CNVs in Three Psychiatric Disorders

BACKGROUND: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). METHODS: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. RESULTS: In genic CNVs, we found an increased burden of smaller (500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25–0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. CONCLUSIONS: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD

The efficacy of lumbar sympathetic nerve block for neurogenic intermittent claudication in lumbar spinal stenosis

Background: The symptoms of LSS include radicular symptoms (RS) and IMC. IMC is thought to be caused by circulatory disturbances in the cauda equina nerves and does not often resolve naturally. There are reports of increased cauda equina nerve blood flow in canine spinal stenosis models as a result of lumbar sympathetic resection. Thus, we believed that improvement of IMC in LSS may be achieved by performing a LSNB to produce a medium-term effect. Materials and Methods: Patients with LSS suffering from IMC in both legs were enrolled in this study. Those with IMC symptoms alone were classified as cauda equina-type (CE group), while those who also suffered from RS were classified as mixed-type (M group). LSNB was performed on both sides using a neurolysis in both groups. Evaluation was using the Zurich claudication questionnaire (ZCQ). Results: Twenty-six subjects were completed the six-month observation period. In contrast to the CE group who, throughout the observation period, experienced significant improvements in Symptom Severity (SS) and Physical Function (PF) scores compared with those before treatment, no such significant differences were observed in the M group throughout the observation period. In addition, a significant decrease in the SS scores of the CE group one-month after treatment and in the PF and Patient Satisfaction (PS) scores both one-month and two-months after treatment was observed in comparison with the M group. Conclusion: Our results show that LSNB for LSS is more effective in improving neurogenic intermittent claudication than radicular symptoms, and this suggests that LSNB could become an effective treatment for cauda equina-type lumbar spinal stenosis that is resistant to other conservative treatment

Recent Advances in <em>In Vivo</em> Genome Editing Targeting Mammalian Preimplantation Embryos

CRISPR-based genome engineering has been widely used for producing gene-modified animals such as mice and rats, to explore the function of a gene of interest and to create disease models. However, it always requires the ex vivo handling of preimplantation embryos, as exemplified by the microinjection of genome editing components into zygotes or in vitro electroporation of zygotes in the presence of genome editing components, and subsequent cultivation of the treated embryos prior to egg transfer to the recipient females. To avoid this ex vivo process, we have developed a novel method called genome-editing via oviductal nucleic acids delivery (GONAD) or improved GONAD (i-GONAD), which enables in situ genome editing of zygotes present in the oviductal lumen of a pregnant female. This technology does not require any ex vivo handling of preimplantation embryos or preparation of recipient females and vasectomized males, all of which are often laborious and time-consuming. In this chapter, recent advances in the development of GONAD/i-GONAD will be described