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Biomedical subjects

J Mitchell

Publications and source records attributed to J Mitchell.

At least 91 records · Page 5Linked to original sources
PubMed1998

Structure of the human cytomegalovirus B capsid by electron cryomicroscopy and image reconstruction.

The three-dimensional structure of B capsids of the beta-herpesvirus human cytomegalovirus (HCMV) was investigated at a resolution of 3.5 nm from electron cryomicrographs by image processing and compared with the structure obtained for the alpha-herpesvirus herpes simplex virus type 1 (HSV-1). The main architectural features of the HSV-1 and HCMV capsids are similar: the T = 16 icosahedral lattice consists of 162 capsomers, composed of two distinct morphological units, 12 pentamers and 150 hexamers, with triplex structures linking adjacent capsomers at positions of local threefold symmetry. The main differences in the HSV-1 and HCMV capsids are found in the diameter of the capsids (125 and 130 nm, respectively); the hexamer spacing and relative tilt (center-to-center hexon spacing at outer, edge, 17.9 and 15.8 nm, respectively); the morphology of the tips of the hexons (similar in length but 33% thinner in HCMV); and the average diameter of the scaffold (44 and 76 nm, respectively). By analogy with HSV-1, the mass on the HCMV hexon tip is attributed to the smallest capsid protein (HCMV gene UL48/49). The differences in capsid structure are discussed in relation to the ability of the HCMV structure to package a genome some 60% larger than that of HSV-1.

Capsid↗
PubMed1998

Effect of pravastatin on cardiovascular events in older patients with myocardial infarction and cholesterol levels in the average range. Results of the Cholesterol and Recurrent Events (CARE) trial.

BACKGROUND: A majority of all myocardial infarctions occur in patients who are 65 years of age or older and have average cholesterol levels, but little information is available on whether cholesterol lowering in such patients reduces the rate of recurrent cardiovascular disease. OBJECTIVE: To determine whether pravastatin reduces the rate of recurrent cardiovascular events in older patients. DESIGN: Subset analysis of a randomized, controlled trial. SETTING: 80 hospitals and affiliates in the United States and Canada. PATIENTS: 1283 patients aged 65 to 75 years who had had myocardial infarction and had a plasma total cholesterol level less than 6.2 mmol/L (240 mg/dL) and a low-density lipoprotein cholesterol level of 3.0 to 4.5 mmol/L (115 to 174 mg/dL). INTERVENTION: Pravastatin, 40 mg/d, or placebo. MEASUREMENTS: Five-year event rates of major coronary events (coronary death, nonfatal myocardial infarction, angioplasty, or bypass surgery) and stroke. RESULTS: Major coronary events occurred in 28.1% of placebo recipients and 19.7% of pravastatin recipients (difference, 9.0 percentage points [95% CI, 4 to 13 percentage points]; relative risk reduction, 32%; P < 0.001). Coronary death occurred in 10.3% of the placebo group and in 5.8% of the pravastatin group (difference, 4.6 percentage points [CI, 1.9 to 6.5 percentage points]; relative risk reduction, 45%; P = 0.004). Stroke incidence was 7.3% in the placebo group and 4.5% in the pravastatin group (absolute reduction, 2.9 percentage points [CI, 0.3 to 4.5 percentage points]; relative reduction, 40%; P = 0.03). The numbers of older patients needed to treat for 5 years were 11 (CI, 8 to 24) to prevent a major coronary event and 22 (CI, 15 to 53) to prevent a coronary death. For every 1000 older patients treated, 225 cardiovascular hospitalizations would be prevented compared with 121 hospitalizations in 1000 younger patients. CONCLUSIONS: In older patients with myocardial infarction and cholesterol levels in the average range, pravastatin is associated with a clinically important reduction in risk for major coronary events and stroke. Given the high cardiovascular event rate in older patients, the potential for absolute benefit in this age group is substantial.

Aged↗
PubMed1998

Purification, G protein activation, and partial amino acid sequence of a novel phospholipase C from squid photoreceptors.

Invertebrate visual signal transduction is initiated by rhodopsin activation of a guanine nucleotide binding protein, Gq, which stimulates phospholipase C (PLC) activity. We have previously purified a 140-kDa PLC enzyme from squid photoreceptors that is regulated by squid Gq. In these studies, an additional PLC enzyme was purified from the cytosol of squid photoreceptors and identified as a 70-kDa protein by SDS-polyacrylamide gel electrophoresis. Hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) by PLC-70 was optimal at pH 5 in the presence of 100 microM Ca2+ with a specific activity of 10.3 micromol min-1 mg-1. A polyclonal antibody raised against purified PLC-70 did not recognize purified PLC-140, and proteolytic digestion of the two purified enzymes with trypsin or Staphylococcus aureaus V8 protease showed distinct patterns of peptide fragments, indicating that PLC-70 is not a fragment of PLC-140. The partial amino acid sequence of the protein showed homology with PLC21 and norpA isozymes cloned from Drosophila, and mammalian PLC beta isozymes. Reconstitution of purified GTPgammaS-bound soluble squid Gq with PLC-70 resulted in significant enhancement of PIP2 hydrolysis over a range of Ca2+ concentrations and shifted the maximum activation by calcium to 1 microM. These results suggest that cephalopod phototransduction is mediated by Gq activation of more than one cytosolic PLC enzyme.

Amino Acid Sequence↗
PubMed1998

Influence of socioeconomic and cultural factors on racial differences in late-stage presentation of breast cancer.

CONTEXT: Breast cancer mortality is higher among African American women than among white women in the United States, but the reasons for the racial difference are not known. OBJECTIVE: To evaluate the influence of socioeconomic and cultural factors on the racial difference in breast cancer stage at diagnosis. DESIGN: Case-control study of patients diagnosed as having breast cancer at the University Medical Center of Eastern Carolina from 1985 through 1992. SETTING: The major health care facility for 2 rural counties in eastern North Carolina. SUBJECTS: Five hundred forty of 743 patients with newly diagnosed breast cancer and 414 control women from the community matched by age, race, and area of residence. MAIN OUTCOME MEASURES: Breast cancer stage at diagnosis. RESULTS: Of the 540 patients, 94 (17.4%) presented with TNM stage III or IV disease. The following demographic and socioeconomic factors were significant predictors of advanced stage: being African American (odds ratio [OR], 3.0; 95% confidence interval [CI], 1.9-4.7); having low income (OR, 3.7; 95% CI, 2.1-6.5); never having been married (OR, 2.9; 95% CI, 1.4-5.9); having no private health insurance (OR, 2.5; 95% CI, 1.6-4.0); delaying seeing a physician because of money (OR, 1.6; 95% CI, 1.1-2.5); or lacking transportation (OR, 2.0; 95% CI, 1.2-3.6). Univariate analysis also revealed a large number of cultural beliefs to be significant predictors. Examples include the following beliefs: air causes a cancer to spread (OR, 2.8; 95% CI, 1.8-4.3); the devil can cause a person to get cancer (OR, 2.1; 95% CI, 1.2-3.5); women who have breast surgery are no longer attractive to men (OR, 1.9; 95% CI, 1.1-3.5); and chiropractic is an effective treatment for breast cancer (OR, 2.4; 95% CI, 1.4-4.4). When the demographic and socioeconomic variables were included in a multivariate logistic regression model, the OR for late stage among African Americans decreased to 1.8 (95% CI, 1.1 -3.2) compared with 3.0 (95% CI, 1.9-4.7) for race alone. However, when the belief measures were included with the demographic and socioeconomic variables, the OR for late stage among African Americans decreased further to 1.2 (95% CI, 0.6-2.5). CONCLUSIONS: Socioeconomic factors alone were not sufficient to explain the dramatic effect of race on breast cancer stage; however, socioeconomic variables in conjunction with cultural beliefs and attitudes could largely account for the observed effect.

Adult↗
PubMed1998

Induction of plasminogen activator inhibitor type 1 and type 1 collagen expression in rat cardiac microvascular endothelial cells by interleukin-1 and its dependence on oxygen-centered free radicals.

BACKGROUND: Ischemia with or without reperfusion induces the release of diverse products from monocytes, including cytokines such as interleukin-1 (IL-1). To determine whether these phenomena modulate fibrinolysis and potentially exacerbate impairment of the macrocirculation, microcirculation, or both, we characterized the effects of IL-1 on the expression of fibrinolytic system and matrix proteins in rat cardiac microvascular endothelial cells (CMECs). METHODS AND RESULTS: Confluent CMECs were exposed to IL-1 in serum-free medium for 24 hours, and cell-conditioned medium was assayed for plasminogen activator inhibitor type 1 (PAI-1), the primary physiological inhibitor of plasminogen activators, and for type 1 collagen with Western blotting. IL-1 (2 ng/mL) specifically increased the accumulation of PAI-1 (4.4 +/- 0.6-fold; mean +/- SD; n = 9) without affecting tissue plasminogen activator (t-PA) or urokinase plasminogen activator (u-PA) levels, which remained unchanged. IL-1 increased the accumulation of collagen in conditioned media by 3.5 +/- 0.7-fold (n = 6). Conversely, the accumulation of both PAI-1 and collagen induced by IL-1 was inhibited with an IL-1 receptor antagonist (200 ng/mL; n = 6) and with cycloheximide (10 micrograms/mL; n = 6), implying that protein synthesis was a requirement for the effect. To determine whether the IL-1 effect was mediated by induction of oxygen-centered free radical production, known to be induced by IL-1, we exposed the cells to the hydroxyl radical scavenger tetramethylthiourea (10 mmol/L) and observed abolition of the IL-1-induced increase in the expression of PAI-1 and collagen (n = 6). Conversely, superoxides (generated with 10 mU/mL xanthine oxidase plus 0.6 mmol/L hypoxanthine, and 100 mumol/L hydrogen peroxide) induced the accumulation of PAI-1 and collagen (n = 6). IL-1 (1 microgram/kg body wt) and lipopolysaccharide (50 micrograms/kg body wt) administered in vivo increased PAI-1 protein in rat hearts as detected with Western blotting and PAI-1 immunostaining of rat heart microvessels, indicating the effects delineated in vitro were paralleled by effects in vivo. CONCLUSIONS: These results indicate that IL-1-induced oxygen-centered free radicals stimulate elaboration of PAI-1 and collagen by CMECs. Accordingly, microvascularly mediated inhibition of fibrinolysis may predispose to the persistence of microvascular thrombi, thereby contributing to impaired microcirculatory function, the no-reflow phenomenon, and cardiac dysfunction after ischemia and reperfusion.

Animals↗
PubMed1998

Histological studies of the dorsal nasal, angularis oculi, and facial veins of sheep (Ovis aries).

Selective brain cooling (SBC) requires vasoactivity in the superficial veins of the face of the animal. This vasoactivity is possible because of an adequate amount of smooth muscle in the tunica media of each of these superficial vessels, enabling it to act as a "muscle sphincter". In this study, the angularis oculi, dorsal nasal, distal, and proximal parts of the facial veins in sheep were examined histologically to describe an anatomical basis for SBC. Measurements of the tunica media thickness, the lumen diameter, and the ratio of these measurements showed that the relative tunica media thicknesses in the angularis oculi vein and the dorsal nasal vein are statistically smaller (P < 0.001) than in the distal or the proximal parts of the facial vein. In the angularis oculi, dorsal nasal, and distal part of the facial vein, the tunicae mediae were composed of five to seven circularly arranged smooth muscle layers, suggesting their ability to vasoconstrict. The proximal part of the facial vein possesses both circularly and longitudinally arranged smooth muscle layers. The circular smooth muscle layers suggest a vasoconstrictory function, whereas the longitudinal smooth muscle layers suggest a vasoconstrictory function in this part of the facial vein. Both the dorsal nasal and the proximal part of the facial vein, but not the angularis oculi or the distal part of the facial vein, possess endothelial valves near their confluences with other veins. It was concluded from this study that the angularis oculi and the distal part of the facial vein vasoconstrict, whereas the proximal part of the facial vein vasodilates, enabling the necessary changes in blood flow in SBC.

Animals↗
PubMed1998

Failure of clonidine to stimulate feeding in healthy humans.

The alpha2-adrenergic system is involved in the regulation of food intake in animals but its effects on feeding in humans are unknown. We hypothesized that clonidine administration would stimulate food intake in healthy human subjects. Ten men and 4 women, all physically and psychiatrically healthy, received clonidine 3 microg/kg or placebo, orally, in blinded, balanced, randomized order. Consumption of a liquid test meal was measured; also, serum growth hormone levels were used as a secondary measure of clonidine effects. Visual analog scale ratings of hunger, satiety, and sedation were obtained before, during, and after the test meal. A subset of five subjects also received 1.5 microg/kg clonidine, in addition to the two trials described above. Test meal consumption was greater following placebo than following clonidine. Sedation ratings were substantially higher at all time points after clonidine and correlated with meal consumption (correlation coefficient r = -0.584; p = 0.028). Hunger and satiety ratings did not differ. The 1.5 microg/kg dose did not provide different effects on feeding from that seen with placebo. Contrary to our hypothesis, clonidine did not stimulate food intake in humans. Sedation associated with clonidine administration may have suppressed any effects on feeding.

Administration, Oral↗
PubMed1998

Interactive effects of cocaine and gender on thymocytes: a study of in vivo repeated cocaine exposure.

This study used a mouse model including both sexes to assess the impact of repeat cocaine exposure on the differentiation and function of T cell in thymus. Cocaine hydrochloride in 0.9% saline, 5 mg or 40 mg/kg, was administrated by i.p. injection to C57BL/6 mice for 10 days. Thymocytes were obtained 24 h after the 10th injection. Repeat in vivo cocaine exposure inhibited the proliferation of T lymphocytes in response to Con-A and Con-A plus anti-CD28. The proliferation induced by IL-2 in the Con-A stimulated T blasts was attenuated in cocaine treated mice. These effects were seen at a lower cocaine dose in female mice. The total number of thymocytes was reduced. Although the percentage of mature thymocytes (CD4+ CD8- and CD4- CD8+ cells) was not altered, the absolute cell numbers were attenuated. Both percentage and absolute cell number of immature thymocytes (CD4+ CD8+) decreased and the pre-mature (CD4- CD8-) cells increased. CD28 and CD25 expression were attenuated in Con-A stimulated thymocytes of mice treated with cocaine at 40 mg/kg. Interleukin 2 production was not significantly altered, however, gamma-IFN production was decreased by cocaine exposure at 40 mg/kg. In conclusion, cocaine exerts inhibitory effects on the function of mature thymocytes, and on the differentiation of thymocytes. A gender difference in response to cocaine was noted in that female mice were more sensitive to lower dose of cocaine exposure.

Animals↗
PubMed1998

Molecular mechanisms that underlie structural and functional changes at the postsynaptic membrane during synaptic plasticity.

The synaptic plasticity that is addressed in this review follows neurodegeneration in the brain and thus has both structural as well as functional components. The model of neurodegeneration that has been selected is the kainic acid lesioned hippocampus. Degeneration of the CA3 pyramidal cells results in a loss of the Schaffer collateral afferents innervating the CA1 pyramidal cells. This is followed by a period of structural plasticity where new synapses are formed. These are associated with changes in the numbers and shapes of spines as well as changes in the morphometry of the dendrites. It is suggested that this synaptogenesis is responsible for an increase in the ratio of NMDA to AMPA receptors mediating excitatory synaptic transmission at these synapses. Changes in the temporal and spatial properties of these synapses resulted in an altered balance between LTP and LTD. These properties together with a reduction in the inhibitory drive increased the excitability of the surviving CA1 pyramidal cells which in turn triggered epileptiform bursting activity. In this review we discuss the insights that may be gained from studies of the underlying molecular machinery. Developments in one of the collections of the cogs in this machinery has been summarized through recent studies characterizing the roles of neural recognition molecules in synaptic plasticity in the adult nervous systems of vertebrates and invertebrates. Such investigations of neural cell adhesion molecules, cadherins and amyloid precursor protein have shown the involvement of these molecules on the morphogenetic level of synaptic changes, on the one hand, and signal transduction effects, on the other. Further complex cogs are found in the forms of the low-density lipoprotein receptor (LDL-R) family of genes and their ligands play pivotal roles in the brain development and in regulating the growth and remodelling of neurones. Evidence is discussed for their role in the maintenance of cognitive function as well as Alzheimer's. The molecular mechanisms responsible for the clustering and maintenance of transmitter receptors at postsynaptic sites are the final cogs in the machinery that we have reviewed. Postsynaptic densities (PSD) from excitatory synapses have yielded many cytoskeletal proteins including actin, spectrin, tubulin, microtubule-associated proteins and calcium/calmodulin-dependent protein kinase II. Isolated PSDs have also been shown to be enriched in AMPA, kainate and NMDA receptors. However, recently, a new family of proteins, the MAGUKs (for membrane-associated guanylate kinase) has emerged. The role of these proteins in clustering different NMDA receptor subunits is discussed. The MAGUK proteins are also thought to play a role in synaptic plasticity mediated by nitric oxide (NO). Both NMDA and non-NMDA receptors are highly clustered at excitatory postsynaptic sites in cortical and hippocampal neurones but have revealed differences in their choice of molecular components. Both GABAA and glycine (Gly) receptors mediate synaptic inhibition in the brain and spinal cord. Whilst little is known about how GABAA receptors are localized in the postsynaptic membrane, considerable progress has been made towards the elucidation of the molecular mechanisms underlying the formation of Gly receptors. It has been shown that the peripheral membrane protein gephyrin plays a pivotal role in the formation of Gly receptor clusters most likely by anchoring the receptor to the subsynaptic cytoskeleton. Evidence for the distribution as well as function of gephyrin and Gly receptors is discussed. Postsynaptic membrane specializations are complex molecular machinery subserving a multitude of functions in the proper communication between neurones. Despite the fact that only a few key players have been identified it will be a fascinating to watch the story as to how they contribute to structural and functional plasticity unfold.

Animals↗
PubMed1998

Peripheral blood manifestations of T(H)2 lymphocyte activation in stable atopic asthma and during exercise-induced bronchospasm.

BACKGROUND: Recently, TH2 lymphocyte activation has been shown to play a key role in initiating and propagating the inflammatory response in asthmatic airways. This is manifest through increased numbers of "activated" CD25-(IL-2R)-bearing T-helper cells and can be seen through the IL-5 driven recruitment of eosinophils and IL-4-mediated B-cell expression of CD23 (low affinity IgE receptor) and ultimately IgE production. OBJECTIVE: To gain a better understanding of the role of immune cells in asthma by describing the peripheral blood immune cell phenotypes in mild atopic asthma. METHODS: We enrolled 13 patients with mild atopic asthma and a group of seven nonatopic, nonasthmatic controls. Objective measures of lung function were obtained. The peripheral blood was analyzed by flow cytometry for specific cellular markers at rest and during the development of exercise induced bronchospasm. RESULTS: At rest the number of CD23-bearing B cells (169/mL versus 117/mL; P = .05) and the number of CD25-bearing T cells (355/mL versus 237/mL; P = .03) were increased in the asthma group. There was a linear relationship between these two lymphocyte subsets and the maximum voluntary ventilation at rest (r = 0.56, P = .01 and r = 0.57, P = .01). With the development of exercise-induced bronchospasm there was a significantly greater increase in CD23-positive B cells (96.7/mL versus 59.7/mL; P = .05) and CD25-positive T cells (111.8/mL versus 45.1; P = .01) in the asthma group. CONCLUSIONS: These data indicate that TH2 lymphocyte activation is manifested by increased numbers of CD23-bearing B cells and CD25-bearing T cells in the peripheral blood of patients with stable mild atopic asthma. Further, these immune cell subsets correlate with markers of resting lung function and increase in the peripheral blood early after the development of exercise-induced bronchospasm.

Adult↗
PubMed1998

HMI education for HIMs.

This paper analyses the curricula of the four Australian university programs for health information managers (HIMs) in relation to their coverage of health and medical informatics (HMI). The overlap between HIMs and HMIs should be increased through exchange of information at conferences such as this as well as communication and co-operation between the Schools of HIM and those offering health informatics related training at other Australian universities.

Administrative Personnel↗
PubMed1998

Haplotype mapping of a major quantitative-trait locus for fetal hemoglobin production, on chromosome 6q23.

Fetal hemoglobin (Hb F) and fetal cell (FC) levels in adults show considerable variation and are influenced by several genetic variants; the major determinants appear to be unlinked to the beta-globin gene cluster. Recently, a trans-acting locus controlling Hb F and FC production has been mapped to chromosome 6q23 in an Asian Indian kindred that includes individuals with heterocellular hereditary persistence of Hb F (HPFH) associated with beta thalassemia. We have extended the kindred by 57 members, bringing the total studied to 210, and have saturated the region with 26 additional markers. Linkage analysis showed tight linkage of the quantitative-trait locus (QTL) to the anonymous markers D6S976 (LOD score 11.3; recombination fraction .00) and D6S270 (LOD score 7.4; recombination fraction .00). Key recombination events now place this QTL within a 1-2-cM interval spanning approximately 1.5 Mb between D6S270 and D6S1626. Furthermore, haplotype analysis has led to a reevaluation of the genealogy and to the identification of additional relationships in the kindred.

Chromosome Mapping↗
PubMed1998

Discretion and service use among older adults: the behavioral model revisited.

Research applying the behavioral model to the use of services among older adults could be enriched by the classification of services along a discretionary dimension. Survey responses from 2,178 community-dwelling older adults were used to test the hypothesis that predisposing, enabling, and need characteristics are better predictors of discretionary than nondiscretionary service use. Logistic regression results predicting the use of a variety of community-based and medical services categorized as most discretionary, partially discretionary, and least discretionary generally support our hypothesis, underscoring the importance of need characteristics for least discretionary service use.

Aged↗
PubMed1998

Production of nitric oxide during surgery involving cardiopulmonary bypass.

OBJECTIVES: Surgery involving cardiopulmonary bypass induces an inflammatory response due to the contact of blood with the extracorporeal circuit. In some patients, this inflammatory response leads to multiple organ failure and death. Inflammatory states may increase the production of nitric oxide, either by increasing the activity of constitutive enzyme systems or by inducing of inflammation-specific systems. We hypothesized that surgery involving cardiopulmonary bypass would increase the production of nitric oxide in association with the inflammatory response. DESIGN: Prospective, single center, observational study. SETTING: University-affiliated, tertiary referral cardiothoracic center. PATIENTS: Eleven adult patients undergoing routine myocardial revascularization. INTERVENTIONS: Surgery for myocardial revascularization. MEASUREMENTS AND MAIN RESULTS: Observations were made after induction of anesthesia, before bypass, after completion of the bypass, and on return to the recovery area. Parameters measured included hemodynamics, exhaled nitric oxide concentrations, plasma nitrate/nitrite concentration, plasma and bronchoalveolar lavage myeloperoxidase concentrations, and protein carbonyl conversion. All patients survived surgery. Oxygenation index fell significantly after bypass. Plasma myeloperoxidase increased significantly during the study period. Plasma carbonyl conversion also increased, although not significantly. Plasma nitrate/nitrite and airway nitric oxide concentrations did not change through the course of the study. CONCLUSION: Surgery involving cardiopulmonary bypass induced a demonstrable inflammatory response, but this response was not associated with increased nitric oxide production.

Aged↗