tbuckley/cabot-search huggingface dataset:
Detection of Regan Variant Type of Alkaline Phosphatase Isoenzyme in Liver Tissue of Indian Childhood Cirrhosis
Authors: S. R. Parekh, B. D. Patel, S. R. Damle, G. M. Thanki, D. Khutti
Journal: Hepatology (2007)

Alkaline phosphatase (ALP) isoenzyme composition was studied in sera and liver from patients with Indian childhood cirrhosis (ICC). A typical pattern consisting of a fast-moving anodal preliver band with slower moving diffuse liver and placental bands followed by an intestinal band was consistently observed in sera of patients in all stages of ICC and in pregnant mothers of index ICC patients. ICC liver ALP was relatively heat-stable and inhibited by L-phenylalanine and L-leucine. The isoenzyme also had similar immunological determinants to placental ALP and adult intestinal ALP isoenzymes. Total serum ALP isoenzyme and its heat-stable component progressively increased in concentration from early to advanced stages of the disease suggesting that the diseased liver in ICC is the source of the abnormal isoenzyme.
Adipose tissue transcriptomic signature highlights the pathological relevance of extracellular matrix in human obesity
Authors: Corneliu Henegar, Joan Tordjman, Vincent Achard, Danièle Lacasa, Isabelle Cremer, Michèle Guerre-Millo, Christine Poitou, Arnaud Basdevant, Vladimir Stich, Nathalie Viguerie, Dominique Langin, Pierre Bedossa, Jean-Daniel Zucker, Karine Clement
Journal: Genome biology (2008)

Abstract Background Investigations performed in mice and humans have acknowledged obesity as a low-grade inflammatory disease. Several molecular mechanisms have been convincingly shown to be involved in activating inflammatory processes and altering cell composition in white adipose tissue (WAT). However, the overall importance of these alterations, and their long-term impact on the metabolic functions of the WAT and on its morphology, remain unclear. Results Here, we analyzed the transcriptomic signature of the subcutaneous WAT in obese human subjects, in stable weight conditions and after weight loss following bariatric surgery. An original integrative functional genomics approach was applied to quantify relations between relevant structural and functional themes annotating differentially expressed genes in order to construct a comprehensive map of transcriptional interactions defining the obese WAT. These analyses highlighted a significant up-regulation of genes and biological themes related to extracellular matrix (ECM) constituents, including members of the integrin family, and suggested that these elements could play a major mediating role in a chain of interactions that connect local inflammatory phenomena to the alteration of WAT metabolic functions in obese subjects. Tissue and cellular investigations, driven by the analysis of transcriptional interactions, revealed an increased amount of interstitial fibrosis in obese WAT, associated with an infiltration of different types of inflammatory cells, and suggest that phenotypic alterations of human pre-adipocytes, induced by a pro-inflammatory environment, may lead to an excessive synthesis of ECM components. Conclusion This study opens new perspectives in understanding the biology of human WAT and its pathologic changes indicative of tissue deterioration associated with the development of obesity.
Fatal infectious mononucleosis: a severe complication in the treatment of Crohn's disease with azathioprine.
Authors: E F Posthuma, R G Westendorp, A van der Sluys Veer, J C Kluin-Nelemans, P M Kluin, C B Lamers
Journal: Gut (1995)

A 19 year old man with a history of Crohn9s disease treated with azathioprine and prednisone, died after a primary infection with Epstein-Barr virus. He had the characteristics of the virus associated haemophagocytic syndrome, a rare complication of viral infections, which consists of fever, constitutional symptoms, hepatosplenomegaly, liver function and coagulation abnormalities, and hypertriglyceridaemia. Additionally, there was pain, cytopenia, and histiocytic hyperplasia in the bone marrow, spleen, or lymph nodes. This severe complication has been reported previously in renal transplant patients, but not in those with inflammatory bowel disease taking azathioprine. The immunosuppressive therapy may have contributed to this fatal complication of infectious mononucleosis, and this complication should be considered when treating a patient with inflammatory bowel disease with azathioprine.
Long-Term Therapy of Chronic Hepatitis B With Lamivudine
Authors: Daryl T.-Y. Lau, Farooq M. Khokhar, Edward Doo, Marc G. Ghany, David Herion, Yoon Park, David E. Kleiner, Peter Schmid, Lynn D. Condreay, Josée Gauthier, Mary C. Kuhns, Jake T. Liang, Jay H. Hoofnagle
Journal: Hepatology (2000)

Lamivudine therapy induces improvements in chronic hepatitis B in a high proportion of patients, but prolonged therapy is limited by the development of viral resistance. We analyzed clinical responses and virologic resistance in 27 patients treated continuously with lamivudine for 2 to 4 years. Serum transaminases, hepatitis B virus (HBV) DNA by both branched DNA (bDNA) signal amplification and quantitative polymerase chain reaction were monitored at 4- to 8-week intervals. Virologic resistance to lamivudine was confirmed by the presence of mutations in the YMDD motif of the polymerase gene by restriction fragment-length polymorphism analysis. Serum HBV-DNA levels decreased rapidly in all treated patients, falling by 4 to 5 logs within 1 year. Transaminase levels also decreased and were normal in 70% of patients at 1 year, at which point liver histology had improved in 81% of patients. Viral resistance began to emerge after 8 months of therapy, eventually developing in 14 patients, including 76% of hepatitis B e antigen (HBeAg)-positive patients but only 10% of HBeAg-negative patients. Lamivudine withdrawal led to reappearance of wild-type HBV species, but retreatment led to more rapid reappearance of the mutant virus. Clinical, serum biochemical, and histologic improvements were maintained in the 13 patients who did not develop resistance. Thus, long-term therapy with lamivudine resulted in maintained improvements in virologic, biochemical, and histologic features of disease in most patients with HBeAg-negative chronic hepatitis B and in the subgroup of HBeAg-positive patients with high serum transaminase levels. A high rate of resistance limited efficacy, particularly in patients who remained HBeAg positive on therapy.
Large scale evidence and replication: insights from rheumatology and beyond
Authors: J P A Ioannidis
Journal: Annals of the Rheumatic Diseases (2004)

Many biomedical and research findings fail to be replicated and validated

Increasing concern has been expressed that biomedical research findings many times fail to be replicated and validated. This may occur across the spectrum from basic research to clinical applications. Small studies, poor design, the play of chance, exaggeration in early claims, data dredging, selective publication and reporting of information, strong expert opinions, biases, and financial or other conflicts of interest all probably combine to create uncertainty about whether research findings will stand the test of time and independent replication. Some research findings or beliefs are not even questioned and no effort is ever made to challenge them, but this does not mean that they are true. The recent advent of molecular medicine has only increased the complexity and number of questions that may be asked. It is unclear though, whether the information derived from the various fascinating discovery-driven approaches, massive as it is, is more likely to be possible to replicate. The ratio of sample size to scientific question asked has been decreased to infinitesimal levels, and uncertainty remains as high as ever.

For rheumatology and autoimmune diseases, the danger is as great as for any other medical discipline. Much of the replication difficulties may have to deal with the fact that claims are made or refuted based on limited data in single studies. The median number of patients in randomised controlled trials in systemic sclerosis is only 28,1 exactly the same as for trials on treatments for systemic lupus erythematosus.2 Including also trials on common diseases like rheumatoid arthritis or osteoarthritis, the median sample size for a rheumatology related trial has barely improved, moving from 46 to 88 patients in the past decade.3 Studies in the sample size ranges encountered in cardiology or oncology mega-trials …
Antioxidant Amelioration of Dilated Cardiomyopathy Caused by Conditional Deletion of NEMO/IKKγ in Cardiomyocytes
Authors: P. Kratsios, M. Huth, L. Temmerman, E. Salimova, M. Al Banchaabouchi, A. Sgoifo, M. Manghi, K. Suzuki, N. Rosenthal, F. Mourkioti
Journal: Circulation Research (2009)

Insight into the function of nuclear factor (NF)-kappaB in the adult heart has been hampered by the embryonic lethality of constitutive NF-kappaB inactivation.The goal of the present study was therefore to gain insights into the role of NF-kappaB pathway specifically in mouse cardiomyocytes by conditional deletion of the NF-kappaB essential modulator (NEMO).Using a Cre/loxP system, we disrupted the Nemo gene in a cardiomyocyte-specific manner in the heart, which simulated gene expression changes underlying human heart failure and caused adult-onset dilated cardiomyopathy accompanied by inflammation and apoptosis. Pressure overload challenges of NEMO-deficient young hearts precociously induced the functional decrements that develop spontaneously in older knockout animals. Moreover, oxidative stress in NEMO-deficient cardiomyocytes is a critical pathological component that can be attenuated with antioxidant diet in vivo.These results reveal an essential physiological role for NEMO-mediated signaling in the adult heart to maintain cardiac function in response to age-related or mechanical challenges, in part through modulation of oxidative stress.
The Pulmonary Complications of Dysphagia
Authors: J. R. Belcher
Journal: Thorax (1949)

London1940 to 1945 complained of slight dysphagia on hurrying food.In 1945 he developed " pneumonia."Acidfast bacilli were found in the sputum.A radiograph (Plate Ila) showed bilateral mid-zone infiltration with a suggestion of cavitation on the right side.Rapid clinical and radiological improvement ensued until his radiograph was almost clear six months later.In March, 1948, a Heller's operation was performed (N.R. Barrett) for increasing dysphagia.He had no pulmonary symptoms in the interim, the radiograph was then clear (Plate Ilb) and no acid-fast bacilli were found in his oesophagus or sputum.Case 3. Achalasia associated with " typical" fibrosis.-Aman aged 50, whose abnormality was discovered on mass radiography (Eley, 1948), had had slight dysphagia for years with recent dyspnoea and repeated bronchitis.The radiograph (Plate Illa) is characteristic of the condition; this and his symptoms have now remained unchanged for a year.Case 4. Carcinoma of lower third of oesophagus and lung abscess.-Aman aged 69 gave a three weeks' history of cough and purulent sputum.A radiograph showed a left dorsal-lobe lung abscess with a fluid level.He improved until he was symptom-free one month later.The radiograph now showed no cavity, on December 13,
Rituximab with high-dose methotrexate in primary central nervous system lymphoma
Authors: Roopesh Kansara, Tamara N. Shenkier, Joseph M. Connors, Laurie H. Sehn, Kerry J. Savage, Alina S. Gerrie, Diego Villa
Journal: American Journal of Hematology (2015)

The addition of rituximab (R) to chemotherapy improves outcomes in patients with systemic B-cell non-Hodgkin lymphomas, but the impact in patients with primary central nervous system lymphoma (PCNSL) receiving high-dose methotrexate (HDMTX) is unknown. Patients diagnosed with PCNSL at the British Columbia Cancer Agency (BCCA) between 2000 and 2013 were treated with ≥1 cycle of HDMTX 8 g/m(2) every 2 weeks, to best response or 10 cycles. After 2006, rituximab 375 mg/m(2) was given every 2 weeks with HDMTX for a total of 4 doses. 49 (66%) patients received HDMTX alone and 25 (34%) HDMTX+R, with a median of 5 (range 1-10) HDMTX cycles, and no difference between groups. The median follow-up was 5 years: 8.8 years (range 3.15-13.5 years) HDMTX and 1.9 years (range 0.5-7 years) HDMTX+R. The 5-year PFS was 17%, with no difference between groups (HR: 0.75, 95% CI: 0.41-1.35; P = 0.33). The 5-year OS was 38%, with no difference between the groups OS (HR: 0.73, 95% CI: 0.35-1.52; P = 0.39). In this retrospective study comparing two subgroups of patients treated in different eras, the addition of R to HDMTX did not appear to improve outcomes in PCNSL, possibly consistent with its known poor CNS penetration. It is possible that with a larger sample size, longer follow-up, or different rituximab dosing/schedule, the addition of rituximab may lead to a statistically significant improvement in outcomes. Prospective randomized trials currently in progress will more definitively estimate the impact of the addition of rituximab to HDMTX-based chemotherapy for PCNSL.
Constitutive Nuclear Factor κB Activity Is Required for Survival of Activated B Cell–like Diffuse Large B Cell Lymphoma Cells
Authors: R. Eric Davis, Keith D. Brown, Ulrich Siebenlist, Louis M. Staudt
Journal: The Journal of Experimental Medicine (2001)

Gene expression profiling has revealed that diffuse large B cell lymphoma (DLBCL) consists of at least two distinct diseases. Patients with one DLBCL subtype, termed activated B cell-like (ABC) DLBCL, have a distinctly inferior prognosis. An untapped potential of gene expression profiling is its ability to identify pathogenic signaling pathways in cancer that are amenable to therapeutic attack. The gene expression profiles of ABC DLBCLs were notable for the high expression of target genes of the nuclear factor (NF)-kappaB transcription factors, raising the possibility that constitutive activity of the NF-kappaB pathway may contribute to the poor prognosis of these patients. Two cell line models of ABC DLBCL had high nuclear NF-kappaB DNA binding activity, constitutive IkappaB kinase (IKK) activity, and rapid IkappaB(alpha) degradation that was not seen in cell lines representing the other DLBCL subtype, germinal center B-like (GCB) DLBCL. Retroviral transduction of a super-repressor form of IkappaBalpha or dominant negative forms of IKKbeta was toxic to ABC DLBCL cells but not GCB DLBCL cells. DNA content analysis showed that NF-kappaB inhibition caused both cell death and G1-phase growth arrest. These findings establish the NF-kappaB pathway as a new molecular target for drug development in the most clinically intractable subtype of DLBCL and demonstrate that the two DLBCL subtypes defined by gene expression profiling utilize distinct pathogenetic mechanisms.
Metabolic Effects of Troglitazone Monotherapy in Type 2 Diabetes Mellitus
Authors: David G. Maggs
Journal: Annals of Internal Medicine (1998)

Background: Troglitazone is a new insulin-sensitizing agent used to treat type 2 diabetes mellitus. The mechanism by which troglitazone exerts its effect on systemic glucose metabolism is unknown. Objective: To determine the effects of 6 months of troglitazone monotherapy on glucose metabolism in patients with type 2 diabetes mellitus. Design: Randomized, double-blind, placebo-controlled trial. Setting: Six general clinical research centers at university hospitals. Patients: 93 patients (mean age, 52 years) with type 2 diabetes mellitus (mean fasting plasma glucose level, 11.2 mmol/L) who were being treated with diet alone or who had discontinued oral antidiabetic medication therapy. Intervention: Patients were randomly assigned to one of five treatment groups (100, 200, 400, or 600 mg of troglitazone daily or placebo) and had metabolic assessment before and after 6 months of treatment. Measurements: Plasma glucose and insulin profiles during a meal tolerance test; basal hepatic glucose production and insulin-stimulated glucose disposal rate during a hyperinsulinemic-euglycemic clamp procedure. Results: Troglitazone at 400 and 600 mg/d decreased both fasting (P < 0.001) and postprandial (P = 0.016) plasma glucose levels by approximately 20%. All four troglitazone dosages also decreased fasting (P = 0.012) and postprandial (P < 0.001) triglyceride levels; 600 mg of the drug per day decreased fasting free fatty acid levels (P = 0.018). Plasma insulin levels decreased in the 200-, 400-, and 600-mg/d groups (P < 0.001), and C-peptide levels decreased in all five study groups (P < 0.001). Basal hepatic glucose production was suppressed in the 600-mg/d group compared with the placebo group (P = 0.02). Troglitazone at 400 and 600 mg/d increased glucose disposal rate by approximately 45% above pretreatment levels (P = 0.003). Stepwise regression analysis showed that troglitazone therapy was the strongest predictor of a decrease in fasting (P < 0.001) or postprandial (P = 0.01) glucose levels. Fasting C-peptide level was the next strongest predictor (higher C-peptide level equaled greater glucose-lowering effect). Conclusion: Troglitazone monotherapy decreased fasting and postprandial glucose levels in patients with type 2 diabetes, primarily by augmenting insulin-mediated glucose disposal.
Reciprocal relationship between APP positioning relative to the membrane and PS1 conformation
Authors: Kengo Uemura, Katherine C Farner, Navine Nasser-Ghodsi, Phill Jones, Oksana Berezovska
Journal: Molecular Neurodegeneration (2011)

Several familial Alzheimer disease (FAD) mutations within the transmembrane region of the amyloid precursor protein (APP) increase the Aβ42/40 ratio without increasing total Aβ production. In the present study, we analyzed the impact of FAD mutations and γ-secretase modulators (GSMs) that alter the Aβ42/40 ratio on APP C-terminus (CT) positioning relative to the membrane, reasoning that changes in the alignment of the APP intramembranous domain and presenilin 1 (PS1) may impact the PS1/γ-secretase cleavage site on APP.By using a Förster resonance energy transfer (FRET)-based technique, fluorescent lifetime imaging microscopy (FLIM), we show that Aβ42/40 ratio-modulating factors which target either APP substrate or PS1/γ-secretase affect proximity of the APP-CT to the membrane and change PS1 conformation.Thus, we propose that there is a reciprocal relationship between APP-CT positioning relative to the membrane and PS1 conformation, suggesting that factors that modulate either APP positioning in the membrane or PS1 conformation could be exploited therapeutically.
Vascular endothelial growth factor-B gene transfer prevents angiotensin II-induced diastolic dysfunction via proliferation and capillary dilatation in rats
Authors: Raisa Serpi, Anna-Maria Tolonen, Jenni Huusko, Jaana Rysä, Olli Tenhunen, Seppo Ylä-Herttuala, Heikki Ruskoaho
Journal: Cardiovascular Research (2010)

AimsHeart growth and function are angiogenesis-dependent, but little is known concerning the effects of key regulators of angiogenesis on diastolic heart failure. Here, we tested the hypothesis that local vascular endothelial growth factor-B (VEGF-B) gene therapy prevents left ventricular diastolic dysfunction.
Carbohydrate and oxygen metabolism during hepatocellular proliferation: A study in perfused livers from mirex-treated rats
Authors: James Yarbrough, Michael Cunningham, Hirofumi Yamanaka, Ronald Thurman, Mostafa Badr
Journal: Hepatology (1991)

Liver regeneration after partial hepatectomy is accompanied by altered hepatic intermediary metabolism. Because the organochlorine compound mirex also causes liver cell growth, the purpose of this study was to investigate hepatic carbohydrate and oxygen metabolism in perfused livers from mirex-treated rats and to localize cell proliferation in this model. Pretreatment with mirex (100 mg/kg, intragastrically) increased liver/body weight ratios and DNA synthesis in livers of fed rats, effects that were markedly diminished in livers of fasted rats. This finding shows that liver growth caused by mirex, as is the case after partial hepatectomy, is hindered when animals are deprived of food. Furthermore, perfused livers from mirex-treated rats had depleted glycogen stores but significantly elevated oxygen uptake compared with livers from control rats. Increases in oxygen uptake and hepatocellular proliferation were observed mostly in periportal regions of the liver lobule. In regenerating livers, most DNA synthesis was reported to also occur in these regions of the liver lobule. Taken together, these data show that liver cell growth caused by mirex is accompanied by changes in hepatic intermediary metabolism and sublobular proliferation similar to those observed after partial hepatectomy. (HEPATOLOGY 1991;13:1229–1234.)
Occurrence of exercise induced bronchospasm in elite runners: dependence on atopy and exposure to cold air and pollen.
Authors: I J Helenius, H O Tikkanen, T Haahtela
Journal: British Journal of Sports Medicine (1998)

OBJECTIVES: To study factors affecting the occurrence of exercise induced bronchospasm (EIB) in elite runners. METHODS: Fifty eight elite runners, 79% of them belonging to Finnish national teams, volunteered. The athletes answered a questionnaire on respiratory symptoms. Skin prick tests were used to investigate atopy, and spirometry to examine lung function at rest and after an exercise challenge test (ECT) at subzero temperature in the winter and after a similar ECT in the summer at the end of the birch pollen season. RESULTS: Definitive EIB (a post-exercise reduction of 10% or more in forced expiratory volume in one second (FEV1) was observed in five (9%) of the 58 runners. A subgroup consisting of 19 non-atopic symptom-free runners with no family history of asthma was used to establish a normal range for post-exercise reduction in FEV1. When this group's mean exercise induced change in FEV1 minus 2 SDs (a reduction of 6.5% or more in FEV1) was taken as the lower limit of the reference range, 15 (26%) of the runners had probable EIB in either the winter or the pollen season. The occurrence of probable EIB depended on atopy (odds ratio increased with number of positive skin prick test reactions, p &lt; 0.05). Nine (22%) of the 41 runners, challenged in both the winter and the pollen season, had probable EIB only in the winter, and three (7%) had it only in the pollen season. Only one runner (2%) had EIB in both tests. CONCLUSIONS: Mild EIB is common in Finnish elite runners and is strongly associated with atopy. Seasonal variability affects the occurrence of EIB, and thus exercise testing should be performed in both cold winter air and the pollen season to detect EIB in elite runners.
716 FIVE-YEAR TELBIVUDINE TREATMENT WITH EFFECTIVE VIRAL SUPPRESSION RESULTS IN RESOLUTION OF LIVER INFLAMMATION AND FIBROSIS REGRESSION IN PATIENTS WITH CHRONIC HEPATITIS B
Authors: J. Hou, D. Xu, G. Shi, Z. Goodman, M. Wan, D. Tan, C. Chen, Q. Xie, L. Wei, J. Niu, Q. Wang, H. Ren, Y. Wang, J. Jia, W. Bao, Y. Dong, A. Trylesinski, N. Naoumov
Journal: Journal of Hepatology (2011)
Real-time transmission of echocardiographic images over high speed networks: effects of bandwidth, cell loss ratio and cell error ratio on image quality
Authors: M. Main, D. Foltz, E. Babinsky, D. Bailey, B. Frantz, D. Pleva, M. Baldizzi, D Myers, K. Jones, M. Spence, K. Freeman, A. Morehead, J. Thomas
Journal: Journal of the American College of Cardiology (1998)