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.     

Prevalence of specific IgA and IgM anti-HBc antibodies compared with HBV DNA in the sera of HBsAg chronic carriers

OBJECTIVE: We evaluated the significance of IgA antibodies directed against the hepatitis B virus core antigen (IgA anti-HBc) as a marker for viral replication. STUDY DESIGN/METHODS: Serum samples of 143 hepatitis B surface antigen (HBsAg) carriers and 189 HBsAg-negative subjects were studied. Hepatitis B virus (HBV) DNA was detected by polymerase chain reaction. IgA anti-HBc was determined by a capture enzyme-linked immunosorbent assay developed in our laboratory. The results were compared with those for IgM anti-HBc, which were determined by a commercially available method. RESULTS: IgA anti-HBc was detected in 57 (40%) and HBV DNA in 38 (27%) of the HBsAg carriers. Among the HBsAg-negative subjects, IgA anti-HBc and HBV DNA were detected simultaneously in four samples. All 42 HBV DNA-positive samples were IgA anti-HBc positive. IgM anti-HBc was detected in 27 (64%) of them. CONCLUSIONS: IgA anti-HBc is a sensitive marker for HBV replication, and its absence may exclude HBV replication. The role of IgA anti-HBc in monitoring response to therapy and predicting clinical course is being evaluated.     

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.     

A Novel Non-Invasive Adjuvant Biomechanical Treatment for Patients with Altered Rehabilitation after Total Knee Arthroplasty: Results of a Pilot Investigation

Background

Many factors contribute to suboptimal results after total knee arthroplasty (TKA) but little is known regarding the value of postsurgical rehabilitation after TKA. We examined the effects of an enhanced closed kinematic chain exercises program (AposTherapy) on gait patterns and clinical outcomes among patients with a lack of progress in their postsurgical rehabilitation.

Methods

Twenty-two patients were prospectively followed during the study. Gait spatiotemporal parameters were measured at the initial evaluation, after 15 minutes of therapy, and after 3 months of therapy. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the short form (SF) 36 health survey were completed by patients before treatment and after 3 months of treatment.

Results

The WOMAC and SF-36 scores improved significantly after 3 months of treatment. Gait velocity, single limb support, and step length of the operated leg improved significantly even after a single 15 minutes treatment. Normal gait velocity was observed in 36% of patients after 3 months of treatment.

Conclusions

A physiotherapy program that included enhanced closed kinematic chain biomechanical therapy was beneficial for patients who experienced a suboptimal rehabilitation course after TKA.