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ScienceWeek
MEDICAL BIOLOGY: CLIMATE AND MALARIA
The following points are made by Christopher Thomas (Nature 2004 427:690):
1) After decades of decline, malaria has been on the rise in many parts of Africa -- an estimate(1) by the World Health Organization is that in some parts of the continent malaria mortality in young children almost doubled from the 1980s to the 1990s. The disease causes some 3000 deaths each day and imposes huge losses in economic productivity(2).
2) Is this resurgence a sign of increased transmission caused by climate change? Probably not, according to results presented by Small et al(3). Several studies have projected that global climate change will increase future malaria transmission in Africa(4,5). However, the link between contemporary changes in malaria and climate is hotly disputed. Alternative explanations such as an increase in parasite resistance to the front-line drugs since the 1960s, poverty, and a decline in many African health services are cited as more likely causes. Undoubtedly, a mix of such reasons is behind the rise in malaria. But identifying the prime factors will help greatly in planning control measures.
3) One problem dogging the interpretation of changes in local disease patterns in relation to climate is that meteorological recording stations are sparsely distributed in many parts of the continent, so that long-term records from the same locality are rare. As an alternative, researchers have used so-called "climate surfaces" -- maps interpolated from these sparse data. But these surfaces often provide only a coarse representation of climate, and their usefulness in relation to the scale of the malaria data has been open to question. To eliminate this mismatch, Small et al(3) used a malaria transmission index calculated directly from the interpolated climate data. They then produced an 85-year "hindcast" against which observed trends in malaria could be compared.
4) The malaria transmission index used by Small et al(3) was formulated in an earlier study to map zones of malaria transmission across Africa. This index is based on the temperature and precipitation constraints within which the mosquito vector and malaria parasite can develop, and is quite simple. It has nonetheless proved remarkably effective for estimating the distribution of stable malaria (as opposed to epidemics at unstable fringes) at coarse scales and is in operational use throughout the continent.
5) As far as climate change is concerned, the main message from Small et al(3) is that malaria transmission needs to be understood in terms of precipitation as well as temperature. No doubt climate models will continue to improve and we can look forward to refinement in the projection of these parameters. Regrettably, however, knowledge of the basic ecology of malaria transmission lags behind -- for instance, we cannot yet relate absolute mosquito abundance to climate. The urgent need is for progress on the entomological front to guide future modelling work on transmission.
References (abridged):
1. World Health Organization The African Malaria Report, 2003 WHO/CDS/MAL/2003.1093 (WHO, Geneva, 2003)
2. Sachs, J. & Malaney, P. Nature 415, 680-685 (2002)
3. Small, J., Goetz, S. J. & Hay, S. I. Proc. Natl Acad. Sci. USA 100, 15341-15345 (2003)
4. Lindsay, S. W. & Martens, W. J. M. Bull. World Health Organ. 76, 33-45 (1998)
5. Martens, P. et al. Glob. Environ. Hum. Policy Dimensions 9, S89-S107 (1999)
Nature http://www.nature.com/nature
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PUBLIC HEALTH: EXPECTED CONSEQUENCES OF GLOBAL WARMING
Climate change produced by global warming is expected to result in melting ice caps, rising sea levels, torrential floods, devastating droughts, and severe harvest failures. What are often not considered in discussions of global warming are the effects of global warming on public health.
The following points are made by Pim Martens (American Scientist 1999 87:534):
1) Concerning heat stress: The author suggests that perhaps the most immediate consequence of increasing global temperatures will be a rise in the number of heat waves and heat-related illnesses. Such temperature extremes can, for example, increase the sensitivity of asthmatics to their condition. There will also be an increasing number of deaths from heat stress brought about by high ambient temperatures lasting days on end. On the other hand, the milder winters associated with global warming will offer a better chance of survival for at-risk groups such as the elderly during the coldest months. Research into the effect of a gradual temperature increase has revealed that we can expect a decline in mortality from cardiovascular and pulmonary disease in the winter. Whether the milder winters could offset the mortality during the summer heat waves is not clear.
2) Concerning malaria: The spread of this disease is limited by conditions that favor the disease vector (the malarial mosquito Anopheles) and the protozoan parasite (Plasmodium). The malarial mosquito is most comfortable at temperatures of approximately 20 to 30 degrees centigrade and at a relative humidity of at least 60 percent. Also, the malaria parasite develops more rapidly inside the mosquito as the temperature rises, and the development ceases entirely below approximately 15 degrees centigrade. Increased rainfall and increased surface water, expected to result from global warming, will produce more breeding grounds for the mosquito. Malaria currently kills 1 to 2 million people each year.
3) Concerning schistosomiasis (bilharzia): The enormous expanse of irrigation systems in many tropical countries has doubled the incidence of this disease in the past 50 years. There are some estimates that nearly 200 million people are infected worldwide. The disease is caused by a parasitic worm (a trematode; also called a "fluke"; a type of flatworm) whose eggs enter the water supply by way of human urine or feces. Infected water snails serve as hosts for the parasites while they develop into free-swimming "mini-worms" (larvae; cercaria). The circle closes when a larva penetrates the skin of a human who comes in contact with the contaminated water. The development of the parasite and the population of the host snails are both governed by the ambient temperature, with warm waters favoring their growth. Also, the warmer the ambient temperature, the more often people come into contact with water. In places where the disease is endemic, it is known that the number of infected snails declines sharply during the winter months. A temperature rise of only a few degrees will ensure that this disease is transmitted throughout the year. It is estimated that currently worldwide approximately 500 million people are at risk of infection by this pathogen.
4) Concerning dengue: Like malaria, this disease is transmitted by mosquitoes (Aedes aegypti, which also transmits yellow fever), but the pathogen is a virus (dengue virus, a flavivirus). The dengue virus is currently restricted to the tropics, approximately between latitudes 30 degrees south and 20 degrees north. Temperature affects the development of both the mosquito and the virus as well as the frequency of mosquito bites. A warmer climate may increase not only the elevations above sea level at which the disease occurs, but also its northern and southern ranges. Dengue hemorrhagic fever, a severe form of the disease, has a mortality of 6 to 30 percent, with most deaths occurring in infants less than 1 year old.
5) Concerning various water-borne diseases: Changes in the amount of precipitation will accompany the temperature changes to a warmer Earth. Many disease-causing organisms require water for survival, and increases in rainfall and flooding will encourage the wider distribution of such pathogens, with higher temperatures increasing the chances of pathogen survival. Various bacteria (e.g., Salmonella and Shigella), viruses (e.g., rotavirus), protozoa (e.g., Giardia and Cryptosporidium) can cause diarrhea, which kills more than 3 million children every year.
6) In general, many factors will interact with a changing climate in a nonlinear way, so their effects on human health are extremely difficult to quantify. Despite the uncertainties, there are increasing indications that a changed global climate may be a major factor in the global distribution of many diseases.
American Scientist http://www.americanscientist.org
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ON THE MALARIAL PATHOGEN
The disease malaria is caused by a type of protozoan with the general name Plasmodium, an organism characterized by a sequence of life cycles involving different organismic forms. The asexual cycle occurs in the liver and red blood cells of vertebrates (including humans), and the sexual cycle occurs in mosquitoes. Essentially, the asexual form is ingested by blood-sucking mosquitoes, and in the mosquito the asexual form is induced to produce the sexual form necessary to complete the total life cycle.
The details of the process are as follows: Plasmodium cells called "gametocytes" (precursors of gametes) in human blood are ingested by the mosquito, and in the mosquito, apparently within seconds, gametocytes are induced into "gametogenesis", producing gametes. These gametes produce a cell-type called "sporozoites", which accumulate in the salivary gland of the mosquito, from where they are injected into the vertebrate blood stream when the mosquito feeds on vertebrate blood. The sporozoites accumulate in the vertebrate liver, where they multiply and produce a form (merozoites) that invades red blood cells, replicates, destroys red blood cells, and so on, with an eventual decline in this asexual replication. However, after invasion of red blood cells, some merozoites produce gametocytes, which have the genomic potential for restarting the total life cycle. These gametocytes cannot self-replicate, and they die unless ingested by a mosquito, but once in the mosquito, the total life cycle begins again. There are apparently 2 inducers of gametogenesis in vivo (i.e., in the mosquito): one inducer is a pH of 7.5 to 7.6, and the other inducer has been thought to be an unknown mosquito-derived gametocyte-activating factor.
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ON MALARIAL MOSQUITOES AND MOSQUITO BITES
The following points are made by Stephen Budiansky (Science 2002 298:80):
1) After millions of years of coexistence, the lives of humans and mosquitoes have become intricately intertwined. The mosquito's ability to exploit almost any type of water -- natural ponds and marshes or human creations such as irrigation ditches and used tires -- is testimony to its evolutionary ingenuity To say that the malaria-carrying mosquito Anopheles gambiae is well adapted to its role as a human parasite is like saying that Pavarotti is a pretty good singer.
2) An. gambiae, native to tropical Africa, is just one of about 60 anopheline mosquitoes throughout the world that can transmit human malaria. But its unrelenting focus on human ways has made it a prodigy as a disease vector. An. gambiae typically breed in temporary, sunlit puddles and pools of a kind found in particular near human habitations and usually directly associated with humans' agricultural modification of the landscape: the water that collects in irrigation ditches and even the small puddles created where livestock have depressed the soil with their hooves. Adult An. gambiae mosquitoes are commonly found sheltering in huts during the heat of the day. At night they emerge from their resting spots and, lured by the odor of human feet and other scents, home in on their preferred prey.
3) The exquisite apparatus that the female employs to penetrate the skin of its victim is less like a simple needle than one of the complex devices surgeons snake through a body to perform remote-control surgery. At the end of the mosquito's slender proboscis are two pairs of cutting stylets that slide against one another to slice through the skin -- like a pair of electric carving knives. Once through the skin, the mosquito's proboscis begins probing for a tiny blood vessel. If it does not strike one on the first try, the mosquito will pull back slightly and try again at another angle through the same hole in the skin. Inside the proboscis are two hollow tubes, one that injects saliva into the microscopic wound and one that withdraws blood. The mosquito's saliva includes a combination of antihemostatic and anti- inflammatory enzymes that disrupt the clotting process and inhibit the pain reaction -- the better not to get swatted --during the minute and a half or so while the insect is feeding. (Only later does the leftover saliva provoke an allergic reaction that often leaves the characteristic raised welt of the mosquito bite.) Some researchers believe that the suite of enzymes produced by particular species of mosquitoes is closely tailored to the biochemistry of its chosen hosts. An. gambiae thus probably produces enzymes that work best against the clotting and inflammatory biochemical pathways of its preferred target: humans.
Science http://www.sciencemag.org
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THE PATHOGENIC BASIS OF MALARIA
The following points are made by L.H. Miller et al (Nature 2002 415:673):
1) Millions of children die from malaria in Africa every year(1). But the clinical outcome of an infection in a child depends on many factors. These factors, often ill-defined, determine the outcome in each child. The top priority must be disease prevention because of the inability of the mothers to access or afford optimal treatment, and the ever-evolving drug resistance. Prevention may be effected through vector control such as insecticide-treated bednets or through the development of antimalarial vaccines.
2) Over the past 10 years, there have been several key shifts in our understanding of what constitutes severe malaria, and these shifts define the issues in pathogenesis that need to be explored to develop better treatments for sick children. The first shift is the increasing recognition that severe malaria is a disorder that affects several tissues and organs, even when the most marked manifestations may seem to involve a single organ such as the brain. In particular, metabolic acidosis, often profound, has been recognized as a principal pathophysiological feature that cuts across the classical clinical syndromes of cerebral malaria and severe malarial anaemia(2). It is the single most important determinant of survival and leads directly to a common, but previously poorly recognized, syndrome of respiratory distress(3). In most cases, this is predominantly (but not exclusively) a lactic acidosis(4). There are several causes of lactic acidosis in children with severe malaria, from increased production of lactic acid by parasites (through direct stimulation by cytokines) to deceased clearance by the liver; however, most important by far is probably the combined effects of several factors that reduce oxygen delivery to tissues(5).
3) A key feature of the biology of Plasmodium falciparum is its ability to cause infected red blood cells (RBCs) to adhere to the linings of small blood vessels. Such sequestered parasites cause considerable obstruction to tissue perfusion. In addition, in severe malaria there may be marked reductions in the deformability of uninfected RBCs. The pathogenesis of this abnormality is not clear, but its strong correlation with acidosis suggests that it may be involved in compromising blood flow through tissues. Individuals affected with malaria are often dehydrated and relatively hypovolemic, which potentially exacerbates microvascular obstruction by reducing perfusion pressure. The destruction of RBCs is also an inevitable part of malaria, and anemia further compromises oxygen delivery.
4) The second and related shift in our concept of severe malaria is the realization that there is no simple one-to-one correlation between the clinical syndromes and the pathogenic processes. Thus, severe anemia may arise from many poorly understood mechanisms including acute hemolysis of uninfected RBCs and dyserythropoiesis, as well as through the interaction of malarial infection with other parasite infections and with nutritional deficiencies. For many desperately sick children a simple "one pathogen/one disease" model is not adequate, as bacteremia caused by common pathogens may be present with acute malaria and may be a factor in mortality. Even the rigorously defined syndrome of cerebral malaria is used to describe children who have arrived at the point of coma through different routes. In many of these children, coma seems to be a response to overwhelming metabolic stress rather than a primary problem in the brain. Such children are often profoundly acidotic and may regain consciousness remarkably quickly after appropriate resuscitation, suggesting that cerebral malaria in this instance cannot be a consequence of the classical histologic picture.
References (abridged):
1. Snow, R. W., Craig, M., Deichmann, U. & Marsh, K. Estimating mortality, morbidity and disability due to malaria among Africa's non-pregnant population. Bull. World Health Organ. 77, 624-640 (1999)
2. Marsh, K. et al. Indicators of life-threatening malaria in African children. N. Engl. J. Med. 332, 1399-1404 (1995)
3. Taylor, T. E., Borgstein, A. & Molyneux, M. E. Acid-base status in paediatric Plasmodium falciparum malaria. Q. J. Med. 86, 99-109 (1993)
4. English, M. et al. Deep breathing in children with severe malaria: indicator of metabolic acidosis and poor outcome. Am. J. Trop. Med. Hyg. 55, 521-524 (1996)
5. English, M. et al. Acidosis in severe childhood malaria. Q. J. Med. 90, 263-270 (1997)
Nature http://www.nature.com/nature
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