Comprehensive investigation of RNF213 nonsynonymous variants associated with intracranial artery stenosis.

Intracranial artery stenosis (ICAS) is the most common cause of ischemic stroke worldwide. RNF213 single nucleotide variant c.14429G > A (p.Arg4810Lys, rs112735431) was recently reported to be associated with ICAS in East Asians. However, the disease susceptibility of other RNF213 variants has not been clarified. This study comprehensively investigated ICAS-associated RNF213 variants in a pool of 168 Japanese ICAS patients and 1,194 control subjects. We found 138 nonsynonymous germline variants by target resequencing of all coding exons in RNF213. Association study between ICAS patients and control subjects revealed that only p.Arg4810Lys had significant association with ICAS (P = 1.5 × 10-28, odds ratio = 29.3, 95% confidence interval 15.31-56.2 [dominant model]). Fourteen of 138 variants were rare variants detected in ICAS patients not harboring p.Arg4810Lys variant. Two of these rare variants (p.Cys118Arg and p.Leu2356Phe) consistent with variants previously reported in moyamoya disease patients characterized by stenosis of intracranial artery and association with RNF213, and three rare variants (p.Ser193Gly, p.Val1817Leu, and p.Asp3329Tyr) were found neither in control subjects and Single Nucleotide Polymorphism Database. The present findings may improve our understanding of the genetic background of intracranial artery stenosis.

Reversible Cerebral Metabolism Changes Using Proton Magnetic Resonance Spectroscopy in a Patient with Intracranial Dural Arteriovenous Fistula: A Case Report.

BACKGROUND: Cerebral metabolism can be disrupted by venous congestion in patients with intracranial dural arteriovenous fistula (DAVF), which may lead to adverse neurological outcomes. However, there are no clear indicators to guide cerebral evaluation and treatment selection in cases of DAVF. We describe a patient with a DAVF whose proton magnetic resonance spectroscopy ((1)H-MRS) findings were associated with improvements in clinical status. CASE DESCRIPTION: An elderly woman with a history of myocardial infarction presented with progressive dementia, aphasia, and a severe headache. We detected a transverse-sigmoid sinus DAVF, as well as abnormal levels of lactate and N-acetylaspartic acid (NAA) in the (1)H-MRS, and successfully treated the patient using surgical sinus skeletonization. However, follow-up (1)H-MRS revealed inconsistent reversals in the levels of lactate and NAA. In addition, we calculated the NAA/creatinine ratios from before and after surgery, which revealed postoperative increases in the ratios for the left temporal, right parietal, and left parietal regions. These increases occurred concurrently with improvements in the patient's cognitive function. CONCLUSIONS: (1)H-MRS may be useful for pretreatment detection of increased lactate levels, decreased NAA levels, and/or decreased NAA/creatinine ratios. These findings may indicate poorer cerebral metabolism, and show a need for more aggressive treatment. Furthermore, (1)H-MRS may be useful for evaluating the effect of conservative treatment and for indicating conversion to a more aggressive treatment.

Genetic Analysis of RNF213 c.14576G>A Variant in Nonatherosclerotic Quasi-Moyamoya Disease.

BACKGROUND: Quasi-moyamoya disease (MMD) and MMD (definite MMD) have similar cerebral angiographic features, but whether these related diseases have similar etiology or genetic background remains unclear. Recently, we have reported that the recently identified MMD susceptibility gene variant RNF213 c.14576G>A (rs112735431) was associated with atherosclerotic intracranial major artery stenosis/occlusion. The present study investigated the occurrence of RNF213 c.14576G>A in patients with nonatherosclerotic quasi-MMD. METHODS: This study was a 2-hospital-based case-control study conducted at the Department of Neurosurgery, The University of Tokyo Hospital and Kanto Neurosurgical Hospital. A total of 87 Japanese patients who agreed to participate in this study were enrolled among both new and revisiting outpatients from October 2011 to December 2013 as follows: 78 patients with definite MMD and 9 patients with nonatherosclerotic quasi-MMD. RESULTS: The 9 patients with nonatherosclerotic quasi-MMD included 3 patients with previous irradiation, 2 with hyperthyroidism, 1 with Turner syndrome, 1 with meningitis, 1 with Behçet disease, and 1 with idiopathic pachymeningitis. The 78 patients with definite MMD included 66 patients (84.6%) with the c.14576G>A variant (64 heterozygotes and 2 homozygous). In contrast, no patients with nonatherosclerotic quasi-MMD had the variant. CONCLUSIONS: Nonatherosclerotic quasi-MMD did not have RNF213 c.14576G>A variant. Moyamoya disease and related diseases might be classified by genetic analysis of the RNF213 c.14576G>A genotype. Further larger studies are required to confirm the present findings.

Genetic variant RNF213 c.14576G>A in various phenotypes of intracranial major artery stenosis/occlusion.

BACKGROUND AND PURPOSE: Recently, we reported a common genetic variant, ring finger protein 213 (RNF213) c.14576G>A variant, a susceptibility gene for moyamoya disease (MMD), among patients with intracranial major artery stenosis/occlusion (ICASO) in a selected Japanese population. The aim of this 2-center-based case-control study was to confirm our previous finding in a larger population. METHODS: Study participants were recruited from The University of Tokyo Hospital and Kanto Neurosurgical Hospital. The occurrence rate of c.14576G>A variant was investigated in 323 patients, 22 with definite MMD, 8 with unilateral MMD, 84 with ICASO in the absence of MMD (non-MMD ICASO), 34 with extracranial carotid atherosclerosis, 44 with cerebral aneurysm, 21 with intracerebral hemorrhage, and 110 control subjects. RESULTS: RNF213 c.14576G>A variant was found in 1.8% (2/110) of the normal control group and had significant associations with definite MMD (P<0.0001; odds ratio, 144.0; 95% confidence interval, 26.7-775.9), unilateral MMD (P=0.0001; odds ratio, 54.0; 95% confidence interval, 7.5-386.8), and non-MMD ICASO (P<0.0001; odds ratio, 16.8; 95% confidence interval, 3.81-74.5). There was no significant association with extracranial carotid atherosclerosis, cerebral aneurysm, or intracerebral hemorrhage. This result replicated our previous findings. CONCLUSIONS: A particular subset of patients with various phenotypes of ICASO has a common genetic variant, RNF213 c.14576G>A, indicating that RNF213 c.14576G>A variant is a high-risk allele for ICASO.

Anaplastic oligodendroglioma with ganglioglioma-like maturation.

Neuronal differentiation of oligodendroglioma has been demonstrated by immunohistochemical and ultrastructural examinations in recent studies. However, oligodendrogliomas displaying a complete neurocytic morphology or even gangliocytic differentiation are rare. We describe a case of anaplastic oligodendroglioma that was characterized by the presence of ganglion cells in a 40-year-old-male. Histologically, the tumor was mainly composed of classical oligodendroglioma cells. The most exceptional finding of this tumor was the presence of ganglion cells and intermediate-sized ganglioid cells. Immunohistochemical analysis revealed that these cells were positive for Olig2 and negative for glial fibrillary acid protein (GFAP). Synaptophysin and microtubule-associated protein 2 (MAP2) were mainly detected in the ganglion cells. Fluorescence in situ hybridization analysis (FISH) revealed the deletion of the 1p and 19q chromosome arms in both the oligodendroglioma cells and ganglion cells. The R132H mutated isocitrate dehydrogenase 1 (IDH1) protein was detected by immunohistochemistry and direct DNA sequencing. The morphological, immunohistochemical, and genetic features of the tumor suggested a diagnosis of anaplastic oligodendroglioma, and this tumor was considered to be a rare form of oligodendroglioma displaying ganglioglioma-like maturation. FISH and mutant IDH1 examinations are useful diagnostic tools for the differential diagnosis of this tumor, i.e., ganglioglioma with anaplastic oligodendroglial features.

Rosai-Dorfman disease presenting as a solitary mediastinal mass.

Rosai-Dorfman disease (RDD) involving an extranodal site is a diagnostic challenge. Reported herein is the case of a 67-year-old man who presented with a solitary superior mediastinal mass. The lesion was clinically suspected of malignancy including lymphoma because of its high uptake during a (67)Ga-scintigram and (18)F-fluorodeoxyglucose-positron emission tomography. There was no evidence of spread of the disease. Histology of thoracoscopic biopsy specimens indicated granulomatous lesion with infiltration of lymphocytes, plasma cells, and histiocytes with lymphocytes engulfed in their cytoplasm. The lesion did not contain lymph node or thymic elements. On immunohistochemistry the histiocytes were positive for S-100 protein, CD68, and CD163 but were negative for CD1a. These findings suggested a diagnosis of RDD. Despite lack of intervention, the lesion remained almost the same size for 3 years. To the best of the authors' knowledge this is the first case of RDD presenting as a solitary mediastinal mass.

Clinical analysis of cases of empyema due to Streptococcus milleri group.

In this study we analyzed 15 cases of empyema due to Streptococcus milleri group treated between January 2000 and December 2007. The majority (87%) were men, and the mean patient age was 62 years (range 36 to 83). An underlying disease was present in 14 of 15 cases. Six cases were complicated by pneumonia. Polymicrobial infection with S. milleri group was recognized in four patients. Most patients underwent chest tube drainage (87%), and all received antibiotic treatment (100%). The average duration of chest tube drainage was 8.4 days and that of antibiotic treatment was 14.0 days. Six cases (40%) underwent video-assisted thoracoscopic surgery for decortication. The duration of hospitalization was 19.6 days. The clinical effect of treatment was comparatively good (93%), and the prognosis was also good (mortality rate 7%).

An asymptomatic case of pulmonary cryptococcosis with endobronchial polypoid lesions and bilateral infiltrative shadow.

A case of pulmonary cryptococcosis with focal endobronchial polypoid lesions is described. A 64-year-old woman consulted our hospital for further evaluation of an abnormal shadow on a chest radiograph. She had been prescribed corticosteroid for rheumatoid arthritis. Chest radiographs revealed an infiltrative shadow in the right lower and left middle and lower lung fields, and chest computed tomography (CT) revealed bilateral airspace consolidations and multiple nodules. A bronchoscopic finding revealed white polypoid lesions at the orifice of the posterior basal bronchus in the left lower lobe. Histopathological examination of transbronchial biopsy specimens demonstrated cryptococcal organisms. After fluconazole therapy for 4 months, the infiltrate had decreased in size and the bronchial polypoid lesions had disappeared.

Pulmonary mucormycosis (Cunninghamella bertholletiae) with cavitation diagnosed using ultra-thin fibre-optic bronchoscopy.

Recently, ultra-thin bronchoscopy has made it possible to observe smaller bronchi not visualized using standard techniques. We describe a case of pulmonary mucormycosis with cavitation, diagnosed using an ultra-thin bronchoscope. A 15-year-old girl with acute myeloid leukaemia had taken oral prednisolone, 60 mg/day, for graft versus host disease after haematopoietic stem cell transplantation. She was admitted to our hospital with fever and a large cavitary lesion in the right hilum. Using an ultra-thin bronchoscope, the interior of the cavity in the superior segment of the right lower lobe was observed. The bronchoscopic findings revealed debris adhering to the cavity wall with a small volume of effusion. Cunninghamella bertholletiae was isolated from the effusion specimen obtained using the bronchoscope. Pulmonary mucormycosis (C. bertholletiae) complicating an immunocompromised state was diagnosed. Ultra-thin bronchoscopy is useful to diagnose complex pulmonary infections and more research is needed to verify its clinical indications and utility.