Hybridization in parasites: consequences for adaptive evolution, pathogenesis and public health in a changing world

[No abstract available

Teratology Primer-2nd Edition (7/9/2010)

Foreword: What is Teratology? “What a piece of work is an embryo!” as Hamlet might have said. “In form and moving how express and admirable! In complexity how infinite!” It starts as a single cell, which by repeated divisions gives rise to many genetically identical cells. These cells receive signals from their surroundings and from one another as to where they are in this ball of cells —front or back, right or left, headwards or tailwards, and what they are destined to become. Each cell commits itself to being one of many types; the cells migrate, combine into tissues, or get out of the way by dying at predetermined times and places. The tissues signal one another to take their own pathways; they bend, twist, and form organs. An organism emerges. This wondrous transformation from single celled simplicity to myriad-celled complexity is programmed by genes that, in the greatest mystery of all, are turned on and off at specified times and places to coordinate the process. It is a wonder that this marvelously emergent operation, where there are so many opportunities for mistakes, ever produces a well-formed and functional organism. And sometimes it doesn’t. Mistakes occur. Defective genes may disturb development in ways that lead to death or to malformations. Extrinsic factors may do the same. “Teratogenic” refers to factors that cause malformations, whether they be genes or environmental agents. The word comes from the Greek “teras,” for “monster,” a term applied in ancient times to babies with severe malformations, which were considered portents or, in the Latin, “monstra.” Malformations can happen in many ways. For example, when the neural plate rolls up to form the neural tube, it may not close completely, resulting in a neural tube defect—anencephaly if the opening is in the head region, or spina bifida if it is lower down. The embryonic processes that form the face may fail to fuse, resulting in a cleft lip. Later, the shelves that will form the palate may fail to move from the vertical to the horizontal, where they should meet in the midline and fuse, resulting in a cleft palate. Or they may meet, but fail to fuse, with the same result. The forebrain may fail to induce the overlying tissue to form the eye, so there is no eye (anophthalmia). The tissues between the toes may fail to break down as they should, and the toes remain webbed. Experimental teratology flourished in the 19th century, and embryologists knew well that the development of bird and frog embryos could be deranged by environmental “insults,” such as lack of oxygen (hypoxia). But the mammalian uterus was thought to be an impregnable barrier that would protect the embryo from such threats. By exclusion, mammalian malformations must be genetic, it was thought. In the early 1940s, several events changed this view. In Australia an astute ophthalmologist, Norman Gregg, established a connection between maternal rubella (German measles) and the triad of cataracts, heart malformations, and deafness. In Cincinnati Josef Warkany, an Austrian pediatrician showed that depriving female rats of vitamin B (riboflavin) could cause malformations in their offspring— one of the early experimental demonstrations of a teratogen. Warkany was trying to produce congenital cretinism by putting the rats on an iodine deficient diet. The diet did indeed cause malformations, but not because of the iodine deficiency; depleting the diet of iodine had also depleted it of riboflavin! Several other teratogens were found in experimental animals, including nitrogen mustard (an anti cancer drug), trypan blue (a dye), and hypoxia (lack of oxygen). The pendulum was swinging back; it seemed that malformations were not genetically, but environmentally caused. In Montreal, in the early 1950s, Clarke Fraser’s group wanted to bring genetics back into the picture. They had found that treating pregnant mice with cortisone caused cleft palate in the offspring, and showed that the frequency was high in some strains and low in others. The only difference was in the genes. So began “teratogenetics,” the study of how genes influence the embryo’s susceptibility to teratogens. The McGill group went on to develop the idea that an embryo’s genetically determined, normal, pattern of development could influence its susceptibility to a teratogen— the multifactorial threshold concept. For instance, an embryo must move its palate shelves from vertical to horizontal before a certain critical point or they will not meet and fuse. A teratogen that causes cleft palate by delaying shelf movement beyond this point is more likely to do so in an embryo whose genes normally move its shelves late. As studies of the basis for abnormal development progressed, patterns began to appear, and the principles of teratology were developed. These stated, in summary, that the probability of a malformation being produced by a teratogen depends on the dose of the agent, the stage at which the embryo is exposed, and the genotype of the embryo and mother. The number of mammalian teratogens grew, and those who worked with them began to meet from time to time, to talk about what they were finding, leading, in 1960, to the formation of the Teratology Society. There were, of course, concerns about whether these experimental teratogens would be a threat to human embryos, but it was thought, by me at least, that they were all “sledgehammer blows,” that would be teratogenic in people only at doses far above those to which human embryos would be exposed. So not to worry, or so we thought. Then came thalidomide, a totally unexpected catastrophe. The discovery that ordinary doses of this supposedly “harmless” sleeping pill and anti-nauseant could cause severe malformations in human babies galvanized this new field of teratology. Scientists who had been quietly working in their laboratories suddenly found themselves spending much of their time in conferences and workshops, sitting on advisory committees, acting as consultants for pharmaceutical companies, regulatory agencies, and lawyers, as well as redesigning their research plans. The field of teratology and developmental toxicology expanded rapidly. The following pages will show how far we have come, and how many important questions still remain to be answered. A lot of effort has gone into developing ways to predict how much of a hazard a particular experimental teratogen would be to the human embryo (chapters 9–19). It was recognized that animal studies might not prove a drug was “safe” for the human embryo (in spite of great pressure from legislators and the public to do so), since species can vary in their responses to teratogenic exposures. A number of human teratogens have been identified, and some, suspected of teratogenicity, have been exonerated—at least of a detectable risk (chapters 21–32). Regulations for testing drugs before market release have greatly improved (chapter 14). Other chapters deal with how much such things as population studies (chapter 11), post-marketing surveillance (chapter 13), and systems biology (chapter 16) add to our understanding. And, in a major advance, the maternal role of folate in preventing neural tube defects and other birth defects is being exploited (chapter 32). Encouraging women to take folic acid supplements and adding folate to flour have produced dramatic falls in the frequency of neural tube defects in many parts of the world. Progress has been made not only in the use of animal studies to predict human risks, but also to illumine how, and under what circumstances, teratogens act to produce malformations (chapters 2–8). These studies have contributed greatly to our knowledge of abnormal and also normal development. Now we are beginning to see exactly when and where the genes turn on and off in the embryo, to appreciate how they guide development and to gain exciting new insights into how genes and teratogens interact. The prospects for progress in the war on birth defects were never brighter. F. Clarke Fraser McGill University (Emeritus) Montreal, Quebec, Canad

Birth weight and cognitive performance in older women: the Rancho Bernardo study

Low birth weight is associated with poorer cognitive function from infancy through early adulthood, but little is known about low birth weight and cognitive performance in the elderly. This study examines the association of birth weight with cognitive function in community-dwelling older women. Participants were 292 community-dwelling women aged 55–89 (median = 71 years) who attended a 1988–91 clinic visit when cognitive function was assessed, and responded to a 1991 mailed questionnaire assessing birth weight. All analyses were adjusted for age and education. Birth weight ranged from 2 to 12 pounds (lbs; mean = 7.4 ± 1.9). When birth weight was categorized into tertiles (2–6.9 lbs, 7–8 lbs, and 8.1–12.4 lbs), women in the lowest tertile had significantly lower (“poorer”) scores on Serial 7’s, a test of concentration and calculation (p < 0.05). Other birth weight categorizations (lowest quartile or quintile, or birth weight <5.5 lbs vs. 5.6–8.9 lbs and ≥9 lbs) did not improve the prediction of poor performance on Serial 7’s. Birth weight as a continuous variable was significantly and positively associated with Serial 7’s test scores (p = 0.04). Results suggest that small decrements in cognitive function tasks involving calculation may persist throughout life in women who were of relatively low birth weight. Although this association could be spurious, it deserves further evaluation

What should psychiatry residents be taught about neurology?: A survey of psychiatry residency directors

To improve our ability to teach psychiatry residents during their required 2 months on neurology rotations, we investigated the perceived needs of psychiatry program training directors. We contacted the program directors organization of the American Psychiatric Association and disseminated a web-based survey to all program directors. The survey asked questions about the format and content of neurology training desired for psychiatry residents. The survey was sent a second time to increase response rate. Sixty (32%) training directors responded. Overall satisfaction with neurologic education was rated at 3.6 out of 5 (standard deviation +/- 0.96). The specific content areas which elicited the most interest for focused training modules were differential diagnosis and biologic substrates of dementia, evaluation and treatment of drug-related and spontaneous movement disorders, evaluation and management of sleep disorders, cognitive and mood effects of stroke, and inherited disorders. Many program directors commented on perceived weaknesses of inpatient-based exposure to neurology; 78% of responders favored outpatient and consultation settings. In an era of deliberation about neurobehavioral integration and cross-training of neurologists and psychiatrists, neurologists should strive to provide the best possible multidisciplinary education to psychiatry trainees

Defective respiratory tract immune surveillance in asthma : a primary causal factor in disease onset and progression

The relative importance of respiratory viral infections vs inhalant allergy in asthma pathogenesis is the subject of ongoing debate. Emerging data from long-term prospective birth cohorts are bringing increasing clarity to this issue, in particular through the demonstration that while both of these factors can contribute independently to asthma initiation and progression, their effects are strongest when they act in synergy to drive cycles of episodic airways infl ammation. An important question is whether susceptibility to infection and allergic sensitization in children with asthma arises from common or shared defect(s). We argue here that susceptibility to recurrent respiratory viral infections, failure to generate protective immunologic tolerance to aeroallergens, and ultimately the synergistic interactions between infl ammatory pathways triggered by concomitant responses to these agents all result primarily from functional defi ciencies within the cells responsible for local surveillance for antigens impinging on airway surfaces: the respiratory mucosal dendritic cell (DC) network. The effects of these defects in DCs from children wtih asthma are accentuated by parallel attenuation of innate immune functions in adjacent airway epithelial cells that reduce their resistance to the upper respiratory viral infections, which are the harbingers of subsequent infl ammatory events at asthma lesion site(s) in the lower airways. An important common factor underpinning the innate immune functions of these unrelated cell types is use of an overlapping series of pattern recognition receptors (exemplifi ed by the Toll-like receptor family), and variations in the highly polymorphic genes encoding these receptors and related molecules in downstream signaling pathways appear likely contributors to these shared defects. Findings implicating recurrent respiratory infections in adult-onset asthma, much of which is nonatopic, suggest a similar role for defi cient immune surveillance in this phenotype of the disease

Increased Allergic Immune Response to Sarcoptes scabiei Antigens in Crusted versus Ordinary Scabies▿

Scabies, a parasitic skin infestation by the burrowing “itch” mite Sarcoptes scabiei, causes significant health problems for children and adults worldwide. Crusted scabies is a particularly severe form of scabies in which mites multiply into the millions, causing extensive skin crusting. The symptoms and signs of scabies suggest host immunity to the scabies mite, but the specific resistant response in humans remains largely uncharacterized. We used 4 scabies mite recombinant proteins with sequence homology to extensively studied house dust mite allergens to investigate a differential immune response between ordinary scabies and the debilitating crusted form of the disease. Subjects with either disease form showed serum IgE against recombinant S. scabiei cysteine and serine proteases and apolipoprotein, whereas naive subjects showed minimal IgE reactivity. Significantly (P < 0.05) greater serum IgE and IgG4 binding to mite apolipoprotein occurred in subjects with crusted scabies than in those with ordinary scabies. Both subject groups showed strong proliferative responses (peripheral blood mononuclear cells) to the scabies antigens, but the crusted scabies group showed increased secretion of the Th2 cytokines interleukin 5 (IL-5) and IL-13 and decreased Th1 cytokine gamma interferon (IFN-γ) in response to the active cysteine protease. These data confirm that a nonprotective allergic response occurs in the crusted disease form and demonstrate that clinical severity is associated with differences in the type and magnitude of the antibody and cellular responses to scabies proteins. A quantitative IgE inhibition assay identified IgE immunoreactivity of scabies mite antigens distinct from that of house dust mite antigens, which is potentially important for specific scabies diagnosis and therapy

APA summit on medical student education task force on informatics and technology: steps to enhance the use of technology in education through faculty development, funding and change management

OBJECTIVE: This article provides an overview of how trainees, faculty, and institutions use technology for acquiring knowledge, skills, and attitudes for practicing modern medicine. METHOD: The authors reviewed the literature on medical education, technology, and change, and identify the key themes and make recommendations for implementing technology in medical education. RESULTS: Administrators and faculty should initially assess their own competencies with technology and then develop a variety of teaching methods that use technology to improve their curricula. Programs should decrease the general knowledge-based content of curricula and increase the use of technology for learning skills. For programs to be successful, they must address faculty development, change management, and funding. CONCLUSIONS: Willingness for change, collaboration, and leadership at all levels are essential factors for successfully implementing technology