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This Week in The Lancet

  • Volume 377 1719 (2011)
  • May 21, 2011

Non-Communicable Diseases

Climate change, diseased fish and food insecurity: What this means to the Ouje-Bougoumou community

Thursday, November 4th, 2010

by Benita Y. Tam
University of Toronto, Canada

Traditional foods are vital to cultural identity and the health of Aboriginal peoples [1]. Personal identity, cultural values, skills and spirituality are all associated with the traditional lifestyle in obtaining wild game meat and fish [2]. A decline in a traditional food source may not only impact the physical health of an Aboriginal community, but it may also affect the representation of their culture. Leaders of Cree communities believe harvesting (e.g. hunting, fishing and trapping) to be integral for their cultural and social health [3]. In a Cree community of the eastern James Bay region, a decline in harvesting and bush activity due to hydroelectric development has been found to be related to greater social and health issues [4]. Aboriginal elders may observe the loss of healthy fish with greater significance and value: they may associate this loss with the loss of a traditional method or the loss of the connection between fish and the First Nations. Thus, a loss of a traditional food source such as fishing may have significant health implications on Aboriginal communities.

Aboriginal members of the Ouje-Bougoumou community in the James Bay region, Quebec, Canada have subsisted on fish for a long time from nearby lakes. As a community member reported:

They like eating fish. I know that. My friends from Chibougamau will ask me, did you go fishing? Can I have a few? [5]

However, in 1999, a documentary revealed the reality of the fish in several lakes of the Ouje-Bougoumou region [6]. It showed elder Albert Mianscum catching fish, and each one he caught was plagued with physical deformities, such as red sores and missing fins and eyes [5, 6]. As a community member reported in an interview several years later:

You got to see the fish, how ugly they look. Their eyes are popping out. Red, red eyeballs. [7]

The physical deformities were later confirmed to be caused by a fish disease called furunculosis [8]. For Albert Mianscum, and like so many other community members, this was a serious concern as fish was a main source of food for him and his family [5]. Many of the community members of Ouje-Bougoumou believe that the onset of furunculosis was caused by the runoff of nearby mines [5]. Another study found that a combination of stress factors, i.e. climate change and mining contaminants, could have induced the susceptibility of certain fish species to furunculosis [7]. As climate change and contaminants are “affecting the traditional food systems” in the Arctic [9]; the unhealthy contaminated fish of the James Bay region may be further exacerbated by climate change.

Climate change has been associated to food security issues particularly in Northern Aboriginal communities due to the impact on traditional harvesting activities and financial insecurity [1, 10]. With a growing population of diseased fish in the James Bay region, climate change may further devastate the fish population, putting Aboriginal community members at risk to health issues such as food insecurity.

Food security

Food security refers to the adequate access, availability, supply, and utilization of food; also known as the four pillars to food security [2]. Education and knowledge on the health benefits of consuming healthy foods has been established to be other influential components of food security. This term is well defined by the World Food Summit in 1996 (obtained in [2]):

Food security exists when all people, at all times, have physical and economic access to sufficient, safe, and nutritious food to meet their dietary needs and food preferences for an active and healthy life.

Food insecurity may presumably be the opposite of this definition; where people do not have physical access and/or economic means to a sufficient amount of safe and nutritious food that would provide them a healthy lifestyle. Food insecurity is a condition that can adversely affect the health and well-being of individuals, households, and communities [2]. Harmful consequences of food insecurity include social, physical, and nutritional detriments. A number of studies reveal that those suffering from food insecurity consume an inadequate amount of nutrients on a daily basis [2]. Subsequently, poorer quality dietary intake may lead to many health problems including obesity, heart disease, and type 2 diabetes [11].

Rates of food insecurity for Aboriginal Canadian households are much higher than those of Non-Aboriginal households [2]. A study surveyed three rural Aboriginal communities and compared the rates of food insecurity between the children and adults within the same household [2]. Results show that in the same household, food insecurity rates for children were much higher than their counterparts [2]. Conversely, food insecurity rates for children were lower than their counterparts when examining western households located in southern Canada [2].

Since game fish is one of the main foods for many Aboriginal members in the Ouje-Bougoumou community [7], a decline in healthy fish due to contamination and climate change may be detrimental to their overall diet. A decline in access to healthy fish in Ouje-Bougoumou may force community members to consume more store bought foods. Simultaneously, availability of readily consumable foods, e.g. canned foods, has been increasing in the region, with a potential adverse influence on the food choices of community members. The cost of store bought food is also an issue. Substituting game fish in one’s diet can indeed create financial strain for households because a diet based on traditional foods obtained through catching, hunting, and fishing is typically less costly than its sold counterpart. This financial strain can in turn lead to greater food insecurity because it can seriously limit food choices. The decrease in available traditional foods (partly attributable of climate change) coupled with inflated food costs and limited availability in Northern Quebec may be detrimental to the overall health status of Aboriginal members of the Ouje-Bougoumou community. Already, obesity and diabetes mellitus are increasingly prevalent in Canadian Aboriginal communities [12]. Furthermore, in light of the results discussed above, the increasing population of diseased fish can be expected to be especially detrimental for the Ouje-Bougougmou children.

Aboriginal children may be vulnerable to living an unhealthy lifestyle at an early age. Just in the past decade, the rate of diabetes occurring in Aboriginal children has skyrocketed [13]. The prevalence of diseased fish may incite adults to feed their families with bought food rather than with traditional foods. A high caloric diet may chronically debilitate the well-being of the child, causing her, for example, to be at a much greater risk for lifestyle debilitating diseases such as diabetes. With the impacts of climate change, harvesting activities may be less practiced. The transmission of traditional ecological knowledge (TEK) may be truncated between the two current generations due to the decline in healthy fish and the increased reliance on a Western lifestyle, leading to greater physical inactivity. “The adoption of a more sedentary lifestyle often accompanies the transition to a modern diet” [12]. And as it has been found, physical inactivity is a risk factor to type 2 diabetes mellitus [12].

Conclusion

Food insecurity is only one aspect of how climate change may impact the Ouje-Bougoumou community. As climate change is a complex issue, detrimental impacts that many Aboriginal communities face are multifaceted. Climate change does not solely affect the fish population; climate change affects the land and resources that many Aboriginal communities depend on [1, 10]. Thus, not only is their food source affected, but also their homes, lifestyle and possibly their sense of traditional purpose. All of these in turn can have repercussions not only on their physical health, but also on their social, mental, and emotional well-being.

Acknowledgements

Special thanks to William A. Gough and  Leonard Tsuji for their support and assistance.

References

  1. Furgal, C. and Seguin, J. Climate Change, Health, and Vulnerability in Canadian Northern Aboriginal Communities. Environmental Health Perspectives 2006; 114-12: 1964-1970.
  2. Power, E. M. Conceptualizing food security for Aboriginal people in Canada. Canadian Journal of Public Health. 2008; March-April: 95-97.
  3. Ohmagari, K. and Berkes, F. Transmission of Indigenous Knowledge and Bush Skills among the Western James Bay Cree Women of Subarctic Canada. Human Ecology 1997; 25-2: 197-222.
  4. Niezen, R. Power and dignity: The social consequences of hydro-electric development for the James Bay Cree. Canadian Review of Sociology and Anthropology 1993; 30: 510-529.
  5. Tam, B. A Climate Change Impact Assessment on the Spread of Furunculosis in the Ouje-Bougoumou Region. Master’s Thesis. University of Toronto. 2010. Available from: https://tspace.library.utoronto.ca/handle/1807/17227
  6. CBC. Albert’s fish part 1. 2001. Documentary on Canadian Broadcasting Company’s Maamuitaau Program. 1999.
  7. Tam, B, Gough, W, and Tsuji, L. The Impact of Warming on the Appearance of Furunculosis in the fish of the James Bay region, Quebec, Canada. Regional Environmental Change. 2010. DOI:10.1007/s10113-010-0122-8.
  8. Penn, A. Memorandum: Report of furunculosis in fish from Obatagamau Lake. November 24 2000.
  9. Lambden, J., Receveur, O. and Kuhnlein, H. Traditional food attributes must be included in studies of food security in the Canadian Arctic. International Journal of Circumpolar Health 2007; 66-4: 308-319.
  10. Ford, J.D. Vulnerability of Inuit food systems to food insecurity as a consequence of climate change: a case study from Igloolik, Nunavut. Regional Environmental Change 2009; 9: 83-100.
  11. Health Canada. A statistical profile on the health of First Nations in Canada. Ottawa: First Nations and Inuit Health Branch. 2003 [cited December 1, 2006]. Available from: http://www.hc-sc.gc.ca/fnih-spni/pubs/gen/stats_profil_e.html.
  12. Young, T. K., Reading, J., Elias, B., and O’Neil, J.D. Type 2 diabetes mellitus in Canada’s First Nations: Status of an epidemic in progress. Canadian Medical Association 2000; 163-3: 561-566.
  13. Couture, J. Children in basic need of better quality of life. Windspeaker 2008; August: 8.

Hypergraphia: a blessing or a curse?

Thursday, October 21st, 2010

By Asfandyar Yousuf
Medical Student, Army Medical College, National University of Science and Technology, Pakistan

Fjodor_Michailowitsch_DostojewskiHe was in his mid-20s when his seizures became much more frequent. In his altered states of consciousness, ecstatic auras would take him over. He would later describe them as ‘Mahomet’s vision of Paradise’. While in his ‘paradise’, he would scream and start twitching, often assuming a death-like expression before the actual tonic-clonic episodes started. Seizures were followed by severe depression, feelings of doom and an incapacity to talk. While coping with his epilepsy, he developed a peculiar personality. He became a compulsive gambler and often had attacks of rage which ultimately landed him in prison for ten years. He had altered sexual drives and at the same time was deeply religious, having great love for morality and mysticism. More importantly, he developed a fondness for writing. He later described how memories and ideas would approach his consciousness, memories so clear and significant to him that they would haunt him till he preserved them in writing. While following his irrepressible drive to write, he wrote 19 lengthy novels, along with comprehensive and voluminous diaries, letters and notebooks. This man lived in the 19th century Russia and is regarded as one of the greatest novelists of all times [1-4]. His name? Fyodor Mikhaylovich Dostoevsky. His diagnosis? Hypergraphia.

Hypergraphia (from the greek roots: hyper “excessive”, and graphia “to write”) is defined as a compulsive drive to write [4]. Hypergraphia presents as a symptom of various neurological and psychiatric illnesses [5]. Alice W. Flaherty, neurologist at MIT and a former hypergraphic, explains that hypergraphic individuals primarily have an increased drive to write that is associated with a lucid flow of ideas.  An ‘inner force’ pushes hypergraphic individuals to put their thoughts in writing, using whatever material they may find: toilet paper, walls, skin, notebooks, etc. The writings holds worlds of meaning to the author; however they do not necessarily appear particularly good or even meaningful to external readers. Formal statistical figures of the prevalence of people with hypergraphia are not available.

Hypergraphia may lead to the birth of gifted writers, poets and artists such as  Danielle Steel, Edgar Allan Poe, Sylvia Plath, Joyce Carol Oates, Stephen King, Isaac Asimov, and Vincent Van Gogh [4]. But hypergraphics do not all end up writing best-sellers: some instead stick to copying the lyrics of a certain song or office memos [4]. Thus, the only commonality in hypergraphic individuals is their excessive writing. Few mechanisms have been proposed to explain the difference between so-called ‘intelligent’ and more mundane writing [5, 6].

According to a common explanation, hypergraphia would be the result of altered brain wave activity in the temporal lobe [5] (see figure). Before describing the mechanism of development of hypergraphia, first exploring the neurophysiology of writing will make it easier to understand the pathology.

Proposed mechanism of hypergraphia development

Neurophysiology of writing

The model Flaherty [5] put forward for explaining the neurophysiology of creative writing includes the temporal lobes, the frontal lobes and the limbic system. Her model emphasises the coordination between the temporal and frontal lobes rather than the conventional left-right hemisphere coordination. In Flaherty’s model, the limbic system is where the drive to communicate originates, while the temporal and frontal lobes are the site of idea generation and idea integration, respectively. Motor coordinations required for writing is the function of the motor areas of the frontal lobes, the basal ganglia (accessory motor areas) and the cerebellum (motor coordination area) [7].

Neurophysiology of hypergraphia

In case of hypergraphia, altered temporal lobe activity – mostly of the right side – is the proposed cause for increased creative drive and greater flow of ideas. The latter is caused by the lack of the presence of an ‘inner critic’ which analyses ideas before they emerge to consciousness. A silenced critic allows ideas to flow with much greater lucidity. The increased creative drive serves as the ‘inner voice’ pushing the hypergraphic to write. The explanation for increased creativity comes from the Darwinian theory of creativity [7]. Since there is an increased creative drive, there is generation of a greater number of ideas… which in turn leads to the generation of more novel and valuable ideas.

Causes
The altered temporal lobe activity present in hypergraphia is most commonly caused by temporal lobe epilepsy (TLE) [9].  Epileptic seizures are caused by abnormal excessive activity of neurons (see figure of an electroencephalogram seizure pattern) and hypergraphia presents as a symptom between episodes of seizure, i.e. as an interictal symptom. Incidence of TLE is 73% in patients exhibiting hypergraphia [10]. Along with identifying the association between TLE and hypergraphia, Norman Geschwind also outlined fifteen symptoms which may be present in a temporal lobe epileptic [9]. He termed the collection of these symptoms (hyper religiosity, altered sexual drives, hypergraphia, etc.) the ‘Geschwind syndrome’.

Manic depressive mood disorder can also lead to hypergraphia and the characteristics are very similar to the Geschwind syndrome [4]. A stroke, a degenerative or a space-occupying disease may also lead to a form of a hypergraphia in which there is automatic compulsive writing rather than the attentive meaningful writing described before [6, 11]. Schizophrenics can also experience a compulsive drive to write [12]. A mechanism to explain hypergraphia in these non-epileptic individuals is however yet to be proposed.

Conclusion
Although hypergraphia is considered as an illness by medical professionals, many consider this disease of hyper-creativity a blessing. In Psychology Today, Flaherty says that “Hypergraphia is abnormal, but it’s not necessarily bad. (…) For us it is mostly pleasurable. You only suffer when you think you’re writing badly.” [13] However, it should be clear that hypergraphics are not always, or usually, creative. And yet, it is a fascinating fact that many pieces of art which we revere so much might actually simply be the by-product of a few neurons in the temporal lobe going haywire.

Acknowledgements

The writer would like to acknowledge the constant support of Arsalan Yousuf and Dr. Aslam Yousuf during the process of writing of this article.

References

  1. Rossettia AO, Bogousslavsky J. Dostoevsky and epilepsy: an attempt to look through the frame. Neurol Neurosci 2005; 19: 65–75.
  2. Voskuil PH. The epilepsy of Fyodor Mikhailovitch Dostoevsky (1821-1881). Epilepsia.  1983 Dec; 24 (6): 658-67 – as cited in [4].
  3. Dostoevsky F. Notes from the underground in three short novels. Garden City NY: Anchor Books; 1960 – as cited from [4].
  4. Flaherty AW. The midnight disease: the drive to write, writer’s block, and the creative brain. New York: Houghton Mifflin Harcourt, 2005.
  5. Flaherty AW. Frontotemporal and dopaminergic control of idea generation and creative drive. J Comp Neurol 2005; 493(1) : 147–53.
  6. Yamadori A, Mori E, Tabuchi M, Kudo Y, Mitani Y. Hypergraphia: a right hemisphere syndrome. J Neurol Neurosurg Psychiatry 1986; 49: 1160-64.
  7. Guyton AC, Hall JE. Textbook of Medical Physiology. 11th edn. Philadelphia: Elsevier, 2006.
  8. Simonton DK. Origins of genius: Darwinian perspectives on creativity. London: Oxford University Press,1999 – as cited in [5].
  9. Waxman SG, Geschwind N. Hypergraphia in temporal lobe epilepsy. Neurology 1974; 24: 629–36.
  10. Sachdev HS, Waxman SG. Frequency of hypergraphia in temporal lobe epilepsy: an index of interictal behaviour syndrome. J Neurol Neurosurg Psychiatry 1981; 44: 358-60.
  11. van Vugt P, Paquier P, Kees L, Cras P. Increased writing activity in neurological conditions: a review and clinical study J Neurol Neurosurg Psychiatry 1996; 61:  510-14.
  12. Hermann BP, Whitman S, Wyler AR, Richey ET, Dell J. The neurological, psychosocial and demographic correlates of hypergraphia in patients with epilepsy. J Neurol Neurosurg Psychiatry 1988; 51: 203-208.
  13. Mourik OV. Quirky Minds: Hypergraphia: A River of Words. Psych Today (Internet). 2007 May 1 [cited 2010 May 25]. Available from http://www.psychologytoday.com/articles/
    200705/quirky-minds-hypergraphia-river-words

The global health burden of HIV transmission attributable to alcohol consumption

Thursday, September 16th, 2010

By Arvinder S Sood
3rd Year medical student, Imperial College London
ass07(a)ic.ac.uk

Despite repeated health warnings from doctors and health ministers, the global health burden of alcohol consumption has shown no signs of slowing. The economic and health implications posed by alcohol are often overlooked in favour of its social benefits, and it is precisely this fact that makes alcohol such a dangerous commodity. The prevalence of alcohol-related chronic diseases and injury are well documented. Between 1999 and 2005 there was a 41% increase in alcohol-related mortality and in the last 30 years, mortality has risen over 450% in the UK1.With this in mind, society cannot underestimate the social complexity of alcohol as a strong risk factor for disease transmission, such as HIV/AIDS, especially in the context of global health.

Recent studies have highlighted the correlation between alcohol consumption and HIV sero-positivity2. A multi-dimensional approach is needed to explain how alcohol acts as a risk factor. However, we must first understand the interdependent relationship between alcohol consumption and HIV transmission. Those who consume excessive amounts of alcohol are more likely than the general population to contract HIV. Equally, those who are HIV-positive are more likely to misuse alcohol during their lifetime3. HIV can be transmitted via several routes, but arguably the two most important ones are high-risk sexual behaviour and injecting drugs, both of which are augmented by alcohol use. Research has proven that a history of heavy alcohol use increases the tendency for a particular individual to engage in high-risk sexual activities, including multiple sex partners, unprotected intercourse, sex with high-risk partners (e.g. injection drug users, prostitutes) and the exchange of sex for money or drugs4, 5-7. The effects of alcohol are known to have profound effects on the mental state, such as impairment of judgement and consciousness. More specifically, alcohol is said to act directly on the brain to reduce inhibitions and reduce risk awareness8. Excessive alcohol use can therefore put the individual in a very vulnerable position – a position of irrational thinking and poor decision-making.

This begs the question as to why alcohol is so commonly abused. The reasoning is not so simple. In many societies, alcohol-use is deep-rooted in social and cultural beliefs – it is recognised as a symbol of masculinity and often viewed as a way of life. According to some critics, the media should be held responsible for promoting advertisements that glamorise alcohol. Furthermore, there are certain privileges attached to alcohol, for instance the pardoning of socially unacceptable behaviour if proven to be under the influence of alcohol. McKirnan and colleagues suggested this practice may be especially common among homosexual men21. Observations have been made that men who drink prior to or during homosexual contact are more likely to part-take in high-risk sexual behaviour than heterosexuals5, 9-11.

To further our discussion, reliable studies have shown that people who strongly believe that alcohol increases sexual arousal and performance are more likely to engage in risky sex after drinking12-15. This is one of several pieces of evidence suggesting that alcohol is a strong risk factor in increasing HIV transmission. What is not yet clear, however, is the definitive science underpinning this association. Preliminary investigations have provided an insight into how alcohol affects the course of HIV transmission. One theory put forward is that alcohol decreases the immune response to HIV infection, allowing the virus to overcome the host’s defence mechanisms. Emerging laboratory evidence suggests that alcohol may alter cellular structures to increase both the HIV infectivity and vulnerability of cells22. In addition, increased viral replication and progression of AIDS related illness are enhanced by alcohol consumption20.

The burden of alcohol is exacerbated by its impact on the medical aspects of AIDS. Evidence has revealed that alcohol increases the susceptibility and severity of opportunistic infections that are more prevalent in people with AIDS16. Infections common to both alcohol and AIDS include tuberculosis, pneumonia caused by the bacterium Streptococcus pneumoniae, and viral hepatitis C which is the principal cause of death amongst the HIV-positive population16-17. Advances in medicine have led to the development of highly active antiretroviral therapy (HAART), a collection of powerful antiviral medications, which is the first line of treatment to slow the progression of HIV and the associated AIDS-related infections. Results for HIV-positive people receiving HAART have been very encouraging with many patients now enjoying a longer and better quality of life. It has been suggested that alcohol hinders antiretroviral therapy and certain evidence has highlighted the troublesome effects of alcohol during this treatment regime. Firstly, alcoholism results in reduced self control due to associated medical and psychiatric complications, which leads to a delay in seeking treatment. Secondly, alcohol can cause gastrointestinal irritation, resulting in a failure to comply with the complex medication schedule18. Moreover, alcohol itself weakens the response of the body to HIV therapy by increasing viral replication and drug resistance, restricting nutrition, and impairing liver function with subsequent poor drug metabolism23.

With the global health burden of alcohol becoming an increasing problem, we must find solutions to tackle this crisis. According to the World Health Organisation (WHO), the harmful use of alcohol causes about 2.3 million premature deaths per year worldwide (3.7% of global mortality) and is responsible for 4.4% of the global disease burden24. Perhaps, the most encouraging aspect of alcohol use is that it is modifiable through community and individual-based interventions. Basic tools such as public campaigns to increase awareness of alcohol-related harms, dispelling certain myths and misconception about alcohol and cognitive counselling are available. Time is also of an essence with regards to effective HIV treatment and prevention. Early detection of HIV infection facilitates the prompt beginning of behavioural changes aimed at reducing transmission25. To compound this further, many people who test HIV-positive fail to seek medical care until the disease has reached an advanced stage26. Having facilities whereby patients seeking treatment for their alcohol and drug-use are also routinely screened for HIV may go some way to alleviate this problem. Furthermore, we must now realise that alcohol-abuse treatment be considered primary HIV prevention. Research has shown that reducing alcohol use among HIV patients not only decreases the medical and psychiatric complications associated with alcohol use, but also reduces other drug use and HIV transmission18. Avins and colleagues found a 58% reduction in injection drug use among heterosexual patients one year after treatment for alcohol abuse27.

Our efforts should be diverted towards focusing on screening and prevention for HIV risk actors on those with severe alcohol dependence. Of a particular concern, however, is prevention of alcoholism amongst the youth population. AIDS is a leading cause of death among people aged 15 to 24 in urban, inner-city North America7, and new injection users usually become infected with HIV or viral hepatitis with two years of starting19. Therefore, sensible policies would suggest that HIV prevention programmes for youths should target alcohol consumption, in addition to injecting drug use and sexual risk reduction.

The problems associated with alcohol are very much common within the public domain. With research ongoing society is now starting to learn about other alcohol-related diseases, such as HIV/AIDS, which were previously discarded. A review of health policies and restructuring of health-care delivery is just a starting point in this journey to tackle the global health burden created by alcohol abuse.

References

1. Calling time: The nation’s drinking as a major health issue, Academy of Medical Sciences, 2004/The human cost of alcohol misuse BMA 2009
2. Mbulaiteye SM, Ruberantwari A, Nakiyingi JS, Carpenter LM, Kamali A, Whitworth JA. Alcohol and HIV: a study among sexually active adults in rural southwest Uganda. Int J Epidemiol. 2000 Oct;29(5):911-5.
1. Petry, N.M. Alcohol use in HIV patients: What we don’t know may hurt us. International Journal of STD and AIDS 10(9):561-570, 1999.
2. Windle, M. The trading of sex for money or drugs, sexually transmitted diseases (STDs), and HIV-related risk behaviors among multisubstance using alcoholic inpatients. Drug and Alcohol Dependence 49(1):33-38, 1997.
3. Avins, A.L.; Woods, W.J.; Lindan, C.P.; et al. HIV infection and risk behaviors among heterosexuals in alcohol treatment programs. JAMA 271(7):515-518, 1994.
4. Boscarino, J.A.; Avins, A.L.; Woods, W.J.; et al. Alcohol-related risk factors associated with HIV infection among patients entering alcoholism treatment: Implications for prevention. Journal of Studies on Alcohol 56(6):642-653, 1995.
5. Malow, R.M.; Dévieux, J.G.; Jennings, T.; et al. Substance-abusing adolescents at varying levels of HIV risk: Psychosocial characteristics, drug use, and sexual behavior. Journal of Substance Abuse 13:103-117, 2001.
6. MacDonald, T.K.; MacDonald, G.; Zanna, M.P.; and Fong, G.T. Alcohol, sexual arousal, and intentions to use condoms in young men: Applying alcohol myopia theory to risky sexual behavior. Health Psychology 19(3):290-298, 2000.
7. Stall, R.; McKusick, L.; Wiley, J.; et al. Alcohol and drug use during sexual activity and compliance with safe sex guidelines for AIDS: The AIDS Behavioral Research Project. Health Education Quarterly 13(4):359-371, 1986.
8. Purcell, D.W.; Parsons, J.T.; Halkitis, P.N.; et al. Substance use and sexual transmission risk behavior of HIV-positive men who have sex with men. Journal of Substance Abuse 13(1-2):185-200, 2001.
9. Maslow, C.B.; Friedman, S.R.; Perlis, T.E.; et al. Changes in HIV seroprevalence and related behaviors among male injection drug users who do and do not have sex with men: New York City, 1990-1999. American Journal of Public Health 92(3):382-384, 2002.
10. Cooper, M.L. Alcohol use and risky sexual behavior among college students and youth: Evaluating the evidence. Journal of Studies on Alcohol (Suppl. 14):101-117, 2002.
11. Dermen, K.H.; Cooper, M.L.; and Agocha, V.B. Sex-related alcohol expectancies as moderators of the relationship between alcohol use and risky sex in adolescents. Journal of Studies on Alcohol 59(1):71-77, 1998.
12. George, W.H.; Stoner, S.A.; Norris, J.; et al. Alcohol expectancies and sexuality: A self-fulfilling prophecy analysis of dyadic perceptions and behavior. Journal of Studies on Alcohol 61(1):168-176, 2000.
13. Dermen, K.H., and Cooper, M.L. Inhibition conflict and alcohol expectancy as moderators of alcohol’s relationship to condom use. Experimental and Clinical Psychopharmacology 8(2):198-206, 2000.
14. Fauci, A.S., and Lane, H.C. Human immunodeficiency virus (HIV) disease: AIDS and related disorders. In: Braunwald, E.; Fauci, A.S.; Kasper, D.L.; et al. Harrison’s Principles of Internal Medicine, 15th Edition. New York: McGraw-Hill, 2001. pp. 1852-1913.
15. Cook, R.T. Alcohol abuse, alcoholism, and damage to the immune system: A review. Alcoholism: Clinical and Experimental Research 22(9):1927-1942, 1998.
16. Lucas, G.M.; Gebo, K.A.; Chaisson, R.E.; and Moore, R.D. Longitudinal assessment of the effects of drug and alcohol abuse on HIV-1 treatment outcomes in an urban clinic. AIDS 16(5):767-774, 2002.
17. Fuller, C.M.; Vlahov, D.; Ompad, D.C.; et al. High-risk behaviors associated with transition from illicit non-injection drug use among adolescent and young adult drug users: A case-control study. Drug and Alcohol Dependence 66(2):189-198, 2002.
18. Marianna K. Baum, Carlin Rafie, Shenghan Lai, Sabrina Sales, John Bryan Page, Adriana Campa. AIDS Research and Human Retroviruses. May 2010, 26(5): 511-518. doi:10.1089/aid.2009.0211.
19. McKirnan, D.J.; Vanable, P.A.; Ostrow, D.G.; and Hope, B. Expectancies of sexual “escape” and sexual risk among drug and alcohol-involved gay and bisexual men. Journal of Substance Abuse 13(1-2):137-154, 2001.
20. Bagby Gregory J, Barve Shirisj, (2006) Alcohol abuse may increase susceptibility to HIV infection, Alcoholism: Clinical & Experimental Research
21. Centers for Disease Control and Prevention (CDC). Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. MMWR-Morbidity and Mortality Weekly Report 47(RR-5):42-82, 1998.
22. Alcohol misuse needs a global response: The Lancet, Volume 373, Issue 9662, Page 433, 7 February 2009. Doi:10.1016/S0140-6736(09)60146-X
23. Samet, J.H.; Mulvey, K.P.; Zaremba, N.; and Plough, A. HIV testing in substance abusers. American Journal of Drug and Alcohol Abuse 25(2):269-280, 1999.
24. Samet, J.H.; Freedberg, K.A.; Stein, M.D.; et al. Trillion virion delay: Time from testing positive for HIV to presentation for primary care. Archives of Internal Medicine 158(7):734-740, 1998.
25. Avins, A.L.; Lindan, C.P.; Woods, W.J.; et al. Changes in HIV-related behaviors among heterosexual alcoholics following addiction treatment. Drug and Alcohol Dependence 44(1):47-55, 1997.

Current worldwide trends of folic acid supplementation and neural tube defects

Thursday, June 24th, 2010

spina bifida

In today’s article, Matt Quinn discusses the relation between folic acid supplementation and neural tube defects.

Each year approximately 220,000 babies are born worldwide with spina bifida or anencephaly due to maternal folic acid deficiency during the periconceptual period. [1] These cases account for roughly 70% of the global incidence of spina bifida and anencephaly and have been termed folic acid-preventable spina bifida and anencephaly, respectively. Fortifying food with folic acid could prevent these debilitating illnesses. The current RDA of 400 mg can be found in most over-the-counter multivitamins. This paper will provide a brief overview of the pathogenesis of spina bifida and anencephaly, the evidence supporting the use of folic acid supplementation during the periconceptual period, the disparities between different countries use of folic acid fortified food, and the ethical and safety concerns for why some countries have chosen not to implement mandatory folic acid fortified food programmes.

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Lancet Seminar: Porphyrias

Friday, March 19th, 2010

Prof Hervé Puy MD, Prof Laurent Gouya MD, Prof Jean-Charles Deybach MD

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.

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Lancet Seminar: Diabetes in Asia

Saturday, February 6th, 2010

Dr Ambady Ramachandran MD, Ronald Ching Wan Ma MRCP, Chamukuttan Snehalatha DSc

Summary

Prevalence of type 2 diabetes has rapidly increased in native and migrant Asian populations. Diabetes develops at a younger age in Asian populations than in white populations, hence the morbidity and mortality associated with the disease and its complications are also common in young Asian people. The young age of these populations and the high rates of cardiovascular risk factors seen in Asian people substantially increase lifetime risk of cardiovascular disease. Several distinctive features are apparent in pathogenetic factors for diabetes and their thresholds in Asian populations. The economic burden due to diabetes at personal, societal, and national levels is huge. National strategies to raise public awareness about the disease and to improve standard of care and implementation of programmes for primary prevention are urgently needed.

Introduction

Diabetes and associated complications pose a major health-care burden worldwide and present major challenges to patients, health-care systems, and national economies (panel 1). WHO estimates that between 2000 and 2030, the world population will increase by 37% and the number of people with diabetes will increase by 114%.1 Asia is the major site of a rapidly emerging diabetes epidemic.1, 2 Conservative estimates based on population growth and ageing and rate of urbanisation in Asia show that India and China will remain the two countries with the highest numbers of people with diabetes (79·4 million and 42·3 million, respectively) by 2030.1 Additionally, among the top ten countries, four more are in Asia—Indonesia, Pakistan, Bangladesh, and the Philippines. Prevalences are probably underestimated because changes due to other diabetes-related risk factors have not been considered.

Panel 1
Burden of type 2 diabetes

*
Prevalence of diabetes is rising worldwide.
*
The incidence is highest in developing countries, especially in Asia.
*
Among Asian countries, India and China have the highest numbers of people with diabetes.
*
The high prevalence and large population size contribute to the huge burden of diabetes on these countries.
*
The poorest economic strata bear the highest cost burden of diabetes treatment.
*
The economic cost increases many times with the development of vascular complications.
*
Developing countries need to increase national capacity for early diagnosis, encourage effective management, and improve primary prevention to combat the rising burden due to this chronic disease.

The world population is expected to reach 7·9 billion by 2025. Six countries account for almost 50% of the population increase every year; among them, three Asian countries, India, China, and Pakistan, contribute 21%, 12%, and 5%, respectively.3 Asian populations are racially heterogeneous and have differing demographic, cultural, and socioeconomic characteristics. Differences in genetic and environmental attributes affecting diabetogenesis could also be heterogeneous. We discuss type 2 diabetes in Asian countries other than Japan.

Epidemiology

In 2003, an estimated 194 million adults worldwide had diabetes (5·1%) and 314 million people had impaired glucose tolerance (8·2%).4 These prevalences increased to 6·0% and 7·5% in 2007 and are predicted to increase to 7·3% and 8·0% by 2025.2 380 million people are expected to have diabetes in 2025.2 85—95% of all diabetes cases are of type 2 in developed countries and this percentage is even higher in developing countries.2 Roughly 80% of people with diabetes are in developing countries, of which India and China share the largest contribution. Prevalence estimates (adjusted to world population) of diabetes and impaired glucose tolerance in all Asian countries are high and are expected to increase further during the next two decades.2

The increase is likely to be most substantial in developing countries that are undergoing the most rapid economic growth. The gross domestic product per head in India and China is lower than in some other Asian countries, despite increases of three and five times, respectively, over the past two decades (figure 1). The increases in diabetes prevalence in India and China are especially alarming compared with more developed regions within Asia, showing a mismatch between affluence and diabetes prevalence—an Asian diabetes paradox. Epidemiological data from Asian countries draw attention to the high prevalence of type 2 diabetes in urban and rural populations (table 1).2,5—38 Prevalence of impaired glucose tolerance is high in many Asian countries, suggesting the presence of a large pool of people with potential to develop diabetes.2 In southeast Asia, the estimated prevalence of impaired glucose tolerance was 6·0% in 2007.2 The rapidly increasing rate of diabetes in Asia is associated with a strong gene—environmental interaction, which is propelled by lifestyle changes caused by modernisation. Migrant Asian groups have a higher susceptibility to adverse environmental influences than do co-inhabitants of different races.39

fig1Economic development and prevalence of diabetes in selected Asian countries, 1981—2008
(A) Real gross domestic product per head. Data from the US Department of Agriculture Economic Research Service (http://www.ers.usda.gov/Data/Macroeconomics/Data/HistoricalRealPerCapitaIncomeValues.xls, accessed April 28, 2009). (B) Prevalence of diabetes. Data derived from table 1. GDP=gross domestic product.

tab1Prevalence of diabetes, number of people with diabetes, and percentage of urbanisation in Asian countries
* As projected by WHO.
† Based on fasting plasma glucose.
‡ Estimated prevalence.
§ Crude prevalence.

Pathophysiology

Asian populations are multiracial and have multifactorial causes of type 2 diabetes. The mechanisms underlying development of the disease are complex and varied, even within these populations. The major aetiological components of type 2 diabetes are impaired insulin secretion and impaired insulin action, which are aggravated by the presence and degree of glucotoxicity. Both components might also be genetically predetermined. Lipotoxicity plays an important part in causing insulin resistance and β-cell damage.40 In the natural history of type 2 diabetes, β-cell function undergoes a series of changes. With the development of obesity and other adverse effects on insulin sensitivity, β cells respond with compensatory hyperinsulinaemia. Such changes are seen even in non-diabetic people with strong familial history of diabetes.41 With increasing duration, β-cell function declines and insulin-to-glucose ratio diminishes, before an ultimate decompensation occurs with expression of clinical diabetes. Asian populations are more insulin resistant than are people of many other races.42—45 Insulin resistance and compensatory hyperinsulinaemia are reported even in children and adolescents of Asian Indian origin.46, 47 These factors probably play a major part in the escalating prevalence of type 2 diabetes in young populations in Asia.

Risk factors for diabetes show substantial racial and geographical variations in expression and intensity. The escalating prevalence of diabetes and cardiovascular diseases in developing countries is mostly related to environmental changes. Asian populations have several important characteristics with respect to biological and environmental risk factors for diabetes (panel 2).

Panel 2
Characteristics of risk factors for type 2 diabetes in Asian countries

*
Most Asian countries are undergoing a socioeconomic transition.
*
Increasing levels of modernisation, industrialisation, and economic advancements adversely affect biological and environmental risk factors for diabetes.
*
Asian populations have low thresholds for conventional risk factors such as age, body-mass index, upper-body adiposity.
*
Adverse effects on health are manifested on pre-existing genetic predisposition, insulin resistance, and other metabolic features, at a younger age in Asian populations than they are in white populations.
*
Diabetes develops at least a decade earlier in Asian than in white people. Prevalence of young-onset diabetes is increasing in Asian populations.
*
Young-onset diabetes and type 2 diabetes in children are common and their rising trend is linked to epigenetic factors, such as maternal imprinting, and to unhealthy lifestyle changes leading to high rates of obesity.
*
Both the thrifty genotype and thrifty phenotype might be operative in Asian groups.
*
These characteristics are heterogeneous in Asian populations.
*
These populations also have high rates of clustering of cardiovascular risk factors—ie, metabolic syndrome even at a young age.

Genetic factors

Type 2 diabetes has a strong genetic component and most Asian patients have a first-degree relative with diabetes.48, 49 Much progress has been made in our understanding of the genetics of this disease. Importantly, most of the loci originally associated with diabetes in European populations have been replicated in Asian populations. Whereas monogenic forms of diabetes result from rare genetic mutations with large effects, such as those seen in maturity-onset diabetes of young people,50 most cases of type 2 diabetes are thought to be due to genetic variations that are more common but exert less effect. In early studies, genetic variants in the peroxisome proliferator-activated receptor-γ gene (PPARG)51 and the ATP-sensitive potassium channel Kir6·2 (KCNJ11) were reproducibly associated with type 2 diabetes.52 In Asian populations, the protective effect of the PPARG*A12Ala allele on insulin resistance and risk of type 2 diabetes was not consistently seen.53 Polymorphisms in the gene encoding transcription-factor-7-like protein 2 (TCF7L2) was reported to be associated with type 2 diabetes in 2006.54 With a combined odds ratio of 1·46 for the rs7903146 variant,55 this gene has the strongest effect on type 2 diabetes. However, the at-risk T allele in rs7903146 is rare, and different genetic variations in TCF7L2 are associated with type 2 diabetes in Asian populations.56, 57

Several other genetic variants have been identified through genome-wide association studies, which is a strategy that uses the genotyping of hundreds of thousands of single-nucleotide polymorphisms on a single array. These variants are associated with type 2 diabetes in different Asian groups, including Chinese, Japanese, Korean, and Indian populations (table 2).53—74 A meta-analysis showed that, although risk alleles of the different variants seem to confer similar risk for type 2 diabetes in European and Asian populations, ethnic differences in their frequencies lead to differences in population-attributable risk, showing the need for population-specific studies.65 Two recent Japanese genome-wide association studies replicated several loci previously identified in Europeans, and reported variants in the KCNQ1 gene that are associated with type 2 diabetes in Japanese and other east Asian populations.73, 74

tab2Replicated type 2 diabetes gene nearest to the identified marker
Genetic variants with suggestive association with type 2 diabetes but without genome-wide statistical significance are not included. OR=Odds ratio.
* Approximate effect size for the variant associated with type 2 diabetes.
† No published data.

Most genetic variants associated with type 2 diabetes seem to be related to insulin secretion rather than insulin resistance, and several of the risk alleles are associated with reduced islet-cell function 58, 59, 68, 73, 75, 76 (table 2 and figure 2). One of the variants, FTO, is associated with changes in fat mass and predisposes to diabetes via the effects of obesity; it is the first common variant to be associated with obesity and diabetes in European as well as Asian populations. However, by contrast with European groups, the association in Asian populations is not entirely mediated through body-mass index.77 Mechanisms linking body size with type 2 diabetes seem to vary between Indian and European populations. Several other variants have been linked to obesity, although none has so far been associated with diabetes. The present catalogue of type 2 diabetes risk variants probably accounts for only a small proportion of the genetic basis of type 2 diabetes. Nevertheless, the identification of these variants has provided insights into pathogenesis of type 2 diabetes.

fig2The role of type 2 diabetes genes in insulin secretion
Pancreatic β-cell genes associated with type 2 diabetes are in italics. G6P=glucose-6-phosphate. Adapted from Florez JC. Newly identified loci highlight beta cell dysfunction as a key cause of type 2 diabetes: where are the insulin resistance genes? Diabetologia 2008; 51: 1100—10, by kind permission of the author and Springer Science + Business Media.

Urbanisation and migration

Rates of urbanisation are variable, but substantial increases in urbanisation will occur in most Asian countries 5 (table 1). By 2010, the proportion of urbanisation will be more than 50% in Singapore, Korea, Malaysia, the Philippines, and Indonesia, and more than 30% in China, Pakistan, India, and Thailand. The remaining countries (Bangladesh and Sri Lanka) have slow rates of urbanisation. Increasing urbanisation is due to natural population growth and expansion of urban areas. It is also affected by rural to urban migration.78 The expected increase in urban population would be a main determinant, besides ageing, of the rise in the global prevalence of diabetes. Data from Asian countries show the effect of urbanisation on diabetes prevalence.5—38 Physical activity decreases and body-mass index and upper-body adiposity increase substantially with urbanisation.79 Internal rural to urban migration results in similar adverse changes. Most Asian countries, in particular India and China, are experiencing rapid socioeconomic progress and are susceptible to such consequences.

The prevalence of diabetes is increasing in urban and rural populations in both India and China, although prevalence is substantially higher in India than in China (table 1 and figure 1). A nationwide study done in China in 2000 revealed that 7·3% of the population are affected by impaired glucose tolerance, with striking rural—urban differences.14 Importantly, only 30% of the 20 million people estimated to have diabetes on the basis of fasting plasma glucose had previously been diagnosed.14 These findings suggest that China is still in the early stages of an evolving diabetes epidemic. The prevalence will probably rise further as China continues to develop economically and becomes increasingly urban.80 This conclusion is supported by higher prevalence rates in Chinese populations in Hong Kong and Taiwan than in their mainland counterparts.80

Urban lifestyles cause enormous changes in diet, physical activity, and health. Urban populations eat more diverse diets and more macronutrients and animal food than do rural residents, but with higher intake of refined carbohydrates, processed foods, and saturated and total fat and lower intake of fibre. Increasing incomes partly account for these differences, but such changes are evident at any income.81 The effect of nutrition transition is large and most of the emerging epidemic of chronic disorders, such as diabetes, cardiovascular diseases, stroke, and hypertension, are diet related.
Migration to more affluent countries results in high prevalence of diabetes in many populations. This effect is seen, for example, in Asian Indian migrants,39, 42 Chinese groups from mainland China,82 and Japanese migrants 82 to several other countries. The rise in prevalence is a result of environmental and behavioural changes and not due to changed gene frequencies, since the increases have occurred within a few decades.

Age

The results of the Diabetes Epidemiology Collaborative Analysis of Diagnosis Criteria in Asia (DECODA) study have shown several variations in age-specific prevalence within Asian populations.83 In Indian populations, the prevalence of diabetes peaks at 60—69 years of age, whereas in Chinese populations it peaks at age 70—89 years. Indian people have higher age-specific prevalence and higher prevalence of impaired glucose regulation at a younger age than do Chinese people.83 Findings from India,6 Pakistan,25 and Sri Lanka 34 are similar. These differences are probably related to environmental and genetic influences.

One of the hallmarks of diabetes in Asian countries is the rapidly increasing prevalence of young-onset diabetes. A high prevalence of maturity-onset diabetes in the young has been reported in India.84 In China, from 1994 to 2000, there was an 88% increase in prevalence in the 35—44 years age group.14 Data from southern India show that the prevalence of diabetes in people younger than 44 years has increased from 25·0% of the total prevalence in 2000 to 35·7% in 2006.6, 8 Factors that have contributed to the epidemic of obesity and young-onset diabetes are the rapid transition in dietary habits, reduced physical activity, changing pattern in leisure activities, longer working hours, and decreasing sleep hours.80, 85, 86 Asian people with young-onset diabetes have substantial phenotypic heterogeneity, many with positive family history, impaired β-cell function, no islet autoantibodies, and coexistence of cardiometabolic risk factors.49, 87 This tendency to impaired β-cell secretory function might be due to genetic factors, although visceral adiposity and lipotoxicity, low birthweight and maternal imprinting,88 β-cell loss and amyloid deposits might also have contributory roles.80, 89

Type 2 diabetes in children is increasing at an alarming rate, especially in Asian children in both native lands and in migrant populations.90 Its prevalence in the UK is 14 times higher in Asian children than in white European children.91 Population-based and community-based studies of type 2 diabetes in children are few,92 but several clinic-based studies have been done.87, 90 The epidemic of type 2 diabetes in children is expected to become worse with the increasing rate of obesity in children in developing countries.90 The 2002 National Nutrition and Health Survey in China showed that 4·1% of children aged 7—12 years and 5·6% of children aged 12—18 years were overweight, and the respective obesity prevalences were 2·5% and 1·6%.93 In Hong Kong, the results of a community-based study showed that 8—10% of children aged 12—13 years were obese.94

Adipose tissue and insulin resistance

The prevalence of insulin resistance and metabolic syndrome is high in Asian people.95 Features of insulin resistance are manifested in children and adolescents of south Asian origin even in the absence of obesity.46, 47 Obesity is a major determinant of type 2 diabetes, and is associated with many metabolic aberrations that impair insulin sensitivity.96, 97 These abnormalities include excess lipolysis causing increased concentrations of non-esterified fatty acids and triglycerides in blood and skeletal muscle. Glucose uptake by muscle is suppressed. Obesity also impairs insulin action by changing secretion of cytokines, specifically of leptin and adiponectin,98 and leads to proinflammatory conditions.99 Features of insulin resistance, including hypertriglyceridaemia 100, 101 and increased abdominal or visceral fat,43—45 are seen even in non-obese Asian populations. Insulin resistance has been studied extensively in Asian Indian groups. Hyperinsulinaemia, a characteristic of insulin resistance, is common in Asian people, especially in southeast Asian populations.43—45

Unusually, Asian Indian groups have high concentrations of non-esterified fatty acids in plasma during fasting despite relative hyperinsulinaemia, and this concentration is not suppressed by oral glucose administration.43 They also concomitantly have high plasma leptin and low plasma adiponectin concentrations. These changes are independent of obesity or intra-abdominal fat distribution. With development of obesity, these abnormalities will be aggravated.42, 43

Asian people generally have a lower body-mass index than do people of many other races, but the association between body-mass index and glucose intolerance is as strong as in any other population. Asian populations seem to differ from European populations in associations between body-mass index and percentage of body fat and health risks. On the basis of the evidence, a WHO expert consultation concluded that a substantially increased risk of type 2 diabetes and cardiovascular diseases occurs at body-mass index lower than 25 kg/m2. However, for Asian populations there is no uniform threshold for body-mass index to identify people who are overweight and obese. Although the WHO body-mass index figure should be retained as an international classification, individual countries could make decisions about the definition of increased risk for their populations.102 WHO recommends that a body-mass index of 18·5—22·0 kg/m2 is healthy for Asian people.102 The International Diabetes Federation criteria for healthy waist circumference for Asian people is less than 90 cm for men and less than 80 cm for women.103 Revised guidelines for diagnosis of obesity, abdominal obesity, and metabolic syndrome in Asian Indian populations were put forward by a consensus group in India.104 According to these guidelines, the criteria are a healthy body-mass index of 18·0—22·9 kg/m2, an overweight body-mass index of 23·0—24·9 kg/m2, and obesity greater than or equal to 25 kg/m2. The healthy waist circumference limits are 90 cm for men and 80 cm for women.

Abdominal obesity is a characteristic feature in many Asian populations, especially in southeast Asia. Insulin resistance is associated with visceral and subcutaneous fat content.105 Young south Asian men in the USA had insulin resistance even without increased intraperitoneal fat mass, unlike the white population studied.42 The ethnic difference in Asian Indian people could be mostly related to the higher amount of truncal fat and to the large dysfunctional subcutaneous fat cells,106 rather than to presence of excess visceral fat. Glucose disposal rate and plasma adiponectin concentration are inversely related to fat-cell size. South Asian groups generally have a low rate of glucose disposal and low adiponectin concentrations, but high leptin concentrations.42 A high proportion of body fat is seen even in newborn babies. A large, prospective study in India has shown that Indian newborn babies are thinner, shorter, and lighter than UK babies, but are relatively fat because of paucity of non-fat tissues.88

Fatty acid influx to the liver is an important pathogenetic factor for fatty liver and is also a determinant of excess triglyceride-rich lipoproteins. Dyslipidaemia in type 2 diabetes is more severe in the presence of fatty liver. Ectopic fat accumulation in the liver and skeletal muscle are important determinants of insulin resistance and can also predispose to development of type 2 diabetes.107 The twin cycle hypothesis put forth in a review by Taylor 108 explains the cycle of reactions linking muscle insulin resistance, ectopic fat deposition in the liver and islets, hepatic insulin resistance, and β-cell dysfunction eventually resulting in onset of type 2 diabetes (figure 3). Such pathogenetic mechanisms are likely to be operating in Asian people who have features of insulin resistance and have been adversely affected by maladaptation to modernisation and affluence.

fig3The twin vicious cycles in pathogenesis of type 2 diabetes108
Cycle A: Development of fatty liver, which leads to increases in basal plasma glucose and basal insulin secretion leading to hepatic insulin resistance. Cycle B: Sequence of changes in tissues when exposed to higher concentrations of triacylglycerols that leads to decreased insulin response to ingested glucose. Postprandial response to glucose becomes blunted. These vicious cycles have inhibitory effects on islet-cell functions leading to a sudden onset of clinical diabetes.

Low adiponectin concentrations in plasma in Asian people have been linked to low insulin sensitivity and high prevalence of diabetes and cardiovascular diseases.109 In Asian populations, low adiponectin concentrations are predictive of type 2 diabetes.110 However, the investigators did not find a direct association between adiponectin and insulin resistance or other cardiometabolic risk variables.111 A study in migrant south Asian women in the USA 112 had similar findings. The mechanism by which adiponectin is linked with diabetes might also differ in south Asian populations. More detailed studies are needed to explain the mechanisms underlying insulin resistance in these populations.

Asian Indian people produce higher amounts of adenosine triphosphate despite being more insulin resistant, and have higher intramuscular triglyceride concentrations than do white people in the USA.113 Concentrations of intramuscular triglycerides are similarly high in Asian Indian people with and without diabetes, suggesting a possible difference in the association of insulin resistance and diabetes in this population.113 Moreover, in Asian Indian populations, plasma triglycerides and non-muscle triglycerides are strongly associated with insulin sensitivity.114

A pathophysiological link has been shown between obstructive sleep apnoea and excess visceral fat, independent of overall body fat.115 Obstructive sleep apnoea might be directly related to insulin resistance in both obese and non-obese people.116 Physical inactivity and sleep deprivation might also be contributing factors for many of the inflammatory, oxidative, endothelial, and coagulation abnormalities that are associated with obstructive sleep apnoea.115

Intrauterine environment and imprinting

Intrauterine and postnatal environment can affect future risk of diabetes and cardiovascular disease via fetal programming.117 The thrifty genotype and thrifty phenotype hypotheses seem to apply to Asian populations. Maternal undernutrition, infant’s low birthweight, and rapid postnatal child growth are all associated with increased risk of diabetes in offspring, and these factors might be especially relevant to developing countries such as India 88 and China.118 Additionally, offspring of women who are obese or have diabetes are at increased risk of diabetes and other cardiometabolic complications.117—119 In view of the increase in childhood obesity and increasing number of women with young-onset diabetes in Asia, this link will further exacerbate the situation by creating a vicious cycle of diabetes begetting diabetes.

The mechanism underlying such transgenerational inheritance of disease risk is under intense investigation; it is thought to involve epigenetic silencing of target genes via methylation or histone modification during development, resulting in a mismatch between the metabolic phenotype that was programmed during development and the nutritionally rich adult environment.117 Again, this mismatch might be most pronounced in countries that are undergoing the most rapid economic development. Improved understanding of the effect of maternal imprinting is needed to help to address the epidemic of diabetes in Asia.

Diagnosis and complications

The latest WHO report on the definition and diagnosis of diabetes recommended that the oral glucose tolerance test be retained as a diagnostic test.120 The need to identify postprandial hyperglycaemia seems especially relevant in Asian populations. In the DECODA study,83 more than half the patients with diabetes had isolated postprandial hyperglycaemia, which is also a powerful predictor of cardiovascular disease and premature death.121 In Asian populations, fasting plasma glucose 83, 122 and glycosylated haemoglobin (HbA1c) concentrations 123 have much lower sensitivity than does 2 h postglucose concentration for detection of diabetes.

Owing to the early onset of disease, Asian patients with diabetes are at high risk of developing long-term diabetic complications. In urban areas, prevalence of diabetes is lower in poor socioeconomic strata than in high-income groups, but glycaemic control is poor, so the occurrence of vascular complications is higher.101, 124 Few population-based data are available for vascular complications of diabetes from developing countries. In Asian countries, an estimated 30% of people with type 2 diabetes have retinopathy. In North America, the prevalence of diabetic end-stage renal disease is nearly 80% higher in Asian than in white patients with diabetes; however, rates of below-the-knee amputations are 60—69% lower and the incidence of cardiovascular disease is 24—33% lower.125 Although the prevalence of peripheral vascular complications is low in Asian Indian people, because of the large population the number with foot complications is high. Prevalence of neuropathy is high and it is a risk factor for foot infections.126

High rates of cardiovascular complications have been reported in native and migrant south Asian populations.127 Heterogeneity in the occurrence of cardiovascular risk variables is manifested in migrant south Asian groups, based on their socioeconomic strata.127 Possible discrepancies in adjustment for comorbidities might explain the conflicting findings. Within Asia, susceptibility to vascular complications varies. In the WHO Multinational Study of Vascular Disease in Diabetes, Chinese patients with diabetes had much lower rates of coronary artery disease than did patients in other centres, but they had substantially higher rates of retinopathy and nephropathy.128 A high prevalence of nephropathy was also shown in the results of the Microalbuminuria Prevalence (MAP) study, which noted a prevalence of 40% for microalbuminuria and 20% for macroalbuminuria in hypertensive patients with type 2 diabetes in Asia.129 In addition to genetic factors, the tendency towards visceral adiposity is also likely to contribute to development of cardiovascular and renal complications.130

Health-care outcome

The diabetes health-care situation is similar across most developing countries. Economic disparities, scarcity of adequate health-care facilities, and low educational status prevalent in these countries pose major hurdles for achievement of optimum glycaemic control. The cost of diabetes care is high and is increasing worldwide. The economic burden is very high, especially in developing countries, and more so in the lower economic groups, who spend 25—34% of their income on diabetes care.131, 132 The cost of care increases substantially when complications occur or when admission to hospital, surgery, or insulin treatment is needed. The results of a few studies suggest that treatment of patients with diabetes in developing countries is far from optimum.133, 134

In the International Diabetes Management Practice Study, investigators analysed diabetes care outcome in urban areas in 18 countries, including eight countries from Asia, and showed that about a third of patients who were treated by diabetologists or endocrinologists had reached the goal of HbA1c concentrations of less than 7%.134 However, the proportion was similar in other developing regions, namely eastern Europe, Latin America, and Africa. Up to 40% of patients were not screened for risk factors or complications. In developing countries, factors pertinent to patients, doctors, and health-care systems all affect glycaemic control.134

Prevention and future action

Prevention of obesity and diabetes is more cost effective than is the treatment of complications resulting from diabetes. A 2—3% reduction in energy intake or an extra 10—15 min of walking each day could offset weight gain in roughly 90% of the population in China.85 Lifestyle intervention can have a sustained benefit, with a 43% reduction in incidence of diabetes over a 20-year period.135 The results of a primary prevention study in India have also shown that lifestyle modification is effective with an approximate reduction of 30% in comparison with the control group.136 Lifestyle modification was the most cost-effective intervention for prevention of diabetes in high-risk groups.137

The challenges for diabetes care in India, China, and other Asian countries will include improved education to alert the population to risk factors for diabetes, training of patients to manage their disease more effectively, and development of more structured care delivery and management of cardiometabolic risk factors.138, 139 A mismatch of national health-care budget and health-care burden, especially due to the epidemic of non-communicable diseases, poses a huge challenge in most countries. More data are needed for the economics of diabetes and the quality of life and cost-effectiveness of various interventions. Well targeted basic research is needed to provide insight into feasible strategies for prevention of diabetes and its complications.

A UN resolution has recognised type 2 diabetes as a serious epidemic for which urgent steps to improve management and prevent disease development are needed. It urges member states to develop national policies towards these goals.140 In many Asian countries (eg, India, China, Pakistan, Bangladesh, Malaysia, Vietnam, and Singapore), governments have initiated national programmes for prevention and control of non-communicable diseases. Programmes targeting greater public awareness of these diseases and strategies to build national capacity by training medical and paramedical personnel to manage the disorders are expected to curb the epidemic.

Search strategy and selection criteria

We searched PubMed using the keywords “diabetes in developing countries”, “diabetes in Asia”, “type 2 diabetes in Asia”, “risk of diabetes in Asian populations”, “obesity and diabetes in Asians”, “genetics of type 2 diabetes in Asian populations”, “Chinese”, “polymorphisms”, and “adipokines and diabetes in Asian populations”. Peer-reviewed reports published between 1980, and 2009, in English and Chinese were included. Several International Diabetes Federation and WHO publications were used, in addition to reviews and book chapters. We also searched the reference lists of reports identified by the search strategy and selected those judged relevant.

Contributors

All authors have seen and approved the revised version of the Seminar. AR had final responsibility for the decision to submit for publication.

Conflicts of interest

We declare that we have no conflicts of interest.

Acknowledgments

We thank S Selvam and C J Thirupurasundari for help with compiling the references, L Vijaya and A Bobby for secretarial assistance, J Chan for her helpful comments, and J C Florez for permission to reproduce figure 2. RM acknowledges research funding support from the research fund of the Department of Medicine and Therapeutics, Chinese University of Hong Kong, the Research Grants Council of Hong Kong (CUHK4724/07M), and the Innovation and Technology Fund of the Government of the Hong Kong Special Administrative Region (ITS/088/08).

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Lancet Seminar: Eating Disorders

Friday, February 19th, 2010

Prof Janet Treasure FRCPsych, Angélica M Claudino PhD, Nancy Zucker PhD

Summary

This Seminar adds to the previous Lancet Seminar about eating disorders, published in 2003, with an emphasis on the biological contributions to illness onset and maintenance. The diagnostic criteria are in the process of review, and the probable four new categories are: anorexia nervosa, bulimia nervosa, binge eating disorder, and eating disorder not otherwise specified. These categories will also be broader than they were previously, which will affect the population prevalence; the present lifetime prevalence of all eating disorders is about 5%. Eating disorders can be associated with profound and protracted physical and psychosocial morbidity. The causal factors underpinning eating disorders have been clarified by understanding about the central control of appetite. Cultural, social, and interpersonal elements can trigger onset, and changes in neural networks can sustain the illness. Overall, apart from studies reporting pharmacological treatments for binge eating disorder, advances in treatment for adults have been scarce, other than interest in new forms of treatment delivery.

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Bronchial Asthma: An Unsolved Health Problem

Thursday, February 25th, 2010

Enrico Heffler, MD, is a young italian allergist & immunologist, and his main clinical research field is asthma and its comorbidity. Enrico is the current Junior Member representative for asthma section board of European Academy of Allergology and Clinical Immunology (EAACI), and the current national coordinator of Junior Members of Italian Society of Allergology and Clinical Immunology (SIAIC).

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

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

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

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

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

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

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

Do people still die from asthma?

Yes they do! It is estimated that asthma accounts for about 1 in every 250 deaths worldwide, with the highest rates of disease-related mortality in China and Russia (36.7 and 28.6 asthma death per 100,000 asthmatics, respectively), Uzbekistan (27.2), Albania (20.8) and South Africa (18.5).

Many of these deaths could be largely preventable improving long-term medical care, giving the opportunity to all patients to access to basic medications, promoting prevention campaigns and reducing the delay in obtaining help during the final attack.

Which is the public health impact/cost for asthma?

The economic cost of asthma is considerable both in terms of direct medical costs (such as costs of medications used to prevent and treat asthma, hospital admissions etc.) and indirect medical costs (such as time lost from work and school, and premature death). As far as costs and disease-related disability, asthma impacts on health-related costs similarly to other chronic diseases such as diabetes, liver cirrhosis or schizophrenia, leading scientific societies, health-care systems and governments to look for the right way to better prevent, diagnose and treat such an impacting disease.

How can we reduce the impact and cost of asthma?

First of all, it is fundamental that governments and health-professionals recognise asthma as an important cause of morbidity and mortality worldwide, so that they can put to use all preventative measures in order to reduce the morbidity and better control symptoms of asthma. Particularly, it is important to reduce environmental factors (such as indoor and outdoor pollution) which may affect respiratory morbidity: promoting anti-tobacco public health policies and reducing occupational exposures may be good starting points!

Since it is acknowledged worldwide that prevalence and economic/health impact of chronic diseases are more elevated where there are poverty, poor education and poor infrastructures, it is fundamental to improve accessibility to essential drugs and medical care for the management of asthma to all social classes and to low- and middle-income countries, also by adapting international asthma guidelines for developing countries to ensure they are practical and realistic in terms of different health care systems.

What is, in your opinion, the major unmet need in asthma management?

The main asthma-related problem that scientific community should find the way to solve is, in my opinion, that about 10% of the patients have a severe form of asthma, characterized by a particular resistance to typical treatment modalities, including administration of high dose of inhaled or systemic corticosteroids and high dose of bronchodilators. This severe end of the disease spectrum accounts for approximately 30% of health care costs of asthma. Thus there is a compelling need to look for new therapeutical tools for patients resistant to typical asthma medications. Different strategies, almost all of them targeting specific different phenotypes of severe asthma, have been proposed, but only few of them are currently used and suggested for severe asthmatics. Omalizumab (an anti-IgE monoclonal antibody) has been recently introduced in clinical practice and it showed to be greatly effective for the treatment of severe allergic asthmatics with high levels of serum IgE. Other therapeutical approaches that have been studied in the last decade include anti-Tumor Necrosis Factor alpha (anti-TNFα) strategies (biological agents against TNFα axis unfortunately gave contrasting results in improving severe asthma outcomes), anti-IL5 drugs (recently Mepolizumab, an anti-IL5 monoclonal antibody has been showed to be effective in reducing severe exacerbations and to improve disease-related quality of life in a particular subset of patients: those with refractory eosinophilic asthma), anti-IL2 biological agents (Daclizumab, a humanized monoclonal antibody against the IL-2R alpha chain, has been recently described to improve pulmonary function and asthma control in patients with moderate to severe chronic asthma inadequately controlled on inhaled corticosteroids), and even interventions to decrease airway smooth muscle, such as bronchial thermoplasty (a bronchoscopic procedure in which controlled thermal energy is applied to the airway wall). Unfortunately, apart from Omalizumab, none of these novel thereapeutical modalities are currently available and recommended to treat patients with severe asthma.

Thus, it is to be hoped that the scientific community focuses the attention on novel and possibly affordable treatments for those asthmatic patients who still are at-risk of severe exacerbations, hospital admissions and death

Savino Sciascia is a TLS RA and an intern at the University of Turin
sciascia.savino@gmail.com

Lancet Seminar: Non-melanoma skin cancer

Friday, February 26th, 2010

Vishal Madan MRCP, Dr John T Lear FRCP, Rolf-Markus Szeimies MD

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.

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Breast Cancer – Lack of Awareness About Screening in India

Thursday, February 18th, 2010

Breast Cancer in India

A 35 year old female presented with bilateral advanced breast carcinoma (Stage 3) with an ulcer in the right breast, bilateral axillary lymphadenopathy and a left supraclavicular lymph node. The description adequately conveys the guarded prognosis.I worked on this case for my Surgery Practical Exam and it reinforced a thought that had been troubling me for a very long time. My patient was seeking medical help for the first time, though the lump had been present over the past two years. She had even continued to breastfeed her baby and stopped only five months ago when she developed excruciating pain. My patient is not one of those surprising exceptions who did not seek medical care on time. I have come across at least 10 such patients of breast cancer during my brief six week surgical rotation. I have tried to interview extensively all these victims, to discover the reason behind not seeking medical advice on time and ignoring a largely noticeable breast lump.

The reasons are so simple and naïve that they are distressing – the present patient did not know that hard lumps in the breasts were of any significance until she developed an ulcer a month ago. She even attributed her pain to excessive breastfeeding. Ignorance comes across as the main factor though other reasons also exist, including abusive and suppressive husbands and in-laws, and lack of knowledge among fellow female well-wishers who also are equally unaware. It is so sad to come across patients like this, especially when women in more developed countries are undergoing regular screening mammographic investigations and are well aware of breast self examination techniques.

In India, cancer of the breast is the most common cancer among women in many regions and has overtaken cervical cancer, which was the most frequent cancer a decade ago (1). It has been estimated that during the year 2001 alone, nearly 80,000 women developed breast cancer in India (2). Studies indicate that as India becomes Westernized, the incidence rate for breast cancer is increasing. A 2005 study conducted by the International Association of Cancer Research, based in Lyon, France, projected that there would be 250,000 cases of breast cancer in India by 2015, a 3% increase per year. Currently, India reports roughly 100,000 new cases annually (3).

Screening and Mortality

Screening by clinical breast examination (CBE) alone has not been demonstrated by randomized controlled trials to reduce mortality although a large trial is currently underway in Bombay by the Tata Memorial Centre(4). An IARC Working Group concluded in 2002 that there is inadequate evidence that breast screening by CBE, either alone or together with mammography, can reduce mortality from breast cancer (5). However, cancers detected by CBE tend to be diagnosed at an earlier stage than those not detected by screening, suggesting a greater potential for effectiveness in a setting where stage at diagnosis is generally poor (6). Although CBE undertaken by health workers seems to offer a cost-effective approach to reducing mortality, the sensitivity of the screening program in the real context was low with a sensitivity of only 25.6% and positive predictive value 1% (7). The UK Preventive Task Force report found that trials for breast self-examination showed no reductions in mortality but increase in benign biopsies. They concluded that no benefit has been shown for clinical breast examination or breast self-examination. On the other hand mammography screening reduces breast cancer mortality by 15% for women aged 39 to 49 years with low radiation exposure and an estimated over diagnosis of 1 to 10% (8).

While studies show that the efficacy of breast self examination is limited, it is imperative to recognize our shortcomings. India’s healthcare system is still in its developing phase, making it virtually impossible for all females to undergo regular screening mammography and general health checkups. Even so, there are still precautions that can be maintained. It is definitely possible to create awareness about the common signs and presentation of breast carcinoma, the common risk factors that may be contributory and the need for breast self examination.

Self-Examination

It is suggested that for very low resource settings in certain parts of India where population based screening, even with clinical breast examination by primary health workers is not feasible, health education combined with access to screening and treatment services, may be a simple and feasible strategy for reduction in cervix and breast cancer mortality (4). A praiseworthy practice about our hospital with a strong focus on women’s health issues, is that they not only perform a “clinical breast examination” on all women but also counsel them regarding the need for regular breast self-examination.

Reeler A et al (9) have defined a public health approach to cancers in developing countries where resources for effective cancer control are very limited and offer a framework for putting women’s cancers in developing countries on the global public health agenda. The key areas as proposed by them are: 1. Proposals for a new, integrated public health approach to women’s cancers (breast and cervical) in resource poor settings; 2. Reviews of the evidence for cost-effective screening and early detection of breast and cervical cancer; 3. Outlines of ways to make a priority of breast and cervical cancers in developing countries on the political agenda of international agencies. Implementation of such an integrated program may be the solution that we are looking for. A multilevel approach can be initiated only with active government policies and we hope that it would take shape in the near future. A number of Breast Cancer support groups and NGOs like Aastha Breast Cancer Support Group, Aarogya etc. are already doing very good work in providing medical and emotional support to affected women. Meanwhile given the current burden of breast cancer in India, it is the duty of everyone associated with medicine and anyone with a good outreach to be aware of the need of breast self-examination and to promote it whichever way they can. It is so unfortunate that even literate, educated, and well-read females are unaware of the need and method of self-examination.

We as a nation have a very long way to go. It is our duty as members of the healthcare delivery team – medical students and physicians alike – to do our part by educating and creating awareness about breast cancer and its early detection.

Gurmeen Kaur is a TLS RA and a final year medical student at Lady Hardinge Medical College, India
kaur.gurmeen(at)gmail.com

The author would like to acknowledge the assistance of Dr. Anurag Srivastava, a Breast Oncosurgeon at the All India Institute of Medical Sciences, New Delhi, India for his contributions to the paper.

References

1. Murthy NS, Agarwal UK, Chaudhry K, Saxena S. A study on time trends in incidence of breast cancer – Indian scenario. Eur J Cancer Care (Engl). 2007 Mar;16(2):185-6.

2. Murthy N.S., Juneja A., Sehgal A. & Luthra U.K. (1990) Cancer projection by the turn of century. Indian Journal of Cancer 27, 74–82.

3. Bagchi S.Breast Cancer rises in India. CMAJ. 2008 July 1; 179(1): 27.

4. Mittra I, Mishra GA, Singh S et al. A cluster randomized, controlled trial of breast and cervix cancer screening in Mumbai, India: methodology and interim results after three rounds of screening. International Journal of Cancer. 2010; 126(4): 976-984.

5. IARC Working Group on the Evaluation of Cancer-Preventive Strategies. IARC Handbooks of Cancer Prevention: Breast Cancer Screening (2002) Lyon, France: IARC Scientific Publications.

6. Duffy SW, Tabar L, Vitak B, Warwick J. Tumor size and breast cancer detection: what might be the effect of a less sensitive screening tool than mammography? Breast J (2006) 12(suppl_1):S91–S95.

7. Pisani P, Parkin DM, Ngelangel C et al. Outcome of screening by clinical examination of the breast in a trial in the Philippines. 2005; 118(1): 149-154.

8. Nelson HD, Tyne K, Naik A et al. Screening for breast cancer: an update for the U.S. Preventive Services Task Force. Ann Intern Med. 2009 Nov 17;151(10):727-37, W237-42.

9. Reeler A, Qiao Y, Dare L, Li J, Zhang AL, Saba J. Women’s cancers in developing countries: from research to an integrated health systems approach. Asian Pac J Cancer Prev. 2009 Jul-Sep;10(3):519-26