Biomedical subjects
Publications and source records attributed to G Gordon.
An entangled multipartite system coupled to a zero-temperature bath undergoes rapid disentanglement in many realistic scenarios due to local, symmetry-breaking differences in the particle-bath couplings. We show that locally controlled perturbations, addressing each particle individually, can impose a symmetry allowing the existence of decoherence-free multipartite entangled systems.
OBJECTIVE: To test the hypothesis that T cell reactivity to self heat-shock protein 60 (Hsp60) in patients with remitting juvenile idiopathic arthritis (JIA) is part of an antiinflammatory, regulatory mechanism. METHODS: Using peripheral blood-derived mononuclear cells (PBMCs) and synovial fluid-derived mononuclear cells (SFMCs) obtained from patients with JIA, we analyzed the expression of CD30 and the induction of regulatory cytokines in response to human and mycobacterial Hsp60. RESULTS: In oligoarticular JIA patients, in vitro activation of PBMCs and SFMCs with Hsp60 induced a high expression of CD30 on CD4+, activated (HLA-DR-positive), memory (CD45RO+) T cells. The expression of CD30 induced by human Hsp60 was much higher than that induced by mycobacterial Hsp60. In oligoarticular JIA patients with active disease, the expression of CD30 in response to human Hsp60 was paralleled by a high interleukin-10 (IL-10):interferon-gamma (IFNgamma) ratio. In addition, restimulated human Hsp60-specific T cell lines from oligoarticular JIA patients showed a high production of IL-10 and a low production of IFNgamma. In contrast, PBMCs and SFMCs from polyarticular JIA patients responded to human Hsp60 with virtually no expression of CD30 and a low IL-10:IFNgamma ratio. CONCLUSION: The results show that T cells responding to human Hsp60 in oligoarticular JIA patients express CD30, and during active phases of the disease, these T cells have a cytokine profile with a high IL-10:IFNgamma ratio. These findings suggest that in oligoarticular JIA patients, human Hsp60-specific CD4+ cells have a regulatory function and contribute to disease remission.
Barrett's esophagus is a premalignant condition in which normal squamous epithelium of the esophagus is replaced by metaplastic columnar epithelium. It is a known risk factor for the development of esophageal adenocarcinoma. With the incidence of esophageal adenocarcinoma rising, it is reasonable to study Barrett's esophagus as a potential target for therapy that may prevent, delay and/or reverse ongoing tumorigenic processes. Epidemiologic and animal studies support the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in the chemoprevention of several cancers, including esophageal cancer. Cyclo-oxygenase-2 (COX-2) inhibitors are a new class of NSAIDs that inhibit prostaglandin synthesis by selectively blocking the COX-2 enzyme. The COX-2 enzyme has been reported to be over-expressed in premalignant and malignant states, including in Barrett's esophagus and esophageal adenocarcinoma. The Chemoprevention for Barrett's Esophagus Trial (CBET) is a phase IIb, multicenter, randomized, double-masked, placebo-controlled study of the selective COX-2 inhibitor, celecoxib, in patients with Barrett's dysplasia. The sample size is 200 patients with high or low grade Barrett's dysplasia. Celecoxib is administered orally, 200 mg twice per day; the dosing schedule for placebo is the same. Randomization is stratified by dysplasia grade and by clinic. Endoscopy with biopsies is performed at specified time intervals according to the highest grade of dysplasia determined at randomization. The primary outcome measure is the change from baseline to 1 year in the proportion of biopsies exhibiting dysplasia. Secondary outcomes include change from baseline in the maximal grade, extent and surface area of dysplasia. Tertiary outcomes will include measurements of various relevant biomarkers.
OBJECTIVE: To determine whether cytomegalovirus (CMV) is associated with gingival overgrowth in paediatric liver graft recipients treated with cyclosporin. STUDY DESIGN: Thirty-four children, 25 of whom were under 5 years of age, who had undergone liver transplantation, were examined. An Index of Severity of Gingival Overgrowth was used to measure the prevalence and severity of the gingival overgrowth. The trough cyclosporin level was recorded and the CMV status of the patient matched to the dental findings. The association between the severity of gingival overgrowth and CMV infection was examined using the contingency coefficient. An anova was used to assess the association between the circulating trough cyclosporin concentration and the severity of gingival overgrowth. Pearson's Product Moment Correlation Coefficient was used to examine the association between the duration of exposure to cyclosporin and the severity of gingival overgrowth. RESULTS: There was a significant inverse association between the duration of exposure to cyclosporin and the severity of gingival overgrowth. There was no relationship between the trough cyclosporin concentration and the severity of gingival overgrowth. There was no association between CMV and gingival overgrowth. CONCLUSION: Gingival overgrowth was related to the duration of cyclosporin therapy but was neither more prevalent nor more severe in subjects who were CMV seropositive.
The oxidation of ClO(2) by OCl(-)is first order with respect to both reactants in the neutral to alkaline pH range: -d[ClO(2)]/dt = 2k(OCl)[ClO(2)][OCl(-)]. The rate constant (T = 298 K, mu = 1.0 M NaClO(4)) and activation parameters are k(OCl) = 0.91 +/- 0.02 M(-1) s(-1), DeltaH = 66.5 +/- 0.9 kJ/mol, and DeltaS(++) = -22.3 +/- 2.9 J/(mol K). In alkaline solution, pH > 9, the primary products of the reaction are the chlorite and chlorate ions and consumption of the hypochlorite ion is not observed. The hypochlorite ion is consumed in increasing amounts, and the production of the chlorite ion ceases when the pH is decreased. The stoichiometry is kinetically controlled, and the reactants/products ratios are determined by the relative rates of the production and consumption of the chlorite ion in the ClO(2)/OCl(-) and HOCl/ClO(2)(-) reactions, respectively.
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Amyloid-beta peptide (Abeta) seems to have a central role in the neuropathology of Alzheimer's disease (AD). Familial forms of the disease have been linked to mutations in the amyloid precursor protein (APP) and the presenilin genes. Disease-linked mutations in these genes result in increased production of the 42-amino-acid form of the peptide (Abeta42), which is the predominant form found in the amyloid plaques of Alzheimer's disease. The PDAPP transgenic mouse, which overexpresses mutant human APP (in which the amino acid at position 717 is phenylalanine instead of the normal valine), progressively develops many of the neuropathological hallmarks of Alzheimer's disease in an age- and brain-region-dependent manner. In the present study, transgenic animals were immunized with Abeta42, either before the onset of AD-type neuropathologies (at 6 weeks of age) or at an older age (11 months), when amyloid-beta deposition and several of the subsequent neuropathological changes were well established. We report that immunization of the young animals essentially prevented the development of beta-amyloid-plaque formation, neuritic dystrophy and astrogliosis. Treatment of the older animals also markedly reduced the extent and progression of these AD-like neuropathologies. Our results raise the possibility that immunization with amyloid-beta may be effective in preventing and treating Alzheimer's disease.
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BACKGROUND: Limited joint mobility (LJM) in childhood insulin-dependent (type 1) diabetes is associated with a substantially increased risk of microvascular complications. Cross-sectional studies have not demonstrated a relationship between LJM and metabolic control. This study was designed to determine whether glycemic control, as measured by glycohemoglobin (hgbA1C) levels from the onset of diabetes, is associated with the occurrence of LJM. METHOD: Probands (n = 18) had hgbA1C values and recorded observation of joint function from soon after onset of their diabetes. Controls (n = 40) were matched to probands for gender and age at diagnosis and had follow-up beyond the age at which the proband was found to have LJM. RESULTS: The odds ratio for occurrence of LJM for the mean hgbA1C from diabetes onset was 1.46, 95% confidence limits 1.07 to 2.00. Thus, for every unit increase in average hgbA1C, there was approximately a 46% increase in the risk of LJM. When hgbA1C was dichotomized, the OR for hgbA1C of more than 8% was 2.55, and the OR was 4.54 if the hgbA1C was greater than 12%. Age at diagnosis and duration of diabetes were not independent prognostic factors for LJM. CONCLUSION: Glycemic control from onset of diabetes is strongly associated with occurrence of LJM.
bcl-2, the prototypic cellular antiapoptotic gene, decreases Sindbis virus replication and Sindbis virus-induced apoptosis in mouse brains, resulting in protection against lethal encephalitis. To investigate potential mechanisms by which Bcl-2 protects against central nervous system Sindbis virus infection, we performed a yeast two-hybrid screen to identify Bcl-2-interacting gene products in an adult mouse brain library. We identified a novel 60-kDa coiled-coil protein, Beclin, which we confirmed interacts with Bcl-2 in mammalian cells, using fluorescence resonance energy transfer microscopy. To examine the role of Beclin in Sindbis virus pathogenesis, we constructed recombinant Sindbis virus chimeras that express full-length human Beclin (SIN/beclin), Beclin lacking the putative Bcl-2-binding domain (SIN/beclinDeltaBcl-2BD), or Beclin containing a premature stop codon near the 5' terminus (SIN/beclinstop). The survival of mice infected with SIN/beclin was significantly higher (71%) than the survival of mice infected with SIN/beclinDeltaBcl-2BD (9%) or SIN/beclinstop (7%) (P < 0.001). The brains of mice infected with SIN/beclin had fewer Sindbis virus RNA-positive cells, fewer apoptotic cells, and lower viral titers than the brains of mice infected with SIN/beclinDeltaBcl-2BD or SIN/beclinstop. These findings demonstrate that Beclin is a novel Bcl-2-interacting cellular protein that may play a role in antiviral host defense.
Many laboratories using the best available technology (ion chromatography) can only reliably measure BrO3- at the 10-20 micrograms/L level. Typically, BrO3- peak resolution is not a problem; however, finished water can contain appreciable amounts of Cl- that can interfere with BrO3- measurement using conductivity detection. Chlorpromazine is a selective reagent that does not react with Cl- and is an ideal postcolumn detection chemistry following IC separation. The chlorpromazine postcolumn method is linear over the 0.5-100 micrograms/L range.
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The PDAPP transgenic mouse, which overexpresses human amyloid precursor protein (APP717V-->F), has been shown to develop much of the pathology associated with Alzheimer disease. In this report, levels of APP and its amyloidogenic metabolites were measured in brain regions of transgenic mice between 4 and 18 months of age. While absolute levels of APP expression likely contribute to the rate of amyloid beta-peptide (Abeta) deposition, regionally specific factors also seem important, as homozygotic mice express APP levels in pathologically unaffected regions in excess of that measured in certain amyloid plaque-prone regions of heterozygotic mice. Regional levels of APP and APP-beta were nearly constant at all ages, while A beta levels dramatically and predictably increased in brain regions undergoing histochemically confirmed amyloidosis, most notably in the cortex and hippocampus. In hippocampus, A beta concentrations increase 17-fold between the ages of 4 and 8 months, and by 18 months of age are over 500-fold that at 4 months, reaching an average level in excess of 20 nmol of A beta per g of tissue. A beta1-42 constitutes the vast majority of the depositing A beta species. The similarities observed between the PDAPP mouse and human Alzheimer disease with regard to A beta42 deposition occurring in a temporally and regionally specific fashion further validate the use of the model in understanding processes related to the disease.
BACKGROUND/AIMS: Autonomic dysfunction is common in cirrhosis, and may be associated with increased mortality and hyperdynamic circulatory changes. Our aim was to investigate whether autonomic disturbances occur in extrahepatic portal vein thrombosis and their correlation with hemodynamic abnormalities. PATIENTS AND METHODS: Heart rate variation in response to standing, deep breathing, and Valsalva maneuver, and blood pressure response to sustained handgrip and to standing, were studied in 16 subjects with portal vein thrombosis (10 males, 30.8+/-2.8 years: mean+/-SE), 12 with cirrhosis (7 males, 52+/-2.3 years), and 10 healthy controls (7 males, 30.8+/-3.0 years). Supine resting, and 10- and 30-min standing epinephrine and norepinephrine levels were measured and results correlated with cardiac output. RESULTS: Autonomic dysfunction occurred in 62% of portal vein thrombosis and 75% of cirrhosis subjects, but in no controls (p<0.02). Similarly, postural hypotension occurred in portal vein thrombosis (-10.25+/-0.65 mmHg, p=0.003) and cirrhosis (-7.42+/-0.82 mmHg, p=0.007) but not in controls. All groups had similar baseline epinephrine and norepinephrine concentrations. Epinephrine increased significantly in controls (45%, p<0.01 and 49%, p<0.02) after 10 of 30 min standing but not in the portal vein thrombosis or the cirrhotic group, and norepinephrine increased after 10 and 30 min standing in cirrhotics (128%, p<0.004 and 130%, p<0.008) and controls (129%, p<0.002 and 116%, p<0.004), but not portal vein thrombosis (34.5% and 39%, NS vs baseline). Portal vein thrombosis and cirrhosis groups had increased cardiac output (4441+/-509 and 3262+/-292) vs controls (1763+/-212 ml/min/m2, p<0.002), but there was no correlation with autonomic neuropathy or with catecholamine levels. CONCLUSIONS: Autonomic dysfunction and impaired catecholamine response to orthostatic stress occur commonly in portal vein thrombosis and suggest an impairment of the autonomic reflex arc, but changes do not correlate with hemodynamic abnormalities.
This paper describes the application of eight statistical and machine-learning methods to derive computer models for predicting mortality of hospital patients with pneumonia from their findings at initial presentation. The eight models were each constructed based on 9847 patient cases and they were each evaluated on 4352 additional cases. The primary evaluation metric was the error in predicted survival as a function of the fraction of patients predicted to survive. This metric is useful in assessing a model's potential to assist a clinician in deciding whether to treat a given patient in the hospital or at home. We examined the error rates of the models when predicting that a given fraction of patients will survive. We examined survival fractions between 0.1 and 0.6. Over this range, each model's predictive error rate was within 1% of the error rate of every other model. When predicting that approximately 30% of the patients will survive, all the models have an error rate of less than 1.5%. The models are distinguished more by the number of variables and parameters that they contain than by their error rates; these differences suggest which models may be the most amenable to future implementation as paper-based guidelines.
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