tbuckley/cabot-search huggingface dataset:
The Korle-Bu Hb Variant in Caucasian Women With Type 1 Diabetes
Authors: Ana Chico, Anna Padrós, Anna Novials
Journal: Diabetes Care (2004)

Measuring HbA1c concentrations in diabetic patients is an established procedure for evaluating the long-term control of diabetes. The Diabetes Control and Complications Trial confirmed the direct relationship between diabetes complications and HbA1c levels in type 1 diabetic patients. As a result, both the American Diabetes Association and the European Group for the Study of Diabetes have drawn up guidelines for assessing glycemic control by measuring HbA1c levels. However, in spite of advances in standardizing methods for measuring HbA1c concentrations, an increasing number of Hb variants produce false HbA1c determinations.

We report the first case of the Korle-Bu Hb variant in a Caucasian woman, which is also the first case described in a diabetic subject. We also describe the interference of this variant in some of the methods used to determine HbA1c concentrations. In our patient, HbA1c levels were underestimated for 20 years and, as a result of this misleadingly good metabolic control, the patient has developed microangiopathic diabetes complications.

A 29-year-old Caucasian type 1 diabetic woman was referred to our center in order to optimize her glycemic control because she was planning to become pregnant. Diabetes had been diagnosed 20 years earlier, and she had since been …
Two-Field Photography Can Identify Patients With Vision-Threatening Diabetic Retinopathy
Authors: Catharina Stellingwerf, Peter L.L.J. Hardus, Johanna M.M. Hooymans
Journal: Diabetes Care (2001)

OBJECTIVE—To compare the effectiveness of two 45° photographic fields per eye in the screening for diabetic retinopathy with the routine ophthalmologist’s examination and to study the effectiveness of visual acuity measurement in the detection of diabetic macular edema. RESEARCH DESIGN AND METHODS—Type 1 and 2 diabetic patients without a known history of more than minimal retinopathy (n = 469) had a routine examination by an ophthalmologist, including visual acuity measurement, indirect retinoscopy, and biomicroscopy. At the same time, two-field nonstereoscopic retinal photographs were made of both eyes and assessed in a masked fashion by a retinal specialist. The results were compared. RESULTS—The prevalence was 4.3% for vision-threatening retinopathy and 24% for any retinopathy. The sensitivity of two-field photography in identifying diabetic patients with sight-threatening retinopathy was 95% (specificity 99%) and sensitivity for detecting any retinopathy was 83% (specificity 88%). The percentage of referrals to an ophthalmologist was 6.2%. All patients with macular edema detected by biomicroscopy were classified as having vision-threatening retinopathy on the photographs. CONCLUSIONS—Two-field retinal photography is a promising alternative to the routine ophthalmologist’s examination in the screening for diabetic retinopathy. Visual acuity measurement is not a sensitive tool for the detection of macular edema. Screening for diabetic retinopathy using two-field retinal photography is feasible in a primary care setting and can substantially lower the number of ophthalmic referrals.
Leukotriene receptor antagonists and biosynthesis inhibitors: potential breakthrough in asthma therapy
Authors: KF Chung
Journal: European Respiratory Journal (1995)

Cysteinyl leukotrienes are potent bronchoconstrictors, inducers of airway microvascular leakage and oedema, and of mucus secretion, in addition to causing an eosinophilic airway infiltration. Increased urinary excretion of the cysteinyl leukotriene E4 (LTE4) has been demonstrated following allergen challenge and during acute asthma attacks. Strategies for inhibition of cysteinyl leukotriene effects include antagonism of cysteinyl leukotriene receptors and inhibition of 5-lipoxygenase activity. In experimental challenge studies in asthmatic patients, these compounds can inhibit bronchoconstriction in response to exercise, aspirin and allergen. Results from clinical studies using receptor antagonists, such as ICI 204,219 and MK-571, and synthesis inhibitors, such as zileuton, demonstrate beneficial effects, with improvement in symptoms and forced expiratory volume in one second (FEV1), and a reduction in the use of beta 2-adrenergic relief medication. Further studies are needed to clarify the exact mechanisms by which these compounds provide beneficial effects. Cysteinyl leukotrienes are important mediators of asthma, and inhibition of their effects may represent a potential breakthrough in the therapy of asthma.
Coronary Inflow and Oxygen Usage Following Cardiac Sympathetic Nerve Stimulation in Unanesthetized Dogs
Authors: LINO GRANATA, RAY A. OLSSON, ANDREW HUVOS, DONALD E. GREGG
Journal: Circulation Research (1965)

The effects of cardiac sympathetic nerve stimulation on coronary inflow were studied in previously operated conscious dogs, using electromagnetic flowmeters. Stimulation caused an increase of coronary inflow which was due mainly to an augmentation of flow during diastole. In systole, inflow changes were smaller and variable according to the strength of stimulation. The data presented indicate that an arteriolar dilatation may play a role in augmenting coronary inflow. In several instances, the increase of coronary inflow was preceded by a phase of reduction which suggested the possibility of coronary vasoconstriction as a primary direct effect of cardiac sympathetic activation.
Pancreatic β-Cell Function in Women With Gestational Diabetes Mellitus Defined by New Consensus Criteria
Authors: Kei Miyakoshi, Yoshifumi Saisho, Mamoru Tanaka, Akira Shimada, Hiroshi Itoh, Yasunori Yoshimura
Journal: Diabetes Care (2010)

Apotential etiology for gestational diabetes mellitus (GDM) is a limitation in β-cell reserves that manifests as hyperglycemia when insulin secretion does not increase to match the escalated insulin needs during pregnancy (1). Recently, the international association of diabetes and pregnancy study groups (IAPDSG) proposed new criteria for diagnosing and classifying diabetes in pregnancy based on the association of maternal hyperglycemia with perinatal outcomes (2). To date, β-cell function in GDM defined by the new consensus criteria has not been reported. β-cell function has been assessed by a disposition index defined as the product of insulin sensitivity and insulin secretion determined by intravenous glucose tolerance test (IVGTT) (3). The recent demonstration of a hyperbolic …
Induction of interferon alpha from human lymphocytes by autologous, dengue virus-infected monocytes.
Authors: I Kurane, F A Ennis
Journal: The Journal of Experimental Medicine (1987)

Human monocytes actively replicate dengue virus. To dissect the primary immune responses to dengue virus-infected monocytes (DV-monocytes), we analyzed the interaction between autologous DV-monocytes and the peripheral blood lymphocytes (PBL) of dengue nonimmune donors. Interferon (IFN) activity was detected when PBL were cultured with DV-monocytes. Cell contact between PBL and DV-monocytes was required for IFN production; however, MHC compatibility between PBL and monocytes was not necessary. DV-monocytes fixed with paraformaldehyde or glutaraldehyde, which produced no infectious virus, also induced high levels of IFN from PBL. The ability of DV-monocytes to induce IFN correlated with the appearance of dengue antigens. The PBL that produce IFN were characterized by FACS sorting using monoclonal and polyclonal antibodies. HLA-DR+ and T3- cells produced high titers of IFN, while HLA-DR- and T3+ cells produced very low or undetectable levels of IFN. Moderate titers of IFN were produced by cells contained in B cell fractions (surface immunoglobulin-positive, B1+, and Leu-12+), and cells contained in natural killer cell fractions (Leu-11+ and OKM1+). Therefore, IFN-producing cells are heterogeneous, and the predominant producer cells are characterized as HLA-DR+ and non-T lymphocytes. The IFN produced was characterized by RIA using mAbs to IFN-alpha and IFN-gamma. The IFN-alpha was the predominant IFN produced; in addition, a low level of IFN-gamma was also detected in some experiments. The culture fluids obtained from PBL exposed to autologous DV-monocytes, which contained high IFN activity, completely inhibited dengue virus infection of monocytes. These results suggest that IFN-alpha produced by PBL exposed to DV-monocytes may play an important role in controlling primary dengue virus infection.
Regression of an established tumor genetically modified to release granulocyte colony-stimulating factor requires granulocyte-T cell cooperation and T cell-produced interferon gamma.
Authors: A Stoppacciaro, C Melani, M Parenza, A Mastracchio, C Bassi, C Baroni, G Parmiani, M P Colombo
Journal: The Journal of Experimental Medicine (1993)

Using the murine colon adenocarcinoma C-26 cell line, engineered to release granulocyte colony-stimulating factor (G-CSF) (C-26/G-CSF), were studied the mechanisms responsible for inhibition of tumor take in syngeneic animals and of regression of an established tumor in sublethally irradiated mice injected with these cells. Immunocytochemistry and in situ hybridization, performed to characterize tumor-infiltrating leukocytes and their cytokine expression, respectively, indicated that polymorphonuclear leukocytes (PMN) were the major cells responsible for inhibition of tumor take and that they expressed mRNA for interleukin 1 alpha (IL-1 alpha), IL-1 beta, and tumor necrosis factor alpha (TNF-alpha). Expression of interferon gamma (IFN-gamma) and of IL-4 was undetectable, consistent with the absence of T lymphocytes at the site of tumor injection. In mice injected with C-26/G-CSF cells after 600-rad irradiation, the tumors grew to approximately 1.5 cm in 30 d, regressing completely thereafter in 70-80% of mice. During the growing phase, tumors were infiltrated first by PMN (between days 15 and 20), then by macrophages, and last by T lymphocytes. Both CD4+ and CD8+ T cells were present but only CD8 depletion significantly abrogated tumor regression. Depletion of PMN by the RB6-8C5 antigranulocytes monoclonal antibody reduced the number of T cells infiltrating the tumor and prevented tumor regression. In situ hybridization performed at the beginning of tumor regression revealed the presence of mRNA for IL-1 alpha, IL-1 beta, and TNF-alpha, but also the presence of cells, with lymphoid morphology, expressing IFN-gamma. Tumors from mice treated with recombinant IFN-gamma (between days 20 and 35) were rejected faster, whereas mice treated with antibodies to IFN-gamma (from day 20) died of progressive tumor. Cyclosporin A treatment (started at day 20) also abrogated tumor regression. These results indicate that inhibition of tumor take and regression in this model occurs through different mechanisms that involve PMN and PMN-T cell interactions, respectively, as well as a combination of cytokines that, for tumor regression, require IFN-gamma. Thus, gene transfer of a single cytokine gene such as G-CSF into tumor cells appears to be sufficient to trigger the cascade of cell interactions and cytokine production necessary to destroy a cancer nodule.
The Prevalence of the Metabolic Syndrome Did Not Increase in Mexico City Between 1990–1992 and 1997–1999 Despite More Central Obesity
Authors: Carlos Lorenzo, Ken Williams, Clicerio Gonzalez-Villalpando, Steven M. Haffner
Journal: Diabetes Care (2005)

OBJECTIVE—Trends in the metabolic syndrome might follow trends in obesity. We examined this hypothesis in the Mexico City Diabetes Study (MCDS), a study that showed rising trends in obesity, and the effect of the metabolic syndrome on the risk of coronary heart disease (CHD). RESEARCH DESIGN AND METHODS—Designed as a population-based study, the MCDS enrolled subjects in 1990–1992 (n = 2,282). Follow-up visits were held in 1993–1995 (n = 1,764) and 1997–1999 (n = 1,754). We used the revised metabolic syndrome definition of the National Cholesterol Education Program and the Framingham equations to estimate the 10-year CHD risk. RESULTS—In men, the age-adjusted prevalence of the metabolic syndrome was 38.9% in 1990–1992, 43.4% in 1993–1995, and 39.9% in 1997–1999; in women, the prevalences were 65.4, 65.7, and 59.9%, respectively. The prevalence did not change in men (P = 0.349) between 1990–1992 and 1997–1999, but decreased in women (P &amp;lt; 0.001). A prevalence increase was demonstrated for elevated waist circumference (men, P &amp;lt; 0.001; women, P &amp;lt; 0.050), elevated fasting glucose value (men and women, P &amp;lt; 0.001), and low HDL cholesterol level (men, P &amp;lt; 0.050; women, P &amp;lt; 0.010); a prevalence decrease was seen for high blood pressure (men and women, P &amp;lt; 0.001) and hypertriglyceridemia (men, P &amp;lt; 0.001; women, P &amp;lt; 0.010). CHD risk decreased marginally in men (P &amp;lt; 0.050) but did not change in women (P = 0.943). CONCLUSIONS—Neither the prevalence of the metabolic syndrome nor CHD risk has increased in Mexico City. Lower blood pressure and triglyceride values appear to have counteracted increases in central obesity and fasting glucose.
Myofilament calcium sensitivity is decreased in skinned cardiac fibres of endotoxin-treated rabbits
Authors: Benoı̂t Tavernier, Delphine Garrigue, Claire Boulle, Benoı̂t Vallet, Pascal Adnet
Journal: Cardiovascular Research (1998)

Objective: The aim was to determine whether myofilament Ca2+ sensitivity is altered in skinned cardiac fibres from endotoxin-treated rabbits. Methods: Endotoxin was injected i.v. in conscious New-Zealand White rabbits at a dose of 0.5 mg/kg (groups I, II, and III) or 1 mg/kg (group IV). A fifth group was used as control. Hearts were excised 4 h (groups I and IV), 24 h (group II), or 5 days (Group III) after injection. Skinned fibres were obtained with chemical (EGTA+Brij 58) treatment of bundles isolated from papillary muscles. Results: The maximal Ca2+-activated force (F0) of skinned cardiac fibres was not different between groups. However, [Ca2+] required to evoke 50% of F0 (Ca50) was higher in the fibres from group I than in controls (1.78±0.05 vs. 1.53±0.03 μM; P<0.05). This effect was dose-dependent (group IV: Ca50=2.08±0.12 μM; P<0.05 vs. group I), larger after 24 h (group II: Ca50=2.12±0.05 μM; P<0.05 vs. group I). By 5 days, myofilament Ca2+ sensitivity had returned to normal (group III: Ca50=1.54±0.05 μM). Conclusion: Myofilament Ca2+ sensitivity is decreased in skinned fibres taken from rabbit myocardium after i.v. endotoxin injection. This effect is dose- and time-dependent, and reversible with time.
Intraislet release of interleukin 1 inhibits beta cell function by inducing beta cell expression of inducible nitric oxide synthase.
Authors: J A Corbett, M L McDaniel
Journal: The Journal of Experimental Medicine (1995)

Cytokines, released in and around pancreatic islets during insulitis, have been proposed to participate in beta-cell destruction associated with autoimmune diabetes. In this study we have evaluated the hypothesis that local release of the cytokine interleukin 1 (IL-1) by nonendocrine cells of the islet induce the expression of inducible nitric oxide synthase (iNOS) by beta cells which results in the inhibition of beta cell function. Treatment of rat islets with a combination of tumor necrosis factor (TNF) and lipopolysaccharide (LPS), conditions known to activate macrophages, stimulate the expression of iNOS and the formation of nitrite. Although TNF+LPS induce iNOS expression and inhibit insulin secretion by intact islets, this combination does not induce the expression of iNOS by beta or alpha cells purified by fluorescence activated cell sorting (Facs). In contrast, IL-1 beta induces the expression of iNOS and also inhibits insulin secretion by both intact islets and Facs-purified beta cells, whereas TNF+LPS have no inhibitory effects on insulin secretion by purified beta cells. Evidence suggests that TNF+LPS inhibit insulin secretion from islets by stimulating the release of IL-1 which subsequently induces the expression of iNOS by beta cells. The IL-1 receptor antagonist protein completely prevents TNF+LPS-induced inhibition of insulin secretion and attenuates nitrite formation from islets, and neutralization of IL-1 with antisera specific for IL-1 alpha and IL-1 beta attenuates TNF+LPS-induced nitrite formation by islets. Immunohistochemical localization of iNOS and insulin confirm that TNF+LPS induce the expression of iNOS by islet beta cells, and that a small percentage of noninsulin-containing cells also express iNOS. Local release of IL-1 within islets appears to be required for TNF+LPS-induced inhibition of insulin secretion because TNF+LPS do not stimulate nitrite formation from islets physically separated into individual cells. These findings provide the first evidence that a limited number of nonendocrine cells can release sufficient quantities of IL-1 in islets to induce iNOS expression and inhibit the function of the beta cell, which is selectively destroyed during the development of autoimmune diabetes.
Isometric and Dynamic Contractile Properties of Porcine Skinned Cardiac Myocytes After Stunning
Authors: Kerry S. McDonald, Pradeep P.A. Mammen, Kevin T. Strang, Richard L. Moss, William P. Miller
Journal: Circulation Research (1995)

Abstract The purpose of this study was to investigate myofibrillar mechanisms of depressed contractile function associated with myocardial stunning. We first tested whether the degree of stunning was directly related to changes in myofilament Ca 2+ sensitivity. Variable degrees and durations of low-flow ischemia were followed by 30 minutes of reperfusion in an open-chest porcine model of regional myocardial stunning (n=27). Ca 2+ sensitivity of isometric tension was measured in skinned myocytes obtained from endocardial biopsies taken during control aerobic flow and after 30 minutes of reperfusion. The degree of stunning, as assessed by percent systolic wall thickening, ranged from −3% to 75% of control but did not correlate ( r =.11) with changes in pCa 50 , ie, pCa for half-maximal tension. Only in the group (n=10) with the most severe level of ischemia was there a significant decrease in pCa 50 (from 5.97±0.06 in the control condition to 5.86±0.07 after ischemia, P &lt;.05). Less severe levels of ischemia (n=17) resulted in significant stunning (percent systolic wall thickening, 38±4% of control) but no change in pCa 50 . To investigate the possibility that alterations in myofibrillar cross-bridge kinetics contribute to depressed function in stunning, maximum velocity of shortening (V o ) was measured in postischemic myocytes. V o in postischemic myocytes was reduced to 56±4% of V o in control myocytes and was independent both of the degree of stunning ( r =.26) and changes in Ca 2+ sensitivity. We conclude that the basis of stunning involves decreased cycling rates of myofibrillar cross-bridges and, after more severe ischemia, a reduction in myofilament Ca 2+ sensitivity.
Characterization of Bradykinin B <sub>2</sub> Receptors in Adult Myocardium and Neonatal Rat Cardiomyocytes
Authors: Richard D. Minshall, Fumiaki Nakamura, Robert P. Becker, Sara F. Rabito
Journal: Circulation Research (1995)

Abstract Specific [ 125 I-Tyr 8 ]bradykinin (BK) binding was observed on myocardial membranes from adult guinea pigs, dogs, rats, and rabbits that was displaced by unlabeled BK with an IC 50 between 0.1 and 30 nmol/L. In the adult guinea pig ventricular myocardium, which displays both high- and low-affinity binding, guanosine 5′- O -(3-thiotriphosphate) (GTPγS; 100 μmol/L) eliminated high-affinity binding and reduced total specific [2,3-prolyl-3,4- 3 H( N )]BK ([ 3 H]BK) binding by &gt;60%. Agonist competition binding to rat myocardial membranes was characterized as being of one affinity for BK in the nanomolar range, and it was not altered by GTPγS. Saturation binding studies with [ 125 I-Tyr 8 ]BK and [ 3 H]BK, performed on cultured neonatal rat cardiac myocytes, revealed a single class of BK binding sites with a K d and B max of 0.24±0.04 nmol/L and 18.4±1.1 fmol/mg protein, respectively (≈1500 receptors per cell). In competitive binding assays, unlabeled BK, Hoe 140 (a specific BK B 2 receptor antagonist), and des-Arg 9 ,[Leu 8 ]BK (a BK B 1 receptor antagonist) displaced [ 125 I-Tyr 8 ]BK with an IC 50 of 4.3, 0.041, and 307 nmol/L, respectively. In the presence of 100 μmol/L GTPγS, [ 3 H]BK binding to myocyte membranes was reduced by 40%, but the IC 50 did not change. Cardiac fibroblasts, evaluated in parallel to the myocytes, contain a single class of [ 3 H]BK binding sites (248±72 fmol/mg) with a 130-fold lower relative affinity (32.4±11.3 nmol/L) than that determined in rat cardiomyocytes. BK stimulated the inositol 1,4,5-trisphosphate (IP 3 ) production by cardiomyocytes, which reached a maximum after 20 seconds of stimulation and increased from a baseline of 138.4±23.2 pmol/mg protein to 1020.7±75.9 pmol/mg with 1 μmol/L BK (EC 50 =15.3 nmol/L). The effect was significantly blocked by 1 μmol/L Hoe 140. The IP 3 response by cardiomyocytes was fourfold greater and sixfold more sensitive than that by cardiac fibroblasts (EC 50 =92.3 nmol/L). These data suggest the presence of high-affinity BK B 2 receptors on cardiomyocytes, which are functionally coupled via a G protein to the production of IP 3 .
Loss of Epigenetic Control of <i>Synuclein-γ</i> Gene as a Molecular Indicator of Metastasis in a Wide Range of Human Cancers
Authors: Haiyan Liu, Wei Liu, Yinwei Wu, Yue Zhou, Rong Xue, Chan Luo, Lan Wang, Wei Zhao, Jian-Dong Jiang, Jingwen Liu
Journal: Cancer Research (2005)

Abstract Metastasis is a major contributing factor to poor prognosis in cancer. Reliable and sensitive biomarkers that indicate the development of metastasis of primary tumors would be of great clinical use. In this study, we show that the neuronal protein synuclein-γ (SNCG) is abnormally expressed in a high percentage (67.5%) of tumor tissues of diversified cancer types, including liver, esophagus, colon, gastric, lung, prostate, cervical, and breast cancer, but rarely expressed in tumor-matched nonneoplastic adjacent tissues (0.6%). Expressions of SNCG protein in different cancer types all display stage-specific patterns of very low expression in stage I and high expression in stages II to IV. Importantly, we observe a strong association between SNCG protein expression in primary tumors with distant metastasis in patients regardless of the cancer type (60.6%, P &amp;lt; 0.001). By performing genomic sequencing and methylation-specific PCR assays, we identify an inclusive demethylation of CpG sites within the CpG island of SNCG gene in every tumor sample (100%) across all cancer types, illustrating a universal loss of the epigenetic control of SNCG gene expression in tumors and further demonstrating that the demethylation of SNCG CpG island is primarily responsible for the aberrant expression of SNCG protein in cancerous tissues. These new findings strongly suggest that reactivation of SNCG gene expression by DNA demethylation is a common critical contributing factor to malignant progression of many solid tumors and its expression in primary carcinomas is an effective molecular indicator of distant metastasis. Our studies also suggest that the methylation status of SNCG gene can be used as a sensitive molecular tool in early detections of tumorigenesis.