tbuckley/cabot-search huggingface dataset:
Promoting Atherosclerosis in Type 1 Diabetes Through the Selective Activation of Arachidonic Acid and PGE <sub>2</sub> Production
Authors: Steven M. Watkins, Gökhan S. Hotamisligil
Journal: Circulation Research (2012)

Type 1 diabetics harbor a greatly elevated risk for progressive atherosclerosis and cardiovascular events, but the mechanistic basis for this phenomenon is not entirely clear. Although this link is likely to involve many factors, the specific activation of a lipid-driven inflammatory phenotype in monocytes and macrophages of people with type 1 diabetes is an attractive causal mechanism, due to the ability of inflamed macrophages to exacerbate plaque deposition, expansion, and instability.
Bile acid absorption kinetics in Crohn's disease on elemental diet after oral administration of a stable-isotope tracer with chenodeoxycholic-11, 12-d2 acid.
Authors: T Nishida, H Miwa, M Yamamoto, T Koga, T Yao
Journal: Gut (1982)

A non-radioactive tracer, deuterium, incorporated in chenodeoxycholic acid, was used to study bile acid absorption kinetics employing gas chromatography-mass fragmentography for its analysis. Eight patients with Crohn9s disease and four control volunteers were administered chenodeoxycholic-11, 12-d2 acid. In order to obtain constant dietary conditions, they were fed by an elemental diet during the study. There were significant reductions of the biological half-life of chenodeoxycholic-11, 12-d2 acid, the pool size of chenodeoxycholic acid, and the total bile acid pool size in patients with Crohn9s disease as compared with those in normal subjects. There was a marked increase in the relative concentration of ursodeoxycholic acid with a concomitant decrease of deoxycholic acid in patients with Crohn9s disease, although such differences did not reach statistical significance. The present study confirms that there are some impairments of enterohepatic circulation of bile acids in patients with Crohn9s disease.
Cardiac-specific leptin receptor deletion exacerbates ischaemic heart failure in mice
Authors: Kenneth R. McGaffin, William G. Witham, Keith A. Yester, Lia C. Romano, Robert M. O'Doherty, Charles F. McTiernan, Christopher P. O'Donnell
Journal: Cardiovascular Research (2010)

The obesity-related adipokine, leptin, has multiple actions on peripheral organs, including the mitigation of adverse cardiovascular outcomes after myocardial infarction (MI). Although we recently demonstrated that leptin, its receptor, and downstream signalling are up-regulated in the heart after MI, the significance of intact cardiomyoctye leptin signalling is unknown. Therefore, our objective was to generate a cardiomyocyte-specific leptin receptor knock-out (ObRKO) mouse to determine whether worse cardiac outcomes after MI result from impaired leptin signalling in cardiomyocytes. Tamoxifen-inducible ObRKO mice were subjected to experimental MI or sham surgeries and studied after 1 month. After MI, ObRKO mice displayed a loss of cardiac signal transducer and activator of transcription (STAT) 3 and adenosine monophosphate-activated protein kinase (AMPK) signalling. Worse survival and cardiac morbidity were also seen in the ObRKO mouse post-MI, including decreased contractile function and glycolytic metabolism, and increased left ventricular dilation, hypertrophy, collagen deposition, matrix metalloproteinase activity, apoptosis, and inflammation. Treatment of ObRKO mice post-MI with an ObR-independent AMPK activator improved cardiac function and restored many of these maladaptive processes to wild-type levels. These data indicate that leptin signalling mitigates cardiac injury in the post-MI failing heart by acting directly on cardiomyocytes to increase STAT3 and AMPK activation, to decrease cardiac hypertrophy, apoptosis, and inflammation, and to limit deleterious changes in cardiac structure, function, and glycolytic metabolism.
Quantifying Health Services Use for Chronic Obstructive Pulmonary Disease
Authors: Andrea S. Gershon, Jun Guan, J. Charles Victor, Roger Goldstein, Teresa To
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

Rationale: Chronic obstructive pulmonary disease (COPD), a common manageable condition, is a leading cause of death. A better understanding of its impact on health-care systems would inform strategies to reduce its burden.Objectives: To quantify health services use in a large, North American COPD population.Methods: We conducted a cohort study using health administrative data from Ontario, a province with a population of 13 million and universal health-care insurance. All individuals with physician-diagnosed COPD in 2008 were identified and followed for 3 years. Proportions of all hospital visits, emergency department visits, ambulatory care visits, long-term care residence places, and homecare made or used by people with COPD were determined and rates of each compared between people with and without COPD.Measurements and Main Results: A total of 853,438 individuals with COPD (11.8% of the population aged 35 yr and older) were responsible for 24% of hospitalizations, 24% of emergency department visits, and 21% of ambulatory care visits; filled 35% of long-term care places; and used 30% of homecare services. After adjusting for several factors, people with COPD had rates of hospital, emergency department, and ambulatory care visits that were, respectively, 63%, 85%, and 48% higher than the rest of the population. Their rates of long-term care and homecare use were 56 and 59% higher, respectively.Conclusions: Individuals with COPD use large and disproportionate amounts of health services. Strategies that target this group are needed to improve their health and minimize their need for health services.
A 3G approach to a 3-dimensional problem
Authors: E Falvey, A Franklyn-Miller, P McCrory
Journal: British Journal of Sports Medicine (2008)

Chronic groin, hip and gluteal pain is a common problem in athletes. Complex anatomy, non-specific presentation and a wide variety of potential causes mean narrowing the differential diagnosis may be difficult.

The experienced practitioner develops the skills to recognise patterns in presentation, which lead the direction of clinical examination. This knowledge base of both basic anatomy and science along with the clinical experience takes a considerable period of time to attain.1

Although some suggest the diagnostic power of history-taking and examination is poor,2 3 there is much evidence that this is due less to the diagnostic power of the test than to …
Induction and Suppression of an Autoimmune Disease by Oligomerized T Cell Epitopes
Authors: Kirsten Falk, Olaf Rötzschke, Laura Santambrogio, Martin E. Dorf, Celia Brosnan, Jack L. Strominger
Journal: The Journal of Experimental Medicine (2000)

T cell epitope peptides derived from proteolipid protein (PLP139–151) or myelin basic protein (MBP86–100) induce experimental autoimmune encephalomyelitis (EAE) in “susceptible” strains of mice (e.g., SJL/J). In this study, we show that the encephalitogenic effect of these epitopes when injected subcutaneously in complete Freund's adjuvant was significantly enhanced if administered to the animal in a multimerized form as a T cell epitope oligomer (i.e., as multiple repeats of the peptide epitope, such as 16-mers). Oligomer-treated SJL/J mice developed EAE faster and showed a more severe progression of the disease than animals treated with peptide alone. In addition, haplotype-matched B10.S mice, “resistant” to EAE induction by peptide, on injection of 16-mers developed a severe form of EAE. Even more striking, however, was the dramatic suppression of incidence and severity of the disease, seen after single intravenous injections of only 50 μg of the PLP139–151 16-mer, administered to SJL/J mice 7 d after the induction of the disease. Although relapse occurred at about day 45, an additional injection several days before that maintained the suppression. Importantly, the specific suppressive effect of oligomer treatment was also evident if EAE was induced with spinal cord homogenate instead of the single peptide antigen. By contrast, the PLP139–151 peptide accelerated rather than retarded the progression of disease.
Delta 4-3-oxosteroid 5 beta-reductase deficiency described in identical twins with neonatal hepatitis. A new inborn error in bile acid synthesis.
Authors: K D Setchell, F J Suchy, M B Welsh, L Zimmer-Nechemias, J Heubi, W F Balistreri
Journal: Journal of Clinical Investigation (1988)

A new inborn error in bile acid synthesis, manifest in identical infant twins as severe intrahepatic cholestasis, is described involving the delta 4-3-oxosteroid 5 beta-reductase catalyzed conversion of the key intermediates, 7 alpha-hydroxy-4-cholesten-3-one and 7 alpha,12 alpha-dihydroxy-4-cholesten-3-one for chenodeoxycholic and cholic acid synthesis, to the respective 3 alpha-hydroxy-5 beta (H) products. This defect was detected by fast atom bombardment ionization-mass spectrometry from an elevated excretion and predominance of taurine conjugated unsaturated hydroxy-oxo-bile acids. Gas chromatography-mass spectrometry confirmed these to be 7 alpha-hydroxy-3-oxo-4-cholenoic and 7 alpha,12 alpha-dihydroxy-3-oxo-4-cholenoic acids (75-92% of total). Fasting serum bile acid concentrations were greater than 37 mumol/liter; chenodeoxycholic acid was the major bile acid, but significant amounts of allo(5 alpha-H)-bile acids (approximately 30%) were present. Biliary bile acid concentration was less than 2 mumol/liter and consisted of chenodeoxycholic, allo-chenodeoxycholic, and allo-cholic acids. These biochemical findings, which were identical in both infants, indicate a defect in bile acid synthesis involving the conversion of the delta 4-3-oxo-C27 intermediates into the corresponding 3 alpha-hydroxy-5 beta(H)-structures, a reaction that is catalyzed by a delta 4-3-oxosteroid-5 beta reductase enzyme. This defect resulted in markedly reduced primary bile acid synthesis and concomitant accumulation of delta 4-3-oxo-and allo-bile acids. These findings indicate a pathway in bile acid synthesis whereby side chain oxidation can occur despite incomplete alterations to the steroid nucleus, and lend support for an active delta 4-3-oxosteroid 5 alpha-reductase catalyzing the conversion of the delta 4-3-oxosteroid intermediates to the respective 3 alpha-hydroxy-5 alpha(H)-structures.
Implication of the GRB2-associated phosphoprotein SLP-76 in T cell receptor-mediated interleukin 2 production.
Authors: D G Motto, S E Ross, J Wu, L R Hendricks-Taylor, G A Koretzky
Journal: The Journal of Experimental Medicine (1996)

Recently we described the molecular cloning of SLP-76, a hematopoietic cell-specific 76-kD protein that was first identified through its association with GST/Grb2 fusion proteins. The primary sequence of SLP-76 predicts a protein of 533 amino acids comprising an amino-terminal region with numerous potential tyrosine phosphorylation sites, a central region rich in proline residues, and a single carboxy-terminal SH2 domain. Here we demonstrate formally that Grb2 associates with unphosphorylated SLP-76 and map the Grb2 binding site on SLP-76 undergoes rapid tyrosine phosphorylation and associates with tyrosine phosphoproteins of 36, 62, and 130 kD. In vitro experiments show that the SH2 domain of SLP-76 associates with the 62- and 130-kD proteins and additionally with a serine/threonine kinase. Finally, we demonstrate that transient overexpression of SLP-76 results in dramatically enhanced TCR-mediated induction of nuclear factor of activated T cells (NFAT) and interleukin (IL) 2 promoter activity; and we provide evidence that a functional SLP-76 SH2 domain is required for this effect. Our data document the in vivo associations of SLP-76 with several proteins that potentially participate in T cell activation and implicate SLP-76 itself as an important molecule in TCR-mediated IL-2 production.
Safety and Efficacy of Neratinib in Combination With Capecitabine in Patients With Metastatic Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer
Authors: Cristina Saura, Jose A. Garcia-Saenz, Binghe Xu, Wael Harb, Rebecca Moroose, Timothy Pluard, Javier Cortés, Corinne Kiger, Caroline Germa, Kongming Wang, Miguel Martin, José Baselga, Sung-Bae Kim
Journal: Journal of Clinical Oncology (2014)

Neratinib is a potent irreversible pan-tyrosine kinase inhibitor with antitumor activity and acceptable tolerability in patients with human epidermal growth factor receptor 2 (HER2) -positive breast cancer. A multinational, open-label, phase I/II trial was conducted to determine the maximum-tolerated dose (MTD) of neratinib plus capecitabine in patients with solid tumors (part one) and to evaluate the safety and efficacy of neratinib plus capecitabine in patients with HER2-positive metastatic breast cancer (part two).Part one was a 3 + 3 dose-escalation study in which patients with advanced solid tumors received oral neratinib once per day continuously plus capecitabine twice per day on days 1 to 14 of a 21-day cycle at predefined dose levels. In part two, patients with trastuzumab-pretreated HER2-positive metastatic breast cancer received neratinib plus capecitabine at the MTD. The primary end point in part two was objective response rate (ORR).In part one (n = 33), the combination of neratinib 240 mg per day plus capecitabine 1,500 mg/m(2) per day was defined as the MTD, which was further evaluated in part 2 (n = 72). The most common drug-related adverse events were diarrhea (88%) and palmar-plantar erythrodysesthesia syndrome (48%). In part two, the ORR was 64% (n = 39 of 61) in patients with no prior lapatinib exposure and 57% (n = 4 of 7) in patients previously treated with lapatinib. Median progression-free survival was 40.3 and 35.9 weeks, respectively.Neratinib in combination with capecitabine had a manageable toxicity profile and showed promising antitumor activity in patients with HER2-positive metastatic breast cancer pretreated with trastuzumab and lapatinib.
Bad Can Act as a Key Regulator of T Cell Apoptosis and T Cell Development
Authors: Chen-Lang Mok, Gabriel Gil-Gómez, Owen Williams, Mark Coles, Samir Taga, Mauro Tolaini, Trisha Norton, Dimitris Kioussis, Hugh J.M. Brady
Journal: The Journal of Experimental Medicine (1999)

Bad is a distant relative of Bcl-2 and acts to promote cell death. Here, we show that Bad expression levels are greatly increased in thymocytes during apoptosis. We generated bad transgenic mice to study the action of upregulated Bad expression on T cell apoptosis. The T cells from these mice are highly sensitive to apoptotic stimuli, including anti-CD95. The numbers of T cells are greatly depleted and the processes of T cell development and selection are perturbed. We show that the proapoptotic function of Bad in primary T cells is regulated by Akt kinase and that Bad overexpression enhances both cell cycle progression and interleukin 2 production after T cell activation. These data suggest that Bad can act as a key regulator of T cell apoptosis and that this is a consequence of its upregulation after exposure to death stimuli.
Psychoeducational Intervention for Patients With Cutaneous Malignant Melanoma: A Replication Study
Authors: Ellen H. Boesen, Lone Ross, Kirsten Frederiksen, Birthe L. Thomsen, Karin Dahlstrøm, Grethe Schmidt, Jesper Næsted, Christen Krag, Christoffer Johansen
Journal: Journal of Clinical Oncology (2005)

Purpose In 1993, a randomized intervention study among patients with malignant melanoma showed a significant decrease in psychological distress and increased coping capacity 6 months after the intervention and enhanced survival 6 years later. We applied a similar intervention with a few modifications in a randomized controlled trial among Danish patients with malignant melanoma and evaluated results on immediate and long-term effects on psychological distress and coping capacity. Patients and Methods A total of 262 patients with primary cutaneous malignant melanoma were randomly assigned to the control or intervention group. Patients in the intervention group were offered six weekly sessions of 2 hours of psychoeducation, consisting of health education, enhancement of problem-solving skills, stress management, and psychological support. The participants were assessed at baseline before random assignment and 6 and 12 months after surgery. The analyses of the main effects of the intervention were based on analyses of covariance. Results The patients in the intervention group showed significantly less fatigue, greater vigor, and lower total mood disturbance compared with the controls, and they used significantly more active-behavioral and active-cognitive coping than the patients in the control group. The improvements were only significant at first follow-up. Conclusion The findings of this study support the results of an earlier intervention study among patients with malignant melanoma and indicate that a psychoeducational group intervention for such patients can decrease psychological distress and enhance effective coping. However, this effect is short term and the clinical relevance is not obvious.
HPV-16 E7 Reveals a Link between DNA Replication Stress, Fanconi Anemia D2 Protein, and Alternative Lengthening of Telomere–Associated Promyelocytic Leukemia Bodies
Authors: Nicole Spardy, Anette Duensing, Elizabeth E. Hoskins, Susanne I. Wells, Stefan Duensing
Journal: Cancer Research (2008)

Abstract Expression of the high-risk human papillomavirus (HPV-16) E7 oncoprotein extends the life span of primary human keratinocytes and partially restores telomere length in the absence of telomerase. The molecular basis of this activity is incompletely understood. Here, we show that HPV-16 E7 induces an increased formation of alternative lengthening of telomeres (ALT)–associated promyelocytic leukemia bodies (APBs) in early passage primary human keratinocytes as well as HPV-negative tumor cells. This activity was found to require sequences of HPV-16 E7 involved in degradation of the retinoblastoma tumor suppressor protein as well as regions in the COOH terminus. HPV-16 E7–induced APBs contained ssDNA and several proteins that are involved in the response to DNA replication stress, most notably the Fanconi anemia D2 protein (FANCD2) as well as BRCA2 and MUS81. In line with these results, we found that FANCD2-containing APBs form in an ATR-dependent manner in HPV-16 E7–expressing cells. To directly show a role of FANCD2 in ALT, we provide evidence that knockdown of FANCD2 rapidly causes telomere dysfunction in cells that rely on ALT to maintain telomeres. Taken together, our results suggest a novel link between replication stress and recombination-based telomere maintenance that may play a role in HPV-16 E7–mediated extension of host cell life span and immortalization. [Cancer Res 2008;68(23):9954–63]
Self-gated MRI motion modeling for respiratory motion compensation in integrated PET/MRI
Authors: Robert Grimm, Sebastian Fürst, Michael Souvatzoglou, Christoph Forman, Jana Hutter, Isabel Dregely, Sibylle I. Ziegler, Berthold Kiefer, Joachim Hornegger, Kai Tobias Block, Stephan G. Nekolla
Journal: Medical Image Analysis (2014)
Hospital admission database or specialist national audits for monitoring gastrointestinal bleeding? both are vital to monitoring our clinical practice
Authors: C. J. Crooks, J. West, S. A. Hearnshaw, M. F. Murphy, P. R. Kelvin, R. F. A. Logan, T. R. Card
Journal: Gut (2011)

<h3>Introduction</h3> There has been much controversy over the use of hospital admission data to measure health outcomes. However with the current implementation of ‘Summary Hospital-level Mortality9 measures, it is more important than ever to understand the quality of Hospital Episode Statistics (HES). Therefore the authors have compared the recent upper gastrointestinal bleeding national audit data with the appropriate data from HES. <h3>Methods</h3> The NHS Blood and Transplant and British Society of Gastroenterology9s 2007 audit of upper gastrointestinal bleeding (UGB) was a national web based audit that occurred between 1 May and 31 June 2007. Using anonymous HES data linked to the Office of National Statistics national death register from the same time period, the authors selected UGB records with provider codes and/or geographical details that matched the participating English hospitals in the audit. The authors compared recorded numbers of admissions, deaths and endoscopies. <h3>Results</h3> The audit contained 7484 records of admission to hospital with UGB from England, and 5582 complete records that were included in the final analysis. Over the same time period HES had 8495 UGB admissions from audit participating hospitals (ie, the audit captured 88.1% of these). There were 5385 admissions primarily for UGB included in the audit compared to 5264 admissions in the HES data. Endoscopy was recorded in 55.6% of all records in the BSG audit compared to 46.3% of all HES data. More deaths within 28 days were identified using the ONS linked dataset than in the national audit (see table 1). <h3>Conclusion</h3> During the recent national audit, HES recorded reassuringly similar numbers for UGB hospital admissions and procedures. This demonstrates the success of the web based system for national audits in picking up a large proportion of bleeds, and with comparable rates of endoscopy suggests HES are not incorrectly coding large numbers of cases as UGB. The value of HES data is its national coverage, linkage to the national death register, and accurate recording of hospitalisation rates. However the strength of the audit in providing data to permit detailed analysis of the predictors of mortality, procedures, blood transfusions, and the calculation of risk scores cannot be reproduced in the HES data. To gain a complete and accurate picture of the risks, burden, and outcome of UGB the results from both sources of data will need to be considered.
Paracetamol sales and atopic disease in children and adults: an ecological analysis
Authors: R.B. Newson, S.O. Shaheen, S. Chinn, P.G.J. Burney
Journal: European Respiratory Journal (2000)

The authors recently observed that frequent paracetamol use was positively associated with asthma and rhinitis in young adults. Therefore, an ecological analysis was performed to measure international associations between paracetamol sales and atopic disease prevalences in children and adults. Published data from the International Study of Asthma and Allergies in Childhood (ISAAC) on the prevalence of four atopic symptoms in 13-14-yr-olds (112 centres) and 67-yr-olds (66 centres) in 1994/1995, and European Community Respiratory Health Survey (ECRHS) data on the prevalence of asthma symptoms, diagnosed asthma and rhinitis (44 centres), prevalence of atopy, mean bronchial responsiveness and mean total immunoglobulin E levels (34 centres) in young adults in 1991/1992, were used. Their associations with national 1994/1995 per capita paracetamol sales were measured using linear regression. Paracetamol sales were high in English-speaking countries, and were positively associated with asthma symptoms, eczema and allergic rhinoconjunctivitis in 13-14-yr-olds, and with wheeze, diagnosed asthma, rhinitis and bronchial responsiveness in adults. The prevalence of wheeze increased by 0.52% in 13-14-yr-olds and by 0.26% in adults (p&lt;0.0005) for each gram increase in per capita paracetamol sales. These ecological findings require cautious interpretation, but raise the possibility that variation in paracetamol usage may explain some of the variation in atopic disease prevalence between countries.