tbuckley/cabot-search huggingface dataset:
Olsalazine is not superior to placebo in maintaining remission of inactive Crohn's colitis and ileocolitis: a double blind, parallel, randomised, multicentre study
Authors: N Mahmud, M A Kamm, J L Dupas, D P Jewell, C A O'Morain, D G Weir, D Kelleher
Journal: Gut (2001)

<h3>BACKGROUND AND AIMS</h3> The benefit of 5-aminosalicylic acid therapy for maintenance of remission in Crohn9s disease is controversial. The primary aim of this study was to evaluate the prophylactic properties of olsalazine in comparison with placebo for maintenance of remission in quiescent Crohn9s colitis and/or ileocolitis. <h3>METHODS</h3> In this randomised, double blind, parallel group study of olsalazine versus placebo, 328 patients with quiescent Crohn9s colitis and/or ileocolitis were recruited. Treatment consisted of olsalazine 2.0 g daily or placebo for 52 weeks. The primary end point of efficacy was relapse, as defined by the Crohn9s disease activity index (CDAI) and by clinical relapse. Laboratory and clinical disease activity indicators were also measured. Safety analysis consisted of documentation of adverse events and laboratory values. <h3>RESULTS</h3> No differences in the frequency of termination due to relapse or time to termination due to relapse were noted between the two treatment groups (olsalazine 48.5% <i>v </i>placebo 45%) for either colitis or ileocolitis. The failure rate, defined as not completing the study, was significantly higher in olsalazine treated patients compared with placebo treated patients for the overall population (colitis and/or ileocolitis: olsalazine 65.4% <i>v </i>53.9%; p=0.038). Similar failure rates were seen for patients with colitis. A significantly higher percentage of olsalazine treated patients experienced adverse gastrointestinal events. Drug attributed adverse events were reported more frequently in the olsalazine treated group with gastrointestinal symptoms being causally related to olsalazine treatment (olsalazine 40.7% <i>v </i>placebo 26.9%; p=0.010). Back pain was reported significantly more often by the placebo treated group. However, serious medical events did not differ between the two groups. Adverse events led to more early withdrawals in the olsalazine treated group than in the placebo treated group; thus average time in the study for patients in the olsalazine treatment group was significantly shorter than that of patients in the placebo group. <h3>CONCLUSIONS</h3> Patients treated with olsalazine were more likely to terminate their participation in the trial than those taking placebo. This difference was not related to relapse of disease, as measured by CDAI and clinical measures, but rather was due to the development of intolerable adverse medical events of a non-serious nature related to the gastrointestinal tract. The gastrointestinal related events in the olsalazine treated group may be due to the difference in gastrointestinal status at baseline which favoured the placebo treatment group.
Genetics of Cardiac Developmental Disorders: Cardiomyocyte Proliferation and Growth and Relevance to Heart Failure
Authors: Lisa Wilsbacher, Elizabeth M. McNally
Journal: Annual Review of Pathology Mechanisms of Disease (2016)

Cardiac developmental disorders represent the most common of human birth defects, and anomalies in cardiomyocyte proliferation drive many of these disorders. This review highlights the molecular mechanisms of prenatal cardiac growth. Trabeculation represents the initial ventricular growth phase and is necessary for embryonic survival. Later in development, the bulk of the ventricular wall derives from the compaction process, yet the arrest of this process can still be compatible with life. Cardiomyocyte proliferation and growth form the basis of both trabeculation and compaction, and mouse models indicate that cardiomyocyte interactions with the surrounding environment are critical for these proliferative processes. The human genetics of left ventricular noncompaction cardiomyopathy suggest that cardiomyocyte cell-autonomous mechanisms contribute to the compaction process. Understanding the determinants of prenatal or early postnatal cardiomyocyte proliferation and growth provides critical information that identifies risk factors for cardiovascular disease, including heart failure and its associated complications of arrhythmias and thromboembolic events.
Abstract PR02: Recurrent oncogenic mutations in the small GTPase <i>RIT1</i> activate PI3K and MEK.
Authors: Alice H. Berger, Fujiko Duke, Marcin Imielinski, Nathan Kaplan, Jeremiah Wala, Geng-Xian Shi, Douglas A. Andres, Matthew Meyerson
Journal: Clinical Cancer Research (2014)

Abstract Recently, we identified somatic mutations in the RAS-family small GTPase gene RIT1 in 2.4% (10/413) of lung adenocarcinoma tumors. Mutation of RIT1 is mutually exclusive with other oncogenic mutations in the receptor tyrosine kinase/RAS pathway, suggesting that RIT1 mutations are rare driver mutations in lung adenocarcinoma. Oncogenic RIT1 mutations cluster in the switch II domain of the protein and are observed not only in lung adenocarcinoma but also in myeloid malignancies, breast carcinoma, cervical carcinoma, and in the germline of Noonan syndrome patients. Here we functionally characterize 26 RIT1 point mutations and in-frame insertions/deletions in murine fibroblasts and human immortalized lung epithelial cells and find that the majority of somatic RIT1 mutations are able to transform cells. Furthermore, we identified a human lung cancer cell line, NCI-H2110, with an endogenous RIT1 p.M90I mutation. Knockdown of RIT1 in NCI-H2110 cells revealed the role of RIT1 in regulation of PI3K and MEK signaling. Consistently, combination PI3K/MEK inhibition could inhibit cellular transformation induced by ectopic expression of mutated RIT1. Furthermore, PI3K inhibition suppressed in vivo growth of NCI-H2110 cells. These data identify RIT1 as an oncogene and nominate combined PI3K and MEK inhibition as a therapeutic strategy in RIT1-mutated cancers. This abstract is also presented as Poster A04. Citation Format: Alice H. Berger, Fujiko Duke, Marcin Imielinski, Nathan Kaplan, Jeremiah Wala, Geng-Xian Shi, Douglas A. Andres, Matthew Meyerson. Recurrent oncogenic mutations in the small GTPase RIT1 activate PI3K and MEK. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr PR02.
Cytotoxic T Lymphocyte Antigen 4 and CD28 Modulate Cell Surface Raft Expression in Their Regulation of T Cell Function
Authors: Margarita Martin, Helga Schneider, Abdallah Azouz, Christopher E. Rudd
Journal: The Journal of Experimental Medicine (2001)

Coreceptors CD28 and cytotoxic T lymphocyte antigen (CTLA)-4 have opposing effects on TcR/CD3 activation of T cells. While CD28 enhances and CTLA-4 inhibits activation, the underlying molecular basis of these effects has yet to be established. In this context, ganglioside and cholesterol enriched membrane microdomains (rafts, GEMs) serve as centers of signaling in T cells. Although CD28 can promote TcR/raft colocalization, evidence is lacking on whether the surface expression of membrane rafts can be targeted by CTLA-4 in its modulation of T cell responses. In this study, we demonstrate that both CD28 and CTLA-4 profoundly alter the surface expression of membrane rafts during T cell activation. While CD28 increased expression and the number of peripheral T cells induced to express surface rafts in response to TcR ligation, CTLA-4 potently inhibited both TcR and TcR × CD28 induced raft expression on the surface of T cells. Consistent with this, CD28 increased the presence of the linker of activated T cells (LAT) in purified membrane rafts, while CTLA-4 coligation effectively blocked this increase. Further, the reversal of the CTLA-4 block with CD3/CD28 ligation was accompanied by an increase in surface raft expression and associated LAT. Our observations demonstrate for the first time that CTLA-4 targets the release of rafts to the surface of T cells, and provides a mechanism for the opposing effects of CD28 and CTLA-4 on costimulation.
Intracoronary Administration of Abciximab in ST-Elevation Myocardial Infarction
Authors: C. Michael Gibson, Cafer Zorkun, Vijayalakshmi Kunadian
Journal: Circulation (2008)

P rimary percutaneous coronary intervention (PCI) is now the preferred method of treating patients with STelevation myocardial infarction (STEMI).2][3] Therefore, studies such as the one by Thiele et al 4 in this issue of Circulation that focus on the prevention and treatment of microvascular dysfunction are informative with respect to the means to improve the primary PCI strategy.
Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus
Authors: Dedee F. Murrell, Sarah Dick, A.R. Ahmed, Masayuki Amagai, Maria A. Barnadas, Luca Borradori, Jean-Claude Bystryn, Giuseppe Cianchini, Luis Diaz, David Fivenson, Russell Hall, Karen E. Harman, Takashi Hashimoto, Michael Hertl, Nico Hunzelmann, Pilar Iranzo, Pascal Joly, Marcel F. Jonkman, Yasuo Kitajima, Neil J. Korman, Linda K. Martin, Daniel Mimouni, Amit G. Pandya, Aimee S. Payne, David Rubenstein, Hiroshi Shimizu, Animesh A. Sinha, David Sirois, Detlef Zillikens, Victoria P. Werth
Journal: Journal of the American Academy of Dermatology (2008)
Chronic obstructive pulmonary disease: current burden and future projections
Authors: A. D. Lopez, K. Shibuya, C. Rao, C. D. Mathers, A. L. Hansell, L. S. Held, V. Schmid, S. Buist
Journal: European Respiratory Journal (2006)

Information about the comparative magnitude of the burden from various diseases and injuries is a critical input into building the evidence base for health policies and programmes.Such information should be based on a critical evaluation of all available epidemiological data using standard and comparable procedures across diseases and injuries, including information on the age at death and the incidence, duration and severity of cases who do not die prematurely from the disease.A summary measure, disability-adjusted life yrs (DALYs), has been developed to simultaneously measure the amount of disease burden due to premature mortality and the amount due to the nonfatal consequences of disease.Approximately 2.7 million deaths from chronic obstructive pulmonary disease (COPD) occurred in 2000, half of them in the Western Pacific Region, with the majority of these occurring in China.About 400,000 deaths occur each year from COPD in industrialised countries.The increase in global COPD deaths between 1990 and 2000 (0.5 million) is likely to be partly real, and partly due to better methods and more extensive data availability in 2000.The regional (adult) prevalence in 2000 varied from 0.5% in parts of Africa to 3-4% in North America.
Risk of AKI with Gentamicin as Surgical Prophylaxis
Authors: Samira Bell, Peter Davey, Dilip Nathwani, Charis Marwick, Thenmalar Vadiveloo, Jacqueline Sneddon, Andrea Patton, Marion Bennie, Stewart Fleming, Peter T. Donnan
Journal: Journal of the American Society of Nephrology (2014)

In 2009, the Scottish government issued a target to reduce Clostridium difficile infection by 30% in 2 years. Consequently, Scottish hospitals changed from cephalosporins to gentamicin for surgical antibiotic prophylaxis. This study examined rates of postoperative AKI before and after this policy change. The study population comprised 12,482 adults undergoing surgery (orthopedic, urology, vascular, gastrointestinal, and gynecology) with antibiotic prophylaxis between October 1, 2006, and September 30, 2010 in the Tayside region of Scotland. Postoperative AKI was defined by the Kidney Disease Improving Global Outcomes criteria. The study design was an interrupted time series with segmented regression analysis. In orthopedic patients, change in policy from cefuroxime to flucloxacillin (two doses of 1 g) and single-dose gentamicin (4 mg/kg) was associated with a 94% increase in AKI (P=0.04; 95% confidence interval, 93.8% to 94.3%). Most patients who developed AKI after prophylactic gentamicin had stage 1 AKI, but some patients developed persistent stage 2 or stage 3 AKI. The antibiotic policy change was not associated with a significant increase in AKI in the other groups. Regardless of antibiotic regimen, however, rates of AKI were high (24%) after vascular surgery, and increased steadily after gastrointestinal surgery. Rates could only be ascertained in 52% of urology patients and 47% of gynecology patients because of a lack of creatinine testing. These results suggest that gentamicin should be avoided in orthopedic patients in the perioperative period. Our findings also raise concerns about the increasing prevalence of postoperative AKI and failures to consistently measure postoperative renal function.
Intestinal absorption of the bile acid analogue 75Se-homocholic acid-taurine is increased in primary biliary cirrhosis, and reverts to normal during ursodeoxycholic acid administration
Authors: A Lanzini, M G De Tavonatti, B Panarotto, S Scalia, A Mora, F Benini, O Baisini, F Lanzarotto
Journal: Gut (2003)

Whether ileal absorption of bile acid is up or downregulated in chronic cholestasis is still debated, and most evidence has come from animal studies.To compare ileal bile acid absorption in patients with primary biliary cirrhosis (PBC) and in healthy control subjects, and to assess the effect of ursodeoxycholic acid (UDCA).We studied 14 PBC patients before and during (n=11) UDCA administration, 14 healthy control subjects, and 14 Crohn's disease patients (as disease controls).We used cholescintigraphy to measure retention in the enterohepatic circulation over five successive days of the bile acid analogue (75)Se-homocholic acid-taurine ((75)SeHCAT) as an index of ileal bile acid absorption. Results were expressed as (75)SeHCAT fractional turnover rate (FTR) and t(1/2)12.(75)SeHCAT FTR was 0.19 (0.11)/day, 0.34 (0.11)/day (p<0.001), and 0.83 (0.32)/day in PBC patients, healthy controls (p<0.0001), and Crohn's patients (p<0.001), respectively, which increased to 0.36 (0.16)/day in PBC patients during UDCA treatment (p<0.005). (75)SeHCAT t(1/2)12 was 4.8 (2.1) days in PBC patients, 2.2 (0.5) days (p<0.001) in healthy controls, and 1.0 (0.5) days (p<0.001) in Crohn's disease patients. (75)SeHCAT t(1/2)12 decreased to 2.2 (0.93) days (p< 0.001) in PBC patients during UDCA treatment.Our results support the concept that ileal bile acid absorption is upregulated in PBC patients, and that this effect may contribute towards damaging the cholestatic liver. This upregulation of bile acid absorption is abolished by UDCA.
Treatment to lipid targets in patients with inflammatory joint diseases in a preventive cardio-rheuma clinic
Authors: Silvia Rollefstad, Tore K Kvien, Ingar Holme, Anne S Eirheim, Terje R Pedersen, Anne Grete P Semb
Journal: Annals of the Rheumatic Diseases (2012)

To perform cardiovascular risk stratification in patients with inflammatory joint diseases (IJD) and treat to lipid targets according to recommendations.We initiated a preventive cardio-rheuma clinic based on the unmet need of adequate cardiovascular prevention in IJD patients. A full cardiovascular risk stratification was performed at the first consultation (history of conventional risk factors and of cardiovascular disease, lipid measurement, blood pressure and ultrasound examination of both carotid arteries), and the patient was classified to either a primary or secondary cardiovascular prevention regime, or to have a low risk (no intervention). Lipid-lowering treatment was adjusted until at least two lipid targets were achieved.Of the 426 patients referred, 36.6% had a systematic coronary risk evaluation less than 5% (no lipid-lowering intervention). The remaining 270 patients ((rheumatoid arthritis (RA), n=165; ankylosing spondylitis (AS), n=70; and psoriatic arthritis (PsA), n=35) were assigned to either primary (n=63) or secondary prevention (n=207). There were significant differences between the patient groups regarding age (p<0.001), sex (p<0.001) and disease duration (p<0.001). Lipid changes in IJD patients were: total cholesterol -1.86±1.20 mmol/l (p<0.001); low-density lipoprotein cholesterol -1.74±1.11 (p<0.001); high-density lipoprotein cholesterol 0.01±0.30 (p=0.61); triglycerides -0.28±0.72 (p<0.001). The proportions of patients reaching at least two lipid targets were for RA 92.1%, AS 90.0% and PsA 82.9%. No serious adverse events were observed.There was indication for cardiovascular prevention in a high proportion of IJD patients referred for cardiovascular risk stratification. Treatment to lipid targets was successful in approximately 90% of patients with IJD.
Long-acting octreotide versus placebo for treatment of advanced HCC: A randomized controlled double-blind study
Authors: Gerhild Becker, Hans-Peter Allgaier, Manfred Olschewski, Andreas Zähringer, Hubert Erich Blum
Journal: Hepatology (2006)

Although numerous treatment modalities have been explored in patients with advanced HCC, the therapeutic options are still limited. Somatostatin has been shown to have antimitotic activity in endocrine as well as in a variety of nonendocrine tumors. Expression of somatostatin receptors is found in HCCs, but the efficacy of the somatostatin analogue octreotide remains controversial. Therefore, a randomized double-blind placebo-controlled multicenter trial was performed to assess the efficacy of long-acting octreotide for the treatment of advanced HCC. One hundred twenty untreated patients with histologically confirmed HCC were randomized to receive either long-acting octreotide (Sandostation LAR 30 mg) intramuscularly every 4 weeks or placebo. The study groups were comparable with respect to clinical characteristics. There was no difference in the cumulative survival. The median survival time was 4.7 months in the octreotide group compared with 5.3 months in the control group. Six-month survival rates were 41% for octreotide patients and 42% for control patients, respectively. The unadjusted relative risk for mortality in the octreotide group compared with patients in the control group was 1.11 (95% CI 0.76-1.63; P = 0.59). When adjusted for Okuda, CTP, and Cancer of the Liver Italian Program (CLIP) scores, the relative risk for octreotide did not change markedly and was 1.05 (95% CI 0.71-1.55; P = 0.83). The CLIP score seems to predict survival better than both Okuda and CTP score. Conclusion: The randomized controlled double-blind HECTOR trial showed no survival benefit for HCC patients treated with long-acting octreotide compared with placebo. (Hepatology 2007;45:9–15.)
Medical tourism can do harm
Authors: R. A Bishop and James A Litch
Journal: BMJ (2000)

We are expatriate doctors living at 3900 metres in the Mount Everest region of Nepal and running a health care system serving a population of 10 000. The area is remote, mountainous, and roadless, with the villages scattered along high valleys. Over the past 32 years a health system of one hospital and eight health clinics has been established so that most residents are within an hour's walk of a health clinic or hospital.

The area is popular with tourists. Last year 19 000 visitors came into the Sagarmartha National Park where Mount Everest, the hospital, and five of the eight health clinics are located. Inevitably, there are many doctors and other healthcare professionals amongthem.

> Can you realistically treat chronic disease after a single consultation?

Although the presence of the hospital is well publicised, many doctors touring the area hold ad hoc clinics along the trail. They often conduct these clinics just …
A randomized 4-arm multicenter study of interferon alfa-2b plus ribavirin in the treatment of patients with chronic hepatitis C relapsing after interferon monotherapy
Authors: Giorgio Saracco, Alda Olivero, Alessia Ciancio, Silvia Carenzi, Antonina Smedile, Giuseppe Cariti, Massimo Andreoni, Pier Giulio Orsi, Alberto Biglino, Marco Tabone, Luigi Roffi, Guido Croce, Aldo Manca, Gianfranco Tappero, Giovannino Ciccone, Mario Rizzetto
Journal: Hepatology (2002)

To determine whether a higher dosage of interferon (IFN) and/or a prolonged time of administration may improve the efficacy of combination therapy, we conducted a 4-arm randomized trial on patients with chronic hepatitis C relapsing after 1 or more previous treatment courses with IFN monotherapy. Group A (n = 70) received 3 MU IFN alfa-2b 3 times per week plus ribavirin 1,000 mg/d for 12 months; group B (n = 70) received 5 MU 3 times per week plus ribavirin for 12 months; group C (n = 82) received 3 MU 3 times per week plus ribavirin for 6 months, and group D (n = 73) received 5 MU 3 times per week plus ribavirin for 6 months. The primary end point was the clearance of viremia at the end of 6-month follow-up: test results for hepatitis C virus (HCV)-RNA were negative in 54% of group A, 56% of group B, 40% of group C, and 49% of group D patients ( P = NS). Among patients with genotype 1 and 4, the sustained response was significantly higher in groups A and B than in group C (45%, 49% vs. 22%, P = .03; group D = 33%, P = NS). In patients with genotype 2 and 3, the sustained virologic response was not affected by the different regimens (group A = 69%, group B = 68%, group C = 62%, group D = 71%, P = NS). In conclusion, duration of therapy rather than IFN dosage is more important in increasing the sustained virologic rate among HCV-positive patients with genotype 1 and 4 relapsing after IFN monotherapy; patients with genotypes 2 and 3 can be effectively retreated with a 6-month course of combination therapy, avoiding unnecessary side effects and waste of resources.
Mitochondrial DNA Sequence Variation and Risk of Pancreatic Cancer
Authors: Ernest T. Lam, Paige M. Bracci, Elizabeth A. Holly, Catherine Chu, Annie Poon, Eunice Wan, Krystal White, Pui-Yan Kwok, Ludmila Pawlikowska, Gregory J. Tranah
Journal: Cancer Research (2011)

Abstract Although the mitochondrial genome exhibits high mutation rates, common mitochondrial DNA (mtDNA) variation has not been consistently associated with pancreatic cancer. Here, we comprehensively examined mitochondrial genomic variation by sequencing the mtDNA of participants (cases = 286, controls = 283) in a San Francisco Bay Area pancreatic cancer case–control study. Five common variants were associated with pancreatic cancer at nominal statistical significance (P &amp;lt; 0.05) with the strongest finding for mt5460g in the ND2 gene [OR = 3.9; 95% confidence interval (CI), 1.5–10; P = 0.004] which encodes an A331T substitution. Haplogroup K was nominally associated with reduced pancreatic cancer risk (OR = 0.32; 95% CI, 0.13–0.76; P = 0.01) when compared with the most common haplogroup, H. A total of 19 haplogroup-specific rare variants yielded nominal statistically significant associations (P &amp;lt; 0.05) with pancreatic cancer risk, with the majority observed in genes involved in oxidative phosphorylation. Weighted-sum statistics were used to identify an aggregate effect of variants in the 22 mitochondrial tRNAs on pancreatic cancer risk (P = 0.02). While the burden of singleton variants in the HV2 and 12S RNA regions was three times higher among European haplogroup N cases than controls, the prevalence of singleton variants in ND4 and ND5 was two to three times higher among African haplogroup L cases than in controls. Together, the results of this study provide evidence that aggregated common and rare variants and the accumulation of singleton variants are important contributors to pancreatic cancer risk. Cancer Res; 72(3); 686–95. ©2011 AACR.