Biomedical subjects
Publications and source records attributed to J Smith.
In order to evaluate ICPs, criteria for success must be identified. The key areas to consider are quality of patient care, staff and patient satisfaction, documentation and cost. Commitment, resources, desire and need, facilitation and management also have an impact. The role of the ICP facilitator is vital to a project's success.
In late summer 1999, an outbreak of human encephalitis occurred in the northeastern United States that was concurrent with extensive mortality in crows (Corvus species) as well as the deaths of several exotic birds at a zoological park in the same area. Complete genome sequencing of a flavivirus isolated from the brain of a dead Chilean flamingo (Phoenicopterus chilensis), together with partial sequence analysis of envelope glycoprotein (E-glycoprotein) genes amplified from several other species including mosquitoes and two fatal human cases, revealed that West Nile (WN) virus circulated in natural transmission cycles and was responsible for the human disease. Antigenic mapping with E-glycoprotein-specific monoclonal antibodies and E-glycoprotein phylogenetic analysis confirmed these viruses as WN. This North American WN virus was most closely related to a WN virus isolated from a dead goose in Israel in 1998.
Comparative mapping, which compares the location of homologous genes in different species, is a powerful tool for studying genome evolution. Comparative maps suggest that rates of chromosomal change in mammals can vary from one to ten rearrangements per million years. On the basis of these rates we would expect 84 to 600 conserved segments in a chicken comparison with human or mouse. Here we build comparative maps between these species and estimate that numbers of conserved segments are in the lower part of this range. We conclude that the organization of the human genome is closer to that of the chicken than the mouse and by adding comparative mapping results from a range of vertebrates, we identify three possible phases of chromosome evolution. The relative stability of genomes such as those of the chicken and human will enable the reconstruction of maps of ancestral vertebrates.
CONTEXT: Persons with cytomegalovirus (CMV) retinitis and acquired immunodeficiency syndrome (AIDS) have required lifelong anti-CMV therapy to prevent the progression of retinal disease and subsequent loss of vision. OBJECTIVE: To determine whether patients who were taking highly active antiretroviral therapy (HAART) and who had stable CMV retinitis could safely discontinue anti-CMV therapy without reactivation of their retinitis or increase in human immunodeficiency virus (HIV) viral load. DESIGN: Prospective nonrandomized interventional trial performed from July 1997 to August 1999. SETTING: Clinical Center of the National Institutes of Health, Bethesda, Md. PATIENTS: Fourteen patients with stable CMV retinitis and HIV infection and CD4+ cell counts higher than 0.1 5 x 10(9)/L and being treated with systemic anti-CMV medications and HAART. INTERVENTIONS: Discontinuation of specific anti-CMV therapy. MAIN OUTCOME MEASURES: Reactivation of CMV retinitis, development of extraocular CMV infection, detection of CMV in blood and urine, HIV burden, immunologic function, quality of life, morbidity, and mortality. RESULTS: Twelve (89.7%) of 14 patients had evidence of immune recovery uveitis before anti-CMV drugs were discontinued. No patient had reactivation of CMV retinitis or development of extraocular CMV disease during mean follow-up of 16.4 months (range, 8.3-22.0 months) without anti-CMV therapy. Human immunodeficiency viral load remained stable following cessation of anti-CMV medications. Blood and urine assays for CMV were briefly positive in 9 patients but did not predict reactivation of CMV disease. Worsening immune recovery uveitis was associated with a substantial (>3 lines) vision loss in 3 patients. CONCLUSIONS: Maintenance anti-CMV medications were safely stopped in those patients who had stable CMV retinitis and elevated CD4+ cell counts and who were taking HAART. The study demonstrates that immune recovery following potent antiretroviral therapy is effective in controlling a major opportunistic infection, even in patients with a history of severe immunosuppression.
Previous epidemiologic studies have suggested an association between maternal sex hormone use during pregnancy, including infertility medication, and an increased risk of neuroblastoma in the offspring. The authors conducted a case-control interview study from 1992 to 1996 that included 504 children less than 19 years of age whose newly diagnosed neuroblastoma was identified by two national collaborative clinical trials groups in the United States and Canada, the Children's Cancer Group and the Pediatric Oncology Group. Controls, matched to cases on age, were identified by random digit dialing. No association was found for use of oral contraceptives before or during pregnancy (first trimester odds ratio (OR) = 1.0, 95% confidence interval (CI): 0.5, 2.1). The odds ratio was slightly elevated for history of infertility (OR = 1.4, 95% CI: 0.9, 2.1) and ever use of any infertility medication (OR = 1.2, 95% CI: 0.7, 2.2). Specifically, ever use of clomiphene was associated with a 1.6-fold increased risk (95% CI: 0.8, 3.0) but not periconceptionally or during the index pregnancy. A suggestive pattern was found for gender of the offspring, with an increased risk for males but not for females after exposure to oral contraceptives or clomiphene. This study did not find consistent and large increased risks for maternal use of hormones, but the suggestion of an association for male offspring requires further consideration.
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The results of previous epidemiologic research on the possible association between maternal smoking during pregnancy and risk of oral clefts in offspring have been inconsistent. This may be due in part to methodological limitations, including imprecise measurement of tobacco use, failure to consider etiologic heterogeneity among types of oral clefts, and confounding. This analysis, based on a large case-control study, further evaluated the effect of first trimester maternal smoking on oral facial cleft risk by examining the dose-response relationship according to specific cleft type and according to whether or not additional malformations were present. A number of factors, including dietary and supplemental folate intake and family history of clefts, were evaluated as potential confounders and effect modifiers. Data on 3,774 mothers interviewed between 1976 and 1992 by the Slone Epidemiology Unit Birth Defects Study were used. Study subjects were actively ascertained from sites in areas around Boston, Massachusetts and Philadelphia, Pennsylvania; the state of Iowa; and southeastern Ontario, Canada. Cases were infants with isolated defects--cleft lip alone (n = 334), cleft lip and palate (n = 494), or cleft palate alone (n = 244)--and infants with clefts plus (+) additional malformations: cleft lip+ (n = 58), cleft lip and palate+ (n = 140), or cleft palate+ (n = 209). Controls were infants with defects other than clefts, excluding defects possibly associated with maternal cigarette use. There were no associations with maternal smoking for any oral cleft group, except for a positive dose response among infants with cleft lip and palate+ (for light smokers, odds ratio (OR) = 1.09 (95% confidence interval (CI): 0.6, 1.9); for moderate smokers, OR = 1.84 (95% CI: 1.2, 2.9); and for heavy smokers, OR = 1.85 (95% CI: 1.0, 3.5), relative to nonsmokers). This finding may be related to the additional malformations rather than to the cleft itself.
The physiological role of the TNF receptor (TNFR) family member, RANK, was investigated by generating RANK-deficient mice. RANK(-/-) mice were characterized by profound osteopetrosis resulting from an apparent block in osteoclast differentiation. RANK expression was not required for the commitment, differentiation, and functional maturation of macrophages and dendritic cells from their myeloid precursors but provided a necessary and specific signal for the differentiation of myeloid-derived osteoclasts. RANK(-/-) mice also exhibited a marked deficiency of B cells in the spleen. RANK(-/-) mice retained mucosal-associated lymphoid tissues including Peyer's patches but completely lacked all other peripheral lymph nodes, highlighting an additional major role for RANK in lymph node formation. These experiments reveal that RANK provides critical signals necessary for lymph node organogenesis and osteoclast differentiation.
The Ottawa Regional Cancer Centre offers an Oncology Rehabilitation Program to patients with cancer. Between January 1997 and December 1998, 254 patients with cancer participated in the program. This paper describes the program and its participants. The program's strengths, limitations and future directions are also discussed.
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To evaluate the safety and potential therapeutic activity of humanized anti-IL-2 receptor mAb (Daclizumab) therapy in the treatment of patients with severe, sight-threatening, intermediate and posterior noninfectious uveitis, a nonrandomized, open-label, pilot study was performed. Patients with uveitis were treated with a minimum of 20 mg of prednisone, cyclosporine, antimetabolites, or any combination of these agents were eligible. Patients were weaned off their systemic immunosuppressive agents according to a standardized schedule, while ultimately receiving Daclizumab infusions every 4 weeks. Anti-IL-2 receptor antibody therapy, given intravenously with intervals of up to 4 weeks in lieu of standard immunosuppressive therapy, appeared to prevent the expression of severe sight-threatening intraocular inflammatory disease in 8 of 10 patients treated over a 12-month period, with noted improvements in visual acuity. One patient met a primary endpoint with a loss of vision of 10 letters or more from baseline in one eye and another patient discontinued therapy because of evidence of increased ocular inflammation. All patients were able to tolerate the study medications without the need for dose reduction. We report effective long-term use of anti-IL-2 therapy for an autoimmune indication. These initial findings would suggest that anti-IL-2 receptor therapy may be an effective therapeutic approach for uveitis and, by implication, other disorders with a predominant Th1 profile.
High-quality, dedicated management support was crucial to the GP commissioning pilots. A fifth of the pilots reported difficult relationships with their health authority. There are concerns about bringing prescribing 'outliers' into line. Involving the public will be a considerable challenge for PCGs.
Primary care trusts are similar to US health maintenance organisations in that they act as both commissioners and providers of services. There are already innovative primary care organisations in the NHS and the private sector that can be classed as embryonic PCTs. Experience of these organisations, assessed in relation to HMOs, can inform the development of PCTs.
The migration of leukocytes into glomeruli in crescentic glomerulonephritis is fundamental to pathogenesis, and offers important therapeutic opportunities. We addressed the importance of VCAM-1, and its leukocyte ligand very late antigen-4 (VLA-4), in such leukocyte migration. In a rat model of nephrotoxic nephritis, glomerular expression of VCAM-1, studied by immunohistochemistry, was up-regulated by day 6 of nephritis. To quantify kidney endothelial VCAM-1 expression, a differential radiolabeled mAb technique was used, which demonstrated that protein expression was not up-regulated by day 2 of nephritis, but rose threefold between days 2 and 5, and remained elevated until at least day 28. An in vivo study was then performed, using blocking mAbs to either VCAM-1 or VLA-4, starting mAb treatment on the day prior to disease induction, and continuing until animals were sacrificed at day 7. mAbs to VLA-4 significantly attenuated renal injury (albuminuria, glomerular fibrinoid necrosis, and crescent formation), but mAbs to VCAM-1 had no significant effect. Surprisingly, the number of leukocytes within glomeruli was unaffected by anti-VLA-4 mAb therapy, despite the reduction in renal injury. Paradoxically, classical markers of macrophage activation were increased in the anti-VLA-4- and anti-VCAM-1-treated animals. This study demonstrates that kidney endothelial VCAM-1, in contrast to ICAM-1, is not up-regulated by day 2 of nephrotoxic nephritis, and plays little part in early leukocyte influx into glomeruli. However, VLA-4 is an important mediator of glomerular injury, operating after transendothelial leukocyte migration, and presumably binding to alternate ligands within the kidney.
Air trapped in bubbles in polar ice cores constitutes an archive for the reconstruction of the global carbon cycle and the relation between greenhouse gases and climate in the past. High-resolution records from Antarctic ice cores show that carbon dioxide concentrations increased by 80 to 100 parts per million by volume 600 +/- 400 years after the warming of the last three deglaciations. Despite strongly decreasing temperatures, high carbon dioxide concentrations can be sustained for thousands of years during glaciations; the size of this phase lag is probably connected to the duration of the preceding warm period, which controls the change in land ice coverage and the buildup of the terrestrial biosphere.