Japanese cases of neuromyelitis optica spectrum disorder associated with myasthenia gravis and a review of the literature.

BACKGROUND: The incidence of concurrent myasthenia gravis (MG) and neuromyelitis optica spectrum disorder (NMOSD) is higher than what chance predicts, yet it remains unclear why MG and NMOSD appear concurrently. OBJECTIVE: The purpose of the present study was to examine the clinical features of the concurrence of these diseases. METHODS: Clinical details were analyzed retrospectively. RESULTS: Three (0.5%) out of 631 MG patients had confirmed (n=2) or suspected (n=1) NMOSD. Two of these patients were women. All showed early-onset MG (EOMG) that preceded NMOSD and were positive for acetylcholine receptor antibody (AChR-Ab). Two patients were tested for aquaporin 4 antibody (AQP4-Ab) and were positive. Two patients were treated with a thymectomy that preceded NMOSD. Two patients had decreased frequency of regulatory T (Treg) cells. We identified in the literature 46 patients with both MG and NMOSD. Our results of female predominance, EOMG, MG preceding NMOSD, and positive AChR-Ab are consistent with previous descriptions. CONCLUSIONS: This is the first report to examine the frequency of NMOSD in Japanese patients with MG. The reduction and/or dysfunction of Treg cells may be one cause of NMOSD development in MG.

Identification of citrullinated cellular fibronectin in synovial fluid from patients with rheumatoid arthritis.

OBJECTIVES: Cellular fibronectin (cFn) has been implicated in the pathogenesis of rheumatoid arthritis (RA), and we previously demonstrated the presence of citrullinated cFn in rheumatoid synovial tissues. The present study aimed to investigate whether citrullinated cFn can be detected in the plasma or synovial fluid of RA patients. METHODS: Twenty-five rheumatoid arthritis synovial fluid (RASF), seven osteoarthritis synovial fluid (OASF) and 12 plasma samples from RA patients were examined. Citrullination of cFn was determined by immunoprecipitation (IP), western blotting and enzyme-linked immunosorbent assay (ELISA), in which peptidyl-citrulline within cFn was detected using a specific anti-cFn monoclonal antibody in combination with anti-modified citrulline antibody after chemical modification. RESULTS: Levels of citrullination associated with cFn, as determined by ELISA, were significantly higher in RASF than in OASF samples. IP and western blotting detected citrullinated cFn in RASF but not in plasma samples from RA patients. Levels of total cFn were elevated in RASF compared with OASF, and 24 out of 25 RASF samples were positive for anti-CCP antibody. However, no correlation was observed between levels of citrullinated cFn and those of total cFn or anti-CCP antibody in RASF. On the other hand, a significant positive correlation was observed between the levels of matrix metalloproteinase-3 (MMP-3) and cFn citrullination in RASF. CONCLUSIONS: Citrullinated cFn appears to be produced within the affected joint and might be involved in the pathogenesis of rheumatoid synovitis.

Pramipexole reduces the prevalence of fatigue in patients with Parkinson's disease.

OBJECTIVE: The aim of this multicenter cross-sectional study was to assess the relation between fatigue in a large number of Japanese patients with Parkinson's disease (PD) and drugs taken to treat PD. METHOD: We used the 16-item Parkinson Fatigue Scale (PFS-16), which was designed to assess fatigue exclusively associated with PD. Multiple logistic regression analyses were used to assess the relation between antiparkinson drugs and fatigue in PD. RESULTS: A total of 350 non-demented PD patients were enrolled. Fatigue (PFS score of ≥4) was revealed in 319 patients (91%). Pramipexole was administered to 24% of PD patients. Multiple logistic regression analysis revealed that the administration of Pramipexole was significantly related to low rates of fatigue in PD patients with Hoehn and Yahr stage <3 (p=0.011, odds ratio=5.23, 95% confidence interval; 1.47-18.63). CONCLUSION: The reduced fatigue in PD patients was observed in taking Pramipexole.

Postural instability at a simulated altitude of 5,000 m before and after an expedition to Mt. Cho-Oyu (8,201 m).

To clarify the effects of altitude acclimatization on postural instability at altitudes, six female climbers stood with their eyes open or closed on a force-measuring platform under normoxia (NC) and hypobaric hypoxia, equivalent to a 5,000 m altitude (HC), before and after an expedition to Mt. Cho-Oyu (8,201 m). The expedition extended over 84 days. We recorded sways in the center of foot pressure, electromyograms (EMGs) of lower-leg muscles, blood components and arterial oxygen saturation (SpO(2)). Before the expedition, the maximum amplitude of sway with the eyes open and integrated EMG from the medial gastrocnemius increased for HC. After the expedition, red blood cell (from 423.4 ± 15.4 to 498.0 ± 24.5 × 10(4) µl(-1)), hemoglobin content (from 12.6 ± 0.32 to 14.5 ± 1.00 g/dl) and 2,3-diphosphoglycerate (from 1.93 ± 0.21 to 2.24 ± 0.34 µmol/ml) increased. The SpO(2) under HC increased from 69.2 ± 9.6 to 77.2 ± 10.0%. The maximum amplitude of sway with the eyes open decreased for HC. No difference in the sway path length and integrated EMGs was observed between NC and HC. These results suggest that acclimatization can improve the impaired postural stability on initial arrival at altitudes. However, it is still unclear how long acclimatization period is needed. Further studies are needed to reveal this point.

A novel nonsense mutation in a Japanese family with ataxia with oculomotor apraxia type 2 (AOA2).

We report a 67-year-old Japanese woman with ataxia with oculomotor apraxia type 2 (AOA2). She was born to consanguineous parents and showed a teenage onset, a slowly progressive cerebellar ataxia and sensory-motor neuropathy and an elevated level of serum alpha-fetoprotein (AFP). All of these clinical features were consistent with typical AOA2. She lacked oculomotor apraxia, as frequently observed in previously reported AOA2 patients. She was homozygous for a novel nonsense mutation, Glu385Ter (E385X), in the senataxin gene (SETX). To our knowledge, this is the fifth Japanese family with genetically confirmed AOA2. The mutations in SETX in Japanese AOA2 families are heterogeneous, except for M274I, which has been found in two unrelated families. More extensive screening by serum AFP followed by molecular genetic analysis of SETX in patients with Friedreich's ataxia-like phenotype may show that AOA2 is more common in Japan than previously thought.

Fatigue in Japanese patients with Parkinson's disease: a study using Parkinson fatigue scale.

The objective of this multicenter cross-sectional study was to determine the prevalence of fatigue and factors contributing to it in a large sample of Japanese patients with Parkinson's disease (PD). We used the 16-item Parkinson Fatigue Scale (PFS-16), which was designed to assess fatigue exclusively associated with PD. We carried out this study using PFS-16, the Unified Parkinson's Disease Rating Scale, Zung's Self-Rating Depression Scale, Parkinson's Disease Sleep Scale (PDSS), and the PD quality of life (QOL) scale (PDQ-39) by interview using questionnaires and physical examination by neurologists in 361 nondemented PD patients. Fatigue (an average PFS score of 3.3 or greater) was revealed in 151 patients (41.8%). Multiple logistic regression analysis indicated that the significant independent variables related to the presence of fatigue were the scores of PDSS and PDQ-39. Depression score was not a significant contributing factor. Our study revealed that the prevalence of fatigue in Japanese PD patients is as high as that in Western countries, and that fatigue is a relatively independent symptom, although sleep disturbance may be associated with fatigue. Since fatigue is significantly related to QOL reduction, therapeutic interventions including treatment of sleep disturbance are important.

[Beta2-glycoprotein I polymorphism].

Antiphopholipid syndrome (APS) is a major cause of ischemic stroke in young adults. In our study, stroke patients with antiphospholipid antibodies (APL) were significantly younger and were more likely to be women than stroke patients without APL. Valvular heart disease, neurological complications, and hematological disorders were more frequent in the APL-positive group. The mean value of thrombin-antithrombin III complex was significantly lower in the APL-positive group. beta2-Glyoprotein I (beta2-GPI) is the antigen primarily responsible for APL. At the DNA level, 4 different types of allelic polymorphisms have been detected in beta2-GPI. The allele at position 247 has codes for either valine (V) or leucine (L), which results in genotypic expression of VV, VL, or LL. In our study, the V and VL genotypes were more frequent in patients with cerebral infarction than in normal controls. The VL genotype was more frequent among patients aged less than 60 years than in those aged more than 60 years. The mean values of beta-thromboglobulin and platelet factor 4 in patients with the VL genotype were significantly higher than those with the LL genotype. The results suggested that V247 beta2-GPI allele is one of the genetic risk factors for the development of cerebral infarction through platelet activation.

Smell identification in Japanese Parkinson's disease patients: using the odor stick identification test for Japanese subjects.

OBJECTIVE: The purpose of the present study was to clarify the olfactory functions of Japanese patients with idiopathic Parkinson's disease (IPD) using the odor stick identification test for Japanese (OSIT-J). METHODS: Fifty-four non-demented IPD patients (33 men and 21 women), ranging in age from 43 to 81 years (69.7+/-8.1 years) and 50 age- and gender-matched healthy controls who reported having no olfactory complaints were enrolled. OSIT-J consisted of 12 odorants familiar to Japanese subjects. Each subject sniffed each odor that was applied to paraffin paper. Next the subject chose 1 of 6 answers: 4 pictures associated with the odors labeled with their names, one of which was correct, and 2 other ones ("unknown" and "not detected"). RESULTS: The number of correct answers was significantly lower in the IPD group (4.4+/-2.7) than in the normal group (8.3+/-2.2) (p<0.0001). Even in IPD patients who could smell normal strength odors in subjective symptom, the number of correct answers decreased. The number of correct answers was not correlated with motor function, disease duration, or medication. CONCLUSION: The present study demonstrated that the smell identification ability of Japanese IPD patients was impaired based on the OSIT-J.

Clinical characteristics of stroke patients with antiphospholipid antibodies.

BACKGROUND: Antiphospholipid syndrome is important as a cause of ischemic stroke, although clinical characteristics of the syndrome are not well documented. METHODS: We analyzed differences in clinical characteristics between 40 antiphospholipid-antibody (aPL)-positive and 40 aPL-negative stroke patients. RESULTS: Stroke patients with aPL were significantly younger and were more likely to be women in comparison with stroke patients without aPL. Valvular heart disease, neurological complications and hematological disorders were more frequent in the aPL-positive group. The mean value of thrombin-antithrombin III complex was significantly lower in the aPL-positive group. Cerebral infarctions in the carotid system were less and large-artery lesions more frequent in the aPL-positive patients. CONCLUSIONS: Stroke patients with aPL have clinical characteristics distinct from stroke patients without aPL.

[Bucillamine-induced dermatomyositis-like clinical features in a patient with rheumatoid arthritis].

A 78 year-old woman was admitted to our hospital because of subacutely progressive dysarthria, dysphagia, proximally dominant muscle weakness and erythema in the neck and back. She was diagnosed as having rheumatoid arthritis (RA) at the age of 60 and treated with bucillamine (BUC) for 8 years. Laboratory tests included a rheumatoid factor of 1,472U/ml. Serum creatine kinase level was slightly elevated. The activated T cells in the peripheral blood were markedly increased. Needle EMG demonstrated myogenic changes. The magnetic resonance image of the left upper arm showed diffuse muscle atrophy and inflammatory changes in the triceps muscle. The muscle biopsy revealed perivascular inflammatory cell infiltraton and type II fiber atrophy. A biopsy from the skin showed mild perivascular inflammatory cell infiltraton. According to the results of these findings, she was thought to have dermatomyositis due to BUC. After withdrawal of BUC followed by the administration of prednisolone 1mg/kg, her symptoms improved and activated T cells in the peripheral blood were decreased. In Japan, BUC is widely accepted as an effective drug in the treatment of RA, even though it is known to induce some autoimmune diseases. However, the mechanism of the development of autoimmune disease is unclear. We considered that the long-term use of bucillamine could trigger an autoimmune response such as an increase in activated T cells and the development of dermatomyositis-like clinical features in our patient. In conclusion, when RA patients treated with BUC show a clinical picture compatible with dermatomyositis, its causative relationship has to be considered.

[Spinal epidural abscess with persistent increase in cerebrospinal fluid protein: a case study].

A 67-year-old man under hemodialysis treatment developed neck stiffness, fever and conscious disturbances. The patient was infected with Methicilin-resistant Staphylococcus aureus (MRSA) sepsis caused by an infection on a dialysis shunt. On admission, he was diagnosed with bacterial meningoencephalitis and underwent a series of antibiotic chemotherapies. The treatment brought cell count in the cerebrospinal fluid to a subnormal level but his clinical status did not improve. The patient continued to have high level of cerebrospinal fluid protein (898 mg/dl). Cervical MRI demonstrated two abscesses deep in the neck as well as in the epidural region of the cervical spinal cord, from C2 to C5 vertebral levels. Based on these findings, spinal epidural abscess (SEA) was diagnosed. Intensive antibiotic chemotherapy especially targeted for MRSA could eradicate abscesses and improve clinical status. However, persistent high protein level in the cerebrospinal fluid could suggest SEA.

Organ culture of the fetal mouse palate for screening the developmental toxicity of chemicals: a validation study.

Using in vitro organ culture of the fetal mouse palate in a chemically defined serumless medium, the toxicity of 24 chemical compounds was investigated. Explanted palates of day-12.5 mouse fetuses were exposed for 72 h in vitro to various concentrations of each chemical, and the fusion rate and growth parameters were compared between the experimental group and respective controls. The average rate of palate fusion was 84% in vehicle controls. For compounds that are teratogenic in experimental animals in vivo, the fusion rates of palatal shelves decreased as the concentration of the test chemicals increased, showing a dose-dependent relationship. Palate fusion was inhibited by 11 of the 15 in vivo teratogens, and the predictability of in vivo developmental toxicity in this culture system was 73%. Cyclophosphamide itself did not inhibit the growth and fusion of explanted palates, but supplementation of hepatic S-9 fraction and cofactors for a monooxygenase system converted it to a toxic substance, as was shown in other in vitro systems. The 50% inhibitory concentration (IC50) value calculated based on the fusion rate was also found to be a useful parameter for evaluating the developmental toxicity of drugs. The teratogenic risk in the human fetus could be assessed by comparing the minimal toxic concentrations of the test compound on cultured palates with the maximal plasma level in pregnant women under therapeutic conditions and with the plasma concentrations when its minimal teratogenic dose is given to pregnant mice. This organ culture system of the fetal palate should be useful for screening the developmental toxicity of drugs and other environmental agents, and its value should increase when it is used in combination with other battery test systems.

Remarkably similar antigen receptors among a subset of patients with chronic lymphocytic leukemia.

Studies of B cell antigen receptors (BCRs) expressed by leukemic lymphocytes from patients with B cell chronic lymphocytic leukemia (B-CLL) suggest that B lymphocytes with some level of BCR structural restriction become transformed. While analyzing rearranged V(H)DJ(H) and V(L)J(L) genes of 25 non-IgM-producing B-CLL cases, we found five IgG(+) cases that display strikingly similar BCRs (use of the same H- and L-chain V gene segments with unique, shared heavy chain third complementarity-determining region [HCDR3] and light chain third complementarity-determining region [LCDR3] motifs). These H- and L-chain characteristics were not identified in other B-CLL cases or in normal B lymphocytes whose sequences are available in the public databases. Three-dimensional modeling studies suggest that these BCRs could bind the same antigenic epitope. The structural features of the B-CLL BCRs resemble those of mAb's reactive with carbohydrate determinants of bacterial capsules or viral coats and with certain autoantigens. These findings suggest that the B lymphocytes that gave rise to these IgG(+) B-CLL cells were selected for this unique BCR structure. This selection could have occurred because the precursors of the B-CLL cells were chosen for their antigen-binding capabilities by antigen(s) of restricted nature and structure, or because the precursors derived from a B cell subpopulation with limited BCR heterogeneity, or both.