Genetic and geographic influence on phenotypic variation in European sarcoidosis patients.

Introduction: Sarcoidosis is a highly variable disease in terms of organ involvement, type of onset and course. Associations of genetic polymorphisms with sarcoidosis phenotypes have been observed and suggest genetic signatures. Methods: After obtaining a positive vote of the competent ethics committee we genotyped 1909 patients of the deeply phenotyped Genetic-Phenotype Relationship in Sarcoidosis (GenPhenReSa) cohort of 31 European centers in 12 countries with 116 potentially disease-relevant single-nucleotide polymorphisms (SNPs). Using a meta-analysis, we investigated the association of relevant phenotypes (acute vs. sub-acute onset, phenotypes of organ involvement, specific organ involvements, and specific symptoms) with genetic markers. Subgroups were built on the basis of geographical, clinical and hospital provision considerations. Results: In the meta-analysis of the full cohort, there was no significant genetic association with any considered phenotype after correcting for multiple testing. In the largest sub-cohort (Serbia), we confirmed the known association of acute onset with TNF and reported a new association of acute onset an HLA polymorphism. Multi-locus models with sets of three SNPs in different genes showed strong associations with the acute onset phenotype in Serbia and Lublin (Poland) demonstrating potential region-specific genetic links with clinical features, including recently described phenotypes of organ involvement. Discussion: The observed associations between genetic variants and sarcoidosis phenotypes in subgroups suggest that gene-environment-interactions may influence the clinical phenotype. In addition, we show that two different sets of genetic variants are permissive for the same phenotype of acute disease only in two geographic subcohorts pointing to interactions of genetic signatures with different local environmental factors. Our results represent an important step towards understanding the genetic architecture of sarcoidosis.

Gaseous nitric oxide to treat antibiotic resistant bacterial and fungal lung infections in patients with cystic fibrosis: a phase I clinical study.

BACKGROUND: Individuals with cystic fibrosis (CF) receive antibiotics continuously throughout their entire life which leads to drug resistant microbial lung infections which are difficult to treat. Nitric oxide (NO) gas possesses antimicrobial activity against a wide variety of microorganisms in vitro, in vivo in animal models and a phase I study in healthy adults showed administration of intermittent 160 ppm NO to be safe. METHODS: We assessed feasibility and safety of inhaled NO in eight CF patients who received 160 ppm NO for 30 min, three times daily for 2 periods of 5 days. RESULTS: The NO treatment was safe and in none of the patients were serious drug-related adverse events observed which caused termination of the study. The intention-to-treat analysis revealed a significant mean reduction of the colony forming units of all bacteria and all fungi, while mean forced expiratory volume 1 s % predicted (FEV1) relative to baseline increased 17.3 ± 8.9 % (P = 0.012). CONCLUSIONS: NO treatment may improve the therapy of chronic microbial lung infections in CF patients, particularly concerning pathogens with intrinsic or acquired resistance to antibiotics.

Circulating anandamide and blood pressure in patients with obstructive sleep apnea.

OBJECTIVE: Obstructive sleep apnea chronically increases blood pressure through sympathetic nervous system activation. In animals, hypertension and sympathetic activity are restrained by cannabinoid receptor activation. Therefore, we hypothesized that increased blood pressure in patients with obstructive sleep apnea is associated with increased circulating endocannabinoid concentrations. METHODS: Arterial oxygen saturation and apnea/hypopnea episodes were recorded in 29 patients with normal glucose tolerance, 26 patients with type 2 diabetes mellitus, and 21 patients obese subjects without sleep apnea. We determined seated blood pressure, insulin, glucose, and high-sensitive C-reactive protein in the morning, and insulin sensitivity by euglycemic-hyperinsulinemic clamp the next day. Anandamide, the sum of 1-arachidonoylglycerol and 2-arachidonoylglycerol, and oleoylethanolamide were measured in plasma by liquid chromatography-tandem mass spectrometry. RESULTS: Endocannabinoid concentrations in sleep apnea patients were increased compared to obese individuals without disordered nocturnal breathing. Correction for variables of obesity and insulin resistance almost completely abrogated this difference in endocannabinoids. Anandamide strongly correlated with blood pressure in sleep apnea patients (r = 0.60 for SBP and r = 0.58 for DBP, P < 0.001). In multivariate regression analysis, anandamide was a stronger determinant of blood pressure than sleep apnea severity, obesity, insulin resistance, and inflammation. CONCLUSION: Obstructive sleep apnea patients show positive correlations between blood pressure and venous anandamide concentrations independent of confounding factors. Our data suggest a previously not recognized role of the endocannabinoid system for blood pressure regulation in patients with high risk for hypertension and cardiovascular disease.

Different mechanisms for changes in glucose uptake of the right and left ventricular myocardium in pulmonary hypertension.

UNLABELLED: In patients with pulmonary hypertension (PH) the right ventricular (RV)-to-left ventricular (LV) ratio of fatty acid uptake is reduced. In animal studies, such a finding was combined with an increased glucose uptake in RV myocardium. The aim of this study was to measure the metabolic rates of glucose uptake for the RV and LV myocardium in patients in relationship to parameters of RV and LV function. METHODS: Thirty patients with PH underwent PET with (18)F-FDG and SPECT with (99m)Tc-tetrofosmine. The metabolic rate of glucose uptake was determined for RV and LV myocardium using the method of Patlak. A right heart catheter, thermodilution, and Doppler sonography were used to characterize RV and LV function. From these methods, the stroke work of both ventricles and the RV Tei index were calculated. RESULTS: RV-to-LV ratios of (18)F-FDG-uptake increased with rising pulmonary arteriolar resistance (PAR). With increasing PAR, the metabolic rate of glucose uptake of the left ventricle decreased (r = -0.547; P < 0.01) together with LV stroke work (r = -0.838; P < 0.001). The metabolic rate of glucose uptake of the right ventricle, however, correlated neither with RV stroke work (r = 0.124) nor with PAR (r = 0.189) but with the Tei index (r = 0.78; P < 0.001). CONCLUSION: Increasing right-to-left ratios of glucose uptake with an increasing pressure load in the right ventricle in PH are caused mainly by a significant reduction in the LV metabolic rate of glucose uptake. This is obviously due to a reduced energy demand of the LV myocardium caused by reduced stroke work. An increased metabolic rate of glucose uptake in the right ventricle presumably indicates RV impairment, correlating with the Tei index, which is an established prognostic parameter for cardiac dysfunction and poor survival.

Analysis of the phospholipid composition of bronchoalveolar lavage (BAL) fluid from man and minipig by MALDI-TOF mass spectrometry in combination with TLC.

Surfaces of lungs are covered by the surfactant, an aqueous mixture of different phospholipids (PL) and proteins. Although the surfactant represents a relatively simple mixture of only a few PL (primarily phosphatidylcholine (PC) and phosphatidylglycerol (PG)), reliable methods of routine lipid analysis of the surfactant are still lacking. It will be shown that matrix-assisted laser desorption and ionisation time-of-flight mass spectrometry (MALDI-TOF MS) represents a suitable technique for the differentiation of the apolar components of the surfactant of different species. Samples of man and minipig are used in this study since both are known to vary in their PL composition. PL of surfactant were separated by thin-layer chromatography (TLC) and the obtained subfractions subjected to MALDI-TOF MS analysis in order to monitor the presence of even minor PL species. It will be shown that besides PG and PC, also phosphatidylethanolamine, -inositol and sphingomyelin can be detected in surfactant of man, whereas only sphingomyelin could be detected in the minipig sample.