tbuckley/cabot-search huggingface dataset:
Potentiation of beta-adrenergic inotropic response by pyruvate in failing human myocardium
Authors: H Hermann
Journal: Cardiovascular Research (2002)

Background: Pyruvate has been shown to increase contractile function in isolated myocardium and to improve hemodynamics in patients with congestive heart failure. We tested the hypothesis that pyruvate potentiates the inotropic response to β-adrenergic stimulation and to elevated extracellular calcium, since this may be of potential therapeutic value in the clinical setting of acute heart failure in order to circumvent deleterious effects on energy demand as can occur during catecholamine therapy. Methods and Results: We investigated isometrically contracting isolated multicellular muscle preparations from terminal failing human hearts at 37°C, pH 7.4, and a stimulation frequency of 1 Hz. At an extracellular calcium concentration of 1.25 mM, pyruvate (10 mM) alone increased developed force (Fdev) from 9.0±2.3 to 21.1±4.3 mN/mm2 (n=9, P<0.001) and isoproterenol (1 μM) alone increased Fdev from 9.5±2.0 to 31.3±5.4 mN/mm2 (P<0.001), whereas the combination of pyruvate and isoproterenol increased Fdev over-proportionally from 9.0±2.3 to 47.4±6.4 mN/mm2 (P<0.01). In a separate series we assessed the combination of pyruvate and calcium. Although Fdev did not increase from 12 to 16 mM [Ca2+]o, 10 mM pyruvate further increased Fdev from 25.8±5.0 to 30.6±4.7 mN/mm2 (P<0.01). Rapid cooling contractures revealed that altered myofilament responsiveness and/or sarcoplasmic reticulum (SR) calcium load must underlie the positive inotropic effect of pyruvate. Conclusion: A combination of pyruvate and β-adrenergic stimulation may be of therapeutic value in acute heart failure by reducing the concentrations of potential deleterious catecholamines that are currently necessary to maintain adequate tissue perfusion.
Treatment-resistant chronic headaches and focal pachymeningitis in a 46-year-old man: a rare presentation of Wegener's granulomatosis
Authors: Jan Dörr, Saban Elitok, Franz-Josef Dieste, Hans-Peter Vogel, Wolfgang Schneider, Jens Wuerfel, Frauke Zipp, Friedemann Paul
Journal: The Lancet Neurology (2008)
Mechanisms and effects of male genital tract infection on sperm quality and fertilizing potential: the andrologist's viewpoint
Authors: F. Comhaire
Journal: Human Reproduction Update (1999)

There are several mechanisms acting in synergism that can impair sperm characteristics of patients with accessory gland infection. In some cases, conventional sperm variables are disturbed with oligo and/or asthenozoospermia. In other patients, these sperm variables may appear normal, but the functional capacity of spermatozoa may be impaired. In particular, changes in the composition of the sperm membrane may result in reduced acrosome reactivity and capacity to fuse with the oolemma, and oxidative damage of the sperm DNA may induce mutagenesis. Changes in the biochemical make-up of seminal plasma can also reduce the in-vivo fertilizing capacity of spermatozoa, and infection-related disruption of the blood-testis barrier can induce the generation of anti-sperm antibodies and immunological infertility. Many of these functional abnormalities will not become evident upon 'basic semen analysis', which explains why some authors are unable to link infection of the accessory sex glands to subfertility. Also, functional and anatomical damage acquired as a result of infection is often permanent and not reversible by (antibiotic) treatment. Clearly, there are many more aspects of male accessory gland infection that require investigation. Available data should stimulate clinicians to place more emphasis on the prevention of infection-related infertility than on its treatment, as the latter is often unsuccessful.
Molecularly Targeted Radiosensitization of Human Prostate Cancer by Modulating Inhibitor of Apoptosis
Authors: Yao Dai, Meilan Liu, Wenhua Tang, Jeffrey DeSano, Ezra Burstein, Mary Davis, Kenneth Pienta, Theodore Lawrence, Liang Xu
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The inhibitor of apoptosis proteins (IAP) are overexpressed in hormone-refractory prostate cancer, rendering the cancer cells resistant to radiation. This study aims to investigate the radiosensitizing effect of small-molecule IAP inhibitor both in vitro and in vivo in androgen-independent prostate cancer and the possible mechanism of radiosensitization. Experimental Design: Radiosensitization of SH-130 in human prostate cancer DU-145 cells was determined by clonogenic survival assay. Combination effect of SH-130 and ionizing radiation was evaluated by apoptosis assays. Pull-down and immunoprecipitation assays were employed to investigate the interaction between SH-130 and IAPs. DU-145 xenografts in nude mice were treated with SH-130, radiation, or combination, and tumor suppression effect was determined by caliper measurement or bioluminescence imaging. Nuclear factor-κB activation was detected by luciferase reporter assay and quantitative real-time PCR. Results: SH-130 potently enhanced radiation-induced caspase activation and apoptosis in DU-145 cells. Both X-linked IAP and cIAP-1 can be pulled down by SH-130 but not by inactive SH-123. Moreover, SH-130 interrupted interaction between X-linked IAP/cIAP-1 and Smac. In a nude mouse xenograft model, SH-130 potently sensitized the DU-145 tumors to X-ray radiation without increasing systemic toxicity. The combination therapy suppressed tumor growth more significantly than either treatment alone, with over 80% of complete tumor regression. Furthermore, SH-130 partially blocked tumor necrosis factor-α- and radiation-induced nuclear factor-κB activation in DU-145 cells. Conclusions: Our results show that small-molecule inhibitors of IAPs can overcome apoptosis resistance and radiosensitize human prostate cancer with high levels of IAPs. Molecular modulation of IAPs may improve the outcome of prostate cancer radiotherapy.
Assessment of the viscosity of the pulmonary artery wall
Authors: Z. Visontai, Z. Lenard, K Karlocai, M Kollai
Journal: European Respiratory Journal (2000)

Large artery wall viscosity reduces the efficiency of heart/vessel coupling. The aim of the present study was to assess pulmonary artery wall viscosity through comparison of the static (Dst) and dynamic distensibility (Ddyn) of the vessel wall. Right pulmonary artery pressure and diameter was measured in 13 patients and eight healthy volunteers. Ddyn was calculated as the relative change in end-diastolic diameter induced by the pressure pulse, and Dst as the relative change in mean diameter induced by the change in mean pressure during steady-state exercise. Dst did not differ significantly from Ddyn (mean+/-SD 22.8+/-19.2 versus 21.0+/-18.3 10(-3) mmHg(-1)), as tested by paired t-test and analysis of covariance, with age as covariant. End-diastolic diameter increased, whereas Dst and Ddyn decreased as a function of age (r=-0.69 and -0.67, respectively; p&lt;0.01 for both). Ddyn did not change from rest to exercise in spite of a 23+/-16-beats-min(-1) increase in cardiac frequency. Pulmonary artery wall viscosity was negligible and no increase in wall viscosity occurred during cardioacceleration.
The ethics and impact on behaviour of knowledge about one's own genome
Authors: M. Levitt
Journal: BMJ (1999)

“People need to know about their genes and be aware of diseases that may occur”; “the more information available the more informed choices are.” These positive comments on the value of genetic testing came from two visitors to a drop-in “gene shop” which gave information about genetics at Manchester airport, funded as part of the Euroscreen 2 project with staff from the Royal Manchester Children's Hospital Trust.1 They were typical of the visitors who were enthusiastic about testing for themselves and their partners. The Genetic Interest Group, many of whose members come from families affected by genetic disorders, is similarly enthusiastic arguing that “genetic services offer people the potential to acquire information about their genetic make up [which] although it might be bad news, at least allows them to plan out their lives and make informed reproductive decisions.”2 For those who are aware that they are at risk, a genetic test for a specific disorder may well be empowering—it will provide either reassurance or confirmation of that risk. But what would knowledge of their own genetic make up mean for the general population? 

The attraction of genetic testing for the health service is the ability to predict; as the Advisory Council on Genetic Testing put it, to “foretell the future with scientific confidence.”3 The possibilities of preventing the onset of a genetic disease and of developing drugs tailored to the individual's genome are promising; at the moment, though, the ability to detect a disorder is outstripping the development of effective treatment. The problems of making a diagnosis, in a currently healthy person, of high risk for a disease that cannot be prevented and may even be untreatable are recognised in the present system. Information, counselling, and support are offered before the individual can decide to be tested, …
Intrarenal and Cellular Localization of CLC-K2 Protein in the Mouse Kidney
Authors: KATSUKI KOBAYASHI, SHINICHI UCHIDA, SHUKI MIZUTANI, SEI SASAKI, FUMIAKI MARUMO
Journal: Journal of the American Society of Nephrology (2001)

Abstract. CLC-K2, a kidney-specific member of the CLC chloride channel family, is thought to play an important role in the transepithelial Cl - transport in the kidney. This consensus was first reached shortly after it was demonstrated that the mutations of the human CLCNKB gene resulted in Bartter's syndrome type III. To clarify the pathogenesis, the exact intrarenal and cellular localization of CLC-K2 by immunohistochemistry of the Clcnk1 -/- mouse kidney were investigated by use of an anti-CLC-K antibody that recognized both CLC-K1 and CLC-K2. CLC-K2 is expressed in the thick ascending limb of Henle's loop and distal tubules, where it is localized to the basolateral membranes. The localization of CLC-K2 to these nephron segments strongly implies that CLC-K2 confers the basolateral chloride conductance in the thick ascending limb of Henle's loop and distal tubules, where Cl - is taken up by the bumetanide-sensitive Na-K-2Cl cotransporter or the thiazide-sensitive Na-Cl cotransporter at the apical membranes. CLC-K2 expression was also shown to extend into the connecting tubule in the basolateral membrane. CLC-K2 was found in basolateral membranes of the type A intercalated cells residing along the collecting duct. This localization strongly suggests that CLC-K2 confers the basolateral conductance in the type A intercalated cells where Cl - is taken up by the anion exchanger in exchange for HCO 3 - at the basolateral membranes. These aspects of CLC-K2 localization suggest that CLC-K2 is important in Cl - transport in the distal nephron segments.
An unusual inflammation of the colon
Authors: C. P. Selinger, G. Howarth, R. P. Willert
Journal: Gut (2010)

A 27-year Caucasian man received an unrelated donor bone marrow transplant for severe aplastic anaemia. Six weeks later he was re-admitted to hospital with a febrile illness. He developed profuse non-bloody diarrhoea and cervical lymphadenopathy was detected. Blood tests showed pancytopenia and peak concentrations of C-reactive protein 100 mg/l, alanine aminotranferase 357 U/l and alkaline phosphatase 197 U/l. Standard stool microscopy and culture did not reveal any abnormalities and tests for Clostridium difficile toxins a and b …
NUTRIENT REGULATION OF CELL CYCLE PROGRESSION
Authors: Brenda L. Bohnsack, Karen K. Hirschi
Journal: Annual Review of Nutrition (2004)

Cell replication is tightly controlled in normal tissues and aberrant during disease progression, such as in tumorigenesis. The replication of cells can be divided into four distinct phases: Gap 1 (G1), synthesis (S), gap 2 (G2), and mitosis (M). The progression from one phase to the next is intricately regulated and has many "checkpoints" that take into account cellular status and environmental cues. Among the modulators of cell cycle progression are specific nutrients, which function as energy sources or regulate the production and/or function of proteins needed to advance cells through a replicative cycle. In this review, we focus on the roles of specific nutrients (vitamin A, vitamin D, iron, folic acid, vitamin B12, zinc, and glucose) in the control of cell cycle progression and discuss how insights into the mechanisms by which these nutrients modulate this process can be and have been used to control aberrant cell growth in the treatment of prevalent pathologies.
Orlistat and the risk of acute liver injury: self controlled case series study in UK Clinical Practice Research Datalink
Authors: I. J. Douglas, J. Langham, K. Bhaskaran, R. Brauer, L. Smeeth
Journal: BMJ (2013)

<b>Objective</b> To measure the association between orlistat and acute liver injury. <b>Design</b> Self controlled case series study. <b>Setting</b> Population based primary care setting, United Kingdom. <b>Participants</b> 94 695 patients receiving orlistat and registered in the UK Clinical Practice Research Datalink and linked with Hospital Episode Statistics data between 1999 and 2011. <b>Main outcome measure</b> Relative incidence of acute liver injury comparing periods when patients were receiving orlistat with periods of non-usage. <b>Results</b> Among 94 695 patients who received orlistat, 988 cases of acute liver injury were identified, with 335 confirmed as definite cases and 653 as probable cases. For all cases an increased incidence of liver injury was detected during the 90 day period before orlistat was first started, with an incidence rate ratio of 1.50 (95% confidence interval 1.10 to 2.06). The incidence remained raised during the first 30 days of treatment (2.21, 1.43 to 3.42), before returning to baseline levels with prolonged treatment. When the risk during the first 90 days of treatment was compared with the 90 days preceding first treatment, the incidence of liver injury was not increased (1.02, 0.67 to 1.56). An analysis restricted to definite cases showed no evidence of an increased risk of liver injury during treatment. <b>Conclusion</b> The incidence of acute liver injury was higher in the periods both immediately before and immediately after the start of orlistat treatment. This suggests that the observed increased risks of liver injury linked to the start of treatment may reflect changes in health status associated with the decision to begin treatment rather than any causal effect of the drug.
cdc25A Is Necessary but Not Sufficient for Optimal c- <i>myc–</i> Induced Apoptosis and Cell Proliferation of Vascular Smooth Muscle Cells
Authors: Kirsty Macdonald, Martin R. Bennett
Journal: Circulation Research (1999)

Abstract —Increasing evidence indicates that the control of cell proliferation and apoptosis are linked. The c- myc proto-oncogene is induced early after cell-cycle entry in vascular smooth muscle cells (VSMCs) in vitro and after arterial injury and regulates both cell proliferation and apoptosis. Although both proliferation and apoptosis are likely to be mediated via transcriptional activation of target genes, few c- myc targets have been identified. Therefore, the recent identification that cdc25A, a cell-cycle phosphatase involved in G 1 progression, is transcriptionally activated by c- myc and regulates c- myc –induced apoptosis has suggested that cdc25A may be the principal mediator of c- myc in VSMCs. We examined cdc25A regulation of c- myc –induced proliferation and apoptosis by expressing cdc25A or antisense cdc25A in primary rat VSMCs or in VSMCs expressing deregulated c- myc or adenovirus E1A. Ectopic c- myc increased cdc25A expression, but cdc25A was still responsive to serum components, which indicated that c- myc alone is not the main determinant of cdc25A expression. Antisense cdc25A inhibited c- myc –induced proliferation and apoptosis; however, drug and metabolic blocks indicated that this effect was limited to G 1 . Ectopic cdc25A augmented the proproliferative and proapoptotic action of c- myc but did not increase cell proliferation or apoptosis in the absence of ectopic c- myc . In contrast, E1A/E2F-induced apoptosis was independent of cdc25A. We conclude that cdc25A expression modulates the ability of c- myc to induce apoptosis in G 1 . However, cdc25A alone does not induce apoptosis and cannot substitute for c- myc in VSMCs. Additional targets of c- myc are therefore involved in apoptosis of both G 1 and post-G 1 VSMCs.
Bronchial hyperresponsiveness and the development of asthma and COPD in asymptomatic individuals: SAPALDIA Cohort Study
Authors: M H Brutsche, S H Downs, C Schindler, M W Gerbase, J Schwartz, M Frey, E W Russi, U Ackermann-Liebrich, P Leuenberger
Journal: Thorax (2006)

<b>Background:</b> Bronchial hyperresponsiveness (BHR) is a common feature of asthma. However, BHR is also present in asymptomatic individuals and its clinical and prognostic significance is unclear. We hypothesised that BHR might play a role in the development of chronic obstructive pulmonary disease (COPD) as well as asthma. <b>Methods:</b> In 1991 respiratory symptoms and BHR to methacholine were evaluated in 7126 of the 9651 participants in the SAPALDIA cohort study. Eleven years later 5825 of these participants were re-evaluated, of whom 4852 performed spirometric tests. COPD was defined as an FEV<sub>1</sub>/FVC ratio of &lt;0.70. <b>Results:</b> In 1991 17% of participants had BHR, of whom 51% were asymptomatic. Eleven years later the prevalence of asthma, wheeze, and shortness of breath in formerly asymptomatic subjects with or without BHR was, respectively, 5.7% <i>v</i> 2.0%, 8.3% <i>v</i> 3.4%, and 19.1% <i>v</i> 11.9% (all p&lt;0.001). Similar differences were observed for chronic cough (5.9% <i>v</i> 2.3%; p = 0.002) and COPD (37.9% <i>v</i> 14.3%; p&lt;0.001). BHR conferred an adjusted odds ratio (OR) of 2.9 (95% CI 1.8 to 4.5) for wheezing at follow up among asymptomatic participants. The adjusted OR for COPD was 4.5 (95% CI 3.3 to 6.0). Silent BHR was associated with a significantly accelerated decline in FEV<sub>1</sub> by 12 (5–18), 11 (5–16), and 4 (2–8) ml/year in current smokers, former smokers and never smokers, respectively, at SAPALDIA 2. <b>Conclusions:</b> BHR is a risk factor for an accelerated decline in FEV<sub>1</sub> and the development of asthma and COPD, irrespective of atopic status. Current smokers with BHR have a particularly high loss of FEV<sub>1</sub>.
Prognostic value of angiographic indices of coronary artery disease from the Coronary Artery Surgery Study (CASS).
Authors: I Ringqvist, L D Fisher, M Mock, K B Davis, H Wedel, B R Chaitman, E Passamani, R O Russell, E L Alderman, N T Kouchoukas, G C Kaiser, T J Ryan, T Killip, D Fray
Journal: Journal of Clinical Investigation (1983)

The Coronary Artery Surgery Study, CASS, enrolled 24,959 patients between August 1975 and June 1979 who were studied angiographically for suspected coronary artery disease. This paper compares the prognostic value for survival without early elective surgery of eight different indices of the extent of coronary artery disease: the number of diseased vessels, two indices using the number of proximal arterial segments diseased, two empirically generated indices from the CASS data, and the published indices of Friesinger, Gensini, and the National Heart and Chest Hospital, London. All had considerable prognostic information. Typically 80% of the prognostic information in one index was also contained in another. Our analysis shows that good prediction from angiographic data results from a combination of left ventricular function and arteriographic extent of disease. Prognosis may reasonably be obtained from three simple indices: the number of vessels diseased, the number of proximal arterial segments diseased, and a left ventricular wall motion score. These three indices account for an estimated 84% of the prognostic information available. 6-yr survival varies between 93 and 16% depending upon the values of these three indices.
Management of Pulmonary Disease in the Forces
Authors: J. H. Hutchison
Journal: BMJ (1942)

It is somewhat peculiar that the subject of pulmonary disease other than tuberculosis in members of H.M. Forces has not received more attention.The main purpose of the clinical sections of the Army Medical Services must be to return the sick soldier to health and duty in as short a time as possiblei Such diseases as tuberculosis and peptic ulcer, and many cases of effort syndrome, although of great clinical interest and much written about, must eventu- ally render the soldiers so affected unfit for further military service or at best fit for service in only a limited capacity.The acute non-tuberculous pulmonary affections, however, should be capable of complete cure in a large propor- tion of cases, and even the chronic varieties, if properly managed, should not be incompatible with a high degree of functional efficiency.Furthermore, with the exception of the dyspepsias, pulmonary diseases form the largest group admitted to the medical wards.This group is therefore of considerable importance to all who have to deal with sick soldiers, whether it be in the form of diagnosis, treatment, or the management of convalescence, the last especially being more complex in the Services than among civilians.The experience of one military hospital in dealing with pulmonary disease over a period of 12 months (Oct., 1940, to Oct., 1941) may be of some interest.During this period 329 patients with respiratory disease were admitted to and discharged from the medical wards, exclusive of cases complicating or occurring in the course of surgical treatment.Table I summarizes theTABLE I.-Summary of Respiratory Diseases in 12 Months in Military Hospital No. Aver.Aver.Aver.
Identification of Cell Cycle Regulatory and Inflammatory Genes As Predominant Targets of p38 Mitogen-Activated Protein Kinase in the Heart
Authors: Olli Tenhunen, Jaana Rysä, Mika Ilves, Ylermi Soini, Heikki Ruskoaho, Hanna Leskinen
Journal: Circulation Research (2006)

Mitogen-activated protein kinases (MAPKs) regulate cardiomyocyte growth and apoptosis in response to extracellular stimulation, but the downstream effectors that mediate their pathophysiological effects remain poorly understood. We determined the targets and role of p38 MAPK in the heart in vivo by using local adenovirus-mediated gene transfer of constitutively active upstream kinase mitogen-activated protein kinase kinase 3b (MKK3bE) and wild-type p38α in rats. DNA microarray analysis of animals with cardiac-specific overexpression of p38 MAPK revealed that 264 genes were upregulated more than 2-fold including multiple genes controlling cell division, cell signaling, inflammation, adhesion, and transcription. A large number of previously unknown p38 target genes were found. Using gel mobility-shift assays we identified several cardiac transcription factors that were directly activated by p38 MAPK. Finally, we determined the functional significance of the altered cardiac gene-expression profile by histological analysis and echocardiographic measurements, which indicated that p38 MAPK overexpression-induced gene expression results in myocardial cell proliferation, inflammation, and fibrosis. In conclusion, we defined the novel target genes and transcription factors as well as the functional effects of p38 MAPK in the heart. Expression profiling of p38 MAPK overexpression identified cell cycle regulatory and inflammatory genes critical for pathological processes in the adult heart.