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1.
Sci Rep ; 9(1): 17288, 2019 11 21.
Article in English | MEDLINE | ID: mdl-31754123

ABSTRACT

Idiopathic basal ganglia calcification (IBGC) is a rare intractable disease characterized by abnormal mineral deposits, including mostly calcium in the basal ganglia, thalamus, and cerebellum. SLC20A2 is encoding the phosphate transporter PiT-2 and was identified in 2012 as the causative gene of familial IBGC. In this study, we investigated functionally two novel SLC20A2 variants (c.680C > T, c.1487G > A) and two SLC20A2 variants (c.82G > A, c.358G > C) previously reported from patients with IBGC. We evaluated the function of variant PiT-2 using stable cell lines. While inorganic phosphate (Pi) transport activity was abolished in the cells with c.82G > A, c.358G > C, and c.1487G > A variants, activity was maintained at 27.8% of the reference level in cells with the c.680C > T variant. Surprisingly, the c.680C > T variant had been discovered by chance in healthy members of an IBGC family, suggesting that partial preservation of Pi transport activity may avoid the onset of IBGC. In addition, we confirmed that PiT-2 variants could be translocated into the cell membrane to the same extent as PiT-2 wild type. In conclusion, we investigated the PiT-2 dysfunction of four SLC20A2 variants and suggested that a partial reduced Pi transport function of PiT-2 might not be sufficient to induce brain calcification of IBGC.


Subject(s)
Basal Ganglia Diseases/genetics , Basal Ganglia/pathology , Calcinosis/genetics , Neurodegenerative Diseases/genetics , Phosphates/metabolism , Sodium-Phosphate Cotransporter Proteins, Type III/deficiency , Adult , Aged, 80 and over , Basal Ganglia/cytology , Basal Ganglia Diseases/pathology , Calcinosis/pathology , Cell Membrane/metabolism , DNA Mutational Analysis , Female , Humans , Male , Middle Aged , Mutation , Neurodegenerative Diseases/pathology , Pedigree , Sodium-Phosphate Cotransporter Proteins, Type III/genetics
2.
Sci Rep ; 9(1): 5698, 2019 04 05.
Article in English | MEDLINE | ID: mdl-30952898

ABSTRACT

Causative genes in patients with idiopathic basal ganglia calcification (IBGC) (also called primary familial brain calcification (PFBC)) have been reported in the past several years. In this study, we surveyed the clinical and neuroimaging data of 70 sporadic patients and 16 families (86 unrelated probands in total) in Japan, and studied variants of PDGFB gene in the patients. Variant analyses of PDGFB showed four novel pathogenic variants, namely, two splice site variants (c.160 + 2T > A and c.457-1G > T), one deletion variant (c.33_34delCT), and one insertion variant (c.342_343insG). Moreover, we developed iPS cells (iPSCs) from three patients with PDGFB variants (c.160 + 2T > A, c.457-1G > T, and c.33_34 delCT) and induced endothelial cells. Enzyme-linked immunoassay analysis showed that the levels of PDGF-BB, a homodimer of PDGF-B, in the blood sera of patients with PDGFB variants were significantly decreased to 34.0% of that of the control levels. Those in the culture media of the endothelial cells derived from iPSCs of patients also significantly decreased to 58.6% of the control levels. As the endothelial cells developed from iPSCs of the patients showed a phenotype of the disease, further studies using IBGC-specific iPSCs will give us more information on the pathophysiology and the therapy of IBGC in the future.


Subject(s)
Basal Ganglia/physiopathology , Brain Diseases/physiopathology , Calcinosis/physiopathology , Lymphokines/genetics , Mutation , Platelet-Derived Growth Factor/genetics , Adolescent , Aged , Basal Ganglia/diagnostic imaging , Brain Diseases/diagnostic imaging , Brain Diseases/genetics , Calcinosis/diagnostic imaging , Calcinosis/genetics , Endothelial Cells , Female , Humans , Induced Pluripotent Stem Cells , Male , Middle Aged , Pedigree
4.
Rinsho Shinkeigaku ; 58(4): 223-228, 2018 Apr 25.
Article in Japanese | MEDLINE | ID: mdl-29607914

ABSTRACT

A 63-year-old man developed a syndrome of cauda equine, with the numbness which is a left lower extremity from the left buttocks, weakness of left leg, and a dysfunction of bladder and bowel. Enhanced MRI revealed the enhancement of lower cauda equine, and a nerve conduction test revealed decreased F-wave persistency in the tibial nerve and increased F-wave latency in the peroneal nerve on the both sides. M-proteinemia was admitted and myeloma was suspected. By a biopsy of a vertebral arch, we diagnosed with diffuse large B-cell lymphoma. We treated with dexamethasone and R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone (prednisolone)), then the symptom was improved. In case of caude equine syndrome with M-proteinemia, a possibility of the malignant lymphoma should also be considered.


Subject(s)
Immunoglobulin M/blood , Lymphoma, Large B-Cell, Diffuse/complications , Lymphoma, Large B-Cell, Diffuse/diagnosis , Marek Disease/complications , Marek Disease/diagnosis , Paraproteinemias/blood , Paraproteinemias/etiology , Polyradiculopathy/etiology , Animals , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cyclophosphamide/administration & dosage , Doxorubicin/administration & dosage , Humans , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/pathology , Magnetic Resonance Imaging , Male , Marek Disease/drug therapy , Marek Disease/pathology , Middle Aged , Polyradiculopathy/diagnostic imaging , Polyradiculopathy/pathology , Positron-Emission Tomography , Prednisone/administration & dosage , Rituximab , Treatment Outcome , Vincristine/administration & dosage
5.
Brain Nerve ; 67(2): 213-7, 2015 Feb.
Article in Japanese | MEDLINE | ID: mdl-25681367

ABSTRACT

We report a case of phenytoin intoxication caused by an interaction between phenytoin and capecitabine. A 41-year-old woman was started on phenytoin (200 mg p.o. daily) for convulsive attacks due to breast cancer brain metastasis. Three months later, chemotherapy with 2,400 mg/d capecitabine (3 weeks on and 1 week off) and 1,250 mg/d lapatinib was initiated for the treatment of breast cancer. Approximately 10 weeks after starting chemotherapy, the patient began to complain of nausea, vomiting, and unsteadiness, and she was admitted to our hospital. Since her serum phenytoin level was more than 40 µg/mL, she was diagnosed with phenytoin intoxication. Phenytoin is metabolized in the liver, primarily by the CYP2C9 isozyme, which can be competitively inhibited by capecitabine. Thus, we determined that the patient developed phenytoin intoxication due to the interaction between phenytoin and capecitabine. This indicates the importance of considering the potential drug-drug interactions while prescribing anticancer agents and antiepileptic drugs simultaneously.


Subject(s)
Anticonvulsants/adverse effects , Antineoplastic Agents/adverse effects , Brain Neoplasms/drug therapy , Drug Interactions/physiology , Phenytoin/adverse effects , Adult , Anticonvulsants/therapeutic use , Antineoplastic Agents/therapeutic use , Brain Neoplasms/pathology , Brain Neoplasms/secondary , Capecitabine , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Female , Fluorouracil/administration & dosage , Fluorouracil/analogs & derivatives , Humans , Magnetic Resonance Imaging , Phenytoin/administration & dosage
6.
J Cardiol ; 65(5): 429-33, 2015 May.
Article in English | MEDLINE | ID: mdl-25129639

ABSTRACT

BACKGROUND: Although smoking is a risk factor for cardiovascular diseases, little is known about the impact of smoking on long-term outcomes in patients with atrial fibrillation (AF). METHODS: In 426 consecutive patients with nonvalvular AF (mean age, 66 years; 307 men; mean follow-up, 5.8±3.2 years), clinical variables including smoking status, CHADS2, and CHA2DS2-VASc score, incidences of cardiovascular events (stroke, myocardial infarction, or admission for heart failure), bleeding, and mortality were determined. RESULTS: Incidences of intracranial bleeding (0.7% vs 0.1%/year, p<0.01), all-cause mortality (4.9% vs 2.6%/year, p<0.01), and death from stroke (0.8% vs 0.2%/year, p<0.05) were higher in patients with history of smoking than in those without it. Incidence of intracranial bleeding was significantly higher in persistent smokers than in non-persistent smokers (1.2% vs 0.2%/year, p<0.01). History of smoking predicted all-cause mortality [hazard ratio (HR), 2.7; 95% confidence interval (CI), 1.7-4.5; p<0.01] and death from stroke (HR 4.7; 95% CI 1.0-22.3; p<0.05) independent of age, antithrombotic treatment, CHADS2, and CHA2DS2-VASc score. Persistent smoking predicted intracranial bleeding (HR 4.4; 95% CI 1.1-17.6; p<0.05) independent of age and antithrombotic treatment. CONCLUSIONS: Smoking status, independent of age, antithrombotic treatment, and clinical risk factors, predicted long-term adverse outcomes including bleeding events in patients with nonvalvular AF. There might be an obvious impact of persistent smoking on intracranial bleeding.


Subject(s)
Atrial Fibrillation/complications , Atrial Fibrillation/diagnosis , Intracranial Hemorrhages/epidemiology , Smoking/adverse effects , Aged , Aged, 80 and over , Female , Follow-Up Studies , Heart Failure/epidemiology , Heart Failure/mortality , Humans , Incidence , Intracranial Hemorrhages/mortality , Kaplan-Meier Estimate , Longitudinal Studies , Male , Middle Aged , Myocardial Infarction/epidemiology , Myocardial Infarction/mortality , Prognosis , Retrospective Studies , Risk Factors , Stroke/epidemiology , Stroke/mortality
7.
Rinsho Shinkeigaku ; 54(11): 876-81, 2014.
Article in Japanese | MEDLINE | ID: mdl-25420560

ABSTRACT

A 76-year-old man was admitted to our hospital presenting with fever, redness and pain in both the periocular regions, and disturbance of consciousness. He had neck stiffness, and cerebrospinal fluid analysis suggested aseptic meningoencephalitis. Laboratory tests showed increased levels of C-reactive protein, soluble IL-2 receptor (sIL-2R) and MPO-ANCA. Magnetic resonance imaging revealed hyperplastic bone marrow in the clivus and cervical vertebra. Although T-cell receptor gene rearrangement was detected in the bone marrow blood, bone marrow biopsy of the ilium showed no malignant findings. Then he experienced bilateral auricular inflammation and painful erythema of the ankle. A leg skin biopsy demonstrated neutrophilic infiltration into the dermis with no signs of vasculitis. His HLA-type was defined as Cw1. He was subsequently diagnosed with neuro-Sweet disease. Intravenous administration of methylprednisolone (1,000 mg/day) for 5 days and subsequent oral intake of prednisolone (60 mg/day) improved his symptoms. When the prednisolone dose was reduced to 30 mg/day, his symptoms returned and a new lesion was detected in the splenium of the corpus callosum. Upon additional treatment with cyclosporine, the prednisolone dose could be reduced without symptom relapse; sIL-2R and MPO-ANCA levels also decreased to normal. The present case suggested that the activity of neuro-Sweet disease may be associated with myeloid hyperplasia, T-cell receptor gene rearrangement and the amounts of soluble interleukin-2 receptor and MPO-ANCA.


Subject(s)
Central Nervous System Diseases/physiopathology , Receptors, Interleukin-2/blood , Sweet Syndrome/blood , Sweet Syndrome/physiopathology , Aged , Central Nervous System Diseases/blood , Humans , Magnetic Resonance Imaging , Male
9.
Neurology ; 82(8): 705-12, 2014 Feb 25.
Article in English | MEDLINE | ID: mdl-24463626

ABSTRACT

OBJECTIVE: To investigate the clinical, genetic, and neuroradiologic presentations of idiopathic basal ganglia calcification (IBGC) in a nationwide study in Japan. METHODS: We documented clinical and neuroimaging data of a total of 69 subjects including 23 subjects from 10 families and 46 subjects in sporadic cases of IBGC in Japan. Mutational analysis of SLC20A2 was performed. RESULTS: Six new mutations in SLC20A2 were found in patients with IBGC: 4 missense mutations, 1 nonsense mutation, and 1 frameshift mutation. Four of them were familial cases and 2 were sporadic cases in our survey. The frequency of families with mutations in SLC20A2 in Japan was 50%, which was as high as in a previous report on other regions. The clinical features varied widely among the patients with SLC20A2 mutations. However, 2 distinct families have the same mutation of S637R in SLC20A2 and they have similar characteristics in the clinical course, symptoms, neurologic findings, and neuroimaging. In our study, all the patients with SLC20A2 mutations showed calcification. In familial cases, there were symptomatic and asymptomatic patients in the same family. CONCLUSION: SLC20A2 mutations are a major cause of familial IBGC in Japan. The members in the families with the same mutation had similar patterns of calcification in the brain and the affected members showed similar clinical manifestations.


Subject(s)
Basal Ganglia Diseases/genetics , Brain/pathology , Calcinosis/genetics , Genetic Predisposition to Disease , Mutation/genetics , Neurodegenerative Diseases/genetics , Sodium-Phosphate Cotransporter Proteins, Type III/genetics , Adult , Aged , DNA Mutational Analysis/methods , Female , Genetic Linkage/genetics , Humans , Japan , Male , Middle Aged , Pedigree , Young Adult
10.
Clin Nucl Med ; 39(6): e334-5, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24097000

ABSTRACT

Reduced cortical benzodiazepine receptor binding potential in late images of I-iomazenil SPECT indicates neuronal damage in the cortex. We present the case of a 31-year-old woman with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) who had focal seizures in the right hand. FLAIR imaging in the ictal state revealed a high-intensity lesion in the left post-central gyrus, while I-iomazenil SPECT showed decreased tracer uptake in this lesion. The lesion completely disappeared on FLAIR imaging performed 1 month after the focal seizures; in contrast, I-iomazenil SPECT still revealed a significant decrease in tracer uptake in this lesion.


Subject(s)
Flumazenil/analogs & derivatives , MELAS Syndrome/complications , MELAS Syndrome/diagnostic imaging , Stroke/complications , Stroke/diagnostic imaging , Tomography, Emission-Computed, Single-Photon , Adult , Female , Humans , Iodine Radioisotopes
13.
Brain Nerve ; 64(11): 1341-5, 2012 Nov.
Article in Japanese | MEDLINE | ID: mdl-23131746

ABSTRACT

As anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis develops with incipient psychiatric symptoms in most patients, they initially seek medical care at psychiatric services. It would be desirable, therefore, for psychiatrists to be well aware of anti-NMDAR encephalitis. From this point of view, we conducted a questionnaire survey of psychiatrists to explore the present status of their level of awareness about anti-NMDAR encephalitis. A questionnaire survey of 115 psychiatrists engaged in medical care in Toyama Prefecture was conducted to explore their level of familiarity with anti-NMDAR encephalitis. Responses to the questionnaire were received from 76 psychiatrists (response collection rate 66.1%). The mean tenure in the medical profession was 23.5 ± 13.8 years for the 76 psychiatrists, of whom 61 (80.3%) were psychiatric specialists. As for the level of awareness of anti-NMDAR encephalitis, there were 37 doctors (48.7%) who were "not aware of this disorder," 23 (30.3%) who were "aware of only the name of this disorder," and 16 (21.0%) who had "knowledge of an outline of this disorder." While the level of familiarity of doctors with "knowledge of an outline of this disorder" was unrelated to whether the doctor was a specialist, the tenure in the medical profession was significantly shorter for these doctors than for the others (P < 0.05). Of the doctors who were "not aware of this disorder" and those who were "aware of only the name of this disorder," a high percentage comprised physicians working at hospitals/clinics specializing in psychiatry (P < 0.05). Only 7 doctors had encountered case(s) of anti-NMDAR encephalitis (9.2%), and among them, a significantly high percentage was on the staff of polyclinic hospitals (P < 0.05). The present survey revealed low levels of familiarity of psychiatrists with anti-NMDAR encephalitis, and this highlights the importance of further improving the awareness of psychiatrists about the concept of anti-NMDAR encephalitis.


Subject(s)
Anti-N-Methyl-D-Aspartate Receptor Encephalitis , Data Collection/methods , Recognition, Psychology , Surveys and Questionnaires , Animals , Humans , Psychiatry , Receptors, N-Methyl-D-Aspartate/physiology , Recognition, Psychology/physiology
14.
J Clin Neurol ; 8(3): 170-6, 2012 Sep.
Article in English | MEDLINE | ID: mdl-23091525

ABSTRACT

BACKGROUND AND PURPOSE: Not only clinical factors, including the CHADS(2) score, but also echocardiographic findings have been reported to be useful for predicting the risk of ischemic stroke in patients with nonvalvular atrial fibrillation (NVAF). However, it remains to be determined which of these factors might be more relevant for evaluation of the risk of stroke in each patient. METHODS: In 490 patients with NVAF who underwent transesophageal echocardiography (TEE), we examined the long-term incidence of ischemic stroke events (mean follow-up time, 5.7±3.3 years). For each patient, the predictive values of gender, the CHADS(2) risk factors (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, history of cerebral ischemia), the CHADS(2) score, and the findings on echocardiography, including TEE risk markers, were assessed. RESULTS: The ischemic stroke rate was significantly correlated with the CHADS(2) score (p<0.05). According to the results of univariate analyses, age ≥75 years, history of cerebral ischemia, CHADS(2) score ≥2, and presence of TEE risk were significantly correlated with the incidence of ischemic stroke. Cox proportional hazards regression analyses identified age ≥75 years and presence of TEE risk as significant predictors of subsequent ischemic stroke events in patients with NVAF. As compared with that in persons below 75 years of age without TEE risk, the ischemic stroke rate was significantly higher in persons who were ≥75 years of age with TEE risk (4.3 vs. 0.56%/year, adjusted hazard ratio=8.94, p<0.001). CONCLUSIONS: TEE findings might be more relevant predictors of ischemic stroke than the CHADS(2) score in patients with NVAF. The stroke risk was more than 8-fold higher in patients aged ≥75 years with TEE risk.

15.
J Stroke Cerebrovasc Dis ; 21(5): 404-10, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22516429

ABSTRACT

BACKGROUND: We studied the usefulness of hemostatic biomarkers in assessing the pathology of thrombus formation, subtype diagnosis, prognosis in the acute phase of cerebral infarction, and differences between various hemostatic biomarkers. METHODS: Our study included 69 patients with acute cerebral infarction who had been hospitalized within 2 days of stroke onset. Fibrin monomer complex (FMC), soluble fibrin (SF), D-dimer, thrombin-antithrombin III complex, fibrinogen, antithrombin III, and fibrin/fibrinogen degradation products (FDPs) were assayed as hemostatic biomarkers on days 1, 2, 3, and 7 of hospitalization. RESULTS: In the cardioembolic (CE) stroke group, FMC and SF levels were significantly higher on days 1 and 2 of hospitalization, and D-dimer levels were significantly higher on day 1 of hospitalization, compared to the noncardioembolic (non-CE) stroke group. FDP levels were significantly higher at all times in the CE group compared to the non-CE group. Neither the National Institute of Health Stroke Scale (NIHSS) used during hospitalization nor the modified Rankin Scale (mRS) used at discharge found any significant correlations to hemostatic biomarkers, but the NIHSS score during hospitalization was significantly higher in the CE group than in the non-CE group. CONCLUSIONS: Measurements of hemostatic biomarkers, such as FMC, SF, and D-dimer on the early stage of cerebral infarction are useful for distinguishing between CE and non-CE stroke.


Subject(s)
Fibrin/metabolism , Fibrinogen/metabolism , Hemostasis , Intracranial Thrombosis/blood , Stroke/blood , Antithrombin III/metabolism , Biomarkers/blood , Female , Fibrin Fibrinogen Degradation Products/metabolism , Humans , Male , Prognosis
19.
Neurosci Res ; 71(3): 294-302, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21839784

ABSTRACT

The concept of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, a severe, potentially lethal, treatment-responsive disorder, mediated by autoantibodies against NMDAR was proposed. Because paraneoplastic anti-NMDAR encephalitis has a better prognosis after tumor resection and immunotherapy, rapid quantitative systems for detecting functional autoantibodies against extracellular epitopes of NMDAR are necessary. To detect autoantibodies recognizing extracellular epitopes of NMDAR, we stably expressed mutant NMDAR that decreases Ca(2+) permeability on a heterologous cell surface without any antagonist. Serum and CSF samples from patients were analysed using the cells expressing mutant NMDAR subunits by immunocytochemistry and on-cell Western analysis using live cells stably expressing mutant NMDAR. Furthermore, we were able to express mutant GluRζ1(NR1, GluN1) subunit of NMDAR alone on the cell surface and obtained direct evidence of the presence of autoantibodies recognizing extracellular epitopes of GluRζ1 and the induction of internalization by autoantibodies in serum and CSF from patients. The specificity of on-cell Western analysis was improved at 37°C. The combination of this rapid quantitative assay using our on-cell western analysis, detailed analysis of extracellular epitopes of NMDAR, and internalization assay of NMDAR will be valuable for the diagnosis, evaluation of clinical treatments, and follow-up of anti-NMDAR encephalitis.


Subject(s)
Autoantibodies/blood , Autoantibodies/cerebrospinal fluid , Epitopes/blood , Epitopes/cerebrospinal fluid , Receptors, N-Methyl-D-Aspartate/immunology , Adolescent , Adult , Aged , Animals , Anti-N-Methyl-D-Aspartate Receptor Encephalitis/diagnosis , Anti-N-Methyl-D-Aspartate Receptor Encephalitis/immunology , Autoantibodies/biosynthesis , Blotting, Western/methods , CHO Cells , Child , Child, Preschool , Cricetinae , Cricetulus , Epitopes/immunology , Female , HEK293 Cells , Humans , Infant , Male , Mice , Middle Aged , Receptors, N-Methyl-D-Aspartate/blood , Young Adult
20.
Rinsho Shinkeigaku ; 51(7): 499-504, 2011 Jul.
Article in Japanese | MEDLINE | ID: mdl-21823510

ABSTRACT

We report a case of a 17-year-old woman with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, who developed psychiatric symptoms. Pelvic MRI revealed a right ovarian tumor that was suspected of being an ovarian teratoma. On the 27th day after onset, the patient underwent right salpingo-oophorectomy. The histopathological diagnosis was immature ovarian teratoma. Subsequently, 4 double filtration plasmapheresises (DFPP) were performed from day 34 to day 43. Methylprednisolone (1,000 mg/day for 3 days) was started on day 38. With these treatments, consciousness disturbance completely improved, and the patient was discharged on day 50. The serum and cerebrospinal fluid were positive for antibodies against the GluRzeta1 (NR1)-EGFP/GluRepsilon2 (NR2B) heteromer and the GluRzeta1 (NR1) subunit of NMDAR. The patient was hence diagnosed as having anti-NMDAR encephalitis with ovarian teratoma Serial analysis show that the antibodies against NMDAR decreased with improvement of symptoms after the immunotherapy including DFPP treatment.


Subject(s)
Autoantibodies/analysis , Limbic Encephalitis/immunology , Ovarian Neoplasms/complications , Receptors, N-Methyl-D-Aspartate/immunology , Teratoma/complications , Adolescent , Female , Humans , Limbic Encephalitis/therapy , Ovarian Neoplasms/surgery , Ovariectomy , Plasmapheresis/methods , Teratoma/surgery
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