tbuckley/cabot-search huggingface dataset:
The <i>SERPINE2</i> Gene Is Associated with Chronic Obstructive Pulmonary Disease in Two Large Populations
Authors: Guohua Zhu, Liling Warren, Jennifer Aponte, Amund Gulsvik, Per Bakke, Wayne H. Anderson, David A. Lomas, Edwin K. Silverman, Sreekumar G. Pillai
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Chronic obstructive pulmonary disease (COPD) is a complex disease influenced by multiple genes and environmental factors. A region on chromosome 2q has been shown to be linked to COPD. A positional candidate gene from the chromosome 2q region SERPINE2 (Serpin peptidase inhibitor, clade E [nexin, plasminogen activator inhibitor type 1], member 2), was previously evaluated as a susceptibility gene for COPD in two association studies, but the results were contradictory.To identify the relationship between SERPINE2 polymorphisms and COPD-related phenotypes using family-based and case-control association studies.In the present study, we genotyped 25 single nucleotide polymorphisms (SNPs) from SERPINE2 and analyzed qualitative and quantitative COPD phenotypes in 635 pedigrees with 1,910 individuals and an independent case-control population that included 973 COPD cases and 956 control subjects. The family data were analyzed using family-based association tests. The case-control data were analyzed using logistic regression and linear models.Six SNPs demonstrated significant associations with COPD phenotypes in the family-based association analysis (0.0016<or=p<or=0.042). Five of these SNPs demonstrated replicated associations in the case-control analysis (0.021<or=p<or=0.031). In addition, the results of haplotype analyses supported the results from single SNP analyses.These data provide further support for SERPINE2 as a COPD susceptibility gene.
Familial risk of urinary incontinence in women: population based cross sectional study
Authors: Yngvild S Hannestad, Rolv Terje Lie, Guri Rortveit, Steinar Hunskaar
Journal: BMJ (2004)

Abstract Objective To determine whether there is an increased risk of urinary incontinence in daughters and sisters of incontinent women. Design Population based cross sectional study. Setting EPINCONT (the epidemiology of incontinence in the county of Nord-Trøndelag study), a substudy of HUNT 2 (the Norwegian Nord-Trøndelag health survey 2), 1995-7. Participants 6021 mothers, 7629 daughters, 332 granddaughters, and 2104 older sisters of 2426 sisters. Main outcome measures Adjusted relative risks for urinary incontinence. Results The daughters of mothers with urinary incontinence had an increased risk for urinary incontinence (1.3, 95% confidence interval 1.2 to 1.4; absolute risk 23.3%), stress incontinence (1.5, 1.3 to 1.8; 14.6%), mixed incontinence (1.6, 1.2 to 2.0; 8.3%), and urge incontinence (1.8, 0.8 to 3.9; 2.6%). If mothers had severe symptoms then their daughters were likely to have such symptoms (1.9, 1.3 to 3.0; 4.0%). The younger sisters of female siblings with urinary incontinence, stress incontinence, or mixed incontinence had increased relative risks of, respectively, 1.6 (1.3 to 1.9; absolute risk 29.6%), 1.8 (1.3 to 2.3; 18.3%), and 1.7 (1.1 to 2.8; 10.8%). Conclusion Women are more likely to develop urinary incontinence if their mother or older sisters are incontinent.
Effect of Darapladib on Major Coronary Events After an Acute Coronary Syndrome
Authors: Michelle L. O’Donoghue, Eugene Braunwald, Harvey D. White, Dylan P. Steen, Mary Ann Lukas, Elizabeth Tarka, P. Gabriel Steg, Judith S. Hochman, Christoph Bode, Aldo P. Maggioni, KyungAh Im, Jennifer B. Shannon, Richard Y. Davies, Sabina A. Murphy, Sharon E. Crugnale, Stephen D. Wiviott, Marc P. Bonaca, David F. Watson, W. Douglas Weaver, Patrick W. Serruys, Christopher P. Cannon
Journal: JAMA (2014)

Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been hypothesized to be involved in atherogenesis through pathways related to inflammation. Darapladib is an oral, selective inhibitor of the Lp-PLA2 enzyme.To evaluate the efficacy and safety of darapladib in patients after an acute coronary syndrome (ACS) event.SOLID-TIMI 52 was a multinational, double-blind, placebo-controlled trial that randomized 13,026 participants within 30 days of hospitalization with an ACS (non-ST-elevation or ST-elevation myocardial infarction [MI]) at 868 sites in 36 countries.Patients were randomized to either once-daily darapladib (160 mg) or placebo on a background of guideline-recommended therapy. Patients were followed up for a median of 2.5 years between December 7, 2009, and December 6, 2013.The primary end point (major coronary events) was the composite of coronary heart disease (CHD) death, MI, or urgent coronary revascularization for myocardial ischemia. Kaplan-Meier event rates are reported at 3 years.During a median duration of 2.5 years, the primary end point occurred in 903 patients in the darapladib group and 910 in the placebo group (16.3% vs 15.6% at 3 years; hazard ratio [HR], 1.00 [95% CI, 0.91-1.09]; P = .93). The composite of cardiovascular death, MI, or stroke occurred in 824 in the darapladib group and 838 in the placebo group (15.0% vs 15.0% at 3 years; HR, 0.99 [95% CI, 0.90-1.09]; P = .78). There were no differences between the treatment groups for additional secondary end points, for individual components of the primary end point, or in all-cause mortality (371 events in the darapladib group and 395 in the placebo group [7.3% vs 7.1% at 3 years; HR, 0.94 [95% CI, 0.82-1.08]; P = .40). Patients were more likely to report an odor-related concern in the darapladib group vs the placebo group (11.5% vs 2.5%) and also more likely to report diarrhea (10.6% vs 5.6%).In patients who experienced an ACS event, direct inhibition of Lp-PLA2 with darapladib added to optimal medical therapy and initiated within 30 days of hospitalization did not reduce the risk of major coronary events.clinicaltrials.gov Identifier: NCT01000727.
Analysis of microsatellite instability in medulloblastoma
Authors: Marta Viana-Pereira, Inês Almeida, Sónia Sousa, Bethânia Mahler-Araújo, Raquel Seruca, José Pimentel, Rui Manuel Reis
Journal: Neuro-Oncology (2009)

Medulloblastoma is the most common malignant brain tumor in children. The presence of microsatellite instability (MSI) in brain tumors, particularly medulloblastomas, has not been properly addressed. The aim of the present study was to evaluate the role of MSI in medulloblastoma carcinogenesis. MSI status was determined in 36 patients using a pentaplex PCR of quasimonomorphic markers (NR27, NR21, NR24, BAT25, and BAT26). Methylation status of mismatch repair (MMR) genes was achieved by methylation-specific multiplex ligation-dependent probe amplification (MLPA). In addition, MutS homolog 6 (MSH6) expression was determined by immunohistochemistry. Mutations of 10 MSI target genes (TCF4, XRCC2, MBD4, MRE11, ATR, MSH3, TGFBR2, RAD50, MSH6, and BAX) were studied by pentaplex PCR followed by analysis with GeneScan 3.7 software. Mutation analysis of hotspot regions of beta-catenin (CTNNB1) and BRAF (v-raf murine sarcoma viral oncogene homolog B1) oncogenes was performed by PCR single-strand conformation polymorphism analysis followed by direct sequencing. Among the 36 tumors, we found four (11%) cases with instability, one with high MSI and three with low MSI. Methylation analysis of MMR genes in cases presenting shifts on the MSI markers revealed mild hypermethylation of MSH6 in 75% of cases, yet MSH6 was expressed in all the tumors. The MSI target genes MBD4 (methyl-CpG binding domain protein 4) and MRE11 (meiotic recombination 11 homolog A) were mutated in two different tumors. No CTNNB1 or BRAF mutations were found. This study is the most comprehensive analysis of MSI in medulloblastomas to date. We observed the presence of MSI together with mutations of MSI target genes in a small fraction of cases, suggesting a new genetic pathway for a role in medulloblastoma development.
Fulminant hepatitis after grand mal seizures: Mechanisms and role of liver transplantation
Authors: Philippe Ichai, Emmanuel Huguet, Catherine Guettier, Daniel Azoulay, Maria Eugenia Gonzalez, Bernard Fromenty, Pascal Masnou, Faouzi Saliba, Bruno Roche, Fahed Zeitoun, Denis Castaing, Didier Samuel
Journal: Hepatology (2003)

Fulminant liver failure is a rare complication of grand mal seizures with a high mortality, the prognosis being largely determined by the combination of the hepatic and neurologic insults. The mechanisms of acute liver failure secondary to grand mal epilepsy and the place of liver transplantation in this context are poorly defined and are the subject of this report. A series of 6 such patients is presented. All had a history of chronic primary or post-traumatic epilepsy and presented with acute liver failure shortly after a grand mal fit. Detailed accounts of background, presentation, and management are given and integrated with blood, radiologic, and histologic investigations. Two of the 6 patients survived, 1 making a full recovery and the other with neurologic sequelae. Two patients underwent liver transplantation but died with severe neurologic sequelae despite improving liver function. The remaining 2 patients were considered too ill to undergo liver transplantation and died in multiple organ failure. Liver histology from needle biopsy and/or native liver explants identified lesions compatible with a combination of steatosis and necrosis. Factor V and transaminase levels may allow early identification of patients in whom liver function is likely to improve spontaneously. In conclusion, the mechanisms of liver failure occurring after grand mal seizures appear multifactorial, including hypoxia, steatosis, and drug-induced components. The neurological prognosis and overall survival of these patients remains poor.
Value of Urinary Albumin-to-Creatinine Ratio as a Predictor of Type 2 Diabetes in Pre-Diabetic Individuals
Authors: Allon Friedman, David Marrero, Yong Ma, Ronald Ackermann, K.M. Venkat Narayan, Elizabeth Barrett-Connor, Karol Watson, William C. Knowler, Edward S. Horton
Journal: Diabetes Care (2008)

OBJECTIVE—The albumin-to-creatinine ratio (ACR) reflects urinary albumin excretion and is increasingly being accepted as an important clinical outcome predictor. Because of the great public health need for a simple and inexpensive test to identify individuals at high risk for developing type 2 diabetes, it has been suggested that the ACR might serve this purpose. We therefore determined whether the ACR could predict incident diabetes in a well-characterized cohort of pre-diabetic Americans. RESEARCH DESIGN AND METHODS—A total of 3,188 Diabetes Prevention Program (DPP) participants with a mean BMI of 34 kg/m2 and elevated fasting glucose, impaired glucose tolerance, and baseline urinary albumin excretion measurements were followed for incident diabetes over a mean of 3.2 years. RESULTS—Of the participants, 94% manifested ACR levels below the microalbuminuria range and 21% ultimately developed diabetes during follow-up. Quartiles of ACR (median [range] within quartiles: 1, 3.0 [0.7–3.7]; 2, 4.6 [3.7–5.5]; 3, 7.1 [5.5–9.7]; and 4, 16.5 [9.7–1,578]) were positively associated with age, markers of adiposity and insulin secretion and resistance, blood pressure, and use of antihypertensive agents with antiproteinuric effects and inversely related to male sex and serum creatinine. An elevated hazard rate for developing diabetes with doubling of ACR disappeared after adjustment for covariates. Within the DPP intervention groups (placebo, lifestyle, and metformin), we found no consistent trend in incident diabetes by quartile or decile of ACR. CONCLUSIONS—An ACR at levels below the microalbuminuria range does not independently predict incident diabetes in adults at high risk of developing type 2 diabetes.
Testing the Role of Genetic Background in Parallel Evolution Using the Comparative Experimental Evolution of Antibiotic Resistance
Authors: Tom Vogwill, Mila Kojadinovic, Victoria Furió, R. Craig MacLean
Journal: Molecular Biology and Evolution (2014)

Parallel evolution is the independent evolution of the same phenotype or genotype in response to the same selection pressure. There are examples of parallel molecular evolution across divergent genetic backgrounds, suggesting that genetic background may not play an important role in determining the outcome of adaptation. Here, we measure the influence of genetic background on phenotypic and molecular adaptation by combining experimental evolution with comparative analysis. We selected for resistance to the antibiotic rifampicin in eight strains of bacteria from the genus Pseudomonas using a short term selection experiment. Adaptation occurred by 47 mutations at conserved sites in rpoB, the target of rifampicin, and due to the high diversity of possible mutations the probability of within-strain parallel evolution was low. The probability of between-strain parallel evolution was only marginally lower, because different strains substituted similar rpoB mutations. In contrast, we found that more than 30% of the phenotypic variation in the growth rate of evolved clones was attributable to among-strain differences. Parallel molecular evolution across strains resulted in divergent phenotypic evolution because rpoB mutations had different effects on growth rate in different strains. This study shows that genetic divergence between strains constrains parallel phenotypic evolution, but had little detectable impact on the molecular basis of adaptation in this system.
Studies of Ribose Metabolism. I. The Pathway of Nucleic Acid Ribose Synthesis in a Human Carcinoma Cell in Tissue Culture1
Authors: Howard H. Hiatt
Journal: Journal of Clinical Investigation (1957)

An impressive body of evidence is available demonstrating the importance of the pentose phosphate pathway (hexose mnonophosphate shunt) in the intermediary metabolism of carbohydrate (1). The pathway is involved in a number of vital biological processes, including photosynthesis (2), carbohydrate utilization by many bacteria (3), the elaboration of the ribose moiety of nucleic acids in the chick (4), in certain microorganisms (5-8), and in the rat (9, 10), the synthesis of the precursor of aromatic amino acids (11 ), and the generation of reduced triphosphopyridine nucleotides, which are required for the synthesis of several substances including fatty acids and cholesterol (12). In addition, it is the route by which a substantial fraction of glucose is catabolized by rat liver slices (13). Recent work has demonstrated its role in the in vivo conversion of ribose and xylose carbon to mouse liver glycogen (14). The present investigation was undertaken to study the mechanism of nucleic acid ribose synthesis by a human carcinoma cell (strain HeLa) grown in tissue culture. The results are consistent with ribose production via both the oxidative and nonoxidative steps of the pentose phosphate pathway, with the nonoxidative route predominating.
Exercise in cardiac rehabilitation
Authors: H J Bethell
Journal: British Journal of Sports Medicine (1999)

Introduction The notion that exercise is dangerous for patients with heart disease dogged the use of such treatment for the first half of the twentieth century. It was a further 30 years before exercise became accepted in rehabilitation. The controversy is made more diYcult by the fact that exercise may be dangerous for some patients in some circumstances. Exercise is now widely believed to benefit a wide variety of patients with heart disease. However, when it is used to treat cardiac patients, exercise should be approached like any other treatment and thought given to the indications, the contraindications, the mode of action, the type, the dose, the duration of treatment, the expected benefits, and the side eVects.
Studies on the Pathogenesis of Hypertensive Vascular Disease
Authors: GARY S. HILL
Journal: Circulation Research (1970)

Repeated high-pressure injection of saline into the arterial system via carotid cannula in normal, ether-anesthetized rats has been previously shown to produce acute necrotizing lesions in the renal vasculature. In this study administration of the vasodilator aminophylline prior to high-pressure injections led to similar lesions, produced in dilated, hyperdistended vessels, at far lower pressures than in control animals, demonstrating that neither vasoconstriction nor the absolute height of blood pressure is a critical determinant in production of lesions. In the second part of the study previous treatment with desoxycorticosterone (DOCA)-saline for 12 to 18 days rendered the renal vasculature abnormally prone to lesions after high-pressure injections, compared with normal rats so injected or those receiving a DOCA-saline regimen only. Glomerular lesions were more severe than can be explained on the basis of simple addition of the lesions resulting from high-pressure injections to those arising from DOCA administration. This increased susceptibility of the vasculature to elevated pressure is probably a function of focal alteration of vascular smooth muscle. These observations support the proposal that hypertensive vascular lesions occur in dilated, hyperdistended vessels and the glomeruli distal to them, the dilatation probably resulting from focal smooth muscle alteration with partial or complete loss of contractility.
Arsenic trioxide induces apoptosis in human T-cell leukemia virus type 1– and type 2–infected cells by a caspase-3–dependent mechanism involving Bcl-2 cleavage
Authors: Renaud Mahieux, Cynthia Pise-Masison, Antoine Gessain, John. N. Brady, René Olivier, Emmanuelle Perret, Tom Misteli, Christophe Nicot
Journal: Blood (2001)
Macronutrients, Food Groups, and Eating Patterns in the Management of Diabetes
Authors: Madelyn L. Wheeler, Stephanie A. Dunbar, Lindsay M. Jaacks, Wahida Karmally, Elizabeth J. Mayer-Davis, Judith Wylie-Rosett, William S. Yancy
Journal: Diabetes Care (2012)

The effectiveness of medical nutrition therapy (MNT) in the management of diabetes has been well established (1). Previous reviews have provided comprehensive recommendations for MNT in the management of diabetes (2,3). The goals of MNT are to 1 ) attain and maintain optimal blood glucose levels, a lipid and lipoprotein profile that reduces the risk of macrovascular disease, and blood pressure levels that reduce the risk for vascular disease; 2 ) prevent and treat the chronic complications of diabetes by modifying nutrient intake and lifestyle; 3 ) address individual nutrition needs, taking into account personal and cultural preferences and willingness to change; and 4 ) maintain the pleasure of eating by only limiting food choices when indicated by scientific evidence (4).

The literature on nutrition as it relates to diabetes management is vast. We undertook the specific topic of the role of macronutrients, eating patterns, and individual foods in response to continued controversy over independent contributions of specific foods and macronutrients, independent of weight loss, in the management of diabetes. The position of the American Diabetes Association (ADA) on MNT is that each person with diabetes should receive an individualized eating plan (4). ADA has received numerous criticisms because it does not recommend one specific mix of macronutrients for everyone with diabetes. The previous literature review conducted by ADA in 2001 supported the idea that there was not one ideal macronutrient distribution for all people with diabetes. This review focuses on literature that has been published since that 2001 date (5). This systematic review will be one source of information considered when updating the current ADA Nutrition Position Statement (4). Other systematic reviews and key research studies that may not be included in this review will also be considered.

When attempting to tease out the role of macronutrients from other dietary …
Altered PTEN Expression as a Diagnostic Marker for the Earliest Endometrial Precancers
Authors: G. L. Mutter
Journal: JNCI Journal of the National Cancer Institute (2000)

Background: PTEN tumor suppressor gene mutations are the most frequent genetic lesions in endometrial adenocarcinomas of the endometrioid subtype. Testing the hypothesis that altered PTEN function precedes the appearance of endometrial adenocarcinoma has been difficult, however, partly because of uncertainties in precancer diagnosis. Methods: Two series of endometrial cancer and precancer (endometrial intraepithelial neoplasia, as diagnosed by computerized morphometric analysis) tissue samples were studied, one for PTEN mutations by the use of denaturing gradient gel electrophoresis and another for PTEN protein expression by immunohistochemistry. Endometria altered by high estrogen levels that are unopposed by progestins—conditions known to increase cancer risk—were also studied by immunohistochemistry. Fisher's exact test was used for statistical analysis. Results: The PTEN mutation rate was 83% (25 of 30) in endometrioid endometrial adenocarcinomas and 55% (16 of 29) in precancers, and the difference in number of mutations was statistically significant (two-sided P = .025). No normal endometria showed PTEN mutations. Although most precancers and cancers had a mutation in only one PTEN allele, endometrioid endometrial adenocarcinomas showed complete loss of PTEN protein expression in 61% (20 of 33) of cases, and 97% (32 of 33) showed at least some diminution in expression. Cancers and most precancers exhibited contiguous groups of PTEN-negative glands, while endometria altered by unopposed estrogens showed isolated PTEN-negative glands. Conclusions: Loss of PTEN function by mutational or other mechanisms is an early event in endometrial tumorigenesis that may occur in response to known endocrine risk factors and offers an informative immunohistochemical biomarker for premalignant disease. Individual PTEN-negative glands in estrogen-exposed endometria are the earliest recognizable stage of endometrial carcinogenesis. Proliferation into dense clusters that form discrete premalignant lesions follows.
Pulmonary manifestation of X-linked agammaglobulinemia
Authors: Malgorzata Pac, Hanna Dmenska, Ewa Bernatowska
Journal: European Respiratory Journal (2014)

Primary immune deficiencies [PID] comprise a heterogeneous group of genetically determined disorders that affect development and/or function of innate or adaptive immunity. Pts with PID suffer from recurrent and/or severe infections that frequently involve the lung. PID is identified as the underlying cause of bronchiectasis. XLA is PID caused by Bruton9s tyrosine kinase gene mutation. XLA is characterized by virtual absence of all immunoglobulin isotypes and of circulating B lymphocytes.   Materials and methods:  The group under study comprises 33 boys meeting definitive criteria for diagnosis of XLA [with Btk sequence analysis]. The retrospective analysis of personal, laboratory and clinical data was carried out.  Results:  First symptoms of XLA occurred at mean age of 1.3 yrs (range 0.2 - 7 yrs). Clinical diagnosis was established at 3.9 yrs (range 0.11-12 yrs). All immunoglobulin classes were below 2 SD. All pts presented normal number of CD3+, CD4+, CD8+ cells. Total number of B cells was decreased (range 0 - 391 cells/μL, mean 0.65). Replacement immunoglobulin therapy was induced at mean age 3.5 yrs (range 0.11 -12 yrs). The most common complications were the lower respiratory tract infections: 71% pts suffered from bronchitis, 51% pneumonia, 30% bronchiectasis (10 pts). Pts with bronchiectasis developed first symptoms at mean age 1.8 yrs (0.6 - 4.7 yrs). Clinical diagnosis was established at 3.9 yrs (2.0 - 5.4 yrs), replacement immunoglobulin therapy was induced at 5.3 yrs (2.3 - 15.7 yrs). 3 pts presented lung cirrhosis.   Conclusions:  Searching for an underlying immune defect in pts with chronic lung disease is very important.  Delayed or suboptimal replacement therapy may result in chronic pulmonary disease or bronchiectasis.