Paraneoplastic Neuromyelitis Optica Spectrum Disorder Related to Glucose-regulated Protein 78 (GRP78) Autoantibodies in a Patient with Lynch Syndrome-associated Colorectal Cancer.

Neuromyelitis optica spectrum disorders have been previously reported in a paraneoplastic context, although there is no clear consensus on their pathogenesis. We herein report a case of aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder in a 64-year-old woman with colorectal cancer. She underwent tumor resection, resulting in serum aquaporin-4 antibody titers subsequently becoming negative. Serum samples were also positive for glucose-regulated protein 78 antibody, which has recently been suggested to be a novel factor in the disruption of the blood-brain barrier. Serological and pathological investigations in this case highlight the role and involvement of aquaporin-4 and glucose-regulated protein 78 antibodies in paraneoplastic conditions.

[Investigation into the Effect of Shitei Extract, a Traditional Chinese Medicine Formulation, on Hiccups].

Hiccups are occasionally experienced by most individuals, and although not life-threatening, they may leadto a decline in quality of life. Shitei extract(shitei, persimmon calyx)may be usedfor the treatment of hiccups. The effects of shitei extract were investigatedin patients admittedto the Japanese RedCross Musashino Hospital between October 2011 andM ay 2016. Numerous prescriptions for shitei extract were reportedin the Department of Respiratory Organs andNeurosurgery. The primary causes of hiccups were chemotherapy andbrain disease. Of 149 patients, 107(71.8%)sufferedfrom hiccups. None of the patients reported adverse events related to the administration of shitei extract. The incidence of hiccups was significantly higher in patients with brain disease(p=0.0075), treatedwith chemotherapy for cancer(p=0.0402), or requiring the insertion of a gastric tube(p=0.0065). Among those treatedwith chemotherapy for cancer, shitei extract was effective against hiccups in 82.0% patients(45 of 55). Furthermore, four patients receivedprophylaxis with shitei extract for the prevention of hiccups after chemotherapy. In conclusion, these results indicate that shitei extract is an effective and safe therapeutic drug for the treatment of hiccups. In particular, shitei extract was effective in the prevention of hiccups after chemotherapy.

The carboxy-terminal fragment of alpha(1A) calcium channel preferentially aggregates in the cytoplasm of human spinocerebellar ataxia type 6 Purkinje cells.

Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant neurodegenerative disease caused by a small polyglutamine (polyQ) expansion (control: 4-20Q; SCA6: 20-33Q) in the carboxyl(C)-terminal cytoplasmic domain of the alpha(1A) voltage-dependent calcium channel (Ca(v)2.1). Although a 75-85-kDa Ca(v)2.1 C-terminal fragment (CTF) is toxic in cultured cells, its existence in human brains and its role in SCA6 pathogenesis remains unknown. Here, we investigated whether the small polyQ expansion alters the expression pattern and intracellular distribution of Ca(v)2.1 in human SCA6 brains. New antibodies against the Ca(v)2.1 C-terminus were used in immunoblotting and immunohistochemistry. In the cerebella of six control individuals, the CTF was detected in sucrose- and SDS-soluble cytosolic fractions; in the cerebella of two SCA6 patients, it was additionally detected in SDS-insoluble cytosolic and sucrose-soluble nuclear fractions. In contrast, however, the CTF was not detected either in the nuclear fraction or in the SDS-insoluble cytosolic fraction of SCA6 extracerebellar tissues, indicating that the CTF being insoluble in the cytoplasm or mislocalized to the nucleus only in the SCA6 cerebellum. Immunohistochemistry revealed abundant aggregates in cell bodies and dendrites of SCA6 Purkinje cells (seven patients) but not in controls (n = 6). Recombinant CTF with a small polyQ expansion (rCTF-Q28) aggregated in cultured PC12 cells, but neither rCTF-Q13 (normal-length polyQ) nor full-length Ca(v)2.1 with Q28 did. We conclude that SCA6 pathogenesis may be associated with the CTF, normally found in the cytoplasm, being aggregated in the cytoplasm and additionally distributed in the nucleus.

[Molecular genetic approach to spinocerebellar ataxias].

Spinocerebellar ataxia (SCA) is a group of degenerative ataxias with autosomal dominant inheritance. The most common form of mutation that causes SCA is the expansion of trinucleotide (CAG) repeat encoding polyglutamine. These "polyglutamine disorders" are, SCA1, SCA2, Machado-Joseph disease, SCA6, SCA7, SCA17 and DRPLA. Another dynamic mutation, yet a non-coding one, has been identified as the cause of SCA8, SCA10 and SCA12. This mutation includes, trinucleotide (CAG/CTG) expansion causing SCA8 and SCA12, and pentanuclotide (ATTCT) expansion leading SCA10. In addition to these dynamic mutations, static mutations, such as missense mutations and deletions, have been identified to cause SCA5, SCA11, SCA13, SCA14, SCA15 and SCA27. Since 1992, authors have been involved in identifying the mutation (s) of autosomal dominant cerebellar ataxia with rather pure cerebellar syndrome (ADCAIII). About a half of our cohort with ADCAIII were SCA6, caused by a small CAG repeat expansion in the alpha1A-voltage-dependent calcium channel gene. Recent study in patients' brains suggested that a small polyglutamine expansion leads a portion of this channel protein to aggregate in the Purkinje cell. Another type of ADCAIII is the chromosome 16q22.1-linked ADCA. By a comprehensive positional cloning strategy, we have found a genetic change that segregate with the disease. Identifying the mutation of 16q-ADCA is imperative for understanding molecular basis of this disease.

Analyses of copy number and mRNA expression level of the alpha-synuclein gene in multiple system atrophy.

Multiple system atrophy (MSA) is a sporadic neurodegenerative disease manifested clinically by progressive ataxia, parkinsonism, and autonomic dysfunction. Its cause is unknown, and there is no curative therapy. Alpha-synuclein is an important protein forming aggregations called glial cytoplasmic inclusions (GCIs) in oligodendroglia; these aggregations are considered important in MSA pathogenesis. Overexpression of the human alpha-synuclein gene in mice induces the formation of GCI-like aggregations in oligodendrocytes, leading mice to exhibit neurological signs similar to those in MSA patients. However, previous studies have excluded mutations within the coding region of the alpha-synuclein gene in MSA patients. To determine whether alteration in the expression level of the alpha-synuclein gene is associated with MSA pathogenesis, we used TaqMan quantitative PCR assay to analyze the alpha-synuclein gene copy number in patients' genomes. We also used quantitative RT-PCR and in situ hybridization to analyze alpha-synuclein mRNA expression in MSA patients' brain tissues. We found no alteration in the alpha-synuclein gene copy number in the patients' genomes (n = 50). Quantitative analysis for alpha-synuclein mRNA by the TaqMan method showed that alpha-synuclein mRNA levels were comparable between control (n = 3) and MSA (n = 3) cerebella. On in situ hybridization, the number of neurons with alpha-synuclein mRNA expression was no greater in the cerebella of MSA patients (n = 3) than in the controls (n = 3). However, GCIs were seen in these MSA specimens on immunohistochemistry for alpha-synuclein. These results suggest that alpha-synuclein gene expression is not the fundamental cause of MSA.