tbuckley/cabot-search huggingface dataset:
Sorting Out Astrocyte Physiology from Pharmacology
Authors: Todd A. Fiacco, Cendra Agulhon, Ken D. McCarthy
Journal: The Annual Review of Pharmacology and Toxicology (2008)

A number of exciting findings have been made in astrocytes during the past 15 years that have led many researchers to redefine how the brain works. Astrocytes are now widely regarded as cells that propagate Ca(2+) over long distances in response to stimulation, and, similar to neurons, release transmitters (called gliotransmitters) in a Ca(2+)-dependent manner to modulate a host of important brain functions. Although these discoveries have been very exciting, it is essential to place them in the proper context of the approaches used to obtain them to determine their relevance to brain physiology. This review revisits the key observations made in astrocytes that greatly impact how they are thought to regulate brain function, including the existence of widespread propagating intercellular Ca(2+) waves, data suggesting that astrocytes signal to neurons through Ca(2+)-dependent release of glutamate, and evidence for the presence of vesicular machinery for the regulated exocytosis of gliotransmitters.
The Capacity to Vote of Persons With Alzheimer’s Disease
Authors: Paul S. Appelbaum, Richard J. Bonnie, Jason H. Karlawish
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: The right to vote can be abrogated when persons become incompetent to cast a ballot. This applies particularly to people with Alzheimer's disease, who at some point will lose capacity. A 2001 federal court decision offered the first clear criteria ("Doe voting capacity standard") for determining voting competence, focused on understanding the nature and effect of voting and on the ability to choose. This article explores how persons with Alzheimer's disease perform on these criteria. METHOD: The Doe standard was operationalized in a brief questionnaire, along with measures of appreciation and reasoning about voting choices. Performance was assessed in 33 patients attending an Alzheimer's disease clinic and was related to dementia severity and demographic characteristics. RESULTS: The interview questions were scored with high reliability. Performance on the Doe questions, along with appreciation and reasoning, correlated strongly with Mini-Mental State Examination (MMSE) scores. Patients with very mild to mild Alzheimer's disease generally retained adequate ability to vote, and most persons with severe Alzheimer's disease did not. Performance was highly variable among persons with moderate Alzheimer's disease. The desire to vote was a poor predictor of voting capacity. CONCLUSIONS: The capacity to vote, as embodied in the Doe voting capacity standard, can be measured simply and reliably. Structured assessment is particularly likely to be useful for people with moderate Alzheimer's disease, whose performance cannot be predicted from MMSE scores alone. This approach can ensure retention of voting rights by capable persons and exclusion of clearly impaired persons from the voting booth.
Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier
Authors: Cristina Martínez, Beatriz Lobo, Marc Pigrau, Laura Ramos, Ana Maria González-Castro, Carmen Alonso, Mar Guilarte, Meritxell Guilá, Ines de Torres, Fernando Azpiroz, Javier Santos, María Vicario
Journal: Gut (2012)

<h3>Objective</h3> Recently, the authors demonstrated altered gene expression in the jejunal mucosa of diarrhoea-predominant irritable bowel syndrome patients (IBS-D); specifically, the authors showed that genes related to mast cells and the intercellular apical junction complex (AJC) were expressed differently than in healthy subjects. The aim of the authors here was to determine whether these alterations are associated with structural abnormalities in AJC and their relationship with mast cell activation and IBS-D clinical manifestations. <h3>Design</h3> A clinical assessment and a jejunal biopsy were obtained in IBS-D patients (n=45) and healthy subjects (n=30). Mucosal mast cell number and activation were determined by quantifying CD117<sup>+</sup> cells/hpf and tryptase expression, respectively. Expression and distribution of AJC specific proteins were evaluated by western blot and confocal microscopy. AJC ultrastructure was assessed by transmission electron microscopy. <h3>Results</h3> Compared with healthy subjects, IBS-D patients exhibited: (a) increased mast cell counts and activation; (b) increased protein expression of claudin-2, reduced occludin phosphorylation and enhanced redistribution from the membrane to the cytoplasm; and (c) increased myosin kinase expression, reduced myosin phosphatase and, consequently, enhanced phosphorylation of myosin. These molecular alterations were associated with ultrastructural abnormalities at the AJC, specifically, perijunctional cytoskeleton condensation and enlarged apical intercellular distance. Moreover, AJC structural alterations positively correlated both with mast cell activation and clinical symptoms. <h3>Conclusion</h3> The jejunal mucosa of IBS-D patients displays disrupted apical junctional complex integrity associated with mast cell activation and clinical manifestations. These results provide evidence for the organic nature of IBS-D, a heretofore model disease of functional gastrointestinal disorders.
Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites
Authors: Thomas Sersté, Christian Melot, Claire Francoz, François Durand, Pierre-Emmanuel Rautou, Dominique Valla, Richard Moreau, Didier Lebrec
Journal: Hepatology (2010)

Abstract Beta-blockers may have a negative impact on survival in patients with cirrhosis and refractory ascites. The aim of this study was to evaluate the effect of the administration of beta-blockers on long-term survival in patients with cirrhosis and refractory ascites. We performed a single-center, observational, case-only, prospective study of patients with cirrhosis and refractory ascites who did or did not receive beta-blockers for the prevention of gastrointestinal bleeding; 151 patients were included. The mean Model for End-Stage Liver Disease score was 18.8 ± 4.1. All patients regularly underwent large-volume paracentesis and intravenous albumin administration. Seventy-seven patients (51%) were treated with propranolol (113 ± 46 mg/day). The median follow-up for the whole group was 8 months. The median survival time was 10 months [95% confidence interval (CI) = 8-12 months]. The probability of survival at 1 year was 41% (95% CI = 33%-49%). The clinical characteristics and laboratory values at enrolment were not significantly different between patients who were receiving propranolol and those who were not. The median survival time was 20.0 months (95% CI = 4.8-35.2 months) in patients not treated with propranolol and 5.0 months (95% CI = 3.5-6.5 months) in those treated with propranolol ( P = 0.0001). The 1-year probability of survival was significantly lower in patients who received propranolol [19% (95% CI = 9%-29%)] versus those who did not [64% (95% CI = 52%-76%), P &lt; 0.0001]. The independent variables of mortality were Child-Pugh class C, hyponatremia and renal failure as causes of refractory ascites, and beta-blocker therapy. Conclusion: The use of beta-blockers is associated with poor survival in patients with refractory ascites. These results suggest that beta-blockers should be contraindicated in these patients.
Oropharyngeal dysphagia is a risk factor for community-acquired pneumonia in the elderly
Authors: Jordi Almirall, Laia Rofes, Mateu Serra-Prat, Roser Icart, Elisabet Palomera, Viridiana Arreola, Pere Clavé
Journal: European Respiratory Journal (2012)

The aim of this study was to explore whether oropharyngeal dysphagia is a risk factor for community-acquired pneumonia (CAP) in the elderly and to assess the physiology of deglutition of patients with pneumonia. In the case-control study, 36 elderly patients (aged ≥ 70 years) hospitalised with pneumonia were matched by age and sex with two independently living controls. All subjects were given the volume-viscosity swallow test to identify signs of oropharyngeal dysphagia. In the pathophysiological study, all cases and 10 healthy elderly subjects were examined using videofluoroscopy. Prevalence of oropharyngeal dysphagia in the case-control study was 91.7% in cases and 40.3% in controls (p<0.001). Adjusting for functionality and comorbidities, dysphagia showed an independent effect on pneumonia (OR 11.9, 95% CI 3.03-46.9). Among cases in the pathophysiological study, 16.7% showed safe swallow, 30.6% high penetrations, 36.1% severe penetrations and 16.7% silent aspirations during videofluoroscopy, while in the healthy elderly subjects these percentages were 80%, 20%, 0% and 0%, respectively (p<0.001). A delay in closure of the laryngeal vestibule (0.414 ± 0.029 s versus 0.200 ± 0.059 s, p<0.01) was the main mechanism of impaired airway protection. In elderly subjects, oropharyngeal dysphagia is strongly associated with CAP, independently of functionality and comorbidities. Elderly patients with pneumonia presented a severe impairment of swallow and airway protection mechanisms. We recommend universal screening of dysphagia in older persons with pneumonia.
AP214, an analogue of α-melanocyte-stimulating hormone, ameliorates sepsis-induced acute kidney injury and mortality
Authors: K. Doi, X. Hu, P.S.T. Yuen, A. Leelahavanichkul, H. Yasuda, S.M. Kim, J. Schnermann, T.E.N. Jonassen, J. Frøkiær, S. Nielsen, R.A. Star
Journal: Kidney International (2008)
A Novel Mitochondrial Gene Order in the Crinoid Echinoderm Florometra serratissima
Authors: Andrea Scouras, Michael J. Smith
Journal: Molecular Biology and Evolution (2001)

The complete nucleotide sequence of the mitochondrial genome of the crinoid Florometra serratissima has been determined. It is a circular DNA molecule, 16,005 bp in length, containing the genes for 13 proteins, small and large ribosomal RNAs, and 22 transfer RNAs (tRNAs). Three regions of unassigned sequence (UAS) greater than 73 bp have been located. The largest, UAS I, is 432 bp long and exhibits sequence similarity to the putative mitochondrial control regions seen in other animals. UAS II (77 bp) and UAS III (73 bp) are located between the 5′ ends of coding sequences and may play roles as bidirectional promoters. Analyses of nucleotide composition revealed that the major peptide-encoding strand is high in T and low in C. This bias is reflected in a specific pattern of codon usage. Molecular phylogenetic analyses based on cytochrome c oxidase (COI, COII, and COIII) amino acid and nucleotide sequences did not resolve all the relationships between echinoderm classes. The overall animal mitochondrial gene content has been maintained in the crinoid, but there is extensive rearrangement with respect to both the echinoid and the asteroid mtDNA gene maps. Florometra serratissima has a novel genome organization in a segment containing most of the tRNA genes, large and small rRNA genes, and the NADH dehydrogenase subunit 1 and 2 genes. Potential pathways and mechanisms for gene rearrangements between mitochondrial gene maps of echinoderm classes and vertebrates are discussed as indicators of early deuterostome phylogeny.
Phase 1 Trial of High-Dose Exogenous Testosterone in Patients with Castration-Resistant Metastatic Prostate Cancer
Authors: Michael J. Morris, Daisy Huang, William K. Kelly, Susan F. Slovin, Ryan D. Stephenson, Caitlin Eicher, Anthony Delacruz, Tracy Curley, Lawrence H. Schwartz, Howard I. Scher
Journal: European Urology (2009)
An Experimentally Tested Scenario for the Structural Evolution of Eukaryotic Cys2His2 Zinc Fingers from Eubacterial Ros Homologs
Authors: Fortuna Netti, Gaetano Malgieri, Sabrina Esposito, Maddalena Palmieri, Ilaria Baglivo, Carla Isernia, James G. Omichinski, Paolo V. Pedone, Nicolas Lartillot, Roberto Fattorusso
Journal: Molecular Biology and Evolution (2013)

The exact evolutionary origin of the zinc finger (ZF) domain is unknown, as it is still not clear from which organisms it was first derived. However, the unique features of the ZF domains have made it very easy for evolution to tinker with them in a number of different manners, including their combination, variation of their number by unequal crossing-over or tandem duplication and tuning of their affinity for specific DNA sequence motifs through point substitutions. Classical Cys2His2 ZF domains as structurally autonomous motifs arranged in multiple copies are known only in eukaryotes. Nonetheless, a single prokaryotic Cys2His2 ZF domain has been identified in the transcriptional regulator Ros from Agrobacterium tumefaciens and recently characterized. The present work focuses on the evolution of the classical ZF domains with the goal of trying to determine whether eukaryotic ZFs have evolved from the prokaryotic Ros-like proteins. Our results, based on computational and experimental data, indicate that a single insertion of three amino acids in the short loop that separates the β-sheet from the α-helix of the Ros protein is sufficient to induce a structural transition from a Ros like to an eukaryotic-ZF like structure. This observation provides evidence for a structurally plausible and parsimonious scenario of fold evolution, giving a structural basis to the hypothesis of a horizontal gene transfer (HGT) from bacteria to eukaryotes.
Inflammasomes Coordinate Pyroptosis and Natural Killer Cell Cytotoxicity to Clear Infection by a Ubiquitous Environmental Bacterium
Authors: Vivien I. Maltez, Alan L. Tubbs, Kevin D. Cook, Youssef Aachoui, E. Liana Falcone, Steven M. Holland, Jason K. Whitmire, Edward A. Miao
Journal: Immunity (2015)
Pulmonary sequelae in survivors of congenital diaphragmatic hernia.
Authors: A R Falconer, R A Brown, P Helms, I Gordon, J A Baron
Journal: Thorax (1990)

Nineteen survivors of congenital diaphragmatic hernia repair were compared with age and sex matched control children six to 11 years after repair. All subjects were examined clinically and underwent lung function testing. The patients also had individual lung volumes assessed radiographically and had radionuclide (krypton-81 m, technetium-99 m macroaggregates) ventilation-perfusion (V/Q) lung scans. Four patients had pectus excavatum and two had mild scoliosis. Spirometric measurements were lower in the patients than in the control subjects but only the differences in peak expiratory flow and flow at 50% of expired vital capacity were significant. The radiographic left lung volumes in patients surviving left diaphragmatic repair were larger than expected at 49.3% (SD 2%), suggesting alveolar overdistension. V/Q scans showed a mismatch in the ipsilateral lung, mean Q (40% (7%] being significantly lower than mean V (47% (6%)). In seven patients who had required ventilation for four days or more perfusion to the ipsilateral lung was significantly lower (34% (6%)) than values for the 12 patients ventilated for less than four days (43% (6%)). Survivors of right diaphragmatic repair had a better outcome in terms of relative radiographic lung volumes and V/Q distribution. More severely affected children are now surviving repair of congenital diaphragmatic herniation, with residual pulmonary abnormalities that could produce functional impairment in adult life.
Studies on the mechanism of destruction of the toxic action of wheat gluten in coeliac disease by crude papain
Authors: M. Messer, C. M. Anderson, L. Hubbard
Journal: Gut (1964)

The toxic action of wheat gluten on two patients was eliminated after predigestion of gluten by crude papain. This change is thought to be due to an enzyme which liberates ammonia from gluten. It is not thought that this particular mechanism operates in the normal intestinal cell but it is envisaged that one of the peptide bonds of the coeliac active constituent (possibly a N-glutaminyl peptide) is normally split by a specific intestinal peptidase which is defective in coeliac patients.
Hematopoietic stem cells, hematopoiesis and disease: lessons from the zebrafish model
Authors: Corey S Martin, Akemi Moriyama, Leonard I Zon
Journal: Genome Medicine (2011)

The zebrafish model is rapidly gaining prominence in the study of development, hematopoiesis, and disease. The zebrafish provides distinct advantages over other vertebrate models during early embryonic development by producing transparent, externally fertilized embryos. Embryonic zebrafish are easily visualized and manipulated through microinjection, chemical treatment, and mutagenesis. These procedures have contributed to large-scale chemical, suppressor, and genetic screens to identify hematopoietic gene mutations. Genomic conservation and local synteny between the human and zebrafish genomes make genome-scale and epigenetic analysis of these mutations (by microarray, chromatin immunoprecipitation sequencing, and RNA sequencing procedures) powerful methods for translational research and medical discovery. In addition, large-scale screening techniques have resulted in the identification of several small molecules capable of rescuing hematopoietic defects and inhibiting disease. Here, we discuss the contributions of the zebrafish model to the understanding of hematopoiesis, hematopoietic stem cell development, and disease-related discovery. We also highlight the recent discovery of small molecules with clinical promise, such as dimethyl prostaglandin E2, 3F8, and thiazole-carboxamide 10A.
Preservation of Myocardial Structure Is Enhanced by Pim-1 Engineering of Bone Marrow Cells
Authors: Pearl Quijada, Haruhiro Toko, Kimberlee M. Fischer, Brandi Bailey, Patrick Reilly, Kristin D. Hunt, Natalie A. Gude, Daniele Avitabile, Mark A. Sussman
Journal: Circulation Research (2012)

Bone marrow-derived cells to treat myocardial injury improve cardiac function and support beneficial cardiac remodeling. However, survival of stem cells is limited due to low proliferation of transferred cells.To demonstrate long-term potential of c-kit(+) bone marrow stem cells (BMCs) enhanced with Pim-1 kinase to promote positive cardiac remodeling.Lentiviral modification of c-kit(+) BMCs to express Pim-1 (BMCeP) increases proliferation and expression of prosurvival proteins relative to BMCs expressing green fluorescent protein (BMCe). Intramyocardial delivery of BMCeP at time of infarction supports improvements in anterior wall dimensions and prevents left ventricle dilation compared with hearts treated with vehicle alone. Reduction of the akinetic left ventricular wall was observed in BMCeP-treated hearts at 4 and 12 weeks after infarction. Early recovery of cardiac function in BMCeP-injected hearts facilitated modest improvements in hemodynamic function up to 12 weeks after infarction between cell-treated groups. Persistence of BMCeP is improved relative to BMCe within the infarct together with increased recruitment of endogenous c-kit(+) cells. Delivery of BMC populations promotes cellular hypertrophy in the border and infarcted regions coupled with an upregulation of hypertrophic genes. Thus, BMCeP treatment yields improved structural remodeling of infarcted myocardium compared with control BMCs.Genetic modification of BMCs with Pim-1 may serve as a therapeutic approach to promote recovery of myocardial structure. Future approaches may take advantage of salutary BMC actions in conjunction with other stem cell types to increase efficacy of cellular therapy and improve myocardial performance in the injured myocardium.
Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial
Authors: Faramarz Ismail-Beigi, Timothy Craven, Mary Ann Banerji, Jan Basile, Jorge Calles, Robert M Cohen, Robert Cuddihy, William C Cushman, Saul Genuth, Richard H Grimm, Bruce P Hamilton, Byron Hoogwerf, Diane Karl, Lois Katz, Armand Krikorian, Patrick O'Connor, Rodica Pop-Busui, Ulrich Schubart, Debra Simmons, Harris Taylor, Abraham Thomas, Daniel Weiss, Irene Hramiak
Journal: The Lancet (2010)
Postnatal manipulation of Pax6 dosage reverses congenital tissue malformation defects
Authors: Cheryl Y. Gregory-Evans, Xia Wang, Kishor M. Wasan, Jinying Zhao, Andrew L. Metcalfe, Kevin Gregory-Evans
Journal: Journal of Clinical Investigation (2013)

Aniridia is a congenital and progressive panocular condition with poor visual prognosis that is associated with brain, olfactory, and pancreatic abnormalities. Development of aniridia is linked with nonsense mutations that result in paired box 6 (PAX6) haploinsufficiency. Here, we used a mouse model of aniridia to test the hypothesis that manipulation of Pax6 dosage through a mutation-independent nonsense mutation suppression strategy would limit progressive, postnatal damage in the eye. We focused on the nonsense suppression drugs 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid (ataluren) and gentamicin. Remarkably, we demonstrated that nonsense suppression not only inhibited disease progression but also stably reversed corneal, lens, and retinal malformation defects and restored electrical and behavioral responses of the retina. The most successful results were achieved through topical application of the drug formulation START (0.9% sodium chloride, 1% Tween 80, 1% powdered ataluren, 1% carboxymethylcellulose), which was designed to enhance particle dispersion and to increase suspension viscosity. These observations suggest that the eye retains marked developmental plasticity into the postnatal period and remains sensitive to molecular remodeling. Furthermore, these data indicate that other neurological developmental anomalies associated with dosage-sensitive genetic mutations may be reversible through nonsense suppression therapeutics.
Kisspeptin Signaling in the Brain
Authors: Amy E. Oakley, Donald K. Clifton, Robert A. Steiner
Journal: Endocrine Reviews (2009)

Abstract Kisspeptin (a product of the Kiss1 gene) and its receptor (GPR54 or Kiss1r) have emerged as key players in the regulation of reproduction. Mutations in humans or genetically targeted deletions in mice of either Kiss1 or Kiss1r cause profound hypogonadotropic hypogonadism. Neurons that express Kiss1/kisspeptin are found in discrete nuclei in the hypothalamus, as well as other brain regions in many vertebrates, and their distribution, regulation, and function varies widely across species. Kisspeptin neurons directly innervate and stimulate GnRH neurons, which are the final common pathway through which the brain regulates reproduction. Kisspeptin neurons are sexually differentiated with respect to cell number and transcriptional activity in certain brain nuclei, and some kisspeptin neurons express other cotransmitters, including dynorphin and neurokinin B (whose physiological significance is unknown). Kisspeptin neurons express the estrogen receptor and the androgen receptor, and these cells are direct targets for the action of gonadal steroids in both male and female animals. Kisspeptin signaling in the brain has been implicated in mediating the negative feedback action of sex steroids on gonadotropin secretion, generating the preovulatory GnRH/LH surge, triggering and guiding the tempo of sexual maturation at puberty, controlling seasonal reproduction, and restraining reproductive activity during lactation. Kisspeptin signaling may also serve diverse functions outside of the classical realm of reproductive neuroendocrinology, including the regulation of metastasis in certain cancers, vascular dynamics, placental physiology, and perhaps even higher-order brain function.