tbuckley/cabot-search huggingface dataset:
Phosphorylation of Thr <sup>495</sup> Regulates Ca <sup>2+</sup> /Calmodulin-Dependent Endothelial Nitric Oxide Synthase Activity
Authors: Ingrid Fleming, Beate Fisslthaler, Stefanie Dimmeler, Bruce E. Kemp, Rudi Busse
Journal: Circulation Research (2001)

Abstract —The activity of the endothelial nitric oxide synthase (eNOS) can be regulated independently of an increase in Ca 2+ by the phosphorylation of Ser 1177 but results only in a low nitric oxide (NO) output. In the present study, we assessed whether the agonist-induced (Ca 2+ -dependent, high-output) activation of eNOS is associated with changes in the phosphorylation of Thr 495 in the calmodulin (CaM)-binding domain. eNOS Thr 495 was constitutively phosphorylated in porcine aortic endothelial cells and was rapidly dephosphorylated after bradykinin stimulation. In the same cells, bradykinin enhanced the phosphorylation of Ser 1177 , which was maximal after 5 minutes, and abolished by the CaM-dependent kinase II (CaMKII) inhibitor KN-93. Bradykinin also enhanced the association of CaMKII with eNOS. Phosphorylation of Thr 495 was attenuated by the protein kinase C (PKC) inhibitor Ro 31-8220 and after PKC downregulation using phorbol 12-myristate 13-acetate. The agonist-induced dephosphorylation of Thr 495 was completely Ca 2+ -dependent and inhibited by the PP1 inhibitor calyculin A. Little CaM was bound to eNOS immunoprecipitated from unstimulated cells, but the agonist-induced dephosphorylation of Thr 495 enhanced the association of CaM. Mutation of Thr 495 to alanine increased CaM binding to eNOS in the absence of cell stimulation, whereas the corresponding Asp 495 mutant bound almost no CaM. Accordingly, NO production by the Ala 495 mutant was more sensitive to Ca 2+ /CaM than the aspartate mutant. These results suggest that the dual phosphorylation of Ser 1177 and Thr 495 determines the activity of eNOS in agonist-stimulated endothelial cells. Moreover, the dephosphorylation of Thr 495 by PP1 precedes the phosphorylation of Ser 1177 by CaMKII. The full text of this article is available at http://www.circresaha.org.
Endogenous cardioprotection by ischaemic postconditioning and remote conditioning
Authors: W. Shi, J. Vinten-Johansen
Journal: Cardiovascular Research (2012)

Persistent myocardial ischaemia causes cell death if not rescued by early reperfusion. Millions of years in nature's laboratory have evolved protective responses that 'condition' the heart (and other tissues) to adapt to stressors, and these responses are applicable to the relatively new societal stress of myocardial ischaemia and reperfusion injury. Conditioning can be applied before (preconditioning), during (perconditioning), or after (postconditioning) the ischaemic stressor by imposing short periods of non-lethal ischaemia separated by brief periods of reperfusion. This conditioning protects multiple cell types and induces or rebalances a number of physiological and molecular pathways that ultimately attenuate necrosis and apoptosis. The seemingly disparate pathways may converge directly or indirectly on the mitochondria as a final effector, but other pathways not affecting mitochondria broaden the mechanisms of cardioprotection. The potential downsides of imposing even brief ischaemia directly on the heart somewhat tempered the enthusiasm for applying conditioning stimuli to the heart, but this hurdle was surmounted by applying ischaemia to remote organs and tissues in pre-, per-, and postconditioning. Although the clinical translation of remote per- and postconditioning has been rapid compared with classical preconditioning, there are numerous basic questions that require further investigation, and wider adoption awaits large-scale randomized clinical trials. Pharmacological mimetics may provide another important therapeutic approach by which to treat evolving myocardial infarction.
Body Composition Is the Main Determinant for the Difference in Type 2 Diabetes Pathophysiology Between Japanese and Caucasians
Authors: Jonas B. Møller, Maria Pedersen, Haruhiko Tanaka, Mitsuru Ohsugi, Rune V. Overgaard, Jan Lynge, Katrine Almind, Nina-Maria Vasconcelos, Pernille Poulsen, Charlotte Keller, Kohjiro Ueki, Steen H. Ingwersen, Bente K. Pedersen, Takashi Kadowaki
Journal: Diabetes Care (2013)

OBJECTIVE This cross-sectional clinical study compared the pathophysiology of type 2 diabetes in Japanese and Caucasians and investigated the role of demographic, genetic, and lifestyle-related risk factors for insulin resistance and β-cell response. RESEARCH DESIGN AND METHODS A total of 120 Japanese and 150 Caucasians were enrolled to obtain comparable distributions of high/low BMI values across glucose tolerance states (normal glucose tolerance, impaired glucose tolerance, and type 2 diabetes), which were assessed by oral glucose tolerance tests. BMI in the two cohorts was distributed around the two regional cutoff values for obesity. RESULTS Insulin sensitivity was higher in Japanese compared with Caucasians, as indicated by the homeostatic model assessment of insulin resistance and Matsuda indices, whereas β-cell response was higher in Caucasians, as measured by homeostatic model assessment of β-cell function, the insulinogenic indices, and insulin secretion ratios. Disposition indices were similar for Japanese and Caucasians at all glucose tolerance states, indicating similar β-cell response relative to the degree of insulin resistance. The main determinants for differences in metabolic indices were measures of body composition, such as BMI and distribution of adipose tissue. Differences in β-cell response between Japanese and Caucasians were not statistically significant following adjustment by differences in BMI. CONCLUSIONS Our study showed similar disposition indices in Japanese and Caucasians and that the major part of the differences in insulin sensitivity and β-cell response between Japanese and Caucasians can be explained by differences in body composition.
Sleep-disordered breathing in nonobese diabetic subjects with autonomic neuropathy
Authors: P. Bottini, M.L. Dottorini, M. Cristina Cordoni, G. Casucci, C. Tantucci
Journal: European Respiratory Journal (2003)

To assess the occurrence and nature of sleep-disordered breathing (SDB) in 26 adult, nonobese diabetics (18 with autonomic neuropathy (DAN+) (age 45 (41–50) yrs; body mass index (BMI) 24.1 (22–26) kg·m −2 ) and eight without autonomic neuropathy (DAN−) (age 45 (35–55) yrs; BMI 24.8 (23–26) kg·m −2 )) overnight full sleep studies and measurements of central and peripheral carbon dioxide (CO 2 ) chemosensitivity were performed. DAN+ were divided in two subgroups, according to the presence (DAN+PH+; n=10) or absence (DAN+PH−; n=8) of postural hypotension. Ten normal subjects were studied as controls (age 42 (36–48) yrs; BMI 24.4 (23–25) kg·m −2 ). In contrast to DAN− and controls, who did not show SDB, five DAN+ (four DAN+PH− and one DAN+PH+) had an apnoea/hypopnoea index ≥10 and four DAN+ (two DAN+PH− and two DAN+PH+) had an apnoea index ≥5. All the events were obstructive, occurring mainly during rapid eye movement (REM) sleep. Ten DAN+ exhibited a mean lowest oxygen saturation &lt;90% during REM sleep. No periodic breathing or central sleep apnoeas were found in DAN+PH+, although they had an enhanced central chemoresponsiveness to CO 2 . Both DAN+ subgroups showed a marked reduction in peripheral CO 2 chemosensitivity. In conclusion, adult nonobese diabetics with autonomic neuropathy, independent of the severity of their dysautonomy, have obstructive sleep apnoea/hypopnoea with a frequency &gt;30%. A decrease in peripheral carbon dioxide chemosensitivity prevents adult nonobese diabetics with autonomic neuropathy and postural hypotension from experiencing posthyperventilatory central sleep apnoea, despite an increased hypercapnic central drive.
A single-institution phase II trial of radiation, temozolomide, erlotinib, and bevacizumab for initial treatment of glioblastoma
Authors: J. L. Clarke, A. M. Molinaro, J. J. Phillips, N. A. Butowski, S. M. Chang, A. Perry, J. F. Costello, A. A. DeSilva, J. E. Rabbitt, M. D. Prados
Journal: Neuro-Oncology (2014)

Both the epidermal growth factor receptor and vascular endothelial growth factor pathways are frequently overexpressed in glioblastoma multiforme. This study combined bevacizumab, a vascular endothelial growth factor inhibitor, and erlotinib, an epidermal growth factor receptor inhibitor, with standard radiation and temozolomide (TMZ), with the goal of improving overall survival (OS). Treatment consisted of fractionated radiotherapy to 60 Gy, with daily TMZ at 75 mg/m2/d and erlotinib 150–200 mg/d (or 500–600 mg/d for patients on enzyme-inducing antiepileptic drugs). Bevacizumab was given at 10 mg/kg every 2 weeks, starting ≥4 weeks after surgery. After radiotherapy, adjuvant TMZ was given at 200 mg/m2/d × 5d per 28-day cycle, with unchanged erlotinib and bevacizumab doses. Treatment continued until progression or for 12 months. Efficacy was compared against an institutional historical control. A sample of 55 patients was calculated to provide 85% power to detect a hazard ratio of 0.67 for OS. Fifty-nine patients were enrolled for efficacy analysis after a 15-patient safety lead-in. For the efficacy group, median age was 54 years; median KPS was 90. Gross total and subtotal resections were achieved in 33% and 53%, respectively. The most frequent related grade 3/4 adverse effects were lymphopenia, thrombocytopenia, neutropenia, diarrhea, weight loss, and fatigue. One patient died of disseminated aspergillosis. Median OS was 19.8 months (vs 18 mo for HC, P = .33) and median progression-free survival was 13.5 months (vs 8.6 mo for HC, P = .03). The combination of bevacizumab, erlotinib, TMZ, and radiotherapy appears to be well tolerated and improved progression-free survival but did not reach the primary endpoint of improved OS.
Expression of peanut agglutinin-binding mucin-type glycoprotein in human esophageal squamous cell carcinoma as a marker.
Authors: Sankaranarayanan Kannan, Reddi A Lakku, Devaraj Niranjali, Kamala Jayakumar, Arulraj H Steven, Taralakshmi VV, Chandramohan S, Ramathilakam Balakrishnan, Christian Schmidt, Devaraj Halagowder
Journal: Molecular Cancer (2003)

The TF (Thomson – Friedenreich) blood group antigen behaves as an onco-foetal carcinoma-associated antigen, showing increased expression in malignancies and its detection and quantification can be used in serologic diagnosis mainly in adenocarcinomas. This study was undertaken to analyze the sera and tissue level detectable mucin-type glycoprotein (TF-antigen) by Peanut agglutinin (PNA) and its diagnostic index in serum as well tissues of human esophageal squamous cell carcinoma as marker. We examined 100 patients for serological analysis by Enzyme Linked Lectin Assay (ELISA) and demonstrated a sensitivity of 87.5%, specificity of 90% and a positive predictive value of 95%. The immuno-histochemical localization of TF antigen by Fluorescence Antigen Technique (FAT) in 25 specimens of normal esophageal squamous epithelium specimens and 92 specimens with different grades of, allowed a quicker and more precise identification of its increased expression and this did not correlate with gender and tumor size. There was a positive correlation between membrane bound TF antigen expression with different histological progression, from well differentiated to poorly differentiated, determined by PNA binding. Specimens showed morphological changes and a pronounced increase in PNA binding in Golgi apparatus, secretory granules of the cytosol of well differentiated and an increased cell membrane labeling in moderately and poorly differentiated, when compared with ESCC and normal tissues. The authors propose that the expression of TF-antigen in human may play an important role during tumorigenesis establishing it as a chemically well-defined carcinoma-associated antigen. Identification of the circulating TF-antigen as a reactive form and as a cryptic form in the healthy individuals, using PNA-ELLA and Immunohistochemical analysis of TF antigen by FAT is positively correlated with the different histological grades as a simple and cost-effective method for the early diagnosis of ESCC. The present study reveals that, during tumorigenesis, an aberrant glycosylation takes place in Golgi apparatus leading to over secretion of TF antigen into the cytoplasm along with mucin granules and later into cell membrane. We suggest that the further characterization of TF antigen may unravel pathogenetic aspects of this silent disease.
European Respiratory Society Guidelines on the use of nebulizers
Authors: J. Boe, J.H. Dennis, B.R. O'Driscoll, T.T. Bauer, M. Carone, B. Dautzenberg, P. Diot, K. Heslop, L. Lannefors
Journal: European Respiratory Journal (2001)

The European Respiratory Society (ERS) recognizes that there are an increasing number of national and international guidelines for the management of asthma, chronic obstructive pulmonary disease (COPD) and other chest diseases. Some of these guidelines recommend nebulizer use in specific circumstances, using either a jet nebulizer or an ultrasonic nebulizer to administer a drug to the airways or lungs in the form of an aerosolized mist of fine droplets. Although many patients with severe chest disease are given nebulized treatment both in hospitals and in their own homes, it is recognized that much of this practice may not be evidence-based. Some present practice may be ineffective or even harmful. The manufacturers of hand-held inhalers are obliged to meet exacting standards such as dose-to-dose reproducibility. However, nebulizer devices are sold separately from nebulized drugs and the dose delivered to the lung can be increased 10-fold or more by changing from an inefficient nebulizer system to a highly efficient one. For these reasons, the ERS commissioned a Task Force to review the scientific and clinical principles of nebulized therapy and to produce a set of guidelines (evidence-based whenever possible) for users of nebulized treatment in Europe.

It is hoped that the guidelines will improve clinical practice in the use of nebulized therapy throughout Europe. The most important considerations should be efficacy and patient safety. The guidelines will also serve as an educational and scientific resource for clinicians and scientists with an interest in inhaled therapy. These guidelines are aimed at a wide group of healthcare professionals practising in very different healthcare systems throughout Europe. The immediate target audience for the guidelines will be pulmonary physicians, but it is hoped that the messages will be communicated to all healthcare workers who are involved in treating patients with nebulized medication (doctors, nurses, pharmacists, paramedics, …
P78 Impact of a pharmacist-led asthma and COPD reviews in general practice: Abstract P78 Table 1.
Authors: H Khachi, P Karikari
Journal: Thorax (2013)

<h3>Introduction</h3> Asthma and COPD account for a significant burden of disease in the UK. Despite comprehensive guidelines, over a 1000 people continue to die from asthma each year and COPD accounts for a leading cause of emergency admissions in the UK. A joint initiative between a tertiary centre for respiratory disease and commissioning support unit (CSU), asthma and COPD reviews were undertaken by a specialist respiratory pharmacist in GP practices. This study assesses the impact of these reviews. <h3>Aims and Objectives</h3> This study aims to assess the impact of the specialist asthma and COPD reviews in accordance with national guidelines and standards of care. <h3>Methods</h3> The study was carried out during eight clinical sessions over a two month period, across three GP surgeries. The reviews included the following assessments: Quality of life: ACT and CAT scores Inhaler technique Assessing adherence to maintenance inhalers based on GP prescription records Assessing if patients were on the correct therapy in accordance with their diagnosis, symptoms and severity of disease Patients were identified for review based use of high dose inhaled corticosteroid and bronchodilator preparations (ICS/LABA) and/or frequency of A&amp;E and hospital admissions. <h3>Results</h3> During the eight clinical sessions, 84 patients with asthma or COPD were reviewed (42.5% male). 63% of patients had asthma (n = 53) with 37% COPD (n = 31), with a mean age 56.3 and 67.0 years respectively. Table 1 shows a significant proportion of patients had uncontrolled disease based on their quality of life scores (QoL), use of reliever inhalers and frequency of exacerbations. Despite use of high dose medicines, this was likely to be due to poor adherence to maintenance inhalers and poor inhaler technique in a large proportion of patients. Interventions were made in most patients, including reducing the beclomethasone dipropionate (BDP) equivalence in the asthma group by 60.4%. Follow up showed that despite a reduction in inhaler therapy, QoL, peak flow measurements and reliever use all improved. <h3>Conclusions</h3> Tailored reviews by the pharmacist resulted in significant interventions that improved QoL, adherenc to therapy, reduced unnecessary over prescribing of high dose medicines and resulted in a large proportion of patients to successfully stop smoking.
How policy informs the evidence
Authors: A. Kazanjian
Journal: BMJ (2001)

Editor—Davey Smith et al have identified some problems with evidence based decision making in health care.1 Nevertheless, when these are set against the deficiencies of much current (non-evidence based) decision making, evidence based decision making still compares favourably.

Administrators, facing complex allocation choices within tight budgets, are inclined to focus on economic notions of efficiency and fair play. The rationale is: “If it's not too expensive and seems to help a disadvantaged group we might be prepared to pay for it.” When people are presented with a problem (often the solution is presented first, implying that there must be a problem) they gather whatever information will confirm the merit of the intended intervention as quickly as possible. Inequalities in health are not remedied, nor the health of the population as a whole benefited, by this short term damage control.

Computed tomography is important in examining efficacy (the safety and benefits of treatments used under ideal conditions). But to be of value to policymakers, research should seek to identify evidence supporting effectiveness (whether an intervention is likely to do more good than harm in routine use). The evidence needed for sound policymaking should thus be much more comprehensive than attempts to extrapolate dubious principles from the findings of computed tomography.

Evidence based decision making is, fundamentally, the process of ensuring that the right questions are asked. Is an intervention safe and effective (will it do more good than harm)? Who needs it? Can it be provided under conditions of equal accessibility? Who is the population at risk, and what are the relevant clinical and social determinants? What change may be expected in the burden of disease? What are the social consequences (what are the implications in power and dominance issues, and what public and private interests are being served)? If decisions are based on such comprehensive evidence then the budgetary issues that follow will be much more accurately circumscribed.

Tools exist that can synthesise such data to scientific standards and provide logical and defensible conclusions about impacts on a system, a population, and society.2 Decisions can be then be made that are based on meaningful comparison with interventions competing for the same budget.


Ultimately, the aim of decision making in health care should be to achieve not equal health standards (however low the ceiling) but good health for all population groups–or, to put it another way, the best care for the greatest number of people. 



SUE SHARPLES
How risks of breast cancer and benefits of screening are communicated to women: analysis of 58 pamphlets
Authors: E. K Slaytor, J. E Ward
Journal: BMJ (1998)

Informed participation in population based screening programmes requires an explicit sharing of information about risks and benefits.1 However, many factors influence perceptions of risk and the value of risk reduction promised through screening. Campaigns that selectively quote incidence to “frighten” women into undergoing mammography have been criticised.2 Perceived risk, not objective risk, explains readiness to undergo screening in most models of health behaviour. Furthermore, the willingness of health purchasers to fund mammographic screening has been shown to be significantly influenced by the way in which data about effectiveness are presented: a programme achieving a 30% reduction in relative risk was more likely to be funded than two others described in terms of absolute risk reduction or numbers needed to screen to avert one death from breast cancer, even though all three were objectively identical in effectiveness.3 No …
A depressing future for cyclosporine?
Authors: V Owen
Journal: Cardiovascular Research (2000)

See article by Janssen et al. [1] (pages 99–107) in this issue. 

In this issue of the journal, Janssen and colleagues [1] examine the in vitro effects of cyclosporine A (CsA) on myocardial contractile function in multi-cellular preparations obtained from human and rabbit hearts.

The effect of CsA on cardiac muscle function is currently highly fashionable following the recent flurry of data concerning its effect on the phosphatase calcineurin in the progression of cardiac muscle hypertrophy [2]. CsA bound to its major binding protein, cyclophilin A, forms a complex that inhibits the phosphatase activity of calcineurin and, in turn, blocks dephosphorylation of the transcription factor NF-AT3 (for review, see [3]). The current paper by Janssen, in conjunction with other published data, provides us with a framework on which to hypothesise the mechanism by which CsA adversely affects cardiac contractility.

The present study by Janssen uses a number of techniques to examine the role of CsA on myocardial contractility. To summarise the key findings; CsA decreased the maximum force produced by end-stage failing and non-failing human and rabbit myocardium in response to electrical stimulation and, in addition, both contraction and relaxation rates were slowed. In an attempt to elucidate the reason for this CsA-mediated depression of twitch parameters, the authors investigate the effect of CsA on calcium handling and the contractile apparatus.

To reiterate the basis of muscle contraction following an action potential, the outer membrane of the cell is depolarized, dihydropyridine (DHP) receptors or L-type calcium channels that reside … 

* Tel.: +44-207-351-8173; fax: +44-207-376-3442 v.j.owen{at}ic.ac.uk
Hereditary Hemorrhagic Telangiectasia With Pulmonary Arteriovenous Fistulas
Authors: Kei Yunoki, Takahiko Naruko, Masaki Komiyama, Junko Ohashi, Kohei Fujimoto, Naoya Shirai, Koichi Shimamura, Ryushi Komatsu, Yuji Sakanoue, Akira Itoh, Kazuo Haze
Journal: Circulation (2006)
Genome-wide discovery of genetic variants affecting tamoxifen sensitivity and their clinical and functional validation
Authors: L. Weng, D. Ziliak, H.K. Im, E.R. Gamazon, S. Philips, A.T. Nguyen, Z. Desta, T.C. Skaar, D.A. Flockhart, R.S. Huang
Journal: Annals of Oncology (2013)