tbuckley/cabot-search huggingface dataset:
Microstructural Brain Tissue Damage in Metabolic Syndrome
Authors: Michiel Sala, Albert de Roos, Annette van den Berg, Irmhild Altmann-Schneider, P. Eline Slagboom, Rudi G. Westendorp, Mark A. van Buchem, Anton J.M. de Craen, Jeroen van der Grond
Journal: Diabetes Care (2013)

We investigated the association between metabolic syndrome risk factors and brain tissue integrity, as assessed by magnetic resonance imaging.From the Leiden Longevity Study, which is a community-based study of long-lived subjects, their offspring, and partners thereof, 130 subjects (61 men; mean age 66 years) were included. A metabolic syndrome score was computed by summing the individual number of components according to the Adult Treatment Panel III criteria. We performed linear and logistic regression analysis and used standardized β-values to assess the association between metabolic syndrome and brain macrostructure (brain volume and white matter lesion load, lacunar infarcts, and cerebral microbleeds) and microstructure (mean magnetization transfer ratio [MTR], MTR histogram peak height, fractional anisotropy, and mean diffusivity [MD]). Linear and stepwise regression analysis was performed to identify the individual contribution of one metabolic syndrome parameter adjusting for the four other parameters. Models were adjusted for age, sex, and relation to long-lived family.Brain macrostructure was not associated with metabolic syndrome. In contrast, metabolic syndrome was associated with decreased gray (β = -0.3 P = 0.001) and white matter peak height (β = -0.3, P = 0.002) and increased gray matter MD (β = 0.2, P = 0.01, P = 0.01). Serum HDL cholesterol (β = 0.22, P = 0.012), triglycerides (β =-0.25, P = 0.002), BMI (β =-0.2, P = 0.014), and diastolic blood pressure (β = -0.17, P = 0.047, and β = -0.23, P = 0.009, for gray and white matter, respectively) were independent factors in these changes in brain microstructure.In early manifest metabolic syndrome, brain tissue decline can be detected. Serum HDL cholesterol, triglycerides, BMI, and diastolic blood pressure were independent factors in brain tissue integrity.
Critical roles of the immunoglobulin intronic enhancers in maintaining the sequential rearrangement of <i>IgH</i> and <i>Igk</i> loci
Authors: Matthew A. Inlay, Tongxiang Lin, Heather H. Gao, Yang Xu
Journal: The Journal of Experimental Medicine (2006)

V(D)J recombination of immunoglobulin (Ig) heavy (IgH) and light chain genes occurs sequentially in the pro– and pre–B cells. To identify cis-elements that dictate this order of rearrangement, we replaced the endogenous matrix attachment region/Igk intronic enhancer (MiEκ) with its heavy chain counterpart (Eμ) in mice. This replacement, denoted EμR, substantially increases the accessibility of both Vκ and Jκ loci to V(D)J recombinase in pro–B cells and induces Igk rearrangement in these cells. However, EμR does not support Igk rearrangement in pre–B cells. Similar to that in MiEκ−/− pre–B cells, the accessibility of Vκ segments to V(D)J recombinase is considerably reduced in EμR pre–B cells when compared with wild-type pre–B cells. Therefore, Eμ and MiEκ play developmental stage-specific roles in maintaining the sequential rearrangement of IgH and Igk loci by promoting the accessibility of V, D, and J loci to the V(D)J recombinase.
Differences in Reporting of Analyses in Internal Company Documents Versus Published Trial Reports: Comparisons in Industry-Sponsored Trials in Off-Label Uses of Gabapentin
Authors: S. Swaroop Vedula, Tianjing Li, Kay Dickersin
Journal: PLoS Medicine (2013)

Using documents obtained through litigation, S. Swaroop Vedula and colleagues compared internal company documents regarding industry-sponsored trials of off-label uses of gabapentin with the published trial reports and find discrepancies in reporting of analyses.
The Progression of Chronic Obstructive Pulmonary Disease Is Heterogeneous
Authors: Ciro Casanova, Juan P. de Torres, Armando Aguirre-Jaíme, Victor Pinto-Plata, Jose M. Marin, Elizabeth Cordoba, Rebeca Baz, Claudia Cote, Bartolome R. Celli
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Chronic obstructive pulmonary disease (COPD) is thought to result in rapid and progressive loss of lung function usually expressed as mean values for whole cohorts.Longitudinal studies evaluating individual lung function loss and other domains of COPD progression are needed.We evaluated 1,198 stable, well-characterized patients with COPD (1,100 males) recruited in two centers (Florida and Tenerife, Spain) and annually monitored their multidomain progression from 1997 to 2009. Patients were followed for a median of 64 months and up to 10 years. Their individual FEV(1) (L) and BODE index slopes, expressed as annual change, were evaluated using regression models for repeated measures. A total of 751 patients with at least three measurements were used for the analyses.Eighteen percent of patients had a statistically significant FEV(1) slope decline (-86 ml/yr; 95% confidence interval [CI], -32 to -278 ml/yr). Higher baseline FEV(1) (relative risk, 1.857; 95% CI, 1.322-2.610; P < 0.001) and low body mass index (relative risk, 1.071; 95% CI, 1.035-1.106; P < 0.001) were independently associated with FEV(1) decline. The BODE index had a statistically significant increase (0.55, 0.20-1.37 point/yr) in only 14% of patients and these had more severe baseline obstruction. Concordance between FEV1 and BODE change was low (κ Cohen, 16%). Interestingly, 73% of patients had no significant slope change in FEV1 or BODE. Only the BODE change was associated with mortality in patients without FEV(1) progression.The progression of COPD is very heterogeneous. Most patients show no statistically significant decline of FEV(1) or increase in BODE. The multidimensional evaluation of COPD should offer insight into response to COPD management.
Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial
Authors: Christopher J Logothetis, Ethan Basch, Arturo Molina, Karim Fizazi, Scott A North, Kim N Chi, Robert J Jones, Oscar B Goodman, Paul N Mainwaring, Cora N Sternberg, Eleni Efstathiou, Dennis D Gagnon, Margaret Rothman, Yanni Hao, Cameron S Liu, Thian S Kheoh, Christopher M Haqq, Howard I Scher, Johann S de Bono
Journal: The Lancet Oncology (2012)
Sodium Channels in Normal and Pathological Pain
Authors: Sulayman D. Dib-Hajj, Theodore R. Cummins, Joel A. Black, Stephen G. Waxman
Journal: Annual Review of Neuroscience (2010)

Nociception is essential for survival whereas pathological pain is maladaptive and often unresponsive to pharmacotherapy. Voltage-gated sodium channels, Na v 1.1–Na v 1.9, are essential for generation and conduction of electrical impulses in excitable cells. Human and animal studies have identified several channels as pivotal for signal transmission along the pain axis, including Na v 1.3, Na v 1.7, Na v 1.8, and Na v 1.9, with the latter three preferentially expressed in peripheral sensory neurons and Na v 1.3 being upregulated along pain-signaling pathways after nervous system injuries. Na v 1.7 is of special interest because it has been linked to a spectrum of inherited human pain disorders. Here we review the contribution of these sodium channel isoforms to pain.
The effects of spontaneous obesity on insulin binding, glucose transport, and glucose oxidation of isolated rat adipocytes.
Authors: J M Olefsky
Journal: Journal of Clinical Investigation (1976)

We have studied insulin, binding, glucose transport, and glucose oxidation, using large adipocytes isolated from older, fatter rats (greater than 12-mo-old, greater than 550 g), and smaller cells obtained from younger, leaner animals (4-5-wk-old, 120-160 g). At media glucose levels less than 5 mM, basal (absence of insulin) rates of glucose oxidation are comparable in both groups of cells. However, in the presence of insulin, the increase in glucose oxidation is much greater in the smaller cells. Maximally effective insulin levels could not overcome the defect in glucose oxidation by larger cells, and thus, even though studies of insulin binding demonstrated a 30-40% decrease in insulin receptors on the larger cells, it is probable that the defect in glucose oxidation is distal to the insulin receptor. Glucose transport was assessed by direct measurement of 2-deoxy glucose uptake. Basal levels of uptake were greater for the larger cells, whereas at maximally effective insulin concentrations, rates of 2-deoxy glucose uptake were the same for both groups of cells. Thus, in the presence of maximally effective levels of insulin, the apparent Km (2.3-2.7 mM) and Vmax values (2.6 and 2.7 nmol/10(5) cells per min) of 2-deoxy glucose uptake were comparable, indicating that the glucose transport system of the larger cells was intact. However, at submaximal levels of insulin, small adipocytes took up more 2-deoxy glucose than larger cells. These findings represent a rightward shift in the insulin dose-response curve in the cells from the older, fatter animals, and this is the predicted functional sequelae of the observed decrease in insulin receptors. Finally, when the amount of insulin bound was plotted as a function of 2-deoxy glucose uptake, no difference was seen between both groups of cells. This indicates that coupling between insulin receptor complexes and the glucose transport system is intact in large adipocytes, and is further evidence that a defect(s) in intracellular glucose metabolism is responsible for the decrease in glucose oxidation of adipocytes from older, fatter rats.(a) insulin-mediated glucose oxidation is markedly decreased in large adipocytes from older, fatter rats, and since this decrease cannot be corrected by maximally effective insulin levels, the defect is probably distal to the insulin receptor; (b) the glucose transport system is basically normal in large adipocytes; (c) insulin binding to receptors is decreased in large cells and the functional sequelae of this decrease in insulin binding i.e., a rightward shift in the insulin dose-response curve for 2-deoxy glucose uptake, was observed, and (d) since the decreased rates of insulin-mediated glucose oxidation can not be attributed to changes in insulin receptors or to changes in glucose transport, an intracellular defect in glucose metabolism is suggested.
Arthritis associated with Ulcerative Colitis
Authors: J. Rotstein, I. Entel, B. Zeviner
Journal: Annals of the Rheumatic Diseases (1963)

Previous reports indicate that arthritis occurs in association with ulcerative colitis in excess of the incidence which would be expected in the general population.Approximately 2 5 per cent. of the general population have a form of arthritis according to Woolsey (1952) and Cobb and Lawrence (1957).Depending on the criteria used for diagnosis, arthritis occurs in 7 to 20 per cent. of patients with ulcerative colitis (Hench and 5 others, 1936; Bargen,
Distinct transcriptional MYCN/c-MYC activities are associated with spontaneous regression or malignant progression in neuroblastomas
Authors: Frank Westermann, Daniel Muth, Axel Benner, Tobias Bauer, Kai-Oliver Henrich, André Oberthuer, Benedikt Brors, Tim Beissbarth, Jo Vandesompele, Filip Pattyn, Barbara Hero, Rainer König, Matthias Fischer, Manfred Schwab
Journal: Genome biology (2008)

Amplified MYCN oncogene resulting in deregulated MYCN transcriptional activity is observed in 20% of neuroblastomas and identifies a highly aggressive subtype. In MYCN single-copy neuroblastomas, elevated MYCN mRNA and protein levels are paradoxically associated with a more favorable clinical phenotype, including disseminated tumors that subsequently regress spontaneously (stage 4s-non-amplified). In this study, we asked whether distinct transcriptional MYCN or c-MYC activities are associated with specific neuroblastoma phenotypes.We defined a core set of direct MYCN/c-MYC target genes by applying gene expression profiling and chromatin immunoprecipitation (ChIP, ChIP-chip) in neuroblastoma cells that allow conditional regulation of MYCN and c-MYC. Their transcript levels were analyzed in 251 primary neuroblastomas. Compared to localized-non-amplified neuroblastomas, MYCN/c-MYC target gene expression gradually increases from stage 4s-non-amplified through stage 4-non-amplified to MYCN amplified tumors. This was associated with MYCN activation in stage 4s-non-amplified and predominantly c-MYC activation in stage 4-non-amplified tumors. A defined set of MYCN/c-MYC target genes was induced in stage 4-non-amplified but not in stage 4s-non-amplified neuroblastomas. In line with this, high expression of a subset of MYCN/c-MYC target genes identifies a patient subtype with poor overall survival independent of the established risk markers amplified MYCN, disease stage, and age at diagnosis.High MYCN/c-MYC target gene expression is a hallmark of malignant neuroblastoma progression, which is predominantly driven by c-MYC in stage 4-non-amplified tumors. In contrast, moderate MYCN function gain in stage 4s-non-amplified tumors induces only a restricted set of target genes that is still compatible with spontaneous regression.
Effects of Moderate-to-Vigorous Intensity Physical Activity on Overnight and Next-Day Hypoglycemia in Active Adolescents With Type 1 Diabetes
Authors: Kristen M. Metcalf, Ajay Singhvi, Eva Tsalikian, Michael J. Tansey, M. Bridget Zimmerman, Dale W. Esliger, Kathleen F. Janz
Journal: Diabetes Care (2014)

Physical activity (PA) provides many benefits to adolescents with type 1 diabetes; however, these individuals tend to have lower fitness and PA levels than their disease-free counterparts. The purpose of this study was to examine the acute temporal associations between moderate-to-vigorous intensity PA (MVPA) and hypoglycemia (continuous glucose monitor [CGM] reading ≤70 mg/dL).Nineteen participants (53% females) 14-20 years old with type 1 diabetes were recruited. Participant fitness was evaluated via indirect calorimetry using a maximal exercise test; body composition was measured using air displacement plethysmography. An accelerometer was worn continuously (3-5 days) and acceleration data used to estimate MVPA (minutes per day). Blood glucose values were simultaneously tracked using CGM. Controlling for sex, percent body fat (%BF), fitness, and concurrent MVPA, the likelihood of nighttime and next-day hypoglycemia due to MVPA was examined using logistic regression.Participants were of average fitness (females: 43.9 mL/kg/min; males: 49.8 mL/kg/min) and adiposity (females: 26.2%; males: 19.2%); 63.2% met the U.S. federal guideline of accumulating 60 min/day of MVPA. Hypoglycemia was 31% more likely in those who accumulated 30 min/day more MVPA in the previous afternoon than those with less (95% CI 1.05-1.63; P = 0.017).The results suggest that participating in afternoon MVPA increases the risk of overnight and next-day hypoglycemia, independent of sex, %BF, fitness, and concurrent MVPA. While promoting PA as a healthy behavior, it is important to educate adolescents with type 1 diabetes on prevention of hypoglycemia following PA.
Effect of Weight Loss and Nutritional Intervention on Arterial Stiffness in Type 2 Diabetes
Authors: Emma Barinas-Mitchell, Lewis H. Kuller, Kim Sutton-Tyrrell, Refaat Hegazi, Patricia Harper, Juliet Mancino, David E. Kelley
Journal: Diabetes Care (2006)

There is increased stiffness of the large central arteries in type 2 diabetic patients, and obesity is a risk factor. However, the effect of intentional weight loss on arterial stiffness is uncertain, and the purpose of the current study was to assess this effect.Arterial stiffness was assessed by measuring aortic pulse wave velocity (aPWV) at baseline and at completion of a 1-year weight loss intervention. Metabolic control of type 2 diabetes was also appraised.Mean weight loss at 1 year in 38 volunteers with type 2 diabetes was 7.8%. There were improvements in HbA1c, LDL cholesterol, homeostasis model assessment of insulin resistance, and inflammatory markers (plasminogen activator inhibitor-1, tumor necrosis factor-alpha, interleukin-6, and C-reactive protein). There was also a significant improvement in aPWV at completion of weight loss intervention, from 740 to 690 cm/s (P < 0.05).Moderate weight loss improves arterial stiffness in type 2 diabetes.
Lack of association between increased mitochondrial DNA 4977 deletion and ATP levels of sputum cells from chronic obstructive pulmonary disease patients versus healthy smokers
Authors: Ayla Karimova, Duran Üstek, Murat Kara, Bülent Tutluoglu, Hülya Azakli, Ilhan Onaran
Journal: European Respiratory Journal (2014)

Levels of the mtDNA mutation including the 9common9 4977 bp mtDNA deletion is elevated in lung tissue of smokers relative to non-smokers.  In this study we looked at smokers with and without COPD in order to evaluate the incidence of mtDNA4977 and mtDNA copy number in sputum cells and in peripheral blood leukocytes (PBLs) in relation to cellular ATP and oxidative stress status  .  The frequency of occurrence of this 4977 bp mutation was significantly higher proportion in the sputum cells of patients with COPD compared to smokers without COPD (p
Effect of Fluticasone With and Without Salmeterol on Pulmonary Outcomes in Chronic Obstructive Pulmonary Disease
Authors: Thérèse S. Lapperre
Journal: Annals of Internal Medicine (2009)

Background: Inhaled corticosteroids (ICSs) and long-acting β2-agonists (LABAs) are used to treat moderate to severe chronic obstructive pulmonary disease (COPD). Objective: To determine whether long-term ICS therapy, with and without LABAs, reduces inflammation and improves pulmonary function in COPD. Design: Randomized, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00158847) Setting: 2 university medical centers in The Netherlands. Patients: 114 steroid-naive current or former smokers with moderate to severe COPD. Measurements: Cell counts in bronchial biopsies and sputum (primary outcome); methacholine responsiveness at baseline, 6, and 30 months; and clinical outcomes every 3 months. Intervention: Random assignment by minimization method to receive fluticasone propionate, 500 µg twice daily, for 6 months (n = 31) or 30 months (n = 26); fluticasone, 500 µg twice daily, and salmeterol, 50 µg twice daily, for 30 months (single inhaler; n = 28); or placebo twice daily (n = 29). Results: 101 patients were greater than 70% adherent to therapy. Fluticasone therapy decreased counts of mucosal CD3+ cells (−55% [95% CI, −74% to −22%]; P = 0.004), CD4+ cells (−78% [CI, −88% to 60%]; P < 0.001), CD8+ cells (−57% [CI, −77% to −18%]; P = 0.010), and mast cells (−38% [CI, −60% to −2%]; P = 0.039) and reduced hyperresponsiveness (P = 0.036) versus placebo at 6 months, with effects maintained after 30 months. Fluticasone therapy for 30 months reduced mast cell count and increased eosinophil count and percentage of intact epithelium, with accompanying reductions in sputum neutrophil, macrophage, and lymphocyte counts and improvements in FEV1 decline, dyspnea, and quality of life. Reductions in inflammatory cells correlated with clinical improvements. Discontinuing fluticasone therapy at 6 months increased counts of CD3+ cells (120% [CI, 24% to 289%]; P = 0.007), mast cells (218% [CI, 99% to 407%]; P < 0.001), and plasma cells (118% [CI, 9% to 336%]; P = 0.028) and worsened clinical outcome. Adding salmeterol improved FEV1 level. Limitations: The study was not designed to evaluate clinical outcomes. Measurement of primary outcome was not available for 24% of patients at 30 months. Conclusion: ICS therapy decreases inflammation and can attenuate decline in lung function in steroid-naive patients with moderate to severe COPD. Adding LABAs does not enhance these effects. Primary Funding Source: Netherlands Organization for Scientific Research, Netherlands Asthma Foundation, GlaxoSmithKline of The Netherlands, University Medical Center Groningen, and Leiden University Medical Center.
Anti-phosphocholine hybridoma antibodies. II. Functional analysis of binding sites within three antibody families.
Authors: C M Andres, A Maddalena, S Hudak, N M Young, J L Claflin
Journal: The Journal of Experimental Medicine (1981)

The present investigation extends our immunochemical characterization of binding site heterogeneity among a large series of monoclonal anti-phosphocholine (PC) antibodies. Hybridoma proteins (HP) from eight genetically distinct strains are included in this study, yet no strain specific characteristics are observed. These HP, as previously shown (5), are divided into three well-defined families based on public or family-specific Id and L chain isotypes characteristic of three PC-binding myeloma proteins: T15, M603, and M511. All antibodies exhibited some degree of inter- or intra-family heterogeneity, or both. Some of this intra-family diversity was reflected by differential reactivity for PC when attached to three different carriers. In spite of this, the specificity profiles for hapten analogues of PC, as measured by hapten inhibition of binding, were the same for all members of the T15 family. Altering the carrier had no effect, thus suggesting that the binding site pocket for PC is essentially preserved, whereas that for carrier is variable. Similar conclusions were reached for most of the M603 HP, although the binding site is different from the T15 HP. The M511 HP stand in sharp contrast to the HP in the other two families because their binding sites exhibit extensive variability. The independence in reactivity for PC and PC plus carrier offers a rational explanation for idiotypic and/or structural heterogeneity within a family. More importantly it suggests interesting strategies for diversification within one group of antibodies.