and Audit Working Group. BSR & BHPR, BOA, RCGP and BSAC guidelines for management of the hot swollen joint in adults. Rheumatology (Oxford) 2006; 45: 1039-1041. CrossRef | PubMed

37 Le Dantec L, Maury F, Flipo RM, et al. Peripheral pyogenic arthritis: a study of one hundred seventy-nine cases. Rev Rhum Engl Ed 1996; 63: 103-110. PubMed

38 Li SF, Henderson J, Dickman E, Darzynkiewicz R. Laboratory tests in adults with monoarticular arthritis: can they rule out a septic joint?. Acad Emerg Med 2004; 11: 276-280. CrossRef | PubMed

39 Soderquist B, Jones I, Fredlund H, Vikerfors T. Bacterial or crystal-associated arthritis? Discriminating ability of serum inflammatory markers. Scand J Infect Dis 1998; 30: 591-596. CrossRef | PubMed

40 Hugle T, Schuetz P, Mueller B, et al. Serum procalcitonin for discrimination between septic and non-septic arthritis. Clin Exp Rheumatol 2008; 26: 453-456. PubMed

41 Mathews CJ, Kingsley G, Field M, et al. Management of septic arthritis: a systematic review. Ann Rheum Dis 2007; 66: 440-445. PubMed

42 Yagupsky P, Peled N, Press J. Use of BACTEC 9240 blood culture system for detection of Brucella melitensis in synovial fluid. J Clin Microbiol 2001; 39: 738-739. CrossRef | PubMed

43 Yagupsky P, Press J. Use of the isolator 1.5 microbial tube for culture of synovial fluid from patients with septic arthritis. J Clin Microbiol 1997; 35: 2410-2412. PubMed

44 Hughes JG, Vetter EA, Patel R, et al. Culture with BACTEC Peds Plus/F bottle compared with conventional methods for detection of bacteria in synovial fluid. J Clin Microbiol 2001; 39: 4468-4471. CrossRef | PubMed

45 Freed JF, Nies KM, Boyer RS, Louie JS. Acute monoarticular arthritis: a diagnostic approach. JAMA 1980; 243: 2314-2316. PubMed

46 Swan A, Amer H, Dieppe P. The value of synovial fluid assays in the diagnosis of joint disease: a literature survey. Ann Rheum Dis 2002; 61: 493-498. CrossRef | PubMed

47 Li SF, Cassidy C, Chang C, Gharib S, Torres J. Diagnostic utility of laboratory tests in septic arthritis. Emerg Med J 2007; 24: 75-77. CrossRef | PubMed

48 Margaretten ME, Kohlwes J, Moore D, Bent S. Does this adult patient have septic arthritis?. JAMA 2007; 297: 1478-1488. CrossRef | PubMed

49 Coutlakis PJ, Roberts WN, Wise CM. Another look at synovial fluid leukocytosis and infection. J Clin Rheumatol 2002; 8: 67-71. CrossRef | PubMed

50 McGillicuddy DC, Shah KH, Friedberg RP, Nathanson LA, Edlow JA. How sensitive is the synovial fluid white blood cell count in diagnosing septic arthritis?. Am J Emerg Med 2007; 25: 749-752. CrossRef | PubMed

51 Abdullah S, Young-Min SA, Hudson SJ, Kelly CA, Heycock CR, Hamilton JD. Gross synovial fluid analysis in the differential diagnosis of joint effusion. J Clin Pathol 2007; 60: 1144-1147. CrossRef | PubMed

52 Martinot M, Sordet C, Soubrier M, et al. Diagnostic value of serum and synovial procalcitonin in acute arthritis: a prospective study of 42 patients. Clin Exp Rheumatol 2005; 23: 303-310. PubMed

53 Stengel D, Bauwens K, Sehouli J, Ekkernkamp A, Porzsolt F. Systematic review and meta-analysis of antibiotic therapy for bone and joint infections. Lancet Infect Dis 2001; 1: 175-188. Summary | Full Text | PDF(236KB) | CrossRef | PubMed

54 Gemmell CG, Edwards DI, Fraise AP, Gould FK, Ridgway GL, Warren RE. Guidelines for the prophylaxis and treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in the UK. J Antimicrob Chemother 2006; 57: 589-608. CrossRef | PubMed

55 Falagas ME, Giannopoulou KP, Ntziora F, Papagelopoulos PJ. Daptomycin for treatment of patients with bone and joint infections: a systematic review of the clinical evidence. Int J Antimicrob Agents 2007; 30: 202-209. CrossRef | PubMed

56 Falagas ME, Siempos II, Papagelopoulos PJ, Vardakas KZ. Linezolid for the treatment of adults with bone and joint infections. Int J Antimicrob Agents 2007; 29: 233-239. CrossRef | PubMed

57 Seaton RA. Daptomycin: rationale and role in the management of skin and soft tissue infections. J Antimicrob Chemother 2008; 62 (suppl 3): iii15-iii23. CrossRef | PubMed

58 Livermore DM, Canton R, Gniadkowski M, et al. CTX-M: changing the face of ESBLs in Europe. J Antimicrob Chemother 2007; 59: 165-174. CrossRef | PubMed

59 Schelenz S, Bramham K, Goldsmith D. Septic arthritis due to extended spectrum beta lactamase producing Klebsiella pneumoniae. Joint Bone Spine 2007; 74: 275-278. CrossRef | PubMed

60 Bean DC, Krahe D, Wareham DW. Antimicrobial resistance in community and nosocomial Escherichia coli urinary tract isolates, London 2005—2006. Ann Clin Microbiol Antimicrob 2008; 7: 13. CrossRef | PubMed

61 Loughrey A, Rooney P, O’Leary M, et al. P1348 Prevalence of an epidemic ESBL-producing Escherichia coli strain in LTCFs in Belfast. Int J Antimicrob 2008; 29 (suppl 2): S373. PubMed

62 Borg MA, Sande-Bruinsma N, Scicluna E, et al. Antimicrobial resistance in invasive strains of Escherichia coli from southern and eastern Mediterranean laboratories. Clin Microbiol Infect 2008; 14: 789-796. CrossRef | PubMed

63 Weston V, Coakley G. Guideline for the management of the hot swollen joint in adults with a particular focus on septic arthritis. J Antimicrob Chemother 2006; 58: 492-493. CrossRef | PubMed

64 Goldenberg DL, Brandt KD, Cohen AS, Cathcart ES. Treatment of septic arthritis: comparison of needle aspiration and surgery as initial modes of joint drainage. Arthritis Rheum 1975; 18: 83-90. CrossRef | PubMed

65 Sakiniene E, Bremell T, Tarkowski A. Addition of corticosteroids to antibiotic treatment ameliorates the course of experimental Staphylococcus aureus arthritis. Arthritis Rheum 1996; 39: 1596-1605. CrossRef | PubMed

66 Odio CM, Ramirez T, Arias G, et al. Double blind, randomized, placebo-controlled study of dexamethasone therapy for hematogenous septic arthritis in children. Pediatr Infect Dis J 2003; 22: 883-888. CrossRef | PubMed

67 Verdrengh M, Carlsten H, Ohlsson C, Tarkowski A. Addition of bisphosphonate to antibiotic and anti-inflammatory treatment reduces bone resorption in experimental Staphylococcus aureus-induced arthritis. J Orthop Res 2007; 25: 304-310. CrossRef | PubMed

68 Puliti M, von Hunolstein C, Verwaerde C, Bistoni F, Orefici G, Tissi L. Regulatory role of interleukin-10 in experimental group B streptococcal arthritis. Infect Immun 2002; 70: 2862-2868. CrossRef | PubMed

69 Puliti M, von Hunolstein C, Bistoni F, Mosci P, Orefici G, Tissi L. The beneficial effect of interleukin-12 on arthritis induced by group B streptococci is mediated by interferon-gamma and interleukin-10 production. Arthritis Rheum 2002; 46: 806-817. CrossRef | PubMed

The Articles are on the prognostic significance of visit-to-visit variability in blood pressure in hypertension patients; the differences between classes of antihypertensive drugs’ effectiveness in preventing stroke and group cognitive behavioural intervention for lower back pain. These are accompanied by Comments on stroke and blood pressure variation and CBT for back pain in primary care.

The World Report is on the final steps for Obama’s healthcare reform bill, mental health in Sri Lanka and free healthcare for mothers and infants in Sierra Leone. Also of interest to global health are Comments on the continuing impact of diarrhoea on child mortality; medical complicity in torture and new WHO HIV treatment guidelines.

In today’s blog Suvash Shrestha TLS Regional Advisor from Nepal writes on a review published in Lancet Infectious Diseases that has raised doubts on the efficacy and usefulness of WHO guidelines to control transmission of tuberculosis in airlines.

Of the total of 2,761 passengers screened after potential contact with a TB case, only 10 showed up positive for the tuberculin skin reaction test, which proved only latent infection by the tubercle bacilli.

Earlier in 2006 and 2008, WHO had recommended all airlines to trace and screen passengers, who have sat for longer than eight hours adjacent to a pulmonary tuberculosis-positive-person. The rule also prohibited an individual with TB from all commercial air travel until he or she is no longer infectious, as proved after two negative tests.

The review mentions that there is little danger of contagion from air travel. Ibrahim Abubakar of the University of East Anglia in eastern England looked into accounts of 41 events when tuberculosis was suspected to be transmitted by air travel. Of the total of 2,761 passengers screened after potential contact with a TB case, only 10 showed up positive for the tuberculin skin reaction test, which proved only latent infection by the tubercle bacilli. None became actively infected.

Thus, the report concluded that the screening was not necessary at all. Besides, the chances of TB transmission in an airplane is too less. In the first place, contagion with TB depends on several factors like the bacterial load in the sputum, duration and nature of contact, ventilation and finally the vulnerability of the exposed people. Those with impaired immune system due to cancer, AIDS or any other disease are vulnerable to get TB, but, luckily most travelers are relatively healthy. Thus, the chance of transmission remains low.

Next, most airliners have such highly efficient air filtration that germs even as small as 0.3 nanometers cannot get through. This means that Mycobacterium practically does not have any chance to get through. In addition, cabin air is generally renewed more than 15 times an hour. This is even more than the standard used in isolation rooms for multidrug resistant TB cases.

“Although an airline cabin is a closed confined space, the cumulative duration of exposure is relative short compared with households or…other modes of transport where individuals might travel on the same route daily,” Abubakar noted.

The evidences showed that WHO guidelines were baseless and not worth following. However, the report did not doubt the severity of the TB epidemic or the need to trace passengers in the event of a genuine emergency. “Resources might be better spent addressing other priorities of tuberculosis control and helping all achieve Millennium Development Goals related to tuberculosis.”

“Six months into her pregnancy, with no medical care to look after, no iron-FA tablets, and no TT immunization. Talking of advanced facilities is irrelevant when there is lack of proper food to meet the extra demand of pregnancy and she is toiling up and down with a heavy load on her head.” I came across such a case in my neighborhood where a construction of a house was taking place. This was the state of a lady living in a so called mega city where the health care facilities are said to be par excellence. I am a student from pre-final year of medicine and the most important part of our curriculum is Preventive and Social Medicine, which teaches us about how our government is working for the improvement of mother and child health in India. No doubt the facilities are excellent but how far they are reaching the population is our main point of concern.

An Introduction to the Problem

Improving maternal health is one of the eight Millennium Development Goals adopted by the international community at the United Nations Millennium Summit in 2000 [2], but every day, 1,500 women die from complications in pregnancy childbirth. In 2005, there were an estimated 536,000 maternal deaths worldwide. Most of these deaths occurred in developing countries, and most were avoidable [1]. It has been reported that 99% of maternal mortality occurs in developing country where 85% of the world population lives [3]. India is just another developing country which nurtures 16.7% of the world’s population [4].

Today, the Maternal Mortality Rate of India is 301 per 1,00,000 as compared to 9 per 1,00,000 of the developed countries and the Infant Mortality Rate is 54 per 1000 [1]. In spite of the growing concern about reproductive health, information on levels, trends and differentials in maternal mortality remains fragmentary in most developing countries and that certainly includes India. Policy initiatives often rest on judgments made on the basis of a small, selective cross section of the population.

Women in our country have many pregnancies on average, therefore their lifetime risk more accurately reflects the overall burden of these women. Maternal mortality in our country is high because of high complications associated with pregnancy, childbirth and postpartum period. The four major killers are severe bleeding (mostly bleeding postpartum), infections (also mostly soon after delivery), hypertensive disorders in pregnancy (eclampsia) and obstructed labor [5]. Complications after unsafe abortion are another cause of maternal deaths. Women die because of poor health at conception and a lack of adequate care needed for the healthy outcome of the pregnancy [5].

My Personal Experience as a Medical Student:

Our school, Lady Hardinge Medical College, is known for its excellence in Pediatrics and Gynecology, so we often see mothers and children seeking health care. And it is very sad to see that most of the childhood diseases and maternal morbidities can be easily prevented. It is sad to see that in India, most of the women and children suffer from infectious diseases which are almost always either an result of poor hygiene or is a sequel to superimposed infection due to deficiency disorders and malnutrition.

During our family rotations to the slums in Delhi we got a chance to closely observe the state of the community. There are many malpractices and skepticism in the society prevalent that is resulting in the poor maternal and child health status in India. Despite many pleas to people to change habits which will give rise to these problems, these issues are still prevelent. Most of the malpractices that we came across were detrimental to the health status of mother and child and as a result, the antenatal attendance was found to be very low. We carried out a study on 500 pregnant women and found that 25% were not registered and 21% of them did not seek medical attention in their last pregnancy. Further enquiry revealed that the reasons for not attending ANC clinics were tragic; 39% did not have any knowledge about them, 42% said that they could not go because of distance of the ANC clinic from their home, rest did not go because they had no time and no one to accompany them.

A study in the slums of Delhi reveals that while 91% of women recieved antenatal care, and an average of three visits were made, a large proportion of these visits were motivated by a health complication; routine monitoring accounted for no more than one-third of all first and second visits and the first contact was typically made in the fifth or sixth month of pregnancy [6].

More Deplorable Facts

Major hindrances include the fact that pregnant women often do not have knowledge of things like TT immunization, the importance of iron folic acid tablets and a balanced diet during pregnancy. Sepsis is one of the most common causes of maternal death in our society, resulting from lack of reproductive hygene.

Deaths of newborns during the first week or month of life are largely the result of inadequate or inappropriate care during pregnancy, childbirth or the first critical hours after birth. Indeed, neonatal mortality is largely dependent on maternal and pregnancy-related health. Major causes of neonatal mortality include neonatal infections (tetanus, sepsis, meningitis, pneumonia and congenital syphilis), birth asphyxia and trauma, pre-term birth and/or low birth weight. These reasons can be easily attributed to fact in our society some people prefer delivery by a Dai (most deliveries in rural areas of India are handled by the local lady who is immediately available to the pregnant lady during the perinatal period) who may not be skilled enough to handle the adversities and complications associated with pregnancy and parturition. Most of the times these Dai’s do not have knowledge of the importance of disinfection and hygiene while handling a delivery. We also observed that early onset of marriage and childbearing in India continues to have disturbing consequences for maternal health. Most of the women we came across in our society were married during their teenage years and majority were illiterate or barely had a primary education. The median age at first cohabitation with husband is 17 years among women aged 25-49 [7] and cultural pressures make it imperative for a women’s security in her marital home for her to conceive as soon as possible after marriage. Higher parity is another cause of concern that is prevalent in our community.

A recent study of pregnant women in Delhi slums reports that 45% of pregnant women were malnourished, that is their caloric intake was less than 60% of the recommended diet during pregnancy, and 80% consumed less than the recommended daily amount; 40% weighed less than 45 kg and 7% were less than 145 cm in height; two-thirds were anemic and 12%were severely anemic [6].

During our rotations we also observed that in most of the families child and mother are kept separated for the initial 40 days depriving the child of immediate nursing by mother. Neonatal health care is constrained by traditional practices that forbid women from leaving the home after they have given birth and the health system’s failure to provide home-based care in this period.

Early weaning is another practice and discarding the colostrums – the first milk – predisposes the child to various infections and deprives the child from the benefits of mother’s milk. Breast milk protects the baby from respiratory and diarrheal diseases which are the major cause of morbidity and mortality in children. In Indian setup exclusive six months of breast feeding is recommended [8].

India Fights Back

There are many national programmes functioning in India which aim at the development of Maternal and Child Health in India. Some of the programmes are Janani Suraksha Yojna under National Rural Health Mission, Reproductive Child Health Care, Integrated Management of Newborn and Childhood Illness. Under the leadership of Smt. Indira Gandhi, Integrated Child Development Services was launched which also has Nursing and Pregnant mothers as its beneficiary and children below 6 years [9]. All the programmes are being designed in a way that their main objective can be summed up as “to improve the availability of and access to quality health care by people, especially for those residing in rural areas, the poor, women and children.” India is currently spending US$109 per capita on the improvement of health and 4.9% of GDP on health [10]. Sadly even with so much expenditure and so many efforts by the government of India, the situation is very slow to improve.

Conclusions and What We Can Do

Pregnant women, their families, and indeed the whole community have not yet recognized the need for skilled attendance at delivery or the array of skills that a birth attendant needs. To summarize, in the communities misconceptions abound, danger signals in the pregnancy are poorly understood, provider-client interactions fail to build awareness, women’s lack of decision making authority, women’s restricted mobility, economic burden, and domestic violence are some of the major issues which we need to fight and to date no national programme has been designed to overcome these obstacles.

Actions are required to inform pregnant women and their families of danger signals and the required responses, ways of gaining appropriate care, nutrition and rest during pregnancy, and their right to recieve skilled and affordable attendance at birth. Efforts are needed to mobilize women, inform them of their rights, enable them to exert a voice in family affairs and make contingency plans for unforeseen pregnancy-related problems, and create amongst them a feeling of entitlement to health care and other services.

Shipra Goel is a third year medical student at Lady Hardinge Medical College in India
goelship(at)gmail.com

References

[1] Maternal mortality in 2005: estimates developed by WHO, UNICEF, UNFPA and the World Bank. Geneva, World Health Organization, 2007 (http://www. who.int/reproductive-health/publications/maternal_mortality_2005/index.html, accessed 14 August 2008).

[2] WHO (2003), The World Health Report 2003, Shaping the future.

[3] The World Health Report – Make every mother and child count, Geneva, World Health Organization, 2005

[4] Govt. of India (2001), Census of India 2001, Provisional Population Totals, Paper-1 of 2001

[5] WHO (2005), Regional Health forum, Vol.9, No.1, 2005

[6] Bhandari, N. and S. Mayank. 1999. A study on the perceptions, prevalence and health seeking behaviour of maternal morbidities in an urban slum. Unpublished report.

[7] IIPS and ORC Macro, 2000; MOHFW, 2000

[8] Govt. of India (2004) National Guidelines on Infant and Young Child Feeding (2004) , Department of Women and Child Development, Govt. of India.

[9] Govt. of India (1978), National Plan of Action for the International Year for the children 1979, Ministry of Education and Social Welfare, New Delhi.

[10] WHO (2003), Health Situation in South East Asia, Basic Indicators 2002

Today we’d like to announce the publication of Shipra Goel’s on the deplorable state of maternal and child health in India. Read it here.

Meanwhile, today’s blog is a reflection from Tiago Gameiro Inacio, 4th year medical student at Newcastle University, currently undertaking the Global Health Student Selected Component (SSC)

People grow in a process of socialisation which determines the way they perceive, incorporate and understand facts, feelings, illness and healing

In our Global Health SSC we have recently had a seminar entitled Mental Health: culture, language and power.

It is fascinating how the perceptions of mental health and healing vary so much across countries, continents and cultures. This seminar turned out to be a much deeper discussion and reflection on culture itself, its definition, components and variability and how those influence global mental health.

We embarked on a journey of self knowledge, discovery and reflection. The fact that we had people from different countries and cultures helped to add different points of view on experiences that unify different societies: death, bereavement, disease and mental health itself.

We discussed language. Being from a different background and having Portuguese as my native tongue I have several times struggled to find corresponding meanings to common symptoms in English and Portuguese. It gets particularly difficult if these symptoms represent emotions. In the seminar we went through what people would present with to their healers (ranging from medical professionals to shamans) and how many of these expressions had no translation and their deep meanings remained in the communities that created them.

The Portuguese language has stolen the word stress into its vocabulary like many other latin languages. The fact is there is no single word in my native language to my knowledge that transmits the exact concept of the word “stress” like the English word does. Why was there this need to incorporate this word? Did Portuguese people not suffer from stress before and thus never needed to create a word equivalent to it? Is it a fruit of the fervent Western Culture?

People grow in a process of socialisation which determines the way they perceive, incorporate and understand facts, feelings, illness and healing. Due to this people from different cultures perceive the same events differently and react differently. As medical professionals we must be aware of these patients in their communities, beliefs, values and then tailor mental healthcare accordingly. Otherwise our “help” could be catastrophic. In many communities the individual prioritises the community rather than himself and to deliver healthcare it is fundamental and more effective to approach the whole community. This has been practised for centuries by the healers of those communities who work depending on the cultural beliefs defined by the latter. Is it not futile to think that western medicine holds the answers for the care of these patients when these are happy with the services provided by traditional healers or shamans? Many psychological phenomena taking place in these communities are considered to be a result of magic or the will of gods or the devil. Many healers “treat” these conditions and the patients do recover. Science acknowledges the power of believing, as in the placebo effect, and its role in recovery but I believe there is much more to learn from the work of these healers. The way they integrate the individual in its family and community, taking into account dimensions like spirituality is remarkable and it might explain the primordial role of these therapies even in medicalized societies. This goes back to the holistic care promoted by Personal Development lectures that we do not see put into practise very often.

However we shall not undervalue the role of pharmacology in mental illness as in psychosis but reconsider its use in the whole spectrum of mental illness, where healers definitely play a role for understanding and addressing the needs of that specific population and its individuals. On the other hand we should perhaps reflect on what that teaches us about our own society. Perhaps we are optimising pharmacological sciences but neglecting basic elements in the core of mental health treatment. Furthermore, the treatment for a mental disorder, like a formula, follows a clustering of symptoms forming a diagnosis. In this formula there is very little space for socio-cultural factors and emotions become lost in translation.

This being the case, are we right in applying the celebrated scientific models of the Western world to these populations and their patients? By ignoring the cultural background that define these patients and their experience of illness and the illness itself are we not delivering an inadequate treatment as its based on false premises?

I hope to be able to incorporate these reflections in my practise. It is not realistic thinking this would not affect us unless we work overseas in a remote village in Africa. Globalisation will bring it to our rounds, clinics, home visits to people from very diverse origins and experiences. Many of these individuals will greatly require good healthcare, not only physically but also psychologically. It is our duty to ensure we provide this, taking into account all these dimensions of an individual which the fast paced Western model wants us to neglect.

Tiago Gameiro Inacio, 4th year medical student at Newcastle University
Email: tiago.gameiro-inacio@newcastle.ac.uk

One of the campaigners Kadiatou Baby Maiga from Mali; Image credit: Oxfam/Sven Torfinn

In today’s blog Global Digital Campaigner from Oxfam, Ian Sullivan writes on a group of eight campaigners seeking to ensure the G8 deliver on their promises.

8 inspirational campaigners from around the world are coming together to call for health and education for all

The W8, a group of 8 prominent health and education campaigners from all 4 corners of the globe, are on a mission. They want to use their experiences from working, organising and campaigning in their own countries, to tell leaders of G8 that now is the time to deliver on the promises that they made at the turn of the century – the Millennium Development Goals (MDGs). It’s time to make sure that mothers and babies can see a doctor when they need to and children get the chance of an education.

The W8 members are truly inspirational women. For instance, Kadiatou Baby Maiga is the president of the Malian coalition ‘Education for All’. She was one of only two girls in her high school class of 80. Now she works to make sure that other girls have the same opportunities as she’s had.

You’ll get to know them all much better over the course of their trip as they blog, tweet and make short videos bringing the voice of their communities to the attention of world leaders and the general public. More specifically, the W8 are visiting Canada (ahead of the G8/G20) and key European Union (EU) countries.

These countries can play a crucial role in helping to get the health and education MDGs back on track. As things stand these promises won’t be kept and that means millions of people will be locked in poverty – mothers will die needlessly in childbirth and millions of children will never learn to read and write. However, it’s not all doom and gloom. With the right will from the G8, these promises to the world’s poorest people can be kept.

I’ll leave the final word with W8 member, Sandhya Venkateswaran, “Something as basic as giving birth to a child is incredibly risky for a large proportion of women, and although there has been a lot of talk about improving maternal health, many women just don’t know whether they will survive childbirth.”

Tell the G8 that you want them to end this scandal and keep their MDG promises.

Follow the W8 on Twitter

More about the W8

The Hospital

Caritas St. Elizabeth’s Medical Centre is a community-based 317-bed tertiary care hospital located in the Brighton neighbourhood of Boston. St Elizabeth is a thoroughly modern inpatient and outpatient facility that is also a major teaching affiliate of Tufts University School of Medicine.

The Experience

I could feel the nervous excitement overwhelm me as I reached the GI Unit at St Elizabeth’s for the very first time. The first day involved meeting with the GI Fellow who was going to be my chief clinical advisor for the next 4 weeks followed by a brief meeting with the program director, Dr Roger Mitty and after that it was straight to work. I was rotating with the GI Consult service where we were expected to see GI consults in the hospital and if required, perform the requisite endoscopic procedures. I was taught the essentials of history taking and physical examination from the GI point of view. Special emphasis was given to delineate the important relevant details from the GI point of view in the history and physical examination of the patient. I was given abundant opportunity to learn and communicate with the patients. Initially I was hesitant in communicating, but with support of my fellow and my attending doctor, my confidence gradually grew and by the end of the elective, I was much more comfortable talking to patients. On a routine day I was expected to see my admitted patients and follow up their symptoms and medications and report any significant changes if they had taken place overnight. Additionally, I was expected to see the GI consults and perform the requisite history taking and physical examinations. Rounds took place in the afternoon where I would present my cases for the attending doctor, followed by a visit to the patients on the hospital floor. I was expected to present a case everyday and I would be questioned regarding the case and its management.

Dr Dennis Lee (Attending)

In addition to the consult service, I was also expected to attend the Joint GI Surgical Conferences, GI Radiological and the GI Pathological conferences. All these conferences had attending doctors, fellows and residents from their respective departments who would be presenting cases .These conferences were extremely interesting and informative, as we were exposed to the more unusual and the interesting cases of the week, enabling us to study them not only from a GI perspective but from a Surgical, Pathological and Radiological perspective as well. I had the distinguished opportunity to present a case at the Joint GI Surgical Conference regarding persistent vomiting in a patient who underwent gastric bypass. The atmosphere in the GI unit was extremely warm and friendly, with everyone from the attending doctors to the nurses and technicians being more than willing to help with problems. During the initial 2 weeks of my elective I was under the guidance of Dr Dennis Lee, and then Dr Michael Foley for the remainder of the elective. Their knowledge and experience in dealing with gastroenterological problems was truly astounding and it was an honour to train under such pioneering doctors. Dr Foley’s sense of humour and his uncanny ability to make even the most troubled patients laugh, momentarily relieving them of their pain, was truly remarkable. I always looked forward to the rounds as they were are mixture of intense discussion and learning combined with a lot of fun. In addition to presenting cases, I was expected to prepare presentations on various topics and present it to the GI Team on a regular basis. I had the chance to witness advanced GI procedures such as APC*, ERCP* and PEG* placement.

Dr Michael Foley (Attending)

During my rotation I had the unique opportunity to interact with patients firsthand and listen to the difficulties encountered as they tried to lead a normal life. However, there was one story which stood out and I can remember it vividly. She was a patient of severe Crohn’s Disease, who had spent the past thirty years with a permanent colectomy and multiple ileostomy revisions. As I walked up to her room I was nervous, at the very least I was expecting an irritated and annoyed patient who would not want to talk to a medical student at. To my surprise I found a quiet charming lady who had long decided that it was she who was going to control the disease and not the other way round. After listening to her about her work as a Medical Laboratory Technician and about her passion for photography I could not help but wonder that here was a woman who has been through pain and suffering but still managed a smile and had a childlike desire to learn! I can never forget the happiness on her face as we managed to discharge her just in time for her photography workshop. With her life as an example she taught me that circumstances can be extremely grim but what matters is not to concede defeat and to stand up to them!

The GI Fellows Erika (L) and Alan (R)

Summing up my experience, the four weeks had a steep learning curve. As a part of your electives you would be expected to make presentations on various topics and your performance is judged on basis of your presentation. To ensure you succeed at this I would strongly recommend future students to familiarize themselves with the common computer programs such as PowerPoint, Excel as well as learn how to use online resources such as pubmed.com and uptodate.com. These skills would help you tremendously help in searching for the relevant information online and in presenting in a simple and concise manner, which is very important. Small details like being punctual, making sure your attire is professional, being courteous and the dedication to work long hours always goes a long way in creating a good impression on everyone around you. Also, Tufts University does not produce housing facilities to visiting students and you would be expected to make your own arrangements. Boston has a wonderful public transport system called the MBTA. Buying a Monthly Link T card will enable you to use the bus as well as the subway systems. It was extremely cost effective and really helped me in my commute everyday and I would strongly recommend it to any future student interested pursuing electives in Boston.

The City

Finally, the elective was not just about going to a great hospital by itself but also to live in and experience the great city of Boston. Bristling with several educational institutions, Boston is a student’s paradise. Its rich cultural and historical heritage can be experienced by walking the Freedom Trail and visiting the Museum of Fine Arts. Boston has a rich sporting history with several teams (the Celtics, Patriots and Red Sox) being among the best in their respective sports. I had the amazing opportunity of attending an Inter-College Ice Hockey game at the Agganis Arena, Boston University between the BU Terriers and UMASS. It was a lot fun and just added to the great experience of living and studying in Boston.

Trinity Church, Boston

I am truly sad that my rotation is Boston is over, but the experience will stay with me forever. I am extremely thankful to have had such a wonderful group of people around me, who helped me immensely in progressing further as a student of medicine.

Purav Mody is a student at the Government Medical College, Surat, India
puravmody(at)gmail.com

Appreciation

I personally want to thank the entire GI team for all their help and cooperation and thank in particular, Dr. Roger Mitty, Dr Michael Foley, Dr Dennis Lee, Dr Alan Bonder and Dr Erika Lee.

Abbreviations

* APC : Argon Plasma Coagulation

* ERCP : Endoscopic retrograde cholangiopancreaticography

* PEG : Percutaneous Endoscopic Gastrostomy

Today we’d like to announce the publication of Purav Mody’s report on his elective working in gastroenterology at St Elizabeth’s hospital in Boston, USA and learning how the surgical, pathological and radiological aspects of GI medicine relate to each other. Read about it here.

Today’s blog written by Manuel Rivera, TLS Regional Advisor for El Salvador, addressed the current evidence on the use of date-rape drugs around the world

Dynamic inter-governmental efforts are required for the regulation of other familiar or derived “date rape” substances being licitly trafficked

The International Narcotics Control Board (INCB) recently emitted its’ 2009 annual report which evidenced a rising trend in the use and abuse of substances facilitating sexual assault. The INCB functions as an independent body of the United Nations (UN) implementing international conventions for drug control. Essentially, it is by the INCB conventions that the UN contributes to different nations in their fight against the illicit traffic of drug. This emergent and rapidly growing problem has unveiled the immediate need for INCB to call on the governments to implement resolution 52/8 from the Commission on Narcotic drugs. Resolution 52/8 demands for greater actions and attention from governments in their duty condemning drug-facilitated sexual assault; several considerations such as reshaping the legal framework or establishing regulations for drugs having the potential of producing this kind of effects are considered hereby.

The repertoire of substances used as ‘date rape’ drugs is vast and not limited to one specific pharmaceutical family. Contrary to what would be normally thought, prescription drugs are far more used than other drugs (e.g. MDMA, cocaine or cannabis). High dose benzodiazepines are among the most frequently used “date-rape” drugs; pharmacologically speaking, benzodiazepines have sedatives, hypnotic, anticonvulsant, anxiolytic, muscle relaxant and, in high doses, amnesic properties. The term “date rape” drug finds its roots from a now scarcely used benzodiazepine: flunitrazepam or rohypnol (also known as “ruffies”). A drug facilitated sexual-assault case usually can be recognized by the following typical story of: “I was at this party, and this guy gave me a drink. Next thing I know, it is morning and I’m in someone’s bed. I have no idea what happened in between”.

Many pharmaceutical companies have declared themselves against the illicit traffic of drug, and as such, have discontinued production of high dose presentations. Moreover, the addition of flavor and colorants renders substances recognizable by the victims and lessens considerably their use by perpetrators. Nevertheless, and even if these positive measures have been proven effective to some degree, dynamic inter-governmental efforts are required for the regulation of other familiar or derived “date rape” substances being licitly trafficked. In addition, the INCB annual report invites nations to review regularly their legislations but more so aims nations where the use of drugs to facilitate the commission of a crime is not considered a felony and thereby cannot be properly sanctioned. According to the INCB, substance mediated sexual-assault is a complex issue affecting many countries especially since drug traffic follows an intricate network closely related with organized crime and held responsible for a great amount of homicides in some Latin-American and African countries.

Finally, the president from the INCB, Professor Sevil Atassoy stresses on the need of drug primary prevention for persons who are either not using or not seriously involved with drugs: forging a partnership early with civil society repays the effort with greater awareness and caution towards the potential risks associated with drug consumption.

References:

1. http://www.incb.org/pdf/annual-report/2009/en/Press_Kit_09_English/05INCBwarnsAboutDrugs_PressKitE.pdf p46-48

2. http://www.unodc.org/documents/commissions/CND-Res-2000-until-present/CND-2009-Session52/CNDResolution_52_8.pdf

3. http://www.un.org/apps/news/story.asp?NewsID=33876&Cr=drugs&Cr1=

Image credit: UN Photo/Marie Frechon

Today’s blog is written by Zena Nyakoojo, BSc in Biomedical Sciences and one of the newest members to the TLS team, who reflects on the meaning of International Women’s Day.

What do you think of this issue? Register your opinions in our poll and then join the debate on our Facebook Group.

Despite globally, women, on average, living six to eight years longer than men, females continue to be affected disproportionately by HIV, and suffer at the hands of sexual, maternal and reproductive ill health

As countries around the world begin their celebrations, it is also an occasion of careful reflection as we consider the accomplishments to-date, and future ambitions.

Following its initial establishment in 1909 in the United States, National Women’s Day became recognised as an international institution with an accompanying conference in Copenhagen the following year. Since then, the campaign has progressed to become an official annual holiday in many countries including China, Russia and Bulgaria, and is continuous in its attempts to liberate and encourage women throughout all areas of life, celebrating their social, political and economic accomplishments on a grand scale.

On a traditional level, the holiday sees women receive small gifts and tokens; this convention however, is only a surface gesture of the much more important and life changing objectives initially envisioned in 1909; objectives which maximised equal rights for all women in all societies in every respect. As such, this year’s global United Nations theme is Equal rights, Equal opportunities: Progress for all – a representation of gender issues around the world.

Globally, there is an obvious difference between the societal representation of men and women, especially in business and financial settings, and this may be the setting most would initially connect with gender inequality; It is however, not just in the workplace that differences are in stark contrast, and legislations involving women’s health and education, raise similarly important issues that need to be addressed.
Whilst it is not easy to summarise the current status of women’s health due to global and regional differences, it is undeniable that health inequalities remain at the forefront of global issues.

Despite globally, women, on average, living six to eight years longer than men[1], females continue to be affected disproportionately by HIV, and suffer at the hands of sexual, maternal and reproductive ill health; all of which demonstrate a need for gender specific healthcare reassessments as well as globally successful family planning regimens.

It seems that the continued failure of societies to fully meet the healthcare needs of females, is preventing girls and women from accessing their full potential; a view that is also emphasised in the World Health Organisation’s recent report, Women and health: today’s evidence tomorrow’s agenda[2]; an article which not only emphasises the negative impact of gender inequities on women’s health, but highlights that the poor distribution of resources including income, education and nutrition, due to such gender inequalities, are all heavily associated with poor health.

Although IWD Progress over the last ten years is undeniable, headlines of the day threaten to overshadow celebratory attitudes with articles emphasising high maternal mortality and labour death rates[3]. Such statistics should however, serve to extinguish complacency, and rather, act as a reminder of targets yet to achieve; a standpoint recently taken by U.N. Secretary-General Ban Ki-moon who also, encourages societies to celebrate the positive aspects rather than highlighting the negative ones.

The general warned that the race is far from over and discrimination against women continues to persist everywhere, with women’s education, health and status remaining unequal.

We should not however feel demoralised. Such words do not serve to belittle or ignore how far the journey towards gender equality has come, but rather, they highlight the importance of continued action, global perseverance and international unity.

Zena Nyakoojo
BSc (hons) Biomedical Sciences
Queen Mary University of London

References:
[1] WHO – Women’s Health. Available at: http://www.who.int/mediacentre/factsheets/fs334/en/index.html
[2] Women and Health: Today’s evidence, tomorrow’s agenda. Available at:
http://whqlibdoc.who.int/publications/2009/9789241563857_eng.pdf
[3] High maternal death rate overshadows International Women’s Day in Afghanistan. Available at: http://www1.voanews.com/english/news/health/High-Maternal-Death-Rate-Overshadows-International-Womens-Day-in-Afghanistan-86759682.html

Pranab - TLS 10 questions

Here are Pranab’s responses:

1. Why did you decide to study medicine?

In India, the stereotype for students with good academic backgrounds is to go into either medicine or engineering. I would be lying if I said that it was not a bit of this stereotype that propelled me into medicine. But also, having seen the kind of social respect, economic prosperity and professional freedom that doctors enjoy, I had been lured to this field. All professions contribute to the growth and prosperity of a nation, and make a difference to the life of people in some way or the other. However, I realized, after seeing my uncle (a GP) that it is the easiest for a doctor to make a positive change in someone’s life in course of everyday activities. This was the final touch that gave me the motivation to move into medicine.

2. What profession would you be in if you weren’t in Medicine?

This is a rather difficult question in that I have not pondered on this much. The entrance examination to the Medicine program (analogous to MCAT) is an intensely and insanely competitive one. Therefore one always had to have alternate career plans ready. Although I never gave those plans much thought, I believe if it was not Medicine, I would most probably be in Biochemistry or Biotechnology. Something related to Medicine and with a possibility of doing research to impact the medical specialties.

3. What is your biggest motivation?

Personally, I believe that motivation for me has morphed from one form to the other as the challenges shifted forms themselves.

In the first couple of years in medical school, when the challenge was to establish oneself as a credible student, the motivation was pretty evident. Yes, I may have been a little guilty of being a gunner in those days. But as the years melted away and the clinical rotations started, I realized that there was much more to Medicine than what one learnt off the books. Man himself, with his frailties and fatalities was a wonder that medical school was slowly but surely unfurling. Through interactions with patients, peer and preceptors, life in all its colors is now opening up before me now. And now, my biggest motivation remains to find a way to unravel the secrets of this wonderfully oiled machine that is so simple, so uniform, yet so different! Whether they be in the body or in the mind, how the same system works in one and breaks down in another intrigues me. Probably a little amorphous and abstract, I realize, but nothing pleases me more than a clinical encounter with a patient…

4. What are you most interested in so far and why?

Every year of medical school brings a different flavor to the buffet. The first couple of years I had been mesmerized by the biochemistry, physiology and pathology of the human body and was immensely motivated to go into basic science oriented research. But when the clinics started I realized that the joy of human interaction, of being able to help them actively was a heady feeling. So it is no surprise that I am a total Internal Medicine junkie. I also am intrigued by the impact of medical research and progress on human life and quality of life in general. From this stems my liking of Global Medicine, Public Health and Multidisciplinary or Translational research.

I believe I am a little intoxicated by the power of medicine to affect human lives and my choices reflect the same as well!

5. What has been your most difficult module so far and why?

I believe it was the module of Microbiology-Pharmacology-Pathology which comprises of the Second MBBS curriculum which I found difficult to cope with due to a number of reasons. First, because a decade-long friend slipped into depression and committed suicide, bringing to the surface the numerous insecurities that medical school spawns in our minds. Second, because of a skewed academic curriculum that discouraged lateral, logical thinking and encouraged (often, actively) a rote-learning system which I refused to bow down to (but of course, I had to, eventually). Third, because it was the year when my first brush with the ever complicated matters of the heart happened, which eventually left me wiser, but made me pay the costs in many other ways!

6. Where do you see yourself in 10 years time?

a. The wishful thinking version:

I would like to thank the committee for considering me for this esteemed award that joins me with the legions of legends… blah blah blah.

That’s how the thank you speech starts in my head when I land the (Ig)Nobel Prize for inventing (place ever-changing earth-shattering idea here).

b. The perhaps slightly more realistic version:

Working at a tertiary academic medical center in Internal Medicine. With an active research life, churning out quality results. Teaching. And becoming a respected member of the profession.

7. What is the most memorable positive moment in your medical studies so far?

There are several moments when the pain medical school puts one through seem worth it all. For me some of the best were getting my first student research grant, diagnosing and reviving my first hypoglycemic patient in the ER, being a part in diagnosing a child with myoclonic jerks and of course, meeting the occasional patient whose resolution to beat the odds remains an inspiration. But some of the best memories remain in the Labor room, delivering the pregnant ladies and seeing their ecstasy at the end of a tremendously painful experience. This has given me the fortitude of bearing the pain life throws at me!

8. What is the worst horror story in your medical studies to date?

I guess having a patient die on us is like a rite of passage. The first patient who died on the unit I was on was absolutely the most horrific experience till date.

He had come in following an AMI and had already gone into shock, and could not be revived despite the best of our last ditch efforts. And then communicating the news to the family. I felt that this is the most difficult job we have to do.

9. Can you share some things that you wish that someone had told you before you applied to study medicine?

1. This is a long and arduous journey and it does not end when you get the degree. That is merely the beginning.
2. The medical education has not changed with the times. And the orthodox ideas that ran the system half a century ago are still deeply entrenched.
3. People do not like it much if you try to change things around!
4. Life is difficult, and doctors get to know of all the various forms in which human suffering manifests – whether it be in the body or in the mind – and if one is not strong in body and mind, it is difficult to cope with that.

10. Can you share some tips/advice for others

a. Wanting to study medicine:

1. Prepare for the toughest entrance exam
2. See answers to Question 9 above!

b. Already studying Medicine:

1. Do remember to get your noses out of the text books occasionally and enjoy life!

Summary

Dilated cardiomyopathy is characterised by left ventricular dilation that is associated with systolic dysfunction. Diastolic dysfunction and impaired right ventricular function can develop. Affected individuals are at risk of left or right ventricular failure, or both. Heart failure symptoms can be exercise-induced or persistent at rest. Many patients are asymptomatic. Chronically treated patients sometimes present acutely with decompensated heart failure. Other life-threatening risks are ventricular arrhythmias and atrioventricular block, syncope, and sudden death. Genetic inheritance arises in 30—48% of patients, and inflammatory disorders such as myocarditis or toxic effects from medications, alcohol, or illicit drugs also result in dilated cardiomyopathy. Genes that cause dilated cardiomyopathy generally encode cytoskeletal and sarcomeric (contractile apparatus) proteins, although disturbance of calcium homeostasis also seems to be important. In children, disrupted mitochondrial function and metabolic abnormalities have a causal role. Treatments focus on improvement of cardiac efficiency and reduction of mechanical stress. Arrhythmia therapy and prevention of sudden death continue to be mainstays of treatment. Despite progress over the past 10 years, outcomes need to be improved.

Introduction

Cardiomyopathies are diseases of the heart muscle, characterised by abnormal findings of chamber size and wall thickness, or functional contractile abnormal findings—mainly systolic or diastolic dysfunction in the absence of coronary artery disease, hypertension, valvular disease, or congenital heart disease.1 Cardiomyopathies are classified as either primary or secondary. Primary cardiomyopathies consist of disorders solely or predominantly confined to the heart muscle, which have genetic, non-genetic, or acquired causes. Secondary cardiomyopathies are disorders that have myocardial damage as a result of systemic or multiorgan disease.2

Dilated cardiomyopathy is the most common cardiomyopathy worldwide and has many causes. In this disorder, dilation and impaired contraction of the left or both ventricles develops. It can be primary (genetic, mixed or predominantly familial non-genetic, or acquired) or secondary (eg, infiltrative or automimmune). This disease can also be diagnosed in association with recognised cardiovascular disease; however, to qualify as dilated cardiomyopathy, the extent of myocardial dysfunction cannot be explained exclusively by abnormal loading or ischaemic damage.3 Dilated cardiomyopathy is associated with sudden cardiac death and heart failure, resulting in a large cost burden because of the very high rate of hospital admission and the potential need for heart transplantation. In this Seminar, we focus on the clinical features, genetics and causative mechanisms, diagnostic strategies, treatments, outcomes, and controversies in the care of primary and secondary dilated cardiomyopathy.

Epidemiology and clinical features

Dilated cardiomyopathy is characterised mainly by left ventricular systolic dysfunction (abnormality of contraction), with an associated increase in mass and volume. In some cases, left ventricular diastolic abnormal findings are present. Right ventricular dilation and dysfunction can also develop but are not needed for diagnosis. Prevalence in the general population remains undefined. This disorder develops at any age, in either sex, and in people of any ethnic origin.2,4—6 In adults, dilated cardiomyopathy arises more commonly in men than in women. In children, the yearly incidence is 0·57 cases per 100 000 per year overall, but is higher in boys than in girls (0·66 vs 0·47 cases per 100 000, p<0·006) in black people than in white people (0·98 vs 0·46 cases per 100 000, p<0·001), and in babies younger than 1 year than in children (4·40 vs 0·34 cases per 100 000, p<0·001). Two-thirds of children are thought to have idiopathic disease.4 In adults, the prevalence is one in 2500 individuals, with an incidence of seven per 100,000 per year (but it could be underdiagnosed).5 In many cases, the disease is inherited, and is called familial dilated cardiomyopathy. The familial type might account for 20—48% of all cases.5 To achieve improved care and outcomes in children and adults, a broadened understanding of the causes of these disorders is needed.

In this disease, the left ventricle is dilated, and more spherical than usual with raised wall stress and depressed systolic function (figure 1). Mitral regurgitation and ventricular arrhythmias can also develop. Occasionally, other rhythm disturbances such as atrioventricular block, supraventricular tachycardia with or without pre-excitation including Wolf-Parkinson-White syndrome, and atrial fibrillation develop. In the most severe cases, affected individuals present with signs and symptoms of heart failure—diaphoresis, breathlessness at rest or with exertion, orthopnoea, exercise intolerance, early onset fatigue, abdominal pain, and pallor. Cachexia and peripheral oedema typically arise late in the course of the disease. Young children often have poor appetite and, similar to adults, cachexia. Sinus tachycardia, gallop rhythm, jugular-venous distention, pallor, cool hands and feet, hepatomegaly, and a murmur that is consistent with mitral regurgitation are common findings at physical examination. Additionally, peripheral oedema and ascites are late signs in children.

Transthoracic echocardiogram of patient with dilated cardiomyopathy
Apical four chamber view shows dilated left ventricle (arrow). In real time, systolic function is greatly diminished.

Diagnosis is dependent on patient history, and clinical, echocardiographic (figure 1), or cardiac MRI features of dilated cardiomyopathy or heart failure, or both. Echocardiographic findings are left ventricular dilation and systolic dysfunction (defined by depressed ejection fraction or shortening fraction), with or without mitral regurgitation. Additionally, pericardial effusion (especially in myocarditis) and rhythm irregularities can be noted. Chest radiographs often show cardiomegaly and increased pulmonary vascular markings that are consistent with pulmonary oedema (figure 2). Electrocardiography, another standard diagnostic test, can show sinus tachycardia, ST-T wave changes, Q waves, conduction disease, bundle-branch block, left ventricular hypertrophy, or ectopy, including supraventricular tachycardia, atrial fibrillation, or ventricular arrhythmias (figure 3). In some cases, patients have complications related to dilated cardiomyopathy, such as thromboembolic disease, including stroke. If the right ventricle is affected, evidence of right heart failure—tricuspid regurgitation, raised jugular venous pulse, hepatomegaly, ascites, and peripheral oedema—are noted in some cases.

Chest radiograph of patient with dilated cardiomyopathy and decompensated heart failure
Image shows pronounced cardiomegaly and pulmonary oedema that is consistent with volume overload.

Electrocardiogram of adult with dilated cardiomyopathy and decompensated heart failure
Shows sinus tachycardia and significant ST-segment changes.

Biomarkers can be of clinical use in diagnosis, management, and prognosis of patients, especially those with heart failure.7—10 The most widely used markers are B-type natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-BNP). In adults and children, BNP differentiates symptoms related to lung disease from heart failure.7—11 Biomarkers are extensively reviewed elsewhere.7 Endomyocardial biopsy sampling can be used to further define the cause of this disease in some cases.12 This histology of heart muscle is clinically useful to distinguish between disease processes that need alternative treatment strategies, such as storage diseases, malignancies, sarcoidosis, and haemochromatosis. Confirmation of viral myocarditis is sometimes possible with endomyocardial biopsy, as is identification of virus-negative, immune-mediated myocarditis, which could result in additional treatment such as immunomodulation or immunosuppression therapies.13—17 From endomyocardial biopsy samples, identification of the causative virus by its viral genome with PCR has been useful to establish the cause of acute myocarditis, and has clarified that some cases of dilated cardiomypathy are the result of chronic myocarditis.18 Additionally, this diagnostic approach sometimes enables improved treatment strategies and accuracy of prognosis.

Dilated cardiomyopathy is associated with complex remodelling of one or both ventricles, resulting in a change of the ventricle shape and the architecture of the myocardium fibres. Macroscopic examination typically shows enlargement of all chambers, with more dilation of the ventricles than the atria. Additionally, the valves and the epicardial coronary arteries are usually normal. In some cases, intracavitary thrombi are present, most easily seen in the apex of the left ventricle. Microscopic examination generally reveals areas of interstitial and perivascular fibrosis, and sometimes areas of necrosis and cellular infiltrate. Myocyte size varies greatly, with some atrophied and hypertrophied cells. In children, abnormal findings such as abnormal shapes, sizes, and numbers of mitochondria (with or without inclusions), abnormal glycogen stores, or abnormal lysosomes with vacuolisation might be seen on microscopy. Causes of dilated cardiomyopathy are many (panel). For primary dilated cardiomyopathy, causes are genetic, mixed (predominantly non-genetic), and acquired. Acquired primary disease can be secondary to inflammatory disease such as myocarditis, stress-provoked (taku-tsobo), secondary to peripartum state, or can be tachycardia induced. Secondary dilated cardiomyopathy has many causes that are systemic in nature.

Panel
Mechanisms responsible for dilated cardiomyopathy

*
Disturbed cytoskeletal-sarcomeric link:
o
Genetic mutation (sarcolemma-sarcomere genes)
o
Viral infection (coxsackievirus myocarditis)
o
Non-viral infection (Chagas disease)
o
Toxicity (adriamycin and alcohol)
*
Apoptosis
*
Autoantibodies and autoimmune disease
*
Metabolic disturbance storage disease
*
Mitochondrial dysfunction
*
Ion-channel disruption
*
Chronic incessant tachyarrhythmias
*
Peripartum
*
Infiltrative disease
*
Endomyocardial disease
*
Endocrinopathies
*
Nutritional deficiencies
*
Electrolyte disturbance

Causes of primary dilated cardiomyopathy

Familial and genetic

Inherited dilated cardiomyopathy was first thought to account for a small percentage of cases only, until Michels and co-workers 19 showed that about 20% of probands had family members with echocardiographic evidence of this disease when family screening was undertaken. Inherited familial dilated cardiomyopathy develops in 30—48% of cases,20 with autosomal-dominant inheritance as the predominant pattern of transmission—X-linked, autosomal recessive, and mitochondrial inheritance are less common than is autosomal-dominant inheritance. At presentation, a family history and pedigree (family tree) should be done to further delineate a possible mode of inheritance. Screening of first-degree relatives should be considered.21

Causative genes in dilated cardiomyopathy seem to predominantly encode two major subgroups of proteins—cytoskeletal and sarcomeric proteins.20,22—24 The cytoskeletal proteins identified so far include dystrophin,25, 26 desmin,27 lamin A/C,28 δ-sarcoglycan,29 β-sarcoglycan,30 and metavinculin 31 (table). In the case of sarcomere-encoding genes, the same genes identified for hypertrophic cardiomyopathy seem to be responsible, including β-myosin heavy chain, myosin-binding protein C, actin, α-tropomyosin, and cardiac troponin T and C.32—35 Additionally, a new group of sarcomeric genes, those encoding Z-disk proteins,36 have been identified—ZASP,37 muscle-LIM (lin11, isl-1, and mec-3) protein,38 α-actinin-2,38 myopallidin,39 cardiac ankyrin repeat protein,40 and telethonin.41 Furthermore, phospholamban,42 tafazzin,43 and the sodium-channel gene SCN5A44 have also been reported (table).

Genetic causes of dilated cardiomyopathy by chromosome locus

Genetic testing for cardiovascular disease is becoming common, with several fee-for-service laboratories offering testing in the USA. For hypertrophic cardiomyopathy, the diagnostic yield of testing is 60—70%; however, testing for dilated cardiomyopathy has a yield much lower than 60%. The most frequently identified gene is lamin A/C, but only when the disease is associated with atrioventricular block (with or without skeletal myopathy). In pure dilated cardiomyopathy, the yield screening for a large number of genes is about 20%. Most frequently identified genes are the Barth syndrome gene TAZ, ZASP, desmin, and in men, dystrophin.

Of the X-linked forms of dilated cardiomyopahty, two disorders have been well characterised—X-linked dilated cardiomyopathy, which presents in adolescence and young adults, and Barth syndrome, which is most frequently identified in babies and children.45 In 1987, Berko and Swift,45 first described X-linked dilated cardiomypathy as dilated cardiomyopathy that develops in young men in the teen years and early twenties, with rapid progression from heart failure to death, which is attributable to ventricular tachycardia or ventricular failure, unless transplantation intervenes. These patients are identified by raised amounts of the muscle isoform of serum creatine kinase. Female carriers (ie, mothers) tend to develop mild-to-moderate dilated cardiomyopathy in the fifth decade, with slow progression. Towbin and colleagues,46 were first to identify the disease-causing gene and characterise the functional defect in which the dystrophin gene was shown to be responsible for abnormal clinical findings.46 Protein analysis by immunoblotting showed severe reduction or absence of dystrophin protein in the heart. These findings were later confirmed by Muntoni and colleagues 47 when a mutation in the muscle promoter and exon 1 of dystrophin was identified in another family with X-linked cardiomyopathy.47 Subsequently, many mutations have been identified in dystrophin in patients with this disease.

The dystrophin gene, when mutated, is also responsible for Duchenne and Becker muscular dystrophy; these skeletal myopathies present early in life. Boys with Duchenne muscular dystrophy become wheelchair-bound before age 12 years, whereas Becker muscular dystrophy is a milder muscle disease than is Duchenne muscular dystrophy, in which boys are ambulatory after the age of 16 years, although this prognosis has been modified by early, high-dose steroid treatment.26, 48 Almost all such patients develop dilated cardiomyopathy before their 21st birthday. In most cases, the muscle isoform of serum creatine kinase is raised, similar to that in X-linked cardiomypathy. Female carriers develop disease late in life, as do those with X-linked cardiomyopathy. Furthermore, immunohistochemical analysis shows reduced concentrations (or absence) of dystrophin, similar to findings in hearts of patients with X-linked cardiomyopathy. Information gained from studies of X-linked cardiomyopathy and Duchenne and Becker muscular dystrophy led us to suggest 22—24 that dilated cardiomyopathy is a disease of the cytoskeleton and sarcolemma that affects the sarcomere—a final common pathway of dilated cardiomyopathy. Our findings that three of 22 boys with idiopathic dilated cardiomyopathy had dystrophin mutations and raised muscle isoform of serum creatine kinase lend support to our results 25 showing that dystrophin mutations play a part in idiopathic dilated cardiomyopathy in male individuals.

Barth syndrome, initially described as X-linked cardioskeletal myopathy with abnormal mitochondria and neutropenia, typically presents in male infants as heart failure associated with neutropenia (cyclic) and 3-methylglutaconic aciduria.49 Mitochondrial dysfunction is noted on electron microscopy and electron transport-chain biochemical analysis. Abnormal findings in cardiolipin are crucial in disease development.50

The genetic basis of Barth syndrome is mutations in the gene tafazzin (TAZ), which encodes the tafazzin protein, an acyltransferase.43 Mutations in TAZ result in a wide range of findings, including dilated cardiomyopathy, hypertrophic dilated cardiomyopathy, endocardial fibroelastosis, or left ventricular non-compaction.20, 51 Arrhythmias are also frequent in these patients, and clinical disease is typically associated with symptoms of heart failure, syncope or sudden death, acidosis, or infectious complications.52

Ion channels in the heart are crucial for normal electrophysiological functioning of the heart. Dysfunction of ion channels leads to rhythm disorders, such as long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, atrial fibrillation, and atrioventricular block.53 This final common pathway for arrhythmias also plays a major part in the clinical behaviour of the heart in dilated cardiomyopathy. Many ion channels seem to interact with the sarcolemmal and sarcomeric proteins, with these binding-partner relations placing the rhythm of the heart at risk. Another ion-channel homeostasis gene associated with dilated cardiomyopathy is phospholamban, which has a role in calcium homeostasis. The importance of these proteins in the clinical presentation of this disease was shown by their inclusion in the American Heart Association’s classification scheme 4 and the National Institutes of Health workshop report.54

Infectious causes

Infectious causes of left ventricular dysfunction that are consistent with the dilated cardiomyopathy phenotype are common, including viral, bacterial, fungal, parasitic, rickettsial, and spirotricheal infections. In viral myocarditis, many viral pathogens cause the human disorder. In the past, causal diagnosis was dependent on viral culture of peripheral specimens (and rarely heart tissue) and serial serological testing. During the past 15—20 years, molecular-based testing of myocardial tissue has become a useful diagnostic method, especially PCR analysis of viral genomes in the heart. The most common viruses identified by this method from endomyocardial biopsy samples are parvovirus B19, adenovirus, coxsackievirus B and other enteroviruses, influenza A, human herpes virus 6, cytomegalovirus, Epstein-Barr virus, herpes simplex virus type 1, and hepatitis C.18, 55

The predominant viral cause of this disease seems to change every decade (coxsackievirus in the 1980s, adenovirus in the 1990s, and parvovirus B19 since 2000). Presentation of disease can vary, ranging from minor symptoms of malaise to acute decompensated heart failure, chest pain and myocardial infarction, or sudden cardiac arrest.56 Use of endomyocardial biopsy sampling in suspected myocarditis remains under-used, especially in children. However, many advances in diagnosis and therapy have occurred on the basis of use of this technique, and from studies with histology and PCR. Use of non-invasive techniques, such as cardiac MRI, are diagnostically effective and are becoming more widely used than they were previously.57 Chagas’ cardiomyopathy, caused by the protozoan Trypanosoma cruzi, remains the leading cause of chronic systolic heart failure in endemic areas.58 It is characterised by heart failure, thromboembolic disease, conduction disease and malignant arrhythmias, and sudden cardiac death.

Causes of secondary dilated cardiomyopathy

Toxicity-related causes

Many causes have been associated with myocardial damage and development of dilated cardiomyopathy. Long-term use of drugs such as cocaine result in heightened activation of the sympathetic nervous system, causing left ventricular dysfunction both directly and through promotion of coronary thrombosis, coronary spasm, and atherosclerosis.59 Chronic alcohol abuse is one of the most important adult causes of this disease in developed countries. Alcohol cardiomyopathy is a diagnosis of exclusion, and relates to the average daily intake of alcohol and duration of alcohol use. Alcohol, taken both acutely and chronically, depresses cardiac contractility by poorly understood mechanisms, activating the neurohormonal system.60 The estimated 4-year mortality rate approaches 50% in patients without complete abstinence after diagnosis.61

Anthracyclines, such as doxorubicin and daunorubicin, are very effective anticancer drugs that are prescribed worldwide. However, many patients treated with these drugs, irrespective of age, develop insidious dilated cardiomyopathy and heart failure. The scope of the problem remains to be adequately defined. Causative mechanism of the disease is multifactorial, but seems to be associated with generation of reactive oxygen species, disruption of mitochondria, and uncoupling of the electron-transport chain.62, 63 Use of dexrazoxane might be cardioprotective by attenuation of the formation of free radicals. Early detection of disease by both non-invasive and serological techniques shows promise.64

Peripartum cardiomyopathy

Peripartum cardiomyopathy is a disorder in which initial left-ventricular systolic dysfunction and symptoms of heart failure develop between the late stages of pregnancy and early postpartum period, typically within 1 month of predelivery and 5 months postdelivery.65 Its causes and pathogenesis are poorly understood. The disorder is common in some countries and rare in others. In most patients with this disorder, molecular markers of an inflammatory process are identified. Affected women generally present clinically with typical signs and symptoms of heart failure; signs of thromboembolism are also frequent. Conventional heart-failure treatment is typically used, such as diuretics, β-blockers, and angiotensin-converting enzyme inhibitors. Effective treatment reduces mortality rates and increases the number of women who fully recover left-ventricular systolic function. Outcomes for subsequent pregnancies after peripartum cardiomyopathy are better for women who have fully recovered heart function after their initial presentation than for those who do not.

Mechanisms responsible for genetically defined dilated cardiomyopathy

Mechanisms associated with disease causation are force generation and transmission defects, metabolic and mechanosensory abnormalities, and disturbed calcium homeostasis.66, 67 Most genes identified so far encode either cytoskeletal or sarcomeric proteins. For cytoskeletal proteins, defects of force transmission are thought to result in the dilated cardiomyopathy phenotype, whereas defects of force generation have been speculated to cause sarcomeric protein-induced dilated cardiomyopathy. However, sarcomeric mutations frequently lead to a clinical phenotype because of force transmission defects.33, 68, 69

Mutations in the sarcomere can produce hyertrophic cardiomyopathy or dilated cardiomyopathy. In cases of dilated cardiomyopathy, abnormalities in force generation or transmission are thought to contribute to development of this phenotype. Apart from mutations in the thin filament protein, actin, mutations in the thick filament protein-encoding gene β-myosin heavy chain have caused dilated cardiomyopathy with associated sudden death in at least one infant, and dilated cardiomyopathy in children and adults. Mutations in this gene are thought to perturb the actin-myosin interaction and force generation or alter cross-bridge movement during contraction. Mutations in cardiac troponin T, a thin filament protein, might disrupt calcium-sensitive troponin C binding.68 Mutations in phospholamban have also been identified, further lending support to calcium handling as a potentially important mechanism in development of this disorder. Haghihi and co-workers 70 identified homozygous mutations that cause dilated cardiomyopathy and heart failure, whereas they noted that heterozygotes had cardiac hypertrophy.70 Recessive mutations in troponin I could impair the interaction with troponin T,71 whereas α-tropomyosin mutations have been identified and were predicted to alter the surface charge of the protein, impairing interaction with actin.31

An area of interest for assessment at the molecular level is the Z disc.36 Knoll and colleagues 72 identified mutations in muscle-LIM protein and showed that these mutations result in defects in the interaction with telethonin.72 With mouse models, they also showed that muscle-LIM protein acts as a stretch sensor and that mutant versions of this protein cause defects in this activity. Additionally, Mohapatra and co-workers 38 identified mutations in this protein in families, described sporadic cases, and identified abnormal findings in the T-tubule system and Z disc architecture by electron microscopy, corresponding to the histopathology seen in muscle-LIM protein knockout mice.72 Findings73 of reduced expression of muscle-LIM protein in chronic human heart failure further lend support to those of Mohapatra and colleagues. Additionally, mutations in α-actinin 2, which has a role in crosslinking actin filaments and shares a common actin-binding domain with dystrophin, were also identified in familial dilated cardiomyopathy, disrupting binding of α-actinin 2 to muscle-LIM protein.

Vatta and co-workers37 identified mutations in the Z-band alternatively spliced PDZ-motif protein (ZASP), the human homolog of the mouse cypher gene, which leads to dilated cardiomyopathy when disrupted.74 This protein, which interacts with α-actinin 2, disrupts the actin cytoskeleton when mutated. The titin gene, encoding for the giant sarcomeric cytoskeletal protein, titin, contributes to maintenance of the sarcomere organisation and myofibrillar elasticity, and interacts with these proteins at the Z disc/I band transition zone.75 Furthermore, mutations have been identified in familial dilated cardiomyopathy.76 Mutations in ANKRD1 cause both dilated and hypertrophic cardiomyopathy, lending support to the idea that sarcomere and Z-disk encoding genes can have variable phenotypes.40, 77

Dilated cardiomyopathy that is associated with atrioventricular block or skeletal myopathy, or both, is most frequently associated with mutations in lamin A/C.78, 79 Lamins are located in the nuclear lamina at the nucleoplasmic side of the inner-nuclear membrane, and lamin A and C are expressed in heart and skeletal muscle. Mutations in this gene were first reported to cause the autosomal-dominant form of Emery-Dreifuss muscular dystrophy,78 which has skeletal myopathy associated with dilated cardiomyopathy and conduction-system disease. These mutations also cause a form of autosomal-dominant limb-girdle muscular dystrophy, which is associated with conduction-system disease.78, 79 Mechanisms that are responsible for the development of this disease, conduction-system abnormalities, and skeletal myopathy are being established.

Immune system and heart failure

Myocarditis is characterised by pathological inflammation of the myocardium, leading to chronic heart failure in a substantial number of patients younger than 40 years.80 Diagnosis for both viral and non-viral causes is based on well-established histological, immunological, and immunohistochemical criteria for endomyocardial biopsy samples. A subset of patients with myocarditis from various causes develop a chronic form of the disease that can be viral, post-infectious immune, or organ-specific immune in genetically predisposed individuals.3, 81 Autoimmune-mediated chronic myocarditis is characterised by autoantibodies to cardiac myosin and other heart antigens.82 Results of clinical and experimental data 83 suggest that, of these antibodies, those that are directed against the cardiac β1-adrenergic receptor induce cardiac dysfunction and cardiomyopathy, and might modulate severity of disease. However, whether patients develop heart disease because they possess harmful antibodies against this receptor or whether they develop these antibodies as a result of cardiac tissue injury remains unclear.

Results of other studies have implicated other autoantibodies; such as a group of autoantibodies against cardiac cellular proteins, including G-protein-linked receptors such as the muscarinic cholinergic receptor, myosin, mitochondrial proteins (eg, adenine nucleotide translocator and keto-acid dehydrogenase), actin, tubulin, heat-shock proteins, the sarcoplasmic reticulum ATPase, myosin, and the troponins.84 Clinical aspects of these autoantibodies remain unclear. However, circulating cardiac autoantibodies are identified in dilated cardiomyopathy and myocarditis patients at a higher frequency than in patients with non-inflammatory heart disease. Furthermore, in healthy relatives of dilated cardiomyopathy patients, serum antiheart autoantibodies are an independent predictor for development of this disease.85 Both innate and adaptive aspects of the immune system could have a role in affecting outcomes for experimental animals and people with viral myocarditis.86

Genetic mechanisms associated with autoimmune-mediated myocarditis remain poorly understood. Most genetic studies in people have suggested a relation between MHC class II antigens and dilated cardiomyopathy.87 However, this relation, especially with HLA-DRB4, existed in a small patient population. Other studies 88 have not supported these findings. Such reported discrepancies could be secondary to differences in patient backgrounds, such as ethnic origin.89 A recent report by Taneja and colleagues 90 of a non-obese diabetic mouse model developing spontaneous myocarditis also implicates a possible role of sex-related genes. The role of MHC class I in autoimmune myocarditis in animals or people has not been well established. Potential gene-specific mutations that cause autoimmune myocarditis have been investigated but rarely defined. Autoimmune diseases, such as diabetes and systemic lupus erythematosus, have overlapping loci with myocarditis, suggesting shared genetic traits. This finding could help to explain the susceptibility to autoimmune myocarditis across different populations.
The failing myocardium also provides signals to assist in leukocyte infiltration via upregulation or secretion of cell-adhesion molecules. The endothelium in the microvasculature of the failing heart increases expression of these molecules such as P-selectin, e-selectin, intracellular cell adhesion molecule-1, and vascular cell-adhesion molecule-1, which allows transendothelial migration of a range of immune cells into the myocardium, including B cells, T cells, natural killer cells, monocytes, and platelets.91, 92

Left ventricular non-compaction

Left ventricular non-compaction has previously been regarded as a rare disease, and has been identified by various names—spongy myocardium, fetal myocardium, and non-compaction of the left ventricular myocardium.93 The abnormality is thought to represent an arrest in the normal process of myocardial compaction, the final stage of myocardial morphogenesis, resulting in persistence of many prominent ventricular trabeculations and deep intertrabecular recesses. Left ventricular non-compaction can be difficult to diagnose unless the physician has a high level of suspicion during echocardiographic assessment. With careful review of echocardiograms and other clinical data, this disorder seems to be common in children, and is also reported in adults.94 About 9% of all cases of cardiomyopathy are diagnosed as left ventricular non-compaction, with only dilated cardiomyopathy and hypertrophic cardiomyopathy being more common. In the most recent American College of Cardiology/American Heart Association (AHA/ACC) cardiomyopathy classification, left ventricular non-compaction was recognised for the first time as a formal form of cardiomyopathy.4 A substantial percentage of these patients have a dilated left ventricle with systolic dysfunction, mimicking dilated cardiomyopathy. Signs, symptoms, and outcomes of these patients mirror those of patients with pure dilated cardiomyopathy, but in young children, outcomes are worse than for those with dilated cardiomyopathy.

Treatment

Therapy of dilated cardiomyopathy is mainly directed at treatment of heart-failure symptoms and prevention of disease progression and related complications, such as end-organ dysfunction and stroke.95 Revised guideline recommendations have been published.95, 96 Diagnosis, severity of disease, and, if possible, cause of the dilated cardiomyopathy should be known so that therapy can be as precise as possible. To improve diagnosis and grading of disease severity, a new method of staging patients who are developing heart failure with accompanying recommended therapies has been developed.95 This new classification system, replacing the New York Heart Association (NYHA) classification, emphasises development and progression of heart failure and identifies patients who are at risk of heart failure and those with structural disease, both in symptomatic and asymptomatic states. On the basis of these recommendations, initial assessment should consist of standard serological testing, transthoracic echocardiography, and, in adults, coronary angiography to assess for possible revascularisation when appropriate. Additionally, testing for secondary or specific causes that mimic dilated cardiomyopathy is suggested—with clinical suspicion of haemochromatosis, sleep-disordered breathing, HIV infection, rheumatological disease, amyloidosis, or pheochromocytoma. MRI can also be helpful for identification of structural and functional abnormal findings, especially in the assessment of myocardial viability and scar tissue.97

Use of serological testing has been widely reported. In patients with heart failure, activation of the neurohormonal axis and inflammatory markers takes place. This activation can be measured and could aid in diagnosis and prognostic assessments. Braunwald 7 reviews the present understanding of biomarkers in heart failure. The most widely used biomarker is BNP. A rise in BNP is associated with reduced left ventricular systolic function, hypertrophy, raised filling pressures, and myocardial ischaemia.98 This peptide is also useful in paediatric populations with chronic systolic dysfunction for prediction of high risk of death, need for hospitalisation, or need for cardiac transplantation.11 Much research about NT-proBNP has been done, with hopes that this peptide is a better biomarker than is BNP, secondary to differences in renal clearance. However, van Kimmenade and co-workers 99 reported no difference in renal clearance between BNP and NT-proBNP.

Medical therapy remains the mainstay in patients with dilated cardiomyopathy and heart failure. Present oral regimen recommendations are outlined elsewhere,100—103 and have led to significant improvements in survival and symptom relief. In short, inhibition of angiotensin-converting enzymes and β-blockade with or without diuretics continue to be standard options. Treatment of decompensated heart failure is focused on diuresis with loop diuretics for volume overload and afterload reduction. Modulation of afterload can be accomplished with use of vasodilator therapy such as nitroglycerin, nitroprusside, or nesiritide. In patients with heart failure and clinical evidence of hypotension associated with hypoperfusion and raised filling pressures, intravenous inotropic support or vasopressor therapy, or both, should be considered. We prefer to avoid inotropes that increase mechanical stress, such as dopamine and dobutamine, in children, with milrinone continuing to be the most popular therapy. Once the need for other inotropic agents becomes clear because of deterioration in blood pressure and perfusion, we consider placement of an assist device. Some institutions use balloon pumps regularly in this instance. A comprehensive list of therapeutic strategies with supportive evidence is provided elsewhere.95

Several clinical trials 104, 105 have assessed use of implantable cardioverter-defibrillators in patients with low left ventricular ejection fractions, with results showing reduced mortality.104, 105 For patients who have a left ventricular ejection fraction of less than 30% and symptomatic heart failure for which they are receiving optimum medical therapy, use of implantable cardioverter-defibrillators is a class I indication, as outlined by the ACC/AHA guidelines.95 Despite the guideline recommendations, such devices have not been used as extensively as suggested, with great variation between hospitals. Additionally, results seem to vary by ethnic origin and sex with these devices.
Use of cardiac resynchronisation therapy has expanded the therapeutic options for both paediatric and adult patients with advanced heart failure and ventricular-conduction delay. This therapy is designed to eliminate the delay in activation of the left ventricular free wall, a finding often seen in adults with left ventricular systolic dysfunction. Hence, cardiac resynchronisation therapy improves mechanical synchrony, which in turn increases left ventricular filling time, decreases mitral regurgitation, and reduces septal dyskinesis, which is frequently reported in adults. This therapy has been shown to restore coordination and relaxation of cardiac chambers, results in favourable cardiac remodelling, and improves survival in this population.106—108 However, up to a third of patients do not have any clinical benefit with present recommended criteria.109 These patients could have identifiable reasons for a poor response and might benefit from further treatment optimisation.110

Surgical management of dilated cardiomyopathy with congestive heart failure is one of the most rapidly expanding areas of cardiovascular surgery, with a goal to improve the biophysics of the left ventricle and reduce the stimulus for unfavourable remodelling.111 Although much of the research has been in patients with ischaemic disease, many of the strategies used could apply to the dilated cardiomyopathy population. Use of palliative surgical procedures as a bridge to transplant in this disorder has had little success. The Batista procedure,112 or partial left ventriculotomy, is useful in patients with end-stage dilated cardiomyopathy. Other interventions include surgical ventricular restoration by recreation of the elliptical shape of the left ventricle by volume reduction with a sizing balloon, achieving a volume of 55—60 mL per m2 body-surface area.113 Long-term results114 of the CorCap Cardiac Support Device (Acron Cardiovascular, St Paul, MN, USA), which reduces left ventricular wall stress, have been reported, suggesting favourable effects on left ventricular size and shape. This device could also improve quality of life and has a similar safety profile to mitral-valve annuloplasty. Surgical mitral-valve annuloplasty is feasible 115 and decreases functional mitral regurgitation. Results of the AMADEUS116 and CARILLON117 trials also show feasibility of percutanoues mitral-valve annuloplasty, with a decrease in functional mitral regurgitation.

Cardiac transplantation is needed in extreme cases. At present, transplants are reserved for patients with the most severe disease—those needing inotropes and usually mechanical ventilatory and mechanical device support. Waiting times for organs remain a significant restriction. Use of ventricular-assist devices has significantly improved survival of adults and children with dilated cardiomyopathy with end-stage disease who are awaiting heart transplant.118, 119 Such devices 120 are highly effective in heart-failure populations that are ineligible for cardiac transplant. We have shown 121 that N-terminal dystrophin is reduced or absent in hearts of patients with all forms of dilated cardiomyopathy (ischaemic, acquired, genetic, and idiopathic) and that reduction of mechanical stress by use of these devices reverses remodelling of dystrophin and of the heart itself. Various ventricular-assist devices exist at present—some are stationary, others ambulatory, and some are fully implantable. The total artificial heart is the most aggressive of these devices and is used for destination therapy (use of long-term mechanical circulatory support in patients with endstage heart failure, without the intention of eventual heart transplantation).

Controversy continues about therapy for myocarditis. In view of the chronic inflammatory nature of the disease and the effects of the immune system, immunomodulatory therapy might be beneficial. However, non-selective therapy has not proved useful.122 Prospective data with combined therapy of steroids and azathioprine show14 long-term benefit in dilated cardiomyopathy patients with evidence of HLA upregulation on biopsy samples. Cooper and co-workers 15 reported usefulness of immunomodulation in giant-cell myocarditis. Frustaci and colleagues 13 reported a beneficial immunosuppressive effect in patients with active lymphocytic myoarditis, circulating cardiac autoantibodies, and no viral genome detected with endomyocardial biopsy sample. Some researchers 122, 123 support use of intravenous gamma globulin. However, McNamara and co-workers 124 did not show a benefit from intravenous gamma globulin in myocarditis on the basis of Dallas criteria. A trial 125 is in progress to test the efficacy of interferon gamma in Europe. These reports all suggest that non-specific therapy might be of no benefit. However, immunomodulatory or antiviral therapy could be of some benefit in very well-defined populations.

Interest in the use of stem-cell therapy as a treatment for end-stage dilated cardiomyopathy has increased during the past decade. Several studies 126 have documented beneficial effects of stem-cell transplantation in patients who have depressed left ventricular systolic dysfunction after myocardial infarction. However, concern has grown that this approach might only result in paracrine growth-factor stimulation or improvement in myocardial scaffolding without generation of new myocardium. Much debate 127 has taken place about the optimum cell source for myocardial regeneration. However, a substantial research effort in both paediatric and adult populations is in progress to improve definition of this therapeutic option.
Although improved outcomes in dilated cardiomyopathy and heart failure have been achieved, improving outcomes for patients with non-ischaemic disease remains problematic. For these reasons, gene-based therapies such as gene therapy,128 stem-cell therapy,129, 130 and targeted treatments are being investigated. The next decade will probably further define causes and mechanisms of this disease, and result in breakthroughs in treatment that will hopefully improve the outcome for these patients.

Search strategy and selection criteria

We searched PubMed for reports mainly from the past 5 years, including some reports from 2000 onwards, Online Mendelian Inheritance in Man, and peer-reviewed reports on dilated cardiomyopathy. We used the search terms “dilated cardiomyopathy”, “heart failure”, “cardiomyopathy”, “DCM genetics” and “final common pathway”. No languages were excluded. We included reports that covered adult and childhood dilated cardiomyopathy from clinical and basic-science journals, and relevant reports of our research. We excluded outdated textbook chapters. Our reference list was modified on the basis of comments from peer reviewers.

Contributors

Both authors contributed equally to the literature search and writing of this Seminar.

Conflicts of interest

We declare that we have no conflicts of interest.

References

1 Elliott P, Andersson B, Arbustini E, et al. Classification of the cardiomyopathies: a position statement from the European Society Of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2008; 29: 270-276. CrossRef | PubMed

2 Maron BJ, Towbin JA, Thiene G, et al. Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation 2006; 113: 1807-1816. CrossRef | PubMed

3 Richardson P, McKenna W, Bristow M, et al. Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies. Circulation 1996; 93: 841-842. PubMed

4 Towbin JA, Lowe AM, Colan SD, et al. Incidence, causes, and outcomes of dilated cardiomyopathy in children. JAMA 2006; 296: 1867-1876. CrossRef | PubMed

5 Taylor MR, Carniel E, Mestroni L. Cardiomyopathy, familial dilated. Orphanet J Rare Dis 2006; 1: 27. PubMed

6 Rosamond W, Flegal K, Furie K, et al. Heart disease and stroke statistics—2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2008; 117: e25-e146. CrossRef | PubMed

7 Braunwald E. Biomarkers in heart failure. N Engl J Med 2008; 358: 2148-2159. CrossRef | PubMed

8 Omland T, Sabatine MS, Jablonski KA, et al. Prognostic value of B-Type natriuretic peptides in patients with stable coronary artery disease: the PEACE Trial. J Am Coll Cardiol 2007; 50: 205-214. CrossRef | PubMed

9 Sugiura T, Takase H, Toriyama T, Goto T, Ueda R, Dohi Y. Circulating levels of myocardial proteins predict future deterioration of congestive heart failure. J Card Fail 2005; 11: 504-509. CrossRef | PubMed

10 Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002; 347: 16167. PubMed

11 Price JF, Thomas AK, Grenier M, et al. B-type natriuretic peptide predicts adverse cardiovascular events in pediatric outpatients with chronic left ventricular systolic dysfunction. Circulation 2006; 114: 1063-1069. CrossRef | PubMed

12 Cooper LT, Baughman KL, Feldman AM, et al. The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology. J Am Coll Cardiol 2007; 50: 1914-1931. CrossRef | PubMed

13 Frustaci A, Chimenti C, Calabrese F, Pieroni M, Thiene G, Maseri A. Immunosuppressive therapy for active lymphocytic myocarditis: virological and immunologic profile of responders versus nonresponders. Circulation 2003; 107: 857-863. CrossRef | PubMed

14 Wojnicz R, Nowalany-Kozielska E, Wojciechowska C, et al. Randomized, placebo-controlled study for immunosuppressive treatment of inflammatory dilated cardiomyopathy: two-year follow-up results. Circulation 2001; 104: 39-45. PubMed

15 Cooper LT, Hare JM, Tazelaar HD, et al. Usefulness of immunosuppression for giant cell myocarditis. Am J Cardiol 2008; 102: 1535-1539. CrossRef | PubMed

16 Dennert R, Crijns HJ, Heymans S. Acute viral myocarditis. Eur Heart J 2008; 29: 2073-2082. CrossRef | PubMed

17 Mobini R, Staudt A, Felix SB, et al. Hemodynamic improvement and removal of autoantibodies against beta1-adrenergic receptor by immunoadsorption therapy in dilated cardiomyopathy. J Autoimmun 2003; 20: 345-350. CrossRef | PubMed

18 Bowles NE, Ni J, Kearney DL, et al. Detection of viruses in myocardial tissues by polymerase chain reaction. evidence of adenovirus as a common cause of myocarditis in children and adults. J Am Coll Cardiol 2003; 42: 466-472. CrossRef | PubMed

19 Michels VV, Moll PP, Miller FA, et al. The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopathy. N Engl J Med 1992; 326: 77-82. PubMed

20 Towbin JA, Bowles NE. The failing heart. Nature 2002; 415: 227-233. CrossRef | PubMed

21 Hershberger RE, Lindenfeld J, Mestroni L, Seidman CE, Taylor MR, Towbin JA. Genetic evaluation of cardiomyopathy—a Heart Failure Society of America practice guideline. J Card Fail 2009; 15: 83-97. CrossRef | PubMed

22 Towbin JA, Bowles NE. Dilated cardiomyopathy: a tale of cytoskeletal proteins and beyond. J Cardiovasc Electrophysiol 2006; 17: 919-926. CrossRef | PubMed

23 Bowles NE, Bowles KR, Towbin JA. The “final common pathway” hypothesis and inherited cardiovascular disease. The role of cytoskeletal proteins in dilated cardiomyopathy. Herz 2000; 25: 168-175. CrossRef | PubMed

24 Towbin JA. The role of cytoskeletal proteins in cardiomyopathies. Curr Opin Cell Biol 1998; 10: 131-139. CrossRef | PubMed

25 Feng J, Yan J, Buzin CH, Towbin JA, Sommer SS. Mutations in the dystrophin gene are associated with sporadic dilated cardiomyopathy. Mol Genet Metab 2002; 77: 119-126. CrossRef | PubMed

26 Cox GF, Kunkel LM. Dystrophies and heart disease. Curr Opin Cardiol 1997; 12: 329-343. PubMed

27 Taylor MR, Slavov D, Ku L, et al. Prevalence of desmin mutations in dilated cardiomyopathy. Circulation 2007; 115: 1244-1251. PubMed

28 van Tintelen JP, Hofstra RM, Katerberg H, et al. High yield of LMNA mutations in patients with dilated cardiomyopathy and/or conduction disease referred to cardiogenetics outpatient clinics. Am Heart J 2007; 154: 1130-1139. CrossRef | PubMed

29 Tsubata S, Bowles KR, Vatta M, et al. Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy. J Clin Invest 2000; 106: 655-662. CrossRef | PubMed

30 Barresi R, Di Blasi C, Negri T, et al. Disruption of heart sarcoglycan complex and severe cardiomyopathy caused by beta sarcoglycan mutations. J Med Genet 2000; 37: 102-107. PubMed

31 Olson TM, Illenberger S, Kishimoto NY, Huttelmaier S, Keating MT, Jockusch BM. Metavinculin mutations alter actin interaction in dilated cardiomyopathy. Circulation 2002; 105: 431-437. CrossRef | PubMed

32 Baryshnikova OK, Robertson IM, Mercier P, Sykes BD. The dilated cardiomyopathy G159D mutation in cardiac troponin C weakens the anchoring interaction with troponin I. Biochemistry 2008; 47: 10950-10960. PubMed

33 Chang AN, Potter JD. Sarcomeric protein mutations in dilated cardiomyopathy. Heart Fail Rev 2005; 10: 225-235. CrossRef | PubMed

34 Kamisago M, Sharma SD, DePalma SR, et al. Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N Engl J Med 2000; 343: 1688-1696. CrossRef | PubMed

35 Karkkainen S, Peuhkurinen K. Genetics of dilated cardiomyopathy. Ann Med 2007; 39: 91-107. CrossRef | PubMed

36 Pyle WG, Solaro RJ. At the crossroads of myocardial signaling: the role of Z-discs in intracellular signaling and cardiac function. Circ Res 2004; 94: 296-305. CrossRef | PubMed

37 Vatta M, Mohapatra B, Jimenez S, et al. Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction. J Am Coll Cardiol 2003; 42: 2014-2027. CrossRef | PubMed

38 Mohapatra B, Jimenez S, Lin JH, et al. Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis. Mol Genet Metab 2003; 80: 207-215. CrossRef | PubMed

39 Duboscq-Bidot L, Xu P, Charron P, et al. Mutations in the Z-band protein myopalladin gene and idiopathic dilated cardiomyopathy. Cardiovasc Res 2008; 77: 118-125. CrossRef | PubMed

40 Moulik M, Vatta M, Witt SH, et al. ANKRD1, the gene encoding cardiac ankyrin repeat protein, is a novel dilated cardiomyopathy gene. J Am Coll Cardiol 2009; 54: 325-333. CrossRef | PubMed

41 Hayashi T, Arimura T, Itoh-Satoh M, et al. Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy. J Am Coll Cardiol 2004; 44: 2192-2201. CrossRef | PubMed

42 Schmitt JP, Kamisago M, Asahi M, et al. Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban. Science 2003; 299: 1410-1413. CrossRef | PubMed

43 Bione S, D’Adamo P, Maestrini E, Gedeon AK, Bolhuis PA, Toniolo D. A novel X-linked gene, G4.5. is responsible for Barth syndrome. Nat Genet 1996; 12: 385-389. CrossRef | PubMed

44 Olson TM, Michels VV, Ballew JD, et al. Sodium channel mutations and susceptibility to heart failure and atrial fibrillation. JAMA 2005; 293: 447-454. CrossRef | PubMed
45 Berko BA, Swift M. X-linked dilated cardiomyopathy. N Engl J Med 1987; 316: 1186-1191. PubMed

46 Towbin JA, Hejtmancik JF, Brink P, et al. X-linked dilated cardiomyopathy. Molecular genetic evidence of linkage to the Duchenne muscular dystrophy (dystrophin) gene at the Xp21 locus. Circulation 1993; 87: 1854-1865. PubMed

47 Muntoni F, Cau M, Ganau A, et al. Brief report: deletion of the dystrophin muscle-promoter region associated with X-linked dilated cardiomyopathy. N Engl J Med 1993; 329: 921-925. CrossRef | PubMed

48 McNally EM, Pytel P. Muscle diseases: the muscular dystrophies. Annu Rev Pathol 2007; 2: 87-109. PubMed

49 Barth PG, Valianpour F, Bowen VM, et al. X-linked cardioskeletal myopathy and neutropenia (Barth syndrome): an update. Am J Med Genet A 2004; 126A: 349-354. PubMed

50 Houtkooper RH, Vaz FM. Cardiolipin, the heart of mitochondrial metabolism. Cell Mol Life Sci 2008; 65: 2493-2506. CrossRef | PubMed

51 Towbin JA. Pediatric myocardial disease. Pediatr Clin North Am 1999; 46: 289-312. CrossRef | PubMed

52 Spencer CT, Byrne BJ, Gewitz MH, et al. Ventricular arrhythmia in the X-linked cardiomyopathy Barth syndrome. Pediatr Cardiol 2005; 26: 632-637. CrossRef | PubMed

53 Wilde AA. Channelopathies in children and adults. Pacing Clin Electrophysiol 2008; 31 (suppl 1): 41-45. PubMed

54 Lehnart SE, Ackerman MJ, Benson DW, et al. Inherited arrhythmias: a National Heart, Lung, and Blood Institute and Office of Rare Diseases workshop consensus report about the diagnosis, phenotyping, molecular mechanisms, and therapeutic approaches for primary cardiomyopathies of gene mutations affecting ion channel function. Circulation 2007; 116: 2325-2345. CrossRef | PubMed

55 Bowles NE, Bowles KR, Towbin JA. Viral genomic detection and outcome in myocarditis. Heart Fail Clin 2005; 1: 407-417. PubMed

56 Ellis CR, Di Salvo T. Myocarditis: basic and clinical aspects. Cardiol Rev 2007; 15: 170-177. CrossRef | PubMed

57 Friedrich MG. Tissue characterization of acute myocardial infarction and myocarditis by cardiac magnetic resonance. JACC Cardiovasc Imaging 2008; 1: 652-662. PubMed

58 Bestetti RB, Muccillo G. Clinical course of Chagas’ heart disease: a comparison with dilated cardiomyopathy. Int J Cardiol 1997; 60: 187-193. CrossRef | PubMed

59 Afonso L, Mohammad T, Thatai D. Crack whips the heart: a review of the cardiovascular toxicity of cocaine. Am J Cardiol 2007; 100: 1040-1043. CrossRef | PubMed

60 Klatsky AL. Alcohol and cardiovascular diseases. Expert Rev Cardiovasc Ther 2009; 7: 499-506. CrossRef | PubMed

61 Laonigro I, Correale M, Di Biase M, Altomare E. Alcohol abuse and heart failure. Eur J Heart Fail 2009; 11: 453-462. CrossRef | PubMed

62 Wallace KB. Adriamycin-induced interference with cardiac mitochondrial calcium homeostasis. Cardiovasc Toxicol 2007; 7: 101-107. CrossRef | PubMed

63 Lebrecht D, Walker UA. Role of mtDNA lesions in anthracycline cardiotoxicity. Cardiovasc Toxicol 2007; 7: 108-113. CrossRef | PubMed

64 Gianni L, Herman EH, Lipshultz SE, Minotti G, Sarvazyan N, Sawyer DB. Anthracycline cardiotoxicity: from bench to bedside. J Clin Oncol 2008; 26: 3777-3784. CrossRef | PubMed

65 Hilfiker-Kleiner D, Sliwa K, Drexler H. Peripartum cardiomyopathy: recent insights in its pathophysiology. Trends Cardiovasc Med 2008; 18: 173-179. CrossRef | PubMed

66 Arimura T, Hayashi T, Kimura A. Molecular etiology of idiopathic cardiomyopathy. Acta Myol 2007; 26: 153-158. PubMed

67 Ahmad F, Seidman JG, Seidman CE. The genetic basis for cardiac remodeling. Annu Rev Genomics Hum Genet 2005; 6: 185-216. CrossRef | PubMed

68 Robinson P, Griffiths PJ, Watkins H, Redwood CS. Dilated and hypertrophic cardiomyopathy mutations in troponin and alpha-tropomyosin have opposing effects on the calcium affinity of cardiac thin filaments. Circ Res 2007; 101: 1266-1273. CrossRef | PubMed

69 LeWinter MM. Functional consequences of sarcomeric protein abnormalities in failing myocardium. Heart Fail Rev 2005; 10: 249-257. CrossRef | PubMed

70 Haghighi K, Kolokathis F, Pater L, et al. Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human. J Clin Invest 2003; 111: 869-876. CrossRef | PubMed

71 Murphy RT, Mogensen J, Shaw A, Kubo T, Hughes S, McKenna WJ. Novel mutation in cardiac troponin I in recessive idiopathic dilated cardiomyopathy. Lancet 2004; 363: 371-372. Summary | Full Text | PDF(79KB) | CrossRef | PubMed

72 Knoll R, Hoshijima M, Hoffman HM, Person V, Lorenzen-Schmidt I, Bang ML, et al. The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy. Cell 2002; 111: 943-955. CrossRef | PubMed

73 Zolk O, Caroni P, Bohm M. Decreased expression of the cardiac LIM domain protein MLP in chronic human heart failure. Circulation 2000; 101: 2674-2677. PubMed

74 Zhou Q, Chu PH, Huang C, et al. Ablation of Cypher, a PDZ-LIM domain Z-line protein, causes a severe form of congenital myopathy. J Cell Biol 2001; 155: 605-612. CrossRef | PubMed

75 Granzier HL, Labeit S. The giant protein titin: a major player in myocardial mechanics, signaling, and disease. Circ Res 2004; 94: 284-295. CrossRef | PubMed

76 Gerull B, Gramlich M, Atherton J, et al. Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nat Genet 2002; 30: 201-204. CrossRef | PubMed

77 Arimura T, Bos JM, Sato , et al. Cardiac ankyrin repeat protein gene (ANKRD1) mutations in hypertrophic cardiomyopathy. J Am Coll Cardiol 2009; 54: 334-342. CrossRef | PubMed

78 Parnaik VK. Role of nuclear lamins in nuclear organization, cellular signaling, and inherited diseases. Int Rev Cell Mol Biol 2008; 266: 157-206. PubMed

79 Parks SB, Kushner JD, Nauman D, et al. Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy. Am Heart J 2008; 156: 161-169. CrossRef | PubMed

80 Drory Y, Turetz Y, Hiss Y, et al. Sudden unexpected death in persons less than 40 years of age. Am J Cardiol 1991; 68: 1388-1392. CrossRef | PubMed

81 MacLellan WR, Lusis AJ. Dilated cardiomyopathy: learning to live with yourself. Nat Med 2003; 9: 1455-1456. CrossRef | PubMed

82 Li HS, Ligons DL, Rose NR. Genetic complexity of autoimmune myocarditis. Autoimmun Rev 2008; 7: 168-173. CrossRef | PubMed

83 Li Y, Heuser JS, Cunningham LC, Kosanke SD, Cunningham MW. Mimicry and antibody-mediated cell signaling in autoimmune myocarditis. J Immunol 2006; 177: 8234-8240. PubMed

84 Caforio AL, Tona F, Bottaro S, et al. Clinical implications of anti-heart autoantibodies in myocarditis and dilated cardiomyopathy. Autoimmunity 2008; 41: 35-45. CrossRef | PubMed

85 Caforio AL, Mahon NG, Baig MK, et al. Prospective familial assessment in dilated cardiomyopathy: cardiac autoantibodies predict disease development in asymptomatic relatives. Circulation 2007; 115: 76-83. CrossRef | PubMed

86 Huang CH, Vallejo JG, Kollias G, Mann DL. Role of the innate immune system in acute viral myocarditis. Basic Res Cardiol 2009; 104: 228-237. CrossRef | PubMed

87 Liu W, Li WM, Yang SS, et al. Association of HLA class II DRB1, DPA1 and DPB1 polymorphism with genetic susceptibility to idiopathic dilated cardiomyopathy in Chinese Han nationality. Autoimmunity 2006; 39: 461-467. CrossRef | PubMed

88 Lozano MD, Rubocki RJ, Wilson JE, McManus BM, Wisecarver JL. Human leukocyte antigen class II associations in patients with idiopathic dilated cardiomyopathy. Myocarditis Treatment Trial Investigators. J Card Fail 1997; 3: 97-103. CrossRef | PubMed

89 Rodriguez-Perez JM, Fragoso JM, Alvarez-Leon E, et al. MHC class II genes in Mexican patients with idiopathic dilated cardiomyopathy. Exp Mol Pathol 2007; 82: 49-52. CrossRef | PubMed

90 Taneja V, Behrens M, Cooper LT, et al. Spontaneous myocarditis mimicking human disease occurs in the presence of an appropriate MHC and non-MHC background in transgenic mice. J Mol Cell Cardiol 2007; 42: 1054-1064. CrossRef | PubMed

91 Jaakkola K, Jalkanen S, Kaunismaki K, et al. Vascular adhesion protein-1, intercellular adhesion molecule-1 and P-selectin mediate leukocyte binding to ischemic heart in humans. J Am Coll Cardiol 2000; 36: 122-129. CrossRef | PubMed

92 Wilhelmi MH, Leyh RG, Wilhelmi M, Haverich A. Upregulation of endothelial adhesion molecules in hearts with congestive and ischemic cardiomyopathy: immunohistochemical evaluation of inflammatory endothelial cell activation. Eur J Cardiothorac Surg 2005; 27: 122-127. CrossRef | PubMed

93 Pignatelli RH, McMahon CJ, Dreyer WJ, et al. Clinical characterization of left ventricular noncompaction in children: a relatively common form of cardiomyopathy. Circulation 2003; 108: 2672-2678. CrossRef | PubMed

94 Pantazis AA, Elliott PM. Left ventricular noncompaction. Curr Opin Cardiol 2009; 24: 209-213. CrossRef | PubMed

95 Hunt SA. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol 2005; 46: 1-82. CrossRef | PubMed

96 Hunt SA, Abraham WT, Chin MH, et al. 2009 focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines developed in collaboration with the International Society for Heart and Lung Transplantation. J Am Coll Cardiol 2009; 53: 1-90. CrossRef | PubMed

97 Bello D, Shah DJ, Farah GM, et al. Gadolinium cardiovascular magnetic resonance predicts reversible myocardial dysfunction and remodeling in patients with heart failure undergoing beta-blocker therapy. Circulation 2003; 108: 1945-1953. CrossRef | PubMed

98 Maisel A, Mueller C, Adams K, et al. State of the art: using natriuretic peptide levels in clinical practice. Eur J Heart Fail 2008; 10: 824-839. CrossRef | PubMed

99 van Kimmenade RR, Januzzi JL, Bakker JA, et al. Renal clearance of B-type natriuretic peptide and amino terminal pro-B-type natriuretic peptide a mechanistic study in hypertensive subjects. J Am Coll Cardiol 2009; 53: 884-890. CrossRef | PubMed

100 The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325: 293-302. PubMed

101 Rogers WJ, Johnstone DE, Yusuf S, Weiner DH, Gallagher P, Bittner VA, et al. Quality of life among 5,025 patients with left ventricular dysfunction randomized between placebo and enalapril: the Studies of Left Ventricular Dysfunction. The SOLVD Investigators. J Am Coll Cardiol 1994; 23: 393-400. PubMed

102 Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med 1996; 334: 1349-1355. CrossRef | PubMed

103 Hernandez AF, Hammill BG, O’Connor CM, Schulman KA, Curtis LH, Fonarow GC. Clinical effectiveness of beta-blockers in heart failure: findings from the OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) Registry. J Am Coll Cardiol 2009; 53: 184-192. CrossRef | PubMed

104 Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002; 346: 877-883. CrossRef | PubMed

105 Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005; 352: 225-237. CrossRef | PubMed

106 Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005; 352: 1539-1549. CrossRef | PubMed

107 Linde C, Leclercq C, Rex S, et al. Long-term benefits of biventricular pacing in congestive heart failure: results from the MUltisite STimulation in cardiomyopathy (MUSTIC) study. J Am Coll Cardiol 2002; 40: 111-118. CrossRef | PubMed

108 Leclercq C, Walker S, Linde C, et al. Comparative effects of permanent biventricular and right-univentricular pacing in heart failure patients with chronic atrial fibrillation. Eur Heart J 2002; 23: 1780-1787. CrossRef | PubMed

109 St John Sutton MG, Plappert T, Abraham WT, et al. Effect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure. Circulation 2003; 107: 1985-1990. CrossRef | PubMed

110 Mullens W, Grimm RA, Verga T, et al. Insights from a cardiac resynchronization optimization clinic as part of a heart failure disease management program. J Am Coll Cardiol 2009; 53: 765-773. CrossRef | PubMed

111 Redmann K, Lunkenheimer PP, Dietl KH, Cryer CW, Batista RJ, Anderson RH. Immediate effects of partial left ventriculectomy on left ventricular function. J Card Surg 1998; 13: 453-462. CrossRef | PubMed

112 Abe T, Fukada J, Morishita K. The Batista procedure: fact, fiction and its role in the management of heart failure. Heart Fail Rev 2001; 6: 195-199. CrossRef | PubMed

113 Koyama T, Nishina T, Ono N, et al. Early and mid-term results of left ventricular volume reduction surgery for dilated cardiomyopathy. J Card Surg 2005; 20: 39-42. PubMed

114 Mann DL, Acker MA, Jessup M, Sabbah HN, Starling RC, Kubo SH. Clinical evaluation of the CorCap Cardiac Support Device in patients with dilated cardiomyopathy. Ann Thorac Surg 2007; 84: 1226-1235. CrossRef | PubMed

115 Tulner SA, Steendijk P, Klautz RJ, et al. Clinical efficacy of surgical heart failure therapy by ventricular restoration and restrictive mitral annuloplasty. J Card Fail 2007; 13: 178-183. CrossRef | PubMed

116 Siminiak T, Hoppe UC, Schofer J, et al. Effectiveness and safety of percutaneous coronary sinus-based mitral valve repair in patients with dilated cardiomyopathy (from the AMADEUS trial). Am J Cardiol 2009; 104: 565-570. CrossRef | PubMed

117 Schofer J, Siminiak T, Haude M, et al. Percutaneous mitral annuloplasty for functional mitral regurgitation: results of the CARILLON Mitral Annuloplasty Device European Union Study. Circulation 2009; 120: 326-333. CrossRef | PubMed

118 Sharma MS, Webber SA, Morell VO, Gandhi SK, Wearden PD, Buchanan JR, et al. Ventricular assist device support in children and adolescents as a bridge to heart transplantation. Ann Thorac Surg 2006; 82: 926-932. CrossRef | PubMed

119 Frazier OH, Rose EA, Oz MC, Dembitsky W, McCarthy P, Radovancevic B, et al. Multicenter clinical evaluation of the HeartMate vented electric left ventricular assist system in patients awaiting heart transplantation. J Thorac Cardiovasc Surg 2001; 122: 1186-1195. CrossRef | PubMed

120 Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-term mechanical left ventricular assistance for end-stage heart failure. N Engl J Med 2001; 345: 1435-1443. CrossRef | PubMed

121 Vatta M, Stetson SJ, Perez-Verdia A, et al. Molecular remodelling of dystrophin in patients with end-stage cardiomyopathies and reversal in patients on assistance-device therapy. Lancet 2002; 359: 936-941. Summary | Full Text | PDF(2781KB) | CrossRef | PubMed

122 Mason JW, O’Connell JB, Herskowitz A, et al. A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators. N Engl J Med 1995; 333: 269-275. CrossRef | PubMed

123 Maisch B, Hufnagel G, Kolsch S, et al. Treatment of inflammatory dilated cardiomyopathy and (peri)myocarditis with immunosuppression and i.v. immunoglobulins. Herz 2004; 29: 624-636. CrossRef | PubMed

124 McNamara DM, Holubkov R, Starling RC, et al. Controlled trial of intravenous immune globulin in recent-onset dilated cardiomyopathy. Circulation 2001; 103: 2254-2259. PubMed

125 Kuhl U, Pauschinger M, Schwimmbeck PL, et al. Interferon-beta treatment eliminates cardiotropic viruses and improves left ventricular function in patients with myocardial persistence of viral genomes and left ventricular dysfunction. Circulation 2003; 107: 2793-2798. CrossRef | PubMed

126 Schachinger V, Erbs S, Elsasser A, Haberbosch W, Hambrecht R, Holschermann H, et al. Improved clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the REPAIR-AMI trial. Eur Heart J 2006; 27: 2775-2783. CrossRef | PubMed

127 Stamm C, Choi YH, Nasseri B, Hetzer R. A heart full of stem cells: the spectrum of myocardial progenitor cells in the postnatal heart. Ther Adv Cardiovasc Dis 2009; 3: 215-229. PubMed

128 Liu J, Sluijter JP, Goumans MJ, et al. Cell therapy for myocardial regeneration. Curr Mol Med 2009; 9: 287-298. CrossRef | PubMed

129 Vinge LE, Raake PW, Koch WJ. Gene therapy in heart failure. Circ Res 2008; 102: 1458-1470. CrossRef | PubMed

130 Yamada S, Nelson TJ, Crespo-Diaz RJ, et al. Embryonic stem cell therapy of heart failure in genetic cardiomyopathy. Stem Cells 2008; 26: 2644-2653. CrossRef | PubMed

The Articles are on treating knee replacement patients with apixaban versus enoxaparin, vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer, treating herpes simplex with aciclovir to reduce HIV-1 progression and reviewing the clinical features that children with serious infections present with. These are accompanied by Comments on apixaban preventing venous thromboembolism after knee replacement, radiotherapy for endometrial cancer, treating HIV-1 with HIV-2 drugs and diagnosing serious infections in children.

The World Report is on the funding shortfall of the GAVI Alliance, increasing the number of medical schools in the USA and reports of female genital mutilation in Iraqi Kurdistan. Also of interest is a Perspective on preventing maternal transmission of HIV in Malawi and the launch of an essay competition for young researchers.

Today’s editorial is on an article published in today’s edition of The Lancet that found that Apixaban is better in preventing thromboembolism after knee replacement surgery compared to the current use of Enoxaparin.

“2·5 mg apixaban twice daily, starting on the morning after total knee replacement, offers a convenient and more effective orally administered alternative to 40 mg per day enoxaparin, without increased bleeding.”

Apixaban is more convenient and effective an anticoagulant than enoxaparin in preventing venous thromboembolism after knee replacement surgery. In addition, apixaban does not increase the risk of bleeding—a concern with anticoagulants, since this can delay recovery and predispose patients to infections that could damage the prosthesis.

Existing prophylactics such as heparins, like enoxaparin, or other drugs such as fondaparinux need regular injections, use of warfarin has various disadvantages in routine practice, and mechanical methods are cumbersome.

Michael Rud Lassen, Department of Orthopaedics, Horsholm Hospital, University of Copenhagen, Denmark, and colleagues undertook a randomised controlled phase 3 trial to see whether apixaban would be better than enoxaparin in both keeping thromboembolism and bleeding to a minimum. The patients either received 2.5 mg of apixaban twice daily or 40 mg enoxaparin once daily. The primary outcome was a composite of deep vein thrombosis, non-fatal pulmonary embolism, and death from any cause.

147 (15% of 976) patients on apixaban and 243 (24% of 997) on enoxaparin had a primary outcome event—a statistically significant difference. There was no significant difference between the groups in the bleeding during treatment.

The authors say: “2·5 mg apixaban twice daily, starting on the morning after total knee replacement, offers a convenient and more effective orally administered alternative to 40 mg per day enoxaparin, without increased bleeding.”

They conclude: “These favourable results might help surgeons to resolve their clinical dilemma when considering anticoagulant prophylaxis for total knee replacement. Bleeding can delay recovery and can predispose to infections that endanger the prosthesis. The small but occasionally important increase in surgical bleeding that is attributed to enoxaparin can contribute to underuse of effective prophylaxis.”

Today we’d like to announce the publication of Kier Philip’s article on the implications for human rights of the endemic tuberculosis in Chiapas, Mexico. Read it here.

Meanwhile, Catherine Carver, TLS Blogger and medical student at University of Aberdeen, reports on the benefits of the female condom for today’s blog.

The female condom is seen as a way of empowering women because they are responsible for wearing the protection

The World Health Organisation’s report AIDS Epidemic Update 2009 stated in December that “women and girls continue to be affected disproportionately by HIV in sub-Saharan Africa.” (1) The main method of HIV transmission in sub-Saharan Africa is heterosexual sex and approximately 60% of estimated HIV infections there occur in women (1). The United Nations Population Fund (UNFPA) has suggested that the female condom could be one way to tackle this problem because it is the only barrier method available “that women and girls can initiate and in some ways control” (2). They argue that women are often unable to insist their partner use a male condom, and consequently end up having unprotected sex. The female condom is seen as a way of empowering women because they are responsible for wearing the protection

There are other potential benefits to female condoms. For one, the female condom can be put in place hours before sex thereby avoiding any awkward interruptions to intimacy. Second, it does not need to be removed immediately on ejaculation like the male condom does. Third, men who believe male condoms reduce sensation during sex may see the looser female condom as an acceptable alternative. Yet despite having these benefits and an efficacy similar to the male condom, the female condom accounts for just 0.2% of worldwide condom use (3).

One of the main reasons for this is cost. The latest female condom design, the FC2, is 30% cheaper than its predecessor (4) but still cost US$0.35 per unit (5) compared to approximately US$0.03 per unit for male condoms (6). These are public sector prices, and they cost considerably more if bought privately. On a practical note, the female condom can make a rather noisy rustling during sex and some object to its appearance as it hangs several centimetres out of the vagina.

The UNFPA has been trying to change the fortunes of the female condom and one of their success stories is Zimbabwe. Their initiative increased public sector distribution of the female condom from 400, 000 in 2005 to more than 2million in 2008. Sales of female condoms also increased greatly from 900, 000 to more than 3 million (3). They attribute their success to a good marketing strategy, which targeted men as much as women. For instance they emphasised the idea that the male condom is not constricting like the male condom, and promoted the idea that the internal ring can enhance pleasure during sex.

Zimbabwe isn’t the only country where a novel approach to marketing has been used to promote the female condom. In Senegal they come packaged with “bine bine” beads which are an erotic accessory worn around the woman’s hips which make a clicking sound, tackling the noise of the condom. In Sri Lanka, female sex workers market the condom itself as a sex toy and sell clients the idea that allowing them to insert it is a thrill (7).

Some might argue that promoting the female condom is counterproductive because it fulfils the same role as the male condom and costs more. However, while it is true to say that many of its pros and cons overlap with the male condom, there are differences and one the guiding principles in sexual health medicine is promoting choice. In the words of ex-director of the International Planned Parenthood Federation Dr Steven Sinding: “More choice equals more protection. It’s that simple.” (8)

References:

(1) World Health Organization, UNAIDS. AIDS Epidemic Update 2009. Geneva, World Health Organization. Available at: http://data.unaids.org/pub/Report/2009/JC1700_Epi_Update_2009_en.pdf (Accessed 21 February 2010).

(2) UNFPA. The Female Condom: Putting Women in Control. Available from: http://www.unfpa.org/hiv/female.htm (Accessed 21 February 2010).

(3) UNAIDS. Empowering women to protect themselves: Promoting the female condom in Zimbabwe. Available from: http://www.unaids.org/en/KnowledgeCentre/Resources/FeatureStories/archive/2009/20091021_UNFPA.asp (Accessed 21 February 2010).

(4) Medscape. FDA Approves FC2 Female Condom. Available from: http://www.medscape.com/viewarticle/589767 (Accessed 21 February 2010)

(5) FDA Approves Next-Generation Female Condom. Podcast. Available from: http://video.unfpa.org/?v=8842875441113737772009 (Accessed 21 February 2010).

(6) UNAIDS. Basic facts on the female condom. Available from: http://data.unaids.org/GCWA/gcwa_bg_femalecondom_en.pdf (Accessed 21 February 2010).

(7) Burt K. Whatever happened to the Femidom? The Guardian [Online] August 23 2005. Available from: http://www.guardian.co.uk/society/2005/aug/23/health.lifeandhealth (Accessed 21 February 2010).

(8) PATH, UNFPA. Female Condom: A Powerful Tool for Protection. Seattle: UNFPA, PATH; 2006.

Sustainable healthcare provision, requires effectively functioning systems from clinical to governmental level. This is a challenging task and only by identify and improving weaknesses within the whole system is will things progress. No matter how good a clinician is, or how hard they work, if the support systems are failing, they will not be able to work effectively.

Human rights have become an invaluable tool for improving health systems, aswell as broader social factors effecting health, such as discrimination and violence. Article 12 of the International Covenant on Economic, Social and Cultural Rights, which has come to be known as ‘the right to health’, requires governmental recoginition of everyone’s right to ‘the highest attainable standard of physical and mental health’. The Universal Declaration of Human Rights also explicitly recognises health rights, particularly in Article 25, where wider social determinants of health including food, clothing and medical care are also specifically noted. The highest attainable standard of health requires health systems to function effectively, on all levels. Failing in this due to incompetance and neglect constitutes violations of these rights, as the ‘highest attainable standard of health’ is not being achieved.

This article discusses how a number of organizations in the Mexican state of Chiapas are applying human rights frameworks to the case of tuberculosis (TB). It will identify failings in the realisation of the highest attainable standard of health, and explore ways to ensure sustainable improvement in health care provision to indigenous populations in this area.

Mexico – Middle-Income, High Inequality

Mexico is classified by The World Bank as a middle-income country, with a Gross National Product of US$1,086 billion. In spite of its financial resources, Mexico has high levels of inequality, with 20% of the population living on less than US$2 per day (1). It also has the poorest Human Development Index rating of all the OECD countries (2). A recent report also criticized for having health indicators well below the average for the OECD, with specific mention of access inequalities and inadequate health insurance coverage for the poor (3).

Chiapas is the southern-most state of Mexico, bordering Guatemala to the south. 26% of the Chiapas population is composed of indigenous groups, the majority of which are of Mayan descent – the inhabitants of this region before the arrival of the Spanish in the early 1500s (4). Despite being rich in a variety of natural resources and a significant producer of Mexico’s hydroelectric power, Chiapas is one of the poorest Mexican states.

The indigenous people of Chiapas have suffered a long history of discrimination, marginalisation and prejudice, punctuated with violent episodes, from the bloody arrival of the Spanish in the early 1500s, to the 1997 ‘Acteal Massacre’ of 15 children, 21 women (four of whom where pregnant) and nine men, in a church by a group of paramilitaries. The situation culminated in the 1994 uprising of anti-governmental groups, predominantly composed of empassioned indigenous peoples. The best known of these groups is the Ejercito Zapatista de Liberacion Nacional (EZLN), more commonly referred to as the ´Zapatistas’. The EZLN intended to force the end of the mistreatment of indigenous people in Mexico, predominantly using a stratagy of non-complaince and civil resistance. The EZLN formed a parallel government which still controls a number of areas in Chiapas

Health as a Political Tool

The political climate in Chiapas has led to the fragmentation, politicisation, and general degradation of already limited governmental provisions, required for the realisation of human rights. Beyond simply not providing it, healthcare has been used as a political tool to fragment, and therefore weaken, some of the poorest communities in Mexico (5). This politicisation of both governmental, and anti-governmental health services, has resulted in people being denied treatment including childhood vaccinations, and receiving abuse from health workers, due to their political affiliation and or ethnicity (5). Attempting to sway pollitical opinion by denying unwell people their right to available treatment, is unacceptable and unjustifiable regardless of context.

Statistics show that healthcare resource allocation inversely correlates with marginalisation in Mexico, with health expenditure per-capita for insured people being up to twelve times higher than for those without health insurance (6). Looking at TB in mexico, these inequalities in health care provision are striking.

TB in Chiapas

Chiapas has one the highest TB incidence rates in Mexico, with a TB mortality rate twice the national average, the highest of any Mexican state (7). However, independent research has found significantly higher rates of TB in Chiapas, indicating that the situation in Chiapas may in fact be much worse than suggested by governmental research (5).

Particular factors relating to the development of TB, that are common in the rural indigenous communities of Chiapas, include high rates of malnutrition, cooking with solid fuels, dirt-floored housing, poor sanitation, cramped and over-crowded accommodation, poor access to medical services and poor working conditions (8,9). Such factors are also central to the development of many other other communicable and non-communicable diseases, hence steps to address such factors can have health implications beyond TB.

The Mexican Official Norm (10) details the specific approach that should be taken concerning the monitoring, identification, and treatment of TB in Mexico. Furthermore, in 2009 Chiapas included a pledge in their constitution to meet the United Nations Millennium Development Goals, including Goal 6, which specifically refers to TB. These developments create the appearance of political will, however, the failings identified by human rights organizations show that in practice, neither national nor international standards are not being met (8).

A number of specific TB cases in Chiapas are presently being used to highlight human rights abuses resulting from failures in healthcare provision, that under international law, Mexico is legally bound to address. Patients failed to recieve health related information in which was culturally, linguistically and contextually appropriate; there were unjustified breaches of patient confidentiality; and experianced politicisation, discrimination, stigmatisation, and cultural insensitivity within service provision. The Direct Observed Short Course (DOTS) as advised by the World Health Organisation (11) was poorly implemented, including inappropriate treatment regimes; lack of medications resulting in gaps during treatment; lack of contact tracing; the failure to provide medication to TB contacts and many people had simply been given incorrect diagnosises (8). All these factors have had significant negative impacts upon patients in Chiapas (8). Using the evidence and understanding from these patient cases will allow for the specific failings in the the system to be addressed and bring about broader health improvements to health care in Chiapas

It is important to identify the key factors that resulted in failures of service provision. For example, it is the state’s responsibility to inform national government of medication requirements relating to patients identified as having TB. This has been highlighted as one of the points at which the system has broken down in the specific cases being investigated. This was compounded through inadequate identification of TB cases (5).

Monitoring systems also show major flaws: for example, all of the 145 cases of TB identified in the Los Altos region of Chiapas during 2000 (8) have had their records lost, and subsequently have received no follow-up (personal correspondence between CCESC-DDS, ECOSUR and Chiapas Health Secretary Jurisdiccion Sanitaria No.II). Furthermore, discrepancies between government and independent research indicate that inadequate TB surveillance mechanisms, through lack of identification, are underestimating disease prevalence, and are not identifying patients in need of treatment (5). The situation has resulted from multiple avoidable factors, for which financial support was available but not used. For example, in 2008, 60% of the health budget for Chiapas was simply not used (12) at the same time as medications for TB were not available at a clinical level. Money that should have been used to purchase medication remained unused, and was subsequently returned to central government resulting in a reduction in the consecutive year’s health budget. Such large scale organisational failings clearly have a considerable impact the standard of health attainable for patients, and are subsiquently completely unacceptable.

Effective management of TB can only be achieved through comprehensive, well executed programmes, with a strong grounding in political will (13). The cases presently being highlighted show multiple failings at all levels of health care provision, indicating a lack of the necessary political will. Human rights form the basis of the legal obligations of states to their population, applicable to all persons without discrimination of any kind. In general, governments are aware that poor human rights records are damaging to their position in the international community. International pressure could therefore influence political will in Mexico where it is needed, but this has not been forthcoming.

Organisations in Chiapas have initially analysed the situation from a human rights perspective, and then used this work to address the situation. For example, CCESC-DDS lobbied at the Mexican Congress using the research that had been done, and successfully ensured an audit and review of the TB program in Chiapas. This process is to be followed up by an independent inter-organisational right to health observatory, who will also monitor other important health issues in Chiapas.

The case of TB is used here to highlight human rights violations. Through legal procedures they hope to initiate improvements in the regulation of human rights in Chiapas, which in turn will improve health care provision for all. Many of the issues raised with reference to TB, such as the lack of medicines, lack of staff, and issues of access are equally applicable to other health and civil society issues. These cases have informed various civil society groups about rights-based issues, many of which are now seeking further education in human rights and ways to use these legal frameworks with reference to their own work in Chiapas.

Conclusions

The example of TB in Chiapas highlights multiple failings in the realisation, and direct abuse, of universal human rights to which the indigenous people of Chiapas are entitled. Human rights are inalienable, and it is clear that appropriate steps for their realisation have not been taken in public health delivery. This lack, in particular the right to health, has resulted from complex interactions between social, political, and historical factors. Although these factors have led to the present situation, they do not justify it. Facilitation the achievment of these rights is the duty of the Mexican, and Chiapas state, government. The failures in the realisation of these rights constitute human rights violations, and therefore requires appropriate attention. It is primarily the responsibility of the Mexican government to identify why such abuses came about, and take the required action to improve the functioning of health provision in Chiapas. It falls to them to compensate people who have suffered as a result of previous rights abuses and to enable the realization of human rights for the people of Chiapas. It is also the responsibility of the international community, including the other members of the OECD, to hold Mexico to its human rights obligations. Ignoring the rights abuses in Mexico undermines one of the most important social developments of our times – universal human rights declarations. This article is an example of the practical application of human rights in relation to health, and we encourage other groups and organizations to look at issues from this angle. For more information please see ccesc-chiapas@blogspot.com, or email observatoriosalud@gmail.com with information about other organizations using a similar approach.

Keir Philip is a fourth year student at the University of Sheffield in the UK
mda05kep@sheffield.ac.uk

The author would like to acknowledge the help of Marcos Arana, his supervisor during his time in Mexico, in the writing of this paper

Acromyms

CCESC-DDS – Centro de Capacitación en Ecología y Salud para Campesinos-Defensoría del Derecho a la Salud (Center for Training in Ecology and Health for Rural workers- Right to Health Defence Group)

ECOSUR – El Colegio de la Frontera Sur (The College of the Southern Border, an academic research institution)

OECD – Organisation for Economic Co-Operation and Development

WHO – World Health Organisation

References

(1) World Bank accessed 15.01.2009 http://web.worldbank.org/WBSITE/EXTERNAL/COUNTRIES/LACEXT/MEXICOEXTN/0,,contentMDK:20185184~menuPK:338403~pagePK:1497618~piPK:217854~theSitePK:338397,00.html

(2) UNDP accessed 15.09.2009 http://hdrstats.undp.org/en/countries/country_fact_sheets/cty_fs_MEX.html

(3) OECD 2009. Economic Survey of Mexico 2009Accessed 15.09.2009 at http://www.oecd.org/documen/53/0,3343,en_33873108_33873610_43393781_1_1_1_1,00.html

(4) INEGI, II conteo de Población y Vivienda 2005

(5) PHR (2006). Excluded People, Eroded Communities: Realizing the Right to Health in Chiapas, Mexico accessed 15.09.2009 at http://physiciansforhumanrights.org/library/report-excludedpeople-2006.html

(6) Loranzo R, Zurita B, Franco F, et al (2001). Mexico: Marginality, Need, and Resource Allocation at the Country level. In: Evens T, Whitehead M, Diderichsen F, Bhuiya A, Wirth M (eds). Challenging Inequalities in Health: From Ethics to Action. New York: Oxford University Press. 290-291

(7) Secretaría de Salud 2009 accessed 15.09.2009 at http://www.salud.df.gob.mx/ssdf/index2.php?option=com_content&do_pdf=1&id=673

(8) Nájera-Ortiz JC, Sánchez-Pérez HJ, et al (2008). Demographic, health services and socio-economic factors associated with pulmonary tuberculosis mortality in Los Altos Region of Chiapas, Mexico. International Journal of Epidemiology. 37(4): 786-795

(9) Bruce N, Perez-Padilla R, Albalak R, (2000). Indoor air pollution in developing countries: a major environmental and public health Challenger. Bull World Health Organ. vol.78 no.9 Genebra 2000

(10) NOM-006-SSA2-1993. NORMA OFICIAL MEXICANA NOM-006-SSA2-1993, PARA LA PREVENCION Y CONTROL DE LA TUBERCULOSIS EN LA ATENCION PRIMARIA A LA SALUD. – 26/01/1995 accessed on 19.09.2009 at http://info4.juridicas.unam.mx/ijure/nrm/1/252/default.htm?s=iste

(11) WHO 2005. Global Tuberculosis Control: Surveillance, Planning, Financing. WHO Report 2005 (WHO/HTM/TB/2005.49). Geneva: World Health Organization, 2005.

(12) El Financiero en Linea. Viernes 7 de agosto 2009 accessed 15.09.09 at http://www.elfinanciero.com.mx/ElFinanciero/Portal/cfpages/contentmgr.cfm?docId=207758&docTipo=1&orderby=docid&sortby=ASC

(13) Maartens G, Wilkinson R, (2007). Tuberculosis. The Lancet; 370: 2030-43 Published on line August 23, 2007 at http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)61262-8/fulltext

This study demostrates the need to carry out more studies to evaluate the role of functional MRI in patients with an alteration of consciousness and how technology may open new diagnostic possibilities

When Jennett and Plum in 1972 coined the term persistent vegetative state, in a Lancet paper subtitled ‘A syndrome in search of a name’ (1), they were neither the first to describe this condition nor the first to propose a name. Actually the vegetative state or “wakefulness without awareness” is defined as a condition that upon examination does not yield evidence of a reproducible, sustained, purposeful, or voluntary behavioural response to visual, auditory, tactile, or noxious stimuli (2).

In 2002, the Aspen Neurobehavioral Conference Work Group coined the term “minimally conscious state” to describe the condition of such patients, with inconsistent but reproducible signs of awareness, including the ability to follow commands, but unable to communicate interactively, adding a new clinical entity.

The results of a study performed by a Belgian-English medical team at University of Cambridge and published in the New England Journal of Medicine (NEJM) (3), has reopened the debate about the ability to classify patients affected by disorders of consciousness, igniting, consequently, a secondary ethical debate around euthnasia and the right to live.

54 patients with consciousness disorder were involved in this study, undergoing functional magnetic resonance imaging (MRI) to assess the patient’s ability to generate and activate two specific consciousness areas represented by supplementary motor area and the parahippocampal gyrus.

All of the patients were asked to perform two imagery tasks. In the motor imagery task, they were instructed to imagine standing still on a tennis court and to swing an arm to “hit the ball” back and forth to an imagined instructor. In the spatial imagery task, participants were instructed to imagine navigating the streets of a familiar city or to imagine walking from room to room in their home and to visualize all that they would “see” if they were there. Of the 54 patients 5 (4 patients in vegetative state and 1 in minimally conscious state), compared with the control group represented by normal subjects, were capable to modulate their brain activity. Also one, of this subgroup, in vegetative state from 5 years, was able to answer correctly yes or no to questions (e.g., “Is your father’s name Alexander?”), documented by functional MRI.

The results of this study show the functional role that MRI has to bridge the dissociation that can occur between behavior that is readily observable during a standardized clinical assessment and the actual level of residual cognitive function after serious brain injury.

The possibility to comunicate with a patient in a vegetative state is a very rare event. James Bernat from the neurology department at Dartmouth Medical School asserts: ” This technique could open a window to human conscience and increase the capability of diagnostic instruments”. Steven Laureys from University of Liegi: “ It is too premature to say something, but in the future we hope to develop this tecnique to allow patients to convey their feelings and thinking, to control the environment and to improve their quality of life”. The scientifict community is concerned about one thing: a two-way communication with a patient affected by several brain damage could open some ethical problems.

An example of such a concern was raised at Weill Cornell Medical College in New York: “ When you ask to a patient if he wants to live or die and he answers YES, are we sure that is right? We know the answer was yes, but we don’t know if he understood the question. Otherwise the answer could be probably be yes BUT we don’t give him possibility to add “but”.

The results of this study demostrates the need to carry out more studies to evaluate the role of functional MRI in patients with an alteration of consciousness and how technology may open new diagnostic possibilities; but on the other hand it will open some ethical issues that the International community, probably, will have to face.

References

1. Jennett B, Plum F. Persistent vegetative state after brain damage. A syndrome in search of a name. Lancet 1972; 1: 734–7

2. Jennett B. The vegetative state: medical aspects, ethical and legal dilemmas. Cambridge, England: Cambridge University Press, 2002S

3. M. Monti, A. Vanhaudenhuyse, M.R. Coleman et al. Willful Modulation of Brain Activity in Disorders of Consciousness. N Engl J Med. 2010 Feb 3. [Epub ahead of print]

I had never been to Mexico, and the expectations I held were drawn from the epidemiological reports I had studied and conversations with Mexican friends. The reality of the situation proved to be an interesting mix of inequalities in health and enthused, active agents for change. It was an amazing experience packed with more than I had expected (and at times a more than I had wanted!). From NGO meetings on health policy, to teaching break dancing lessons in a clinic in the rainforest, my time in Mexico was definitely one to be remembered.

Arriving into Mexico City by night is really impressive, the unending sea of streetlights leaves no doubt that your entering one the biggest cities in the world. I then travelled to the southern state of Chiapas, a state with a high proportion of indigenous people, and one of the poorest in Mexico.

A Clinic in the Rainforest

The view out of my bedroom window of the jungle

I went to work in a clinic in an area called Poza Rica, situated in the mountainous region near the border of Guatemala. The clinic had consultation rooms, minor surgery facilities, a reading room, laboratory, pharmacy, delivery suite and two beds for patients requiring admission. Due to a lack of funding and resource provision, a doctor only worked a few days a week. On most days the whole clinic was staffed by one health promoter, or occasionally, if no one else was available, me.

The area suffers from high levels of poverty and malnutrition, with the disease burden dominated by infections and – being a rural, agricultural area – machete wounds. The clinic’s resource shortage became most apparent when, during a power cut in the middle of the night, a 13-month-old child was brought to the clinic with a two-hour history of repeated vomiting. The child was febrile, with decreased consciousness, and my torch light examination suggested photophobia. With one year of clinical experience, broken Spanish, and no trained health workers to help me, I felt well out of my depth. I insisted that the child be taken to the closest town with adequate medical facilities, and felt thankful that at least I was there to simply direct the family to medical help – if I hadn’t been there, the clinic would have been closed.

This highlighted a key learning point for me, that rural areas in Mexico are often underserved by medical services and receive inadequate funding for even basic medical facilities. I discussed this at great length with health workers in the area, and was left hopeful from the passion and commitment with which they were pushing for change.

Break Dancing Lessons

In the UK, I work as a break dance performer and teacher. Whilst working at the clinic in Poza Rica I ran lessons for the young trainee health workers in the local area. About 15 of them came, which was really impressive considering not one of them had any idea what break dancing was. After I explained it and gave a short demonstration, they were one of the most enthusiastic classes I have ever had, and had me teach a lesson every day from then until I left for the second half of my trip to Mexico. I really valued this opportunity to contribute one of my skills in exchange for the insight these young people gave me into how the challenges in the area were being met.

Human Rights

The office I was doing the human rights work from in San Cristobal

On leaving the clinic I went to San Cristobal de las Casas – a small city that was once the state capital. Here I was able to pursue my interest in Public Health by working with a Human Rights organization that focus on realizing the right to health for the indigenous people of Chiapas. I was also able to observe meetings concerning the development of a human rights watch group in the area. It was fascinating to see how human rights declarations can be used to promote equality in healthcare development. It was great to see people were really addressing issues at a governmental level, in ways that will help to ensure primary healthcare for underserved populations such as those that I saw in the clinic. My time in San Cristobal really brought home to me the situation for the indigenous people of Mexico who remain largely marginalized from the rest of society. Organisations such as the one that I was working for, are attempting to reduce the inequalities experienced by indigenous people, and are making slow but real progress.

A couple of men busking in the street, in San Cristobal

I learnt a lot during my time in Mexico. One of the most valuable things for me was being able to look at health care in Mexico from both a clinical and policy perspective. Working in the clinic, I became very aware of my limitations, which left me humbled and eager to work hard on my clinical placements. The human rights work fed my interest in public health. Since returning to the UK, I spent a week with the South Yorkshire Health Protection Agency, which was quite a contrast. In Mexico I had been looking at a 10-year period in which multiple failings in the identification, monitoring, and treatment of disease had resulted in adverse outcomes for a number of people with tuberculosis. In the UK I helped to map out cases of cryptosporidium that were being reported almost daily, to look for potential sources of the outbreak. The different experiences showed me how inter-reliant the components of health systems are, from policy to clinical level. Many of the problems I saw in Mexico resulted from specific points at which the system had failed, with significant impacts in other areas of the system. For example, not using existing funding to purchase medications needed, resulting in gaps in treatment regimes. For diseases such as tuberculosis this can have grave consequences.

My time in Mexico was both enjoyable and fascinating. The experience taught me a lot about medicine in Mexico, from both a clinical and policy perspective, which I believe will be invaluable in my future studies and career.

Keir Philip is a fourth year medical student at the University of Sheffield
I hope you’ve enjoyed reading my report, are thinking that Mexico looks like a good prospect for an elective. For more information, please email me at mda05@sheffield.ac.uk

Image source: NHS Greenwich

Today we’d like to announce the publication of Kier Philip’s report on his elective experiencing medical care and human rights issues in southern Mexico. Read it here.

In today’s blog Thomas Yeoman, fifth year medical student at Dundee University, writes on his experiences with the recent swine flu cases and the consequences of inaccurate pandemic algorithms

There are reports of patients initially diagnosed with swine flu that were later treated in hospital for meningococcal meningitis, malaria, appendix abscess, acute myeloblastic leukaemia, gastroenteritis, cellulitus and bacteraemia

With the National Pandemic Flu Service (NPFS) closing on the 11th February 2010, I feel it is time to reflect upon aspects of this service. As a medical student I witnessed its short comings first hand through a patient who was misdiagnosed with swine flu.

The NPFS was initiated to reduce GP and NHS burden by providing telephone and online assessments for people with symptoms of swine flu. However a patient I saw during my cardiothoracic surgery module in England in late 2009 made me realize the potential danger of assuming a patient with ‘flu-like’ symptoms has swine flu.

The patient in question was admitted to hospital after sudden onset of right arm pain. His arm was pale, paralyzed and pulse-less. He had a 10 day history of flu-like symptoms and had taken Tamiflu for three days after being advised by the NPFS help line.

Brachial thrombo-embolism secondary to dehydration was suspected. The patient underwent brachial embolectomy. A day later a murmur was heard and an echocardiogram identified a mobile mass on a regurgitant aortic valve. Positive blood cultures confirmed infective endocarditis (IE). The patient had an aortic valve replacement and antibiotic treatment.

Due to the suspicion of swine flu this patient did not receive a comprehensive GP assessment that could have led to earlier diagnosis and treatment. The incidence of IE ranges between 1.7-6.2 cases per 100 000 patients and mortality ranges between 4 – >50% depending upon the infective organism (1,2,3). Fortunately this patient presented with one of its treatable complications before it became life threatening.

This patient was not an isolated case. There are reports of patients initially diagnosed with swine flu that were later treated in hospital for meningococcal meningitis, malaria, appendix abscess, acute myeloblastic leukaemia, gastroenteritis, cellulitus and bacteraemia (4,5). It is recognized that it can be very difficult to distinguish between symptoms of swine flu and the early symptoms of diseases such as meningococcal meningitis (6).

During a pandemic algorithms, such as those used by the NPFS, have been considered indispensable for remote diagnosis and issue of antiviral drugs (5,7). However concerns have been raised as to the specificity of the standard H1N1 algorithm used during the current pandemic (4,5,6).

The NPFS played a beneficial role and this may have been more evident if the swine flu pandemic had escalated as originally predicted. However I feel that it is now time to reflect upon factors that led to the misdiagnosis of these patients, so changes can be made to this service in order to protect patients during future pandemics.

References:
1. Mylonakis E, Calderwood SB. Infective endocarditis in adults. N Engl JMed 2001;345:1318-30.

2. Cabell CH, Jollis JG, Peterson GE, Corey GR, Anderson DJ, Sexton DJ, et al. Changing patient characteristics and the effect on mortality in endocarditis. Arch Intern Med 2002;162:90-4.

3. Garg N, Kandpal B, Garg N, Tewari S, Kapoor A, Goel P, et al. Characteristics of infective endocarditis in a developing country—clinical profile and outcome in 192 Indian patients, 1992-2001. Int J Cardiol2005;98:253-60.

4. Payne R, Darton TC, Greig JM. Systematic telephone 2 triage of possible “swine” influenza leads to potentially serious misdiagnosis of infectious diseases. J Infect 2009;59:371-2.

5. Houlihan CF, Patel S, Price DA, Valappil M. Life threatening infections labelled swine flu. BMJ 2010;340:c137

6. Bourke TW, Shields MD. A/H1N1 pandemic: misdiagnosis in the time of meningitis. BMJ 2009;339:b3423.

7. Maynard A, Bloor K. The economic impact of pandemic 1 influenza. BMJ 2009;339:b4888.

Image credit: WorldHealthOrganization.int

Today’s blog written by TLS Regional Advisor in India and Medical Student at Lady Hardinge Medical College, Gurmeen Kaur explores the implications of the ageing population in the United Kingdom.

What do you think of this issue? Register your opinions in our poll and join the debate on our Facebook Group

Every year, about £9 billion is spent on care services for elderly people in England, and spending could almost double by 2026

England’s population is ageing and the trend is accelerating. The number of older people will increase rapidly in the next 20 years. In 2026, 40% of the population of United Kingdom would be over 50 years. With increasing population above 50 there is also a rise in the diversity of the ageing groups. The ethnic balance is shifting and there is a need to make appropriate provisions for the Black and multi-ethnic population (1).

The changing demographic scenario has profound financial implications. With the rising geriatric population there is mounting emphasis on ‘care of this ageing population’ and hence a massive increase the resources involved. Every year, about £9 billion is spent on care services for elderly people in England, and spending could almost double by 2026 (2).

Tackling the financial challenges of an ageing population is a herculean task and so the Audit Commission has prepared a detailed report titled ‘Under Pressure’ (3) to highlight how unprepared the country is to deal with the burden of the ageing population and how huge discrepancies exist among different councils. In their report, they have also outlined recommendations and suggested a uniform plan for all councils.

The Audit commission has made recommendations on how the country ‘can get more for less’. The challenge and review questions are included in their national report Under Pressure – Tackling the Financial Challenge for Councils of an Ageing Population and are grouped around four basic themes: namely taking a strategic view, managing costs, prevention and early intervention; and using information.

The Health and Social care policy of the Central Government of UK has been shifting from a ‘need-determined’ to a ‘people-centered’ approach in developing services for the people over the age of 50. ‘Opportunity Initiative’- a central government report in 2005 laid down four major objectives (4):

· Identify and tackle issues that limit older people’s ability to get the most out of life, including rooting out age discrimination and dealing with crime and the fear of crime and poor housing.

· Ensure that older people can get actively engaged in influencing decisions that affect their lives like planning and public transport.

· Ensure that older people have access to opportunities for learning, leisure and volunteering activity.

· Promote healthy living at all ages – older people will be more able to enjoy good health in later life if they have looked after themselves when they were younger.

Changing policy decisions are reflected in the 2006 Partnerships for Older People Project and the 2007 initiative called Putting People First: A Shared Vision and Commitment to the Transformation of Adult Social Care. The most accepted and popular 2008 Audit committee recommendations –‘Don’t stop me now’ conclude that (4),

“The statutory duty to deliver social care is only one dimension of a much broader role. In addition to fulfilling their statutory responsibilities, councils need to: understand, engage and mobilize the community to maximize the opportunities in the older population; ensure that mainstream services are accessible to as many of the older population as possible, for as long as possible; and shape and deliver targeted services aimed at promoting independence and well-being in later life.”

Geriatric care in Britain has been popularly divided into ‘acute’ and subacute/ chronic/ community based care. The geriatricians have to strike a fine balance between delivery of both acute as well as community based care to prevent overloading the already burdened general practitioner. The committee report suggests that prevention and early intervention can reduce costs without compromising on the dignity and independence of the ageing population (3).

While social care makes up for the major share of the finances spent, housing, transport, other activities including leisure and recreational stuff also have a minor contribution. Social care costs are the biggest cost related to the ageing population for single-tier and county councils. Local authorities spent £8.8 billion on personal social care for older people in 2007/08 (2). Involving the elderly in the decision making process and helping them to be financially independent are parts of the schemes suggested. Redesign of care services to focus on prevention, early intervention, and active ageing is needed to reduce social isolation, improve health and wellbeing, and ultimately delay the need for care (5).

Tighter finances create an opportunity to rethink and redesign services to improve lives, while spending less public money. And hence it is the need of the hour for all councils in UK, geriatricians, primary care providers, policy makers and everyone concerned to follow a strategic, long-term, financially viable set of recommendations to improve quality of life and provide dignity to all our respected elderly.

References:

1. Audit Commission (2008) ‘Don’t stop me now: Preparing for an ageing population’, Local Government National Report, July 2008. http://www.audit-commission.gov.uk/SiteCollectionDocuments/AuditCommissionReports/NationalStudies/DontStopMeNow17July08REP.pdf

2. http://www.audit-commission.gov.uk/SiteCollectionDocuments/AuditCommissionReports/NationalStudies/financialimpactsofanageingpoplitreview.pdf

3. Audit Commission report “Under Pressure”. http://www.audit-commission.gov.uk/SiteCollectionDocuments/Downloads/20100218-underpressure-nationalstudy-summary.pdf

4. http://www.audit-commission.gov.uk/SiteCollectionDocuments/AuditCommissionReports/NationalStudies/InlogovAgeingPopulationsstrategiesforbestpractice.pdf

5. How would you spend £1 million to tackle ageing? The Lancet. doi:10.1016/S0140-6736(10)60287-5.

Visit theLancetStudent.com to read this week’s blogs and articles; you can also vote in our pole this week on ‘aid commitments in an economic crisis’ and join the facebook debate. We are always looking for writers, so please get in touch by emailing us at student@lancet.com if you would like to write an article, elective report or blog for us. In addition, in our hope of expanding our podcasts, social media and online video content we are now looking for those with an eye for editing audio/visual content who would be happy to assist the Editorial Team.

Please don’t forget to tell a Friend about what the TheLancetStudent.com can do for you! And of course – please get in touch – we love hearing from you!

This week in TLS News

Actions before Apologies

Ana Amaya, TLS Student Editor and DrPH student at London School of Hygiene and Tropical Medicine, discusses a recent report which projects a reduction in promised aid from OECD countries in 2010.

Village in India may hold key to beating Dementia

Gurmeen Kaur, our TLS Regional advisor from Delhi, discusses findings from a village in India with surprisingly low dementia rates.

People Can’t Make Healthy Choices Without Healthy Options

Andrey Ostrovsky, Coordinator of the HSAN Student Section and medical student at Boston University, explores the important role of students in health systems strengthening around the world

Identity: A place for the incurably curious

Catherine Carver, fourth year medical student at University of Aberdeen, describes an exhibition about Identity going on now at the Wellcome Trust in London.

Lymphadenectomy in Endometrial Cancer

This week’s editorial examines a study published Online First this week by The Lancet seeking to determine the best approach to lymphadenectomy for patients with endometrial cancer.

This week’s Article

Bronchial Asthma: An Unsolved Health Problem

Savino Sciascia interviews Enrico Heffler, thenational coordinator of Junior Members of Italian Society of Allergology and Clinical Immunology, on the global asthma epidemic.

This week’s Elective Report

Research at King’s College, London

Sara Bughio’s report on her elective researching genetics and embryonic development in mice at the Department of Craniofacial Development at King’s College, London.

Have a great weekend and please get in touch,

The Lancet Student Editorial Team

Summary

The rising incidence and morbidity of non-melanoma skin cancers has generated great interest in unravelling of their pathogenesis and in the search for new non-invasive treatments. Whereas the role of cumulative sun exposure in pathogenesis of squamous-cell carcinoma seems clear, the relation between sun-exposure patterns and subtypes of basal-cell carcinoma remains undetermined. Several complex genotypic, phenotypic, and environmental factors contribute to pathogenesis of non-melanoma skin cancers. Unlike basal-cell carcinoma, squamous-cell carcinomas can arise from precursor lesions. Diagnosis of non-melanoma skin cancer is made clinically and confirmed by histological testing. Prognosis depends on lesion and host characteristics, which also dictate choice of treatment. Prevention strategies aim at reduction of sun exposure, but are of unproven benefit, especially for basal-cell carcinoma. Surgical excision with predetermined margins is the mainstay of treatment for squamous-cell carcinoma and for most basal-cell carcinomas. Of the new non-invasive treatments, only photodynamic therapy and topical imiquimod have become established treatments for specific subtypes of basal-cell carcinoma, and the search for more effective and tissue-salvaging therapies continues.

Introduction

The term non-melanoma skin cancers (or keratinocyte carcinomas) encompasses cutaneous lymphomas, adnexal tumours, Merkel-cell carcinomas, and other rare primary cutaneous neoplasms, but is mainly used to define basal-cell carcinomas and squamous-cell carcinomas. Grouping of these two carcinomas under a common umbrella term poses challenges, because clear differences exist in their aetiopathogenesis, clinical course, and management strategies. Non-melanoma skin cancers are the most common human cancers, and despite growing public awareness of the harmful effects of sun exposure, incidence continues to rise.1, 2 A 3—8% yearly increase in incidence of non-melanoma skin cancer has been reported since 1960 worldwide.3, 4 Incidence of basal-cell carcinoma alone is increasing by 10% per year worldwide, suggesting that prevalence of this tumour will soon equal that of all other cancers combined.5 Furthermore, an estimated 40—50% of patients with a primary carcinoma will develop at least one or more further basal-cell carcinomas within 5 years. The estimated incidence of non-melanoma skin cancer in the USA is more than 1 000 000 cases per year, of which roughly 20—30% are of squamous-cell carcinoma.6

Epidemiology

Unfortunately, because of variation between registries in data capture, recording, and processing for skin-cancer registration, accurate figures for incidence of non-melanoma skin cancer in the UK are difficult to obtain.7 More than 76 000 new cases of non-melanoma skin cancer were registered in the UK in 2005, but the actual incidence is estimated to be at least 100 000 cases per year.8 Results of a Welsh study9 showed that the crude incidence of non-melanoma skin cancer increased from 173·5 to 265·4 per 100 000 population yearly between 1988 and 1998. In Northern Ireland, in the 10 years after 1993, incidence of melanoma and non-melanoma skin cancer increased by 62% in the overall number of skin-cancer samples processed by local pathology laboratories. A 20% increase in total number of patients was also noted.2 Rising incidence of non-melanoma skin cancer might partly be due to increased patient and physician awareness of the disease, in addition to improved coding.

The age shift in the population has resulted in an overall increase in total number of skin cancers, since incidence of non-melanoma skin cancer increases with age. Indeed, 80% of cases occur in people aged 60 years and older.10 By 2030, the number of cases presenting to dermatologists could increase by an estimated 50%.10 Incidence is higher in men than in women. Table 1 shows international trends in incidence of non-melanoma skin cancer.2,9,11—15

International trends in incidence of non-melanoma skin cancers

Risk of development of non-melanoma skin cancer depends on genotypic, phenotypic, and environmental factors. Risk is greatest in residents of high ambient solar irradiance who have markers of ultraviolet (UV) susceptibility, such as light skin, eye, and hair colour, or an inability to tan, and those with benign sun-related skin disorders—eg, actinic keratoses and solar lentigines.16 The finding that non-melanoma skin cancer occurs mainly on sun-exposed body sites and that its frequency can be reduced by sun protection provides indirect but crucial evidence for the role of ambient solar radiation.17

The geographic variation in incidence of non-melanoma skin cancer is associated with ambient sun irradiance, providing further evidence for the relation between this disease and sun exposure. Incidence within countries is associated with increasing proximity to the equator. Gradients are similar for men and women, and all ages.18 The thinner ozone layer and shorter distance traversed by UVB at lower latitudes than at high latitudes make residents of these regions most vulnerable to the effects of this radiation.19 An inverse association with latitude for both basal-cell and squamous-cell carcinoma was shown in a survey of eight geographically diverse locations in the USA, suggesting a strong association between UV radiation and development of non-melanoma skin cancer.

Although UV radiation is the most important risk factor for pathogenesis of both basal-cell and squamous-cell carcinoma, the effect on risk of squamous-cell carcinoma is greatest.20 Cumulative lifetime sun exposure has a strong dose-response association with squamous-cell carcinoma, whereas for basal-cell carcinoma, intermittent sun exposure and exposure during childhood might be more important.21, 22 The relation between sun exposure and development of basal-cell carcinoma remains unclear, and epidemiological studies suggest that the quantitative effect could be quite small. Additionally, various sun-exposure patterns might cause specific histotypes at different sites.23 Morphological subtypes of basal-cell carcinoma might have distinct gene expression profiles, which partly account for their complex behaviour.24

Pathogenesis

UVB radiation causes direct damage to DNA and RNA by inducing covalent bond formation between adjacent pyrimidines, leading to generation of mutagenic photoproducts such as cyclopyrimidine dimers (TT) and pyrimidine-pyrimidine (6-4) adducts.25 UVA is less mutagenic than is UVB, and causes indirect DNA damage via a photo-oxidative-stress-mediated mechanism, resulting in formation of reactive oxygen species, which interact with lipids, proteins, and DNA to generate intermediates that combine with DNA to form adducts.26 Several complex DNA repair systems are needed to prevent the harmful effects of these premutagenic adducts.27

Reports in patients with a rare cell-mediated immunity disorder, epidermodysplasia verruciformis, of high rates of malignant transformation of atypical warts infected with β human papillomaviruses (HPV) provided initial clues about the association between HPV and non-melanoma skin cancer.28 Further evidence arose from estimates that up to 90% of non-melanoma skin cancers in immunocompromised individuals and up to 50% in immunocompetent individuals contain DNA from cutaneous or β HPV types.28, 29 Unlike for cervical carcinoma, however, no specific HPV subtypes have been associated with non-melanoma skin cancer.

Although the association between warts and squamous-cell carcinoma is well described, oncogenic HPV subtypes are also present in 60% of basal-cell carcinomas from immunosuppressed patients and 36% of basal-cell carcinomas from immunocompetent patients, suggesting that these viruses could be involved in development of basal-cell carcinoma.30 However, risk of squamous-cell but not basal-cell carcinoma is associated with seropositivity for HPV.31

The versatility of HPV in lesional, non-lesional, normal sun-exposed, and non-sun-exposed skin suggests that these viruses might be indirectly involved in pathogenesis of non-melanoma skin cancer by facilitating UV-related carcinogenesis via mechanisms such as prevention of UV-induced apoptosis or impaired DNA repair.32 In this context, psoralen and UVA (PUVA) therapy-induced immunosuppression could play an important part in PUVA-related carcinogenesis by affecting extent and pathogenicity of HPV infection.33

In white transplant recipients, risk of squamous-cell carcinoma increases 65—250-fold and risk of basal-cell carcinoma ten-fold to 16-fold compared with the non-transplanted population.34, 35 The ratio of squamous-cell to basal-cell carcinoma also reverses in iatrogenic immunosuppression, because squamous-cell carcinomas occur more frequently in transplant recipients than do basal-cell carcinomas, whereas in the general population basal-cell carcinoma is three to six times more frequent than are squamous-cell carcinomas.36

Age, skin colour, male sex, UV dose, and duration of immunosuppression are key components in pathogenesis of post-transplant non-melanoma skin cancer. However, complex genetic factors affecting the extent and consequences of immunosuppression can determine individual risk.37 Patients with HIV/AIDS or non-Hodgkin lymphoma, specifically chronic lymphocytic leukaemia, also have aggressive squamous-cell carcinomas.38, 39Table 2 lists factors linked to development of non-melanoma skin cancer.16,17,20—22,28—48

Environmental risk factors for non-melanoma skin cancers.
UV=ultraviolet. BCC=basal-cell carcinoma. SCC=squamous-cell carcinoma. PUVA=psoralen and UVA.

Naevoid basal-cell carcinoma syndrome (Gorlin syndrome), which is an autosomal dominant disorder with distinct morphological features including multiple basal-cell carcinomas, results from germline mutations in PTCH1, a segment polarity gene (9q22.3) originally identified in Drosophila melanogaster, which plays a crucial part in vertebrate development.49PTCH1 has tumour suppressor functions and encodes a 12-pass putative transmembrane protein that acts like the receptor of the diffusible morphogen protein, sonic hedgehog (figure 1).51 Loss of function mutations of PTCH1 result in reduced suppression of intracellular signalling by another transmembrane protein, the G-protein-coupled receptor, smoothened (SMO). SMO targets the GLI family of transcription factors, and PTCH1 mutations result in sustained activation of target genes. Somatic PTCH1 mutations have a high frequency in familial basal-cell carcinoma,52 and are present in up to 68% of sporadic basal-cell carcinomas.53 Pathogenesis of basal-cell carcinoma in naevoid basal-cell carcinoma syndrome is due to a spontaneous defect in maintenance of epidermal homoeostasis and an intrinsic property of the cells that is independent of external mutagenic stress, such as short-wavelength UVB.54PTCH1 loss has also been reported as an early event in pathogenesis of squamous-cell carcinoma.55 Figure 2 shows the major pathogenic pathways involved in non-melanoma skin cancer.

Sonic hedgehog signalling and pathogenesis of basal-cell carcinoma
SHH=sonic hedgehog. PTCH=patched. SMO=smoothened. Fu=fused. SUFU=suppressor of fused. TGFβ=transforming growth factor β. WNT=wingless. BMP=bone morphogenetic protein. Reproduced from reference 50 by permission of Blackwell Publishing.

Major pathways involved in the pathogenesis of non-melanoma skin cancers
Pathways exert unequal effects on pathogenesis of basal and squamous cell carcinoma. CDKN2A=cyclin-dependent kinase inhibitor 2A. GSTT1=glutathione S-transferase theta 1. CYP2D6=cytochrome P450, family 2, subfamily D, polypeptide 6. PTCH1=patched homolog 1. XPC=xeroderma pigmentosum, complementation group C. MC1R=melanocortin 1 receptor. TP53=tumour protein 53.

The melanocortin-1 receptor (MC1R) gene variants ASIP and TYR are associated with fair skin, red hair, and increased melanoma risk, and evidence suggests that they might be important independent risk factors for non-melanoma skin cancer.56, 57 UVB and UVC radiation result in DNA damage, leading to production of signature cyclobutane-type pyrimidine dimers, which activate mechanisms for removal of damaged DNA, a delay in cell-cycle progression, DNA repair, or apoptosis by transcriptional activation of TP53 and related genes such as CDKN1A, BCL2, and BAX.58, 59

Signature UV-DNA lesions are repaired via the nucleotide excision repair pathways, which can be subdivided into transcription-coupled repair and global genome repair. The XPC protein is specific to the genome repair pathway, and recognises helix-distorting lesions and starts their repair. Inactivating XPC mutations are associated with xeroderma pigmentosum, a rare autosomal recessive syndrome in which several skin cancers—especially squamous-cell carcinoma—are seen.60 Keratinocytes from DNA repair-deficient patients are more prone to apoptosis than are those with normal DNA repair capacity.61

Inactivation of the TP53 tumour suppressor gene has an important role in induction of non-melanoma skin cancer by UV radiation, and transcription factor P53 is often mutated in this disease. P53 mutation renders cells resistant to apoptosis, resulting in the clonal expansion of precancerous keratinocytes. Roughly 90% of squamous-cell and 50% of basal-cell carcinomas have a P53 mutation.59, 62, 63 Additionally, inactivation of the CDKN2A locus (encoding a cell-cycle inhibitor protein) has been detected in squamous-cell carcinomas from patients with xeroderma pigmentosum and sporadic non-melanoma skin cancer.64, 65

The cytochrome P450 (CYP) supergene family has more than 30 isoforms, which catalyse biotransformation of several xenobiotics, often as the first step of a two-phase detoxification. The resulting highly reactive intermediate serves as a substrate for phase-two enzymes, including members of the glutathione S-transferase (GST) supergene family. GSTs can also catalyse detoxification of the products of oxidative stress (eg, lipid and DNA hydroperoxides). Polymorphisms in GSTT1 and CYP2D6 are associated with susceptibility to non-melanoma skin cancer, and polymorphisms in CYP2D6 (together with vitamin D receptor and tumour necrosis factor α) with increasing tumour numbers.66, 67 Additionally, some allelic variants of CYP2D6 are associated with a multiple presentation phenotype of basal-cell carcinoma.68

Human telomerase is a unique enzyme that uses RNA as a template to add telomere repeats at chromosome ends to compensate for telomere loss during cell division. Unlike healthy cells, most immortal and tumour cells have substantial telomerase activity and show no net loss of telomere length during proliferation. Therefore, telomerase reactivation in cells results in tumour immortalisation.69 Investigators have shown telomerase activation to be important in pathogenesis of basal-cell and squamous-cell carcinoma.70, 71 Table 3 lists syndromes predisposing to squamous-cell carcinoma.

Syndromes predisposing to cutaneous squamous-cell carcinomaSyndromes predisposing to cutaneous squamous-cell carcinoma

Diagnosis

Early basal-cell carcinomas are usually small, translucent, or pearly, with raised telangiectatic edges. Roughly 80% of all basal-cell carcinomas occur on the head and neck, and clinical diagnosis is fairly straightforward.72 In addition to the classic rodent ulcer with an indurated edge and ulcerated centre, nodular or cystic, superficial, morphoeic, and pigmented basal-cell carcinomas are other common subtypes (figure 3). 10—40% of basal-cell carcinomas contain a mixed pattern of two or more of these histological subtypes, drawing attention to the need for a clinicopathological diagnosis.73, 74 By contrast with nodulocystic basal-cell carcinoma—which is the most common subtype, usually presenting on the head and neck—superficial basal-cell carcinomas predominantly present on the trunk. Superficial basal-cell carcinomas can sometimes be difficult to differentiate from psoriasis, discoid eczema, or Bowen’s disease, and pigmented and nodular subtypes can cause diagnostic confusion with melanoma. 5% of all basal-cell carcinomas are morphoeic lesions, which have ill-defined borders, can be difficult to diagnose clinically, and often present late.75 Midfacial basal-cell carcinomas have been suggested to occur on embryonic fusion planes—a notion that has been challenged.76, 77 Patients with initially truncal basal-cell carcinomas of superficial histology have the highest rate of increasing carcinoma numbers.78

Clinical subtypes of basal-cell carcinoma
(A) Classic rodent ulcer. (B) Nodular or cystic. (C) Superficial. (D) Morphoeic. (E) Pigmented basal-cell carcinoma.

Unlike basal-cell carcinoma, squamous-cell carcinomas can have precursor lesions, such as actinic keratoses and squamous-cell carcinoma in situ (Bowen’s disease; figure 4), which are considered premalignant.79 Although the rate of progression of individual actinic keratoses to invasive squamous-cell carcinoma has been estimated as 1—10% over 10 years, this risk could be much higher in patients with more than five actinic keratoses.80, 81 Presence of actinic keratoses is an important marker of high UV exposure and increased risk of non-melanoma skin cancer generally.82 This marker can sometimes allow early identification and treatment of in-situ squamous-cell carcinoma to avoid metastasis and tissue destruction, since squamous-cell carcinomas are more invasive than are basal-cell carcinomas.

Clinical appearance of squamous-cell carcinoma and precursor lesions
(A) Actinic keratosis. (B) Squamous-cell carcinoma in situ (Bowen’s disease). (C) Keratoacanthoma. (D) Squamous-cell carcinoma.

Squamous-cell carcinoma usually develops on sun-exposed sites because of photodamage of the skin. Lesions of Bowen’s disease usually present as slowly enlarging erythematous scaly or crusted plaques and have a 3—5% risk of progression to squamous-cell carcinoma.83 Keratoacanthomas (figure 4) are characterised by rapid onset, progression, and regression within months, and can have clinical and histological similarities to well differentiated squamous-cell carcinoma.84 Induration is a common feature of all squamous-cell carcinomas and is usually the first sign of malignancy. The typical lesion has an adherent crust and ill-defined edges, indicating spread beyond visible margins (figure 4).

In case of diagnostic confusion, a confirmatory diagnosis can be achieved by histopathological examination, which remains the gold standard for diagnosis of non-melanoma skin cancer. The UK Royal College of Pathologists’ minimum dataset for the histopathological reporting of basal-cell carcinoma includes growth patterns (nodular, superficial, infiltrative or morphoeic, and micronodular types), differentiation of severely atypical or malignant squamous type (basosquamous carcinoma), and involvement or clearance of deep and peripheral margins.85 Similarly, the histological report for squamous-cell carcinoma should include pathological pattern, morphological changes to cells, degree of differentiation, histological grade, depth, extent of dermal invasion, and presence of perineural, vascular, or lymphatic invasion.86

As further novel non-invasive therapeutic modalities for non-melanoma skin cancers become available, interest in non-invasive screening and diagnosis of these lesions has also increased. Dermoscopy (dermatoscopy) with cross-polarised light, high-frequency (20—100 MHz) ultrasound, optical coherence tomography with infrared light, and in-vivo confocal microscopy have been used for early diagnosis of non-melanoma skin cancer.87 The technique of fluorescence lifetime imaging generates image contrast between different states of tissue because of differences in fluorescence decay rates, and has a potential clinical role in imaging of basal-cell carcinoma.88 Besides dermoscopy—which is a useful diagnostic aid for pigmented lesions—clinical applications of other non-invasive diagnostic techniques for non-melanoma skin cancers have not yet been defined.

Prognosis and staging

Non-melanoma skin cancers, especially basal-cell carcinomas, have low metastatic potential and are associated with low mortality. The likelihood of metastases and recurrence of squamous-cell and basal-cell carcinoma depends on several prognostic indicators (table 4).86,89—91 These indicators draw attention to the importance of a detailed pathological description, since individual lesion and host characteristics have to be taken into account when determining the prognosis of non-melanoma skin cancer.

Factors indicating poor prognosis in non-melanoma skin cancer 86,89–91
* Squamous-cell carcinoma greater than 2·0 mm in thickness, and especially those greater than 6·0 mm, are associated with high risk of metastasis and local recurrence.89

In addition to the factors outlined in table 4, incomplete excision should be considered a poor prognostic indicator for both basal-cell and squamous-cell carcinomas, since patients with an inadequately excised lesion are at risk of local recurrence. Additionally, patients with squamous-cell carcinoma are at risk of developing subsequent nodal metastases, and this risk is most pronounced in patients with recurrent disease.89, 90 Tumour thickness of more than 6 mm and desmoplasia independently affect risk of local recurrence of squamous-cell carcinoma.91 Routine sentinel-lymph-node biopsy is not justified in patients with high-risk squamous-cell carcinoma—a notion that is lent support by most guidelines for management of this disease.86, 92 Mucosal—cutaneous junctional and mucosal squamous-cell carcinomas have a worse prognosis than does cutaneous disease.

Perineural invasion is an infrequent complication of squamous-cell (2·5—14·0%) and basal-cell (3%) carcinomas, and is associated with high risk of recurrence and metastases and risk of significant clinical morbidity due to neurological deficits.93 Treatment of these patients remains challenging, since the role of adjuvant radiotherapy has not yet been defined.94 Patients with non-melanoma skin cancer have a ten-fold increased risk of developing a subsequent non-melanoma skin cancer and non-cutaneous malignancy compared with the general population, and this risk diminishes with increasing age at diagnosis of first non-melanoma skin cancer.95

In view of the rarity of nodal and visceral metastases in basal-cell carcinoma (1:50 000), clinical and pathological staging is seldom done. The TNM system, recommended by the American Joint Committee on Cancer, is a staging system for all histological types of skin cancer but is most often used for staging squamous-cell carcinoma (panel 1). Because of its deficiencies and failure to recognise several of the well known prognostic indicators for squamous-cell carcinoma, this staging system has often been criticised.89, 96, 97

Panel 1
American Joint Committee on Cancer staging system for cutaneous basal-cell and squamous-cell carcinoma of the skin (excluding eyelid, vulva, and penis)
Primary tumour (T)*
TX: Primary tumour cannot be assessed
T0: No evidence of primary tumour
Tis: Carcinoma in situ
T1: Tumour 2 cm or less in greatest dimension
T2: Tumour 2—5 cm in greatest dimension
T3: Tumour more than 5 cm in greatest dimension
T4: Tumour invades deep extradermal structures (ie, cartilage, skeletal muscle, or bone)
Regional lymph nodes (N)
NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Regional lymph node metastasis
Distant metastasis (M)
MX: Distant metastasis cannot be assessed
M0: No distant metastasis
M1: Distant metastasis
Stage grouping
Stage 0: Tis, N0, M0
Stage I: T1, N0, M0
Stage II: T2, N0, M0; T3, N0, M0
Stage III: T4, N0, M0; any T, N1, M0
Stage IV: any T, any N, M1
Histopathologic grade (G)
GX: Grade cannot be assessed
G1: Well differentiated
G2: Moderately differentiated
G3: Poorly differentiated
G4: Undifferentiated
* For several simultaneous tumours, the tumour with the highest T category will be classified and the number of separate tumours given in parentheses—eg, T2 (5).

Treatment

Management

The British Association of Dermatologists has issued guidelines for management of non-melanoma skin cancers.86, 98 Interventions for management of basal-cell carcinomas in immunocompetent patients and prevention of non-melanoma skin cancers in high-risk groups have been systematically reviewed.99, 100 Routine use of sunscreen might prevent squamous-cell carcinoma, but is of unproven benefit in basal-cell carcinoma.101 Several government and charitable organisations have launched prevention programmes for skin cancer targeting excessive sun exposure as the most important pathogenic factor.102, 103 The main messages of these programmes are to restrict time in midday sun, watch the UV index, stay in the shade, use topical sunscreens, wear protective clothing, and avoid sunlamps and tanning parlours.103

The primary aim of treatment is complete removal or destruction of the lesion while achieving a good and acceptable cosmetic outcome as an important secondary goal. Choice of treatment depends on several factors, including clinical and histological nature, size, and site of the lesion; comorbidities; local expertise; availability; and treatment costs. The National Institute for Health and Clinical Excellence and National Collaborating Centre for Cancer have recommended that cancer networks establish two levels of multidisciplinary teams: a local hospital skin-cancer team and a specialist skin-cancer team.104

Histological examination of excisional margins is usually necessary to ensure complete removal of non-melanoma skin cancer, but not all surgical techniques allow this assessment. Often, clinical judgment alone is applied when destructive surgical techniques are used. Unfortunately, such techniques frequently result in a poor cosmetic outcome. The continuing search for tissue-sparing and non-surgical treatments has led to development of several non-invasive and novel experimental treatment modalities for basal-cell carcinoma. However, for basal-cell carcinoma, and more so for squamous-cell carcinoma, surgical excision or destruction is still the mainstay of treatment. Treatments for non-melanoma skin cancer can be broadly classified into surgical and medical (panel 2).

Panel 2
Treatments for non-melanoma skin cancer
Surgical (physical)

*
Excision
*
Curettage and electrodesiccation
*
Cryosurgery
*
Mohs micrographic surgery
*
Radiotherapy
*
Erbium: yttrium-aluminum-garnet laser ablation, carbon dioxide laser vaporisation

Non-surgical (medical)

*
Topical fluorouracil*
*
Topical imiquimod*
*
Photodynamic therapy (systemic or topical)*
*
GDC-0449*†
*
Intralesional interferon alfa-2b†
*
Ingenol mebutate,*† cyclophilin*†
*
Histone deacetylase inhibitors (valproic acid, vorinostat)†

* Not recommended for treatment of squamous-cell carcinomas.
† Drugs under investigation.

Surgical treatments

Excision with predetermined margins is one of the most common and effective treatment strategies for well defined basal-cell carcinoma and most squamous-cell carcinomas. Unlike many other destructive surgical techniques, it allows for histological examination of the excised tissue and accurate assessment of excisional margins. A 4—5 mm surgical margin ensures peripheral clearance in roughly 95% of well defined small basal-cell and squamous-cell carcinomas.105 By contrast, treatment of morphoeic or large basal-cell carcinoma needs a 3—15 mm margin to obtain a similar clearance rate.105 For large and high-risk squamous-cell carcinomas, an excision margin of greater than 6 mm with histological examination of tissue margins or Mohs micrographic surgery is recommended.86 The recommended excision margins vary between guidelines issued by professional organisations in different countries. Apart from being highly effective (recurrence rate of <2% in 5 years after histologically complete excision of basal-cell carcinoma), excision is usually associated with a good cosmetic outcome.106, 107

Since recurrent basal-cell carcinoma is associated with poor cure rates after excision, a 5—10 mm excision margin is recommended. Treatment options for incompletely excised basal-cell carcinomas include immediate retreatment, especially when dealing with high-risk disease at crucial midfacial sites (in which the deep surgical margin is often involved). Other problematic lesions are those that have been treated with complex surgical procedures (eg, flaps or grafts), and incompletely excised low-risk primary tumours with possible lateral margin involvement.98 Most authorities recommend re-excision of incompletely excised basal-cell carcinomas, with or without frozen-section control or with histologically controlled margins.98, 108, 109 However, adjuvant radiotherapy for postsurgical histologically involved margins can be an acceptable alternative when further excision would be difficult.

The primary aim of Mohs micrographic surgery is to identify and excise the entire tumour and its residues to ensure complete resection. As a result, 5-year cure rates of up to 98·9% have been reported for both primary and recurrent basal-cell and squamous-cell carcinoma, with the additional benefit of preservation of healthy peripheral skin.110, 111 Main indications for this procedure are centrofacially located tumours, large tumours, morphoeic, infiltrative, micronodular, or basosquamous basal-cell carcinoma, poorly defined tumour margins, recurrent lesions, and those with perineural or perivascular involvement.98 Apart from availability of skilled practitioners, setting up of a service for this surgery has financial and resource-related implications that can be limiting factors in this context.

Investigators comparing quality-of-life measurements for patients who underwent different surgical treatments reported that excision and Mohs micrographic surgery equally improved all quality-of-life domains.112 In a randomised controlled trial,113 recurrence of primary facial basal-cell carcinoma did not differ after Mohs micrographic surgery or surgical excision, but there were significantly fewer recurrences of recurrent facial basal-cell carcinoma after Mohs micrographic surgery than after excision.
After surgical excision, curettage and electrodesiccation (curettage and cautery) is the second most common surgical procedure for treatment of basal-cell carcinoma in the UK.114 5-year cure rates of up to 92·3% have been achieved for selected primary basal-cell carcinomas with this procedure.115 Indications include low-risk lesions at sites other than the head and neck, although very high cure rates have been obtained when treating primary non-fibrosing basal-cell carcinoma at facial sites of medium to high risk.116 However, number of cycles used can vary and several modified techniques exist, so comparison of this procedure with other treatment modalities is difficult. As with other destructive surgical techniques, curettage and electrodesiccation should not be considered for treatment of recurrent or ill-defined tumours or for high-risk histological subtypes of basal-cell carcinoma.98

Curettage and electrodesiccation of small, well differentiated, primary slow-growing squamous-cell carcinoma, can also achieve excellent results.115 Long-term follow-up studies and those investigating treatment of large squamous-cell carcinomas and different subtypes of squamous-cell carcinoma have not been undertaken with this procedure. Curettage and electrodesiccation is not recommended for treatment of recurrent disease.86 Compared with surgical excision and Mohs micrographic surgery, curettage and electrodesiccation did not improve tumour-related quality of life.116

Cold-induced destruction of non-melanoma skin cancer can be achieved with liquid nitrogen cryosurgery. Several variations in spray technique and duration and number of freeze/thaw cycles have been used to improve results.117 This technique is considered appropriate for treatment of low-risk primary basal-cell and squamous-cell carcinomas.86, 98 Recurrence rates were similar for cryosurgery and surgical excision in one study,118 and results of another study119 showed a higher recurrence rate for basal-cell carcinoma treated with cryosurgery (39%) than for carcinoma treated with radiotherapy (4%) at 2-year follow-up. Cosmetic results were similar for cryosurgery and radiotherapy, whereas results of surgical excision were better than were those of cryosurgery.118, 119

Precise ablation of the tumour can be readily achieved with a carbon dioxide (CO2) laser. Although laser treatment of non-melanoma skin cancer has rarely been studied, successful use of pulsed CO2 laser in treatment of superficial basal-cell carcinoma has been described.120 Another study121 reported a clinical and histopathological cure in 140 patients with superficial and nodular basal-cell carcinoma treated with superpulse CO2 laser, with no recurrences at a 3-year follow-up. As with other ablative therapies, histological confirmation of cure is not possible with CO2 laser ablation, therefore use should be restricted to low-risk basal-cell carcinoma. Flashlamp-pumped pulse dye laser is effective in treatment of superficial basal-cell carcinoma.122

Superficial and electron beam radiotherapy and brachytherapy are effective adjuvant therapeutic strategies for treatment of primary and surgically recurrent basal-cell carcinoma.98, 123, 124 These methods have even been suggested as the treatment of choice for high-risk non-melanoma skin cancer in patients who are unwilling or unable to tolerate surgery.85, 97, 123 Radiotherapy can be used as a palliative modality to improve quality of life of patients with advanced or incurable disease.125

Results of a randomised controlled trial126 comparing surgical excision with use of frozen section margin control with radiotherapy for basal-cell carcinoma showed that persistent tumours and recurrences were most common in the radiotherapy group. Some patients develop dyspigmentation, telangiectasia, and radiodystrophy at sites treated with radiotherapy, resulting in a poor cosmetic outcome.126, 127 Furthermore, radiotherapy is contraindicated in treatment of basal-cell carcinomas that have recurred after radiotherapy.98 Modifications in radiotherapy techniques have successfully overcome issues with cosmesis and effiacy.128

In squamous-cell carcinoma of the lip, nasal vestibule, and ear, radiotherapy can provide the best cosmetic and functional result.86 Additionally, long-term results of squamous-cell carcinoma treated with radiotherapy are similar to those of other treatment modalities.115, 127 Radiotherapy adjuvant to surgery offers the best chance of achieving locoregional control in head and neck nodal metastases from squamous-cell carcinoma.129 Risk of latent non-melanoma skin cancer and other skin cancers after 15—20 years of exposure suggests that radiotherapy should be used cautiously in young patients (aged <65 years).130 Patients with naevoid basal-cell carcinoma syndrome have increased sensitivity to radiation and a tendency to develop several basal-cell carcinomas in the irradiated field; radiotherapy is therefore also contraindicated in these patients.131

Medical treatments

Fluorouracil is an antineoplastic antimetabolite that disrupts DNA and RNA synthesis by inhibiting the enzyme thymidylate synthetase, thereby preventing purine and pyrimidine from becoming incorporated into DNA during the S-phase of the cell cycle.132 It has been established as a topical treatment for actinic keratoses and Bowen’s disease since the late 1960s but is rarely used to treat basal-cell carcinoma, even though high histological cure rates and good cosmetic results have been reported with topical fluorouracil treatment of small and superficial basal-cell lesions.133 Local irritation, erythema, swelling, desquamation, and tenderness are common treatment-site reactions. Topical fluorouracil is not recommended for squamous-cell carcinoma, and high recurrence rates (21·4%) reported at 10-year follow-up suggest that this treatment is not appropriate for nodular basal-cell carcinoma.134

Imiquimod is a synthetic immune response modifier belonging to the imidazoquinolone family. It acts by stimulating toll-like receptor 7, which is expressed on dendritic cells and monocytes, leading to increased production of cytokines and chemokines, which in turn promote both T-helper-1 innate and adaptive cell-mediated immune responses.135 Topical 5% imiquimod cream is an emerging non-invasive therapeutic option for superficial and nodular basal-cell carcinoma. A 69—100% response rate for superficial basal-cell carcinoma, and 42—76% for nodular disease, has been reported for once daily, five times per week treatment for 6 weeks with topical 5% imiquimod cream.136, 137 Similar response rates have been shown in two 5-year follow-up studies138, 139 investigating imiquimod treatment of superficial basal-cell carcinoma, suggesting that clinical assessment of the initial response is predictive of outcome in the long term. Long-term follow-up studies for imiquimod treatment of nodular basal-cell carcinoma are scarce, but results from a phase 3 clinical trial suggest that imiquimod applied three times per week for 8—12 weeks has only slight activity against small nodular lesions. This finding could be confirmed by histopathological analyses of treatment sites, which showed presence of residual tumour in more than a third of treated patients.140 Local skin reactions including erythema, oedema, pruritus, erosion, ulceration, dyspigmentation, and scabbing are common side-effects.

Photodynamic therapy refers to activation of a topically applied or systemically delivered photosensitiser in neoplastic or dysplastic tissue, by light of appropriate wavelength and in the presence of oxygen. This process leads to the production of reactive oxygen species, especially singlet oxygen, which modify cellular functions or result in cell death by necrosis or apoptosis, thus promoting tumour destruction.141 Topical methyl aminolevulinate and 5-aminolevulinic acid photodynamic therapy are effective treatments for superficial basal-cell carcinoma.142 Results of a study directly comparing these two photosensitisers in treatment of nodular basal-cell carcinoma showed no difference in efficacy.143 Further research has shown that photodynamic therapy could be an effective treatment for nodular basal-cell carcinoma, and that previous debulking of the tumour with curettage and routine double photodynamic therapy or fractionation of light can improve clearance rates.142, 144, 145

Results of a 5-year follow-up study comparing surgical excision with methyl aminolevulinate photodynamic therapy show a significantly higher lesional recurrence rate (4% vs 14%) but a much better cosmetic outcome for photodynamic therapy than for surgical excision.146 Other investigators have also shown surgical excision to be more effective than is fractionated illuminated 5-aminolevulinic acid photodynamic therapy for treatment of nodular basal-cell carcinoma, with a 3-year recurrence rate much higher in the photodynamic therapy group (30·3%) than in the surgical excision group (2·3%).147 For patients with superficial basal-cell carcinoma, methyl aminolevulinate photodynamic therapy has a similar response to that of cryosurgery at 3-month and 5-year follow-up. Cosmetic outcome was best for photodynamic therapy.148

Since data are scarce for the efficacy of topical photodynamic therapy in primary cutaneous invasive squamous-cell carcinoma, topical therapy cannot be recommended for this subtype of non-melanoma skin cancer.142 The main side-effects are burning or stinging pain during light exposure, post-treatment erythema, oedema, and temporary postinflammatory hypopigmentation or hyperpigmentation. In addition to topical therapy, systemic photodynamic therapy with intravenous porfimer has been tested as treatment for basal-cell carcinoma. Cure rates of 50—100% have been reported, which might be most appropriate for individuals presenting with several basal-cell carcinomas or naevoid basal-cell carcinoma syndrome.149, 150

Perilesional and intralesional interferon alfa-2b treatment of basal-cell carcinoma has been associated with high cure rates (approaching 98% at 12 years) and good cosmetic outcomes. However, the main limiting factors of this treatment are many treatment sessions, necessitating frequent office visits, and high treatment costs.151
Non-invasive treatment options for non-melanoma skin cancer are increasingly being explored. Safety and efficacy of several treatments are under investigation. Solasodine glycosides are naturally occurring glycoalkaloids found in plants of the nightshade family—eg, aubergine. In a cream formulation, 0·005% solasodine glycosides (containing mainly solasonine and solamargine) are effective in treatment of basal-cell carcinoma.152 A novel iron-chelating agent, CP94 (1,2-diethyl-3-hydroxypyridin-4-one hydrochloride), added to topical 5-aminolevulinic acid temporarily increases accumulation of photosensitiser in the tumour and achieves significantly greater clearance rates in nodular basal-cell carcinoma than does 5-aminolevulinic acid photodynamic therapy alone.153

Other investigational agents for treatment of actinic keratoses and basal-cell carcinoma are tazarotene, cidofovir, ingenol mebutate, cyclopamin, calcium dobesilate, and histone deacetylase inhibitors such as valproic acid, vorinostat, and GDC-0449 (figure 5, panel 2). Further studies are needed to ascertain the efficacy and adverse-effect profiles of these treatments. Capecitabine, an oral selective fluorouracil precursor, is metabolised to fluorouracil within tumour cells, providing the advantage of being selectively uptaken at the tumour site with subsequent sustained exposure of the tumour cells to fluorouracil. Reports of inflammation of actinic keratoses during capecitabine treatment suggest that this drug could have a role in treatment of actinic keratoses and other non-melanoma skin cancers.155

Pathogenesis-oriented therapeutic approaches for non-melanoma skin cancer
COX=cyclo-oxygenase. AP1=activator protein 1. ROS=reactive oxygen species. Reproduced from reference 154 with permission of Blackwell Publishing.

Our understanding of the pathogenesis of non-melanoma skin cancers—and especially basal-cell carcinoma—has improved substantially in recent decades. Improvement has been associated with development of newer non-invasive treatments, such as photodynamic therapy and topical imiquimod, which have become established in the treatment of some basal-cell carcinomas and premalignant skin lesions. For most non-melanoma skin cancers, however, conventional surgical and destructive treatments remain the first-choice treatment strategies. Coupled with adequate sun-avoidance advice, behavioural modification, and sun-protection education, new non-invasive treatment approaches are a welcome addition to the management of the most common human cancers.

Search strategy and selection criteria

We searched PubMed, Medline, Embase, and the Cochrane Library (from January, 1985, to March, 2009) using the terms “non melanoma skin cancer melanoma”, “basal cell carcinoma”, and “squamous cell carcinoma”, with relevant subheadings. Reference lists of identified reports were searched for additional relevant articles. Several review articles providing comprehensive overviews of topics outside the scope of this Seminar were included as references.

Contributors

All authors contributed to the search of published work and took part in writing the first draft and subsequent versions of the report.

Conflicts of interest

VM declares that he has no conflicts of interest. JTL has received honoraria for presentations and research funding from 3M Healthcare, Galderma, LEO, Novartis, Shire, Stiefel, and Almirall. R-MS has received honoraria for presentations and research funding from Almirall-Hermal, Biocam, Energist, Galderma, Intendis, Meda, Photocure, Photonamic, Waldmann Medizintechnik, and 3M Healthcare, and is a member of the advisory boards of Galderma, Peplin, and Intendis.

References

1 Diepgen TL, Mahler V. The epidemiology of skin cancer. Br J Dermatol 2002; 146 (suppl 61): 1-6. CrossRef | PubMed

2 Hoey SE, Devereux CE, Murray L, et al. Skin cancer trends in Northern Ireland and consequences for provision of dermatology services. Br J Dermatol 2007; 156: 1301-1307. CrossRef | PubMed

3 Green A. Changing patterns in incidence of nonmelanoma skin cancer. Epithelial Cell Biol 1992; 1: 47-51. PubMed

4 Glass AG, Hoover RN. The emerging epidemic of melanoma and squamous cell skin cancer. JAMA 1989; 262: 2097-2100. PubMed

5 Karagas MR, Greenberg ER. Unresolved issues in the epidemiology of basal cell and squamous cell skin cancer. In: Mukhtar H, ed. Skin cancer: mechanisms and human relevance. Boca Raton: CRC Press, 1995: 79-86.

6 American Cancer Society. Detailed guide: skin cancer—basal and squamous cell. http://www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_are_the_key_statistics_for_skin_cancer_51.asp?rnav=cri. (accessed May 1, 2009).

7 Goodwin RG, Holme SA, Roberts DL. Variations in registration of skin cancer in the United Kingdom. Clin Exp Dermatol 2004; 29: 328-330. CrossRef | PubMed

8 Cancer Research UK. CancerStats Key facts on skin cancer. How common is skin cancer?. http://info.cancerresearchuk.org/cancerstats/types/skin/#incidence. (accessed May 1, 2009).

9 Holme SA, Malinovszky K, Roberts DL. Changing trends in non-melanoma skin cancer in South Wales, 1988—98. Br J Dermatol 2000; 143: 1224-1229. CrossRef | PubMed

10 Diffey BL, Langtry JA. Skin cancer incidence and the ageing population. Br J Dermatol 2005; 153: 679-680. CrossRef | PubMed

11 Katalinic A, Kunze U, Schäfer T. Epidemiology of cutaneous melanoma and non-melanoma skin cancer in Schleswig-Holstein, Germany: incidence, clinical subtypes, tumour stages and localization (epidemiology of skin cancer). Br J Dermatol 2003; 149: 1200-1206. CrossRef | PubMed

12 de Vries E, Louwman M, Bastiaens M, de Gruijl F, Coebergh JW. Rapid and continuous increases in incidence rates of basal cell carcinoma in the southeast Netherlands since 1973. J Invest Dermatol 2004; 123: 634-638. CrossRef | PubMed

13 Staples MP, Elwood M, Burton RC, Williams JL, Marks R, Giles GG. Non-melanoma skin cancer in Australia: the 2002 national survey and trends since 1985. Med J Aust 2006; 184: 6-10. PubMed

14 Brewster DH, Bhatti LA, Inglis JH, Nairn ER, Doherty VR. Recent trends in incidence of nonmelanoma skin cancers in the East of Scotland, 1992—2003. Br J Dermatol 2007; 156: 1295-1300. CrossRef | PubMed

15 Incidence of nonmelanoma skin cancer in New Brunswick, Canada, 1992 to 2001. J Cutan Med Surg 2007; 11: 45-52. PubMed

16 Neale RE, Davis M, Pandeya N, Whiteman DC, Green AC. Basal cell carcinoma on the trunk is associated with excessive sun exposure. J Am Acad Dermatol 2007; 56: 380-386. CrossRef | PubMed

17 English DR, Armstrong BK, Kricker A, Fleming C. Sunlight and cancer. Cancer Causes Control 1997; 8: 271-283. CrossRef | PubMed

18 Scotto J, Fears TR, Fraumeni JF. Incidence of non-melanoma skin cancer in the United States. NIH Pub No 82-2433. Bethesda: US Department of Health and Human Services, 1983.

19 Lim HW, Cooper K. The health impact of solar radiation and prevention strategies: report of the Environment Council, American Academy of Dermatology. J Am Acad Dermatol 1999; 41: 81-99. CrossRef | PubMed

20 Kricker A, Armstrong BK, English DR, Heenan PJ. A dose-response curve for sun exposure and basal cell carcinoma. Int J Cancer 1995; 60: 482-488. CrossRef | PubMed

21 Kricker A, Armstrong BK, English DR, Heenan PJ. Does intermittent sun exposure cause basal cell carcinoma? A case-control study in Western Australia. Int J Cancer 1995; 60: 489-494. CrossRef | PubMed

22 Rosso S, Zanetti R, Martinez C, et al. The multicentre south European study “Helios” II: different sun exposure patterns in the aetiology of basal cell and squamous cell carcinomas of the skin. Br J Cancer 1996; 73: 1447-1454. PubMed

23 Bastiaens MT, Hoefnagel JJ, Bruijn JA, Westendorp RG, Vermeer BJ, Bavinck JN Bouwes. Differences in age, site distribution, and sex between nodular and superficial basal cell carcinoma indicate different types of tumors. J Invest Dermatol 1998; 110: 880-884. CrossRef | PubMed

24 Yu M, Zloty D, Cowan B, et al. Superficial, nodular, and morpheiform basal-cell carcinomas exhibit distinct gene expression profiles. J Invest Dermatol 2008; 128: 1797-1805. CrossRef | PubMed

25 Rünger TM. How different wavelengths of the ultraviolet spectrum contribute to skin carcinogenesis: the role of cellular damage responses. J Invest Dermatol 2007; 127: 2103-2105. CrossRef | PubMed

26 Ridley AJ, Whiteside JR, McMillan TJ, Allinson SL. Cellular and sub-cellular responses to UVA in relation to carcinogenesis. Int J Radiat Biol 2009; 85: 177-195. CrossRef | PubMed

27 Lear JT, Smith AG, Strange RC, Fryer AA. Detoxifying enzyme genotypes and susceptibility to cutaneous malignancy. Br J Dermatol 2000; 142: 8-15. CrossRef | PubMed

28 Harwood CA, Surentheran T, McGregor JM, et al. Human papillomavirus infection and non-melanoma skin cancer in immunosuppressed and immunocompetent individuals. J Med Virol 2000; 61: 289-297. CrossRef | PubMed

29 Asgari MM, Kiviat NB, Critchlow CW, et al. Detection of human papillomavirus DNA in cutaneous squamous cell carcinoma among immunocompetent individuals. J Invest Dermatol 2008; 128: 1409-1417. CrossRef | PubMed

30 Shamanin V, zur Hausen H, Lavergne D. Human papillomavirus infections in non melanoma skin cancers from renal transplant recipients and non immunosuppressed patients. J Natl Cancer Inst 1996; 88: 802-811. CrossRef | PubMed

31 Karagas MR, Nelson HH, Sehr P, et al. Human papillomavirus infection and incidence of squamous cell and basal cell carcinomas of the skin. J Natl Cancer Inst 2006; 98: 389-395. PubMed

32 Bavinck JN Bouwes, Plasmeijer EI, Feltkamp MC. Beta-papillomavirus infection and skin cancer. J Invest Dermatol 2008; 128: 1355-1358. CrossRef | PubMed

33 Weinstock MA, Coulter S, Bates J, et al. Human papillomavirus and widespread cutaneous carcinoma after PUVA photochemotherapy. Arch Dermatol 1995; 131: 701-704. PubMed

34 Lindelof B, Sigurgeirsson B, Gabel H, et al. Incidence of skin cancer in 5356 patients following organ transplantation. Br J Dermatol 2000; 143: 513-519. CrossRef | PubMed

35 Moloney FJ, Comber H, Conlon PJ, et al. The role of immunosuppression in the pathogenesis of basal cell carcinoma. Br J Dermatol 2006; 154: 790-791. CrossRef | PubMed

36 Moloney FJ, Comber H, O’Lorcain P, et al. A population-based study of skin cancer incidence and prevalence in renal transplant recipients. Br J Dermatol 2006; 154: 498-504. CrossRef | PubMed

37 Ho WL, Murphy GM. Update on the pathogenesis of post-transplant skin cancer in renal transplant recipients. Br J Dermatol 2008; 158: 217-224. PubMed

38 Wilkins K, Turner R, Dolev JC, et al. Cutaneous malignancy and human immunodeficiency virus disease. J Am Acad Dermatol 2006; 54: 189-206. CrossRef | PubMed

39 Otley CC. Non-Hodgkin lymphoma and skin cancer: a dangerous combination. Australas J Dermatol 2006; 47: 231-236. CrossRef | PubMed

40 Stern RS, Liebman EJ, Väkevä L. Oral psoralen and ultraviolet-A light (PUVA) treatment of psoriasis and persistent risk of nonmelanoma skin cancer. PUVA Follow-up Study. J Natl Cancer Inst 1998; 90: 1278-1284. PubMed

41 Lindelöf B, Sigurgeirsson B, Tegner E, et al. PUVA and cancer: a large-scale epidemiological study. Lancet 1991; 338: 91-93. Summary | CrossRef | PubMed

42 Karagas MR, Stukel TA, Umland V, et al. Reported use of photosensitizing medications and basal cell and squamous cell carcinoma of the skin: results of a population-based case-control study. J Invest Dermatol 2007; 127: 2901-2903. PubMed

43 Man I, Crombie IK, Dawe RS, Ibbotson SH, Ferguson J. The photocarcinogenic risk of narrowband UVB (TL-01) phototherapy: early follow-up data. Br J Dermatol 2005; 152: 755-757. CrossRef | PubMed

44 Lichter MD, Karagas MR, Mott LA, et al. Therapeutic ionizing radiation and the incidence of basal cell carcinoma and squamous cell carcinoma. The New Hampshire Skin Cancer Study Group. Arch Dermatol 2000; 136: 1007-1011. CrossRef | PubMed

45 Gawkrodger DJ. Occupational skin cancers. Occup Med (Lond) 2004; 54: 458-463. CrossRef | PubMed

46 Marehbian J, Colt JS, Baris D, et al. Occupation and keratinocyte cancer risk: a population-based case-control study. Cancer Causes Control 2007; 18: 895-908. PubMed

47 Kennedy C, Bajdik CD, Willemze R, Bavinck JN Bouwes. Chemical exposures other than arsenic are probably not important risk factors for squamous cell carcinoma, basal cell carcinoma and malignant melanoma of the skin. Br J Dermatol 2005; 152: 194-197. CrossRef | PubMed

48 Odenbro A, Bellocco R, Boffetta P, Lindelöf B, Adami J. Tobacco smoking, snuff dipping and the risk of cutaneous squamous cell carcinoma: a nationwide cohort study in Sweden. Br J Cancer 2005; 92: 1326-1328. CrossRef | PubMed

49 Hahn H, Wicking C, Zaphiropoulous PG, et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 1996; 85: 841-851. CrossRef | PubMed

50 Lear JT, Hoban P, Strange RC, Fryer AA. Basal cell carcinoma: from host response and polymorphic variants to tumour suppressor genes. Clin Exp Dermatol 2005; 30: 49-55. CrossRef | PubMed

51 Marigo V, Davey RA, Zuo Y, et al. Biochemical evidence that patched is the Hedgehog receptor. Nature 1996; 384: 176-179. CrossRef | PubMed

52 Soufir N, Gerard B, Portela M, et al. PTCH mutations and deletions in patients with typical nevoid basal cell carcinoma syndrome and in patients with a suspected genetic predisposition to basal cell carcinoma: a French study. Br J Cancer 2006; 95: 548-553. CrossRef | PubMed

53 Reifenberger J, Wolter M, Knobbe CB, et al. Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas. Br J Dermatol 2005; 152: 43-51. CrossRef | PubMed

54 Brellier F, Valin A, Chevallier-Lagente O, et al. Ultraviolet responses of Gorlin syndrome primary skin cells. Br J Dermatol 2008; 159: 445-452. CrossRef | PubMed

55 Danaee H, Karagas MR, Kelsey KT, et al. Allelic loss at Drosophila patched gene is highly prevalent in basal and squamous cell carcinomas of the skin. J Invest Dermatol 2006; 126: 1152-1158. CrossRef | PubMed

56 Bastiaens MT, ter Huurne JA, Kielich C, et al. Melanocortin-1 receptor gene variants determine the risk of nonmelanoma skin cancer independently of fair skin and red hair. Am J Hum Genet 2001; 68: 884-894. CrossRef | PubMed

57 Gudbjartsson DF, Sulem P, Stacey SN, et al. ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma. Nat Genet 2008; 40: 886-891. CrossRef | PubMed

58 Kuerbitz SJ, Plunkett BS, Walsh WV, Kastan MB. Wild-type p5 is a cell cycle checkpoint determinant following irradiation. Proc Natl Acad Sci USA 1992; 89: 7491-7495. CrossRef | PubMed

59 Benjamin CL, Ananthaswamy HN. p53 and the pathogenesis of skin cancer. Toxicol Appl Pharmacol 2007; 224: 241-248. CrossRef | PubMed

60 Otto AI, Riou L, Marionnet C, et al. Differential behaviors toward UVA and B radiation of fibroblasts and keratinocytes from normal and DNA repair deficient patients. Cancer Res 1999; 59: 1212-1218. PubMed

61 Sands AT, Abuin A, Sanchez A, Conti CJ, Bradley A. High susceptibility to ultraviolet-induced carcinogenesis in mice lacking XPC. Nature 1995; 377: 162-165. CrossRef | PubMed

62 Brash DE. Roles of the transcription factor p53 in keratinocyte carcinomas. Br J Dermatol 2006; 154 (suppl 1): 8-10. CrossRef | PubMed

63 Demirkan NC, Colakoglu N, Duzcan E. Value of p53 protein in biological behavior of basal cell carcinoma and in normal epithelia adjacent to carcinomas. Pathol Oncol Res 2000; 6: 272-274. PubMed

64 Soufir N, Ribojad M, Magnaldo T, et al. Germline and somatic mutations of the INK4a-ARF gene in a xeroderma pigmentosum group C patient. J Invest Dermatol 2002; 119: 1355-1360. CrossRef | PubMed

65 Pacifico A, Goldberg LH, Peris K, et al. Loss of CDKN2A and p14ARF expression occurs frequently in human nonmelanoma skin cancers. Br J Dermatol 2008; 158: 291-297. PubMed

66 Lear JT, Heagerty AHM, Smith A, et al. Multiple cutaneous basal cell carcinomas: Glutathione S-transferase (GSTM1, GSTT1) and cytochrome P450 (CYP2D6, CYP1A1) polymorphisms influence tumour numbers and accrual. Carcinogenesis 1996; 17: 1891-1896. CrossRef | PubMed

67 Lear JT, Smith AG, Strange RC, Fryer AA. Detoxifying enzyme genotypes and susceptibility to cutaneous malignancy. Br J Dermatol 2000; 142: 8-15. CrossRef | PubMed

68 Ramachandran S, Fryer AA, Smith AG, et al. Basal cell carcinomas: association of allelic variants with a high-risk subgroup of patients with the multiple presentation phenotype. Pharmacogenetics 2001; 11: 247-254. CrossRef | PubMed

69 Shay PJW, Wright WE. The reactivation of telomerase activity in cancer progression. Trends Genet 1996; 12: 129-131. CrossRef | PubMed

70 Saleh S, Lam A King-Yin, Gertraud BP, et al. Telomerase activity of basal cell carcinoma in patients living in North Queensland, Australia. Hum Pathol 2007; 38: 1023-1029. PubMed

71 Boldrini L, Loggini B, Gisfredi S, et al. Evaluation of telomerase in non-melanoma skin cancer. Int J Mol Med 2003; 11: 607-611. PubMed

72 McCormack CJ, Kelly JW, Dorevitch AP. Differences in age and body site distribution of the histological subtypes of basal cell carcinoma: a possible indicator of differing causes. Arch Dermatol 1997; 133: 593-596. PubMed

73 Sexton M, Jones DB, Maloney ME. Histologic pattern analysis of basal cell carcinoma. Study of a series of 1039 consecutive neoplasms. J Am Acad Dermatol 1990; 23: 1118-1126. CrossRef | PubMed

74 Rippey JJ. Why classify basal cell carcinomas?. Histopathology 1998; 32: 393-398. CrossRef | PubMed

75 Wong CS, Strange RC, Lear JT. Basal cell carcinoma. BMJ 2003; 327: 794-798. PubMed

76 Newman JC, Leffell DJ. Correlation of embryonic fusion planes with the anatomical distribution of basal cell carcinoma. Dermatol Surg 2007; 33: 957-964. CrossRef | PubMed

77 Wentzell JM, Wisco OJ. Embryologic fusion planes: a plea for more precise analysis. Dermatol Surg 2008; 34: 851-853. CrossRef | PubMed

78 Ramachandran S, Fryer A, Smith A, Lear J, et al. Cutaneous basal cell carcinomas. Cancer 2001; 92: 354-358. PubMed

79 Röwert-Huber J, Patel MJ, Forschner T, et al. Actinic keratosis is an early in situ squamous cell carcinoma: a proposal for reclassification. Br J Dermatol 2007; 156: 8-12. CrossRef | PubMed

80 Marks R, Rennie G, Selwood TS. Malignant transformation of solar keratosis to squamous cell carcinoma. Lancet 1998; 331: 795-797. Summary | CrossRef | PubMed

81 Glogau RG. The risk of progression to invasive disease. J Am Acad Dermatol 2000; 42 (1 Pt 2): 23-24. CrossRef | PubMed

82 Salasche SJ. Epidemiology of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol 2000; 42: 4-7. PubMed

83 Cox NH, Eedy DJ, Morton CATherapy Guidelines and Audit Subcommittee, British Association of Dermatologists. Guidelines for management of Bowen’s disease: 2006 update. Br J Dermatol 2007; 156: 11-21. CrossRef | PubMed

84 Beham A, Regauer S, Soyer HP, Beham-Schmid C. Keratoacanthoma: a clinically distinct variant of well differentiated squamous cell carcinoma. Adv Anat Pathol 1998; 5: 269. PubMed

85 Slater DN, McKee PH. In: Minimum dataset for the histopathological reporting of common skin cancers. London: The Royal College of Pathologists, 2002: 1-23.

86 Motley R, Kersey P, Lawrence CBritish Association of Dermatologists; British Association of Plastic Surgeons. Multiprofessional guidelines for the management of the patient with primary cutaneous squamous cell carcinoma. Br J Plast Surg 2003; 56: 85-91. CrossRef | PubMed

87 Ulrich M, Stockfleth E, Roewert-Huber J, Astner S. Noninvasive diagnostic tools for nonmelanoma skin cancer. Br J Dermatol 2007; 157 (suppl 2): 56-58. PubMed

88 Galletly NP, McGinty J, Dunsby C, et al. Fluorescence lifetime imaging distinguishes basal cell carcinoma from surrounding uninvolved skin. Br J Dermatol 2008; 159: 152-161. CrossRef | PubMed

89 Veness MJ. Defining patients with high-risk cutaneous squamous cell carcinoma. Australas J Dermatol 2006; 47: 28-33. CrossRef | PubMed

90 Cherpelis BS, Marcusen C, Lang PG. Prognostic factors for metastasis in squamous cell carcinoma of the skin. Dermatol Surg 2002; 28: 268-273. CrossRef | PubMed

91 Brantsch KD, Meisner C, Schönfisch B, et al. Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study. Lancet Oncol 2008; 9: 713-720. Summary | Full Text | PDF(148KB) | CrossRef | PubMed

92 Drake LA, Ceilley RI, Cornelison RL, et al. Guidelines for cutaneous squamous cell carcinoma. J Am Acad Dermatol 1993; 28: 289-292. CrossRef | PubMed

93 McCord MW, Mendenhall WM, Parsons JT, et al. Skin cancer of the head and neck with clinical perineural invasion. Int J Radiat Oncol Biol Phys 2000; 47: 89-93. CrossRef | PubMed

94 Han A, Ratner D. What is the role of adjuvant radiotherapy in the treatment of cutaneous squamous cell carcinoma with perineural invasion?. Cancer 2007; 109: 1053-1059. PubMed

95 Chen J, Ruczinski I, Jorgensen TJ. Nonmelanoma skin cancer and risk for subsequent malignancy. J Natl Cancer Inst 2008; 100: 1215-1222. CrossRef | PubMed

96 Dinehart SM, Peterson S. Evaluation of the American Joint Committee on Cancer staging system for cutaneous squamous cell carcinoma and proposal of a new staging system. Dermatol Surg 2005; 31: 1379-1384. PubMed

97 Veness MJ. Time to rethink TNM staging in cutaneous SCC. Lancet Oncol 2008; 9: 702-703. Full Text | PDF(41KB) | CrossRef | PubMed

98 Telfer NR, Colver GB, Morton CABritish Association of Dermatologists. Guidelines for the management of basal cell carcinoma. Br J Dermatol 2008; 159: 35-48. CrossRef | PubMed

99 Bath-Hextall FJ, Perkins W, Bong J, Williams HC. Interventions for basal cell carcinoma of the skin. Cochrane Database Syst Rev 2007; 24. CD003412. PubMed

100 Bath-Hextall F, Leonardi-Bee J, Somchand N, Webster A, Delitt J, Perkins W. Interventions for preventing non-melanoma skin cancers in high-risk groups. Cochrane Database Syst Rev 2007; 4. CD005414. PubMed

101 Green A, Williams G, Neale R, et al. Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomised controlled trial. Lancet 1999; 354: 723-729. Summary | Full Text | PDF(90KB) | CrossRef | PubMed

102 Cancer Research UK. About SunSmart. http://info.cancerresearchuk.org/healthyliving/sunsmart/about-sunsmart/?a=5441. (accessed May 1, 2009).

103 WHO. Ultraviolet radiation and the INTERSUN Programme. Sun protection: simple precautions in the sun. http://www.who.int/uv/sun_protection/en/. (accessed May 1, 2009).

104 National Collaborating Centre for Cancer. Improving outcomes for people with skin tumours including melanoma. London: National Institute for Health and Clinical Excellence, 2006. http://www.nice.org.uk/nicemedia/pdf/CSG_Skin_Manual.pdf. (accessed May 1, 2009).

105 Wolf DJ, Zitelli JA. Surgical margins for basal cell carcinoma. Arch Dermatol 1987; 123: 340-404. PubMed

106 Walker P, Hill D. Surgical treatment of basal cell carcinomas using standard postoperative histological assessment. Australas J Dermatol 2006; 47: 1-12. CrossRef | PubMed

107 Griffiths RW, Suvarna SK, Stone J. Do basal cell carcinomas recur after complete conventional surgical excision?. Br J Plast Surg 2005; 58: 795-805. CrossRef | PubMed

108 Rowe DE, Carroll RJ, Day CL. Mohs surgery is the treatment of choice for recurrent (previously treated) basal cell carcinoma. J Dermatol Surg Oncol 1989; 15: 424-431. PubMed

109 Sterry WEuropean Dermatology Forum Guideline Committee. Guidelines: the management of basal cell carcinoma. Eur J Dermatol 2006; 16: 467-475. PubMed

110 Leibovitch I, Huilgol SC, Selva D, et al. Basal cell carcinoma treated with Mohs surgery in Australia II. Outcome at 5-year follow-up. J Am Acad Dermatol 2005; 53: 452-457. CrossRef | PubMed

111 Rowe DE, Carroll RJ, Day CL. Prognostic factors for local recurrence, metastasis and survival rates in squamous cell carcinoma of the skin, ear and lip. J Am Acad Dermatol 1992; 26: 976-990. CrossRef | PubMed

112 Chren MM, Sahay AP, Bertenthal DS, Sen S, Landefeld CS. Quality-of-life outcomes of treatments for cutaneous basal cell carcinoma and squamous cell carcinoma. J Invest Dermatol 2007; 127: 1351-1357. CrossRef | PubMed

113 Mosterd K, Krekels GAM, Nieman FHM, et al. Surgical excision versus Mohs’ micrographic surgery for primary and recurrent basal-cell carcinoma of the face: a prospective randomised controlled trial with 5-years’ follow-up. Lancet Oncol 2008; 9: 1149-1156. Summary | Full Text | PDF(197KB) | CrossRef | PubMed

114 Motley RJ, Gould DJ, Douglas WS, Simpson NB. Treatment of basal cell carcinoma by dermatologists in the United Kingdom. British Association of Dermatologists Audit Subcommittee and the British Society for Dermatological Surgery. Br J Dermatol 1995; 132: 437-440. CrossRef | PubMed

115 Rowe DE, Carroll RJ, Day CL, et al. Long-term recurrence rates in previously untreated (primary) basal cell carcinoma: implications for patient follow-up. J Dermatol Surg Oncol 1989; 15: 315-328. PubMed

116 Rodriguez-Vigil T, Vázquez-López F, Perez-Oliva N. Recurrence rates of primary basal cell carcinoma in facial risk areas treated with curettage and electrodesiccation. J Am Acad Dermatol 2007; 56: 91-95. CrossRef | PubMed

117 Mallon E, Dawber R. Cryosurgery in the treatment of basal cell carcinoma. Assessment of one and two freeze-thaw cycle schedules. Dermatol Surg 1996; 22: 854-858. CrossRef | PubMed

118 Thissen M, Nieman F, Ideler A, Berretty P, Neumann H. Cosmetic results of cryosurgery versus surgical excision for primary uncomplicated basal cell carcinomas of the head and neck. Dermatol Surg 2000; 26: 759-764. CrossRef | PubMed

119 Hall V, Leppard B, McGill J, et al. Treatment of basal-cell carcinoma: comparison of radiotherapy and cryotherapy. Clin Radiol 1986; 37: 33-34. CrossRef | PubMed

120 Humphreys TR, Malhotra R, Scharf MJ, et al. Treatment of superficial basal cell carcinoma and squamous cell carcinoma in situ with a high-energy pulsed carbon dioxide laser. Arch Dermatol 1998; 134: 1247-1252. CrossRef | PubMed

121 Campolmi P, Brazzini B, Urso C, et al. Superpulsed CO2 laser treatment of basal cell carcinoma with intraoperatory histopathologic and cytologic examination. Dermatol Surg 2002; 28: 909-911. CrossRef | PubMed

122 Campolmi P, Troiano M, Bonan P, Cannarozzo G, Lotti T. Vascular based non-conventional dye laser treatment for basal cell carcinoma. Dermatol Ther 2008; 21: 402-405. CrossRef | PubMed

123 Childers BJ, Goldwyn RM, Ramos D, et al. Long-term results of irradiation for basal cell carcinoma of the skin of the nose. Plast Reconstr Surg 1994; 93: 1169-1173. PubMed

124 Caccialanza M, Piccinno R, Grammatica A. Radiotherapy of recurrent basal and squamous cell skin carcinomas: a study of 249 re-treated carcinomas in 229 patients. Eur J Dermatol 2001; 11: 25-28. PubMed

125 Veness MJ. The important role of radiotherapy in patients with non-melanoma skin cancer and other cutaneous entities. J Med Imaging Radiat Oncol 2008; 52: 278-286. PubMed

126 Avril M, Auperin A, Margulis A, et al. Basal cell carcinoma of the face: surgery or radiotherapy? Results of a randomized study. Br J Cancer 1997; 76: 100-106. PubMed

127 Petit J, Avril M, Margulis A, et al. Evaluation of cosmetic results of a randomised trial comparing surgery and radiotherapy in the treatment of basal cell carcinoma of the face. Plast Reconstr Surg 2000; 105: 2544-2551. CrossRef | PubMed

128 Veness MJ, Morgan GJ, Palme CE, Gebski V. Surgery and adjuvant radiotherapy in patients with cutaneous head and neck squamous cell carcinoma metastatic to lymph nodes: combined treatment should be considered best practice. Laryngoscope 2005; 115: 870-875. CrossRef | PubMed

129 Sedda AF, Rossi G, Cipriani C, Carrozzo AM, Donati P. Dermatological high-dose-rate brachytherapy for the treatment of basal and squamous cell carcinoma. Clin Exp Dermatol 2008; 33: 745-749. CrossRef | PubMed

130 Landthaler M, Hagspiel HJ, Braun-Falco O. Late irradiation damage to the skin caused by soft X-ray radiation therapy of cutaneous tumors. Arch Dermatol 1995; 131: 182-186. PubMed

131 Kleinerman RA. Radiation-sensitive genetically susceptible pediatric sub-populations. Pediatr Radiol 2009; 39: S27-S31. PubMed

132 Sloan KB, Sherertz EF, McTiernan RG. The effect of 5-fluorouracil on inhibition of epidermal DNA synthesis in vivo: a comparison of the effect of formulations and a prodrug of 5-FU. Arch Dermatol Res 1990; 282: 484-486. CrossRef | PubMed

133 Gross K, Kircik L, Kricorian G. 5% 5-Fluorouracil cream for the treatment of small superficial basal cell carcinoma: efficacy, tolerability, cosmetic outcome, and patient satisfaction. Dermatol Surg 2007; 33: 433-439. CrossRef | PubMed

134 Reymann F. Treatment of basal cell carcinoma of the skin with 5-fluorouracil ointment. A 10-year follow-up study. Dermatologica 1979; 158: 368-372. PubMed

135 Dummer R, Urosevic M, Kempf W, et al. Imiquimod in basal cell carcinoma: how does it work?. Br J Dermatol 2003; 149 (suppl 66): 57-58. CrossRef | PubMed

136 Geisse J, Caro I, Lindholm J, Golitz L, Stampone P, Owens M. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two phase III, randomized, vehicle-controlled studies. J Am Acad Dermatol 2004; 50: 722-733. CrossRef | PubMed

137 Huber A, Huber JD, Skinner RB, et al. Topical imiquimod treatment for nodular basal cell carcinomas: an open-label series. Dermatol Surg 2004; 30: 429-430. CrossRef | PubMed

138 Gollnick H, Barona CG, Frank RG, et al. Recurrence rate of superficial basal cell carcinoma following treatment with imiquimod 5% cream: conclusion of a 5-year long-term follow-up study in Europe. Eur J Dermatol 2008; 18: 677-682. PubMed

139 Vidal D, Matías-Guiu X, Alomar A. Fifty-five basal cell carcinomas treated with topical imiquimod: outcome at 5-year follow-up. Arch Dermatol 2007; 143: 266-268. CrossRef | PubMed

140 Eigentler TK, Kamin A, Weide BM, et al. A phase III, randomized, open label study to evaluate the safety and efficacy of imiquimod 5% cream applied thrice weekly for 8 and 12 weeks in the treatment of low-risk nodular basal cell carcinoma. J Am Acad Dermatol 2007; 57: 616-621. CrossRef | PubMed

141 Zeitouni NC, Oseroff AR, Shieh S. Photodynamic therapy for non melanoma skin cancers. Mol Immunol 2003; 39: 1133-1136. CrossRef | PubMed

142 Morton CA, McKenna KE, Rhodes LEon behalf of the British Association of Dermatologists Therapy Guidelines and Audit Subcommittee and the British Photodermatology Group. Guidelines for topical photodynamic therapy: update. Br J Dermatol 2008; 159: 1245-1266. CrossRef | PubMed

143 Kuijpers D, Thissen MR, Thissen CA, Neumann MH. Similar effectiveness of methyl aminolevulinate and 5-aminolevulinate in topical photodynamic therapy for nodular basal cell carcinoma. J Drugs Dermatol 2006; 5: 642-645. PubMed

144 de Haas ER, Kruijt B, Sterenborg HJ, et al. Fractionated illumination significantly improves the response of superficial basal cell carcinoma to aminolevulinic acid photodynamic therapy. J Invest Dermatol 2006; 126: 2679-2686. CrossRef | PubMed

145 Soler AM, Warloe T, Berner A, Giercksky KE. A follow-up study of recurrence and cosmesis in completely responding superficial and nodular basal cell carcinomas treated with methyl 5-aminolaevulinate-based photodynamic therapy alone and with prior curettage. Br J Dermatol 2001; 145: 467-471. CrossRef | PubMed

146 Rhodes LE, de Rie MA, Leifsdottir R, et al. Five-year follow-up of a randomized, prospective trial of topical methyl aminolevulinate photodynamic therapy vs surgery for nodular basal cell carcinoma. Arch Dermatol 2007; 143: 1131-1136. CrossRef | PubMed

147 Mosterd K, Thissen MR, Nelemans P, et al. Fractionated 5-aminolaevulinic acid-photodynamic therapy vs. surgical excision in the treatment of nodular basal cell carcinoma: results of a randomized controlled trial. Br J Dermatol 2008; 159: 864-870. CrossRef | PubMed

148 Basset-Seguin N, Ibbotson SH, Emtestam L, et al. Topical methyl aminolaevulinate photodynamic therapy versus cryotherapy for superficial basal cell carcinoma: a 5 year randomized trial. Eur J Dermatol 2008; 18: 547-553. PubMed

149 Wilson BD, Mang TS, Stoll H, Jones C, Cooper M, Dougherty TJ. Photodynamic therapy for the treatment of basal cell carcinoma. Arch Dermatol 1992; 28: 1597-1601. PubMed

150 Madan V, Loncaster JA, Allan D, et al. Systemic photodynamic therapy with Photofrin for naevoid basal cell carcinoma syndrome-A pilot study. Photodiagnosis Photodyn Ther 2005; 2: 273-281. PubMed

151 Tucker SB, Polasek JW, Perri AJ, Goldsmith EA. Long-term follow-up of basal cell carcinomas treated with perilesional interferon alfa 2b as monotherapy. J Am Acad Dermatol 2006; 54: 1033-1038. CrossRef | PubMed

152 Punjabi S, Cook LJ, Kersey P, Marks R, Cerio R. Solasodine glycoalkaloids: a novel topical therapy for basal cell carcinoma. A double-blind, randomized, placebo-controlled, parallel group, multicenter study. Int J Dermatol 2008; 47: 78-82. PubMed

153 Campbell SM, Morton CA, Alyahya R, et al. Clinical investigation of the novel iron-chelating agent, CP94, to enhance topical photodynamic therapy of nodular basal cell carcinoma. Br J Dermatol 2008; 159: 387-393. CrossRef | PubMed

154 Szeimies RM, Karrer S. Towards a more specific therapy: targeting non-melanoma skin cancer cells. Br J Dermatol 2006; 154 (suppl 1): 16-21. CrossRef | PubMed

155 Liu CY. Fluorouracil for allergic reactions to capecitabine. Ann Pharmacother 2002; 36: 1897-1899. PubMed

The Articles are on remote ischemic conditioning before hospital admission to increase myocardial salvage in heart attack patients, how much the use of statins increases risk of diabetes and manual closed-loop insulin delivery in children. These are accompanied by Comments on preventing heart ischemia, statins versus diabetes risk and closed loop insulin delivery.

The World Report this week is on the increased funding for medical research in China, reforming Australia’s healthcare system and investigating cancer in the Czech Republic. Also of interest to global health are Comments on sharing health research data and rare diseases in China.

This week’s editorial examines a study published Online First this week in The Lancet seeking to determine the best approach to lymphadenectomy for patients with endometrial cancer.

Patients at intermediate or high risk of recurrence of endometrial cancer who underwent both pelvic and para-aortic lymph node removal were found to have a 56% reduced risk of death

A study was carried out in Japan that sought to measure if there was any difference in terms of overall survival between performing pelvic lymphadenectomy compared with pelvic and para-aortic lympadenectomy among patients with endometrial carcinoma.

Prior studies had found that pelvic lymphadenectomy did not have any therapeutic benefit in patients with endometrial cancer. The researchers decided to compare if removing the para-aortic lymph nodes, a group of lymph nodes located in front of the lumbar vertebral bodies near the aorta, in addition to the pelvic lymph nodes, would increase the overall survival of patients.

Reports from 671 patients treated between 1986 and 2004 with endometrial cancer were included in the study. 325 of them were treated with complete, systematic pelvic lymphadenectomy and 346 had both pelvic and para-aortic lymphadenectomy. The results confirmed that pelvic lymphadenectomy is insufficient to stop lymph node metastasis.

Patients at intermediate or high risk of recurrence of endometrial cancer who underwent both pelvic and para-aortic lymph node removal were found to have 56% reduced risk of death, compared to those who only received pelvic lymphadenectomy. Furthermore, patients with intermediate or high risk of recurrence receiving adjuvant radiotherapy and chemotherapy, in addition to the pelvic and para-aortic lymphadenectomy, were found to have a reduction in their risk of death. Those receiving adjuvant radiotherapy had a 52% reduction, and similarly those who received adjuvant chemotherapy showed a 41% decrease in risk of death. Patients with low-risk of recurrence did not demonstrate any change in their overall survival as a result of the removal of the para-aortic lymph nodes, in addition to the pelvic lymphadenectomy.

Although the study demonstrated significant findings, it will be necessary to carry out a randomised control trial in order to validate the results. Furthermore, Dr Sean C Dowdy, and Dr Andrea Mariani from the Mayo Clinic point out in the subsequent Comment, that disease-specific survival is only one of the relevant factors to take into account, other factors would include morbidity, quality of life and death due to other comorbidities. Until a randomised control study of pelvic and para-aortic lymphadenectomy is effectuated can a standard of care be determined for endometrial cancer patients, which at the moment does not exist.

Click here to read this article.

Ana B. Amaya is a TLS Editor and DrPH Student at London School of Hygiene and Tropical Medicine
Email: ana.amaya@lshtm.ac.uk

References:
1.Todo Y, Kato H, Kaneuchi M, Watari H, Takeda M, Sakuragi N. Survival effect of para-aortic lymphadenectomy in endometrial cancer (SEPAL study): a retrospective cohort analysis. Lancet 2010; published online Feb 25. DOI:10.1016/S0140-6736(09)62002-X.
2.Dowdy S & Mariani A. Comment: Lymphadenectomy in endometrial cancer: when, not if. Lancet 2010; Published Online February 25, 2010 DOI:10.1016/S0140- 6736(09)62068-7

Today we’d like to announce the publication of Savino Sciascia’s interview with Enrico Heffler national coordinator of Junior Members of Italian Society of Allergology and Clinical Immunology, on the global asthma epidemic. Read it here.

Meanwhile, in today’s blog, Catherine Carver, fourth year medical student at University of Aberdeen, describes an exhibition about Identity going on now at the Wellcome Trust in London.

To my mind, the real strength of Identity is that it allows you to gain not only knowledge, but understanding

“We all have a working idea of self; we know ‘who we are’ or we think we do.”
Identity, The Wellcome Collection, London(1)

So opens Identity, the latest exhibition from the Wellcome Collection. Free to the incurably curious, the Wellcome Collection provides a fantastic array of delights for the medically inclined. It contains two permanent exhibitions and a third which changes regularly, with “Identity” being its current incarnation.

Why write a global health blog on an exhibition dedicated to individual identity? Because individuals are why global health matters. The millions of mortalities caused by diseases such as malaria and measles are shocking because every single one represents a unique loss to the world. Moreover, identity is involved in every disease which affects people. It influences the diseases you are likely to get, how you cope with them, which treatments are available to you, which treatments are acceptable to you. As medics we take family histories because they may reveal a person’s genetic identity, we take travel and sexual histories to reveal their behavioural identity.

Feeling curious? Let’s step inside…

Identity comprises eight distinct rooms, each beginning with the story of someone who represents a way of thinking about identity. The first introduces us to Samuel Pepys (1633-1703), who kept a diary covering events such as The Great Fire of London and the plague. This room reflects on the diary as a “uniquely candid but still often carefully considered”(1) presentation of the self.

From personal identity to public identity, we move on to Claude Cahun, an artist who took on an increasingly masculine exterior, changing her name from Lucie to Claude. Cahun plays with her external identity through a series of self-portraits. The room of actress Fiona Shaw furthers explores manipulation of the external identity by highlighting the skills actors use to convince us of their chosen identity.

Next we meet April Ashley, one of the first people in Britain to undergo a full sex change operation. This room illustrates the complex nature of gender identity, and society’s changing attitude to it, as exemplified by the Gender Recognition Act 2004. We also see that April’s identity is far more than her gender- she has led a colourful life modelling for Vogue and meeting Elvis, Dali and Picasso.

The remaining rooms look at how science has tried to quantify identity. Franz Joseph Gall’s room discusses his theory of phrenology. Popular in the 19th century, phrenology suggested that an individual’s moral, psychological and intellectual traits could be determined from their skull shape. While Gall’s theory has been discredited, the room of fingerprint advocate Sir Francis Galton shows that some objective measurements can almost uniquely identify us. Even more current is the room of Alec Jeffreys, the scientist credited with the technique of DNA fingerprinting. This room reviews the concept of genetic identity, which could be seen as one of the most abstract definitions in Identity. Yet the final room reminds us of the human side of genetics by showing us family photos of three generations of twins in the Hinch family and discussing how different the genetically identical can be.

To my mind, the real strength of Identity is that it allows you to gain not only knowledge, but understanding. The knowledge comes from the wealth of colourful facts on offer. For instance, the Alec Jeffreys room tells us that DNA fingerprinting was used to identify the body of Nazi Doctor Josef Mengele, who had evaded capture and died in Brazil. But the room goes beyond imparting facts; it’s smarter than that, stimulating you to question the concept of identity. Jeffreys suggests our genome can reveal much about our identity, perhaps even our surname. However, the inclusion of a display of Jeffreys personal items makes you question the importance of DNA to identity. He chose a track by The Killers for BBC Radio 4’s Desert Island Discs programme. He still owns his dad’s microscope. Could his DNA ever help us understand his identity as well as these personal insights?

Your answer probably depends on your identity. This is looked at briefly by the exhibition, with several mirrors set in the warehouse to encourage self-reflection. There is also a computer which lets you see where in the world your name is most common. For instance I found that my maiden name seems to appear mainly in the north west of England, which is where my dad is from. This was really interesting and it would have been good if self-identity had been expanded because I was left wanting more.

If your identity involves being incurably curious and you find yourself in London before April 6th, I recommend a trip to the Wellcome Collection. If you can’t get to London, have a look at this http://www.wellcomecollection.org/whats-on/the-identity-project.aspx

References
(1) Identity Exhibition, Wellcome Collection, London.

Enrico, which is the current prevalence of asthma and which is the predictable trend of it for the next decades?

Asthma is one of the most common chronic diseases in the world: its global prevalence is estimated about 1-18% of the population, depending on the considered country. Around 300 million people in the world currently have asthma and probably there is still a large proportion of asthmatic patients, particularly in low income countries, who are not included in this estimate because they are not properly diagnosed.

In the last decades, the worldwide prevalence of asthma dramatically increased both in children and adults, similar to what happened to other allergic diseases such as rhinitis or eczema, in parallel with an increase in atopic sensitisation which seems to be somehow related to western lifestyle and to urbanisation. It is estimated that in 2025 about 60% of the whole world’s population will live in urban settings and that will be probably accompanied with a further increase of about 100 million people suffering for asthma in the next 15 years.

Is there any difference in prevalence and impact of asthma in different countries?

There is now evidence that there is a progressive increase of asthma symptoms prevalence in regions where prevalence was previously low, such as Africa, South America and some regions of Asia, while the prevalence decreases in North America and Western Europe. The result of these different trends in prevalence of asthma is that, despite the fact that international differences are lessening, the global burden of asthma is continuing to rise, particularly in countries in which patients may have difficulties to access to basic asthma medication or medical care.

Hence, disadvantaged countries are now experiencing an increase of need of asthma medications and cures, but without enough resources to face this emerging clinical problem; in these countries it is particularly troublesome to correctly treat patients with more severe asthma.

As happens for several other diseases, the economic condition of a country deeply influences the way asthma is diagnosed and treated; increasing the economic wealth and improving the distribution of resources between and within countries should represent important priorities to enable better health care to be provided.

Do people still die from asthma?

Yes they do! It is estimated that asthma accounts for about 1 in every 250 deaths worldwide, with the highest rates of disease-related mortality in China and Russia (36.7 and 28.6 asthma death per 100,000 asthmatics, respectively), Uzbekistan (27.2), Albania (20.8) and South Africa (18.5).

Many of these deaths could be largely preventable improving long-term medical care, giving the opportunity to all patients to access to basic medications, promoting prevention campaigns and reducing the delay in obtaining help during the final attack.

Which is the public health impact/cost for asthma?

The economic cost of asthma is considerable both in terms of direct medical costs (such as costs of medications used to prevent and treat asthma, hospital admissions etc.) and indirect medical costs (such as time lost from work and school, and premature death). As far as costs and disease-related disability, asthma impacts on health-related costs similarly to other chronic diseases such as diabetes, liver cirrhosis or schizophrenia, leading scientific societies, health-care systems and governments to look for the right way to better prevent, diagnose and treat such an impacting disease.

How can we reduce the impact and cost of asthma?

First of all, it is fundamental that governments and health-professionals recognise asthma as an important cause of morbidity and mortality worldwide, so that they can put to use all preventative measures in order to reduce the morbidity and better control symptoms of asthma. Particularly, it is important to reduce environmental factors (such as indoor and outdoor pollution) which may affect respiratory morbidity: promoting anti-tobacco public health policies and reducing occupational exposures may be good starting points!

Since it is acknowledged worldwide that prevalence and economic/health impact of chronic diseases are more elevated where there are poverty, poor education and poor infrastructures, it is fundamental to improve accessibility to essential drugs and medical care for the management of asthma to all social classes and to low- and middle-income countries, also by adapting international asthma guidelines for developing countries to ensure they are practical and realistic in terms of different health care systems.

What is, in your opinion, the major unmet need in asthma management?

The main asthma-related problem that scientific community should find the way to solve is, in my opinion, that about 10% of the patients have a severe form of asthma, characterized by a particular resistance to typical treatment modalities, including administration of high dose of inhaled or systemic corticosteroids and high dose of bronchodilators. This severe end of the disease spectrum accounts for approximately 30% of health care costs of asthma. Thus there is a compelling need to look for new therapeutical tools for patients resistant to typical asthma medications. Different strategies, almost all of them targeting specific different phenotypes of severe asthma, have been proposed, but only few of them are currently used and suggested for severe asthmatics. Omalizumab (an anti-IgE monoclonal antibody) has been recently introduced in clinical practice and it showed to be greatly effective for the treatment of severe allergic asthmatics with high levels of serum IgE. Other therapeutical approaches that have been studied in the last decade include anti-Tumor Necrosis Factor alpha (anti-TNFα) strategies (biological agents against TNFα axis unfortunately gave contrasting results in improving severe asthma outcomes), anti-IL5 drugs (recently Mepolizumab, an anti-IL5 monoclonal antibody has been showed to be effective in reducing severe exacerbations and to improve disease-related quality of life in a particular subset of patients: those with refractory eosinophilic asthma), anti-IL2 biological agents (Daclizumab, a humanized monoclonal antibody against the IL-2R alpha chain, has been recently described to improve pulmonary function and asthma control in patients with moderate to severe chronic asthma inadequately controlled on inhaled corticosteroids), and even interventions to decrease airway smooth muscle, such as bronchial thermoplasty (a bronchoscopic procedure in which controlled thermal energy is applied to the airway wall). Unfortunately, apart from Omalizumab, none of these novel thereapeutical modalities are currently available and recommended to treat patients with severe asthma.

Thus, it is to be hoped that the scientific community focuses the attention on novel and possibly affordable treatments for those asthmatic patients who still are at-risk of severe exacerbations, hospital admissions and death

Savino Sciascia is a TLS RA and an intern at the University of Turin
sciascia.savino@gmail.com

Image credit: HSANet.org

Today’s blog by Andrey Ostrovsky, Coordinator of the HSAN Student Section and medical student at Boston University, explores the important role of students in health systems strengthening around the world

All I see around me are experts that have been researching health systems as a career, but the HSS movement is lacking the creativity and enthusiasm of students

With only a year of clinical experience under my belt, I’m already frustrated with treating chronic disease only to have the patient readmitted a few months later with the same problems. As a physician (in-training), I recognize the value of alleviating suffering on an individual basis. But what about preventing the situation that caused the problem in the first place?

I’m not even referring to preventative medicine through education, prophylaxis, or behavior change. Informing my diabetic patient about the value of exercise and healthy eating has its value. But he can’t make healthy choices without having healthy options. In other words, my patient with diabetes can’t choose to exercise if there is no option of safe parks to walk in. He can’t choose to eat healthy if there is no option of nearby fresh-food stores. Don’t take my word for it; listen to the experts: in a cross-sectional analysis of the OECD (developed) countries, the data “strongly suggest that environmental factors […] are more important than medical inputs in explaining variations in premature mortality.”1 The role of environment is even more pervasive in developing countries.

What if I could get the police department to scale-up surveillance to make it safe for my patient to go into the park? What if I could influence local tax codes to provide financial incentives for grocery stores to open in underserved areas?

During interviews with my diabetic patient, I often find myself thinking about these questions when I should instead be focusing on asking him whether he can feel his toes. In searching for a way to channel my “big-picture” inquiries, I stumbled upon the nebulous concept of health system strengthening (HSS). The more I learned about HSS, the more I was enthralled. Through several years of networking, I found a group of experts in HSS that shared my interest and showed me ways to impact health by influencing the system.

Now that I’m hooked into the system, all I see around me are experts that have been researching health systems as a career. But the HSS movement is lacking the creativity and enthusiasm of students. To try to fill that gap, I’ve helped to create a platform where students can learn about and contribute to HSS.

I hope the student section of the Health Systems Action Network (HSAN) can be a useful resource for those of you interested in the “big picture” of health (http://hsanet.org/pages/studentmain.aspx). And, I hope that we as students can find novel HSS approaches to give our patients healthy options for healthy choices.

Reference:

1) Or, Zeynep. Determinants of Health Outcomes in Industrialized Countries: A Pooled, Cross-country, Time-series Analysis. 2000. OECD Economic Studies: 30(1).

Being accepted at King’s College London was an honor as the institute holds a great name and is among one of the world’s top 25 universities. With immense delight I immediately applied for a visa, with which I had no difficulties and enthusiastically started preparing for my trip. Luckily, a family friend of ours offered to give me a room in their house which made matters much simpler as accommodation in London can be quite expensive.

On my first day on Floor 23rd CFD of the Guy’s Hospital, I was warmly welcomed and introduced to the team. I was assigned a workstation and found out everything I needed to know about the project I was to work on. My supervisor kept things simple and I was taught precise protocols. Soon, I started working independently at my bench and could address questions regarding my project. It was entirely up to me as to how many hours I wanted to work, and I made full use of this wonderful opportunity. I would leave home at 8am, arrive around 9:15am; and would work till late at night. I tried to do as much work as possible so that there was a valuable contribution from my side in the project.

Dr Isabelle Miletich and me at the lab

What I Learned

It was amazing to do experiments that I would normally just read about in books. The aim of the project was to study the early development of the jaws in mouse embryo. I learnt a variety of techniques in my short attachment which included preparation of plasmid DNA, transforming bacteria with plasmid DNA, use of restriction enzymes (e.g. EcoR1) and analysis on agarose gel, preparation of RNA probes labeled with Digoxygenin, dissection of mouse embryos under the microscope and whole mount in situ hybridization on mouse embryo. Every minute of it was incredibly interesting. Though the research environment was new to me, it didn’t take me long to settle in. I also attended weekly lab meetings and seminars.

Students from KCL, Germany, Switzerland and Pakistan at the meet-up

The Social Life

London is a lively city and just travelling through it is mesmerizing. Weekends were always spent roaming and of course shopping at Oxford Street.

There was a gathering organized by the KCL students for the visiting electives students in all departments of KCL were we exchanged cultural and academic knowledge. I made friends for life at CFD, and also had a chance to revisit them this year.

In Conclusion

It’s entirely up to you how you make your elective useful; my interest in medical genetics grew with each day of lab work. I now have clear vision of how genetic mapping and research is being done, something which unfortunately is not much emphasized in Pakistan for an undergraduate student. I have a new approach to research and I took up courses on coming home which polished my skills further. At present, I have submitted a case report regarding something totally different from my research elective at King’s but it was because of this elective experience that I was constantly re-exploring things. It was because of Dr Paul T Sharpe that I had the opportunity to work with such an excellent team and Dr Isabelle Miletich made my attachment easier by helping me through lab work and otherwise. It was an excellent educational experience one should have at least once in a lifetime.

Sara Bughio is an intern at Liaquat University Hospital, Jamshoro, Sindh, Pakistan
sara_bughio@hotmail.com

Today, we’d like to announce the publication of Sara Bughio’s report on her elective researching genetics and embryonic development in mice at the Department of Craniofacial Development at King’s College, London. Read about it here.

Meanwhile, in today’s blog, Gurmeen Kaur, TLS Regional advisor from Delhi, India discusses findings from a village in India with surprisingly low dementia rates

Global projections estimate that 24·3 million people have dementia today, with 4·6 million new cases of dementia every year and this number will number of people affected will double every 20 years to 81·1 million by 2040

An Indo–US Cross-National Dementia Epidemiology Study (1991–1999) shows unusually low levels of Alzheimer’s disease in village in North India called Ballabgarh. A community survey of a cohort of 5,126 individuals aged 55 years and older showed an overall prevalence rate of 0.84% (95% CI, 0.61 to 1.13) for all dementias above 55 years and 1.36% above 65 years of age with Alzheimer’s in 0.62%. These rates are amongst the lowest in the world (1).

Global projections estimate that 24·3 million people have dementia today, with 4·6 million new cases of dementia every year and this number will number of people affected will double every 20 years to 81·1 million by 2040 (2). The rate of increase in numbers of people with dementia is predicted to be three to four times higher in developing areas than in developed regions (2).

Dementia contributes to more disability weight and years than almost any other health condition, even more than stroke, cardiovascular and musculoskeletal diseases (3). As the life expectancy and average age of survival of people worldwide is increasing, we need to shift our emphasis on geriatric diseases in which dementia is a forerunner. Since dementia leads to impairment in the cognitive domains of memory, attention, language, and problem solving affecting the higher mental functions first and finally leading to disorientation to time, place and person, it is a very debilitating disease for patients as well as for spouses and care-givers.

The rates of dementia vary widely among different countries and continents. While some studies from India (like the one in Ballabgarh) report extremely low rates, researches from other parts of the country do not show such consistency. Indian Kashmiri Pandits had a prevalence of 6.5% (4) and studies from Kerala (5) prove that dementia is an important cause of morbidity in the geriatric population in that region. Similarly China which is India’s neighbor, has nearly the same climatic conditions besides having healthier eating habits, shows rates comparable to developed countries with the highest incidence including UK and North America (2).

Possible theories given by the authors to explain this reduced prevalence include lower cholesterol levels, hypolipidemia, lower cardiovascular risk and more physical activity in this farming community of Ballabgarh. Other explanations include lower life expectancy leading to death before the mean age of disease onset and reduced survival after acquiring disease which again leads to early death. Researchers postulated that environmental risk or protective factors, for dementia or gene-environment interactions, in the Indian population may be related to diet, comorbid chronic or infectious diseases. In fact to find out genetic differences an effort was made to see whether Indians had lower levels of a gene APOE4 which predisposes to Alzheimer’s disease but the natives of Ballabgarh had levels comparable to the rest of the world.

Lifestyle and dietary factors are likely causes for variable incidence of dementia. Diets rich in fruits, vegetables, and fibre improve human well-being and significantly reduce development of the pathological processes that are characteristic of neurodegenerative disorders (6). Green tea consumption is considered a protective factor for Alzheimer’s in China (7). Since stroke, hypertension, obesity, dyslipidemia are considered pro-dementia factors, improving cardiovascular health may lead to its diminution (8).

While researchers strive to find reasons for this disparity in dementia prevalence in Northern India we can try to achieve a healthier lifestyle, improve our eating habits and physical fitness hoping to reverse the potential dementia flood on its way!

Gurmeen Kaur is a TLS RA and  final year medical student at Lady Hardinge Medical College, India
Email: kaur.gurmeen@gmail.com

References:

1. Chandra V, Pandav R, Dodge HH et al. Incidence of Alzheimer’s disease in a rural community in India: The Indo–US study. Neurology 2001;57;985-989

2. Ferri CP, Prince M, Brayne C et al. Global prevalence of dementia: a Delphi consensus study. Lancet 2005; 366: 2112–17

3. World Health Organization. World Health Report 2003—Shaping the future. Geneva: WHO, 2003.

4. Raina S, Razdan S, Pandita K et al. Prevalence of dementia among Kashmiri migrants. Ann Indian Acad Neurol. 2008; 11(2): 106–108.
5. Shaji S, Promodu K, Abraham T et al. An epidemiological study of dementia in a rural community in Kerala, India. Br J Psychiatry. 1996;168(6):745-9.

6. A Martin, A Cherubini and C Andres-Lacueva et al., Effects of fruits and vegetables on levels of vitamins E and C in the brain and their association with cognitive performance, J Nutr Health Aging 2002; 6: 392–404

7. QH Wang, ZX Zhang and MN Tang et al., Smoking, alcohol and tea drinking on Alzheimer’s disease, Chin J Neurol 2004; 7: 234–238.

8. SS Richards, CL Emsley and J Roberts et al., The association between vascular risk factor-mediating medications and cognition and dementia diagnosis in a community-based sample of African-Americans, J Am Geriatr Soc 2000; 48:1035–1041.

Visit theLancetStudent.com to read this week’s blogs and articles; you can also vote in our pole this week on Global Health Programmes and join the facebook debate. We are always looking for writers, so please get in touch by emailing us at student@lancet.com if you would like to write an article, elective report or/and blog for us. In addition, in our hope of expanding our podcasts, social media and online video content we are now looking for those with an eye for editing audio/visual content who would be happy to assist the Editorial Team.

Please don’t forget to tell a Friend about what the TheLancetStudent.com can do for you!

This week in TLS News

Evaluating Global Health Programmes
Simukai Chigudu, our TLS Regional Advisor and fifth year medical student at Newcastle University, comments on the need for accountability of all parties involved in health.

The ‘See and Treat’ Approach to Cervical Cancer
Gurmeen Kaur and Aashim Singh, who are both medical students at University of Delhi, explore a new affordable test to diagnose cervical cancer that can be applied in developing countries.

The Miracle of Vaccines, can we defeat Rotavirus in the near future?
Niccolò Giaj Levra and Giulia Cossu, medical students at University of Turin, examine the evidence supporting the introduction of a Rotavirus vaccine into immunisation programmes in developing countries.

Swine Flu: Paranoia or Precaution?
Inderjeet Sahota, an MSc. student at Simon Fraser University in Canada, discusses concerns over the worldwide reaction to the H1N1 pandemic.

Placebos as the cure?
This week’s editorial examines the findings of a review on placebo effects published in today’s edition of The Lancet.

This week’s Article

Breast Cancer – Lack of Awareness About Screening in India
Gurmeen Kaur’s talks about health problems in India caused by insufficient screening for breast cancer and the ways the situation could be improved.

This week’s Elective Report

Elective: Department of Rehabilitation Medicine
Sayantani Ghosh’s reports on her elective, where she studied rehabilitation medicine in Philadelphia, USA.

Image credit: UN Photo/Albert Gonzalez Farran

Today’s blog written by Ana Amaya, TLS Student Editor and DrPH student at London School of Hygiene and Tropical Medicine, discusses a recent report which projects a reduction in promised aid from OECD countries in 2010.

What do you think of this issue? Register your opinions in our poll and join the debate on our Facebook Group

Although overall aid will reach $107.4 billion, a 35% increase compared to 2004, it will be far less than the amount promised by donors five years ago

The Organisation for Economic Co-operation and Development (OECD)* released its 2010 review of aid disbursements from member countries last week. Although overall aid will reach $107.4 billion, a 35% increase compared to 2004, it will be far less than the amount promised by donors five years ago. The $21 billion shortage is the result of several countries falling short of their commitments, mainly France, Germany, Austria, Portugal, Greece and Italy. Given that these countries contribute a large amount of their aid to Africa, this continent stands to receive less than half than what was originally projected. Other countries such as Sweden, the United States, Canada and Australia will reach their goals (1).

The first cause most will point to will be the economic downturn. It is not a coincidence that most of the countries falling short of their commitments belong to what is now affectionately referred to by analysts as PIIGS (Portugal, Italy, Ireland, Greece and Spain), used to denote the European countries most affected by the crisis (2). However, the OECD is quick to note that of the $21 billion deficit, only $4 billion is the result of lower than expected GNI (Gross National Income) due to the economic crisis (1).

Another issue arising from the narrowing of the number of countries providing aid is that it focuses the power that comes from donating into less hands. It is no surprise that in the majority of the cases funders hold the last decision in how money is spent (3). Usually the decision on what they are willing to invest in follows a political agenda with inevitable ’strings attached’, rather than letting the country identify their priorities; this manipulation ultimately in detriment of the population.

A prime example of this comes from Somalia where recent reports describe a slow-down in the distribution of aid by humanitarian workers on the ground due to increasing conditions set by the United States government. While civilians suffer the consequences of an entrenched war, the US continues to put restrictions on how aid is handled for fear that it will reach Islamist insurgents. Moreover, Somalia has experienced a reduction in its aid from $270 million in 2008, to almost half this amount last year (4), further affecting the supply of food in the country.

What many fail to understand is that aid is not a gift provided to people in another country. It is much more than that. It arises from observing the difficulties that other countries are going through and the humanitarian impulse to help those that need it. Countries develop plans based on the commitments made to them so it is crucial that governments fulfill their pledges. It is evident that the world is feeling the brunt of the economic crisis, but what do you tell the child in eastern Congo who hasn’t eaten for three days? The mother who had to flee her village due to the war and has no home or way to provide for her family? Are we going to blame the housing bubble burst or stay firm on our promises?

The OECD review provides further evidence of the disjuncture between commitments and actual disbursements in aid. There is no other way to describe this incompatibility other than denoting it as clear irresponsibility on behalf of donors whose actions will surely resonate on already debilitated countries in need of external funding. It is the poor who will have to cope with lack of adequate shelter, potable water and live-saving medications and it is the international community who will have to respond, either with an apology or with actions.

* The OECD is an organisation that includes the 30 richest countries in the world

Ana B. Amaya is a TLS Editor and DrPH Student at London School of Hygiene and Tropical Medicine
Email: ana.amaya@lshtm.ac.uk

References

1.OECD. Donors’ mixed aid performance for 2010 sparks concern. Retrieved from http://www.oecd.org/document/20/0,3343,en_2649_34447_44617556_1_1_1_37413,00.html, accessed February 20, 2010.

2.TheNewYorkTimes.com. Stock market turns up its nose at PIIGS’ woes. Retrieved from http://www.nytimes.com/aponline/2010/02/18/business/AP-US-Of-Mutual-Interest-Greek-Lesson.html?scp=1&sq=piigs&st=cse, accessed February 19, 2010.

3.Mosley, P, Hudson, J, Verschoor, A. Aid, poverty reduction and the ‘new conditionality’. The Economic Journal, 2004; 114:217-243.

4.BBCNews.com. US aid rules in Somalia are impossible, says UN envoy. Retrieved from http://news.bbc.co.uk/1/hi/world/africa/8520035.stm, accessed February 20, 2010.

Summary

This Seminar adds to the previous Lancet Seminar about eating disorders, published in 2003, with an emphasis on the biological contributions to illness onset and maintenance. The diagnostic criteria are in the process of review, and the probable four new categories are: anorexia nervosa, bulimia nervosa, binge eating disorder, and eating disorder not otherwise specified. These categories will also be broader than they were previously, which will affect the population prevalence; the present lifetime prevalence of all eating disorders is about 5%. Eating disorders can be associated with profound and protracted physical and psychosocial morbidity. The causal factors underpinning eating disorders have been clarified by understanding about the central control of appetite. Cultural, social, and interpersonal elements can trigger onset, and changes in neural networks can sustain the illness. Overall, apart from studies reporting pharmacological treatments for binge eating disorder, advances in treatment for adults have been scarce, other than interest in new forms of treatment delivery.

Introduction

This Seminar adds to the previous Lancet Seminar about eating disorders, which was published in 2003.1 We provide a concise review of eating disorders in young people, focusing on factors of particular relevance to the clinician such as diagnosis, epidemiology, pathogenesis, treatment, and prognosis. In this Seminar we draw attention to biological factors that could contribute to new interventions. Eating disorders also occur in prepubertal children, but studies in this age group are scarce and there is no consensus about either diagnosis or treatment.

Classification and diagnosis

Diagnosis is challenging because diagnostic symptoms and associated behaviours substantially overlap across the range of eating disorders. For example, extreme dietary restraint, binge eating, and overvalued ideas about weight and shape can be present in all forms of eating disorder. Additionally, the subjective interpretation and justification behind diagnostic behaviours is often not clear or is limited by developmental constraints (as in childhood anorexia nervosa), further complicating diagnosis.

In the diagnostic and statistical manual of mental disorders fourth edition (DSM-IV),2 three broad categories are delineated: anorexia nervosa, bulimia nervosa, and eating disorder not otherwise specified. The international classification of diseases tenth revision (ICD-10) has three categories: anorexia nervosa, bulimia nervosa, and atypical eating disorder.3 Briefly, anorexia nervosa is characterised by extremely low bodyweight and a fear of its increase; bulimia nervosa comprises repeated binge eating, followed by behaviours to counteract it. The category of eating disorder not otherwise specified encompasses variants of these disorders, but with subthreshold symptoms (eg, menstruation still present despite clinically significant weight loss, purging without objective binging). The panel shows some key symptoms of eating disorders in general (more detailed information about the clinical features of each disorder is available in the previous Seminar1). The weight criteria used for diagnosis need to be adjusted for age,4 height, sex, and the developmental weight trajectory of the individual.

Panel
Common symptoms in eating disorders
Behaviours
Restrictive behaviour

*
Cutting back on amount of food eaten
*
Strict rules about eating (eg, time of day, specific macronutrient content)
*
Prolonged fasting (greater than 8 waking hours)
*
Ritualised behaviour associated with the purchase, preparation, and consumption of food
*
Little variety in foods (eg, extreme vegan diets, avoidance of fat, etc)
*
Avoidance of social eating
*
Secret eating
*
Social competitiveness around eating

Binge eating

*
Eating an amount of food in a discrete time that is considered excessive in view of the situational context (objective)
*
Eating an amount of food that is not excessive in view of the context but is considered large by the individual because of associated feelings of loss of control over eating (subjective)

Associated features of binge eating

*
Eating more rapidly than normal
*
Eating until uncomfortably full
*
Eating large amounts when not hungry
*
Eating alone because of embarrassment
*
Feeling disgusted, depressed, or very guilty because of eating

Purgative behaviour

*
Self-induced vomiting; spitting
*
Misuse of laxatives, diuretics, diet pills, etc

Excessive exercise

*
Intense, highly driven exercising of a compulsive nature
*
The drive to exercise is associated with impaired social or physical function, or both

Drinking

*
Limited drinking (<0·5 L per day)
*
Excess drinking (>1·5 L per day)

Body checking

*
Repeated weighing
*
Pinching or measuring the size of body parts (eg, circumference of wrist)
*
Repeatedly checking the protrusion of specific bones
*
Checking that specific clothes fit
*
Mirror gazing
*
Comparison with others’ bodies

Body avoidance

*
Avoidance of behaviours above (eg, refusal to weigh, avoidance of mirrors, wearing bulky clothes)

Psychopathology
Body image disturbance

*
Weight and shape concerns (eg, preoccupation with weight, shape, or both)
*
Overvaluation of shape and weight in determination of self-worth
*
Minimisation or denial of symptom severity
*
Disturbance in the way body is experienced
*
Intense fear of weight gain, even though underweight

Physical symptoms

*
Weight loss or failure of growth with associated features of starvation—eg, amenorrhoea
*
Absence of at least three consecutive menstrual cycles (women)
*
Reduced libido
*
Reduction in waking erections (men)
*
Reduced beard growth in men
*
Sensitivity to cold
*
Weakness, fatigue, etc

This panel outlines the most common symptoms of eating disorder. A range of symptoms caused by starvation are also present in anorexia nervosa, which are not all detailed here. All these symptoms are not usually volunteered by the patient and often have to be gently elicited or are noted by informants.

More than 50% of cases in the community fall into the category termed eating disorder not otherwise specified (or atypical).5 Proposals to reduce the specificity of some of the diagnostic criteria in anorexia nervosa and bulimia nervosa have been made, which would reduce the proportion of cases that fall within the not-otherwise-specified category.6 Subgroups within obesity with mental or behavioural components, such as binge eating disorder and night eating syndrome, can be delineated.7

Binge eating disorder is a subcategory of eating disorder not otherwise specified, and is defined as frequent binge eating distinguished from bulimia nervosa by the absence of recurrent inappropriate compensatory behaviours. Hence binge eating disorder is often associated with obesity. Transition from severe restriction into binge eating behaviour is common;8 however, the reverse process (a shift from binge eating into restriction) is less usual. The criteria for diagnosis of binge eating disorder in DSM-IV appendix B include associated behavioural and affective features,2 and these criteria have been extensively used in research in the past 15 years. Support is growing for recognition of binge eating disorder as a specific entity 9 on the basis of taxometric analyses,10 family aggregation studies,11 treatment response research,12 and studies of clinical course.13

Furthermore, interest is growing in a transdiagnostic approach to eating disorders, both within14 and outside the category of eating disorders, with proposals for links to the obsessive compulsive and autistic spectrum of disorders15 and anxiety and mood disorders.16, 17 Several articles present the arguments for diagnostic change in DSM-V.7, 18

Psychiatric comorbidity

Comorbidity is the rule rather than the exception for patients with eating disorders.19, 20 Developmental disorders (eg, those of the autistic spectrum and attention-deficit hyperactivity disorder) have been reported to affect about a fifth of patients with anorexia nervosa.21, 22 Moreover, a small proportion of adults with attention-deficit hyperactivity disorder have additional symptoms of eating disorders.23 Obsessive compulsive traits 24, 25 or disorder,26 and anxiety disorders 27, 28 and some borderline traits,25 have been reported both before and after the onset of eating disorders, and are also diagnosed in family members.29, 30 Bulimia nervosa and binge eating disorder are associated with affective disorders 31, 32 and with alcohol 33 or substance 34 misuse.

Epidemiology

Eating disorders and related behaviours are common in young people. Investigators of a study of a large sample of American children aged 9—14 years reported that 7·1% of boys and 13·4% of girls displayed disordered eating behaviours.35 The pivotal effect on health has led to the inclusion of eating disorders among the priority mental illnesses for children and adolescents identified by WHO.36 Eating disorders have been reported worldwide both in developed regions and emerging economies such as Brazil and China.37, 38 The lifetime prevalence of eating disorders in adults is about 0·6% for anorexia nervosa, 1% for bulimia nervosa, and 3% for binge eating disorder.19, 20 Women are more affected than are men, and the sex differences in lifetime prevalence in adults could be less substantial than that quoted in standard texts: 0·9% for anorexia nervosa, 1·5% for bulimia nervosa, and 3·5% for binge eating disorder in women; and 0·3%, 0·5%, and 2·0%, respectively, in men.20 Many people with eating disorders, who were detected in community studies in the USA, do not seek treatment.20

Pathogenesis

A comprehensive review published in 2004 summarised the risk factors for eating disorders,39 and a position paper from the Academy of Eating Disorders outlined the evidence supporting these diseases as biologically-based forms of severe mental illnesses.40 In this section we draw attention to some present areas of emphasis.

Genetic factors

The most potent risk factor is female gender. How much this association can be attributed to biological rather than social factors is uncertain. Sexual divergence is less pronounced in binge eating disorder23 and in prepubertal anorexia nervosa.41 Twin and family studies suggest that anorexia nervosa, bulimia nervosa, and binge eating disorder are complex genetic diseases, and for each disorder the estimated heritability ranges between 50% and 83%.11, 42, 43 Linkage studies have identified loci for anorexia and bulimia nervosa and for associated behavioural traits such as compulsivity.44—46 About a third of genetic risk for eating disorders and depression,47 anxiety disorders,48 and addictive disorders49 is shared. All the above studies are limited because of low power; however, international collaborations are working at pooling cases and using newer forms of analysis such as genome-wide associations.

Biological factors

Although many of the biological findings in eating disorders can be best understood as results of starvation and disturbed eating behaviours, some are causally linked as risk or maintaining factors. The brain is particularly vulnerable to the consequences of poor nutrition since it uses around 20% of the caloric intake and is especially dependent on glucose. Therefore, poor nutrition has a general effect on brain function in addition to the specific effect on the appetite system. Most eating disorders emerge during adolescence—a vulnerable period of brain reorganisation—and malnutrition during this crucial period can negatively affect illness trajectories.

Starvation shrinks the brain and is associated with many behavioural and psychosocial disturbances such as rigidity, emotional dysregulation, and social difficulties.50 Many symptoms resolve with weight gain and when brain mass is restored.51 Concentrations of brain-derived neurotrophic factor, a regulator of brain plasticity, in blood are reduced in acute anorexia nervosa,52 and genetic studies suggest a trait-related disturbance in this system.53

The characterisation of the central control of appetite54, 55 could improve our understanding of eating disorders. A simplified heuristic is to consider three components. First is the homoeostatic system that is centred mainly in the brain stem and hypothalamus, which integrates peripheral metabolic markers with information from the gastrointestinal tract to affect subjective states of hunger, satiety, and autonomic nervous activity. Second is the drive system, with distributed neural circuitry within the mesolimbic cortex and striatum that has afferent inputs from sense organs and neural structures that are implicated in learning and memory. This system registers the reward value associated with food and is involved in the motivation to seek food and eat. Third is the self-regulation system, within which a form of so-called top-down control contextualises appetite within life goals, values, and meaning.

Abnormal changes in all three of these systems have a role in the risk and maintenance of eating disorders. A hypothesis suggests that these disorders could result from pervasive deficits in self-regulatory systems.56 Furthermore, eating disorder behaviours affect the drive system, as shown by models of binge eating in laboratory rodents for which scientists have replicated the conditions implicated in the increase of binge eating—ie, food restriction, gastric drainage (an analogue of vomiting), stress, and intermittent access to highly palatable food—and produced animals with an addiction to food. The investigators noted that not only did these animals binge eat, but they also showed withdrawal effects. Moreover, they had a propensity to relapse after a time, and cross-tolerance to alcohol and cocaine.57, 58 Underpinning these behavioural changes are alterations in the chemical transmitters (dopamine and opioids). Finally, the response to changes in food intake of the putative homoeostatic system could contribute—eg, anorexia nervosa is often linked to premorbid and familial leanness,59 whereas the reverse is the case for bulimia nervosa and binge eating disorder.60

Brain monoamine function in eating disorders has been studied in the acute state (which can be confounded by illness effects) and after recovery with specific ligands and positron emission tomography. These findings for anorexia nervosa have been synthesised into an explanatory model.61 5HT2A receptors are reduced and 5HT1A receptors are increased in both the acute and recovered state, and dopamine receptors (DA2) within the striatum are increased after recovery.62 Less research has been done into binge eating disorders and bulimia nervosa, but anomalies in the dopamine system could heighten food reward.63

Abnormalities in both illness-related (food and body shape) and non-illness-related information processing are detected in eating disorders. An attentional bias is evident towards food and body shape 64 associated with increased activation in distributed neural networks connected with self-regulation and hedonic motivation.61, 65 General problems include difficulties in decision making,66 abnormal striatal activation by reward,67, 68 reduced flexibility 69 associated with decreased activation in the striatum and associated areas,70 a bias towards focusing on detail at the expense of seeing the general picture (weak central coherence),71 problems in social cognition,72 and dysfunctional emotional regulation.73 These functional anomalies can maintain eating disorder behaviours. For example, an eye for detail and inflexibility can allow an individual to understand the laws of thermodynamics in relation to energy intake and expenditure and succeed in weight loss, whereas impaired social and emotional regulation could isolate the individual.

Environmental context

The environment shapes the developmental course of the individual beginning at the time of conception. For example, mothers of people who later develop an eating disorder might be more exposed to stress during pregnancy.74 Birth-related perinatal complications (eg, cephalohaematoma) and premature delivery increase the risk of development of an eating disorder.75 Epigenetic mechanisms or damage to the brain from hypoxia can also mediate these effects.

In some developed countries, the excess value placed on thinness encourages extreme dieting and weight control practices. Negative comparisons between an individual’s body shape and that of the ideal contributes to poor self-esteem.76 Criticism, teasing, and bullying focused on food, weight, and shape issues specifically increase the risk of developing an eating disorder.77 The tension between the stigmatisation of fatness, idealisation of thinness, and easy access to highly palatable foods, perhaps eaten in secret, could lead to weight control behaviours that can have a destabilising effect on the biology of appetite control. In addition to food-related and weight-related harmful experiences, general adversity (neglect and physical and sexual abuse) also increases the risk of developing an eating disorder.

Interactions between the environment and individual biology

The postpubertal years are a crucial time of vulnerability. Developmental changes of puberty (the hormonal fluxes and synaptic pruning and myelination within the brain), stressful events, and challenges (eg, changes in social affiliation and ranking) could trigger eating disorder behaviours. The consequent nutritional deficits can induce factors that maintain the illness. These factors have been grouped into four broad domains: the medical effect on the body and brain, the interpersonal effect, the exaggeration of avoidant coping, and obsessive compulsive traits.78

Treatment

Medical complications

Although eating disorders can begin in adulthood, the highest incidence is between 10 and 19 years of age,79 potentially disrupting optimum growth and development. Most pathophysiological complications are reversible with improved nutritional status or remittance of abnormal eating and purging behaviours. However, some physical consequences can be life-threatening, such as electrolyte imbalances (eg, hypokalaemia) due to excessive vomiting or laxative and diuretic misuse. Additionally, nutritional deficiencies increase the risk of cardiac arrhythmias and intercurrent infection. Comprehensive reviews 80, 81 and the previous Seminar1 discuss the physical abnormalities of eating disorders in great depth.

Many practice guidelines discuss how to measure and assess medical risk.82—84 Children and adolescents have less nutritional reserve than do adults, so their risk can rapidly escalate. Body-mass index (BMI) is not a useful index of nutritional compromise for men, children, tall and muscular individuals, and those with water retention. Other comorbid medical disorders also increase vulnerability and might need regular monitoring, such as diabetes mellitus, which can increase risk at any level of BMI. Apart from these caveats, standard forms present a means of giving both personalised and normative feedback on medical risk. (Examples include the Maudsley BMI chart and the Risk Assessment in Eating Disorders). Table 1 shows an abridged set of markers of nutritional and cardiovascular decompensation that signal the need for increased or urgent care. These markers should be considered in the context of the complete clinical picture, expertise of the treating team, and local availability of eating disorder units. Signs of increased medical risk suggest the need for immediate specialist consultation or inpatient treatment, or both, especially in people with a recent, acute onset.

An abridged set of markers of nutritional and cardiovascular decompensation that signal the need for increased or urgent care in people with eating disorders
+=present. FBC=full blood count. LFT=liver function test.
* The instructions for the squat test are that the patient squats on her/his haunches and has to stand up without, if possible, using her/his hands.

The deficits in anorexia nervosa gradually evolve and are general rather than specific. Therefore they should be rectified slowly, orally, and with food supplemented with multivitamin and multimineral preparations. In the first phase (3—7 days), a soft diet of about 5—10 kcal/kg per day with thiamine and vitamin B co-strong in small portions throughout the day, and foods with high phosphorus content (eg, milk-based products) accords with guidelines from the UK National Institute for Health and Clinical Excellence (NICE) describing refeeding of severely undernourished patients, and reduces the risk of refeeding syndrome.85 On special units with skilled nursing, feeding by tube is rarely necessary. At moderate levels of risk the aim is to produce a weight gain between 250 g and 450 g per week in outpatients, and around 1 kg in those treated in hospital.83

Some weight change strategies—such as vomiting or misuse of diuretics, laxatives, or caffeinated and carbonated drinks—can result in underhydration or overhydration and electrolyte imbalance. Acute renal failure can occur in severe cases. Oral replacement is usually the first line of management, but the full clinical diagnosis and level of risk (table 1) decide the appropriate setting and method of replacement. Persistent hypokalaemia can be linked to low calcium and magnesium (which also need rectification), or to sustained purging behaviours. Proton-pump inhibitors to inhibit gastric acid secretion reduce metabolic alkalosis and help to conserve potassium.86 They can also prevent oesophageal and tooth damage.

Long-term effects on physical health

Some medical consequences of eating disorders can be irreversible or have later repercussions on health, especially those affecting the skeleton, the reproductive system, and the brain. Dental problems, growth retardation, and osteoporosis are some of the long-term problems. Bone loss in lumbar spine, radius, and proximal femur can be detected within a year of illness and progresses to produce fractures, kyphoscoliosis, and chronic pain. Weight gain alone improves bone density, especially if it is sufficient to restore menses. Several treatments have been investigated, including antiresorptive agents, oestrogens, insulin growth factor, and calcium supplementation, but none can be recommended on the basis of present evidence.87

The fertility and maternity rate of women with anorexia nervosa is reduced; a Swedish study 88 suggested that the rate of fertility was 70% of that in the general population. Infant birthweight is lower in mothers with anorexia nervosa 89 but higher in those with bulimia nervosa.90 The miscarriage rate for women with bulimia nervosa is higher than for healthy women—those with bulimia nervosa were twice as likely to have two or more miscarriages compared with the general population.89 Perinatal problems can be increased,91 and feeding difficulties reducing infant growth have been reported.92 Infertile and pregnant women should be screened for eating disorders and offered treatment to optimise the wellbeing of their offspring.82

Pathways of care

High levels of health-care use are common across all forms of eating disorders.93 The management of bulimia nervosa and binge eating disorder can be complicated by medical (eg, diabetes and obesity) and psychiatric (eg, affective disorders and addictions) comorbidity, but acute medical risk is less of a problem than it is for anorexia nervosa, and care is typically delivered on an outpatient basis in adult services.

NICE guidelines recommended that people with anorexia nervosa should first be offered outpatient treatment 82 and that inpatient care be used for those who do not respond or who present with high risk and little psychosocial resources. Whether inpatient admissions should be short to alleviate acute risk or prolonged to attain full weight restoration (thought to reduce relapse) is controversial.94 Models of day treatment provide an intermediate service model.95

Practice recommendations emphasise the importance of specialised care for the treatment of eating disorders, but such care is not often accessible. Hence, new forms of service delivery (eg, e-mailing, text-messaging) with use of treatment directed via mobile phones, the internet, or telemedicine (eg, cognitive behavioural therapy [CBT] delivered by a therapist via the internet) are being assessed.96—99 A systematic review 98 of self-help interventions (computerised or manual) modelled after empirically validated approaches concluded that with professional oversight (guided self-help) these interventions could have benefit in bulimia nervosa and binge eating disorder, although some uncertainty still remains.98, 100, 101

Evidence-based treatments

Anorexia nervosa

The evidence base relating to the treatment of anorexia nervosa is meagre.82 Two main factors contribute to difficulties in trials of treatment for this disease: clinician-instigated protocol withdrawal because of failure to stabilise risk, and patient withdrawal and difficulties in recruitment because of poor acceptability of treatments. Thus, treatment guidelines rely on expert recommendations. These recommendations emphasise the importance of a multidisciplinary approach including medical, nutritional, social, and psychological components.82—84 Psychotherapy can be delivered individually or with the family. The involvement of families in treatment depends on several factors—eg, age of the patient, living arrangements, the patient’s level of risk and dependence, and the ethos of the treatment team.

For adolescents with anorexia nervosa, family psychotherapy as practised according to the Maudsley method is recommended (table 2).102 6 months of treatment can be sufficient unless there is obsessive compulsive comorbidity or non-intact families.103 Families with extremes of overprotection or criticism have better outcomes in separated family therapy (child and parents seen separately) than in combined family therapy.104 Parents are distressed and burdened by symptoms and behaviours of eating disorders.105 These feelings can be alleviated by group educational interventions.106

Treatments for anorexia nervosa, bulimia nervosa, and binge eating disorder and strength of their empirical support
SSRIs=selective serotonin reuptake inhibitors. TCAs=tricyclic antidepressants. SNRIs=serotonin-norepinephrine reuptake inhibitors. GSH=guided self-help. PSH=pure self-help. Evidence grades: ..=non-existent or not applicable; grades weak/moderate/strong. Beneficial effect (reduction of symptoms or behaviours or maintenance of improvements): ..=no randomised controlled trial available; −=no beneficial effect; −/+=mixed results or still inconsistent results (possible beneficial effect); +=slight beneficial effect; ++=moderate beneficial effect; +++=strong beneficial effect.
* At least one trial included adolescents (<18 years).

A Cochrane collaboration review (updated in 2008) concluded that the evidence accumulated so far does not lend support to any one particular psychotherapeutic method for adults with anorexia nervosa, although support from a non-specialist clinician might be less efficacious than might that from a specialist delivering a specific form of psychotherapy.107

No strong evidence lends support to drug treatment either in the acute or maintenance phases of the illness.108, 109 A few randomised controlled trials have been done since the last Seminar. The previous expectation that fluoxetine could have a role in prevention of relapse in anorexia nervosa 110 weakened after the negative findings from a large and thorough study.111 Interest has been renewed in the potential use of atypical antipsychotic drugs to target dopaminergic dysregulation and comorbid features of this disease.112 The idea is that by reducing distorted cognitions and anxiety symptoms, resistance to weight gain decreases. Initial, small randomised studies 113, 114 report decreases in obsessive symptoms and an increased rate of weight gain. Larger trials are necessary, however, to substantiate these benefits and elucidate harms with this drug, such as a potential increase of QTc interval with the risk of cardiac arrhythmias.

Bulimia nervosa

The evidence base 115 for the original CBT model of bulimia nervosa 116 and its use as the first-line treatment is strong. Although CBT has good acceptability, binge remission rates (cessation of binge eating or purging) at the end of treatments are only 30—40%.117, 118 An enhanced form of CBT with a broader focus including interpersonal factors, emotional tolerance, perfectionism, and self-esteem did not substantially improve this outcome.119 Furthermore, combining antidepressants (tricyclics or fluoxetine) with CBT did not significantly add to the effect of CBT alone.117 Interpersonal therapy is efficacious as a treatment alternative, although it showed a slower response of symptom change than did CBT (similar results to CBT only after 1 year of follow-up).115, 117 Other models of treatment are being considered for use in bulimia nervosa, such as those with a focus on emotional regulation (eg, dialectical behaviour therapy).120

Two studies have assessed the role of family-based psychotherapy for adolescent bulimia nervosa.121, 122 One suggested that guided CBT could have advantages compared with family-based treatment in terms of cost and speed of response,121 whereas the other suggested that family-based treatment had advantages compared with individual supportive therapy.122

A 2004 review of treatment for bulimia nervosa and binging included seven trials in which participants with the form of eating disorder not otherwise specified that was similar to bulimia nervosa formed part of the sample.123 The conclusion from this and from a recent trial119 is that CBT is as effective for non-specified eating disorder similar to bulimia nervosa as it is for bulimia nervosa itself.

Pharmacotherapy has been recommended in the treatment of bulimia nervosa and binge eating disorder, especially if psychotherapy is either unavailable or unacceptable.82, 83 Evidence from pharmacological trials in bulimia nervosa is strong, and it is increasing in studies of binge eating disorder, but this finding mainly indicates efficacy in the acute stage after short-term treatment. Overall, evidence for long-term effects after medication is scarce. Additionally, pharmacological agents have been mainly tested in adults, and the results might not be generalised to adolescents and children. Moreover, use of antidepressant drugs in children and young people is controversial because of increased suicidal risk.124

Three systematic reviews detected strong evidence for the use of antidepressants to treat bulimia nervosa in the short term (around 8 weeks).115, 117, 125 However, the pooled effect from one meta-analysis (with eight studies, 901 patients) was judged only moderate for clinical improvement, which was defined as the number of patients with 50% or more reduction of binge eating (57% of patients receiving antidepressants vs 33% receiving placebo), and remission rates with antidepressants were usually less than 20% (similar to placebo).125 Overall acceptability of antidepressant treatment is low (around 40% dropout rates) when drugs are given alone.125 Fluoxetine is the main drug tested in trials and approved for use in bulimia nervosa by health regulatory agencies; it is recommended in a dose (60 mg per day) that is higher than is usually necessary to treat depression (20—40 mg per day).115 There is less evidence of efficacy for other serotonin reuptake inhibitors (citalopram, sertraline, fluvoxamine).117, 126 Whether antidepressant treatment can prevent relapse in bulimia nervosa is not yet known, since the few trials that were done were limited by their high attrition rates.115, 117, 127 Topiramate can be effective in reduction of bulimic and purging symptoms, but the safety profile of this drug still needs to be established in this disease.117, 128, 129

Binge eating disorder

Psychological interventions that have shown efficacy in treatment of bulimia nervosa have also been tested in binge eating disorder with positive results, particularly modified CBT, interpersonal therapy, and dialectical behaviour therapy.130 Large effect sizes in a meta-analysis have been reported for CBT compared with a control for reduction of binge frequency and for binge abstinence.100 An additional challenge in the treatment of binge eating disorder is weight management, since individuals are often classified as being overweight or obese. So far, psychological interventions for this disorder have not consistently shown clinically relevant weight losses.100 However, behavioural weight loss treatments have shown a moderate reduction in weight and improvement in binge abstinence.100 Binge abstinence is an important treatment goal because it has been associated with increased weight loss in both psychological and pharmacological trials.131, 132 A few studies with long-term follow-up suggest that abstinence from bingeing could persist for 12 months 132, 133 and 24 months.134

Systematic reviews130 and meta-analyses 100, 135 of treatments for binge eating disorder suggest that drug treatments show, at least, a moderate effectiveness in reduction of binge frequencies and promotion of binge remission in the short term, with a remission rate of 48·7% reported with pharmacotherapy (including antidepressants, anticonvulsants, and obesity drugs) compared with 28·5% with placebo.135 Several guidelines recommend short-term treatment with antidepressants (mainly serotonin reuptake inhibitors) as an alternative first approach to CBT. Although antidepressants are usually effective in reducing binges,100, 135 some studies have reported negative findings,130, 136 and their effect on depressive symptoms and on weight is uncertain.135, 137

Modest weight loss and binge remission have been reported with drugs approved for use in obesity,135 such as sibutramine 138, 139 and orlistat,140 and with drugs associated with weight loss, such as topiramate,141 zonisamide,142 and atomoxetine.143 Sibutramine and topiramate have both been tested in multicentre trials and showed binge remission rates greater than with serotonin reuptake inhibitors compared with placebo.138, 139, 144 Supplementation of CBT or behavioural weight loss treatments with the obesity drug orlistat 145 or topiramate 144 might increase weight loss.146 Although these drugs can be considered as part of the available regimen to treat binge eating disorder, the short-term duration of trials (12—24 weeks), high dropout rate, and placebo-response rates restrict the conclusions about their use.100, 130 Additionally, the risk—benefit balance is uncertain since intolerable adverse effects have been reported with some drugs (eg, zonisamide, topiramate).117, 130, 142

Prognosis

Recovery from anorexia nervosa becomes much less likely the longer that the illness has persisted. This finding contrasts with that of bulimia nervosa, for which the chance of recovery becomes higher the longer the illness duration.147 A systematic review 148 has compiled data for all outcomes for eating disorders and reported an increased mortality rate for anorexia nervosa (the reported range is wide, varying with case mix and length of follow-up) and persistent psychiatric problems in many cases.

In anorexia nervosa, a young age at onset and short duration of illness was associated with a good outcome, and somatic and psychiatric comorbidity with a poor outcome.149 This disease disrupts education 150 and vocational functioning, which contributes to difficulties in independent living in 20% of cases up to 10—20 years after the onset of the illness.88 Less is known about the effect of other eating disorders in this domain of life.

Little research has been done into the long-term outcome of bulimia nervosa and binge eating disorder. Of a cohort of patients with both these diseases admitted for hospital treatment in Germany, a third had an eating disorder diagnosis 12 years later; 36% of patients with binge eating disorder and 3·6% with bulimia nervosa had a BMI greater than 30 kg/m2.151

Conclusions

This Seminar has attempted to synthesise new developments in eating disorders that have arisen since the previous Lancet Seminar, and to integrate these developments into the knowledge that is relevant for clinicians. The diagnostic criteria for anorexia nervosa and bulimia nervosa are under consideration and could be broadened in DSM-V, reducing the size of the population in the category for eating disorders not otherwise specified. Binge eating disorders will probably be accepted as an additional form of eating disorder.
Eating disorders arise from an interaction between environmental events and the biological and developmental features of the individual. Abnormal eating behaviours produce both medical and psychosocial results. The psychosocial consequences derive partly from the effects of starvation on the brain and can perpetuate the illness. Several treatments and their combinations have been tested for binge eating disorder, with possible efficacy in the short term. New forms of treatment delivery have also been tested for bulimia nervosa and binge eating disorder with promising results. Progress has been made in treatment of adolescent anorexia nervosa, although not for the adult expression of this disorder.

Search strategy and selection criteria

We searched the Cochrane Library, Medline, and Embase up to March, 2009. We used the search terms: “anorexia nervosa”, “bulimia nervosa”, “binge eating disorder”, and “eating disorders” in combination with the terms “treatment”, “biology”, “outcome”, “epidemiology”, “comorbidity”, “personality”, “osteoporosis”, “medical”, “neuropsychology”, “neuroimaging”, “psychotherapy”, and “pharmacotherapy”. We manually searched the main eating disorder specialist journals and reference lists of articles identified by this search strategy. Several review articles or books are included because they provide comprehensive overviews that are beyond the scope of this Seminar. We largely selected publications in the past 6 years, but did not exclude commonly referenced and highly regarded older publications, or more recent ones published during the review process and that we considered of relevance to the scope of the Seminar. Whenever possible we have cited systematic reviews on a topic.

Contributors

All authors contributed to the search and selection of the literature and to the writing of the Seminar.

Conflicts of interest

JT has written several books on eating disorders for which she receives royalties. AMC has received honoraria as speaker for Meddley and Janssen-Cilag pharmaceutical industries, and has participated in multicentre trials supported by Abbott and Janssen-Cilag (without grants) between 2001 and 2007. NZ declares that she has no conflicts of interest.

Acknowledgments

We thank the anonymous reviewers for their comments on early drafts of this Seminar. JT was partly funded by a UK Department of Health National Institute for Health Research (NIHR) Programme Grant for Applied Research (reference number RP-PG-0606-1043) and receives support from the NIHR Specialist Biomedical Research Centre for Mental Health award to the South London and Maudsley NHS Foundation Trust and the Institute of Psychiatry, King’s College London. The views expressed herein are not necessarily those of the Department of Health or NIHR. AMC was funded by CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior), Ministry of Education, Brazil, with a post-doctoral grant at the Institute of Psychiatry, King’s College London, during 2008 (during the writing and review process of this Seminar). NZ is partly funded by the US National Institutes of Health (K23-MH-070418).

References

1 Fairburn CG, Harrison PJ. Eating disorders. Lancet 2003; 361: 407-416. Summary | Full Text | PDF(131KB) | CrossRef | PubMed

2 American Psychiatric Association. Diagnostic and statistical manual of mental disorders. Washington, DC: American Psychiatric Association, 1994.

3 WHO. International statistical classification of diseases and related health problems (ICD-10). Geneva: World Health Orgaganization, 1992.

4 Cole TJ, Flegal KM, Nicholls D, Jackson AA. Body mass index cut offs to define thinness in children and adolescents: international survey. BMJ 2007; 335: 194. PubMed

5 Fairburn CG, Cooper Z. Thinking afresh about the classification of eating disorders. Int J Eat Disord 2007; 40 (suppl): S107-S110. CrossRef | PubMed

6 Walsh BT, Sysko R. Broad categories for the diagnosis of eating disorders (BCD-ED): an alternative system for classification. Int J Eat Disord 200910.1002/eat.20722. published online July 31. PubMed

7 Marcus MD, Wildes JE. Obesity: is it a mental disorder?. Int J Eat Disord 200910.1002/eat.20725. published online July 16. PubMed

8 Eddy KT, Dorer DJ, Franko DL, Tahilani K, Thompson-Brenner H, Herzog DB. Diagnostic crossover in anorexia nervosa and bulimia nervosa: implications for DSM-V. Am J Psychiatry 2008; 165: 245-250. CrossRef | PubMed

9 Wilfley DE, Bishop ME, Wilson GT, Agras WS. Classification of eating disorders: toward DSM-V. Int J Eat Disord 2007; 40 (suppl): S123-S129. CrossRef | PubMed

10 Williamson DA. Does the evidence point to a binge eating phenotype? Comment on Gordon, et al (2007) and Wonderlich, et al. (2007). Int J Eat Disord 2007; 40 (suppl): S72-S75. CrossRef | PubMed

11 Javaras KN, Laird NM, Reichborn-Kjennerud T, Bulik CM, Pope HG, Hudson JI. Familiality and heritability of binge eating disorder: results of a case-control family study and a twin study. Int J Eat Disord 2008; 41: 174-179. CrossRef | PubMed

12 Wilson GT, Grilo CM, Vitousek KM. Psychological treatment of eating disorders. Am Psychol 2007; 62: 199-216. CrossRef | PubMed

13 Pope HG, Lalonde JK, Pindyck LJ, et al. Binge eating disorder: a stable syndrome. Am J Psychiatry 2006; 163: 2181-2183. CrossRef | PubMed

14 Fairburn CG, Cooper Z, Shafran R. Cognitive behaviour therapy for eating disorders: a “transdiagnostic” theory and treatment. Behav Res Ther 2003; 41: 509-528. CrossRef | PubMed

15 Hollander E, Kim S, Khanna S, Pallanti S. Obsessive-compulsive disorder and obsessive-compulsive spectrum disorders: diagnostic and dimensional issues. CNS Spectr 2007; 12: 5-13. PubMed

16 Pallister E, Waller G. Anxiety in the eating disorders: understanding the overlap. Clin Psychol Rev 2008; 28: 366-386. CrossRef | PubMed

17 Hudson JI, Pope HG. Genetic epidemiology of eating disorders and co-occurring conditions: the role of endophenotypes. Int J Eat Disord 2007; 40 (suppl): S76-S78. CrossRef | PubMed

18 Thomas JJ, Vartanian LR, Brownell KD. The relationship between eating disorder not otherwise specified (EDNOS) and officially recognized eating disorders: meta-analysis and implications for DSM. Psychol Bull 2009; 135: 407-433. CrossRef | PubMed

19 Jacobi F, Wittchen HU, Holting C, et al. Prevalence, co-morbidity and correlates of mental disorders in the general population: results from the German Health Interview and Examination Survey (GHS). Psychol Med 2004; 34: 597-611. CrossRef | PubMed

20 Hudson JI, Hiripi E, Pope HG, Kessler RC. The prevalence and correlates of eating disorders in the National Comorbidity Survey Replication. Biol Psychiatry 2007; 61: 348-358. CrossRef | PubMed

21 Wentz E, Lacey JH, Waller G, Rastam M, Turk J, Gillberg C. Childhood onset neuropsychiatric disorders in adult eating disorder patients. A pilot study. Eur Child Adolesc Psychiatry 2005; 14: 431-437. CrossRef | PubMed

22 Gillberg IC, Gillberg C, Rastam M, Johansson M. The cognitive profile of anorexia nervosa: a comparative study including a community-based sample. Compr Psychiatry 1996; 37: 23-30. CrossRef | PubMed

23 Nazar BP, Pinna CM, Coutinho G, et al. Review of literature of attention-deficit/hyperactivity disorder with comorbid eating disorders. Rev Bras Psiquiatr 2008; 30: 384-389. PubMed

24 Anderluh MB, Tchanturia K, Rabe-Hesketh S, Treasure J. Childhood obsessive-compulsive personality traits in adult women with eating disorders: defining a broader eating disorder phenotype. Am J Psychiatry 2003; 160: 242-247. CrossRef | PubMed

25 Lilenfeld LR, Wonderlich S, Riso LP, Crosby R, Mitchell J. Eating disorders and personality: a methodological and empirical review. Clin Psychol Rev 2006; 26: 299-320. CrossRef | PubMed

26 Halmi KA, Tozzi F, Thornton LM, et al. The relation among perfectionism, obsessive-compulsive personality disorder and obsessive-compulsive disorder in individuals with eating disorders. Int J Eat Disord 2005; 38: 371-374. CrossRef | PubMed

27 Kaye WH, Bulik CM, Thornton L, Barbarich N, Masters K. Comorbidity of anxiety disorders with anorexia and bulimia nervosa. Am J Psychiatry 2004; 161: 2215-2221. CrossRef | PubMed

28 Godart NT, Flament MF, Curt F, et al. Anxiety disorders in subjects seeking treatment for eating disorders: a DSM-IV controlled study. Psychiatry Res 2003; 117: 245-258. CrossRef | PubMed

29 Strober M, Freeman R, Lampert C, Diamond J. The association of anxiety disorders and obsessive compulsive personality disorder with anorexia nervosa: evidence from a family study with discussion of nosological and neurodevelopmental implications. Int J Eat Disord 2007; 40 (suppl): S46-S51. CrossRef | PubMed

30 Lilenfeld LR, Kaye WH, Greeno CG, et al. A controlled family study of anorexia nervosa and bulimia nervosa: psychiatric disorders in first-degree relatives and effects of proband comorbidity. Arch Gen Psychiatry 1998; 55: 603-610. CrossRef | PubMed

31 McElroy SL, Kotwal R, Keck PE. Comorbidity of eating disorders with bipolar disorder and treatment implications. Bipolar Disord 2006; 8: 686-695. CrossRef | PubMed

32 Mangweth B, Hudson JI, Pope HG, et al. Family study of the aggregation of eating disorders and mood disorders. Psychol Med 2003; 33: 1319-1323. CrossRef | PubMed

33 Gadalla T, Piran N. Co-occurrence of eating disorders and alcohol use disorders in women: a meta analysis. Arch Womens Ment Health 2007; 10: 133-140. CrossRef | PubMed

34 Calero-Elvira A, Krug I, Davis K, Lopez C, Fernandez-Aranda F, Treasure J. Meta-analysis on drugs in people with eating disorders. Eur Eat Disord Rev 2009; 17: 243-259. PubMed

35 Neumark-Sztainer D, Hannan PJ. Weight-related behaviors among adolescent girls and boys: results from a national survey. Arch Pediatr Adolesc Med 2000; 154: 569-577. PubMed

36 WHO (Europe). Mental health of children and adolescents. (Facing the challenges and finding solutions). Geneva: World Health Organization, 2005.

37 Chen H, Jackson T. Prevalence and sociodemographic correlates of eating disorder endorsements among adolescents and young adults from China. Eur Eat Disord Rev 2008; 16: 375-385. PubMed

38 de Souza Ferreira JE, da Veiga GV. Eating disorder risk behavior in Brazilian adolescents from low socio-economic level. Appetite 2008; 51: 249-255. CrossRef | PubMed

39 Jacobi C, Hayward C, de Zwaan M, Kraemer HC, Agras WS. Coming to terms with risk factors for eating disorders: application of risk terminology and suggestions for a general taxonomy. Psychol Bull 2004; 130: 19-65. CrossRef | PubMed

40 Klump KL, Bulik CM, Kaye WH, Treasure J, Tyson E. Academy for eating disorders position paper: eating disorders are serious mental illnesses. Int J Eat Disord 2009; 42: 97-103. PubMed

41 Olivry E, Corcos M. [Eating disorders. Prepubertal anorexia nervosa]. Presse Med 1999; 28: 100-102. PubMed

42 Bulik CM, Landt MC Slof-Op’t, van Furth EF, Sullivan PF. The genetics of anorexia nervosa. Ann Rev Nutr 2007; 27: 263-275. PubMed

43 Bulik CM, Tozzi F. The genetics of bulimia nervosa. Drugs Today (Barc) 2004; 40: 741-749. PubMed

44 Bacanu SA, Bulik CM, Klump KL, et al. Linkage analysis of anorexia and bulimia nervosa cohorts using selected behavioral phenotypes as quantitative traits or covariates. Am J Med Genet B Neuropsychiatr Genet 2005; 139B: 61-68. CrossRef | PubMed

45 Bergen AW, Yeager M, Welch R, et al. Candidate gene analysis of the Price Foundation anorexia nervosa affected relative pair dataset. Curr Drug Targets CNS Neurol Disord 2003; 2: 41-51. CrossRef | PubMed

46 Bulik CM, Devlin B, Bacanu SA, et al. Significant linkage on chromosome 10p in families with bulimia nervosa. Am J Hum Genet 2003; 72: 200-207. CrossRef | PubMed

47 Wade TD, Bulik CM, Neale M, Kendler KS. Anorexia nervosa and major depression: shared genetic and environmental risk factors. Am J Psychiatry 2000; 157: 469-471. CrossRef | PubMed

48 Keel PK, Klump KL, Miller KB, McGue M, Iacono WG. Shared transmission of eating disorders and anxiety disorders. Int J Eat Disord 2005; 38: 99-105. CrossRef | PubMed

49 Baker JH, Mazzeo SE, Kendler KS. Association between broadly defined bulimia nervosa and drug use disorders: common genetic and environmental influences. Int J Eat Disord 2007; 40: 673-678. CrossRef | PubMed

50 Keys A, Brozek J, Henschel A. The biology of human starvation. Minneapolis: University of Minnesota Press, 1950.

51 Castro-Fornieles J, Bargallo N, Lazaro L, et al. A cross-sectional and follow-up voxel-based morphometric MRI study in adolescent anorexia nervosa. J Psychiatr Res 2009; 43: 331-340. CrossRef | PubMed

52 Nakazato M, Tchanturia K, Schmidt U, et al. Brain-derived neurotrophic factor (BDNF) and set-shifting in currently ill and recovered anorexia nervosa (AN) patients. Psychol Med 2009; 39: 1029-1035. CrossRef | PubMed

53 Ribases M, Gratacos M, Fernandez-Aranda F, et al. Association of BDNF with restricting anorexia nervosa and minimum body mass index: a family-based association study of eight European populations. Eur J Hum Genet 2005; 13: 428-434. CrossRef | PubMed

54 Berthoud HR, Morrison C. The brain, appetite, and obesity. Ann Rev Psychol 2008; 59: 55-92. PubMed

55 Berridge KC. ‘Liking’ and ‘wanting’ food rewards: brain substrates and roles in eating disorders. Physiol Behav 2009; 97: 537-550. CrossRef | PubMed

56 Marsh R, Maia TV, Peterson BS. Functional disturbances within frontostriatal circuits across multiple childhood psychopathologies. Am J Psychiatry 2009; 166: 664-674. CrossRef | PubMed

57 Avena NM. Examining the addictive-like properties of binge eating using an animal model of sugar dependence. Exp Clin Psychopharmacol 2007; 15: 481-491. CrossRef | PubMed

58 Boggiano MM, Artiga AI, Pritchett CE, Chandler-Laney PC, Smith ML, Eldridge AJ. High intake of palatable food predicts binge-eating independent of susceptibility to obesity: an animal model of lean vs obese binge-eating and obesity with and without binge-eating. Int J Obes (Lond) 2007; 31: 1357-1367. CrossRef | PubMed

59 Hebebrand J, Remschmidt H. Anorexia nervosa viewed as an extreme weight condition: genetic implications. Hum Genet 1995; 95: 1-11. PubMed

60 Hudson JI, Lalonde JK, Berry JM, et al. Binge-eating disorder as a distinct familial phenotype in obese individuals. Arch Gen Psychiatry 2006; 63: 313-319. CrossRef | PubMed

61 Kaye WH, Fudge JL, Paulus M. New insights into symptoms and neurocircuit function of anorexia nervosa. Nat Rev Neurosci 2009; 10: 573-584. PubMed

62 Frank GK, Bailer UF, Henry SE, et al. Increased dopamine D2/D3 receptor binding after recovery from anorexia nervosa measured by positron emission tomography and [(11)C]raclopride. Biol Psychiatry 2005; 58: 908-912. CrossRef | PubMed

63 Davis C, Patte K, Levitan R, Reid C, Tweed S, Curtis C. From motivation to behaviour: a model of reward sensitivity, overeating, and food preferences in the risk profile for obesity. Appetite 2007; 48: 12-19. CrossRef | PubMed

64 Lee M, Shafran R. Information processing biases in eating disorders. Clin Psychol Rev 2004; 24: 215-238. CrossRef | PubMed

65 Van den Eynde F, Treasure J. Neuroimaging in eating disorders and obesity: implications for research. Child Adolesc Psychiatr Clin N Am 2009; 18: 95-115. CrossRef | PubMed

66 Liao PC, Uher R, Lawrence N, et al. An examination of decision making in bulimia nervosa. J Clin Exp Neuropsychol 2009; 31: 455-461. CrossRef | PubMed

67 Wagner A, Aizenstein H, Venkatraman VK, et al. Altered reward processing in women recovered from anorexia nervosa. Am J Psychiatry 2007; 164: 1842-1849. CrossRef | PubMed

68 Wagner A, Aizenstein H, Venkatraman VK, et al. Altered striatal response to reward in bulimia nervosa after recovery. Int J Eat Disord 200910.1002/eat.20699. published online May 11. PubMed

69 Roberts ME, Tchanturia K, Stahl D, Southgate L, Treasure J. A systematic review and meta-analysis of set-shifting ability in eating disorders. Psychol Med 2007; 37: 1075-1084. CrossRef | PubMed

70 Zastrow A, Kaiser S, Stippich C, et al. Neural correlates of impaired cognitive-behavioral flexibility in anorexia nervosa. Am J Psychiatry 2009; 166: 608-616. CrossRef | PubMed

71 Lopez C, Tchanturia K, Stahl D, Treasure J. Central coherence in eating disorders: a systematic review. Psychol Med 2008; 38: 1393-1404. PubMed

72 Zucker NL, Losh M, Bulik CM, LaBar KS, Piven J, Pelphrey KA. Anorexia nervosa and autism spectrum disorders: guided investigation of social cognitive endophenotypes. Psychol Bull 2007; 133: 976-1006. CrossRef | PubMed

73 Harrison A, Sullivan S, Tchanturia K, Treasure J. Emotion recognition and regulation in anorexia nervosa. Clin Psychol Psychother 2009; 16: 348-356. PubMed

74 Shoebridge P, Gowers SG. Parental high concern and adolescent-onset anorexia nervosa. A case-control study to investigate direction of causality. Br J Psychiatry 2000; 176: 132-137. CrossRef | PubMed

75 Favaro A, Tenconi E, Santonastaso P. Perinatal factors and the risk of developing anorexia nervosa and bulimia nervosa. Arch Gen Psychiatry 2006; 63: 82-88. CrossRef | PubMed

76 Groesz LM, Levine MP, Murnen SK. The effect of experimental presentation of thin media images on body satisfaction: a meta-analytic review. Int J Eat Disord 2002; 31: 1-16. CrossRef | PubMed

77 Wade TD, Gillespie N, Martin NG. A comparison of early family life events amongst monozygotic twin women with lifetime anorexia nervosa, bulimia nervosa, or major depression. Int J Eat Disord 2007; 40: 679-686. CrossRef | PubMed

78 Schmidt U, Treasure J. Anorexia nervosa: valued and visible. A cognitive-interpersonal maintenance model and its implications for research and practice. Br J Clin Psychol 2006; 45: 1-25. CrossRef | PubMed

79 Currin L, Schmidt U, Treasure J, Jick H. Time trends in eating disorder incidence. Br J Psychiatry 2005; 186: 132-135. CrossRef | PubMed

80 Gowers S, Bryant-Waugh R. Management of child and adolescent eating disorders: the current evidence base and future directions. J Child Psychol Psychiatry 2004; 45: 63-83. CrossRef | PubMed

81 Williams PM, Goodie J, Motsinger CD. Treating eating disorders in primary care. Am Fam Physician 2008; 77: 187-195. PubMed

82 National Collaborating Centre for Mental Health. National Clinical Practice Guideline: eating disorders: core interventions in the treatment and management of anorexia nervosa, bulimia nervosa, and related eating disorders. National Institute for Clinical Excellence. http://www.nice.org.uk/search/guidancesearchresults. (accessed Oct 27, 2009).

83 American Psychiatric Association. In: Practice guidelines for the treatment of patients with eating disorders. Practice guidelines for the treatment of psychiatric disorders, 3rd edn. Arlington: American Psychiatric Association, 2006: 1097-1222.

84 Beumont P, Hay P, Beumont D, et al. Australian and New Zealand clinical practice guidelines for the treatment of anorexia nervosa. Aust N Z J Psychiatry 2004; 38: 659-670. CrossRef | PubMed

85 National Collaborating Centre for Acute Care. Nutritional support in adults: NICE Clinical Guideline 32. London: National Institute for Health and Clinical Excellence (NICE) NHS, 2006.

86 Eiro M, Katoh T, Watanabe T. Use of a proton-pump inhibitor for metabolic disturbances associated with anorexia nervosa. N Engl J Med 2002; 346: 140. CrossRef | PubMed

87 Mehler PS, Mackenzie TD. Treatment of osteopenia and osteoporosis in anorexia nervosa: a systematic review of the literature. Int J Eat Disord 2009; 42: 195-201. CrossRef | PubMed

88 Hjern A, Lindberg L, Lindblad F. Outcome and prognostic factors for adolescent female in-patients with anorexia nervosa: 9- to 14-year follow-up. Br J Psychiatry 2006; 189: 428-432. CrossRef | PubMed

89 Micali N, Simonoff E, Treasure J. Risk of major adverse perinatal outcomes in women with eating disorders. Br J Psychiatry 2007; 190: 255-259. CrossRef | PubMed

90 Bulik CM, Von Holle A, Siega-Riz AM, et al. Birth outcomes in women with eating disorders in the Norwegian Mother and Child cohort study (MoBa). Int J Eat Disord 2009; 42: 9-18. CrossRef | PubMed

91 Sollid CP, Wisborg K, Hjort J, Secher NJ. Eating disorder that was diagnosed before pregnancy and pregnancy outcome. Am J Obstet Gynecol 2004; 190: 206-210. CrossRef | PubMed

92 Stein A, Woolley H, Cooper S, Winterbottom J, Fairburn CG, Cortina-Borja M. Eating habits and attitudes among 10-year-old children of mothers with eating disorders: longitudinal study. Br J Psychiatry 2006; 189: 324-329. CrossRef | PubMed

93 Patton GC, Coffey C, Carlin JB, Sanci L, Sawyer S. Prognosis of adolescent partial syndromes of eating disorder. Br J Psychiatry 2008; 192: 294-299. CrossRef | PubMed

94 Kaplan AS, Walsh BT, Olmsted M, et al. The slippery slope: prediction of successful weight maintenance in anorexia nervosa. Psychol Med 2009; 39: 1037-1045. CrossRef | PubMed

95 Fittig E, Jacobi C, Backmund H, Gerlinghoff M, Wittchen HU. Effectiveness of day hospital treatment for anorexia nervosa and bulimia nervosa. Eur Eat Disord Rev 2008; 16: 341-351. PubMed

96 Hailey D, Roine R, Ohinmaa A. The effectiveness of telemental health applications: a review. Can J Psychiatry 2008; 53: 769-778. PubMed

97 Mitchell JE, Crosby RD, Wonderlich SA, et al. A randomized trial comparing the efficacy of cognitive-behavioral therapy for bulimia nervosa delivered via telemedicine versus face-to-face. Behav Res Ther 2008; 46: 581-592. CrossRef | PubMed

98 Perkins SJ, Murphy R, Schmidt U, Williams C. Self-help and guided self-help for eating disorders. Cochrane Database Syst Rev 2006; 3. CD004191. PubMed

99 Robinson P, Serfaty M. Getting better byte by byte: a pilot randomised controlled trial of email therapy for bulimia nervosa and binge eating disorder. Eur Eat Disord Rev 2008; 16: 84-93. PubMed

100 Vocks S, Tuschen-Caffier B, Pietrowsky R, Rustenbach SJ, Kersting A, Herpertz S. Meta-analysis of the effectiveness of psychological and pharmacological treatments for binge eating disorder. Int J Eat Disord 200910.1002/eat.20696. published online April 28. PubMed

101 Sysko R, Walsh BT. A critical evaluation of the efficacy of self-help interventions for the treatment of bulimia nervosa and binge-eating disorder. Int J Eat Disord 2008; 41: 97-112. CrossRef | PubMed

102 Keel PK, Haedt A. Evidence-based psychosocial treatments for eating problems and eating disorders. J Clin Child Adolesc Psychol 2008; 37: 39-61. CrossRef | PubMed

103 Lock J, Agras WS, Bryson S, Kraemer HC. A comparison of short- and long-term family therapy for adolescent anorexia nervosa. J Am Acad Child Adolesc Psychiatry 2005; 44: 632-639. CrossRef | PubMed

104 Eisler I, Simic M, Russell GF, Dare C. A randomised controlled treatment trial of two forms of family therapy in adolescent anorexia nervosa: a five-year follow-up. J Child Psychol Psychiatry 2007; 48: 552-560. CrossRef | PubMed

105 Zablana M, Macdonald P, Treasure J. Appraisal of caregiving burden, expressed emotion and psychological distress in families of people with eating disorders: a systematic review. Eur Eat Disord Rev 2009; 17: 327-330. PubMed

106 Zucker NL, Marcus M, Bulik C. A group parent-training program: a novel approach for eating disorder management. Eat Weight Disord 2006; 11: 78-82. PubMed

107 Hay PPJ, Bacltchuk J, Byrnes RT, Claudino AM, Ekmejian SS, Yong PY. Individual psychotherapy in the outpatient treatment of adults with anorexia nervosa (review), 2nd edn. Cochrane Database Syst Rev 2008; 1. CD003909. PubMed

108 Crow SJ, Mitchell JE, Roerig JD, Steffen K. What potential role is there for medication treatment in anorexia nervosa?. Int J Eat Disord 2009; 42: 1-8. CrossRef | PubMed

109 Claudino AM, Hay P, Lima MS, Bacaltchuk J, Schmidt U, Treasure J. Antidepressants for anorexia nervosa. Cochrane Database Syst Rev 2006; 1. CD004365. PubMed

110 Kaye WH, Nagata T, Weltzin TE, et al. Double-blind placebo-controlled administration of fluoxetine in restricting- and restricting-purging-type anorexia nervosa. Biol Psychiatry 2001; 49: 644-652. CrossRef | PubMed

111 Walsh BT, Kaplan AS, Attia E, et al. Fluoxetine after weight restoration in anorexia nervosa: a randomized controlled trial. JAMA 2006; 295: 2605-2612. CrossRef | PubMed

112 Bosanac P, Norman T, Burrows G, Beumont P. Serotonergic and dopaminergic systems in anorexia nervosa: a role for atypical antipsychotics?. Aust N Z J Psychiatry 2005; 39: 146-153. CrossRef | PubMed

113 Brambilla F, Garcia CS, Fassino S, et al. Olanzapine therapy in anorexia nervosa: psychobiological effects. Int Clin Psychopharmacol 2007; 22: 197-204. CrossRef | PubMed

114 Bissada H, Tasca GA, Barber AM, Bradwejn J. Olanzapine in the treatment of low body weight and obsessive thinking in women with anorexia nervosa: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry 2008; 165: 1281-1288. CrossRef | PubMed

115 Shapiro JR, Berkman ND, Brownley KA, Sedway JA, Lohr KN, Bulik CM. Bulimia nervosa treatment: a systematic review of randomized controlled trials. Int J Eat Disord 2007; 40: 321-336. CrossRef | PubMed

116 Fairburn CG, Marcus MD, Wilson GT. Cognitive-behavioral therapy for binge eating and bulimia nervosa: a comprehensive treatment manual. In: Fairburn CG, Wilson GT, eds. Binge eating: nature, assessment, and treatment. New York: The Guilford Press, 1993: 361-404.

117 Hay PJ, Bacaltchuk J. Bulimia nervosa. Clin Evid (Online) 2008: 1009. June 12, pii: PubMed

118 Mitchell JE, Agras S, Wonderlich S. Treatment of bulimia nervosa: where are we and where are we going?. Int J Eat Disord 2007; 40: 95-101. CrossRef | PubMed

119 Fairburn CG, Cooper Z, Doll HA, et al. Transdiagnostic cognitive-behavioral therapy for patients with eating disorders: a two-site trial with 60-week follow-up. Am J Psychiatry 2009; 166: 311-319. CrossRef | PubMed

120 Chen EY, Matthews L, Allen C, Kuo JR, Linehan MM. Dialectical behavior therapy for clients with binge-eating disorder or bulimia nervosa and borderline personality disorder. Int J Eat Disord 2008; 41: 505-512. CrossRef | PubMed

121 Schmidt U, Lee S, Beecham J, et al. A randomized controlled trial of family therapy and cognitive behavior therapy guided self-care for adolescents with bulimia nervosa and related disorders. Am J Psychiatry 2007; 164: 591-598. CrossRef | PubMed

122 Ie GD, Crosby RD, Rathouz PJ, Leventhal BL. A randomized controlled comparison of family-based treatment and supportive psychotherapy for adolescent bulimia nervosa. Arch Gen Psychiatry 2007; 64: 1049-1056. CrossRef | PubMed

123 Hay PJ, Bacaltchuk J, Stefano S. Psychotherapy for bulimia nervosa and binging. Cochrane Database Syst Rev 2004; 3. CD000562. PubMed

124 Stone M, Laughren T, Jones ML, et al. Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. BMJ 2009; 339: b2880. PubMed

125 Bacaltchuk J, Hay P. Antidepressants versus placebo for people with bulimia nervosa. Cochrane Database Syst Rev 2003; 4. CD003391. PubMed

126 Milano W, Siano C, Putrella C, Capasso A. Treatment of bulimia nervosa with fluvoxamine: a randomized controlled trial. Adv Ther 2005; 22: 278-283. CrossRef | PubMed

127 Romano SJ, Halmi KA, Sarkar NP, Koke SC, Lee JS. A placebo-controlled study of fluoxetine in continued treatment of bulimia nervosa after successful acute fluoxetine treatment. Am J Psychiatry 2002; 159: 96-102. CrossRef | PubMed

128 Nickel C, Tritt K, Muehlbacher M, et al. Topiramate treatment in bulimia nervosa patients: a randomized, double-blind, placebo-controlled trial. Int J Eat Disord 2005; 38: 295-300. CrossRef | PubMed

129 Hedges DW, Reimherr FW, Hoopes SP, et al. Treatment of bulimia nervosa with topiramate in a randomized, double-blind, placebo-controlled trial, part 2: improvement in psychiatric measures. J Clin Psychiatry 2003; 64: 1449-1454. PubMed

130 Brownley KA, Berkman ND, Sedway JA, Lohr KN, Bulik CM. Binge eating disorder treatment: a systematic review of randomized controlled trials. Int J Eat Disord 2007; 40: 337-348. CrossRef | PubMed

131 Devlin MJ, Goldfein JA, Petkova E, et al. Cognitive behavioral therapy and fluoxetine as adjuncts to group behavioral therapy for binge eating disorder. Obes Res 2005; 13: 1077-1088. PubMed

132 Wilfley DE, Welch RR, Stein RI, et al. A randomized comparison of group cognitive-behavioral therapy and group interpersonal psychotherapy for the treatment of overweight individuals with binge-eating disorder. Arch Gen Psychiatry 2002; 59: 713-721. CrossRef | PubMed

133 Agras WS, Telch CF, Arnow B, Eldredge K, Marnell M. One-year follow-up of cognitive-behavioral therapy for obese individuals with binge eating disorder. J Consult Clin Psychol 1997; 65: 343-347. CrossRef | PubMed

134 Devlin MJ, Goldfein JA, Petkova E, Liu L, Walsh BT. Cognitive behavioral therapy and fluoxetine for binge eating disorder: two-year follow-up. Obesity (Silver Spring) 2007; 15: 1702-1709. CrossRef | PubMed

135 Reas DL, Grilo CM. Review and meta-analysis of pharmacotherapy for binge-eating disorder. Obesity (Silver Spring) 2008; 16: 2024-2038. CrossRef | PubMed

136 Guerdjikova AI, McElroy SL, Kotwal R, et al. High-dose escitalopram in the treatment of binge-eating disorder with obesity: a placebo-controlled monotherapy trial. Hum Psychopharmacol 2008; 23: 1-11. CrossRef | PubMed

137 Stefano SC, Bacaltchuk J, Blay SL, Appolinario JC. Antidepressants in short-term treatment of binge eating disorder: systematic review and meta-analysis. Eat Behav 2008; 9: 129-136. CrossRef | PubMed

138 Appolinario JC, Bacaltchuk J, Sichieri R, et al. A randomized, double-blind, placebo-controlled study of sibutramine in the treatment of binge-eating disorder. Arch Gen Psychiatry 2003; 60: 1109-1116. CrossRef | PubMed

139 Wilfley DE, Crow SJ, Hudson JI, et al. Efficacy of sibutramine for the treatment of binge eating disorder: a randomized multicenter placebo-controlled double-blind study. Am J Psychiatry 2008; 165: 51-58. CrossRef | PubMed

140 Golay A, Laurent-Jaccard A, Habicht F, et al. Effect of orlistat in obese patients with binge eating disorder. Obes Res 2005; 13: 1701-1708. PubMed

141 McElroy SL, Hudson JI, Capece JA, Beyers K, Fisher AC, Rosenthal NR. Topiramate for the treatment of binge eating disorder associated with obesity: a placebo-controlled study. Biol Psychiatry 2007; 61: 1039-1048. PubMed

142 McElroy SL, Kotwal R, Guerdjikova AI, et al. Zonisamide in the treatment of binge eating disorder with obesity: a randomized controlled trial. J Clin Psychiatry 2006; 67: 1897-1906. CrossRef | PubMed

143 McElroy SL, Guerdjikova A, Kotwal R, et al. Atomoxetine in the treatment of binge-eating disorder: a randomized placebo-controlled trial. J Clin Psychiatry 2007; 68: 390-398. CrossRef | PubMed

144 Claudino AM, de Oliveira IR, Appolinario JC, et al. Double-blind, randomized, placebo-controlled trial of topiramate plus cognitive-behavior therapy in binge-eating disorder. J Clin Psychiatry 2007; 68: 1324-1332. CrossRef | PubMed

145 Grilo CM, Masheb RM, Salant SL. Cognitive behavioral therapy guided self-help and orlistat for the treatment of binge eating disorder: a randomized, double-blind, placebo-controlled trial. Biol Psychiatry 2005; 57: 1193-1201. CrossRef | PubMed

146 Reas DL, Grilo CM. Review and meta-analysis of pharmacotherapy for binge-eating disorder. Obesity (Silver Spring) 2008; 16: 2024-2038. CrossRef | PubMed

147 Von HA, Pinheiro AP, Thornton LM, et al. Temporal patterns of recovery across eating disorder subtypes. Aust N Z J Psychiatry 2008; 42: 108-117. CrossRef | PubMed

148 Berkman ND, Lohr KN, Bulik CM. Outcomes of eating disorders: a systematic review of the literature. Int J Eat Disord 2007; 40: 293-309. CrossRef | PubMed

149 Papadopoulos FC, Ekbom A, Brandt L, Ekselius L. Excess mortality, causes of death and prognostic factors in anorexia nervosa. Br J Psychiatry 2009; 194: 10-17. CrossRef | PubMed

150 Byford S, Barrett B, Roberts C, et al. Economic evaluation of a randomised controlled trial for anorexia nervosa in adolescents. Br J Psychiatry 2007; 191: 436-440. CrossRef | PubMed

151 Fichter MM, Quadflieg N, Hedlund S. Long-term course of binge eating disorder and bulimia nervosa: relevance for nosology and diagnostic criteria. Int J Eat Disord 2008; 41: 577-586. CrossRef | PubMed

This week’s editorial examines the findings of a review on placebo effects published in today’s edition of The Lancet.

Studies have demonstrated that placebo effects are a genuine psychobiological event highly linked with the treatment environment

The intrinsic relationship of placebos with deception has generally not granted them the best reputation in medicine. These inert substances are used in trials as markers of success or failure of a new treatment, yet some believe they have potential for more. Which leads us to ask, what if the cure were the placebo?

The concept of placebo can be traced back hundreds of years. The first reported use of a dummy to distinguish between real and delusive effects occurred in the 16th century when Catholics utilised false holy objects in exorcisms to prove if the person was really possessed or it was a result of their imagination. Still, the incursion of placebos into the medical field as controls in experiments did not take place until Franklin’s 1784 study of the psychic force of mesmerism.

In the years that followed, until today, placebos have been continuously employed to ensure that treatment results are not principally due to endogenous effects. The use of these substances has not been devoid of controversy, mainly stemming from ethical concerns that patients were being deprived of life saving treatment for the sake of science. Nevertheless, increased interest in placebos was sparked after researchers noticed that patients in control groups given placebos experienced significant improvements.

Sceptics argue that placebo effects occur as the result of the natural progression of the disease and not due to the substance itself. However, studies have demonstrated that placebo effects are a genuine psychobiological event highly linked with the treatment environment.

A RCT compared placebo effects versus no-treatment by examining 262 patients with irritable bowel syndrome. The placebo group received acupuncture utilising a device with a retractable needle; the placebo plus supportive treatment group experienced a supportive patient-doctor interaction, as well as receiving the false acupuncture treatment; and finally, the third group received no treatment. After three weeks, 62% of the patients in the placebo plus supportive care group reported improvements, compared with 44% in the placebo-alone group, and 28% in the no-treatment group (p<0.001). Studies of other diseases and in different settings show demonstrable laboratory and clinical effects of placebos.

The invariability of placebos with deceit brings up important questions about how to ethically employ them in clinical settings. Although physicians often prescribe supportive treatment expecting some sort of placebo effect in patients, the situation changes when treatment is given for its placebo effect alone. The authors of the review stress the need to inform the patient of the expected benefits of treatment and disclosing the reasons for prescribing it. Little is known of the result of full disclosure of placebos to patients, which would seem to negate the effect altogether, but before betraying a patient’s trust we must remember that above all the most important component of a cure is not the treatment, but the patient her/himself.

Ana B. Amaya is a TLS Editor and DrPH Student at London School of Hygiene and Tropical Medicine
Email: ana.amaya@lshtm.ac.uk

Reference:
Finniss, D, Kaptchuk, T, Miller, F, et al. Biological, clinical, and ethical advances of placebo effects. Lancet 2010; 375: 686–95.

Today we’d like to announce the publication of Gurmeen Kaur’s article on the health problems in India caused by insufficient screening for breast cancer and the ways the situation could be improved. Read it here.

Meanwhile, in today’s blog Inderjeet Sahota, MSc. Student at Simon Fraser University in Canada, discusses concerns over the worldwide reaction to the H1N1 pandemic

As the dust begins to settle on the entire saga, health officials are beginning to ask themselves whether the global reaction to swine flu was necessarily precautionary or simply over-reactive

In April 2009 news reports began to surface of an influenza-like outbreak in Mexico. Mexican officials did whatever they could to curb its spread but the world watched anxiously as their efforts seemed insufficient in preventing further outbreaks. Cases of this swine flu, as it was now being referred to, were emerging in cities all across North America, Europe and Asia. Just two months after the initial reports in Mexico the World Health Organization (WHO) would declare this swine flu a pandemic and would begin putting protocols in place in the hope that it would help stop further spread. One after another countries began declaring this virus a national priority and pharmaceutical companies dedicated themselves to finding a vaccination. News reports tirelessly warned us of the immediate threat this virus posed to health and a genuine sense of paranoia ensued as people became too scared to even be in public places.

Not even a year later the situation is very different.

You’d be hard pressed to find a news report on the swine flu now. News reports here in Vancouver are focused more on the Winter Olympic Games and the international news seems to be pre-occupied with the global financial crisis. So, what happened? As the dust begins to settle on the entire saga, health officials are beginning to ask themselves whether the global reaction to swine flu was necessarily precautionary or simply over-reactive. Around 12,700 people worldwide died from H1N1, an unfortunately sizable number (1). However, this value needs to be taken into context. According to the Centre for Disease Control in the United States, about 36,000 people die from seasonal flu-related causes each year in the United States alone (2). Of course, this does not necessarily mean the flu was the primary cause of death but even still, the numbers indicate how relatively small the deaths from H1N1 really were in comparison to how many people die from the seasonal flu each year. Also, even before mass vaccination programs were introduced most people infected with H1N1 were able to recover within weeks with no long-term complications. However, although the physical loss from H1N1 remains fortunately small, the economic cost may not be so minute. The final global cost of the pandemic has yet to be determined, however, analysts believe it will be well into the billions of dollars (1). Wealthier countries have already confirmed to have spent that much on medicines and vaccinations alone and many governments are now trying to resell their stockpiles of the swine flu vaccine.

The WHO is now under threat as there have been accusations that the organization may have “faked” the pandemic to bring economic benefits to the pharmaceutical industry. Although this situation is unlikely, the allegations were serious enough to warrant the WHO to release an official statement on January 22, 2010 discussing the matter specifically (3). As months go by it will be interesting to see what the results of an independent study, comprised of scientists and health professionals, will be on how this emergency was handled and whether the global response was appropriate or grossly disproportionate.

The swine flu vaccinations themselves offer another potential problem. In Canada, and much of the rest of the world, there have been serious questions regarding the safety of the H1N1 vaccinations that were administered. As the need for deployment was paramount, pharmaceutical companies had a limited time to administer these vaccinations around the world. As such, appropriate long-term testing was pushed aside as vaccinations were fast-tracked through the process in the name of curbing this influenza pandemic. It remains to be seen whether there are any long-term effects of these vaccinations. Unfortunately, as many people have already undergone the treatment, the first results we have may be from case reports, not lab reports.

So, was the global response an over-reaction or a necessary precaution? I believe that even though there are many factors that need to be considered now that we can sit back and analyze the results, the overall response was in the right direction. Many health officials echo the concerns listed above but ultimately understand that the risk of this viral strain killing millions was worth the swift response (4). However, I do feel that although the response was in the right direction it wasn’t the right magnitude. If health officials were able to determine early on that this influenza strain was relatively moderate then an action plan that better suited the situation, rather than a seemingly all-or-nothing reaction, may have been more efficient. A tiered response where global protocols are issued according to a more accurate level of severity would probably be best when dealing with future pandemics. In the next year it will be interesting to see what the WHO and other governmental organizations determine from their analysis of the response and what changes may be made for similar emergencies in the future.

References

1. http://news.bbc.co.uk/2/hi/health/8455035.stm
2. http://www.cdc.gov/flu/about/disease/us_flu-related_deaths.htm
3. http://www.who.int/mediacentre/news/statements/2010/h1n1_pandemic_20100122/en/index.html
4. http://news.bbc.co.uk/2/hi/health/8458668.stm

A 35 year old female presented with bilateral advanced breast carcinoma (Stage 3) with an ulcer in the right breast, bilateral axillary lymphadenopathy and a left supraclavicular lymph node. The description adequately conveys the guarded prognosis.I worked on this case for my Surgery Practical Exam and it reinforced a thought that had been troubling me for a very long time. My patient was seeking medical help for the first time, though the lump had been present over the past two years. She had even continued to breastfeed her baby and stopped only five months ago when she developed excruciating pain. My patient is not one of those surprising exceptions who did not seek medical care on time. I have come across at least 10 such patients of breast cancer during my brief six week surgical rotation. I have tried to interview extensively all these victims, to discover the reason behind not seeking medical advice on time and ignoring a largely noticeable breast lump.

The reasons are so simple and naïve that they are distressing – the present patient did not know that hard lumps in the breasts were of any significance until she developed an ulcer a month ago. She even attributed her pain to excessive breastfeeding. Ignorance comes across as the main factor though other reasons also exist, including abusive and suppressive husbands and in-laws, and lack of knowledge among fellow female well-wishers who also are equally unaware. It is so sad to come across patients like this, especially when women in more developed countries are undergoing regular screening mammographic investigations and are well aware of breast self examination techniques.

In India, cancer of the breast is the most common cancer among women in many regions and has overtaken cervical cancer, which was the most frequent cancer a decade ago (1). It has been estimated that during the year 2001 alone, nearly 80,000 women developed breast cancer in India (2). Studies indicate that as India becomes Westernized, the incidence rate for breast cancer is increasing. A 2005 study conducted by the International Association of Cancer Research, based in Lyon, France, projected that there would be 250,000 cases of breast cancer in India by 2015, a 3% increase per year. Currently, India reports roughly 100,000 new cases annually (3).

Screening and Mortality

Screening by clinical breast examination (CBE) alone has not been demonstrated by randomized controlled trials to reduce mortality although a large trial is currently underway in Bombay by the Tata Memorial Centre(4). An IARC Working Group concluded in 2002 that there is inadequate evidence that breast screening by CBE, either alone or together with mammography, can reduce mortality from breast cancer (5). However, cancers detected by CBE tend to be diagnosed at an earlier stage than those not detected by screening, suggesting a greater potential for effectiveness in a setting where stage at diagnosis is generally poor (6). Although CBE undertaken by health workers seems to offer a cost-effective approach to reducing mortality, the sensitivity of the screening program in the real context was low with a sensitivity of only 25.6% and positive predictive value 1% (7). The UK Preventive Task Force report found that trials for breast self-examination showed no reductions in mortality but increase in benign biopsies. They concluded that no benefit has been shown for clinical breast examination or breast self-examination. On the other hand mammography screening reduces breast cancer mortality by 15% for women aged 39 to 49 years with low radiation exposure and an estimated over diagnosis of 1 to 10% (8).

While studies show that the efficacy of breast self examination is limited, it is imperative to recognize our shortcomings. India’s healthcare system is still in its developing phase, making it virtually impossible for all females to undergo regular screening mammography and general health checkups. Even so, there are still precautions that can be maintained. It is definitely possible to create awareness about the common signs and presentation of breast carcinoma, the common risk factors that may be contributory and the need for breast self examination.

Self-Examination

It is suggested that for very low resource settings in certain parts of India where population based screening, even with clinical breast examination by primary health workers is not feasible, health education combined with access to screening and treatment services, may be a simple and feasible strategy for reduction in cervix and breast cancer mortality (4). A praiseworthy practice about our hospital with a strong focus on women’s health issues, is that they not only perform a “clinical breast examination” on all women but also counsel them regarding the need for regular breast self-examination.

Reeler A et al (9) have defined a public health approach to cancers in developing countries where resources for effective cancer control are very limited and offer a framework for putting women’s cancers in developing countries on the global public health agenda. The key areas as proposed by them are: 1. Proposals for a new, integrated public health approach to women’s cancers (breast and cervical) in resource poor settings; 2. Reviews of the evidence for cost-effective screening and early detection of breast and cervical cancer; 3. Outlines of ways to make a priority of breast and cervical cancers in developing countries on the political agenda of international agencies. Implementation of such an integrated program may be the solution that we are looking for. A multilevel approach can be initiated only with active government policies and we hope that it would take shape in the near future. A number of Breast Cancer support groups and NGOs like Aastha Breast Cancer Support Group, Aarogya etc. are already doing very good work in providing medical and emotional support to affected women. Meanwhile given the current burden of breast cancer in India, it is the duty of everyone associated with medicine and anyone with a good outreach to be aware of the need of breast self-examination and to promote it whichever way they can. It is so unfortunate that even literate, educated, and well-read females are unaware of the need and method of self-examination.

We as a nation have a very long way to go. It is our duty as members of the healthcare delivery team – medical students and physicians alike – to do our part by educating and creating awareness about breast cancer and its early detection.

Gurmeen Kaur is a TLS RA and a final year medical student at Lady Hardinge Medical College, India
kaur.gurmeen(at)gmail.com

The author would like to acknowledge the assistance of Dr. Anurag Srivastava, a Breast Oncosurgeon at the All India Institute of Medical Sciences, New Delhi, India for his contributions to the paper.

References

1. Murthy NS, Agarwal UK, Chaudhry K, Saxena S. A study on time trends in incidence of breast cancer – Indian scenario. Eur J Cancer Care (Engl). 2007 Mar;16(2):185-6.

2. Murthy N.S., Juneja A., Sehgal A. & Luthra U.K. (1990) Cancer projection by the turn of century. Indian Journal of Cancer 27, 74–82.

3. Bagchi S.Breast Cancer rises in India. CMAJ. 2008 July 1; 179(1): 27.

4. Mittra I, Mishra GA, Singh S et al. A cluster randomized, controlled trial of breast and cervix cancer screening in Mumbai, India: methodology and interim results after three rounds of screening. International Journal of Cancer. 2010; 126(4): 976-984.

5. IARC Working Group on the Evaluation of Cancer-Preventive Strategies. IARC Handbooks of Cancer Prevention: Breast Cancer Screening (2002) Lyon, France: IARC Scientific Publications.

6. Duffy SW, Tabar L, Vitak B, Warwick J. Tumor size and breast cancer detection: what might be the effect of a less sensitive screening tool than mammography? Breast J (2006) 12(suppl_1):S91–S95.

7. Pisani P, Parkin DM, Ngelangel C et al. Outcome of screening by clinical examination of the breast in a trial in the Philippines. 2005; 118(1): 149-154.

8. Nelson HD, Tyne K, Naik A et al. Screening for breast cancer: an update for the U.S. Preventive Services Task Force. Ann Intern Med. 2009 Nov 17;151(10):727-37, W237-42.

9. Reeler A, Qiao Y, Dare L, Li J, Zhang AL, Saba J. Women’s cancers in developing countries: from research to an integrated health systems approach. Asian Pac J Cancer Prev. 2009 Jul-Sep;10(3):519-26

In today’s blog Niccolò Giaj Levra and Giulia Cossu, both medical students at University of Turin, examine the evidence supporting the introduction of a Rotavirus vaccine into immunisation programmes in developing countries

Rotavirus is considered the most important cause of severe gastroenteritis among children worldwide and the World Health Organization (WHO) estimates that 527,000 of the deaths occuring each year among children are associated with this virus

“…immunisation is one of the most cost-effective ways to save children’s lives” – Julian Lob-Levyt, GAVI CEO

Diarrhoea is a marginal problem in rich countries, but in the developing world it is a leading cause of death in children. Despite improved safety of food, water and sanitation, diarrhoea remains the second leading infectious cause of death among children. Rotavirus is considered the most important cause of severe gastroenteritis among children worldwide and the World Health Organization (WHO) estimates that 527,000 of the deaths occuring each year among children are associated with this virus (1); more than 230,000 of these occur in sub-Saharan Africa. Six of the seven countries with the highest mortality due to rotavirus diarrhoea are located in Africa (2).

Vaccines represent the best hope for preventing the severe consequences of infections as Rotavirus, Pneumococcus, Hepatitis B, and Haemophilus influenzae type B; especially in impoverished regions where resources and access to care may be limited.

Recently the Bill and Melinda Gates Foundation, in association with GAVI Alliance, decided to invest US$10billion in the next 10 years for the development and delivery of vaccines to the world’s poorest countries (3); this enthusiasm and economical effort are justified by the Global Health needs and the results in the International clinical studies.

In these last days, for the first time ever, the New England Journal of Medicine published the results concerning two trials conducted in Mexico (4) and Africa (5) (Malawi and South Africa), demonstrating a reduction in diarrhoeal disease deaths following rotavirus vaccine. Both studies underscore the importance of vaccination in achieving significant reduction of severe rotavirus infections among children and the WHO recommends the introduction of rotavirus vaccines in every nation’s immunisation programme.

In an editorial accompanying the studies’ results, Mathuram Santosham, Professor of International Health and Pediatrics at Johns Hopkins University, Baltimore supports and sentizes the use of rotavirus vaccines. “We now have another powerful weapon to add to our armamentarium to combat diarrhoeal deaths—rotavirus vaccines,” wrote Santosham. “Rotavirus vaccine should be introduced immediately in high mortality areas and it should be used as a trigger to energize diarrhoea control programs and improve coverage for all the proven interventions for diarrhoea.”

In Mexico from 1990 to 2002 substantial reductions in diarrhoea-related death and complications was observed. These results occurred concurrent with improved sanitation and potable water, promotion of breast feeding and oral rehydration, and supplementation with a megadose of vitamin A. These measures have decreased the number of diarrhoea-related deaths occurring in the spring and summer months, but deaths during the fall and winter months, when the probability of rotavirus infection increased, have persisted (6). In 2006 Mexico became the first country worldwide to introduce the rotavirus vaccine in its national immunization program. In 2009 a decrease of diarrhoeal disease associated of more than 65 percent was found in this country among children age two and under during rotavirus season. Also the study showed that among infants younger than 11 months, the target age group for this vaccine, diarrhoea deaths fell by more than 40 percent. In children between the ages of one and two, diarrhoea deaths fell almost 30 percent, even though only 10-15 percent of this population was eligible for vaccination. The conclusions are that vaccination of susceptible young infants may protect unimmunised children who live in the same community by reducing the exposure of rotavirus to children.

In South Africa and Malawi, clinical trials proved that the vaccine significantly reduced severe rotavirus disease by 61.2 percent in African infants during the first year of life. The efficacy of the rotavirus vaccine in preventing episodes of severe rotavirus gastroenteritis was lower than that observed in European and Latin American studies. This finding is supported by other studies of live oral vaccines, such as the oral poliovirus vaccine, the cholera vaccine, oral typhoid vaccines, and earlier rotavirus vaccines, none of which were as immunogenic or effective in populations in developing countries as they were in populations in industrialized countries. Causes are associated with poor nutritional status, interference due to maternal antibodies or due to coadministration of the oral poliovirus vaccine and breast milk.

Shabir Madhi, Co-Director of the South African Medical Research Council at the University of Witwatersrand in Johannesburg said: “The vaccine can make a significant impact in global public health if investments are made to bring them to all children, particularly those in the world’s poorest countries.”In consideration of these results GAVI Alliance supports the introduction of rotavirus vaccines in at least 44 low-income countries by 2015.

In consideration of these importants results global public health organizations must continue to invest in vaccines in order to achieve important reductions in diarrhoeal disease morbidity and mortality in the near future.

References:

1. World Health Organization. Rotavirus vaccines. Wkly Epidemiol Rec 2007;82:285-96

2. Assessing vaccine-preventable diseases burden and immunization impact. Geneva: World Health Organization. Accessed December 31, 2009, at http://www.who.int/immunization_monitoring/burden/en/

3. http://www.gatesfoundation.org/Pages/home.aspx

4. S.A. Madhi, N.A. Cunliffe, D. Steele et al. Effect of Human Rotavirus Vaccine on Severe Diarrhea in African Infants. N Eng J Med 2010 Jan 28;362(4):289-98.

5. V.Richardson, J. Hernandez-Pichardo, M.Quintanar-Solares et al. Effect of Human Rotavirus Vaccine on death from Childhood Diarrhea in Mexico. N Eng J Med 2010 Jan 28;362(4):299-305

6. FR. Velázquez, H.Garcia-Lozano, E.Rodriguez, et al. Diarrhea morbidity and mortality in Mexican children: impact of rotavirus disease. Pediatr Infect Dis J 2004; 23:Suppl:S149-S155

Light microscope. Credit: National Institutes of Health Images

Today we’d like to announce the publication of Sayantani Ghosh’s report on her elective studying rehabilitation medicine in Philadelphia, USA. Read it here.

Meanwhile, today’s blog written by Gurmeen Kaur and Aashim Singh, both medical students at University of Delhi, explores a new affordable test to diagnose cervical cancer that can be applied in developing countries.

Around 300,000 women worldwide die from cervical cancer each year and up to 85 percent of those deaths occur in developing countries.

A simple “see and treat” approach using a test costing $2 could help doctors prevent 100,000 cervical cancer deaths a year in women in poorer countries. This approach encourages the use of Visual inspection with acetic acid (VIA), visual inspection with Lugol’s iodine (VILI) and direct visual inspection (DVI).

Cervical cancer is one of the leading causes of cancer-related deaths for middle-aged women in the developing world, yet it is almost completely preventable, if precancerous lesions are identified and treated in a timely manner. (1) Around 300,000 women worldwide die from cervical cancer each year and up to 85 percent of those deaths occur in developing countries.

Asia, Africa and South America account for a major part of the global burden of cervical cancer (2) but lack the necessary resources to use the Papanicolaou (Pap) smear as a screening tool for cervical abnormalities. Unlike in developed nations, where cervical screening programs are well established and vaccination programs against HPV are growing, access to tests and vaccines in these countries is limited.

This is why there is a need for alternative and more cost efficient methods of cervical cancer screening particularly the visual screening methods such as VIA and VILI (3).

VIA and VILI and known as the ‘see and treat’ methods because they can be performed on an outpatient basis with hardly any equipment. The learning curve is not steep and hence social workers, nurses, midwives and community workers can be trained to effectively perform the tests (4). The test results are available immediately and treatment or colposcopy can be performed as soon as the lesions are visualized. The link between VIA and same visit cryotherapy has been found to be suitable for large-scale implementation at a population level.(5)

VILI uses Lugol’s Iodine which is taken up by the normal columnar, glycogen containing cervical cells and the cancerous zone remains unstained. Visual Inspection with acetic acid (VIA) uses 4% acid to stain the precancerous and cancerous zones. Besides obviously exophytic or ulcerative lesions are also visualized by direct visual inspection.

A meta-analysis shows that screening with VIA or VILI allows detecting presence of cervical cancer and its precursors with an accuracy as good or even better than the standard Pap smear test although VIA and VILI are less specific in comparison to the Pap smear test, they are more sensitive in detecting pre-invasive lesions.(2,6)

The availability of cost-effective screening methods for mass screening programmes is an important intervention against the cancer related deaths in developing countries because early detection of precancerous lesions will be subject to early and easier treatment options like cryotherapy and electrodiathermy. Hence, a large burden of disease can be attended to and tackled before it reaches an irreversible stage.

VILI and VIA can hence serve as excellent alternatives to tide over resource crises in poor countries while they strive to vaccinate all young girls against HPV using the new Gardasil and Cervarix vaccines, make PAP testing universally available and have well formulated national screening protocols.

References:

1. Carr KC, Sellors JW. Cervical cancer screening in low resource settings using visual inspection with acetic acid. J Midwifery Womens Health. 2004 Jul-Aug;49(4):329-37.

2. Marc Arbyn, Rengaswamy Sankaranarayanan,