tbuckley/cabot-search huggingface dataset:
Differential Effects of Insulin on Splanchnic and Peripheral Glucose Disposal after an Intravenous Glucose Load in Man
Authors: Luigi Saccà, Marco Cicala, Bruno Trimarco, Biagio Ungaro, Carlo Vigorito
Journal: Journal of Clinical Investigation (1982)

The present study was designed to investigate the mechanisms by which insulin regulates the disposal of an intravenous glucose load in man. A combined tracer-hepatic vein catheter technique was used to quantitate directly the components of net splanchnic glucose balance (NSGB), i.e., splanchnic glucose uptake and hepatic glucose output, and peripheral (extrasplanchnic) glucose uptake. Four different protocols were performed: (a) intravenous infusion of glucose alone (6.5 mg kg−1 min−1) for 90 min (control group); (b) glucose plus somatostatin (0.6 mg/h) and glucagon (0.8 ng kg−1 min−1; (c) glucose plus somatostatin, glucagon, and insulin (0.15 mU kg−1 min−1); and (d) glucose plus somatostatin, glucagon, and insulin (0.4 m U kg−1 min−1). In groups 2-4, arterial blood glucose was raised to comparable levels to those of controls (≃170 mg/dl) by a variable glucose infusion. In the control group, plasma insulin levels reached 40 μU/ml at 90 min. NSGB switched from a net output of 1.71±0.13 to a net uptake of 1.5-1.6 mg kg−1 min−1 due to a 90-95% suppression of hepatic glucose output (P < 0.01) and a 105-130% elevation of splanchnic glucose uptake (from 0.78±0.13 to 1.6-1.8 mg kg−1 min−1; P < 0.01). Peripheral glucose uptake rose by 150-160% (P < 0.01). In group 2, plasma insulin fell to <5 μU/ml. Net splanchnic glucose output initially rose twofold but later returned to basal values. This response was entirely accounted for by similar changes in hepatic glucose output since splanchnic glucose uptake remained totally unchanged in spite of hyperglycemia. In contrast, peripheral glucose uptake rose consistently by 100% (P < 0.01) despite insulin deficiency. In an additional group of experiments, glucose metabolism by the forearm muscle tissue was quantitated during identical conditions to those of group 2 (hyperglycemia plus insulin deficiency). Both the arterial-deep venous blood glucose difference and forearm glucose uptake increased markedly by 300-400% (P < 0.05 - <0.01). In group 3, plasma insulin was maintained at near-basal, peripheral levels (12-14 μU/ml). Hepatic glucose output decreased slightly by 35-40% (P < 0.05) while splanchnic glucose uptake remained unchanged. Consequently, the net glucose overproduction seen in group 2 was totally prevented although NSGB still remained as a net output. In group 4, peripheral insulin levels were similar to those of the control group (35-40 μU/ml). The suppression of hepatic glucose output was more pronounced (60-65%) and splanchnic glucose uptake rose consistently by 65% (P < 0.01). Consequently, NSGB did not remain as a net output but eventually switched to a small uptake (0.3 mg kg−1 min−1). Peripheral glucose uptake rose to the same extent as in controls.
From DNA to Fitness Differences: Sequences and Structures of Adaptive Variants of Colias Phosphoglucose Isomerase (PGI)
Authors: Christopher W. Wheat, Ward B. Watt, David D. Pollock, Patricia M. Schulte
Journal: Molecular Biology and Evolution (2005)

Colias eurytheme butterflies display extensive allozyme polymorphism in the enzyme phosphoglucose isomerase (PGI). Earlier studies on biochemical and fitness effects of these genotypes found evidence of strong natural selection maintaining this polymorphism in the wild. Here we analyze the molecular features of this polymorphism by sequencing multiple alleles and modeling their structures. PGI is a dimer with rotational symmetry. Each monomer provides a critical residue to the other monomer's catalytic center. Sequenced alleles differ at multiple amino acid positions, including cryptic charge-neutral variation, but most consistent differences among the electromorph alleles are at the charge-changing amino acid sites. Principal candidate sites of selection, identified by structural and functional analyses and by their variants' population frequencies, occur in interpenetrating loops across the interface between monomers, where they may alter subunit interactions and catalytic center geometry. Comparison to a second (and basal) species, Colias meadii, also polymorphic for PGI under natural selection, reveals one fixed amino acid difference between their PGIs, which is located in the interpenetrating loop and accompanies functional differences among their variants. We also study nucleotide variability among the PGI alleles, comparing these data to similar data from another glycolytic enzyme gene, glyceraldehyde-3-phosphate dehydrogenase. Despite extensive nonsynonymous and synonymous polymorphism at PGI in each species, the only base changes fixed between species are the two causing the amino acid replacement; this absence of synonymous fixation yields a significant McDonald-Kreitman test. Analyses of these data suggest historical population expansion. Positive peaks of Tajima's D statistic, representing regions of neutral "hitchhiking," are found around the principal candidate sites of selection. This study provides novel views of molecular-structural mechanisms, and beginnings of historical evidence, for a long-persistent balanced enzyme polymorphism at PGI in these and perhaps other species.
Mechanisms of improvement of respiratory failure in patients with restrictive thoracic disease treated with non-invasive ventilation
Authors: A H Nickol
Journal: Thorax (2005)

Nocturnal non-invasive ventilation (NIV) is an effective treatment for hypercapnic respiratory failure in patients with restrictive thoracic disease. We hypothesised that NIV may reverse respiratory failure by increasing the ventilatory response to carbon dioxide, reducing inspiratory muscle fatigue, or enhancing pulmonary mechanics.Twenty patients with restrictive disease were studied at baseline (D0) and at 5-8 days (D5) and 3 months (3M).Mean (SD) daytime arterial carbon dioxide tension (Paco(2)) was reduced from 7.1 (0.9) kPa to 6.6 (0.8) kPa at D5 and 6.3 (0.9) kPa at 3M (p = 0.004), with the mean (SD) hypercapnic ventilatory response increasing from 2.8 (2.3) l/min/kPa to 3.6 (2.4) l/min/kPa at D5 and 4.3 (3.3) l/min/kPa at 3M (p = 0.044). No increase was observed in measures of inspiratory muscle strength including twitch transdiaphragmatic pressure, nor in lung function or respiratory system compliance.These findings suggest that increased ventilatory response to carbon dioxide is the principal mechanism underlying the long term improvement in gas exchange following NIV in patients with restrictive thoracic disease. Increases in respiratory muscle strength (sniff oesophageal pressure and sniff nasal pressure) correlated with reductions in the Epworth sleepiness score, possibly indicating an increase in the ability of patients to activate inspiratory muscles rather than an improvement in contractility.
<i>Atm</i>-Deficient Mice Exhibit Increased Sensitivity to Dextran Sulfate Sodium–Induced Colitis Characterized by Elevated DNA Damage and Persistent Immune Activation
Authors: Aya M. Westbrook, Robert H. Schiestl
Journal: Cancer Research (2010)

Abstract The role of ataxia telangiectasia mutated (ATM), a DNA double-strand break recognition and response protein, in inflammation and inflammatory diseases is unclear. We have previously shown that high levels of systemic DNA damage are induced by intestinal inflammation in wild-type mice. To determine the effect of Atm deficiency in inflammation, we induced experimental colitis in Atm−/−, Atm+/−, and wild-type mice via dextran sulfate sodium (DSS) administration. Atm−/− mice had higher disease activity indices and rates of mortality compared with heterozygous and wild-type mice. Systemic DNA damage and immune response were characterized in peripheral blood throughout and after three cycles of treatment. Atm−/− mice showed increased sensitivity to levels of DNA strand breaks in peripheral leukocytes, as well as micronucleus formation in erythroblasts, compared with heterozygous and wild-type mice, especially during remission periods and after the end of treatment. Markers of reactive oxygen and nitrogen species–mediated damage, including 8-oxoguanine and nitrotyrosine, were present both in the distal colon and in peripheral leukocytes, with Atm−/− mice manifesting more 8-oxoguanine formation than wild-type mice. Atm−/− mice showed greater upregulation of inflammatory cytokines and significantly higher percentages of activated CD69+ and CD44+ T cells in the peripheral blood throughout treatment. ATM, therefore, may be a critical immunoregulatory factor dampening the deleterious effects of chronic DSS-induced inflammation, necessary for systemic genomic stability and homeostasis of the gut epithelial barrier. Cancer Res; 70(5); 1875–84
C5a Receptor (CD88) Blockade Protects against MPO-ANCA GN
Authors: Hong Xiao, Daniel J. Dairaghi, Jay P. Powers, Linda S. Ertl, Trageen Baumgart, Yu Wang, Lisa C. Seitz, Mark E.T. Penfold, Lin Gan, Peiqi Hu, Bao Lu, Norma P. Gerard, Craig Gerard, Thomas J. Schall, Juan C. Jaen, Ronald J. Falk, J. Charles Jennette
Journal: Journal of the American Society of Nephrology (2013)

Necrotizing and crescentic GN (NCGN) with a paucity of glomerular immunoglobulin deposits is associated with ANCA. The most common ANCA target antigens are myeloperoxidase (MPO) and proteinase 3. In a manner that requires activation of the alternative complement pathway, passive transfer of antibodies to mouse MPO (anti-MPO) induces a mouse model of ANCA NCGN that closely mimics human disease. Here, we confirm the importance of C5aR/CD88 in the mediation of anti-MPO-induced NCGN and report that C6 is not required. We further demonstrate that deficiency of C5a-like receptor (C5L2) has the reverse effect of C5aR/CD88 deficiency and results in more severe disease, indicating that C5aR/CD88 engagement enhances inflammation and C5L2 engagement suppresses inflammation. Oral administration of CCX168, a small molecule antagonist of human C5aR/CD88, ameliorated anti-MPO-induced NCGN in mice expressing human C5aR/CD88. These observations suggest that blockade of C5aR/CD88 might have therapeutic benefit in patients with ANCA-associated vasculitis and GN.
Perceptions, Knowledge, and Satisfaction With Contralateral Prophylactic Mastectomy Among Young Women With Breast Cancer
Authors: Shoshana M. Rosenberg, Michaela S. Tracy, Meghan E. Meyer, Karen Sepucha, Shari Gelber, Judi Hirshfield-Bartek, Susan Troyan, Monica Morrow, Lidia Schapira, Steven E. Come, Eric P. Winer, Ann H. Partridge
Journal: Annals of Internal Medicine (2013)

Chinese translationRates of contralateral prophylactic mastectomy (CPM) have increased dramatically, particularly among younger women with breast cancer, but little is known about how women approach the decision to have CPM.To examine preferences, knowledge, decision making, and experiences of young women with breast cancer who choose CPM.Cross-sectional survey.8 academic and community medical centers that enrolled 550 women diagnosed with breast cancer at age 40 years or younger between November 2006 and November 2010.123 women without known bilateral breast cancer who reported having bilateral mastectomy.A 1-time, 23-item survey that included items related to decision making, knowledge, risk perception, and breast cancer worry.Most women indicated that desires to decrease their risk for contralateral breast cancer (98%) and improve survival (94%) were extremely or very important factors in their decision to have CPM. However, only 18% indicated that women with breast cancer who undergo CPM live longer than those who do not. BRCA1 or BRCA2 mutation carriers more accurately perceived their risk for contralateral breast cancer, whereas women without a known mutation substantially overestimated this risk.The survey, which was administered a median of 2 years after surgery, was not validated, and some questions might have been misinterpreted by respondents or subject to recall bias. Generalizability of the findings might be limited.Despite knowing that CPM does not clearly improve survival, women who have the procedure do so, in part, to extend their lives. Many women overestimate their actual risk for cancer in the unaffected breast. Interventions aimed at improving risk communication in an effort to promote evidence-based decision making are warranted.Susan G. Komen for the Cure.
Boceprevir for Untreated Chronic HCV Genotype 1 Infection
Authors: Fred Poordad, Jonathan McCone, Bruce R. Bacon, Savino Bruno, Michael P. Manns, Mark S. Sulkowski, Ira M. Jacobson, K. Rajender Reddy, Zachary D. Goodman, Navdeep Boparai, Mark J. DiNubile, Vilma Sniukiene, Clifford A. Brass, Janice K. Albrecht, Jean-Pierre Bronowicki
Journal: New England Journal of Medicine (2011)

Peginterferon-ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies.We conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon-ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately.A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P<0.001), and in 213 of the 311 patients (68%) in group 3 (P<0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (P=0.04), and in 29 of the 55 patients (53%) in group 3 (P=0.004). In group 2, a total of 44% of patients received peginterferon-ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively.The addition of boceprevir to standard therapy with peginterferon-ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir. (Funded by Schering-Plough [now Merck]; SPRINT-2 ClinicalTrials.gov number, NCT00705432.).
Chest Compression–Only Cardiopulmonary Resuscitation for Out-of-Hospital Cardiac Arrest With Public-Access Defibrillation
Authors: Taku Iwami, Tetsuhisa Kitamura, Takashi Kawamura, Hideo Mitamura, Ken Nagao, Morimasa Takayama, Yoshihiko Seino, Hideharu Tanaka, Hiroshi Nonogi, Naohiro Yonemoto, Takeshi Kimura
Journal: Circulation (2012)

It remains unclear which is more effective to increase survival after out-of-hospital cardiac arrest in those with public-access defibrillation, bystander-initiated chest compression-only cardiopulmonary resuscitation (CPR) or conventional CPR with rescue breathing.A nationwide, prospective, population-based observational study covering the whole population of Japan and involving consecutive out-of-hospital cardiac arrest patients with resuscitation attempts has been conducted since 2005. We enrolled all out-of-hospital cardiac arrests of presumed cardiac origin that were witnessed and received shocks with public-access automated external defibrillation (AEDs) by bystanders from January 1, 2005, to December 31, 2009. The main outcome measure was neurologically favorable 1-month survival. We compared outcomes by type of bystander-initiated CPR (chest compression-only CPR and conventional CPR with compressions and rescue breathing). Multivariable logistic regression was used to assess the relationship between the type of CPR and a better neurological outcome. During the 5 years, 1376 bystander-witnessed out-of-hospital cardiac arrests of cardiac origin in individuals who received CPR and shocks with public-access AEDs by bystanders were registered. Among them, 506 (36.8%) received chest compression-only CPR and 870 (63.2%) received conventional CPR. The chest compression-only CPR group (40.7%, 206 of 506) had a significantly higher rate of 1-month survival with favorable neurological outcome than the conventional CPR group (32.9%, 286 of 870; adjusted odds ratio, 1.33; 95% confidence interval, 1.03-1.70).Compression-only CPR is more effective than conventional CPR for patients in whom out-of-hospital cardiac arrest is witnessed and shocked with public-access defibrillation. Compression-only CPR is the most likely scenario in which lay rescuers can witness a sudden collapse and use public-access AEDs.
A systematic review of serial peak expiratory flow measurements in the diagnosis of occupational asthma
Authors: Vicky C Moore, Maritta S Jaakkola, P Sherwood Burge
Journal: European Respiratory Journal (2011)

This work systematically reviews literature on the application of serial peak expiratory flow (PEF) measurements in the diagnosis of occupational asthma (OA) and calculates summary estimates of the sensitivity, specificity and feasibility of serial PEFs.  Methods: Papers were searched for on the Medline database via the PubMed website (http://www.ncbi.nlm.nih.gov/sites/entrez) and on the Birmingham Chest Clinic departmental website www.occupationalasthma.com from 2004 until April 2009 using the search terms “Peak flow AND occupational asthma” and “Peak flow AND work related asthma”. Abstracts were screened to select those justifying a full paper review. Papers used in the British Occupational Health Research Foundation (BOHRF) guidelines (current until June 2004) were also reviewed. Case studies and narrative reviews were excluded. Type of analysis, quality of paper, sensitivity and specificity of serial PEFs compared to reference tests and return rates were documented. Results were pooled from all studies to produce overall estimates.  Results: A total of 80 abstracts were reviewed, leading to 23 full papers plus 15 papers from the 2004 BOHRF review. 7 papers were excluded. The pooled sensitivity of serial PEF fulfilling minimum data quantity requirements for a diagnosis of OA was 82% (95% CI 76-90) and the pooled specificity 88% (95% CI 80-95). Return rates were similar between PEFs requested through workplace studies (85%) and those requested in a clinical setting (78%).  Conclusion: Based on a systematic literature search, serial PEF measurement is a feasible, sensitive and specific test for the diagnosis of OA, when potential sources of error are understood.
Walking with continuous positive airway pressure
Authors: W. Dieperink, J. F. Goorhuis, W. de Weerd, A. Hazenberg, J. G. Zijlstra, M. W. N. Nijsten
Journal: European Respiratory Journal (2006)

A ventilator-dependent child had been in the paediatric intensive care unit (PICU) ever since birth. As a result, she had fallen behind considerably in her development. After 18 months, continuous positive airway pressure was successfully administered via a tracheostomy tube with a novel lightweight device. This enabled her to walk in the PICU. With this device, the child was discharged home where she could walk with an action range of 10 m. Subsequently, her psychomotor development improved remarkably. To the authors' knowledge, this is the first case report of a patient, adult or paediatric, who could actually walk with a sufficient radius of action while receiving long-term respiratory support.
Acute folic acid deficiency of unknown aetiology: temperate sprue
Authors: W. T. Cooke, D. J. Fone, E. V. Cox, M. J. Meynell, R. Gaddie
Journal: Gut (1963)

The 20 patients described could be included in the group of patients diagnosed as ;idiopathic steatorrhoea'. However, their histories were short and diarrhoea was not a major feature. Since megaloblastic anaemia due to folic acid deficiency was a common feature it is suggested that these patients may form a homogeneous group and the diagnostic label of temperate sprue is suggested.
Expression of Peroxisome Proliferator-Activated Receptor-γ in Vascular Smooth Muscle Cells Is Upregulated in Cystic Medial Degeneration of Annuloaortic Ectasia in Marfan Syndrome
Authors: Yasunari Sakomura, Hirotaka Nagashima, Yoshikazu Aoka, Kenta Uto, Akiko Sakuta, Shigeyuki Aomi, Hiromi Kurosawa, Toshio Nishikawa, Hiroshi Kasanuki
Journal: Circulation (2002)

Cystic medial degeneration (CMD) is a histological abnormality that is common in annuloaortic ectasia (AAE) and aortic dissection with Marfan syndrome. Apoptosis and loss of vascular smooth muscle cells (VSMCs) is one of the features of CMD, but little is known about its pathogenesis. Peroxisome proliferator-activated receptor-gamma (PPARgamma), a transcription factor of the nuclear receptor superfamily, has been reported to show antiproliferative effects on VSMCs as well as anti-inflammatory effects on macrophages. PPARgamma agonist has been recently reported to induce apoptosis of cultured VSMCs.We examined the histopathology of ascending aortas in AAE of Marfan patients (n=21) and control patients (n=6) at surgery. RT-PCR was performed to demonstrate expression of PPARgamma in CMD. Localization of PPARgamma was determined by double immunostaining using antibodies against PPARgamma and cell-specific markers (ie, SMCs, macrophages, and T lymphocytes).PPARgamma expression was upregulated in AAE samples but minimal in control samples by RT-PCR (P=0.07). Immunoreactivity against PPARgamma in numerous nuclei of VSMCs was observed in CMD lesions. Severity of CMD correlated with positive immunoreactivity of PPARgamma in medial VSMCs (P=0.03). No inflammatory cells (ie, macrophages or T lymphocytes) were detected in CMD lesions.PPARgamma expression is upregulated in SMCs of CMD without any inflammatory response. Activated PPARgamma in VSMCs might be involved in the pathogenesis of CMD in Marfan's aortas. Regulation of PPARgamma might lead to clinical implication in protection against progression of AAE.
Tumor-Associated MICA Is Shed by ADAM Proteases
Authors: Inja Waldhauer, Dennis Goehlsdorf, Friederike Gieseke, Toni Weinschenk, Mareike Wittenbrink, Andreas Ludwig, Stefan Stevanovic, Hans-Georg Rammensee, Alexander Steinle
Journal: Cancer Research (2008)

Abstract The immunoreceptor NKG2D promotes immunosurveillance of malignant cells and protects the host from tumor initiation by activating natural killer cells and costimulating CD8 T cells. NKG2D-mediated recognition of malignant cells by cytotoxic lymphocytes is enabled through the tumor-associated expression of NKG2D ligands (NKG2DL) resulting from cellular or genotoxic stress. Shedding of NKG2DL is thought to constitute a major countermechanism of tumor cells to subvert NKG2D-mediated immunosurveillance. Here, we report that the prototypical NKG2DL MICA is released by proteolytic cleavage in the stalk of the MICA ectodomain, where deletions, but not alanine substitutions, impede MICA shedding. Small compound-mediated stimulation and inhibition of MICA shedding adduced characteristics that indicated an involvement of members of the “a disintegrin and metalloproteinase” (ADAM) family. Accordingly, MICA shedding by tumor cells was inhibited by silencing of the related ADAM10 and ADAM17 proteases, which are known to promote tumor growth by releasing epidermal growth factor receptor ligands. Collectively, our data show that ADAM10 and ADAM17 are critically involved in the tumor-associated proteolytic release of soluble MICA facilitating tumor immune escape. Hence, therapeutic blockade of ADAM10 and ADAM17 seems promising for cancer treatment by targeting both growth and immune escape of tumors. [Cancer Res 2008;68(15):6368–76]