tbuckley/cabot-search huggingface dataset:
Glycated Albumin and Glycated Hemoglobin Are Influenced Differently by Endogenous Insulin Secretion in Patients With Type 2 Diabetes
Authors: Masafumi Koga, Jun Murai, Hiroshi Saito, Soji Kasayama
Journal: Diabetes Care (2009)

OBJECTIVE Glycated albumin (GA) relative to A1C is a useful marker of short-term glycemic control. We investigated whether endogenous insulin secretion in type 2 diabetes has different effects on GA and A1C levels. RESEARCH DESIGN AND METHODS A1C, GA, and GA-to-A1C ratio were compared in 202 type 2 diabetic patients by type of treatment. Effect of β-cell function determined by homeostasis model assessment (HOMA-%β) on GA-to-A1C ratio was examined. In addition, GA-to-A1C ratio was compared between type 2 diabetic patients and 16 patients with type 1 diabetes. RESULTS In type 2 diabetic patients, GA-to-A1C ratio was significantly higher in those treated with insulin than in those treated with diet or oral hypoglycemic agents. HOMA-%β showed a significant inverse correlation with GA-to-A1C ratio. This ratio was higher in type 1 diabetic patients than in type 2 diabetic patients. CONCLUSIONS In diabetic patients with decreased insulin secretion, serum GA levels are higher relative to A1C.
Immunological response to the prolonged administration of heterologous and homologous insulin in cattle.
Authors: A E Renold, J Steinke, J S Soeldner, H N Antoniades, R E Smith
Journal: Journal of Clinical Investigation (1966)

ever, the binding of insulin to its antibody and the neutralization of insulin activity are not neces- sarily synonymous.All these studies have assumed that the anti- genicity of insulin is related primarily to species difference.However, suitable control experi- ments, in which 'the insulin used for immunization was of the same species, have been reported only recently.Pancreatic insulin, extracted and puri- fied for administration, may not be identical with circulating insulin, and therefore it should not be taken for granted that homologous insulin admin- istered to the same species will not produce an im- munological response.The present study was un- dertaken to compare, in the bovine species, the immunological responses to, heterologous (por- cine) and homologous (bovine) insulin adminis- tered over long periods of time.Some of the re- sults of these studies have been reported in preliminary form (11,12). Similar and entirely independent studies have been reported in the pig by Lockwood and Prout (13, 14) and also by Brunfeldt and Deckert (15). MethodsExperimental animals.The 15 heifers used were pure- bred Holstein, Guernsey, Jersey, and Ayrshire breeds of comparable ages from the stock of the Department of Veterinary Science in the College of Agriculture at the University of Massachusetts.They were divided into three groups of five each.Five animals serving as con- trols received only injections of adjuvant, five animals received injections of crystalline porcine insulin in ad- juvant, and five animals received injections of crystalline bovine insulin in adjuvant.Care was taken to achieve comparable distribution of the different breeds in each experimental group.The distribution of breeds, the ini- tial weights, and base-line serum glucose levels are shown in Table I.Antigens.The insulin for injection assayed 24.8 U per
Weekly Carboplatin and Paclitaxel Followed by Concomitant Paclitaxel, Fluorouracil, and Hydroxyurea Chemoradiotherapy: Curative and Organ-Preserving Therapy for Advanced Head and Neck Cancer
Authors: Everett E. Vokes, Kerstin Stenson, Fred R. Rosen, Merrill S. Kies, Alfred W. Rademaker, Mary Ellyn Witt, Bruce E. Brockstein, Marcy A. List, Bing Bing Fung, Louis Portugal, Bharat B. Mittal, Harold Pelzer, Ralph R. Weichselbaum, Daniel J. Haraf
Journal: Journal of Clinical Oncology (2003)

Purpose: The paclitaxel, fluorouracil, and hydroxyurea regimen of paclitaxel, infusional fluorouracil, hydroxyurea, and twice-daily radiation therapy (TFHX) administered every other week has resulted in 3-year survival rates of 60% of stage IV patients. Locoregional and distant failure rates were 13% and 23%, respectively. To reduce distant failure rates, we added a brief course of induction chemotherapy to TFHX. Patients and Methods: Sixty-nine patients received six weekly doses of carboplatin (AUC2) and paclitaxel (135 mg/m 2 ) followed by five cycles of TFHX. Results: Ninety-six percent had stage IV disease. Response to induction chemotherapy was partial response 52% and complete response (CR) 35%. Symptomatically, there was a significant reduction in mouth and throat pain. The most common grade 3 or 4 toxicity was neutropenia (36%). Best response following completion of TFHX was CR in 83%. Toxicities of TFHX consisted of grade 3 or 4 mucositis (74% and 2%) and dermatitis (47% and 14%). At a median follow-up of 28 months, locoregional or systemic disease progression were each noted in five patients. The overall 3-year progression-free survival was 80% (95% confidence interval [CI], 71% to 90%), and the 2- and 3-year overall survival rates were 77% (95% CI, 66% to 87%) and 70% (95% CI, 59% to 82%), respectively. At 12 months, five patients were completely feeding-tube dependent. Conclusion: Administration of carboplatin and paclitaxel before TFHX chemoradiotherapy results in high response activity and may decrease distant failure rates. Overall survival, progression, and organ preservation/functional outcome data support definitive evaluation of this approach.
Imatinib for Melanomas Harboring Mutationally Activated or Amplified <i>KIT</i> Arising on Mucosal, Acral, and Chronically Sun-Damaged Skin
Authors: F. Stephen Hodi, Christopher L. Corless, Anita Giobbie-Hurder, Jonathan A. Fletcher, Meijun Zhu, Adrian Marino-Enriquez, Philip Friedlander, Rene Gonzalez, Jeffrey S. Weber, Thomas F. Gajewski, Steven J. O'Day, Kevin B. Kim, Donald Lawrence, Keith T. Flaherty, Jason J. Luke, Frances A. Collichio, Marc S. Ernstoff, Michael C. Heinrich, Carol Beadling, Katherine A. Zukotynski, Jeffrey T. Yap, Annick D. Van den Abbeele, George D. Demetri, David E. Fisher
Journal: Journal of Clinical Oncology (2013)

Amplifications and mutations in the KIT proto-oncogene in subsets of melanomas provide therapeutic opportunities.We conducted a multicenter phase II trial of imatinib in metastatic mucosal, acral, or chronically sun-damaged (CSD) melanoma with KIT amplifications and/or mutations. Patients received imatinib 400 mg once per day or 400 mg twice per day if there was no initial response. Dose reductions were permitted for treatment-related toxicities. Additional oncogene mutation screening was performed by mass spectroscopy.Twenty-five patients were enrolled (24 evaluable). Eight patients (33%) had tumors with KIT mutations, 11 (46%) with KIT amplifications, and five (21%) with both. Median follow-up was 10.6 months (range, 3.7 to 27.1 months). Best overall response rate (BORR) was 29% (21% excluding nonconfirmed responses) with a two-stage 95% CI of 13% to 51%. BORR was significantly greater than the hypothesized null of 5% and statistically significantly different by mutation status (7 of 13 or 54% KIT mutated v 0% KIT amplified only). There were no statistical differences in rates of progression or survival by mutation status or by melanoma site. The overall disease control rate was 50% but varied significantly by KIT mutation status (77% mutated v 18% amplified). Four patients harbored pretreatment NRAS mutations, and one patient acquired increased KIT amplification after treatment.Melanomas that arise on mucosal, acral, or CSD skin should be assessed for KIT mutations. Imatinib can be effective when tumors harbor KIT mutations, but not if KIT is amplified only. NRAS mutations and KIT copy number gain may be mechanisms of therapeutic resistance to imatinib.
Quality-of-Life Comparisons in a Randomized Trial of Interval Secondary Cytoreduction in Advanced Ovarian Carcinoma: A Gynecologic Oncology Group Study
Authors: Lari Wenzel, Helen Q. Huang, Bradley J. Monk, Peter G. Rose, David Cella
Journal: Journal of Clinical Oncology (2005)

To compare self-reported quality of life (QOL) in patients who did versus did not undergo interval secondary cytoreduction after initial surgery and combination chemotherapy for advanced ovarian cancer and to assess the association between baseline QOL scores and survival.Consenting patients participating in a Gynecologic Oncology Group (GOG) phase III treatment trial (GOG 152) completed the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) questionnaire and treatment-specific supplemental questions at the third and sixth chemotherapy cycles and at 6 and 12 months after starting treatment.For all patients, QOL decreased approximately 1 unit from the first to second assessment. Significant improvement observed at 6 months (P < .001) was sustained at 12 months, with no appreciable between-group difference. The baseline FACT-O score was associated with overall survival (P = .048) but not progression-free survival. Less neurotoxicity was reported among patients who did (38.4%) versus did not (54.0%) undergo interval secondary cytoreduction at the third assessment (P = .005), and older patients experienced more long-term effects.This is the first multicenter randomized trial in ovarian cancer to longitudinally examine self-reported QOL and establish a predictive value of baseline QOL on survival, attributed primarily to the lowest-scoring quartile. Although interval secondary cytoreduction resulted in no notable long-term difference, a clinically significant improvement was seen in both arms at 6 and 12 months after starting therapy. Interestingly, there were fewer complaints of neurotoxicity at 6 months among patients who did versus did not undergo interval secondary cytoreduction.
Asthma prescription trends in the emirate of Abu-Dhabi
Authors: Mohammed AlSamri, Olfat Maarouf, Salim Adib
Journal: European Respiratory Journal (2013)

Asthma-related data, completely available for the first time in 2010 through the information system of the Health Authority of Abu Dhabi were analyzed for the patients’ demographic variables, encounters characteristics, management costs and prescription patterns.  In Abu Dhabi, 155,379 cases were recorded as requiring care for asthma in 2010, of whom 57% were males, 47% UAE nationals, and 46% pediatric (0-14 years) cases. There were 449,967 medical encounters for asthma, with a regional distribution reflecting that of the population, 49% were pediatric visits. Asthma care is available in 246 facilities, but only 66 use spirometry in assessing asthma. Leukotriene modifiers were the asthma-related drugs most frequently dispensed (49.4%); and the most costly drug category (67.7% of total costs). Anticholinergics and oral corticosteroids were next in prescription frequency (23.9% & 23.8% respectively).  Of all drugs, 33.3% were dispensed to children less than 5 years.  Findings support the recommendations for on-going asthma surveillance focusing on epidemiological data and outcome quality. Promotion of evidence-based management standards is needed for all health providers involved in asthma care.
Interleukin-17–mediated Immunopathogenesis in Experimental Hypersensitivity Pneumonitis
Authors: Amrita D. Joshi, Daniel J. Fong, Sameer R. Oak, Glenda Trujillo, Kevin R. Flaherty, Fernando J. Martinez, Cory M. Hogaboam
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

T cells play a critical role in the development of Saccharopolyspora rectivirgula-induced hypersensitivity pneumonitis (HP) but little is known about the role of IL-17A in this disease.We examined the role of IL-17A in a murine model of S. rectivirgula antigen (SR-Ag)-induced HP.Experimental HP was induced by oropharyngeal instillation of SR-Ag in wild-type and IL-17 gene-deficient mice.SR-Ag-induced murine HP was characterized by increased transcript levels of IFN-gamma and IL-12p35 compared with saline-treated control mice. Furthermore, mice with HP showed increased IL-17 in lung homogenates, bronchoalveolar lavage fluid, and ex-vivo lung cultures compared with control mice. Flow cytometric analysis of SR-Ag-challenged lungs revealed increased Th17 and CD11c(+) cells. The role of IL-17 in SR-induced HP was examined in IL-17 deficient (IL17(-/-)) and in wild-type (IL-17(+/+)) mice immunodepleted of IL-17. Histological examination of IL17(-/-) mice challenged with SR-Ag revealed reduced inflammatory cell infiltration, decreased CD11c(+) cells, and reduced levels of inflammatory mediators such as IL-12p70, CCL3, and CXCL9 compared with similarly treated IL17(+/+) mice. Anti-IL-17 antibody treatment of IL-17(+/+) mice with HP resulted in reduced inflammation and a lower percentage of CD11c(+) cells compared with IgG-treated IL-17(+/+) mice with HP.SR-Ag-induced IL-17 plays a pivotal role in the immunopathology of HP and targeting IL-17 is an attractive therapeutic option for this disease.
Effects of ACE inhibitor and AT blocker on dystrophin-related proteins and calpain in failing heart
Authors: M TAKAHASHI, K TANONAKA, H YOSHIDA, R OIKAWA, M KOSHIMIZU, T DAICHO, T TOYOOKA, S TAKEO
Journal: Cardiovascular Research (2004)

Genetic depletion of dystrophin-related protein (DRP) complex causes cardiomyopathy in animals and humans. We found in a previous study that some types of DRP were degraded and that calpain content was increased in rats with non-genetically induced heart failure. The present study was aimed at examining the effects of an angiotensin-I-converting enzyme inhibitor (ACEI) trandolapril (Tra) or an angiotensin II type 1 receptor blocker (ARB) candesartan (Can), both of which are known to improve the pathophysiology of chronic heart failure (CHF) on degradation of DRP in failing hearts.Coronary artery-ligated (CAL) and sham-operated rats (Sham rats) were treated orally with 3 mg/kg/day trandolapril (Tra) or 1 mg/kg/day candesartan (Can) from the 2nd to 8th week after surgery.Hemodynamic parameters of CAL rats at the 8th week after CAL (8w-CAL) indicated heart failure. alpha-Sarcoglycan (SG) and dystrophin in the surviving left ventricle (surviving LV) of 8w-CAL rats decreased, whereas beta-, gamma-, and delta-SGs remained unchanged. Calcium-activated neutral proteases mu-calpain and m-calpain increased in the surviving LV at the 8th week of postmyocardial infarction. Proteolytic activity in the presence of 5 mM Ca2+ markedly increased at the 2nd and 8th weeks, whereas 50 microM Ca2+ slightly but significantly increased proteolysis of casein. Tra or Can treatment improved the hemodynamic parameters, attenuated changes in alpha-SG and dystrophin, and reversed both calpain contents and activities of the failing heart back to sham levels.These results suggest that attenuation in calpain-induced degradation of DRP complex is a possible mechanism for the Tra- or Can-mediated improvement of the pathogenesis of CHF following myocardial infarction.
Conventional and Monocyte-Derived CD11b+ Dendritic Cells Initiate and Maintain T Helper 2 Cell-Mediated Immunity to House Dust Mite Allergen
Authors: Maud Plantinga, Martin Guilliams, Manon Vanheerswynghels, Kim Deswarte, Filipe Branco-Madeira, Wendy Toussaint, Leen Vanhoutte, Katrijn Neyt, Nigel Killeen, Bernard Malissen, Hamida Hammad, Bart N. Lambrecht
Journal: Immunity (2013)
Suppression of Phosphoinositide 3-Kinase Prevents Cardiac Aging in Mice
Authors: Yasutaka Inuzuka, Junji Okuda, Tsuneaki Kawashima, Takao Kato, Shinichiro Niizuma, Yodo Tamaki, Yoshitaka Iwanaga, Yuki Yoshida, Rie Kosugi, Kayo Watanabe-Maeda, Yoji Machida, Shingo Tsuji, Hiroyuki Aburatani, Tohru Izumi, Toru Kita, Tetsuo Shioi
Journal: Circulation (2009)

Heart failure is a typical age-associated disease. Although age-related changes of heart are likely to predispose aged people to heart failure, little is known about the molecular mechanism of cardiac aging.We analyzed age-associated changes in murine heart and the manner in which suppression of the p110alpha isoform of phosphoinositide 3-kinase activity modified cardiac aging. Cardiac function declined in old mice associated with the expression of senescence markers. Accumulation of ubiquitinated protein and lipofuscin, as well as comprehensive gene expression profiling, indicated that dysregulation of protein quality control was a characteristic of cardiac aging. Inhibition of phosphoinositide 3-kinase preserved cardiac function and attenuated expression of the senescence markers associated with enhanced autophagy. Suppression of target of rapamycin, a downstream effector of phosphoinositide 3-kinase, also prevented lipofuscin accumulation in the heart.Suppression of phosphoinositide 3-kinase prevented many age-associated changes in the heart and preserved cardiac function of aged mice.
Renal and pressor effects of aminoguanidine in cirrhotic rats with ascites.
Authors: M C Ortíz, L A Fortepiani, C Martínez, N M Atucha, J García-Estañ
Journal: Journal of the American Society of Nephrology (1996)

Recent work indicates that nitric oxide (NO) plays an important role in the systemic and renal alterations of liver cirrhosis. This study used aminoguanidine (AG), a preferential inhibitor of inducible nitric oxide synthase (iNOS), to evaluate the role of this NOS isoform in the systemic and renal alterations of an experimental model of liver cirrhosis with ascites (carbon tetrachloride/ phenobarbital). Experiments have been performed in anesthetized cirrhotic rats and their respective control rats prepared for clearance studies. Administration of AG (10 to 100 mg/kg, iv) elevated dose-dependent mean arterial pressure (MAP, in mm Hg) in the cirrhotic rats from a basal level of 79.3 +/- 3.6 to 115.0 +/- 4.7, whereas in the control animals, MAP increased only with the highest dose of the inhibitor (from 121.8 +/- 3.6 to 133.3 +/- 1.4). In the cirrhotic group, AG also significantly increased sodium and water excretion, whereas these effects were very modest in the control group. Plasma concentration of nitrates+nitrites, measured as an index of NO production, were significantly increased in the cirrhotic animals in the basal period and decreased with AG to levels not significantly different from the control animals. Similar experiments performed with the nonspecific NOS inhibitor N omega-nitro-L-arginine (NNA) also demonstrated an increased pressor sensitivity of the cirrhotic rats, but the arterial hypotension was completely corrected. These results, in an experimental model of liver cirrhosis with ascites, show that AG exerts a beneficial effect as a result of inhibition of NO production, increasing blood pressure and improving the reduced excretory function. Because NNA, but not AG, completely normalized the arterial hypotension, it is suggested that the constitutive NOS isoform is also contributing in an important degree. It is concluded that the activation of both inducible and constitutive NOS isoforms plays an important role in the lower systemic blood pressure and associated abnormalities that characterize liver cirrhosis.
Cbl-b Negatively Regulates B Cell Antigen Receptor Signaling in Mature B Cells through Ubiquitination of the Tyrosine Kinase Syk
Authors: Hae Won Sohn, Hua Gu, Susan K. Pierce
Journal: The Journal of Experimental Medicine (2003)

Members of the Cbl family of molecular adaptors play key roles in regulating tyrosine kinase-dependent signaling in a variety of cellular systems. Here we provide evidence that in B cells Cbl-b functions as a negative regulator of B cell antigen receptor (BCR) signaling during the normal course of a response. In B cells from Cbl-b-deficient mice cross-linking the BCRs resulted in sustained phosphorylation of Igalpha, Syk, and phospholipase C (PLC)-gamma2, leading to prolonged Ca2+ mobilization, and increases in extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal protein kinase (JNK) phosphorylation and surface expression of the activation marker, CD69. Image analysis following BCR cross-linking showed sustained polarization of the BCRs into large signaling-active caps associated with phosphorylated Syk in Cbl-b-deficient B cells in contrast to the BCRs in Cbl-b-expressing B cells that rapidly proceeded to form small, condensed, signaling inactive caps. Significantly, prolonged phosphorylation of Syk correlated with reduced ubiquitination of Syk indicating that Cbl-b negatively regulates BCR signaling by targeting Syk for ubiquitination.
Hypoxia-induced neutrophil survival is mediated by HIF-1α–dependent NF-κB activity
Authors: Sarah R. Walmsley, Cristin Print, Neda Farahi, Carole Peyssonnaux, Randall S. Johnson, Thorsten Cramer, Anastasia Sobolewski, Alison M. Condliffe, Andrew S. Cowburn, Nicola Johnson, Edwin R. Chilvers
Journal: The Journal of Experimental Medicine (2005)

Neutrophils are key effector cells of the innate immune response and are required to migrate and function within adverse microenvironmental conditions. These inflammatory sites are characterized by low levels of oxygen and glucose and high levels of reductive metabolites. A major regulator of neutrophil functional longevity is the ability of these cells to undergo apoptosis. We examined the mechanism by which hypoxia causes an inhibition of neutrophil apoptosis in human and murine neutrophils. We show that neutrophils possess the hypoxia-inducible factor (HIF)-1α and factor inhibiting HIF (FIH) hydroxylase oxygen-sensing pathway and using HIF-1α–deficient myeloid cells demonstrate that HIF-1α is directly involved in regulating neutrophil survival in hypoxia. Gene array, TaqMan PCR, Western blotting, and oligonucleotide binding assays identify NF-κB as a novel hypoxia-regulated and HIF-dependent target, with inhibition of NF-κB by gliotoxin or parthenolide resulting in the abrogation of hypoxic survival. In addition, we identify macrophage inflammatory protein-1β as a novel hypoxia-induced neutrophil survival factor.
Btk inhibition suppresses agonist-induced human macrophage activation and inflammatory gene expression in RA synovial tissue explants
Authors: Linda M Hartkamp, Jay S Fine, Inge E van Es, Man Wai Tang, Michael Smith, John Woods, Satwant Narula, Julie DeMartino, Paul P Tak, Kris A Reedquist
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objectives</h3> Bruton9s tyrosine kinase (Btk) is required for B lymphocyte and myeloid cell contributions to pathology in murine models of arthritis. Here, we examined the potential contributions of synovial Btk expression and activation to inflammation in rheumatoid arthritis (RA). <h3>Materials and methods</h3> Btk was detected by immunohistochemistry and digital image analysis in synovial tissue from biologically naive RA (n=16) and psoriatic arthritis (PsA) (n=12) patients. Cell populations expressing Btk were identified by immunofluorescent double labelling confocal microscopy, quantitative (q-) PCR and immunoblotting. The effects of a Btk-specific inhibitor, RN486, on gene expression in human macrophages and RA synovial tissue explants (n=8) were assessed by qPCR, ELISA and single-plex assays. <h3>Results</h3> Btk was expressed at equivalent levels in RA and PsA synovial tissue, restricted to B lymphocytes, monocytes, macrophages and mast cells. RN486 significantly inhibited macrophage IL-6 production induced by Fc receptor and CD40 ligation. RN486 also reduced mRNA expression of overlapping gene sets induced by IgG, CD40 ligand (CD40L) and RA synovial fluid, and significantly suppressed macrophage production of CD40L-induced IL-8, TNF, MMP-1 and MMP-10, LPS-induced MMP-1, MMP-7 and MMP-10 production, and spontaneous production of IL-6, PDGF, CXCL-9 and MMP-1 by RA synovial explants. <h3>Conclusions</h3> Btk is expressed equivalently in RA and PsA synovial tissue, primarily in macrophages. Btk activity is needed to drive macrophage activation in response to multiple agonists relevant to inflammatory arthritis, and promotes RA synovial tissue cytokine and MMP production. Pharmacological targeting of Btk may be of therapeutic benefit in the treatment of RA and other inflammatory diseases.