Study of carrier frequency of Warsaw breakage syndrome in the Ashkenazi Jewish population and presentation of two cases

Warsaw breakage syndrome (WABS), caused by bi‐allelic variants in the DDX11 gene, is a rare cohesinopathy characterized by pre‐ and postnatal growth retardation, microcephaly, intellectual disability, facial dysmorphia, and sensorineural hearing loss due to cochlear hypoplasia. The DDX11 gene codes for an iron–sulfur DNA helicase in the Superfamily 2 helicases and plays an important role in genomic stability and maintenance. Fourteen individuals with WABS have been previously reported in the medical literature. Affected individuals have been of various ethnic backgrounds with different pathogenic variants. We report two unrelated individuals of Ashkenazi Jewish descent affected with WABS, who are homozygous for the c.1763‐1G>C variant in the DDX11 gene. Their phenotype is consistent with previously reported individuals. RNA studies showed that this variant causes an alternative splice acceptor site leading to a frameshift in the open reading frame. Carrier screening of the c.1763‐1G>C variant in the Jewish population revealed a high carrier frequency of 1 in 68 in the Ashkenazi Jewish population. Due to the high carrier frequency and the low number of affected individuals, we hypothesize a high rate of miscarriage of homozygous fetuses and/or subfertility for carrier couples. If the carrier frequency is reproducible in additional Ashkenazi Jewish populations, we suggest including DDX11 to Ashkenazi Jewish carrier screening panels.     

Inhibition of ras by farnesylthiosalicylate significantly reduces the levels of autoantibodies in two animal models of the antiphospholipid syndrome

BACKGROUND: Stimulation and proliferation of lymphocytes require activation of Ras. S-farnesylthiosalicylic acid (FTS) is a synthetic substance that detaches Ras from the inner cell membrane and induces its rapid degradation. Antiphospholipid antibodies (aPL) are a heterogeneous group of antibodies detected in patients with antiphospholipid syndrome (APS), which is associated with thrombosis, pregnancy losses, and thrombocytopenia. OBJECTIVE: To examine the effect of FTS treatment on aPL levels in a genetic autoimmune model (the MRL/lpr mice) and in an induced model of APS. METHODS: Female Balb/C mice immunized once with beta2-glycoprotein I (beta2-GPI) in complete Freund's adjuvant (CFA) and female MRL/lpr mice were treated intraperitoneally with either FTS (5 mg/Kg/day) or saline 3-5 times a week. aPL and anti-beta2-GPI antibodies were measured by ELISA. RESULTS: FTS treatment 3 times a week resulted in significant decreases of aPL and anti-beta2-GPI antibodies in both animal models. In contrast, more frequent treatment (5 times a week) had no significant effect on autantibody levels in both animal models. We further compared 2 protocols in the induced APS model, one for alternate day treatment and the other for daily treatment on the first 3 days each week, and found a decrease in autoantibody levels only in the alternate day protocol. CONCLUSIONS: Inhibition of Ras activation by FTS is effective in decreasing autoantibody levels in models of APS. The differential modulation of immune function by alternate day compared to daily treatment may provide better understanding of the role of Ras activation in this system.     

A Cross-Country Network Analysis of Adolescent Resilience

PurposeIn situations of adversity, young people draw on individual, relational, and contextual (community and cultural) resources to foster their resilience. Recent literature defines resilience as a capacity that is underpinned by a network of interrelated resources. Although empirical studies show evidence of the value of a network approach, little is known regarding how different country contexts influence which resources are most critical within a resource network and how resources interact for adolescent resilience.MethodsNetwork analysis was conducted with data from studies that had used the Child and Youth Resilience Measure. Regularized partial correlation networks of 17 resources were estimated for 14 countries (Botswana, Canada, China, Colombia, Equatorial Guinea, India, Indonesia, Italy, Jordan, New Zealand, the Philippines, Romania, South Africa, and Syrian refugees living in Jordan). The sample size was 18,914 (mean age = 15.70 years, 48.8% female).ResultsWe observed mostly positive associations between the resources of interest. The salience and strength of associations between resources varied by country. The most central resource across countries was having supportive caregivers during stressful times because this resource had the most and strongest positive associations with other resources.ConclusionsThis study gives first empirical evidence from multiple countries that an interplay of social–ecological resources (such as individual skills, peer, caregiver and community support, and educational aspirations and opportunities) matter for adolescent resilience. Across countries, caregiver support appears to be most central for adolescent resilience. Future resilience interventions might apply this network approach to identify important, contextually relevant resources that likely foster additional resources.     

The use of insulin detemir during pregnancy: a safety evaluation

Introduction: Diabetes during pregnancy causes both fetal and maternal complications. Insulin is the most effective pharmacological treatment for controlling hyperglycemia during gestation and can limit adverse outcomes. Insulin detemir (IDet), a novel basal insulin, has already been used for this indication for several years. It was reclassified in 2012 by the FDA from category C to category B for the treatment of pregnant women with diabetes.

Areas covered: This article reviews published data regarding the use of IDet during pregnancy. We discuss pharmacokinetic and pharmacodynamic qualities of IDet and potential advantages for its use during pregnancy.

Expert opinion: IDet is a viable option for the management of diabetes during pregnancy. Though data is limited, its safety and efficacy is probably comparable to human insulin, and in some aspects superior to it. More data, specifically for IDet in pregnancies complicated by gestational diabetes (GDM) or type 2 diabetes, is needed.     

Gas flow during bronchoscopic ablation therapy causes gas emboli to the heart: a comparative animal study

BACKGROUND: Thermal ablation is one of the most commonly used modalities to treat central airway obstruction. Both laser and argon plasma coagulation (APC) have been reported to cause gas emboli and cardiac arrest. We sought to determine whether bronchoscopic ablation therapy can result in systemic gas emboli, correlate their presence with the rate of gas flow, and establish whether a zero-flow (ZF) modality would result in the significant reduction or elimination of emboli. METHODS: CO(2) laser delivered through a photonic bandgap fiber (PBF) and APC were applied in the trachea and mainstem bronchi of six anesthetized sheep at varying dosages and gas flow rates. Direct epicardial echocardiography was used to obtain a four-chamber view and detect gas emboli. RESULTS: The presence of gas flow accompanying APC and the CO(2) laser with forward flow correlated significantly with the appearance of gas bubbles in the atria. A definite dose response was observed between the gas flow rate and the number of bubbles seen. When the CO(2) laser was delivered through a PBF with ZF to the trachea or bronchi, no bubbles were observed. CONCLUSION: Bronchoscopic thermal ablation therapy using gas flow is associated with gas emboli in a dose-dependent fashion. The use of the flexible PBF with ZF is not associated with the development of gas emboli. Further study is required to determine whether a clinically safe threshold of gas emboli exists, and the relationships among the pathologic depth of tissue destruction, gas flow, pulse duration, and the development of gas emboli.     

Facile continuous process for gas phase halogen exchange over supported alkyl phosphonium salts

Chloride–bromide halogen exchange was realized when a mixture of an alkyl chloride and an alkyl bromide were reacted over a supported molten alkyl phosphonium catalyst. Conversion was found to be near equilibrium in a tubular flow reactor at 150 °C and 1500 GHSV. The catalyst was prepared by impregnation of alumina or silica support and found to be highly stable for relatively long periods of time. A pathway for the catalytic cycle is proposed.

Chloride–bromide halogen exchange was realized when a mixture of an alkyl chloride and an alkyl bromide were reacted over a supported molten alkyl phosphonium catalyst.     

Time-dependent effect of ethanol on GnRH and GnRH receptor mRNA expression in hypothalamus and testis of adult and pubertal rats

Chronic exposure to ethanol suppresses the male reproductive activity which is primarily involved in the release of hypothalamic gonadotropin-releasing hormone (GnRH). The testicular GnRH and GnRH receptors (GnRH-R) are found in seminiferous tubules, which are predicted to act as a local regulator of spermatogenesis, although the function is not well known. In this study, we investigated the chronic ethanol effect on GnRH mRNA expression in hypothalamus and testis using in situ hybridization and RNase protection assay (RPA). The effect of ethanol on expressional changes of GnRH and GnRH-R mRNA was observed in adult and pubertal rats according to age and time from 2 weeks (short term) and 4 weeks (long term) periods. The results showed that GnRH mRNA expression in adult and pubertal rats was dramatically decreased in the testis while no significant change was observed in hypothalamus after both short and long term exposure to ethanol. The pubertal rats showed decrease in testicular GnRH and GnRH-R mRNA expression, whereas GnRH mRNA was increased significantly, while GnRH-R mRNA was further decreased after long term exposure in adults. This study suggested that chronic ethanol administration is more effective to testicular GnRH and GnRH-R mRNA expression than hypothalamus and causes a negative effect on the spermatogenesis process. Furthermore, our finding suggests that the deteriorative effects of ethanol on gonadal activity are more lethal in puberty than adults.     

Halichondramine,a new tetracyclic bipiperidine alkaloid from the marine sponge Halichondria sp

Halichondramine (1), a new tetracyclic alkylbipiperidine alkaloid, has been isolated from the marine sponge Halichondria sp., collected in the Dahlak archipelago (the Red Sea), Eritrea. The structure of halichondramine was elucidated by interpretation of MS, COSY, HMQC, HMBC, TOCSY, and HSQC-TOCSY data.