Deletion of claudin-10 (Cldn10) in the thick ascending limb impairs paracellular sodium permeability and leads to hypermagnesemia and nephrocalcinosis

In the kidney, tight junction proteins contribute to segment specific selectivity and permeability of paracellular ion transport. In the thick ascending limb (TAL) of Henle's loop, chloride is reabsorbed transcellularly, whereas sodium reabsorption takes transcellular and paracellular routes. TAL salt transport maintains the concentrating ability of the kidney and generates a transepithelial voltage that drives the reabsorption of calcium and magnesium. Thus, functionality of TAL ion transport depends strongly on the properties of the paracellular pathway. To elucidate the role of the tight junction protein claudin-10 in TAL function, we generated mice with a deletion of Cldn10 in this segment. We show that claudin-10 determines paracellular sodium permeability, and that its loss leads to hypermagnesemia and nephrocalcinosis. In isolated perfused TAL tubules of claudin-10-deficient mice, paracellular permeability of sodium is decreased, and the relative permeability of calcium and magnesium is increased. Moreover, furosemide-inhibitable transepithelial voltage is increased, leading to a shift from paracellular sodium transport to paracellular hyperabsorption of calcium and magnesium. These data identify claudin-10 as a key factor in control of cation selectivity and transport in the TAL, and deficiency in this pathway as a cause of nephrocalcinosis.     

Impact of chronic total occlusions on markers of reperfusion,infarct size,and long‐term mortality: A substudy from the TAPAS‐trial

Objectives: This study evaluated the impact of a chronic total occlusion (CTO) in a non‐infarct related coronary artery (IRA) on markers of reperfusion, infarct size, and long‐term cardiac mortality in patients with ST‐elevation myocardial infarction (STEMI). Background: A concurrent CTO in STEMI patients has been associated with impaired left ventricular function and outcome. However, the impact on markers of reperfusion is unknown. Methods: All 1,071 STEMI patients included in the TAPAS‐trial between January 2005 and December 2006 were used for this substudy. Endpoints were the association between a CTO in a non‐IRA and myocardial blush grade (MBG) of the IRA, ST‐segment elevation resolution (STR), enzymatic infarct size, and clinical outcome. Results: A total of 90 patients (8.4%) had a CTO. MBG 0 or 1 occurred more often in the CTO group (34.2% versus 20.6% (Odds Ratio [OR] 2.00, 95% confidence interval [CI]: 1.22–3.23, P = 0.006)). Incomplete STR occurred more often in the CTO group, (63.6% versus 48.2% [OR 1.96, 95% CI: 1.22–3.13, P = 0.005]). Median level of maximal myocardial‐band of creatinin kinase (CK‐MB) in the CTO group was 75 μg/l (IQR 28‐136) and 51 μg/l (IQR 18–97) in the no‐CTO group (P = 0.021). The presence of a CTO in a non‐IRA in STEMI patients was an independent risk factor for cardiac mortality (HR 2.41, 95% CI: 1.26–4.61, P = 0.008) at 25 months follow‐up. Conclusion: A CTO in a non‐IRA is associated with impaired reperfusion markers and impaired long‐term outcome in STEMI patients. © 2010 Wiley‐Liss, Inc.     

Intravenous glucose intake independently related to intensive care unit and hospital mortality: an argument for glucose toxicity in critically ill patients

OBJECTIVE: It is assumed that the toxic effects of glucose play a role in the outcome of critically ill patients. We studied the impact of the amount of infused glucose as a determinant of mortality. DESIGN: A retrospective cohort study design was used as blood glucose levels in critically ill patients are nowadays tightly controlled. PATIENTS: Long-stay critically ill patients (7-30 days). MEASUREMENTS: The association between the mean amount of glucose infusion and both intensive care unit (ICU) and hospital mortality was determined. We corrected for the mean glucose serum concentration, the mean dosage of insulin and for severity of illness, using the acute physiology and chronic health evaluation (APACHE II) score. RESULTS: Of the 2,042 admitted patients, 273 met the inclusion criteria. The mean length of stay was 14.4 days [interquartile range (IQR) 9-18]. Hospital mortality was significantly lower for patients with a mean glucose level below 8 mmol/l (30/79; 38%) compared to patients with a level above 8 mmol/l (104/194; 54%, P=0.023). Logistic stepwise multivariate regression analysis for both ICU and hospital mortality as dependent variables showed that APACHE II score and the mean daily amount of infused glucose were associated with mortality. CONCLUSION: In long-stay ICU patients without blood glucose level control, the ICU and hospital mortality was independently related to the mean amount of infused glucose. In addition, mortality in patients with a mean glucose level above 8.0 mmol/l was higher. Both these determinants of mortality can exert their effects by insulin-independent uptake of glucose with subsequent toxic intracellular effects.     

Efficacy and safety of controlled-release versus immediate-release oxycodone: randomized, double-blind evaluation in patients with chronic back pain.

OBJECTIVE: To compare the efficacy and safety of controlled-release oxycodone given every 12 hours with immediate-release oxycodone given four times daily in patients with persistent back pain. DESIGN: Randomized, double-blind, active-controlled, two-period crossover trial. PATIENTS: Fifty-seven adult outpatients with stable, chronic, moderate-to-severe low back pain despite analgesic therapy were enrolled; 47 were randomized; 11 discontinued for side effects, most commonly nausea and vomiting. INTERVENTIONS: Controlled-release oxycodone tablets given every 12 hours; immediate-release oxycodone tablets given four times daily; dose titration with controlled-release or immediate-release for up to 10 days; double-blind treatment for 4-7 days each. OUTCOME MEASURES: Patients' pain scores (0 = none, 1 = slight, 2 = moderate, 3 = severe). RESULTS: Pain intensity decreased from moderate to severe at baseline to slight at the end of titration with both oxycodone formulations. The daily oxycodone dose was 40 mg or less in 68% of patients. During double-blind treatment, mean pain intensity was maintained at 1.2 (0.1 SE) with controlled-release and at 1.1 (0.1 SE) with immediate-release oxycodone. The most common adverse events were constipation, nausea, pruritus, somnolence, and dizziness. CONCLUSIONS: Controlled-release oxycodone given every 12 hours was comparable with immediate-release oxycodone given four times daily in efficacy and safety, and it provides convenient, twice-daily, around-the-clock treatment for selected patients with persistent back pain that is inadequately controlled by nonopioids or as-needed opioid therapy.     

Treatment of osteoarthritis pain with controlled release oxycodone or fixed combination oxycodone plus acetaminophen added to nonsteroidal antiinflammatory drugs: a double blind, randomized, multicenter, placebo controlled trial

OBJECTIVE: To compare the efficacy and safety of controlled release oxycodone given every 12 h around the clock with immediate release oxycodone-acetaminophen (APAP) given 4 times daily for osteoarthritis (OA) pain. METHODS: Adults (n=167) with moderate to severe OA pain despite regular use of nonsteroidal antiinflammatory drugs (NSAID) entered open label titration for 30 days with immediate release oxycodone qid; 107 qualified for randomization to double blind, parallel group treatment for 30 days with placebo, controlled release oxycodone, or immediate release oxycodone-APAP. RESULTS: Following titration with immediate release oxycodone, mean (SE) pain intensity (0, none to 3, severe) decreased from 2.44 (0.04) to 1.38 (0.05) (p=0.0001), and quality of sleep (1, very poor; 5, excellent) improved from 2.58 (0.08) to 3.57 (0.07) (p=0.0001). Mean dose was about 40 mg/day. Pain intensity and quality of sleep were significantly improved in both active groups compared with the placebo group (p< or =0.05) during the double blind trial. Pain intensity and sleep scores were comparable in both active groups during double blind treatment. Nausea (p=0.03) and dry mouth (p=0.09) were less common with controlled release oxycodone than immediate release oxycodone-APAP. CONCLUSION: Controlled release oxycodone q12h and immediate release oxycodone-APAP qid, added to NSAID, were superior to placebo for reducing OA pain and improving quality of sleep. The active treatments provided comparable pain control and sleep quality. Controlled release oxycodone was associated with a lower incidence of some side effects.     

Über bemerkenswerte Abweichungen in der zeitlichen Folge der spasmophilen Erscheinungen

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Zur Frage der zuckerarmen und fettreichen Ernährung

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