tbuckley/cabot-search huggingface dataset:
Association of CYP1A1 Polymorphisms with Differential Metabolic Activation of 17β-Estradiol and Estrone
Authors: Pyotr Kisselev, Wolf-Hagen Schunck, Ivar Roots, Dieter Schwarz
Journal: Cancer Research (2005)

Abstract Several epidemiologic studies associate certain CYP1A1 genotypes, alone or in combination, with an increased risk of estrogen-related cancers. To answer the question of whether genotype-dependent activation of estrogens by CYP1A1 could be the underlying mechanism, we studied the hydroxylation activity of the most common allelic variants of human CYP1A1 towards both endogenously occurring estrogens, 17β-estradiol (E2) and estrone (E1). We expressed and purified CYP1A1.1 (wild-type), CYP1A1.2 (Ile462Val), and CYP1A1.4 (Thr461Asn) and did enzymatic assays of NADPH-dependent estrogen hydroxylation in reconstituted CYP1A1 systems. All CYP1A1 variants catalyzed the formation of 2-, 4-, 6α-, and 15α-hydroxylated estrogen metabolites from E2 and E1, yet with varying catalytic efficiency and distinct regiospecificity. Whereas the variant CYP1A1.2 (Ile462Val) had a significant higher catalytic activity for all hydroxylation sites and both substrates, it was most pronounced for 2-hydroxylation. Catalytic efficiencies for the formation of the major metabolites, 2-OH-E2 and 2-OH-E1, by CYP1A1.2 were 5.7- and 12-fold higher, respectively, compared with the wild-type enzyme. The catalytic efficiencies for hydroxylations catalyzed by CYP1A1.4 were roughly comparable with those of the wild-type enzyme. Enzyme kinetics showed that the superior activity of CYP1A1.2 (Ile462Val) is mainly caused by a higher Vmax, whereas Km values of all variants were similar. The data suggest that risk of estrogen-induced cancers and cardiovascular diseases might be—at least partially—determined by the CYP1A1 genotype.
Induction of Leukemias and Digestive Tract Tumors in Donryu Rats by I-Propyl-1-nitrosourea&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;
Authors: T Ogiu, M Nakadate, S Odashima
Journal: JNCI Journal of the National Cancer Institute (1975)

Three groups of female Donryu rats were continuously given 600, 300, or 150 ppm solution of 1-propyl-1-nitrosourea in their drinking water. Leukemias developed in 62 of 109 (57%) rats surviving for more than 17 weeks and tumors developed in the digestive tracts of 31 (28%) animals. Of the leukemias, the differentiated myelocytic type was the most frequent, followed by myeloblastic leukemia and erythroleukemia. Tumors in the digestive tract, predominantly in the glandular stomach and duodenum, were both epithelial and nonepithelial. The other induced tumors were mainly in the mammary glands, ear ducts, and thymus, though the incidence was less than 15%.
Reflex Effects of Cephalic Hypoxia, Hypercapnia, and Ischemia Upon Ventricular Contractility
Authors: HILAIRE DEGEEST, MATTHEW N. LEVY, HARRISON ZIESKE, Geraldine Nelson, Thomas Rogoff
Journal: Circulation Research (1965)

The effects of brief periods of cephalic hypoxia, hypercapnia, and ischemia upon the contractility of the normally oxygenated ventricular myocardium were studied in an innervated, isovolumetric, canine left ventricle preparation. The majority of responses to cephalic hypoxia were of two types in preparations with vagi and carotid sinus nerves still intact. (a) More frequently, peak left ventricular pressure changed in biphasic fashion, consisting of an initial depression of contractility followed by subsequent augmentation. (b) Less frequently, a monophasic enhancement of contractility appeared. After transection of either the vagi or the carotid sinus nerves, a monophasic facilitation of contractility was usually evoked by cephalic hypoxia. From these data, it was concluded that two opposing influences act simultaneously upon the ventricular myocardium during cephalic hypoxia in preparations with intact vagi and carotid sinus nerves. Central nervous system hypoxia enhances myocardial contractility; its effect is mediated principally via sympathetic pathways. Hypoxia at the level of the carotid chemoreceptors depresses contractility reflexly; the efferent limb of this reflex is mediated chiefly via the vagi. At any moment in time, the effect upon ventricular contractility is the result of these opposing influences. Cephalic hypercapnia produced effects similar to those of hypoxia. Cephalic ischemia always evoked a marked, positive inotropic effect upon the ventricles.
P74 A Novel Measure of Physical Exercise Capacity in COPD: Abstract 74 Table 1
Authors: AM Albarrati, NG Gale, J Duckers, S Enright, I Munnery, M Munnery, JR Cockcroft, DJ Shale
Journal: Thorax (2012)

<h3>Introduction</h3> Chronic obstructive pulmonary disease (COPD) is associated with progressive impairment of physical performance. However, determination of physical performance in routine clinical practise is difficult due to limited resources. This study compared the timed up and go (TUG) test and a range of assessments of physical performance, easily applied in the routine care of COPD, with the 6 minute walk test (6MWT). <h3>Method</h3> As part of a longitudinal study of comorbidities in COPD, sub-maximal physical performance was examined in 300 patients and 50 comparators using the 6MWT. The TUG test, spirometry, COPD assessment test (CAT), St George’s Respiratory Questionnaire (SGRQ) and gait speed were also determined. Gait speed was determined by dividing 6MWTd istance by time. <h3>Results</h3> Patients and comparators were similar in age, BMI and gender. There were between group differences in 6MWT, TUG and gait speed (Table 1), ANOVA showed a difference between comparators and the GOLD stages of COPD for all these variables (all p&lt;0.01). The TUG time differed across BMI categories in COPD but not comparators (ANOVA p=0.007 and p=0.195 respectively). The TUG time was inversely related to 6MWT (r=0.64, p&lt;0.0001), gait speed (r=0.63, p&lt;0.0001)and lung function (r=0.15, p&lt;0.01), and directly to the activity (r=0.35, p&lt;0.0001)and total SGRQ scores (r=0.35, p&lt;0.0001) and CAT (r=0.39, p&lt;0.0001). Stepwise regression analysis, adjusted for age and BMI, indicated that TUG time, SGRQ activity score and CAT score explained 73% of variance in 6MWT in patients, with lung function excluded from the analysis. <h3>Conclusions</h3> The TUG time identified the difference in physical performance between patients and comparators and also across GOLD categories. In the elderly the TUG test has been used as an indicator of physical performance, being an integrated measure of gait speed, balance and functional capacity. It appears to apply in the same way to the physical deficits in COPD and also to link to health related quality of life. The application of TUG test and validated questionnaires may be a useful measure of physical performance, which because of its rapidity and ease of application could be used in assessments in clinical practise.
Familial aggregation of gout and relative genetic and environmental contributions: a nationwide population study in Taiwan
Authors: Chang-Fu Kuo, Matthew J Grainge, Lai-Chu See, Kuang-Hui Yu, Shue-Fen Luo, Ana M Valdes, Weiya Zhang, Michael Doherty
Journal: Annals of the Rheumatic Diseases (2013)

<b>Background:</b> Acute exacerbations of chronic obstructive pulmonary disease (AE-COPD) are a common cause of hospital admission. Many exacerbations are believed to be due to upper and/or lower respiratory tract viral infections, but the incidence of these infections in patients with COPD is still undetermined. <b>Methods:</b> Respiratory syncytial virus (RSV), influenza A and B, parainfluenza 3, and picornaviruses were detected by nested reverse transcription polymerase chain reaction (RT-PCR) in upper (nasal lavage) and lower respiratory tract specimens (induced sputum). In a 2:1 case-control set up, 85 hospitalised patients with AE-COPD and 42 patients with stable COPD admitted for other medical reasons were studied. <b>Results:</b> Respiratory viruses were found more often in sputum and nasal lavage of patients with AE-COPD (48/85, 56%) than in patients with stable COPD (8/42, 19%, p&lt;0.01). The most common viruses were picornaviruses (21/59, 36%), influenza A (15/59, 25%), and RSV (13/59, 22%). When specimens were analysed separately, this difference was seen in induced sputum (exacerbation 40/85 (47%) <i>v</i> stable 4/42 (10%), p&lt;0.01) but was not significant in nasal lavage (exacerbation 26/85 (31%) <i>v</i> stable 7/42 (17%), p=0.14). In patients with AE-COPD, fever was more frequent in those in whom viruses were detected (12/48, 25%) than in those in whom viruses were not detected (2/37, 5%, p=0.03). <b>Conclusion:</b> Viral respiratory pathogens are found more often in respiratory specimens of hospitalised patients with AE-COPD than in control patients. Induced sputum detects respiratory viruses more frequently than nasal lavage in these patients. These data indicate that nasal lavage probably has no additional diagnostic value to induced sputum in cross-sectional studies on hospitalised patients with AE-COPD and that the role of viral infection in these patients is still underestimated.
Development and Characterization Of a Murine Model Of Repeated Dry Exposure To Aerosolized Fungal Conidia
Authors: Ajay Nayak, Amanda Buskirk, W.Travis Goldsmith, Angela Lemons, Justin Hettick, Michael Kashon, Amy Cumpston, Jared Cumpston, Howard Leonard, Walter McKinney, David Frazer, Donald H. Beezhold, Brett J. Green
Journal: Journal of Allergy and Clinical Immunology (2014)
Standard endoscopy with random biopsies versus narrow band imaging targeted biopsies in Barrett's oesophagus: a prospective, international, randomised controlled trial
Authors: Prateek Sharma, Robert H Hawes, Ajay Bansal, Neil Gupta, Wouter Curvers, Amit Rastogi, Mandeep Singh, Matt Hall, Sharad C Mathur, Sachin B Wani, Brenda Hoffman, Srinivas Gaddam, Paul Fockens, Jacques J Bergman
Journal: Gut (2012)

<h3>Background</h3> White light endoscopy with random biopsies is the standard for detection of intestinal metaplasia (IM) and neoplasia in patients with Barrett9s oesophagus (BO). Narrow band imaging (NBI) highlights surface patterns that correlate with IM and neoplasia in BO. <h3>Objective</h3> To compare high-definition white light (HD-WLE) and NBI for detection of IM and neoplasia in BO. <h3>Design</h3> International, randomised, crossover trial comparing HD-WLE and NBI. Patients referred for BO screening/surveillance at three tertiary referral centres were prospectively enrolled and randomised to HD-WLE or NBI followed by other procedures in 3–8 weeks. During HD-WLE, four quadrant biopsies every 2 cm, together with targeted biopsies of visible lesions (Seattle protocol), were obtained. During NBI examination, mucosal and vascular patterns were noted and targeted biopsies were obtained. All biopsies were read by a single expert gastrointestinal pathologist in a blinded fashion. <h3>Results</h3> 123 patients with BO (mean age 61; 93% male; 97% Caucasian) with mean circumferential and maximal extents of 1.8 and 3.6 cm, respectively, were enrolled. Both HD-WLE and NBI detected 104/113 (92%) patients with IM, but NBI required fewer biopsies per patient (3.6 vs 7.6, p&lt;0.0001). NBI detected a higher proportion of areas with dysplasia (30% vs 21%, p=0.01). During examination with NBI, all areas of high-grade dysplasia and cancer had an irregular mucosal or vascular pattern. <h3>Conclusions</h3> NBI targeted biopsies can have the same IM detection rate as an HD-WLE examination with the Seattle protocol while requiring fewer biopsies. In addition, NBI targeted biopsies can detect more areas with dysplasia. Regular appearing NBI surface patterns did not harbour high-grade dysplasia/cancer, suggesting that biopsies could be avoided in these areas.
Abnormal expression of wild type p53 protein in normal cells of a cancer family patient
Authors: D.M. Barnes, C.E. Gillett, L.G. Bobrow, A.M. Hanby, S. Mohammed, S. Hodgson, I.M. Leigh, T. Purkis, C. MacGeoch, N.K. Spurr, J. Bartek, B. Vojtesek, S.M. Picksley, D.P. Lane
Journal: The Lancet (1992)
Evidence from nuclear sequences that invariable sites should be considered when sequence divergence is calculated.
Authors: J S Shoemaker, W M Fitch
Journal: Molecular Biology and Evolution (1989)

It has long been known, from the distribution of multiple amino acid replacements, that not all amino acids of a sequence are replaceable. More recently, the phenomenon was observed at the nucleotide level in mitochondrial DNA even after allowing for different rates of transition and transversion substitutions. We have extended the search to globin gene sequences from various organisms, with the following results: (1) Nearly every data set showed evidence of invariable nucleotide positions. (2) In all data sets, substitution rates of transversions and transitions were never in the ratio of 2/1, and rarely was the ratio even constant. (3) Only rarely (e.g., the third codon position of beta hemoglobins) was it possible to fit the data set solely by making allowance for the number of invariable positions and for the relative rates of transversion and transition substitutions. (4) For one data set (the second codon position of beta hemoglobins) we were able to simulate the observed data by making the allowance in (3) and having the set of covariotides (concomitantly variable nucleotides) be small in number and be turned over in a stochastic manner with a probability that was appreciable. (5) The fit in the latter case suggests, if the assumptions are correct and at all common, that current procedures for estimating the total number of nucleotide substitutions in two genes since their divergence from their common ancestor could be low by as much as an order of magnitude. (6) The fact that only a small fraction of the nucleotide positions differ is no guarantee that one is not seriously underestimating the total amount of divergence (substitutions). (7) Most data sets are so heterogeneous in their number of transition and transversion differences that none of the current models of nucleotide substitution seem to fit them even after (a) segregation of coding from noncoding sequences and (b) splitting of the codon into three subsets by codon position. (8) These frequently occurring problems cannot be seen unless several reasonably divergent orthologous genes are examined together.
The collaborative phenotype of secondary B cells is determined by T lymphocytes during in vivo immunization.
Authors: N A Speck, S K Pierce
Journal: The Journal of Experimental Medicine (1982)

Previous studies have demonstrated that the B cells in immune and nonimmune mice manifest different major histocompatibility complex (MHC) collaborative phenotypes with antigen-specific T cells. Immune, or secondary B cells require syngeneic-like MHC recognition by collaborating T cells, and in its absence fail to be stimulated. Primary B cells manifest a much less stringent requisite for MHC recognition by T cells, and under conditions in which secondary B cells fail to be stimulated, primary B cells are stimulated to secrete IgM antibody. Experiments were conducted to determine whether the acquisition of the secondary B cells' MHC collaborative phenotype was dependent on the presence of T cells during in vivo immunization. B cell populations from T dependently and T independently immunized conventional BALB/c and athymic BALB/c nu/nu mice were compared in their ability to collaborate with allogeneic T cells. Although antigen alone promotes the differentiation of several secondary B cell characteristics, including an increase in the frequency of antigen-specific B cells and a preference for IgG1 antibody synthesis in vitro, the acquisition of the secondary B cells' MHC collaborative phenotype was dependent on the presence of T cells during in vivo immunization. B cell populations from T dependently and T independently immunized conventional BALB/c and athymic BALB/c nu/nu mice were compared in their ability to collaborate with allogeneic T cells. Although antigen alone promotes the differentiation of several secondary B cell characteristics, including an increase in the frequency of antigen-specific B cells and a preference of IgG1 antibody synthesis in vitro, the acquisition of the secondary B cells' MHC collaborative phenotype was found to be dependent on the presence of T cells during in vivo immunization. Thus, the restriction imposed on T cell-B-cell-collaborative interactions in secondary humoral immune responses appears to be the result of T dependent antigen-driven events.
Unitary Chloride Channels Activated by Protein Kinase C in Guinea Pig Ventricular Myocytes
Authors: Mei Lin Collier, Joseph R. Hume
Journal: Circulation Research (1995)

Abstract Recent evidence suggests that protein kinase A (PKA)-activated Cl − channels in heart are encoded by an isoform of the epithelial cystic fibrosis transmembrane conductance regulator gene (CFTR). Macroscopic current measurements indicate that a similar time-independent Cl − conductance can be activated through a protein kinase C (PKC)-dependent pathway in guinea pig and feline ventricle. However, it is presently not clear whether PKC is activating the same population of channels as PKA or a separate class of Cl − channels, even though the regulatory (R) domain of CFTR is known to contain consensus phosphorylation sites for both PKA and PKC. In the present study we directly compare the properties of single Cl − channels activated by PKC and PKA in cell-attached patches of guinea pig ventricular myocytes. Pipette and bath solutions contained N -methyl- d -glucamine and Cs + or tetraethylammonium as substitutes for Na + and K + , respectively, and Cl − concentration in the patch pipette was either 150 mmol/L or 40 mmol/L. Bath application of phorbol 12,13-dibutyrate or phorbol 12-myristate 13-acetate (PDBu or PMA; 50 nmol/L), activators of PKC, resulted in the appearance of unitary Cl − channels with a mean conductance of 9.31±0.94 pS (n=8) and 8.8 pS (n=2), respectively, and reversal potentials were close to predicted E Cl . Addition of staurosporine (500 nmol/L) reduced open probability (P o ) of channels activated by PDBu. Bath application of the phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (IBMX, 500 μmol/L) resulted in the activation of Cl − channels with a conductance (mean 8.76±0.67 pS, n=3) similar to those activated by PDBu. Open probability (P o ) of both PKC- and PKA-activated Cl − channels exhibited voltage independence and both were insensitive to block by 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS). In patches containing channels preactivated by PDBu, subsequent bath application of IBMX (500 μmol/L) resulted in an increase in P o without any evidence for the activation of a separate population of channels with a different unitary conductance. These results suggest either that PKC can activate cardiac CFTR Cl − channels and that once activated by PKC, the channels can be further modulated by PKA or that PKC and PKA activate separate populations of Cl − channels with similar conductance and kinetic properties.
489 CLINICAL IMPACT AND BEHAVIOUR OF SERUM AUTOANTIBODIES IN ADULT LIVER TRANSPLANTATION
Authors: A. Granito, A. Vannini, C. Quarneti, P. Muratori, L. Muratori, G. Pappas, F. Piscaglia, P. Andreone, G. Bianchi, M.R. Tamè, C. Morelli, F.B. Bianchi, A.D. Pinna, M. Lenzi
Journal: Journal of Hepatology (2010)
Cohort study of examination performance of undergraduate medical students learning in community settings
Authors: P. Worley
Journal: BMJ (2004)

<h3>Abstract</h3> <b>Objectives</b> To determine whether moving clinical medical education out of the tertiary hospital into a community setting compromises academic standards. <b>Design</b> Cohort study. <b>Setting</b> Flinders University four year graduate entry medical course. In their third year, students are able to choose to study at the tertiary teaching hospital in Adelaide, in rural general practices, or at Royal Darwin Hospital, a regional secondary referral hospital. <b>Participants</b> All 371 medical students who did their year 3 study from 1998-2002. <b>Main outcome measures</b> Mean student examination score (%) at the end of year 3. <b>Results</b> The unadjusted mean year 3 scores at each location differed significantly (P &lt; 0.001); the mean score was 65.2 (SE = 0.43) for Adelaide students, 68.2 (0.83) for Darwin students, and 69.3 (0.97) for students on the rural programme. Mean year 2 scores were similar for each location. Post hoc tests of means adjusted for sex, age, year 2 score, and cohort year showed that the rural and Darwin groups had a significantly improved score in year 3 compared with the Adelaide group (adjusted mean difference = 3.08, 95% confidence interval 1.25 to 4.90, P &lt; 0.001 for rural group; 1.91, 0.47 to 3.36, P = 0.001 for Darwin group). <b>Conclusions</b> These findings show that the concern that student academic performance in the tertiary hospital would be better than that of students in the regional hospital and community settings is not justified. This challenges the orthodoxy of a tertiary hospital education being the gold standard for undergraduate medical students.
Lymphedema After Breast Cancer: Incidence, Risk Factors, and Effect on Upper Body Function
Authors: Sandra C. Hayes, Monika Janda, Bruce Cornish, Diana Battistutta, Beth Newman
Journal: Journal of Clinical Oncology (2008)

Purpose Secondary lymphedema is associated with adverse physical and psychosocial consequences among women with breast cancer (BC). This article describes the prevalence and incidence of lymphedema between 6 and 18 months after BC treatment; personal, treatment, and behavioral correlates of lymphedema status; and the presence of other upper-body symptoms (UBS) and function (UBF). Patients and Methods A population-based sample of Australian women (n = 287) with recently diagnosed, invasive BC were evaluated on five occasions using bioimpedance spectroscopy. Lymphedema was diagnosed when the ratio of impedance values, comparing treated and untreated sides, was three standard deviations more than normative data. UBF was assessed using the validated Disability of the Arm, Shoulder, and Hand questionnaire. Results From 6 to 18 months after surgery, 33% (n = 62) of the sample were classified as having lymphedema; of these, 40% had long-term lymphedema. Although older age, more extensive surgery or axillary node dissection, and experiencing one or more treatment-related complication(s) or symptom(s) at baseline were associated with increased odds, lower socioeconomic status, having a partner, greater child care responsibilities, being treated on the dominant side, participation in regular activity, and having good UBF were associated with decreased odds of lymphedema. Not surprisingly, lymphedema leads to reduced UBF; however, BC survivors report high prevalences of other UBS (34% to 62%), irrespective of their lymphedema status. Conclusion Lymphedema is a public health issue deserving greater attention. More systematic surveillance for earlier detection and the potential benefits of physical activity to prevent lymphedema and mitigate symptoms warrant further clinical integration and research.
T cell responses in hepatitis C: the good, the bad and the unconventional
Authors: Paul Klenerman, Robert Thimme
Journal: Gut (2011)

Over recent years, it has become increasingly accepted that virus-specific CD4+ and CD8+ T cell responses play a major role in outcome and pathogenesis of hepatitis C virus (HCV) infection. Indeed, while the emergence of strong and multispecific T cell responses may correlate with spontaneous viral clearance, the virus has developed several mechanisms to avoid T cell control in the majority of acutely HCV-infected patients that subsequently develop persistent HCV infection. In this review, we will discuss the current knowledge about the role of cellular immune responses in HCV infection. Specifically, we will emphasise recent new insights into the effector functions of T cells, possible mechanisms of their failure and the host–virus interactions occurring at the site of the disease, the liver.