The severe phenotype of human females whose karyotype includes tiny ring X chromosomes has been attributed to the inability of the small ring X chromosome to inactivate. The XIST locus is expressed only from the inactive X chromosome, resides at the putative X inactivation center, and is considered a prime player in the initiation ofmammalian X dosage compensation. Using PCR, Southern blot analysis, and in situ hybridization, we have looked for the presence ofthe XIST locus in tiny ring X chromosomes from eight females who have multiple congenital malformations and severe mental retardation. Our studies reveal heterogeneity within this group; some rings lack the XIST locus, while others have sequences homologous to probes for XIST. However, in the latter, the locus is either not expressed or negligibly expressed, based on reverse trasrlption-PCR analysis. Therefore, what these tiny ring chromosomes have in common is a level ofXIST tanscription comparable to an active X. AsXIST anscription Is an indicator ofX chromosome inactivity, the absence ofXIST transcription strongly suggests that tiny ring X chromosomes in females with severe phenotypes are mutants in the X chromosome inactivation pathway and that the inability of these rings to inactivate is responsible for the severe phenotypes.Although most conceptuses with X chromosomal monosomies are found among spontaneous abortions, some survive fetal life. In fact, most survivors are remarkably healthy individuals whose intelligence is within the normal range (1, 2). Their phenotypes usually include short stature and failure to maintain normal ovarian structure and function. Commonly, but not invariably, they have dysmorphic features such as widely spaced nipples, narrow palate, small mandible, webbed neck, and lymphedema-a constellation of abnormalities referred to as Turner syndrome. Turner syndrome is also associated with karyotypes that include 46 chromosomes with one normal X chromosome and a second X that is structurally abnormal-i.e., having deletions or reduplications of the long arm. Occasionally the abnormal X is one with breaks in both short and long arms that have led to the formation of a ring X chromosome. The relatively benign nature of the anomalies associated with an X monosomy or the presence of a structurally abnormal X is explained by the fact that females normally have only a single active X chromosome (3). The abnormal (genetically deficient) X is usually inactive due to selection favoring cells in which the normal X is active, and therefore the phenotypes of such females are similar to those with a true X monosomy.On the other hand, some females who are mosaic, 45,X/ The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.46,X,r(X), and whose ring X chromosome is tiny (i.e., Fig. 1) are much more severely affected than those with a nonmosaic 45,X karyotype. They have severe mental ret...

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Angiogenesis inhibitors were superior to non-angiogenesis inhibitors in terms of ORR, DCR, PFS and OS in advanced NSCLC patients. Further studies are warranted to explore the predictive biomarkers to pick up those who may gain utmost benefit from anti-angiogenic therapy.

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BackgroundThe safety and long‐term outcome of systemic thrombolysis in patients receiving antiplatelet medications remain subjects of great clinical significance. The objective of this meta‐analysis was to determine how prestroke antiplatelet therapy affects the risks and benefits of intravenous thrombolysis in patients with acute ischemic stroke.Methods and ResultsA dual‐reviewer search was conducted in PubMed and EMBASE databases through November 2015, from which 19 studies involving a total of 108 588 patients with acute ischemic stroke were identified based on preset inclusion criteria. Information on study designs, patient characteristics, exposures, outcomes, and adjusting confounders was extracted, and estimates were combined by using random‐effects models. The pooled crude estimates suggested that taking long‐term antiplatelet medications was associated with higher odds of symptomatic intracranial hemorrhage (odds ratio [OR] 1.70, 95% CI 1.47–1.97) and death (OR 1.46, 95% CI 1.22–1.75) and lower odds of favorable functional outcomes (OR 0.86, 95% CI 0.80–0.93). However, the combined confounder‐adjusted results only confirmed a relatively weak positive association between prior antiplatelet therapy and symptomatic intracranial hemorrhage (OR 1.21, 95% CI 1.02–1.44) and demonstrated no significant relationship between antiplatelet therapy and the other 2 outcomes (favorable outcome OR 1.09, 95% CI 0.96–1.24; death OR 1.02, 95% CI 0.98–1.07). Subgroup analyses revealed that the associations between prestroke antiplatelet therapy and outcomes were dependent on time and antiplatelet agents.ConclusionsPatients with acute ischemic stroke receiving long‐term antiplatelet medications were associated with greater risks of developing symptomatic intracranial hemorrhage after systemic thrombolysis. However, the overall independent association between prestroke antiplatelet therapy and unfavorable outcomes or mortality was insignificant.

Background and objectivesData are scarce on blood metabolite associations with proteinuria, a strong risk factor for adverse kidney outcomes. We sought to investigate associations of proteinuria with serum metabolites identified using untargeted profiling in populations with CKD.Design, setting, participants, & measurementsUsing stored serum samples from the African American Study of Kidney Disease and Hypertension (AASK; n=962) and the Modification of Diet in Renal Disease (MDRD) study (n=620), two rigorously conducted clinical trials with per-protocol measures of 24-hour proteinuria and GFR, we evaluated cross-sectional associations between urine protein-to-creatinine ratio and 637 known, nondrug metabolites, adjusting for key clinical covariables. Metabolites significantly associated with proteinuria were tested for associations with CKD progression.ResultsIn the AASK and the MDRD study, respectively, the median urine protein-to-creatinine ratio was 80 (interquartile range [IQR], 28–359) and 188 (IQR, 54–894) mg/g, mean age was 56 and 52 years, 39% and 38% were women, 100% and 7% were black, and median measured GFR was 48 (IQR, 35–57) and 28 (IQR, 18–39) ml/min per 1.73 m2. Linear regression identified 66 serum metabolites associated with proteinuria in one or both studies after Bonferroni correction (P<7.8×10−5), 58 of which were statistically significant in a meta-analysis (P<7.8×10−4). The metabolites with the lowest P values (P<10−27) were 4-hydroxychlorthalonil and 1,5-anhydroglucitol; all six quantified metabolites in the phosphatidylethanolamine pathway were also significant. Of the 58 metabolites associated with proteinuria, four were associated with ESKD in both the AASK and the MDRD study.ConclusionsWe identified 58 serum metabolites with cross-sectional associations with proteinuria, some of which were also associated with CKD progression.PodcastThis article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_02_07_CJASNPodcast_19_03_.mp3

The discovery of endothelial progenitor cells (EPCs), a group of cells that play important roles in angiogenesis and the maintenance of vascular endothelial integrity, has led to considerable improvements in our understanding of the circulatory system and the regulatory mechanisms of vascular homoeostasis. Despite lingering disputes over where EPCs actually originate and how they facilitate angiogenesis, extensive research in the past decade has brought about significant advancements in this field of research, establishing EPCs as an essential element in the pathogenesis of various diseases. EPC and hypertensive disorders, especially essential hypertension (EH, also known as primary hypertension), represent one of the most appealing branches in this area of research. Chronic hypertension remains a major threat to public health, and the exact pathologic mechanisms of EH have never been fully elucidated. Is there a relationship between EPC and hypertension? If so, what is the nature of such relationship-is it mediated by blood pressure alterations, or other factors that lie in between? How can our current knowledge about EPCs be utilized to advance the prevention and clinical management of hypertension? In this review, we set out to answer these questions by summarizing the current concepts about EPC pathophysiology in the context of hypertension, while attempting to point out directions for future research on this subject.