tbuckley/cabot-search huggingface dataset:
Androgen-Receptor Gene CAG Repeats, Plasma Testosterone Levels, and Risk of Hepatitis B-Related Hepatocellular Carcinoma
Authors: M.-W. Yu
Journal: JNCI Journal of the National Cancer Institute (2000)

Background: Worldwide, hepatocellular carcinoma (HCC) is more prevalent in men than in women, suggesting that sex hormones and/or X-chromosome-linked genes may be involved in hepatocarcinogenesis. We investigated the association of a trinucleotide (CAG) repeat in the androgen receptor (AR) gene (located on the X chromosome) termed "AR-CAG repeats," levels of plasma testosterone, and the risk of HCC in Taiwanese men. Chronic hepatitis B virus (HBV) infection, which is associated with risk of HCC, is hyperendemic in Taiwan. Methods: We compared the number of AR-CAG repeats in 285 HBV carriers with HCC and in 349 HBV carriers without HCC. We also conducted a nested case–control study on participants in a cohort study. Blood was collected prospectively from 110 case patients and 239 control subjects and was used to determine the number of AR-CAG repeats and plasma testosterone level. All statistical tests were two-sided. Results: The overall odds ratio (OR) for HCC was 1.72 (95% confidence interval [CI] = 1.03–2.89) for HBV carriers with 20 or fewer AR-CAG repeats compared with those with more than 24 repeats. This association was observed only in patients with late-onset HCC (OR = 2.37; 95% CI = 1.28–4.38). In the nested case–control study, HBV carriers in the highest tertile of testosterone levels had a statistically significantly increased risk of HCC (OR = 2.06; 95% CI = 1.14–3.70) compared with those in the lowest tertile. Elevated testosterone was more strongly associated with early-onset (OR = 4.67; 95% CI = 1.41–15.38) than late-onset disease. HBV carriers with 20 or fewer AR-CAG repeats and higher testosterone levels had a fourfold increase in HCC risk compared with those with more than 24 repeats and testosterone levels in the lowest tertile. Conclusions: Higher levels of androgen signaling, reflected by higher testosterone levels and 20 or fewer AR-CAG repeats, may be associated with an increased risk of HBV-related HCC in men.
Glycemic Variability Correlates Strongly With Postprandialβ-Cell Dysfunction in a Segment of Type 2 Diabetic Patients Using Oral Hypoglycemic Agents
Authors: Klaus-Dieter Kohnert, Petra Augstein, Eckhard Zander, Peter Heinke, Karolina Peterson, Ernst-Joachim Freyse, Roman Hovorka, Eckhard Salzsieder
Journal: Diabetes Care (2009)

OBJECTIVE Glucose fluctuations trigger activation of oxidative stress, a main mechanism leading to secondary diabetes complications. We evaluated the relationship between glycemic variability and β-cell dysfunction. RESEARCH DESIGN AND METHODS We conducted a cross-sectional study in 59 patients with type 2 diabetes (aged 64.2 ± 8.6 years, A1C 6.5 ± 1.0%, and BMI 29.8 ± 3.8 kg/m2[mean ± SD]) using either oral hypoglycemic agents (OHAs) (n = 34) or diet alone (nonusers). As a measure of glycemic variability, the mean amplitude of glycemic excursions (MAGE) was computed from continuous glucose monitoring data recorded over 3 consecutive days. The relationships between MAGE, β-cell function, and clinical parameters were assessed by including postprandial β-cell function (PBCF) and basal β-cell function (BBCF) obtained by a model-based method from plasma C-peptide and plasma glucose during a mixed-meal test as well as homeostasis model assessment of insulin sensitivity, clinical factors, carbohydrate intake, and type of OHA. RESULTS MAGE was nonlinearly correlated with PBCF (r = 0.54, P &amp;lt; 0.001) and with BBCF (r = 0.31, P = 0.025) in OHA users but failed to correlate with these parameters in nonusers (PBCF P = 0.21 and BBCF P = 0.07). The stepwise multiple regression analysis demonstrated that PBCF and OHA combination treatment were independent contributors to MAGE (R2 = 0.50, P &amp;lt; 0.010), whereas insulin sensitivity, carbohydrate intake, and nonglycemic parameters failed to contribute. CONCLUSIONS PBCF appears to be an important target to reduce glucose fluctuations in OHA-treated type 2 diabetes.
Coagulation factors in the airways in moderate and severe asthma and the effect of inhaled steroids
Authors: F J H Brims, A J Chauhan, B Higgins, J K Shute
Journal: Thorax (2009)

<h3>Background:</h3> There is evidence of activation of the extrinsic coagulation cascade in the asthmatic airway, and both plasma and locally derived factors may be involved. The hypothesis that the normal haemostatic balance of healthy airways sampled by sputum induction favours fibrin formation in asthmatic airways, and that inhaled corticosteroids (ICS) and plasma exudation influence this balance, was tested. <h3>Methods:</h3> ELISA and activity assays were used to measure α<sub>2</sub>-macroglobulin (an index of plasma leakage) and coagulation factors in hypertonic saline-induced sputum of 30 stable subjects (10 controls, 10 with moderate asthma and 10 with severe asthma). Additionally, the moderate cohort were weaned off their ICS, followed by further sputum induction 5 days after cessation of steroids. <h3>Results:</h3> ICS wean induced a significant rise in plasminogen (median (interquartile range (IQR)): 13.92 (6.12–16.17) vs 4.82 (2.14–13.32) ng/ml; 95% CI 0.003 to 8.596, p = 0.0499) and tissue plasminogen activator (tPA; 5.57 (3.57–14.35) vs 3.88 (1.74–4.05) ng/ml; 95% CI 0.828 to 9.972, p = 0.0261) levels in sputum, such that tPA in untreated moderate asthma was significantly (p = 0.0029) higher than normal (2.14 (0.0–2.53) ng/ml). Subjects with severe asthma had significantly more α<sub>2</sub>-macroglobulin (p = 0.0003), tissue factor (p = 0.023), plasminogen activator inhibitor (p = 0.0091), thrombin-activatable fibrinolysis inhibitor (p = 0.0031) and fibrin degradation products (p = 0.0293) in their sputum than control subjects. <h3>Conclusion:</h3> Untreated moderate asthma is associated with increased fibrinolysis that is corrected by ICS. Severe asthma and high dose corticosteroid therapy is associated with a profibrinogenic, antifibrinolytic environment in the airways. This study suggests that inhibition of fibrin deposition in severe asthma may be a therapeutic approach.
PREGNANCY AND CHLOROFORM ANESTHESIA
Authors: G. H. Whipple
Journal: The Journal of Experimental Medicine (1912)

Pregnant dogs are susceptible to chloroform administered shortly before delivery or during labor, and show the same degree of liver injury as normal dogs, or even a somewhat greater one. Chloroform anesthesia may cause more or less hyaline necrosis in the border zone between the maternal and fetal parts of the placenta that may lead to hemorrhage, placental separation, and premature delivery. Chloroform anesthesia causes no injury to the liver of the fetus nor to any other fetal organ, in spite of the fact that it can be demonstrated to be present in these tissues. These experiments raise objections to the use of chloroform in pregnant women where an anesthetic must be continued for half an hour or longer. Chloroform anesthesia may be admissible for the few minutes at the end of the delivery, but when operative measures are necessary, before or after delivery, it is a dangerous anesthetic and surely capable of producing injury to the liver in the manner recognized in the case of normal persons. Objections may be raised to the application of conclusions derived from experiments on dogs to human cases; but the similarity of the effects of chloroform in man and dog surely affords a sound basis of comparison. Two fundamental facts would seem to be now established: (1) Normal human adults may be fatally poisoned (late chloroform poisoning) by chloroform anesthesia of one half to one hour's duration. (2) Normal and pregnant dogs are equally susceptible to late chloroform poisoning, and may be fatally poisoned by an anesthesia of two hours' duration. Hence one may conclude that probably normal and pregnant human beings are equally susceptible to chloroform poisoning, that chloroform anesthesia during any part of the pregnant period is capable of causing liver necrosis, and, consequently, that chloroform is a dangerous anesthetic.
Phase I Study of Vismodegib in Children with Recurrent or Refractory Medulloblastoma: A Pediatric Brain Tumor Consortium Study
Authors: Amar Gajjar, Clinton F. Stewart, David W. Ellison, Sue Kaste, Larry E. Kun, Roger J. Packer, Stewart Goldman, Murali Chintagumpala, Dana Wallace, Naoko Takebe, James M. Boyett, Richard J. Gilbertson, Tom Curran
Journal: Clinical Cancer Research (2013)

To investigate the safety, dose-limiting toxicities, and pharmacokinetics of the smoothened inhibitor vismodegib in children with refractory or relapsed medulloblastoma.Initially, vismodegib was administered daily at 85 mg/m(2) and escalated to 170 mg/m(2). The study was then revised to investigate a flat-dosing schedule of 150 mg for patients with small body surface area (BSA, 0.67-1.32 m(2)) or 300 mg for those who were larger (BSA, 1.33-2.20 m(2)). Pharmacokinetics were performed during the first course of therapy, and the right knees of all patients were imaged to monitor bone toxicity. Immunohistochemical analysis was done to identify patients with Sonic Hedgehog (SHH)-subtype medulloblastoma.Thirteen eligible patients were enrolled in the initial study: 6 received 85 mg/m(2) vismodegib, and 7 received 170 mg/m(2). Twenty eligible patients were enrolled in the flat-dosing part of the study: 10 at each dosage level. Three dose-limiting toxicities were observed, but no drug-related bone toxicity was documented. The median (range) vismodegib penetration in the cerebrospinal fluid (CSF) was 0.53 (0.26-0.78), when expressed as a ratio of the concentration of vismodegib in the CSF to that of the unbound drug in plasma. Antitumor activity was seen in 1 of 3 patients with SHH-subtype disease whose tumors were evaluable, and in none of the patients in the other subgroups.Vismodegib was well tolerated in children with recurrent or refractory medulloblastoma; only two dose-limiting toxicities were observed with flat dosing. The recommended phase II study dose is 150 or 300 mg, depending on the patient's BSA. Clin Cancer Res; 19(22); 6305-12. ©2013 AACR.
On the mechanism of renal potassium wasting in renal tubular acidosis associated with the Fanconi syndrome (type 2 RTA)
Authors: Anthony Sebastian, Elisabeth McSherry, R. Curtis Morris
Journal: Journal of Clinical Investigation (1971)

The mechanism of renal potassium wasting in renal tubular acidosis associated with the Fanconi syndrome (type 2 RTA) was investigated in 10 patients, each of whom had impaired proximal renal tubular reabsorption of bicarbonate as judged from a greater than 15-20% reduction of renal tubular bicarbonate reabsorption (THCO(3) (-)) at normal plasma bicarbonate concentrations. When the plasma bicarbonate concentration ([HCO(3) (-)]p) was experimentally increased to normal levels in three patients with a fractional potassium excretion (C(K)/C(in)) of less than 1.0 during acidosis, C(K)/C(in) and urinary potassium excretion (U(K)V/C(in)) increased strikingly and concurrently with a striking increase in urinary sodium (U(Na)V/C(in)) and bicarbonate (U(HCO3-)V/C(in)) excretion. When [HCO(3) (-)]p was increased to normal levels in two patients with a C(K)/C(in) of greater than 1.0 during acidosis and in whom U(Na)V/C(in) and U(HCO3-)V/C(in) were already markedly increased, C(K)/C(in) did not increase further. When [HCO(3) (-)]p was decreased to subnormal levels in a patient given ammonium chloride, U(K)V/C(in), C(K)/C(in), and U(HCO3-)V/C(in) decreased concurrently. In the six patients in whom [HCO(3) (-)]p was maintained at normal levels (oral alkali therapy) for 2 months or longer, C(K)/C(in) was directly related to the urinary excretion rates of sodium and bicarbonate, hence was directly related to the magnitude of reduction of THCO(3) (-) at normal [HCO(3) (-)]p; C(K)/C(in) was greater than 0.55 in all six patients and greater than 1.0 in four. In eight patients with classic RTA (type 1 RTA), proximal renal tubular reabsorption of bicarbonate was largely intact as judged from a trivial reduction of THCO(3) (-) at normal [HCO(3) (-)]p. When [HCO(3) (-)]p was either increased from subnormal to normal levels, or decreased from normal to subnormal levels, U(HCO3-)V/C(in) remained essentially constant, and U(K)V/C(in) did not change significantly. When correction of acidosis was sustained, U(HCO3-)V/C(in) remained a trivial fraction of that filtered, and C(K)/C(in) was consistently less than 0.55. These results provide evidence that renal potassium wasting in type 2 RTA is physiologically separable from that in type 1 RTA and in part the result of a reduction in the rate at which the proximal tubule reabsorbs bicarbonate and the distal delivery of supernormal amounts of sodium bicarbonate. With an increased stimulus to distal sodium reabsorption, indicated by the finding of hyperaldosteronism, delivery to the distal nephron of supernormal amounts of sodium with the relatively impermeant bicarbonate anion would be expected to increase intraluminal negativity in the distal nephron, and as a consequence, increase potassium secretion and promote renal potassium wasting.
Racial Comparisons of Diabetes Care and Intermediate Outcomes in a Patient-Centered Medical Home
Authors: Joseph A. Simonetti, Michael J. Fine, Yi-Fan Chen, Deborah Simak, Rachel Hess
Journal: Diabetes Care (2013)

OBJECTIVE To assess racial differences in diabetes processes and intermediate outcomes of care in an internal medicine, patient-centered medical home (PCMH) group practice. RESEARCH DESIGN AND METHODS We conducted a retrospective cohort study of 1,457 adults with diabetes receiving care from 89 medical providers within a PCMH-designated academic practice between 1 July 2009 and 31 July 2010. We used mixed models to assess independent associations between patient race (non-Hispanic white or black) and 1) receipt of processes of care (A1C and LDL testing, foot and retinal examination, and influenza and pneumococcal vaccination) and 2) achievement of intermediate outcomes (LDL &amp;lt;100 mg/dL, blood pressure [BP] &amp;lt;140/90 mmHg, A1C &amp;lt;7.0% [&amp;lt;53 mmol/mol], and A1C &amp;gt;9.0% [&amp;gt;75 mmol/mol]), controlling for sociodemographic factors, health status, treatment intensity, and clinical continuity. RESULTS Compared with non-Hispanic white patients, black patients were younger, were more often single, had lower educational attainment, and were less likely to have commercial insurance. In unadjusted analyses, fewer black patients received a retinal examination and influenza vaccination during the study period or any lifetime pneumococcal vaccination (P &amp;lt; 0.05 [all comparisons]). Fewer black patients achieved an LDL &amp;lt;100 mg/dL, BP &amp;lt;140/90 mmHg, or A1C &amp;lt;7.0% (&amp;lt;53 mmol/mol), while more black patients had an A1C &amp;gt;9.0% (&amp;gt;75 mmol/mol) (P &amp;lt; 0.05 [all comparisons]). In multivariable models, black patients were less likely to receive A1C testing (odds ratio [OR] 0.57 [95% CI 0.34–0.95]) or influenza vaccination (OR 0.75 [95% CI 0.57–0.99]) or to achieve an LDL &amp;lt;100 mg/dL (OR 0.74 [95% CI 0.55–0.99]) or BP &amp;lt;140/90 mmHg (OR 0.64 [95% CI 0.49–0.84]). CONCLUSIONS Racial differences in processes and intermediate outcomes of diabetes care were present within this PCMH-designated practice, controlling for differences in sociodemographic, clinical, and treatment factors.
Complete blood count alterations after 6 months of continuous positive airway pressure treatment in patients with severe obstructive sleep apnea
Authors: Sinem Sökücü, Cengiz Özdemir, Levent Dalar, Levent Karasulu, Senay Aydin, Sedat Altin
Journal: European Respiratory Journal (2013)

Study Objectives: The cardiovascular complications caused by obstructive sleep apnea (OSA) have been shown to be decreased after continuous positive airway pressure (CPAP). Mean platelet volume (MPV), platelet distribution width (PDW), and red cell distribution width (RDW) are newly recognized tools for assessment of cardiovascular risk.  Methods: From a selection of patients with symptoms of nocturnal snoring and/or excessive day time sleepiness, 25 males with an apnea-hypopnea index (AHI) > 30/hr and 22 age-matched normal male controls with AHI 5/hr were included and complete blood count parameters were evaluated.  Results: Compared to controls, MPV values were significantly higher ( p =0.025) in the OSA patients but no significant differences in PDW or RDW were found ( p >0.05). Six months of CPAP therapy was found to significantly lower MPV values but to increase the PDW and RDW in patients with severe OSA ( p =0.001;  p =0.007;  p =0.001).  Conclusion: Our data suggest that in OSA patients, complete blood count parameters, such as MPV, PDW and RDW, change significantly after CPAP therapy.
Antibiotic use and inflammatory bowel diseases in childhood
Authors: A. Hviid, H. Svanstrom, M. Frisch
Journal: Gut (2010)

The composition of the intestinal microflora has been proposed as an important factor in the development of inflammatory bowel diseases (IBD). Antibiotics have the potential to alter the composition of the intestinal microflora. A study was undertaken to evaluate the potential association between use of antibiotics and IBD in childhood.A nationwide cohort study was conducted of all Danish singleton children born from 1995 to 2003 (N=577,627) with individual-level information on filled antibiotic prescriptions, IBD and potential confounding variables. Using Poisson regression, rate ratios (RRs) of IBD were calculated according to antibiotic use. Antibiotic use was classified according to time since use, type, number of courses used and age at use.IBD was diagnosed in 117 children during 3,173,117 person-years of follow-up. The RR of IBD was 1.84 (95% CI 1.08 to 3.15) for antibiotic users compared with non-users. This association appeared to be an effect on Crohn's disease (CD) alone (RR 3.41) and was strongest in the first 3 months following use (RR 4.43) and among children with ≥7 courses of antibiotics (RR 7.32).Antibiotic use is common in childhood and its potential as an environmental risk factor for IBD warrants scrutiny. This is the first prospective study to show a strong association between antibiotic use and CD in childhood. However, as with any observational study, causality cannot be inferred from our results and confounding by indication--in particular, prescribing of antibiotics to children with intestinal symptoms of as yet undiagnosed CD--should also be considered as a possible explanation.
The antiviral factor APOBEC3G improves CTL recognition of cultured HIV-infected T cells
Authors: Nicoletta Casartelli, Florence Guivel-Benhassine, Romain Bouziat, Samantha Brandler, Olivier Schwartz, Arnaud Moris
Journal: The Journal of Experimental Medicine (2009)

The cytidine deaminase APOBEC3G (A3G) enzyme exerts an intrinsic anti–human immunodeficiency virus (HIV) defense by introducing lethal G-to-A hypermutations in the viral genome. The HIV-1 viral infectivity factor (Vif) protein triggers degradation of A3G and counteracts this antiviral effect. The impact of A3G on the adaptive cellular immune response has not been characterized. We examined whether A3G-edited defective viruses, which are known to express truncated or misfolded viral proteins, activate HIV-1–specific (HS) CD8+ cytotoxic T lymphocytes (CTLs). To this end, we compared the immunogenicity of cells infected with wild-type or Vif-deleted viruses in the presence or absence of the cytidine deaminase. The inhibitory effect of A3G on HIV replication was associated with a strong activation of cocultivated HS-CTLs. CTL activation was particularly marked with Vif-deleted HIV and with viruses harboring A3G. Enzymatically inactive A3G mutants failed to enhance CTL activation. We also engineered proviruses bearing premature stop codons in their genome as scars of A3G editing. These viruses were not infectious but potently activated HS-CTLs. Therefore, the pool of defective viruses generated by A3G represents an underestimated source of viral antigens. Our results reveal a novel function for A3G, acting not only as an intrinsic antiviral factor but also as an inducer of the adaptive immune system.
The respiratory health effects of nitrogen dioxide in children with asthma
Authors: J. Gillespie-Bennett, N. Pierse, K. Wickens, J. Crane, P. Howden-Chapman
Journal: European Respiratory Journal (2010)

There is growing evidence that asthma symptoms can be aggravated or events triggered by exposure to indoor nitrogen dioxide (NO 2 ) emitted from unflued gas heating. The impact of NO 2 on the respiratory health of children with asthma was explored as a secondary analysis of a randomised community trial, involving 409 households during the winter period in 2006 (June to September). Geometric mean indoor NO 2 levels were 11.4 μg·m −3 , while outdoor NO 2 levels were 7.4 μg·m −3 . Higher indoor NO 2 levels (per logged unit increase) were associated with greater daily reports of lower (mean ratio 14, 95% CI 1.12–1.16) and upper respiratory tract symptoms (mean ratio 1.03, 95% CI 1.00–1.05), more frequent cough and wheeze, and more frequent reliever use during the day, but had no effect on preventer use. Higher indoor NO 2 levels (per logged unit increase) were associated with a decrease in morning (-17.25 mL, 95% CI -27.63– -6.68) and evening (-13.21, 95% CI -26.03– -0.38) forced expiratory volume in 1 s readings. Outdoor NO 2 was not associated with respiratory tract symptoms, asthma symptoms, medication use or lung function measurements. These findings indicate that reducing NO 2 exposure indoors is important in improving the respiratory health of children with asthma.
PTK6 Activation at the Membrane Regulates Epithelial–Mesenchymal Transition in Prostate Cancer
Authors: Yu Zheng, Zebin Wang, Wenjun Bie, Patrick M. Brauer, Bethany E. Perez White, Jing Li, Veronique Nogueira, Pradip Raychaudhuri, Nissim Hay, Debra A. Tonetti, Virgilia Macias, André Kajdacsy-Balla, Angela L. Tyner
Journal: Cancer Research (2013)

The intracellular tyrosine kinase protein tyrosine kinase 6 (PTK6) lacks a membrane-targeting SH4 domain and localizes to the nuclei of normal prostate epithelial cells. However, PTK6 translocates from the nucleus to the cytoplasm in human prostate tumor cells. Here, we show that while PTK6 is located primarily within the cytoplasm, the pool of active PTK6 in prostate cancer cells localizes to membranes. Ectopic expression of membrane-targeted active PTK6 promoted epithelial-mesenchymal transition in part by enhancing activation of AKT, thereby stimulating cancer cell migration and metastases in xenograft models of prostate cancer. Conversely, siRNA-mediated silencing of endogenous PTK6 promoted an epithelial phenotype and impaired tumor xenograft growth. In mice, PTEN deficiency caused endogenous active PTK6 to localize at membranes in association with decreased E-cadherin expression. Active PTK6 was detected at membranes in some high-grade human prostate tumors, and PTK6 and E-cadherin expression levels were inversely correlated in human prostate cancers. In addition, high levels of PTK6 expression predicted poor prognosis in patients with prostate cancer. Our findings reveal novel functions for PTK6 in the pathophysiology of prostate cancer, and they define this kinase as a candidate therapeutic target. Cancer Res; 73(17); 5426-37. ©2013 AACR.