tbuckley/cabot-search huggingface dataset:
The role of cyclic adenosine 3', 5'-monophosphate and calcium in the regulation of contractility and glycogen phosphorylase activity in guinea pig papillary muscle.
Authors: J G Dobson, J Ross, S E Mayer
Journal: Circulation Research (1976)

We studied the relationships between the positive inotropic effects of isoproterenol, increased frequency of contraction or paired electrical stimulation, and cyclic AMP concentration and phosphorylase activity in isolated guinea pig papillary muscles. The minimum concentration of isoproterenol (10 nM) that augmented isometric force development increased cyclic AMP concentration. However 100 nM isoproterenol was required to increase the phosphorylase activity ratio (-AMP/+AMP) from 0.15 +/- 0.03 to 0.25 +/- 0.03. After addition of 1 muM isoproterenol to the bath, cyclic AMP increased within 0.5 minute from 0.58 +/- 0.03 to 1.04 +/- 0.13 mol/kg (wet weight), peak contractile force was elevated 2-fold at 1 minute, and the phosphorylase activity ratio rose to 0.40 +/- 0.02 in 4 minutes. Although an increase in contraction frequency (6/min to 36/ min) and paired stimulation produced more than a 3-fold increase in peak contractile force, there were no changes in cyclic AMP and phosphorylase activity. The cyclic AMP concentration during diastole was 0.60 +/- 0.04 and in midsystole, 0.55 +/- 0.03 mumol/kg. Anoxia increased the phosphorylase activity ratio from 0.19 +/-0.02 to 0.41 +/- 0.04 without elevation of cyclic AMP concentration. Removal of Ca2+ from the bathing medium prevented active force development and the anoxic increase in phosphorylase activity, but did not prevent the isoproterenol-induced increase in cyclic AMP and phosphorylase. These results suggest that cyclic AMP is a factor in the catecholamine-induced enhancement of inotropic state. However, it does not appear to play a role in the maintained augmentation of inotropic state produced by increased contraction frequency and paired stimulation, nor does the concentration of the cycle nucleotide appear to vary during the contraction cycle or during anoxia. Extracellular Ca2+ is required for contraction, the positive inotropic aciton of catecholamines and phosphorylase b to a conversion by anoxia.
Relationship between several surrogate estimates of insulin resistance and quantification of insulin-mediated glucose disposal in 490 healthy nondiabetic volunteers.
Authors: H Yeni-Komshian, M Carantoni, F Abbasi, G M Reaven
Journal: Diabetes Care (2000)

OBJECTIVE: The goal of this study was to define the relationship between a quantitative measure of the ability of physiological hyperinsulinemia to stimulate glucose disposal and several surrogate measures of insulin resistance. RESEARCH DESIGN AND METHODS: Insulin-mediated glucose disposal was quantified in 490 healthy nondiabetic volunteers by determining the steady-state plasma glucose (SSPG) concentration in response to a continuous infusion of somatostatin, insulin, and glucose. Because the steady-state plasma insulin concentration was similar in all subjects during the infusion (approximately 60 microU/ml), the SSPG concentration provided a direct estimate of insulin-mediated glucose disposal. Relationships between this specific measure of insulin resistance and several surrogate estimates of insulin resistance based on plasma glucose and insulin concentrations were then defined. RESULTS: The surrogate measure of insulin resistance most closely related to the direct determination of insulin action was the total integrated insulin response to a 75-g oral glucose challenge with correlation coefficients (r) varying from 0.67 to 0.79. Fasting plasma insulin concentration was significantly correlated (r = 0.61, P&amp;lt;0.001) to the specific estimate of insulin action. Two other surrogate estimates of insulin action, the ratio of fasting glucose-to-fasting insulin concentration and the homeostasis model assessment for insulin resistance, were no more closely related to SSPG than the fasting plasma insulin concentration. CONCLUSIONS: The total integrated insulin response to oral glucose is the best surrogate measure of insulin resistance, accounting for approximately two-thirds of the variability in insulin-mediated glucose disposal. Fasting insulin concentration accounted for approximately one-third of the variability in insulin-mediated glucose disposal, and the use of fasting plasma glucose and insulin concentrations to calculate more sophisticated estimates of insulin resistance appears to offer little advantage over the fasting plasma insulin concentration. Given the large number of nondiabetic individuals in this study, the results should have general application in population-based studies, providing evidence for both the utility and limitation of the use of these surrogate measures.
Isolation and biochemical characterization of a thaumatin-like kiwi allergen
Authors: Marija Gavrović-Jankulović, Tanja Ćirković, Olga Vučković, Marina Atanasković-Marković, Arnd Petersen, Gordana Gojgić, Lidija Burazer, Ratko M. Jankov
Journal: Journal of Allergy and Clinical Immunology (2002)
Prevalence of the Metabolic Syndrome and Its Components
Authors: Pirjo Ilanne-Parikka, Johan G. Eriksson, Jaana Lindström, Helena Hämäläinen, Sirkka Keinänen-Kiukaanniemi, Mauri Laakso, Anne Louheranta, Marjo Mannelin, Merja Rastas, Virpi Salminen, Sirkka Aunola, Jouko Sundvall, Timo Valle, Jorma Lahtela, Matti Uusitupa, Jaakko Tuomilehto
Journal: Diabetes Care (2004)

OBJECTIVE—To assess the prevalence of the metabolic syndrome (MetS) in two independent Finnish study cohorts. RESEARCH DESIGN AND METHODS—The prevalence of the MetS by modified World Health Organization criteria was analyzed in different categories of glucose tolerance in a cross-sectional, population-based sample of 2,049 individuals (FINRISK) aged 45–64 years and in 522 participants of the Finnish Diabetes Prevention Study (DPS) with impaired glucose tolerance (IGT). RESULTS—In the FINRISK cohort, the MetS was present in 38.8% of the men and 22.2% of the women. The prevalence was 14.4 and 10.1% in subjects with normal glucose tolerance, 74.0 and 52.2% in subjects with impaired fasting glucose, 84.8 and 65.4% in subjects with IGT, and 91.5 and 82.7% in subjects with type 2 diabetes in men and women, respectively. Among women, the prevalence of the MetS increased with increasing age. In the DPS cohort, the MetS was present in 78.4% of the men and 72.2% of the women with IGT. CONCLUSIONS—The MetS was extremely common in middle-aged subjects The high prevalence in men was mostly due to their high waist-to-hip ratio. The prevalence of the MetS increased in both sexes with deterioration in glucose regulation. Approximately 75% of the subjects with IGT had the MetS. Because the syndrome includes the major risk factors for atherosclerotic vascular diseases and is the major antecedent for type 2 diabetes, concerted preventive action should be targeted to control all the features of the MetS.
Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling
Authors: Ju-Seog Lee, In-Sun Chu, Jeonghoon Heo, Diego F. Calvisi, Zongtang Sun, Tania Roskams, Anne Durnez, Anthony J. Demetris, Snorri S. Thorgeirsson
Journal: Hepatology (2004)

We analyzed global gene expression patterns of 91 human hepatocellular carcinomas (HCCs) to define the molecular characteristics of the tumors and to test the prognostic value of the expression profiles. Unsupervised classification methods revealed two distinctive subclasses of HCC that are highly associated with patient survival. This association was validated via 5 independent supervised learning methods. We also identified the genes most strongly associated with survival by using the Cox proportional hazards survival analysis. This approach identified a limited number of genes that accurately predicted the length of survival and provides new molecular insight into the pathogenesis of HCC. Tumors from the low survival subclass have strong cell proliferation and antiapoptosis gene expression signatures. In addition, the low survival subclass displayed higher expression of genes involved in ubiquitination and histone modification, suggesting an etiological involvement of these processes in accelerating the progression of HCC. In conclusion, the biological differences identified in the HCC subclasses should provide an attractive source for the development of therapeutic targets (e.g., HIF1a) for selective treatment of HCC patients. Supplementary material for this article can be found on the HEPATOLOGY Web site (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html)
Genetic regulation of the antibody response to H-2Db alloantigens in mice. I. Differences in activation of helper T cells in C57BL/10 and BALB/c congenic strains.
Authors: D Wernet, F Lilly
Journal: The Journal of Experimental Medicine (1975)

B10.A(5R) mice immunized with C57BL/10 spleen cells demonstrate a normal T-cell-mediated cytotoxicity to H-2Db tumor cells but they do not mount any IgG antibody response to H-2Db alloantigens. B10.A(5R) mice do show a high titered IgG response when immunized with A.BY cells, which differ at H-2Db plus non-H-2 cell surface antigens, or with B10.A(2R) cells, which differ at H-2Db, H-2Kk, and H-2Ik cell surface antigens. These findings indicate a failure of the T-helper cells to induce the switch from IgM to IgG when the H-2Db alloantigens are the only difference on the immunizing cell. In immunizing H-2d mice with congenic H-g2 cells which differ only in the H-2Db region, mice of the C57BL/10 background made only IgM antibodies whereas mice of the BALB/c background made IgG antibodies. This comparison confirms that genes separate from H-2 regulate the T-cell helper function. The genes that influence the T-cell helper function do not regulate the T-cell-mediated cytotoxicity.
Presence of IgE antibodies to staphylococcal exotoxins on the skin of patients with atopic dermatitis. Evidence for a new group of allergens.
Authors: D Y Leung, R Harbeck, P Bina, R F Reiser, E Yang, D A Norris, J M Hanifin, H A Sampson
Journal: Journal of Clinical Investigation (1993)

In the current study, we investigated whether Staphylococcus aureus grown from affected skin of atopic dermatitis (AD) patients secreted identifiable toxins that could act as allergens to induce IgE-mediated basophil histamine release. The secreted toxins of S. aureus grown from AD patients were identified by ELISA using antibodies specific for staphylococcal enterotoxin (SE) exfoliative toxin (ET), or toxic shock syndrome toxin (TSST-1). S. aureus isolates from 24 of 42 AD patients secreted identifiable toxins with SEA, SEB, and TSST accounting for 92% of the isolates. 32 of 56 AD sera (57%) tested contained significant levels of IgE primarily to SEA, SEB, and/or TSST. In contrast, although SEA, SEB, or TSST secreting S. aureus could be recovered from the skin of psoriasis patients, their sera did not contain IgE antitoxins. Freshly isolated basophils from 10 AD patients released 5-59% of total histamine in response to SEA, SEB, or TSST-1 but only with toxins to which patients had specific IgE. Basophils from eight other AD patients and six normal controls who had no IgE antitoxin failed to demonstrate toxin-induced basophil histamine release. Stripped basophils sensitized with three AD sera containing IgE to toxin released 15-41% of total basophil histamine only when exposed to the relevant toxin, but not to other toxins. Sensitization of basophils with AD sera lacking IgE antitoxin did not result in release of histamine to any of the toxins tested. These data indicate that a subset of patients with AD mount an IgE response to SEs that can be grown from their skin. These toxins may exacerbate AD by activating mast cells, basophils, and/or other Fc epsilon-receptor bearing cells armed with the relevant IgE antitoxin.
Risk for Addiction-Related Disorders Following Mild Traumatic Brain Injury in a Large Cohort of Active-Duty U.S. Airmen
Authors: Shannon C. Miller, Suzanne H. Baktash, Timothy S. Webb, Casserly R. Whitehead, Charles Maynard, Timothy S. Wells, Clifford N. Otte, Russel K. Gore
Journal: American Journal of Psychiatry (2013)

Military personnel are at increased risk for traumatic brain injury (TBI) from combat and noncombat exposures. The sequelae of moderate to severe TBI are well described, but little is known regarding long-term performance decrements associated with mild TBI. Furthermore, while alcohol and drug use are well known to increase risk for TBI, little is known regarding the reverse pattern. The authors sought to assess possible associations between mild TBI and addiction-related disorders in active-duty U.S. military personnel.A historical prospective study was conducted using electronically recorded demographic, medical, and military data for more than a half million active-duty U.S. Air Force service members. Cases were identified by ICD-9-CM codes considered by an expert panel to be indicative of mild TBI. Outcomes included ICD-9-CM diagnoses of selected addiction-related disorders. Cox proportional hazards modeling was used to calculate hazard ratios while controlling for varying lengths of follow-up and potential confounding variables.Airmen with mild TBI were at increased risk for certain addiction-related disorders compared with a similarly injured non-mild TBI comparison group. Hazards for alcohol dependence, nicotine dependence, and nondependent abuse of drugs or alcohol were significantly elevated, with a consistent decrease over time.A novel finding of this study was the initial increased risk for addiction-related disorders that decreased with time, thus eroding war fighter performance in a military population. Moreover, these results suggest that mild TBI is distinguished from moderate to severe TBI in terms of timing of the risk, indicating that there is a need for screening and prevention of addiction-related disorders in mild TBI. Screening may be warranted in military troops as well as civilians at both short- and long-term milestones following mild TBI.
Postural changes, dysphagia, and systemic sclerosis
Authors: P Barrera, A A den Broeder, F H van den Hoogen, B G van Engelen, L B van de Putte
Journal: Annals of the Rheumatic Diseases (1998)

In 1993, a 61 year old, previously healthy man, developed stiffness and skin thickening of the hands and upper limbs, Raynaud’s phenomenon, and exertional dyspnea. Examination showed a diffuse systemic sclerosis (SSc), moderate hypertension (160/95 mm Hg), a reduced pulmonary diffusion capacity (TLC 107% predicted, DLCO 68% predicted), and asymptomatic oesophageal dysmotility. Treatment with D-penicillamine (D-Pen) 750 mg/day and enalapril was started and, except for extension of the skin involvement to the trunk and lower limbs, the disease’s course was uneventful for three years.#### Key messages

In August 1996 he was examined in another centre because of complaints of progressive fatigue, cervical anteflexion, proximal dysphagia, and weight loss. The patient denied having low back pain, and there were no symptoms suggesting arthritis, psoriasis, Reiter’s syndrome or inflammatory bowel diseases. Routine laboratory investigations showed an increased erythrocyte sedimentation rate (ESR) (63 mm/1st h), creatinine (108 μM/l; normal 60–100 μM/l), aspartate aminotransferase (ASAT 53 u/l; normal <25), and alanine aminotransferase (ALAT 38 u/l; normal <25) and a slight proteinuria (0.44 g/day).

The diagnosis ankylosing spondylitis was considered mainly because of his posture. HLA B27 typing was positive, however radiological examination showed only cervical arthrosis and periarticular calcifications in hands and feet. Radiographs and computed tomography of the pelvic joints showed no evidence of sacroiliitis. The anteflexion of the head was considered to …
Methotrexate polyglutamates in erythrocytes are associated with lower disease activity in juvenile idiopathic arthritis patients
Authors: Maja Bulatović Ćalasan, Ethan den Boer, Maurits C F J de Rotte, Sebastiaan J Vastert, Sylvia Kamphuis, Robert de Jonge, Nico M Wulffraat
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objective</h3> To determine association of erythrocyte methotrexate polyglutamates (MTX-PG) with disease activity and adverse effects in a prospective juvenile idiopathic arthritis (JIA) cohort. <h3>Methods</h3> One hundred and thirteen JIA patients were followed from MTX start until 12 months. Erythrocyte MTX-PGs with 1–5 glutamate residues were measured at 3 months with tandem mass spectrometry. The outcomes were Juvenile Arthritis Disease Activity Score (JADAS)-27 and adverse effects. To determine associations of MTX-PGs with JADAS-27 at 3 months and during 1 year of MTX treatment, linear regression and linear mixed-model analyses were used. To determine associations of MTX-PGs with adverse effects during 1 year of MTX treatment, logistic regression was used. Analyses were corrected for JADAS-27 at baseline and co-medication. <h3>Results</h3> Median JADAS-27 decreased from 12.7 (IQR: 7.8–18.2) at baseline to 2.9 (IQR: 0.1–6.5) at 12 months. Higher concentrations of MTX-PG3 (β: −0.006, p=0.005), MTX-PG4 (β: −0.015, p=0.004), MTX-PG5 (β: −0.051, p=0.011) and MTX-PG3–5 (β: −0.004, p=0.003) were associated with lower disease activity at 3 months. Higher concentrations of MTX-PG3 (β: −0.005, p=0.028), MTX-PG4 (β: −0.014, p=0.014), MTX-PG5 (β: −0.049, p=0.023) and MTX-PG3–5 (β: −0.004, p=0.018) were associated with lower disease activity over 1 year. None of the MTX-PGs was associated with adverse effects. <h3>Conclusions</h3> In the first prospective study in JIA, long-chain MTX-PGs were associated with lower JADAS-27 at 3 months and during 1 year of MTX treatment. Erythrocyte MTX-PG could be a plausible candidate for therapeutic drug monitoring of MTX in JIA.
Alpha-Catenins Control Cardiomyocyte Proliferation by Regulating Yap Activity
Authors: Jifen Li, Erhe Gao, Alexia Vite, Roslyn Yi, Ludovic Gomez, Steven Goossens, Frans van Roy, Glenn L. Radice
Journal: Circulation Research (2014)

Rationale: Shortly after birth, muscle cells of the mammalian heart lose their ability to divide. Thus, they are unable to effectively replace dying cells in the injured heart. The recent discovery that the transcriptional coactivator Yes-associated protein (Yap) is necessary and sufficient for cardiomyocyte proliferation has gained considerable attention. However, the upstream regulators and signaling pathways that control Yap activity in the heart are poorly understood. Objective: To investigate the role of α-catenins in the heart using cardiac-specific αE- and αT-catenin double knockout mice. Methods and Results: We used 2 cardiac-specific Cre transgenes to delete both αE-catenin ( Ctnna1 ) and αT-catenin ( Ctnna3 ) genes either in the perinatal or in the adult heart. Perinatal depletion of α-catenins increased cardiomyocyte number in the postnatal heart. Increased nuclear Yap and the cell cycle regulator cyclin D1 accompanied cardiomyocyte proliferation in the α-catenin double knockout hearts. Fetal genes were increased in the α-catenin double knockout hearts indicating a less mature cardiac gene expression profile. Knockdown of α-catenins in neonatal rat cardiomyocytes also resulted in increased proliferation, which could be blocked by knockdown of Yap. Finally, inactivation of α-catenins in the adult heart using an inducible Cre led to increased nuclear Yap and cardiomyocyte proliferation and improved contractility after myocardial infarction. Conclusions: These studies demonstrate that α-catenins are critical regulators of Yap, a transcriptional coactivator essential for cardiomyocyte proliferation. Furthermore, we provide proof of concept that inhibiting α-catenins might be a useful strategy to promote myocardial regeneration after injury.
Cytokine Modulators as Novel Therapies for Asthma
Authors: Peter J. Barnes
Journal: The Annual Review of Pharmacology and Toxicology (2002)

Cytokines play a critical role in orchestrating and perpetuating inflammation in asthmatic airways and several specific cytokine and chemokine inhibitors are now in development for the treatment of asthma. Inhibition of IL-4 with soluble IL-4 receptors has shown promising early results in asthma. Anti-IL-5 antibody is very effective at inhibiting peripheral blood and airway eosinophils but does not appear to be effective in symptomatic asthma. Inhibitory cytokines, such as IL-10, interferons, and IL-12 are less promising because systemic delivery produces intolerable side effects. Inhibition of TNF-α may be useful in severe asthma. Many chemokines are involved in the inflammatory response of asthma, and small-molecule inhibitors of chemokine receptors are in development. CCR3 antagonists are now in clinical development for the treatment of asthma. Because so many cytokines are involved in asthma, drugs that inhibit the synthesis of multiple cytokines may prove to be more useful. Several such classes of drug are now in clinical development, and the risk of side effects with these nonspecific inhibitors may be reduced by the inhaled route of delivery.
Common Genetic Variation in IGF1 and Prostate Cancer Risk in the Multiethnic Cohort
Authors: Iona Cheng, Daniel O. Stram, Kathryn L. Penney, Malcolm Pike, Loïc Le Marchand, Laurence N. Kolonel, Joel Hirschhorn, David Altshuler, Brian E. Henderson, Matthew L. Freedman
Journal: JNCI Journal of the National Cancer Institute (2006)

Background: Insulin-like growth factor I (IGF-I) appears to play a role in prostate development and carcinogenesis. We investigated whether genetic variation at the IGF1 locus is associated with prostate cancer risk. Methods: We sequenced IGF1 exons in germline DNA from 95 men with advanced prostate cancer to identify missense variants. IGF1 linkage disequilibrium patterns and common haplotypes were characterized by genotyping 64 single-nucleotide polymorphisms (SNPs) spanning 156 kilobases in 349 control subjects. Associations between IGF1 haplotypes and genotypes were investigated among 2320 patients with prostate cancer and 2290 control subjects from the Multiethnic Cohort. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression to determine the association between prostate cancer and IGF1 haplotypes and genotypes. We used permutation testing to correct for multiple hypothesis testing. All statistical tests were two-sided. Results: No IGF1 missense variants were observed. We identified four blocks of strong linkage disequilibrium and selected a subset of 29 tagging SNPs that could accurately predict both the common IGF1 haplotypes and the remaining SNPs. Haplotype analysis revealed nominally statistically significant associations with prostate cancer risk in each of the four haplotype blocks: haplotype 1B (OR = 1.21, 95% CI = 1.04 to 1.40), haplotype 2C (OR = 1.24, 95% CI = 1.06 to 1.44), haplotype 3C (OR = 1.25, 95% CI = 1.03 to 1.50), and haplotype 4D (OR = 1.19, 95% CI = 1.02 to 1.39). Two SNPs—rs7978742 ( Ptrend = .002) and rs7965399 ( Ptrend = .002)—were perfectly correlated (correlation coefficient = 1.0) with one another and also associated with prostate cancer risk. These two SNPs were strong proxies for haplotypes 1B, 2C, 3C, and 4D and could account for the haplotype findings. Permutation testing revealed that a similarly strong result would be observed by chance only 5.6% of the time. Conclusion: Inherited variation in IGF1 may play a role in the risk of prostate cancer.