Genetic variants in the NOD2/CARD15 gene are associated with early mortality in sepsis patients.

OBJECTIVE: Genetic variants in the NOD2/CARD15 gene resulting in a diminished capacity to activate NF-kappaB in response to bacterial cell wall products have been associated with Crohn's disease (CD). Recently, we found an association between the variant Leu1007fsinsC of the NOD2/CARD15 gene (SNP13) and a significantly increased rate of transplant related mortality (TRM) due to intestinal and pulmonary complications in stem cell transplantation (SCT). To assess a possible contribution of variants in the NOD2/CARD15 gene to sepsis related mortality (SRM) we investigated 132 prospectively characterised, consecutive patients with sepsis. DESIGN AND PATIENTS: The three most common NOD2/CARD15 variants (Arg702Trp, Gly908Arg, and Leu1007fsinsC) were determined in 132 prospectively characterised patients with sepsis attended to three intensive care units at the University of Regensburg by Taqman PCR. NOD2/CARD15 genotype and major patients' characteristics were correlated with SRM. RESULTS: Patient groups with and without NOD2/CARD15 variants did not differ in their clinical characteristics such as median age, gender, reason for admission or APACHE score; however, SRM (day 30) was increased in patients with NOD2/CARD15 coding variants (42 vs. 31%) and was highest (57%) in 8 patients carrying the Leu1007fsinsC variant (p < 0.05). Multivariate analysis demonstrated the Leu1007fsinsC genetic variant as an independent risk factor for SRM. CONCLUSION: Our findings indicate a major role of NOD2/CARD15 coding variants for SRM. This may be indicative for a role of impaired barrier function and bacterial translocation in the pathophysiology of early sepsis related death.

Effectiveness of parathyroid-hormone measurement in detecting patients with multiple gland disease causing primary hyperparathyroidism.

BACKGROUND AND AIM: Intraoperative parathyroid hormone measurement (iPTH) has strengthened the successful use of minimal-invasive approaches in surgery of primary hyperparathyroidism (pHPT). The aim of the study was to evaluate the efficacy of iPTH monitoring in treating pHPT resulting from multiple gland disease. MATERIALS AND METHODS: In this retrospective study, 58 patients with pHPT underwent surgery (minimally invasive or open exploration) between January 2003 and July 2005. iPTH levels were routinely measured at the start of anesthesia, in any case before skin incision, and 10 as well as 15 min after removal of abnormal gland(s). A drop in iPTH >50% after 10 min and >60% after 15 min was considered adequate to prove the success of the removal of the abnormal gland(s). The removed tissue was examined histologically by immediate frozen section. RESULTS: A single gland disease was found in 51 (88%) cases, a multiple gland disease (double adenoma or hyperplasia) in 7 (12%) cases. In all cases of single adenoma, an adequate drop of iPTH was seen after removal of the pathologic gland. In contrast, in all cases with a second adenoma, an adequate drop in iPTH was detected only after removal of both adenoma/hyperplasia. Immediate sectioning was only helpful for identification of removed tissue, but was no help in deciding whether to search for an additional gland. The follow-up showed no late disease recurrence. CONCLUSION: The measurement of iPTH is an effective and safe means in treating single gland disease as well as multiple gland disease (adenoma/hyperplasia) causing pHPT and also allows a successful limited dissection via minimally invasive parathyroidectomy.

Restoration of neutrophil immunocompetence after cardiopulmonary bypass by beta-adrenergic blockers.

BACKGROUND: To evaluate the possible protective effect of sympatholytic medications with respect to neutrophil function, we evaluated the influence of a nonselective beta-blocker medication on the interaction of neutrophils and epinephrine after cardiopulmonary bypass. Therefore, we studied the importance of adrenoceptors for the immunomodulation of neutrophils by catecholamines in vitro. METHODS: First, we investigated the modulation of neutrophils from healthy volunteers, after stimulation with n-formyl-l-methionyl-l-leucyl-l-phenylalanin (FMLP) in the presence of epinephrine with or without the addition of one of the following adrenergic receptor antagonists: atenolol, butoxamine, pindolol, prazosin, or RS79984. The second part included an investigation of the modulation of neutrophils from patients after operative coronary revascularization with or without extracorporeal circulation after stimulation with FMLP and addition of epinephrine. After loading with anti-CD62l or anti-CD11b antibodies or dihydrorhodamine, the expression of CD62l and CD11b and generation of oxidative free radicals were assessed by flow cytometry. RESULTS: The suppression of oxidative free radical generation, inhibition of CD62l downregulation after stimulation with FMLP, and suppression of CD11b upregulation after FMLP stimulation from epinephrine were all mediated by beta(2)-adrenoceptors. After cardiac surgery with cardiopulmonary bypass, epinephrine inhibited the CD62l downregulation, the suppression of CD11b upregulation, and the generation of oxidative free radicals after FMLP stimulation. The pre-operative administration of beta-blockers abolished the immunomodulatory effects of epinephrine on CD62l and CD11b expression and the generation of oxidative free radicals. CONCLUSION: The immunomodulatory effects of epinephrine on neutrophils remained unchanged irrespective of cardiopulmonary bypass and could contribute to the detrimental effects of epinephrine after heart surgery. The preoperative administration of nonselective beta-blockers abolished the immunomodulatory effects of epinephrine in vitro and in patients, and it enhanced the immunocompetence of neutrophils in a context of increased catecholamine levels.