Immunoadsorption therapy for neuromyelitis optica spectrum disorders long after the acute phase

Neuromyelitis optica (NMO) is a severe inflammatory demyelinating disease with exacerbations involving recurrent or bilateral optic neuritis and longitudinally extensive transverse myelitis. Pulse steroid therapy is recommended as the initial, acute‐phase treatment for NMO. If ineffective, treatment with plasma exchange (PE) should commence. However, no evidence exists to support the effectiveness of PE long after the acute phase. Immunoadsorption therapy (IA) eliminates pathogenic antibodies while sparing other plasma proteins. With IA, side effects of PE resulting from protein substitution can be avoided. However, whether IA is effective for NMO remains unclear. We describe a patient with anti‐aquaporin‐4‐positive myelitis who responded to IA using a tryptophan polyvinyl alcohol gel column that was begun 52 days after disease onset following the acute phase. Even long after the acute phase when symptoms appear to be stable, IA may be effective and should not be excluded as a treatment choice. J. Clin. Apheresis 30:43–45, 2015. © 2014 Wiley Periodicals, Inc.     

PATHOGENESIS OF 1,2-DIMETHYLHYDRAZINE-INDUCED CARCINOMAS IN RAT INTESTINE

Seventy four white male Wistar rats were divided into two groups and given weekly subcutaneous injections of 30 rag 1,2-dimethylhydrazine (DMH) 2HCl/kg body weight for 10 or 15 weeks, respectively, and the histological properties and distribution of DMH-induced rat carcinomas were investigated. The carcinomas induced by DMH were classified mainly into mucin producing carcinomas and non-mucln producing ones. In the large intestine, the group treated for 15 weeks induced significant incidences of mucin producing carcinomas composed mainly of cells containing intracellular mucin. Mucin producing carcinomas consisted of poorly differentiated adenocarcinoma, signet ring cell carcinoma and mucinous carcinoma, and these often coexisted within the same tumor mass. Mucin producing carcinomas tended to develop in the proximal colon and caecum, while non-mucin producing carcinomas were frequent in the distal colon. This method was thought to be a useful model to sudy glycoproteins of cancer cells.     

ATM mutations in patients with ataxia telangiectasia screened by a hierarchical strategy

ATM has been identified as a gene that is responsible for ataxia telangiectasia (AT), a pleiotropic disorder of autosomal recessive inheritance. While many mutations of this gene in AT patients of various ethnicities have been reported, data on Japanese patients are scarce. In this report, we present the results of a thorough survey of ATM mutations in 14 unrelated AT patients, with an emphasis on Japanese subjects. We used a hierarchical strategy in which we extensively analyzed the entire coding region of the cDNA. In the first stage, point mutations were sought by PCR-SSCP in short patches. In the second and third stages, the products of medium- and long-patch PCR, each covering the entire region, were examined by agarose gel electrophoresis to search for length changes. We found a total of 15 mutations (including 12 new) and 4 polymorphisms. Abnormal splicing of ATM was frequent among Japanese, and no hotspot was obvious, suggesting no strong founder effects in this ethnic group. Eleven patients carried either one homozygous or two compound heterozygous mutations, one patient carried only one detectable heterozygous mutation, and no mutation was found in two patients. Overall, mutations were found in at least 75% of the different ATM alleles examined. Possible reasons for the inability to detect mutations in some patients are discussed. Hum Mutat 12:186–195, 1998. © 1998 Wiley-Liss, Inc.     

Inhibition of the Rho/ROCK pathway prevents neuronal degeneration in vitro and in vivo following methylmercury exposure

Methylmercury (MeHg) is an environmental neurotoxicant which induces neuropathological changes in both the central nervous and peripheral sensory nervous systems. Our recent study demonstrated that down-regulation of Ras-related C3 botulinum toxin substrate 1 (Rac1), which is known to promote neuritic extension, preceded MeHg-induced damage in cultured cortical neurons, suggesting that MeHg-mediated axonal degeneration is due to the disturbance of neuritic extension. Therefore we hypothesized that MeHg-induced axonal degeneration might be caused by neuritic extension/retraction incoordination. This idea brought our attention to the Ras homolog gene (Rho)/Rho-associated coiled coil-forming protein kinase (ROCK) pathway because it has been known to be associated with the development of axon and apoptotic neuronal cell death. Here we show that inhibition of the Rho/ROCK pathway prevents MeHg-intoxication both in vitro and in vivo. A Rho inhibitor, C3 toxin, and 2 ROCK inhibitors, Fasudil and Y-27632, significantly protected against MeHg-induced axonal degeneration and apoptotic neuronal cell death in cultured cortical neuronal cells exposed to 100 nM MeHg for 3 days. Furthermore, Fasudil partially prevented the loss of large pale neurons in dorsal root ganglia, axonal degeneration in dorsal spinal root nerves, and vacuolar degeneration in the dorsal columns of the spinal cord in MeHg-intoxicated model rats (20 ppm MeHg in drinking water for 28 days). Hind limb crossing sign, a characteristic MeHg-intoxicated sign, was significantly suppressed in this model. The results suggest that inhibition of the Rho/ROCK pathway rescues MeHg-mediated neuritic extension/retraction incoordination and is effective for the prevention of MeHg-induced axonal degeneration and apoptotic neuronal cell death.     

IGSF4 is a novel TCR ζ-chain-interacting protein that enhances TCR-mediated signaling

Immunoglobulin superfamily member 4 (IGSF4) is a known ligand of CRTAM, a receptor expressed in activated NKT and CD8(+) T cells, but its function in T cell immunity has not been elucidated. In this study, we show that IGSF4 directly interacts with the T cell receptor (TCR) ζ-chain and enhances TCR signaling by enhancing ζ-chain phosphorylation. Ectopic overexpression of IGSF4 enhances TCR-mediated T cell activation. In contrast, IGSF4 knockdown shows a dramatic decrease in markers associated with T cell activation compared with those in control small interfering RNA. The transmembrane domain is essential for TCR ζ-chain association and clustering to the immunological synapse, and the ectodomain is associated with T cell interaction with antigen-presenting cells (APCs). IGSF4-deficient mice have impaired TCR-mediated thymocyte selection and maturation. Furthermore, these mice reveal attenuated effector T cell functions accompanied by defective TCR signaling. Collectively, the results indicate that IGSF4 plays a central role in T cell functioning by dual independent mechanisms, control of TCR signaling and control of T cell-APC interaction.     

Clinical training in department of general dentistry at Tokyo Dental College Chiba Hospital

A compulsory postgraduate clinical training program was established in April 2006 in Japan, and an applicants-only postgraduate training program 9 years ago at Tokyo Dental College. In addition, a training program was also established in the Department of General Dentistry at Tokyo Dental College Chiba Hospital in April 2002. The curriculum consists of training in the outpatient clinic and the following: 1) clinical training (preparation of written treatment plans, simulation practice, submission of evaluation sheets, and submission of training journals), 2) tutorials, and 3) case reports. In 1), trainees write treatment plans for new patients, discuss them with their instructor, perform simulation practice using dummies based on those discussions, submit evaluation sheets and training journals concerning treatment, and receive their instructor's assessment. In 2), trainees are divided into small groups, independently study themes they have chosen, and present the results. In 3), they orally report cases they have treated and receive evaluation by other trainees and instructors in general discussion meetings. In addition, a course was also established at the Department of General Dentistry, Tokyo Dental College Chiba Hospital in April 2002. We report the training curriculum of this course.     

Functional characterization of melanocyte stem cells in hair follicles

In mice, coat pigmentation requires a stem cell (SC) system in which the survival, proliferation, and differentiation of melanocytes (MCs) are regulated by microenvironments in hair follicles (HFs). In vitro systems are required to analyze the behavior of single melanocyte stem cells (MCSCs) and their potential to form SC systems in vivo. We describe here an experimental system for the isolation, self-renewal, and differentiation of MCSCs, as well as an in vivo reconstitution assay for assessing their potential. Using Dct(tm1(Cre)Bee)/CAG-CAT-GFP mice, we show that, in the presence of stem cell factor and basic fibroblast growth factor and the XB2 feeder cell line, purified MCSCs can undergo clonogenic proliferation, resulting in c-Kit(low) side scatter(low) cells. In culture, these cells maintain their capacity to differentiate and reconstitute an MCSC system in HFs. As these cells are present in the upper part of the HF near the bulge region, express only low levels of housekeeping genes, and are resistant to neonatal treatment with ACK2, it is likely that only MCSCs that are quiescent in vivo have clonogenic activity in vitro. We also found that MCSCs can be purified from wild-type mice by fluorescent cell sorting and can be characterized in vitro.