Risk of stroke in imaging-proven subclavian steal syndrome

To determine the risk of stroke in patients with subclavian steal syndrome (SSS). We identified 165 patients with imaging-proven SSS from two hospitals. Demographic, clinical and imaging data were retrospectively collected. Patients were followed up for stroke events. Stroke occurred in 43 patients with a median follow-up of 28 months. Seven of these cases were identified prospectively and 36 cases retrospectively. On multivariate analysis, presence of symptoms at presentation (p = 0.029) was a significant predictor of stroke. Presence of symptoms at presentation predicted stroke in imaging-proven SSS.     

Impact of Omega-3 supplementation on homocysteine levels in humans: A systematic review and meta-regression analysis of randomized controlled trials

AimsAlthough some evidence suggests that omega-3 polyunsaturated fatty acids (PUFAs) supplementation influences enzymes involved in forming homocysteine (Hcy) and improving hyperhomocysteinemia, these findings are still contradictory in humans. The aim of this systematic and meta-analysis study was to investigate the effects of omega-3 supplementation on Hcy using existing randomized controlled trials (RCTs).Data synthesisAvailable databases, including PubMed/MEDLINE, Web of Science, Scopus, Cochrane Library, and Embase, were searched to find relevant RCTs up to June 2021. The effect size was expressed as weighted mean difference (WMD) and 95% confidence interval (CI).ConclusionA total of 20 RCT studies with 2676 participants were included in this article. Our analyses have shown that omega-3 supplementation significantly reduced plasma Hcy levels (WMD: 1.34 μmol/L; 95% CI: 1.97 to ?0.72; P < 0.001) compared to the control group. The results of subgroup analysis showed that omega-3 supplementation during the intervention <12 weeks and with a dose ≥3 gr per day causes a more significant decrease in Hcy levels than the intervention ≥12 weeks and at a dose <3 gr. In addition, omega-3 supplements appear to have more beneficial effects in individuals with high levels of normal Hcy. This meta-analysis showed that omega-3 supplementation significantly improved Hcy. However, further studies are needed to confirm the findings.     

Heterozygous loss-of-function variants in LHX8 cause female infertility characterized by oocyte maturation arrest

PurposeThe genetic causes of oocyte maturation arrest leading to female infertility are largely unknown, and no population-based genetic analysis has been applied in cohorts of patients with infertility. We aimed to identify novel pathogenic genes causing oocyte maturation arrest by using a gene-based burden test.MethodsThrough comparison of exome sequencing data from 716 females with infertility characterized by oocyte maturation arrest and 3539 controls, we performed a gene-based burden test and identified a novel pathogenic gene LHX8. Splicing event was evaluated using a minigene assay, expression of LHX8 protein was assessed in HeLa cells, and nuclear subcellular localization was determined in both HeLa cells and mouse oocytes.ResultsA total of 5 heterozygous loss-of-function LHX8 variants were identified from 6 independent families (c.389+1G>T, c.412C>T [p.Arg1381], c.282C>A [p.Cys941]; c.257dup [p.Tyr861]; and c.180del, [p.Ser61Profs130]). All the identified variants in LHX8 produced truncated LHX8 protein and resulted in loss of LHX8 nuclear localization in both HeLa cells and mouse oocytes.ConclusionBy combining genetic evidence and functional evaluations, we identified a novel pathogenic gene LHX8 and established the causative relationship between LHX8 haploinsufficiency and female infertility characterized by oocyte maturation arrest.     

Cyclooxygenase-2 derived thromboxane A2 and reactive oxygen species mediate flow-induced constrictions of venules in hyperhomocysteinemia

ObjectiveHyperhomocysteinemia (HHcy) has been shown to impair the endothelial function of arterial vessels and promote thrombosis. There are no studies, however, assessing the effects of HHcy on the vasomotor function of venules. We hypothesized that HHcy activates pathophysiological mechanisms impairing flow/shear stress-dependent responses of venules.Methods and resultsChanges in diameter of isolated gracilis muscle venules (diameter: ～250 μm at 10 mmHg) of control and HHcy rats (induced by methionine diet for 5 weeks) to increases in intraluminal flow were measured. Increases in flow elicited dilations in control (at max.: 14 ± 1%), but induced constrictions in HHcy venules (at max.: ?24 ± 4%). Flow-induced constrictions in HHcy venules were converted to dilations in the presence of the thromboxane A₂ (TxA₂) receptor (TP) antagonist SQ 29,548, which were then abolished by the simultaneous administration of nitric oxide (NO) synthase inhibitor, L-NAME and non-selective cyclooxygenase (COX) blocker, indomethacin. In addition, the selective COX-2 inhibitor NS 398 reversed flow-induced constrictions to dilations, which were significantly decreased by additional COX-1 inhibitor, SC 560. Also, as compared to controls, a SOD/CAT sensitive increased ethidium bromide fluorescence was detected in HHcy small veins, indicating substantial production of reactive oxygen species (ROS) in HHcy. Correspondingly, SOD/CAT diminished flow-induced constrictions in venules of HHcy rats.ConclusionsIn hyperhomocysteinemia increases in flow/shear stress increases the production of COX-2-derived TxA₂, and reactive oxygen species – that overcome the dilator effects of NO and prostaglandins – eliciting constrictions in skeletal muscle venules; changes which can increase vascular resistance and favor thrombus formation in the venular circulation.     

Reprint of: MicroRNA profiling of human intermediate monocytes

Among the three human monocyte subsets, intermediate CD14++CD16+ monocytes have been characterized as particularly proinflammatory cells in experimental studies and as potential biomarkers of cardiovascular risk in clinical cohorts. To further substantiate the distinct role of intermediate monocytes within human monocyte heterogeneity, we assessed subset-specific expression of miRNAs as central epigenetic regulators of gene expression. We hypothesized that intermediate monocytes have a distinct miRNA profile compared to classical and non-classical monocytes.By using small RNA-seq we analyzed 662 miRNAs in the three monocyte subsets. We identified 38 miRNAs that are differentially expressed in intermediate monocytes compared to both classical and non-classical monocytes with a p value of <10⁻¹⁰, of which two miRNAs – miR-6087 (upregulated) and miR-150-5p (downregulated) – differed in their expression more than ten-fold. Pathway analysis of the 38 differentially expressed miRNAs linked intermediate monocytes to distinct biological processes such as gene regulation, cell differentiation, toll-like receptor signaling as well as antigen processing and presentation. Moreover, differentially expressed miRNAs were connected to those genes that we previously identified as markers of intermediate monocytes.In aggregation, we provide first genome-wide miRNA data in the context of monocyte heterogeneity, which substantiate the concept of monocyte trichotomy in human immunity. The identification of miRNAs that are specific for intermediate monocytes may allow to develop strategies, which particularly target this cell population while sparing the other two subsets.     

Retrospective efficacy and safety analyses of erlotinib,pemetrexed, and docetaxel in EGFR-mutation-negative patients with previously treated advanced non-squamous non-small-cell lung cancer

ObjectiveSeveral guidelines recommend erlotinib, pemetrexed, or docetaxel for second-line chemotherapy in patients with advanced non-squamous non-small-cell lung cancer (NSCLC). The aim of this study was to retrospectively evaluate the efficacy of erlotinib, pemetrexed, and docetaxel in epidermal growth factor receptor (EGFR) mutation-negative patients with previously treated advanced non-squamous NSCLC.Materials and methodsWe analyzed the efficacy of these agents in patients with previously treated advanced non-squamous NSCLC who had EGFR wild-type tumors, performance status (PS) of 0, 1, or 2 and received erlotinib, pemetrexed, or docetaxel between December 2007 and September 2011. Variability among patient backgrounds was evaluated using propensity scores to assess comparability. The efficacy of these agents was evaluated in patient subgroups with low variability.ResultsThe propensity scores showed that the backgrounds of the groups that received second-line therapy with each agent had low variability and were adequate for comparison. Patients were divided into the PS0/1 and PS2 groups for analysis. The median progression-free survival (PFS) in patients treated with erlotinib was 2.8 months in the PS0/1 group, as compared with 1.0 month in the PS0/1/2 group and 0.90 months in the PS2 group. PFS in PS0/1 patients who received erlotinib was comparable to that in PS0/1 patients who received pemetrexed (2.5 months) or docetaxel (1.9 months). Overall survival (OS) in erlotinib-, pemetrexed-, and docetaxel-treated PS0/1 patients was 16.1, 7.4 and 10.0 months, respectively. The study had limited power to detect differences in PFS and OS because of the small sample size.ConclusionsErlotinib appears to be a useful second-line option in PS0/1 patients with EGFR mutation-negative advanced non-squamous NSCLC given its mild adverse effects. The results should be carefully interpreted because of the small sample size, limited power, and retrospective nature of the study.     

The prevalence of aminoglycoside-modifying enzymes among coagulase negative staphylococci in Iranian pediatric patients

In spite of widespread emergence of aminoglycoside resistance, these drugs are still used in the treatment of staphylococcal infections. This study aimed to investigate the distribution of aminoglycoside resistance and genes encoding aminoglycoside – modifying enzymes (AMEs) as well as Staphylococcal Cassette Chromosome mec (SCCmec) type in coagulase negative staphylococci (CoNS) in pediatric patients. Totally, 93 CoNS isolates were examined for susceptibility to aminoglycosides using disk diffusion and/or E-test methods. AMEs genes and SCCmec types were detected using multiplex PCR. Strain typing was performed using repetitive extragenic palindromic (REP) – PCR assay. The non-susceptibility rates to kanamycin, tobramycin, gentamicin, amikacin and netilmicin were 73%, 59%, 49.5%, 16% and 7.5%, respectively. aac(6′)-Ie-aph(2″)-Ia, ant(4′)-Ia and aph(3′)-IIIa were encountered in 56 (60.2%), 38 (40.8%) and 18 (19.3%) isolates, respectively. In aac(6′)-Ie-aph(2″)-Ia- positive isolates, the non- susceptibility rates to kanamycin, gentamicin, tobramycin, amikacin and netilmicin were 83%, 74%, 73%, 49% and 43%, respectively. SCCmec types included type IV (n = 31), I (n = 17), II (n = 5), III (n = 4), and V (n = 2). Three isolates had two types; I + III (n = 2) and III + IV (n = 1) whereas 11 isolates were non-typeable. AMEs genes carriers were distributed frequently into type IV. We found diverse fingerprint patterns among our isolates. In conclusion, there was a strong correlation between alarming rate of aminoglycoside resistance and methicillin resistance. Discordances between phenotypic and genotypic detection of aminoglycoside resistance were discernible. AMEs genes might be related to SCCmec types.