tbuckley/cabot-search huggingface dataset:
Vardenafil, a New Phosphodiesterase Type 5 Inhibitor, in the Treatment of Erectile Dysfunction in Men With Diabetes
Authors: Irwin Goldstein, Jay M. Young, Jerome Fischer, Keith Bangerter, Thomas Segerson, Terry Taylor
Journal: Diabetes Care (2003)

OBJECTIVE—This study evaluated the efficacy and safety of vardenafil treatment for erectile dysfunction (ED) in men with diabetes. RESEARCH DESIGN AND METHODS—In this prospective multicenter double-blind placebo-controlled fixed-dose parallel-group phase III trial, 452 patients with diabetes (type 1 or type 2) and ED were randomized to take 10 or 20 mg vardenafil or placebo as needed for 12 weeks. Efficacy responses were assessed by International Index of Erectile Function domain scores, rates of vaginal penetration and successful intercourse, and a global assessment question (GAQ) about erection improvement during the previous 4 weeks. RESULTS—After 12 weeks of treatment, a dose-dependent (P = 0.02) improvement in erections was noted for the GAQ, with 57 and 72% of men taking 10 mg or 20 mg vardenafil, respectively, reporting improved erections, in contrast to 13% after taking placebo (P &amp;lt; 0.0001). For the erectile function domain, dose-dependent (P = 0.03) final scores for the 10- and 20-mg dose were 17.1 and 19.0 compared with 12.6 for placebo (P &amp;lt; 0.0001). Both vardenafil doses significantly enhanced the rates of successful penetration (P &amp;lt; 0.0001) and successful intercourse (P &amp;lt; 0.0001) compared with placebo. Vardenafil treatment was effective in increasing intercourse success rates at all levels of baseline ED severity, at each level of plasma HbA1c, and for type 1 and 2 diabetes. Treatment-emergent adverse events were primarily mild to moderate headache (≤13%), flushing (≤10%), and rhinitis (≤10%). CONCLUSIONS—Vardenafil statistically improved erectile function and was generally well tolerated in these diabetic patients with ED.
Thermic Stress Syndrome
Authors: Robert W. Meyers
Journal: JAMA (1982)

<h3>To the Editor.—</h3> The letter by James D. Lydiatt, MD, and Gary E. Hill, MD, entitled "Treatment of Heat Stroke by Dantrolene" (1981;246:41), again emphasizes that "heat stroke" and "malignant hyperthermia" may be identical conditions with different triggering mechanisms that respond to the same treatment. Other variations of thermic stress syndrome are "sudden death syndrome in athletes," "idiopathic recurrent rhabdomyolysis with myoglobinuria," "exercise myohemoglobinuria," "fulminant hyperthermic porcine stress syndrome" and "neuroleptic malignant syndrome." Each of these syndromes has been described in the literature with scant recognition that other authors, using different titles, have described what seems to be the same malady. Measures used for successful treatment of fulminant hyperthermic porcine stress syndrome, malignant hyperthermia, and heat stroke appear to be the same.<sup>1</sup>In 1973, Meltzer<sup>2</sup>discussed the similarities between the neuroleptic malignant syndrome and malignant hyperpyrexia. Probably, treatment will prove to be the same. These thermic stress syndromes
Rhinitis is associated with a greater risk of intermittent claudication in adults
Authors: M. Ferrari, G. Pesce, A. Marcon, P. Vallerio, A. M. Fratta Pasini, R. de Marco
Journal: Allergy (2014)

Abstract Background Chronic inflammatory airway disorders have been reported to be associated with vascular diseases of the heart and central nervous system, but their association with peripheral arterial disease ( PAD ), a high‐prevalence vascular illness, has not been investigated. Objective To evaluate the association of asthma and rhinitis with intermittent claudication, which is a typical symptom of PAD . Methods The data were collected in the gene–environment interaction in respiratory disease survey, a population‐based, multicase–control study. Participants underwent a standardized interview, skin prick tests and pulmonary function tests. The associations between respiratory diseases and intermittent claudication (i.e. pain in the leg during walking that disappears within 10 min when standing still) were estimated through relative risk ratios ( RRR ) by multinomial logistic regression models. Results 1174 subjects (aged 20–64 years, of which 52% were females) underwent clinical examinations and were classified into four groups: asthma only ( n = 81), asthma–rhinitis overlap ( n = 292), rhinitis only ( n = 299) and controls ( n = 345). The prevalence of intermittent claudication in these groups was, respectively, 2.5%, 3.4%, 6.4% and 2.3%. After adjusting for smoking habits and a wide range of established and potential vascular risk factors, rhinitis without asthma was associated with intermittent claudication ( RRR :4.63, 95% CI :1.72–12.5), whereas no significant association was found with asthma alone ( RRR :1.45, 95% CI :0.27–7.76) or asthma–rhinitis overlap ( RRR :2.89, 95% CI :0.91–9.18). Atopy did not modify the observed association between intermittent claudication and rhinitis. Conclusions Our findings suggest that rhinitis is associated with PAD , a predictor of future cerebrovascular and cardiovascular events, independently of the presence of atopy.
Gastric outlet obstruction as a presenting manifestation of systemic lupus erythematosus.
Authors: E F Posthuma, P Warmerdam, M P Chandie Shaw, F C Breedveld, J D Macfarlane, A van der Sluys Veer, C B Lamers
Journal: Gut (1994)

A patient with nausea and vomiting who subsequently proved to have systemic lupus erythematosus is described. Although gastrointestinal involvement is common in systemic lupus erythematosus it is rare as an initial manifestation. Gastric outlet obstruction was shown on the air contrast examination while the mucosa at endoscopy was normal. The gastric symptoms regressed after treatment with high dose corticosteroids and a repeat air contrast examination of the stomach was normal. This stricturing process may have been caused by a local peritonitis.
Platelet-derived HMGB1 is a critical mediator of thrombosis
Authors: Sebastian Vogel, Rebecca Bodenstein, Qiwei Chen, Susanne Feil, Robert Feil, Johannes Rheinlaender, Tilman E. Schäffer, Erwin Bohn, Julia-Stefanie Frick, Oliver Borst, Patrick Münzer, Britta Walker, Justin Markel, Gabor Csanyi, Patrick J. Pagano, Patricia Loughran, Morgan E. Jessup, Simon C. Watkins, Grant C. Bullock, Jason L. Sperry, Brian S. Zuckerbraun, Timothy R. Billiar, Michael T. Lotze, Meinrad Gawaz, Matthew D. Neal
Journal: Journal of Clinical Investigation (2015)

Thrombosis and inflammation are intricately linked in several major clinical disorders, including disseminated intravascular coagulation and acute ischemic events. The damage-associated molecular pattern molecule high-mobility group box 1 (HMGB1) is upregulated by activated platelets in multiple inflammatory diseases; however, the contribution of platelet-derived HMGB1 in thrombosis remains unexplored. Here, we generated transgenic mice with platelet-specific ablation of HMGB1 and determined that platelet-derived HMGB1 is a critical mediator of thrombosis. Mice lacking HMGB1 in platelets exhibited increased bleeding times as well as reduced thrombus formation, platelet aggregation, inflammation, and organ damage during experimental trauma/hemorrhagic shock. Platelets were the major source of HMGB1 within thrombi. In trauma patients, HMGB1 expression on the surface of circulating platelets was markedly upregulated. Moreover, evaluation of isolated platelets revealed that HMGB1 is critical for regulating platelet activation, granule secretion, adhesion, and spreading. These effects were mediated via TLR4- and MyD88-dependent recruitment of platelet guanylyl cyclase (GC) toward the plasma membrane, followed by MyD88/GC complex formation and activation of the cGMP-dependent protein kinase I (cGKI). Thus, we establish platelet-derived HMGB1 as an important mediator of thrombosis and identify a HMGB1-driven link between MyD88 and GC/cGKI in platelets. Additionally, these findings suggest a potential therapeutic target for patients sustaining trauma and other inflammatory disorders associated with abnormal coagulation.
IL-11 Is Required for A1 Adenosine Receptor–Mediated Protection against Ischemic AKI
Authors: Joo Yun Kim, Mihwa Kim, Ahrom Ham, Kevin M. Brown, Robert W. Greene, Vivette D. D’Agati, H. Thomas Lee
Journal: Journal of the American Society of Nephrology (2013)

A1 adenosine receptor activation ameliorates ischemic AKI through the induction of renal proximal tubular sphingosine kinase-1. However, systemic adverse effects may limit A1 adenosine receptor-based therapy for ischemic AKI, indicating a need to identify alternative therapeutic targets within this pathway. Here, we evaluated the function of renal proximal tubular IL-11, a clinically approved hematopoietic cytokine, in A1 adenosine receptor-mediated induction of sphingosine kinase-1 and renal protection. Treatment of human proximal tubule epithelial (HK-2) cells with a selective A1 adenosine receptor agonist, chloro-N(6)-cyclopentyladenosine (CCPA), induced the expression of IL-11 mRNA and protein in an extracellular signal-regulated kinase-dependent manner, and administration of CCPA in mice induced renal synthesis of IL-11. Pretreatment with CCPA protected against renal ischemia-reperfusion injury in wild-type mice, but not in IL-11 receptor-deficient mice. Administration of an IL-11-neutralizing antibody abolished the renal protection provided by CCPA. Similarly, CCPA did not induce renal IL-11 expression or protect against renal ischemia-reperfusion injury in mice lacking the renal proximal tubular A1 adenosine receptor. Finally, treatment with CCPA induced sphingosine kinase-1 in HK-2 cells and wild-type mice, but not in IL-11 receptor-deficient or renal proximal tubule A1 adenosine receptor-deficient mice. Taken together, these results suggest that induction of renal proximal tubule IL-11 is a critical intermediary in A1 adenosine receptor-mediated renal protection that warrants investigation as a novel therapeutic target for the treatment of ischemic AKI.
A prospective study on antiribosomal P proteins in two cases of familial lupus and recurrent psychosis.
Authors: R H Derksen, A P van Dam, F H Gmelig Meyling, J W Bijlsma, R J Smeenk
Journal: Annals of the Rheumatic Diseases (1990)

In two siblings with systemic lupus erythematosus (SLE), who experienced two episodes of psychosis each, a longitudinal study of autoantibodies, including antibodies to ribosomal P proteins, is described. In two of three evaluable periods of 15 weeks antedating psychosis a rise followed by a spontaneous drop in anti-P levels was recorded. In the third period antibodies to ribosomal protein P were absent. It is concluded that results with single samples are not informative, and that frequent measurement of antibodies to ribosomal protein P in patients with SLE may have limited predictive value for psychosis.
Causes and investigation of increasing dyspnoea in rheumatoid arthritis.
Authors: J C Hacking, C D Flower
Journal: Annals of the Rheumatic Diseases (1995)

Fibrosing alveolitis and bronchiolitis obliterans are two of the many pulmonary manifestations of the connective tissue disorders. When shortness of breath is the main complaint, it is often difficult to diagnose the individual causative lesion from the clinical examination, lung function tests, and chest radiographic findings. In such cases high resolution computed tomography, with its increased sensitivity and specificity for analysis of the pulmonary parenchyma, provides an excellent diagnostic tool for determining the presence and type of pulmonary abnormality.
The forgotten Barcroft/Edholm reflex: potential role in exercise associated collapse
Authors: T D Noakes
Journal: British Journal of Sports Medicine (2003)

Adenosine A<sub>2a</sub> receptor antagonists reduce symptom severity in Parkinson disease (PD) and animal models. Rodent studies support the hypothesis that A<sub>2a</sub> antagonists produce this benefit by reducing the inhibitory output of the basal ganglia indirect pathway. One way to test this hypothesis in humans is to quantify regional pharmacodynamic responses with cerebral blood flow (CBF) imaging. That approach has also been proposed as a tool to accelerate pharmaceutical dose finding, but has not yet been applied in humans to drugs in development. We successfully addressed both these aims with a perfusion magnetic resonance imaging (MRI) study of the novel adenosine A<sub>2a</sub> antagonist SYN115. During a randomized, double-blind, placebo-controlled, crossover study in 21 PD patients on levodopa but no agonists, we acquired pulsed arterial spin labeling MRI at the end of each treatment period. SYN115 produced a highly significant decrease in thalamic CBF, consistent with reduced pallidothalamic inhibition via the indirect pathway. Similar decreases occurred in cortical regions whose activity decreases with increased alertness and externally focused attention, consistent with decreased self-reported sleepiness on SYN115. Remarkably, we also derived quantitative pharmacodynamic parameters from the CBF responses to SYN115. These results suggested that the doses tested were on the low end of the effective dose range, consistent with clinical data reported separately. We conclude that (1) SYN115 enters the brain and exerts dose-dependent regional effects, (2) the most prominent of these effects is consistent with deactivation of the indirect pathway as predicted by preclinical studies; and (3) perfusion MRI can provide rapid, quantitative, clinically relevant dose-finding information for pharmaceutical development.
Antimicrobial prophylaxis in allogeneic bone marrow transplantation. Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Haematology and Oncology
Authors: W.H. Krüger, J. Bohlius, O.A. Cornely, H. Einsele, H. Hebart, G. Massenkeil, S. Schüttrumpf, G. Silling, A.J. Ullmann, D.T. Waldschmidt, H.-H. Wolf
Journal: Annals of Oncology (2005)
Transfusion Strategies for Patients in Pediatric Intensive Care Units
Authors: Jacques Lacroix, Paul C. Hébert, James S. Hutchison, Heather A. Hume, Marisa Tucci, Thierry Ducruet, France Gauvin, Jean-Paul Collet, Baruch J. Toledano, Pierre Robillard, Ari Joffe, Dominique Biarent, Kathleen Meert, Mark J. Peters
Journal: New England Journal of Medicine (2007)

The optimal hemoglobin threshold for erythrocyte transfusions in critically ill children is unknown. We hypothesized that a restrictive transfusion strategy of using packed red cells that were leukocyte-reduced before storage would be as safe as a liberal transfusion strategy, as judged by the outcome of multiple-organ dysfunction.
Network motif analysis of a multi-mode genetic-interaction network
Authors: R James Taylor, Andrew F Siegel, Timothy Galitski
Journal: Genome biology (2007)

Different modes of genetic interaction indicate different functional relationships between genes. The extraction of biological information from dense multi-mode genetic-interaction networks demands appropriate statistical and computational methods. We developed such methods and implemented them in open-source software. Motifs extracted from multi-mode genetic-interaction networks form functional subnetworks, highlight genes dominating these subnetworks, and reveal genetic reflections of the underlying biochemical system.
Phase II Study of Sorafenib in Patients With Advanced Hepatocellular Carcinoma
Authors: Ghassan K. Abou-Alfa, Lawrence Schwartz, Sergio Ricci, Dino Amadori, Armando Santoro, Arie Figer, Jacques De Greve, Jean-Yves Douillard, Chetan Lathia, Brian Schwartz, Ian Taylor, Marius Moscovici, Leonard B. Saltz
Journal: Journal of Clinical Oncology (2006)

This phase II study of sorafenib, an oral multikinase inhibitor that targets Raf kinase and receptor tyrosine kinases, assessed efficacy, toxicity, pharmacokinetics, and biomarkers in advanced hepatocellular carcinoma (HCC) patients.Patients with inoperable HCC, no prior systemic treatment, and Child-Pugh (CP) A or B, received continuous, oral sorafenib 400 mg bid in 4-week cycles. Tumor response was assessed every two cycles using modified WHO criteria. Sorafenib pharmacokinetics were measured in plasma samples. Biomarker analysis included phosphorylated extracellular signal regulated kinase (pERK) in pretreatment biopsies (immunohistochemistry) and blood-cell RNA expression patterns in selected patients.Of 137 patients treated (male, 71%; median age, 69 years), 72% had CP A, and 28% had CP B. On the basis of independent assessment, three (2.2%) patients achieved a partial response, eight (5.8%) had a minor response, and 46 (33.6%) had stable disease for at least 16 weeks. Investigator-assessed median time to progression (TTP) was 4.2 months, and median overall survival was 9.2 months. Grade 3/4 drug-related toxicities included fatigue (9.5%), diarrhea (8.0%), and hand-foot skin reaction (5.1%). There were no significant pharmacokinetic differences between CP A and B patients. Pretreatment tumor pERK levels correlated with TTP. A panel of 18 expressed genes was identified that distinguished "nonprogressors" from "progressors" with an estimated 100% accuracy.Although single-agent sorafenib has modest efficacy in HCC, the manageable toxicity and mechanisms of action support a role for combination regimens with other anticancer agents.
Antigen-specific T-helper cells stimulate H-2-compatible and H-2-incompatible B-cell blasts polyclonally.
Authors: M H Schreier, J Andersson, W Lernhardt, F Melchers
Journal: The Journal of Experimental Medicine (1980)

Lipopolysaccharide (LPS)-activated B-cell blasts from C57BL/6J nu/nu spleen cells develop into IgM-secreting clones after stimulation by antigen-specific T-helper cells of C57BL/6J origin. Although induction of help is antigen-dependent, help itself acts polyclonally. 1 of 1--3 B-cell blasts is restimulated in a homologous fashion by LPS, or in a heterologous fashion by sheep erythrocyte (SRC)- or horse erythrocyte (HRC)-activated T-helper cells. The repertoire of activated B-cell blasts reflects the polyclonal nature of activation: approximately 1 in 1,000--3,000 restimulated B-cell blasts is specific for SRC, 1 in 300--1,000 is specific for HRC, and 1 in 100--300 specific for trinitrophenylated SRC (TNP30-SRC). B-cell blasts that are either H-2 compatible or H-2 incompatible with the antigen-activated T-cell help are stimulated polyclonally in similar high frequencies. Thus, neither antigen nor H-2 compatibility are required to stimulate a B-cell blast into the next cell cycle.
The Complete Mitochondrial DNA Sequence of the Basal Hexapod Tetrodontophora bielanensis: Evidence for Heteroplasmy and tRNA Translocations
Authors: F Nardi, A Carapelli, P P Fanciulli, R Dallai, F Frati
Journal: Molecular Biology and Evolution (2001)

We present the complete 15,455-nt mitochondrial DNA sequence of the springtail Tetrodontophora bielanensis (Arthropoda, Hexapoda, Collembola). The gene content is typical of most metazoans, with 13 protein-coding genes (PCGs), 2 genes encoding for ribosomal RNA subunits, and 22 tRNA genes. The nucleotide sequence shows the well-known A+T bias typical of insect mtDNA; its A+T content is lower (72.7%) than that observed in other insect species, but still higher than that in other arthropodan taxa. The bias appears to be uniform across the whole molecule, unlike other insect taxa, which show increased A+T content in the so-called A+T-rich region. However, the bias is slightly higher in the third codon positions of the PCGs (81.4%). Anomalous initiation codons have been observed in the nad2 and the cox1 genes. In the latter, the ATTTAA hexanucleotide is suggested to be involved in the initiation signaling. All tRNAs could be folded into the typical cloverleaf secondary structure, but the tRNA for cysteine appears to be missing the DHU arm. Long tandemly repeated regions (193 nt) were found in the A+T-rich region, which in turn was shown to have the possibility of forming a complex array of secondary structures. One of these structures encompassed the junction between the repeats. The A+T-rich region was also interesting in that it showed heteroplasmy in the number of repeats. Three haplotypes were found, possessing 2, 3, and 4 identical repeats, respectively. The order of protein coding and rRNA genes in the molecule was determined and was identical to that of all insects studied so far. However, two tRNA translocations were found which were unprecedented among Arthropoda. These involved the trnQ, which was found between the rrnS and the A+T-rich region, and the trnS(ucn), which was located between trnM and trnI. A preliminary phylogenetic analysis based on the amino acid sequence of the PCGs failed to find support for the monophyly of Hexapoda.
Pressure–Volume Curves in Acute Respiratory Distress Syndrome
Authors: Antoine Vieillard-Baron, Sebastien Prin, Jean-Marie Schmitt, Roch Augarde, Bernard Page, Alain Beauchet, François Jardin
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

The presence of an initial segment with a low compliance on the static pressure-volume (PV) curve in patients with acute respiratory distress syndrome (ARDS) indicates that some lung compartments do not initially receive insufflated gas. We tested the hypothesis that an uneven distribution of time constants, producing a "slow compartment," was in part responsible for the change in compliance between the initial and the intermediate segment of the PV curve. In 16 patients with ARDS submitted to mechanical ventilation in volume-controlled mode with a supportive respiratory rate of 15 breaths/minute, we constructed the static PV curve on the first day of respiratory support and determined the intrinsic positive end-expiratory pressure (PEEPi4) during a prolonged end-expiratory pause (4 seconds). We also measured the volume of a "slow compartment" during a prolonged expiration (> 6 seconds), and determined an external PEEP (PEEPe) suppressing PEEPi4. Among the 16 patients studied, 11 exhibited a low inflection point, associated with a "slow compartment" of 172 +/- 83 ml, responsible for a PEEPi4 of 3 +/- 2 cm H2O. Conversely, the five remaining patients had a linear PV curve, associated with a minimal "slow compartment" of 28 +/- 10 ml, responsible for a negligible PEEPi4. We observed that individual slopes of the initial segment of the PV curve were inversely and significantly correlated with the proportion of the "slow compartment" (r = -0.85). We concluded that the shape of the inspiratory PV curve in ARDS might be dependent on the presence of a "slow compartment," and demonstrated that a low external PEEP appeared sufficient to achieve a substantial mechanical improvement in clinical practice.
Mitochondrial inhibition of uracil-DNA glycosylase is not mutagenic.
Authors: Sushant Kachhap, Keshav K Singh
Journal: Molecular Cancer (2004)

Uracil DNA glycosylase (UDG) plays a major role in repair of uracil formed due to deamination of cytosine. UDG in human cells is present in both the nucleus and mitochondrial compartments. Although, UDG's role in the nucleus is well established its role in mitochondria is less clear. In order to identify UDG's role in the mitochondria we expressed UGI (uracil glycosylase inhibitor) a natural inhibitor of UDG in the mitochondria. Our studies suggest that inhibition of UDG by UGI in the mitochondria does not lead to either spontaneous or induced mutations in mtDNA. Our studies also suggest that UGI expression has no affect on cellular growth or cytochrome c-oxidase activity. These results suggest that human cell mitochondria contain alternatives glycosylase (s) that may function as back up DNA repair protein (s) that repair uracil in the mitochondria.