tbuckley/cabot-search huggingface dataset:
RANTES antagonism: A promising approach to treat chronic liver diseases
Authors: Silvia Affò, Ramón Bataller
Journal: Journal of Hepatology (2011)

Activation of hepatic stellate cells in response to chronic inflammation represents a crucial step in the development of liver fibrosis. However, the molecules involved in the interaction between immune cells and stellate cells remain obscure. Herein, we identify the chemokine CCL5 (also known as RANTES), which is induced in murine and human liver after injury, as a central mediator of this interaction. First, we showed in patients with liver fibrosis that CCL5 haplotypes and intrahepatic CCL5 mRNA expression were associated with severe liver fibrosis. Consistent with this, we detected Ccl5 mRNA and CCL5 protein in 2 mouse models of liver fibrosis, induced by either injection of carbon tetrachloride (CCl(4)) or feeding on a methionine and choline-deficient (MCD) diet. In these models, Ccl5(-/-) mice exhibited decreased hepatic fibrosis, with reduced stellate cell activation and immune cell infiltration. Transplantation of Ccl5-deficient bone marrow into WT recipients attenuated liver fibrosis, identifying infiltrating hematopoietic cells as the main source of Ccl5. We then showed that treatment with the CCL5 receptor antagonist Met-CCL5 inhibited cultured stellate cell migration, proliferation, and chemokine and collagen secretion. Importantly, in vivo administration of Met-CCL5 greatly ameliorated liver fibrosis in mice and was able to accelerate fibrosis regression. Our results define a successful therapeutic approach to reduce experimental liver fibrosis by antagonizing Ccl5 receptors.
Identification of 12/15-lipoxygenase as a suppressor of myeloproliferative disease
Authors: Melissa Kristine Middleton, Alicia Marie Zukas, Tanya Rubinstein, Michele Jacob, Peijuan Zhu, Liang Zhao, Ian Blair, Ellen Puré
Journal: The Journal of Experimental Medicine (2006)

Though Abl inhibitors are often successful therapies for the initial stages of chronic myelogenous leukemia (CML), refractory cases highlight the need for novel molecular insights. We demonstrate that mice deficient in the enzyme 12/15-lipoxygenase (12/15-LO) develop a myeloproliferative disorder (MPD) that progresses to transplantable leukemia. Although not associated with dysregulation of Abl, cells isolated from chronic stage 12/15-LO–deficient (Alox15) mice exhibit increased activation of the phosphatidylinositol 3–kinase (PI3-K) pathway, as indicated by enhanced phosphorylation of Akt. Furthermore, the transcription factor interferon consensus sequence binding protein (ICSBP) is hyperphosphorylated and displays decreased nuclear accumulation, translating into increased levels of expression of the oncoprotein Bcl-2. The ICSBP defect, exaggerated levels of Bcl-2, and prolonged leukemic cell survival associated with chronic stage Alox15 MPD are all reversible upon treatment with a PI3-K inhibitor. Remarkably, the evolution of Alox15 MPD to leukemia is associated with additional regulation of ICSBP on an RNA level, highlighting the potential usefulness of the Alox15 model for understanding the transition of CML to crisis. Finally, 12/15-LO expression suppresses the growth of a human CML–derived cell line. These data identify 12/15-LO as an important suppressor of MPD via its role as a critical upstream effector in the regulation of PI3-K–dependent ICSBP phosphorylation.
Functional diversification of duplicate genes through subcellular adaptation of encoded proteins
Authors: Ana C Marques, Nicolas Vinckenbosch, David Brawand, Henrik Kaessmann
Journal: Genome biology (2008)

Abstract Background Gene duplication is the primary source of new genes with novel or altered functions. It is known that duplicates may obtain these new functional roles by evolving divergent expression patterns and/or protein functions after the duplication event. Here, using yeast ( Saccharomyces cerevisiae ) as a model organism, we investigate a previously little considered mode for the functional diversification of duplicate genes: subcellular adaptation of encoded proteins. Results We show that for 24-37% of duplicate gene pairs derived from the S. cerevisiae whole-genome duplication event, the two members of the pair encode proteins that localize to distinct subcellular compartments. The propensity of yeast duplicate genes to evolve new localization patterns depends to a large extent on the biological function of their progenitor genes. Proteins involved in processes with a wider subcellular distribution (for example, catabolism) frequently evolved new protein localization patterns after duplication, whereas duplicate proteins limited to a smaller number of organelles (for example, highly expressed biosynthesis/housekeeping proteins with a slow rate of evolution) rarely relocate within the cell. Paralogous proteins evolved divergent localization patterns by partitioning of ancestral localizations ('sublocalization'), but probably more frequently by relocalization to new compartments ('neolocalization'). We show that such subcellular reprogramming may occur through selectively driven substitutions in protein targeting sequences. Notably, our data also reveal that relocated proteins functionally adapted to their new subcellular environments and evolved new functional roles through changes of their physico-chemical properties, expression levels, and interaction partners. Conclusion We conclude that protein subcellular adaptation represents a common mechanism for the functional diversification of duplicate genes.
Assessment of meal induced gastric accommodation by a satiety drinking test in health and in severe functional dyspepsia
Authors: J Tack
Journal: Gut (2003)

<b>Aims:</b> Impaired gastric accommodation is a major pathophysiological mechanism in functional dyspepsia. The aim of the present work was to assess a satiety drinking test in the evaluation of accommodation in health and dyspepsia. <b>Methods:</b> Twenty five controls and 37 severely dyspeptic patients seen at a tertiary care centre completed a dyspepsia questionnaire, and gastric emptying and gastric barostat studies. The amount of liquid meal ingested at maximum satiety during a slow satiety drinking test was determined. In controls, we studied the influence of caloric density and of pharmacological agents that influence accommodation. <b>Results:</b> In patients, satiety scores were higher and maximum satiety occurred at lower calories (542 (50) <i>v</i> 1508 (53) kcal; p&lt;0.0001). Six patients had required nutritional support, but excluding these did not alter the correlations. With increasing severity of early satiety, less calories were ingested at maximum satiety. In multivariate analysis, the amount of calories was significantly correlated to accommodation but not to gastric emptying or sensitivity. Sensitivity and specificity of the satiety test in predicting impaired accommodation reached 92% and 86%, respectively. At different caloric densities, ingested volume rather than caloric load determined maximum satiety. Pharmacological agents (sumatriptan, cisapride, erythromycin) affected the satiety test according to their effect on accommodation. <b>Conclusion:</b> A slow caloric drinking test can be used to evaluate accommodation and early satiety. It provides a non-invasive method of predicting impaired accommodation and quantifying pharmacological influences on accommodation.
Absorption of prednisolone in patients with Crohn's disease.
Authors: J A Shaffer, S E Williams, L A Turnberg, J B Houston, M Rowland
Journal: Gut (1983)

The absorption of prednisolone in patients with Crohn9s disease was investigated. Seven patients with Crohn9s disease and eight normal control subjects were given a tracer dose of tritiated prednisolone with 20 mg cold prednisolone by mouth. On a separate occasion they were given an intravenous injection of radiolabelled prednisolone. After oral ingestion only 53.4 +/- 11.7% of labelled material was excreted in the urine of Crohn9s patients compared with 82.5 +/- 3.6% in the normal subjects. The oral/intravenous availability ratio was 0.61 +/- 0.14 in Crohn9s patients and 0.89 +/- 0.07 in the normal group. Areas under plasma concentration-time curves were lower in patients than normal subjects and the oral/intravenous ratios were 0.6 +/- 0.2 and 0.86 +/- 0.09 respectively. Faecal excretion of radioactivity after oral ingestion was greater in Crohn9s patients (19.3 +/- 2.5%, n = 3) than in normal subjects (7 +/- 2.8%, n = 4). The range for each type of measurement was much wider in the patient group than in the normal subjects. These data suggest that patients with Crohn9s disease do not absorb prednisolone normally and that absorption varies between patients.
Use of Coronary Artery Bypass Surgery in the United States and Canada
Authors: Geoffrey M. Anderson
Journal: JAMA (1993)

To compare overall rates of coronary artery bypass surgery (CABS) in several Canadian and US jurisdictions and to compare use by age and income groups in the two countries.Survey, using computerized hospital discharge abstracts.All nonfederal hospitals in New York, California, Ontario, Manitoba, and British Columbia between 1983 and 1989.All adult residents of the five jurisdictions who underwent CABS in a hospital in their jurisdiction.Between 1983 and 1989, the CABS rates were consistently highest in California and lowest in the Canadian jurisdictions. In 1989, the age-adjusted rate of CABS in California (112.5/100,000 adults) was 27% higher than in New York (88.4/100,000) and 80% higher than in the three Canadian provinces combined (62.4/100,000). The CABS rates increased for those aged 65 years and older and decreased for those aged 20 to 54 years in all five jurisdictions. In 1989, CABS rates were three times higher in California than in Canada for those aged 75 years and older, and the higher rates for those aged 65 years and older accounted for 75% of the overall difference in rates between California and Canada. In Canada, CABS rates for the nonelderly varied little by income of area of residence, but in New York and California, rates increased steadily with the income of area of residence.Control over the supply of resources in Canada is associated with markedly lower CABS rates for the elderly than found in the United States. While overall rates are lower in Canada, the Canadian universal health insurance system reduces the influence of income on access to CABS found in the United States. However, even without universal health insurance, CABS rates for the nonelderly living in the poorest areas in California are similar to the rates for those living in the poorest parts of Canada.
Neither baseline tests of molecular hypercoagulability nor D-dimer levels predict deep venous thrombosis in critically ill medical-surgical patients
Authors: M. A. Crowther, D. J. Cook, L. E. Griffith, M. Meade, S. Hanna, C. Rabbat, S. M. Bates, W. Geerts, M. Johnston, G. Guyatt
Journal: Intensive Care Medicine (2004)
Multidimensional Frailty Score for the Prediction of Postoperative Mortality Risk
Authors: Sun-wook Kim, Ho-Seong Han, Hee-won Jung, Kwang-il Kim, Dae Wook Hwang, Sung-Bum Kang, Cheol-Ho Kim
Journal: JAMA Surgery (2014)

The number of geriatric patients who undergo surgery has been increasing, but there are insufficient tools to predict postoperative outcomes in the elderly.To design a predictive model for adverse outcomes in older surgical patients.From October 19, 2011, to July 31, 2012, a single tertiary care center enrolled 275 consecutive elderly patients (aged ≥65 years) undergoing intermediate-risk or high-risk elective operations in the Department of Surgery.The primary outcome was the 1-year all-cause mortality rate. The secondary outcomes were postoperative complications (eg, pneumonia, urinary tract infection, delirium, acute pulmonary thromboembolism, and unplanned intensive care unit admission), length of hospital stay, and discharge to nursing facility.Twenty-five patients (9.1%) died during the follow-up period (median [interquartile range], 13.3 [11.5-16.1] months), including 4 in-hospital deaths after surgery. Twenty-nine patients (10.5%) experienced at least 1 complication after surgery and 24 (8.7%) were discharged to nursing facilities. Malignant disease and low serum albumin levels were more common in the patients who died. Among the geriatric assessment domains, Charlson Comorbidity Index, dependence in activities of daily living, dependence in instrumental activities of daily living, dementia, risk of delirium, short midarm circumference, and malnutrition were associated with increased mortality rates. A multidimensional frailty score model composed of the above items predicted all-cause mortality rates more accurately than the American Society of Anesthesiologists classification (area under the receiver operating characteristic curve, 0.821 vs 0.647; P = .01). The sensitivity and specificity for predicting all-cause mortality rates were 84.0% and 69.2%, respectively, according to the model's cutoff point (>5 vs ≤5). High-risk patients (multidimensional frailty score >5) showed increased postoperative mortality risk (hazard ratio, 9.01; 95% CI, 2.15-37.78; P = .003) and longer hospital stays after surgery (median [interquartile range], 9 [5-15] vs 6 [3-9] days; P < .001).The multidimensional frailty score based on comprehensive geriatric assessment is more useful than conventional methods for predicting outcomes in geriatric patients undergoing surgery.
Screening Women and Elderly Adults for Family and Intimate Partner Violence: A Review of the Evidence for the U.S. Preventive Services Task Force
Authors: Heidi D. Nelson, Peggy Nygren, Yasmin McInerney, Jonathan Klein
Journal: Annals of Internal Medicine (2004)

Background: Family and intimate partner violence is common in the United States and is often associated with acute and chronic health problems. Although the clinician's role in identification and intervention is considered a professional, ethical, and sometimes legal responsibility, the effectiveness of screening is uncertain. Purpose: To examine evidence on the benefits and harms of screening women and elderly adults in health care settings for family and intimate partner violence. Data Sources: MEDLINE, PsycINFO, CINAHL, Health & Psychosocial Instruments, AARP Ageline, Cochrane Controlled Trials Register, reference lists, and experts. Study Selection: The authors selected English-language studies that included original data focusing on the performance of screening instruments (14 studies for women, 3 for elderly persons) and the effectiveness of interventions based in health care settings (2 studies for women, none for elderly persons). Data Extraction: Study design, patient samples and settings, methods of assessment or intervention, and outcome measures were extracted, and a set of criteria was applied to evaluate study quality. Data Synthesis: No trials of the effectiveness of screening in a health care setting for reducing harm have been published. Several screening instruments have been developed; some have demonstrated fair to good internal consistency and some have been validated with longer instruments, but none have been evaluated against measurable violence or health outcomes. Few intervention studies have been conducted. Existing intervention studies focused on pregnant women, and study limitations restrict their interpretation. Conclusion: Although the literature on family and intimate partner violence is extensive, few studies provide data on detection and management to guide clinicians.
Financial Ties and Conflicts of Interest Between Pharmaceutical and Tobacco Companies
Authors: Bhavna Shamasunder
Journal: JAMA (2002)

Corporate diversification allows for well-hidden financial ties between pharmaceutical and tobacco companies, which can cause a conflict of interest in the development and marketing of pharmaceutical products. In our investigation of tobacco company documents released and posted on the Internet as a result of the Master Settlement Agreement, we have found that these financial ties have fostered both competition and collaboration between the tobacco and pharmaceutical industries. We present 3 case studies. One shows how tobacco companies pressured pharmaceutical companies to scale back their smoking cessation educational materials that accompanied Nicorette. The second shows how they restricted to whom the pharmaceutical company could market its transdermal nicotine patch. In the third case, we show how subsidiary tobacco and pharmaceutical companies of a parent company collaborated in the production of a nicotine-release gum. Thus, because tobacco cessation product marketing has been altered as a result of these financial conflicts, disclosure would serve the interest of public health.
Lymphocytic autoimmune hidradenitis, cutaneous leucocytoclastic vasculitis and primary Sjögren's syndrome
Authors: None Sais, None Admella, None Fantova, None Montero
Journal: British Journal of Dermatology (1998)

We describe a 60-year-old woman with primary Sjögren's syndrome, mixed cryoglobulinaemia and cutaneous leucocytoclastic vasculitis who developed generalized hypohidrosis with a markedly decreased sweating response to pilocarpine chloride. Skin biopsies demonstrated dense peri-eccrine lymphocytic infiltrates in the lower reticular dermis, with glandular atrophy. From previous studies it is evident that although patients with Sjögren's syndrome commonly have skin dryness, a lymphocytic hidradenitis has been documented only in a few cases. The histological findings in this case support the role of autoimmune hidradenitis in the development of hypohidrosis in Sjögren's syndrome.
Association of Gene Variants of the Renin-Angiotensin System With Accelerated Hippocampal Volume Loss and Cognitive Decline in Old Age
Authors: Anthony S. Zannas, Douglas R. McQuoid, Martha E. Payne, James R. MacFall, Allison Ashley-Koch, David C. Steffens, Guy G. Potter, Warren D. Taylor
Journal: American Journal of Psychiatry (2014)

Genetic factors confer risk for neuropsychiatric phenotypes, but the polygenic etiology of these phenotypes makes identification of genetic culprits challenging. An approach to this challenge is to examine the effects of genetic variation on relevant endophenotypes, such as hippocampal volume loss. A smaller hippocampus is associated with gene variants of the renin-angiotensin system (RAS), a system implicated in vascular disease. However, no studies to date have investigated longitudinally the effects of genetic variation of RAS on the hippocampus.The authors examined the effects of polymorphisms of AGTR1, the gene encoding angiotensin-II type 1 receptor of RAS, on longitudinal hippocampal volumes of older adults. In all, 138 older adults (age ≥60 years) were followed for an average of about 4 years. The participants underwent repeated structural MRI and comprehensive neurocognitive testing, and they were genotyped for four AGTR1 single-nucleotide polymorphisms (SNPs) with low pairwise linkage disequilibrium values and apolipoprotein E (APOE) genotype.Genetic variants at three AGTR1 SNPs (rs2638363, rs1492103, and rs2675511) were independently associated with accelerated hippocampal volume loss over the 4-year follow-up period in the right but not left hemisphere. Intriguingly, these AGTR1 risk alleles also predicted worse episodic memory performance but were not related to other cognitive measures. Two risk variants (rs2638363 and rs12721331) interacted with the APOE4 allele to accelerate right hippocampal volume loss.Risk genetic variants of the RAS may accelerate memory decline in older adults, an effect that may be conferred by accelerated hippocampal volume loss. Molecules involved in this system may hold promise as early therapeutic targets for late-life neuropsychiatric disorders.
On Nonharming: The Debate Continues in Stage I Testicular Cancer
Authors: Silke Gillessen, Maria De Santis, Christian Rothermundt
Journal: Journal of Clinical Oncology (2015)

The originally Greek principle of “primum non nocere” (“first, do no harm”) is said to have been translated into Latin by Scribonius Largus, the private physician of the emperor Tiberius Claudius. Scribonius Largus apparently recommended this strategy to his colleagues to improve the image of Roman medics, who at the time had a reputation as poisoners.

In the context of the editorial recently published in Journal of Clinical Oncology, “Active Surveillance for Clinical Stage I Testicular Cancer,”1 this statement probably means that you should not harm a patient by giving adjuvant treatment. As a profession, we have made some progress since the time of Scribonius Largus (approximately 50 AD). However, the case vignette presented by Vaughn1 in his editorial illustrates that despite our best intentions, we may expose individual patients to even greater harm by trying to avoid harm. Most physicians would agree in retrospect that despite the attempt to avoid adverse effects of adjuvant treatment, the patient presented was eventually exposed to even greater toxicity with intensive combination chemotherapy.
Neighborhood Effects on Heat Deaths: Social and Environmental Predictors of Vulnerability in Maricopa County, Arizona
Authors: Sharon L. Harlan, Juan H. Declet-Barreto, William L. Stefanov, Diana B. Petitti
Journal: Environmental Health Perspectives (2012)

Most heat-related deaths occur in cities, and future trends in global climate change and urbanization may amplify this trend. Understanding how neighborhoods affect heat mortality fills an important gap between studies of individual susceptibility to heat and broadly comparative studies of temperature-mortality relationships in cities.
Tyrosine hydroxylase polymorphisms associated with manic-depressive illness
Authors: M. Leboyer, A. Malafosse, S. Boularand, D. Campion, F. Gheysen, D. Samolyk, B. Henriksson, E. Denise, A. Des Lauriers, J.-P. Lepine, E. Zarifian, F. Clerget-Darpoux, J. Mallet
Journal: The Lancet (1990)
Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials
Authors: David Grimwade, Robert K. Hills, Anthony V. Moorman, Helen Walker, Stephen Chatters, Anthony H. Goldstone, Keith Wheatley, Christine J. Harrison, Alan K. Burnett
Journal: Blood (2010)