tbuckley/cabot-search huggingface dataset:
Mortality among "never smokers" living with smokers: two cohort studies, 1981-4 and 1996-9
Authors: Sarah Hill, Tony Blakely, Ichiro Kawachi, Alistair Woodward
Journal: BMJ (2004)

2][3][4] We present results from two population cohorts of adults who had never smoked ("never smokers"), followed for three year mortality according to household exposure to secondhand smoke.
Acute exercise increases triglyceride synthesis in skeletal muscle and prevents fatty acid–induced insulin resistance
Authors: Simon Schenk, Jeffrey F. Horowitz
Journal: Journal of Clinical Investigation (2007)

Fatty acid oversupply is a key mediator of skeletal muscle insulin resistance in obesity, primarily via accumulation of fatty acid metabolites and activation of proinflammatory pathways. Herein, we demonstrate that fatty acid–induced insulin resistance in humans is completely prevented the day after 1 session of endurance exercise. Because skeletal muscle is the primary site for systemic glucose disposal and is highly susceptible to impaired insulin action by elevated fatty acid availability, we obtained skeletal muscle samples to investigate possible mechanisms mediating this protective effect of exercise. Prevention of fatty acid–induced insulin resistance after exercise accompanied enhanced skeletal muscle protein expression of key lipogenic enzymes and an increase in muscle triglyceride synthesis. Partitioning more fatty acids toward triglyceride synthesis within muscle reduced the accumulation of fatty acid metabolites and suppressed the proinflammatory response in skeletal muscle, as evidenced by decreased phosphorylation and activation of JNK and increased abundance of inhibitor of NF-κB α (IκB-α) and IκB-β. We believe this is the first study to demonstrate that 1 session of exercise completely reverses fatty acid–induced insulin resistance in humans. Reversal of insulin resistance accompanied enhanced lipogenic capacity within skeletal muscle, reduced accumulation of highly bioactive fatty acid metabolites, and suppressed activation of proinflammatory pathways known to impair insulin action.
The natural killer cell receptor specific for HLA-A allotypes: a novel member of the p58/p70 family of inhibitory receptors that is characterized by three immunoglobulin-like domains and is expressed as a 140-kD disulphide-linked dimer.
Authors: D Pende, R Biassoni, C Cantoni, S Verdiani, M Falco, C di Donato, L Accame, C Bottino, A Moretta, L Moretta
Journal: The Journal of Experimental Medicine (1996)

Human natural killer (NK) cells express inhibitory receptors that are specific for different groups of HLA-C or HLA-B alleles. The majority of these receptors belong to the immunoglobulin (Ig) superfamily and are characterized by two or three extracellular Ig-like domains. Here we describe a novel inhibitory NK receptor that is specific for a group of HLA-A alleles. The HLA-A3-specific NK cell clone DP7 has been used for mice immunization. Two mAbs, termed Q66 and Q241, bound to the immunizing clone and stained only a subset of NK cell populations or clones. Among Q66 mAb-reactive clones, we further selected those that did not express any of the previously identified HLA-class I-specific NK receptors. These clones did not lyse HLA-A3+ (or -A11+) target cells, but lysis of these targets could be detected in the presence of Q66 or Q241 mAbs. On the other hand, target cells expressing other HLA-A alleles, including -A1, -A2, and -A24, were efficiently lysed. Moreover, none of the HLA-C or HLA-B alleles that were tested exerted a protective effect. Q66+, but not Q66- NK cell clones, expressed messenger RNA coding for a novel 3 Ig domain protein homologous to the HLA-C (p58) and HLA-B (p70) receptors. The corresponding cDNA (cl.1.1) was used to generate transient and stable transfectants in COS7 and NIH3T3 cell lines, respectively. Both types of transfectants were specifically stained by Q66 and Q241 mAbs. Since the cytoplasmic tail of Q66-reactive molecules was at least 11 amino acid longer than the other known p58/p70 molecules, we could generate an antiserum specific for the COOH-terminus of Q66-reactive molecules, termed PGP-3. PGP-3 immunoprecipitated, only from Q66+ NK cells, molecules displaying a molecular mass of 140 kD, under nonreducing conditions, which resolved, under reducing conditions, in a 70-kD band. Thus, differently from the other p58/p70 receptors, Q66-reactive molecules appear to be expressed as disulphide-linked dimers and were thus termed p140. The comparative analysis of the amino acid sequences of p58, p70, and p140 molecules revealed the existence of two cysteins proximal to the transmembrane region, only in the amino acid sequence of p140 molecules.
Mitochondrial Type Iron-Sulfur Cluster Assembly in the Amitochondriate Eukaryotes Trichomonas vaginalis and Giardia intestinalis, as Indicated by the Phylogeny of IscS
Authors: Jan Tachezy, Lidya B. Sánchez, Miklós Müller
Journal: Molecular Biology and Evolution (2001)

Pyridoxal-5′-phosphate-dependent cysteine desulfurase (IscS) is an essential enzyme in the assembly of FeS clusters in bacteria as well as in the mitochondria of eukaryotes. Although FeS proteins are particularly important for the energy metabolism of amitochondrial anaerobic eukaryotes, there is no information about FeS cluster formation in these organisms. We identified and sequenced two IscS homologs of Trichomonas vaginalis (TviscS-1 and TviscS-2) and one of Giardia intestinalis (GiiscS). TviscS-1, TviscS-2, and GiiscS possess the typical conserved regions implicated in cysteine desulfurase activity. N-termini of TviscS-1 and TviscS-2 possess eight amino acid extensions, which resemble the N-terminal presequences that target proteins to hydrogenosomes in trichomonads. No presequence was evident in GiiscS from Giardia, an organism that apparently lacks hydrogenosmes or mitochondria. Phylogenetic analysis showed a close relationship among all eukaryotic IscS genes including those of amitochondriates. IscS of proteobacteria formed a sister group to the eukaryotic clade, suggesting that isc-related genes were present in the proteobacterial endosymbiotic ancestor of mitochondria and hydrogenosomes. NifS genes of nitrogen-fixing bacteria, which are IscS homologs required for specific formation of FeS clusters in nitrogenase, formed a more distant group. The phylogeny indicates the presence of a common mechanism for FeS cluster formation in mitochondriates as well as in amitochondriate eukaryotes. Furthermore, the analyses support a common origin of Trichomonas hydrogenosomes and mitochondria, as well as secondary loss of mitochondrion/hydrogenosome-like organelles in Giardia.
Critical Oxygen Delivery in Conscious Septic Rats under Stagnant or Anemic Hypoxia
Authors: Yoshihisa Morita, Ian Chin-Yee, Pei Yu, William J. Sibbald, Claudio M. Martin
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Although evidence shows that critical O2 delivery (QO2crit), the point at which oxygen consumption becomes limited by O2 delivery (QO2), is not affected by the method used to decrease QO2 in healthy subjects, microcirculatory injury caused by sepsis may modify QO2crit in a unique manner. We therefore designed this study to compare QO2crit in anemic and stagnant hypoxia in conscious septic rats. Rats were randomized to control or sepsis induced by cecal ligation and perforation; 24 hours later, oxygen consumption was measured using expired gas analysis, whereas QO2 was calculated from standard formula. Rats were further randomized to anemic hypoxia by isovolemic hemodilution or stagnant hypoxia by stepwise inflation of a balloon-tip catheter in the right atrium. QO2crit and critical hemoglobin concentration were calculated by dual linear regression analysis. We found that (1) QO2crit was not different between anemic and stagnant hypoxia in sepsis and that (2) the critical hemoglobin concentration in anemic hypoxia was similar between sepsis and control, indicating that tolerance to acute anemia is not altered by sepsis. Further studies are needed before the clinical relevance of these conclusions can be fully understood.
Mycophenolate Mofetil for Maintenance Therapy of Wegener's Granulomatosis and Microscopic Polyangiitis
Authors: Rainer Nowack, Ursula Göbel, Pieter Klooker, Olaf Hergesell, Konrad Andrassy, Fokko J. Van Der Woude
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Successful maintenance therapy with mycophenolate mofetil (MMF) 2 g/d and low-dose oral corticosteroids (OCS) over a period of 15 mo was given to patients with Wegener's granulomatosis (WG) ( n = 9) and microscopic polyangiitis (MPA) ( n = 2). All patients had severe generalized disease with pauci-immune necrotizing glomerulonephritis and received standard induction therapy with oral cyclophosphamide and OCS for a mean of 14 wk until remission was achieved. Of 11 patients, only one WG patient relapsed in the 14th month of maintenance therapy. Maintenance therapy with MMF was able to further reduce grumbling disease activity as measured by the Birmingham vasculitis activity score (BVAS2) and proteinuria that were still present by the end of induction therapy. OCS could be reduced to a median daily dose of 5 mg and discontinued in three patients. Possible drug-related adverse effects were transient and included abdominal pain, respiratory infection, diarrhea, leukopenia, and a cytomegalovirus-colitis in one patient that was successfully treated with ganciclovir. It is concluded that MMF in combination with low-dose OCS is well tolerated and effective for maintenance therapy of WG and MPA. Long-term treatment with MMF in these diseases is attractive because of its low toxicity. MMF will have to be studied further and compared with cyclophosphamide or azathioprine maintenance therapy in randomized trials.
Translating the Diabetes Prevention Program Into an Urban Medically Underserved Community
Authors: Miriam C. Seidel, Robert O. Powell, Janice C. Zgibor, Linda M. Siminerio, Gretchen A. Piatt
Journal: Diabetes Care (2008)

OBJECTIVE—The objective of this study was to determine if a community-based modified Diabetes Prevention Program Group Lifestyle Balance (GLB) intervention, for individuals with metabolic syndrome, was effective in decreasing risk for type 2 diabetes and cardiovascular disease (CVD) in an urban medically underserved community, and subsequently to determine if improvements in clinical outcomes could be sustained in the short term. RESEARCH DESIGN AND METHODS—This nonrandomized prospective intervention study used a one-group design to test the effectiveness of a community-based GLB intervention. Residents from 11 targeted neighborhoods were screened for metabolic syndrome (n = 573) and took part in a 12-week GLB intervention (n = 88) that addressed safe weight loss and physical activity. RESULTS—A marked decline in weight (46.4% lost ≥5% and 26.1% lost ≥7%) was observed in individuals after completion of the intervention. Of these subjects, 87.5% (n = 28) and 66.7% (n = 12) sustained the 5% and 7% reduction, respectively, at the 6-month reassessment. Over one-third of the population (43.5%, n = 30) experienced improvements in one or more component of metabolic syndrome, and 73.3% (n = 22) sustained this improvement at the 6-month reassessment. Additional improvements occurred in waist circumference (P &amp;lt; 0.009) and blood pressure levels (P = 0.04) after adjustment for age, sex, race, mean number of GLB classes attended, and time. CONCLUSIONS—Adults in an urban medically underserved community can decrease their risk for type 2 diabetes and CVD through participation in a GLB intervention, and short-term sustainability is feasible. Future research will include long-term follow-up of these subjects.
Teaching in marine mammals? Anecdotes versus science
Authors: Dario Maestripieri, Jessica Whitham
Journal: Behavioral and Brain Sciences (2001)

The use of anecdotes is not a viable research strategy to study animal culture. Social learning processes can often be documented with careful quantitative analyses of observational data. Unfortunately, suggestions that killer whales engage in teaching are entirely based on subjective interpretations of qualitative observations. Thus, “evidence” of teaching in killer whales cannot be used to argue for the occurrence of culture in marine mammals.
Trisodium Nitriloacetate Monohydrate: Promoting Effect in Urinary Bladder Carcinogenesis in Rats Treated With &lt;italic&gt;N&lt;/italic&gt;-Buty1-&lt;italic&gt;N&lt;/italic&gt;-(4-hydroxybutyl)nitrosamine&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Y Hiasa, Y Kitahori, N Konishi, T Shimoyama, A Miyashiro
Journal: JNCI Journal of the National Cancer Institute (1985)

The effect of trisodium nitrilotriacetate monohydrate [(Na3NTA X H2O) CAS: 18662-53-8] on development of urinary bladder tumors in rats initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine [(BBN) CAS: 3817-11-6] was studied. Twenty-one male inbred W rats 6 weeks of age were given drinking water containing 500 ppm of BBN for 4 weeks and then put on diet containing 10,000 ppm of Na3NTA X H2O for 28 weeks. Na3NTA X H2O promoted the development of urinary bladder tumors in rats treated with BBN. The incidences of papilloma and transitional cell carcinomas in the urinary bladder were 90% (18/20) and 25% (4/20), respectively, in rats treated with BBN and then Na3NTA X H2O and 0 in those treated with BBN or Na3NTA X H2O alone. The incidence of papillary or nodular hyperplasia in week 32 was 100% (20/20) in rats treated with BBN and then Na3NTA X H2O and 61% (13/21) in rats treated with BBN only.
Modeling Total Heart Function
Authors: Peter J. Hunter, Andrew J. Pullan, Bruce H. Smaill
Journal: Annual Review of Biomedical Engineering (2003)

▪ Abstract Computational models of the electrical and mechanical function of the heart are reviewed. These models attempt to explain the integrated function of the heart in terms of ventricular anatomy, the structure and material properties of myocardial tissue, the membrane ion channels, and calcium handling and myofilament mechanics of cardiac myocytes. The models have established the computational framework for linking the structure and function of cardiac cells and tissue to the integrated behavior of the intact heart, but many more aspects of physiological function, including metabolic and signal transduction pathways, need to be included before significant progress can be made in understanding many disease processes.
SPERMINE OXIDASE: AN AMINE OXIDASE WITH SPECIFICITY FOR SPERMINE AND SPERMIDINE
Authors: James G. Hirsch
Journal: The Journal of Experimental Medicine (1953)

Sheep serum and bovine serum contain an enzyme which brings about a rapid oxidative deamination of certain biological amines. This enzyme differs from previously described amine oxidases in several regards and especially in its substrate specificity. Studies thus far indicate that only spermine and the closely related compound spermidine serve as substrates for the enzyme in sheep serum. For this reason, the enzyme has been named spermine oxidase. Spermine oxidase is active in a variety of fluids of various ionic strength and buffer composition. The reaction takes place between pH 6.0 and pH 8.0 with an optimal rate in the vicinity of neutrality. Under certain conditions, the rate of oxygen consumption during the initial phase of the reaction is independent of the concentration of substrate. The diminution in rate observed during the latter phase of the enzymatic attack appears to be due to an alteration in the kinetics at low concentrations of substrate, or to competitive inhibition by a product of the reaction. Carbonyl reagents almost completely block the action of spermine oxidase, while certain amines and the cyanide ion bring about partial inhibition. Thiol reagents and sequestering compounds do not alter the course of the oxidative process. In the presence of low concentrations of mercuric chloride, the sheep serum-spermine system consumes approximately twice as much oxygen as controls containing no mercuric ion. The mechanism by which the mercuric ion stimulates additional oxygen uptake is obscure.
Copy number polymorphisms and anticancer pharmacogenomics
Authors: Eric R Gamazon, R Stephanie Huang, M Eileen Dolan, Nancy J Cox
Journal: Genome biology (2011)

Abstract Background Recent studies have investigated the contribution of copy number variants (CNVs) to disease susceptibility in a multitude of complex disorders, including systemic lupus erythematosus, Crohn's disease, and various neurodevelopmental disorders. Relatively few CNV studies, however, have been conducted on pharmacologic phenotypes even though these structural variants are likely to play an important role. We developed a genome-wide method to identify CNVs that contribute to heterogeneity in drug response, focusing on drugs that are widely used in anticancer treatment regimens. Results We conducted a comprehensive genome-wide study of CNVs from population-scale array-based and sequencing-based surveys by analyzing their effect on cellular sensitivity to platinating agents and topoisomerase II inhibitors. We identified extensive CNV regions associated with cellular sensitivity to functionally diverse chemotherapeutics, supporting the hypothesis that variation in copy number contributes to variation in drug response. Interestingly, although single nucleotide polymorphisms (SNPs) tag some of the CNVs associated with drug sensitivity, several of the most significant CNV-drug associations are independent of SNPs; consequently, they represent genetic variations that have not been previously interrogated by SNP studies of pharmacologic phenotypes. Conclusions Our findings demonstrate that pharmacogenomic studies may greatly benefit from the study of CNVs as expression quantitative trait loci, thus contributing broadly to our understanding of the complex traits genetics of CNVs. We also extend our PACdb resource, a database that makes available to the scientific community relationships between genetic variation, gene expression, and sensitivity to various drugs in cell-based models.
A new NOS2 promoter polymorphism associated with increased nitric oxide production and protection from severe malaria in Tanzanian and Kenyan children
Authors: Maurine R Hobbs, Venkatachalam Udhayakumar, Marc C Levesque, Jennifer Booth, Jacquelin M Roberts, Ariana N Tkachuk, Ann Pole, Hilary Coon, Simon Kariuki, Bernard L Nahlen, Esther D Mwaikambo, Altaf L Lal, Donald L Granger, Nicholas M Anstey, J Brice Weinberg
Journal: The Lancet (2002)
Metabolic effects of intravenous salbutamol in the course of acute severe asthma.
Authors: S G Nogrady, J P Hartley, A Seaton
Journal: Thorax (1977)

Peak expiratory flow rate and plasma free fatty acids, potassium, insulin, and glucose were measured in 10 patients admitted with acute severe asthma before and at frequent intervals for one hour after an infusion of salbutamol, 4 microgram/kg over 10 minutes. These studies were repeated during the recovery phase and again before discharge. Effective bronchodilatation seen after the infusion was similar in the acute and recovery phases. Baseline plasma free fatty acids were elevated but rose significantly after the infusion. There was also a significant fall in plasma potassium. These changes occurred in all individuals. There were no significant differences in mean baseline or peak changes of plasma free fatty acids, potassium or insulin on any of the study days. There was no evidence of beta receptor blockade in the acute phase in any patient.
CLINICAL DEVELOPMENT OF HISTONE DEACETYLASE INHIBITORS AS ANTICANCER AGENTS
Authors: Daryl C. Drummond, Charles O. Noble, Dmitri B. Kirpotin, Zexiong Guo, Gary K. Scott, Christopher C. Benz
Journal: The Annual Review of Pharmacology and Toxicology (2004)

▪ Abstract Acetylation is a key posttranslational modification of many proteins responsible for regulating critical intracellular pathways. Although histones are the most thoroughly studied of acetylated protein substrates, histone acetyltransferases (HATs) and deacetylases (HDACs) are also responsible for modifying the activity of diverse types of nonhistone proteins, including transcription factors and signal transduction mediators. HDACs have emerged as uncredentialed molecular targets for the development of enzymatic inhibitors to treat human cancer, and six structurally distinct drug classes have been identified with in vivo bioavailability and intracellular capability to inhibit many of the known mammalian members representing the two general types of NAD + -independent yeast HDACs, Rpd3 (HDACs 1, 2, 3, 8) and Hda1 (HDACs 4, 5, 6, 7, 9a, 9b, 10). Initial clinical trials indicate that HDAC inhibitors from several different structural classes are very well tolerated and exhibit clinical activity against a variety of human malignancies; however, the molecular basis for their anticancer selectivity remains largely unknown. HDAC inhibitors have also shown preclinical promise when combined with other therapeutic agents, and innovative drug delivery strategies, including liposome encapsulation, may further enhance their clinical development and anticancer potential. An improved understanding of the mechanistic role of specific HDACs in human tumorigenesis, as well as the identification of more specific HDAC inhibitors, will likely accelerate the clinical development and broaden the future scope and utility of HDAC inhibitors for cancer treatment.
A signalling role for muscle glycogen in the regulation of pace during prolonged exercise
Authors: H G L Rauch, A St Clair Gibson, E V Lambert, T D Noakes
Journal: British Journal of Sports Medicine (2004)

Introduction: In this study we examined the pacing strategy and the end muscle glycogen contents in eight cyclists, once when they were carbohydrate loaded and once when they were non-loaded. Methods: Cyclists completed 2 hours of cycling at ∼73% of maximum oxygen consumption, which included five sprints at 100% of peak sustained power output every 20 minutes, followed immediately by a 1 hour time trial. Muscle biopsies were performed before and immediately after exercise, while blood samples were taken during the 2 hour steady state rides and immediately after exercise. Results: Carbohydrate loading improved mean power output during the 1 hour time trial (mean (SEM) 219 (17) v 233 (15) W; p&lt;0.05) and enabled subjects to use significantly more muscle glycogen than during the trial following their normal diet. Significantly, the subjects, kept blind to all feedback except for time, started both time trials at similar workloads (∼30 W), but after 1 minute of cycling, the workload average 14 W higher throughout the loaded compared with the non-loaded time trial. There were no differences in subjects’ plasma glucose and lactate concentrations and heart rates in the carbohydrate loaded versus the non-loaded trial. Of the eight subjects, seven improved their time trial performance after carbohydrate loading. Finishing muscle glycogen concentrations in these seven subjects were remarkably similar in both trials (18 (3) v 20 (3) mmol/kg w/w), despite significantly different starting values and time trial performances (36.55 (1.47) v 38.14 (1.27) km/h; p&lt;0.05). The intra-subject coefficient of variation (CV) for end glycogen content in these seven subjects was 10%, compared with an inter-subject CV of 43%. Conclusions: As seven subjects completed the time trials with the same end exercise muscle glycogen concentrations, diet induced changes in pacing strategies during the time trials in these subjects may have resulted from integrated feedback from the periphery, perhaps from glycogen content in exercising muscles.
Statin Induced Proteinuria
Authors: Rajiv Agarwal
Journal: Journal of the American Society of Nephrology (2004)

Meticulous blood pressure control, particularly with antiproteinuric medications, such as ACE inhibitors and angiotensin receptor blockers (ARBs), have proven to be effective in slowing the progression of kidney disease and are pillars in the modern management of chronic kidney disease (CKD).