tbuckley/cabot-search huggingface dataset:
Heat shock protein 70 prevents secretagogue-induced cell injury in the pancreas by preventing intracellular trypsinogen activation
Authors: Lakshmi Bhagat, Vijay P. Singh, Antti J. Hietaranta, Sudhir Agrawal, Michael L. Steer, Ashok K. Saluja
Journal: Journal of Clinical Investigation (2000)

Rodents given a supramaximally stimulating dose of cholecystokinin or its analogue cerulein develop acute pancreatitis with acinar cell injury, pancreatic inflammation, and intrapancreatic digestive enzyme (i.e., trypsinogen) activation. Prior thermal stress is associated with heat shock protein 70 (HSP70) expression and protection against cerulein-induced pancreatitis. However, thermal stress can also induce expression of other HSPs. The current studies were performed using an in vitro system to determine whether HSP70 can actually mediate protection against pancreatitis and, if so, to define the mechanism underlying that protection. We show that in vitro exposure of freshly prepared rat pancreas fragments to a supramaximally stimulating dose of cerulein results in changes similar to those noted in cerulein-induced pancreatitis, i.e., intra-acinar cell trypsinogen activation and acinar cell injury. Short-term culture of the fragments results in HSP70 expression and loss of the pancreatitis-like changes noted after addition of cerulein. The culture-induced enhanced HSP70 expression can be prevented by addition of either the flavonoid antioxidant quercetin or an antisense oligonucleotide to HSP70. Under these latter conditions, addition of a supramaximally stimulating concentration of cerulein results in trypsinogen activation and acinar cell injury. These findings indicate that the protection against cerulein-induced pancreatitis that follows culture-induced (and possibly thermal) stress is mediated by HSP70. They suggest that the HSP acts by preventing trypsinogen activation within acinar cells.
CME and anterior uveitis with latanoprost use11The following letters address an article that appeared in the February 1998 issue of the Journal:Warwar RE, Bullock JD, Ballal D. Cystoid macular edema and anterior uveitis associated with latanoprost use. Experience and incidence in a retrospective review of 84 patients.(Ophthalmology 1998;105:263–8)
Authors: Dan Eisenberg
Journal: Ophthalmology (1998)
Combined high-resolution magnetic resonance imaging and histological examination to explore the role of ligaments and tendons in the phenotypic expression of early hand osteoarthritis
Authors: A L Tan
Journal: Annals of the Rheumatic Diseases (2006)

<b>Background:</b> The pathogenesis of the early stages of hand osteoarthritis is poorly understood, but recent high-resolution magnetic resonance imaging (hrMRI) studies suggest that the joint ligaments have a major role in the phenotypic expression of the disease. <b>Objective:</b> To combine hrMRI and cadaveric histological studies to better understand the mechanisms of damage, and especially the role of joint ligaments and tendons in disease expression. <b>Methods:</b> hrMRI was carried out in the distal interphalangeal (DIP) and proximal interphalangeal (PIP) joints in 20 patients with osteoarthritis,with a disease duration ⩽12 months. Histological sections of the DIP and PIP joints were obtained from three dissecting-room specimens for comparative analysis. <b>Results:</b> The collateral ligaments influenced the location of both hrMRI-determined bone oedema and bone erosion in early osteoarthritis. These changes were best understood in relation to the enthesis organ concept, whereby the interaction between ligament fibrocartilages leads to bone disease. Normal ligaments were commonly associated with microdamage at insertions corresponding to ligament thickening noted in early osteoarthritis. The ligaments also influenced the location of node formation in early osteoarthritis. The DIP extensor tendon insertions were associated with the development of a neoarticular surface. <b>Conclusions:</b> Small-joint collateral ligaments and tendons have a central role in the early stages of hand osteoarthritis, and determine the early expression of both the soft tissue and bony changes in disease.
Widespread Ulcerated and Vegetative Plaques With an Unusual Rhinophymatous Nose
Authors: Caroline Champagne, Emily Davies, Sophie Grabczynska
Journal: JAMA Dermatology (2014)

Atattooartist inhis40spresentedwitha5-monthhistoryofpainful, oozing lesions over his trunk and limbs. A year earlier, he was a victim in an armed robbery and was shot in the right thigh. He reported that he has had problems with widespread abscess formation since then. His only medical history is of long-standing fulminant rhinophyma. He is a smoker but drinks minimal alcohol. On examination,hehadmultipleulcerativeandvegetativeplaqueswith several pustulesonhis scalp, arms, groin, legs, andback (Figure, A). Healsohadamarkedrhinophymatousnose,whichwas inflamedand ulcerated superiorly (Figure, B). There was no mucosal involvement and no lymphadenopathy, and he was apyrexial. Bloodtests revealedamicrocyticanemiaandfeaturesofchronic inflammation or infection, but all other tests, including a vasculitis screen, human immunodeficiency virus (HIV) test, and chest radiograph, had normal results. Serum bromide and iodide levels were normal. Skin swabsamples culturedStaphylococcusaureus,and tissue culture grew coliforms and enterococci after a prolonged periodof enrichment. A shavebiopsy sample from thenose (Figure, C and D) revealed histological features similar to those of punch biopsy samples from the vegetative plaques. Direct and indirect immunofluorescence had negative results. What is your diagnosis?
A novel Rac-dependent checkpoint in B cell development controls entry into the splenic white pulp and cell survival
Authors: Robert B. Henderson, Katarzyna Grys, Anne Vehlow, Carine de Bettignies, Agnieszka Zachacz, Tom Henley, Martin Turner, Facundo Batista, Victor L.J. Tybulewicz
Journal: The Journal of Experimental Medicine (2010)

Rac1 and Rac2 GTPases transduce signals from multiple receptors leading to cell migration, adhesion, proliferation, and survival. In the absence of Rac1 and Rac2, B cell development is arrested at an IgD− transitional B cell stage that we term transitional type 0 (T0). We show that T0 cells cannot enter the white pulp of the spleen until they mature into the T1 and T2 stages, and that this entry into the white pulp requires integrin and chemokine receptor signaling and is required for cell survival. In the absence of Rac1 and Rac2, transitional B cells are unable to migrate in response to chemokines and cannot enter the splenic white pulp. We propose that loss of Rac1 and Rac2 causes arrest at the T0 stage at least in part because transitional B cells need to migrate into the white pulp to receive survival signals. Finally, we show that in the absence of Syk, a kinase that transduces B cell antigen receptor signals required for positive selection, development is arrested at the same T0 stage, with transitional B cells excluded from the white pulp. Thus, these studies identify a novel developmental checkpoint that coincides with B cell positive selection.
Clinical and Metabolic Features of Adult-Onset Diabetes Caused by <i>ABCC8</i> Mutations
Authors: Jean-Pierre Riveline, Elise Rousseau, Yves Reznik, Sabrina Fetita, Julien Philippe, Aurélie Dechaume, Agnès Hartemann, Michel Polak, Catherine Petit, Guillaume Charpentier, Jean-François Gautier, Philippe Froguel, Martine Vaxillaire
Journal: Diabetes Care (2011)

Gain-of-function ABCC8/sulfonylurea (SU) receptor 1 mutations cause neonatal diabetes mellitus (NDM) or late-onset diabetes in adult relatives. Given the effectiveness of SU treatment in ABCC8-NDM patients, we further characterized late-onset ABCC8-associated diabetes.Seven adult subjects from three NDM families and one family with type 2 diabetes were studied. Insulin secretion and insulin sensitivity were assessed using clamp techniques. We screened 139 type 2 diabetic patients who were well controlled by SU for ABCC8 mutations.ABCC8 mutation carriers exhibited glucose intolerance, frank diabetes, or insulin-requiring diabetes since diagnosis. HbA(1c) improved in five SU-treated patients. Insulin secretion capacity was impaired in three patients compared with adult control subjects but was restored after a 4-week SU trial in two patients. Cohort screening revealed four SU-treated patients with ABCC8 mutations, two of which are likely causal.Although of rare occurrence, recognition of adult-onset ABCC8-associated diabetes may help in targeting patients for SU therapy.
Intracoronary Infusion of Skeletal Myoblasts Improves Cardiac Function in Doxorubicin-Induced Heart Failure
Authors: Ken Suzuki, Bari Murtuza, Noriko Suzuki, Ryszard T. Smolenski, Magdi H. Yacoub
Journal: Circulation (2001)

Skeletal myoblast transplantation is promising for the treatment of end-stage heart failure. Direct intramyocardial injection is useful for local cell delivery but may not be effective in global dissemination of cells into the heart, which would be advantageous in treating generalized cardiac dysfunction as in dilated cardiomyopathy. We hypothesized that intracoronary infusion of myoblasts would disseminate cells more effectively, leading to functional improvement in global heart failure.Heart failure was induced by the intraperitoneal administration of doxorubicin (total dose 15 mg/kg) in rat. One million primary skeletal myoblasts were then infused via the coronary arteries of an excised, failing doxorubicin-treated heart. After incubation under increased intracoronary pressure, the hearts were subsequently transplanted into syngeneic recipients. For the control group, doxorubicin-treated hearts were infused with medium only and transplanted. Four weeks after transplantation, Langendorff perfusion demonstrated that both maximum dP/dt (2797.6+/-103.3 versus 2326.9+/-133.1 mm Hg/s, P=0.01) and minimum dP/dt (-2067.4+/-88.1 versus -1718.8+/-91.3 mm Hg/s, P=0.02) were improved in myoblast-transplanted hearts compared with medium-infused hearts. This was associated with a sharper slope of the left ventricular developed pressure-volume curve and a reduced slope of the end-diastolic pressure-volume relation in the myoblast-transplanted hearts. Immunohistochemistry for skeletal myosin heavy chain showed that globally disseminated myoblasts had survived and differentiated into multinucleated myotubes that had aligned with the cardiac fiber axis within host myocardium. No significant myocardial infarction was observed.We demonstrated the feasibility and efficiency of skeletal myoblast transplantation via the intracoronary route as a promising strategy for improving cardiac function in global heart failure.
An international prospective general population-based study of respiratory work disability
Authors: K Toren, J-P Zock, M Kogevinas, E Plana, J Sunyer, K Radon, D Jarvis, H Kromhout, A d'Errico, F Payo, J M Anto, P D Blanc
Journal: Thorax (2009)

Previous cross-sectional studies have shown that job change due to breathing problems at the workplace (respiratory work disability) is common among adults of working age. That research indicated that occupational exposure to gases, dust and fumes was associated with job change due to breathing problems, although causal inferences have been tempered by the cross-sectional nature of previously available data. There is a need for general population-based prospective studies to assess the incidence of respiratory work disability and to delineate better the roles of potential predictors of respiratory work disability.A prospective general population cohort study was performed in 25 centres in 11 European countries and one centre in the USA. A longitudinal analysis was undertaken of the European Community Respiratory Health Survey including all participants employed at any point since the baseline survey, 6659 subjects randomly sampled and 779 subjects comprising all subjects reporting physician-diagnosed asthma. The main outcome measure was new-onset respiratory work disability, defined as a reported job change during follow-up attributed to breathing problems. Exposure to dusts (biological or mineral), gases or fumes during follow-up was recorded using a job-exposure matrix. Cox proportional hazard regression modelling was used to analyse such exposure as a predictor of time until job change due to breathing problems.The incidence rate of respiratory work disability was 1.2/1000 person-years of observation in the random sample (95% CI 1.0 to 1.5) and 5.7/1000 person-years in the asthma cohort (95% CI 4.1 to 7.8). In the random population sample, as well as in the asthma cohort, high occupational exposure to biological dust, mineral dust or gases or fumes predicted increased risk of respiratory work disability. In the random sample, sex was not associated with increased risk of work disability while, in the asthma cohort, female sex was associated with an increased disability risk (hazard ratio 2.8, 95% CI 1.3 to 5.9).Respiratory work disability is common overall. It is associated with workplace exposures that could be controlled through preventive measures.
Bruton's Tyrosine Kinase Cooperates with the B Cell Linker Protein SLP-65 as a Tumor Suppressor in Pre-B Cells
Authors: Rogier Kersseboom, Sabine Middendorp, Gemma M. Dingjan, Katarina Dahlenborg, Michael Reth, Hassan Jumaa, Rudolf W. Hendriks
Journal: The Journal of Experimental Medicine (2003)

Expression of the pre-B cell receptor (pre-BCR) leads to activation of the adaptor molecule SLP-65 and the cytoplasmic kinase Btk. Mice deficient for one of these signaling proteins have an incomplete block in B cell development at the stage of large cycling pre-BCR+CD43+ pre-B cells. Our recent findings of defective SLP-65 expression in ∼50% of childhood pre-B acute lymphoblastic leukemias and spontaneous pre-B cell lymphoma development in SLP-65−/− mice demonstrate that SLP-65 acts as a tumor suppressor. To investigate cooperation between Btk and SLP-65, we characterized the pre-B cell compartment in single and double mutant mice, and found that the two proteins have a synergistic role in the developmental progression of large cycling into small resting pre-B cells. We show that Btk/SLP-65 double mutant mice have a dramatically increased pre-B cell tumor incidence (∼75% at 16 wk of age), as compared with SLP-65 single deficient mice (&amp;lt;10%). These findings demonstrate that Btk cooperates with SLP-65 as a tumor suppressor in pre-B cells. Furthermore, transgenic low-level expression of a constitutive active form of Btk, the E41K-Y223F mutant, prevented tumor formation in Btk/SLP-65 double mutant mice, indicating that constitutive active Btk can substitute for SLP-65 as a tumor suppressor.
Epigenetic factors and cardiac development
Authors: J. H. van Weerd, K. Koshiba-Takeuchi, C. Kwon, J. K. Takeuchi
Journal: Cardiovascular Research (2011)

Congenital heart malformations remain the leading cause of death related to birth defects. Recent advances in developmental and regenerative cardiology have shed light on a mechanistic understanding of heart development that is controlled by a transcriptional network of genetic and epigenetic factors. This article reviews the roles of chromatin remodelling factors important for cardiac development with the current knowledge of cardiac morphogenesis, regeneration, and direct cardiac differentiation. In the last 5 years, critical roles of epigenetic factors have been revealed in the cardiac research field.
Extremely low frequency electromagnetic fields (EMF) and brain cancer in adults and children: Review and comment
Authors: James G. Gurney, Edwin van Wijngaarden
Journal: Neuro-Oncology (1999)

Epidemiologic and experimental research on the potential carcinogenic effects of extremely low frequency electromagnetic fields (EMF) has now been conducted for over two decades. Cancer epidemiology studies in relation to EMF have focused primarily on brain cancer and leukemia, both from residential sources of exposure in children and adults and from occupational exposure in adult men. Because genotoxic effects of EMF have not been shown, most recent laboratory research has attempted to show biological effects that could be related to cancer promotion. In this report, we briefly review residential and occupational EMF studies on brain cancer. We also provide a general review of experimental studies as they relate both to the biological plausibility of an EMF-brain cancer relation and to the insufficiency of such research to help guide exposure assessment in epidemiologic studies. We conclude from our review that no recent research, either epidemiologic or experimental, has emerged to provide reasonable support for a causal role of EMF on brain cancer.
Biological Availability of Digoxin from Lanoxin Produced in the United Kingdom
Authors: B. F. Johnson, A. S. E. Fowle, S. Lader, J. Fox, A. D. Munro-Faure
Journal: BMJ (1973)

Though established quality control standards were maintained, the bioavailability of digoxin from Lanoxin tablets produced in the United Kingdom fell in 1969, and was restored in 1972. After 1·5 mg doses of representative batches, tablets made between 1969 and 1972 produced mean values for area under the 50 hours plasma concentration/time curve of 36·6 ng/ml/hr and four-day urinary excretion of 340 μg, compared with respective values of 67·5 ng/ml/hr and 696 μg for recently produced tablets. After 0·5 mg doses of four recent independently produced batches of Lanoxin tablets no significant between-batch difference was found for area under the plasma concentration/time curve or cumulative urinary excretion. Absorption of digoxin from batches of Lanoxin manufactured since May 1972 is uniform and consistent. Content uniformity is an inadequate measure of tablet quality, and consistent digoxin bioavailability cannot be ensured by existing regulations.
Negative Regulation of Mast Cell Signaling and Function by the Adaptor LAB/NTAL
Authors: Petra Volná, Pavel Lebduška, Lubica Dráberová, Šárka Šímová, Petr Heneberg, Michael Boubelík, Viktor Bugajev, Bernard Malissen, Bridget S. Wilson, Václav Hořejší, Marie Malissen, Petr Dráber
Journal: The Journal of Experimental Medicine (2004)

Engagement of the Fcε receptor I (FcεRI) on mast cells and basophils initiates signaling pathways leading to degranulation. Early activation events include tyrosine phosphorylation of two transmembrane adaptor proteins, linker for activation of T cells (LAT) and non–T cell activation linker (NTAL; also called LAB; a product of Wbscr5 gene). Previous studies showed that the secretory response was partially inhibited in bone marrow–derived mast cells (BMMCs) from LAT-deficient mice. To clarify the role of NTAL in mast cell degranulation, we compared FcεRI-mediated signaling events in BMMCs from NTAL-deficient and wild-type mice. Although NTAL is structurally similar to LAT, antigen-mediated degranulation responses were unexpectedly increased in NTAL-deficient mast cells. The earliest event affected was enhanced tyrosine phosphorylation of LAT in antigen-activated cells. This was accompanied by enhanced tyrosine phosphorylation and enzymatic activity of phospholipase C γ1 and phospholipase C γ2, resulting in elevated levels of inositol 1,4,5-trisphosphate and free intracellular Ca2+. NTAL-deficient BMMCs also exhibited an enhanced activity of phosphatidylinositol 3-OH kinase and Src homology 2 domain–containing protein tyrosine phosphatase-2. Although both LAT and NTAL are considered to be localized in membrane rafts, immunogold electron microscopy on isolated membrane sheets demonstrated their independent clustering. The combined data show that NTAL is functionally and topographically different from LAT.
Indirect comparison meta-analysis of aspirin therapy after coronary surgery
Authors: E. Lim
Journal: BMJ (2003)

<b>Objectives</b> To evaluate the efficacy of low and medium dose aspirin therapy after coronary surgery by using an indirect comparison meta-analysis. <b>Data sources</b> Systematic literature search of Medline, Embase, Cochrane controlled trials register, and trial register sites on the internet. <b>Study selection</b> Outcome was evaluated by angiography and reported as graft occlusion and rate of events in patients. Trials that did not include aspirin as the sole therapy or did not have a placebo control arm were excluded. Articles were assessed for eligibility and quality and grouped according to dosage. The estimated difference in effect of low and medium dose aspirin on graft occlusion was obtained by combining the estimated log relative risks of low dose with placebo and medium dose with placebo. <b>Results</b> For graft occlusion, the medium dose trials yielded a relative risk reduction of 45% compared with 26% for the low dose trials. The greater effect in the medium dose trials is summarised by a relative risk ratio of 0.74 (95% confidence interval 0.52 to 1.06; P = 0.10) for graft occlusion and 0.81 (0.57 to 1.16; P = 0.25) for events in patients. <b>Conclusions</b> Medium dose aspirin may more successfully reduce graft occlusion than low dose regimens within the first year after coronary surgery.
Randomized Trial of Radiotherapy Plus Concurrent-Adjuvant Chemotherapy vs Radiotherapy Alone for Regionally Advanced Nasopharyngeal Carcinoma
Authors: A. W. M. Lee, S. Y. Tung, D. T. T. Chua, R. K. C. Ngan, R. Chappell, R. Tung, L. Siu, W. T. Ng, W. K. Sze, G. K. H. Au, S. C. K. Law, B. O'Sullivan, T. K. Yau, T. W. Leung, J. S. K. Au, W. M. Sze, C. W. Choi, K. K. Fung, J. T. Lau, W. H. Lau
Journal: JNCI Journal of the National Cancer Institute (2010)

Current practice of adding concurrent–adjuvant chemotherapy to radiotherapy (CRT) for treating advanced nasopharyngeal carcinoma is based on the Intergroup-0099 Study published in 1998. However, the outcome for the radiotherapy-alone (RT) group in that trial was substantially poorer than those in other trials, and there were no data on late toxicities. Verification of the long-term therapeutic index of this regimen is needed. Patients with nonkeratinizing nasopharyngeal carcinoma staged T1-4N2-3M0 were randomly assigned to RT (176 patients) or to CRT (172 patients) using cisplatin (100 mg/m 2 ) every 3 weeks for three cycles in concurrence with radiotherapy, followed by cisplatin (80 mg/m 2 ) plus fluorouracil (1000 mg per m 2 per day for 4 days) every 4 weeks for three cycles. Primary endpoints included overall failure-free rate (FFR) (the time to first failure at any site) and progression-free survival. Secondary endpoints included overall survival, locoregional FFR, distant FFR, and acute and late toxicity rates. All statistical tests were two-sided. The two treatment groups were well balanced in all patient characteristics, tumor factors, and radiotherapy parameters. Adding chemotherapy statistically significantly improved the 5-year FFR (CRT vs RT: 67% vs 55%; P = .014) and 5-year progression-free survival (CRT vs RT: 62% vs 53%; P = .035). Cumulative incidence of acute toxicity increased with chemotherapy by 30% (CRT vs RT: 83% vs 53%; P < .001), but the 5-year late toxicity rate did not increase statistically significantly (CRT vs RT: 30% vs 24%; P = .30). Deaths because of disease progression were reduced statistically significantly by 14% (CRT vs RT: 38% vs 24%; P = .008), but 5-year overall survival was similar (CRT vs RT: 68% vs 64%; P = .22; hazard ratio of CRT = 0.81, 95% confidence interval = 0.58 to 1.13) because deaths due to toxicity or incidental causes increased by 7% (CRT vs RT: 1.7% vs 0, and 8.1% vs 3.4%, respectively; P = .015). Adding concurrent–adjuvant chemotherapy statistically significantly reduced failure and cancer-specific deaths when compared with radiotherapy alone. Although there was no statistically significant increase in major late toxicity, increase in noncancer deaths narrowed the resultant gain in overall survival.