tbuckley/cabot-search huggingface dataset:
Role of T-type calcium channel subunits in post-myocardial infarction remodelling probed with genetically engineered mice
Authors: Khai Le Quang, Patrice Naud, Xiao-Yan Qi, Francine Duval, Yan-Fen Shi, Marc-Antoine Gillis, Philippe Comtois, Jean-Claude Tardif, Danshi Li, Paul C. Levesque, Dobromir Dobrev, Flavien Charpentier, Stanley Nattel
Journal: Cardiovascular Research (2011)

AimsPrevious studies suggested that T-type Ca2+-current (ICaT)-blockers improve cardiac remodelling, but all available ICaT-blockers have non-specific actions on other currents and/or functions. To clarify the role of ICaT in cardiac remodelling, we studied mice with either of the principal cardiac ICaT-subunits (Cav3.1 or Cav3.2) knocked out.
BRAIN LESIONS OF THE DOMESTIC RABBIT
Authors: James E. McCartney
Journal: The Journal of Experimental Medicine (1924)

Lesions of meningoencephalitis were found in 55 per cent of 372 rabbits comprising the laboratory stock regarded as healthy, others with snuffles or dying from different affections while being kept under observation, and still others which were employed for experimental purposes, such as tumor transplantation and Treponema pallidum inoculation. None was injected intracerebrally. The lesions consist in the main of infiltration with mononuclear cells occurring around the blood vessels, in the meninges, in the cortex, and under the ependyma of the lateral ventricles, together with particular focal necrotic areas in the cortex. The incidence of these histopathological changes varies in different series of animals; in those supposedly normal and in rabbits inoculated with a transplantable tumor or with Treponema pallidum material, the percentage of positives was from 40 to 60; in those suffering from miscellaneous diseases, such as pneumonia, septicemia, etc., the percentage was 70, and in rabbits ill with snuffles, as many as 76 per cent were affected. Marked lesions were observed in 47.5 per cent of the total. The histopathological picture observed in these rabbits corresponds to those offered by a number of investigators as evidence of the transmission of certain nervous diseases of man to this animal. The accidental cerebral lesions in the rabbit, of a wide variety, and of frequent occurrence, are to be regarded as existing before any experimental procedure is begun. Their recognition is of the utmost importance in the interpretation of experimental results based on the presence of similar changes in this animal.
Identification of a Common Risk Haplotype for Diabetic Nephropathy at the Protein Kinase C-β1 (PRKCB1) Gene Locus
Authors: Shin-ichi Araki, Daniel P.K. Ng, Bozena Krolewski, Lucjan Wyrwicz, John J. Rogus, Luis Canani, Yuichiro Makita, Masakazu Haneda, James H. Warram, Andrzej S. Krolewski
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Abnormal activation of protein kinase C-β isoforms in the diabetic state has been implicated in the development of diabetic nephropathy. It is thus plausible that DNA sequence differences in the protein kinase C-β1 gene (<i>PRKCB1</i>), which encodes both βI and βII isoforms, may influence susceptibility to nephropathy. Nine single-nucleotide polymorphisms (SNP) in <i>PRKCB1</i> were tested for association with diabetic nephropathy in type I diabetes mellitus, by using both case-control and family-study designs. Allele and genotype distributions of two SNP in the promoter (−1504C/T and −546C/G) differed significantly between case patients and control patients (<i>P</i> &lt; 0.05). These associations were particularly strong with diabetes mellitus duration of &lt;24 yr (<i>P</i> = 0.002). The risk of diabetic nephropathy was higher among carriers of the T allele of the −1504C/T SNP, compared with noncarriers (odds ratio, 2.54; 95% confidence interval, 1.39 to 4.62), and among carriers of the G allele of the −546C/G SNP (odds ratio, 2.45; 95% confidence interval, 1.37 to 4.38). Among individuals with diabetes mellitus duration of ≥24 yr, these two SNP were not associated with diabetic nephropathy. These positive findings were confirmed by using the family-based transmission disequilibrium test. The T-G haplotype, with both risk alleles, was transmitted more frequently than expected from heterozygous parents to offspring who developed diabetic nephropathy during the first 24 yr of diabetes mellitus. It is concluded that DNA sequence differences in the promoter of <i>PRKCB1</i> contribute to diabetic nephropathy susceptibility in type I diabetes mellitus. E-mail: andrzej.krolewski@joslin.harvard.edu
1370 CAN AST VALUES BE USED INSTEAD OF ALT TO CALCULATE THE PATTERN OF DRUG INDUCED LIVER INJURY (DILI)?
Authors: M.M. Robles Díaz, M. García Cortes, A. Fernandez Castaner, C. Stephens, Y. Borraz, E. Ulzurrum, M.I. Lucena, R.J. Andrade Bellido
Journal: Journal of Hepatology (2012)
Insulin Sensitivity, β-Cell Function, and Incretin Effect in Individuals With Elevated 1-Hour Postload Plasma Glucose Levels
Authors: Maria A. Marini, Elena Succurro, Simona Frontoni, Simona Mastroianni, Franco Arturi, Angela Sciacqua, Renato Lauro, Marta L. Hribal, Francesco Perticone, Giorgio Sesti
Journal: Diabetes Care (2012)

Individuals with normal glucose tolerance (NGT), whose 1-h postload plasma glucose is ≥155 mg/dL (NGT 1h-high), have an increased risk of type 2 diabetes. The purpose of this study was to characterize their metabolic phenotype.A total of 305 nondiabetic offspring of type 2 diabetic patients was consecutively recruited. Insulin secretion was assessed using both indexes derived from oral glucose tolerance test (OGTT) and intravenous glucose tolerance test (IVGTT). Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp.Compared with individuals with a 1-h postload plasma glucose <155 mg/dL (NGT 1h-low), NGT 1h-high individuals exhibited lower insulin sensitivity after adjustment for age, sex, and BMI. Insulin secretion estimated from the OGTT did not differ between the two groups of individuals. By contrast, compared with NGT 1h-low individuals, the acute insulin response during an IVGTT and the disposition index were significantly reduced in NGT 1h-high individuals after adjustment for age, sex, and BMI. Incretin effect, estimated as the ratio between total insulin responses during OGTT and IVGTT, was higher in NGT 1h-high individuals compared with NGT 1h-low individuals.NGT 1h-high individuals may represent an intermediate state of glucose intolerance between NGT and type 2 diabetes characterized by insulin resistance and reduced β-cell function, the two main pathophysiological defects responsible for the development of type 2 diabetes. Postload hyperglycemia is the result of an intrinsic β-cell defect rather than impaired incretin effect.
Optical Imaging Using Endogenous Contrast to Assess Metabolic State
Authors: Irene Georgakoudi, Kyle P. Quinn
Journal: Annual Review of Biomedical Engineering (2012)

Optical microscopic imaging offers opportunities to perform noninvasive assessments of numerous parameters associated with the biochemistry, morphology, and functional state of biological samples. For example, it is possible to detect the endogenous fluorescence from a small number of important biomolecules, including NADH and FAD, which are two coenzymes involved in key metabolic pathways such as glycolysis, the Krebs cycle, and oxidative phosphorylation. Here, we review different imaging approaches to isolate the fluorescence from these chromophores in two- and three-dimensional samples and discuss the origins and potential interpretation of the observed signals in terms of cell metabolic status. Finally, we discuss the challenges and limitations of these approaches, as well as important research directions that we expect will evolve in the near future.
Renal Actions of RGS2 Control Blood Pressure
Authors: Susan B. Gurley, Robert C. Griffiths, Michael E. Mendelsohn, Richard H. Karas, Thomas M. Coffman
Journal: Journal of the American Society of Nephrology (2010)

G protein-coupled receptors (GPCRs) have key roles in cardiovascular regulation and are important targets for the treatment of hypertension. GTPase-activating proteins, such as RGS2, modulate downstream signaling by GPCRs. RGS2 displays regulatory selectivity for the Gαq subclass of G proteins, and mice lacking RGS2 develop hypertension through incompletely understood mechanisms. Using total body RGS2-deficient mice, we used a kidney crosstransplantation strategy to examine separately the contributions of RGS2 actions in the kidney from those in extrarenal tissues with regard to BP regulation. Loss of renal RGS2 was sufficient to cause hypertension, whereas the absence of RGS2 from all extrarenal tissues including the peripheral vasculature did not significantly alter BP. Accordingly, these results suggest that RGS2 acts within the kidney to modulate BP and prevent hypertension. These data support a critical role for the renal epithelium and/or vasculature as the final determinants of the intra-arterial pressure in hypertension.
Identification of Tumor-Specific Molecular Signatures in Intracranial Ependymoma and Association With Clinical Characteristics
Authors: Piergiorgio Modena, Elena Lualdi, Federica Facchinetti, Joris Veltman, James F. Reid, Simone Minardi, Irene Janssen, Felice Giangaspero, Marco Forni, Gaetano Finocchiaro, Lorenzo Genitori, Flavio Giordano, Riccardo Riccardi, Eric F.P.M. Schoenmakers, Maura Massimino, Gabriella Sozzi
Journal: Journal of Clinical Oncology (2006)

Purpose To delineate clinically relevant molecular signatures of intracranial ependymoma. Materials and Methods We analyzed 24 primary intracranial ependymomas. For genomic profiling, microarray-based comparative genomic hybridization (CGH) was used and results were validated by fluorescent in situ hybridization and loss of heterozygosity mapping. We performed gene expression profiling using microarrays, real-time quantitative reverse transcriptase polymerase chain reaction, and methylation analysis of selected genes. We applied class comparison analyses to compare both genomic and expression profiling data with clinical characteristics. Results A variable number of genomic imbalances were detected by array CGH, revealing multiple regions of recurrent gain (including 2q23, 7p21, 12p, 13q21.1, and 20p12) and loss (including 5q31, 6q26, 7q36, 15q21.1, 16q24, 17p13.3, 19p13.2, and 22q13.3). An ependymoma-specific gene expression signature was characterized by the concurrent abnormal expression of developmental and differentiation pathways, including NOTCH and sonic hedgehog signaling. We identified specific differentially imbalanced genomic clones and gene expression signatures significantly associated with tumor location, patient age at disease onset, and retrospective risk for relapse. Integrated genomic and expression profiling allowed us to identify genes of which the expression is deregulated in intracranial ependymoma, such as overexpression of the putative proto-oncogene YAP1 (located at 11q22) and downregulation of the SULT4A1 gene (at 22q13.3). Conclusion The present exploratory molecular profiling study allowed us to refine previously reported intervals of genomic imbalance, to identify novel restricted regions of gain and loss, and to identify molecular signatures correlating with various clinical variables. Validation of these results on independent data sets represents the next step before translation into the clinical setting.
Exercise in cardiac rehabilitation
Authors: Terence Kavanagh
Journal: British Journal of Sports Medicine (2000)

There is a saying that “what goes around comes around”, and exercise training as a treatment for patients suffering from coronary heart disease is no exception to the rule. The eighteenth century English physician, William Heberden, recorded the case of a patient suffering from angina “who set himself the task of sawing wood every day and was nearly cured”.1 Almost a century later in 1854, the Irish doctor, William Stokes wrote “the symptoms of debility of the heart are often removable by a regulated course of gymnastics, or by pedestrian exercise”.2 His “pedestrian cure” consisted of comfortable walking initially on level ground, the distance and gradient being increased as tolerance improved—always, however, cautioning against excessive fatigue, breathlessness, or chest pain. Have we progressed that far since then? Over the ensuing years, Stokes' exercise training regime was largely forgotten, obscured by the teaching of the London surgeon John Hilton, who stressed the value of strict bed rest.3 Unfortunately Hilton's precept was carried to extremes. Prolonged immobilisation in bed became the cornerstone …
Use of Aspirin Associates with Longer Primary Patency of Hemodialysis Grafts
Authors: Bradley S. Dixon, Gerald J. Beck, Laura M. Dember, Miguel A. Vazquez, Arthur Greenberg, James A. Delmez, Michael Allon, Jonathan Himmelfarb, Bo Hu, Tom Greene, Milena K. Radeva, Ingemar J. Davidson, T. Alp Ikizler, Gregory L. Braden, Jeffrey H. Lawson, James R. Cotton, John W. Kusek, Harold I. Feldman
Journal: Journal of the American Society of Nephrology (2011)

Extended-release dipyridamole plus low-dose aspirin (ERDP/ASA) prolongs primary unassisted graft patency of newly created hemodialysis arteriovenous grafts, but the individual contributions of each component are unknown. Here, we analyzed whether use of aspirin at baseline associated with primary unassisted graft patency among participants in a randomized trial that compared ERDP/ASA and placebo in newly created grafts. We used Cox proportional hazards regression, adjusting for prespecified baseline comorbidities and covariates. Of all participants, 43% reported use of aspirin at baseline; of these, 82% remained on nonstudy aspirin (<i>i.e.</i>, excluding ERDP/ASA) at 1 year. After 1 year of follow-up, the incidence of primary unassisted patency among participants using aspirin at baseline was 30% (95% CI: 24 to 35%) and among those not using aspirin was 23% (95% CI: 18 to 27%). Use of aspirin at baseline associated with a dose-dependent prolongation of primary unassisted graft patency that approached statistical significance (adjusted HR, 0.83; 95% CI: 0.68 to 1.01; <i>P</i> = 0.06). Use of aspirin at baseline did not associate with prolongation of cumulative graft patency or participant survival. In conclusion, use of aspirin associates with a trend toward longer primary unassisted patency of newly placed hemodialysis grafts similar to that observed for ERDP/ASA.
Myopathy and external pulmonary artery compression caused by sarcoidosis.
Authors: M M Khan, D S Gill, B McConkey
Journal: Thorax (1981)

Myopathy caused by sarcoidosis, though rare, is now well documented.1 Pulmonary artery narrowing from sar- coidosis, however, is extremely rare and only three cases have been previously reported.2 4We describe a patient with sarcoidosis presenting as a rapidly progressive myopathy and pulmonary artery compression.This combination has not been reported before. Case reportA 30-year-old Jamaican man was admitted with a month's history of progressive weakness of his arms and difficulty with walking.He was not on any medication.There was no relevant family history.
Derivation of HLA types from shotgun sequence datasets
Authors: René L Warren, Gina Choe, Douglas J Freeman, Mauro Castellarin, Sarah Munro, Richard Moore, Robert A Holt
Journal: Genome Medicine (2012)

Abstract The human leukocyte antigen (HLA) is key to many aspects of human physiology and medicine. All current sequence-based HLA typing methodologies are targeted approaches requiring the amplification of specific HLA gene segments. Whole genome, exome and transcriptome shotgun sequencing can generate prodigious data but due to the complexity of HLA loci these data have not been immediately informative regarding HLA genotype. We describe HLAminer, a computational method for identifying HLA alleles directly from shotgun sequence datasets ( http://www.bcgsc.ca/platform/bioinfo/software/hlaminer ). This approach circumvents the additional time and cost of generating HLA-specific data and capitalizes on the increasing accessibility and affordability of massively parallel sequencing.
The management of ascites in cirrhosis: Report on the consensus conference of the International Ascites Club
Authors: Kevin P. Moore, Florence Wong, Pere Gines, Mauro Bernardi, Andreas Ochs, Francesco Salerno, Paolo Angeli, Michael Porayko, Richard Moreau, Guadelupe Garcia-Tsao, Wladimiro Jimenez, Ramon Planas, Vicente Arroyo
Journal: Hepatology (2003)

Ascites is a common complication of cirrhosis, and heralds a new phase of hepatic decompensation in the progression of the cirrhotic process. The development of ascites carries a significant worsening of the prognosis. It is important to diagnose noncirrhotic causes of ascites such as malignancy, tuberculosis, and pancreatic ascites since these occur with increased frequency in patients with liver disease. The International Ascites Club, representing the spectrum of clinical practice from North America to Europe, have developed guidelines by consensus in the management of cirrhotic ascites from the early ascitic stage to the stage of refractory ascites. Mild to moderate ascites should be managed by modest salt restriction and diuretic therapy with spironolactone or an equivalent in the first instance. Diuretics should be added in a stepwise fashion while maintaining sodium restriction. Gross ascites should be treated with therapeutic paracentesis followed by colloid volume expansion, and diuretic therapy. Refractory ascites is managed by repeated large volume paracentesis or insertion of a transjugular intrahepatic portosystemic stent shunt (TIPS). Successful placement of TIPS results in improved renal function, sodium excretion, and general well–being of the patient but without proven survival benefits. Clinicians caring for these patients should be aware of the potential complications of each treatment modality and be prepared to discontinue diuretics or not proceed with TIPS placement should complications or contraindications develop. Liver transplantation should be considered for all ascitic patients, and this should preferably be performed prior to the development of renal dysfunction to prevent further compromise of their prognosis.
Bone-marrow transplant from father to son and subsequent graft from son to father
Authors: R.L Powles, P.M Parikh, G Helenglass, H.H Aboud, C.L Smith, I.A Mrazek, V Shepherd, S.T Milliken, J Treleaven, C Sharrock, S.W Feary, S.T Meller, S Lawler
Journal: The Lancet (1990)
Carrier Screening for Gaucher Disease
Authors: Shachar Zuckerman, Amnon Lahad, Amir Shmueli, Ari Zimran, Leah Peleg, Avi Orr-Urtreger, Ephrat Levy-Lahad, Michal Sagi
Journal: JAMA (2007)

ContextThe aim of carrier screening is to prevent severe, untreatable genetic disease by identifying couples at risk before the birth of an affected child, and providing such couples with options for reproductive outcomes for affected pregnancies. Gaucher disease (GD) is an autosomal recessive storage disorder, relatively frequent in Ashkenazi Jews. Carrier screening for GD is controversial because common type 1 GD is often asymptomatic and effective treatment exists. However, screening is offered to Ashkenazi Jews worldwide and has been offered in Israel since 1995.ObjectiveTo examine the scope and outcomes of nationwide GD screening.Design, Setting, and ParticipantsAll Israeli genetic centers provided data on the number of individuals screened for GD, the number of carriers identified, the number of carrier couples identified, and the mutations identified in these couples between January 1, 1995, and March 31, 2003. Carrier couples were interviewed via telephone between January 21, 2003, and August 31, 2004, using a structured questionnaire for relevant outcome measures.Main Outcome MeasuresScreening scope (number of testing centers, tested individuals, and carrier couples), screening process (type of pretest and posttest consultations), and screening outcomes (utilization of prenatal diagnosis and pregnancy terminations).ResultsBetween January 1, 1995, and March 31, 2003, 10 of 12 Israeli genetic centers (83.3%) offered carrier screening. Carrier frequency was 5.7%, and 83 carrier couples were identified among an estimated 28 893 individuals screened. There were 82 couples at risk for offspring with type 1 GD. Seventy of 82 couples (85%) were at risk for asymptomatic or mildly affected offspring and 12 of 82 couples (15%) were at risk for moderately affected offspring. At postscreening, 65 interviewed couples had 90 pregnancies, and prenatal diagnosis was performed in 68 pregnancies (76%), detecting 16 fetuses with GD (24%). Pregnancies were terminated in 2 of 13 fetuses (15%) predicted to be asymptomatic or mildly affected and 2 of 3 fetuses (67%) with predicted moderate disease. There were significantly fewer pregnancy terminations in couples who in addition to genetic counseling had medical counseling with a GD expert (1 of 13 [8%] vs 3 of 3 with no medical counseling [100%], P = .007).ConclusionsIn this study of GD screening among Ashkenazi Jewish couples in Israel, most couples did not terminate affected pregnancies, although screening was associated with a few pregnancy terminations. The main possible benefit was providing couples with knowledge and control. The divergence of these outcomes from stated goals of screening programs is likely to confront carrier screening programs for low-penetrance diseases.
<i>CASPASE-8</i> Gene Is Inactivated by Somatic Mutations in Gastric Carcinomas
Authors: Young Hwa Soung, Jong Woo Lee, Su Young Kim, Jin Jang, Yong Gyu Park, Won Sang Park, Suk Woo Nam, Jung Young Lee, Nam Jin Yoo, Sug Hyung Lee
Journal: Cancer Research (2005)

Abstract Several lines of evidence indicate that deregulation of apoptosis is involved in the mechanisms of cancer development. Caspase-8 activation plays a central role in the initiation phase of apoptosis. The aim of this study was to explore the possibility that genetic alteration of CASPASE-8 gene is involved in the development of human cancers, including gastric cancers. We have analyzed the entire coding region of human CASPASE-8 gene for the detection of somatic mutations in 162 gastric carcinomas (40 early and 122 advanced cancers), 185 non–small cell lung cancers, 93 breast carcinomas, and 88 acute leukemias by PCR-single-strand conformation polymorphism. Of the cancers analyzed, 13 cancers harbored CASPASE-8 somatic mutations. Interestingly, all of the mutations were detected in the advanced gastric cancers (10.7% of the 122 samples). We expressed the tumor-derived caspase-8 mutants in 293T, 293, and HT1080 cells and found that most of the mutants (9 of the 10 mutations tested) markedly decreased the cell death activity of caspase-8. In addition, in the cells with the inactivating caspase-8 mutants, cleavage of poly(ADP-ribose)polymerase was markedly reduced compared with that of wild-type caspase-8. The occurrence of CASPASE-8 mutation and the inactivation of cell death activity by the mutants suggest that CASPASE-8 gene mutation may affect the pathogenesis of gastric cancers, especially at the late stage of gastric carcinogenesis.
The Role of Chemokine Receptors in Primary, Effector, and Memory Immune Responses
Authors: Federica Sallusto, Charles R. Mackay, Antonio Lanzavecchia
Journal: Annual Review of Immunology (2000)

The immune system is composed of single cells, and its function is entirely dependent on the capacity of these cells to traffic, localize within tissues, and interact with each other in a precisely coordinated fashion. There is growing evidence that the large families of chemokines and chemokine receptors provide a flexible code for regulating cell traffic and positioning in both homeostatic and inflammatory conditions. The regulation of chemokine receptor expression during development and following cell activation explains the complex migratory pathways taken by dendritic cells, T and B lymphocytes, providing new insights into the mechanisms that control priming, effector function, and memory responses.