tbuckley/cabot-search huggingface dataset:
Chronic hyperglycemia is associated with impaired glucose influence on insulin secretion. A study in normal rats using chronic in vivo glucose infusions.
Authors: J L Leahy, H E Cooper, D A Deal, G C Weir
Journal: Journal of Clinical Investigation (1986)

We have proposed that chronic hyperglycemia alters the ability of glucose to modulate insulin secretion, and have now examined the effects of different levels of hyperglycemia on B cell function in normal rats using chronic glucose infusions. Rats weighing 220-300 g were infused with 0.45% NaCl or 20, 30, 35, or 50% glucose at 2 ml/h for 48 h, which raised the plasma glucose by 18 mg/dl in the 30% rats, 37 mg/dl in the 35% rats, and 224 mg/dl in the 50% group. Insulin secretion was then examined using the in vitro isolated perfused pancreas. Glucose-induced insulin secretion remained intact in the normoglycemic 20% glucose rats and it was potentiated in the mildly hyperglycemic 30% glucose rats. However, with even greater hyperglycemia in the 35% glucose group the insulin response to a high glucose perfusate was severely blunted, and it was totally lost in the most hyperglycemic 50% glucose rats. In a second protocol that examined glucose potentiation of arginine-stimulated insulin release, a similar impairment in the ability of glucose to modulate the insulin response to arginine was found with increasing levels of chronic hyperglycemia. On the other hand, the ability of a high glucose concentration to inhibit arginine-stimulated glucagon release was preserved in all glucose-infused rats, but the glucagon levels attained in response to the arginine at 2.8 mM glucose were much less in the 50% glucose rats than in all the other groups. These data clearly show that after 48 h of marked hyperglycemia, glucose influence upon insulin secretion in the rat is severely impaired. This model provides a relatively easy and reproducible method to study the effects of long-term hyperglycemia on B cell function.
Epinephrine and dexamethasone reduce hospital admission in children with bronchiolitis
Authors: P T. Fiandeiro
Journal: Thorax (2009)

(<i>S</i>)-5-Chloro-1-(1-cyclopropylethyl)-3-(2,6-dichloro-4-(trifluoromethyl)phenylamino)pyrazin-2(1<i>H</i>)-one (BMS-665053), a pyrazinone-containing compound, is a potent and selective antagonist of corticotropin-releasing factor receptor-1 (CRF-R1) that showed efficacy in the defensive withdrawal model for anxiety in rats, suggesting its use as a potential treatment for anxiety and depression. In vitro metabolism studies of BMS-665053 in rat and human liver microsomes revealed cytochrome P450-mediated oxidation of the pyrazinone moiety, followed by ring opening, as the primary metabolic pathway. Detection of a series of GSH adducts in trapping experiments suggested the formation of a reactive intermediate, probably as a result of epoxidation of the pyrazinone moiety. In addition, BMS-665053 (20 mg/kg i.v.) underwent extensive metabolism in bile duct-cannulated (BDC) rats. The major drug-related materials in rat plasma were the pyrazinone oxidation products. In rat bile and urine (0–7 h), only a trace amount of the parent drug was recovered, whereas significant levels of the pyrazinone epoxide-derived metabolites and GSH-related conjugates were detected. Further evidence suggested that GSH-related conjugates also formed at the dichloroarylamine moiety possibly via an epoxide or a quinone imine intermediate. Other major metabolites in BDC rat bile and urine included glucuronide conjugates. To reduce potential liability due to metabolic activation of BMS-665053, a number of pyrazinone analogs with different substituents were synthesized and investigated for reactive metabolite formation, leading to the discovery of a CRF-R1 antagonist with diminished in vitro metabolic activation.
Epigenetics, Development, and the Kidney
Authors: Gregory R. Dressler
Journal: Journal of the American Society of Nephrology (2008)

How cells partition the genome into active and inactive genes and how that information is established and propagated during embryonic development are fundamental to maintaining the normal differentiated state. The molecular mechanisms of epigenetic action and cellular memory are increasingly amenable to study primarily as a result of the rapid progress in the area of chromatin biology. Methylation of DNA and modification of histones are critical epigenetic marks that establish active and silent chromatin domains. During development of the kidney, DNA-binding factors such as Pax2/8, which are essential for the intermediate mesoderm and the renal epithelial lineage, could provide the locus and tissue specificity for histone methylation and chromatin remodeling and thus establish a kidney-specific fate. The role of epigenetic modifications in development and disease is under intense investigation and has already affected our view of cancer and aging.
Non-Overlapping and Non–Cell-Type–Specific Gene Expression Signatures Predict Lung Cancer Survival
Authors: Zhifu Sun, Dennis A. Wigle, Ping Yang
Journal: Journal of Clinical Oncology (2008)

Gene expression profiling for outcome prediction of non-small-cell lung cancer (NSCLC) remains clouded by heterogeneous and unvalidated results. This study applied multivariate approaches to identify and evaluate value-added gene expression signatures in two types of NSCLC.Two NSCLC oligonucleotide microarray data sets of adenocarcinoma and squamous cell carcinoma were used as training sets to select prognostic genes independent of conventional predictors. The top 50 genes from each set were used to predict the outcomes of two independent validation data sets of 84 and 91 NSCLC cases.Adenocarcinomas with the 50-gene signature from adenocarcinoma in both validation data sets had a 2.4-fold (95% CI, 1.3 to 4.4 and 1.0 to 5.8) increased mortality after adjustment for conventional predictors. Squamous cell carcinoma with this high-risk signature had an adjusted risk of 1.1 (95% CI, 0.4 to 3.2) in one data set and 2.5 (95% CI, 1.1 to 5.8) in another consisting of stage I tumors. Adenocarcinoma with the 50-gene signature from squamous cell carcinoma had an elevated risk of 3.5 (95% CI, 1.4 to 9.0) after adjustment for conventional predictors. Squamous cell carcinoma with this high risk signature had an adjusted risk of 1.8 (95% CI, 0.7 to 4.6). Despite the little overlap in individual genes, the two gene signatures had significant functional connectedness in molecular pathways.Two non-overlapping but functionally related gene expression signatures provide consistently improved survival prediction for NSCLC regardless of histologic cell type. Multiple sets of genes may exist for NSCLC with predictive value, but ones with independent predictive value beyond clinical predictors will be required for clinical translation.
Induction of BIM Is Essential for Apoptosis Triggered by EGFR Kinase Inhibitors in Mutant EGFR-Dependent Lung Adenocarcinomas
Authors: Yixuan Gong, Romel Somwar, Katerina Politi, Marissa Balak, Juliann Chmielecki, Xuejun Jiang, William Pao
Journal: PLoS Medicine (2007)

Background Mutations in the epidermal growth factor receptor (EGFR) gene are associated with increased sensitivity of lung cancers to kinase inhibitors like erlotinib. Mechanisms of cell death that occur after kinase inhibition in these oncogene-dependent tumors have not been well delineated. We sought to improve understanding of this process in order to provide insight into mechanisms of sensitivity and/or resistance to tyrosine kinase inhibitors and to uncover new targets for therapy. Methods and Findings Using a panel of human lung cancer cell lines that harbor EGFR mutations and a variety of biochemical, molecular, and cellular techniques, we show that EGFR kinase inhibition in drug-sensitive cells provokes apoptosis via the intrinsic pathway of caspase activation. The process requires induction of the proapoptotic BH3-only BCL2 family member BIM (i.e., BCL2-like 11, or BCL2L11); erlotinib dramatically induces BIM levels in sensitive but not in resistant cell lines, and knockdown of BIM expression by RNA interference virtually eliminates drug-induced cell killing in vitro. BIM status is regulated at both transcriptional and posttranscriptional levels and is influenced by the extracellular signal-regulated kinase (ERK) signaling cascade downstream of EGFR. Consistent with these findings, lung tumors and xenografts from mice bearing mutant EGFR-dependent lung adenocarcinomas display increased concentrations of Bim after erlotinib treatment. Moreover, an inhibitor of antiapoptotic proteins, ABT-737, enhances erlotinib-induced cell death in vitro. Conclusions In drug-sensitive EGFR mutant lung cancer cells, induction of BIM is essential for apoptosis triggered by EGFR kinase inhibitors. This finding implies that the intrinsic pathway of caspase activation may influence sensitivity and/or resistance of EGFR mutant lung tumor cells to EGFR kinase inhibition. Manipulation of the intrinsic pathway could be a therapeutic strategy to enhance further the clinical outcomes of patients with EGFR mutant lung tumors.
A meta-analysis on the influence of inflammatory bowel disease on pregnancy
Authors: J Cornish, E Tan, J Teare, T G Teoh, R Rai, S K Clark, P P Tekkis
Journal: Gut (2006)

<b>Background:</b> Inflammatory bowel disease (IBD) has a typical onset during the peak reproductive years. Evidence of the risk of adverse pregnancy outcomes in IBD is important for the management of pregnancy to assist in its management. <b>Aim:</b> To provide a clear assessment of risk of adverse outcomes during pregnancy in women with IBD. <b>Design:</b> The Medline literature was searched to identify studies reporting outcomes of pregnancy in patients with IBD. Random-effect meta-analysis was used to compare outcomes between women with IBD and normal controls. <b>Patients and setting:</b> A total of 3907 patients with IBD (Crohn's disease 1952 (63%), ulcerative colitis 1113 (36%)) and 320 531 controls were reported in 12 studies that satisfied the inclusion criteria. <b>Results:</b> For women with IBD, there was a 1.87-fold increase in incidence of prematurity (&lt;37 weeks gestation; 95% CI 1.52 to 2.31; p&lt;0.001) compared with controls. The incidence of low birth weight (&lt;2500 g) was over twice that of normal controls (95% CI 1.38 to 3.19; p&lt;0.001). Women with IBD were 1.5 times more likely to undergo caesarean section (95% CI 1.26 to 1.79; p&lt;0.001), and the risk of congenital abnormalities was found to be 2.37-fold increased (95% CI 1.47 to 3.82; p&lt;0.001). <b>Conclusion:</b> The study has shown a higher incidence of adverse pregnancy outcomes in patients with IBD. Further studies are required to clarify which women are at higher risk, as this was not determined in the present study. This has an effect on the management of patients with IBD during pregnancy, who should be treated as a potentially high-risk group.
Vascular smooth muscle cell phenotypic plasticity: focus on chromatin remodelling
Authors: J. M. Spin, L. Maegdefessel, P. S. Tsao
Journal: Cardiovascular Research (2012)

Differentiated vascular smooth muscle cells (SMCs) retain the capacity to modify their phenotype in response to inflammation or injury. This phenotypic switching is a crucial component of vascular disease, and is partly dependent on epigenetic regulation. An appreciation has been building in the literature for the essential role chromatin remodelling plays both in SMC lineage determination and in influencing changes in SMC behaviour and state. This process includes numerous chromatin regulatory elements and pathways such as histone acetyltransferases, deacetylases, and methyltransferases and other factors that act at SMC-specific marker sites to silence or permit access to the cellular transcriptional machinery and on other key regulatory elements such as myocardin and Kruppel-like factor 4 (KLF4). Various stimuli known to alter the SMC phenotype, such as transforming growth factor beta (TGF-β), platelet-derived growth factor (PDGF), oxidized phospholipids, and retinoic acid, appear to act in part through effects upon SMC chromatin structure. In recent years, specific covalent histone modifications that appear to establish SMC determinacy have been identified, while others alter the differentiation state. In this article, we review the mechanisms of chromatin remodelling as it applies to the SMC phenotype.
Large vessel pulmonary arteritis mimicking chronic thromboembolic disease.
Authors: K M Kerr, W R Auger, P F Fedullo, R H Channick, E S Yi, K M Moser
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

Chronic obstruction of pulmonary arteries can be due to a variety of disease processes, including chronic thromboembolic disease, fibrosing mediastinitis, or neoplasia. Large vessel arteritis is another unusual cause of pulmonary artery obstruction and can be difficult to distinguish from the above-listed etiologies. We present four patients referred to our institution with the provisional diagnosis of chronic thromboembolic pulmonary hypertension who were subsequently diagnosed with Takayasu's arteritis involving the pulmonary arteries. We review the historical, physical examination, and radiologic characteristics that help distinguish Takayasu's arteritis from chronic thromboembolic disease.
Results of secondary prophylaxis in children with severe hemophilia
Authors: Marilyn J. Manco‐Johnson, Rachelle Nuss, Susan Geraghty, Sharon Funk, Ray Kilcoyne
Journal: American Journal of Hematology (1994)

Abstract In this study, 13 children with severe hemophilia were given routine replacement infusions of factor VIII or IX to treat arthropathy. The children who had a mean age of 6.9 years (range 2.0–12.5) at initiation of prophylaxis had experienced an average of 43 acute hemorrhages (range 8–127) in the year prior to prophylaxis, of which a mean of 24 (range 5–46) were into joints. Therapy was begun in five children, using factor VIII concentrate at 20 U/kg three times a week, and one boy received factor IX concentrate 40 U/kg twice a week. This dose schedule was inadequate for three factor VIII‐deficient boys and for the one factor IX‐deficient boy. Two of three factor VIII‐deficient boys responded to an increase to 30 U/kg prior to the 3‐day interval. The dose frequency was increased to three times a week for the factor IX‐deficient boy, but he continued to bleed and was taken to synovectomy. One of the original five factor VIII‐deficient boys plus seven other factor VIII‐deficient boys were begun on factor VIII 20 U/kg every other day; 3 boys ceased bleeding. Trough factor VIII levels were measured 24 hr after an infusion in the five boys who continued to bleed. Factor VIII dosage was adjusted to achieve a trough level of &gt;1%; 4 responded to an increase in the dose of factor VIII; 1 had an adequate trough but, due to compliance issues, was taken to synovectomy. Serial clinical and radiographic assessments determined stabilization of joint disease in more than one‐half of the boys. No child showed reversal of abnormal radiographic findings. Institution of aggressive factor VIII and IX concentrate in children with established hemophilic arthropathy does not reverse joint disease but may alter the clinical course of hemophilia. Future studies to compare this intervention with primary prophylaxis instituted prior to the onset of recurrent joint hemorrhage are warranted. © 1994 Wiley‐Liss, Inc.
URTICARIA EVOKED BY EMOTION
Authors: JOHN ALEXANDER DRAKE
Journal: British Journal of Dermatology (1931)

Journal Article URTICARIA EVOKED BY EMOTION Get access JOHN ALEXANDER DRAKE, M.D., F.R.C.P. JOHN ALEXANDER DRAKE, M.D., F.R.C.P. Physician for Diseases of the Skin, King's College Hospital Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology and Syphilis, Volume 43, Issue 4, 1 April 1931, Pages 184–185, https://doi.org/10.1111/j.1365-2133.1931.tb09487.x Published: 01 April 1931
Myocardial Na,K-ATPase: the molecular basis for the hemodynamic effect of digoxin therapy in congestive heart failure
Authors: K Kjeldsen
Journal: Cardiovascular Research (2002)

Congestive heart failure may be deemed the epidemic of cardiology in the 21st century in the industrialized part of the world. Although new therapies improving morbidity and mortality from chronic heart failure have emerged it is likely that there is a growing role for digoxin. Thus, digoxin treatment is known to control symptoms of congestive heart failure when added to standard therapy. In this setting, we review the prevailing knowledge of the Na,K-ATPase, the cellular receptor for the inotropic action of digitalis glycosides, in relation to the hemodynamic effect of digoxin. It is concluded that if improvement of hemodynamics is needed in congestive heart failure, this knowledge should be taken into account and in many cases digoxin should be added to standard therapy. Digoxin is still the only safe inotropic drug for oral use that improves hemodynamics. Digoxin should be used to heart failure patients in sinus rhythm when they after institution of mortality reducing treatment still have heart failure symptoms, and to patients intolerant to heart failure mortality reducing drugs. Digoxin should probably in heart failure patients with sinus rhythm be given in the lowest possible dose that relieves symptoms sufficiently.
Minimizing Shear and Compressive Stress During Pancreaticojejunostomy
Authors: Vladimir K. Neychev, Pierre F. Sladinger
Journal: JAMA Surgery (2013)

The failure of the pancreaticojejunal anastomosis remains an important and potentially lethal postoperative complication after pancreaticoduodenectomy. During the pancreaticojejunostomy, creation of compressive and shear forces during suture placement and knot tying may cause deformation of and cutting through the fragile pancreatic parenchyma. We sought to understand the mechanics of needle-pancreas interaction and make adjustments to our pancreaticojejunostomy technique so that the creation of shear and compressive stress could be minimized. We provide a detailed description, a mathematical model, and analysis of the outcomes of our new technical modifications.
P233 Judicious use of oximetry can help deliver cost effective sleep service
Authors: C. L. Collins, B. Balakrishnan, J. Madieros
Journal: Thorax (2011)

<h3>Background</h3> Referrals to sleep service are increasing rapidly and make up to 30% of referrals to the Queen9s Medical Centre campus of Nottingham Respiratory Department. Limited channel polysomnography (PSG) at home (PSH-H) or video (PSG_V) are time consuming and costly. In a retrospective study we assessed the role of oximetry in delivering cost effective sleep service. <h3>Methods</h3> We reviewed new referrals to sleep clinic during February and March 2011. We aimed to quantify referrals, assess what investigations were done, the results of these and subsequent management. Cost analysis was then performed to assess impact of the tests ordered on service delivery. Costs of various tests at our centre are: oximetry £28, PSG-H—£ 200 and PSG-V—£350. <h3>Results</h3> In February and March this year 79 new referrals were identified for snoring or sleep disturbance. 53 patients (67%) had oximetry as first test and 26 (33%) had PSG-H or PSG limited or video PSG. The two groups had similar baseline characteristics with BMI of and Epworth Sleepiness Scale (ESS) score of 11. Of those who initially had oximetry 15 (29%) went on to have PSG. Thus 52% of all referrals had PSG whereas 48% were managed with oximetry only. There was statistically significant correlation between 4% oxygen desaturation index per hour (4% ODI) and apnoea-hypopnoea index (AHI) obtained from PSG (R=0.96; p=0.05). The type of diagnostic test used had no impact on CPAP use. We see 600 new referrals per year. Had all patients been subjected to PSG it would cost the service £120 000 to £210 000 depending on the type of polysomnography requested. With nearly 50% patients managed with oximetry it would cost £68 400 to £113 000 leading to huge cost saving without compromising on the quality of service. <h3>Conclusion</h3> Judicious use of oximetry can help deliver cost effective sleep service.
Pharmacology of Penile Erection
Authors: K.-E. Andersson
Journal: Pharmacological Reviews (2001)

Erection is basically a spinal reflex that can be initiated by recruitment of penile afferents, but also by visual, olfactory, and imaginary stimuli. The reflex involves both autonomic and somatic efferents and is modulated by supraspinal influences. Several central transmitters involved in the erectile control have been identified. Dopamine, acetylcholine, nitric oxide (NO), and peptides, such as oxytocin and adrenocorticotropic/alpha-melanocyte-stimulating hormone, seem to have a facilitatory role, whereas serotonin may be either facilitatory or inhibitory, and enkephalins are inhibitory. Peripherally, the balance between contractant and relaxant factors controls the degree of contraction of the smooth muscle of the corpora cavernosa and determines the functional state of the penis. Noradrenaline contracts both corpus cavernosum and penile vessels via stimulation of alpha(1)-adrenoceptors. Neurogenic NO is considered the most important factor for relaxation of penile vessels and corpus cavernosum. The role of other mediators released from nerves or endothelium has not been definitely established. Erectile dysfunction (ED) may be due to inability of penile smooth muscles to relax. This inability can have multiple causes. However, patients with ED respond well to the pharmacological treatments that are currently available. The drugs used are able to substitute, partially or completely, the malfunctioning endogenous mechanisms that control penile erection. Most drugs have a direct action on penile tissue facilitating penile smooth muscle relaxation, including prostaglandin E(1), NO donors, phosphodiesterase inhibitors, and alpha-adrenoceptor antagonists. Dopamine receptors in central nervous centers participating in the initiation of erection have been targeted for the treatment of ED. Apomorphine, administered sublingually, is the first of such drugs.
Meeting Highlights: International Consensus Panel on the Treatment of Primary Breast Cancer
Authors: Aron Goldhirsch, William C. Wood, Hans-Jörg Senn, John H. Glick, Richard D. Gelber
Journal: JNCI Journal of the National Cancer Institute (1995)

Journal Article Meeting Highlights: International Consensus Panel on the Treatment of Primary Breast Cancer Get access Aron Goldhirsch, Aron Goldhirsch Search for other works by this author on: Oxford Academic PubMed Google Scholar William C. Wood, William C. Wood Search for other works by this author on: Oxford Academic PubMed Google Scholar Hans-Jörg Senn, Hans-Jörg Senn Search for other works by this author on: Oxford Academic PubMed Google Scholar John H. Glick, John H. Glick Search for other works by this author on: Oxford Academic PubMed Google Scholar Richard D. Gelber Richard D. Gelber Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 87, Issue 19, 4 October 1995, Pages 1441–1445, https://doi.org/10.1093/jnci/87.19.1441 Published: 04 October 1995 Article history Received: 09 May 1995 Revision received: 06 July 1995 Accepted: 21 July 1995 Published: 04 October 1995