tbuckley/cabot-search huggingface dataset:
Severe uremia depresses the ability of perifused rat pituitary cells to secrete growth hormone in response to growth hormone releasing hormone.
Authors: J Rodríguez, F Santos, M J García de Boto, E García, V Martínez, P Fernández, E Carbajo-Pérez, R J Krieg
Journal: Journal of the American Society of Nephrology (1997)

To examine whether growth hormone (GH) secretion is impaired by chronic renal failure (CRF) and to gain some insight into the influence of uremia itself and associated malnutrition, the GH secretory response of dispersed anterior pituitary cells perifused with GH-releasing hormone (GHRH) was investigated in 5/6 nephrectomized (UREM, N = 15) and three groups (N = 15 each) of normal renal function, sham-operated rats under three different nutritional conditions: fed "ad libitum" (SAL), pair-fed with a diet similar to the UREM group (SPF), and pair-fed with a diet similar to the UREM group in terms of protein ingestion but calorically supplemented up to intake of SAL group (SPF+). Ten days after nephrectomy, UREM rats had severe CRF, as shown by much higher (P < 0.0001) serum urea nitrogen concentrations (X +/- mean +/- SE) than sham groups (59 +/- 6 versus 8 +/- 0, 9 +/- 0, and 5 +/- 0 mmol/L, respectively), and they were growth retarded, as shown by lower gains (P < 0.0001) in weight (13.5 +/- 2.5 versus 62 +/- 2.1, 20.5 +/- 1.9, and 50.4 +/- 1.0 g) and length (2.9 +/- 0.2 versus 5.8 +/- 0.1, 3.6 +/- 0.1, and 5.6 +/- 0.1 cm). Perifusion studies showed similar basal GH secretory rate (ng/min/10(7) cells) in the four groups. A fixed sequence of progressively increasing GHRH doses resulted in a lower overall mean GH secretion in UREM rats (15.8 +/- 1.6 ng/min/10(7) cells), as compared with SAL (50.8 +/- 9.0 ng/min/10(7) cells, P < 0.01), SPF (33.0 +/- 3.3 ng/min/10(7) cells, P < 0.05), and SPF+ (49.4 +/- 5.1 ng/min/10(7) cells, P < 0.01) groups. Analysis of dose-response curves showed that the maximal secretory response was produced by the same concentration of GHRH (10 nM) in the four groups and was lower (P < 0.01) in UREM than SAL and SPF+ rats (34.9 +/- 5.0 versus 115.7 +/- 28.4 and 98.9 +/- 9.8 ng/min/10(7) cells). The concentration of GHRH that caused the half of maximal effect was identical, close to 1 nM, in the four groups of animals. This study provides direct evidence that the ability of pituitary cells to secrete GH in response to GHRH is depressed in severe CRF. The lower secretory capacity of pituitary gland is only partly dependent on caloric malnutrition associated with CRF. Data of dose-response curves suggest that decreased GH secretion may be related to a lesser number of pituitary receptors for GHRH.
Polymorphisms in Genes of Nucleotide and Base Excision Repair: Risk and Prognosis of Colorectal Cancer
Authors: Victor Moreno, Federica Gemignani, Stefano Landi, Lydie Gioia-Patricola, Amélie Chabrier, Ignacio Blanco, Sara González, Elisabet Guino, Gabriel Capellà, Federico Canzian
Journal: Clinical Cancer Research (2006)

Abstract Objectives: We have undertaken a comprehensive study of common polymorphisms in genes of DNA repair, exploring both the risk of developing colorectal cancer and the prognosis of patients. Methods: Subjects from a case-control study (377 cases and 329 controls) designed to assess gene-environment interactions were genotyped by use of an oligonucleotide microarray and the arrayed primer extension technique. Twenty-eight single nucleotide polymorphisms in 15 DNA repair genes were included. The candidate genes belong to different DNA repair pathways: base excision repair (OGG1, LIG3, APEX, POLB, XRCC1, PCNA, and MUTYH), nucleotide excision repair (ERCC1, ERCC2, ERCC4, and ERCC5), double-strand breaks repair (XRCC2, XRCC3, and XRCC9), and reversion repair (MGMT) genes. Results: Polymorphism OGG1 S326C was associated with an increased risk of colorectal cancer [odds ratio (OR), 2.3; 95% confidence interval (95% CI), 1.1-5.0], the risk being higher in younger individuals. A haplotype of ERCC1 was associated with increased risk (OR, 2.3; 95% CI, 1.0-5.3). POLB P242R was also associated with decreased risk (OR, 0.23; 95% CI, 0.05-0.99), although the number of variant allele carriers was low. In the univariate analysis, adjusted for age, sex, and Dukes' stage, three polymorphisms were significantly associated with better prognosis: XRCC1 R399Q [hazard ratio (HR), 0.38; 95% CI, 0.17-0.85], XRCC3 T141M (HR, 0.66; 95% CI, 0.45-0.97), and MGMT L84F (HR, 0.14; 95% CI, 0.02-0.99). ERCC1 19007T&amp;gt;C was associated with worse prognosis (HR, 1.51; 95% CI, 1.01-2.27). In a multivariate analysis, only XRCC1 R399Q and ERCC1 19007T&amp;gt;C remained significant. These associations were stronger among patients receiving adjuvant chemotherapy. Conclusions: Although the overall effect of DNA repair genes in colorectal cancer etiology seems limited, their influence in the response to chemotherapy and prognosis may be more relevant. This knowledge may help to clarify the utility of specific adjuvant treatments according to the individual genetic background.
The Relationship Between Craniofacial Morphology and Obstructive Sleep Apnea in Whites and in African-Americans
Authors: BANU CAKIRER, MARK G. HANS, GREG GRAHAM, JOAN AYLOR, PETER V. TISHLER, SUSAN REDLINE
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Previous studies of craniofacial risk factors for obstructive sleep apnea (OSA) have been based predominantly on cephalometry. However, differences in head form (measured by the cranial index [CI]) and facial form (measured by the facial index [FI]) are considered by anthropologists to provide a basis for structural variation in craniofacial anatomy. We assessed the association of head and facial form with the apnea hypopnea index (AHI) in 364 white individuals and 165 African-Americans. Data collected included cranial and facial dimensions (using anthropometric calipers), body mass index (BMI), neck circumference, and the AHI. CI and FI differed for whites with OSA (AHI ⩾ 15) versus those without OSA (AHI < 5) (increased CI and decreased FI in subjects with OSA, p = 0.005 and p = 0.006, respectively). CI and FI did not differ in OSA versus non-OSA groups of African-Americans. In subjects with OSA, the CI in whites was again greater and the FI smaller than those in African-Americans (p = 0.007 and p = 0.004, for CI and FI.) We conclude that brachycephaly is associated with an increased AHI in whites but not in African-Americans. The CI may useful in phenotyping and identifying population subsets with OSA.
National statistics for diet, alcohol consumption, and chronic pancreatitis in England and Wales, 1960-88.
Authors: C D Johnson, S Hosking
Journal: Gut (1991)

This study compared national statistics for consumption of alcohol and dietary intake with the numbers of cases of chronic pancreatitis as recorded in a 10% sample of all hospital discharges (Hospital In-Patient Enquiry) and with the annual number of deaths. Hospital discharges for chronic pancreatitis became more common throughout the study period (7.0-11.1 discharges per million per year in 1960-4; 26.8-32.4 discharges per million per year in 1980-4). The most rapid increase was from 1975-82. The rate increased fourfold in men, but only twofold in women, and the increase began earlier in men (1976) than in women (1980). Annual deaths from chronic pancreatitis also rose progressively (46-70 in 1960-4; 64-91 in 1985-8). The annual per capita consumption of alcohol rose from 4.0-4.9 litres in 1960-4 to a peak of 7.7 litres in 1979; it has been relatively stable (6.9-7.6 litres) in 1980-8. Total dietary energy intake assessed in the National Food Survey fell progressively, with a correspondingly greater fall in carbohydrate intake, so that the energy contributions of fat and protein rose slightly, although total fat and protein consumption fell from 1965-9 to 1980-4. These changes were small in relation to total dietary intake and seemed to be unrelated to the changes in the numbers of chronic pancreatitis discharges. There was a close correlation (r = 0.96) between per capita alcohol consumption and the numbers of discharges with chronic pancreatitis six years later. This suggests that epidemiological trends in chronic pancreatitis in the United Kingdom might be predictable from population based statistics of alcohol consumption.
Inhibiting Mitochondrial Na <sup>+</sup> /Ca <sup>2+</sup> Exchange Prevents Sudden Death in a Guinea Pig Model of Heart Failure
Authors: Ting Liu, Eiki Takimoto, Veronica L. Dimaano, Deeptankar DeMazumder, Sarah Kettlewell, Godfrey Smith, Agnieszka Sidor, Theodore P. Abraham, Brian O’Rourke
Journal: Circulation Research (2014)

Rationale : In cardiomyocytes from failing hearts, insufficient mitochondrial Ca 2+ accumulation secondary to cytoplasmic Na + overload decreases NAD(P)H/NAD(P) + redox potential and increases oxidative stress when workload increases. These effects are abolished by enhancing mitochondrial Ca 2+ with acute treatment with CGP-37157 (CGP), an inhibitor of the mitochondrial Na + /Ca 2+ exchanger. Objective : Our aim was to determine whether chronic CGP treatment mitigates contractile dysfunction and arrhythmias in an animal model of heart failure (HF) and sudden cardiac death (SCD). Methods and Results : Here, we describe a novel guinea pig HF/SCD model using aortic constriction combined with daily β-adrenergic receptor stimulation (ACi) and show that chronic CGP treatment (ACi plus CGP) attenuates cardiac hypertrophic remodeling, pulmonary edema, and interstitial fibrosis and prevents cardiac dysfunction and SCD. In the ACi group 4 weeks after pressure overload, fractional shortening and the rate of left ventricular pressure development decreased by 36% and 32%, respectively, compared with sham-operated controls; in contrast, cardiac function was completely preserved in the ACi plus CGP group. CGP treatment also significantly reduced the incidence of premature ventricular beats and prevented fatal episodes of ventricular fibrillation, but did not prevent QT prolongation. Without CGP treatment, mortality was 61% in the ACi group &lt;4 weeks of aortic constriction, whereas the death rate in the ACi plus CGP group was not different from sham-operated animals. Conclusions : The findings demonstrate the critical role played by altered mitochondrial Ca 2+ dynamics in the development of HF and HF-associated SCD; moreover, they reveal a novel strategy for treating SCD and cardiac decompensation in HF.
Dysfunctional Prefrontal Regional Specialization and Compensation in Schizophrenia
Authors: Hao-Yang Tan, Steven Sust, Joshua W. Buckholtz, Venkata S. Mattay, Andreas Meyer-Lindenberg, Michael F. Egan, Daniel R. Weinberger, Joseph H. Callicott
Journal: American Journal of Psychiatry (2006)

Objective: It has been suggested that in healthy persons higher-order cognitive processing engaged by incremental working memory load hierarchically employs more dorsal than ventral prefrontal resources in healthy individuals. Given that working memory performance is impaired in schizophrenia, especially at higher executive loads, the authors investigated how this prefrontal functional organization might be altered in disease, independent of performance deficits. Method: Using N-back working memory functional magnetic resonance imaging (fMRI) data, the authors studied 15 patients with schizophrenia and 26 healthy comparison subjects. Subgroups based on median performance accuracy at 2-back were analyzed; high performers included eight schizophrenia patients and 14 comparison subjects, and low performers included seven patients and 12 comparison subjects. Results: High-performing but not low-performing comparison subjects responded to incremental working memory executive load with disproportionately greater dorsal but not ventral prefrontal cortex activation, which also predicted performance accuracy. In the high- and low-performing patient groups, incremental working memory load caused a disproportionate increase in ventral but not dorsal prefrontal cortex activation relative to the respective comparison group, which also correlated with accuracy. Functional connectivity between the ventral prefrontal cortex and posterior parietal cortex was relatively greater in patients, whereas comparison subjects had greater functional connectivity between the dorsal prefrontal cortex and posterior parietal cortex. Conclusions: The hierarchical organization of the prefrontal cortex may be compromised in schizophrenia, resulting in loss of functional specialization and integration at the dorsal prefrontal cortex and in compensatory activation from the ventral prefrontal cortex, which may ultimately affect working memory and executive cognition.
Identification and assessment of endocrine disruptors: limitations of in vivo and in vitro assays.
Authors: T Zacharewski
Journal: Environmental Health Perspectives (1998)

It has been suggested that chemicals and complex mixtures capable of modulating the endocrine system may contribute to adverse health, reproduction, and developmental effects in humans and wildlife. These effects include increased incidence of hormone-dependent cancers, compromised reproductive fitness, and abnormal reproductive system development. In response to public concern, regulatory agencies in North America and Europe are formulating potential strategies to systematically test chemicals and complex mixtures for their endocrine-disrupting activities. Because of the complexity of the endocrine system and the number of potential endocrine disruptor targets, a tiered approach involving a complementary battery of short- and long-term in vivo and in vitro assays that assesses both receptor and nonreceptor-mediated mechanisms of action is being considered. However, the available established assays use a limited number of end points, and significant information gaps exist for other potential targets in the endocrine system. In addition to discussing the merits and limitations of the assays that may be adopted, this paper also highlights potential problems associated with the use of a tiered testing strategy.
Targeting iron homeostasis induces cellular differentiation and synergizes with differentiating agents in acute myeloid leukemia
Authors: Celine Callens, Séverine Coulon, Jerome Naudin, Isabelle Radford-Weiss, Nicolas Boissel, Emmanuel Raffoux, Pamella Huey Mei Wang, Saurabh Agarwal, Houda Tamouza, Etienne Paubelle, Vahid Asnafi, Jean-Antoine Ribeil, Philippe Dessen, Danielle Canioni, Olivia Chandesris, Marie Therese Rubio, Carole Beaumont, Marc Benhamou, Hervé Dombret, Elizabeth Macintyre, Renato C. Monteiro, Ivan C. Moura, Olivier Hermine
Journal: The Journal of Experimental Medicine (2010)

Differentiating agents have been proposed to overcome the impaired cellular differentiation in acute myeloid leukemia (AML). However, only the combinations of all-trans retinoic acid or arsenic trioxide with chemotherapy have been successful, and only in treating acute promyelocytic leukemia (also called AML3). We show that iron homeostasis is an effective target in the treatment of AML. Iron chelating therapy induces the differentiation of leukemia blasts and normal bone marrow precursors into monocytes/macrophages in a manner involving modulation of reactive oxygen species expression and the activation of mitogen-activated protein kinases (MAPKs). 30% of the genes most strongly induced by iron deprivation are also targeted by vitamin D3 (VD), a well known differentiating agent. Iron chelating agents induce expression and phosphorylation of the VD receptor (VDR), and iron deprivation and VD act synergistically. VD magnifies activation of MAPK JNK and the induction of VDR target genes. When used to treat one AML patient refractory to chemotherapy, the combination of iron-chelating agents and VD resulted in reversal of pancytopenia and in blast differentiation. We propose that iron availability modulates myeloid cell commitment and that targeting this cellular differentiation pathway together with conventional differentiating agents provides new therapeutic modalities for AML.
A T cell receptor V alpha domain expressed in bacteria: does it dimerize in solution?
Authors: D Plaksin, S Chacko, P McPhie, A Bax, E A Padlan, D H Margulies
Journal: The Journal of Experimental Medicine (1996)

To evaluate the potential for dimerization through a particular T cell receptor (TCR) domain, we have cloned the cDNA encoding a TCR V alpha from a hybridoma with specificity for the human immunodeficiency virus (HIV) envelope glycoprotein 120-derived peptide P18-110 (RGPGRAFVTI) bound to the murine major histocompatibility complex (MHC) class I molecule, H-2Dd. This cDNA was then expressed in a bacterial vector, and protein, as inclusion bodies, was solubilized, refolded, and purified to homogeneity. Yield of the refolded material was from 10 to 50 mg per liter of bacterial culture, the protein was soluble at concentrations as high as 25 mg/ml, and it retained a high level of reactivity with an anti-V alpha 2 monoclonal antibody. This domain was monomeric both by size exclusion gel chromatography and by sodium dodecyl sulfate polyacrylamide gel electrophoresis. Circular dichroism spectra indicated that the folded V alpha domain had secondary structure similar to that of single immunoglobulin or TCR domains, consisting largely of beta sheet. Conditions for crystallization were established, and at least two crystal geometries were observed: hexagonal bipyramids that failed to diffract beyond approximately 6 A, and orthorhombic crystals that diffracted to 2.5 A. The dimerization of the V alpha domain was investigated further by solution nuclear magnetic resonance spectroscopy, which indicated that dimeric and monomeric forms of the protein were about equally populated at a concentration of 1 mM. Thus, models of TCR-mediated T cell activation that invoke TCR dimerization must consider that some V alpha domains have little tendency to form homodimers or multimers.
The Effects of Tamoxifen and Estrogen on Brain Metabolism in Elderly Women
Authors: T. Ernst
Journal: JNCI Journal of the National Cancer Institute (2002)

Background: Tamoxifen is used to treat breast cancer and may reduce the risk of breast cancer. However, there are conflicting reports as to whether tamoxifen use is associated with changes in brain metabolism and function or cognitive impairment. Consequently, we assessed the effects of tamoxifen and estrogen on the brain chemistry of elderly women. Methods: We used proton magnetic resonance spectroscopy to measure the concentrations of N-acetyl-containing compounds, myo-inositol (MI), total creatine (creatine plus phosphocreatine), and choline-containing compounds in the frontal white matter, basal ganglia, and hippocampus of 76 elderly women of whom 16 had received tamoxifen therapy, 27 had received estrogen as hormone replacement therapy (HRT), and 33 had received neither (control group). A two-way analysis of variance (ANOVA) was performed to determine the statistical significance of differences in cerebral metabolite concentrations among subject groups and brain regions. All statistical tests were two-sided. Results: Women in the tamoxifen and HRT groups had lower concentrations of MI in all areas than women in the control group (P = .02; overall group effect on ANOVA). Compared with the control group, the tamoxifen group (P = .004) and the HRT group (P = .06) had lower concentrations of MI in their basal ganglia. The MI concentration in the basal ganglia was inversely correlated with the duration of tamoxifen treatment (ρ = –.72; P = .005). Conclusions: The reduced concentrations of MI in the brains of women treated with tamoxifen and HRT, compared with those of control women, suggest that tamoxifen has an effect similar to that of estrogen. These results, if confirmed, may alleviate concerns about the safety of using tamoxifen to reduce breast cancer risk in elderly women.
Late-breaking abstract: Sleep quality in chronic obstructive pulmonary disease patients and its relationship with general well being
Authors: Krishna Sharma, Titiksha Choyal, Rudradev Pandey
Journal: European Respiratory Journal (2014)

Background: Alteration in sleep patterns is one of the vital changes which may affect daytime functioning and well-being of the Chronic obstructive pulmonary disease (COPD) patients.  Aims and objectives: The aim of this study was to assess the perception of quality of sleep among stable COPD patients and to examine its relationship with general well-being.  Methods: Randomly selected 100 outpatient department patients with COPD (forced expired volume in 1 second [FEV1] 53.8 ± 13.4%, 50 male, 50 female, aged 57.6 ± 12.5 years) were administered Pittsburgh Sleep Quality Index (PSQI) and General Well-Being Scale (GWBS) to assess quality of sleep and general well-being respectively. Results were analyzed across gender.  Results: Mean PSQI scores obtained are 9.53 ± 4.02 and 11.23 ± 3.79 for male and female COPD patients respectively, indicating poor sleep quality in both the groups. Significant gender differences were observed in sleep quality (p   Conclusions: Disturbed sleep is observed in most of the patients with COPD, which may have significant effects on daytime functioning and well-being, the effect being more on female than male patients. Poor sleep quality may add on to already present several comorbidities in COPD patients.
Adalimumab for maintenance treatment of Crohn's disease: results of the CLASSIC II trial
Authors: W J Sandborn, S B Hanauer, P Rutgeerts, R N Fedorak, M Lukas, D G MacIntosh, R Panaccione, D Wolf, J D Kent, B Bittle, J Li, P F Pollack
Journal: Gut (2007)

Adalimumab induced clinical remission after four weeks in patients with active Crohn's disease in the CLASSIC I trial.To evaluate long term efficacy and safety of adalimumab maintenance therapy in Crohn's disease in a follow-on randomised controlled trial (CLASSIC II).In the preceding CLASSIC I trial, 299 patients with moderate to severe Crohn's disease naive to tumour necrosis factor antagonists received induction therapy with adalimumab 40 mg/20 mg, 80 mg/40 mg, or 160 mg/80 mg, or placebo, at weeks 0 and 2. In all, 276 patients from CLASSIC I enrolled in CLASSIC II and received open-label adalimumab 40 mg at weeks 0 (week 4 of CLASSIC I) and 2; 55 patients in remission at both weeks 0 and 4 were re-randomised to adalimumab 40 mg every other week, 40 mg weekly, or placebo for 56 weeks. Patients not in remission at both weeks 0 and 4 were enrolled in an open-label arm and received adalimumab 40 mg every other week. With non-response or flare, these patients could have their dosages increased to 40 mg weekly. Patients in the randomised arm with continued non-response or disease flare could switch to open-label adalimumab 40 mg every other week and again to 40 mg weekly. The primary end point was maintenance of remission (CDAI <150) in randomised patients through week 56.Of 55 patients randomised at week 4, 79% who received adalimumab 40 mg every other week and 83% who received 40 mg weekly were in remission at week 56, v 44% for placebo (p<0.05). In all, 204 patients entered the open-label arm. Of these, 93 (46%) were in clinical remission at week 56. Adalimumab was generally well-tolerated in all patients.Adalimumab induced and maintained clinical remission for up to 56 weeks in patients with moderate to severe Crohn's disease naive to anti-TNF treatment.