tbuckley/cabot-search huggingface dataset:
Mechanisms of increased epithelial lung clearance of DTPA in diffuse fibrosing alveolitis
Authors: S Labrune, T Chinet, MA Collignon, L Barritault, GJ Huchon
Journal: European Respiratory Journal (1994)

The aim of this study was to elucidate possible mechanisms of increased epithelial lung clearance in diffuse fibrosing alveolitis (DFA). We investigated the relationships between epithelial lung clearance as assessed by the clearance of aerosolized 99mTc-diethylene-triamine-penta-acetic acid (RC-DTPA), luminal alveolitis as assessed by bronchoalveolar lavage, and pulmonary function, in 30 nonsmokers with DFA. In 14 of these patients, RC-DTPA and lung function were determined before and during therapy with prednisolone (0.5 mg.kg-1 daily). RC-DTPA was higher in patients with DFA (4.45 +/- 2.50%.min-1) than in normal subjects (1.18 +/- 0.31%.min-1). RC-DTPA did not correlate with the number of alveolar neutrophils, but correlated positively with the number of alveolar lymphocytes, and negatively with vital capacity (VC). RC-DTPA decreased from 6.1 +/- 2.8 to 3.8 +/- 1.9%.min-1 with prednisolone. RC-DTPA before prednisolone correlated positively with the prednisolone-associated improvement in VC. We conclude that in patient with DFA, RC-DTPA is increased, and decreases but does not return to normal with corticosteroid therapy. Our data suggest that in DFA the increase in RC-DTPA could be related to the recoil-induced stretch of the respiratory epithelium and to alveolar lymphocytic inflammation.
A Genome-Scale Vector Resource Enables High-Throughput Reverse Genetic Screening in a Malaria Parasite
Authors: Ana Rita Gomes, Ellen Bushell, Frank Schwach, Gareth Girling, Burcu Anar, Michael A. Quail, Colin Herd, Claudia Pfander, Katarzyna Modrzynska, Julian C. Rayner, Oliver Billker
Journal: Cell Host & Microbe (2015)

The genome-wide identification of gene functions in malaria parasites is hampered by a lack of reverse genetic screening methods. We present a large-scale resource of barcoded vectors with long homology arms for effective modification of the Plasmodium berghei genome. Cotransfecting dozens of vectors into the haploid blood stages creates complex pools of barcoded mutants, whose competitive fitness can be measured during infection of a single mouse using barcode sequencing (barseq). To validate the utility of this resource, we rescreen the P. berghei kinome, using published kinome screens for comparison. We find that several protein kinases function redundantly in asexual blood stages and confirm the targetability of kinases cdpk1, gsk3, tkl3, and PBANKA_082960 by genotyping cloned mutants. Thus, parallel phenotyping of barcoded mutants unlocks the power of reverse genetic screening for a malaria parasite and will enable the systematic identification of genes essential for in vivo parasite growth and transmission.
B Lymphocytes Differentially Use the Rel and Nuclear Factor κB1 (NF-κB1) Transcription Factors to Regulate Cell Cycle Progression and Apoptosis in Quiescent and Mitogen-activated Cells
Authors: Raelene J. Grumont, Ian J. Rourke, Lorraine A. O'Reilly, Andreas Strasser, Kensuke Miyake, William Sha, Steve Gerondakis
Journal: The Journal of Experimental Medicine (1998)

Rel and nuclear factor (NF)-kappaB1, two members of the Rel/NF-kappaB transcription factor family, are essential for mitogen-induced B cell proliferation. Using mice with inactivated Rel or NF-kappaB1 genes, we show that these transcription factors differentially regulate cell cycle progression and apoptosis in B lymphocytes. Consistent with an increased rate of mature B cell turnover in naive nfkb1-/- mice, the level of apoptosis in cultures of quiescent nfkb1-/-, but not c-rel-/-, B cells is higher. The failure of c-rel-/- or nfkb1-/- B cells to proliferate in response to particular mitogens coincides with a cell cycle block early in G1 and elevated cell death. Expression of a bcl-2 transgene prevents apoptosis in resting and activated c-rel-/- and nfkb1-/- B cells, but does not overcome the block in cell cycle progression, suggesting that the impaired proliferation is not simply a consequence of apoptosis and that Rel/NF-kappaB proteins regulate cell survival and cell cycle control through independent mechanisms. In contrast to certain B lymphoma cell lines in which mitogen-induced cell death can result from Rel/NF-kappaB-dependent downregulation of c-myc, expression of c-myc is normal in resting and stimulated c-rel-/- B cells, indicating that target gene(s) regulated by Rel that are important for preventing apoptosis may differ in normal and immortalized B cells. Collectively, these results are the first to demonstrate that in normal B cells, NF-kappaB1 regulates survival of cells in G0, whereas mitogenic activation induced by distinct stimuli requires different Rel/NF-kappaB factors to control cell cycle progression and prevent apoptosis.
The changing role of mechanical ventilation in COPD
Authors: JM Shneerson
Journal: European Respiratory Journal (1996)

<b>Objective:</b> To determine practice and attitudes of emergency physicians regarding procedural anaesthesia for nasogastric tube insertion (NGT). <b>Methods:</b> Survey of resident/attending emergency physicians working in a tertiary care medical centre. <b>Results:</b> Of 68 physicians, 46 responded: 98% believed that awake and alert patients find NGT insertion uncomfortable/painful; 93% used measures to reduce this, most commonly lubricant gel, topical anaesthetic spray, lidocaine gel, and distraction/use of a child life worker; 28% believed these provided adequate pain control and 37% believed they were inadequate. Topical anaesthetic spray, lidocaine gel, and nebulised/atomised anaesthetics were believed the most practical to administer and 44% actually used these. Nebulised/atomised anaesthetics, systemic anxiolytics, and topical anaesthetic spray were believed the most effective at pain control but only 24% actually used these. While 39% of respondents were satisfied with their current practice, 46% were dissatisfied: 91% would change their practice if new literature were to show a convenient way to effectively reduce this pain. <b>Conclusions:</b> Emergency physicians do not actually use the measures they believe are most practical/most effective at reducing the pain associated with NGT insertion. Thus, there may be a barrier to the use of these measures. Improvement in procedural anaesthesia for NGT insertion in emergency departments is needed and desired by emergency physicians.
Recent updates on the role of microRNAs in prostate cancer
Authors: Oudai Hassan, Aamir Ahmad, Seema Sethi, Fazlul H Sarkar
Journal: Journal of Hematology & Oncology (2012)

Abstract MicroRNAs (miRNAs) are short non-coding RNAs that are involved in several important biological processes through regulation of genes post-transcriptionally. Carcinogenesis is one of the key biological processes where miRNAs play important role in the regulation of genes. The miRNAs elicit their effects by binding to the 3' untranslated region (3'UTR) of their target mRNAs, leading to the inhibition of translation or the degradation of the mRNA, depending on the degree of complementary base pairing. To-date more than 1,000 miRNAs are postulated to exist, although the field is moving rapidly. Currently, miRNAs are becoming the center of interest in a number of research areas, particularly in oncology, as documented by exponential growth in publications in the last decade. These studies have shown that miRNAs are deregulated in a wide variety of human cancers. Thus, it is reasonable to ask the question whether further understanding on the role of miRNAs could be useful for diagnosis, prognosis and predicting therapeutic response for prostate cancer (PCa). Therefore, in this review article, we will discuss the potential roles of different miRNAs in PCa in order to provide up-to-date information, which is expected to stimulate further research in the field for realizing the benefit of miRNA-targeted therapeutic approach for the treatment of metastatic castrate resistant prostate cancer (mCRPC) in the near future because there is no curative treatment for mCRPC at the moment.
Prevention of Accelerated Atherosclerosis by Angiotensin-Converting Enzyme Inhibition in Diabetic Apolipoprotein E–Deficient Mice
Authors: Riccardo Candido, Karin A. Jandeleit-Dahm, Zemin Cao, Stefan P. Nesteroff, Wendy C. Burns, Stephen M. Twigg, Rodney J. Dilley, Mark E. Cooper, Terri J. Allen
Journal: Circulation (2002)

Background — Atherosclerosis is a major complication of diabetes, but the mechanisms by which diabetes promotes macrovascular disease have not been fully delineated. Although several animal studies have demonstrated that inhibition of ACE results in a decrease in the development of atherosclerotic lesions, information about the potential benefits of these agents on complex and advanced atherosclerotic lesions as observed in long-term diabetes is lacking. The aim of this study was to evaluate whether treatment with the ACE inhibitor perindopril affects diabetes-induced plaque formation in the apolipoprotein E (apoE)-deficient mouse. Methods and Results — Diabetes was induced by injection of streptozotocin in 6-week-old apoE-deficient mice. Diabetic animals received treatment with perindopril (4 mg · kg −1 · d −1 ) or no treatment for 20 weeks. Nondiabetic apoE-deficient mice were used as controls. Induction of diabetes was associated with a 4-fold increase in plaque area compared with nondiabetic animals. This accelerated atherosclerosis was associated with a significant increase in aortic ACE expression and activity and connective tissue growth factor and vascular cell adhesion molecule-1 expression. Perindopril treatment inhibited the development of atherosclerotic lesions and diabetes-induced ACE, connective tissue growth factor, and vascular cell adhesion molecule-1 overexpression in the aorta. Conclusions — The activation of the local renin-angiotensin system in the diabetic aorta and the reduction in atherosclerosis with ACE inhibitor treatment provides further evidence that the renin-angiotensin system plays a pivotal role in the development and acceleration of atherosclerosis in diabetes.
Lipoprotein profile in men with peripheral vascular disease. Role of intermediate density lipoproteins and apoprotein E phenotypes.
Authors: M Sentí, X Nogués, J Pedro-Botet, J Rubiés-Prat, F Vidal-Barraquer
Journal: Circulation (1992)

The role of lipoprotein disturbances in the development of peripheral vascular disease (PVD) has not been sufficiently clarified.The relations among concentrations of intermediate density lipoproteins (IDL), apoprotein (apo) B, apo E, and other lipoproteins were studied in 102 men with PVD and 100 healthy men who formed the control group. Patients with PVD had significantly higher levels of serum triglycerides, very low density lipoprotein (VLDL) cholesterol, VLDL triglycerides, VLDL proteins, IDL cholesterol, and IDL triglycerides and lower levels of high density lipoproteins (HDL) than controls. Serum cholesterol and triglycerides were normal in 30 patients (cholesterol, less than 5.2 mmol/l; triglycerides, less than 2.3 mmol/l), who had significant increases in IDL triglycerides and significant decreases in HDL cholesterol compared with the 47 controls, who had normal cholesterol and triglyceride levels. Patients with more severe distal involvement showed higher cholesterol and triglycerides carried by IDL and a greater reduction in HDL cholesterol. Smoking patients with PVD showed increased VLDL cholesterol and VLDL triglycerides and lower HDL concentrations. Apo E polymorphism in our study population does not differ from that reported for other European populations. Alleles epsilon 2 and epsilon 4 had a major impact on serum triglycerides and VLDL lipids in our patients with PVD.Lipoprotein disturbances are a major risk factor for PVD. IDL abnormalities play an important role in the development and severity of PVD and should also be considered a vascular risk factor in normocholesterolemic and normotriglyceridemic patients.
Electron microscopic investigation of endomyocardial biopsy samples in hypertrophy and cardiomyopathy. A semiquantitative study in 48 patients.
Authors: U Baandrup, R A Florio, F Roters, E G Olsen
Journal: Circulation (1981)

Electron microscopic and statistical analyses of 66 right ventricular biopsies from 48 patients were undertaken to investigate whether quantitative differences exist between those patients with "ordinary" myocardial hypertrophy and those suffering from a form of cardiomyopathy. The electron microscopic changes were scored and correlated with hemodynamic variables such as ejection fraction (EF), left ventricular end-diastolic pressure (LVEDP) and length of history. The patients were followed for an average of 22.5 months, permitting an assessment of prognosis. The results show that the three diagnostic groups--"ordinary" hypertrophy, hypertrophic cardiomyopathy (HOCM) and congestive cardiomyopathy (COCM)--overlap, but crossover of sarcomeres is more frequent in patients in whom HOCM is diagnosed. Except for a tenuous relationship between EF, and the electron microscopy (EM) (r = -0.46, p less than 0.1) and between LVEDP and EM score (r = 0.61, p less than 0.01), in the COCM group, no correlation could be established between EF, LVEDP and length of history when the patients were grouped according to histologic or clinical diagnosis. This study shows that the various claims regarding relationships between morphologic changes and the functional status of patients or prognosis cannot be confirmed.
Detection of Silent Myocardial Ischemia in Asymptomatic Diabetic Subjects
Authors: Frans J.Th. Wackers, Lawrence H. Young, Silvio E. Inzucchi, Deborah A. Chyun, Janice A. Davey, Eugene J. Barrett, Raymond Taillefer, Steven D. Wittlin, Gary V. Heller, Neil Filipchuk, Samuel Engel, Robert E. Ratner, Ami E. Iskandrian
Journal: Diabetes Care (2004)

OBJECTIVE—To assess the prevalence and clinical predictors of silent myocardial ischemia in asymptomatic patients with type 2 diabetes and to test the effectiveness of current American Diabetes Association screening guidelines. RESEARCH DESIGN AND METHODS—In the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study, 1,123 patients with type 2 diabetes, aged 50–75 years, with no known or suspected coronary artery disease, were randomly assigned to either stress testing and 5-year clinical follow-up or to follow-up only. The prevalence of ischemia in 522 patients randomized to stress testing was assessed by adenosine technetium-99m sestamibi single-photon emission–computed tomography myocardial perfusion imaging. RESULTS—A total of 113 patients (22%) had silent ischemia, including 83 with regional myocardial perfusion abnormalities and 30 with normal perfusion but other abnormalities (i.e., adenosine-induced ST-segment depression, ventricular dilation, or rest ventricular dysfunction). Moderate or large perfusion defects were present in 33 patients. The strongest predictors for abnormal tests were abnormal Valsalva (odds ratio [OR] 5.6), male sex (2.5), and diabetes duration (5.2). Other traditional cardiac risk factors or inflammatory and prothrombotic markers were not predictive. Ischemic adenosine-induced ST-segment depression with normal perfusion (n = 21) was associated with women (OR 3.4). Selecting only patients who met American Diabetes Association guidelines would have failed to identify 41% of patients with silent ischemia. CONCLUSIONS—Silent myocardial ischemia occurs in greater than one in five asymptomatic patients with type 2 diabetes. Traditional and emerging cardiac risk factors were not associated with abnormal stress tests, although cardiac autonomic dysfunction was a strong predictor of ischemia.
HER2-Specific T Cells Target Primary Glioblastoma Stem Cells and Induce Regression of Autologous Experimental Tumors
Authors: Nabil Ahmed, Vita S. Salsman, Yvonne Kew, Donald Shaffer, Suzanne Powell, Yi J. Zhang, Robert G. Grossman, Helen E. Heslop, Stephen Gottschalk
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Glioblastoma multiforme (GBM) is the most aggressive human primary brain tumor and is currently incurable. Immunotherapies have the potential to target GBM stem cells, which are resistant to conventional therapies. Human epidermal growth factor receptor 2 (HER2) is a validated immunotherapy target, and we determined if HER2-specific T cells can be generated from GBM patients that will target autologous HER2-positive GBMs and their CD133-positive stem cell compartment. Experimental Design: HER2-specific T cells from 10 consecutive GBM patients were generated by transduction with a retroviral vector encoding a HER2-specific chimeric antigen receptor. The effector function of HER2-specific T cells against autologous GBM cells, including CD133-positive stem cells, was evaluated in vitro and in an orthotopic murine xenograft model. Results: Stimulation of HER2-specific T cells with HER2-positive autologous GBM cells resulted in T-cell proliferation and secretion of IFN-γ and interleukin-2 in a HER2-dependent manner. Patients' HER2-specific T cells killed CD133-positive and CD133-negative cells derived from primary HER2-positive GBMs, whereas HER2-negative tumor cells were not killed. Injection of HER2-specific T cells induced sustained regression of autologous GBM xenografts established in the brain of severe combined immunodeficient mice. Conclusions: Gene transfer allows the reliable generation of HER2-specific T cells from GBM patients, which have potent antitumor activity against autologous HER2-positive tumors including their putative stem cells. Hence, the adoptive transfer of HER2-redirected T cells may be a promising immunotherapeutic approach for GBM. Clin Cancer Res; 16(2); 474–85
Smoking in the home after the smoke-free legislation in Scotland: qualitative study
Authors: Richard Phillips, Amanda Amos, Deborah Ritchie, Sarah Cunningham-Burley, Claudia Martin
Journal: BMJ (2007)

<b>Objective</b> To explore the accounts of smokers and non-smokers (who live with smokers) of smoking in their homes and cars after the Scottish smoke-free legislation; to examine the reported impact of the legislation on smoking in the home; and to consider the implications for future initiatives aimed at reducing children9s exposure to secondhand smoke in the home. <b>Design and setting</b> A qualitative cross sectional study involving semistructured interviews conducted across Scotland shortly after the implementation of the legislation on 26 March 2006. <b>Participants</b> A purposively selected sample of 50 adults (aged 18-75) drawn from all socioeconomic groups, included smokers living with smokers, smokers living with non-smokers, and non-smokers living with smokers. <b>Results</b> Passive smoking was a well recognised term. Respondents had varied understandings of the risks of secondhand smoke, with a few rejecting evidence of such risks. Children, however, were perceived as vulnerable. Most reported that they restricted smoking in their homes, with a range of restrictions across social classes and home smoking profiles. Spatial, relational, health, and aesthetic factors influenced the development of restrictions. Children and grandchildren were important considerations in the development and modification of restrictions. Other strategies were also used to militate against secondhand smoke, such as opening windows. The meaning of the home as somewhere private and social identity were important underlying factors. Respondents reported greater restrictions on smoking in their cars. There were diverse views on the smoke-free legislation. Few thought it had influenced their smoking in the home, and none thought it had affected how they restricted smoking in their homes. <b>Conclusions</b> These data suggest two normative discourses around smoking in the home. The first relates to acceptable social identity as a hospitable person who is not anti-smoker. The second relates to moral identity as a caring parent or grandparent. Awareness of the risks of secondhand smoke, despite ambivalence about health messages and the fluidity of smoking restrictions, provides clear opportunities for public health initiatives to support people attain smoke-free homes.
Boom in the development of non‐peptidic β‐secretase (BACE1) inhibitors for the treatment of Alzheimer's disease
Authors: Romano Silvestri
Journal: Medicinal Research Reviews (2008)

Abstract β‐Amyloid cleaving enzyme‐1 (BACE1) has become a significant target for the therapy of Alzheimer's disease. After the discovery of the first non‐peptidomimetic β‐secretase inhibitors by Takeda Chemicals in 2001, several research teams focused on SAR development of these agents. The non‐peptidic BACE1 inhibitors may potentially overcome the classical problems associated with the peptide structure of first generation, such as blood–brain barrier crossing, poor oral bioavailability and susceptibility to P‐glycoprotein transport. In the past 6 years a boom in research of non‐peptidic BACE1 inhibitors has disseminated findings over hundreds of publications and patents. The rapidly growing literature has been reviewed with particular emphasis on literature of pharmaceutical companies. © 2008 Wiley Periodicals, Inc. Med Res Rev, 29, No. 2, 295–338, 2009
Sexual transmission of hepatitis C virus among monogamous heterosexual couples: The HCV partners study
Authors: Norah A. Terrault, Jennifer L. Dodge, Edward L. Murphy, John E. Tavis, Alexi Kiss, T. R. Levin, Robert G. Gish, Michael P. Busch, Arthur L. Reingold, Miriam J. Alter
Journal: Hepatology (2012)

The efficiency of hepatitis C virus (HCV) transmission by sexual activity remains controversial. We conducted a cross-sectional study of HCV-positive subjects and their partners to estimate the risk for HCV infection among monogamous heterosexual couples. A total of 500 anti-HCV-positive, human immunodeficiency virus-negative index subjects and their long-term heterosexual partners were studied. Couples were interviewed separately for lifetime risk factors for HCV infection, within-couple sexual practices, and sharing of personal grooming items. Blood samples were tested for anti-HCV, HCV RNA, and HCV genotype and serotype. Sequencing and phylogenetic analysis determined the relatedness of virus isolates among genotype-concordant couples. The majority of HCV-positive index subjects were non-Hispanic white, with a median age of 49 years (range, 26-79 years) and median of 15 years (range, 2-52 years) of sexual activity with their partners. Overall, HCV prevalence among partners was 4% (n=20), and nine couples had concordant genotype/serotype. Viral isolates in three couples (0.6%) were highly related, consistent with transmission of virus within the couple. Based on 8,377 person-years of follow-up, the maximum incidence rate of HCV transmission by sex was 0.07% per year (95% confidence interval, 0.01-0.13) or approximately one per 190,000 sexual contacts. No specific sexual practices were related to HCV positivity among couples.The results of this study provide quantifiable risk information for counseling long-term monogamous heterosexual couples in which one partner has chronic HCV infection. In addition to the extremely low estimated risk for HCV infection in sexual partners, the lack of association with specific sexual practices provides unambiguous and reassuring counseling messages.