tbuckley/cabot-search huggingface dataset:
Cardiovascular Autonomic Neuropathy, HDL Cholesterol, and Smoking Correlate With Arterial Stiffness Markers Determined 18 Years Later in Type 1 Diabetes
Authors: Catherine T. Prince, Aaron M. Secrest, Rachel H. Mackey, Vincent C. Arena, Lawrence A. Kingsley, Trevor J. Orchard
Journal: Diabetes Care (2009)

OBJECTIVE To examine the relationship between cardiovascular autonomic neuropathy and pulse waveform analysis (PWA) measures of arterial stiffness in a childhood-onset type 1 diabetes population. RESEARCH DESIGN AND METHODS Cardiac autonomic nerve function was measured in the baseline examination of the Pittsburgh Epidemiology of Diabetes Complications Study of childhood-onset type 1 diabetes by heart rate variability (R-R interval) during deep breathing and expressed as expiration-to-inspiration (E/I) ratio. Other cardiovascular and diabetes factors were also assessed. PWA was performed using SphgymoCor Px on 144 participants at the 18-year follow-up examination. Univariate and multivariate analyses for associations between baseline nerve function and other cardiovascular and diabetes-related factors were performed for augmentation index (AIx), augmentation pressure (AP), and subendocardial viability ratio (SEVR), a surrogate marker of myocardial perfusion. RESULTS E/I ratio correlated negatively with both AIx (r = −0.18, P = 0.03) and AP (r = −0.32, P &amp;lt; 0.001) and positively with SEVR (r = 0.47, P &amp;lt; 0.001) univariately. Lower baseline E/I ratio, HDL cholesterol, and a history of smoking were associated with higher follow-up (18 years later) AIx and AP and lower SEVR in multivariate analyses. Higher baseline HbA1 was also associated with higher AP and lower SEVR multivariately. CONCLUSIONS Cardiovascular autonomic neuropathy is associated with increased arterial stiffness measures and decreased estimated myocardial perfusion in those with type 1 diabetes some 18 years later. This association persists after adjustment for potential confounders as well as for baseline HbA1, HDL cholesterol, and smoking history, which were also associated with these PWA measures.
Intravenous aminophylline in patients admitted to hospital with non-acidotic exacerbations of chronic obstructive pulmonary disease: a prospective randomised controlled trial
Authors: N Duffy
Journal: Thorax (2005)

Intravenous aminophylline is commonly used in the treatment of exacerbations of chronic obstructive pulmonary disease (COPD), despite limited evidence for its efficacy and known risks of toxicity. We hypothesised that adding intravenous aminophylline to conventional treatment would not produce clinically important changes in the speed of spirometric or symptomatic recovery or shorten hospital stay in patients with exacerbations of COPD.Eighty patients admitted to hospital with non-acidotic exacerbations of COPD were recruited at admission to a randomised, double blind, placebo controlled study comparing intravenous aminophylline 0.5 mg/kg/hour after an appropriate loading dose with an equivalent volume of 0.9% saline. The primary outcome was the change in post-bronchodilator forced expiratory volume in 1 second (FEV(1)) over the first 5 days of the admission. Secondary end points were changes in self-reported breathlessness, arterial blood gas tensions, forced vital capacity (FVC), and length of hospital stay.There was no difference in the post-bronchodilator FEV(1) over the first 5 days between the aminophylline and placebo groups. In the aminophylline group, 2 hours of treatment produced a small but significant rise in arterial pH (p = 0.001) and a fall in arterial carbon dioxide tension (p = 0.01) compared with placebo treatment. There were no differences in the severity of breathlessness, post-bronchodilator FVC, or length of hospital stay between the groups. Nausea was a more frequent side effect in the aminophylline group (46% v 22%; p<0.05), but palpitations and headache were noted equally in both groups.Although intravenous aminophylline produced small improvements in acid-base balance, these did not influence the subsequent clinical course. No evidence was found for any clinically important additional effect of aminophylline treatment when used with high dose nebulised bronchodilators and oral corticosteroids. Given its known toxicity, we cannot therefore recommend the use of intravenous aminophylline in the treatment of non-acidotic COPD exacerbations.
Antioxidants in acute pancreatitis
Authors: C D Johnson
Journal: Gut (2007)

Antioxidant supplements may be ineffective for the treatment or prevention of organ failure in predicted severe acute pancreatitis

Oxygen-derived free radicals are produced when a period of intracellular anaerobic respiration is followed by re-oxygenation. These extremely reactive radicals combine with a large number of different protein and lipid molecules causing tissue damage and cell injury. The normal defences against such free radical attack include the presence in the tissues of antioxidant compounds and pathways of metabolism. A lack of sufficient antioxidant reserve during times of increased production of free radicals leads to the state of oxidative stress.

There has been increasing awareness over the last 20 years of the role played by oxidative stress in many inflammatory illnesses. Acute pancreatitis is no exception and in several models it has been demonstrated that oxygen-derived free radicals are generated during acute pancreatitis. It has been suggested that free radical generation, or the inability to quench free radicals, is an important factor in the pathogenesis of acute pancreatitis.1 However, a careful experimental study suggested that oxidative stress alone cannot cause pancreatitis.2 It is much more plausible that oxidative stress may contribute to worsening of the local inflammatory changes after onset of pancreatitis.3–6 Some experimental studies suggest that antioxidant therapy can diminish tissue injury in acute pancreatitis.3,7 It is also clear that oxidative mechanisms are an integral part of the inflammatory response and oxidative stress may contribute to pulmonary injury in severe acute pancreatitis.8,9 Oxidative stress is recognised as part of the pathophysiology of adult respiratory distress syndrome,10 and there is experimental evidence that antioxidants can protect against …
Folding defects in P-type ATP 8B1 associated with hereditary cholestasis are ameliorated by 4-phenylbutyrate
Authors: Lieke M. van der Velden, Janneke M. Stapelbroek, Elmar Krieger, Peter V. E. van den Berghe, Ruud Berger, Patricia M. Verhulst, Joost C. M. Holthuis, Roderick H. J. Houwen, Leo W. J. Klomp, Stan F. J. van de Graaf
Journal: Hepatology (2009)

Deficiency in P-type ATP8B1 is a severe and clinically highly variable hereditary disorder that is primarily characterized by intrahepatic cholestasis. It presents either as a progressive (progressive familial intrahepatic cholestasis type 1 [PFIC1]) or intermittent (benign recurrent intrahepatic cholestasis type 1 [BRIC1]) disease. ATP8B1 deficiency is caused by autosomal recessive mutations in the gene encoding ATP8B1, a putative aminophospholipid-translocating P-type adenosine triphosphatase. The exact pathogenesis of the disease is elusive, and no effective pharmacological therapy is currently available. Here, the molecular consequences of six distinct ATP8B1 missense mutations (p.L127P, p.G308V, p.D454G, p.D554N, p.I661T, and p.G1040R) and one nonsense mutation (p.R1164X) associated with PFIC1 and/or BRIC1 were systematically characterized. Except for the p.L127P mutation, all mutations resulted in markedly reduced ATP8B1 protein expression, whereas messenger RNA expression was unaffected. Five of seven mutations resulted in (partial) retention of ATP8B1 in the endoplasmic reticulum. Reduced protein expression was partially restored by culturing the cells at 30 degrees C and by treatment with proteasomal inhibitors, indicating protein misfolding and subsequent proteosomal degradation. Protein misfolding was corroborated by predicting the consequences of most mutations onto a homology model of ATP8B1. Treatment with 4-phenylbutyrate, a clinically approved pharmacological chaperone, partially restored defects in expression and localization of ATP8B1 substitutions G308V, D454G, D554N, and in particular I661T, which is the most frequently identified mutation in BRIC1.A surprisingly large proportion of ATP8B1 mutations resulted in aberrant folding and decreased expression at the plasma membrane. These effects were partially restored by treatment with 4-phenylbutyrate. We propose that treatment with pharmacological chaperones may represent an effective therapeutic strategy to ameliorate the recurrent attacks of cholestasis in patients with intermittent (BRIC1) disease.
RGS6, a Modulator of Parasympathetic Activation in Heart
Authors: Jianqi Yang, Jie Huang, Biswanath Maity, Zhan Gao, Ramón A. Lorca, Hjalti Gudmundsson, Jingdong Li, Adele Stewart, Paari Dominic Swaminathan, Stella-Rita Ibeawuchi, Andrew Shepherd, Ching-Kang Chen, William Kutschke, Peter J. Mohler, Durga P. Mohapatra, Mark E. Anderson, Rory A. Fisher
Journal: Circulation Research (2010)

Parasympathetic regulation of heart rate is mediated by acetylcholine binding to G protein-coupled muscarinic M2 receptors, which activate heterotrimeric G(i/o) proteins to promote G protein-coupled inwardly rectifying K(+) (GIRK) channel activation. Regulator of G protein signaling (RGS) proteins, which function to inactivate G proteins, are indispensable for normal parasympathetic control of the heart. However, it is unclear which of the more than 20 known RGS proteins function to negatively regulate and thereby ensure normal parasympathetic control of the heart.To examine the specific contribution of RGS6 as an essential regulator of parasympathetic signaling in heart.We developed RGS6 knockout mice to determine the functional impact of loss of RGS6 on parasympathetic regulation of cardiac automaticity. RGS6 exhibited a uniquely robust expression in the heart, particularly in sinoatrial and atrioventricular nodal regions. Loss of RGS6 provoked dramatically exaggerated bradycardia in response to carbachol in mice and isolated perfused hearts and significantly enhanced the effect of carbachol on inhibition of spontaneous action potential firing in sinoatrial node cells. Consistent with a role of RGS6 in G protein inactivation, RGS6-deficient atrial myocytes exhibited a significant reduction in the time course of acetylcholine-activated potassium current (I(K)(ACh)) activation and deactivation, as well as the extent of I(K)(ACh) desensitization.RGS6 is a previously unrecognized, but essential, regulator of parasympathetic activation in heart, functioning to prevent parasympathetic override and severe bradycardia. These effects likely result from actions of RGS6 as a negative regulator of G protein activation of GIRK channels.
Graft-versus-host disease in cyclosporin A-treated rats after syngeneic and autologous bone marrow reconstitution.
Authors: A Glazier, P J Tutschka, E R Farmer, G W Santos
Journal: The Journal of Experimental Medicine (1983)

Lethally irradiated rats treated with cyclosporin A (CsA) for 20-40 d develop classic graft-versus-host disease (GVHD) when reconstituted with syngeneic or autologous bone marrow, upon discontinuation of CsA, whereas normal rats do not. Syngeneic GVHD may be transferred to irradiated but not normal syngeneic recipients. Normal spleen cells fail to prevent the development or adoptive transfer of syngeneic GVHD.
Phase III Noninferiority Trial Comparing Irinotecan With Oxaliplatin, Fluorouracil, and Leucovorin in Patients With Advanced Colorectal Carcinoma Previously Treated With Fluorouracil: N9841
Authors: George P. Kim, Daniel J. Sargent, Michelle R. Mahoney, Kendrith M. Rowland, Philip A. Philip, Edith Mitchell, Abraham P. Mathews, Tom R. Fitch, Richard M. Goldberg, Steven R. Alberts, Henry C. Pitot
Journal: Journal of Clinical Oncology (2009)

The primary goal of this multicenter phase III trial was to determine whether overall survival (OS) of fluorouracil (FU) -refractory patients was noninferior when treated with second-line infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4; arm B) versus irinotecan (arm A). Cross-over to the other treatment on disease progression was mandated.Patients who experienced treatment failure with one prior FU-based therapy and had not received prior irinotecan or oxaliplatin, either for metastatic disease or within 6 months of adjuvant FU therapy, were randomly assigned to arm A (irinotecan 350 or 300 mg/m(2) every 3 weeks) or arm B (FOLFOX4).A total of 491 patients were randomly assigned (arm A, n = 245; arm B, n = 246); 288 (59%) had experienced treatment failure with FU for metastatic colorectal cancer. Two hundred twenty-seven patients (46%) received protocol-mandated third-line therapy (arm A, 43%; arm B, 57%). Median survival was 13.8 months (95% CI, 12.2 to 15.0 months) for initial treatment with FOLFOX4 and 14.3 months (95% CI, 12.0 to 15.9 months) for irinotecan (P = .38; hazard ratio = 0.92; 95% CI, 0.8 to 1.1). Response rates (RR; 28% v 15.5%; P = .0009) and time to progression (TTP; 6.2 v 4.4 months; P = .0009) were significantly superior with FOLFOX4. In the nonrandom subset of patients who crossed over, RR and TTP improvements with FOLFOX4 continued into third-line treatment. Irinotecan therapy was associated with more grade 3 nausea, vomiting, diarrhea, and febrile neutropenia; FOLFOX4 was associated with more neutropenia and paresthesias.In patients who experienced treatment failure with front-line FU therapy, OS does not significantly differ whether second-line therapy begins with irinotecan or FOLFOX4. FOLFOX4 produces higher RR and longer TTP. Both arms had notable OS in patients who experienced treatment failure with first-line FU therapy.
The Balance Between Pax5 and Id2 Activities Is the Key to AID Gene Expression
Authors: Hiroyuki Gonda, Manabu Sugai, Yukiko Nambu, Tomoya Katakai, Yasutoshi Agata, Kazuhiro J. Mori, Yoshifumi Yokota, Akira Shimizu
Journal: The Journal of Experimental Medicine (2003)

Pax5 activity is enhanced in activated B cells and is essential for class switch recombination (CSR). We show that inhibitor of differentiation (Id)2 suppresses CSR by repressing the gene expression of activation-induced cytidine deaminase (AID), which has been shown to be indispensable for CSR. Furthermore, a putative regulatory region of AID contains E2A- and Pax5-binding sites, and the latter site is indispensable for AID gene expression. Moreover, the DNA-binding activity of Pax5 is decreased in Id2-overexpressing B cells and enhanced in Id2−/− B cells. The kinetics of Pax5, but not E2A, occupancy to AID locus is the same as AID expression in primary B cells. Finally, enforced expression of Pax5 induces AID transcription in pro–B cell lines. Our results provide evidence that the balance between Pax5 and Id2 activities has a key role in AID gene expression.
Glomerular Oxidative and Antioxidative Systems in Experimental Mesangioproliferative Glomerulonephritis
Authors: Soeren A. Gaertner, Ulf Janssen, Tammo Ostendorf, Karl-Martin Koch, Ju[Combining Diaeresis]urgen Floege, Wilfried Gwinner
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Increased mesangial cell proliferation is a hallmark of many glomerulopathies in humans. Whereas the pathogenic role of reactive oxygen species (ROS) in the development of experimental mesangioproliferative glomerulonephritis (GN) is well established, very little is known about the mechanisms leading to increased ROS concentrations in the glomerulus. This study therefore examined glomerular ROS and the activities of oxidative and antioxidative enzymes during the early course of mesangioproliferative anti-Thy 1.1 GN. Anti-Thy 1.1 GN was induced in male Wistar rats, and glomeruli were isolated 2, 24, and 120 h after disease induction to examine ROS levels as well as oxidative and antioxidative enzyme expression in comparison to non-nephritic controls. At all time points, increased glomerular ROS levels, particularly of hydrogen peroxide and superoxide anions, were observed. Activities of NADH-dependent and NADPH-dependent oxidative enzymes were also increased during the course of GN, whereas no increased activity of xanthine oxidase, another potential source of ROS, was detectable. Despite glomerular oxidative stress, no compensatory increase of antioxidative enzyme activities occurred. On the contrary, catalase, superoxide dismutase, and glutathione peroxidase activities even decreased during the course of disease. In tubulointerstitial samples, no increase in oxidative activity was observed in the course of disease, thus confirming that detected ROS were of glomerular origin. Our data document for the first time a pronounced dysregulation of pro-oxidative and antioxidative enzymes in mesangioproliferative GN, leading to a net increase in glomerular ROS levels. Detailed knowledge of such pathways may lead to new therapeutic approaches for GN in humans.
Technology and badminton
Authors: Gurmeet Singh, None Yogesh
Journal: British Journal of Sports Medicine (2010)

Badminton is fastest racket game and now days there are great changes in the playing pattern and speed. Technological innovations have a great influence in today's game of badminton. In this paper the influence of technology is explained, that how the technology has changed the standard of the game by use of technology and new material in construction of the equipments like court, racket, shuttle, shoes and clothing. The game or badminton is now more skill and technology oriented. Better quality courts are used now for better grip of shoes and power cushion is used in shoes according to presser points, light weight and titanium made very powerful rackets are used now, much better aerodynamic shuttles are used in a lot of variety according to the conditions. Video technology is the most important these days for complete analysis of the skill performed by the player, video recording and analysis is very useful for improvement of the technique of skill accusation. So technology has developed lot in the game of badminton.
Ingleby Lectures on Some Functional Disorders of Females
Authors: W. Francis
Journal: BMJ (1886)

kJtp{q4k .kX1A1redfold bhat even, er Ma)evt,y', honours were, ievr better be- #pwed"than they are now upon John'Hllnter-'and, it I may, in con- clusion, be allowed to tell how great the honour is, r Will do 7so in w,ds, not of my own, but in those of an eloquence which this Uni- versity has often heard -in the words of Xr.Ruskin, =He says, in ,w;iting of the design of having the statues in the museum: "There iM.no man of woith or heart who would, not feel It a high and' price- e reward that his statue should be placed where it 'mi'bt reiind the youth of England of what had been exemplAry,in s life, or useful in hie labousr, and might be regarded with no empty reverence, no fruit- 1&5M peusiveness, but with the emulative, eager, unstin-ted passionkate- nes fionour which youth pays So the dea.lea&ers of the cause it loyesf or4isqoverers of the rlgi,t by whic it lives.To b4e buried under w4ght of'arble, or with splen4our of ceremoinial, is stll o more than burial; but to be remerabeted daily, with profitable teA,deress, by the activest intelligences,of the nation we have pserved, and 'to have power granted ovento the shadows of the poor feates4 suaOk into dust, stW to warn, to animate, to command, as the father's 1rqw rules and e,qalti the toil of his children: this is not buriaj, but immortality."
Public Health and Individual Liberty
Authors: D E Beauchamp
Journal: Annual Review of Public Health (1980)

The focus of this article is upon the growing tensions between the goals of protecting the public health and individual liberty. This issue is especially acute in the present period in which the limits of medicine in effecting substantial future improvements of the health of the public are widely discussed. The term lifestyle has entered the vocabulary of health policy. The document that precipitated this shift in attention was undoubtedly Canada's New Perspectives on the Health of Canadians (1). Few policy
PWE-044 Gastrointestinal symptoms in the joint hypermobility syndrome: Abstract PWE-044 Table 1
Authors: A Fikree, R Aktar, R Grahame, Q Aziz
Journal: Gut (2012)

<h3>Introduction</h3> The Joint Hypermobility Syndrome (JHS) is a hereditary connective tissue disorder, characterised by hyperflexibility of the skin and joints and musculoskeletal symptoms. A high prevalence of JHS has been found in patients presenting to GI clinics with unexplained symptoms.<sup>1</sup> However, the range and prevalence of gastrointestinal (GI) symptoms in JHS patients coming from rheumatology clinics has never been adequately characterised or compared to other patient groups. This was our aim. <h3>Methods</h3> Multicentre, cross sectional study in new referrals to GI clinics between April 2010 and December 2011. Patients between the ages of 16–70 with a rheumatological diagnosis of JHS were compared to those in whom JHS had been excluded, at their first GI clinic visit. The validated Bowel Disease Questionnaire was completed for GI symptom information. Clinical examination confirmed or excluded the diagnosis of JHS, using the 1998 Brighton criteria. Patients outside the age range or with limited English were excluded. GI symptoms were considered significant if they occurred at least once a week, and were compared between the two groups, adjusting for sex and age. In view of the multiple comparisons, the significance level was set at 0.005. <h3>Results</h3> 413 patients participated: 43 with a previous rheumatological diagnosis of JHS, and 370 in whom JHS had been excluded. There were significantly more females in the JHS group (95% vs 54%, p=0.000), and they were younger (mean age: 34.6±10.97 vs 43.3±14.2, p=0.000). Abdominal pain was present in all JHS patients and was significantly more likely to be of more than 5 years duration:(OR 4.38 CI 2.1 to 9.1). Other symptoms which were significantly different between the two groups are shown in Abstract PWE-044 table 1. There was no significant difference in the prevalence of constipation (OR 1.1), diarrhoea (OR 0.2), heartburn (OR 1.3), retrosternal chest pain (OR 2), vomiting (OR 1.2), or dyspepsia (OR 2). <h3>Conclusion</h3> This is the first comparative study of GI symptoms in JHS patients. They have significantly more upper GI symptoms, bloating and alternating bowel habit even when adjusting for age and sex. In view of the association between JHS and unexplained GI symptoms, it is important to consider the diagnosis of JHS in patients with intractable functional GI symptoms, to enable multidisciplinary management. Further studies are needed to determine the mechanism of symptoms in these patients. <h3>Competing interests</h3> None declared. <h3>Reference</h3> 1. <b>Zarate N</b>, Farmer AD, Grahame R, <i>et al.</i> Unexplained gastrointestinal symptoms and joint hypermobility: is connective tissue the missing link? <i>Neurogastroenterol Motil</i> 2009;<b>22</b>:252–e78.