tbuckley/cabot-search huggingface dataset:
Triiodothyronine induces over-expression of alpha-smooth muscle actin, restricts myofibrillar expansion and is permissive for the action of basic fibroblast growth factor and insulin-like growth factor I in adult rat cardiomyocytes.
Authors: M A Gosteli-Peter, B A Harder, H M Eppenberger, J Zapf, M C Schaub
Journal: Journal of Clinical Investigation (1996)

Effects of triiodothyronine (T3) on the expression of cytoskeletal and myofibrillar proteins in adult rat cardiomyocytes (ARC) were followed during two weeks of culture in the presence of 20% T3-depleted (stripped) FCS. Control cultures expressed mainly beta-myosin heavy chain (MHC) mRNA. T3 caused a switch to alpha-MHC expression and a dose-dependent increase of alpha-smooth muscle (alpha-sm) actin mRNA and protein. In parallel, the number of alpha-sm actin immunoreactive cells increased from 1% in controls to 29 and 62% in ARC treated with 5 and 100 nM T3. In the presence of T3, cells exhibited a higher beating rate than controls. The distribution of myofibrils in T3-treated cells was restricted to the perinuclear area with a sharp boundary. Only 5% of the control cells but 30 and 62% of the T3-treated (5 and 100 nM) ARC showed this restricted myofibrillar phenotype. Basic fibroblast growth factor (bFGF) which restricts myofibrillar growth and upregulates alpha-sm actin in ARC cultured with normal FCS had no effect on alpha-sm actin in ARC cultured in stripped FCS, but potentiated the effect of T3. In contrast, insulin-like growth factor I (IGF I), which suppresses alpha-sm actin and stimulates myofibrillogenesis in the presence of normal FCS suppressed T3-induced alpha-sm actin expression in stripped FCS. Thus, T3 appears to be permissive for the action of bFGF and IGF I on alpha-sm actin expression.
Incidence of Lactic Acidosis in Patients With Type 2 Diabetes With and Without Renal Impairment Treated With Metformin: A Retrospective Cohort Study
Authors: Florent F. Richy, Meritxell Sabidó-Espin, Sandra Guedes, Frank A. Corvino, Ulrike Gottwald-Hostalek
Journal: Diabetes Care (2014)

OBJECTIVE To determine whether the use of metformin in type 2 diabetic patients with various kidney functions is associated with an increased risk of lactic acidosis (LA). RESEARCH DESIGN AND METHODS This study was a retrospective analysis of U.K. patient records from the Clinical Practice Research Datalink database from 1 January 2007 to 31 December 2012. Inclusion criteria were 1) diagnosis of type 2 diabetes before 1 January 2007, 2) treatment with metformin, and 3) at least one assessment of renal function between 2007 and 2012. Renal function was assessed by glomerular filtration rate and categorized as normal (N), mildly reduced (Mi), moderately reduced (Mo), or severely reduced (Se) function. The outcome of the study was LA. RESULTS A total of 77,601 patients treated with metformin for type 2 diabetes were identified. There were 35 LA events (10.37 [95% CI 7.22–14.42] per 100,000 patient-years) of which none were fatal and 23 were linked to a comorbidity. No significant difference in the incidence of LA was observed across N, Mi, Mo and Se renal function groups (7.6 [0.9–27.5], 4.6 [2.00–9.15], 17 [10.89–25.79], and 39 [4.72–140.89] cases per 100,000 patient-years, respectively). CONCLUSIONS The overall LA incidence rate for patients on metformin in this study was within the range of rates reported in the literature for patients with type 2 diabetes, and no significant difference was observed among patients with N, Mi, Mo, and Se function.
Ischemia-induced alterations in myocardial (Na+ + K+)-ATPase and cardiac glycoside binding.
Authors: G A Beller, J Conroy, T W Smith
Journal: Journal of Clinical Investigation (1976)

The effects of ischemia on the canine myocardial (Na+ + K+)-ATPase complex were examined in terms of alterations in cardiac glycoside binding and enzymatic activity. Ability of the myocardial cell to bind tritiated ouabain in vivo was assessed after 1, 2, and 6 h of coronary occlusion followed by 45 min of reperfusion, and correlated with measurements of in vitro (Na+ + K+)-ATPase activity and in vitro [3H]ouabain binding after similar periods of ischemia. Regional blood flow alterations during occlusion and reperfusion were simultaneously determined utilizing 15 mum radioactive microspheres to determine the degree to which altered binding of ouabain might be flow related. Anterior wall infarction was produced in 34 dogs by snaring of confluent branches of the left coronary system. Epicardial electrograms delineated ischemic and border zone areas. Coronary reperfusion after 2 and 6 h of occlusion was associated with impaired reflow of blood and markedly impaired uptake of [3H]ouabain in ischemic myocardium. In both groups, in vivo [3H]ouabain binding by ischemic tissue was reduced out of proportion to the reduction in flow. Despite near-complete restoration of flow in seven dogs occluded for 1 h and reperfused, [3H]ouabain remained significantly reduced to 58 +/- 9% of nonischemic uptake in subendocardial layers of the central zone of ischemia. Thus, when coronary flow was restored to areas of myocardium rendered acutely ischemia for 1 or more hours, ischemic zones demonstrated progressively diminished ability to bind ouabain. To determine whether ischemia-induced alteration in myocardial (Na+ + K+)-ATPase might underlie these changes, (Na+ + K+)-ATPase activity and [3H]ouabain binding were measured in microsomal fractions from ischemic myocardium after 1, 2, and 6 h of coronary occlusion. In animals occluded for 6 h, (Na+ + K+)-ATPase activity was significantly reduced by 40% in epicardial and by 35% in endocardial layers compared with nonischemic myocardium. Comparable reductions in in vitro [3H]ouabain binding were also demonstrated. Reperfusion for 45 min after occlusion for 6 h resulted in no significant restoration of enzyme activity when compared to the nonreperfused animals. In six animals occluded for 2 h, a time at which myocardial creatine phosphokinase activity remains unchanged, (Na+ + K+)-ATPase activity was reduced by 25% compared with nonischemic enzyme activity. In five dogs occluded for 1 h, (Na+ + K+)-ATPase activity in ischemic myocardium was unchanged from control levels. We conclude that reduced regional myocardial blood flow, local alterations in cellular milieu, and altered glycoside-binding properties of (Na+ + K+)-ATPase all participate in the reduction of cardiac glycoside binding observed after reperfusion of ischemic myocardium. In addition, after 2 or more hours of severe ischemia, myocardial (Na+ + K+)-ATPase catalytic activity is significantly reduced despite incubation in the presence of optimal substrate concentrations.
Mesothelin Overexpression Is a Marker of Tumor Aggressiveness and Is Associated with Reduced Recurrence-Free and Overall Survival in Early-Stage Lung Adenocarcinoma
Authors: Stefan S. Kachala, Adam J. Bograd, Jonathan Villena-Vargas, Kei Suzuki, Elliot L. Servais, Kyuichi Kadota, Joanne Chou, Camelia S. Sima, Eva Vertes, Valerie W. Rusch, William D. Travis, Michel Sadelain, Prasad S. Adusumilli
Journal: Clinical Cancer Research (2013)

In an effort to identify molecular markers of tumor aggressiveness and therapeutic targets in lung adenocarcinoma (ADC), we investigated the expression of mesothelin (MSLN) in lung ADC, as well as its biologic and clinical relevance.In a training and validation set of patients with early-stage (I-III) lung ADC (n = 1,209), a tissue microarray consisting of tumors and normal lung tissue was used to examine the association between MSLN expression and recurrence-free survival (RFS) and overall survival (OS). The influence of MSLN overexpression on lung ADC was investigated in vitro and in vivo by use of clinically relevant orthotopic and metastatic xenogeneic and syngeneic mouse models.MSLN was expressed in 69% of lung ADC tumors, with one in five patients strongly expressing MSLN and no expression in normal lung tissue. Increased MSLN expression was associated with reduced OS [HR = 1.78; 95% confidence interval (CI), 1.26-2.50; P < 0.01] and RFS (HR = 1.67; 95% CI, 1.21-2.27; P < 0.01) in multivariate analyses, even after adjustment for currently known markers of tumor aggressiveness in lung ADC: male sex, smoking history, increasing stage, morphologic pattern, visceral pleural invasion, lymphatic or vascular invasion, and mutation status. In vitro, lung ADC cells overexpressing MSLN demonstrated increased cell proliferation, migration, and invasion; in vivo, mice with MSLN(+) tumors demonstrated decreased survival (P = 0.001).MSLN expression in patients with early-stage lung ADC is associated with increased risk of recurrence and reduced OS, indicating that MSLN expression is a molecular marker of tumor aggressiveness and a potential target for therapy.
Prevalence of hip osteoarthritis in Iceland
Authors: Thorvaldur Ingvarsson, Gunnar Hägglund, L Stefan Lohmander
Journal: Annals of the Rheumatic Diseases (1999)

To assess the prevalence of primary hip osteoarthritis (OA) in Iceland. To compare the prevalence of primary hip OA in Iceland with published rates of primary hip OA for related Scandinavian populations.Roentgenographs were examined of 1530 Icelandic people 35 years or older (653 males, 877 females) subjected to colon radiography during the years 1990-1996. The radiographs examined represent approximately 40% of all colon radiographs taken in Iceland during this period. After exclusion of non-primary hip OA cases, the minimum hip joint space was measured with a mm ruler. Presence of hip OA was defined as a minimum joint space of 2.5 mm or less on an anteroposterior radiograph. Intraclass correlation coefficients for inter and intraobserver variability of assessment of mm joint space were 0.91 and 0.95, respectively.Of the 1517 people included, 227 hips in 165 patients (77 men, 88 women) were diagnosed as having radiological primary hip OA. The mean age at colon examination for these patients was 68 (35-89) years. The overall prevalence of coxarthrosis among all examined patients 35 years and older was 10.8% (12% for men, 10% for women), rising from 2% at 35-39 years to 35.4% for those 85 years or older. If the population structure (age and sex distribution) for those older than 35 years in Iceland was used to standardise prevalence for both Iceland and south Sweden (using previously published data for south Sweden), the age and sex standardised prevalence of hip OA for those older than 35 years in Iceland was 8%, compared with 1.2% for south Sweden.The prevalence of radiological primary hip OA is very high in Iceland, and in excess of fivefold higher than the prevalence found by using similar techniques in studies on related populations in southern Scandinavia. The rate difference is particularly notable for those younger than 70 years.
Infection of human endothelial cells with Epstein-Barr virus.
Authors: K Jones, C Rivera, C Sgadari, J Franklin, E E Max, K Bhatia, G Tosato
Journal: The Journal of Experimental Medicine (1995)

Interleukin-6 (IL-6) promotes growth and tumorigenicity of Epstein-Barr virus (EBV)-immortalized B cells, and is abnormally elevated in the serum of solid organ transplant recipients who develop EBV-positive posttransplant lymphoproliferative disease (PTLD), but not in control transplant recipients. Endothelial cells derived from PTLD lesions were found to secrete spontaneously high levels of IL-6 in vitro for up to 4 mo. We examined possible mechanisms for sustained IL-6 production by endothelial cells. Here, we show that EBV can infect endothelial cells in vitro. After 3-4 wk incubation with lethally irradiated EBV-positive, but not EBV-negative cell lines, a proportion of human umbilical cord-derived endothelial cells (HUVECs) expressed in situ the EBV-encoded small RNAs (EBER). Southern blot analysis after polymerase chain reaction showed EBV DNA in HUVEC that had been incubated with lethally irradiated EBV-positive cells, but not in the controls. Exposure of HUVECs to lethally irradiated EBV-positive but not EBV-negative cell lines induced IL-6 production that was sustained for up to 120 d of culture. These studies identify endothelial cells as targets for EBV infection and raise the possibility that this infection may be important in the life cycle and pathology of EBV.
Acetazolamide for severe hyperventilation and apnea in a child with Pitt-Hopkins syndrome
Authors: Stijn Verhulst, Wilfried De Backer
Journal: European Respiratory Journal (2011)

Case report: We present the case of a 9 year old boy with Pitt-Hopkins syndrome who had severe attacks of hyperventilation followed by apnea and syncope while awake. These episodes occurred on a daily basis. A magnetic resonance scan of the brain at the age of 4 years showed a normal aspect of the brain stem and cerebellum. Figure 1 shows serious oxygen desaturation and hypocapnia.

![Figure][1] 

Figure 1





In view of the hyperventilation, we started the patient on 250 mg of acetazolamide once daily. The patient was reevaluated one and a half month later. The clinical picture was markedly improved: long lasting apneas and episodes of syncope were no longer observed. A blood gas showed a pH of 7.35 with a pCO2 of 32.9 mmHg and a base excess of -6.5 mmol/L. Polygraphic monitoring showed the presence of several short central apneas but with preserved oxygen saturation and a more stable CO2 curve.

Discussion: Pitt-Hopkins syndrome is due to de novo mutations at the TCF4 locus and is characterised by distinct facial features, mental retardation and episodic hyperventilation with apnea while awake. Both the pathogenesis of these hyperventilation episodes as its treatment are unknown. This is the first report on the positive effect of acetazolamide on daytime hyperventilation and apnea in this syndrome. In this view; it would also be interesting to study the effects of acetazolamide in patients with similar syndromes including Rett and Joubert syndrome.

 [1]: pending:yes
Increased natural killer cell expression of CD16, augmented binding and ADCC activity to rituximab among individuals expressing the FcγRIIIa-158 V/V and V/F polymorphism
Authors: Evdoxia Hatjiharissi, Lian Xu, Daniel Ditzel Santos, Zachary R. Hunter, Bryan T. Ciccarelli, Sigitas Verselis, Michael Modica, Yang Cao, Robert J. Manning, Xavier Leleu, Elizabeth A. Dimmock, Alexandros Kortsaris, Constantine Mitsiades, Kenneth C. Anderson, Edward A. Fox, Steven P. Treon
Journal: Blood (2007)
Activation of Endothelial Toll-Like Receptor 3 Impairs Endothelial Function
Authors: Sebastian Zimmer, Martin Steinmetz, Tobias Asdonk, Inga Motz, Christoph Coch, Evelyn Hartmann, Winfried Barchet, Sven Wassmann, Gunther Hartmann, Georg Nickenig
Journal: Circulation Research (2011)

Endothelial dysfunction and atherosclerosis are chronic inflammatory diseases characterized by activation of the innate and acquired immune system. Specialized protein receptors of the innate immune system recognize products of microorganisms and endogenous ligands such as nucleic acids. Toll-like receptor 3 (TLR3), for example, detects long double-stranded RNA and is abundantly expressed in endothelial cells. Whether innate immunity contributes to atherogenic mechanisms in endothelial cells is poorly understood.We sought to determine the effects of TLR3 activation in endothelial cells.We first investigated whether stimulation of TLR3 influences endothelial biology in mice. Intravenous injection of polyinosine polycytidylic acid, a synthetic double-stranded RNA analog and TLR3 ligand, impaired endothelium-dependent vasodilation, increased vascular production of reactive oxygen species, and reduced reendothelialization after carotid artery injury in wild-type mice compared with controls but had no effect in TLR3(-/-) animals. TLR3 stimulation not only induced endothelial dysfunction but also enhanced the formation of atherosclerotic plaques in apolipoprotein E-deficient mice. In vitro incubation of endothelial cells with polyinosine polycytidylic acid induced production of the proinflammatory cytokines interleukin-8 and interferon-γ-induced protein 10, increased formation of reactive oxygen species, diminished proliferation, and increased apoptosis, which suggests that endothelial cells are able to directly detect and respond to TLR3 ligands. Neutralization of interleukin-8 and interferon-γ-induced protein 10 antagonizes the observed negative effects of polyinosine polycytidylic acid. We found elevated levels of circulating endothelial progenitor cells in polyinosine polycytidylic acid-treated mice, although they displayed increased endothelial dysfunction. Stimulation of TLR3 in cultured endothelial progenitor cells, however, led to increased formation of reactive oxygen species, increased apoptosis, and reduced migration. Injection of endothelial progenitor cells that had been incubated with polyinosine polycytidylic acid ex vivo hindered reendothelialization after carotid artery injury. Therefore, endothelial progenitor cell function was affected by TLR3 stimulation. Finally, apolipoprotein E-deficient/TLR3-deficient mice exhibited improved endothelial function compared with apolipoprotein E-deficient/TLR3(+/+) littermates.Immunorecognition of long double-stranded RNA by endothelial cells may be an important mechanism involved in endothelial cell activation and development of endothelial dysfunction.
STUDIES ON PSEUDORABIES (INFECTIOUS BULBAR PARALYSIS, MAD ITCH)
Authors: E. Weston Hurst
Journal: The Journal of Experimental Medicine (1933)

The histology of pseudorabies differs materially in various animal species. In the rabbit, subcutaneous, intradermal or intramuscular inoculation leads to local inflammation and necrosis. The infection ascends the peripheral nerve (possibly both interstitially and by the axis-cylinders) to the corresponding spinal ganglia and segments of the spinal cord, where primary degeneration of nerve and glial cells takes place. The nerve cell changes are probably responsible for the cardinal symptom of the disease, itching. Death ensues soon after virus reaches the medulla, before visible changes have been produced here. Intracerebral inoculation is followed by characteristic lesions in the meninges, in subpial glial cells and in superficially placed nerve cells. Morbid changes in the lungs are not necessarily related to the presence of virus, but specific lesions may be present. Intranuclear inclusions bearing some resemblance to those in herpetic encephalitis, yellow fever, etc., occur in cells derived from all embryonic layers. The disease in the guinea pig resembles closely that in the rabbit and is modified only by the slightly greater resistance of the animal. In the monkey after intracerebral inoculation, widespread degeneration and necrosis of cortical nerve cells are accompanied by the appearance of specific nuclear alterations in nerve and glial cells, but not in cells of mesodermal origin. No lesions are found in other viscera. In the spontaneous disease in the cow lesions approximate more closely to those in the monkey than to those in the rabbit. In the pig vascular and interstitial lesions predominate, nerve cell degeneration is relatively slight and typical inclusions are not observed. These differences probably explain the benign course of the malady following subcutaneous inoculation in this animal. The lymphatic system, too, participates in the reaction to the virus.
Year in review in Intensive Care Medicine 2014: III. Severe infections, septic shock, healthcare-associated infections, highly resistant bacteria, invasive fungal infections, severe viral infections, Ebola virus disease and paediatrics
Authors: Jean-François Timsit, Anders Perner, Jan Bakker, Matteo Bassetti, Dominique Benoit, Maurizio Cecconi, J. Randall Curtis, Gordon S. Doig, Margaret Herridge, Samir Jaber, Michael Joannidis, Laurent Papazian, Mark J. Peters, Pierre Singer, Martin Smith, Marcio Soares, Antoni Torres, Antoine Vieillard-Baron, Giuseppe Citerio, Elie Azoulay
Journal: Intensive Care Medicine (2015)

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
Alkaline reflux oesophagitis.
Authors: D L Stoker, J G Williams
Journal: Gut (1991)

Duodenal and gastric contents do reflux into the oesophagus and acid alone certainly causes oesophageal damage which will be worsened by pepsin. In the patient who has undergone gastrectomy duodenal secretions may also be harmful. There is evidence that when the two mix there may be a toxic synergism, leading to mucosal disruption and intracellular damage to oesophageal cells which produces the clinical picture of reflux oesophagitis, with or without symptoms. Clear evidence of the toxicity of duodenal refluxate in humans is lacking, but the ability to measure bile and acid reflux continuously, together with a method of detecting oesophageal damage at a cellular level should help to solve this long debated problem.
Activation of the cardiac endothelin system in left ventricular hypertrophy before onset of heart failure in TG(mREN2)27 rats
Authors: O Zolk
Journal: Cardiovascular Research (2002)

Objective: To characterize the cardiac angiotensin and endothelin (ET) system in compensated left ventricular hypertrophy due to long standing arterial hypertension and to assess the role of angiotensin and ET converting enzymes in mediating the observed changes of angiotensin and ET levels, respectively. Methods: We studied the left ventricular renin–angiotensin system (RAS) and ET system in 20-week-old male transgenic hypertensive TG(mREN2)27 rats, a model of the monogenic renin-dependent form of severe hypertension. Age-matched Sprague–Dawley rats served as controls. Results: TG(mREN2)27 rats exhibited left ventricular hypertrophy without signs of congestion. Transgene overexpression led to an activation of the tissue RAS with increased angiotensin II levels in spite of unchanged angiotensin converting enzyme (ACE) activity and ACE mRNA levels. ET-1 production was markedly increased in TG(mREN2)27 rats indicating that the ET-system was activated. Cardiac ET-1 in TG(mREN2)27 originated most likely from increased preproET-1 production because preproET-1 mRNA levels were increased but ET converting enzyme gene expression and activity were unchanged. Furthermore, ET-1 binding sites were significantly increased in TG(mREN2)27 rats without changes in KD values and ETA/ETB receptor ratios. ETA receptor gene expression was not altered whereas ETB receptor mRNA levels were up-regulated twofold in TG(mREN2)27 rats suggesting that ETA and ETB receptor expression may be regulated differentially. Conclusions: Cardiac ET and angiotensin systems are co-activated in compensated cardiac hypertrophy before onset of heart failure, and thus may be involved in the mechanism by which cardiac remodelling and progression of left ventricular dysfunction occur in TG(mREN2)27 rats.