tbuckley/cabot-search huggingface dataset:
Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors.
Authors: J I Weitz, M Hudoba, D Massel, J Maraganore, J Hirsh
Journal: Journal of Clinical Investigation (1990)

Propagation of venous thrombi or rethrombosis after coronary thrombolytic therapy can occur despite heparin administration. To explore potential mechanisms, we set out to determine whether clot-bound thrombin is relatively protected from inhibition by heparin-antithrombin III but susceptible to inactivation by antithrombin III-independent inhibitors. Using plasma fibrinopeptide A (FPA) levels as an index of thrombin activity, we compared the ability of thrombin inhibitors to block FPA release mediated by fluid-phase thrombin with their activity against the clot-bound enzyme. Incubation of thrombin with citrated plasma results in concentration-dependent FPA generation, which reaches a plateau within minutes. In contrast, there is progressive FPA generation when fibrin clots are incubated with citrated plasma. Heparin, hirudin, hirudin dodecapeptide (hirugen), and D-phenylalanyl-L-prolyl-L-arginyl chloromethyl ketone (PPACK) produce concentration-dependent inhibition of FPA release mediated by fluid-phase thrombin. However, heparin is much less effective at inhibiting thrombin bound to fibrin because a 20-fold higher concentration is necessary to block 70% of the activity of the clot-bound enzyme than is required for equivalent inhibition of fluid-phase thrombin (2.0 and 0.1 U/ml, respectively). In contrast, hirugen and PPACK are equally effective inhibitors of fluid- and solid-phase thrombin, while hirudin is only 50% as effective against the clot-bound enzyme. None of the inhibitors displace bound 125I-labeled thrombin from the clot. These studies indicate that (a) clot-bound thrombin is relatively protected from inhibition by heparin, possibly because the heparin binding site on thrombin is inaccessible when the enzyme is bound to fibrin, and (b) clot-bound thrombin is susceptible to inactivation by antithrombin III-independent inhibitors because the sites of their interaction are not masked by thrombin binding to fibrin. For these reasons, antithrombin III-independent inhibitors may be more effective than heparin in certain clinical settings.
Association of Molecular Markers With Toxicity Outcomes in a Randomized Trial of Chemotherapy for Advanced Colorectal Cancer: The FOCUS Trial
Authors: Michael S. Braun, Susan D. Richman, Lindsay Thompson, Catherine L. Daly, Angela M. Meade, Julian W. Adlard, James M. Allan, Mahesh K.B. Parmar, Philip Quirke, Matthew T. Seymour
Journal: Journal of Clinical Oncology (2009)

Predicting efficacy and toxicity could potentially allow individualization of cancer therapy. We investigated putative pharmacogenetic markers of chemotherapy toxicity in a large randomized trial.Patients were randomly assigned to different sequences of chemotherapy for advanced colorectal cancer. First-line therapy was fluorouracil (FU), irinotecan/FU (IrFU) or oxaliplatin/FU (OxFU). Patients allocated first-line FU had planned second-line irinotecan alone, IrFU, or OxFU. The primary toxicity outcome measure was toxicity-induced delay or dose reduction; the secondary outcome was Common Terminology Criteria of Adverse Events grade >or= 3 toxicity. DNA was analyzed in 1,188 patients; 1,036 were assessable for the primary outcome, including 688 treated with FU, 270 with IrFU (first or second line), 280 with OxFU (first or second line), 184 with irinotecan alone, and 454 with any irinotecan-containing regimen. Ten polymorphisms were assessed: thymidylate synthase-enhancer region (TYMS-ER), thymidylate synthase 1494 (TYMS-1494), dihydropyrimidine dehydrogenase (DPYD), methylenetetrahydrofolate reductase (MTHFR), mutL homolog 1 (MLH1), UDP glucuronyltransferase (UGT1A1), ATP-binding cassette group B gene 1 (ABCB1), x-ray cross-complementing group 1 (XRCC1), glutathione-S-transferase P1 (GSTP1), and excision repair cross-complementing gene 2 (ERCC2). Results Using the primary outcome measure, no polymorphism was significantly associated (P < .01) with the toxicity of any regimen or with the difference in toxicity of IrFU or OxFU versus FU alone. Trends (of doubtful significance) were seen for associations of XRCC1, ERCC2, and GSTP1 with toxicity during irinotecan regimens: XRCC1, primary end point, any irinotecan-containing regimen (P = .045); ERCC2, secondary end point, irinotecan alone (P = .003); GSTP1, secondary end point; IrFU (P = .039); and irinotecan alone (P = .05). There was no evidence of association of UGT1A1*28 with irinotecan toxicity.These results do not support the routine clinical use of the evaluated polymorphisms, including UGT1A1*28. Further investigation of XRCC1, ERCC2, and GSTP1 as potential predictors of irinotecan toxicity is warranted.
A phase II randomized multicenter trial of gefitinib plus FOLFIRI and FOLFIRI alone in patients with metastatic colorectal cancer
Authors: A. Santoro, A. Comandone, L. Rimassa, C. Granetti, V. Lorusso, C. Oliva, M. Ronzoni, S. Siena, M. Zuradelli, E. Mari, T. Pressiani, C. Carnaghi
Journal: Annals of Oncology (2008)
The NHS is right to fund homoeopathy
Authors: S. C. Stanford
Journal: BMJ (2011)

ROB WHITE

The campaign to expel homoeopathy from the NHS continues unabated despite a position statement from the Department of Health: “We believe in patients being able to make informed choices about their treatment, and in a clinician being able to prescribe the treatment they feel most appropriate … which includes … homeopathy.” To put this skirmish into perspective, the NHS spends about £4m (€4.5m; $6.6m) a year on homoeopathic prescriptions, which is peanuts. Even if subsidiary costs are rolled in, this battle is clearly more about winning a scientific argument, and protecting patients from themselves, than preserving NHS coffers.

To avoid being misrepresented, let me be clear that I am not pro-homoeopathy. I would not use homoeopathic preparations myself, and I do not believe that they have actions that can be measured in vitro. So should homoeopathy be available on the NHS? Absolutely. That is not to say that all alternative treatments should be funded by the state. Homoeopathy within the NHS is an historical accident. By analogy, most people can live with the fact that nicotine and alcohol …
A Figure of Merit For Catheter Sampling Systems
Authors: H. SHERMAN, R. C. SCHLANT, W. L. KRAUS, C. B. MOORE
Journal: Circulation Research (1959)

The distortion of indicator dilution curves by catheter sampling systems is predictable from theoretic considerations based on laminar flow. Over a wide range of catheter and flow parameters, deductions can be made regarding distortion, by the arterial system or by sampling catheters, of indicator dilution curves coming from an idealized pump. A figure of merit for the sampling system is given by the volume of the catheter divided by twice the flow rate. This number should be less than the time in which significant changes in indicator concentration occur, i.e., the interval between pump strokes, if significant distortion of the indicator dilution curve is to be avoided.
A Phase I Study of the P-Glycoprotein Antagonist Tariquidar in Combination with Vinorelbine
Authors: Jame Abraham, Maureen Edgerly, Richard Wilson, Clara Chen, Ann Rutt, Susan Bakke, Rob Robey, Andrew Dwyer, Barry Goldspiel, Frank Balis, Olaf Van Tellingen, Susan E. Bates, Tito Fojo
Journal: Clinical Cancer Research (2009)

Abstract Purpose: P-glycoprotein (Pgp) antagonists have had unpredictable pharmacokinetic interactions requiring reductions of chemotherapy. We report a phase I study using tariquidar (XR9576), a potent Pgp antagonist, in combination with vinorelbine. Experimental Design: Patients first received tariquidar alone to assess effects on the accumulation of 99mTc-sestamibi in tumor and normal organs and rhodamine efflux from CD56+ mononuclear cells. In the first cycle, vinorelbine pharmacokinetics was monitored after the day 1 and 8 doses without or with tariquidar. In subsequent cycles, vinorelbine was administered with tariquidar. Tariquidar pharmacokinetics was studied alone and with vinorelbine. Results: Twenty-six patients were enrolled. Vinorelbine 20 mg/m2 on day 1 and 8 was identified as the maximum tolerated dose (neutropenia). Nonhematologic grade 3/4 toxicities in 77 cycles included the following: abdominal pain (4 cycles), anorexia (2), constipation (2), fatigue (3), myalgia (2), pain (4) and dehydration, depression, diarrhea, ileus, nausea, and vomiting, (all once). A 150-mg dose of tariquidar: (1) reduced liver 99mTc-sestamibi clearance consistent with inhibition of liver Pgp; (2) increased 99mTc-sestamibi retention in a majority of tumor masses visible by 99mTc-sestamibi; and (3) blocked Pgp-mediated rhodamine efflux from CD56+ cells over the 48 hours examined. Tariquidar had no effects on vinorelbine pharmacokinetics. Vinorelbine had no effect on tariquidar pharmacokinetics. One patient with breast cancer had a minor response, and one with renal carcinoma had a partial remission. Conclusions: Tariquidar is a potent Pgp antagonist, without significant side effects and much less pharmacokinetic interaction than previous Pgp antagonists. Tariquidar offers the potential to increase drug exposure in drug-resistant cancers.
Reflex Regulation of Arterial Pressure during Sleep in Man
Authors: HARLEY S. SMYTH, PETER SLEIGHT, GEORGE W. PICKERING
Journal: Circulation Research (1969)

The control of arterial pressure during sleep was studied in 13 untreated, unsedated subjects aged 20 to 46, including 7 with hypertension. Arterial pressure was measured directly. A transient rise of arterial pressure up to 30 mm Hg was produced by the sudden intravenous injection of 0.25 to 2 µg of angiotensin. Linear plots were obtained in 10 of 13 subjects when the systolic pressures of successive pulses during the pressure rise were plotted against the pulse intervals which began the next beat. The relationship was disturbed by movement or arousal, and was better when pulse intervals falling in inspiration were discarded. The slope of the line (milliseconds of cardiac slowing per millimeter rise in systolic pressure) in the awake subject ranged from 2 to 15.5 msec/mm Hg, and from 4.5 to 28.9 during sleep. Reflex sensitivity was highest in dreaming sleep. In 7 of 10 subjects, baroreflex sensitivity increased significantly during sleep; in 6, the prevailing arterial pressure was inversely correlated with the baroreflex sensitivity. The pressure appeared to be the dependent variable. It is concluded that the baroreceptor reflex are can be rapidly reset, particularly during sleep. The lower arterial pressures during sleep may be actively maintained in some subjects by increased baroreflex sensitivity.
Comparison of Insulin Monotherapy and Combination Therapy With Insulin and Metformin or Insulin and Troglitazone in Type 2 Diabetes
Authors: Suzanne M. Strowig, M. Larissa Avilés-Santa, Philip Raskin
Journal: Diabetes Care (2002)

OBJECTIVE—To evaluate the safety and efficacy of treatment with insulin alone, insulin plus metformin, or insulin plus troglitazone in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS—A total of 88 type 2 diabetic subjects using insulin monotherapy (baseline HbAlc 8.7%) were randomly assigned to insulin alone (n = 31), insulin plus metformin (n = 27), or insulin plus troglitazone (n = 30) for 4 months. The insulin dose was increased only in the insulin group. Metformin was titrated to a maximum dose of 2,000 mg and troglitazone to 600 mg. RESULTS—HbAlc levels decreased in all groups, the lowest level occurring in the insulin plus troglitazone group (insulin alone to 7.0%, insulin plus metformin to 7.1%, and insulin plus troglitazone to 6.4%, P &amp;lt; 0.0001). The dose of insulin increased by 55 units/day in the insulin alone group (P &amp;lt; 0.0001) and decreased by 1.4 units/day in the insulin plus metformin group and 12.8 units/day in the insulin plus troglitazone group (insulin plus metformin versus insulin plus troglitazone, P = 0.004). Body weight increased by 0.5 kg in the insulin plus metformin group, whereas the other two groups gained 4.4 kg (P &amp;lt; 0.0001 vs. baseline). Triglyceride and VLDL triglyceride levels significantly improved only in the insulin plus troglitazone group. Subjects taking metformin experienced significantly more gastrointestinal side effects and less hypoglycemia. CONCLUSIONS—Aggressive insulin therapy significantly improved glycemic control in type 2 diabetic subjects to levels comparable with those achieved by adding metformin to insulin therapy. Troglitazone was the most effective in lowering HbAlc, total daily insulin dose, and triglyceride levels. However, treatment with insulin plus metformin was advantageous in avoiding weight gain and hypoglycemia.
Risk Associated With the Metabolic Syndrome Versus the Sum of Its Individual Components
Authors: Johan Sundström, Erik Vallhagen, Ulf Risérus, Liisa Byberg, Björn Zethelius, Christian Berne, Lars Lind, Erik Ingelsson
Journal: Diabetes Care (2006)

Current guidelines for the prevention of cardiovascular disease (CVD) encourage identification of the metabolic syndrome (a clustering of CVD risk factors) in clinical practice (1,2), but an important unanswered question is whether the metabolic syndrome predicts risk above and beyond its individual components (3). We investigated this issue using a large cohort of men examined on two occasions 20 years apart and followed for a maximum of 32.7 years.

In a community-based cohort of men of the same age (available at www.pubcare.uu.se/ULSAM) (4), we investigated four baseline samples: two defined at age 50 years (the whole cohort [ n = 2,322] and a primary preventive sample [ n = 2,198], excluding people with a myocardial infarction, stroke, or diabetes at or before baseline) and two at a reexamination at age 70 years (the whole cohort [ n = 1,221] …
Signet Ring Cell Lymphoma in a Patient With Elevated CA-125
Authors: Bryan N. Coffing, Megan S. Lim
Journal: Journal of Clinical Oncology (2011)

does not appear to affect the prognosis of the underlying subtype of lymphoma.However, recognizing this rare variant of lymphoma is important in order to avoid making an erroneous diagnosis of metastatic signet ring cell carcinoma, which carries a dismal prognosis in most cases.
Ambient Temperature and Mortality From Unintentional Cocaine Overdose
Authors: Peter M. Marzuk
Journal: JAMA (1998)

Hot weather taxes cardiovascular function and is associated with increased deaths from heart disease. Cocaine can cause hypertension, tachycardia, coronary vasospasm, arrhythmias, and increased core temperature.To determine the association between mortality from cocaine overdose and hot weather.New York, NY.Retrospective review of medical examiner cases from 1990 through 1995.All fatal unintentional cocaine overdoses from 1990 through 1992 (n = 1382) and all hyperthermia deaths of cocaine users (n = 10) were used to identify a maximum daily temperature threshold above which mortality from cocaine intoxication increased. The study population consisted of all fatal unintentional cocaine overdoses from 1993 through 1995 (n = 2008) and 4 contemporaneous comparison groups that included fatal unintentional opiate overdoses (n = 793), all other fatal unintentional overdoses (n = 85), and a subset of homicides (n = 4638) and fatalities from motor vehicle crashes (n = 815).The number of overdose deaths and the proportion of homicides and traffic fatalities with a positive cocaine toxicology test result on days with a maximum temperature above or below the temperature threshold.A threshold temperature of 31.1 degrees C (88 degrees F) was identified, above which the mean daily number of fatal cocaine overdoses increased steadily. On days with a maximum daily temperature of 31.1 degrees C (88 degrees F) or higher ("hot days"), the mean daily number of cocaine overdose deaths was 2.34 (SD = 1.68), which was 33% higher than the mean on days with a maximum temperature of less than 31.1 degrees C (88 degrees F) (mean = 1.76 [SD=1.37] (P<.001). In contrast, the mean number of opiate overdose deaths per day was 0.81 (SD = 0.94) on hot days and 0.71 (SD = 0.86) on other days (P=.28). For other drug overdose deaths, the mean number of deaths per day was 0.08 (SD = 0.28) on hot days and 0.08 (SD = 0.28) on other days (P=.69). Among homicides, the proportion with a positive cocaine toxicology test result was 18.9% on hot days and 19.5% on other days (P=.69), and among traffic fatalities, the proportions with positive cocaine toxicology test results were 9.5% on hot days and 10.3% on other days (P=.91).High ambient temperature is associated with a significant increase in mortality from cocaine overdose. Based on our comparison groups, the increase is not explained by changes in cocaine use among the general population. Although cocaine use is dangerous on all days, it appears to be even more dangerous on hot days.
The Use of Deception in Public Health Behavioral Intervention Trials: A Case Study of Three Online Alcohol Trials
Authors: Jim McCambridge, Kypros Kypri, Preben Bendtsen, John Porter
Journal: The American Journal of Bioethics (2013)

Some public health behavioral intervention research studies involve deception. A methodological imperative to minimize bias can be in conflict with the ethical principle of informed consent. As a case study, we examine the specific forms of deception used in three online randomized controlled trials evaluating brief alcohol interventions. We elaborate our own decision making about the use of deception in these trials, and present our ongoing findings and uncertainties. We discuss the value of the approach of pragmatism for examining these kinds of ethical issues that can arise in research on public health interventions.
Effects of altered ephrin-A5 and EphA4/EphA7 expression on tumor growth in a medulloblastoma mouse model
Authors: Shilpa Bhatia, Kellen Hirsch, Nimrah A. Baig, Olga Rodriguez, Olga Timofeeva, Kevin Kavanagh, Yi Chien Lee, Xiao-Jing Wang, Christopher Albanese, Sana D. Karam
Journal: Journal of Hematology & Oncology (2015)

Members of the Eph/ephrin gene families act as key regulators of cerebellar development during embryogenesis. Aberrant signaling of Eph family of receptor tyrosine kinases and their ephrin ligands has also been implicated in human cancers. Medulloblastoma is an aggressive primitive neuroectodermal tumor that originates from granule neuron precursors in the cerebellum. Previous studies have suggested a role for the ephrin-A5 ligand and its receptors, EphA4 and EphA7, in granule cell-precursor formation and in guiding cell migration. In the present study, we investigated the effects of genetic loss of ephrin-A5, EphA4, and EphA7 on the spatiotemporal development of medulloblastoma tumors in the context of the smoothened transgenic mouse model system. Radiographic magnetic resonance imaging (MRI) was performed to monitor tumor growth in a genetically engineered mouse model of medulloblastoma. Tumor tissue was harvested to determine changes in the expression of phosphorylated Akt by Western blotting. This helped to establish a correlation between genotype and/or tumor size and survival. Our in vivo data establish that in ND2-SmoA1 transgenic mice, the homozygous deletion of ephrin-A5 resulted in a consistent pattern of tumor growth inhibition compared to their ephrin-A5 wild-type littermate controls, while the loss of EphA4/EphA7 failed to produce consistent effects versus EphA4/EphA7 wild-type mice. A positive correlation was evident between tumor size, p-Akt, and proliferating cell nuclear antigen (PCNA) expression in our transgenic mouse model system, regardless of genotype. Taken together, our findings underscore the importance of targeting specific members of the Eph/ephrin families in conjunction with the Akt pathway in order to inhibit medulloblastoma tumor growth and progression.
Molecular Genetic Analysis of an Endotoxin Nonresponder Mutant Cell Line
Authors: Andra B. Schromm, Egil Lien, Philipp Henneke, Jesse C. Chow, Atsutoshi Yoshimura, Holger Heine, Eicke Latz, Brian G. Monks, David A. Schwartz, Kensuke Miyake, Douglas T. Golenbock
Journal: The Journal of Experimental Medicine (2001)

Somatic cell mutagenesis is a powerful tool for characterizing receptor systems. We reported previously two complementation groups of mutant cell lines derived from CD14-transfected Chinese hamster ovary--K1 fibroblasts defective in responses to bacterial endotoxin. Both classes of mutants expressed a normal gene product for Toll-like receptor (TLR)4, and fully responded to stimulation by tumor necrosis factor (TNF)-alpha or interleukin (IL)-1 beta. We identified the lesion in one of the complementation groups in the gene for MD-2, a putative TLR4 coreceptor. The nonresponder phenotype of this mutant was reversed by transfection with MD-2. Cloning of MD-2 from the nonresponder cell line revealed a point mutation in a highly conserved region resulting in a C95Y amino acid exchange. Both forms of MD-2 colocalized with TLR4 on the cell surface after transfection, but only the wild-type cDNA reverted the lipopolysaccharide (LPS) nonresponder phenotype. Furthermore, soluble MD-2, but not soluble MD-2(C95Y), functioned to enable LPS responses in cells that expressed TLR4. Thus, MD-2 is a required component of the LPS signaling complex and can function as a soluble receptor for cells that do not otherwise express it. We hypothesize that MD-2 conformationally affects the extracellular domain of TLR4, perhaps resulting in a change in affinity for LPS or functioning as a portion of the true ligand for TLR4.
PPAR attenuates intimal hyperplasia by inhibiting TLR4-mediated inflammation in vascular smooth muscle cells
Authors: L.-L. Zhang, C.-Y. Gao, C.-Q. Fang, Y.-J. Wang, D. Gao, G.-E. Yao, J. Xiang, J.-Z. Wang, J.-C. Li
Journal: Cardiovascular Research (2011)

Peroxisome proliferator-activated receptor γ (PPARγ) has been reported to attenuate intimal hyperplasia. This study aimed to test the hypothesis that PPARγ inhibits intimal hyperplasia through suppressing Toll-like receptor 4 (TLR4)-mediated inflammation in vascular smooth muscle cells. TLR4−/− mice on a C57BL/6J background were used. Increased TLR4 and pro-inflammatory cytokines were observed in wire-injury-induced carotid neointima and in platelet-derived growth factor (PDGF)-activated vascular smooth muscle cells. The TLR4 deficiency protected the injured carotid from neointimal formation and impaired the cellular proliferation and migration in response to lipopolysaccharide and PDGF. Rosiglitazone attenuated intimal hyperplasia. Overexpression of PPARγ suppressed PDGF-induced proliferation and migration and inhibited TLR4-mediated inflammation in vascular smooth muscle cells, while PPARγ silencing exerted the opposite effect. Lipopolysaccharide counteracted the inhibitory effect of PPARγ on PDGF-induced proliferation and migration. Eritoran suppressed the proliferation and migration induced by PDGF and PPARγ silencing. Vascular smooth muscle cells derived from TLR4−/− mice showed impaired proliferation and migration upon PDGF activation and displayed no response to PPARγ manipulation. PPARγ inhibits vascular smooth muscle cell proliferation and migration by suppressing TLR4-mediated inflammation and ultimately attenuates intimal hyperplasia after carotid injury.
Myocarditis in newborn wild-type BALB/c mice infected with the murine gamma herpesvirus MHV-68
Authors: M HAUSLER, B SELLHAUS, S SCHEITHAUER, B GAIDA, S KUROPKA, K SIEPMANN, A PANEK, W BERG, A TEUBNER, K RITTER
Journal: Cardiovascular Research (2007)

Objectives Animal models of human Epstein–Barr virus (EBV) infection include EBV infection of primates and infection of mice with MHV-68, a further gamma herpesvirus (δ-HV). We aimed at extending the MHV-68 model to study δ-HV-related cardiac disease.