Differential inflammatory microRNA and cytokine expression in pulmonary sarcoidosis

Sarcoidosis is a granulomatous disease of unknown etiology. The disease has an important inflammatory and immune component; however, its immunopathogenesis is not completely understood. Recently, the role of microRNAs (miRNAs), the small non-coding RNAs, has attracted attention as both being involved in pathogenesis and serving as disease markers. Accordingly, changes in the expression of some miRNAs have been also associated with different autoimmune pathologies. However, not much is known about the role of miRNAs in sarcoidosis. Therefore, the aim of this study was to compare the level of expression of selected miRNAs in healthy individuals and patients with sarcoidosis. We detected significantly increased level of miR-34a in peripheral blood mononuclear cells isolated from sarcoidosis patients. Moreover, significantly up-regulated levels of interferon (IFN)-γ, IFN-γ inducible protein (IP-10) and vascular endothelial growth factor were detected in sera of patients when compared to healthy subjects. Our results add to a known inflammatory component in sarcoidosis. Changes in the levels of miR-34a may suggest its involvement in the pathology of this disease

Antihypertensive efficacy and safety of manidipine versus amlodipine in elderly subjects with isolated systolic hypertension: MAISH study

Background and objective: Isolated systolic hypertension (ISH) affects 10-20% of the elderly population and is strongly related to the risk of cardiovascular events. Elevated systolic BP values are primarily caused by reduced large vessel compliance with a consequent increase in total peripheral resistance. Vasodilating drugs, such as calcium channel antagonists, have proven to be effective in controlling ISH in elderly patients. This study set out to compare the antihypertensive efficacy and safety of two different calcium channel antagonists, manidipine and amlodipine, administered once daily in elderly subjects with ISH. Methods: In a European, randomised, double-blind, multicentre, parallel-group study, after a 2-week placebo run-in period, 195 patients aged ≥60 years with ISH received manidipine 10-20mg once daily or amlodipine 5-10mg once daily. Chlortalidone 25mg once daily could be added to the high dose of test drug in the event of insufficient antihypertensive control. The primary efficacy parameter was the proportion of patients with a reduction in office sitting systolic BP (SBP) ≥15mm Hg, measured at trough, at the final visit. Secondary efficacy parameters included: the proportion of patients with a normal sitting SBP value (<140mm Hg) at the final visit; a change from baseline to the final visit in mean office trough sitting SBP; a change from baseline to the final visit in the cardiovascular risk score as measured by the INDANA (INdividual Data ANalysis of Antihypertensive intervention trials) project score; the proportion of patients with at least a two-point reduction in the cardiovascular risk score; the percentage of patients requiring upward dose titration and diuretic add-on treatment and the investigator's final judgement. Safety and tolerability evaluations were based on adverse events, ECG and laboratory tests, and clinically relevant reports of abnormalities. Results: In the intention-to-treat population (n = 189), 76% and 72% of patients in the manidipine and amlodipine groups, respectively, had a reduction in sitting SBP of ≥15mm Hg (p-value not significant for between-group comparison). The percentage of patients with a normal sitting SBP value was 52% in the manidipine group and 51% in the amlodipine group (p-value not significant for between-group comparison). Sitting SBP reductions at the end of treatment were -19.5 ± 11.8mm Hg in patients receiving manidipine and -18.4 ± 11.1mm Hg in patients receiving amlodipine. Both treatments induced a small reduction in cardiovascular risk score, with 45% of patients in both treatment groups having a two-point reduction in the final score. At the final visit, approximately half of the patients in both treatment groups were still being treated with the low dose of one of the test drugs (manidipine 10mg or amlodipine 5mg). Chlortalidone was added to the high dose of test drugs in 7% and 11% of patients in the amlodipine and manidipine groups, respectively. Both drugs were well tolerated, with a higher incidence of oedema in the amlodipine group (9% vs 4%). No clinically relevant changes in heart rate were induced by either treatment. Conclusion: In elderly patients with ISH, treatment with manidipine for 12 weeks was well tolerated and effective and the antihypertensive effects obtained with manidipine were the same as those obtained with amlodipine

Overexpression of leukotriene C₄ synthase in bronchial biopsies from patients with aspirin-intolerant asthma

Aspirin causes bronchoconstriction in aspirin-intolerant asthma (AIA) patients by triggering cysteinyl-leukotriene (cys-LT) production, probably by removing PGE2-dependent inhibition. To investigate why aspirin does not cause bronchoconstriction in all individuals, we immunostained enzymes of the leukotriene and prostanoid pathways in bronchial biopsies from AIA patients, aspirin-tolerant asthma (ATA) patients, and normal (N) subjects. Counts of cells expressing the terminal enzyme for cys-LT synthesis, LTC4 synthase, were fivefold higher in AIA biopsies (11.5±2.2 cells/mm2, n = 10) than in ATA biopsies (2.2±0.7, n = 10; P = 0.0006) and 18-fold higher than in N biopsies (0.6±0.4, n = 9; P = 0.0002). Immunostaining for 5-lipoxygenase, its activating protein (FLAP), LTA4 hydrolase, cyclooxygenase (COX)-1, and COX-2 did not differ. Enhanced baseline cys-LT levels in bronchoalveolar lavage (BAL) fluid of AIA patients correlated uniquely with bronchial counts of LTC4 synthase+ cells (p = 0.83, P = 0.01). Lysine-aspirin challenge released additional cys-LTs into BAL fluid in AIA patients (200±120 pg/ml, n = 8) but not in ATA patients (0.7±5.1, n = 5; P = 0.007). Bronchial responsiveness to lysine-aspirin correlated exclusively with LTC4 synthase+ cell counts (p = -0.63, P = 0.049, n = 10). Aspirin may remove PGE2- dependent suppression in all subjects, but only in AIA patients does increased bronchial expression of LTC4 synthase allow marked overproduction of cys-LTs leading to bronchoconstriction.</p

Fusion of TTYH1 with the C19MC microRNA cluster drives expression of a brain-specific DNMT3B isoform in the embryonal brain tumor ETMR

Embryonal tumors with multilayered rosettes (ETMRs) are rare, deadly pediatric brain tumors characterized by high-level amplification of the microRNA cluster C19MC. We performed integrated genetic and epigenetic analyses of 12 ETMR samples and identified, in all cases, C19MC fusions to TTYH1 driving expression of the microRNAs. ETMR tumors, cell lines and xenografts showed a specific DNA methylation pattern distinct from those of other tumors and normal tissues. We detected extreme overexpression of a previously uncharacterized isoform of DNMT3B originating at an alternative promoter that is active only in the first weeks of neural tube development. Transcriptional and immunohistochemical analyses suggest that C19MC-dependent DNMT3B deregulation is mediated by RBL2, a known repressor of DNMT3B. Transfection with individual C19MC microRNAs resulted in DNMT3B upregulation and RBL2 downregulation in cultured cells. Our data suggest a potential oncogenic re-engagement of an early developmental program in ETMR via epigenetic alteration mediated by an embryonic, brain-specific DNMT3B isoform