tbuckley/cabot-search huggingface dataset:
Sea level and acute responses to hypoxia: do they predict physiological responses and acute mountain sickness at altitude?
Authors: S Grant, N MacLeod, J W Kay, M Watt, S Patel, A Paterson, A Peacock
Journal: British Journal of Sports Medicine (2002)

Objectives: To compare a range of physiological responses to acute sea level hypoxia at simulated altitudes with the same physiological responses and acute mountain sickness (AMS) scores measured at altitude (similar to the simulated altitudes) during a 17 day trek in the Himalayas. Methods: Twenty men and women aged 18–54 years took part in the study. End tidal CO 2 tension (P etco 2 ) and saturated oxygen (Sa o 2 ) were measured using a capnograph. Observations made at sea level and some simulated altitudes were compared with those in the Himalayas. Pairwise correlations were used to examine the correlation between variables and regression, with 95% prediction intervals providing information on how well one variable could be predicted from another for a given subject. Results: There was only a significant correlation for a few comparisons. The 95% prediction intervals for individual Sa o 2 values at a range of simulated altitudes were fairly wide going from ± 4% to ± 5%. All of the correlations between laboratory and Himalayan P etco 2 values were not statistically significant. There was a significant correlation for the relation between Sa o 2 and P etco 2 at sea level for the laboratory data (r=−0.51; p=0.05). For the Himalayan data, there were significant correlations at Namche Bazaar (3450 m; day 3) ( r =−0.56; p=0.01) and Dingboche (4300 m; day 6) ( r =−0.48; p=0.03). The correlation between Sa o 2 and P etco 2 and AMS was generally poor. Conclusions: The results indicate that limited information can be gained on a subject's response to altitude by assessing physiological variables at sea level and a range of simulated altitudes before the subject carries out a trek at altitude.
BIOCHEMICAL, CELLULAR, AND PHARMACOLOGICAL ASPECTS OF THE MULTIDRUG TRANSPORTER
Authors: Suresh V. Ambudkar, Saibal Dey, Christine A. Hrycyna, Muralidhara Ramachandra, Ira Pastan, Michael M. Gottesman
Journal: The Annual Review of Pharmacology and Toxicology (1999)

▪ Abstract Considerable evidence has accumulated indicating that the multidrug transporter or P-glycoprotein plays a role in the development of simultaneous resistance to multiple cytotoxic drugs in cancer cells. In recent years, various approaches such as mutational analyses and biochemical and pharmacological characterization have yielded significant information about the relationship of structure and function of P-glycoprotein. However, there is still considerable controversy about the mechanism of action of this efflux pump and its function in normal cells. This review summarizes current research on the structure-function analysis of P-glycoprotein, its mechanism of action, and facts and speculations about its normal physiological role.
Selective immunosuppression by administration of major histocompatibility complex (MHC) class II-binding peptides. I. Evidence for in vivo MHC blockade preventing T cell activation.
Authors: J C Guéry, A Sette, J Leighton, A Dragomir, L Adorini
Journal: The Journal of Experimental Medicine (1992)

Draining lymph node cells (LNC) from mice immunized with hen egg white lysozyme (HEL) display at their surface antigen-MHC complexes able to stimulate, in the absence of any further antigen addition, HEL peptide-specific, class II-restricted T cell hybridomas. Chloroquine addition to these LNC cultures fails to inhibit antigen presentation, indicating that antigenic complexes of class II molecules and HEL peptides are formed in vivo. MHC class II restriction of antigen presentation by LNC from HEL-primed mice was verified by the use of anti-class II monoclonal antibodies. Coinjection of HEL and the I-Ak-binding peptide HEL 112-129 in mice of H-2k haplotype inhibits the ability of LNC to stimulate I-Ak-restricted, HEL 46-61-specific T cell hybridomas. Similar results are obtained in mice coinjected with the HEL peptides 46-61 and 112-129. Inhibition of T hybridoma activation can also be observed using as antigen-presenting cells irradiated, T cell-depleted LNC from mice coinjected with HEL 46-61 and HEL 112-129, ruling out the possible role of either specific or nonspecific suppressor T cells. Inhibition of T cell proliferation is associated with MHC-specific inhibition of antigen presentation and with occupancy by the competitor of class II binding sites, as measured by activation of peptide-specific T cell hybridomas. These results demonstrate that administration of MHC class II binding peptide competitors selectively inhibits antigen presentation to class II-restricted T cells, indicating competitive blockade of class II molecules in vivo.
Pharmacodynamic Analysis of Target Inhibition and Endothelial Cell Death in Tumors Treated with the Vascular Endothelial Growth Factor Receptor Antagonists SU5416 or SU6668
Authors: Darren W. Davis, Ryan Takamori, Chandrajit P. Raut, Henry Q. Xiong, Roy S. Herbst, Walter M. Stadler, John V. Heymach, George D. Demetri, Asif Rashid, Yu Shen, Sijin Wen, James L. Abbruzzese, David J. McConkey
Journal: Clinical Cancer Research (2005)

To determine the effects of small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR)-2 (SU5416 and SU6668) on receptor phosphorylation in tumor xenografts and in paired tumor biopsies obtained in three clinical trials in patients with advanced solid malignancies.The dose-dependent effects of SU6668 on angiogenesis and tumor growth were investigated in orthotopic L3.6pl pancreatic tumors. Excisional or 18G core biopsies were obtained from patients before and after therapy with SU5416 or SU6668. Laser scanning cytometry-mediated analysis was used to quantify levels of phosphorylated and total VEGFRs and platelet-derived growth factor receptors (PDGFR), tumor microvessel densities, vessel sizes, and endothelial and tumor cell apoptosis.Significant inhibition of tumor microvessel density and growth and increased apoptosis were observed at SU6668 maximum tolerated dose (100 mg/kg) in L3.6pl xenografts. At 6 hours post therapy, SU6668 reduced VEGFR and PDGFR phosphorylation in the tumors by 50% and 92%, respectively, but levels rebounded beyond the baselines by 24 hours. Levels of phosphorylated VEGFR-2 and PDGFR also decreased significantly ( approximately 50%) 6 hours after therapy in 1 of 6 primary human tumors treated with SU6668, but these effects were not associated with increased apoptosis. A significant increase in endothelial cell apoptosis was observed in one tumor exposed to SU5416 and was associated with an increase in vessel size, but these changes occurred without an increase in tumor cell death.SU5416 and SU6668 displayed biological activity in xenografts. However, neither drug produced marked biological activity in primary patient tumors.
Phase II study of epirubicin, cisplatin and continuous infusion 5-fluorouracil (ECF) for carcinoma of unknown primary site
Authors: F.X. Parnis, I.N. Olver, D. Kotasek, J. Norman, A. Taylor, J. Russell, K. Patterson, D. Keefe, T. Marafioti
Journal: Annals of Oncology (2000)
Does Diabetes Care Differ by Type of Chronic Comorbidity?
Authors: Sri Ram Pentakota, Mangala Rajan, B. Graeme Fincke, Chin-Lin Tseng, Donald R. Miller, Cindy L. Christiansen, Eve A. Kerr, Leonard M. Pogach
Journal: Diabetes Care (2012)

OBJECTIVE To evaluate the relationship between diabetes care and types of comorbidity, classified by the degree to which their treatment is concordant with that for diabetes. RESEARCH DESIGN AND METHODS Retrospective cohort study (fiscal year [FY] 2001 to FY 2004) of 42,826 veterans with new-onset diabetes in FY 2003. Veterans were classified into five chronic comorbid illness groups (CCIGs): none, concordant only, discordant only, both concordant and discordant, and dominant. Five diabetes-related care measures were assessed in FY 2004 (guideline-consistent testing and treatment goals for HbA1c and LDL cholesterol and diabetes-related outpatient visits). Analyses included logistic regressions adjusting for age, race, sex, marital status, priority code, and interaction between CCIGs and visit frequency. RESULTS Only 20% of patients had no comorbidities. Mean number of visits per year ranged from 7.8 (no CCIG) to 17.5 (dominant CCIG). In unadjusted analyses, presence of any illness was associated with equivalent or better care. In the fully adjusted model, we found interaction between CCIG and visit frequency. When visits were &amp;lt;7 per year, the odds of meeting the goal of HbA1c &amp;lt;8% were similar in the concordant (odds ratio 0.96 [95% CI 0.83–1.11]) and lower in the discordant (0.90 [0.81–0.99]) groups compared with the no comorbidity group. Among patients with &amp;gt;24 visits per year, these odds were insignificant. Dominant CCIG was associated with substantially reduced care for glycemic control for all visit categories and for lipid management at all but the highest visit category. CONCLUSIONS Our study indicates that diabetes care varies by types of comorbidity. Concordant illnesses result in similar or better care, regardless of visit frequency. Discordant illnesses are associated with diminished care: an effect that decreases as visit frequency increases.
Calcitriol Controls the Epithelial Calcium Channel in Kidney
Authors: JOOST G. J. HOENDEROP, DOMINIK MU[Combining Diaeresis]LLER, ANNEMIETE W. C. M. VAN DER KEMP, ANITA HARTOG, MAKOTO SUZUKI, KENICHI ISHIBASHI, MASASHI IMAI, FRED SWEEP, PETER H. G. M. WILLEMS, CAREL H. VAN OS, RENÉ J. M. BINDELS
Journal: Journal of the American Society of Nephrology (2001)

Abstract. The recently cloned epithelial Ca 2+ channel (ECaC), which is expressed primarily in 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 )-responsive Ca 2+ -transporting epithelia, is postulated to constitute the rate-limiting step in active Ca 2+ reabsorption. In the present study, the effect of 1,25(OH) 2 D 3 was investigated on ECaC mRNA and protein levels in kidneys of rats that were raised on a vitamin D—depleting diet. This diet decreased the serum 1,25(OH) 2 D 3 concentration significantly, which was accompanied by a marked drop in serum Ca 2+ level. Both 1,25(OH) 2 D 3 and Ca 2+ levels were normalized within 48 h after 1,25(OH) 2 D 3 administration. In 1,25(OH) 2 D 3 -deficient rats, ECaC mRNA and protein levels of the kidney cortex were significantly decreased compared with the repleted animals, suggesting that 1,25(OH) 2 D 3 exerts its stimulatory effect on Ca 2+ reabsorption via increased ECaC expression. In agreement with this observation, the elucidated human ECaC promoter contains several consensus vitamin D—responsive elements. ECaC was restricted to the apical membrane of the distal part of the distal convoluted and the connecting tubule. This conclusion was based on only minor overlap with the localization of the thiazide-sensitive NaCl co-transporter and complete co-localization with the 1,25(OH) 2 D 3 -dependent Ca 2+ binding protein, calbindin-D 28K . In conclusion, ECaC, present in the distal part of the nephron, is an important target for 1,25(OH) 2 D 3 -mediated Ca 2+ reabsorption.
Blocking follistatin-like 1 attenuates bleomycin-induced pulmonary fibrosis in mice
Authors: Yingying Dong, Yan Geng, Lian Li, Xiaohe Li, Xiaohua Yan, Yinshan Fang, Xinxin Li, Siyuan Dong, Xue Liu, Xue Li, Xiuhong Yang, Xiaohong Zheng, Ting Xie, Jiurong Liang, Huaping Dai, Xinqi Liu, Zhinan Yin, Paul W. Noble, Dianhua Jiang, Wen Ning
Journal: The Journal of Experimental Medicine (2015)

Progressive tissue fibrosis is a cause of major morbidity and mortality. Pulmonary fibrosis is an epithelial-mesenchymal disorder in which TGF-β1 plays a central role in pathogenesis. Here we show that follistatin-like 1 (FSTL1) differentially regulates TGF-β and bone morphogenetic protein signaling, leading to epithelial injury and fibroblast activation. Haplodeletion of Fstl1 in mice or blockage of FSTL1 with a neutralizing antibody in mice reduced bleomycin-induced fibrosis in vivo. Fstl1 is induced in response to lung injury and promotes the accumulation of myofibroblasts and subsequent fibrosis. These data suggest that Fstl1 may serve as a novel therapeutic target for treatment of progressive lung fibrosis.
Coronary Sinus-Ventricular Accessory Connections Producing Posteroseptal and Left Posterior Accessory Pathways
Authors: Yingxian Sun, Mauricio Arruda, Kenichiro Otomo, Karen Beckman, Hiroshi Nakagawa, James Calame, Sunny Po, Peter Spector, Daniel Lustgarten, Lisa Herring, Ralph Lazzara, Warren Jackman
Journal: Circulation (2002)

Background— The coronary sinus (CS) has a myocardial coat (CSMC) with extensive connections to the left and right atria. We postulated that some posteroseptal and left posterior accessory pathways (CSAPs) result from connections between a cuff of CSMC extending along the middle cardiac vein (MCV) or posterior coronary vein (PCV) and the ventricle. The purpose of the present study was to use CS angiography and mapping to define and determine the incidence of CSAPs and determine the relationship to CS anatomy. Methods and Results— CSAP was defined by accessory pathway (AP) potential or earliest activation in the MCV or PCV and late activation at anular endocardial sites. A CSAP was identified in 171 of 480 patients undergoing ablation of a posteroseptal or left posterior AP. CS angiography revealed a CS diverticulum in 36 (21%) and fusiform or bulbous enlargement of the small cardiac vein, MCV, or CS in 15 (9%) patients. The remaining 120 (70%) patients had an angiographically normal CS. A CSMC extension potential (CSE), like an AP potential, was recorded in the MCV in 98 (82%), in the PCV in 13 (11%), in both the MCV and PCV in 6 (5%), and in the CS in 3 (2%) of 120 patients. CSMC potentials were recorded between the timing of atrial and CSE potentials. Conclusions— CSAPs result from a connection between a CSMC extension (along the MCV or PCV) and the ventricle. The CS is angiographically normal in most patients.
At Face Value
Authors: Karen Donley-Hayes
Journal: JAMA (2006)

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Osmotic modulation of slowly activating IKs in guinea-pig ventricular myocytes
Authors: Sergey Missan, Lesya M. Shuba, Pavel Zhabyeyev, Terence F. McDonald
Journal: Cardiovascular Research (2011)

The aims of the study were to determine the effects of anisosmotic bathing solution on selected properties of IKs, the slowly activating delayed-rectifier K+ current important for repolarization of the action potential in cardiac cells. Guinea-pig ventricular myocytes were voltage-clamped using either the ruptured-patch or perforated-patch technique, and the amplitude, time course, and voltage dependence of IKs were determined before [isosmotic (1T)] and during superfusion of hyposmotic (<1T) or hyperosmotic (>1T) bathing solution. Hyposmotic solution increased the amplitude of IKs, and hyperosmotic solution decreased it. Anisosmotic-induced changes in IKs amplitude were complete in 2–5 min, well-maintained, reversible, and not accompanied by significant changes in IKs time course and voltage dependence. There was little difference in the results obtained with the ruptured-patch technique and those obtained with the perforated-patch technique. The amplitude of IKs was sensitive to small (±10%) changes in osmolarity, maximally increased by hyposmotic solution with T < 0.7, and strongly decreased by hyperosmotic solution with T > 1.5. Experimental data on a plot of relative (1T = 1.0) IKs amplitude vs. the reciprocal of relative osmolarity are well-described by a Hill equation that has a lower asymptote of 0.0, an upper asymptote of 2.0, and a slope factor of 1.87 ± 0.07. Modulation of IKs amplitude by anisosmotic solution is independent of patch configuration, unaccompanied by changes in current gating, and well-described by a Hill dose–response relation that predicts relatively strong responses of IKs to small perturbations in external osmolarity.
Asthma from birth to age 23: incidence and relation to prior and concurrent atopic disease.
Authors: H R Anderson, A C Pottier, D P Strachan
Journal: Thorax (1992)

Few studies present prospective data on the incidence of asthma. Its associations with sex and with prior and concurrent hay fever and eczema were examined in a nationally representative sample followed from birth to 23 years of age (British 1958 birth cohort).Reports of asthma or wheezy bronchitis, hay fever and eczema were obtained by interview of parents of children at ages 7, 11, and 16 years, and of cohort members at age 23 years. Linked data from all four interviews were available on 7225 subjects (43% of the original birth cohort).The cumulative incidence of asthma or wheezy bronchitis was 18.2%, 21.8%, 24.5%, and 28.6% by the ages of 7, 11, 16, and 23 years respectively. Over the four incidence periods examined (0 to 7 years, 8 to 11 years, 12 to 16 years, 17 to 23 years) the average annual incidence of new cases was 2.6%, 1.1%, 0.71%, and 0.76% respectively. The male:female incidence ratio rose from 1.23 in the 0 to 7 year period to 1.48 at 12 to 16 years but had reversed to 0.59 at 17 to 23 years. A prior report of hay fever or eczema each increased the subsequent incidence of asthma or wheezy bronchitis by a factor of 1.7 to 2.0 independently of sex. This effect of prior atopic illness, however, was largely explained by the strong independent association of incidence of asthma and wheezy bronchitis with atopic disease at the end of each incidence period (odds ratios 2.0 to 2.5 per atopic condition, p < 0.01).Gender differences in the incidence of asthma or wheezy bronchitis vary with age and are not explained by atopy. The incidence of asthma or wheezy bronchitis can be predicted from a clinical history of hay fever or eczema but is more strongly associated with the presence of atopic disease at the time of onset.
The Evolutionary Fate of the Genes Encoding the Purine Catabolic Enzymes in Hominoids, Birds, and Reptiles
Authors: A. C. Keebaugh, J. W. Thomas
Journal: Molecular Biology and Evolution (2010)

Gene loss has been proposed to play a major role in adaptive evolution, and recent studies are beginning to reveal its importance in human evolution. However, the potential consequence of a single gene-loss event upon the fates of functionally interrelated genes is poorly understood. Here, we use the purine metabolic pathway as a model system in which to explore this important question. The loss of urate oxidase (UOX) activity, a necessary step in this pathway, has occurred independently in the hominoid and bird/reptile lineages. Because the loss of UOX would have removed the functional constraint upon downstream genes in this pathway, these downstream genes are generally assumed to have subsequently deteriorated. In this study, we used a comparative genomics approach to empirically determine the fate of UOX itself and the downstream genes in five hominoids, two birds, and a reptile. Although we found that the loss of UOX likely triggered the genetic deterioration of the immediate downstream genes in the hominoids, surprisingly in the birds and reptiles, the UOX locus itself and some of the downstream genes were present in the genome and predicted to encode proteins. To account for the variable pattern of gene retention and loss after the inactivation of UOX, we hypothesize that although gene loss is a common fate for genes that have been rendered obsolete due to the upstream loss of an enzyme a metabolic pathway, it is also possible that same lack of constraint will foster the evolution of new functions or allow the optimization of preexisting alternative functions in the downstream genes, thereby resulting in gene retention. Thus, adaptive single-gene losses have the potential to influence the long-term evolutionary fate of functionally interrelated genes.
Muscarinic-3 acetylcholine receptor autoantibody in patients with systemic sclerosis: contribution to severe gastrointestinal tract dysmotility
Authors: Y Kawaguchi, Y Nakamura, I Matsumoto, E Nishimagi, T Satoh, M Kuwana, T Sumida, M Hara
Journal: Annals of the Rheumatic Diseases (2008)

Patients with systemic sclerosis (SSc) complicated by severe gastrointestinal tract (GIT) dysmotility at an early stage are difficult to treat and mortality is high. To clarify the pathogenesis of GIT involvement, the occurrence of autoantibody was investigated for muscarinic-3 acetylcholine receptor (M3R) in patients with SSc.Fourteen patients with severe GIT involvement (malabsorption syndrome and/or pseudo-obstruction) within 2 years of SSc onset (group 1) were enrolled in the present study. Sixty-two patients with SSc without severe GIT involvement within 2 years of onset (group 2) were also recruited, along with 70 healthy control subjects. Using an established enzyme immunoassay (EIA) system detecting autoantibody against the second loop domain of M3R, the presence of an anti-M3R antibody was examined in SSc patients.The mean optical density (OD) titres of group 1 were significantly higher than those of group 2 (0.65 (SD 0.58) vs 0.066 (SD 0.13), p<0.001). The positivity of anti-M3R antibody was significantly higher in group 1 than in group 2 (9/14 vs 3/62, p = 2.5 x 10(-6) by Fisher's exact test). The cutoff OD was calculated from the EIA reaction of the 70 healthy controls (the mean value plus 2 SD was 0.295).The findings indicated that anti-M3R antibody very frequently appears in patients with SSc, which is accompanied by severe GIT involvement, suggesting that M3R-mediated enteric cholinergic neurotransmission may provide a pathogenic mechanism for GIT dysmotility in SSc.
Overseas doctors and the staffing structure of hospitals.
Authors: D I Williams
Journal: BMJ (1985)

The introduction of the new immigration rules will considerably reduce the number of overseas doctors available for junior hospital appointments over the next five years. To offset this sponsorship schemes should be offered by universities and colleges comprising training courses, entry to examinations, and hospital appointments, and training programmes should be adapted to make objectives attainable in the four years available to overseas doctors. Employment of overseas doctors can ease the transition within the staffing structure to fewer juniors and more consultants, but planning is urgently required, and in particular the service and manpower needs of the National Health Service must be considered.