5-HT1A Receptor Agonist Treatment Partially Ameliorates Rett Syndrome Phenotypes in mecp2-Null Mice by Rescuing Impairment of Neuron Transmission and the CREB/BDNF Signaling Pathway.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the gene that encodes methyl CpG-binding protein 2 (MECP2) and is characterized by the loss of acquired motor and language skills, stereotypic movements, respiratory abnormalities and autistic features. There has been no effective treatment for this disorder until now. In this study, we used a Mecp2-null (KO) mouse model of RTT to investigate whether repeated intraperitoneal treatment with the 5-HT1A receptor agonist tandospirone could improve the RTT phenotype. The results showed that administration of tandospirone significantly extended the lifespan of Mecp2-KO mice and obviously ameliorated RTT phenotypes, including general condition, hindlimb clasping, gait, tremor and breathing in Mecp2-KO mice. Tandospirone treatment significantly improved the impairment in GABAergic, glutaminergic, dopaminergic and serotoninergic neurotransmission in the brainstem of Mecp2-KO mice. Decreased dopaminergic neurotransmission in the cerebellum of Mecp2-KO mice was also significantly increased by tandospirone treatment. Moreover, RNA-sequencing analysis found that tandospirone modulates the RTT phenotype, partially through the CREB1/BDNF signaling pathway in Mecp2-KO mice. These findings provide a new option for clinical treatment.

Biallelic KARS pathogenic variants cause an early-onset progressive leukodystrophy.

The leukodystrophies cause severe neurodevelopmental defects from birth and follow an incurable and progressive course that often leads to premature death. It has recently been reported that abnormalities in aminoacyl t-RNA synthetase (ARS) genes are linked to various unique leukodystrophies and leukoencephalopathies. Aminoacyl t-RNA synthetase proteins are fundamentally known as the first enzymes of translation, catalysing the conjugation of amino acids to cognate tRNAs for protein synthesis. It is known that certain aminoacyl t-RNA synthetase have multiple non-canonical roles in both transcription and translation, and their disruption results in varied and complicated phenotypes. We clinically and genetically studied seven patients (six male and one female; aged 2 to 12 years) from five unrelated families who all showed the same phenotypes of severe developmental delay or arrest (7/7), hypotonia (6/7), deafness (7/7) and inability to speak (6/7). The subjects further developed intractable epilepsy (7/7) and nystagmus (6/6) with increasing age. They demonstrated characteristic laboratory data, including increased lactate and/or pyruvate levels (7/7), and imaging findings (7/7), including calcification and abnormal signals in the white matter and pathological involvement (2/2) of the corticospinal tracts. Through whole-exome sequencing, we discovered genetic abnormalities in lysyl-tRNA synthetase (KARS). All patients harboured the variant [c.1786C>T, p.Leu596Phe] KARS isoform 1 ([c.1702C>T, p.Leu568Phe] of KARS isoform 2) either in the homozygous state or compound heterozygous state with the following KARS variants, [c.879+1G>A; c.1786C>T, p.Glu252_Glu293del; p.Leu596Phe] ([c.795+1G>A; c.1702C>T, p.Glu224_Glu255del; p.Leu568Phe]) and [c.650G>A; c.1786C>T, p.Gly217Asp; p.Leu596Phe] ([c.566G>A; c.1702C>T, p.Gly189Asp; p.Leu568Phe]). Moreover, similarly disrupted lysyl-tRNA synthetase (LysRS) proteins showed reduced enzymatic activities and abnormal CNSs in Xenopus embryos. Additionally, LysRS acts as a non-canonical inducer of the immune response and has transcriptional activity. We speculated that the complex functions of the abnormal LysRS proteins led to the severe phenotypes in our patients. These KARS pathological variants are novel, including the variant [c.1786C>T; p.Leu596Phe] (c.1702C>T; p.Leu568Phe) shared by all patients in the homozygous or compound-heterozygous state. This common position may play an important role in the development of severe progressive leukodystrophy. Further research is warranted to further elucidate this relationship and to investigate how specific mutated LysRS proteins function to understand the broad spectrum of KARS-related diseases.

[One hath more ado to preserve than to get--two examples of extracurricular course for cultivating a sense of research mind].

Japanese medical schools currently confront a serious problem endangering the carrier path of medical students or doctors to the medical research activities in academic institutions. To address this issue, we have established an elective research promotion curriculum for medical students at the University of Yamanashi School of Medicine in 2006. While this system goes well in recruiting medical students to both basic and clinical research, we encounter now several issues that have to be fixed to consolidate this curriculum. To promote our system, we take part in the consortium of 4 universities in Kanto area (University of Tokyo, Chiba University, Gunma University, University of Yamanashi) for facilitating the interchange of medical students interested in research activities. We have just finished the 3rd summer meeting of affiliates lodging together in Gunma. This system serves for a lieu, where the "habitus" of researcher is shared among medical students and mentors. In the last part, three authors in different generations summarize what's important and problematic in recruiting and settling medical students to academic carrier.

Rare multiple combined anomaly of the vertebral vessels and bronchial artery.

Reported herein is a rare case of multiple vascular anomalies involving the vertebral vessels and the bronchial artery. In the present case the vertebral artery, which normally originates from the subclavian artery, arose directly from the cranial side of the aortic arch, just between the left common carotid and subclavian artery. Furthermore, the bilateral entry of the vertebral artery deviated to the upper level of the transverse foramen of the cervical vertebrae (C5). In addition, the left vertebral vein went through the transverse canal via the 5th and 7th transverse foramen, and drained into the left venous angle. Another conspicuous variation observed in this cadaver was the bronchial artery stemming from the left subclavian artery. This phenotype is an additional branch of bronchial arteries, which in normal cases arises from the descending aorta. These two anomalies could be explained by the deviation of the anlage for the left subclavian artery. The present report should be of interest for the clinician with regard to vascular anomalies in the neck and thoracic region, and may give insight into elucidating the developmental mechanism of angiogenesis.

Large-caliber persistent sciatic artery with aneurysm.

Herein is reported a rare case of right persistent sciatic artery (PSA) in the cadaver of a 96-year-old woman who did not have any clinical manifestations related to this anomaly when alive. The anomalous PSA originated from the internal iliac artery, directed toward the infrapiriform foramen, and descended the dorsal side of the thigh. Approximately 20 mm inferior to the infrapiriform foramen, the PSA formed a relatively large aneurysm elongating for approximately 30 mm in length. It then passed under the long head of the femoral biceps muscles, and reached the popliteal fossa, maintaining a constant caliber (approx. 13 mm) as it went down distally. In contrast, the femoral artery was very narrow, and tapered at the level of the knee joint. In addition, the popliteal vein gave rise to two branches, one ran along with the sciatic artery and the other pierced the adductor muscles, and appeared on the ventral side of the thigh. It then drained into the deep femoral vein, which reached the pelvis via the femoral vein. The present case is an interesting example for clinicians who work in pelvic surgery.