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ScienceWeek
MEDICAL BIOLOGY: GENES AND ASTHMA
The following points are made by W. Cookson and M. Moffatt (New Engl. J. Med. 2004 351:1794):
1) There are two causes of asthma -- the environment and genetic variants. Each cause accounts for approximately 50 percent of the risk of the disease. The power of the public databases and the methods of genotyping used in genetics mean that the discovery of genes and the genetic variation underlying the various forms of asthma is increasing quickly. Oguma et al(1) have described an investigation of the prostaglandin D2 receptor gene (PTGDR) as a candidate for a role in the susceptibility to asthma in young adults.
2) Genetics concerns polymorphism (variation) in genes. The most obvious effects of polymorphisms appear when they alter protein coding sequences and cause mutations. However, most of the polymorphisms that cause common diseases alter gene function through more subtle mechanisms. Such mechanisms may affect upstream sequences for the promotion and initiation of gene transcription and intronic sequences, which regulate both the timing and cellular or tissue expression of the gene and the factors that regulate splicing.
3) The sheer volume of the genetic information available is causing problems. With the completion of the Human Genome Project, all 30,000 human genes may now be studied. Several hundred of them could be plausible candidates for a role in any inflammatory disorder. Common single-nucleotide polymorphisms and other polymorphisms appear in the human genome in every 500 to 1000 base pairs. A typical gene may therefore contain 20 to 40 polymorphisms, only a small proportion of which will have any effect on the function of the gene. To avoid a deluge of suggestive but inconclusive information, the authors propose that journals should apply stringent criteria for the publication of studies of candidate genes.
4) Prostanoid DP mediates the chemotaxis of T cells that follows the degranulation of mast cells. Its gene was identified as a candidate asthma gene in a mouse model of asthma. The mouse, which was deficient in functional Ptgdr, was unable to mount an airway inflammatory response to allergen.(2) Oguma et al(1) first observed an association between PTGDR polymorphisms and asthma in case-control studies of white patients recruited in the United States. The authors took pains to replicate this finding in a second population with a different ancestry -- black Americans. They showed that the implicated polymorphisms affect the binding of regulatory factors to the PTGDR gene promoter and that these polymorphisms alter the level of transcription of the gene. The conclusion that variation in the expression of the receptor influences susceptibility to asthma suggests that the receptor is a therapeutic target.(3)
References:
1. Oguma T, Palmer LJ, Birben E, Sonna LA, Asano K, Lilly CM. Role of prostanoid DP receptor variants in susceptibility to asthma. N Engl J Med 2004;351:1752-1763
2. Matsuoka T, Hirata M, Tanaka H, et al. Prostaglandin D2 as a mediator of allergic asthma. Science 2000;287:2013-2017
3. Lemanske RF Jr, Sorkness CA, Mauger EA, et al. Inhaled corticosteroid reduction and elimination in patients with persistent asthma receiving salmeterol: a randomized controlled trial. JAMA 2001;285:2594-2603
New Engl. J. Med. http://www.nejm.org
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PEDIATRICS: CHILDHOOD ASTHMA AND PHYSICAL ACTIVITY
The following points are made by D.M. Lang et al (Pediatrics 2004 113:e341):
1) Asthma is a chronic inflammatory disease of the airways associated with significant medical and social morbidity.(1-3) The National Asthma Education and Prevention Program and the American Academy of Pediatrics include normal activity in their stated goals of asthma therapy.(1,4) With appropriate control, children with asthma can lead normal lives, including participation in physical activity. Physical activity is an important part of both a healthy lifestyle and a child's daily routine.(5) Development of good health and fitness habits in childhood is associated with physical fitness as an adult.
2) Participation in physical activity is an important part of a child's normal psychosocial development and self-image. Children should not be excluded from physical activity without a compelling medical contraindication. Physical activity is especially important in children with asthma. Activities such as running and swimming are associated with improved fitness and decreased severity of asthma symptoms. Regular exercise and level of physical conditioning are major determinants of exercise tolerance in children with controlled asthma. Recent studies indicate a comorbidity of asthma and obesity in urban children; however, the direction of the association is uncertain. Regardless of the cause and effect, physical activity is an important contributor to fitness in children with asthma.
3) The physical activity level of children with asthma varies in different studies. In the US, an analysis of the 1988 National Health Interview Survey found that 30% of children with asthma had some parent-reported limitation in physical activity. This analysis of a large data set linked asthma with reported limitations but did not quantify activity or investigate asthma-related predictors of activity. Outside of the US, a survey of school children in New Zealand found that children with asthma were more active than their peers and had favorable attitudes toward physical activity. A survey of students in Norway found no difference in the frequency of activity between children with and without asthma. The authors of the New Zealand study hypothesized an association with a current publicity campaign about the benefits of exercise for people with asthma. Other reports have found that children may have difficulty with specific activities but that asthma did not prevent their overall participation in sports or physical education. In addition to the influences of activity in all children, children with asthma may be influenced by symptoms of bronchospasm, attitudes toward activity, and maternal beliefs about the safety of exercise in children with asthma.
4) The authors report a study to compare the activity of inner-city children with asthma to their peers and to evaluate the factors associated with the activity level of children with asthma. The authors hypothesized that children with asthma are less active than their peers and that a combination of biomedical and psychosocial factors influence their activity level.
5) The authors conclude: Disease severity and parental health beliefs contribute to the lower activity level of children with asthma. Pediatricians should evaluate exercise level as an indicator of disease control and address exercise and its benefits with patients and caregivers to help achieve the goal of normal physical activity in children with asthma.
References (abridged):
1. National Asthma Education and Prevention Program. Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma. Pub no 97-4051. Bethesda, MD: Department of Health and Human Services, National Institutes of Health; 1997
2. Newacheck PW, Halfon N. Prevalence, impact, and trends in childhood disability due to asthma. Arch Pediatr Adolesc Med. 2000;154:287-293
3. Akinbami LJ, Schoendorf KC. Trends in childhood asthma: prevalence, health care utilization, and mortality. Pediatrics. 2002;110:315-322
4. American Academy of Pediatrics, Committee on Sports Medicine and Fitness. Metered-dose inhalers for young athletes with exercise-induced asthma. Pediatrics. 1994;94:129-130
5. Sallis JF, McKenzie TL, Alcaraz JE. Habitual physical activity and health-related physical fitness in fourth-grade children. Am J Dis Child. 1993;147:890-896
Pediatrics http://www.pediatrics.org
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MEDICAL BIOLOGY: ON OZONE AND ASTHMA
The following points are made by J.F. Gent et al (J. Am. Med. Assoc. 2003 290:1859):
1) Children with asthma are particularly vulnerable to the adverse health effects of high levels of air pollution. Studies of children with asthma living in some of the most highly polluted regions of the world conclude that exposure to levels of ozone or particulate matter (especially particles 2.5 microns in diameter [PM2.5]) regularly in excess of US Environmental Protection Agency (EPA) air quality standards significantly enhances the risk of respiratory symptoms, asthma medication use, and reduced lung function.1-5.
2) Studies of children with asthma living in regions with levels of pollution within or near compliance with EPA air quality standards suggest that the current standards do not protect these more vulnerable members of the population. Asthma severity, as measured by symptoms, medication use, restrictions in activity, or use of medical services, has been shown to be affected by exposure to ozone or PM2.5.
3) Of interest in many recent studies of children with asthma are the simultaneous effects of ozone and particulates on asthma severity.(2,3) Simultaneous exposure to high levels of both ozone and PM2.5 (fine particles)(2) or PM10(coarse particles)(3) found in Mexico City, Mexico, contributed to increased respiratory symptoms among children with asthma. In a region of lower pollution, asthma symptoms were associated with both ozone and course particles.
4) The authors examined the simultaneous effects of ozone and fine particles on daily respiratory symptoms and rescue medication use of children with asthma residing in southern New England during spring and summer 2001. From their results, the authors conclude that after controlling for exposure to fine particles, asthmatic children using maintenance medication are particularly vulnerable to ozone at levels below EPA standards.
References (abridged):
1. Gold DR, Damokosh AI, Pope CA III, et al. Particulate and ozone pollutant effects on the respiratory function of children in southwest Mexico City. Epidemiology. 1999;10:8-16
2. Romieu I, Meneses F, Ruiz S, et al. Effects of air pollution on the respiratory health of asthmatic children living in Mexico City. Am J Respir Crit Care Med. 1996;154:300-307
3. Romieu I, Meneses F, Ruiz S, et al. Effects of intermittent ozone exposure on peak expiratory flow and respiratory symptoms among asthmatic children in Mexico City. Arch Environ Health. 1997;52:368-376
4. Peters A, Dockery DW, Heinrich J, Wichmann HE. Medication use modifies the health effects of particulate sulfate air pollution in children with asthma. Environ Health Perspect. 1997;105:430-435
5. Ostro BD, Lipsett MJ, Mann JK, Braxton-Owens H, White MC. Air pollution and asthma exacerbations among African-American children in Los Angeles. Inhal Toxicol. 1995;7:711-722
J. Am. Med. Assoc. http://www.jama.com
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MEDICAL BIOLOGY: ON ASTHMA PREVENTION
The following points are made by Fernando D. Martinez (New Engl. J. Med. 2003 349:1473):
1) Patients with asthma and their caregivers are currently faced with a remarkable paradox. Considerable progress has been made during the past 20 years in the pharmacotherapy, educational tools, and environmental measures available for the control of symptoms of asthma. As a result of these advances, more than 90 percent of patients with asthma now have the potential to lead a normal life. The bad news, however, is the absence of any universally accepted strategy for the prevention of the disease. With the exception, perhaps, of measures for the avoidance of infrequent forms of asthma caused by very specific types of exposure (e.g., occupational or aspirin-induced asthma), no single action has been irrefutably demonstrated to decrease the risk of the development of persistent asthma in persons who do not already have the disease.
2) The greatest obstacle to the development of approaches for the prevention of asthma has been the lack of a clear understanding of its natural history. In the past, the cross-sectional surveys on which we have relied have proved misleading. These types of surveys are based heavily on patients' recall of past events, which is particularly susceptible to bias. Most adults, for example, have no direct memory of events that occurred during their preschool years. It is thus not surprising that until quite recently it was widely believed that chronic asthma was equally likely to begin at any age. In addition, asthma was considered to be a progressive disease: the longer it lasted, it was thought, the more likely it was that irreversible changes would develop in the structure and function of the lungs.(1)
3) These conceptions had important consequences from the point of view of public health. Asthma is a disease in which both genetic and environmental factors have important roles,(2) and thus considerable attention was paid to the search for environmental causes of the disease that could affect persons of all ages. On the basis of the results of cross-sectional studies, factors such as environmental tobacco smoke,(3) air pollution,(4) and exposure to common aeroallergens(5) that were known to trigger asthma symptoms in persons who already had the disease were widely reputed to cause it as well.
4) The publication in recent years of the results of adequately powered, well-designed longitudinal studies with follow-up starting during the first years of life has produced a remarkable change in our understanding of asthma, its beginnings, its clinical expression, and its evolution. First, most persons of any age who have chronic, persistent asthma have their first symptoms during their preschool years. Environmental factors, acting during early life and interacting with specific "asthma genes," are apparently crucial for the development of the chronic, persistent form of the disease.(2) The identification of these factors will thus be crucial for a primary-prevention strategy, which will necessarily be focused on events that occur in infancy and early childhood.
5) A second conclusion has to do with the timing of the changes in lung function that are characteristic of the disease. As a group, patients with asthma have lower values than persons without asthma on several measures of lung function, including the ratio of the forced expiratory volume in one second to the forced vital capacity. These deficits are strongly associated with the severity of disease and are believed to represent alterations in lung function and structure that contribute to the persistence of symptoms of asthma. Until recently, the origin of these deficits was not well understood. It now appears that lower levels of lung function are already present by the early school years in patients in whom persistent asthma will ultimately develop, with no further deterioration after that age.
6) A third but not less important conclusion that may be derived from longitudinal studies is that the most common clinical expression of asthma -- namely, episodic wheezing -- has a high frequency in developed countries. There is an urgent need for tools with which to identify young children with symptoms of asthma who are at high risk for the development of the more persistent forms of the disease, so that potential preventive measures can be targeted to those who will benefit the most. The prevention of asthma will require interventions focused on the types of early environmental exposure that predispose children to or protect them against the onset and progression of the disease.
References (abridged):
1. Agertoft L, Pedersen S. Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children. Respir Med 1994;88:373-381
2. Patino CM, Martinez FD. Interactions between genes and environment in the development of asthma. Allergy 2001;56:279-286
3. Cook DG, Strachan DP. Health effects of passive smoking. 10. Summary of effects of parental smoking on the respiratory health of children and implications for research. Thorax 1998;54:357-366
4. Mortimer KM, Neas LM, Dockery DW, Redline S, Tager IB. The effect of air pollution on inner-city children with asthma. Eur Respir J 2002;19:699-705
5. Rosenstreich DL, Eggleston P, Kattan M, et al. The role of cockroach allergy and exposure to cockroach allergen in causing morbidity among inner-city children with asthma. N Engl J Med 1997;336:1356-1363
New Engl. J. Med. http://www.nejm.org
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