tbuckley/cabot-search huggingface dataset:
Efficacy of TNF switch after failure of one TNF inhibitor – results from a nation-wide observational study: Table 1
Authors: Katerina Chatzidionysiou, Jonas Eriksson, Johan Askling, Ronald F van Vollenhoven
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background/purpose</h3> The purpose of this study was to determine whether patients who failed one anti-TNF benefit from switching to another anti-TNF and whether the specific order of agents and reason for switch is significant. <h3>Methods</h3> Data from the ARTIS registry were used. Patients with RA, who received an anti-TNF (etanercept (ETA), adalimumab (ADA) or infliximab (INF)) as first biologic and subsequently switched to an alternative anti-TNF, were included in the analysis. Treatment segments were analysed according to DAS28 and HAQ reduction and EULAR response at 6 months after baseline. Treatment results were analysed for each biologic, by type of previous anti-TNF and reason for discontinuation (primary and secondary inefficacy or intolerance). Multiple treatment segments with the same anti-TNF were disregarded for this analysis. <h3>Results</h3> A total of 1080 patients were included. Of these, 520 switched to ETA, 466 to ADA, and 94 to INF. Complete data were available for appr. 50% of patients and were evenly distributed between groups. At baseline (BL=start of 2nd anti-TNF) no differences in age, sex, disease duration, RF, HAQ and concomitant NSAIDs were observed between groups. BL DAS28 (mean±SD) was significantly lower for ADA (4.79±1.32) than ETA (5.15±1.32, p&lt;0.0001) and INF (5.13±1.22, p=0.04). INF was more often combined with DMARDs (81.9%) than ETA (69.3%, p=0.007) and ADA (65.7%, p=0.001), but less often with glucocorticoids (39.4%) than ETA (51.2%, p=0.02) and ADA (50.6%, p=0.03). Significant clinical improvements were observed for the whole cohort of patients. DAS28 improvement at 6 months was 1.59±1.47 for ETA, 1.17±1.35 for INF and 1.00±1.32 for ADA (p=0.002 ETA vs ADA, p=0.29 ETA vs INF; p values adjusted for age, sex, BL DAS28, conc DMARDs and glucocorticoids). HAQ improvement at 6 months =0.26±0.52 for ETA, 0.14±0.50 for INF and 0.14±0.43 for ADA (adjusted p=0.42 ETA vs INF, p=0.23 ETA vs ADA). The percentages of EULAR Good/Moderate/Non-responders were 28/43/29% for ETA, 21/46/33% for INF and 17/45/38% for ADA (p=0.02 between groups). In table 1 the effectiveness of each anti-TNF by type and reason for discontinuation of the previous anti-TNF is summarised. <h3>Conclusions</h3> In this large observational cohort, patients who failed anti-TNF therapy do benefit from switching to other TNF inhibitors. ETA as 2nd anti-TNF yielded significantly greater DAS28 reductions than INF and ADA, but due to the relatively large number of incomplete data this finding must be interpreted with caution. For patients who discontinued anti-TNF because of secondary inefficacy, switching to ETA appeared more effective than switching to ADA.
Disruption of Leptin Signaling Contributes to Cardiac Hypertrophy Independently of Body Weight in Mice
Authors: Lili A. Barouch, Dan E. Berkowitz, Robert W. Harrison, Christopher P. O’Donnell, Joshua M. Hare
Journal: Circulation (2003)

Whether left ventricular hypertrophy (LVH) in obesity results from increased hemodynamic load or altered neurohormonal signaling remains controversial. Dysregulation of leptin, a neurohormone essential to energy homeostasis, is implicated in the pathogenesis of obesity. Because leptin has cardiovascular bioactivity, we hypothesized that disruption of leptin signaling mediates the development of obesity-associated LVH.We measured left ventricular (LV) wall thickness and LV mass with echocardiography in mice lacking leptin (ob/ob, n=15) or functional receptor (db/db, n=10) and controls at 2, 4, and 6 months of age. None of the mice had LVH at 2 months. Progressive obesity developed in ob/ob and db/db mice. At 6 months, LVH occurred in ob/ob and db/db compared with controls. We observed corresponding myocyte hypertrophy by light microscopy. To separate the direct contribution of leptin deficiency from mechanical effects of obesity, we induced weight loss in 6- to 8-month-old ob/ob mice either by leptin infusion or caloric restriction. Mice in both groups lost similar weight compared with placebo-treated controls. Leptin infusion completely reversed the increase in wall thickness with partial resolution of myocyte hypertrophy, whereas calorie-restricted mice had no decrease in wall thickness and a lesser change in myocyte size.Together these data show that the effect of leptin on LV remodeling is not attributable to weight loss alone, indicating that leptin has antihypertrophic effects on the heart, either directly or through a leptin-regulated neurohumoral pathway. Disruption of leptin signaling may represent a novel mechanism in LVH and related cardiovascular disorders.
Challenges to the development of bryostatin‐type anticancer drugs based on the activation mechanism of protein kinase Cδ
Authors: Kazuhiro Irie, Ryo C. Yanagita, Yu Nakagawa
Journal: Medicinal Research Reviews (2010)

Abstract Protein kinase C (PKC) isozymes are widely recognized as targets for anticancer therapy, and recent investigations demonstrated that PKC activators are potential therapeutic candidates for Alzheimer's disease and acquired immune deficiency syndrome. However, concerns exist about their therapeutic uses because most PKC activators are potent tumor promoters. Bryostatin 1 (bryo‐1) is a unique PKC activator with little tumor‐promoting activities. Bryo‐1 is currently undergoing clinical trials for the treatment of cancer. However, its limited availability from natural sources and difficulty in the synthesis hamper further studies on its mode of action and structural optimization. Although excellent practical methods for synthesizing several bryo‐1‐related compounds have been developed, the identification of synthetically more accessible compounds with bryo‐1‐like activity also provides a promising way to circumvent the problem of supply. The authors focused on the bryo‐1's unique mechanism of activating PKCδ that plays a tumor suppressor role, and found that a simple and less lipophilic analogue (aplog‐1) of the tumor‐promoting aplysiatoxin showed PKCδ‐activating behavior similar to bryo‐1. Aplog‐1 was easily synthesized in only 22 steps using standard reactions. Moreover, its tumor‐promoting activity in vitro was very weak, and its cell growth‐inhibitory activities were comparable to those of bryo‐1. These data suggest that aplog‐1 could become another therapeutic lead for cancer. © 2010 Wiley Periodicals, Inc. Med Res Rev, 32, No. 3, 518–535, 2012
A STUDY OF THE DISTRIBUTION OF INCOMPLETE RHESUS ANTIBODIES AMONG THE SERUM IMMUNOGLOBULIN FRACTIONS
Authors: Barbara E. Dodd, P. C. Wilkinson
Journal: The Journal of Experimental Medicine (1964)

Sera containing Rh antibodies were taken from Rh-negative women at intervals during pregnancy and postpartum. A selection of these was fractionated on DEAE cellulose and by density gradient ultracentrifugation. The distribution among the immunoglobulin fractions gamma(SS), gamma(1)A, and gamma(1)M of Rh antibodies in the sera of Rh-negative women during pregnancy was analysed by these fractionation procedures and also by treatment with 2-mercaptoethanol and by testing with rabbit antisera prepared against purified immunoglobulin fractions. The experiments showed that incomplete Rh antibodies occurred in the 7(SS)-, gamma(1)A-, and gamma(1)M-globulin fractions, although the bulk of the antibody was in the 7(SS). In addition, evidence that the previously described (13) "papain-type" antibody is an incomplete gamma(1)M-globulin is presented.
Coffee intake is associated with lower rates of liver disease progression in chronic hepatitis C # ∥ ‡
Authors: Neal D. Freedman, James E. Everhart, Karen L. Lindsay, Marc G. Ghany, Teresa M. Curto, Mitchell L. Shiffman, William M. Lee, Anna S. Lok, Adrian M. Di Bisceglie, Herbert L. Bonkovsky, John C. Hoefs, Jules L. Dienstag, Chihiro Morishima, Christian C. Abnet, Rashmi Sinha
Journal: Hepatology (2009)

Higher coffee consumption has been associated inversely with the incidence of chronic liver disease in population studies. We examined the relationship of coffee consumption with liver disease progression in individuals with advanced hepatitis C-related liver disease. Baseline coffee and tea intake were assessed in 766 participants of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial who had hepatitis C-related bridging fibrosis or cirrhosis on liver biopsy and failed to achieve a sustained virological response to peginterferon plus ribavirin treatment. Participants were followed for 3.8 years for clinical outcomes and, for those without cirrhosis, a 2-point increase in Ishak fibrosis score on protocol biopsies. At baseline, higher coffee consumption was associated with less severe steatosis on biopsy, lower serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, alpha-fetoprotein, insulin, and homeostatic model assessment (HOMA2) score, and higher albumin (P < 0.05 for all). Two hundred thirty patients had outcomes. Outcome rates declined with increasing coffee intake: 11.1/100 person-years for none, 12.1 for less than 1 cup/day, 8.2 for 1 to fewer than 3 cups/day, and 6.3 for 3 or more cups/day (P-trend = 0.0011). Relative risks (95% confidence intervals) were 1.11 (0.76-1.61) for less than 1 cup/day; 0.70 (0.48-1.02) for 1 to fewer than 3 cups/day; and 0.47 (0.27-0.85) for 3 or more cups/day (P-trend = 0.0003) versus not drinking. Risk estimates did not vary by treatment assignment or cirrhosis status at baseline. Tea intake was not associated with outcomes.In a large prospective study of participants with advanced hepatitis C-related liver disease, regular coffee consumption was associated with lower rates of disease progression.
Enteric glial cells: new players in mucosal defence against bacteria?
Authors: G. Matteoli
Journal: Gut (2011)

The main task of the gastrointestinal system is to digest food and absorb nutrients, while preventing systemic dissemination of pathogens and limiting the diffusion of commensal microorganisms. To facilitate these functions, the digestive tract is lined with a highly dynamic and specialised structure known as the intestinal epithelial barrier (IEB), which consists of a monolayer of epithelial cells in association with goblet cells, enterochromaffin cells and Paneth cells.1 Due to the presence of serrated tight junctions, mucus layer and the secreted antimicrobial molecules, the IEB acts as an essential line of defence to shield the deeper tissues from the external environment, avoiding colonisation of harmful agents.1 Alterations in the IEB leading to increased intestinal permeability are indeed observed in a wide range of gastrointestinal diseases, such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), caeliac disease and enteric infections.1 Whether deregulation of the IEB is an initial detrimental step perturbing intestinal homeostasis or rather a consequence of an established pathology is still a matter of controversial but interesting debate.

Accumulating evidence strongly indicates that the enteric nervous system (ENS) is emerging as one of the principal regulators of the IEB. …
Glomerular Endothelial Glycocalyx Constitutes a Barrier to Protein Permeability
Authors: Anurag Singh, Simon C. Satchell, Chris R. Neal, Edward A. McKenzie, John E. Tooke, Peter W. Mathieson
Journal: Journal of the American Society of Nephrology (2007)

Glycocalyx, composed of glycoproteins including proteoglycans, coats the luminal surface of the glomerular capillaries. Human heparanase degrades heparan sulphate glycosaminoglycans and is up-regulated in proteinuric states. In this study, we analyze the structure of the human glomerular endothelial cell glycocalyx in vitro and examine its functional relevance, especially after treatment with human heparanase. Electron microscopy of conditionally immortalized glomerular endothelial cells revealed a 200-nm thick glycocalyx over the plasma membrane, which was also demonstrated by confocal microscopy. Neuraminidase treatment removed the majority of glycocalyx, reduced trans-endothelial electrical resistance by 59%, and increased albumin flux by 207%. Heparinase III and human heparanase specifically cleaved heparan sulphate: this caused no change in trans-endothelial electrical resistance, but increased the albumin passage across the monolayers by 40% and 39%, respectively. Therefore, we have characterized the glomerular endothelial cell glycocalyx and have shown that it contributes to the barrier to flux of albumin across the cell layer. These results suggest an important role for this glycocalyx in the restriction of glomerular protein passage in vivo and suggest ways in which human heparanase levels may be linked to proteinuria in clinical disease.
Spherocytosis and pulmonary hypertension coincidental occurrence or causal relationship?
Authors: D Verresen, W De Backer, J Van Meerbeeck, I Neetens, E Van Marck, P Vermeire
Journal: European Respiratory Journal (1991)

A report is given on a 59 yr old man with hereditary spherocytosis and progressive shortness of breath on exertion, due to severe pulmonary hypertension and cor pulmonale. An open lung biopsy was performed in order to exclude all known aetiologies of secondary pulmonary hypertension. Pathological examination revealed in situ thrombosis and asymmetric fibromuscular hyperplasia of small- and medium-sized pulmonary arteries. Both primary pulmonary hypertension and hereditary spherocytosis have a low incidence in the general population and their simultaneous occurrence has not been reported previously; the possibility that this was due to a causal relationship and not to coincidence cannot be ruled out, in view of some similarities with pulmonary hypertension complicating sickle cell anaemia.
A new role for an old marker, HBsAg
Authors: Maurizia Rossana Brunetto
Journal: Journal of Hepatology (2010)

Detection in the serum of the “Australia antigen”, namely hepatitis B surface antigen (HBsAg), was the Nobel prize discovery that identified hepatitis B virus (HBV) about 40years ago; to this day HBsAg remains the hallmark of overt HBV infection [1,2]. HBsAg circulates in a wide array of particulate forms: competent virions (42nm, Dane particles), 20nm diameter filaments of variable length, and 20–22nm spherical defective particles, corresponding to empty viral envelopes [3]. Serum HBsAg results from the different combinations of three proteins (small, medium and large), either glycosylated or not, that are specified by a single open reading frame providing 3 carboxy-terminal colinear HBsAg proteins of different length.
Bladder Cancer Stage and Outcome by Array-Based Comparative Genomic Hybridization
Authors: Ekaterini Blaveri, Jeremy L. Brewer, Ritu Roydasgupta, Jane Fridlyand, Sandy DeVries, Theresa Koppie, Sunanda Pejavar, Kshama Mehta, Peter Carroll, Jeff P. Simko, Frederic M. Waldman
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Bladder carcinogenesis is believed to follow alternative pathways of disease progression driven by an accumulation of genetic alterations. The purpose of this study was to evaluate associations between measures of genomic instability and bladder cancer clinical phenotype. Experimental Design: Genome-wide copy number profiles were obtained for 98 bladder tumors of diverse stages (29 pTa, 14 pT1, 55 pT2-4) and grades (21 low-grade and 8 high-grade superficial tumors) by array-based comparative genomic hybridization (CGH). Each array contained 2,464 bacterial artificial chromosome and P1 clones, providing an average resolution of 1.5 Mb across the genome. A total of 54 muscle-invasive cases had follow-up information available. Overall outcome analysis was done for patients with muscle-invasive tumors having “good” (alive &amp;gt;2 years) versus “bad” (dead in &amp;lt;2 years) prognosis. Results: Array CGH analysis showed significant increases in copy number alterations and genomic instability with increasing stage and with outcome. The fraction of genome altered (FGA) was significantly different between tumors of different stages (pTa versus pT1, P = 0.0003; pTa versus pT2-4, P = 0.02; and pT1 versus pT2-4, P = 0.03). Individual clones that differed significantly between different tumor stages were identified after adjustment for multiple comparisons (false discovery rate &amp;lt; 0.05). For muscle-invasive tumors, the FGA was associated with patient outcome (bad versus good prognosis patients, P = 0.002) and was identified as the only independent predictor of overall outcome based on a multivariate Cox proportional hazards method. Unsupervised hierarchical clustering separated “good” and “bad” prognosis muscle-invasive tumors into clusters that showed significant association with FGA and survival (Kaplan-Meier, P = 0.019). Supervised tumor classification (prediction analysis for microarrays) had a 71% classification success rate based on 102 unique clones. Conclusions: Array-based CGH identified quantitative and qualitative differences in DNA copy number alterations at high resolution according to tumor stage and grade. Fraction genome altered was associated with worse outcome in muscle-invasive tumors, independent of other clinicopathologic parameters. Measures of genomic instability add independent power to outcome prediction of bladder tumors.
Gestational Diabetes Mellitus and Obesity
Authors: Zachary T. Bloomgarden
Journal: Diabetes Care (2010)

This is the sixth of a series of articles based on presentations at the American Diabetes Association (ADA) Scientific Sessions held 5–9 June 2009 in New Orleans, Louisiana.

### Gestational diabetes mellitus

In a symposium on advances in the understanding of obesity and weight gain during pregnancy, Teresa A. Hillier (Portland, OR) discussed the implications that pregnancy weight gain in gestational diabetes mellitus (GDM) has for the fetus. Much of the discussion following her lecture and those of the other speakers concerned the May 2009 guidelines of the Institute of Medicine (IOM) for weight gain during pregnancy (www.iom.edu/pregnancyweightgain), which suggest that recommendations to patients be based on prepregnancy BMI. For BMI levels  30 kg/m2, weight gain ranges are suggested at 28–40, 25–35, 15–25, and 11–20 pounds, respectively, and the recommended rates of weight gain are 1–1.3, 0.8–1, 0.5–0.7, and 0.4–0.6 pounds/week.

GDM is defined as any degree of glucose intolerance with onset or first recognition during pregnancy. Hillier noted the lack of consensus on screening and diagnostic criteria for GDM. In the U.S. two steps are used, a 1-h 50-g glucose challenge followed by a 75- or 100-g oral glucose tolerance test (OGTT); outside the U.S., a 2-h 75-g OGTT is recommended. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study of providers blinded to GDM status reported correlations between fasting, 1-h, and 2-h glucose levels and adverse outcomes, including Caesarian section (1). The Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) was a randomized controlled trial of 1,000 women with normal fasting glucose not having GDM by World Health Organization criteria (2-h glucose 140–199 mg/dl) assigned to treatment with dietary advice, self-monitoring, and insulin as required or to routine care (2). There was gestational weight gain of 8.1 vs. 9.8 kg, and adverse fetal outcomes occurred in 7 …
Musings on genome medicine: Hepatitis C
Authors: David G Nathan, Stuart H Orkin
Journal: Genome Medicine (2010)

Hepatitis C is a viral disease transmitted principally by blood, which affects millions of people worldwide. A significant proportion of those affected develop severe liver disease as a result. Only a fraction of patients are responsive to interferon treatment, highlighting the need for further research into genetic factors involved in response to therapy in order to optimize treatment. The only current approach for end-stage disease is liver transplant, which ironically does not cure the condition, and thus poses a clinical dilemma in the face of liver-donor shortage.
Observations on ENCEPHALITIS, POLIOENCEPHALITIS, AND VACCINIAL ENCEPHALITIS IN CHILDREN
Authors: C. P. Lapage
Journal: BMJ (1933)

ENCEPHALITIS IN CHILDREN [tHE BRTTTIR 811 been reported, especially in Holland, England, and Ger.Observations many.Rolleston4 shows that out of 5i million people ON vaccinated there were roughly 175 cases and 91 died.ENCEPHALITIS, POLIOENCEPHALITIS, This is one case in 33,000 vaccinations and one death in E 60,000.In Holland there were 146 cases, and the deaths AND VACCINIAL ENCEPHALITIS were 1 in 5,000.It is curious how groups of cases are IN CHILDREN * reported from some countries and not others.The lymph BY is not at faul-t, because in Holland the vaccine was C. PAGET LAPAGE, M.D., F.R.C.P. brought in from several different countries.
Lung Cancer Occurrence in Never-Smokers: An Analysis of 13 Cohorts and 22 Cancer Registry Studies
Authors: Michael J Thun, Lindsay M Hannan, Lucile L Adams-Campbell, Paolo Boffetta, Julie E Buring, Diane Feskanich, W. Dana Flanders, Sun Ha Jee, Kota Katanoda, Laurence N Kolonel, I-Min Lee, Tomomi Marugame, Julie R Palmer, Elio Riboli, Tomotaka Sobue, Erika Avila-Tang, Lynne R Wilkens, Jon M Samet
Journal: PLoS Medicine (2008)

Better information on lung cancer occurrence in lifelong nonsmokers is needed to understand gender and racial disparities and to examine how factors other than active smoking influence risk in different time periods and geographic regions.We pooled information on lung cancer incidence and/or death rates among self-reported never-smokers from 13 large cohort studies, representing over 630,000 and 1.8 million persons for incidence and mortality, respectively. We also abstracted population-based data for women from 22 cancer registries and ten countries in time periods and geographic regions where few women smoked. Our main findings were: (1) Men had higher death rates from lung cancer than women in all age and racial groups studied; (2) male and female incidence rates were similar when standardized across all ages 40+ y, albeit with some variation by age; (3) African Americans and Asians living in Korea and Japan (but not in the US) had higher death rates from lung cancer than individuals of European descent; (4) no temporal trends were seen when comparing incidence and death rates among US women age 40-69 y during the 1930s to contemporary populations where few women smoke, or in temporal comparisons of never-smokers in two large American Cancer Society cohorts from 1959 to 2004; and (5) lung cancer incidence rates were higher and more variable among women in East Asia than in other geographic areas with low female smoking.These comprehensive analyses support claims that the death rate from lung cancer among never-smokers is higher in men than in women, and in African Americans and Asians residing in Asia than in individuals of European descent, but contradict assertions that risk is increasing or that women have a higher incidence rate than men. Further research is needed on the high and variable lung cancer rates among women in Pacific Rim countries.
PSYCHIATRIC RESEARCH IN SPACE MEDICINE
Authors: GEORGE E. RUFF, EDWIN Z. LEVY
Journal: American Journal of Psychiatry (1959)

An attempt has been made to suggest problems of space flight of interest to psychiatrists. Many psychological stresses cannot be simulated in the laboratory, and thus can be dealt with only by projecting from data now available. Since emotional hazards analagous to those likely to arise in space have been overcome on earth, we infer that space flight will impose no intolerable stress on carefully selected, trained crews. Several aspects of exploratory studies of isolation and confinement have been selected for discussion. These suggest that meaningful structuring of experience is necessary for adaptation to drastic alterations in environment. Our conclusion is that the best qualification for a space crew member is a sound ego. His environment should offer both meaning and variety in sensory input to prevent disorganization of perception and thought.