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Background and purpose: The prevalence of multiple sclerosis (MS) is considered to be lower in East Asia than in Western countries. An increasing trend has been reported globally for the prevalence of MS. We investigated the changes in the prevalence and clinical characteristics of MS in the Tokachi province of Hokkaido, northern Japan from 2001 to 2016. Methods: Prevalence was determined on 31 March 2016. Data‐processing sheets were collected from all MS‐related institutions in Tokachi province. We applied Poser's diagnostic criteria for MS as used in our previous three studies. Cases of neuromyelitis optica spectrum disorders were excluded. Results: In 2016, the crude MS prevalence was 18.6/100 000 (95% confidence interval, 14.3–23.8) in northern Japan. Over the last 15 years, the prevalence of MS in the same area was 8.1, 12.6 and 16.2 in 2001, 2006 and 2011, respectively. The female:male ratio was 3.57, which increased from 2.63 in 2001. The ratios of primary progressive, relapsing–remitting and secondary progressive MS types were 2%, 84% and 14%, respectively. Conclusion: Our results demonstrated a consistent increase in MS prevalence among the northern Japanese population, particularly in females, and relatively lower rates of progressive MS in northern Japan than in Western countries. [ABSTRACT FROM AUTHOR]

Diet is one of the important factors that modulate immune responses. In the present study, we have examined the capacity of dietary lipids to modify immune responses in mice and we have investigated the contribution of glycolipid-reactive natural killer T (NKT) cells in this process. Mice fed, high fat diet (HFD; 21.2% fat, 0.20% cholesterol) for 3 weeks, as compared with mice fed standard fat diet (SFD; 4.3% fat, 0.03% cholesterol), showed significantly reduced interferon-γ production in sera at 6 or 12 h after intraperitoneal injection of an NKT cell ligand, α-galactosylceramide. In contrast, production of interleukin-13 was significantly higher at 2 and 6 h in HFD fed mice compared with mice on SFD. No difference was detected in the serum interleukin-4 levels between these two groups of animals. The proportion of NKT cells in spleen and liver was reduced in mice fed HFD compared with those on SFD. In addition, activation of NKT cells assessed by up-regulation of CD69 was suppressed specifically in liver from mice fed HFD. Recall responses of conventional T cells and delayed-type hypersensitivity (Th1 type) against ovalbumin were significantly suppressed in mice fed HFD in comparison with those fed SFD. This suppression was not observed in CD1d−/− mice, suggesting that NKT cells in mice fed HFD played a role in suppressing Th1 responses. Taken together, our findings suggest a critical link between NKT cells, dietary lipid and adaptive immune responses. [ABSTRACT FROM AUTHOR]

Despite the strength of the association of multiple sclerosis (MS) and human leukocyte antigen (HLA)-DR2, other genetic elements could have a role in the pathophysiology of MS. We investigated possible associations with polymorphic susceptibility genes located within the HLA complex, i.e., heat-shock protein (HSP)70-1, HSP70-2, and HSP70-hom in Japanese patients with MS. Furthermore, we analyzed the influence of HSP70 gene polymorphisms on the severity of the disease, clinical course, magnetic resonance imaging findings, and oligoclonal bands in the cerebrospinal fluid, and HLA in MS patients. The results of the present study indicated that there were no significant differences in the distribution of all HSP70 genotypes and allele frequencies between Japanese MS patients and controls. In MS patients, there were no associations between HSP70 gene polymorphisms and the clinical data. Moreover, there were no significant differences in HSP70 genotype or allele frequencies between MS patients positive for HLA-DRB1*1501 alleles and matched controls. Our data indicate that HSP70 gene polymorphisms are not relevant in the susceptibility to or the severity of Japanese MS patients. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses a case study involving a 79-year-old woman with neuromyelitis optica (NMO) spectrum disorder, who exhibited seroconversion of AQP4 antibody and hyperCKemia at the onset of myelitis.

Objectives: This study was conducted to screen thyroid abnormality evaluated with ultrasonography (US) in patients with myasthenia gravis (MG) and investigate further when malignancy is suspected., Methods: Thyroid screening using US was conducted in 162 patients with MG. In cases where malignancy was suspected, further investigations were performed., Results: Abnormal US findings were detected in 125 of 162 patients with MG (72 patients with nodules, 74 patients with cysts, 27 patients with diffuse findings such as enlargement, atrophy, a hypoechoic pattern or a heterogenous echoic pattern, and 28 patients with calcification). From among these 125 subjects, 30 patients underwent further examinations such as needle aspiration cytology. As a result, six patients (3.7% of 162 cases) were positive for papillary carcinoma. The size of the carcinoma in three patients was <10 mm, yet the stage of thyroid carcinomas was high (stage III or IVa) in all six cases., Conclusions: Our data suggest that the prevalence of thyroid carcinoma in cases of MG may be higher than that of the general population. Furthermore, in patients with MG, there is a possibility that the stage of the carcinoma is higher even when the carcinoma is of a very small size. Patients with MG, when diagnosed, should be advised to undergo US screening of the thyroid because most cases of thyroid carcinoma are highly curable., (© 2011 John Wiley & Sons A/S.)

The mitochondrial pyruvate dehydrogenase complex (PDC) catalyzes the oxidative decarboxylation of pyruvate to acetyl-CoA. PDC activity is tightly regulated by four members of a family of pyruvate dehydrogenase kinase isoforms (PDK1-4), which phosphorylate and inactivate PDC. Recently, the development of specific inhibitors of PDK4 has become an especially important focus for the pharmaceutical management of diabetes and obesity. In this study, crystal structures of human PDK4 complexed with either AMPPNP, ADP or the inhibitor M77976 were determined. ADP-bound PDK4 has a slightly wider active-site cleft and a more disordered ATP lid compared with AMPPNP-bound PDK4, although both forms of PDK4 assume open conformations with a wider active-site cleft than that in the closed conformation of the previously reported ADP-bound PDK2 structure. M77976 binds to the ATP-binding pocket of PDK4 and causes local conformational changes with complete disordering of the ATP lid. M77976 binding also leads to a large domain rearrangement that further expands the active-site cleft of PDK4 compared with the ADP- and AMPPNP-bound forms. Biochemical analyses revealed that M77976 inhibits PDK4 with increased potency compared with the previously characterized PDK inhibitor radicicol. Thus, the present structures demonstrate for the first time the flexible and dynamic aspects of PDK4 in the open conformation and provide a basis for the development of novel inhibitors targeting the nucleotide-binding pocket of PDK4.

The 70 kDa heat-shock proteins (Hsp70s) are highly conserved chaperones that are involved in several cellular processes, such as protein folding, disaggregation and translocation. In this study, the crystal structures of the human Hsp70 nucleotide-binding domain (NBD) fragment were determined in the nucleotide-free state and in complex with adenosine 5'-(beta,gamma-imido)triphosphate (AMPPNP). The structure of the nucleotide-free NBD fragment is similar to that of the AMPPNP-bound NBD fragment and is designated as the ;closed form'. In the nucleotide-free NBD fragment the closed form is intrinsically supported through interactions between Tyr15, Lys56 and Glu268 which connect subdomains IA, IB and IIB at the centre of the protein. Interaction with the substrate-binding domain (SBD) of Hsp70 or the BAG domain of BAG1 impairs this subdomain connection and triggers the rotation of subdomain IIA around a hydrophobic helix from subdomain IA. The subdomain rotation is limited by Asp199 and Asp206 from subdomain IIA and clearly defines the open form of the NBD. The open form is further stabilized by a new interaction between Gly230 from subdomain IIB and Ser340 from subdomain IIA. The structure of the NBD in the nucleotide-free state is determined by switching of the inter-subdomain interactions.

UNC5Hs (UNC5H1-4) are netrin 1 receptors that are involved in axonal guidance and neuronal migration. They are dependence receptors that mediate apoptosis in the absence of netrin 1. UNC5H2-induced apoptosis depends on the interaction of the death domain at the C-terminus with the DAP-kinase death domain and caspase cleavage near the transmembrane region. Here, the crystal structure of the mouse UNC5H2 death domain has been determined at 2.1 A resolution. The domain adopts a six-helix bundle fold, which is similar to those of the other members of the death-domain superfamily. The UNC5H2 death domain is a dimer in the crystal and in solution. This homodimerized structure may represent the structure of the death domain when netrin 1 binds to the UNC5H2 receptor. Homodimerization of UNC5H2 may block the access of caspase to the cleavage site. In the death-domain dimer, residues in alpha3 and the 3(10)-helix preceding alpha3 and the residues in alpha4 make significant contacts, mainly by hydrophobic and van der Waals interactions.

A male patient had a relapse of myelodysplastic syndrome (MDS) 2 years after BMT from a female matched unrelated donor. Conventional cytogenetics, FISH, and short-tandem repeat chimerism analysis proved a relapse of donor origin. He underwent reduced-intensity BMT after a conditioning with fludarabine and busulfan, since he had impaired renal, liver, and pulmonary functions. Chimerism analysis on day 28 after the second BMT showed mixed chimerism of the first and the second donors, which later turned to full second-donor chimerism on day 60. He developed grade II acute GVHD of the skin and cytomegalovirus reactivation, but both were improved with methylprednisolone and ganciclovir, respectively. He remains in complete remission 6 months after the second BMT. Reduced-intensity second BMT from an alternative donor appeared to be a tolerable treatment option for donor-derived leukemia/MDS after the first conventional transplantation., (Copyright 2003 Wiley-Liss, Inc.)

Polymerase chain reaction (PCR) is a sensitive method for detection of Aspergillus DNA in bronchoalveolar lavage fluid, but it has not yet been able to distinguish infection from contamination. We have established a technique to quantify Aspergillus DNA using a real-time PCR method to resolve this problem, and we report herein a successful application of real-time PCR to diagnose invasive pulmonary aspergillosis by comparing the amount of Aspergillus DNA in bronchial lavage fluid from an affected area to that from an unaffected area. This novel tool will provide rapid, sensitive, and specific diagnosis of pulmonary aspergillosis., (Copyright 2002 Wiley-Liss, Inc.)