tbuckley/cabot-search huggingface dataset:
O2 deprivation inhibits Ca2+-activated K+ channels via cytosolic factors in mice neocortical neurons
Authors: Huajun Liu, Edward Moczydlowski, Gabriel G. Haddad
Journal: Journal of Clinical Investigation (1999)

O2 deprivation induces membrane depolarization in mammalian central neurons. It is possible that this anoxia-induced depolarization is partly mediated by an inhibition of K+ channels. We therefore performed experiments using patch-clamp techniques and dissociated neurons from mice neocortex. Three types of K+ channels were observed in both cell-attached and inside-out configurations, but only one of them was sensitive to lack of O2. This O2-sensitive K+ channel was identified as a large-conductance Ca2+-activated K+ channel (BKCa), as it exhibited a large conductance of 210 pS under symmetrical K+ (140 mM) conditions, a strong voltage-dependence of activation, and a marked sensitivity to Ca2+. A low-O2 medium (PO2 = 10–20 mmHg) markedly inhibited this BKCa channel open probability in a voltage-dependent manner in cell-attached patches, but not in inside-out patches, indicating that the effect of O2 deprivation on BKCa channels of mice neocortical neurons was mediated via cytosol-dependent processes. Lowering intracellular pH (pHi), or cytosolic addition of the catalytic subunit of a cAMP-dependent protein kinase A in the presence of Mg-ATP, caused a decrease in BKCa channel activity by reducing the sensitivity of this channel to Ca2+. In contrast, the reducing agents glutathione and DTT increased single BKCa channel open probability without affecting unitary conductance. We suggest that in neocortical neurons, (a) BKCa is modulated by O2 deprivation via cytosolic factors and cytosol-dependent processes, and (b) the reduction in channel activity during hypoxia is likely due to reduced Ca2+ sensitivity resulting from cytosolic alternations such as in pHi and phosphorylation. Because of their large conductance and prevalence in the neocortex, BKCa channels may be considered as a target for pharmacological intervention in conditions of acute anoxia or ischemia.
Carcinogenicity of airborne combustion products observed in subcutaneous tissue and lungs of laboratory rodents.
Authors: F Pott, W Stöber
Journal: Environmental Health Perspectives (1983)

Most air pollution in West Germany is caused by combustion products. Particulate organic matter released by incomplete combustion is suspected to contribute to the "urban factor" of lung cancer frequency in urban-industrial centers. The carcinogenic potential of single components, groups of compounds and total source emissions of combustion processes was investigated in laboratory animals by subcutaneous injection, intratracheal instillation or inhalation. Tests by subcutaneous injection of condensates of automobile exhaust, extracts of coal furnace emissions and of airborne particles and different fractions of these extracts showed that the polycyclic aromatic hydrocarbons (PAH) with four to six benzene rings have the strongest experimental carcinogenicity. However, polar compounds (heterocyclic nitrogen-containing PAH, phenols, and others) also show remarkable carcinogenic potency. There were large differences between the dose-response relationships of several PAHs. In the subcutaneous tissue, benzo(a)pyrene and dibenz(a,h)anthracene are the most carcinogenic of the tested airborne PAHs. Furthermore, they can induce high tumor rates in the lung after subcutaneous injection in newborn mice and after intratracheal instillation of mice or hamsters. The tumor rate of benzo(a)pyrene did not further increase after simultaneous instillation of carbon black, but lead chloride may have a promoting effect. Far more than 100 PAHs are found in the urban atmosphere. However, because of the remarkable similarity of the PAH profiles in the examined samples, it may be sufficient to measure just a few stable PAHs in the urban air in order to facilitate an assessment of the carcinogenic potency of the PAH content in the atmosphere. To examine the carcinogenic or cocarcinogenic effects of gas and vapor emissions, studies with a two-phase model were carried out: phase 1 relates to the induction of a basic tumor rate in the lung by a well known carcinogen, while phase 2 is characterized by an inhalation of the substance under investigation. In an experiment with mice, the inhalation of a mixture of SO2 and NO2 seemed to increase the basic tumor rate induced by dibenz(a,h)anthracene. In a similar two-phase experiment conducted with hamsters, the inhalation of diesel exhaust (total exhaust as well as exhaust without particles) increased a basic tumor rate induced by diethyl nitrosamine. These experiments deserve confirmation before a detailed interpretation is attempted.
Chromosomal and MicroRNA Expression Patterns Reveal Biologically Distinct Subgroups of 11q− Neuroblastoma
Authors: Patrick G. Buckley, Leah Alcock, Kenneth Bryan, Isabella Bray, Johannes H. Schulte, Alexander Schramm, Angelika Eggert, Pieter Mestdagh, Katleen De Preter, Jo Vandesompele, Frank Speleman, Raymond L. Stallings
Journal: Clinical Cancer Research (2010)

Abstract Purpose: The purpose of this study was to further define the biology of the 11q− neuroblastoma tumor subgroup by the integration of array-based comparative genomic hybridization with microRNA (miRNA) expression profiling data to determine if improved patient stratification is possible. Experimental Design: A set of primary neuroblastoma (n = 160), which was broadly representative of all genetic subtypes, was analyzed by array-based comparative genomic hybridization and for the expression of 430 miRNAs. A 15-miRNA expression signature previously shown to be predictive of clinical outcome was used to analyze an independent cohort of 11q− tumors (n = 37). Results: Loss of 4p and gain of 7q occurred at a significantly higher frequency in the 11q− tumors, further defining the genetic characteristics of this subtype. The 11q− tumors could be split into two subgroups using a miRNA expression survival signature that differed significantly in clinical outcome and the overall frequency of large-scale genomic imbalances, with the poor survival subgroup having significantly more imbalances. miRNAs from the expression signature, which were upregulated in unfavorable tumors, were predicted to target downregulated genes from a published mRNA expression classifier of clinical outcome at a higher-than-expected frequency, indicating the miRNAs might contribute to the regulation of genes within the signature. Conclusion: We show that two distinct biological subtypes of neuroblastoma with loss of 11q occur, which differ in their miRNA expression profiles, frequency of segmental imbalances, and clinical outcome. A miRNA expression signature, combined with an analysis of segmental imbalances, provides greater prediction of event-free survival and overall survival outcomes than 11q status by itself, improving patient stratification. Clin Cancer Res; 16(11); 2971–8. ©2010 AACR.
Hypertrophy in the Distal Convoluted Tubule of an 11β-Hydroxysteroid Dehydrogenase Type 2 Knockout Model
Authors: Robert W. Hunter, Jessica R. Ivy, Peter W. Flatman, Christopher J. Kenyon, Eilidh Craigie, Linda J. Mullins, Matthew A. Bailey, John J. Mullins
Journal: Journal of the American Society of Nephrology (2014)

Na(+) transport in the renal distal convoluted tubule (DCT) by the thiazide-sensitive NaCl cotransporter (NCC) is a major determinant of total body Na(+) and BP. NCC-mediated transport is stimulated by aldosterone, the dominant regulator of chronic Na(+) homeostasis, but the mechanism is controversial. Transport may also be affected by epithelial remodeling, which occurs in the DCT in response to chronic perturbations in electrolyte homeostasis. Hsd11b2(-/-) mice, which lack the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) and thus exhibit the syndrome of apparent mineralocorticoid excess, provided an ideal model in which to investigate the potential for DCT hypertrophy to contribute to Na(+) retention in a hypertensive condition. The DCTs of Hsd11b2(-/-) mice exhibited hypertrophy and hyperplasia and the kidneys expressed higher levels of total and phosphorylated NCC compared with those of wild-type mice. However, the striking structural and molecular phenotypes were not associated with an increase in the natriuretic effect of thiazide. In wild-type mice, Hsd11b2 mRNA was detected in some tubule segments expressing Slc12a3, but 11βHSD2 and NCC did not colocalize at the protein level. Thus, the phosphorylation status of NCC may not necessarily equate to its activity in vivo, and the structural remodeling of the DCT in the knockout mouse may not be a direct consequence of aberrant corticosteroid signaling in DCT cells. These observations suggest that the conventional concept of mineralocorticoid signaling in the DCT should be revised to recognize the complexity of NCC regulation by corticosteroids.
Increased Thrombosis After Arterial Injury in Human C-Reactive Protein–Transgenic Mice
Authors: Haim D. Danenberg, Alexander J. Szalai, Rajesh V. Swaminathan, Lin Peng, Zhiping Chen, Philip Seifert, William P. Fay, Daniel I. Simon, Elazer R. Edelman
Journal: Circulation (2003)

C-reactive protein (CRP), an acute-phase reactant long considered merely an innocent bystander in the inflammatory process, is now recognized as a powerful predictor of cardiovascular events. Emerging in vitro evidence suggests that CRP may have direct proinflammatory and prothrombotic effects on monocytes and endothelial cells. To determine whether CRP directly modulates vascular cell function in vivo, we subjected wild-type mice, which do not express CRP, and human CRP-transgenic (CRPtg) mice to 2 models of arterial injury.Baseline serum CRP levels in CRPtg mice were 18+/-6 mg/L. CRP levels were undetectable in wild-type mice. Transluminal wire injury led to complete thrombotic occlusion of the femoral artery at 28 days in 75% of CRPtg arteries (6 of 8) compared with 17% (2 of 12) in wild-type mice (P<0.05). In a model of arterial photochemical injury, clot formation time was shortened in CRPtg mice; mean time to occlusion was 33+/-19 minutes compared with 59+/-19 minutes in wild-type mice (n=10; P<0.05).Arterial injury in CRPtg mice results in an expedited and higher rate of thrombotic occlusion. This is the first report of a prothrombotic phenotype directly attributable to the presence of human CRP in vivo. Investigation of the inflammatory-thrombotic axis in CRPtg mice may elucidate the prothrombotic actions of CRP in unstable arterial diseases and may pave the way for novel therapeutic interventions for preventing cardiovascular events.
Phase II Study of Bevacizumab, Temozolomide, and Hypofractionated Stereotactic Radiotherapy for Newly Diagnosed Glioblastoma
Authors: Antonio Omuro, Kathryn Beal, Philip Gutin, Sasan Karimi, Denise D. Correa, Thomas J. Kaley, Lisa M. DeAngelis, Timothy A. Chan, Igor T. Gavrilovic, Craig Nolan, Adilia Hormigo, Andrew B. Lassman, Ingo Mellinghoff, Christian Grommes, Anne S. Reiner, Katherine S. Panageas, Raymond E. Baser, Viviane Tabar, Elena Pentsova, Juan Sanchez, Renata Barradas-Panchal, Jianan Zhang, Geraldine Faivre, Cameron W. Brennan, Lauren E. Abrey, Jason T. Huse
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Bevacizumab is associated with decreased vascular permeability that allows for more aggressive radiotherapy schedules. We conducted a phase II trial in newly diagnosed glioblastoma utilizing a novel hypofractionated stereotactic radiotherapy (HFSRT) schedule combined with temozolomide and bevacizumab. Experimental Design: Patients with tumor volume ≤60 cc were treated with HFSRT (6 × 6 Gy to contrast enhancement and 6 × 4 Gy to FLAIR hyperintensity with dose painting) combined with concomitant/adjuvant temozolomide and bevacizumab at standard doses. Primary endpoint was 1-year overall survival (OS): promising = 70%; nonpromising = 50%; α = 0.1; β = 0.1. Results: Forty patients were enrolled (median age: 55 years; methylated MGMT promoter: 23%; unmethylated: 70%). The 1-year OS was 93% [95% confidence interval (CI), 84–100] and median OS was 19 months. The median PFS was 10 months, with no pseudo-progression observed. The objective response rate (ORR) was 57%. Analysis of The Cancer Genome Atlas glioblastoma transcriptional subclasses (Nanostring assay) suggested patients with a proneural phenotype (26%) fared worse (ORR = 14%, vs. 77% for other subclasses; P = 0.009). Dynamic susceptibility-contrast perfusion MRI showed marked decreases in relative cerebral blood volume over time (P &amp;lt; 0.0001) but had no prognostic value, whereas higher baseline apparent diffusion coefficient (ADC) ratios and persistent hypermetabolism at the 6-month FDG-PET predicted poor OS (P = 0.05 and 0.0001, respectively). Quality-of-life (FACT-BR-4) and neuropsychological test scores were stable over time, although some domains displayed transient decreases following HFSRT. Conclusions: This aggressive radiotherapy schedule was safe and more convenient for patients, achieving an OS that is comparable with historical controls. Analysis of advanced neuroimaging parameters suggests ADC and FDG-PET as potentially useful biomarkers, whereas tissue correlatives uncovered the poor prognosis associated with the proneural signature in non–IDH-1–mutated glioblastoma. Clin Cancer Res; 20(19); 5023–31. ©2014 AACR.
Cost effectiveness of treatment for gastro-oesophageal reflux disease Reply
Authors: J A CRAWLEY, A HAYCOX
Journal: Gut (1998)

Editor,—A reading of the recent article by Eggleston et al ( Gut 1998; 42 :13–16) left several unanswered questions and concerns. The first issue was the authors’ statement that clinical equivalence between cisapride, ranitidine, and omeprazole had been established for uncomplicated gastro-oesophageal reflux disease (GORD) in standard practice. To my knowledge, there are no published studies which have reported a similar finding of clinical equivalence of omeprazole to either cisapride or ranitidine. A quick review of the literature revealed 11 studies in which omeprazole was statistically significantly better than cisapride or ranitidine in GORD.1-11 

In a review of the reference abstract12 in which the case for clinical equivalence is postulated, the conclusion of equivalence was highly dependent upon the authors’ definition of treatment failure. I take exception to the authors’ definition that use of medication for longer than three months was a therapy failure. A retrospective database analysis does not have the ability to distinguish between continuing a medication in order to maintain successfully achieved symptom resolution and continued use of medication due to unsuccessful resolution of symptoms. Initiation of maintenance therapy after successful symptom resolution would not require any change in dosage in the case of omeprazole as 20 mg once daily is the recommended dose for healing and maintenance. Defining success as any use of medication for less than three months that did not involve a change in drug also opens up the possibility of misclassification. Those patients who stop using a drug as a result of treatment failure and who do not return for further care would not only be misclassified in this retrospective analysis as a success but could erroneously contribute to a lower economic burden in the therapy group. In the Methods, the authors state that case records for a total of …
Role of Peroxynitrite in the Development of Diabetic Peripheral Neuropathy
Authors: Joshua F. Edwards, Carolina M. Casellini, Henri K. Parson, Irina G. Obrosova, Mark Yorek, Aaron I. Vinik
Journal: Diabetes Care (2015)

Approximately 50% of patients with diabetes (DM) will eventually develop neuropathy. Large-scale studies have demonstrated that the regulation of blood glucose levels aids in the prevention and progression of diabetic peripheral neuropathy (DPN), but glycemic control does not impact established neuropathy or its severity (1). Causative factors also include microvascular insufficiency, defective neurotrophism, abnormal lipid metabolism, and oxidative and nitrosative stress (2). A key component of nitrosative stress, nitrotyrosine (NT), has multiple cytotoxic effects. Accumulation of NT has been identified in several neural structures in both rodents and humans (3), reflected by raised NT concentrations in the plasma of subjects with DM (4).

The aim of this study was to evaluate the relationship between NT concentrations with the presence and severity of possible/probable (PP-DM-DPN) and established (DM-DPN) neuropathy in subjects with DM compared with healthy control subjects …
Molecular Characterization and Evolution of a Gene Family Encoding Both Female- and Male-Specific Reproductive Proteins in Drosophila
Authors: Laura K. Sirot, Geoffrey D. Findlay, Jessica L. Sitnik, Dorina Frasheri, Frank W. Avila, Mariana F. Wolfner
Journal: Molecular Biology and Evolution (2014)

Gene duplication is an important mechanism for the evolution of new reproductive proteins. However, in most cases, each resulting paralog continues to function within the same sex. To investigate the possibility that seminal fluid proteins arise through duplicates of female reproductive genes that become "co-opted" by males, we screened female reproductive genes in Drosophila melanogaster for cases of duplication in which one of the resulting paralogs produces a protein in males that is transferred to females during mating. We identified a set of three tandemly duplicated genes that encode secreted serine-type endopeptidase homologs, two of which are expressed primarily in the female reproductive tract (RT), whereas the third is expressed specifically in the male RT and encodes a seminal fluid protein. Evolutionary and gene expression analyses across Drosophila species suggest that this family arose from a single-copy gene that was female-specific; after duplication, one paralog evolved male-specific expression. Functional tests of knockdowns of each gene in D. melanogaster show that one female-expressed gene is essential for full fecundity, and both female-expressed genes contribute singly or in combination to a female's propensity to remate. In contrast, knockdown of the male-expressed paralog had no significant effect on female fecundity or remating. These data are consistent with a model in which members of this gene family exert effects on females by acting on a common, female-expressed target. After duplication and male co-option of one paralog, the evolution of the interacting proteins could have resulted in differential strengths or effects of each paralog.
Hepatocyte proliferation induced in rats by lead nitrate is suppressed by several tumor necrosis factor ? inhibitors
Authors: Y Kubo, M Yasunaga, M Masuhara, S Terai, T Nakamura, K Okita
Journal: Hepatology (1996)

Lead nitrate induces liver cell proliferation in rats without accompanying liver cell necrosis. However, the mechanism of this proliferation and its effect on hepatocytes remain unknown. Therefore, we examined the liver and blood level of hepatocyte growth factor and tumor necrosis factor alpha (TNF-alpha) at various intervals to determine whether lead nitrate modifies hepatocyte proliferation by altering the production of these cytokines. We also administered several TNF-alpha inhibitors, dexamethasone, adenosine, (2E)-3-[5-(2,3-dimethoxy-6-methyl-1,4-benzoquinoyl)]-2-nonyl-2- propenoic acid (E 3330), and pentoxifylline, to rats to clarify whether pretreatment with these inhibitors suppresses the increase of TNF-alpha messenger RNA (mRNA) in the liver and prevents the hepatocyte proliferation induced by lead nitrate. Hepatocyte proliferation occurred by 24 hours and reached a peak 48 hours after a single intravenous injection of lead nitrate (100 mumol/kg). TNF-alpha mRNA expression in the liver was increased 1, 6, and 12 hours after the injection, whereas no alteration was observed in liver or blood level of hepatocyte growth factor. Pretreatment with dexamethasone (4.0 mg/kg), E3330 (100 mg/kg) adenosine (0.3 mmol/kg), and pentoxifylline (100 mg/kg), inhibited both TNF-alpha mRNA expression and hepatocyte proliferation 48 hours after the injection. These experimental results strongly support the hypothesis that TNF-alpha positively regulates the hepatocyte proliferation induced in rats by the mitogen, lead nitrate.
Enhanced care review for people with COPD in primary care addressing quality, cost-effectiveness and productivity
Authors: Wendy Fairhurst, Sandra Burns, Sam Lacy, Ram Sundar
Journal: European Respiratory Journal (2012)

An enhanced care review, delivered by nurses working for a social enterpirise within Primary Care and supported by a Respiratory Physician has proved to be a cost effective way of improving the quality of life with patients with COPD.  The aim of the project was to improve the quality of care on a number of parameters such as accurate diagnosis, treatment of excacerbations, self management plans, referral to preventative services. This was delivered through a nurse led service supported by a respiratory consultant in primary care to reduce hospital admissiona and outpatients referrals.  The 12 month pilot project was delivered to 23 GP practices within an urban, deprived setting in the North of England. Specilaist Respiratory nurses and practice nurses delivered the service within GP practices following education and training identifying patients at risk of excacerbations or hospital admissions and post exacerbation assessment and prevention using specialist computer software which also provided a data colection template- data was collected through GP practice readcod searches together with admission data from the Primary Care Trust.  Hospital admissions were reduced amounting to savings of £90,000 in comparison to other parts of the borough. Medicines management savings amounted to £40,000 were achieved through treatment optimisation.  Prevalence of COPD was increased by 12.3% and there was a 56% increase in pts being diagnosed between the ages of 35-50. There was a 63% increase in referral to pulmonary rehab and 20% increase in patients coded now as ex-smokers. There was a 58% increase in patients being given a self managemnt plan.
Current Challenges in Using Patient-Reported Outcomes for Surgical Care and Performance Measurement
Authors: Karl Y. Bilimoria, David Cella, Zeeshan Butt
Journal: JAMA Surgery (2014)

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