tbuckley/cabot-search huggingface dataset:
Influence of endotracheal tube diameter on forced deflation flow-volume curves in rhesus monkeys
Authors: J Hammer, CJ Newth
Journal: European Respiratory Journal (1997)

The forced deflation (FD) technique is the recommended gold standard to generate forced expiratory vital capacity (FVC) curves and to measure maximum expiratory flow-volume (MEFV) relationships in intubated infants and children. However, the influence of the endotracheal tube (ETT) on the site of flow limitation, the shape and the analysis of the resultant MEFV curves have not been defined. Nine anaesthetized (thiopentone, 8 mg x kg(-1) x h(-1)) rhesus monkeys (mean weight (+/-SEM) 10+/-1 kg) were intubated consecutively with ETTs of different internal diameters (ID 3.0-5.5 mm, at intervals of 0.5 mm); the largest representing the appropriate ETT size for the animal. Quadruplicate MEFV curves were generated by FD using the standard +40 cmH2Oinsp/-40 cmH2Oexp pressures and recorded at each ETT diameter. The effect of the different ETT diameters on the FD flow-volume curve was analysed by comparing maximum expiratory flows at isovolume points at 50, 25 and 10% FVC (MEF50, MEF25 and MEF10, respectively). The shape of the resulting MEFV curves could be divided into an initial horizontal part (tube-dependent), and a final descending slope (airway-dependent). No difference in FVC occurred irrespective of the ETT size (p&gt;0.05 by analysis of variance (ANOVA)). MEF50 increased with increasing tube diameter (p&lt;0.05). MEF25 remained unchanged using ETTs which were less than 1.5 mm smaller than the largest ETT. Smaller ETTs resulted in significantly reduced MEF25 (p&lt;0.05). MEF10 was not influenced by the ETT size. We conclude that maximum expiratory flows measured by the forced deflation technique are not influenced by an appropriately sized endotracheal tube at lung volumes below 25% forced vital capacity in our monkey model with normal lungs. We postulate that the effect of endotracheal tubes on maximum expiratory flow volume curves in intubated infants might be of similar or even smaller magnitude, which remains to be established.
Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase
Authors: Michael A Simpson, Harold Cross, Christos Proukakis, David A Priestman, David C A Neville, Gabriele Reinkensmeier, Heng Wang, Max Wiznitzer, Kay Gurtz, Argyro Verganelaki, Anna Pryde, Michael A Patton, Raymond A Dwek, Terry D Butters, Frances M Platt, Andrew H Crosby
Journal: Nature Genetics (2004)
Novel Adenovirus-Based Vaccines Induce Broad and Sustained T Cell Responses to HCV in Man
Authors: Eleanor Barnes, Antonella Folgori, Stefania Capone, Leo Swadling, Stephen Aston, Ayako Kurioka, Joel Meyer, Rachel Huddart, Kira Smith, Rachel Townsend, Anthony Brown, Richard Antrobus, Virginia Ammendola, Mariarosaria Naddeo, Geraldine O’Hara, Chris Willberg, Abby Harrison, Fabiana Grazioli, Maria Luisa Esposito, Loredana Siani, Cinzia Traboni, Ye Oo, David Adams, Adrian Hill, Stefano Colloca, Alfredo Nicosia, Riccardo Cortese, Paul Klenerman
Journal: Science Translational Medicine (2012)

Currently, no vaccine exists for hepatitis C virus (HCV), a major pathogen thought to infect 170 million people globally. Many studies suggest that host T cell responses are critical for spontaneous resolution of disease, and preclinical studies have indicated a requirement for T cells in protection against challenge. We aimed to elicit HCV-specific T cells with the potential for protection using a recombinant adenoviral vector strategy in a phase 1 study of healthy human volunteers. Two adenoviral vectors expressing NS proteins from HCV genotype 1B were constructed based on rare serotypes [human adenovirus 6 (Ad6) and chimpanzee adenovirus 3 (ChAd3)]. Both vectors primed T cell responses against HCV proteins; these T cell responses targeted multiple proteins and were capable of recognizing heterologous strains (genotypes 1A and 3A). HCV-specific T cells consisted of both CD4+ and CD8+ T cell subsets; secreted interleukin-2, interferon-γ, and tumor necrosis factor-α; and could be sustained for at least a year after boosting with the heterologous adenoviral vector. Studies using major histocompatibility complex peptide tetramers revealed long-lived central and effector memory pools that retained polyfunctionality and proliferative capacity. These data indicate that an adenoviral vector strategy can induce sustained T cell responses of a magnitude and quality associated with protective immunity and open the way for studies of prophylactic and therapeutic vaccines for HCV.
Positive and Purifying Selection on the Drosophila Y Chromosome
Authors: Nadia D. Singh, Leonardo B. Koerich, Antonio Bernardo Carvalho, Andrew G. Clark
Journal: Molecular Biology and Evolution (2014)

Y chromosomes, with their reduced effective population size, lack of recombination, and male-limited transmission, present a unique collection of constraints for the operation of natural selection. Male-limited transmission may greatly increase the efficacy of selection for male-beneficial mutations, but the reduced effective size also inflates the role of random genetic drift. Together, these defining features of the Y chromosome are expected to influence rates and patterns of molecular evolution on the Y as compared with X-linked or autosomal loci. Here, we use sequence data from 11 genes in 9 Drosophila species to gain insight into the efficacy of natural selection on the Drosophila Y relative to the rest of the genome. Drosophila is an ideal system for assessing the consequences of Y-linkage for molecular evolution in part because the gene content of Drosophila Y chromosomes is highly dynamic, with orthologous genes being Y-linked in some species whereas autosomal in others. Our results confirm the expectation that the efficacy of natural selection at weakly selected sites is reduced on the Y chromosome. In contrast, purifying selection on the Y chromosome for strongly deleterious mutations does not appear to be compromised. Finally, we find evidence of recurrent positive selection for 4 of the 11 genes studied here. Our results thus highlight the variable nature of the mode and impact of natural selection on the Drosophila Y chromosome.
Ornithine Decarboxylase Polymorphism Modification of Response to Aspirin Treatment for Colorectal Adenoma Prevention
Authors: Elizabeth L. R. Barry, John A. Baron, Shubha Bhat, Maria V. Grau, Carol A. Burke, Robert S. Sandler, Dennis J. Ahnen, Robert W. Haile, Thomas G. O'Brien
Journal: JNCI Journal of the National Cancer Institute (2006)

Background: Previous research suggests that the G315A single-nucleotide polymorphism in the ornithine decarboxylase (ODC) gene may be a genetic marker for risk of colorectal neoplasia and may also modify the association of aspirin use with risk. Methods: We tested these hypotheses among participants in the Aspirin/Folate Polyp Prevention Study who were randomly assigned to placebo or to aspirin treatment (81 or 325 mg daily) and followed for 3 years for the occurrence of new adenomas. Genomic DNA from 973 subjects was analyzed for ODC genotype. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated to test the association between ODC genotype and adenoma occurrence and interactions with aspirin treatment. All statistical tests were two-sided. Results: Of the 973 subjects, 54% were homozygous wild-type (GG), 7% were homozygous variant (AA), and 39% were heterozygous individuals; the allele frequencies varied statistically significantly by race and ethnicity. Among these subjects, the absolute risk of any adenoma was 45% and the risk of an advanced lesion was 10%. Overall, no association was found between ODC genotype and the occurrence of new adenomas, but genotype did modify the effect of aspirin on adenoma risk. Although aspirin treatment had no protective effect among subjects with a GG genotype, among subjects with at least one A allele, it was associated with statistically significant reduced risks of any adenoma (RR = 0.77, 95% CI = 0.63 to 0.95; P = .02, Pinteraction = .04) and of advanced lesions (RR = 0.51, 95% CI = 0.29 to 0.90; P = .02, Pinteraction = .02). Among subjects with at least one A allele, 40.8% who took aspirin versus 52.9% who took placbo developed adenomas; 7.1% versus 14.0% developed advanced lesions. Conclusion: ODC genotype may modify the response to aspirin treatment for colorectal adenoma prevention.
Management of Venous Thromboembolism
Authors: Jeffrey Stephen Ginsberg
Journal: New England Journal of Medicine (1996)

Venous thromboembolism, which includes deep-vein thrombosis (usually involving leg veins) and pulmonary embolism, is a common cause of death. Treatment of affected patients reduces the incidence of fatal pulmonary embolism, but therapy should be based on the severity of disease and the potential for side effects. Decisions about the duration of therapy should be made by balancing the risks of continuing therapy against the risk of recurrence. In this review, the care of patients with venous thromboembolism will be discussed, with emphasis on recent advances.DiagnosisApproximately 75 percent of patients who present with suspected venous thrombosis or pulmonary embolism . . .
Pathology of the Pulmonary Vascular Tree
Authors: ROGER C. SMITH, HOWARD B. BURCHELL, JESSE E. EDWARDS
Journal: Circulation (1954)

Previous studies in this series demonstrated structural changes in the pulmonary vascular bed as the result of mitral valvular disease and other cardiac disorders. The present study demonstrates changes in the lungs as the result of chronic left ventricular failure; these changes were like those produced by mitral stenosis. The most pronounced disturbance was medial hypertrophy. The exact mechanism is not known, but it probably is related to increased pulmonary venous pressure.
Amelioration of ischemic brain damage by peritoneal dialysis
Authors: María del Carmen Godino, Victor G. Romera, José Antonio Sánchez-Tomero, Jesus Pacheco, Santiago Canals, Juan Lerma, José Vivancos, María Angeles Moro, Magdalena Torres, Ignacio Lizasoain, José Sánchez-Prieto
Journal: Journal of Clinical Investigation (2013)

Ischemic stroke is a devastating condition, for which there is still no effective therapy. Acute ischemic stroke is associated with high concentrations of glutamate in the blood and interstitial brain fluid. The inability of the tissue to retain glutamate within the cells of the brain ultimately provokes neuronal death. Increased concentrations of interstitial glutamate exert further excitotoxic effects on healthy tissue surrounding the infarct zone. We developed a strategy based on peritoneal dialysis to reduce blood glutamate levels, thereby accelerating brain-to-blood glutamate clearance. In a rat model of stroke, this simple procedure reduced the transient increase in glutamate, consequently decreasing the size of the infarct area. Functional magnetic resonance imaging demonstrated that the rescued brain tissue remained functional. Moreover, in patients with kidney failure, peritoneal dialysis significantly decreased glutamate concentrations. Our results suggest that peritoneal dialysis may represent a simple and effective intervention for human stroke patients.
Assessment of liver microcirculation in human cirrhosis.
Authors: P M Huet, C A Goresky, J P Villeneuve, D Marleau, J O Lough
Journal: Journal of Clinical Investigation (1982)

Alterations in the liver microcirculation were characterized by use of the multiple-indicator dilution technique in 25 cirrhotic patients undergoing hemodynamic evaluation of portal hypertension. Hepatic vein outflow dilution curves were obtained after portal vein or hepatic artery injections of a vascular reference substance (labeled erythrocytes) and of diffusible substances (labeled albumin and sucrose). In 23 of these patients (19 with alcoholic cirrhosis and 4 with postnecrotic cirrhosis), unimodal erythrocytes and albumin curves were obtained; the immediately accessible albumin space ranged from normal values (that were substantially larger than the erythrocyte space) to low values (that were little larger than the erythrocyte space). In parallel with this, the hepatic extraction of indocyanine green decreased and was correlated with the albumin space (r = 0.821, P less than 0.001). The form of labeled sucrose curves showed progressive changes indicating limited diffusion into the interstitial space. In contrast, bimodal curves were found in two patients (with macronodular cirrhosis); a large proportion of all labels appeared simultaneously in the early part of the outflow curves. Model analysis of the unimodal data indicated that the spectrum of findings could best be explained by progressive development of a barrier to exchange by progressive capillarization of the microvascular bed, and the form of the bimodal data suggested that large vessel shunting was occurring. Both changes, in turn, will contribute to the reduced extraction of protein-bound materials in cirrhosis.
The “Big Dog” Effect: Variability Assessing the Causes of Error in Diagnoses of Patients With Lung Cancer
Authors: Stephen S. Raab, Frederick A. Meier, Richard J. Zarbo, D. Chris Jensen, Kim R. Geisinger, Christine N. Booth, Uma Krishnamurti, Chad H. Stone, Janine E. Janosky, Dana M. Grzybicki
Journal: Journal of Clinical Oncology (2006)

Purpose The frequency of diagnostic error in patients who have a lung mass and a pathology specimen is as high as 15%. This study examined the role of inter-pathologist agreement in identifying the cause of error in these patients. Methods Pathologists from six institutions reviewed the slides of 40 patients who had a pulmonary specimen false-negative diagnosis. The initial assessment of error cause arose from cytologic-histologic correlation slide review of discrepant diagnostic samples in patients who had both a bronchial brushing cytologic and surgical specimen. The cause of error was attributed either to clinical sampling (diagnostic material obtained in one but not the other sample) or interpretation (pathologist failed to identify the salient diagnostic features). The pairwise kappa (κ) statistic was used to calculate interobserver agreement between the review and original diagnoses and between the separate review diagnoses. Results The pairwise κ statistic ranged widely from −0.154 to 1.0, and the pairwise κ statistic of the slides from one institution was undetermined because that institutional pathologist never made the assessment that error was secondary to interpretation. Agreement for observers within the same institution was better than agreement between observers from different institutions. Conclusion Pathologists exhibit poor agreement in determining the cause of error for pulmonary specimens sent for cancer diagnosis. We developed a psychosocial hypothesis (the “Big Dog” Effect) that partially explains biases in error assessment. This lack of agreement precludes confident targeting of these errors for quality improvement interventions with prospects of success across a variety of institutions.
Local anesthetics as effectors of allosteric gating. Lidocaine effects on inactivation-deficient rat skeletal muscle Na channels.
Authors: J R Balser, H B Nuss, D W Orias, D C Johns, E Marban, G F Tomaselli, J H Lawrence
Journal: Journal of Clinical Investigation (1996)

Time- and voltage-dependent local anesthetic effects on sodium (Na) currents are generally interpreted using modulated receptor models that require formation of drug-associated nonconducting states with high affinity for the inactivated channel. The availability of inactivation-deficient Na channels has enabled us to test this traditional view of the drug-channel interaction. Rat skeletal muscle Na channels were mutated in the III-IV linker to disable fast inactivation (F1304Q: FQ). Lidocaine accelerated the decay of whole-cell FQ currents in Xenopus oocytes, reestablishing the wild-type phenotype; peak inward current at -20 mV was blocked with an IC50 of 513 microM, while plateau current was blocked with an IC50 of only 74 microM (P < 0.005 vs. peak). In single-channel experiments, mean open time was unaltered and unitary current was only reduced at higher drug concentrations, suggesting that open-channel block does not explain the effect of lidocaine on FQ plateau current. We considered a simple model in which lidocaine reduced the free energy for inactivation, causing altered coupling between activation and inactivation. This model readily simulated macroscopic Na current kinetics over a range of lidocaine concentrations. Traditional modulated receptor models which did not modify coupling between gating processes could not reproduce the effects of lidocaine with rate constants constrained by single-channel data. Our results support a reinterpretation of local anesthetic action whereby lidocaine functions as an allosteric effector to enhance Na channel inactivation.
Erasing Disability in Peripheral Artery Disease
Authors: Mary McGrae McDermott
Journal: JAMA (2015)

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Cotargeting survival signaling pathways in cancer
Authors: Steven Grant
Journal: Journal of Clinical Investigation (2008)

Mammalian target of rapamycin (mTOR) is a component of a signaling pathway (PTEN/PI3K/AKT) that is frequently dysregulated in cancer. However, its precise relationship to the MAPK cascade (Ras/Raf/MEK/ERK), another pathway often implicated in tumorigenesis, has not been well defined. Recent evidence from tissue specimens obtained from patients who have received mTOR inhibitors suggests that ERK may be activated in response to mTOR interruption. In this issue of the JCI, Waugh Kinkade et al. and Carracedo et al. examine the relationship between these pathways in prostate and breast cancer cell model systems (see the related articles beginning on pages 3051 and 3065, respectively). Their findings suggest a link between inhibition of mTOR and ERK activation, possibly reflecting interruption of a novel negative S6K1-dependent feedback loop. Significantly, both groups observed that simultaneous inhibition of MEK/ERK and mTOR resulted in substantially enhanced antitumor effects both in vitro and in vivo. Together, these findings suggest that concurrent interruption of complementary signaling pathways warrants further investigation in cancer therapy.
Myeloperoxidase-Generated Oxidants Modulate Left Ventricular Remodeling but Not Infarct Size After Myocardial Infarction
Authors: Nikolay Vasilyev, Timothy Williams, Marie-Luise Brennan, Samuel Unzek, Xiaorong Zhou, Jay W. Heinecke, Douglas R. Spitz, Eric J. Topol, Stanley L. Hazen, Marc S. Penn
Journal: Circulation (2005)

Background— Inflammation after myocardial infarction (MI) heralds worse left ventricular (LV) function and clinical outcomes. However, whether inflammation affects LV function by extending myonecrosis and/or altering LV remodeling remains unknown. We hypothesized that cytotoxic aldehydes generated during oxidative stress may adversely affect remodeling and infarct size. One theoretical source of reactive aldehydes is oxidation of common α-amino acids by myeloperoxidase (MPO) released by leukocytes. However, a role for MPO in formation of aldehydes in vivo and the functional consequences of MPO-generated oxidants in ischemia/reperfusion models of MI have not been established. Methods and Results— In studies with cell types found in vascular tissue, MPO-oxidation products of glycine (formaldehyde) and threonine (acrolein) were the most cytotoxic. Mass spectrometry studies of myocardial tissue from murine models of acute MI (both chronic left anterior descending coronary artery ligation and ischemia/reperfusion injury) confirmed that MPO serves as a major enzymatic source in the generation of these cytotoxic aldehydes. Interestingly, although MPO-null mice experienced 35.1% ( P &lt;0.001) less LV dilation and a 52.2% ( P &lt;0.0001) improvement in LV function compared with wild-type mice 24 days after ischemia/reperfusion injury, no difference in infarct size between wild-type and MPO-null mice was noted. Conclusions— The present data separate inflammatory effects on infarct size and LV remodeling and demonstrate that MPO-generated oxidants do not significantly affect tissue necrosis after MI but rather have a profound adverse effect on LV remodeling and function.
Acute mountain sickness is related to nocturnal hypoxemia but not to hypoventilation
Authors: P. Erba, S. Anastasi, O. Senn, M. Maggiorini, K.E. Bloch
Journal: European Respiratory Journal (2004)

The purpose of the study was to investigate determinants of acute mountain sickness after rapid ascent to high altitude. A total of 21 climbers were studied ascending from <1,200 m to Capanna Regina Margherita, a hut in the Alps at 4,559 m, within <24 h. During their overnight stay at 4,559 m, breathing patterns and ventilation were recorded by calibrated respiratory inductive plethysmography along with pulse oximetry. In the following morning, acute mountain sickness was assessed. Altogether, 11 mountaineers developed pronounced symptoms of acute mountain sickness (Lake Louise score > or =5) and 10 did not (controls). Compared to controls, subjects with acute mountain sickness had lower nocturnal oxygen saturation (mean+/-SD 59+/-13% versus 73+/-6%), higher minute ventilation (7.94+/-2.35 versus 6.06+/-1.34 L x min(-1)), and greater mean inspiratory flow, a measure of respiratory centre drive (0.29+/-0.09 versus 0.22+/-0.05 L x s(-1)). Periodic respiration was prevalent but not significantly different among the two groups (apnoea/hypopnea index 60.1+/-34.6 versus 47.1+/-42.6 events per h). The data suggest that pronounced nocturnal hypoxemia, which was not related to hypoventilation, may have promoted acute mountain sickness. Periodic breathing seems not to play a predominant role in the pathogenesis of acute mountain sickness.
Alcohol linked deaths three times higher than official figures, MPs hear
Authors: A. O'Dowd
Journal: BMJ (2009)

Deaths related to alcohol consumption in the United Kingdom are about three times higher than official figures indicate, MPs have been told.

The scale of the problem is underestimated, MPs on the parliamentary health select committee heard last week at the first evidence session of their inquiry into alcohol.

Ian Gilmore, president of the Royal College of Physicians, giving evidence, said that the problem was worse than the estimated 8700 deaths caused by alcohol consumption recorded by the Office for National Statistics (ONS).

“The figures we hear are almost certainly significant underestimates. The 8700 figure is an ONS figure where alcohol is named on the death certificate as the cause of …