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To assess the efficacy and safety of subcutaneous administration of 30 mg or 80 mg of ozoralizumab plus methotrexate (MTX) in patients with rheumatoid arthritis (RA) whose disease remained active despite MTX therapy.In this multicenter, double-blind, parallel-group, placebo-controlled phase II/III trial, 381 patients were randomized to receive placebo, ozoralizumab 30 mg, or ozoralizumab 80 mg, plus MTX subcutaneously injected every 4 weeks for 24 weeks. The primary end points were the response rates based on the American College of Rheumatology 20% improvement criteria (ACR20) at week 16 and change in the Sharp/van der Heijde score (ΔSHS) from baseline to week 24.The proportion of patients with an ACR20 response at week 16 was significantly higher (P 0.001) in both ozoralizumab groups (79.6% for 30 mg, 75.3% for 80 mg), compared with placebo (37.3%); these improvements were observed from the first week of treatment. The proportion of the patients with structural nonprogression (ΔSHS ≤0) was significantly higher in both ozoralizumab groups than in the placebo group. For some secondary end points, significantly greater improvements were observed starting from as early as day 3. Serious adverse events occurred in 4 patients in the ozoralizumab 30-mg group and 5 patients in the ozoralizumab 80-mg group.In patients with active RA who received ozoralizumab in combination with MTX, the signs and symptoms of RA were significantly reduced as compared with the outcomes in those receiving placebo. Ozoralizumab demonstrated acceptable tolerability with no new safety signals when compared with other antibodies against tumor necrosis factor.

Objectives The aim is to assess the efficacy and safety of a 52-week subcutaneous ozoralizumab treatment at 30 and 80 mg without methotrexate (MTX) in active rheumatoid arthritis. Methods This randomised, open-label, multicentre phase III trial randomly allocated 140 patients in 2:1 ratio as subcutaneous ozoralizumab at 30 or 80 mg every 4 weeks for 52 weeks without MTX. Results Both groups administered ozoralizumab at 30 and 80 mg showed good clinical improvement. The American College of Rheumatology response rates were high at Week 24 and maintained through 52 weeks. The ozoralizumab groups also showed good improvement in other end points, and improvements observed from Week 1 were maintained through 52 weeks. Improvements in many efficacy assessments were similar between doses. No deaths were reported, and serious adverse events occurred in a total of 20 patients in the ozoralizumab groups. Increased antidrug antibodies were observed in approximately 40% of patients in the ozoralizumab groups, and 27.7% of the patients in the 30 mg group were neutralising antibody-positive. Conclusions Ozoralizumab, at 30 and 80 mg, demonstrated significant therapeutic effects without MTX, and the efficacy was maintained for 52 weeks with active rheumatoid arthritis. Ozoralizumab showed an acceptable tolerability profile over 52 weeks.

Objective To assess the efficacy and safety through a 52-week treatment with subcutaneous ozoralizumab at 30 or 80 mg in patients with active rheumatoid arthritis despite methotrexate therapy. Methods This multicentre, randomized, placebo-controlled, double-blind, parallel-group confirmatory trial included a 24-week double-blind treatment period followed by a 28-week open-label treatment period. The double-blind treatment period randomized 381 (2:2:1) patients to placebo and ozoralizumab at 30 or 80 mg, and patients receiving placebo were re-randomized (1:1) to ozoralizumab at 30 or 80 mg in the open-label period. Results The ozoralizumab groups showed good clinical improvement, with high American College of Rheumatology response rates at 52 weeks, as well as good improvements in other endpoints, which were observed from Day 3 and maintained through Week 52. Furthermore, the ozoralizumab groups showed a high remission rate in clinical and functional remission at Week 52. Serious adverse events occurred in a total of 23 patients in the ozoralizumab groups, without differences in incidence between doses. Conclusions Ozoralizumab demonstrated significant therapeutic effects and efficacy, which was maintained for 52 weeks. The safety profile was consistent with the evaluated results in interim analysis at Week 24, and ozoralizumab was well-tolerated up to Week 52.

Motivated by developments in information technology, recording personal parameters with health devices is effective in health promotion. Today’s indoor individual lifestyles often involve using electrical appliances. We developed a health support system combined with wireless electricity monitoring and investigated whether electricity use is associated with residents’ vital data and lifestyles. We recruited 116 participants in February 2013. Their vital and electricity use data were collected daily. They completed a self-administered questionnaire. Among participants living alone, electricity from 20 February to 11 March 2013 was negatively associated with high-density lipoprotein (HDL) (P = 0.008) and positively associated with low-density lipoprotein (LDL) (P = 0.007) and neutral fat (P = 0.020) levels. Among all participants, electricity use was negatively associated with vegetable intake (P = 0.044) and step count (P = 0.040). Temperature sensitivity in winter was negatively associated with the LDL/HDL ratio for both men and women. For men, temperature sensitivity in winter was negatively related with alcohol intake; for women, it was positively related to body fat percentage and abdominal circumference and negatively correlated to vegetable intake. Temperature sensitivity in summer was positively associated with vegetable intake for men and women. In conclusion, electricity use was related to vital data and lifestyles and influenced by temperature.

Preoperative chemoradiation therapy is a promising strategy for pancreatic cancer. Peritoneal recurrence is a major recurrence pattern after surgery for pancreatic cancer following preoperative chemoradiation therapy, even in patients with negative peritoneal lavage fluid cytology. Previous reports have indicated that the detection of carcinoembryonic antigen mRNA by reverse transcription polymerase chain reaction is useful for evaluating subclinical tumor cell dissemination in peritoneal lavage fluid.Patients with resectable and borderline resectable pancreatic cancer treated with preoperative gemcitabine-based chemoradiation therapy and subsequent surgery were enrolled in this study. In all patients, a conventional cytologic examination of peritoneal lavage fluid from laparotomy confirmed the negative peritoneal cytology status. Carcinoembryonic antigen mRNA was detected in the peritoneal lavage fluid at laparotomy using reverse transcription polymerase chain reaction. Recurrence patterns and survival were evaluated in association with the carcinoembryonic antigen mRNA status in the peritoneal lavage fluid.The peritoneal lavage fluid from 57 of the 237 patients (24%) was carcinoembryonic antigen mRNA(+). The carcinoembryonic antigen mRNA(+) patients had a significantly higher incidence of peritoneal recurrence than the carcinoembryonic antigen mRNA(-) patients (36% vs. 15%, P.001). The 5-year survival rates of the carcinoembryonic antigen mRNA(+) and carcinoembryonic antigen mRNA(-) patients were 31% and 51%, respectively (P = .037). A multivariable analysis for survival revealed that borderline resectability, positive nodal status, and positive carcinoembryonic antigen mRNA status were independent variables for impaired survival.Carcinoembryonic antigen mRNA(+) status was associated with a significantly increased incidence of peritoneal recurrence in patients with pancreatic cancer treated with preoperative chemoradiation therapy, resulting in impaired survival.

For patients at high risk, such as those with lower-gastrointestinal perforations, it is important to establish a preventive method that reduces the incidence of surgical site infections (SSIs) significantly. We applied negative-pressure wound therapy (NPWT) as part of a delayed primary closure approach to prevent SSIs. This study evaluated the value of this technique.We included prospectively 28 patients undergoing abdominal surgery for peritonitis caused by a lower-gastrointestinal perforation between May 2014 and November 2015. Historical controls comprised retrospective data on 19 patients who had undergone primary suturing for managing peritonitis incisions for a lower-gastrointestinal perforation from January to December 2013.We found a significant association between the SSI incidence and the type of incision management (10.7% with NPWT and delayed closure vs. 63.2% with primary suturing; p 0.001). There was no significant difference between the groups in the length of the hospital stay (22 days for NPWT and delayed closure vs. 27 days for primary suturing; p = 0.45). No severe adverse events were observed related to NPWT.The use of NPWT and delayed primary closure was an effective measure for preventing SSI in patients undergoing abdominal surgery for peritonitis caused by lower-gastrointestinal perforation.

The change of biotin level during production of natto (Japanese fermented soybean) was investigated in this study. The total biotin level was measured by an agar plate bioassay using Lactobacillus plantarum ATCC 8014. The total biotin level decreased during water soaking, but increased after the fermentation of soybeans using Bacillus subtilis var. natto (B. natto) and reached a maximum level. The increase of total biotin was not affected by Asp, Arg, and Ile which promoted the growth of L. plantarum in high concentrations. The peak level of biotin in the fermented soybeans was significantly higher than that of dry soybeans. The fermented soybeans at the biotin peak level were adequate for food. In addition, we detected 9 and 4 biotinylated polypeptides in the soybeans and B. natto used in this study, respectively. We speculated that the increase of biotin level may depend on the increase of the 4 biotinylated polypeptides and free biotin in B. natto.

Twenty-seven treatment-naive patients with relapsing-remitting multiple sclerosis (MS) and 13 with neuromyelitis optica spectrum disorder (NMOSD) were enrolled during a time of acute flare-up. Common cerebrospinal fluid (CSF) features were increased CD29- and/or CD45RO-positive helper T cells capable of propagating inflammation in the central nervous system (CNS). B cell activation in the CSF was unique to MS, while an increase in CD4+CD192 (CCR2)+ cells in blood and breakdown of the blood-brain barrier (BBB) characterized NMOSD. Intravenous corticosteroid therapy suppressed neuroinflammation via modulation of cellular immunity in MS, as opposed to restoration of the BBB in NMOSD.

Background Rheumatoid meningitis (RM) is a rare disorder that often develops during a remission phase of rheumatoid arthritis (RA). This is the first study to demonstrate differences in regard to immunological disturbance between blood and cerebrospinal fluid (CSF) samples obtained from a patient with RM using flow cytometry. Case presentation A 36-year-old woman with RA and generalized myasthenia gravis (MG) developed RM during a remission phase. Although both RA and MG were stable and well controlled, she noticed fever, headache, and transient sensory disturbance. Blood and CSF examination findings suggested aseptic meningitis, while brain magnetic resonance imaging revealed restricted portions of meningitis and associated cortical lesions, compatible with a diagnosis of RM. The dose of oral prednisolone was increased, which ameliorated the symptoms within 1 week along with improvement in CSF findings. This patient exhibited features of RM that were manifested in a manner independent of the activity of RA. An investigation of cellular immunity using CSF specimens with flow cytometry showed differences in regard to the pathogenesis of inflammation in the CSF as compared to outside of the central nervous system. In contrast to results obtained with paired blood samples, CSF cells at the peak stage of RM showed a marked increase in CCR3+ Th2 cells and marked decrease in CD8+ cells, suggesting an immunoregulatory disturbance in the CSF. Those findings indicated a CSF-specific activation of humoral immunity, resulting in augmentation of meningeal inflammation, as shown by excess synthesis of intrathecal IgG and markedly elevated interleukin-6 level. Results of the present detailed investigation of lymphocyte subsets revealed a discrepancy regarding the process of inflammation in this RM patient between CSF and blood samples. Conclusions RM is not a simple reflection of the immune status of RA, as the pathogenesis seems related to, at least in part, CSF-specific immunological dysregulation.

It is known that mumps is an acute and highly contagious systemic viral infection that occurs in childhood, the hallmark of which is parotid gland swelling. Although mumps infection in the central nervous system (CNS) is uncommon among adults in association with vaccinations generally administered in developed countries, CNS involvement can occur without parotitis. Here, we report such a case of severe meningitis due to reinfection by the mumps virus. Based on our findings, we propose that mumps meningitis can mimic tuberculous meningitis in regard to clinical symptoms and course, as well as laboratory test results of cerebrospinal fluid. Follow-up investigations that include key cytokines such as IL-6, IFN-γ, and TNF-β in the CSF are important for differential diagnosis.

Aggregation behavior of the organic-soluble semi-aromatic polyimides, whose degrees of imidization range from 69 to 96%, obtained using 4,4′-oxydianiline, 4,4′-diamino-3,3′dihydroxybiphenyl, and bicyclo[2.2.2]-oct-7-ene-2,3,5,6-tetracarboxylic dianhydride (BCDA) in N-methylpyrrolidone (NMP), NMP/cyclohexanone, and NMP/γ-butyrolactone (BCDA-based polyimides) were studied by static light scattering (SLS) and dynamic light scattering (DLS). The DLS analyses for the multirelaxation modes demonstrated the specific character unlike flexible polymers that the single BCDA-based polyimide chains first associate with each other to form small clusters in the dilute region, and then expand to large aggregates by the entanglements between the small clusters with an increasing concentration into the semi-dilute region. Given the semi-aromatic structure of BCDA-based polyimides weakening the charge transfer (CT) interaction between the diamine and the dianhydride unit, it is concluded that the unique aggregation behavior of BCDA-based polyimides is dominated by the balance between the driving force for the “organic solubility” given by both the increase in bulkiness and the decrease in the CT interaction, and that for the “organic insolubility” derived from both the hydrogen-bonded interaction of the phenolic hydroxyl groups and the π–π interaction of the phenyl rings. © 2012 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys, 2012

Moyamoya disease is the angiographic diagnosis of a clinical syndrome showing bilateral stenosis or occlusion of the distal internal carotid arteries and their major branches with extensive parenchymal, leptomeningeal, or transdural anastomoses. The clinical features normally present as reversible ischemic neurologic deficits, sensory-motor attacks with acute hemiplegia, and motor convulsion. An acute confusional state (ACS) among hospitalized patients is a frequent and serious problem. It is characterized by an acute neurologic deficit with a fluctuating course of impaired attention span, unorganized thinking, and altered levels of consciousness. We report a case of 66-year-old woman who presented with an ACS in the emergency department. The subsequent workups including a neuroradiological examination revealed a rare case of moyamoya disease with bifrontal ischemic infarction. The recognition of an ACS as a manifestation of moyamoya disease should therefore be included in the differential diagnosis of elderly patients who present with an acutely altered neuropsychiatric state. A prompt diagnosis may help to select the most appropriate therapy for this rare disorder especially in elderly patients.

Several lines of evidence have suggested roles for pituitary adenylate cyclase-activating polypeptide (PACAP) in the developing nervous system. Previously, we showed that mRNA for PACAP, vasoactive intestinal peptide (VIP), and their three receptor subtypes, is differentially expressed in embryonic stem (ES) cells, ES cell-derived, neural stem cell-enriched cultures, and differentiated neurons, by using the five steps of the in vitro neuronal culture model of ES cell differentiation. Here, we examined the effects of PACAP on self-renewal and cell lineage determination of neural progenitor/stem cells. PACAP inhibited the basic fibroblast growth factor-induced proliferation (self-renewal), as assessed by neurosphere formation. PACAP increased microtubule-associated protein 2-positive neurons without affecting the number of cells positive for the neural stem cell marker nestin, astrocyte marker glial fibrillary acidic protein, and oligodendrocyte marker CNPase. These results suggest that PACAP inhibits self-renewal but, instead, induces early neuronal differentiation of neural progenitor cells.

To clarify the molecular background underlying the heterogeneity of multiple sclerosis (MS), we characterized the gene expression profile of peripheral blood CD3+ T cells isolated from MS and healthy control (CN) subjects by using a cDNA microarray. Among 1258 cDNAs on the array, 286 genes were expressed differentially between 72 untreated Japanese MS patients and 22 age- and sex-matched CN subjects. When this set was used as a discriminator for hierarchical clustering analysis, it identified four distinct subgroups of MS patients and five gene clusters differentially expressed among the subgroups. One of these gene clusters was overexpressed in MS versus CN, and particularly enhanced in the clinically most active subgroup of MS. After 46 of the MS patients were treated with interferon-beta (IFNbeta-1b) for two years, IFNbeta responders were clustered in two of the four MS subgroups. Furthermore, the IFNbeta responders differed from nonresponders in the kinetics of IFN-responsive genes at 3 and 6 months after starting IFNbeta treatment. These results suggest that T-cell gene expression profiling is valuable to identify distinct subgroups of MS associated with differential disease activity and therapeutic response to IFNbeta.

The expressions of mRNAs for pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP), and their receptors (PAC1, VPAC1 and VPAC2) were examined in the five steps of the in vitro neuronal culture model of embryonic stem (ES) cell differentiation. mRNAs for PACAP, VIP, PAC1 receptor, and VPAC2 receptor were moderately expressed in neural stem cell-enriched cultures, while VPAC1 receptor mRNA was most prominently expressed in embryoid bodies (EBs). The expression of PAC1 receptor mRNA was further upregulated after terminal differentiation into neurons. In contrast, the expressions of PAC1 receptor and PACAP mRNAs were markedly decreased after glial differentiation. These results suggest that this in vitro neuronal culture system will be a useful model for future studies on the functional role of the PACAPergic system during different stages of neuronal development.

Department of Neurology, Kanazawa Medical University, Ishikawa, Japan Division of Nephrology, Kanazawa Medical University, Ishikawa, Japan Department of Virology I, National Institute of Infectious Disease, Tokyo, Japan Department of Neurosurgery, Brain Research Institute, University of Niigata, Niigata, Japan Department of Pathology, Brain Research Institute, University of Niigata, Niigata, Japan

Mental stress is an important factor contributing to recognized mechanisms underlying cardiovascular events. Among these, stress-related endothelial dysfunction is an early risk factor that predicts future development of severe cardiovascular disorders. Acute mental stress by a variety of tests impairs endothelial function in humans, although the opposite results have been reported by some investigators. Chronic stress always deteriorates endothelial function in humans and experimental animals. Stress hormones, such as glucocorticoids and pro-inflammatory cytokines, and endothelin-1 liberated in response to mental stress participate in endothelial dysfunction possibly via downregulation of endothelial nitric oxide synthase (eNOS) expression, eNOS inactivation, decreased nitric oxide (NO) actions, and increased NO degradation, together with vasoconstriction counteracting against NO-induced vasodilatation. Catecholamines do not directly affect endothelial function but impair its function when blood pressure elevation by the amines is sustained. Endogenous opioids favorably affect endothelial function, which counteract deteriorating effects of other stress hormones and mediators. Inhibition of cortisol and endothelin-1 production, prevention of pro-inflammatory mediator accumulation, hypnotics, mirthful laughter, humor orientation, and lifestyle modification would contribute to the prevention and treatment for stress-related endothelial dysfunction and future serious cardiovascular disease.

Chorea-acanthocytosis (ChAc) is a hereditary disease characterized by involuntary movements and amyotrophy with elevation of serum creatine kinase. Although skeletal muscle involvement in ChAc has been suggested, the mechanism remains unclear. To investigate chorein abnormalities of the skeletal muscles of ChAc patients with an apparently heterozygous VPS13A mutation compared with those of other hereditary choreic diseases, we performed histological and immunohistochemical studies of the skeletal muscles from 3 ChAc, 1 Huntington's disease (HD), 1 McLeod syndrome (MLS), and 1 normal control (NC) with 2 originally generated anti-chorein antibodies. Chorein immunoreactivities in HD, MLS, and NC were found linearly along the sarcolemma and appeared as speckles in the sarcoplasma, but those in ChAc were uneven and discontinuous along the sarcolemmas and increased in the sarcoplasma especially in type I fibers. This histological observation suggests chorein abnormalities of skeletal muscles might be associated with primary involvement of skeletal muscles in this disorder. © 2007 Movement Disorder Society

Nitric oxide (NO) is widely recognized to be quite an important intercellular messenger in the cardiovascular and nervous systems or immunological reactions, including that in the eye. This molecule formed by constitutive NO synthase (NOS), endothelial (eNOS) and neuronal (nNOS), contributes to physiologically regulate ocular hemodynamics and cell viability and protects vascular endothelial cells and nerve cells or fibers against pathogenic factors associated with glaucoma, ischemia, and diabetes mellitus. Ocular blood flow is regulated by NO derived from the endothelium and efferent nitrergic neurons. Endothelial dysfunction impairs ocular hemodynamics by reducing the bioavailability of NO and increasing the production of reactive oxygen species (ROS). On the other hand, NO formed by inducible NOS (iNOS) expressed under influences of inflammatory mediators evokes neurodegeneration and cell apoptosis, leading to serious ocular diseases. NO over-produced by nNOS in the retina stimulated by excitotoxic amino acids or exposed to ischemia also mediates retinal injury. Because of these dichotomous roles of NO, which has both beneficial and pathogenic actions, one may face difficulties in constructing therapeutic strategies with NO supplementation or NOS inhibition. Up-to-date information concerning physiological roles of NO produced by the different NOS isoforms in the eye and interactions between NO and glaucoma, retinal ischemia, or diabetic retinopathy would help clinicians to select a valid pharmacological therapy that would be appropriate for a specific ocular disease.

Paraneoplastic cerebellar degeneration (PCD) is a potent autoimmune disorder in which antigen-driven responses toward the onconeural antigen are assumed to occur in patients. Yeast cell wall has adjuvant capacity and provides immunostimulatory effects of the antigen expressing in viable cells. The recombinant yeast expressing the PCD-associated antigen may become an immunogen for inducing PCD-associated autoimmunity in mice. We attempted to induce autoimmune responses with whole recombinant yeast expressing PCD-associated antigen. SJL/J strain of mouse is found to be a responder to the major epitope on the antigen for anti-Purkinje cell antibodies, and whole recombinant yeast could induce cellular and humoral autoimmune responses in vivo ion SJL/J mice. The immunization technique based on the recombinant yeast expressing a PCD-associated antigen provides a new tool for analyzing the underlying immunological pathomechanisms of PCD.

We evaluated changes in ocular hemodynamics induced by nipradilol, an NO donor, applied as an eye drop. Eight volunteers underwent color Doppler imaging for measurement of hemodynamic parameters in the central retinal artery (CRA) and ophthalmic artery (OA) after instillation of nipradilol. Intraocular pressure (IOP) and systemic blood pressure were also measured. Two months later, the same volunteers were examined after instillation of saline into the same eyes to obtain control data. The pulsatility index in the CRA was significantly lowered in the eyes treated with nipradilol compared with control eyes. Blood velocities in the CRA, hemodynamic parameters in the OA, IOP, blood pressure, and ocular perfusion pressure were unaffected by nipradilol. The current study suggests that nipradilol may dilate the CRA as a result of reduced vascular resistance in humans.

We report a patient with sporadic amyotrophic lateral sclerosis (ALS) with a novel fusion in malignant liposarcoma (FUS) gene mutation whose neurological signs were conspicuous left-sided rigidity and apraxia. A novel heterozygous guanine (G)-to-thymine (T) transition at position 1392, c.1392G>T, leading to a methionine-to-isoleucine substitution (p.Met464Ile), was found in exon13 of FUS. Re-sequencing of the genes for superoxide dismutase 1 (SOD1) and transactive response-DNA binding protein (TARDBP) revealed no mutations. The present findings suggest that this novel FUS mutation (p.Met464Ile) is related to manifestations of ALS as well as clinical features of corticobasal degeneration.