Runner-up in the young physician's section of the Gowers' prize 2000. Epilepsy and the physical basis of consciousness.
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The issue of human consciousness, in both its popular and neuroscientific sense, is considered from a clinical perspective. The ictal semiologies of the various epilepsies, together with associated clinical features, are demonstrated to highlight certain neuroanatomical and neurophysiological facets of consciousness. It is suggested that further insights into consciousness, even those bordering on the philosophical, may be led by clinical neurological phenomena and emerging neuroinvestigative techniques. (+info)
Longevity of screenwriters who win an academy award: longitudinal study.
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OBJECTIVE: To determine whether the link between high success and longevity extends to academy award winning screenwriters. DESIGN: Retrospective cohort analysis. PARTICIPANTS: All screenwriters ever nominated for an academy award. MAIN OUTCOME MEASURES: Life expectancy and all cause mortality. RESULTS: A total of 850 writers were nominated; the median duration of follow up from birth was 68 years; and 428 writers died. On average, winners were more successful than nominees, as indicated by a 14% longer career (27.7 v 24.2, P=0.004), 34% more total films (23.2 v 17.3, P<0.001), 58% more four star films (4.8 v 3.1, P<0.001), and 62% more nominations (2.1 v 1.3, P<0.001). However, life expectancy was 3.6 years shorter for winners than for nominees (74.1 v 77.7 years, P=0.004), equivalent to a 37% relative increase in death rates (95% confidence interval 10 to 70). After adjustment for year of birth, sex, and other factors, a 35% relative increase in death rates was found (7% to 70%). Additional wins were associated with a 22% relative increase in death rates (3% to 44%). Additional nominations and additional other films in a career otherwise caused no significant increase in death rates. CONCLUSION: The link between occupational achievement and longevity is reversed in screenwriters who win academy awards. Doubt is cast on simple biological theories for the survival gradients found for other members of society. (+info)
The Novartis-ILAR Rheumatology Prize 2001 Osteoarthritis: from molecule to man.
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During our careers, we have developed new and innovative concepts pertaining to the pathophysiology of osteoarthritis which have assisted in the development of new therapeutic approaches. Moreover, our laboratory has long sought to develop protective agents for osteoarthritic structural joint tissues. The most significant concepts that have originated from our lab are briefly outlined in this commentary. (+info)
Optident prize 2000.
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This paper describes the orthodontic treatment of two cases, which were awarded the 2000 Optident prize. (+info)
Theodore E. Woodward Award. How bacterial enterotoxins work: insights from in vivo studies.
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Clostridium difficile is a spore forming, gram-positive anaerobic bacillus first described in 1935 by Hall and O'Toole as a commensal organism in the fecal flora of healthy newborn infants (1). The organism was given its unusual name because it grew slowly and was difficult to isolate in pure culture. Its presence in the stool of healthy neonates suggested that C. difficile was a nonpathogen, even though it produced toxins in broth culture. Following its original description, C. difficile passed quickly into relative obscurity in the 1960's and 1970's when antibiotic-associated pseudomembranous colitis became prevalent following the introduction into clinical practice of broad spectrum antibiotics. The frequent association of clindamycin and lincomycin therapy with pseudomembranous colitis led to the term "clindamycin colitis" (2). A breakthrough occurred in 1978 when C. difficile was identified as the source of a cytotoxin in the stool of patients with pseudomembranous colitis (3). During the two decades since its rediscovery, a great deal has been learned about the pathophysiology, epidemiology and management of C. difficile infection, yet many challenges remain. Currently this organism infects over 30% of individuals admitted to United States hospitals, making C. difficile colitis one of the most common nosocomial infections (4). It is estimated that approximately 10-12 million adults are infected with this organism each year in the United States, about a third of whom become symptomatic. The disease burden in the elderly is particularly severe as they are hospitalized more frequently and for longer duration. The pathophysiology of C. difficile diarrhea requires alteration of the colonic microflora by antibiotics, colonization by C. difficile, and release of two potent enterotoxins designated A and B (5). The toxins of Clostridium difficile are required virulence factors in both animals and humans since non-toxigenic strains do not cause disease. Recent cloning and sequencing of the toxin genes reveals extensive amino acid homology between them that is reflected in common molecular and cellular mechanisms. Both toxins damage cells by modifying the rho family of proteins, key regulators of cellular actin. C. difficile infection causes a florid acute inflammatory response seen in patients with pseudomembranous colitis. It is now realized that neurons and immune cells of the lamina propria are major determinants of toxin-induced diarrhea and mucosal damage. Early critical events following toxin exposure are release of the neuropeptides substance P and calcitonin gene related peptide (CGRP) from sensory afferent neurons and activation of lamina propria macrophages and intestinal mast cells. These peptides in turn release a complex cascade of other inflammatory mediators from lamina propria cells (5). The importance of the host immune response, specifically serum IgG directed against toxin A, is now recognized as a critical determinant of disease expression in man. (+info)
Hunting for electrophiles that harm human DNA: Frits Sobels Award Lecture.
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This lecture is dedicated to Frits Sobels and his farsighted vision on research directions in genetic toxicology. Some accomplishments by the author's research group in the area of cancer etiology research and pre-clinical drug safety evaluation are presented. Praziquantel, an antischistosomal drug, was found to be devoid of any genetic effects which determined the drug companies to proceed with further safety evaluation and marketing. This highly efficient life-saving drug is now in use world wide. Biomonitoring methods have been developed to quantitate carcinogens, their metabolites or DNA adducts in humans exposed environmentally and endogenously to genotoxic agents. The methods were applied in ecological and case-control studies aimed at establishing causal relationships between exposure and disease. Results from both field studies in Iran and laboratory investigations supported the hypothesis that opium use, in particular ingestion of its pyrolysates, may be a risk factor for esophageal cancer in this region, probably acting together with nutritional deficiencies and thermal injury. By applying the nitrosoproline (NPRO) test in ecological studies on esophageal cancer causation in China some support was obtained for the involvement of N-nitroso compounds. In inhabitants of high risk areas endogenous nitrosamine synthesis could be markedly reduced by ingestion of vitamin C. Ultrasensitive detection methods for etheno-DNA adducts, which are formed by lipid peroxidation products resulting from increased oxidative stress, have been developed. Known cancer risk factors such as metal storage, chronic inflammatory processes and a high omega-6 PUFA fat diet increased the background level of these miscoding DNA adducts many times. They were found to increase progressively in premalignant lesions of cancer-prone tissues of humans and rodents, probably contributing to the genetic instability that drives cells to malignancy. Etheno-DNA adducts are thus promising markers to verify the efficiency of chemopreventive measures in humans. (+info)
HLA B27 in health and disease: a double-edged sword?
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The strong association of the HLA class 1 allele HLA B27 with ankylosing spondylitis (AS) has been recognized for over 25 yr, however the pathogenic mechanism linking HLA B27 with AS and other spondyloarthropathies remains a mystery. We now know that the principal natural function of HLA B27 is an immunologic one, namely to bind antigenic peptides and then present them to T lymphocytes. I have shown that HLA B27 functions as an excellent antigen-presenting molecule in both spondyloarthropathy patients and healthy individuals. A working molecular model of how T cells recognize HLA B27 has been generated and tested. Evidence that T cells have a role in spondyloarthritis has also been found. First, expanded populations of T lymphocytes were found in both the blood and synovial fluid of patients with reactive arthritis (ReA). Secondly, a strong cytotoxic T-cell response to an HLA B27-restricted peptide epitope from Chlamydia trachomatis was found in a patient with ReA. This peptide, derived from a bacterium known to trigger ReA, is thus a candidate 'arthritogenic' peptide. We have also found evidence that HLA B27 has an unusual cell biology compared with other HLA molecules. HLA B27 demonstrates an unusual ability to form heavy chain homodimers in vitro. Dimerization is dependent upon disulphide bonding through an unpaired cysteine at position 67. Remarkably these dimers lack beta2 microglobulin, previously thought to be an essential component of all mature MHC class 1 molecules. HLA B27 homodimer formation has also been demonstrated in certain cell lines in vivo, and preliminary data suggest that significant numbers of T cells from patients with spondyloarthropathy express a ligand for HLA B27 homodimers. These findings have extended our understanding of the beneficial immunologic function of HLA B27, and have also led us to propose the testable new hypothesis that HLA B27 heavy chain dimerization may be involved in the pathogenesis of spondyloarthritis. (+info)
From development to evolution: the re-establishment of the "Alexander Kowalevsky Medal".
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The Saint Petersburg Society of Naturalists has reinstated the Alexander O. Kowalevsky Medal. This article announces the winners of the first medals and briefly reviews the achievements of A.O. Kowalevsky, the Russian comparative embryologist whose studies on amphioxus, tunicates and germ layer homologies pioneered evolutionary embryology and confirmed the evolutionary continuity between invertebrates and vertebrates. In re-establishing this international award, the Society is pleased to recognize both the present awardees and the memory of Kowalevsky, whose work pointed to that we now call evolutionary developmental biology. (+info)