tbuckley/cabot-search huggingface dataset:
Aberrant Splicing in the PKD2 Gene as a Cause of Polycystic Kidney Disease
Authors: DAVID M. REYNOLDS, TOMOHITO HAYASHI, YIQIANG CAI, BARBERA VELDHUISEN, TERRY J. WATNICK, XOSE M. LENS, TOSHIO MOCHIZUKI, FENG QIAN, YOSHIKO MAEDA, LI LI, RAGNHEIDUR FOSSDAL, ELIECER COTO, GUANQING WU, MARTIJN H. BREUNING, GREGORY G. GERMINO, DORIEN J. M. PETERS, STEFAN SOMLO
Journal: Journal of the American Society of Nephrology (1999)

It is estimated that approximately 15% of families with autosomal dominant polycystic kidney disease (ADPKD) have mutations in PKD2. Identification of these mutations is central to identifying functionally important regions of gene and to understanding the mechanisms underlying the pathogenesis of the disorder. The current study describes mutations in six type 2 ADPKD families. Two single base substitution mutations discovered in the ORF in exon 14 constitute the most COOH-terminal pathogenic variants described to date. One of these mutations is a nonsense change and the other encodes an apparent missense variant. Reverse transcription-PCR from patient lymphoblast RNA showed that, in addition, both mutations resulted in out-of-frame splice variants by activating cryptic splice sites via different mechanisms. The apparent missense variant produced such a strong splicing signal that the processed transcript from the mutant chromosome did not contain any of the normally spliced, missense product. A third mutation, a nonconservative missense change effecting a negatively charged residue in the third transmembrane span, is likely pathogenic and defines a highly conserved residue consistent with a potential channel subunit function for polycystin-2. The remaining three mutations included two frame shifts resulting from deletion of one or two bases in exons 6 and 10, respectively, and a nonsense mutation due to a single base substitution in exon 4. The study also defined a novel intragenic polymorphism in exon 1 that will be useful in analyzing "second hits" in PKD2. Finally, the study demonstrates that there are reduced levels of normal polycystin-2 protein in lymphoblast lines from PKD2-affected individuals and that truncated mutant polycystin-2 cannot be detected in patient lymphoblasts, suggesting that the latter may be unstable in at least some tissues. The mutations described will serve as critical reagents for future functional studies in PKD2.
Effect of Antiviral Treatment With Nucleotide/Nucleoside Analogs on Postoperative Prognosis of Hepatitis B Virus–Related Hepatocellular Carcinoma: A Two-Stage Longitudinal Clinical Study
Authors: Jianhua Yin, Nan Li, Yifang Han, Jie Xue, Yang Deng, Jie Shi, Weixing Guo, Hongwei Zhang, Hongyang Wang, Shuqun Cheng, Guangwen Cao
Journal: Journal of Clinical Oncology (2013)

Purpose Postoperative prognosis of hepatitis B virus (HBV) –related hepatocellular carcinoma (HCC) is poor. The effect of nucleotide/nucleoside analog (NA) treatment on the prognosis has not been fully clarified. Patients and Methods We carried out a two-stage longitudinal study that included a randomized clinical trial (RCT) to evaluate the effect of NA treatment on postoperative prognosis of HBV-HCC. Seven hundred eighty patients (163 in the RCT) were enrolled onto this study following radical hepatectomy. Lamivudine, adefovir dipivoxil, or entecavir were postoperatively administered to antiviral groups. Surgical specimens were examined immunohistochemically for carboxylic acid–terminal truncated HBV X protein (Ct-HBx). Results In the nonrandomized cohort, high viral load (≥ 10 4 copies/mL) significantly predicted unfavorable overall survival and recurrence-free survival (RFS), whereas antiviral treatment significantly improved both types of survival. In the RCT, antiviral treatment significantly decreased HCC recurrence and HCC-related death, with hazard ratios (HRs) of 0.48 (95% CI, 0.32 to 0.70) and 0.26 (95% CI, 0.14 to 0.50), respectively, in multivariate Cox analyses. Patients who received antiviral treatment had significantly decreased early recurrence (HR, 0.41; 95% CI, 0.27 to 0.62) and improved liver function 6 months after surgery compared with the controls (P &lt; .001). Those with recovered liver function had a higher 2-year RFS rate than those without (P = .003). Ct-HBx expression in adjacent hepatic tissues significantly predicted an unfavorable RFS in the antiviral group (P &lt; .001). Conclusion Although it might not affect the HCC-promoting potential of Ct-HBx, NA treatment is effective in normalizing liver function, decreasing HBV-HCC recurrence, and improving postoperative survival. This effect should be validated in a multicenter phase III RCT.
Woodchuck hepatocytes remain permissive for hepadnavirus infection and mouse liver repopulation after cryopreservation
Authors: Maura Dandri, Martin R. Burda, Andreas Gocht, Eva Török, Jörg M. Pollok, Charles E. Rogler, Hans Will, Jörg Petersen
Journal: Hepatology (2001)

Isolated hepatocytes represent a relevant model of the liver and are highly required both for research and therapeutic applications. However, sources of primary liver cells from human beings and from some animal species are limited. Therefore, cryopreservation of hepatocytes could greatly facilitate advances in various research areas. The aim of this study was to evaluate whether cryopreserved primary woodchuck hepatocytes could be used for woodchuck hepatitis B virus (WHV) infection studies, and whether they could maintain their regenerative potential in vivo after thawing. Critical steps for good quality of cryopreserved hepatocytes included the use of University of Wisconsin (UW) solution as a main component of the freezing medium, stepwise reduction of dimethylsulfoxide (DMSO) to avoid osmotic shock, and maintenance of low concentrations of DMSO in the culture medium. After cryopreservation, cell viability was still high (70% to 80%), and 50% to 60% of thawed cells attached to the plates. The appearance of covalently closed circular (ccc)DNA and of WHV-replicative forms a few days after in vitro infection demonstrated that thawed woodchuck hepatocytes were still susceptible to viral infection, thus proving maintenance of a very high hepatocyte-specific differentiation status. Furthermore, transplantation of woodchuck hepatocytes into the liver of urokinase-type plasminogen activator (uPA)/recombination activation gene-2 (RAG-2) mice, a model of liver regeneration, demonstrated that cryopreserved cells retained the ability to divide and to extensively repopulate a xenogenic liver. Notably, in vivo susceptibility to infection with WHV and proliferative capacity of frozen/thawed woodchuck hepatocytes in recipient mice were identical to those observed by transplanting fresh hepatocytes.
Killer Cell Inhibitory Receptor Recognition of Human Leukocyte Antigen (HLA) Class I Blocks Formation of a pp36/PLC-γ Signaling Complex in Human Natural Killer (NK) Cells
Authors: Nicholas M. Valiante, Joseph H. Phillips, Lewis L. Lanier, Peter Parham
Journal: The Journal of Experimental Medicine (1996)

The killer cell inhibitory receptors (KIR) of human natural killer (NK) cells recognize human leukocyte antigen class I molecules and inhibit NK cell cytotoxicity through their interaction with protein tyrosine phosphatases (PTP). Here, we report that KIR recognition of class I ligands inhibits distal signaling events and ultimately NK cell cytotoxicity by blocking the association of an adaptor protein (pp36) with phospholipase C-gamma in NK cells. In addition, we demonstrate that pp36 can serve as a substrate in vitro for the KIR-associated PTP, PTP-1C (also called SHP-1), and that recognition of class I partially disrupts tyrosine phosphorylation of NK cell proteins, providing evidence for KIR-induced phosphatase activity.
Birth-and-Death Long-Term Evolution Promotes Histone H2B Variant Diversification in the Male Germinal Cell Line
Authors: R. Gonzalez-Romero, C. Rivera-Casas, J. Ausio, J. Mendez, J. M. Eirin-Lopez
Journal: Molecular Biology and Evolution (2010)

The rich diversity within each of the five histone families (H1, H2A, H2B, H3, and H4) can hardly be reconciled with the notion of homogenizing evolution. The prevalence of birth-and-death long-term evolution over concerted evolution has already been demonstrated in the linker histone H1 family as well as for the H2A, H3, and H4 core histone families. However, information about histone H2B is lacking. In the present work, we have analyzed the diversity of the members of this histone family across different eukaryotic genomes and have characterized the mechanisms involved in their long-term evolution. Our results reveal that, quite in contrast with other histones, H2B variants are subject to a very rapid process of diversification that primarily affects the male germinal cell lineage and involves their functional specialization probably as a consequence of neofunctionalization and subfunctionalization events after gene duplication. The overall parallelism observed between the molecular phylogenies and the relationships among the electrostatic potentials of the different variants suggests that the latter may have played a major structural selective constraint during H2B evolution. It thus seems that the reorganization of chromatin structure during spermiogenesis might have affected the evolutionary constraints driving histone H2B evolution, leading to an increase in diversity.
Stroma is critical for preventing or permitting immunological destruction of antigenic cancer cells.
Authors: S Singh, S R Ross, M Acena, D A Rowley, H Schreiber
Journal: The Journal of Experimental Medicine (1992)

Inoculated immunogenic cancer cells after initial growth are potentially rejected by specific host immunity; however, the outcome of the interaction between host and inoculated cancer cells is a function of multiple factors including the route of inoculation, the number of cells, the density of antigens on the injected cancer cells, and the state of the immune system of the host. In the present study, we have examined a different kind of variable: the stroma that inoculated tumor cells initially reside in. The impetus to examine this factor arises from observations that cancer cells from several lines inoculated as fragments of solid tumors often grow progressively, whereas the same number or more than 10-fold larger numbers of identical type cells injected as a suspension are rejected, even though fragments or suspended cells are both tumorigenic at the same doses in nude mice. In the present studies, we found that: (a) indeed, cancer cells inoculated as fragments were more tumorigenic than cancer cells in suspension; (b) the tumorigenicity of suspended cancer cells was increased by injection of the cells into polyurethane sponge implants; (c) cancer cells were more tumorigenic embedded in syngeneic stroma than in transgenic antigenic stroma expressing the K216 major histocompatibility complex class I antigen; and (d) antigenic, bone marrow-derived, stromal components (presumably passenger leukocytes) were sufficient to cause rejection of immunogenic but antigenically unrelated cancer.(ABSTRACT TRUNCATED AT 250 WORDS)
Reciprocal and coactivation commands are not sufficient to describe muscle activation patterns
Authors: C. C. A. M. Gielen, B. van Bolhuis
Journal: Behavioral and Brain Sciences (1995)

Abstract Recent results have shown that the relative activation of muscles is different for isometric contractions and for movements. These results exclude an explanation of muscle activation patterns by a combination ofreciprocal and coactivation commands. These results also indicate that joint stiffness is not uniquely determined and that it may be different for isometric contractions and movements.
Phase 2 trial of imatinib mesylate in myelofibrosis with myeloid metaplasia
Authors: Ayalew Tefferi, Ruben A. Mesa, Leigh A. Gray, David P. Steensma, John K. Camoriano, Michelle A. Elliott, Animesh Pardanani, Stephen M. Ansell, Timothy G. Call, Gerardo Colon-Otero, Georgene Schroeder, Curtis A. Hanson, Gordon W. Dewald, Scott H. Kaufmann
Journal: Blood (2002)
Amyloid in basal cell carcinomas
Authors: DAVID WEEDON, ELIZABETH SHAND
Journal: British Journal of Dermatology (1979)

Stromal or intratumour deposits of amyloid were found in thirty of forty-six randomly selected basal cell carcinomas. Amyloid was found less often in histologically aggressive tumours than in other sub-types. Immunoglobulins, predominantly IgM, were demonstrated in all but one of these thirty cases, corresponding to the distribution of the amyloid deposits. Electron microscopy revealed 'early' amyloid in one case which showed numerous stromal IgM bodies on immunofluorescence but no evidence of amyloid by routine histochemical methods.
Mitral Ratio of Peak Early to Late Diastolic Filling Velocity as a Predictor of Mortality in Middle-Aged and Elderly Adults
Authors: Jonathan N. Bella, Vittorio Palmieri, Mary J. Roman, Jennifer E. Liu, Thomas K. Welty, Elisa T. Lee, Richard R. Fabsitz, Barbara V. Howard, Richard B. Devereux
Journal: Circulation (2002)

With aging, left ventricular filling tends to decrease in early diastole, reducing the mitral ratio of peak early to late diastolic filling velocity (E/A). However, the prognostic significance of low or high E/A in older adults remains to be elucidated in population-based samples.Doppler echocardiograms were analyzed in 3008 American Indian participants in the second Strong Heart Study examination who had no more than mild mitral or aortic regurgitation. Participants were followed for a mean of 3 years after Doppler echocardiography to assess risks of all-cause and cardiac death associated with E/A <0.6 or >1.5; 2429 (81%) participants had normal E/A ratio, 490 (16%) had E/A <0.6, and 89 (3%) had E/A >1.5. All-cause mortality was higher with E/A <0.6 or E/A >1.5 (12% and 13% versus 6%), as was cardiac mortality (4.5% and 6.5% versus 1.6%; both P<0.001). Adjusting for age, sex, body mass index, systolic blood pressure, HDL and LDL cholesterol, smoking, hypertension, diabetes, coronary heart disease, left ventricular hypertrophy, and low ejection fraction (<40%), the relative risk of all-cause death with E/A >1.5 was 1.73 (95% CI, 0.99 to 3.03; P=0.05); the relative risk of cardiac death was 2.8 (95% CI, 1.19 to 6.75; P<0.05). E/A <0.6 was not independently associated with increased all-cause or cardiac mortality (P=0.19 and 0.31, respectively) after adjusting for covariates.In a population-based sample of middle-aged and elderly adults, mitral E/A >1.5 at baseline Doppler echocardiography is associated with 2-fold increased all-cause and 3-fold increased cardiac mortality independent of covariates; mitral E/A <0.6 was also associated with 2-fold increased all-cause and cardiac mortality but not independent of covariates.
PONTIAC (NT-proBNP Selected PreventiOn of cardiac eveNts in a populaTion of dIabetic patients without A history of Cardiac disease)
Authors: Martin Huelsmann, Stephanie Neuhold, Michael Resl, Guido Strunk, Helmut Brath, Claudia Francesconi, Christopher Adlbrecht, Rudolf Prager, Anton Luger, Richard Pacher, Martin Clodi
Journal: Journal of the American College of Cardiology (2013)
Tales from the crypts: regulatory peptides and cytokines in gastrointestinal homeostasis and disease
Authors: Juanita L. Merchant
Journal: Journal of Clinical Investigation (2007)

The gastrointestinal (GI) tract is composed of a diverse set of organs that together receive extracorporeal nutrition and convert it to energy substrates and cellular building blocks. In the process, it must sort through all that we ingest and discriminate what is useable from what is not, and having done that, it discards what is "junk." To accomplish these many and varied tasks, the GI tract relies on endogenous enteric hormones produced by enteroendocrine cells and the enteric nervous system. In many instances, the mediators of these tasks are small peptides that home to the CNS and accessory gut organs to coordinate oral intake with digestive secretions. As the contents of ingested material can contain harmful agents, the gut is armed with an extensive immune system. A breach of the epithelial barrier of the GI tract can result in local and eventually systemic disease if the gut does not mount an aggressive immune response.
Isolated nail fold vasculitis in rheumatoid arthritis.
Authors: R A Watts, D M Carruthers, D G Scott
Journal: Annals of the Rheumatic Diseases (1995)

OBJECTIVES--To establish the clinical significance of isolated nail fold vasculitis in patients with rheumatoid arthritis (RA). METHODS--Patients attending hospital with established RA were assessed by a single observer using unaided vision. Isolated nail fold vasculitis (NFV) was diagnosed as small nail edge or nail fold lesions without any evidence of other extra-articular or systemic vasculitis. Patients were followed prospectively. RESULTS--Thirty patients with isolated NFV were identified and followed for a median interval of 22 months. Three patients died within three months of diagnosis and six developed complications possibly indicative of extra-articular disease: xerostomia (three), pericarditis (one), pleural effusion and empyaema (one), pulmonary fibrosis (one). No patient developed systemic vasculitis. CONCLUSION--Isolated NFV has a favourable prognosis compared with systemic vasculitis. There is a low risk of developing systemic or extra-articular disease.
PWE-121 Comparison Of Kings Score, Apri and AST/ALT Ratio in Determining Severity of Liver Disease Versus Liver Biopsy
Authors: C Holdstock, M Joseph, N Thomas, T Bracey, T J Cross
Journal: Gut (2013)

<h3>Introduction Background and Aims</h3> Non-invasive markers of liver fibrosis are used to stratify the severity of Liver disease. The aim of the study was to compare the accuracy of the AST/ALT ratio, AST-platelet ratio index (APRI), and the Kings score in determining significant liver disease using liver biopsy as the reference standard. <h3>Methods</h3> A retrospective analysis of patients presenting for liver biopsy at the South West liver unit was reviewed. All patients had routine demographic, biochemical and haematological parameters collected including: aspartate aminotransferase (AST), alanine aminotransferase (ALT), platelets, international normalised ratio (INR) and patient age. The quality of the liver biopsy specimen was recorded including sample length, fragments, and number of portal tracts. Liver biopsy fibrosis was staged using the Ishak score. Non-invasive tests were assessed in their ability to correctly identify significant fibrosis (Ishak stage ≥ F3) or cirrhosis (Ishak Stage ≥F5). The scores were calculated as follows: AST/ALT; APRI = ((AST/AST upper limit of normal))/(Platelets) x100, and Kings score = (AST x Age x INR)/platelets. The accuracy of each test was compared to the reference standard using area under the receiver operated characteristic curve (AUROC). <h3>Results</h3> 170 patients were identified. 130 patients had complete data to calculate the scores. The median age 56 years (IQR 45–65), 55% patients were male. Numbers of patients by disease were: autoimmune hepatitis n = 23 (18%), PBC n = 3 (2.3%), PSC n = 2 (1.6%), Fatty Liver disease n = 24 (19%), ALD n = 26 (20%), HCV n = 12 (9.3%), Others n = 40 (30%). The median biopsy length 20mm (17 – 26), portal tracts 9 (5 – 13), biopsy cores 2 (1 – 2). AUROC for significant fibrosis (≥ F3) : AST/ALT = 0.84 (0.77 – 0.91), p = &lt; 0.0001, Kings Score = 0.73 (0.64 – 0.83), p &lt; 0.0001, APRI = 0.69 (0.60 – 0.79), p &lt; 0.0001. AUROC for cirrhosis (≥ F5): AST/ALT = 0.82 (0.75 – 0.90), p &lt; 0.0001, Kings Score = 0.71 (0.61 – 0.80), p &lt; 0.0001, APRI = 0.66 (0.57 – 0.76), p &lt; 0.0001. <h3>Conclusion Conclusions</h3> The AST/ALT ratio had the greatest diagnostic accuracy in determining significant fibrosis or cirrhosis. The Kings score performed better than APRI. AST/ALT is a simple guide to determine significant fibrosis and cirrhosis in liver disease. <h3>Disclosure of Interest</h3> None Declared.
Nothing left in store . . . but how do we measure attentional capacity?
Authors: Sergio Morra
Journal: Behavioral and Brain Sciences (2001)

I compare the concepts of “activation” and “storage” as foundations of short-term memory, and suggest that an attention-based view of STM does not need to posit specialized short-term stores. In particular, no compelling evidence supports the hypothesis of time-limited stores. Identifying sources of activation, examining the role of activated procedural knowledge, and studying working memory development are central issues in modelling capacity-limited focal attention.
Fluid Shear Stress Increases the Production of Granulocyte-Macrophage Colony-Stimulating Factor by Endothelial Cells via mRNA Stabilization
Authors: Keisuke Kosaki, Joji Ando, Risa Korenaga, Takahide Kurokawa, Akira Kamiya
Journal: Circulation Research (1998)

Abstract —To investigate whether the production of colony-stimulating factors (CSFs) by vascular endothelial cells is regulated by hemodynamic force, we exposed cultured human umbilical vein endothelial cells (HUVECs) to controlled levels of shear stress in a flow-loading apparatus and examined changes in the production of CSFs at both the protein and mRNA level. Exposure of HUVECs to a shear stress of 15 and 25 dyne/cm 2 markedly increased the release of granulocyte-macrophage CSF (GM-CSF) detected by ELISA to 5.0 and 9.5 times, respectively, the amount released by the static controls at 24 hours, but it had no significant influence on the release of granulocyte CSF or macrophage CSF. The results of reverse transcriptase–polymerase chain reaction demonstrated that GM-CSF mRNA began to increase as early as 2 hours after initiation of 15 dyne/cm 2 shear stress and continued to increase with time, reaching a peak of about four times the control levels at 24 hours. This increase in GM-CSF mRNA levels in response to shear stress depended on protein synthesis, because it was blocked by cycloheximide. Neither nuclear run-on assay or luciferase assay using a reporter gene containing GM-CSF gene promoter showed any significant change in transcription of the GM-CSF gene even after 24-hour exposure to a shear stress of 15 dyne/cm 2 . Actinomycin D chase experiments using a competitive polymerase chain reaction showed that shear stress extended the half-life of GM-CSF mRNA from ≈23 to 42 minutes in HUVECs. These findings suggest that fluid shear stress increases the production of GM-CSF in HUVECs via mRNA stabilization.
Relationship between microbiologic and histologic features in bacterial pneumonia.
Authors: C H Marquette, F Wallet, M C Copin, D Wermert, A Desmidt, P Ramon, R Courcol, A B Tonnel
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

To investigate the relationship between the lung damage resulting from pneumonia and the local bacterial burden, we conducted a study comparing histologic and bacteriologic findings in pigs infected with bacterial pneumonia while free of antibiotic therapy and previous or concomitant lung disease. Seventy-eight lung specimens were obtained from 17 animals. The main findings are the following: (1) histologic lesions of pneumonia as well as parenchymal bacterial burden were unevenly distributed within the lungs and even within the lung segments; (2) specimens showing histologic evidence of pneumonia had significantly higher bacterial counts than specimens with bronchial infection and specimens with neither bronchial nor lung infection; (3) there was no significant difference in bacterial counts between lesions defined as pneumonia, confluent pneumonia and abscessed pneumonia; (4) we could not define a clearcut threshold for quantitative cultures to discriminate the presence or absence of pneumonia. This study providing experimental insights into the relationship between microbiologic and histologic features in bacterial pneumonia confirms previous findings in humans. Although, for investigational purpose, lung cultures can be helpful in determining the bacterial etiology of pneumonia, these data do not support the use of quantitative cultures for establishing a definite diagnosis of pneumonia.