tbuckley/cabot-search huggingface dataset:
Impaired <scp>l</scp> -Arginine Transport and Endothelial Function in Hypertensive and Genetically Predisposed Normotensive Subjects
Authors: Markus P. Schlaich, Melinda M. Parnell, Belinda A. Ahlers, Samara Finch, Tanneale Marshall, Wei-Zheng Zhang, David M. Kaye
Journal: Circulation (2004)

Background— Impaired endothelium-dependent NO-mediated vasodilation is a key feature of essential hypertension and may precede the increase in blood pressure. We investigated whether transport of the NO precursor l -arginine is related to decreased endothelial function. Methods and Results— Radiotracer kinetics ([ 3 H] l -arginine) were used to measure forearm and peripheral blood mononuclear cell arginine uptake in hypertensive subjects (n=12) and in 2 groups of healthy volunteers with (n=15) and without (n=15) a family history of hypertension. In conjunction, forearm blood flow responses to acetylcholine and sodium nitroprusside were measured before and after a supplemental intra-arterial infusion of l -arginine. In vivo and in vitro measures of l -arginine transport were substantially reduced in the essential hypertension and positive family history groups compared with the negative family history group; however, no difference was detected in peripheral blood mononuclear cell mRNA or protein expression levels for the cationic amino acid transporter CAT-1. Plasma concentrations of l -arginine and N G , N G′ -dimethylarginine (ADMA) did not differ between groups. l -Arginine supplementation improved the response to acetylcholine only in subjects with essential hypertension and positive family history. Conclusions— Similar to their hypertensive counterparts, normotensive individuals at high risk for the development of hypertension are characterized by impaired l -arginine transport, which may represent the link between a defective l -arginine/NO pathway and the onset of essential hypertension. The observed transport defect is not due to apparent alterations in CAT-1 expression or elevated endogenous ADMA.
Persistent Changes in Myocardial Glucose Metabolism In Vivo During Reperfusion of a Limited-Duration Coronary Occlusion
Authors: Patrick H. McNulty, Dinesh Jagasia, Gary W. Cline, Chin K. Ng, Jennifer M. Whiting, Pradeep Garg, Gerald I. Shulman, Robert Soufer
Journal: Circulation (2000)

Rapid reperfusion of an occluded coronary artery salvages regional mechanical function, but this benefit may not be realized for hours or days because of postischemic stunning. Recovery from stunning is incompletely understood but may involve adaptive changes in heart glucose metabolism.To examine whether reversible coronary occlusion produces sustained changes in regional glucose metabolism in vivo, we performed a 20-minute left coronary artery occlusion followed by 24 hours of open-artery reperfusion in intact rats. Coronary occlusion produced stunning of the anterolateral left ventricle that resolved over 24 hours. When examined at 24 hours, reperfused regions were fully contractile and viable by vital staining and microscopy but demonstrated 25% reduction in blood flow and 50% increased uptake of circulating glucose, as estimated by in vivo [(13)N]NH(3) and [(18)F]fluorodeoxyglucose (FDG) tracer uptake. Reperfused regions had largely inactive glycogen synthase, low rates of glycogen synthesis, and persistent 50% glycogen depletion but increased flux of plasma [1-(13)C]glucose into myocardial [3-(13)C]alanine, indicating preferential shunting of imported glucose away from storage and into glycolysis.Sustained increases in regional glycolytic consumption of circulating glucose occur during reperfusion of a limited-duration coronary occlusion. This suggests a role for glycolytic ATP in the recovery from postischemic stunning in vivo. Furthermore, [(13)N]NH(3) /FDG regional mismatch may constitute a clinically accessible late metabolic signature of regional myocardial ischemia.
Systematic Review and Cumulative Analysis of Perioperative Outcomes and Complications After Robot-assisted Radical Cystectomy
Authors: Giacomo Novara, James W.F. Catto, Timothy Wilson, Magnus Annerstedt, Kevin Chan, Declan G. Murphy, Alexander Motttrie, James O. Peabody, Eila C. Skinner, Peter N. Wiklund, Khurshid A. Guru, Bertram Yuh
Journal: European Urology (2015)
Transactivation of Epidermal Growth Factor Receptor Is Involved in Leptin-Induced Activation of Janus-Activated Kinase 2 and Extracellular Signal–Regulated Kinase 1/2 in Human Gastric Cancer Cells
Authors: Dai Shida, Joji Kitayama, Ken Mori, Toshiaki Watanabe, Hirokazu Nagawa
Journal: Cancer Research (2005)

Abstract Leptin is known to act as a growth factor through the Janus-activated kinase (JAK)/signal transducer and activator of transcription signaling pathway as well as the mitogen-activated protein kinase pathway. In this study, we showed a novel signal transduction pathway using two human gastric cancer cell lines, MKN28 and MKN74. Both gastric cancer cells expressed leptin and its receptors (Ob-R) at the protein level. We found that leptin, even at as low as 0.1 ng/mL, induced significant tyrosine phosphorylation of epidermal growth factor receptor (EGFR). Time-course experiments revealed that phosphorylation was maximal after 5 minutes of stimulation and declined thereafter. We also revealed that tyrosine phosphorylation of EGFR induced by leptin was significantly attenuated by two inhibitors, an EGFR tyrosine kinase inhibitor, AG1478, and a broad-spectrum matrix metalloproteinase inhibitor, GM6001. This indicates that the pathway of EGFR transactivation induced by leptin is dependent on proteolytically released EGFR ligands. Leptin induced JAK2 activation and extracellular signal–regulated kinase (ERK) 1/2 activation in these gastric cancer cells, both of which occurred after the peak of EGFR transactivation. Pretreatment of gastric cancer cells with AG1478 significantly reduced the degree of phosphorylation of both JAK2 and ERK1/2. These findings indicate the involvement of EGFR transactivation in the activation of JAK2 and ERK1/2. Our results reveal that EGFR transactivation is involved in the leptin signaling pathway in gastric cancer cells, which extends the physiologic action of leptin beyond its central effects in the hypothalamus to regulate body weight.
Genome-wide, large-scale production of mutant mice by ENU mutagenesis
Authors: Martin Hrabé de Angelis, Heinrich Flaswinkel, Helmut Fuchs, Birgit Rathkolb, Dian Soewarto, Susan Marschall, Stephan Heffner, Walter Pargent, Kurt Wuensch, Martin Jung, André Reis, Thomas Richter, Francesca Alessandrini, Thilo Jakob, Edith Fuchs, Helmut Kolb, Elisabeth Kremmer, Karlheinz Schaeble, Boris Rollinski, Adelbert Roscher, Christoph Peters, Thomas Meitinger, Tim Strom, Thomas Steckler, Florian Holsboer, Thomas Klopstock, Florian Gekeler, Catherine Schindewolf, Thomas Jung, Karen Avraham, Heidrun Behrendt, Johannes Ring, Andreas Zimmer, Klaus Schughart, Klaus Pfeffer, Eckhard Wolf, Rudi Balling
Journal: Nature Genetics (2000)
Tracking and Prediction of Arterial Blood Pressure From Childhood to Young Adulthood in 868 Patients With Type 1 Diabetes
Authors: Ina Knerr, Axel Dost, Rudolf Lepler, Klemens Raile, Edith Schober, Wolfgang Rascher, Reinhard W. Holl
Journal: Diabetes Care (2008)

OBJECTIVE—Arterial blood pressure was followed in 868 patients with type 1 diabetes aged 6.0–19.9 years in 95 centers in Germany and Austria. RESEARCH DESIGN AND METHODS—European blood pressure reference data for 28,043 children and adolescents were used with respect to age and sex. Data were stratified into three groups: prepubertal, pubertal, and postpubertal. RESULTS—Up to 4% of the participants in the younger age-groups and 13.9% of the postpubertal patients exhibited blood pressure values &amp;gt;97th centile. Blood pressure levels correlated with A1C level and BMI Z score. Tracking of blood pressure revealed that children with elevated blood pressure had higher blood pressure in adolescence and young adulthood. CONCLUSIONS—Patients with higher blood pressure in childhood showed elevated blood pressure later in life. We need to focus on the diagnosis of hypertension in children with type 1 diabetes and to study the efficacy of early intervention.
Steady state generation of mucosal IgA+ plasmablasts is not abrogated by B cell depletion therapy with rituximab
Authors: H. Mei, D. Frolich, C. Giesecke, C. Loddenkemper, K. Reiter, S. Schmidt, E. Feist, C. Daridon, H.-P. Tony, A. Radbruch, T. Dorner
Journal: Annals of the Rheumatic Diseases (2011)

B cell depletion therapy with rituximab (anti-CD20) has been established for treating RA. While rituximab efficiently removes circulating B cells, its effects on tissue-based B cells, especially on those in gut-associated lymphoid tissues, remained unclear and are discussed as potential reasons for individual unresponsiveness. Here we studied the ffect of rituxuimab treatment on circulating and tissue-resident IgA plasmablasts as correlates of mucosal B cell activation in patients with RA. Patients with rheumatoid arthritis were given 2x1g rituximab and peripheral blood was analyzed for circulating B cells and plasmablasts by flow cytometry before and at 2-9 months after rituximab infusion. Some patients were also analyzed additionally analyzed during a second treatment course. Cell proliferation was analyzed using Ki-67 expression and plasmablast migration was assessed towards CXCL12 and CCL28 using an in vitro transwell system. Peripheral blood CD20+ naïve and memory B cell numbers were reduced to &gt;0.02% of their intial numbers before therapy, while plasmablasts/plasma cells were persistently detectable in the blood at ∼26-119%. These circulating plasmablasts/plasma cells expressed a mucosal phenoytpe, i.e. IgA, beta7 integrin and CCR10 before and throughout the B cell depletion phase. Recently activated plasmablasts were revelead by high epxression of HLA-DR, in vitro migration towards CXCL12 and CCL28 and Ki-67 expression. Consistently, IgA+ plasmablasts and plasma cells were also identified in lamina propria biopsies of rituxuimab treated patients. Numbers of circulating plasmablasts did not significantly correlate with DAS28 values. Notably, antibody produced by peripheral blood IgA+ plasmablasts generated during B cell depletion frequently bound to bacterial antigens. Our results suggest the persistent generation of mucosal plasmablasts during B cell depletion with rituximab, pointing towards the resistance of some functional B cells, residing in the mucosa and permitting the differentiation of IgA+ plasmablasts. Our data suggest that rituximab has a limited capacity to target mucosal B cells and antibody production.
Direct costs of ankylosing spondylitis and its determinants: an analysis among three European countries
Authors: A Boonen, D van der Heijde, R Landewé, F Guillemin, M Rutten-van Mölken, M Dougados, H Mielants, K de Vlam, H van der Tempel, S Boesen, A Spoorenberg, H Schouten, Sj van der Linden
Journal: Annals of the Rheumatic Diseases (2003)

<b>Objective:</b> To assess direct costs associated with ankylosing spondylitis (AS). To determine which variables, including country, predict costs. <b>Methods:</b> 216 patients with AS from the Netherlands, France, and Belgium participated in a two year observational study and filled in bimonthly economic questionnaires. Disease related healthcare resource use was measured and direct costs were calculated from a societal perspective (true cost estimates) and from a financial perspective (country-specific tariffs). Predictors of costs were assessed using Cox's regression analysis. <b>Results:</b> 209 patients provided sufficient data for cost analysis. Mean annual societal direct costs for each patient were €2640, of which 82% were direct healthcare costs. In univariate analysis costs were higher in the Netherlands than in Belgium, but this difference disappeared after adjusting for baseline differences in patients' characteristics among countries. Longer disease duration, lower education, worse physical function, and higher disease activity were predictors of costs. Mean annual direct costs from a financial perspective were €2122, €1402, and €941 per patient in the Netherlands, France, and Belgium, respectively. For each country, costs from a financial perspective were significantly lower than costs from a societal perspective. <b>Conclusion:</b> Direct costs for AS are substantial in three European countries but not significantly different after adjusting for baseline characteristics among countries. Worse physical function and higher disease activity are important determinants of costs, suggesting better disease control might reduce the costs of AS. The difference in costs from a societal and financial perspective emphasises the importance of an economic analysis.
MutS homologue hMSH5: role in cisplatin-induced DNA damage response
Authors: Joshua D Tompkins, Xiling Wu, Chengtao Her
Journal: Molecular Cancer (2012)

Abstract Background Cisplatin ( cis -diamminedichloroplatinum (II), CDDP) and its analogues constitute an important class of anticancer drugs in the treatment of various malignancies; however, its effectiveness is frequently affected by mutations in genes involved in the repair and signaling of cisplatin-induced DNA damage. These observations necessitate a need for a better understanding of the molecular events governing cellular sensitivity to cisplatin. Results Here, we show that hMSH5 mediates sensitization to cisplatin-induced DNA damage in human cells. Our study indicates that hMSH5 undergoes cisplatin-elicited protein induction and tyrosine phosphorylation. Silencing of hMSH5 by RNAi or expression of hMSH5 phosphorylation-resistant mutant hMSH5 Y742F elevates cisplatin-induced G2 arrest and renders cells susceptible to cisplatin toxicity at clinically relevant doses. In addition, our data show that cisplatin promotes hMSH5 chromatin association and hMSH5 deficiency increases cisplatin-triggered γ-H2AX foci. Consistent with a possible role for hMSH5 in recombinational repair of cisplatin-triggered double-strand breaks (DSBs), the formation of cisplatin-induced hMSH5 nuclear foci is hRad51-dependent. Conclusion Collectively, our current study has suggested a role for hMSH5 in the processing of cisplatin-induced DSBs, and silencing of hMSH5 may provide a new means to improve the therapeutic efficacy of cisplatin.
Injuries in a Russian male professional volleyball team during the 2009-2010 season
Authors: Y M Demin, G Y Shipulin
Journal: British Journal of Sports Medicine (2011)

Background There are few studies of injury rates in Russia's Volleyball Championship. Objective To investigate incidence and characteristics of injuries in one male volleyball team. Design Prospective cohort pilot study, 2009–2010 (preseason and the competitive season). Setting Professional athletes of elite male division of Russia's Championship (Super League). Participants 16 players had been taking part in preparation and competitions from 23 June 2009 to 15 May 2010 as The ‘Lokomotiv-Belogorie’ volleyball team. Interventions Volleyball exposure during training and matches was recorded by the coach. The team physician recorded all injuries which had occurred. The incidence of injury was expressed as number of injuries per 1000 player hours. Results 105 injuries were recorded, 22 (20.95%) resulted in one or more days of missed practice or competition. The overall incidence of time-loss injuries was estimated as 2.37 per 1000 player hours. The game incidence was 10.7 and the practice incidence was 1.84. Majority of injuries (86.36%) had slight or minor severity. The most common location of time-loss injuries was the ankle/foot (32.82%), followed by the spine/back (27.27%) and shoulder (13.63%). The most common types were sprain (22.73%) and overuse injuries (63.64%). Many slight and overuse injuries did not cause player to stop playing (only 32.6% of the acute and 11.86% of the overuse were time-loss injuries). Among all registered injuries the prevalence locations were spine/back (22 cases or 21.95%), shoulder (21 cases or 20%) and knee (18 cases or 17.14%) and 71.43% were overuse and 28.57% traumatic. Conclusions The study revealed a high injury incidence rate in games compared to practice. The majority of injuries were overuse injuries. Slight and minor injuries often occurred and most of them were not time-loss. Future investigations are required.
From Drought Sensing to Developmental Control: Evolution of Cyclic AMP Signaling in Social Amoebas
Authors: A. V. Ritchie, S. van Es, C. Fouquet, P. Schaap
Journal: Molecular Biology and Evolution (2008)

Amoebas and other protists commonly encyst when faced with environmental stress. Although little is known of the signaling pathways that mediate encystation, the analogous process of spore formation in dictyostelid social amoebas is better understood. In Dictyostelium discoideum, secreted cyclic AMP (cAMP) mediates the aggregation of starving amoebas and induces the differentiation of prespore cells. Intracellular cAMP acting on cAMP-dependent protein kinase (PKA) triggers the maturation of spores and prevents their germination under the prevalent conditions of high osmolality in the spore head. The osmolyte-activated adenylate cyclase, ACG, produces cAMP for prespore differentiation and inhibition of spore germination. To retrace the origin of ACG function, we investigated ACG gene conservation and function in species that span the dictyostelid phylogeny. ACG genes, osmolyte-activated ACG activity, and osmoregulation of spore germination were detected in species that represent the 4 major groups of Dictyostelia. Unlike the derived species D. discoideum, many basal Dictyostelia have retained the ancestral mechanism of encystation from solitary amoebas. In these species and in solitary amoebas, encystation is independently triggered by starvation or by high osmolality. Osmolyte-induced encystation was accompanied by an increase in cAMP and prevented by inhibition of PKA, indicating that ACG and PKA activation mediate this response. We propose that high osmolality signals drought in soil amoebas and that developmental cAMP signaling in the Dictyostelia has evolved from this stress response.
Timeliness of Tissue-Type Plasminogen Activator Therapy in Acute Ischemic Stroke
Authors: Gregg C. Fonarow, Eric E. Smith, Jeffrey L. Saver, Mathew J. Reeves, Deepak L. Bhatt, Maria V. Grau-Sepulveda, DaiWai M. Olson, Adrian F. Hernandez, Eric D. Peterson, Lee H. Schwamm
Journal: Circulation (2011)

The benefits of intravenous tissue-type plasminogen activator (tPA) in acute ischemic stroke are time dependent, and guidelines recommend an arrival to treatment initiation (door-to-needle) time of ≤60 minutes.Data from acute ischemic stroke patients treated with tPA within 3 hours of symptom onset in 1082 hospitals participating in the Get With the Guidelines-Stroke Program from April 1, 2003, to September 30, 2009 were studied to determine frequency, patient and hospital characteristics, and temporal trends in patients treated with door-to-needle times ≤60 minutes. Among 25 504 ischemic stroke patients treated with tPA, door-to-needle time was ≤60 minutes in only 6790 (26.6%). Patient factors most strongly associated with door-to-needle time ≤60 minutes were younger age, male gender, white race, or no prior stroke. Hospital factors associated with ≤60 minute door-to-needle time included greater annual volumes of tPA-treated stroke patients. The proportion of patients with door-to-needle times ≤60 minutes varied widely by hospital (0% to 79.2%) and increased from 19.5% in 2003 to 29.1% in 2009 (P<0.0001). Despite similar stroke severity, in-hospital mortality was lower (adjusted odds ratio, 0.78; 95% confidence interval, 0.69 to 0.90; P<0.0003) and symptomatic intracranial hemorrhage was less frequent (4.7% versus 5.6%; P<0.0017) for patients with door-to-needle times ≤60 minutes compared with patients with door-to-needle times >60 minutes.Fewer than one-third of patients treated with intravenous tPA had door-to-needle times ≤60 minutes, with only modest improvement over the past 6.5 years. These findings support the need for a targeted initiative to improve the timeliness of reperfusion in acute ischemic stroke.
Controlling Natural Killer Cell Responses: Integration of Signals for Activation and Inhibition
Authors: Eric O. Long, Hun Sik Kim, Dongfang Liu, Mary E. Peterson, Sumati Rajagopalan
Journal: Annual Review of Immunology (2013)

Understanding how signals are integrated to control natural killer (NK) cell responsiveness in the absence of antigen-specific receptors has been a challenge, but recent work has revealed some underlying principles that govern NK cell responses. NK cells use an array of innate receptors to sense their environment and respond to alterations caused by infections, cellular stress, and transformation. No single activation receptor dominates; instead, synergistic signals from combinations of receptors are integrated to activate natural cytotoxicity and cytokine production. Inhibitory receptors for major histocompatibility complex class I (MHC-I) have a critical role in controlling NK cell responses and, paradoxically, in maintaining NK cells in a state of responsiveness to subsequent activation events, a process referred to as licensing. MHC-I-specific inhibitory receptors both block activation signals and trigger signals to phosphorylate and inactivate the small adaptor Crk. These different facets of inhibitory signaling are incorporated into a revocable license model for the reversible tuning of NK cell responsiveness.
Identification of a variant of gross leukemia virus that induces disease in mice inoculated as adults.
Authors: J H Wolfe, K J Blank
Journal: The Journal of Experimental Medicine (1983)

Gross murine leukemia virus normally induces leukemia (thymic lymphoma) in mice inoculated as neonates, but not as adults. We have isolated an apparent variant of this virus which induces thymomas when inoculated i.p. into susceptible adult mice. Using H-2 congenic BALB and C57BL mice, susceptibility to virus-induced thymomagenesis was found to be linked to the H-2 complex. In addition, a radioresistant immune mechanism leading to inhibition of tumor growth was observed in mice with a C57BL but not a BALB background.
Ultrastructural immunocytochemical analysis of lymphocytes infiltrating bile duct epithelia in primary biliary cirrhosis
Authors: Gotaro Yamada, Ichinosuke Hyodo, Kazuo Tobe, Motowo Mizuno, Takashi Nishihara, Toshinari Kobayashi, Hideo Nagashima
Journal: Hepatology (1986)

Subpopulations of lymphocytes in portal areas, especially infiltrating bile duct epithelia were analyzed by light and electron microscopy using indirect peroxidaselabeled antibody method and monoclonal antibodies against pan-T (Leu 1), cytotoxic/suppressor T (Leu 2a), helper/inducer T (Leu 3a) and natural killer/K (Leu 7) and suppressor T (Leu 15) cells in liver biopsy specimens from four patients with primary biliary cirrhosis. Bile ducts with chronic nonsuppurative destructive cholangitis were observed in two patients. Leu 1+ and Leu 2+ cells were frequently seen in intimate contact with epithelial ductal cells. The majority of intraepithelial cells possessing Leu 2a antigen did not react with anti-Leu 15 antibody. Leu 3a+ or Leu 7+ cells seldom infiltrated ductal epithelia. These findings indicate that the majority of intraepithelial lymphocytes in bile ducts most likely represent Leu 2a+15- cytotoxic T cells. By immunoelectron microscopy, Leu 1+ or Leu 2a+ lymphocytes often breached the basement membrane of bile ducts and were present within dilated intercellular spaces between biliary epithelial cells. Furthermore, they often formed sharp or broad contacts with the epithelial cells, and occasionally pseudopods projecting from the surfaces of Leu 2a+ cells extended into the epithelial cells. Most of Leu 2a+ lymphocytes contained little cytoplasm with few granules and a small Golgi apparatus. Such findings suggest that cytotoxic T cells may contribute to the pathogenesis of chronic nonsuppurative destructive cholangitis in primary biliary cirrhosis.