tbuckley/cabot-search huggingface dataset:
Peripheral Benzodiazepine Receptor Mapping in Rat Kidney. Effects of Angiotensin II-Induced Hypertension
Authors: Estelle Bribes, Pierre Casellas, Hubert Vidal, Danielle Dussossoy, Daniel Casellas
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Intrarenal distribution and function(s) of the peripheral benzodiazepine receptor (PBR) remain uncertain. The goals of this study were to (1) develop a specific anti-rat PBR antibody and (2) map intrarenal immunoreactive PBR (irPBR) in untreated rats and in rats that received chronic angiotensin II infusion (200 ng/kg per min, subcutaneously, 17 d). A polyclonal rabbit antibody was raised against the C-terminal end of rat PBR (aa 159 to 169). The antibody specifically recognized a single 18-kD protein in whole kidney extracts, and confocal microscopy showed exclusive mitochondrial localization of irPBR in cultured rat glial C6 cells. In control rats, irPBR was found along thick ascending limbs of Henle's loops, including the macula densa area, along distal tubules, and along collecting ducts. Vascular smooth-muscle cells were PBR-positive. General irPBR distribution was unaffected by angiotensin II treatment (systolic BP, 205 ± 9 mmHg). However, irPBR appeared in parietal glomerular epithelial cells, atrophic proximal tubules, and infiltrating mononuclear cells. In conclusion, the results suggest previously unsuspected roles of PBR in the control of glomerular dynamics and in proximal tubular injury/repair processes.
Testing for Associations between Loci and Environmental Gradients Using Latent Factor Mixed Models
Authors: Eric Frichot, Sean D. Schoville, Guillaume Bouchard, Olivier François
Journal: Molecular Biology and Evolution (2013)

Adaptation to local environments often occurs through natural selection acting on a large number of loci, each having a weak phenotypic effect. One way to detect these loci is to identify genetic polymorphisms that exhibit high correlation with environmental variables used as proxies for ecological pressures. Here, we propose new algorithms based on population genetics, ecological modeling, and statistical learning techniques to screen genomes for signatures of local adaptation. Implemented in the computer program "latent factor mixed model" (LFMM), these algorithms employ an approach in which population structure is introduced using unobserved variables. These fast and computationally efficient algorithms detect correlations between environmental and genetic variation while simultaneously inferring background levels of population structure. Comparing these new algorithms with related methods provides evidence that LFMM can efficiently estimate random effects due to population history and isolation-by-distance patterns when computing gene-environment correlations, and decrease the number of false-positive associations in genome scans. We then apply these models to plant and human genetic data, identifying several genes with functions related to development that exhibit strong correlations with climatic gradients.
Osteoarthritis revisited and revived.
Authors: C Hutton
Journal: Annals of the Rheumatic Diseases (1994)

The coronary artery calcium (CAC) score is a readily and widely available tool for the noninvasive diagnosis of atherosclerotic coronary artery disease (CAD). The aim of this study was to investigate the added value of the CAC score as an adjunct to gated SPECT for the assessment of CAD in an intermediate-risk population. <b>Methods:</b> Seventy-seven prospectively recruited patients with intermediate risk (as determined by the Framingham Heart Study 10-y CAD risk score) and referred for coronary angiography because of suspected CAD underwent stress <sup>99m</sup>Tc-tetrofosmin SPECT myocardial perfusion imaging (MPI) and CT CAC scoring within 2 wk before coronary angiography. The sensitivity and specificity of SPECT alone and of the combination of the 2 methods (SPECT plus CAC score) in demonstrating significant CAD (≥50% stenosis on coronary angiography) were compared. <b>Results:</b> Forty-two (55%) of the 77 patients had CAD on coronary angiography, and 35 (45%) had abnormal SPECT results. The CAC score was significantly higher in subjects with perfusion abnormalities than in those who had normal SPECT results (889 ± 836 [mean ± SD] vs. 286 ± 335; <i>P</i> &lt; 0.0001). Similarly, with rising CAC scores, a larger percentage of patients had CAD. Receiver-operating-characteristic analysis showed that a CAC score of greater than or equal to 709 was the optimal cutoff for detecting CAD missed by SPECT. SPECT alone had a sensitivity and a specificity for the detection of significant CAD of 76% and 91%, respectively. Combining SPECT with the CAC score (at a cutoff of 709) improved the sensitivity of SPECT (from 76% to 86%) for the detection of CAD, in association with a nonsignificant decrease in specificity (from 91% to 86%). <b>Conclusion:</b> The CAC score may offer incremental diagnostic information over SPECT data for identifying patients with significant CAD and negative MPI results.
Association between economic growth and early childhood undernutrition: evidence from 121 Demographic and Health Surveys from 36 low-income and middle-income countries
Authors: Sebastian Vollmer, Kenneth Harttgen, Malavika A Subramanyam, Jocelyn Finlay, Stephan Klasen, S V Subramanian
Journal: The Lancet Global Health (2014)

BackgroundEconomic growth is widely regarded as a necessary, and often sufficient, condition for the improvement of population health. We aimed to assess whether macroeconomic growth was associated with reductions in early childhood undernutrition in low-income and middle-income countries.MethodsWe analysed data from 121 Demographic and Health Surveys from 36 countries done between Jan 1, 1990, and Dec 31, 2011. The sample consisted of nationally representative cross-sectional surveys of children aged 0–35 months, and the outcome variables were stunting, underweight, and wasting. The main independent variable was per-head gross domestic product (GDP) in constant prices and adjusted for purchasing power parity. We used logistic regression models to estimate the association between changes in per-head GDP and changes in child undernutrition outcomes. Models were adjusted for country fixed effects, survey-year fixed effects, clustering, and demographic and socioeconomic covariates for the child, mother, and household.FindingsSample sizes were 462 854 for stunting, 485 152 for underweight, and 459 538 for wasting. Overall, 35·6% (95% CI 35·4–35·9) of young children were stunted (ranging from 8·7% [7·6–9·7] in Jordan to 51·1% [49·1–53·1] in Niger), 22·7% (22·5–22·9) were underweight (ranging from 1·8% [1·3–2·3] in Jordan to 41·7% [41·1–42·3] in India), and 12·8% (12·6–12·9) were wasted (ranging from 1·2% [0·6–1·8] in Peru to 28·8% [27·5–30·0] in Burkina Faso). At the country level, no association was seen between average changes in the prevalence of child undernutrition outcomes and average growth of per-head GDP. In models adjusted only for country and survey-year fixed effects, a 5% increase in per-head GDP was associated with an odds ratio (OR) of 0·993 (95% CI 0·989–0·995) for stunting, 0·986 (0·982–0·990) for underweight, and 0·984 (0·981–0·986) for wasting. ORs after adjustment for the full set of covariates were 0·996 (0·993–1·000) for stunting, 0·989 (0·985–0·992) for underweight, and 0·983 (0·979–0·986) for wasting. These findings were consistent across various subsamples and for alternative variable specifications. Notably, no association was seen between per-head GDP and undernutrition in young children from the poorest household wealth quintile. ORs for the poorest wealth quintile were 0·997 (0·990–1·004) for stunting, 0·999 (0·991–1·008) for underweight, and 0·991 (0·978–1·004) for wasting.InterpretationA quantitatively very small to null association was seen between increases in per-head GDP and reductions in early childhood undernutrition, emphasising the need for direct health investments to improve the nutritional status of children in low-income and middle-income countries.FundingNone.
Risk in primary care of colorectal cancer from new onset rectal bleeding: 10 year prospective study
Authors: Jennifer du Toit, William Hamilton, Kevin Barraclough
Journal: BMJ (2006)

<h3>Abstract</h3> <b>Objective</b> To measure the risk of colorectal cancer and adenoma with new onset rectal bleeding reported to primary care. <b>Design</b> Cohort study. <b>Setting</b> A rural general practice in the United Kingdom. <b>Participants</b> Patients aged 45 or more with new onset rectal bleeding, irrespective of other symptoms. <b>Main outcome measures</b> Percentage of participants in whom colorectal cancer or colonic adenoma was identified after investigation of the bowel. <b>Results</b> During a 10 year period, 265 patients reported new rectal bleeding. Of these, 15 (5.7%, 95% confidence interval 3.2% to 9.2%) had colorectal cancer, and 13 (4.9%, 2.6% to 8.4%) had colonic adenoma. Only two of the patients with cancer had had diarrhoea. <b>Conclusions</b> One in 10 patients aged 45 or more with new onset rectal bleeding had colonic neoplasia, so investigation of the bowel should be offered to all such patients, whether or not they have other symptoms.
DOKing TLR4 signals
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

Two adaptor proteins prevent cells from overreacting to bacterial lipopolysaccaride (LPS), report Shinohara et al. on page 333. Dok-1 and Dok-2 dampen intracellular signals from the LPS receptor, Toll-like receptor 4 (TLR4), which may help explain how cells mount a potent response to invading bacteria without also triggering destructive inflammatory responses.
EULAR recommendations for the management of primary small and medium vessel vasculitis
Authors: C Mukhtyar, L Guillevin, M C Cid, B Dasgupta, K de Groot, W Gross, T Hauser, B Hellmich, D Jayne, C G M Kallenberg, P A Merkel, H Raspe, C Salvarani, D G I Scott, C Stegeman, R Watts, K Westman, J Witter, H Yazici, R Luqmani
Journal: Annals of the Rheumatic Diseases (2008)

Objectives: To develop European League Against Rheumatism (EULAR) recommendations for the management of small and medium vessel vasculitis. Methods: An expert group (consisting of 10 rheumatologists, 3 nephrologists, 2 immunologists, 2 internists representing 8 European countries and the USA, a clinical epidemiologist and a representative from a drug regulatory agency) identified 10 topics for a systematic literature search using a modified Delphi technique. In accordance with standardised EULAR operating procedures, recommendations were derived for the management of small and medium vessel vasculitis. In the absence of evidence, recommendations were formulated on the basis of a consensus opinion. Results: In all, 15 recommendations were made for the management of small and medium vessel vasculitis. The strength of recommendations was restricted by low quality of evidence and by EULAR standardised operating procedures. Conclusions: On the basis of evidence and expert consensus, recommendations have been made for the evaluation, investigation, treatment and monitoring of patients with small and medium vessel vasculitis for use in everyday clinical practice.
Role of glycolytic products in damage to ischemic myocardium. Dissociation of adenosine triphosphate levels and recovery of function of reperfused ischemic hearts.
Authors: J R Neely, L W Grotyohann
Journal: Circulation Research (1984)

The mechanism of irreversible damage to ischemic myocardium was investigated in the perfused rat heart. The time of transition from reversible to irreversible damage to contractile function was accelerated by accumulation of glycolytic products and increases in extracellular calcium. Both of these effects were largely independent of adenine nucleotide levels in the tissue. With zero coronary flow and 1.25 mM calcium the decrease in ability of the heart to recover ventricular function with reperfusion after 30 minutes of ischemia was directly correlated with accumulation of glycolytic products (as estimated by tissue lactate) during ischemia. The extent of lactate accumulation during ischemia was varied by preperfusing the hearts for 0, 10, or 15 minutes under anoxic, high coronary flow conditions to deplete tissue glycogen prior to ischemia, and by adding lactate back to the perfusate of these hearts during the ischemic period. Recovery of ventricular function was inversely related to tissue lactate during ischemia and varied from 28 to 92%, even though there was little or no change in tissue levels of residual adenosine triphosphate. Increasing extracellular calcium accelerated the time of onset of irreversible damage with little or no change in residual adenosine triphosphate levels. At any given calcium concentration, the time-dependent declines in the ability of the heart to recover ventricular function was also largely independent of adenosine triphosphate levels. These studies suggest a major role of anaerobic glycolytic products (lactate, hydrogen ion, or NADH) in ischemic damage to the heart that is unrelated to loss of tissue adenine nucleotides. With zero or low flow ischemia, this effect may result in irreversible damage to the myocardium before adenine nucleotides are reduced to critically low levels.
Multiple SNP testing improves risk prediction of first venous thrombosis
Authors: Hugoline G. de Haan, Irene D. Bezemer, Carine J. M. Doggen, Saskia Le Cessie, Pieter H. Reitsma, Andre R. Arellano, Carmen H. Tong, James J. Devlin, Lance A. Bare, Frits R. Rosendaal, Carla Y. Vossen
Journal: Blood (2012)
SNAREing the Basis of Multicellularity: Consequences of Protein Family Expansion during Evolution
Authors: T. H. Kloepper, C. N. Kienle, D. Fasshauer
Journal: Molecular Biology and Evolution (2008)

Vesicle trafficking between intracellular compartments of eukaryotic cells is mediated by conserved protein machineries. In each trafficking step, fusion of the vesicle with the acceptor membrane is driven by a set of distinctive soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) proteins that assemble into tight 4-helix bundle complexes between the fusing membranes. During evolution, about 20 primordial SNARE types were modified independently in different eukaryotic lineages by episodes of duplication and diversification. Here we show that 2 major changes in the SNARE repertoire occurred in the evolution of animals, each reflecting a main overhaul of the endomembrane system. In addition, we found several lineage-specific losses of distinct SNAREs, particularly in nematodes and platyhelminthes. The first major transformation took place during the transition to multicellularity. The primary event that occurred during this transformation was an increase in the numbers of endosomal SNAREs, but the SNARE-related factor lethal giant larvae also emerged. Apparently, enhanced endosomal sorting capabilities were an advantage for early multicellular animals. The second major transformation during the rise of vertebrates resulted in a robust expansion of the secretory set of SNAREs, which may have helped develop a more versatile secretory apparatus.
Pulmonary hypertension in patients with combined pulmonary fibrosis and emphysema syndrome
Authors: V. Cottin, J. Le Pavec, G. Prévot, H. Mal, M. Humbert, G. Simonneau, J-F. Cordier
Journal: European Respiratory Journal (2009)

This study aims to describe the haemodynamic and survival characteristics of patients with pulmonary hypertension in the recently individualised syndrome of combined pulmonary fibrosis and emphysema. A retrospective multicentre study was conducted in 40 patients (38 males; age 68±9 yrs; 39 smokers) with combined pulmonary fibrosis and emphysema, and pulmonary hypertension at right heart catheterisation. Dyspnoea was functional class II in 15%, III in 55% and IV in 30%. 6-min walk distance was 244±126 m. Forced vital capacity was 86±18%, forced expiratory volume in 1 s 78±19%, and carbon monoxide diffusion transfer coefficient 28±16% of predicted. Room air arterial oxygen tension was 7.5±1.6 kPa (56±12 mmHg). Mean pulmonary artery pressure was 40±9 mmHg, cardiac index 2.5±0.7 L·min −1 ·m −2 and pulmonary vascular resistance 521±205 dyn·s·cm −5 . 1-yr survival was 60%. Higher pulmonary vascular resistance, higher heart rate, lower cardiac index and lower carbon monoxide diffusion transfer were associated with shorter survival. Patients with combined pulmonary fibrosis and emphysema syndrome and pulmonary hypertension confirmed by right heart catheterisation have a dismal prognosis despite moderately altered lung volumes and flows and moderately severe haemodynamic parameters.
Selective human enterovirus and rhinovirus inhibitors: An overview of capsid‐binding and protease‐inhibiting molecules
Authors: Shin‐Ru Shih, Shu‐Jen Chen, Gholam Hossein Hakimelahi, Hsing‐Jang Liu, Chen‐Tso Tseng, Kak‐Shan Shia
Journal: Medicinal Research Reviews (2004)

The absence of effective vaccines for most viral infections highlights an urgent necessity for the design and development of effective antiviral drugs. Due to the advancement in virology since the late 1980s, several key events in the viral life cycle have been well delineated and a number of molecular targets have been validated, culminating in the emergence of many new antiviral drugs in recent years. Inhibitors against enteroviruses and rhinoviruses, responsible for about half of the human common colds, are currently under active investigation. Agents targeted at either viral protein 1 (VP1), a relatively conserved capsid structure mediating viral adsorption/uncoating process, or 3C protease, which is highly conserved among different serotypes and essential for viral replication, are of great potential to become antipicornavirus drugs.
Molecular Imaging in the Development of Cancer Therapeutics
Authors: Johannes Czernin, Wolfgang A. Weber, Harvey R. Herschman
Journal: Annual Review of Medicine (2006)

Researchers have made great progress in defining genetic and molecular alterations that contribute to cancer. New therapeutic targets have been identified and targeted therapeutic agents have been developed, but our ability to evaluate potential drugs has not kept pace. Molecular imaging technologies that monitor biological processes and/or measure levels of targeted macromolecules can contribute significantly to preclinical and clinical drug evaluation. This article describes the drug discovery process, economic problems facing drug discovery and development, and successes and failures in this realm. We briefly describe the available molecular imaging tools, with emphasis on positron emission tomography. We discuss biological processes that are altered in tumors and can be measured by molecular imaging; examples include gene expression, signal transduction, tumor cell metabolism, proliferation, apoptosis, hypoxia, and angiogenesis. We conclude with a proposal to integrate molecular imaging into the drug development process.
Influence of 5- and 6-hydroxydopamine on adrenergic transmission and nerve terminal morphology in the canine pulmonary vascular bed.
Authors: P J Kadowitz, D S Knight, R G Hibbs, J P Ellison, P D Joiner, M J Brody, A L Hyman
Journal: Circulation Research (1976)

We studied the effects of 5- and 6-hydroxydopamine on adrenergic neurotransmission, fluorescence histochemistry, and nerve terminal ultrastructure in the canine pulmonary vascular bed. Fluorescence histochemistry on stretched preparations and sections of intrapulmonary artery and vein demonstrated that these vessels are well supplied with adrenergic nerves electron microscopy revealed adrenergic terminals in the adventitia and outer third of the media in the artery, but only in the adventitia in the vein. Adrenergic terminals in artery and vein contained many small and a few large dense-core vesicles. At least 20% of the terminals in the artery contained many small agranular vesicles and a few large opaque vesicles; this suggests that they were of the cholinergic type; Such terminals were not found in intrapulmonary veins. Under conditions of controlled blood flow, stimulation of the sympathetic nerves to the lung and intralobar injection of norepinephrine increased pressure in the perfused lobar artery and small intrapulmonary vein in a stimulus-related manner. The rise in pressure in the lobar artery and vein in response to nerve stimulation was blocked after administration of either 5- and 6-hydroxydopamine; Neither agent modified the response of the pulmonary vascular bed to norepinephrine; In contrast, the rise in pressure in the lobar artery and vein in response to both norepinephrine and to nerve stimulation was blocked by phenoxybenzamine, an alpha-receptor blocking agent. The attenuated neurogenic vasoconstrictor response in dogs treated with 5- and 6-hydroxydopamine was associated with a marked decrease in intensity of fluorescence of the abundant adrenergic innervation in both intrapulmonary artery and vein, and with the appearance of an osmiophilic material in dense-core vesicles of adrenergic terminals in artery and vein. We believe that these data suggest that 5- and 6-hydroxydopamine interfere with adrenergic transmission in intrapulmonary vessels by depleting norepinephrine from adrenergic terminals. Furthermore, we conclude from hemodynamic, histochemical, and ultrastructural studies that vasomotor tone in the pulmonary vascular bed can be regulated by the sympathetic nervous system.
COX-2 Inhibition Potentiates Antiangiogenic Cancer Therapy and Prevents Metastasis in Preclinical Models
Authors: Lihong Xu, Janine Stevens, Mary Beth Hilton, Steven Seaman, Thomas P. Conrads, Timothy D. Veenstra, Daniel Logsdon, Holly Morris, Deborah A. Swing, Nimit L. Patel, Joseph Kalen, Diana C. Haines, Enrique Zudaire, Brad St. Croix
Journal: Science Translational Medicine (2014)

Inhibition of cyclooxygenase-2 (COX-2) inhibits angiogenesis, suppresses tumor growth, and augments the effects of traditional angiogenesis inhibitors.
The arrhythmogenic actions of histamine on human atrial fibers.
Authors: R Levi, J R Malm, F O Bowman, M R Rosen
Journal: Circulation Research (1981)

We used standard microelectrode techniques to study the effects of histamine on right atrial tissues from patients undergoing corrective cardiac surgery. In the 10(-6) to 10(-4) M range, histamine increased maximum diastolic potential, action potential amplitude, and automaticity. In some preparations, histamine also induced delayed afterdepolarizations and triggered activity. The potency of histamine in increasing automaticity was about 10 times less than that of epinephrine. Propranolol (2 x 10(-7)M), which abolished the chronotropic effect of epinephrine, did not alter the effect of histamine. Conversely, the effect of histamine but not that of epinephrine was antagonized by cimetidine (3 x 10(-6) to 1 x 10(-5) M). This suggests that H2 receptors mediate the chronotropic effects of histamine on the human heart. The slow channel blocker verapamil (2 x 10(-8) to 2 x 10(-6) M) counteracted the effects of histamine on automaticity, delayed afterdepolarizations, and triggered activity, suggesting that in human atrium histamine may act by increasing slow inward (presumably Ca2+) current. If one considers these arrhythmogenic effects of histamine and the fact that human cardiac tissue contains large amounts of histamine, our experiments lend further support to the concept that histamine release can induce arrhythmias.
Incidence, predictors at admission, and impact of worsening renal function among patients hospitalized with heart failure
Authors: Daniel E. Forman, Javed Butler, Yongfei Wang, William T. Abraham, Christopher M. O'Connor, Stephen S. Gottlieb, Evan Loh, Barry M. Massie, Michael W. Rich, Lynne Warner Stevenson, James B. Young, Harlan M. Krumholz
Journal: Journal of the American College of Cardiology (2004)