tbuckley/cabot-search huggingface dataset:
Effect of low-dose beclomethasone dipropionate on asthma control and airway inflammation
Authors: JV Fahy, HA Boushey
Journal: European Respiratory Journal (1998)

The effects of usual or low doses of inhaled corticosteroids on airway mucosal inflammation have not yet been examined. We therefore, compared the effects of inhaled beclomethasone dipropionate (BDP) 336 microg x day(-1) on asthma control outcomes and markers of airway inflammation. Twenty-four adult subjects with mild and moderate asthma were randomized to receive either BDP or placebo for four weeks; then subjects entered a single blind four week placebo run-in period. We found that the BDP group had significantly greater improvements in forced expiratory volume in one second (FEV1), morning peak flow, and rescue salbutamol use than the placebo-treated group. The improvement in FEV1 largely reversed one week after treatment was stopped. The decrease in the median percentage of eosinophils in induced sputum in the BDP group from 3.8% to 3.4% was not significant, but because eosinophils increased from 8.4% to 12.7% in the placebo group, there was a significant difference between treatment groups (p=0.03). There was no significant difference between groups during treatment in the levels of eosinophil cationic protein (ECP), tryptase mucin-like glycoprotein, or fibrinogen in induced sputum. The change in FEV1 in the BDP group did not correlate significantly with the change in eosinophil percentage or ECP levels. We concluded that four weeks of treatment with inhaled beclomethasone dipropionate 336 microg x day(-1) was associated with significant improvements in peak flow, forced expiratory volume in one second, and rescue salbutamol use in asthmatic subjects but was not associated with large reductions in markers of eosinophilic inflammation, bronchovascular permeability, or mucus hypersecretion.
Endoplasmic Reticulum Stress in Nonalcoholic Fatty Liver Disease
Authors: Michael J. Pagliassotti
Journal: Annual Review of Nutrition (2012)

The underlying causes of nonalcoholic fatty liver disease are unclear, although recent evidence has implicated the endoplasmic reticulum in both the development of steatosis and progression to nonalcoholic steatohepatitis. Disruption of endoplasmic reticulum homeostasis, often termed ER stress, has been observed in liver and adipose tissue of humans with nonalcoholic fatty liver disease and/or obesity. Importantly, the signaling pathway activated by disruption of endoplasmic reticulum homeostasis, the unfolded protein response, has been linked to lipid and membrane biosynthesis, insulin action, inflammation, and apoptosis. Therefore, understanding the mechanisms that disrupt endoplasmic reticulum homeostasis in nonalcoholic fatty liver disease and the role of the unfolded protein response in the broader context of chronic, metabolic diseases have become topics of intense investigation. The present review examines the endoplasmic reticulum and the unfolded protein response in the context of nonalcoholic fatty liver disease.
A cost analysis on the pattern of asthma prescribing in the UK
Authors: R.g. Neville, M.g. Pearson, N. Richards, J Patience, S Sondhi, B Wagstaff, N Wells
Journal: European Respiratory Journal (1999)

There is a need to establish the proportion of adult asthmatics at each step of the recommended asthma management guidelines, the cost of their prescribed treatment, and a revised cost of treatment assuming patients who were suboptimally controlled were moved up a step. Actual prescription and cost figures and a theoretical projection of an ideal scenario was calculated from a sample of general practices in Great Britain from the Doctors Independent Network. They comprised 102 nationally distributed practices and 17,206 adult patients with a diagnosis of, and prescription related to, asthma recorded between October 1993 and March 1994. Ninety-one per cent of patients received treatment within a recognized step of the guidelines. Of these, 80% were at steps 1 and 2. Employing excess inhaled beta-agonist use as a proxy for control of asthma, between 55% and 69% of patients at Steps 1-3 should receive treatment at a higher step. This could lead to an increased expenditure of up to Pound Sterling 4.66 per adult patient per month. This would imply a rise in the annual UK cost of antiasthma prescriptions for adults from Pound Sterling 388m to a possible Pound Sterling 533m. The United Kingdom Government audit commission has suggested that current expenditure on asthma treatment appears to be insufficient. Using an entirely different approach this study has confirmed that a significant increase in asthma prescribing costs is likely to be needed if optimal control of asthma is to be achieved.
Amino Acid Imbalance and Hepatic Encephalopathy
Authors: Plinio Bernardini, Josef E. Fischer
Journal: Annual Review of Nutrition (1982)

Hepatic encephalopathy is one of the most frequent terminal episodes of primary liver disease. It was already known at the time of Hippocrates, and it was well described by Johanne Baptista Margagni, teacher at the Padua Medical School, in the 18th century. Hepatic encephalopathy is a neuropsychiatric syndrome seen in the pres­ ence of hepatic functional impairment secondary to acute liver failure or chronic parenchymal liver disease with or without spontaneous or surgi­ cally induced portalsystemic shunting of portal blood. The neuropsychiatric symptoms of liver failure are varied and range from subtle alterations, including mild personality change and disturbance in sleep rhythm, to confusion, drowsiness, stupor, and finally deep coma. In acute liver failure the progression of events may be extremely rapid, taking place in only a few hours. In chronic encephalopathy, in contrast, consciousness may be slowly altered over months, and may occasionally present as progressive and irre­ versible neurological symptomatology with dementia, parkinsonism, or other extrapyramidal signs suggesting involvement of the cerebellum or basal ganglia (170). Most often in the chronic situation, however, episodes of mental impairment are episodic, the result of defined stresses, and recov­ ery to the premorbid state is the rule. Other symptoms of hepatic encephalopathy are not specific for liver disease. Asterixis (flapping tremor of the extremities) is probably the most characteristic neurological sign of hepatic encephalopathy, is more common
NON-MICHAELIS-MENTEN KINETICS IN CYTOCHROME P450-CATALYZED REACTIONS
Authors: William M. Atkins
Journal: The Annual Review of Pharmacology and Toxicology (2004)

The cytochrome P450 monooxygenases (CYPs) are the dominant enzyme system responsible for xenobiotic detoxification and drug metabolism. Several CYP isoforms exhibit non-Michaelis-Menten, or "atypical," steady state kinetic patterns. The allosteric kinetics confound prediction of drug metabolism and drug-drug interactions, and they challenge the theoretical paradigms of allosterism. Both homotropic and heterotropic ligand effects are now widely documented. It is becoming apparent that multiple ligands can simultaneously bind within the active sites of individual CYPs, and the kinetic parameters change with ligand occupancy. In fact, the functional effect of any specific ligand as an activator or inhibitor can be substrate dependent. Divergent approaches, including kinetic modeling and X-ray crystallography, are providing new information about how multiple ligand binding yields complex CYP kinetics.
Seasonality in airway pathogens during the first year after lung transplantation: A single center experience
Authors: Zsuzsanna Kovats, Zoltan Sutto, Gabriella Murakozy, Aniko Bohacs, Csaba Vajai, Krisztina Czebe, Gyorgy Losonczy, Veronika Muller
Journal: European Respiratory Journal (2012)

After lung transplantation (LuTx) high level of immunosuppression is needed to prevent rejection, which makes recipients more susceptible to infections. Pulmonary infections are a major clinical problem during the first postoperative year and regular surveillance examinations and immediate adequate treatment is mandatory. As seasonality of respiratory tract infections is well known in chronic pulmonary diseases, we assessed pathogen spectrum and number of infections in the first postoperative year in LuTx recipients.  Airway pathogens registered during the first posttransplant year in 16 Hungarian LuTx patients (underlying disease: cystic fibrosis: 8, interstitial lung disease: 4, obstructive lung disease: 3, primary pulmonary hypertension: 1) were analyzed. Microbiological samples were taken from upper and/or lower respiratory tract and serum as part of the routine care. Number of positive samples was analyzed according summer (S=March to August) and winter (W=September to February) period.  A total of 107 infections were registered during the first posttransplant year. The most frequent pathogens were Gram negative bacteria (n=48) and fungi (n=33). Total number of respiratory infections in S were significantly less frequent as compared to W (S=40, W=67; including Gram positive: S=8, W=11; Gram negative: S=16, W=31; fungi: S=13, W=20; other: S=4, W=4) independent of the season when LuTx was performed. We report increased number of respiratory tract infection in W period in the first postoperative year in LuTx recipients. More intensive vigilance for possible infections is needed during the W period in these patients.
P10 Whole-exome-Sequencing-based discovery of novel syndromic form of neonatal cholestasis
Authors: J. L. Hartley, M. Simpson, L. Tee, R. M. Brown, S. Kirkham, S. Pasha, R. C. Trembath, P. Gissen, E. R. Maher, D. A. Kelly, N. V. Morgan
Journal: Gut (2011)

<h3>Introduction</h3> Two cousins from a consanguineous family presented with low γ glutamyl transferase (GGT) cholestasis, trichorrhexis nodosa (TN) and severe hypoglycaemia which required diazoxide to stabilise. One child also had life threatening diarrhoea necessitating parenteral nutrition, which suggested the possible diagnosis of trichohepatoenteric syndrome (THES). However screening of the THES gene (<i>TTC37</i>) excluded mutations. <h3>Aim</h3> The aim of this study was to identify the molecular genetic defect in this family and hence further understanding of unexplained cholestasis within a multisystem disorder. <h3>Method</h3> We used a novel combination of autozygosity mapping combined with whole-exome-sequencing (WES). An Affymetrix 250K SNP chip genome-wide linkage scan was used to identify common regions of shared homozygosity. SureSelect human All Exon kit (Agilent Technologies) and Illumina GaIIx was used for WES of both individuals. Single nucleotide substitutions and small insertion deletions were identified. Filtering of variants for novelty was performed by comparison to dbSNP131 and 1000 Genomes pilot SNP calls (March 2010) and variants identified in 40 control exomes sequenced and analysed by the same method described above. <h3>Results</h3> The largest overlapping autozygous regions were at chromosome 7, 16, 20, 12 and 4. The whole exome sequencing identified 17 844 and 17 867 variations in patients 1 and 2 respectively. Of these only three homozygous non-synonymous variants and one frameshift variant were found in both patients in the identified homozygous regions. The frameshift was a homozygous single base G deletion (c.587delG) in exon 6 of <i>AKR1D1</i> which mapped within the candidate homozygous region in chromosome 7. The variant results in a frameshift at amino acid 196 leading to a premature stop codon 11 amino acids downstream (p.Cys196SerfsX11).<i>AKR1D1</i> encodes the enzyme δ<sup>4</sup>-3-oxosteroid 5β-reductase that is required for the synthesis of chenodeoxycholic and cholic acids important for normal bile flow. Mutations in <i>AKR1D1</i> have previously been described in patients with severe neonatal liver disease. <h3>Conclusion</h3> In conclusion we have extended the clinical features of bile salt synthesis disorders resulting from mutations in <i>AKR1D1</i> to include a severe form of low GGT cholestasis, TN and severe hypoglycaemia which may be amenable to treatment with bile salt supplementation. Combining the technique of whole genome linkage mapping and WES creates a powerful tool to elucidate the molecular basis of uncharacterised genetic disorders.
Psychologists seek the unexpected, not the negative, to provoke innovative theory construction
Authors: John Darley, Alexander Todorov
Journal: Behavioral and Brain Sciences (2004)

Krueger &amp; Funder (K&amp;F) see social psychologists as driven to demonstrate that people's behavior falls below relevant moral and intellectual standards. We suggest that social psychologists search for demonstrations of when it is that people's actual behaviors and decisions deviate from expected or ideal behaviors and decisions, and what these “deviations” tell us about general decision processes, including those that do not produce unexpected actions. Often the discoveries are of positive rather than negative behaviors.
Reduced Cardiocirculatory Complications With Unrestrictive Visiting Policy in an Intensive Care Unit
Authors: Stefano Fumagalli, Lorenzo Boncinelli, Antonella Lo Nostro, Paolo Valoti, Giorgio Baldereschi, Mauro Di Bari, Andrea Ungar, Samuele Baldasseroni, Pierangelo Geppetti, Giulio Masotti, Riccardo Pini, Niccolò Marchionni
Journal: Circulation (2006)

Background— Observational studies suggest that open visiting policies are preferred by most patients and visitors in intensive care units (ICUs), but no randomized trial has compared the safety and health outcomes of unrestrictive (UVP) and restrictive (RVP) visiting policies. The aim of this pilot, randomized trial was to compare the complications associated with UVP (single visitor with frequency and duration chosen by patient) and RVP (single visitor for 30 minutes twice a day). Methods and Results— Two-month sequences of the 2 visiting policies were randomly alternated for 2 years in a 6-bed ICU, with 226 patients enrolled (RVP/UVP, n=115/111). Environmental microbial contamination, septic and cardiovascular complications, emotional profile, and stress hormones response were systematically assessed. Patients admitted during the randomly scheduled periods of UVP received more frequent (3.2±0.2 versus 2.0±0.0 visits per day, mean±SEM) and longer (2.6±0.2 versus 1.0±0.0 h/d) visits ( P &lt;0.001 for both comparisons). Despite significantly higher environmental microbial contamination during the UVP periods, septic complications were similar in the 2 periods. The risk of cardiocirculatory complications was 2-fold (odds ratio 2.0; 95% CI, 1.1 to 3.5; P =0.03) in the RVP periods, which were also associated with a nonsignificantly higher mortality rate (5.2% versus 1.8%; P =0.28). The UVP was associated with a greater reduction in anxiety score and a significantly lower increase in thyroid stimulating hormone from admission to discharge. Conclusions— Despite greater environmental microbial contamination, liberalizing visiting hours in ICUs does not increase septic complications, whereas it might reduce cardiovascular complications, possibly through reduced anxiety and more favorable hormonal profile.
What is the biochemical and physiological rationale for using cold-water immersion in sports recovery? A systematic review
Authors: Chris M Bleakley, Gareth W Davison
Journal: British Journal of Sports Medicine (2009)

Cold-water immersion (CWI) is a popular recovery intervention after exercise. The scientific rationale is not clear, and there are no clear guidelines for its use. The aim of this review was to study the physiological and biochemical effect of short periods of CWI. A computer-based literature search, citation tracking and related articles searches were undertaken. Primary research studies using healthy human participants, immersed in cold water (&lt;15°C), for 5 min durations or less were included. Data were extracted on body temperature, cardiovascular, respiratory and biochemical response. 16 studies were included. Sample size was restricted, and there was a large degree of study heterogeneity. CWI was associated with an increase in heart rate, blood pressure, respiratory minute volume and metabolism. Decreases in end tidal carbon dioxide partial pressure and a decrease in cerebral blood flow were also reported. There was evidence of increases in peripheral catecholamine concentration, oxidative stress and a possible increase in free-radical-species formation. The magnitude of these responses may be attenuated with acclimatisation. CWI induces significant physiological and biochemical changes to the body. Much of this evidence is derived from full body immersions using resting healthy participants. The physiological and biochemical rationale for using short periods of CWI in sports recovery still remains unclear.
A cause-specific hazard rate analysis of prognostic factors among 199 adults with acute lymphoblastic leukemia: the Memorial Hospital experience since 1969.
Authors: J Gaynor, D Chapman, C Little, S McKenzie, W Miller, M Andreeff, Z Arlin, E Berman, S Kempin, T Gee
Journal: Journal of Clinical Oncology (1988)

Results of a multivariable analysis of prognostic factors are reported for 199 previously untreated adults with acute lymphoblastic leukemia (ALL). These patients have long-term follow-up, and the probability of cure is estimated at approximately 35%. The cause-specific hazard rate analysis found lower rates of achieving complete remission (CR) in patients with WBC greater than 10,000/microL, AUL (undifferentiated) morphology, and older age. Since these patients required additional time to respond, fewer of them actually achieved CR. Characteristics directly associated with a higher rate of death during induction therapy due to severe bone marrow suppression were low serum albumin concentration (less than or equal to 3.5 g/dL), age greater than 50 years, acute undifferentiated leukemia (AUL) morphology, low Karnofsky performance status, and weight loss greater than 5%. Factors associated with a higher rate of relapse were WBC greater than 20,000/microL, non-T cell ALL, age greater than 60 years, Ph' + ALL, and time to achieve CR greater than 5 weeks. These criteria were used to identify patients at high risk of relapse. In addition, the predictive value of high WBC was found to disappear by 18 months of continuous CR. Finally, the rate of death following first relapse was higher in patients with a short first remission duration, high percentage weight loss at initial diagnosis, and older age. In summary, factors associated with a higher rate of death during attempted induction (ie, low albumin, high percent weight loss, and poor performance status) had no association with the patient's ability to remain relapse-free. Conversely, factors correlating with more extensive or resistant disease (ie, high WBC, null or B cell ALL, or Ph' + ALL) showed no association with the ability to tolerate therapy. Thus, a less toxic but more effective induction regimen is needed for patients with a poor clinical status, whereas a more intensive form of therapy appears warranted for patients presenting with more extensive or resistant disease.
High-Density Lipoprotein Hydrolysis by Endothelial Lipase Activates PPARα
Authors: Waleed Ahmed, Gabriela Orasanu, Vedika Nehra, Liana Asatryan, Daniel J. Rader, Ouliana Ziouzenkova, Jorge Plutzky
Journal: Circulation Research (2006)

Although high-density lipoprotein (HDL) is known to inhibit endothelial adhesion molecule expression, the mechanism for this anti-inflammatory effect remains obscure. Surprisingly, we observed that HDL no longer decreased adhesion of U937 monocytoid cells to tumor necrosis factor (TNF)alpha-stimulated human endothelial cells (EC) in the presence of the general lipase inhibitor tetrahydrolipstatin. In considering endothelial mechanisms responsible for this effect, we found that endothelial lipase (EL) overexpression in both EC and non-EL-expressing NIH/3T3 mouse embryonic fibroblasts cells significantly decreased TNFalpha-induced VCAM1 expression and promoter activity in a manner dependent on HDL concentration and intact EL activity. Given recent evidence for lipolytic activation of peroxisome proliferator-activated receptors (PPARs)-nuclear receptors implicated in metabolism, atherosclerosis, and inflammation-we hypothesized HDL hydrolysis by EL is an endogenous endothelial mechanism for PPAR activation. In both EL-transfected NIH cells and bovine EC, HDL significantly increased PPAR ligand binding domain activation in the order PPAR-alpha> >-gamma>-delta. Moreover, HDL stimulation induced expression of the canonical PPARalpha-target gene acyl-CoA-oxidase (ACO) in a PPARalpha-dependent manner in ECs. Conditioned media from EL-adenovirus transfected cells but not control media exposed to HDL also activated PPARalpha. PPARalpha activation by EL was most potent with HDL as a substrate, with lesser effects on LDL and VLDL. Finally, HDL inhibited leukocyte adhesion to TNFalpha-stimulated ECs isolated from wild-type but not PPARalpha-deficient mice. This data establishes HDL hydrolysis by EL as a novel, distinct natural pathway for PPARalpha activation and identifies a potential mechanism for HDL-mediated repression of VCAM1 expression, with significant implications for both EL and PPARs in inflammation and vascular biology.
Additive Value of Immunoassay-Measured Fibrinogen and High-Sensitivity C-Reactive Protein Levels for Predicting Incident Cardiovascular Events
Authors: Samia Mora, Nader Rifai, Julie E. Buring, Paul M Ridker
Journal: Circulation (2006)

Current guidelines suggest measuring high-sensitivity C-reactive protein (hs-CRP) as an aid to coronary risk assessment in adults without cardiovascular disease (CVD). Whether other inflammatory biomarkers, such as fibrinogen, add further prognostic information is uncertain.In a prospective study of 27,742 initially healthy middle-aged women, the associations of baseline immunoassay fibrinogen and hs-CRP measurements with incident CVD were examined over a 10-year follow-up period. Compared with women in the bottom biomarker quintile, age-adjusted hazard ratios (95% confidence intervals [CIs]) for incident CVD for quintiles 2 to 5 of fibrinogen were 1.10 (0.86 to 1.41), 1.30 (1.03 to 1.65), 1.46 (1.16 to 1.85), and 2.43 (1.95 to 3.02); for hs-CRP they were 1.48 (1.06 to 2.05), 1.70 (1.24 to 2.33), 2.20 (1.63 to 2.96), and 3.24 (2.43 to 4.31). After further adjustment for established risk factors, both biomarkers remained associated (P for trend < or = 0.001) with incident CVD (hazard ratio, 1.35; 95% CI, 1.07 to 1.71 for top fibrinogen quintile; and hazard ratio, 1.68; 95% CI, 1.22 to 2.29 for top hs-CRP quintile compared with the bottom quintiles). Further adjustment for the other biomarker resulted in hazard ratios of 1.23 and 1.56 (P for trend = 0.02 and 0.002), respectively. Although fibrinogen correlated positively with hs-CRP (rs = 0.41, P < 0.001), the highest CVD risk was associated with elevated levels of both fibrinogen and hs-CRP: age-adjusted hazard ratio of 3.45 (95% CI, 2.60 to 4.57) for women with fibrinogen > 393 mg/dL and hs-CRP > 3 mg/L compared with < 329 mg/dL and < 1 mg/L, respectively.In this cohort of initially healthy women, baseline levels of fibrinogen measured with a high-quality immunoassay provided additive value to hs-CRP and traditional risk factors in predicting incident CVD.