tbuckley/cabot-search huggingface dataset:
Effect of Rimonabant on Progression of Atherosclerosis in Patients With Abdominal Obesity and Coronary Artery Disease
Authors: Steven E. Nissen, Stephen J. Nicholls, Kathy Wolski, Josep Rodés-Cabau, Christopher P. Cannon, John E. Deanfield, Jean-Pierre Després, John J. P. Kastelein, Steven R. Steinhubl, Samir Kapadia, Muhammad Yasin, Witold Ruzyllo, Christophe Gaudin, Bernard Job, Bo Hu, Deepak L. Bhatt, A. Michael Lincoff, E. Murat Tuzcu, for the STRADIVARIUS Investigators
Journal: JAMA (2008)

BESITY HAS REACHED EPIdemic proportions in many developed countries, particularly the United States, where 66% of the adult population is considered overweight and 34% are obese, defined as a body mass index greater than 30. 1,2Epidemiologists predict that the epidemic of obesity and its public health consequences will continue to increase over the next several decades, affecting both the developed and developing worlds. 3,4An abdominal pattern of fat distribution produces
Sulindac induced regression of colorectal adenomas in familial adenomatous polyposis: evaluation of predictive factors.
Authors: F M Giardiello, J A Offerhaus, A C Tersmette, L M Hylind, A J Krush, J D Brensinger, S V Booker, S R Hamilton
Journal: Gut (1996)

BACKGROUND--Sulindac, a non-steroidal anti-inflammatory drug, causes regression of colorectal adenomas in patients with familial adenomatous polyposis (FAP) but the response is variable. Specific clinical factors predictive of sulindac induced regression have not been studied. METHODS--22 patients with FAP were given sulindac 150 mg orally twice a day. Polyp number and size were determined before treatment and at three months. The relation of nine clinical factors to polyp regression (per cent of baseline polyp number after treatment) was evaluated by univariate and multivariate analysis. RESULTS--After three months of sulindac, polyp number had decreased to 45 per cent of baseline and polyp size to 50 per cent of baseline (p &lt; 0.001 and p &lt; 0.01, respectively). Univariate analysis showed greater polyp regression in older patients (p = 0.004), those with previous colectomy and ileorectal anastomosis (p = 0.001), and patients without identifiable mutation of the APC gene responsible for FAP (p = 0.05). With multivariate regression analysis, response to sulindac treatment was associated with previous subtotal colectomy. CONCLUSIONS--Sulindac treatment seems effective in producing regression of colorectal adenomas of FAP patients with previous subtotal colectomy regardless of baseline polyp number and size. Changed sulindac metabolism, reduced area of the target mucosa, or changed epithelial characteristics after ileorectal anastomosis may explain these findings.
A Dose-Ranging Trial to Optimize the Dose of Rifampin in the Treatment of Tuberculosis
Authors: Martin J. Boeree, Andreas H. Diacon, Rodney Dawson, Kim Narunsky, Jeannine du Bois, Amour Venter, Patrick P. J. Phillips, Stephen H. Gillespie, Timothy D. McHugh, Michael Hoelscher, Norbert Heinrich, Sunita Rehal, Dick van Soolingen, Jakko van Ingen, Cecile Magis-Escurra, David Burger, Georgette Plemper van Balen, Rob E. Aarnoutse
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Rifampin at a dose of 10 mg/kg was introduced in 1971 based on pharmacokinetic, toxicity, and cost considerations. Available data in mice and humans showed that an increase in dose may shorten the duration of tuberculosis treatment.To evaluate the safety and tolerability, the pharmacokinetics, and the extended early bactericidal activity of increasing doses of rifampin.Patients with drug-susceptible tuberculosis were enrolled into a control group of eight patients receiving the standard dose of 10 mg/kg rifampin, followed by consecutive experimental groups with 15 patients each receiving rifampin 20, 25, 30, and 35 mg/kg, respectively, for 14 days. In all patients isoniazid, pyrazinamide, and ethambutol were added in standard doses for the second 7 days of treatment. Safety, pharmacokinetics of rifampin, and fall in bacterial load were assessed.Grade 1 and 2 adverse events were equally distributed between the five dose groups; there were five grade 3 events of which one was a possibly related hepatotoxicity. Areas under the time-concentration curves and peak serum concentrations of rifampin showed a more than proportional increase with dose. The daily fall in bacterial load over 14 days was 0.176, 0.168, 0.167, 0.265, and 0.261 log10 colony-forming units/ml sputum in the 10, 20, 25, 30, and 35 mg/kg groups, respectively.Two weeks of rifampin up to 35 mg/kg was safe and well tolerated. There was a nonlinear increase in exposure to rifampin without an apparent ceiling effect and a greater estimated fall in bacterial load in the higher dosing groups. Clinical trial registered with www.clinicaltrials.gov (NCT 01392911).
Antiarrhythmic Efficacy of Dipyridamole in Treatment of Reperfusion Arrhythmias
Authors: Yukihiko Yoshida, Makoto Hirai, Takumi Yamada, Yukiomi Tsuji, Takahisa Kondo, Yasuya Inden, Makoto Akahoshi, Yoshimasa Murakami, Makoto Tsuda, Naoya Tsuboi, Haruo Hirayama, Mitsuhiro Okamoto, Teruo Ito, Hidehiko Saito, Junji Toyama
Journal: Circulation (2000)

Background —Intracellular calcium overload is believed to play an important role in development of reperfusion arrhythmias. Dipyridamole, an inhibitor of cellular uptake of adenosine, may prevent or terminate reperfusion arrhythmias by reducing intracellular calcium overload. Methods and Results —First, we tested for a preventive effect of dipyridamole. Sixty-one patients who underwent primary PTCA for treatment of acute anterior wall myocardial infarction were enrolled in this prospective study. Patients were divided into dipyridamole (DP) and nondipyridamole (non-DP) groups. The 2 groups had similar baseline characteristics. In the DP group, dipyridamole 0.5 mg/kg was infused intravenously for 3 minutes immediately before reperfusion during primary PTCA. Arrhythmias after reperfusion were analyzed from continuous ECG recordings. None of the patients in the DP group (n=23) had accelerated idioventricular rhythms (AIVR) or ventricular tachycardia (VT). In contrast, 7 (18.4%) had AIVR and 3 (7.9%) had VT in the non-DP group (n=38; P &lt;0.01). Second, we tested for a termination effect of dipyridamole. Dipyridamole 0.5 mg/kg was infused intravenously while continuous ECG recordings were obtained in 9 patients who had either sustained AIVR (n=7) or sustained VT (n=2) after reperfusion of occluded coronary artery. Arrhythmias were terminated in all patients. Conclusions —These results indicate that administration of dipyridamole can prevent and terminate reperfusion arrhythmias such as AIVR and VT. cAMP-mediated triggered activity may, at least in part, be responsible for reperfusion-induced AIVR and VT.
DURAbility of Basal Versus Lispro Mix 75/25 Insulin Efficacy (DURABLE) Trial 24-Week Results
Authors: John B. Buse, Bruce H.R. Wolffenbuttel, William H. Herman, Natalie K. Shemonsky, Honghua H. Jiang, Jessie L. Fahrbach, Jamie L. Scism-Bacon, Sherry A. Martin
Journal: Diabetes Care (2009)

OBJECTIVE To compare the ability of two starter insulin regimens to achieve glycemic control in a large, ethnically diverse population with type 2 diabetes. RESEARCH DESIGN AND METHODS During the initiation phase of the DURABLE trial, patients were randomized to a twice-daily lispro mix 75/25 (LM75/25; 75% lispro protamine suspension, 25% lispro) (n = 1,045) or daily glargine (GL) (n = 1,046) with continuation of prestudy oral antihyperglycemic drugs. RESULTS Baseline A1C was similar (LM75/25: 9.1 ± 1.3%; GL: 9.0 ± 1.2%; P = 0.414). At 24 weeks, LM75/25 patients had lower A1C than GL patients (7.2 ± 1.1 vs. 7.3 ± 1.1%, P = 0.005), greater A1C reduction (–1.8 ± 1.3 vs. –1.7 ± 1.3%, P = 0.005), and higher percentage reaching A1C target &amp;lt;7.0% (47.5 vs. 40.3%, P &amp;lt; 0.001). LM75/25 was associated with higher insulin dose (0.47 ± 0.23 vs. 0.40 ± 0.23 units · kg−1· day−1, P &amp;lt; 0.001) and more weight gain (3.6 ± 4.0 vs. 2.5 ± 4.0 kg, P &amp;lt; 0.0001). LM75/25 patients had a higher overall hypoglycemia rate than GL patients (28.0 ± 41.6 vs. 23.1 ± 40.7 episodes · pt−1· year−1, P = 0.007) but lower nocturnal hypoglycemia rate (8.9 ± 19.3 vs. 11.4 ± 25.3 episodes · pt−1· year−1, P = 0.009). Severe hypoglycemia rates were low in both groups (LM75/25: 0.10 ± 1.6 vs. GL: 0.03 ± 0.3 episodes · pt−1· year−1, P = 0.167). CONCLUSIONS Compared with GL, LM75/25 resulted in slightly lower A1C at 24 weeks and a moderately higher percentage reaching A1C target &amp;lt;7.0%. Patients receiving LM75/25 experienced more weight gain and higher rates of overall hypoglycemia but lower rates of nocturnal hypoglycemia. Durability of regimens will be evaluated in the following 2-year maintenance phase.
Azimilide Reduces Emergency Department Visits and Hospitalizations in Patients With an Implantable Cardioverter-Defibrillator in a Placebo-Controlled Clinical Trial
Authors: Paul Dorian, Hussein R. Al-Khalidi, Stefan H. Hohnloser, Jose M. Brum, Preston M. Dunnmon, Craig M. Pratt, Michael J. Holroyde, Peter Kowey
Journal: Journal of the American College of Cardiology (2008)
Antitumor Activity of ZSTK474, a New Phosphatidylinositol 3-Kinase Inhibitor
Authors: Shin-ichi Yaguchi, Yasuhisa Fukui, Ichiro Koshimizu, Hisashi Yoshimi, Toshiyuki Matsuno, Hiroaki Gouda, Shuichi Hirono, Kanami Yamazaki, Takao Yamori
Journal: JNCI Journal of the National Cancer Institute (2006)

Background : We previously synthesized a novel s -triazine derivative, ZSTK474 [2-(2-difluoromethylbenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine], that strongly inhibited the growth of tumor cells. We identified its molecular target, investigated its effects on cellular signaling pathways, and examined its antitumor efficacy and toxicity in vivo. Methods : We used COMPARE analysis of chemosensitivity measurements from 39 human cancer cell lines and identified phosphatidylinositol 3-kinase (PI3K) as a molecular target for ZSTK474. PI3K was immunoprecipitated from A549 cell lysates, and its activity was measured by assessing the incorporation of 32 P into phosphatidylinositol. We used the crystal structure of the PI3K–LY294002 complex to model the binding of ZSTK474 to PI3K (where LY294002 is a known PI3K inhibitor). PI3K downstream activity was analyzed by immunoblotting. Antitumor activity of ZSTK474 was examined against A549, PC-3, and WiDr xenografts in nude mice. Phosphorylation of Akt, a serine/threonine protein kinase and a major signaling component downstream of PI3K, was assessed in vivo by immunohistochemistry. Results : PI3K was identified as a molecular target for ZSTK474 by COMPARE analysis. We confirmed that ZSTK474 directly inhibited PI3K activity more efficiently than the PI3K inhibitor LY294002. At concentrations of 1 μM, ZSTK474 and LY2194002 reduced PI3K activity to 4.7% (95% confidence interval [CI] = 3.2% to 6.1%) and 44.6% (95% CI = 38.9% to 50.3%), respectively, of the untreated control level. Molecular modeling of the PI3K–ZSTK474 complex indicated that ZSTK474 could bind to the ATP-binding pocket of PI3K. ZSTK474 inhibited phosphorylation of signaling components downstream from PI3K, such as Akt and glycogen synthase kinase 3β, and mediated a decrease in cyclin D1 levels. ZSTK474 administered orally to mice had strong antitumor activity against human cancer xenografts without toxic effects in critical organs. Akt phosphorylation was reduced in xenograft tumors after oral administration of ZSTK474. Conclusion : ZSTK474 is a new PI3K inhibitor with strong antitumor activity against human cancer xenografts without toxic effects in critical organs. ZSTK474 merits further investigation as an anticancer drug.
THE EFFECT OF ION EXCHANGE RESINS IN THE PAROXYSMAL DISORDERS OF THE NERVOUS SYSTEM
Authors: WALTER O. KLINGMAN
Journal: American Journal of Psychiatry (1954)

Paroxysmal disorders of the nervous system such as epilepsy, migraine, and Meniere's disease can develop a disturbance of electrolyte and water balance of cerebral and labyrinthine tissues when the paroxysms of the attack become frequent and severe. Experimental work and tissue analysis support this assumption. The introduction of ion exchange resins into the field of therapy has offered an opportunity to influence electrolyte (particularly Na and K) and water balance in these conditions. Clinical experience and results from the use of these resins have established their usefulness in the therapy of epilepsy, migraine, and Meniere's disease.
Genetic contribution to postpartum haemorrhage in Swedish population: cohort study of 466 686 births
Authors: A. S. Oberg, S. Hernandez-Dia , T. Frisell, M. F. Greene, C. Almqvist, B. T. Bateman
Journal: BMJ (2014)

<b>Objective</b> To investigate the familial clustering of postpartum haemorrhage in the Swedish population, and to quantify the relative contributions of genetic and environmental effects. <b>Design</b> Register based cohort study. <b>Setting</b> Swedish population (multi-generation and medical birth registers). <b>Main outcome measure</b> Postpartum haemorrhage, defined as &gt;1000 mL estimated blood loss. <b>Participants</b> The first two live births to individuals in Sweden in 1997-2009 contributed to clusters representing intact couples (n=366 350 births), mothers with separate partners (n=53 292), fathers with separate partners (n=47 054), sister pairs (n=97 228), brother pairs (n=91 168), and mixed sibling pairs (n=177 944). <b>Methods</b> Familial clustering was quantified through cluster specific tetrachoric correlation coefficients, and the influence of potential sharing of known risk factors was evaluated with alternating logistic regression. Relative contributions of genetic and environmental effects to the variation in liability for postpartum haemorrhage were quantified with generalised linear mixed models. <b>Results</b> The overall prevalence of postpartum haemorrhage after vaginal deliveries in our sample was 4.6%. Among vaginal deliveries, 18% (95% confidence interval 9% to 26%) of the variation in postpartum haemorrhage liability was attributed to maternal genetic factors, 10% (1% to 19%) to unique maternal environment, and 11% (0% to 26%) to fetal genetic effects. Adjustment for known risk factors only partially explained estimates of familial clustering, suggesting that the observed shared genetic and environmental effects operate in part through pathways independent of known risk factors. There were similar patterns of familial clustering for both of the main subtypes examined (atony and retained placenta), though strongest for haemorrhage after retained placenta. <b>Conclusions</b> There is a maternal genetic predisposition to postpartum haemorrhage, but more than half of the total variation in liability is attributable to factors that are not shared in families.
Randomized Comparison of Pramlintide or Mealtime Insulin Added to Basal Insulin Treatment for Patients With Type 2 Diabetes
Authors: Matthew Riddle, Richard Pencek, Supoat Charenkavanich, Karen Lutz, Ken Wilhelm, Lisa Porter
Journal: Diabetes Care (2009)

To compare the efficacy and safety of adding mealtime pramlintide or rapid-acting insulin analogs (RAIAs) to basal insulin for patients with inadequately controlled type 2 diabetes.
WT1-Dependent Sulfatase Expression Maintains the Normal Glomerular Filtration Barrier
Authors: Valérie A. Schumacher, Ursula Schlötzer-Schrehardt, S. Ananth Karumanchi, Xiaofeng Shi, Joseph Zaia, Stefanie Jeruschke, Dongsheng Zhang, Hermann Pavenstädt, Astrid Drenckhan, Kerstin Amann, Carrie Ng, Sunny Hartwig, Kar-Hui Ng, Jacqueline Ho, Jordan A. Kreidberg, Mary Taglienti, Brigitte Royer-Pokora, Xingbin Ai
Journal: Journal of the American Society of Nephrology (2011)

Paracrine signaling between podocytes and glomerular endothelial cells through vascular endothelial growth factor A (VEGFA) maintains a functional glomerular filtration barrier. Heparan sulfate proteoglycans (HSPGs), located on the cell surface or in the extracellular matrix, bind signaling molecules such as VEGFA and affect their local concentrations, but whether modulation of these moieties promotes normal crosstalk between podocytes and endothelial cells is unknown. Here, we found that the transcription factor Wilms' Tumor 1 (WT1) modulates VEGFA and FGF2 signaling by increasing the expression of the 6-O-endosulfatases Sulf1 and Sulf2, which remodel the heparan sulfate 6-O-sulfation pattern in the extracellular matrix. Mice deficient in both Sulf1 and Sulf2 developed age-dependent proteinuria as a result of ultrastructural abnormalities in podocytes and endothelial cells, a phenotype similar to that observed in children with WT1 mutations and in Wt1+/− mice. These kidney defects associated with a decreased distribution of VEGFA in the glomerular basement membrane and on endothelial cells. Collectively, these data suggest that WT1-dependent sulfatase expression plays a critical role in maintaining the glomerular filtration barrier by modulating the bioavailability of growth factors, thereby promoting normal crosstalk between podocytes and endothelial cells.
Circulating inhibitors of blood coagulation associated with procainamide‐induced lupus erythematosus
Authors: Stephen Davis, Barbara C. Furie, John H. Griffin, Bruce Furie
Journal: American Journal of Hematology (1978)

Abstract We studied a patient being treated with procainamide in whom we observed a high antinuclear antibody titer and prolonged activated partial thromboplastin (PTT), prothrombin (PT), and Stypven times (ST). Serum antibody concentrations against single‐stranded DNA were elevated while those against native DNA were not elevated, suggesting the procainamide‐induced lupus syndrome. Dilution of the patient's plasma with normal plasma failed to correct the PTT and PT, indicating the presence of an inhibitor(s) to blood coagulation. The anticoagulant activity was associated with the IgG fraction of the patient's serum. Addition of purified or partially purified human factors IX, X, VIII, VII, XIa, prekallikrein, high molecular weight kininogen, or phospholipids to the patient's plasma failed to correct the PTT, PT, or ST; however, purified human factor XII and prothrombin corrected the PTT and ST, respectively. These results indicate that production of antibodies directed against antigenic determinants on coagulation proteins can be a manifestation of procainamide‐induced lupus erythematosus.
Use of intensive case management to reduce time in hospital in people with severe mental illness: systematic review and meta-regression
Authors: Tom Burns, Jocelyn Catty, Michael Dash, Chris Roberts, Austin Lockwood, Max Marshall
Journal: BMJ (2007)

<b>Objectives</b> To explain why clinical trials of intensive case management for people with severe mental illness show such inconsistent effects on the use of hospital care. <b>Design</b> Systematic review with meta-regression techniques applied to data from randomised controlled trials. <b>Data Sources</b> Cochrane central register of controlled trials, CINAHL, Embase, Medline, and PsychINFO databases from inception to January 2007. Additional anonymised data on patients were obtained for multicentre trials. <b>Review methods</b> Included trials examined intensive case management compared with standard care or low intensity case management for people with severe mental illness living in the community. We used a fidelity scale to rate adherence to the model of assertive community treatment. Multicentre trials were disaggregated into individual centres with fidelity data specific for each centre. A multivariate meta-regression used mean days per month in hospital as the dependent variable. <b>Results</b> We identified 1335 abstracts with a total of 5961 participants. Of these, 49 were eligible and 29 provided appropriate data. Trials with high hospital use at baseline (before the trial) or in the control group were more likely to find that intensive case management reduced the use of hospital care (coefficient −0.23, 95% confidence interval −0.36 to −0.09, for hospital use at baseline; −0.44, −0.57 to −0.31, for hospital use in control groups). Case management teams organised according to the model of assertive community treatment were more likely to reduce the use of hospital care (coefficient −0.31, −0.59 to −0.03), but this finding was less robust in sensitivity analyses and was not found for staffing levels recommended for assertive community treatment. <b>Conclusions</b> Intensive case management works best when participants tend to use a lot of hospital care and less well when they do not. When hospital use is high, intensive case management can reduce it, but it is less successful when hospital use is already low. The benefits of intensive case management might be marginal in settings that have already achieved low rates of bed use, and team organisation is more important than the details of staffing. It might not be necessary to apply the full model of assertive community treatment to achieve reductions in inpatient care.
Selfishness examined: Cooperation in the absence of egoistic incentives
Authors: Linnda R. Caporael, Robyn M. Dawes, John M. Orbell, Alphons J. C. van de Kragt
Journal: Behavioral and Brain Sciences (1989)

Abstract Social dilemmas occur when the pursuit of self-interest by individuals in a group leads to less than optimal collective outcomes for everyone in the group. A critical assumption in the human sciences is that people's choices in such dilemmas are individualistic, selfish, and rational. Hence, cooperation in the support of group welfare will only occur if there are selfish incentives that convert the social dilemma into a nondilemma. In recent years, inclusive fitness theories have lent weight to such traditional views of rational selfishness on Darwinian grounds. To show that cooperation is based on selfish incentives, however, one must provide evidence that people do not cooperate without such incentives. In a series of experimental social dilemmas, subjects were instructed to make single, anonymous choices about whether or not to contribute money for a shared “bonus” that would be provided only if enough other people in the group also contributed their money. Noncontributors cited selfish reasons for their choices; contributors did not. If people are allowed to engage in discussion, they will contribute resources at high rates, frequently on irrational grounds, to promote group welfare. These findings are consistent with previous research on ingroup biasing effects that cannot be explained by “economic man” or “selfish gene” theories. An alternative explanation is that sociality was a primary factor shaping the evolution of Homo sapiens . The cognitive and affective mechanisms underlying such choices evolved under selection pressures on small groups for developing and maintaining group membership and for predicting and controlling the behavior of other group members. This sociality hypothesis organizes previously inexplicable and disparate phenomena in a Darwinian framework and makes novel predictions about human choice.
Loss of Cannabinoid Receptor 1 Accelerates Intestinal Tumor Growth
Authors: Dingzhi Wang, Haibin Wang, Wei Ning, Michael G. Backlund, Sudhansu K. Dey, Raymond N. DuBois
Journal: Cancer Research (2008)

Although endocannabinoid signaling is important for certain aspects of gastrointestinal homeostasis, the role of the cannabinoid receptors (CB) in colorectal cancer has not been defined. Here we show that CB1 expression was silenced in human colorectal cancer due to methylation of the CB1 promoter. Our genetic and pharmacologic studies reveal that loss or inhibition of CB1 accelerated intestinal adenoma growth in Apc(Min/+) mice whereas activation of CB1 attenuated intestinal tumor growth by inducing cell death via down-regulation of the antiapoptotic factor survivin. This down-regulation of survivin by CB1 is mediated by a cyclic AMP-dependent protein kinase A signaling pathway. These results indicate that the endogenous cannabinoid system may represent a potential therapeutic target for prevention or treatment of colorectal cancer.