Nephrotic Syndrome and Atypical Posterior Reversible Encephalopathy Syndrome in a Patient with Parkinson's Disease.

A 59-year-old man with advanced Parkinson's disease treated using levodopa-carbidopa intestinal gel (LCIG) presented with leg edema, hypoalbuminemia, and proteinuria at 1 year after the treatment. He subsequently developed a generalized tonic-clonic seizure, and brain magnetic resonance imaging indicated vasogenic edema in the white matter of the left frontal subcortex. He was diagnosed with nephrotic syndrome (NS) and atypical posterior reversible encephalopathy syndrome (PRES). LCIG cessation and corticosteroid treatment improved the NS. To our knowledge, this is the first case report of NS and atypical PRES in patients with Parkinson's disease. Patients being treated with LCIG should be closely monitored for NS.

Effect of etelcalcetide on parathyroid hormone secretion by primary hyperparathyroidism patient-derived primary parathyroid cells.

INTRODUCTION: Etelcalcetide (Parsabiv®, AMG 416/ONO-5163) is a novel allosteric modulator for the calcium-sensing receptor approved for hemodialysis patients with secondary hyperparathyroidism of uremia. Etelcalcetide reduced parathyroid hormone levels in hemodialysis patients with secondary hyperparathyroidism of uremia in clinical studies. However, its direct effect on parathyroid hormone secretion in human parathyroid cells remains unknown. This study aimed to determine if etelcalcetide suppresses parathyroid hormone secretion by human parathyroid cells in vitro. MATERIALS AND METHODS: We prepared primary cell cultures from human parathyroid tissue and determined calcium-sensing receptor expression levels by immunohistochemistry. Pathyroid tumors were removed from fourteen patients with primary hyperparathyrodism. Parathyroid tissue was dispersed with collagenase, resuspended in culture medium, incubated for 2 h with etelcalcetide and Ca2+, and the medium was then collected. Final etelcalcetide concentrations in the medium were 0.005-50 µmol/L. Levels of human parathyroid hormone in the medium were determined by enzyme-linked immunosorbent assay. RESULTS: In eight of the fourteen parathyroid cell cultures, extracellular Ca2+ reduced parathyroid hormone levels. In four of the eight parathyroid cell cultures which responded extracellular Ca2+, etelcalcetide reduced hormone secretion with the 50% effective concentrations of 0.57, 20.8, 0.42, and 0.57 µmol/L. Expression levels of the calcium-sensing receptor were significantly lower in primary hyperparathyroidism patient-derived parathyroid tissues compared with controls. CONCLUSION: This is the first report that etelcalcetide directly reduced parathyroid hormone secretion from the primary cultured human parathyroid cells from patients with primary hyperparathyroidism. To verify this conclusion, further studies are needed using secondary hyperparathyroidism patient-derived parathyroid cells.

Effects of lifestyle on hepatobiliary enzyme abnormalities following the Fukushima Daiichi nuclear power plant accident: The Fukushima health management survey.

Dramatic lifestyle changes due to the Fukushima Daiichi Nuclear Power Plant accident increased the prevalence of hepatobiliary enzyme abnormalities (HEA). We aimed to evaluate associations of HEA with specific lifestyle- and disaster-related factors in residents who lived near the Fukushima Daiichi Nuclear Power Plant.This cross-sectional study included 22,246 residents who underwent a Comprehensive Health Check and the Mental Health and Lifestyle Survey from June 2011 to March 2012. Residents were divided into 2 groups based on residential area and housing status after the accident. Associations between HEA and lifestyle- and disaster-related factors, including psychological distress, were estimated using logistic regression analysis adjusted for demographic and lifestyle factors.HEA was present in 27.3% of subjects. The prevalence of HEA was significantly higher in evacuees than controls (29.5% vs 25.7%, P < .001). There were significant differences in various lifestyle characteristics and the prevalence of post-traumatic stress disorder between evacuees and controls. Multivariable logistic regression analysis showed that age, sex, moderate to heavy drinking, and low/no physical activity were significantly associated with HEA regardless of evacuation status. Changes in jobs and unemployment were significantly associated with HEA in controls and evacuees, respectively.Lifestyle and disaster-related factors, but not psychological distress, were associated with HEA among subjects who lived near the Fukushima Daiichi Nuclear Power Plant accident.

Discovery of a Slow Tight Binding LPA1 Antagonist (ONO-0300302) for the Treatment of Benign Prostatic Hyperplasia.

Scaffold hopping from the amide group of lead compound ONO-7300243 (1) to a secondary alcohol successfully gave a novel chemotype lysophosphatidic acid receptor 1 (LPA1) antagonist 4. Wash-out experiments using rat isolated urethra showed that compound 4 possesses a tight binding feature to the LPA1 receptor. Further modification of two phenyl groups of 1 to pyrrole and an indane moiety afforded an optimized compound ONO-0300302 (19). Despite its high i.v. clearance, 19 inhibited significantly an LPA-induced increase of intraurethral pressure (IUP) in rat (3 mg/kg, p.o.) and dog (1 mg/kg, p.o.) over 12 h. Binding experiments with [3H]-ONO-0300302 suggest that the observed long duration action is because of the slow tight binding character of 19.

Cryptogenic NORSE: Its distinctive clinical features and response to immunotherapy.

OBJECTIVE: To report the distinctive clinical features of cryptogenic new-onset refractory status epilepticus (C-NORSE) and the C-NORSE score based on initial clinical assessments. METHODS: A retrospective study was conducted for 136 patients with clinically suspected autoimmune encephalitis who underwent testing for autoantibodies to neuronal surface antigens between January 1, 2007, and August 31, 2016. Eleven patients with C-NORSE were identified. Their clinical features were compared with those of 32 patients with anti-NMDA receptor encephalitis (NMDARE). RESULTS: The clinical outcome of 11 patients (median age, 27 years; 7 [64%] women) with C-NORSE was evaluated after a median follow-up of 11 months (range, 6-111 months). Status epilepticus was frequently preceded by fever (10/11 [91%]). Brain MRIs showed symmetric T2/fluid-attenuated inversion recovery hyperintensities (8/11 [73%]) and brain atrophy (9/11 [82%]). Only 2 of the 10 treated patients responded to the first-line immunotherapy, and 4 of the 5 patients treated with IV cyclophosphamide responded to the therapy. The long-term outcome was poor in 8 patients (73%). Compared with 32 patients with NMDARE (median age, 27 years; 24 [75%] women), those with C-NORSE had more frequent prodromal fever, status epilepticus, ventilatory support, and symmetric brain MRI abnormalities, had less frequent involuntary movements, absent psychobehavioral symptoms, CSF oligoclonal bands, or tumor association, and had a worse outcome. The C-NORSE score was higher in patients with C-NORSE than those with NMDARE. CONCLUSIONS: Patients with C-NORSE have a spectrum of clinical-immunological features different from those with NMDARE. The C-NORSE score may be useful for discrimination between them. Some patients could respond to immunotherapy.

A possible role of low regulatory T cells in anti-acetylcholine receptor antibody positive myasthenia gravis after bone marrow transplantation.

BACKGROUND: Chronic graft-versus-host disease (GVHD) appears several months following allogenic hematopoietic stem cell transplantation (HSCT) and is clinically analogous to autoimmune disorder. Polymyositis is a common neuromuscular disorder in chronic GVHD, but myasthenia gravis (MG) is extremely rare. Hence, its pathophysiology and treatment have not been elucidated. CASE PRESENTATION: A 63-year-old man with a history of chronic GVHD presented with ptosis, dropped head, and dyspnea on exertion, which had worsened over the previous several months. He showed progressive decrement of compound muscle action potential in the deltoid muscle evoked by 3-Hz repetitive nerve stimulation, a positive edrophonium test, and elevated levels of serum anti-acetylcholine receptor antibodies, which suggested a diagnosis of generalized MG. No thymoma was found. Flow cytometric analysis revealed a remarkable depletion of peripheral Tregs (CD4+CD25highFOXP3+ cells, 0.24% of the total lymphocytes). Administration of prednisolone and tacrolimus was insufficient to alleviate his symptoms; however, the use of rituximab successfully improved his condition. CONCLUSIONS: Myasthenic symptoms appeared in the process of tapering prednisolone for the treatment of chronic GVHD, supporting the diagnosis of MG associated with chronic GVHD. The present case proposes a possibility that reduction of Tregs might contribute to the pathogenesis of MG underlying chronic GVHD. Immunotherapy with rituximab is beneficial for treatment of refractory MG and GVHD.

Changes in Hepatobiliary Enzyme Abnormality After the Great East Japan Earthquake: The Fukushima Health Management Survey.

Although the incidence of hepatobiliary enzyme abnormality increased immediately after the Great East Japan Earthquake and subsequent Fukushima Daiichi Nuclear Power Plant accident, longer-term trends remain unclear. The aims of this study were to determine longer-term trends in hepatobiliary enzyme abnormality and to elucidate lifestyle factors associated with such changes among residents of a nuclear-disaster-affected area. This longitudinal survey enrolled 20,395 adults living in the vicinity of Fukushima Daiichi Nuclear Power Plant. Data were obtained from the records of annual health checkups of adults aged ≥40 years between 2011 and 2012. Follow-up examinations were conducted from June 2013 to March 2014. Associations were assessed between changes in hepatobiliary enzyme abnormality immediately and 3-4 years after the disaster and lifestyle factors. The overall prevalence of hepatobiliary enzyme abnormality significantly decreased over the study period, from 29.9% to 27.1%. Multivariate logistic regression analysis revealed significant associations between improved hepatobiliary enzyme abnormality and improvements in daily physical activity and frequency of breakfast consumption. The results suggest that improvements in daily physical activity and frequency of breakfast consumption significantly reduced the incidence of hepatobiliary enzyme abnormality 3-4 years after the Great East Japan Earthquake and Fukushima Daiichi Nuclear Power Plant accident.

The impact of evacuation on the incidence of chronic kidney disease after the Great East Japan Earthquake: The Fukushima Health Management Survey.

BACKGROUND: About 146,000 people were forced into long-term evacuation due to the nuclear power plant accident caused by the Great East Japan Earthquake in 2011. Disaster is known to induce hypertension in survivors for a certain period, but it is unclear whether prolonged disaster stress influences chronic kidney disease (CKD). We conducted an observational cohort study to elucidate the effects of evacuation stress on CKD incidence. METHODS: Participants were individuals living in communities near the Fukushima nuclear power plant, aged 40-74 years without CKD as of their 2011 general health checkup (non-evacuees: n = 9780, evacuees: n = 4712). We followed new-onset CKD [estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 or proteinuria] using general annual health checkup data from 2012 to 2014. Association between evacuation and CKD incidence was analyzed using the Cox proportional hazard model. RESULTS: Mean age of the participants at baseline was 65 years, 46.7% were men, and baseline eGFR was 75.7 ml/min/1.73 m2. During the mean follow-up period of 2.46 years, CKD incidence rate was 80.8/1000 and 100.2/1000 person-years in non-evacuees and evacuees, respectively. Evacuation was a significant risk factor of CKD incidence after adjusting for age, gender, obesity, hypertension, diabetes, dyslipidemia, smoking, and baseline eGFR [hazard ratio (HR): 1.45; 95% confidence interval (CI) 1.35-1.56]. Evacuation was significantly associated with the incidence of eGFR <60 ml/min/1.73 m2 (HR: 1.48; 95% CI 1.37-1.60), but not with the incidence of proteinuria (HR: 1.21; 95% CI 0.93-1.56). CONCLUSION: Evacuation was a risk factor associated with CKD incidence after the disaster.

Persistent prevalence of polycythemia among evacuees 4 years after the Great East Japan Earthquake: A follow-up study.

We previously reported that the lifestyle of evacuees significantly increased the prevalence of polycythemia compared with non-evacuees at an average of 1.6 years (2011-2012) from the previous annual health checkup before the Great East Japan Earthquake (GEJE). Here we analyzed how the prolonged evacuation affected the prevalence of polycythemia an average of 2.5 years (2013-2014) after the previous data. Subjects were individuals aged 40-90 years living in the vicinity of the Fukushima Daiichi Nuclear Power Plant in Fukushima Prefecture who had attended the annual health checkups since 2008. The prevalence of polycythemia and changes in its defining factors of red blood cell count (RBC), hemoglobin (Hb) level, hematocrit (Ht) level were compared between before and after the GEJE in 7713 individuals (3349 men and 4364 women) receiving follow-up examinations both 2011-2012 and 2013-2014. RBC, Hb levels and Ht levels in 2011-2012 were higher among evacuees than non-evacuees in both men and women. However, all levels in 2013-2014 were on the decline from those in 2011-2012. On the other hand, among evacuees, Hb and Ht levels continued to be higher than before the GEJE in both men and women evacuees. The prevalence of polycythemia, which was diagnosed if one of the defining factors was beyond the standard value, was significantly higher among evacuees than non-evacuees regardless of the presence or the absence of overweight/obesity, smoking, and hypertension. Therefore, prolonged evacuation is a cause of polycythemia even 3 to 4 years after the GEJE and regular health management of evacuees is important.

Epilepsy and ion channels.

Many mutations of genes for ion channels result in some epilepsies. Their electrophysiological studies reveal pathophysiological mechanisms underlining epilepsy and also mechanism of action of several antiepileptic drugs. In this review, We briefly summarize pathophysiology of epilepsy and the mechanisms of antiepileptic drugs.

A case of lymphomatosis cerebri mimicking inflammatory diseases.

BACKGROUND: Lymphomatosis cerebri (LC) is a rare subtype of primary central nervous system malignant lymphoma. The typical features of this disease exhibited on magnetic resonance imaging (MRI) without contrast enhancement are similar to those observed with diffuse leukoencephalopathy, mimicking white matter disorders such as encephalitis. Clinical features and examination findings that are suggestive of inflammatory diseases may indeed confound the diagnosis of LC. CASE PRESENTATION: A 66-year-old woman with continuous fever over a two-month period developed left hemiparesis despite presenting in an alert state with normal cognitive function. Sampling tests showed autoantibodies in the serum and inflammatory changes in the cerebrospinal fluid. The results from an MRI demonstrated multiple non-enhanced brain lesions in the splenium of the corpus callosum and deep white matter. Single photon emission computed tomography revealed increases in blood flow in the basal ganglia, thalamus and brainstem. No systemic malignancies were found. The patient was suspected of having a diagnosis of nonvasculitic autoimmune inflammatory meningoencephalitis and treated with intravenous methylprednisolone pulse therapy. Her fever transiently dropped to within the normal range. However, she had a sudden seizure and a second MRI exhibited infiltrative lesions gradually extending throughout the whole brain. We performed a brain biopsy, and LC was histologically diagnosed. The patient received whole-brain radiation therapy, which diminished the fever and seizures. The patient died one year after the initial onset of fever. CONCLUSIONS: The present case yields an important consideration that brain neoplasms, especially LC, cannot be ruled out, even in cases with clinical characteristics and examinations consistent with inflammatory diseases. Careful follow-up and histological study are vital for the correct diagnosis of LC.

Impact of platelet transfusion on survival of patients with intracerebral hemorrhage after administration of anti-platelet agents at a tertiary emergency center.

This study examined the impact of platelet transfusion (PLT) on the survival of intracerebral hemorrhage (ICH) patients who had been administered anti-platelet agents (APA). This retrospective cohort analysis investigated 432 patients (259 men, 60%) who were newly diagnosed with ICH between January 2006 and June 2011 at the tertiary emergency center of Kitasato University Hospital. Median age on arrival was 67.0 years (range, 40-95 years). ICH was subcortical in 72 patients (16.7%), supratentorial in 233 (53.9%), and infratentorial in 133 (30.8%). PLT was performed in 16 patients (3.7%). Within 90 days after admission to the center, 178 patients (41.2%) had died due to ICH. Before the onset of ICH, 66 patients had been prescribed APA because of atherosclerotic diseases. Multivariate regression analysis indicated APA administration was an independent risk factor for death within 7 days (odds ratio, 5.12; P = 0.006) and within 90 days (hazard ratio, 1.87; P = 0.006) after arrival. Regarding the effect of a PLT in ICH patients with APA, no patient with PLT died. PLT had a survival benefit on patients with ICH, according to our analysis. Further prospective analysis is necessary to confirm the effects of PLT on survival in ICH with APA.

Mitogen-activated protein kinases-dependent induction of hepatocyte growth factor production in human dermal fibroblasts by the antibiotic polymyxin B.

Hepatocyte growth factor (HGF) stimulates migration and proliferation of keratinocytes and has been suggested to be involved in wound healing. The cationic antibiotic polymyxin B (PMB) is commonly used as a topical antibiotic for wound care. If PMB possesses an HGF-inducing activity, the antibiotic is potentially beneficial for wound healing in addition to minimizing chances of infection. In this study, we found that PMB markedly induced HGF production from various types of cells including human dermal fibroblasts. Its effect was stronger than the effects of epidermal growth factor and cholera toxin and was comparable to the effect of 8-bromo-cAMP. Among the polymyxin family and polymyxin derivatives, colistin was also effective, whereas colistin methanesulfonate had only a marginal effect and PMB nonapeptide was ineffective. The stimulatory effect of PMB was accompanied by upregulation of HGF gene expression. Increase in phosphorylation of extracellular signal-regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) was observed from 0.25 h to 6h after the addition of PMB, while increase in phosphorylation of p38 mitogen-activated protein kinase (MAPK) was detected from 24h to 60 h after PMB addition. The MAPK/ERK kinase inhibitor PD98059, the JNK inhibitor SP600125 and the p38 MAPK inhibitor SB203580 all potently inhibited PMB-induced HGF production. Lastly, proliferation of human dermal fibroblasts was significantly stimulated by PMB. These results indicate that PMB-induced HGF production and proliferation of human dermal fibroblasts and suggest that activation of MAPKs is involved in the induction of HGF production.

Enantioselective direct aminalization with primary carboxamides catalyzed by chiral ammonium 1,1'-binaphthyl-2,2'-disulfonates.

A highly effective catalytic enantioselective direct aminal synthesis was developed. Chiral ammonium 1,1'-binaphthyl-2,2'-disulfonates, which were prepared in situ from (R)-BINSA and achiral amines, promoted the enantioselective addition of primary amides to aromatic aldimines.

Different degrees of loss of function between GEFS+ and SMEI Nav 1.1 missense mutants at the same residue induced by rescuable folding defects.

Generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI) differ in their clinical severity and prognosis even though mutations of the Na(v) 1.1 sodium channel are responsible for both disorders. We compared the electrophysiologic properties of two mutant Na(v) 1.1 channels characterized by distinct amino acid substitutions at the same residue position: GEFS+ (A1685V) and SMEI (A1685D). Both the mutants showed complete loss of function when expressed alone. However, the function of A1685V can be partly rescued by the ß(1) subunit, consistently with a folding defect, whereas that of A1685D was not rescued. These electrophysiologic differences are consistent with the divergence in clinical severity between GEFS+ and SMEI.

Chemical preconditioning-induced reactive astrocytosis contributes to the reduction of post-ischemic edema through aquaporin-4 downregulation.

Aquaporins are a family of membrane proteins that promote the transmembrane diffusion of water. Aquaporin-4 (AQP4) is a predominant water channel protein in the brain and is concentrated in the end-feet of astrocytes. A critical question is what role astrocytic AQP4 plays in pathological conditions. Another matter to be elucidated is the relationship between morphological changes in astrocytes and AQP4 expression in such cases. We investigated the correlation between AQP4 expression and post-ischemic brain edema formation with astrocytic molecular markers after 3-nitropropionic acid (3NP) preconditioning. 3NP is a mitochondrial toxin, which can induce tolerance to ischemia at subtoxic levels. Rats were treated with 3NP at the tolerance-inducible and the non-tolerance-inducible stage (TS or NTS) before focal ischemia. The control group was injected with physiological saline. After ischemia, the hemispheric enlargement (HE) was volumetrically measured. Immunohistochemical and immunofluorescence analyses of AQP4, glial fibrillary acidic protein (GFAP), and glutamine synthetase (GS) were also conducted after the 3NP treatment and a vehicle was applied. HE was found to be significantly smaller in the TS group than in the vehicle group or the NTS group. The immunofluorescence analyses demonstrated that the AQP4 immunoreactivity in the cortex and striatum was significantly reduced in the TS group but not in the NTS group. In contrast, both GFAP expression and GS expression in the TS group were enhanced, with reactive astrocytosis. AQP4 downregulation in reactive astrocytosis may be one of the factors contributing to the role of 3NP preconditioning in attenuating post-ischemic edema.