tbuckley/cabot-search huggingface dataset:
Identification of SOX3 as an XX male sex reversal gene in mice and humans
Authors: Edwina Sutton, James Hughes, Stefan White, Ryohei Sekido, Jacqueline Tan, Valerie Arboleda, Nicholas Rogers, Kevin Knower, Lynn Rowley, Helen Eyre, Karine Rizzoti, Dale McAninch, Joao Goncalves, Jennie Slee, Erin Turbitt, Damien Bruno, Henrik Bengtsson, Vincent Harley, Eric Vilain, Andrew Sinclair, Robin Lovell-Badge, Paul Thomas
Journal: Journal of Clinical Investigation (2010)

Sex in mammals is genetically determined and is defined at the cellular level by sex chromosome complement (XY males and XX females). The Y chromosome-linked gene sex-determining region Y (SRY) is believed to be the master initiator of male sex determination in almost all eutherian and metatherian mammals, functioning to upregulate expression of its direct target gene Sry-related HMG box-containing gene 9 (SOX9). Data suggest that SRY evolved from SOX3, although there is no direct functional evidence to support this hypothesis. Indeed, loss-of-function mutations in SOX3 do not affect sex determination in mice or humans. To further investigate Sox3 function in vivo, we generated transgenic mice overexpressing Sox3. Here, we report that in one of these transgenic lines, Sox3 was ectopically expressed in the bipotential gonad and that this led to frequent complete XX male sex reversal. Further analysis indicated that Sox3 induced testis differentiation in this particular line of mice by upregulating expression of Sox9 via a similar mechanism to Sry. Importantly, we also identified genomic rearrangements within the SOX3 regulatory region in three patients with XX male sex reversal. Together, these data suggest that SOX3 and SRY are functionally interchangeable in sex determination and support the notion that SRY evolved from SOX3 via a regulatory mutation that led to its de novo expression in the early gonad.
Frequency and characteristics of prolonged viral shedding of influenza A/H1N1 virus in lung transplant recipients
Authors: Macé M. Schuurmans, Alice Zuercher, Gabrielo M. Tini, Gregory Fretz, Christian Benden, Erich W. Russi, Annette Boehler
Journal: European Respiratory Journal (2011)

Influenza infection may harm lung transplant recipients (LTR) because it potentially triggers allograft rejection. Prolonged viral shedding (PVS) is defined as positive detection of influenza A/H1N1 virus (H1N1) by real-time reverse-transcriptase polymerase chain reaction (RT-PCR) at day 7 or later after diagnosis. The aim was to quantify and characterise PVS of H1N1 infections among LTR in consecutive influenza seasons.   Methods:  Influenza vaccination is routinely offered at follow-up visits in our outpatient clinic. LTR are also instructed to contact and visit our clinic when signs of infection occur or home lung function deteriorates 10% or more. We then frequently perform nasopharyngeal swabs (NPS) for viral and bacterial analysis. In case of suggestive symptoms for influenza infection we start oseltamivir (Tamiflu) and moxifloxacin treatment pending NPS results. For proven H1N1 infection we continue treatment until weekly NPS return negative.   Results:  In winter 2009/2010 7 patients had H1N1 infection of which 2 had PVS (28%). No serious complication occurred. 2/7 LTR were vaccinated for H1N1. For 2010/2011 we have so far documented 11 H1N1 infections and PVS in 8 LTR (73%). All LTR were vaccinated with at least 1 dose containing H1N1. Three LTR were hospitalised. 5 LTR had PVS for 2-6 weeks. Quantification of viral results and drug resistance testing are being performed. Influenza B was detected in 4 other LTR.   Conclusion:  In this ongoing study we report an increase in frequency of PVS for H1N1 infections in LTR from 28 to 73% in consecutive influenza seasons. Most infections occurred despite vaccination and had a favourable outcome rarely requiring hospitalisation.
Vesicular Transport of Horseradish Peroxidase during Chronic Bile Duct Obstruction in the Rat
Authors: Richard H. Renston, Gyula Zsigmond, Robin A. Bernhoft, Susan J. Burwen, Albert L. Jones
Journal: Hepatology (1983)

The vesicular transport system for biliary secretion of plasma-derived proteins was investigated in rats with chronic bile duct obstruction. Horseradish peroxidase, previously demonstrated to be a suitable tracer for vesicular transport, was employed in these studies. Both the time course of horseradish peroxidase secretion into bile and the morphological events in its uptake, transport, and biliary secretion were found to proceed in a manner essentially identical to that of sham-operated control animals. In addition, fragmentation of hepatocytes leading to sloughing into bile of large pieces of cytoplasm bearing horseradish peroxidase-containing endocytic transport vesicles frequently was observed in the cholestatic animals. These data suggest that the vesicular transport system for the secretion into bile of plasma-derived proteins remains intact and functional during chronic bile duct obstruction and that another mechanism, possibly fragmentation and solubilization of hepatocyte membranes followed by regurgitation of proteins released from endocytic vesicles, may be responsible for the elevation of biliary proteins within plasma seen during cholestasis.
Localization of beta 1- and beta 2-adrenergic receptors in rat kidney by autoradiography.
Authors: D P Healy, P A Münzel, P A Insel
Journal: Circulation Research (1985)

beta-Adrenergic receptor subtypes were localized and differentiated in rat kidney slices by in vitro autoradiography using the nonselective beta-antagonist [125I]iodocyanopindolol in the presence of the selective agents betaxolol (beta 1) and zinterol (beta 2). [125I]Iodocyanopindolol binding to kidney sections in the presence of these agents could be differentiated into high- and low-affinity components as predicted by the subtype selectivity of the compounds. Autoradiography revealed that: beta-adrenergic receptors were highly concentrated within the renal cortex, especially in glomeruli and juxtaglomerular granule cells, and to tubular sites in the cortex and medulla; [125I]iodocyanopindolol labeling of the juxtaglomeruluar granule cells was abolished at lower concentrations (10(-8) M) of betaxolol than was the labeling of glomeruli (10(-6)--10(-4) M); and zinterol had little effect on labeling of juxtaglomerular granule cells and glomeruli unless high concentrations were used, whereas the tubular labeling in medulla was much more sensitive to incubation with zinterol. These results indicate that beta 1- and beta 2-adrenergic receptor subtypes are differentially distributed within the kidney: beta 1, predominantly contained in juxtaglomerular granule cells and glomeruli, and beta 2, predominantly in medullary tubules. In vitro autoradiography provides a useful means to examine different receptor populations in discrete tissue areas.
HEMORRHAGE DUE TO SELF-MEDICATION WITH BISHYDROXYCOUMARIN
Authors: Stuart W. Cosgriff
Journal: JAMA (1953)

Bishydroxycoumarin (Dicumarol) has been a useful agent in the therapy of thromboembolic disease, although, even when carefully controlled, there is an appreciable risk of hemorrhage (4 to 10%) associated with its administration and the subsequent therapeutic hypoprothrombinemia. Obviously, excessive dosage or an unusually sensitive prothrombin mechanism may further increase the risk of bleeding.  This report deals with a patient who was observed and studied and in whom profound hypoprothrombinemia and serious bleeding occurred on two occasions secondary to bishydroxycoumarin administration, apparently self-administered as a manifestation of malingering. The causative role of bishydroxycoumarin was documented by obtaining an elevated value for the plasma level of the drug one month after the last acknowledged dose of the drug.  REPORT OF CASE  A 36-year-old graduate nurse was admitted to Presbyterian Hospital on Dec. 5, 1950, with generalized bleeding of two days' duration. Her history included inactive rheumatoid arthritis; inactive rheumatic heart disease, with mitral
A Parabrachial-Hypothalamic Cholecystokinin Neurocircuit Controls Counterregulatory Responses to Hypoglycemia
Authors: Alastair S. Garfield, Bhavik P. Shah, Joseph C. Madara, Luke K. Burke, Christa M. Patterson, Jonathan Flak, Rachael L. Neve, Mark L. Evans, Bradford B. Lowell, Martin G. Myers, Lora K. Heisler
Journal: Cell Metabolism (2014)

Hypoglycemia engenders an autonomically mediated counterregulatory (CR)-response that stimulates endogenous glucose production to maintain concentrations within an appropriate physiological range. Although the involvement of the brain in preserving normoglycemia has been established, the neurocircuitry underlying centrally mediated CR-responses remains unclear. Here we demonstrate that lateral parabrachial nucleus cholecystokinin (CCKLPBN) neurons are a population of glucose-sensing cells (glucose inhibited) with counterregulatory capacity. Furthermore, we reveal that steroidogenic-factor 1 (SF1)-expressing neurons of the ventromedial nucleus of the hypothalamus (SF1VMH) are the specific target of CCKLPBN glucoregulatory neurons. This discrete CCKLPBN→SF1VMH neurocircuit is both necessary and sufficient for the induction of CR-responses. Together, these data identify CCKLPBN neurons, and specifically CCK neuropeptide, as glucoregulatory and provide significant insight into the homeostatic mechanisms controlling CR-responses to hypoglycemia.
PT-09 * TARGETED THERAPY IN GLIOBLASTOMA MULTIFORME PRESENTING AS GLIOMATOSIS CEREBRI
Authors: O. M. Maher, M. F. McAleer, D. I. Sandberg, L. Ketonen, S. Khatua, W. Z. MD
Journal: Neuro-Oncology (2014)

BACKGROUND: Glioblastoma multiforme (GBM) presenting as gliomatosis cerebri (GC) is a rare aggressive neoplasm of the central nervous system (CNS) with a median survival of less than one year. To-date no well-defined therapeutic strategy exists for these tumors. We report our experience of the likely benefit of using an individualized personalized therapeutic (IPT) approach to profile a new combinatorial treatment regimen in a child with GBM/GC of the CNS. CASE REPORT: An 8-year-old male with a Lansky score of 50 presented with headache, dysarthria and ataxia. MRI of the CNS showed tumor involvement of the thalamus, cerebellum, brain stem and spinal cord. Pathology of the biopsy performed was consistent with GBM. Diffuse positivity of the tumor for epidermal growth factor receptor (EGFR) was noted by immunohistochemistry. He received radiation therapy along with temozolomide followed by adjuvant therapy with temozolomide, irinotecan, and bevacizumab every 28 days. After 2 cycles, he demonstrated disease progression. Based on the diffuse EGFR expression profile of his tumor, Erlotinib (EGFR tyrosine-kinase inhibitor) was started orally daily. Marked response was noted clinically and by neuroimaging. However, following six cycles, MRI of the brain demonstrated a new lesion in the frontal lobe. Temsirolimus (m-TOR inhibitor) was added to Erlotinib. Currently he continues to tolerate this regimen, remains well with a Lansky scale of 80, 16 months post-diagnosis. DISCUSSION: EGFR-AKT-mTOR pathway is known to be up-regulated in GBM justifying targeting multiple oncogenic drivers and report the likely benefit of using erlonitib with temsirolimus. Prospective studies are warranted to standardize an IPT approach for such rare pediatric CNS tumors. Future studies will explore the potential benefit of this regimen targeting key molecules of this signaling pathway driving GBM tumorogenesis and evaluate its therapeutic efficacy in improving overall survival in comparison to historical controls.
Mutations in a Novel, Cryptic Exon of the Luteinizing Hormone/Chorionic Gonadotropin Receptor Gene Cause Male Pseudohermaphroditism
Authors: Nina Kossack, Manuela Simoni, Annette Richter-Unruh, Axel P. N Themmen, Jörg Gromoll
Journal: PLoS Medicine (2008)

Background Male pseudohermaphroditism, or Leydig cell hypoplasia (LCH), is an autosomal recessive disorder in individuals with a 46,XY karyotype, characterized by a predominantly female phenotype, a blind-ending vagina, absence of breast development, primary amenorrhea, and the presence of testicular structures. It is caused by mutations in the luteinizing hormone/chorionic gonadotropin receptor gene (LHCGR), which impair either LH/CG binding or signal transduction. However, molecular analysis has revealed that the LHCGR is apparently normal in about 50% of patients with the full clinical phenotype of LCH. We therefore searched the LHCGR for novel genomic elements causative for LCH. Methods and Findings In the present study we have identified a novel, primate-specific bona fide exon (exon 6A) within the LHCGR gene. It displays composite characteristics of an internal/terminal exon and possesses stop codons triggering nonsense-mediated mRNA decay (NMD) in LHCGR. Transcripts including exon 6A are physiologically highly expressed in human testes and granulosa cells, and result in an intracellular, truncated LHCGR protein of 209 amino acids. We sequenced exon 6A in 16 patients with unexplained LCH and detected mutations in three patients. Functional studies revealed a dramatic increase in the expression of the mutated internal exon 6A transcripts, indicating aberrant NMD. These altered ratios of LHCGR transcripts result in the generation of predominantly nonfunctional LHCGR isoforms, thereby preventing proper expression and functioning. Conclusions The identification and characterization of this novel exon not only identifies a new regulatory element within the genomic organization of LHCGR, but also points toward a complex network of receptor regulation, including events at the transcriptional level. These findings add to the molecular diagnostic tools for LCH and extend our understanding of the endocrine regulation of sexual differentiation.
The early prediction of mortality in acute pancreatitis: a large population-based study
Authors: B U Wu, R S Johannes, X Sun, Y Tabak, D L Conwell, P A Banks
Journal: Gut (2008)

Identification of patients at risk for mortality early in the course of acute pancreatitis (AP) is an important step in improving outcome.Using Classification and Regression Tree (CART) analysis, a clinical scoring system was developed for prediction of in-hospital mortality in AP. The scoring system was derived on data collected from 17,992 cases of AP from 212 hospitals in 2000-2001. The new scoring system was validated on data collected from 18,256 AP cases from 177 hospitals in 2004-2005. The accuracy of the scoring system for prediction of mortality was measured by the area under the receiver operating characteristic curve (AUC). The performance of the new scoring system was further validated by comparing its predictive accuracy with that of Acute Physiology and Chronic Health Examination (APACHE) II.CART analysis identified five variables for prediction of in-hospital mortality. One point is assigned for the presence of each of the following during the first 24 h: blood urea nitrogen (BUN) >25 mg/dl; impaired mental status; systemic inflammatory response syndrome (SIRS); age >60 years; or the presence of a pleural effusion (BISAP). Mortality ranged from >20% in the highest risk group to <1% in the lowest risk group. In the validation cohort, the BISAP AUC was 0.82 (95% CI 0.79 to 0.84) versus APACHE II AUC of 0.83 (95% CI 0.80 to 0.85).A new mortality-based prognostic scoring system for use in AP has been derived and validated. The BISAP is a simple and accurate method for the early identification of patients at increased risk for in-hospital mortality.
254 THE ASSOCIATION OF INTESTINAL INOS EXPRESSION AND OXIDATIVE STRESS IN EXPERIMENTAL CIRRHOSIS
Authors: M.R. Mas, B. Savas, R. Ocal, A. Ensari, B. Comert, S. Yilmaz, A.T. Isik, N. Mas, O. Uzunalimoglu
Journal: Journal of Hepatology (2008)
Critical roles of junctophilin-2 in T-tubule and excitation–contraction coupling maturation during postnatal development
Authors: Biyi Chen, Ang Guo, Caimei Zhang, Rong Chen, Yanqi Zhu, Jiang Hong, William Kutschke, Kathy Zimmerman, Robert M. Weiss, Leonid Zingman, Mark E. Anderson, Xander H.T. Wehrens, Long-Sheng Song
Journal: Cardiovascular Research (2013)

Emerging evidence indicates a critical role for junctophilin-2 (JP2) in T-tubule integrity and assembly of cardiac dyads in adult ventricular myocytes. In the postnatal stage, one of the critical features of myocyte maturation is development of the T-tubule system, though the mechanisms remain poorly understood. In this study, we aim to determine whether JP2 is required for normal cardiac T-tubule maturation. Using in situ confocal imaging of intact murine hearts, we found T-tubules were absent in both left- and right-ventricular myocytes at postnatal Day 8 and did not appear until Day 10. Quantification of T-tubule structural integrity using the T-tubule power (TTpower) index revealed a progressive increase in TTpower between postnatal Days 10 and 19. By postnatal Day 19, TTpower was similar to that in adult murine cardiomyocytes, indicative of a nearly matured T-tubule network. JP2 levels increased dramatically during development, reaching levels observed in adult hearts by postnatal Day 14. Deficiency of JP2, using a mouse model in which a JP2-specific shRNA is expressed during embryonic development, severely impaired T-tubule maturation, with equivalent decreases in the left- and right-ventricular TTpower. We also detected a gradual increase in the density of transverse but not longitudinal tubules during development, and JP2 deficiency abolished the increase in the density of transverse elements. Alterations in T-tubules caused significant reduction in Ca2+ transient amplitude and marked increase in Ca2+ release dyssynchrony, Ca2+ alternans, and spontaneous Ca2+ waves, leading to contractile failure. Our data identify a critical role for JP2 in T-tubule and excitation–contraction coupling maturation during development.
Mitochondrial COII sequences and modern human origins.
Authors: M Ruvolo, S Zehr, M von Dornum, D Pan, B Chang, J Lin
Journal: Molecular Biology and Evolution (1993)

The aim of this study is to measure human mitochondrial sequence variability in the relatively slowly evolving mitochondrial gene cytochrome oxidase subunit II (COII) and to estimate when the human common ancestral mitochondrial type existed. New COII gene sequences were determined for five humans (Homo sapiens), including some of the most mitochondrially divergent humans known; for two pygmy chimpanzees (Pan paniscus); and for a common chimpanzee (P. troglodytes). COII sequences were analyzed with those from another relatively slowly evolving mitochondrial region (ND4-5). From class 1 (third codon position) sequence data, a relative divergence date for the human mitochondrial ancestor is estimated as 1/27 th of the human-chimpanzee divergence time. If it is assumed that humans and chimpanzees diverged 6 Mya, this places a human mitochondrial ancestor at 222,000 years, significantly different from 1 Myr (the presumed time of an H. erectus emergence from Africa). The mean coalescent time estimated from all 1,580 sites of combined mitochondrial data, when a 6-Mya human-chimpanzee divergence is assumed, is 298,000 years, with 95% confidence interval of 129,000-536,000 years. Neither estimate is compatible with a 1-Myr-old human mitochondrial ancestor. The mitochondrial DNA sequence data from COII and ND4-5 regions therefore do not support this multiregional hypothesis for the emergence of modern humans.
Simple functional performance tests and mortality in COPD
Authors: Milo A. Puhan, Lara Siebeling, Marco Zoller, Patrick Muggensturm, Gerben ter Riet
Journal: European Respiratory Journal (2013)

Exercise tests are important to characterise chronic obstructive pulmonary disease patients and predict their prognosis, but are often not available outside of rehabilitation or research settings. Our aim was to assess the predictive performance of the sit-to-stand and handgrip strength tests. The prospective cohort study in Dutch and Swiss primary care settings included a broad spectrum of patients (n=409) with Global Initiative for Chronic Obstructive Lung Disease stages II to IV. To assess the association of the tests with outcomes, we used Cox proportional hazards (mortality), negative binomial (centrally adjudicated exacerbations) and mixed linear regression models (longitudinal health-related quality of life) while adjusting for age, sex and severity of disease. The sit-to-stand test was strongly (adjusted hazard ratio per five more repetitions of 0.58, 95% CI 0.40–0.85; p=0.004) and the handgrip strength test moderately strongly (0.84, 95% CI 0.72–1.00; p=0.04) associated with mortality. Both tests were also significantly associated with health-related quality of life but not with exacerbations. The sit-to-stand test alone was a stronger predictor of 2-year mortality (area under curve 0.78) than body mass index (0.52), forced expiratory volume in 1 s (0.61), dyspnoea (0.63) and handgrip strength (0.62). The sit-to-stand test may close an important gap in the evaluation of exercise capacity and prognosis of chronic obstructive pulmonary disease patients across practice settings.
Anthrax Lethal Toxin Inhibits Growth of and Vascular Endothelial Growth Factor Release from Endothelial Cells Expressing the Human Herpes Virus 8 Viral G Protein–Coupled Receptor
Authors: Philippe Depeille, John J. Young, Elissa A. Boguslawski, Bree D. Berghuis, Eric J. Kort, James H. Resau, Arthur E. Frankel, Nicholas S. Duesbery
Journal: Clinical Cancer Research (2007)

Abstract Purpose: In this study, we tested the hypothesis that inhibition of mitogen-activated protein kinase kinases (MKK) inhibits tumor growth by acting on angiogenic signaling and by extension may form the basis of an effective strategy for treatment of Kaposi's sarcoma. Experimental Design: Murine endothelial cells expressing the human herpes virus 8 G protein–coupled receptor (vGPCR-SVEC) were treated with anthrax lethal toxin (LeTx). LeTx is a binary toxin ordinarily secreted by Bacillus anthracis and is composed of two proteins: protective antigen (the binding moiety) and lethal factor (the active moiety). Lethal factor is a protease that cleaves and inactivates MKKs. Results: In vitro, treatment of vGPCR-SVEC with LeTx inhibited MKK signaling, moderately inhibited cell proliferation, and blocked the ability of these cells to form colonies in soft agar. Treatment with LeTx also blocked the ability of these cells to release several angioproliferative cytokines, notably vascular endothelial growth factor (VEGF). In contrast, inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 with U0126 caused a substantial inhibition of proliferation but only modestly inhibited VEGF release. In xenograft models, i.v. injection of LeTx caused reduced tumor growth characterized immunohistochemically by inhibition of MKK signaling, decreased rates of proliferation, and reduced levels of VEGF and VEGF receptor 2, with a corresponding decrease in vascular density. Conclusions: These data support a role for MKK signaling in tumor growth and vascularization and are consistent with the hypothesis that inhibition of MKK signaling by LeTx or a similar agent may be an effective strategy for the treatment of Kaposi's sarcoma as well as other vascular tumors.