T-lymphocyte cytokine production patterns in nonimmune severe hypothyroid state and after thyroid hormone replacement therapy.

The influence of thyroid hormones on the immune system is controversial. We analyzed the cytokine expression pattern of T lymphocytes in patients with severe nonimmune hypothyroidism in order to establish the role of thyroid hormones on the immune system. The study comprised 7 patients (1 male and 6 females) 20 to 76 years of age (mean age, 53 years), without signs of chronic thyroiditis, verified by histology and laboratory data. The patients were studied 5 weeks after total thyroidectomy. Peripheral blood mononuclear cell (PBMC) cultures and intracellular cytokine detection by flow cytometry before and after thyroid hormone replacement therapy were performed (free thyroxine [FT4] 0.030 +/- 0.034 ng/dL, versus FT4: 2.16 +/- 0.68 ng/dL). The control group consisted of 7 healthy subjects (FT4: 1.20 +/- 0.21 ng/dL). We found no significant differences in the cytokine pattern (interferon [IFN]-gamma, IL-2, interleukin [IL]-4, IL-5, IL-6, IL-10, IL-13, tumor necrosis factor [TNF]-alpha, TNF-beta) of CD4+ and CD8+ between the matched groups (hypothyroid subjects versus controls, levothyroxine treated subjects versus controls). Our data show no change in the type 1/type 2 balance of peripheral CD4+ and CD8+ T lymphocytes from patients with nonimmune hypothyroidism. According to our results, the hypothyreotic state does not contribute to the reported changes in cytokine production patterns in Hashimoto's thyroiditis.     

Increasing systemic exposure of methotrexate by active efflux mediated by multidrug resistance-associated protein 3 (mrp3/abcc3)

The aim of this study was to investigate the functional importance of multidrug resistance-associated protein (Mrp)3/Abcc3 and Mrp4/Abcc4 in the pharmacokinetics of methotrexate. Compared with the corresponding wild-type mice, the plasma concentrations of methotrexate given orally were similar in Abcc4(-/-) mice and were significantly lower in Abcc3(-/-) mice. Pharmacokinetic parameters related to hepatobiliary transport were determined under steady-state conditions in wild-type and Abcc3(-/-) mice that were given a constant intravenous infusion of methotrexate. The biliary clearance, based on the plasma concentration, was 1.6-fold greater in Abcc3(-/-) mice than in wild-type mice (23 and 15 ml/min/kg, respectively, P < 0.05). Because the basolateral uptake and canalicular efflux clearances of methotrexate were similar in wild-type and Abcc3(-/-) mice, this result suggests that the basolateral efflux clearance of methotrexate is decreased in the liver of Abcc3(-/-) mice. Furthermore, a lower fraction of absorption of methotrexate (F(a) F(g)) was suggested in Abcc3(-/-) mice (0.49 and 0.29 in wild-type and Abcc3(-/-) mice, respectively). The mucosal-to-serosal transport rate of methotrexate, determined in vitro using everted sacs, was highest in the duodenum and was significantly decreased in Abcc3(-/-) mice compared with wild-type mice. This is ascribed to the reduced intrinsic efflux clearance of methotrexate across the serosal membrane (22 and 5.3 mul/min/sac in wild-type and Abcc3(-/-) mice, respectively, P < 0.05). These results suggest that Mrp3 mediates basolateral efflux of methotrexate in the liver and duodenum, thereby serving to increase systemic exposure, whereas Mrp4 is likely to play only a limited role in the systemic methotrexate exposure.     

Covered transjugular intrahepatic portosystemic stents maintain lower portal pressure and require fewer reinterventions than uncovered stents

BACKGROUND: The purpose of this study was to evaluate the patency, functional and haemodynamic results of expanded-polytetrafluoroethylene (ePTFE)-covered transjugular intrahepatic portosystemic shunts in patients with liver cirrhosis. METHODS: Thirteen patients with an ePTFE-covered transjugular intrahepatic portosystemic shunt stent (TIPSS) were prospectively evaluated at 6 and 12 months and compared with matched controls with mesh-wire uncovered TIPSS. RESULTS: At 6 months, ePTFE-TIPSS showed a significantly lower porto-caval pressure gradient (PCPG) (9 (3-21) mmHg, P = 0.006), a lower rate of dysfunction (8% versus 54%, P = 0.03) and required fewer reinterventions (2 versus 13, P = 0.02); similar results were obtained after 12 months. This resulted in a reduction in the median cost for angiographic surveillance in the covered TIPSS group at 6 and 12 months (36% and 56% compared to the uncovered TIPSS group, P = 0.002), but total procedure-related costs were higher with the ePTFE-TIPSS (6 months: 3730 (3245-6759) versus 1850 (1466-5479) euro/patient; 12 months: 3945 (3460-6759) versus 2295 (1728-5694) euro/patient) due to the higher initial cost of the ePTFE-covered TIPSS. CONCLUSIONS: The insertion of ePTFE-covered TIPSS results in better maintenance of lowered portal pressure and fewer reinterventions in patients with liver cirrhosis. There is strong evidence that the use of ePTFE-TIPSS does not require regular surveillance to maintain primary patency, which may then improve cost-effectiveness.     

Effect of hyperglycaemia on inflammatory and stress responses and clinical outcome of pneumonia in non-critical-care inpatients: results from an observational cohort study

Aims/hypothesis

Despite the condition’s high prevalence, the influence of hyperglycaemia on clinical outcomes in non-critical-care inpatients with infections remains ill defined. In this study, we analysed associations of glucose levels at admission and during initial inpatient treatment with the inflammatory response and clinical outcome in community-acquired pneumonia (CAP) patients.

Methods

This secondary observational analysis included 880 confirmed CAP patients. We used severity-adjusted multivariate regression models to investigate associations of initial and 96 h mean glucose levels with serially measured biomarker levels over 7 days (C-reactive protein [CRP], procalcitonin, white blood cell count [WBC], pro-adrenomedullin [ProADM]) and adverse clinical course (death and intensive-care unit admission).

Results

In the 724 non-diabetic patients (82.3% of the study population), moderate or severe hyperglycaemia (glucose 6–11 mmol/l and >11 mmol/l, respectively) was associated with increased risk for adverse clinical course (adjusted OR [95% CI] 1.4 [0.8, 2.4] and 3.0 [1.1, 8.0], respectively) and with higher CRP, WBC and ProADM levels over 7 days (p?<?0.05, ANOVA, all days). In diabetic patients (n?=?156), no similar associations were found for initial hyperglycaemia, although mean 96 h glucose levels ?≥?9 mmol/l were associated with adverse clinical course (adjusted OR 5.4 [1.1, 25.8]; p?=?0.03). No effect modification by insulin treatment was detected (interaction terms p?>?0.2 for all analyses).

Conclusions/interpretation

Initial hyperglycaemia in non-diabetic CAP patients, and prolonged hyperglycaemia in diabetic or non-diabetic CAP patients, are associated with a more pronounced inflammatory response and CAP-related adverse clinical outcome. Optimal glucose targets for insulin treatment of hyperglycaemia in non-critical-care settings should be defined.     

6',7'-Dihydroxybergamottin in grapefruit juice and Seville orange juice: effects on cyclosporine disposition, enterocyte CYP3A4, and P-glycoprotein

BACKGROUND: 6',7'-Dihydroxybergamottin is a furanocoumarin that inhibits CYP3A4 and is found in grapefruit juice and Seville orange juice. Grapefruit juice increases the oral bioavailability of many CYP3A4 substrates, including cyclosporine (INN, ciclosporin), but intestinal P-glycoprotein may be a more important determinant of cyclosporine availability. OBJECTIVES: To evaluate the contribution of 6',7'-dihydroxybergamottin to the effects of grapefruit juice on cyclosporine disposition and to assess the role of CYP3A4 versus P-glycoprotein in this interaction. METHODS: The disposition of oral cyclosporine was compared in healthy subjects after ingestion of water, grapefruit juice, and Seville orange juice. Enterocyte concentrations of CYP3A4 were measured in 2 individuals before and after treatment with Seville orange juice. The effect of 6',7'-dihydroxybergamottin on P-glycoprotein was assessed in vitro. RESULTS: Area under the whole blood concentration-time curve and peak concentration of cyclosporine were increased by 55% and 35%, respectively, with grapefruit juice (P < .05). Seville orange juice had no influence on cyclosporine disposition but reduced enterocyte concentrations of CYP3A4 by an average of 40%. 6',7'-Dihydroxybergamottin did not inhibit P-glycoprotein at concentrations up to 50 micromol/L. CONCLUSIONS: 6',7'-Dihydroxybergamottin is not responsible for the effects of grapefruit juice on cyclosporine. Because the interaction did not occur with Seville orange juice despite reduced enterocyte concentrations of CYP3A4, inhibition of P-glycoprotein activity by other compounds in grapefruit juice may be responsible. Reduced enterocyte CYP3A4 by 6',7'-dihydroxybergamottin could be important for other drugs whose bioavailability is less dependent on P-glycoprotein.     

Infarct Size Reduction by Ischemic Preconditioning Is a Monophasic, Short-Lived Phenomenon in Anesthetized Pigs

BACKGROUND: Controversy exists concerning the duration of infarct size reduction with ischemic preconditioning in different species. In the present study, we (a) evaluated the time course of protection with preconditioning and (b) sought to determine whether late protection (the "second window") after 24 hours is manifest in the open-chest pig model. METHODS AND RESULTS: Six groups of pentobarbital-anesthetized pigs underwent 1 hour of left anterior descending coronary artery occlusion and 2 hours of reperfusion. Group 1 served as control, and pigs in group 2 received two 10-minute episodes of preconditioning ischemia followed by 30 minutes of reperfusion before the sustained 1-hour occlusion. In groups 3-6, the period of intervening reperfusion between the preconditioning stimulus and the index ischemia was extended to 60, 90, and 300 minutes and 24 hours, respectively. The area at risk was determined by fluorescein dye injection, and infarct size was measured by incubation in p-nitrobluetetrazolium and expressed as percent of the risk area. Infarct size in preconditioned pigs (group 2) was significantly reduced compared with controls (25.6 +/- 3.9% v 71.3 +/- 5.9%, P <.001). Extension of the intervening reperfusion to 60, 90, and 300 minutes and 24 hours resulted in infarct sizes of 64.5 +/- 5.5%, 67.2 +/- 8%, 62.6 +/- 6.1%, and 75.3 +/- 7%, respectively (P = NS v control). CONCLUSIONS: The infarct size-limiting effects of ischemic preconditioning last less than 1 hour in the pig model. Moreover, in contrast to other species, a late protection at 24 hours after the preconditioning stimulus was not detected. These results indicate that precondition-induced reduction of infarct size is monophasic in anesthetized pigs.