The universal solution.
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Developing Countries↗
Biomedical subjects
J Lewis
Publications and source records attributed to J Lewis.
Disruption of hsp90 function results in degradation of the death domain kinase, receptor-interacting protein (RIP), and blockage of tumor necrosis factor-induced nuclear factor-kappaB activation.
The death domain kinase, receptor interacting protein (RIP), is one of the major components of the tumor necrosis factor receptor 1 (TNFR1) complex and plays an essential role in tumor necrosis factor (TNF)-mediated nuclear factor kappaB (NF-kappaB) activation. The activation of NF-kappaB protects cells against TNF-induced apoptosis. Heat-shock proteins (Hsps) are chaperone molecules that confer protein stability and help to restore protein native folding following heat shock and other stresses. The most abundant Hsp, Hsp90, is also involved in regulating the stability and function of a number of cell-signaling molecules. Here we report that RIP is a novel Hsp90-associated kinase and that disruption of Hsp90 function by its specific inhibitor, geldanamycin (GA), selectively causes RIP degradation and the subsequent inhibition of TNF-mediated IkappaB kinase and NF-kappaB activation. MG-132, a specific proteasome inhibitor, abrogated GA-induced degradation of RIP but failed to restore the activation of IkappaB kinase by TNF, perhaps because, in the presence of GA and MG-132, RIP accumulated in a detergent-insoluble subcellular fraction. Most importantly, the degradation of RIP sensitizes cells to TNF-induced apoptosis. These data indicate that Hsp90 plays an important role in TNF-mediated NF-kappaB activation by modulating the stability and solubility of RIP. Thus, inhibition of NF-kappaB activation by GA may be a critical component of the anti-tumor activity of this drug.
Apoptosis↗
Missense tau mutations identified in FTDP-17 have a small effect on tau-microtubule interactions.
Frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) is a group of related disorders frequently characterized by the formation of tau inclusions in neurons and glial cells. To determine whether the formation of tau inclusions in FTDP-17 results from an alteration in the ability of mutant tau to maintain the microtubule (MT) system, we compared wild type four-repeat tau with three FTDP-17 mutants (P301L, V337M and R406W) for their ability to bind MT, promote MT assembly and bundling. According to in vitro binding and assembly assays, P301L is the only mutant that demonstrates a small, yet significant reduction, in its affinity for MT while both P301L and R406W have a small reduction in their ability to promote tubulin assembly. Based on studies of neuroblastoma and CHO cells transfected with GFP-tagged tau DNA constructs, both mutant and wild type tau transfectants were indistinguishable in the distribution pattern of tau in terms of co-localization with MT and generation of MT bundles. These results suggest that missense mutation of tau gene do not have an immediate impact on the integrity of MT system, and that exposure of affected neurons to additional insults or factors (e.g., aging) may be needed to initiate the formation of tau inclusions in FTDP-17.
Animals↗
Patients with X-linked lymphoproliferative disease have a defect in 2B4 receptor-mediated NK cell cytotoxicity.
Patients with the X-linked lymphoproliferative disorder (XLPD) are unable to control Epstein-Barr virus (EBV)-induced infections and lymphoproliferation. This disease is caused by a deficit of SAP, an adapter protein involved in the signal transduction of several cell surface receptors of the CD2 superfamily. One of these receptors, called 2B4, is expressed on NK cells, cytotoxic T cells and myeloid cells and activates NK cell cytotoxicity. Here we show that XLPD patients have a defect of 2B4 receptor-mediated NK cell cytotoxicity. This defect may contribute to the pathogenesis of XLPD by reducing NK cell lysis of EBV-infected B cells.
Antigens, CD↗
Continuity of contact with psychiatric services: immigrant and Australian-born patients.
BACKGROUND: Under-representation of ethnic minority groups in psychiatric services has been widely reported in Western nations. The present study examined whether there were differences between immigrant and Australian-born patients in their maintenance of contact with a statewide psychiatric service system. METHODS: Groups were selected on the empirical grounds that they are differently represented in this service system. Employing a form of case-control design, four groups of patients were compared: those born in Australia, the United Kingdom, Southern Europe, and South East/East Asia respectively (n = 79 for each). Groups were identically matched on sex, age, diagnosis (either schizophrenia or bipolar illness) and locality of service. The groups did not differ as to the timing of their first appearance in the 3-year period in which their psychiatric contact was examined. RESULTS: Despite their different representation in the psychiatric service system, the four groups did not differ on measures of continuity of contact. Measures included number of contacts with mental health community services, number of admissions to inpatient wards, length of stay in hospital and the longest interval between any two successive service contacts. CONCLUSIONS: The commonly reported underrepresentation of immigrant groups in the psychiatric service system does not appear to be due to greater discontinuation of contact with services. If the assumption of equal community prevalence of disorder is made, then the observed under-representation may be due to differential rates of access to (that is, initial contact with) psychiatric services.
Analysis of Variance↗
The molecular genetics of the tauopathies.
The identification of mutations in the tau gene in frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) demonstrated that there is a direct link between tau dysfunction and neurodegeneration. At least 11 missense mutations and a three base pair deletion (DeltaK280) have been identified in exons 9-13. Additionally, five splice site mutations have been found in intron 10. The different FTDP-17 mutations have multiple effects on the biology and function of tau. These varied pathogenic mechanisms likely explain the wide range of clinical and neuropathological features observed in different families with FTDP-17. In addition to the tau mutations, a common extended haplotype in the tau gene also appears to be a risk factor in the development of the apparently sporadic tauopathies progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). The mechanism by which this common variability in the tau gene influences the development of these neurodegenerative diseases is unclear; however, it further suggests a central role for tau in the pathogenesis of several neurodegenerative conditions including Alzheimer's disease (AD).
Alzheimer Disease↗
Sequence and embryonic expression of deltaC in the zebrafish.
Four genes - deltaA, deltaB, deltaC and deltaD - coding for homologues of the Notch ligand Delta have been discovered in zebrafish (Haddon et al., 1998b). We report here the cDNA sequence and expression pattern of deltaC. Its closest relatives are deltaB and Xenopus X-Delta-2. Unlike deltaA, deltaB, and deltaD, deltaC is not expressed in the majority of nascent primary neurons; but it is strongly expressed in the early retina, where it precedes other delta genes. It is also expressed in cranial ganglia, in sensory epithelia including ear and lateral line, and in scattered epidermal cells. In the mesoderm, expression is visible by 50% epiboly; it is seen subsequently in the tail bud, in stripes in the presomitic mesoderm and in the posterior half of each somite. There is expression also in notochord, blood vessels and pronephros.
Animals↗
Lack of effect of dietary chromium supplementation on glucose tolerance, plasma insulin and lipoprotein levels in patients with type 2 diabetes.
Chromium is essential for the regulation of insulin action, thereby influencing carbohydrate and lipid metabolism. An uncontrolled pilot study was designed to measure the habitual daily intake of chromium in a group of healthy individuals with type 2 diabetes and to monitor the effect of daily supplementation with high chromium yeast on glucose tolerance, plasma insulin and lipoproteins. Twelve free-living adults with type 2 diabetes underwent a glucose tolerance test (GTT) on recruitment, at 4 weeks (after a 7-d duplicate diet collection) and at 12 weeks (following 8 weeks daily supplementation with 100 micrograms of chromium). Urine samples were collected on the day before and the day of each GTT. Blood samples were taken at half hourly intervals for 3 hours during the GTT and the plasma glucose, cholesterol, triglyceride, HDL, LDL and insulin concentration measured. The chromium content of diets and urine samples was determined. Fasting glucose concentrations and glucose area under the curve profiles did not alter significantly post supplementation with the chromium rich yeast. No significant changes in insulin and lipoprotein concentrations were observed. The results of this study do not support the hypothesis that individuals with type 2 diabetes benefit from yeast-based chromium supplements (100 micrograms/day).
Aged↗
SIVcpz from a naturally infected Cameroonian chimpanzee: biological and genetic comparison with HIV-1 N.
Thus far, simian immunodeficiency virus from chimpanzees (SIVcpz) genomes have been characterized as Pan troglodytes troglodytes and show a strong relation with human immunodeficiency virus (HIV)-1 N in their env genes. We fully characterized another SIVcpz from P. t. troglodytes. This chimpanzee (Cam5) was, as was also the host of SIVcpz-cam3, wild born in Cameroon, a region where all three groups of HIV-1 (M, N and O) co-occur. In contrast to other SIVcpz, SIVcpz-cam5 was isolated immediately after the rescue of the animal. Our data demonstrate that SIVcpz-cam5, like SIVcpz-cam3, grows easily on human peripheral blood mononuclear cells (PBMCs) and uses CCR5 as a co-receptor similar to HIV-1 N YBF30. Phylogenetic analysis based on the entire env gene shows that SIVcpz-cam5 falls into the same unique subcluster as HIV-1 N YBF30, SIVcpz-cam3 and SIVcpz-US. A phylogenetic relationship was also found with the vif gene of HIV-1 N. This study provides proof that HIV-1 N related viruses circulate in wild P. t. troglodytes.
Amino Acid Sequence↗
Getting to the guts of enteroendocrine differentiation.
The endodermal epithelium of vertebrates generates many types of enteroendocrine cells, including the insulin- and glucagon-secreting cells of the islets of Langerhans. Two studies disclose that Notch signalling controls which cells differentiate as enteroendocrine cells-a finding with implications for therapeutic strategy.
Animals↗
Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein.
Neurofibrillary tangles (NFT) composed of the microtubule-associated protein tau are prominent in Alzheimer disease (AD), Pick disease, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Mutations in the gene (Mtapt) encoding tau protein cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), thereby proving that tau dysfunction can directly result in neurodegeneration. Expression of human tau containing the most common FTDP-17 mutation (P301L) results in motor and behavioural deficits in transgenic mice, with age- and gene-dose-dependent development of NFT. This phenotype occurred as early as 6.5 months in hemizygous and 4.5 months in homozygous animals. NFT and Pick-body-like neuronal lesions occurred in the amygdala, septal nuclei, pre-optic nuclei, hypothalamus, midbrain, pons, medulla, deep cerebellar nuclei and spinal cord, with tau-immunoreactive pre-tangles in the cortex, hippocampus and basal ganglia. Areas with the most NFT had reactive gliosis. Spinal cord had axonal spheroids, anterior horn cell loss and axonal degeneration in anterior spinal roots. We also saw peripheral neuropathy and skeletal muscle with neurogenic atrophy. Brain and spinal cord contained insoluble tau that co-migrated with insoluble tau from AD and FTDP-17 brains. The phenotype of mice expressing P301L mutant tau mimics features of human tauopathies and provides a model for investigating the pathogenesis of diseases with NFT.
Amino Acid Substitution↗
Biologist Paul R. Ehrlich. Six billion and counting.
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Biology↗
Comparison of three intra-oral storage phosphor systems using subjective image quality.
OBJECTIVE: To compare the subjective image quality of three intra-oral storage phosphor systems. METHODS: DenOptix (Dentsply/Gendex, Chicago, IL, USA), Digora (Soredex, Helsinki, Finland), and CD-Dent (DigiDent Digital Imaging Technologies, Nesher, Israel) were compared. Two different imaging plates (IPs), BAS300 and HR300 (Fuji Photo Film Co., Tokyo, Japan) were used with the DenOptix system. The specimen was the maxilla and surrounding soft tissues of an adult cadaver. Imaging was at 70 kVp and 8 mA with a focus-detector distance of 38 cm using an optical bench. The exposure times were varied and a panel of five dentists independently evaluated the images produced with each system/IP receptor for seven features; proximal caries, gingival soft tissues, cortical bone, root canal space, root apices, periodontal ligament space and endodontic instrument clarity on a three-interval confidence scale. The best three exposures were chosen according to the highest scores for each system. These images were re-read in random order a total of 10 times. Pair-wise comparisons were made by use of odd's ratio analysis. A 95% confidence interval was applied. RESULTS: Images made with the DenOptix system/BAS IP combination were perceived to have the best overall image quality. The DenOptix/HR IP combination and Digora were rated almost equally in second place. The DigiDent system was ranked inferior. The Digora was considered to be the best for demonstrating gingival soft tissues (P < 0.05) and the DenOptix/HR300 combination the best for clarity of endodontic instruments (P < 0.05). CONCLUSIONS: While the DenOptix/BAS 300 combination was rated highest overall, the ranking of image quality by modality was found to be task-dependent. Digora was rated best for demonstrating gingival soft tissues.
Adult↗
Reproducibility of left ventricular measurements with acoustic quantification: the influence of training.
Acoustic quantification (AQ) of two-dimensional (2-D) echocardiograms provides online estimation of left ventricular (LV) size and function. However, edge detection with AQ is influenced by gain settings and is therefore operator dependent. Our purpose was to compare AQ and conventional 2-D echo measurements of LV size and function obtained by different operators and to evaluate the influence of training on these measurements. A cardiac sonographer without previous experience with the AQ system was trained by an experienced operator. Twenty-two normal males (age, 28 +/- 4 years) participated in the study. Images were recorded with conventional 2-D and AQ echo from the short-axis and apical four-chamber views. During the initial training period, five subjects were imaged by the sonographer under the supervision of the trainer. At the initial study session, 12 subjects were imaged independently by the two operators. Following a second training period with five different subjects, the same initial 12 subjects were again imaged at a second study session. LV cavity areas were traced from the conventional 2-D echocardiograms and measured from the AQ waveforms at end-diastole and end-systole. Volumes were calculated using the single-plane area-length method. Ejection fraction (EF) was calculated from volumes. Reproducibility was determined by comparing the variability of AQ and conventional 2-D echo measurements obtained at the two sessions. A second training session reduced the operator variability only of the short-axis end-diastolic area measurement (17 +/- 11% vs 6 +/- 5%, P < 0.025). We conclude that a single training session may be adequate for the reproducible estimation of ventricular volumes with the AQ method.
Adult↗
Atrial natriuretic factor in oliguric acute renal failure. Anaritide Acute Renal Failure Study Group.
Atrial natriuretic peptide (ANP), an endogenous hormone synthesized by the cardiac atria, has been shown to improve renal function in multiple animal models of acute renal failure. In a recent multicenter clinical trial of 504 patients with acute tubular necrosis (oliguric and nonoliguric), ANP decreased the need for dialysis only in the oliguric patients. In the present study, 222 patients with oliguric acute renal failure were enrolled into a multicenter, randomized, double-blind, placebo-controlled trial designed to assess prospectively the safety and efficacy of ANP compared with placebo. Subjects were randomized to treatment with a 24-hour infusion of ANP (anaritide, 0.2 microgram/kg/min; synthetic form of human ANP) or placebo. Dialysis and mortality status were followed up for 60 days. The primary efficacy end point was dialysis-free survival through day 21. Dialysis-free survival rates were 21% in the ANP group and 15% in the placebo group (P = 0.22). By day 14 of the study, 64% and 77% of the ANP and placebo groups had undergone dialysis, respectively (P = 0.054), and 9 additional patients (7 patients, ANP group; 2 patients, placebo group) needed dialysis but did not receive it. Although a trend was present, there was no statistically significant beneficial effect of ANP in dialysis-free survival or reduction in dialysis in these subjects with oliguric acute renal failure. Mortality rates through day 60 were 60% versus 56% in the ANP and placebo groups, respectively (P = 0.541). One hundred two of 108 (95%) versus 63 of 114 (55%) patients in the ANP and placebo groups had systolic blood pressures less than 90 mm Hg during the study-drug infusion (P < 0.001). The maximal absolute decrease in systolic blood pressure was significantly greater in the anaritide group than placebo group (33.6 versus 23.9 mm Hg; P < 0.001). This well-characterized population with oliguric acute renal failure had an overall high morbidity and mortality.
Adult↗
Morphology and Stomatal Function of Douglas Fir Needles Exposed to Climate Change: Elevated CO2 and Temperature.
Climate change may have an impact on the productivity of conifer trees by influencing the morphology (size and surface characteristics) and function (capacity for gas exchange) of conifer needles. In order to test the responses of needles to climatic variables, Douglas fir (Pseudotsuga menziesii [Mirb.] Franco), saplings were grown in sunlit controlled environment chambers at ambient or elevated (+200 parts per million above ambient) CO2 and at ambient or elevated temperature (+4 degrees C above ambient). Needle characteristics, including length, width, area, stomatal density (stomata per mm2), percentage of stomatal occlusion, and the morphology of epicuticular wax, were evaluated. Needle function was evaluated as stomatal conductance to water vapor and transpiration. Needle length increased significantly with elevated temperature but not with elevated CO2. Neither elevated CO2 nor elevated temperature affected stomatal density or stomatal number in these hypostomatous needles. Epicuticular wax was less finely granular at elevated than at ambient temperature and was similar in appearance at elevated and ambient CO2. Stomatal conductance and transpiration increased with elevated temperature and associated increased vapor pressure deficit; however, neither conductance nor transpiration was affected by elevated CO2. These results indicate that simulated climate change influences Douglas fir needle structure and function.
Journal Article↗
A National Institute for Occupational Safety and Health Alert sent to hospitals and the intentions of hospital decision makers to advocate for latex allergy control measures.
This study evaluated a National Institute for Occupational Safety and Health (NIOSH), Centers for Disease Control and Prevention, Alert concerning the risk and prevention of latex allergy among health care workers. It has been estimated that 8-12% of health care workers are sensitized to latex. NIOSH Alerts are publications that are intended to educate stakeholders about risks in the workplace; this Alert contained four recommendations for administrative control measures that hospital decision makers could adopt to reduce the risk of latex allergy to employees. The Alert was mailed to a random selection of Directors of Infection Control and Directors of Nursing in hospitals in the US. A random sample of these targeted recipients and a control group were surveyed by telephone (N = 298). Although nearly all of the respondents were concerned about latex allergy (96%), those reporting having seen the Alert were significantly more likely to report an intention to advocate for one or more of the control measures.
Decision Making, Organizational↗
The concept of social care and the analysis of contemporary welfare states.
Care is now a widely-used concept in welfare state research, firmly established in the literature by feminist analysis. We believe that the concept as it has been used and developed to date has limitations that have hampered its development as a general category of welfare state analysis. In essence we argue that the political economy aspects of the concept have remained underdeveloped. The main purpose of this article is to elaborate a care-centered concept--which we name social care--that countenances and develops care as an activity and set of relations lying at the intersection of state, market and family (and voluntary sector) relations. We are especially concerned to examine what the concept of social care can tell us about welfare state variation and welfare state change and development. The article works systematically through these themes, beginning with a brief historical sketch of the concept of care and then moving on to elaborate the analytic potential of the concept of social care. In the latter regard we make the case that it can lead to a more encompassing analysis, helping to overcome especially the fragmentation in existing scholarship between the cash and service dimensions of the welfare state and the relative neglect of the latter. The concept of social care serves to shift the centre of analysis from specific policy domains so that instead of focusing on cash benefits or services in isolation it becomes possible to consider them as part of a broader set of inter-relating elements. In this and other regards, the concept has the potential to say something new about welfare states.
Adult↗