KCNE1 reverses the response of the human K+ channel KCNQ1 to cytosolic pH changes and alters its pharmacology and sensitivity to temperature

Previous studies have shown that heteromultimeric KCNQ1/KCNE1 (KvLQT1/minK) channels and homomultimeric KCNQ1 (KvLQT1) channels exhibit different current properties, e.g. distinct kinetics and different sensitivities to drugs. In this study we report on the divergent responses to internal pH changes and further characterize some of the current properties of the human isoforms of KCNQ1 and KCNE1 expressed in Chinese hamster ovary (CHO) cells or Xenopus laevis oocytes. Decreasing the bath temperature from 37 degrees C to 20 degrees C increased the half-activation time by a factor of 5 for KCNQ1/KCNE1 currents (IKs) but by only twofold (not significant) for KCNQ1 currents (IK) in CHO cells. Acidification of cytosolic pH (pHi) increased IKs but decreased 1K whereas intracellular alkalinization decreased I(Ks) but increased IK. pHi-induced changes in intracellular Ca2+ activity ([Ca2+]i) did not correlate with the current responses. At 20 degrees C mefenamic acid (0.1 mM) significantly augmented IKs but slightly decreased IK. It changed the slow activation kinetics of I(Ks) to an instantaneous onset. The form of the current/voltage (I/V) curve changed from sigmoidal to almost linear. In contrast, at 37 degrees C, mefenamic acid also increased I(Ks) but slowed the activation kinetics and shifted the voltage activation to more hyperpolarized values without markedly affecting the sigmoidal shape of the I/V curve. The potassium channel blockers clotrimazole and tetrapentylammonium (TPeA) inhibited I(Ks) with a lower potency than I(K). These results show that coexpression of KCNE1 reversed pH regulation of KCNQ1 from inhibition to activation by acidic pHi. In addition, KCNE1 altered the pharmacological properties and sensitivity to temperature of KCNQ1. The pH-dependence of I(Ks) might be of clinical and pathophysiological relevance in the pathogenesis of ischaemic cardiac arrhythmias.     

Predominant pathogenic role of tumor necrosis factor in experimental colitis in mice

Antibodies to tumor necrosis factor (TNF)-α have been recently proposed as effective treatment for patients with Crohn's disease. Here, we analyze the functional role of TNF-α in a mouse model of chronic intestinal inflammation induced by the hapten reagent 2,4,6,-trinitrobenzene sulfonic acid (TNBS) that mimics some characteristics of Crohn's disease in humans. Macrophage-enriched lamina propria (LP) mononuclear cells from mice with TNBS-induced colitis produced 10–30-fold higher levels of TNF-α mRNA and protein than cells from control mice. When mice with chronic colitis were treated by intraperitoneal injection of antibodies to TNF-α, an improvement of both the clinical and histopathologic signs of disease was found. Isolated macrophage-enriched LP cells from anti-TNF-α-treated mice produced strikingly less pro-inflammatory cytokines such as interleukin (IL)-1 and IL-6 in cell culture. The predominant role of TNF-α in the mouse TNBS-induced colitis model was further underlined by the finding that striking colonic inflammation and lethal pancolitis was induced in TNF-α-transgenic mice upon TNBS treatment. Conversely, no significant TNBS-induced colitis could be induced in mice in which the TNF-α gene had been inactivated by homologous recombination. Complementation of TNF-α function in TNF^?/? mice by the expression of a mouse TNF-α transgene was sufficient to reverse this effect. Taken together, the data provide direct evidence for a predominant role of TNF-α in a mouse model of chronic intestinal inflammation and encourage further clinical trials with antibodies to TNF-α for the treatment of patients with Crohn's disease.     

Aktion ?Gesunde Ern?hrung? im Kanton St.Gallen

Zusammenfassung Die Aktion «Gesunde Ernährung» in der Gemeinde-wurde vom Gesundheitsdepartement des Kanton St. Gallen unter der Leitung des kantonalen Präventivmediziners gemeinsam mit den interessierten Gemeinden geplant, koordiniert und durchgeführt.Im Zentrum der Aktion standen gemeindeeigene, individuell gestaltete Aktivitäten von Vereinen, Schulen und des lokalen Gewerbes. Das Gesundheitsdepartement ergänzte die Aktion mit einer Wanderausstellung über Ernährungsfragen, begleitet von einer Ernährungsberaterin. Der Aufbau der Ausstellung erfolgte nach den 10 goldenen Regeln der gesunden Ernährung.Diese Aktion stellt ein konkretes Beispiel der Arbeitsteilung zwischen Kanton und Gemeinde in der Gesundheitsvorsorge dar. Das Beispiel dieser einmaligen Aktion soll Behörden, Vereinen und Einzelpersonen Wege und Methoden aufzeigen, Anliegen der Gesundheitsvorsorge auf längerfristiger Basis in der Gemeinde zu planen.

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Healthy Nutrition an experience of health promotion in the county of St. Gall

Summary The drive Healthy Nutrition in communities was planned, co-ordinated und carried out as a joint action by the Health Department of the County of St. Gall, and 37 communities interested in the idea. The drive centred around the activities of the community itself, individuals, clubs, schools and local industry.The County Health Department supplemented the activity with a travelling exhibition about nutrition problems, attended by an advisor to answer questions. The build-up of the exhibition followed the 10 Golden Rules of sound nutrition.This drive was an excellent example of how health-promotion programms can be shared by county und community.This unique action should set an example to other authorities, clubs, and individuals, and show the ways and means needed to provide long-term planning for health promotion in the community.

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«Alimentation saine»: le programme du canton de St-Gall

Résumé Un programme «Alimentation saine» a été planifié, coordonné et réalisé en étroite collaboration entre le Service cantonal de médecine préventive et les communes intéressées.Les activités développées par les sociétés locales, les écoles et les commerÇants ont été les éléments essentiels du programme. Le canton a, quant à lui, engagé une diététicienne et mis un bus à disposition ce qui a permis d'organiser une exposition itinérante conÇue selon les 10 règles d'or de l'alimentation saine.Ce programme est une expérience de collaboration entre le canton et les communes pour la promotion de la santé. Il devrait servir d'exemple aux autorités, sociétés locales et individus qui désirent répondre au défi de la promotion de la santé.

     

Plasminogen activators in human malignant melanoma

Metastatic malignant melanomas from 16 patients, extracted with Triton X-100, were analyzed for plasminogen activator activity by azocaseinolysis . In 6 cases tumor explants were set up also in short-term organ culture, and the rate of plasminogen activator secretion into the culture medium was determined. Both the extractable activator content [8.66 +/- 7.8 "Committee on Thrombolytic Agents" (CTA) U/g tissue] and the activator secretion rates (0.90 +/- 1.6 CTA U/g/hr) were low in comparison with values for other human tumors. In addition to the activity, the type of plasminogen activator also was determined by immunoinhibition with goat antihuman urokinase antibody in the azocaseinolytic assay, as well as by sodium dodecyl sulfate (SDS) gel electrophoresis followed by zymography on fibrin-agar, in the presence and absence of antibody. On the average, 77% of the activator activity was of the urokinase type in the extracts, and 90% in the culture fluids. Immunoperoxidase reaction for the detection of urokinase showed this enzyme to be localized mainly in the cell membrane of the melanoma cells; stromal elements showed no specific staining. These results are of interest in view of the findings made recently by investigators in several laboratories that in all but one of the melanoma cell cultures derived from metastatic human tumors, only the vascular type ("tissue activator") was cell associated or was secreted into the culture medium. The possible reasons for this discrepancy are discussed.     

Impact of postanesthesia care unit delirium on self-reported cognitive function and perceived health status: a prospective observational cohort study

Quality of Life Research - The objective of this study was to determine the influence of postanesthesia care unit (PACU) delirium on self-reported cognitive function and perceived health...     

Maternal Vitamin C and Iron Intake during Pregnancy and the Risk of Islet Autoimmunity and Type 1 Diabetes in Children: A Birth Cohort Study

Our aim was to study the associations between maternal vitamin C and iron intake during pregnancy and the offspring’s risk of developing islet autoimmunity and type 1 diabetes. The study was a part of the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) prospective birth cohort including children genetically at risk of type 1 diabetes born between 1997–2004. The diets of 4879 mothers in late pregnancy were assessed with a validated food frequency questionnaire. The outcomes were islet autoimmunity and type 1 diabetes. Cox proportional hazards regression analysis adjusted for energy, family history of diabetes, human leukocyte antigen (HLA) genotype and sex was used for statistical analyses. Total intake of vitamin C or iron from food and supplements was not associated with the risk of islet autoimmunity (vitamin C: HR 0.91: 95% CI (0.80, 1.03), iron: 0.98 (0.87, 1.10)) or type 1 diabetes (vitamin C: 1.01 (0.87, 1.17), iron: 0.92 (0.78, 1.08)), neither was the use of vitamin C or iron supplements associated with the outcomes. In conclusion, no association was found between maternal vitamin C or iron intake during pregnancy and the risk of islet autoimmunity or type 1 diabetes in the offspring.     

Liver transplantation in a patient after COVID-19 – Rapid loss of antibodies and prolonged viral RNA shedding

To date, little is known about the duration and effectiveness of immunity as well as possible adverse late effects after an infection with SARS-CoV-2. Thus it is unclear, when and if liver transplantation can be safely offered to patients who suffered from COVID-19. Here, we report on a successful liver transplantation shortly after convalescence from COVID-19 with subsequent partial seroreversion as well as recurrence and prolonged shedding of viral RNA.     

Evidence against a role of nitric oxide in the indirect negative inotropic-effect of M-cholinoceptor stimulation in human ventricular myocardium

Nitric oxide (NO) has been reported to mediate several effects in response to muscarinic cholinergic stimulation in cardiovascular tissues. Recently, an attenuation of guinea pig cardiac myocyte contraction by NO has been described. The aim of the present study was to determine whether the indirect negative inotropic effect of M-cholinoceptor stimulation in human myocardium is in part due to an effect of endogenous NO. Therefore, the effect of carbachol was studied under control conditions and during inhibition of NO-synthase by pretreatment with N^G-monomethyl-l-arginine (NMMA). Functional experiments were performed in isolated, electrically driven (1 Hz, 37°C) left ventricular papillary muscle strips of human myocardium. Since cytokines have been reported to be increased in the serum of patients with heart failure and could induce NO-synthase activity in failing myocardium, we compared samples from nonfailing and terminally failing (classified as NYHA IV) hearts. The indirect negative inotropic effect of carbachol (10 mol/l) was studied in the presence of the \-adrenoceptor agonist isoprenaline (0.03 mol/l).After stimulation with isoprenaline, carbachol significantly (P < 0.05) reduced force of contraction. This effect was diminished in failing myocardium compared to nonfailing, probably due to the diminished inotropic response most likely due to the lower cAMP levels in response to \-adrenoceptor stimulation in the former condition. Pretreatment with NMMA (100 mol/l) altered the antiadrenergic effect of carbachol neither in nonfailing nor in failing preparations. Furthermore, inhibition of guanylyl cyclase, the target enzyme of NO, by preincubation with methylene blue (10 mol/l) for 30 min had no effect on the carbachol-induced decrease in force of contraction. Basal force of contraction, as well as the positive inotropic effect of isoprenaline remained unaffected by NMMA or methylene blue.The present study provides evidence that the indirect negative inotropic effect of M-cholinoceptor agonists is not due to an effect of NO in the human myocardium. Furthermore, the well known enhancement of cGMP in response to M-cholinoceptor stimulation appears not to be involved in this antiadrenergic effect.