tbuckley/cabot-search huggingface dataset:
Increased Risk of Hepatocellular Carcinoma and Liver Cirrhosis in Vinyl Chloride Workers: Synergistic Effect of Occupational Exposure with Alcohol Intake
Authors: Giuseppe Mastrangelo, Ugo Fedeli, Emanuela Fadda, Flavio Valentini, Roberto Agnesi, Giancarlo Magarotto, Teresio Marchì, Andrea Buda, Massimo Pinzani, Diego Martines
Journal: Environmental Health Perspectives (2004)

Hepatocellular carcinoma (HCC) and liver cirrhosis (LC) are not well-established vinyl chloride monomer (VCM)-induced diseases. Our aim was to appraise the role of VCM, alcohol intake, and viral hepatitis infection, and their interactions, in the etiology of HCC and LC. Thirteen cases of HCC and 40 cases of LC were separately compared with 139 referents without chronic liver diseases or cancer in a case-referent study nested in a cohort of 1,658 VCM workers. The odds ratios (ORs) and the 95% confidence intervals (CIs) were estimated by common methods and by fitting models of logistic regression. We used Rothman's synergy index (S) to evaluate interactions. By holding the confounding factors constant at logistic regression analysis, each extra increase of 1,000 ppm times years of VCM cumulative exposure was found to increase the risk of HCC by 71% (OR = 1.71; 95% CI, 1.28-2.44) and the risk of LC by 37% (OR = 1.37; 95% CI, 1.13-1.69). The joint effect of VCM exposure above 2,500 ppm times years and alcohol intake above 60 g/day resulted in ORs of 409 (95% CI, 19.6-8,553) for HCC and 752 (95% CI, 55.3-10,248) for LC; both S indexes suggested a synergistic effect. The joint effect of VCM exposure above 2,500 ppm times years and viral hepatitis infection was 210 (95% CI, 7.13-6,203) for HCC and 80.5 (95% CI, 3.67-1,763) for LC; both S indexes suggested an additive effect. In conclusion, according to our findings, VCM exposure appears to be an independent risk factor for HCC and LC interacting synergistically with alcohol consumption and additively with viral hepatitis infection.
Impact of NHS Direct on demand for immediate care: observational study
Authors: J. Munro
Journal: BMJ (2000)

<h3>Abstract</h3> <b>Objectives:</b> To quantify the impact of NHS Direct on the use of accident and emergency, ambulance, and general practitioner cooperative services. <b>Design:</b> Observational study of trends in use of NHS Direct and other immediate care services over 24 months spanning introduction of NHS Direct. <b>Setting:</b> Three areas in England in first wave of introduction of NHS Direct, and six nearby general practitioner cooperatives as controls. <b>Subjects:</b> All contacts with these immediate care services. <b>Main outcome measures:</b> Changes in trends in use after introduction of NHS Direct. <b>Results:</b> NHS Direct received about 68 500 calls from a population of 1.3 million in its first year of operation, of which 72% were out of hours and 22% about a child aged under 5 years. Changes in trends in use of accident and emergency departments and ambulance services after introduction of NHS Direct were small and non-significant. Changes in trends in use of general practitioner cooperatives were also small but significant, from an increase of 2.0% a month before introduction of NHS Direct to −0.8% afterwards (relative change −2.9% (95% confidence interval −4.2% to −1.5%)). This reduction in trend was significant both for calls handled by telephone advice alone and for those resulting in direct contact with a doctor. In contrast, the six control cooperatives showed no evidence of change in trend; an increase of 0.8% a month before NHS Direct and 0.9% after (relative change 0.1% (−0.9% to 1.1%)). <b>Conclusion:</b> In its first year NHS Direct did not reduce the pressure on NHS immediate care services, although it may have restrained increasing demand on one important part—general practitioners9 out of hours services.
Serum cytokine biomarker panels for discriminating pancreatic cancer from benign pancreatic disease
Authors: Victoria E Shaw, Brian Lane, Claire Jenkinson, Trevor Cox, William Greenhalf, Christopher M Halloran, Joseph Tang, Robert Sutton, John P Neoptolemos, Eithne Costello
Journal: Molecular Cancer (2014)

We investigated whether combinations of serum cytokines, used with logistic disease predictor models, could facilitate the detection of pancreatic ductal adenocarcinoma (PDAC). The serum levels of 27 cytokines were measured in 241 subjects, 127 with PDAC, 49 with chronic pancreatitis, 20 with benign biliary obstruction and 45 healthy controls. Samples were split randomly into independent training and test sets. Cytokine biomarker panels were selected by identifying the top performing cytokines in best fit logistic regression models during multiple rounds of resampling from the training dataset. Disease prediction by logistic models, built using the resulting cytokine panels, was evaluated with training and test sets and further examined using resampled performance evaluation. For the discrimination of PDAC patients from patients with benign disease, a panel of IP-10, IL-6, PDGF plus CA19-9 offered improved diagnostic performance over CA19-9 alone in the training (AUC 0.838 vs. 0.678) and independent test set (AUC 0.884 vs. 0.798). For the discrimination of PDAC from CP, a panel of IL-8, CA19-9, IL-6 and IP-10 offered improved diagnostic performance over CA19-9 alone with the training (AUC 0.880 vs. 0.758) and test set (AUC 0.912 vs. 0.848). Finally, for the discrimination of PDAC in the presence of jaundice from benign controls with jaundice, a panel of IP-10, IL-8, IL-1b and PDGF demonstrated improvement over CA19-9 in the training (AUC 0.810 vs. 0.614) and test set (AUC 0.857 vs. 0.659). These findings support the potential role for cytokine panels in the discrimination of PDAC from patients with benign pancreatic diseases and warrant additional study.
Perinatal paracetamol exposure in mice does not affect the development of allergic airways disease in early life
Authors: Debbie C P Lee, Simone A Walker, Adam J Byrne, Lisa G Gregory, James Buckley, Andrew Bush, Seif O Shaheen, Sejal Saglani, Clare M Lloyd
Journal: Thorax (2015)

Current data concerning maternal paracetamol intake during pregnancy, or intake during infancy and risk of wheezing or asthma in childhood is inconclusive based on epidemiological studies. We have investigated whether there is a causal link between maternal paracetamol intake during pregnancy and lactation and the development of house dust mite (HDM) induced allergic airways disease (AAD) in offspring using a neonatal mouse model.Pregnant mice were administered paracetamol or saline by oral gavage from the day of mating throughout pregnancy and/or lactation. Subsequently, their pups were exposed to intranasal HDM or saline from day 3 of life for up to 6 weeks. Assessments of airway hyper-responsiveness, inflammation and remodelling were made at weaning (3 weeks) and 6 weeks of age.Maternal paracetamol exposure either during pregnancy and/or lactation did not affect development of AAD in offspring at weaning or at 6 weeks. There were no effects of maternal paracetamol at any time point on airway remodelling or IgE levels.Maternal paracetamol did not enhance HDM induced AAD in offspring. Our mechanistic data do not support the hypothesis that prenatal paracetamol exposure increases the risk of childhood asthma.
Tetrabenazine is neuroprotective in Huntington's disease mice
Authors: Hongyu Wang, Xi Chen, Yuemei Li, Tie-Shan Tang, Ilya Bezprozvanny
Journal: Molecular Neurodegeneration (2010)

Huntington's disease (HD) is a neurodegenerative disorder caused by a polyglutamine (polyQ) expansion in Huntingtin protein (Htt). PolyQ expansion in Httexp causes selective degeneration of striatal medium spiny neurons (MSN) in HD patients. A number of previous studies suggested that dopamine signaling plays an important role in HD pathogenesis. A specific inhibitor of vesicular monoamine transporter (VMAT2) tetrabenazine (TBZ) has been recently approved by Food and Drug Administration for treatment of HD patients in the USA. TBZ acts by reducing dopaminergic input to the striatum.In previous studies we demonstrated that long-term feeding with TBZ (combined with L-Dopa) alleviated the motor deficits and reduced the striatal neuronal loss in the yeast artificial chromosome transgenic mouse model of HD (YAC128 mice). To further investigate a potential beneficial effects of TBZ for HD treatment, we here repeated TBZ evaluation in YAC128 mice starting TBZ treatment at 2 months of age ("early" TBZ group) and at 6 months of age ("late" TBZ group). In agreement with our previous studies, we found that both "early" and "late" TBZ treatments alleviated motor deficits and reduced striatal cell loss in YAC128 mice. In addition, we have been able to recapitulate and quantify depression-like symptoms in TBZ-treated mice, reminiscent of common side effects observed in HD patients taking TBZ.Our results further support therapeutic value of TBZ for treatment of HD but also highlight the need to develop more specific dopamine antagonists which are less prone to side-effects.
New Insights into Diuretic Use in Patients with Chronic Renal Disease
Authors: Christopher S. Wilcox
Journal: Journal of the American Society of Nephrology (2002)

Patients with chronic renal insufficiency (CRI) or the nephrotic syndrome frequently manifest diuretic resistance. Factors limiting diuretic responsiveness in patients with CRI may include a reduced basal level of fractional Na(+) reabsorption that places an upper limit on diuretic response, and enhanced NaCl reabsorption in downstream segments, combined with a reduced delivery of diuretic to the kidney. Diuretics are secreted by the recently characterized organic anion transporters (OATs), which are expressed in proximal tubule cells. Secretion may be inhibited by retained organic anions, urate, or acidosis. These limitations necessitate an increased diuretic dosage, up to a defined ceiling level, and consideration of the use of a nonrenally metabolized loop diuretic rather than furosemide. Diuretic responsiveness in patients with the nephrotic syndrome is limited by avid Na(+) reabsorption by the terminal nephron. Experimental studies have shown that a reduced serum albumin concentration can increase the volume of distribution of loop diuretics, reduce their tubular secretion, and enhance the inactivation of furosemide within the kidney by glucuronidization. Binding of loop diuretics can curtail their action in the loop of Henle. Recent clinical investigations have challenged the importance of some of these mechanisms that were identified in animal models. Strategies to improve loop diuretic responsiveness include increasing diuretic dosage, concurrent use of a thiazide diuretic to inhibit downstream NaCl reabsorption and attempts to maximally reduce albumin excretion. Strategies to limit albumin excretion include the use of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker and appropriate limitation of protein intake. These measures are more logical, effective, and less expensive than infusion of albumin solutions.
Mice lacking calsarcin-1 are sensitized to calcineurin signaling and show accelerated cardiomyopathy in response to pathological biomechanical stress
Authors: Norbert Frey, Tomasa Barrientos, John M Shelton, Derk Frank, Hartmut Rütten, Doris Gehring, Christian Kuhn, Matthias Lutz, Beverly Rothermel, Rhonda Bassel-Duby, James A Richardson, Hugo A Katus, Joseph A Hill, Eric N Olson
Journal: Nature Medicine (2004)
Clinicians have grasped the need to do more to tackle female genital mutilation, MPs are told
Authors: A. O'Dowd
Journal: BMJ (2015)

Clinical leaders have denied claims that the medical profession is not taking the issue of female genital mutilation (FGM) seriously enough and is failing to report cases.

MPs on the parliamentary home affairs committee held an evidence session on 27 January as part of its follow-up inquiry into FGM and questioned Nigel Mathers, honorary secretary of the Royal College of General Practitioners.

The committee produced a report on the subject last summer with various recommendations,1 and in July the government and Unicef hosted the first global Girl Summit in the United Kingdom, aimed at mobilising domestic and international efforts to end FGM and early, forced, and child marriage.

Keith Vaz, committee chair …
Racial differences in primary central nervous system lymphoma incidence and survival rates
Authors: Jose S. Pulido, Robert A. Vierkant, Janet E. Olson, Lauren Abrey, David Schiff, Brian Patrick O'Neill
Journal: Neuro-Oncology (2009)

To determine racial and ethnic differences in incidence and survival in patients with primary central nervous system lymphoma (PCNSL), NCI Surveillance, Epidemiology, and End Results (SEER) program data from 1992 to 2002 were queried. Data were substratified by age (20-49 years vs. 50 or above) and race (White, Black, Asian/Pacific Islander [A/PI], American Indian/Alaskan Native [AI/AN]). Incidence of PCNSL and survival were calculated by SEER(*)Stat software. The incidence rates were 0.94 per 100,000 per year (95% confidence interval [CI] 0.90-0.98) for Whites, 1.10 (95% CI 0.98-1.22) for Blacks, 0.51 (95% CI 0.28-0.74) for AI/AN, and 0.64 (95% CI 0.56-0.72) for A/PI. In patients aged 20-49 years the rates were 0.72 (95% CI 0.68-0.76) for Whites, 1.43 (95% CI 1.27-1.59) for Blacks, 0.58 (95% CI 0.30-0.86) for AI/AN, and 0.21 (CI 0.15-0.27) for A/PI. In patients over 49 years, the rates were 1.30 (95% CI 1.22-1.38) for Whites, 0.56 (95% CI 0.40-0.72) for Blacks, 0.34 (95% CI 0-0.70) for AI/AN, and 1.31 (95% CI 1.00-1.53) for A/PI. PCNSL incidence for ages 20-49 years for Black patients was twice that for Whites. Incidence for ages over 49 years for Whites was twice that for Blacks. Survival at 12 months, 24 months, and 60 months was higher among Whites than Blacks. Research is needed to determine the origin of these differences.
Increased Expression of Heme Oxygenase (HO)-1 in Alveolar Spaces and HO-2 in Alveolar Walls of Smokers
Authors: PIERO MAESTRELLI, ABDUL H. EL MESSLEMANI, ORIETTA DE FINA, YOHANN NOWICKI, MARINA SAETTA, CRISTINA MAPP, LEONARDO M. FABBRI
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

It has been suggested that oxidative stress protein heme oxygenase (HO)-1 plays a role in chronic airway diseases including chronic obstructive pulmonary disease (COPD). The inducible isoform HO-1 and the constitutive HO-2 catalyze the same reaction. Their distribution in situ was studied in lungs of 10 nonsmoking subjects, 6 healthy smokers, and 10 smokers with COPD. Paraffin-embedded sections of surgical lung specimens were immunostained with antibodies against HO-1 and HO-2. HO-1 immunoreactivity was observed mainly in alveolar macrophages. HO-1-positive macrophages were increased in smokers with COPD (median: 36%) as compared with nonsmoking subjects (13%; p < 0.02), whereas no differences were observed between patients with COPD and healthy smokers (34%). HO-2 had a more widespread distribution in cells of the alveolar wall, in adventitia of pulmonary arteries and bronchioles, and in vascular smooth muscle. Lower percentages of alveolar macrophages exhibited positive staining for HO-2 without significant differences between the three groups. HO-2+ cells in the alveolar wall were increased in smokers with (15/mm) and without COPD (12/mm) as compared with nonsmokers (8/mm, p < 0.01). In conclusion, inducible HO-1 and constitutive HO-2 are detectable in human lung tissue and their expression is increased in smokers, suggesting that oxidative stress due to cigarette smoke may increase lung cells expressing HO-1 and HO-2.
Liver galactose-l-phosphate uridyl transferase: activity in normal and galactosemic subjects
Authors: Stanton Segal, Shirley Rogers, Philip G. Holtzapple
Journal: Journal of Clinical Investigation (1971)

The kinetic characteristics of galactose-l-phosphate uridyl transferase have been determined in homogenates of human liver biopsies obtained from control subjects and in 50-fold purified enzyme preparations from liver obtained at autopsy. A standardized assay procedure employing linear kinetics was used to assess the enzyme activity in homogenates of liver biopsy specimens from five control subjects and four patients with congential galactosemia with demonstrated absence of the enzyme activity in red blood cells. Activity of control specimens ranged from 11.8 to 17.2 mmumoles of UDPgalactose formed per min mg of protein. Liver of two galactosemic patients, both Caucasian, possessed no detectable enzyme activity (less than 1-2% of normal). The tissue of two others, both Negro, who are known to be capable of metabolizing intravenously administered galactose, contained easily detectable enzyme at approximately 10% of the controls. No alternate enzymatic activity for formation of UDPgalactose was found in the liver of Negroes with galactosemia that was as active as the residual galactose-l-phosphate uridyl transferase. The data suggest that the residual liver enzyme activity accounts for the ability of Negroes with galactosemia to metabolize limited but significantly large quantities of galactose.
Two distinct mechanisms regulate the in vivo generation of cytotoxic T cells.
Authors: M S Sy, S H Lee, M Tsurufuji, K L Rock, B Benacerraf, R Finberg
Journal: The Journal of Experimental Medicine (1982)

Treatment of responder cells with monoclonal anti-Ly-1,2 antibodies plus complement in vitro completely eliminated their ability to generate azobenzenearsonate (ABA)-specific cytolytic T lymphocytes (CTL). However, addition of the concanavalin A-stimulated supernatants of rat spleen cells (Con A-Sup) can fully reconstitute the response. Therefore, Lyt-1,2-bearing T cells are required for the generation of ABA-specific CTL, and such requirement can be replaced by factors present in the Con A- sup. Suppressor T cells (Ts), when adoptively transferred into naive recipients, will inhibit the in vivo priming of CTL. This inhibition can also be reversed by in vitro addition of Con A-Sup. furthermore, mice serving as donors of Ts also show profound unresponsiveness when primed and restimulated in vitro. In contrast to the Ts-mediated inhibition, in vitro addition of Con A-Sup was unable to abolish the unresponsiveness observed in these cultures. Thus, we identified two unresponsive states in a hapten-specific killing system that differ in their ability to be reconstituted by Con A-Sup.
Mortality From Lymphohematopoietic Malignancies Among Workers in Formaldehyde Industries
Authors: M. Hauptmann
Journal: JNCI Journal of the National Cancer Institute (2003)

Many U.S. factory workers are exposed to formaldehyde. Although increased risks for leukemia have been found in medical workers and other professionals exposed to formaldehyde, studies in industrial workers, who are thought to have higher exposures, have shown inconsistent associations. We extended follow-up of a cohort of industrial workers to evaluate the association between formaldehyde exposure and lymphohematopoietic cancers.The cohort consisted of 25 619 workers (865 708 person-years) employed before January 1, 1966, at one of 10 U.S. industrial plants and followed through December 31, 1994. We analyzed formaldehyde exposure (peak exposure, average exposure intensity, cumulative exposure, and duration of exposure) and mortality from lymphohematopoietic malignancies using standardized mortality ratios and relative risks and 95% confidence intervals (CIs) based on Poisson regression. Statistical tests were two-sided.Among the cohort, there were 178 deaths from lymphohematopoietic malignancies. Relative risks for leukemia (69 deaths), particularly for myeloid leukemia (30 deaths), increased with formaldehyde exposure. Compared with workers exposed to low peak levels of formaldehyde (0.1-1.9 ppm), relative risks for myeloid leukemia were 2.43 (95% CI = 0.81 to 7.25) and 3.46 (95% CI = 1.27 to 9.43) for workers exposed to peak levels of 2.0-3.9 ppm and > or = 4.0 ppm, respectively (P(trend) =.009). Compared with workers exposed to low levels of average exposure intensity of formaldehyde (0.1-0.4 ppm), workers exposed to 0.5-0.9 ppm and > or = 1.0 ppm average intensity had relative risks of 1.15 (95% CI = 0.41 to 3.23) and 2.49 (95% CI = 1.03 to 6.03), respectively (P(trend) =.088). The relative risk for leukemia was not associated with cumulative exposure but was weakly associated with duration of exposure. Relative risks for Hodgkin's disease also increased with formaldehyde exposure.Exposure to formaldehyde may cause leukemia, particularly myeloid leukemia, in humans. However, results from other investigations are mixed, suggesting caution in drawing definitive conclusions.
12-h pretreatment with methylprednisolone versus placebo for prevention of postextubation laryngeal oedema: a randomised double-blind trial
Authors: Bruno François, Eric Bellissant, Valérie Gissot, Arnaud Desachy, Sandrine Normand, Thierry Boulain, Olivier Brenet, Pierre-Marie Preux, Philippe Vignon
Journal: The Lancet (2007)
Survival and complications in a cohort of patients with anti-Delta positive liver disease presenting in a tertiary referral clinic
Authors: Robert A. de Man, Renate P. Sprey, Hubert G.M. Niesters, Ruud A. Heijtink, Pieter E. Zondervan, Wim Hop, Solko W. Schalm
Journal: Journal of Hepatology (1995)
Abstract 1560: VE-PTP inhibitor AKB-9778 mitigates IL-2-induced VLS and interacts positively with IL-2 against melanoma and renal cancer tumors in mice
Authors: Mingli Cao, Dan Lindner, Ernest Borden, Robert Shalwitz, Taolin Yi
Journal: Cancer Research (2010)

Abstract IL-2 induces complete responses (CR) durable more than 10 years in a subpopulation of patients with advanced melanoma or renal cell carcinoma, establishing the clinical effectiveness of immunotherapy for human malignancies. However, the application and clinical efficacy of IL-2 have been limited by its major dose-limiting toxicity vascular leak syndrome (VLS), which occurs in the majority (∼65%) of the patients and often necessitates cessation of the cytokine treatment. Being a life-threatening toxicity, VLS is managed by supportive care with no specific treatment. Therapeutics for IL-2-induced VLS might improve the efficacy and tolerance of the cytokine. Recent studies implicated heightened Ang2 as a potential mediator of VLS via antagonizing Ang1 and thus blocking Tie2/AKT signaling in endothelial cells. Being a regulator of Tie2 phosphorylation, vascular endothelial protein tyrosine phosphatase (VE-PTP) might be targeted to modulate Tie2/AKT signaling although tthe effects and tolerance of targeting VE-PTP were not well-defined. Our work herein identified compound AKB-9778 as a VE-PTP inhibitor capable of inducing pTie2 and down stream pAKT in endothelial cells, interacting positively with Ang1 and/or Ang2 to increase cellular pTie2 levels, reducing IL-2-induced circulating Ang2 in mice and protecting mice from IL-2-induced VLS. AKB-9778 also interacted positively with IL-2 against B16 melanoma and Renca renal cancer tumors in mice in a tolerated manner. These data provide pre-clinical proof of concept evidence of targeting VE-PTP to mitigate IL-2-induced VLS. AKB-9778 may provide beneficial adjunctive therapy in combination with IL-2 in cancer treatment by reducing VLS and enhancing efficacy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1560.