The Articles are on comparing carotid artery stenting with endarterectomy to treat symptomatic carotid stenosis, lowering LDL cholesterol with the apolipoprotein B synthesis inhibitor mipomersen, comparative demographics of the European cystic fibrosis population and a global review of HIV treatment and care for injecting drug users. These are accompanied by Comments on carotid artery stenting, lowering LDL cholesterol, and increasing HIV prevention in injecting drug users.

The World Report is on a European agreement to improve environmental health, decrease in global vaccination rates and the crisis for Polish nurses. Also of interest to global health are a Comment and a Perspective about HIV and HIV prevention.

In today’s blog, Anna Bulbeck, fourth year Medical Student at Newcastle University currently undertaking the Global Health Student Selected Component, reflects on the problem of chronic disease care in developing countries.

The ongoing and progressive nature of many such diseases has lead to widespread beliefs about demons and past life misconduct justifying the patient’s present condition

During the second week of the Global Health Student Selected Component (SSC), we have been asked to consider the burden of chronic non-communicable diseases on developing countries. The first question that sprung to my mind, rightly or wrongly, was how big can this burden really be when compared to the huge hurdle that is represented by infectious diseases? My small insight into the problems in the developing world as an English citizen is confined to two minute comic relief adverts and short trips abroad, and during this exposure we are bombarded with information about HIV, malaria, cholera and other rife communicable diseases. Guest speakers this week discussed the impacts and issues faced by people with chronic non-communicable diseases throughout the developing world, with specific references to epilepsy, Parkinson’s Disease, hypertension and stroke.

One difference between the plight of developing countries and the west, is the beliefs surrounding chronic illness. The ongoing and progressive nature of many such diseases has lead to widespread beliefs about demons and past life misconduct justifying the patient’s present condition. Stigma surrounding these conditions is widespread, leading to isolation and neglect of patients who proportionately require increased levels of care and support. Education, in a way that respect local beliefs as much as possible may be the way forward on this particular issue. Proving that medicines for diseases such as epilepsy and Parkinson’s are effective may also reduce stigma and discriminatory beliefs, but then there is the constant problem of provision.

Provision of medicines is an ongoing problem in low income countries. Not only is money to afford drugs a major issue here, but getting the medications to patients is a massive logistical consideration. Pharmacies that are accessed only via dusty bumpy roads from rural villages 2 hours away are nearly impossible to get to if you are sick, poor with no means of transport. Repeated journeys are a further problem. Added to this, many diseases in discussion are completely symptomless (e.g. hypertension) and motivation to obtain drugs is likely to wear thin early on. How can this issue be overcome? Our suggestions are limited to bettering resources of health systems, increasing access to these resources, alongside further education about disease on diagnosis to increase motivation to keep obtaining medication.

A shocking revelation this week for me was the startlingly high incidence of burns in patients with epilepsy in developing countries. In communities that rely on open fires for cooking food, people who suffer from seizures can and commonly do suffer horrendous and disfiguring burns. Other issues that were brought to light this week included the lack of palliation for people with end stage disease, and the plight of stroke victims.

With two thirds of all older people living in the developing world, and an expected increase to 75% by 2025, should there be any surprise that 80% of chronic disease deaths occur in low and middle income countries? When quoted the statistics it is blindingly obvious, and yet the WHO calls this the ‘invisible epidemic’, due to our complete lack of awareness. The problem arises because it is not a fashionable issue amongst aid agencies, therefore donated resources are pooled into infectious diseases. But as President Obasanjo of Nigeria was quoted saying in reference to chronic diseases; “if we wait even 10 years, we will find that the problem is even larger and more expensive to address”. The first tasks to address in my opinion are education, awareness and further education.

Summary

Hereditary porphyrias are a group of eight metabolic disorders of the haem biosynthesis pathway that are characterised by acute neurovisceral symptoms, skin lesions, or both. Every porphyria is caused by abnormal function of a separate enzymatic step, resulting in a specific accumulation of haem precursors. Seven porphyrias are the result of a partial enzyme deficiency, and a gain of function mechanism has been characterised in a new porphyria. Acute porphyrias present with acute attacks, typically consisting of severe abdominal pain, nausea, constipation, confusion, and seizure, and can be life-threatening. Cutaneous porphyrias present with either acute painful photosensitivity or skin fragility and blisters. Rare recessive porphyrias usually manifest in early childhood with either severe cutaneous photosensitivity and chronic haemolysis or chronic neurological symptoms with or without photosensitivity. Porphyrias are still underdiagnosed, but when they are suspected, and dependent on clinical presentation, simple first-line tests can be used to establish the diagnosis in all symptomatic patients. Diagnosis is essential to enable specific treatments to be started as soon as possible. Screening of families to identify presymptomatic carriers is crucial to decrease risk of overt disease of acute porphyrias through counselling about avoidance of potential precipitants.

Introduction

Porphyrias are a group of eight panethnic inherited metabolic disorders of haem biosynthesis. Each results from a specific enzymatic alteration in the haem biosynthesis pathway (figure 1). Specific patterns of accumulation of the haem precursors 5-aminolaevulinic acid, porphobilinogen, and porphyrins are associated with characteristic clinical features—acute neurovisceral attacks, skin lesions, or both.1, 2 Eight enzymes bring about haem synthesis from glycine and succinyl CoA. The biosynthetic pathway begins in the mitochondria and, after three cytoplasmic stages, the final steps of haem formation take place in the mitochondria (figure 1).

Regulation of haem biosynthesis in the liver and in the bone marrow
PGc1—α=peroxisome proliferator-activated receptor-γ coactivator 1α. ALA=5-aminolaevulinic acid. ALAS1=ALA-synthase. ALAD=ALA-dehydratase. PBGD= porphobilinogen deaminase. UROS=uroporphyrinogen synthase. UROD=uroporphyrinogen decarboxylase. CPO=coproporphyrinogen oxidase. PPOX=protoporphyrinogen oxidase. FECH=mitochondrial ferrochelatase. NO=nitric oxide. HO=haem oxygenase. CO=carbon monoxide. Fe2+=ferrous iron. Tf=transferring. rTf=transferrin receptor. mRNA=messenger RNA.

Although haem is synthesised in every human cell for respiratory and oxidation-reduction reactions, it is mostly produced in the erythropoietic cells for haemoglobin synthesis and the liver parenchymal cells for synthesis of cytochromes and haemoproteins. Control of haem production differs between these two tissues, mostly because of differences in rates of synthesis of 5-aminolaevulinic acid. The first enzyme, 5-aminolaevulinic acid synthase (ALAS), is coded by two genes3—one erythroid specific (ALAS2 on chromosome X) and one ubiquitous (ALAS1 on chromosome 3). ALAS1 is the rate-limiting enzyme in the production of haem in the liver and is controlled via negative-feedback regulation by the intracellular uncommitted haem pool 4, 5 (figure 2).

Regulation of haem biosynthesis in the liver and in the bone marrow
PGc1—α=peroxisome proliferator-activated receptor-γ coactivator 1α. ALA=5-aminolaevulinic acid. ALAS1=ALA-synthase. ALAD=ALA-dehydratase. PBGD= porphobilinogen deaminase. UROS=uroporphyrinogen synthase. UROD=uroporphyrinogen decarboxylase. CPO=coproporphyrinogen oxidase. PPOX=protoporphyrinogen oxidase. FECH=mitochondrial ferrochelatase. NO=nitric oxide. HO=haem oxygenase. CO=carbon monoxide. Fe2+=ferrous iron. Tf=transferring. rTf=transferrin receptor. mRNA=messenger RNA.

In erythroid cells, synthesis of haem is regulated during erythroid differentiation in response to erythropoietin. In these cells, ALAS2 synthesis is induced only during active haem synthesis. The rate is limited by iron availability and is not inhibited by haem.6 Spleen and liver macrophages degrade haem and recycle iron after erythrophagocytosis through inducible haem oxygenase 1 (figure 2). Porphyrias are often classified as hepatic or erythropoietic according to the organ in which haem precursors accumulate (figure 1). However, a classification as acute porphyrias, cutaneous porphyrias, and rare recessive porphyrias based on clinical presentation is directly related to a simple biological diagnosis strategy and is more practical than are other classifications (figure 3).

First-line tests for diagnosis of porphyrias
PBG=porphobilinogen. ALA=5-aminolaevulinic acid.

Acute porphyrias

Presentation

People with autosomal-dominant acute porphyrias—acute intermittent porphyria, variegate porphyria, and hereditary coproporphyria—can present with a sudden life-threatening crisis. These attacks are infrequent because penetrance is low and they are difficult to diagnose because they are non-specific. Acute attacks happen in all acute porphyrias. Skin lesions never develop in acute intermittent porphyria but are the only clinical manifestation in some patients with variegate porphyria (60% of patients), and rarely (5%) develop in patients with hereditary coprophorphyria (figure 4).1 Acute intermittent porphyria is estimated to affect about one in 75 000 people in European countries, apart from in northern Sweden, where, because of a founder effect, it is more frequent (one in 1000).7, 8 Variegate porphyria might be half as prevalent as acute intermittent porphyria in most European countries and is especially common in South Africa because of a founder effect.9 Acute attacks are very rare before puberty and after menopause, with a peak occurrence within the third decade. They are more common in women than in men.10, 11 Most patients have one or a few attacks and then recover fully for the rest of their lives. Less than 10% develop recurrent acute attacks.

Clinical features of porphyrias
AIP=acute intermittent porphyria. ADP=5-aminolaevulinic acid (ALA) dehydratase porphyria. HC=hereditary coproporphyria. VP=variegate porphyria. PCT=familial and sporadic porphyria cutanea tarda. HEP=hepatoerythropoietic porphyria. CEP=congenital erythropoietic porphyria. EPP=erythropoietic protoporphyria. X-LDPP=X-linked dominant erythropoietic protoporphyria.

Porphyric attacks begin with a prodromic phase including minor behavioural changes such as anxiety, restlessness, and insomnia.12, 13 Most people with acute attacks present with severe abdominal pain, but this pain might also be felt in the back or thighs. Nausea, vomiting, and constipation are common. Tachycardia, excess sweating, and hypertension, which are symptoms of increased sympathetic activity, are often present.14 Physical examination shows no abnormalities and X-ray analysis is normal or shows mild ileus of the bowel in most cases. During acute attacks, patients frequently become dehydrated and electrolyte imbalanced. Hyponatraemia attributable to inappropriate antidiuretic hormone secretion syndrome develops in 40% of cases, and when severe can lead to convulsions. Seizures in acute attacks can develop because of hyponatraemia or hypomagnesaemia or as a manifestation of porphyria. Occasionally, excretion of red or dark-coloured urine helps physicians with their investigations.

In 20—30% of patients, signs of mental disturbance such as anxiety, depression, disorientation, hallucinations, paranoia, or confusional states are reported. Most acute attacks last for no longer than 1 or 2 weeks. When they last longer, gastrointestinal manifestations frequently lead to weight loss. Acute attacks can also be life threatening because of severe neurological complications. Neuropathy often develops when drugs that are known to be porphyrinogenic are used during an attack. Neuropathy is mostly motor—in the early stages, pain in the arms and legs is very common (muscle pain), and weakness generally begins in the proximal muscles, more frequently in the arms than in the legs. Limb paresis, when it occurs, can be very local. Muscle weakness can progress and lead to tetraplegia, with respiratory and bulbar paralysis and death. Recovery from paralysis is gradual and in some cases incomplete, with sequelae mostly in the arms and legs. Pyramidal signs, cerebellar syndrome, transitory blindness, or consciousness abnormalities (from somnolence to coma) can arise. Cerebrospinal fluid is normal in most cases. Porphyric neuropathy is far less common than it was in the past, and acute attacks are rarely fatal. Clinical manifestations are non-specific in most cases. Biochemical analysis is necessary for diagnosis of an acute attack and to define the type of porphyria.

Diagnosis

Examination of urine for excess porphobilinogen is the essential first-line test for patients with a suspected attack of acute porphyria (figure 3).15—17 Measurement of 5-aminolaevulinic acid is not essential to establish the diagnosis but can be helpful for differentiation of the disorder from other metabolic causes of abdominal pain, eg, lead poisoning or the rare 5-aminolaevulinic acid dehydratase porphyria. Urinary porphobilinogen and 5-aminolaevulinic acid are increased in all three acute hepatic porphyrias (acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria) although the concentrations are higher and longer lasting in acute intermittent porphyria than in the other two types (hereditary coporphyria and variegate porphyria). Measurement of urinary porphyrins is unhelpful and might be misleading because of frequent and non-specific coproporphyrinuria in many common disorders. With a recorded porphobilinogen overexcretion (>10 times the upper limit), treatment can be started immediately, with further laboratory investigations used to define the porphyria type in the proband (table 1).

Diagnosis of porphyria type (OMIM) in a proband and strategies for family investigations
Investigations should be done in association with specialist porphyria centres. ALA=5-aminolaevulinic acid. PBG=porphobilinogen. AIP=acute intermittent porphyria. VP=variegate porphyria. HC=hereditary coproporphyria. Uro=uroporphyrin. Copro=coproporphyrin. Proto=protoporphyrin. Isocopro=isocoproporphyrin. Hepta=heptacarboxyl-porphyrin. I or III=type isomers. Zn=zinc. OMIM=Online Mendelian Inheritance in Man.
* DNA analysis should be used whenever possible to confirm diagnosis in proband. Identification of mutation in unequivocally affected family member is a prerequisite for family investigation.
† Fluorescence emission peak in nm.
‡ X-linked erythroid-specific transcription factor GATA-binding protein 1 mutation has been reported in one case of congenital erythropoietic porphyria.

For diagnosis of the type of acute porphyria in the proband, plasma fluorescence emission spectroscopy is a first-line test because a peak at 624—628 nm establishes the diagnosis of variegate porphyria.18, 19 However, it does not distinguish acute intermittent porphyria from hereditary coproporhyria, for which the emission peak at 620 nm is usually present for both types.20 Urinary porphyrin analysis alone is not sufficient for discrimation (table 1). Total faecal porphyrin concentration is increased in variegate porphyria, with protoporphyrin concentrations (protoporphyrin IX) greater than those for coproporphyrin, whereas it is usually normal in acute intermittent porphyria. Total faecal porphyrin concentration is raised in hereditary coproporphyria, with coproporphyrin as the main component and a ratio of isomer III to isomer I greater than 2·0 (table 1). When present, a 50% decrease of porphobilinogen-deaminase activity can positively identify acute intermittent porphyria patients.

During remission, urine, faecal, and plasma porphyrin concentrations are generally normal in all three acute porphyrias.17 The most sensitive metabolite test for variegate porphyria that is in remission or presymptomatic is fluorescence emission spectroscopy of plasma (if patient is older than 15 years, with a 60% sensitivity and 100% specificity). For hereditary coproporphyria, a ratio of faecal coproporphyrin isomer III to isomer I of more than 2·0 is sensitive in adults but the sensitivity of this ratio is not established in children.20—22 Family screening is essential to prevent acute attacks in those with latent disease. DNA analysis to identify the mutation is the gold standard.23—26 For DNA analysis, previous identification of the mutation in an unequivocally affected family member is needed. Genes for all porphyrias have been characterised, and large numbers of disease-specific mutations have been identified. Regularly updated lists of mutations are available from the Human Gene Mutation Database. Enzyme measurements are reserved for families in which a mutation cannot be identified (table 1). However, measurement of protoporphyrinogen, coproporphyringen oxidases, and even the widely used porphobilinogen-deaminase assay should be undertaken in a porphyria reference centre.27, 28

Pathogenesis and treatment

All clinical features of an acute attack can be explained by lesions of the nervous system. The leading hypothesis is that 5-aminolaevulinic acid or other metabolites that are overproduced by the liver are neurotoxic,29, 30 and this notion is consistent with the substantial benefit of liver transplantation in patients with severe acute intermittent porphyria.31 Acute attacks are precipitated by events that either directly induce ALAS132 or increase the demand for haem synthesis in the liver and subsequently deinhibit ALAS1 (figure 2).29 These events include hormonal fluctuations during the menstrual cycle, fasting, smoking,33 infections, and exposure to porphyrinogenic drugs. Most drugs that exacerbate porphyria are closely associated with induction of cytochrome P450 enzymes, which increase hepatic haem turnover. Inflammatory and infectious diseases induce hepatic expression of the acute-phase protein haem oxygenase 1, which catabolises haem. Transcription of ALAS1 seems to be upregulated by the transcriptional factors peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α)34 and peroxisome proliferator-activated receptor α (PPARα).35 This finding could explain why acute intermittent porphyria is associated with impaired liver energy metabolism and chronic undernutrition.36

Treatment (table 2) should be started promptly and any precipitating factors—especially drugs (including oestrogens and progestagens)—avoided, underlying infection should be treated and hypocaloric diets corrected.37 Complete lists of potentially safe and unsafe drugs are available on the internet (for the USA, and the European Union countries, South Africa, and Canada).

Management of acute porphyrias
IV=intravenous. CNS=central nervous system.
* Human haemin stabilised with arginine (Normosang) is available worldwide, apart from in the USA where lyophilised haemin is available.

Patients often need high doses of opiates in combination with an antiemetic and a phenothiazine, such as chlorpromazine for anxiety and restlessness and to decrease need for analgesics. Careful management of fluid balance, with avoidance of large volumes of hypotonic dextrose, is necessary to limit the risk of severe hyponatraemia, which could provoke convulsions. An adequate intake of calories should be ensured, given orally as carbohydrate-rich food supplements (more than half of energy intake), or infused as normal saline with 5% dextrose when the patient has severe vomiting. Cardiovascular complications such as hypertension and tachycardia are rarely severe, therapy with β blockers is needed in some cases.

Very occasionally, acute attacks are accompanied by a severe adrenergic crisis with dangerous hypertension, encephalopathy, seizures, and ischaemic changes on a CT brain scan. Posterior reversible encephalopathy syndrome has been shown on MRI during acute attacks with severe encephalopathy. Intravenous infusion of magnesium sulphate can be effective for control of adrenergic symptoms. Onset of a motor neuropathy is often characterised by severe pain and stiffness in the thighs and back, and then loss of tendon reflexes and motor paralysis. When vital capacity becomes severely reduced by paralysis of the intercostal muscles, artificial ventilation is necessary.

Intravenous haemin administration, which inhibits upregulated ALAS1 and curtails urinary excretion of 5-aminolaevulinic acid and porphobilinogen, is the specific (or aetiopathogenic) treatment of choice.38, 39 Most patients with uncomplicated attacks improve within 5 days.12 However, human haemin will not reverse an established neuropathy, but might prevent neuropathy onset and halt further progression if given sufficiently early. A stable preparation of human haemin solution stabilised with arginine (Normosang)40 is widely available, whereas in the USA a form of lyophilised haemin (Panhaematin)41 is available. Measurement of urinary porphobilinogen excretion is useful to document the metabolic response to human haemin. Few side-effects have been reported for short-term use of human haemin stabilised with arginine. Coagulopathies reported with other haem preparations do not develop with stabilised haemin with arginine.12 Administration after 1:1 dilution in 4—20% human serum albumin increases haem solubility and stability and lowers the risk of vein injury.38, 42 Attacks during pregnancy have been treated without any apparent adverse effects to either mother or child.43, 44

Less than 10% of patients have recurrent acute attacks without clearly identified precipitating factors. Advice about management of these attacks should be sought from a reference porphyria centre. Management of repeated attacks that are severe enough to need admission is difficult, and long-term treatment with human haemin is needed. Regular treatment with a once-per-week single dose can help to control the disease. The most frequently reported event after several courses of haem therapy is the disappearence of the superficial venous system. Most of these patients will probably need permanent indwelling venous catheters, which have many attendant complications. A single dose of human haemin contains 22·7 mg of iron. Therefore, iron overload is possible in patients who are given regular doses. A few patients with severe acute intermittent porphyria have received liver transplants. This intervention returns 5-aminolaevulinic acid and porphobilinogen excretion to normal, abolishes acute attacks, and improves quality of life. Thus, liver transplantation should be considered for selected patients with the most severe form of acute intermittent porphyria.45

Carriers of the gene defect, symptomatic or not, should be counselled about maintenance of a healthy diet with regular meals, avoidance of alcohol 46 and smoking, and use of the list of potentially safe and unsafe drugs.47 When drugs are prescribed for porphyria, benefit versus risk should always be considered in conjunction with the severity of the underlying disorder that needs treatment and the disease activity of the porphyria. When difficult decisions about treatment have to be made, a national porphyria reference centre should be contacted. Early and accurate diagnosis combined with efficient counselling and treatment has greatly reduced fatality rates in acute porphyrias. Finally, patients with both symptomatic and latent disease have increased risks of hypertension,10, 48 hepatocellular carcinoma,10,49—52 and chronic renal failure,53 and these risks need to be discussed individually with the patients.

Cutaneous porphyrias

Bullous porphyrias

Variegate porphyria, hereditary coproporphyria, and porphyria cutanea tarda share the same chronic cutaneous photosensitivity. Porphyria cutanea tarda is the most frequent type of porphyria worldwide and presents with skin symptoms only. Variegate porphyria and hereditary coproporphyria can present with either cutaneous or neuropsychiatric symptoms (figure 4). Laboratory diagnosis is essential to avoid misclassification and unexpected acute attacks (figure 3 and table 1). Lesions are restricted to sun-exposed areas such as the backs of the hands, face and neck; some women might also develop lesions on the legs and feet (figure 5).54 Skin fragility is perhaps the most specific feature, in which negligible trauma is followed by superficial erosion that is soon covered by a crust. Secondary infection is common. Bullae, blisters, or vesicles take several weeks to heal. White papules (milia) can develop in areas of bullae, especially on the backs of hands. Previous areas of blisters appear atrophic or brownish. Hypertrichosis is common on the upper cheeks, ears, and arms (figure 5). Increased pigmentation of sun-exposed areas is common. Skin symptoms show seasonal variations, with greater intensity in the summer and autumn than in other seasons. Rare ocular complications have been reported in porphyria cutanea tarda, such as ocular pain and photophobia.55 Variable degrees of liver dysfunction are frequent in patients with this disorder, especially in association with excessive alcoholic intake. However, in patients with alcoholic cirrhosis, porphyria cutanea tarda is very rare, suggesting an underlying constitutional abnormality that might predispose the liver to development of the disease.

Signs and clinical symptoms of cutaneous hepatic and hepatoerythropoietic porphyrias
Cutaneous symptoms in variegate porphyria, hereditary coproporphyria, and porphyria cutanea tarda; blisters (arrow heads) and bullae (arrow; A); hypertrichosis (B); uroporphyrin needles (arrows) and iron overload (Perls staining) in liver biopsy samples of patients with porphyria cutanea tarda (C); and clinical presentation of hepatoerythropoietic porphyria (D).

In bullous porphyrias, large amounts of porphyrins accumulate in the skin. The tetrapyrrolic nucleus of porphyrins renders them highly photoreactive and they absorb radiation energy in the visible range of about 400 nm. Once excited to a singlet state, porphyrin molecules might return to their ground state by a transfer of energy to various biological molecules that promotes peroxidation of membrane lipids and oxidation of nucleic acids and polypeptides.56 Histological examination of skin reveals cell-poor blisters beneath the epidermis, the multilayering of the basement membranes, and deposition of hyaline material, in and surrounding dermal blood vessels. These protein deposits stain positively with periodic acid Schiff reagent. Results of immunochemical studies 57—59 show immunoglobulin, fibrinogen, and complement in the vicinity of vessel walls. Altogether, these findings suggest that the principal site of photo injury is the blood vessels of the papillary dermis. A skin biopsy sample is useless and even contraindicated for both positive and causal diagnoses that are easily achieved with biochemical tests.
Plasma fluorescent spectrum is the best initial test for diagnosis of cutaneous porphyrias,60 differentiating between variegate porphyria 19 and porphyria cutanea tarda (figure 3 and table 1). Excretion profiles of urinary and faecal porphyrins are also useful diagnostic measures (table 1). In patients with symptomatic porphyria cutanea tarda, the typical porphyrin excreted in the faeces, other than a large excretion of uroporphyrin and 7-carboxy-porphyrin, is isocoproporphyrin.61, 62 However, excretion profiles become normal after long-term remission. Porphyria cutanea tarda is caused by a deficiency of uroporphyrinogen decarboxylase activity—at least in the liver.63 It is a heterogeneous disease.

The sporadic subtype (75% of cases) is most often identified in male patients without a family history of the disease. In this disorder, uropophyrinogen decarboxylase activity is deficient only in the liver during overt disease.64 Sporadic porphyria cutanea tarda is a complex disease in which both a multigenic predisposition and environmental risk factors are needed for symptoms to develop. The familial subtype (25% of cases) has an earlier onset than does the sporadic subtype, and arises equally in both sexes. It is transmitted as an autosomal-dominant mendelian disorder of low penetrance, attributable to a family-specific UROD gene defect that leads to a constitutive 50% uropophyrinogen decarboxylase deficiency. The ability to differentiate between the sporadic and familial subtypes is useful in genetic counselling to detect presymptomatic familial subtype patients and prevent their exposure to precipitating factors. However, benefits of identification of patients with familial subtypes are still controversial and need to be assessed. Activity of erythrocyte uropophyrinogen decarboxylase is normal in the sporadic subtype and reduced in the familial subtype, in which mutation screening is useful to detect symptom-free relatives (table 1). 65, 66

The same risk factors contribute to either a partial inactivation of hepatic uropophyrinogen decarboxylase in sporadic porphyria cutanea tarda or severe inactivation in the familial subtype.67 Porphyria cutanea tarda seems to be a disease in which symptoms develop when residual, hepatic uropophyrinogen decarboxylase decrease below a threshold of about 25%. The risk factors that contribute to inactivation or inhibition of this enzyme are mainly alcohol abuse, oestrogens, hepatitis C, and to a lesser extent HIV infections and genetic haemochromatosis.67—72 These precipitating factors act either alone or in combination with hepatic iron overload, an almost universal finding in porphyria cutanea tarda, to generate an iron-dependent oxidative mechanism. Results of a meta-analysis 73 show that HFE C282Y and H63D alleles in different genotypic combinations are associated with a three to 48 times greater risk of porphyria cutanea tarda than is the wild type genotype. Liver biopsy samples frequently show siderosis (figure 5). Transferrin saturation and serum iron and ferritin concentrations are frequently increased.74, 75 Additionally, polymorphisms in TFRC1 and CYP1A2 genes76 confer a heightened risk of porphyria cutanea tarda.

Hepatic siderosis in porphyria cutanea tarda results in part from deregulated hepcidin (HAMP) expression, independent of the HFE genotype.77 Hepatic uropophyrinogen decarboxylase inactivation in this disorder could be mediated by uroporphomethene, a competitive inhibitor, resulting from partial oxidation of uroporphyrinogen by a cytochrome P450 (CYP1A2) in an iron-dependent oxidative mechanism.78 Liver dysfunction is common in patients with porphyria cutanea tarda, especially in association with excessive alcoholic intake, varying in sensitivity from mild cytolysis to cirrhosis. Frequency of hepatic cancer is higher in patients with porphyria cutanea tarda and cirrhosis than in those with cirrhosis alone.79, 80 Haemodialysis in patients with chronic renal failure can predispose to this disorder,81 but in chronic renal failure and end-stage liver disease, skin blisters resembling those of porphyria cutanea tarda and often referred to as pseudoporphyria can develop.82, 83 The differential diagnosis between pseudoporphyria and porphyria cutanea tarda should be established by undertaking porphyrin analysis of plasma or faeces, which is abnormal only in porphyria cutanea tarda.

Once variegate porphyria and hereditary coproporphyria have been excluded and sporadic and familial porphyria cutanea tarda has been diagnosed, an initial appraisal should be made of the patients’ lifestyle, alcohol and oestrogen intake, hepatitis C virus and HIV infection status, liver and renal function, iron metabolism, and haemochromatosis genotyping.84, 85 Alcohol intake should be prohibited. Sun avoidance, use of protective clothing, and whenever possible, use of opaque sunscreens are crucial to lessen skin symptoms in porphyria cutanea tarda and are the only way to manage skin symptoms in variegate porphyria and hereditary coproporphyria (table 3).

Types of treatment in management of cutaneous porphyrias
VP=variegate porphyria. HC=hereditary coproporphyria. PCT=porphyria cutanea tarda. HEP=hepato-erythroporphyria. CEP=congenital erythropoietic porphyria. EPP=erythropoietic protoporphyria. X-LDPP=X-linked dominant protoporphyria.
* Contraindicated in smokers.
† Being assessed by Clinuvel Pharmaceuticals (Melbourne, Australia)

In patients with porphyria cutanea tarda who do not have haemochromatosis, low-dose chloroquine treatment (100—200 mg twice per week) is now widely used.86, 87 Chloroquine complexes porphyrins slowly mobilises them from the liver and increases their excretion into urine. Duration of treatment and relapse rates are only slightly higher without than with venesection. High-dose chloroquine treatment should be avoided because it causes a hepatitis-like syndrome in patients with porphyria cutanea tarda. Phlebotomy is the treatment of choice in such patients with haemochromatosis 88—even when serum iron or ferritin concentrations are only slightly raised.67 A unit of blood (350—500 mL) is removed every week until iron stores return to normal. This approach is continued until transferrin saturation falls below 16% or ferritin concentrations reach the low limit of normal, but can be interrupted early if haemoglobin falls bellow 110 g/L.89 Urinary or plasma concentrations of porphyrin are monitored every 3 months and return to normal within 6 months in most cases. Clinical remission is achieved within 6—9 months.89 In some severe cases, the combination of blood-letting and chloroquine therapy results in faster remission than does either treatment alone.84 To detect relapse, and because of the high rate of liver disease, urinary or plasma porphyrin concentrations, iron metabolism, and liver function should be assessed yearly. In porphyria cutanea tarda with chronic renal failure, erythropoietin supplementation is given because it mobilises iron in haemoglobin synthesis, thereby depleting excessive body-iron stores.90, 91

Acute painful photosensitive porphyrias

Erythropoietic protoporphyria is an inherited disorder that is caused by partial deficiency in mitochondrial ferrochelatase, the terminal enzyme of haem biosynthesis (figures 1 and 6). Accumulation of free protoporphyrin, mainly in erythrocytes and secondarily in other tissues (skin and liver) or biological fluids (bile and faeces), leads to painful photosensitivity and potential liver complications. The most common clinical manifestation is seasonal lifelong acute photosensitivity of sun-exposed skin.92 Photosensitivity develops in early childhood, but in rare cases symptoms manifest in adulthood. Skin symptoms of erythropoietic protoporphyria include burning, stinging, and pruritus in sun-exposed skin. Phototoxic reactions take place within minutes of sun exposure, and acute burning pain is ameliorated by application of cold water. Mild symptoms such as oedema and erythema arise immediately after sun exposure, and chronic lesions such as thickening of the hand skin and wax-like scarring on the face are common. Seasonal palmar keratoderma has been reported 93 in some patients who are compound heterozygotes or homozygotes for FECH mutations. Many patients have a slight microcytic, hypochromic anaemia.94—96 Although erythropoietic protoporphyria is generally a benign disease, biochemical evidence of liver dysfunction can be identified in 10—20% of these patients. Gallstones can form from protoporphyrin, and these patients are at increased risk of cholelithiasis. In about 2%, a rapidly progressing and irreversible cholestatic liver failure develops.92, 97, 98 Liver dysfunction is caused by accumulation of protoporphyrin in hepatocytes and bile canaliculi, resulting in cell damage, cholestasis, cytolysis, and further retention of protoporphyrin.

Physiopathological pathways of acute painful photosensitive porphyrias
EPP=erythropoietic protoporphyria. XLDPP=X-linked dominant protoporphyria. XLSA=X-linked sideroblastic anaemia. ALA=5-aminolaevulinic acid. PPIX=FECH=mitochondrial ferrochelatase. ALAS2=ALA synthase.

The mode of erythropoietic protoporphyria inheritance is complex but is almost always associated with two molecular defects. In about 94% of patients with overt disease, clinical expression usually requires coinheritance of a private FECH mutation 99 that is trans to a hypomorphic FECH*IVS3-48C allele. The effect of this allele is to lower mitochondrial ferrochelatase activity below a crucial threshold of about 35%.100—103 About 4% of families have this disorder with either homozygous or compound heterozygous FECH mutations, and these homo-allelic or hetero-allelic patients have a raised risk of severe liver disease.104 Finally, acquired somatic FECH mutations have been described105, 106 in patients who developed erythropoietic protoporphyria in association with myelodysplasia or myeloproliferative disorder after age 40 years.

Because protoporphyrin is strictly lypophilic, excretion of porphyrin in urine does not increase. Diagnosis is based on a large increase in free protoporphyrin concentrations in erythrocytes.107 Plasma porphyrin fluorescence assay shows a characteristic peak at 634 nm in symptomatic patients. Mitochondrial ferrochelatase enzyme activity, measured in nucleated cells, is reduced to 10—35% of the normal value in symptomatic patients and about 50% in asymptomatic carriers.101 Screening for mutation and for the hypomorphic IVS3-48C/T identifies symptom-free family members and allows definition of the mode of inheritance in that family.100

Protection from sunlight is the mainstay of erythropoietic protoporphyria management. Special clothes, opaque topical sunscreens, or UVB phototherapy can ameliorate photointolerance.108 Afamelanotide, an α melanocyte-stimulating hormone analogue, has been suggested as a means to induce photo-protective epidermal melanin formation.109 Oral β carotene (75—200 mg per day) improves light tolerance in about a third of patients, but it is contraindicated in smokers (table 3).108 Prediction of which patients will develop severe liver disease is impossible, and management should include yearly biochemical assessment of liver function.110 When liver dysfunction develops, treatment with cholestyramine (which depletes hepatic protoporphyrin) or activated charcoal (which binds protoporphyrin in the gut) should be attempted, but their effectiveness remains to be proven.110 When liver failure is advanced, transplantation is the only treatment likely to ensure survival.110, 111 During surgery, protection with a physical barrier and modification of surgical lighting (yellow filter) are recommended to reduce potential phototoxic injury of intra-abdominal organs.112 After liver transplantation, protoporphyrin might accumulate in the donor liver, which shows the key role of bone marrow in protoporphyrin overproduction. Concomitant liver and bone-marrow transplantation should be undertaken to prevent relapse of liver disease;113 however, the exact role of the cotransplantation remains to be investigated.

A previously unrecognised form of porphyria 114 has a clinical presentation very similar to that of erythropoietic protoporphyria, with huge amounts of protoporphyrin in erythrocytes, of which about 40% is bound to zinc, but without ferrochelatase deficiency. This new porphyria, called X-linked dominant erythropoietic protoporphyria, results from increased activity of ALAS2 attributable to gain-of-function deletions in ALAS2 (figure 6). All other previously described mutations in ALAS2 are loss-of-function mutations that cause recessive X-linked sideroblastic anaemia. ALAS2 gain of function leads to production of protoporphyrin in excess of the amount needed for haemoglobin synthesis, and in quantities sufficient to cause photosensitivity and liver damage—despite healthy mitochondrial ferrochelatase activity. Supportive and preventive treatments are similar to those for erythropoietic protoporphyria.

Rare recessive porphyrias

Congenital erythropoietic porphyria

Congenital erythropoietic porphyria (or Günther disease) is the most frequent of the rare recessive porphyrias. Inheritance is autosomal recessive, and the disorder results from a pronounced deficiency of uroporphyrinogen III synthase enzymatic activity (UROS). The enzymatic defect causes specific overproduction and excretion of the non-physiological and pathogenic isomer I of uroporphyrin and coproporphyrin (figures 1 and 3).115 Molecular study 116, 117 of the UROS gene in these patients has identified various mutations. However, a common missense mutation, p.Cys73Arg, is identified in 40% of disease alleles of white people.118 Moreover, congenital erythropoietic porphyria features attributable to UROS deficiency that is secondary to a GATA-1 erythroid-specific transcription-factor gene mutation have also been reported (table 1).119 Clinical features combine cutaneous photosensitivity and chronic haemolysis, the severity of which varies.

Most patients have severe photosensitivity, leading to bullae, scarring, and eventually disfigurement of the light-exposed parts of the body such as hands, ears, nose, and eyelids. Ocular involvement includes chronic ulcerative keratitis and corneal scarring.55 Secondary infections of lesions can lead to scarring, deformities, and loss of fingernails and digits. Erythrodontia (figure 7), osteodystrophia, combining osteolysis and osteoporosis, and hypercellular bone marrow are present in almost all patients. Red fluorescent urine in nappies provides an easy early diagnosis. Mild-to-severe haemolysis and hypersplenism are suggestive of impaired haem metabolism in erythrocytes. Phenotypic heterogeneity is typical of congenital erythropoietic porphyria. Adult late-onset forms show either a mild phenotype often restricted to skin photosensitivity because of a mild inherited UROS mutations or, in older patients, a congenital erythropoietic porphyria-like syndrome as a complication of myeloid malignancy, which precedes the onset of skin lesions.120

Clinical presentation of congenital erythropoietic porphyria (Günther’s disease).
Severe presentation in adults (A); severe presentation in a newborn before (B) and 2 years after (C) bone marrow transplantation with persistence of erythrodontia.

Extremely severe forms of congenital erythropoietic porphyria, starting during embryogenesis, are dominated by severe haemolytic anaemia that leads to hydrops fetalis and death in utero. The earliest possible diagnosis is advisable because special care should be taken with affected babies to avoid phototherapy for treatment of neonatal jaundice. Allogeneic bone-marrow transplantation is the only curative treatment and has been successful in several patients with moderate-to-severe disease (figure 7).120—122 The crucial supportive treatment for congenital erythropoietic porphyria is based on protection from sunlight and UV exposure, associated with meticulous skin care (table 3). Anaemia can be so severe that some patients are transfusion-dependent. Splenectomy can reduce need for transfusions.121, 123 Gene-based therapy is being investigated.124

Hepatoerythropoietic porphyria

Hepatoerythropoietic porphyria is caused by a homozygous or compound heterozygous deficiency of uroporphyrinogen decarboxylase.125 Only about 34 cases of this disorder have been reported. It is predominantly a hepatic porphyria that rarely resembles congenital erythropoietic porphyria clinically and tends to presents in infancy or childhood with red urine, blistering skin lesions, hypertrichosis, and scarring (figure 5). Sclerodermoid skin changes are the predominant feature in some cases. Erythrocyte porphyrin concentrations are increased, but protoporphyrins predominate. Some patients also have haemolytic anaemia and splenomegaly. However, biochemical findings in hepatoerythropoietic porphyria resemble those reported for porphyria cutanea tarda (table 1). Treatment is based on sun avoidance measures and blood-letting and chloroquine are not effective in this disorder.

Rare recessive acute hepatic porphyrias

The variants of this subgroup are 5-aminolaevulinic acid dehydratase porphyria, acute intermittent porphyria, variegate porphyria, and hereditary coproporphyria. In these rare variants that manifest in infants or early childhood, orange urine in nappies could suggest porphyrias (figure 3). Five homozygous cases of acute intermittent porphyria have presented with phenotypes of variable severity. The clinical situation is wholly different from that of dominant acute intermittent porphyria—affected children have porencephaly, severe developmental retardation, neurological defects, cataract, psychomotor retardation, ataxia, and convulsions.126, 127

Recessive variegate porphyria with cutaneous lesions accompanied by skeletal abnormalities of the hand has been reported in about 15 individuals.128—130 Short stature, mental retardation, and convulsions also arise but less frequently than lesions or hand abnormalities. Two different types of homozygous hereditary coproporphyria cases have been described 131—133 with a documented genotype-phenotype relation. In the first type, patients were small and showed skin photosensitivity, developmental retardation, neurological defects, and psychomotor retardation.131 In the second type, so-called harderoporphyria, patients presented with intense jaundice and haemolytic anaemia at birth without neurological symptoms.132, 133 The pattern of faecal porphyrin excretion was not typical, with large amounts of harderoporphyrin in addition to coproporphyrin.

Six cases of recessive 5-aminolaevulinic acid dehydratase porphyria have been reported and genetically substantiated as ALAD mutations.134 The disease can manifest in childhood or in adulthood with severe neurological symptoms that have features of chronic neuropathy sometimes associated with acute attacks.135 This disorder subtype is characterised by greatly increased excretion of 5-aminolaevulinic acid and coproporphyrin (table 1) in urine, accompanied by low 5-aminolaevulinic acid dehydratase activity measured in erythrocytes.136 In hereditary tyrosinaemia type I, symptoms of this disorder develop as a result of accumulation of succinylacetone,137 the most potent inhibitor of 5-aminolaevulinic acid dehydratase in the liver, which is identified in urine and blood of patients. As a result, about 40% of these children have symptoms resembling attacks of acute porphyria.138 Treatment is the same as that for acute attacks and is effective in some but not all cases. Liver transplantation in these patients has little effect on the symptoms or biochemical profile, suggesting irreversible neural damage.139 Future attacks are prevented by avoidance of agents known to stimulate ALAS1 activity and also those known to inhibit 5-aminolaevulinic acid dehydratase activity (eg, lead).138

European porphyria network

The European Porphyria Network (EPNET) is a collaborative project between European porphyria centres that was established to provide improved health care for patients and their families. It has been partly funded by the EU Commission Public Health Executive Agency (PHEA). The overall aim is to develop a common approach to diagnosis and clinical management of porphyrias so that patients, their families, and health-care professionals can benefit from access to evidence-based, consensus-agreed information in their own languages through easily accessible support. EPNET was developed after successful establishment of a collaborative research initiative European Porphyria Initiative (EPI) on the acute porphyrias between reference porphyria centres from many European countries 140 and the development of a porphyria drug database.

Search strategy and selection criteria

We searched Embase, Medline, Ovid, and PubMed, with no restrictions on language or dates. We used the search terms “porphyria” and “genotype”, in combination with “phenotype”, “drugs”, “precipitating factors”, “pathogenesis”, “neuropathy”, “symptoms”, “pharmacogenetics”, “CYP450”, “gene therapy”, “mouse model”, “treatment”, “iron metabolism”, and “haem” plus “enzymes”. We largely selected publications from the past 5 years, but did not exclude commonly referenced and highly regarded older publications. We also searched the reference lists of articles identified by this search strategy and selected those we judged relevant. Review articles and book chapters are cited to provide readers with more details and references than this Seminar can give. Our reference list was modified on the basis of comments from peer reviewers.

Contributors

HP contributed to editing the text on hepatic porphyrias and designed the figures. LG contributed to editing the section on erythropoietic porphyrias, and J-CD coordinated the study design and was the head supervisor. All authors contributed to writing the report.

Conflicts of interest

We declare that we have no conflicts of interest.

Acknowledgments

We thank Bernard Grandchamp, Carole Beaumont, Mike Badminton, and George Elder for informative and helpful discussions related to clinical and physiopathological details in genetic and haematology; and Jean-Pierre Laigneau for graphical support. All authors were supported by Grant Public Health and Consumer Protection Directorate Public Health Executive Agency from the European Commission, Brussels, Belgium, and grant number ANR-07-MRAR-008-01 from ANR-GIS Maladies rares, Paris, France.

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108 Minder EI, Schneider-Yin X, Steurer J, Bachmann LM. A systematic review of treatment options for dermal photosensitivity in erythropoietic protoporphyria. Cell Mol Biol 2009; 55: 84-97. PubMed

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110 Anstey AV, Hift RJ. Liver disease in erythropoietic protoporphyria: insights and implications for management. Postgrad Med J 2007; 83: 739-748. CrossRef | PubMed

111 McGuire BM, Bonkovsky HL, Carithers RL, et al. Liver transplantation for erythropoietic protoporphyria liver disease. Liver Transpl 2005; 11: 1590-1596. CrossRef | PubMed

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113 Rand EB, Bunin N, Cochran W, Ruchelli E, Olthoff KM, Bloomer JR. Sequential liver and bone marrow transplantation for treatment of erythropoietic protoporphyria. Pediatrics 2006; 118: e1896-e1899. PubMed

114 Whatley SD, Ducamp S, Gouya L, et al. C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload. Am J Hum Genet 2008; 83: 408-414. CrossRef | PubMed

115 Fritsch C, Bolsen K, Ruzicka T, Goerz G. Congenital erythropoietic porphyria. J Am Acad Dermatol 1997; 36: 594-610. CrossRef | PubMed

116 Fontanellas A, Bensidhoum M, de Salamanca R Enriquez, Tirado A Moruno, de Verneuil H, Ged C. A systematic analysis of the mutations of the uroporphyrinogen III synthase gene in congenital erythropoietic porphyria. Eur J Hum Genet 1996; 4: 274-282. PubMed

117 Desnick RJ, Glass IA, Xu W, Solis C, Astrin KH. Molecular genetics of congenital erythropoietic porphyria. Semin Liver Dis 1998; 18: 77-84. CrossRef | PubMed

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119 Phillips JD, Steensma DP, Pulsipher MA, Spangrude GJ, Kushner JP. Congenital erythropoietic porphyria due to a mutation in GATA1: the first trans-acting mutation causative for a human porphyria. Blood 2007; 109: 2618-2621. CrossRef | PubMed

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More than 140 million people live at altitudes over 2,500 m. In certain areas of the world, such as in the highlands of Peru, East Africa and South-Central Asia, some populations live at altitudes over 4,000 m where ambient oxygen availability is a meager 60% of sea-level values (1). By comparison, the peak of the highest mountain in Western Europe, Mont Blanc, is only 4807 m. At these altitudes, even functioning normally is no small feat. Yet for generations these populations have somehow managed to survive in the face of extreme hypoxia, freezing temperatures and low pressure. These three populations, however, have not adapted equally to high-altitude living (3). A theory of migration attempts to solve this disparity by stating that how well populations have adapted to high-altitude is dependent on the time they have been resident there. Understanding the physiology of these populations could therefore yield important implications. Firstly, as many people now ascend to higher altitudes for recreation, determining how the body best copes with hypoxia from populations that have adapted well could help these amateur sojourners cope with the extreme environment. Secondly, understanding the physiology of those populations that do adapt well could help inform treatment on how to help those populations that don’t. Knowing this, a research team of physiologists from Canada, the UK and the USA set their sights on the Ethiopian highlands. As an M.Sc. student studying cardiovascular control at Simon Fraser University in Vancouver, Canada it was difficult to say no to the opportunity to be involved in some field research overseas.

The story so far

Arrival in Bale

The team had experience of similar research amongst native high-altitude residents over the past 6 years and over 3 continents. Results from research amongst Highland Peruvians, Tibetans and Ethiopians had shown a spectrum of hypoxic adaptation between the Peruvians who seemed the least-adapted and the Ethiopians who seemed to be best-adapted to the altitude (3). An underlying theory of human migration has been put forward in an attempt to solve this disparity, in proposing that the Ethiopians’ adaptation may be due to their residence at such a high altitude for longer; Homo sapiens, after all, are considered to have originated from what today would be Kenya-Ethiopia. Peruvians, on the other hand, would have migrated to their resident altitude much later on in an evolutionary timescale and, therefore, would not have adapted so effectively (4). Chronic Mountain Sickness (CMS), related to cerebral autoregulatory dysfunction, is often used as a marker of mal-adaptation to high-altitude (5) and anecdotal reports were beginning to surface of CMS incidence in an Ethiopian population in the southern Bale Mountains. Previous studies performed in the northern Simien Mountains of Ethiopia failed to find any cases of CMS (2). Given the close proximity of these populations, the above theory would suggest they share a similar genetic makeup and adaptation profile to the high altitude. However, if the reported cases of CMS were in fact true, and we could determine that the two populations differed in cardiovascular responses to the altitude, we would discredit the prevailing migration theory for human high-altitude adaptation.

The joys of high altitude

Our research campsite in the Simien Mountains of Ethiopia

Our campsite in the Bale Mountains was desolate. At 4,118 m there wasn’t much wildlife save some small birds and the odd Ethiopian wolf. The high altitude became more than a research topic as it began to have its effect on me personally: with an ambient barometric pressure of approximately 460 mmHg at the campsite, oxygen levels were about 60% of that at sea-level. Consequently, my blood oxygen saturation had dropped to about 70% and my average heart rate floated around 130 beats/min (compared to 60 beats/min at sea level). A huge headache, nausea, fatigue, lack of appetite and wanting to vomit all welcomed me to life at high altitude. Thankfully, I was surrounded by doctors at the campsite who were able to keep an eye out for the more serious symptoms of the deadly pulmonary oedema and cerebral oedema. Often these two problems affect altitude sojourners and as I had never camped above 1,000 m prior to this trip it was a real worry that had to be addressed. Whilst the rest of the team set up, the only thing I could do was try to sleep and get better as soon as possible; the research would need to begin soon.

Researching above the clouds

Field research

Researching on the mountains was hectic. Everyone was up at sunrise and we would be testing continually till sunset. We only had a few days to test eight locals with each test taking about four hours. It was up here that I realized how different field research is to that conducted in labs across the world. All the equipment had to be set up in the morning and taken down at night in fear of animals ruining it. Generators became both our best friends and worst enemies as they often broke down leaving all teams stranded. No power meant there was no way to collect data and out there sticking to deadlines was hard enough as is. Power failures in Bale were a constant problem and oftentimes we would be stranded in the middle of our experiments, already hungry, hypoxic and tired, knowing that we still have another subject before the end of the day. In a makeshift tent on top of an African mountain, maintaining clinical standards became a full-time job. Equipment was constantly being sanitized and cleaned and dirt would somehow find its way into absolutely everything. Up on the mountains it really was machine versus nature. Kicked-up dirt managed to destroy one of the teams’ ultrasound equipment and our laptop and gas analyzer were beginning to show signs of trouble. As the temperatures dropped below zero overnight all equipment would collect condensation and at sunrise we would waste no time in taking out the equipment and drying out the components to prevent them from dying as well. Passing on messages to a subject in Bale had to cross three languages beforehand and given the complexity of the Ethiopian languages, learning to pronounce just “hello”, “thank you” and “how do you feel” properly took a lot of work. Nevertheless, it really was exciting. The idea that we were studying people that have probably never been studied before with the possibility of finding something new must have been enough to excite any medical professional.

There are important adjustments that, I feel, researchers need to make when working in these environments. Firstly, never expect anything to go to plan. From problems with getting customs approval for our equipment to constant power failures hindering data collection, stalls are the only things that are guaranteed when conducting field research. Secondly, understand the volunteers who are involved in the tests. It is extremely important to understand local customs and viewpoints so as to not offend people in your interaction with them or question why something that is normal to you is not as normal to somebody else. A lot of this grows out of respect for other people but its importance makes it worth noting in any case. Third and finally, be prepared. Environmental conditions, equipment damage, problems with subject recruitment; there are many factors that cannot be controlled for when operating in the field outside of the laboratory. It is important to be conscious of all the potential challenges and be prepared for them as well as possible.

Cultural issues in overseas field research

Conducting research in a foreign country poses other cultural and ethical issues as well. Informed consent is a particularly important one. Informed consent forms are documents that fully explain the test procedures along with the benefits and possible negative effects the research may have. When conducting human research it is imperative that informed consent is obtained from the volunteers. The problems in Ethiopia were, firstly, the language. The informed consent forms we had for the protocols had to be translated into all of the local languages, which made sense. However, most of the villagers could not read thereby making the informed consent forms largely biased by the way they are interpreted and explained by the researcher. We had independent doctors travel with us to accurately discuss the test protocols in as unbiased a manner as possible, but this is a potentially dangerous loophole that other researchers or medical professionals could exploit as research in these places is not well regulated. Another issue that commonly arose in researching this population was that many locals did not feel comfortable in certain test protocols, notably, giving blood samples. Of course, if locals did not feel comfortable we did not force them and they were welcome to complete certain protocols while leaving others incomplete. The doctors later informed us that many locals see giving blood as giving more than just biological material and that it’s almost viewed as giving away part of something more metaphysical. To many of us this was new but, as always, it was important to respect the wishes of the volunteers and so we happily removed those test protocols for the volunteers that were uncomfortable with it.

The locals we were testing were remarkable people. Almost all of them were subsistence farmers and they seemed taller and more muscular than the average Ethiopians I had seen in Addis Ababa. None of the villagers spoke English and my Orominya (the local language) was virtually non-existent, but through one of the Ethiopian doctors travelling with us I was able to talk to a lot of the locals that came up to the campsite. tThey all confused me for being a Muslim, and being Muslims themselves an occasional salaam would make a lot of the elders happy. The few attempts I did make to explain that I wasn’t Arab and that my grandparents were from India were futile but I must admit, I thoroughly enjoyed my interactions with the people in Bale. We were generally well-received by the local population we studied although there was an element of trust that had to be built before we reached that point. We noticed in the first couple of days of testing that most of the villagers would bring hunting knives with them to the testing campsite. However, towards the middle and end of our stay they no longer brought them. The doctors had spoken to some of the villagers who told them that they had previously brought the knives for protection to make sure we do not harm them! After they had realized we intended to do no harm they started coming without the knives. Although it at first may seem odd to require protection as we normally trust researchers to conduct ethical research, it makes sense that a people who may have never been exposed to the concept of research before would need to make sure we’re not setting out to hurt them. When the locals stopped coming for tests with their knives we took that as a sign that we’re doing something right!

Another thing I learnt in Bale in particular, but Ethiopia in general, was that I brought with me many false preconceptions about the place. Thanks to charity advertisements I’d seen back home I envisioned a drought-stricken and poor Ethiopia where almost everybody was starving and urgent humanitarian interventions were needed. However, what I saw in Ethiopia and in Bale were a proud people who worked hard and a country that seemed to be relatively prosperous. Sure, they have faced hardship in the past and as water is such a precious commodity there remains the possibility they may also have to face it in the future, but I was taken aback by the strength of the Ethiopian people and was left admiring the resolve they showed. I can only hope to convey this message to others to help curb any misconceptions they may have of the country and its people.

Conclusions

Although the results of the experiments are still being disseminated we hope that our research may provide many answers for us. Already high altitude field research like ours has helped identify certain drugs, such as acetazolomide, in helping people with CMS (6). As the results slowly begin to surface we also hope to be able to provide a better anthropological understanding of how some populations are better adapted to high altitude then others. Ultimately though, the research is about helping those high altitude populations that suffer with CMS and through better understanding the different cardiovascular and genetic profiles of well-adapted high altitude populations we may be able to confer better treatment for CMS in less adapted populations.

Inderjeet Sahota is studying for an MSc in cardiovascular physiology at Simon Fraser University in Canada
isahota(at)sfu.ca

References

1. Hainsworth R and Drinkhill MJ. (2007) Cardiovascular adjustments for life at high altitude. Respiratory Physiology & Neurobiology 158, 204-211.

2. Claydon VE, et.al. (2008). Cerebrovascular responses to hypoxia and hypocapnia in Ethiopian high altitude dwellers. Stroke 39, 336-342.

3. Xing G, et al. (2008) Adaptation and Mal-Adaptation to Ambient Hypoxia; Andean, Ethiopian and Himalayan Patterns. PLoS ONE 3(6): e2342.

4. Brugniaux JV, et al. (2007). Cerebrovascular responses to altitude. Respiratory Physiology & Neurobiology 158, 212-223.

5. Hultgren, Herb. (1997) High Altitude Medicine. Stanford, USA: Hultgren Publications.

6. Richalet, Jean-Paul, et al. (2005) Acetazolamide: A Treatment for Chronic Mountain Sickness. American Journal of Respiratory and Critical Care Medicine 172, 1427-1433.

Image Credit: Viren Kaul

Today we’d like to announce the publication of Inderjeet Sahota’s article on his experience doing field research in the highlands of Ethiopia where he learned about everything researchers have to do to get any results at all. Read it here.

Viren Kaul, TLS RA and final year student at Sir Ganga Ram Hospital in Delhi, India, writes the first entry of a series of blogs discussing a community outreach camp organised by the United Youth of India’s Health wing

With around 300 people of varying ages and from a wide area in attendance, the camp was a huge success

United Youth of India, Indian Medical Students’ Association and Himachal Children & Development Organization community outreach programme

“This is the duty of our generation as we enter the twenty-first century — solidarity with the weak, the persecuted, the lonely, the sick, and those in despair.” – So Elie Wiesel said. It was a cold February afternoon that we were discussing on the same lines and we got to thinking on what activities we could take up with the newly formed United Youth of India’s Health wing. We wanted to do something that could in a true sense be said to have been “giving back to the community”.

All the logistical details suddenly became important since we gave ourselves around a week to work the details out and proceed. We decided on doing a community outreach camp which would focus more on awareness other than on the treatment aspects of diseases. The next and probably (as we eventually realized), the most important question was: where to hold the camp. And this is where Himachal Children and Development Organization came in and assured us that we could come to a rural area in Himachal, which was perfect for our “outreach” plan. The best part about District Soldah in Himachal Pradesh was the fact that despite having a medical college and hospital quite close by, people found it very tedious to travel there since the terrain was mountainous and not easily negotiable. The Indian Medical Students’ Association members pitched in with ideas on execution and planning the actual camp.

I am going to cover the outreach visit, its pros and cons and the lessons learnt from the impact in great detail in the coming weeks, since I believe a replicable model of conducting camps by medical interns and students can be created.

How we got there!

The distance between New Delhi (where we started) and District Soldah, Himachal Pradesh is approximately 454 kilometers to one side drive. We decided to prepare for all technical eventualities and the night before leaving we packed all sorts of equipment. Starting from laptops, extra batteries, cameras and extra tube tyres, and so on – we were convinced that nothing should turn up to be a hindering factor once we get to the place and start communicating with the local population.

The second half of the drive was through an extremely hilly area with a two lane mountain road and this turned out to be a challenge since we managed to carry a lot of luggage that eventually was no required in some cases.

Having planned on conducting an interactive awareness and treatment planned, everyone from IMSA decided to focus mainly on issues that concern particular age groups and then address general concerns. Keeping this in mind, we created Volunteer Involvement Flyers, which provided concise information to volunteers (who would be joining us on ground) on as to what all they had to keep in mind while they helped us educate the people. These pointers were made in strict compliance with the national health guidelines/ WHO guidelines.

The innovative element of this awareness campaign was that we worked on a flexible plan. We had visual presentations and material ready on a range of common health concerns. We agreed to adapt to the situation on ground. Once at the camp, we got all the assembled people together and asked them which of the topics were of concern to them and dealt with the same in greater detail. For example, women in Slodah were very concerned about gynecological problems and many had questions on breast lumps. Similarly a huge majority of old men and women had arthritic issues. Since we had been ready to deal with these common issues using AV aids for creating awareness, the local population was very impressed and interactive since they felt important and involved. This was the best way of breaking the ice as we eventually realised.

This was followed by a one on one round of consultations and medicines were distributed or handed out as required.

The camp!

With around 300 people of varying ages and from a wide area in attendance, the camp was a huge success. Towards the end of it, the people of Soldah were satisfied enough to welcome us to their local monastery for a visit. The demographical details would follow in the next series of posts.

Culmination –

Having planned the camp in less than a week, and executed it in 72 hours including a 1300 km drive and a nearly 18 hour camp session, the UYOI Medical Wing is convinced that many such visits may be carried out in the future and in the coming trips proper statistical impact will be evaluated.

Here are K.B. Ashok’s responses:

1) Why did you decide to study medicine?

Well, being a son of a loving responsible teacher-cum-nurse (Mrs. Meera) and a dedicated surgeon (Dr. Nirmal) from the day I was born, I grew up in the environment of medicine. On the other hand, I am one of three brothers and one of my brothers has a FEAR for BLOOD. So they decided not to study medicine. It was left to me to fulfill the dreams of our parents of becoming a GOOD doctor in the future. Papa helped others all the time and I saw a divine personality inside him. His patients who came to have treatment, became friends of my Papa. This quality moved me and made me want to go into medicine, to be like him and to fulfill their dream as well.

2) What profession would you be in if you weren’t in medicine?

I don’t usually answer this question as it was a dream for me to become a WRITER which is really odd to hear especially from a doctor. I love literacy and after coming down to West Bengal (a state of India), I fell in love with the state language BENGALI. So, I wish I could be a writer in Bengali.

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

Here there is only one thing that I want share, which is that medicine is a well known place of corruption and honesty in one package. Papa said it is you to decide which one you will choose and there is only one chance you will have. You will never have to answer your soul for any issue if you are honest but you can’t even take a nap properly being with corruption.

4) What is your biggest motivation?

Before coming to this course it seemed only a story to me about the large population of people who suffer due to lack of treatment in villages and most parts of India. Now being here, watching patients everyday from each level of economy, advising drugs to them, I came to realise that most of them can’t even buy drugs! This is exactly what motivated me to be someone who can understand the agony going inside those people and who can do something for them.

5) What are you most interested in so far and why?

Frankly speaking my interests are always changing according to the options and new information. But, my main focuse of my life is to be a drug researcher. Yeah…helping people is not a thing to be mentioned again and again as this is what I promised my parents and which is their dream as well.

6) What has been your most difficult module so far and why?

Microbiology!!! Oh My God!!! It was really a subject that forced me to as the question “This profession is not for me?”. But my Lord Krsna helped me a lot to be stable and strong and with his mercy at least I passed that subject in one go. However, when I came to final year of study, I became interested to some extent with this subject.

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

It was in the labour room. An asphyxiated new born was delivered and I was the only on-duty student there at that time. The baby was not crying, taking a breath or moving any part of his body. After cutting the umbilical cord, the use of cardiac massage and resuscitation for his LIFE; this was a great experience. When the baby cried for the first time, I felt like…Yes!!! Yes!!! Yes!!! I hope you understand.

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

During the Forensic Medicine and Toxicology in second year we have to attend the Post Mortem classes. A body came in following a family fight and he had a head injury from a sharp, heavy metal object and his head and neck had been divided into two equal parts. I was standing in front of the dissection table and the staff just opened the packed dead body. I don’t know what I felt that time; I just dropped down and fainted. Still now the memory makes my hairs stand on its roots and I am shocked!

9) Where do you see yourself in 10 years time?

a) The wishful thinking version

I don’t have any dream except to be pure, honest and very friendly to my patients just like my Papa is. I wish when people will say loudly, “yeah…doctors are not always corrupted. They can be a good friend of society here in India too”.

b) The perhaps slightly more realistic version

I don’t ever think that my wishful thinking version is an unrealistic one. So, no word I want to give for this column. Thank you!

10) Can you share some tips/advice for others?

a) Wanting to study medicine

· First you think and discuss with eligible people about the course, look at the pressure and the future aspects with a proper sense about the course. Don’t wander in a dreamland.

· Decide in strong mind.

· Don’t try to do something only for the sake of people around you. Do it if you think you can.

· If you are ready in mind, time to get ready for the battle of entrance.

b) Already studying medicine?

Nothing special from medicine I want to add as I am still a student. Still:

· Have faith in your God and yourself. Please do remember to respect your dignity.

· It does not matter how many marks you get in examination; but how you get it, always matters.

· Don’t bother about your marks, think about the knowledge you aquired.

· Help people, God will help you.

· Learn to be thankful which we usually forget to be.

Map of Lebanon; Image credit: CIA World Factbook

Today’s blog, written by Elias Melhem TLS Regional Advisor and fifth year medical student at Université Saint Joseph in Beirut, Lebanon, discusses the stigma surrounding organ donation in this country.

Out of the 800 road deaths in Lebanon in 2008, not one organ was harvested from the dead victims.

There are more than a thousand people on waiting lists in Lebanon, and the number keeps increasing at an accelerated pace. Most of the 800 patients on the kidney waiting lists must wait more than five years. Furthermore, the majority of organ donations come from living rather than dead donors. Out of the 800 road deaths in Lebanon in 2008, not one organ was harvested from the dead victims. That is why the situation is so desperate, especially that dead donors are an important source of potential organ donations.

The reason for these low numbers of dead donors is the fact that the majority of Lebanese do not understand the idea of brain death. Some of them don’t believe in it, and consider the person to be dead only when his heart stops. Others think that it is religiously unacceptable to defile a human being’s body by taking organs that were granted to him by God, although all religious authorities in Lebanon – whether it is the different Christians Churches, the Shiite Ayatollah, or the Sunnite Dar-Al-Ifta’ – encourage organ donation from dead donors, and recognize brain death as a scientific fact. Other reasons are the lack of motivation of physicians, the absence of a unified national waiting list, objective criteria for selection, and a national model for detection of potential donors.

To address these issues, the National Organization on Organ and Tissue Donation and Transplant – Lebanon (NOOTDT-Lb), in association with the Lebanese Ministry Of Public Health (MOPH) launched a national campaign for organ and tissue donation and transplant.

The organization asked its Spanish equivalent, who has developed the transplant model with the highest rates of success in the world, to offer its expertise. Together, they developed the Lebanese model for organ and tissue donation and transplant. NOOTDT-Lb recruited one or two transplant procurement managers (TPM) in every hospital, who have to detect potential donors in their hospital’s ICU. These TPM then have to contact the NOOTDT-Lb head office, where volunteer medical students (such as myself) would be on call to answer them, and make sure that the patient is a true potential donor. The medical students would then have to contact the regional coordinator. The coordinator must follow up the potential donor on a daily basis until brain death is declared and confirmed. The local ICU physician immediately declares brain death to the family and explains this concept until the family understands it “correctly”, otherwise everything done so far would be lost. The local ICU TPM would then approach the family after making sure they have correctly understood the idea of brain death, to request their permission for the donation of the organs. In case the family accepts, NOOTDT-Lb is notified and all the necessary lab tests are done. The organ retrieval team is then called to the hospital to perform the harvesting of organs, which will be immediately delivered and transplanted to the patients at the top of the waiting lists. The costs of these operations are fully covered by the Lebanese MOPH. This model is supposed to increase the rate of brain dead donations to an acceptable level.

NOOTDT-Lb is also organizing awareness campaigns in schools, where volunteers teach students about the idea of brain death and the necessity of signing an organ donation card. The organization also reached an agreement with the Ministry of Interior to make it mandatory to mention the organ donor status on the driver’s license.

Hopefully all these efforts will lead to an increase in organ donation from dead donors. It is truly a shame to see someone die while his death could have been prevented if others were willing to give away what they no longer need, for there is nothing greater than to give someone the gift of life.

Visit theLancetStudent.com to read this week’s blogs , articles and Lancet Seminars; you can also vote in our poll this week on ‘equality for women’ 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 for any of the TLS sections: articles, elective reports, blogs or Education Experiences. And of course – in our hope of expanding our podcasts, social media and online video content we are always looking for those with an eye for editing audio/visual content who would be happy to assist the Editorial Team.

This week in TLS News

Monday 8th March marks the centennial celebration of International Women’s Day (IWD).

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

The Alarming Increase in the Use of ‘Date-Rape’ Drugs

Manuel Rivera, our TLS Regional Advisor for El Salvador, addresses the current evidence on the use of date-rape drugs around the world.

The W8 on a health and education mission

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

Mental Health: Culture, Language and Power

A reflection, by Tiago Gameiro Inacio, 4th year medical student at Newcastle University, currently undertaking the Global Health Student Selected Component (SSC).

WHO guidelines to control airlines transmitted TB expensive and worthless

Suvash Shrestha, our 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.

This week’s Article

Mother and Child Health in India

Shipra Goel’s writes about the deplorable state of maternal and child health in India.

This week’s Elective Report

Gastroenterology at St Elizabeth’s, Boston

Purav Mody’s reports on his elective working in gastroenterology at St Elizabeth’s hospital in Boston, USA, where he learns how the surgical, pathological and radiological aspects of GI medicine relate to each other.

This week’s Lancet Seminar

Lancet Seminar: Bacterial septic arthritis in adults

We would also like to announce that The London School of Hygiene & Tropical Medicine is hosting its first Annual Student Symposium on Global Health on 1st July 2010. And there is a call for abstracts, no longer than 250 words, which should be submitted by 12 noon, 1st May 2010. For further details on submission please visit the website: http://www.lshtm.ac.uk/events/globalhealthsymposium/

Have a great weekend,
The Lancet Student Editors

Today we’d like to announce the publication of Zhi Yang’s report on his experience combining several disciplines in his experience of plastic surgery in Glasgow. Read it here.

Meanwhile, today we present the winning essay from the 2009-2010 Friends of MSF Essay Competition written by Piyush Sarmah who discusses the struggle of the Biharis as stateless people.

A stateless person in broad terms is an individual who has neither nationality nor citizenship of any country, either because their country does not exist or because the state which they claim to be part of does not accept them as its citizens

On June 11th 2010 more than a billion pairs of eyes from across the globe will shift their gaze to South Africa, where the fortunes of 32 countries competing in the FIFA World Cup ™ will be followed eagerly by many fans. And yet even today in the 21st century there are still surprisingly large numbers of people who would not have anyone to support in such a tournament because they are without a nation. These are the so-called ‘stateless people’, some 6.6 million of whom the United Nations High Commissioner for Refugees (UNHCR) identified in 58 countries worldwide in 2008. This is more than double the figure for 2007, although it has been estimated that the true figure of stateless persons around the world may actually be almost twice as large. [1] Nevertheless, ‘statelessness’ has been described by Refugees International as an ‘international blind spot’ for it is a humanitarian issue that has received relatively little attention, and progress on finding solutions has been slow.

A stateless person in broad terms is an individual who has neither nationality nor citizenship of any country, either because their country does not exist or because the state which they claim to be part of does not accept them as its citizens. According to the 1954 Convention Relating to the Status of Stateless Persons, they have no legal bond of nationality with any state. [2] As a result they are denied basic rights including work, education, property ownership, minimal healthcare from the state and free movement. There are some people whose statelessness is better known: the plights of the Kurds in the Middle East, the Roma in Europe and the Palestinians are known worldwide. But there are many lesser known groups who find themselves marginalised and whose situations are virtually unknown. For example, two million members of so-called ‘hill tribes’ in Thailand lack numerous legal rights despite being born in the country, [1] and two million Rohingya Muslims in Burma were stripped of their citizenship by the government in 1982 to try and force them to leave the country. [3] The issues and problems that stateless people worldwide face can be illustrated in the case of a large group of people who until very recently thought their struggle for recognition would never cease.

On August 15th 1947, India gained its independence from the British Empire but was partitioned along religious lines into modern-day India, composed of mainly Sikhs and Hindus, and the Muslim state of Pakistan with two countries, East and West, situated on either side of India. [4] The largest mass migration in human history occurred with approximately 14.5 million people crossing the borders between India and Pakistan; Hindus and Sikhs moved into India and Muslims travelled to East and West Pakistan, precipitated by communal violence that had taken hold throughout the country. [4, 5, 6] One group of people that migrated into East Pakistan from India were Urdu-speaking Muslims from the Indian state of Bihar in the northeast of the country, lured by the promise of a Muslim homeland but also fleeing from religious persecution in India. [7] At this point it is important to note that within the South Asian countries there are many different people with their own cultures, values and languages. This is why the Biharis in their new country found themselves to be a minority amongst the majority Bengali population, but they identified more with the West Pakistani elite that dominated both countries. [8]

In 1970 the Bengali population in East Pakistan declared independence from the West. In the ensuing conflict that followed, in which many atrocities were committed by both sides, the Biharis sided with West Pakistan in fighting to keep a united country. [9] However, after the entry of India into the war, and the subsequent victory and independence that followed in 1971 for the new nation of Bangladesh as it stands today, the Biharis were outcast because of their collaboration with the ‘enemy’ of Pakistan and their identification as ‘Pakistani’. Incredibly though, the very state that the Biharis had supported throughout the entire conflict, and whose very existence had brought them to migrate from India in the first place, also refused to accept them, possibly for fears of heightening cultural and ethnic tensions in an already fragile society. [10, 11] A promise was made to repatriate these individuals and bring them to Pakistan, but although approximately 100000 people ended up being repatriated, the rest of the process stalled and this promise was not realised. As a result, approximately 250000-300000 people became stateless and have existed in this manner for almost four decades. [1, 4, 12]

To this day 66 refugee camps located throughout Bangladesh (the biggest one of which is ironically named ‘Camp Geneva’) house the Biharis, who live in the squalid conditions synonymous with these places: severe overcrowding, poor sanitation, lack of water supplies, lack of an infrastructure and just abject poverty. ‘Accommodation’ for families is limited to small spaces which may measure as little as ten by eight square feet and yet within the same spaces families of up to 12 people, sometimes even more, somehow manage to sleep. [10] Sanitation is so poor that within some camps it has been reported that there is only one toilet for 3000 people. With this lack of sanitation come infectious diseases and water-borne illnesses and these are compounded by the lack of refuse collection and disposal in the camps and co-habitation with animals. These conditions become even worse in a country with a monsoon season, as rainwater gets through the inadequate roofing of many of the refugees’ homes. The vast majority of children in the camps do not receive a proper education, for example in Geneva Camp, which has an estimated population of more than 35000 inhabitants, there is one non-governmental school available to only 371 pupils. [13] These children are therefore unlikely to develop the skills and knowledge necessary for future employment, if indeed they have any chance at all of acquiring this.

Despite the scale of the crisis and the seriousness of the conditions in the camps, medical care is very limited, sometimes even non-existent. A quick search on MedLine for medical articles on the Biharis does not even yield any results for papers reporting on the medical conditions within the camps themselves in Bangladesh, only on the Bihari refugees that were eventually repatriated to Pakistan. Not only have the world’s governments failed to act for the Biharis in trying to end their statelessness, but likewise it seems that international humanitarian organisations have also failed to provide the minimum standards of the appropriate healthcare required in such disasters. [14] The UNHCR, although putting pressure on the Governments of Bangladesh and Pakistan to find a solution, has not properly addressed the plight of the Biharis, [15] and according to the terms of the 1951 United Nations Convention Relating to the Status of Refugees [16] does not actually recognise them as ‘refugees’, thus depriving them of the benefits that are extended to refugee populations. [12] Another problem lies in the fact that only 65 countries are party to the 1954 Convention, not including large nations such as the USA, Canada, India, Russia or China. [17] This only adds more fuel to the argument that not only have the Biharis’ problems, to a huge extent, been ignored by the whole world, but also those of the other populations of stateless people scattered globally. [18]

Fortunately in recent times events have taken a turn for the better, raising hopes for an end to the many years of suffering of the Biharis. In May of 2008 the Bangladesh High Court in Dhaka ruled that any Urdu speaker born in Bangladesh, or whose father or grandfather were born in Bangladesh, and who had permanently resided in the country since 1971 were eligible for Bangladeshi citizenship. They also became eligible to register on the electoral roll for the country’s general elections which took place in December of that year, and after doing this to register in order to receive their national identity card and then a Bangladeshi passport. [19, 20] The sudden passing of the judgement represented a breakthrough in the Biharis’ struggle for recognition by a state, and for many of the young people living in the camps it represented the chance to escape the complete misery that they had experienced from birth. It also brought a modicum of hope to all stateless people around the world, showing that positive and possibly decisive action had been brought about after much persistence by the Biharis and those acting on behalf of their fight for recognition.

But despite the seemingly happy news there are many unanticipated matters. Firstly, the ruling of the High Court does not apply to those Biharis who were adults at the time of Bangladesh’s independence in 1971 but who were not born there, or who were born in India and crossed the border into the former East Pakistan in 1947. [21] This creates a problem for the younger generation seeking citizenship because they cannot simply abandon the elder members of their families. Moreover, some of the older Biharis do not want Bangladeshi citizenship at all and still pledge allegiance to Pakistan, clinging to the belief that the latter will eventually repatriate them to their desired homeland. [16] In addition, while the Biharis will gain many of the basic rights afforded with nationality to a specific country, there is no guarantee that the existing prejudice and hatred directed towards them from the Bengali population will cease. Their ambitions to work their way up through Bangladeshi society may be abruptly halted by the discrimination against them that still persists amongst Bengalis and which will take a long time to be eradicated. Integration into Bangladeshi society is likely to be difficult, due in part to cultural differences as is found all through the subcontinent. The refugees are also continuing to live in the camps; the younger generation, those happiest about the ruling, may take many years to work and earn enough money before they can leave, and even then finding significantly improved living conditions in one of the poorest countries on Earth will prove to be a challenge for them. The time and resources that Bangladesh can commit to ensuring successful integration of more than 150 000 people are questionable, and it is to be expected that outside aid from the UN and international donors will be required to achieve this.

All of the issues regarding the Biharis apply to stateless persons worldwide. It is important to understand the history and complex political issues which lie at the heart of all cases of statelessness, and unless these are resolved then no solution will ever be found. Unfortunately there is no international organisation specifically representing stateless people; while the UNHCR has set out plans to improve their identification, another large stumbling block in finding solutions, [22] it is likely that neither it nor other humanitarian organisations has sufficient resources and funds to bring about legal action against the countries involved to force many rulings. While the Biharis may have scored a sizeable victory, cynics can point to the extreme goodwill from the Bangladeshi government that occurred without much external pressure, something unlikely to be exhibited in other countries. For the time being, the least that the world’s governments can do is to speak out to acknowledge the presence of the problem, its scale and to recognise that swift action is needed. Pressure should be maintained on the nations concerned to bring about solutions and ensure that people like the 103 000 Hindu-speaking Nepali Bhutanese, forced to leave Bhutan in 1991 to ‘preserve its Buddhist character’ and now living in refugee camps in Nepal where they are prohibited from working, [23] can finally end their torment – brought about by political actions and events that many of them do not understand, and which have prevented them from leading normal lives with the basic rights that should be afforded to every human being, including that of nationality [24].

References:

1. United Nations High Commissioner for Refugees. Global Trends 2008: Refugees, Asylum-seekers, Returnees, Internally Displaced and Stateless Persons. United Nations High Commissioner for Refugees, 2009
2. United Nations. Convention Relating to the Status of Stateless Persons. United Nations Economic and Social Council resolution 526 A (XVII), 1954
3. Garcia S, Olson C. Rohingya: Burma’s forgotten minority. Refugees International Field Report. Washington: Refugees International, 2008
4. Berkeley B. Stateless people, violent states. World Policy Journal. 2009; 26(1): 3-15
5. French P. Liberty or Death: India’s journey to independence and division. London: Flamingo, 1997
6. Collins L, Lapirerre D. Freedom at Midnight. London: Harper Collins Publishers, 1997
7. Sen S. Stateless refugees and the right to return: the Bihari refugees of South Asia – part 1. International Journal of Refugee Law. 1999; 11(4): 625-45
8. Rahman MDM, van Schendel W. ‘I am not a refugee’: rethinking partition migration. Modern Asian Studies. 2003; 37(3): 551-84
9. Hashmi TU. The ‘Bihari’ minorities in Bangladesh: victims of nationalisms. [Online]. Available from: http://www.statelesspeopleinbangladesh.net/uploaded_files/articles/TheBihariMinoritiesInBangladesh.pdf
10. Lynch M, Cook T. Stateless Biharis in Bangladesh: a humanitarian nightmare. Refugees International Bulletin. Washington: Refugees International, 2004
11. U.S. Committee for Refugees and Immigrants. World Refugee Survey 2000. U.S. Committee for Refugees and Immigrants, 2000
12. Farzana KF. The neglected stateless Bihari community in Bangladesh: victims of political and diplomatic onslaught. Journal of Humanities and Social Sciences. 2008; 2(1): 1-19
13. Southwick K, Calabia D. Bangladesh: maintain momentum to guarantee citizenship rights. Refugees International Bulletin. Washington: Refugees International, 2008
14. Steering Committee for Humanitarian Response I. The sphere project: humanitarian charter and minimum standards in disaster response. Geneva: Sphere Project, 1998
15. Lynch M. Lives on Hold: the human cost of statelessness. Washington: Refugees International, 2005
16. United Nations. Convention Relating to the Status of Refugees. United Nations General Assembly resolution 429 (V), 1951
17. United Nations High Commissioner for Refugees. States Parties to the 1954 Convention Relating to the Status of Stateless Persons. [Online]. Available from: http://www.unhcr.org/3bbb0abc7.html
18. Frelick B, Lynch M. Statelessness: a forgotten human rights crisis. Forced Migration Review. 2005; 24: 65-6
19. Majumder A. Bangladesh citizenship right divides Biharis. Reuters India. [Online] May 20 2008. Available from:http://in.reuters.com/article/southAsiaNews/idINIndia-33670220080520?sp=true
20. BBC News. Citizenship for Bihari refugees. BBC News. [Online] May 19 2008. Available from: http://news.bbc.co.uk/1/hi/world/south_asia/7407757.stm
21. Aziz S. Stranded Biharis: saga of a forgotten people continues. Saudi Gazette. [Online] December 16 2008. Available from:http://www.saudigazette.com.sa/index.cfm?method=home.regcon&contentID=2009121657192#
22. United Nations High Commissioner for Refugees. UNHCR Global Appeal 2010-2011 – Addressing Statelessness. [Online]. Available from: http://www.unhcr.org/4b02c5e39.html
23. Spiegel PB, Qassim M. Forgotten refugees and other displaced populations. The Lancet. 2003; 362: 72-4
24. United Nations. The Universal Declaration of Human Rights. United Nations General Assembly resolution 217 A (III), 1948

The word “plastic” in plastic surgery is derived from plastikos, an ancient-Greek word for “to mold”. Indeed, the roots of such practice can be traced as far back as 1500 B.C., during which it was a common practice in Indian societies to amputate the nose as a punishment for committing adultery. With the advent of anaesthesia in the mid-19th century, new techniques for the treatment of battlefield wounds were developed for those injured and scarred in the World Wars. In 2005 however, according to statistics from the American Society of Plastic Surgeons (ASPS), more than ten million cosmetic plastic surgery procedures were performed in the USA, an increase of almost 40% since 2000 (1). You don’t have to be a medical student but surely you must be a little bit interested by this? And what-ever happened to the credit crunch?

With this in mind, and having previously done two Special Study Modules (SSMs) in Anatomy, I decided to do an elective at the Glasgow Royal Infirmary’s Canniesburn Plastic Surgery Unit, the regional referral centre for the West of Scotland and also the biggest in the UK. I also became involved in a Plastics-related research project at my university’s Anatomy department during this time.

I was assigned to the Blue team (Head and Neck), which my supervisor belonged to, and I was able to rotate through the Red (Breast and Trunk) and Green (Limbs and Trauma) teams as well for thorough exposure during my time at Canniesburn. My weekly schedule included ward rounds, clinics and clerking in new patients on Mondays and Wednesdays, theatre all-day on Thursdays, and research on Tuesdays and Fridays. While this might seem somewhat disjointed, I found this setup to be quite enjoyable actually as it gave me sufficient time between clinical days to read up on what I had seen and how it related to my research project.

Perhaps it was a blessing in disguise, but I certainly felt that I was thrown in at the deep end when I first started my elective. There are usually not many students around but despite the surgeons’ keenness on explaining the procedures, I was inundated with a myriad of technical terms. Free flap? Pedicled flap? Z-plasty? V-Y advancement? It was a steep learning curve but with support from my supervisor and a logbook of cases that I observed and assisted in, I gradually began to find my feet and I progressed from passive observation to assisting in surgeries – scrubbing-in, performing different sutures, taking skin grafts, and even, making simple incisions. I was also fortunate enough to have several unique experiences such as observing cosmetic practice at my supervisor’s private clinic and being filmed live while assisting on a procedure that was broadcasted throughout the UK!

Example of pre-operative planning

In medical school, we are taught to always ask if the patient has any other concerns. I always felt this to be a bit redundant for why else would a patient come to hospital? That was until I met this particular patient who presented with a basal cell carcinoma above her lip and told me “I just wish it wasn’t there” because she was getting married next month. It was at this very moment when I could fully appreciate the aim of plastic surgery – to seek a fine balance between the restoration of function and an aesthetically pleasing appearance. It was also this very patient who enabled me to finally appreciate the relevance of my research project on the anatomy of facial artery perforators in the design and use of local flaps for the reconstruction of such facial defects.

Overall, I feel that I have grown and matured both personally and professionally over the course of my elective. I might sound biased but I strongly feel that plastic surgery should become a part of the core undergraduate curriculum. Not only will it dispel any unfair, preconceived ideas of the discipline as one being indulgent in cosmetic procedures as fuelled by the media’s portrayal, it will also provide ample opportunity for the student to learn the anatomy of various body regions during the same timeframe as compared to rotations in other surgical disciplines, and to have a continuum in learning that covers all aspects of the biopsychosocial model of health care.

Zhi Yang is a fourth year medical student at the University of Glasgow
0609608n(at)student.gla.ac.uk

References

1. American Society of Plastic Surgeons. Industry leaders, analysts forecast cosmetic plastic surgery market [homepage on the Internet]. Illinois, USA: American Society of Plastic Surgeons Plastic Surgery Educational Foundation; c2010 [cited 2010 February 15]. Available from: http://www.plasticsurgery.org/Media/Press_Releases/Industry_Leaders_Analysts_Forecast_Cosmetic_Plastic_Surgery_Market.html

Benedict Warner, third year Medical Student at University of Dundee, discusses the financial and health costs of food-borne diseases for today’s blog.

The most common clinical presentation of food-borne diseases takes the form of gastrointestinal symptoms, but such diseases can also lead to chronic, life-threatening symptoms including neurological, gynecological or immunological disorders and in the United States lead to around 5,000 deaths a year

Food-borne disease has been described as a ‘global concern’[1] that will be a defining issue of the 21st century’s increasing globalization. As the food we eat becomes more and more processed, and travels further to our tables, the opportunities for pathogens to enter the production chain, and to reach more consumers, continues to grow. Despite this threat, the scale of the problem has remained largely unknown and unmeasured.

Since 2006, this problem has been recognized by the WHO’s Initiative to estimate the Global Burden of Food-borne Diseases[2]. Under this Initiative, the Food-borne Disease Burden Epidemiology Reference Group (FERG) was established, to measure the burden of such disease globally.

However, in spite of these efforts, a study released this month by the Product Safety Project has revealed that the cost of food-borne illness has been massively underestimated until now. The study Health-Related Costs from Food-borne Illness in the United States updates previous estimates of around $6.9 – 35 billion a year in health-related costs of food-borne illness to the far greater figure of $152 billion.

How did the figures change so suddenly? Dr Scharff, of Ohio State University and author of the report, described his estimates as ‘more complete… summing both medical costs (hospital services, physician services, and drugs) and quality-of-life losses (deaths, pain, suffering, and functional disability) for each of the major pathogens associated with food-borne illness’[3]. His study also includes 27 pathogens across the whole of the United States, against only five pathogens used in the past. Even his figures are probably a ‘lower bound estimate’ of the total cost to society, as the study did not include costs to industry or government.

Food-borne disease does not carry the headline clout of other infectious diseases such as HIV and malaria, perhaps, as Dr Scharff suggests, because so many of us are familiar with the mild forms of the problem. The most common clinical presentation of food-borne diseases takes the form of gastrointestinal symptoms, but such diseases can also lead to chronic, life-threatening symptoms including neurological, gynecological or immunological disorders[4], and in the United States lead to around 5,000 deaths a year.

Food safety is a truly international concern, with many of the constituents of any one food product often coming from multiple countries. The International Food Safety Authorities Network is another WHO initiative which aims to promote sharing of information between national food safety authorities, and releases information notes on outbreaks of food-borne illnesses around the world.

The incidence of food-borne illnesses also varies between countries. In the UK, the Food Standards Agency was created in 2000 in the wake of an outbreak of Bovine Spongiform Encephalitis (BSE – the notorious ‘mad cow disease’) and other serious incidents, and is a strongly independent Government department. In its first six years, it achieved its self-set target to cut food-borne disease by 20%[5]. Such forthright and open leadership by a particular department is in contrast to the US’s more convoluted system, where multiple agencies are involved in the overlapping jurisdictions covering food safety and health, and these differences are reflected in the respective incidences of food-borne illnesses: 26000 cases per 100,000 in the US against 3400 per 100000 in the UK[6].

The US is catching up, however, and a bill extending the powers of the Secretary of Health and Human Services to regulate food and food facilities (S. F10: FDA Food Safety Modernization Act) has been passed by the House and awaits a vote by the Senate – albeit once healthcare reform has been settled.

Food is central to health, and many global health challenges of the coming century will have their roots in our diets – obesity, diabetes, heart disease – even the impact of cattle rearing on climate change. The hidden costs of food-borne illness are only now coming to light, and it is imperative that the regulatory mechanisms are strong enough, within and between countries, to maintain standards from farm to fork.

Ben Warner
3rd Year Medical Student
University of Dundee
benedict.warner@googlemail.com

References:

[1] Marilynn Larkin, Food-borne Illness – a global concern. The Lancet Infectious Diseases, Volume 4, Issue 4, Pages 250 – 251, April 2004

[2] http://www.who.int/foodsafety/foodborne_disease/ferg/en/index.html

[3] http://www.producesafetyproject.org/reports?id=0008 Press Release PDF

[4] http://www.who.int/foodsafety/foodborne_disease/ferg/en/index.html

[5] http://www.food.gov.uk/safereating/microbiology/58736

[6] http://www.cdc.gov/ncidod/EID/vol5no5/mead.htm

Today we present the 2009-2010 Highly Commended Essay from the Friends of MSF Essay Competition, written by Ruth Allen who explores the challenges of neutrality in humanitarian relief.

The birth of MSF and its outspoken approach to humanitarian relief solidified the clear conceptual distinction between two groups of humanitarians: the traditional ‘classicist’ and the new era ‘solidarist’

Introduction

Neutrality is the key stone to the principles of humanitarian relief. Classical humanitarianism prides itself on neutrality and impartiality, as proclaimed by the Red Cross Code of Conduct. These twin principles are set front and centre of humanitarian action and are enshrined in the Geneva Conventions and Additional Protocols (1,2).

This essay will assess the challenges to the principle of neutrality that are faced by INGOs involved in humanitarian relief in today’s “new era of humanitarianism” (3). It will illustrate, with empirical evidence, that humanitarian relief can not be neutral. Aid is often manipulated and politicized at some level, regardless of neutral intent. Politicization has become inevitable in this new era, when working within an environment where maintaining humanitarian access (4) is precariously balanced with speaking out against visible abuses and advocating for change.

The debate as to whether humanitarian relief should or can be neutral is widely covered in the literature. The academic division between a classically neutral position will be compared to a new inherently political approach to humanitarian relief (5), to illustrate how both positions raise moral dilemmas and practical challenges in this new era.

This essay will argue that by maintaining a classically neutral ideology, and refusing to publicly recognise non-neutral political elements of their work, organisations are devaluing their efforts and reputation, and losing respect. Support for INGO actions at national and international level will ultimately come into question, as pursuing unachievable goals equates to making empty promises. Therefore, the fundamental core principles, set out in an ‘old war’ world, are no longer adequate in the context of today’s humanitarian challenges and must be reviewed.

Neutrality Challenges

Humanitarian relief is taken to be the provision of material assistance, with the aim of combating suffering, irrespective of political root or historical context, in short: to provide aid (6,7). This classical approach to humanitarianism stems from one man’s provision of assistance to a wounded soldier on the battle fields in 1863 and resulting in the formation of the International Committee of the Red Cross (8). Humanitarian need has mutated significantly since then but principles have not altered to meet the changing context.

The battle fields and front lines of an ‘old war’ (9) era have been superseded by a more complex environment that humanitarian actors now operate in. The extended ‘space’ of operation and proliferation of INGOs in a post cold war period (10) in which humanitarian relief now operates forms a ‘new environment’ and a ‘new era of humanitarianism’ (3,11).

The proliferation of ‘new wars’, (9) protracted civil intra-state conflicts and complex political emergencies inherently produce neutrality challenges. The existence of non-uniformed, highly mobile combatants living amongst and indistinguishable from civilian populations is one complication for actors seeking to provide neutral relief. This complication resulted in political manipulation of humanitarian relief in 1994 in the refugee camps of Zaire. Aid was abused to fuel the Rwandan genocide to control, recruit and rearm civilian populations (12), demonstrating the confusion that humanitarian relief organisations face in this new era.

In a ‘new war’ environment, as in Rwanda, material aid acted as oil rather than water and exacerbated the conflict. These physical manipulations can be categorized in four groups. First, by providing resources in the form of aid, opportunity arises for its manipulation and diversion to the purposes of war by feeding militants, sustaining and protecting militant supporters, hijacking assets and thereby contributing to the war economy. Second, aid leads to distortion of local economies through the influx of resources, affecting employment opportunities and market prices. Third, humanitarian intervention provides legitimacy to combatants by acknowledging their presence on the ground and negotiating terms. Finally, dependence on INGOs develops. (2,4,11-13). The Rwandan case shows these manipulations and political engagements in action and demonstrates the greater, more complex challenges of the new war context. The traditional intention to provide neutral aid which “will not be used to further a particular political standpoint” (14) clearly failed, revealing the darker, negative impact of relief operations and raising the moral dilemma as to whether aid can do harm as well as good, and if so, does benefit outweigh cost (3,12).

This moral dilemma had earlier been evident during the Biafran War as aid was manipulated and politicized at national level. Relief supplies were delivered by buying space on military flights from which the Biafran government collected fees which supported the war effort. Once again the war economy was directly maintained by the humanitarian effort (15). The aim that “aid will not be used to further a particular political standpoint” (14) was far from evident in Biafra.

The Biafran case “stands out as a formative experience in contemporary humanitarianism” (15): it demonstrated the politizisation of material aid at national level and was the birth of a new type of humanitarianism in a new era. This new humanitarianism was marked by the breakaway of several ICRC field staff in Biafra. They were not prepared to remain silent about the visible manipulation of humanitarian relief and no longer wanted to abide by the ICRCs strict principles of neutrality. They established a new organisation: Médecins sans Frontières, (5) creating a new ideology and new voice. MSF founders were of the opinion that; “by keeping silent, we doctors were accomplices to the systematic massacre of a population” (16). The founders of MSF acknowledges the difficulty of reconciling the two legitimate humanitarian desires; to speak out loud and expose a situation, and to maintain good relations with actors on the ground to enable access and continue to help victims (17). Reconciling these legitimate but seemingly conflicting desires is the biggest challenge in the neutrality debate. There is a negative effect of both actions; by remaining silent but blind to atrocities but maintaining access, the whistle is not blown, as ICRC did in WWII over the existence of the Nazi concentration camps (15). However, speaking out risks reduced access to beneficiaries, as occurred when MSF were evicted from Ethiopia during the 1984 famine. The line which INGOs walk is a very fine one.

The birth of MSF and its outspoken approach to humanitarian relief solidified the clear conceptual distinction between two groups of humanitarians: the traditional ‘classicist’ and the new era ‘solidarist’. These two groups sit at opposing ends of a horizontal spectrum in the neutrality debate. The classicists, led by the ICRC, believe humanitarian action should be neutral and completely separate from politics; “humanitarianism is neutral or it is nothing” (18). The solidarists believe political and humanitarian actions are and should be closely associated (4,5).

The new era and birth of a solidarist approach with larger mandates has brought new challenges to INGOs. The initial definition of humanitarian relief given in this essay was the classical one – the provision of neutral material assistance. However a combination of humanitarian failures and the protracted nature of conflicts in this new era (5,11) have resulted in organisations “looking for something else beyond relief” (7). Organisations are now carrying out multi-mandate operations, moving away from traditional aid distribution and towards advocating for human rights and involvement in peace building.

Classicists would argue such activity takes humanitarianism beyond the role it is suited for (18) and brings a political dimension to humanitarian relief. This change towards a solidarist approach has come at a price; by over-reaching into new realms and thereby directly interacting with politics, humanitarianism has become hijacked by political motivation (18). This politizisation has prevented any chance of adhering to neutrality, but is a realistic consequence of operating in today’s environment. Brauman notes that the provision of impartial and neutral aid is the main strength of humanitarianism, but also “sets its structural limits” (6). This political hijacking of humanitarianism steps beyond the structural limits inherent in neutrality and raises the question as to how INGOs working in this era can remain neutral.

The host country’s political manipulation of aid at national level, as outlined above, is only half of the political equation. Foreign policy and an international agenda complete the circle of entrapping challenges for INGOs with neutral intent. This new era of humanitarianism is distinguished by the emergence of humanitarianism as a strategic instrument in the foreign policy of western powers (3). The international funding which can be argued to direct INGO activities and allow a means of western dictation to aid operation is preventing neutral action. A solidarist approach of advocating and lobbying at donor government level further concretes relations between non-government and government actors. This double edged sword of politicization is currently playing out in an increased environment and on more publicly exposed stages: more humanitarian need, more INGOs, more government funding and larger mandates.

The public and highly political stage on which INGO political relations have erupted is evident in Darfur. In March 2009 the International Criminal Court issued the arrest warrant for the serving Sudanese President Omar al-Bashir, publicly referring to evidence received from humanitarian agencies (19). Within an hour, the Sudanese government insisted on the eviction of ‘outspoken’ INGOs from Darfur claiming timing was not related to the ICC ruling, and organisations were not selected on the basis of regions of work or ethnicity of target beneficiaries.

Darfur demonstrates the tension and danger of moving away from classic neutrality and the repercussions that doing so has on access to those on the ground. More importantly it illustrates the realism of challenging states asserting their sovereignty, and demonstrates the need to demand and ensure humanitarian access by work beyond the confines of mere service delivery and emergency response. The relations between organisations and host governments (who ultimately hold the power over INGO operations) are very fragile, a mix of sensitive advocacy and fig leaf waving service delivery. The moral dilemma of ‘do no harm’ (3,12) is faced again. Aid is shown to have negative effects, but that does not mean doing some good is outweighed by unintentional harm. The dilemmas will remain, but insisting that humanitarian relief can be neutral and non political appears no longer to be plausible.

Conclusions

This essay has demonstrated that despite a desire for neutrality, it is very difficult for humanitarian relief to be neutral. Neutrality challenges have been shown to come from two sides: material manipulation for political gain by national actors, and increasing political associations through advocacy work and implementation of a foreign policy agenda through donor funding.

The ‘new era of humanitarianism’ which developed within proliferating protracted conflicts and ‘new wars’ has led to extending the demanded engagement for INGOs in terms of scale and longevity. Organisations have looked beyond basic service provision to address humanitarian issues and become engaged in political realms. These politicizing factors distance INGOs from the classic neutrality of the Red Cross Code of Conduct to which most ascribe. In reality it must be acknowledged that humanitarian action, especially in conflict, will have political consequences and engagements, regardless of the non political intention (13).

The new era also gives rise to increased moral dilemmas for INGOs. The challenge of reconciling an aim to ‘do no harm’ (3.12) is, and will remain, ongoing. The evidence from Biafra, Rwanda, and more recently Sudan, ratifies the argument that neutral intent has been almost impossible to realize. Maintaining a classical position leads to avoidance of whistle blowing which could prevent further harm, but increases the likelihood of access to beneficiaries and therefore ensures continued service provision. Taking a solidarist view, where humanitarianism and politics are closely related can result in co-option by foreign governments and denied access to the very population INGOs are intending to assist. Therefore both a classicist and solidarist approach to humanitarian relief face challenges and moral dilemmas regarding neutrality.

This essay suggests that INGOs should accept that the politicization of their actions is inevitable and that strict neutrality is impossible. The political dimension to their work is increased and magnified in this new era of humanitarianism. Therefore, empty intent, from both ends of the spectrum is devaluing humanitarian relief operations. Despite empirical evidence that political and humanitarian action cannot be disassociated (5,6) organizations maintain they are ‘neutral’. MSF, as many other INGOs still refrained from removing ‘neutral’ from their mandate. Contrary to the Code of Conduct, aid will continue to be used to further particular political standpoints. Humanitarian agencies need to re-conceptualize their core principles to update them for the new era in which they now operate. An element of realism needs to be included in a review of humanitarian intent and ambition before credibility is undermined any further and the already fragile faith in humanitarian relief is lost.

References

1. Barakat S. After the conflict: reconstruction and development in the aftermath of war. London; New York: I.B. Tauris; 2005.

2. Slim H. Relief agencies and moral standing in war: principles of humanity, neutrality, impartiality and solidarity. Development in Practice. 1997; 7(4); 352.

3. Slim H. Doing the Right Thing: Relief Agencies, Moral Dilemmas and Moral Responsibility. Political Emergencies and War; Report 6: Studies on Emergencies and Disaster Relief; Nordiska Afrikainstitutet. 1997; 4.

4. Duffield, M. The Political Economy of Internal War: Asset Transfer, Complex Emergencies and International aid. In: Macrae, J. and A. Zwi, with M. Duffield and H. Slim. War and Hunger: Rethinking International Responses to Complex Emergencies, London: Zed Books/Save the Children Fund. 1994.

5. Weiss Thomas G. Principles, Politics, and Humanitarian Action. Ethics & International Affairs; 1999; 13; 1-22.

6. Brauman R. Refugee Camps, Population Transfers, and NGOs. In: Hard Choices: Moral Dilemmas in Humanitarian Intervention, ed. J. Moore. Boulder, CO: Rowman & Littlefield Publishers, Inc; 1998; 192.

7. Rieff D. A Bed for the Night: Humanitarianism in Crisis, London: Vintage; 2002; 21-22.

8. International Committee of the Red Cross, Founding and early years of the ICRC, http://www.icrc.org/Web/Eng/siteeng0.nsf/htmlall/section_founding?OpenDocument

9. Kaldor M. New and old wars: organized violence in a global era. 2nd edition. Stanford, Calif: Stanford University Press; 2007.

10. Howell J. and Pearce J. Civil Society and Development: A Critical Exploration. London: Rienner; 2001.

11. Cushing C. Humanitarian Assistance and the Role of NGOs. Centre for Foreign Policy Studies, Dalhousie University Working Papers Series; 1995, 6.

12. Anderson M. You Save My Life Today, But What for Tomorrow? Some Moral Dilemmas of Humanitarian Aid. In: Hard Choices: Moral Dilemmas in Humanitarian Intervention ed. J. Moore. Boulder, CO: Rowman & Littlefield Publishers, Inc.; 1998; 145.

13. Lischer S. K. Collateral Damage: Humanitarian Assistance as a Cause of Conflict. In: International Security; 28(1);79-109.

14. International Committee of the Red Cross, Principles of Conduct for The International Red Cross and Red Crescent Movement and NGOs in Disaster Response Programmes, http://www.ifrc.org/publicat/conduct/code.asp. 1994.

15. De Waal A. Retreat from Accountability II: The Humanitarian International. In:

Famine crimes: politics and the disaster relief industry in Africa. London: James Currey Publishers; 1997; 65-85

16. Benthall J. Disasters, relief and the Media. London: I.B. Tauris; 1993; 125.

17. MSF (1997) World in crisis : the politics of survival at the end of the twentieth century, edited by Médecins sans Frontières: project coordinator, Groenewold, J. and Porter E., London; New York: Routledge

18. Rieff D. A Bed for the Night: Humanitarianism in Crisis, London: Vintage; 2002; 330, 306.

19. Flint J. and de Waal, A. To put justice before peace spells disaster for Sudan. London: The Guardian, 6 March 2009, http://www.guardian.co.uk/commentisfree/2009/mar/06/sudan-war-crimes.

The fashion industry is worth 36 billion pounds a year in the United Kingdom alone at present, instigating fierce competition among high street outlets to attract the masses through lowering prices

I watched the news the other day. I never usually watch the news, not because I don’t care what is going on in other parts of the world but because I’m a twenty-one year old male and all the news I need is on the BBC sport website. I find that if something notable happens outside of this niche it reaches me via the news outlet that the cavemen created – word of mouth.

But it is the Christmas holiday, I am back home and I no longer have free reign over the remote control. The ITV news room has had a make-over since I last watched the news, but I can’t remember when that was. They have gone for a black, yellow and grey look. I have just googled it and apparently “after months of deliberation” the ITV executives felt a change was needed. This was due to the fact that the opening sequence was seen as too “London-centric” as Big Ben played a starting role and they didn’t want to alienate viewers from outside the London area[1]. Personally I struggle to recall the previous opening sequence.

The first and headline story on the news was about shopping and the third story down was the war in Afghanistan with yet another soldier killed. I wonder if the executives had had lengthy deliberations over the order and importance of the news stories. Anyway back to the headline – images show hordes of people racing into shops having queued for hours fresh from their turkey dinners. The reporter, who I am glad to see has not had a make-over in line with that of the rest of ITV news, does the vox pop interviews. The general public seem to be enjoying themselves and all are getting what they refer to as “bargains”. That may be true.

A few years ago now, when I was still at school and still towards the bottom of the remote control pecking order, I do remember a feature on sweatshops appearing on the news when there was less yellow and more of a damson colour scheme on the set. Images of workers chock-a-block, ensnared in the factory walls like flies to a spider’s web appeared in front of me. All faces possessed vacant expressions while working at full tilt sewing familiar garments that we have all seen hung under comforting lighting on the high streets. Subsequently there was an interview with one of the big wigs representing the company which was supplied by the pictured factory, the large man claimed that they were appalled by the whole thing and that there would be drastic changes implemented. They went back to the studio where the news reader didn’t look best pleased but let’s face it they never do until they start purposefully shuffling their papers when the credits roll.

I’m not surprised to find that little progress has been made since that feature and there are still reports of poor working conditions and inexplicably low pay. The fashion industry is worth 36 billion pounds a year in the United Kingdom alone at present, instigating fierce competition among high street outlets to attract the masses through lowering prices[2]. Corners are cut and the factory workers in countries half way round the world are given paltry pay[2]. The simple truth is that somewhere somebody made the clothes and bags that those queues on the news crave. It is likely that this nameless person was working at a rate of around a mere two pounds per hour or less[2].

War on Want, a movement that campaigns for human rights, produced a report towards the end of 2006 focusing on the Bangladeshi garment industry in particular factories that supplied Tesco, Asda and Primark. They found that workers far exceeded the 48 hour working week plus 12 hours of voluntary overtime detailed in the common code of conduct that Tesco, Asda and Primark have all signed up to[3]. They spoke to one worker, called Rahimul, who had worked 140 hours of overtime in just one month[3]. Overtime is formally optional but it was discovered that if workers chose not to work overtime after being instructed to do so by management they instantly lost their jobs[3]. This overtime was often documented incorrectly by management to satisfy foreign buyers and local labour laws[3].

Working hours were not the only problem uncovered. The minimum wage is now £12 per month (around 6-7p per hour) in Bangladesh but War on Want found the starting wage in the factories they investigated range from £7.54 to £8.33 per month[4]. This is despite many experts indicating that the living wage for Bangladesh should be in the region of at least £22 – a living wage is deemed to be enough for a worker to provide food, clean water, shelter, clothes, education, health care and transport for their family[4]. Consequently the workers were forced to live in crowded environments with no running water or sanitation. Any union activity by the workers to levy changes or expose working conditions resulted in instant dismissal[4].

Two years on from this first report War on Want produced a follow up report to assess if any changes had been made. Unfortunately nothing had changed. Illegal overtime was still enforced, wages were still not enough to live off, and physical assault by factory bosses was not uncommon if they felt targets were not being reached[5]. In the two years since the report the living wage had doubled due to increases in food prices5. The price of low quality rice had increased by 70% and other essential cooking items including oil, onions, pulses and flour saw and increase in price of between 30-60%[5]. Somewhat predictably no increase in wage had been given in line with the increased price of food[5].

Without the living wage workers are forced to live in cramped conditions with over ten family members sleeping in one room. Factories are highly unregulated and buildings unsafe, fires and deaths are unfortunately not an uncommon occurrence. In conditions which mirror Dickensian workhouse life it is not surprising that workers health is at best poor. Anton Foek, a free-lance journalist travelled to Thailand to investigate the production of Barbie dolls where he found workers suffering from musculoskeletal pains, nausea, hair loss, dizziness and memory loss6. Most commonly (over 75%) the workers complained of infection and breathing problems including chronic lead poisoning due to the thick mist of dusty air that enveloped them and the harmful chemicals with which they worked each day[6]. Protective masks are made available for purchase but the worker’s wages do not allow for such a luxury[6].

This report by Foek was published in 1997 around 7 years after the first large expose of sweatshop labour at the beginning of the 1990s. On Christmas eve in 2002, another 5 years on, the Independent newspaper reported that workers in China, where 1.5 million girls aged between 17 and 23 years of age supply 70% of the world’s toys, were being exploited “more than ever”[7]. Many workers were again found suffering from headaches and rashes from the spray paints, glue fumes and toxic dust that they were exposed to just like the workers in Bangkok[7].

There are countless reports of sweatshop labour across the globe throughout the last two decades. People are suffering and progress is slow. There are a number of organisations, including War on Want, that are constantly campaigning to raise awareness and offer solutions to this humanitarian problem. No Sweat, Buy Nothing Day and Students Against Sweatshops are just some examples of organisations have had success in exposing and boycotting companies that use sweatshop labour in the manufacture of their products[8].

Labour behind the Label has proposed a four-pronged approach to tackling the elephant in the room[2]. The first requires a collaborative approach between companies within the Ethical Trading Initiative to identify problems in shared supply chains and enforce changes[2]. Secondly it is encouraged that the companies not just allow union activity but ensure that discussion about the work place and wages takes place between workers[2]. Thirdly they ask retailers to increase prices on the high street or cut profit margins to increase wages and they finally requested that companies should set targets to increase pay to that of a living wage[2]. None of those demands are drastic. Small changes are needed but these are large companies driven and blinded by profit. In Labour behind the Label’s latest survey only Monsoon, Gap, Next and New Look have committed to this approach with the goal of increasing wages, improving living conditions and the health of all workers[2].

This year FairTrade is celebrating its 15th anniversary, the company’s mark ensures shoppers that the product they buy has been ethically sourced and workers are paid a fair price. This certainly begs the question as to why I have seen no FairTrade marks on clothing on the high street or in fact why all products are not assessed as to their origin. A quick internet search reveals that there are clothes that carry the FairTrade mark but seem to be a rarity. Strategies such as these need to be expanded and backed by the shopper. Surveys on the high street have shown that consumers are willing to pay over 15% more on an item if they felt it had been produced under “good conditions”[8]. You and I, the consumer, could certainly play a major role in changing our attitudes as to how and where we shop causing a shift in product demand and concomitantly a change in the chief executive psyche.

Again I have memories of the big-wig I saw on the news years ago. We have seen that although there has been some progress there is long way to go to eradicate sweatshops and the secondary health effects ensue. I do have some sympathy for the executives that are interviewed in the flashy news rooms. It is difficult to regulate working conditions in countries half way round the world. One of the main barriers to solving the problem is the sub-contracting and sub-sub-contracting of work by the large western firms of the production of their goods. It is not necessarily their firm but their suppliers that are responsible. But with turnover and profit in the millions and even billions of British pounds surely anything is possible. One thing is for sure in the case of sweatshops, which can be deduced without a board meeting – a definite change in attitude is needed. As Bob Dylan so aptly put it “How many times can a man turn his head, pretending he just doesn’t see? The answer my friend, is blowing in the wind, The answer is blowing in the wind.”

References:

1. English, P. (2009). Big Ben to be dropped from News at Ten titles over fears it’s too “London-centric”. In Daily Record, pp. http://www.dailyrecord.co.uk/showbiz/television-news/2009/2010/2023/big-ben-to-be-dropped-from-news-at-ten-titles-over-fears-it-s-too-london-centric-86908-21767324/.

2. McMullen, A.M., S (2009). Let’s Clean Up Fashion – The state of pay behind the UK high street (Labour Behind the Label).

3. Alam, K. (2006). Fashion Victims (War on Want).

4. Alam, K. (2008). Fashion Victims II (War on Want).

5. Foek, A. (1997). Sweatshop Barbie: exploitation of Third World labor. The Humanist 57, 9.

6. Becker, J. (2002). China’s exploited toy workers still toil in toxic sweatshops. In The Independant.

7. Crewe, L. (2008). Counting the Cost of Fashion. Geography 93.

8. Pollin, R.B., J; Heintz, J (2002). Global Apparel Production and Sweatshop Labor: Can Raising Retail Prices Finance Living Wages. Cambridge Journal of Economics 28.

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.

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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

In addition to our new ‘write-for-us’ section, we have also started to publish the Lancet Seminars on the Lancet Student webpage – read them here.

On top of all this, we have also started to publish our newsletters each week on the website, as well as adding a ‘What’s New’ section on our homepage– to keep everyone updated with what’s going on at the TLS!

This week in TLS News

The senescent endowment of United Kingdom and its implications

Gurmeen Kaur , our TLS Regional Advisor in India and Medical Student at Lady Hardinge Medical College, explores the implications of the ageing population in the United Kingdom.

Not the Flu

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

Functional magnetic resonance imaging (MRI): opening a window on human consciousness.

Daniela Rognone and Niccolò Giaj Levra, who are both medical students at University of Turin, describe the use of Magnetic Resonance Imaging to measure brain activity in patients in vegetative state.

Girl Power: The Female Condom

Catherine Carver, a TLS Blogger and medical student at University of Aberdeen, reports on the benefits of the female condom.

Apixaban a better anticoagulant than Enoxaparin

This week’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.

This week’s Article

Tuberculosis in Chiapas, Mexico: A Human Rights Perspective

Kier Philip writes about the implications for human rights of the endemic tuberculosis in Chiapas, Mexico.

This week’s Elective Report

A Clinic in the Rainforest, Break-dancing Lessons, and Human Rights in Mexico

Kier Philip’s writes an elective report on his experiences in medical care and human rights issues in southern Mexico.

This week’s TLS 10-point Medical School Questionnaire

Pranab Chatterjee’s TLS Ten Question Challenge

Pranab Chatterjee, a final year medical student at the Kolkata medical school in the West Bengal University of Health sciences, India, has accepted the TLS challenge to take the 10-point medical school questionnaire.

This week’s Lancet Seminar

Read this week’s Lancet Seminar: Lancet Seminar: Dilated Cardiomyopathy

We would also like to announce that the registration is now open for the 8th Annual Western Regional International Health Conference at www.wrihc.org, presented by the University of Washington, Department of Global Health and Physicians for Social Responsibility and is being organized by an interdisciplinary group of over 20 undergraduate, graduate, professional students!

Have a great weekend and please get in touch,

The Lancet Student Editorial Team

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.

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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 basa