Current Issue : July - September Volume : 2013 Issue Number : 3 Articles : 5 Articles
Background: Aim of this prospective study was to compare clinical and genetic findings in children with idiopathic\r\nor heritable pulmonary arterial hypertension (I/HPAH) with children affected with congenital heart defects\r\nassociated PAH (CHD-APAH).\r\nMethods: Prospectively included were 40 consecutive children with invasively diagnosed I/HPAH or CHD-APAH\r\nand 117 relatives. Assessment of family members, pedigree analysis and systematic screening for mutations in TGF�Ÿ\r\ngenes were performed.\r\nResults: Five mutations in the bone morphogenetic protein type II receptor (BMPR2) gene, 2 Activin A receptor\r\ntype II-like kinase-1 (ACVRL1) mutations and one Endoglin (ENG) mutation were found in the 29 I/HPAH children.\r\nTwo mutations in BMPR2 and one mutation in ACVRL1 and ENG, respectively, are described for the first time. In the\r\n11 children with CHD-APAH one BMPR2 gene mutation and one Endoglin gene mutation were found. Clinical\r\nassessment of relatives revealed familial aggregation of the disease in 6 children with PAH (HPAH) and one\r\nCHD-APAH patient. Patients with mutations had a significantly lower PVR.\r\nConclusion: Mutations in different TGF�Ÿ genes occurred in 8/29 (27.6%) I/HPAH patients and in 2/11 (18.2%)\r\nCHD-APAH patients and may influence the clinical status of the disease. Therefore, genetic analysis in children with\r\nPAH, especially in those with I/HPAH, may be of clinical relevance and shows the complexity of the genetic\r\nbackground....
Background: Human leukocyte antigen (HLA)-G is a nonclassical class I antigen with immunomodulatory roles\r\nincluding up-regulation of suppressor T regulatory lymphocytes. HLA-G was recently identified as an asthma\r\nsusceptibility gene, and expression of a soluble isoform, HLA-G5, has been demonstrated in human airway\r\nepithelium. Increased presence of HLA-G5 has been demonstrated in bronchoalveolar lavage fluid recovered from\r\npatients with mild asthma; this suggests a role for this isoform in modulating airway inflammation though the\r\nmechanisms by which this occurs is unclear. Airway inflammation associated with Th2 cytokines such as IL-4 and\r\nIL-13 is a principal feature of asthma, but whether these cytokines elicit expression of HLA-G is not known.\r\nMethods: We examined gene and protein expression of both soluble (G5) and membrane-bound (G1) HLA-G\r\nisoforms in primary differentiated human airway epithelial cells collected from normal lungs and grown in air-liquid\r\ninterface culture. Cells were treated with up to 10 ng/ml of either IL-4, IL-5, or IL-13, or 100 ng/ml of the\r\nimmunomodulatory cytokine IL-10, or 10,000 U/ml of the Th1-associated cytokine interferon-beta, for 24 hr, after\r\nwhich RNA was isolated for evaluation by quantitative PCR and protein was collected for Western blot analysis.\r\nResults: HLA-G5 but not G1 was present in dAEC as demonstrated by quantitative PCR, western blot and confocal\r\nmicroscopy. Neither G5 nor G1 expression was increased by the Th2-associated cytokines IL-4, IL-5 or IL-13 over\r\n24 hr, nor after treatment with IL-10, but was increased 4.5 �± 1.4 fold after treatment with 10,000 U/ml interferonbeta.\r\nConclusions: These data demonstrate the constitutive expression of a T lymphocyte regulatory molecule in\r\ndifferentiated human airway epithelial cells that is not modulated by Th2-associated cytokines....
Background: Both chronic hypoxia and allergic inflammation induce vascular remodeling in the lung, but only\r\nchronic hypoxia appears to cause PH. We investigate the nature of the vascular remodeling and the expression and\r\nrole of hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELMa) in explaining this differential response.\r\nMethods: We induced pulmonary vascular remodeling through either chronic hypoxia or antigen sensitization and\r\nchallenge. Mice were evaluated for markers of PH and pulmonary vascular remodeling throughout the lung\r\nvascular bed as well as HIMF expression and genomic analysis of whole lung.\r\nResults: Chronic hypoxia increased both mean pulmonary artery pressure (mPAP) and right ventricular (RV)\r\nhypertrophy; these changes were associated with increased muscularization and thickening of small pulmonary\r\nvessels throughout the lung vascular bed. Allergic inflammation, by contrast, had minimal effect on mPAP and\r\nproduced no RV hypertrophy. Only peribronchial vessels were significantly thickened, and vessels within the lung\r\nperiphery did not become muscularized. Genomic analysis revealed that HIMF was the most consistently\r\nupregulated gene in the lungs following both chronic hypoxia and antigen challenge. HIMF was upregulated in the\r\nairway epithelial and inflammatory cells in both models, but only chronic hypoxia induced HIMF upregulation in\r\nvascular tissue.\r\nConclusions: The results show that pulmonary vascular remodeling in mice induced by chronic hypoxia or antigen\r\nchallenge is associated with marked increases in HIMF expression. The lack of HIMF expression in the vasculature of\r\nthe lung and no vascular remodeling in the peripheral resistance vessels of the lung is likely to account for the\r\nfailure to develop PH in the allergic inflammation model....
Background: Reduced gas transfer in patients with pulmonary arterial hypertension (PAH) is traditionally attributed\r\nto remodeling and progressive loss of pulmonary arterial vasculature that results in decreased capillary blood\r\nvolume available for gas exchange.\r\nMethods: We tested this hypothesis by determination of lung diffusing capacity (DL) and its components, the\r\nalveolar capillary membrane diffusing capacity (Dm) and lung capillary blood volume (Vc) in 28 individuals with PAH\r\nin comparison to 41 healthy individuals, and in 19 PAH patients over time. Using single breath simultaneous\r\nmeasure of diffusion of carbon monoxide (DLCO) and nitric oxide (DLNO), DL and Dm were respectively determined,\r\nand Vc calculated. Dm and Vc were evaluated over time in relation to standard clinical indicators of disease severity,\r\nincluding brain natriuretic peptide (BNP), 6-minute walk distance (6MWD) and right ventricular systolic pressure\r\n(RVSP) by echocardiography.\r\nResults: Both DLCO and DLNO were reduced in PAH as compared to controls and the lower DL in PAH was due to\r\nloss of both Dm and Vc (all p < 0.01). While DLCO of PAH patients did not change over time, DLNO decreased by\r\n24 ml/min/mmHg/year (p = 0.01). Consequently, Dm decreased and Vc tended to increase over time, which led to\r\ndeterioration of the Dm/Vc ratio, a measure of alveolar-capillary membrane functional efficiency without changes in\r\nclinical markers.\r\nConclusions: The findings indicate that lower than normal gas transfer in PAH is due to loss of both Dm and Vc,\r\nbut that deterioration of Dm/Vc over time is related to worsening membrane diffusion....
Lung cancer is the leading cause of cancer-related death in the United States.\r\nHere, we evaluated the potential clinical utility of soluble human epidermal growth factor\r\nreceptor 2 (sHER2) for the risk assessment, screening, and diagnosis of non-small cell\r\nlung cancer (NSCLC) using an unmatched case-control study design. Serum sHER2\r\nconcentrations were measured by immunoassay in 244 primary NSCLC cases and\r\n218 healthy controls. Wilcoxon rank-sum tests, logistic regression models, and receiver\r\noperating characteristic plots were used to assess whether sHER2 is associated with lung\r\ncancer. Median serum sHER2 concentrations are higher in patients with adenocarcinoma\r\nthan squamous cell carcinoma regardless of gender, and sHER2 is a weak, independent\r\nbiomarker of adenocarcinoma, but not of squamous cell carcinoma, adjusted for age and\r\ngender. The age-adjusted relative risk (odds) of adenocarcinoma is 3.95 (95% CI: 1.22,\r\n12.81) and 7.93 (95% CI: 2.26, 27.82) greater for women and men with high sHER2\r\nconcentrations (=6.60 ng/mL) vs. low sHER2 concentrations (=1.85 ng/mL), respectively.\r\nWhen adjusted for each other, sHER2, age, and gender discern healthy controls from\r\npatients with primary adenocarcinomas of the lung with 85.9% accuracy. We conclude that\r\neven though serum sHER2 is not a strong, stand-alone discriminatory biomarker of\r\nadenocarcinoma, sHER2 may be a useful, independent covariate in multivariate risk\r\nassessment, screening, and diagnostic models of lung cancer....
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