Seiji Hama

Recurrence of meningiomas

Macroscopic total resection with removal of involved dura and bone does not always prevent the recurrence of meningioma of histologically benign subtype. Many causative factors have been investigated, although the mechanism of recurrence remains unclear. Vascular endothelial growth factor (VEGF) is a key factor in meningiomas neovascularization, and the authors investigated whether VEGF expression can predict the recurrence of histologically benign meningiomas after macroscopic total resection.

Expression of Survivin in Astrocytic Tumors Correlation with Malignant Grade and Prognosis

Astrocytic tumors are the most common tumors of the central nervous system. The mechanisms of genetic change of astrocytic tumors have not been understood completely. Recently, survivin has been identified as a member of the inhibitor‐of‐apoptosis family. Survivin expression is considered an important prognostic factor of many tumors.

Monoallelic BUB1B mutations and defective mitotic-spindle checkpoint in seven families with premature chromatid separation (PCS) syndrome.

Cancer‐prone syndrome of premature chromatid separation (PCS syndrome) with mosaic variegated aneuploidy (MVA) is a rare autosomal recessive disorder characterized by growth retardation, microcephaly, childhood cancer, premature chromatid separation of all chromosomes, and mosaicism for various trisomies and monosomies. Biallelic BUB1B mutations were recently reported in five of eight families with MVA syndrome (probably identical to the PCS syndrome). We here describe molecular analysis of BUB1B (encoding BubR1) in seven Japanese families with the PCS syndrome. Monoallelic BUB1B mutations were found in all seven families studied: a single‐base deletion (1833delT) in four families; and a splice site mutation, a nonsense mutation, and a missense mutation in one family each. Transcripts derived from the patients with the 1833delT mutation and the splice site mutation were significantly reduced, probably due to nonsense‐mediated mRNA decay. No mutation was found in the second alleles in the seven families studied, but RT‐PCR of BUB1B and Western blot analysis of BubR1 indicated a modest decrease of their transcripts. BubR1 in the cells from two patients showed both reduced protein expression and diminished kinetochore localization. Their expression level of p55cdc, a specific activator of anaphase‐promoting complex, was normal but its kinetochore association was abolished. Microcell‐mediated transfer of chromosome 15 (containing BUB1B) into the cells restored normal BubR1 levels, kinetochore localization of p55cdc, and the normal responses to colcemid treatment. These findings indicate the involvement of BubR1 in p55cdc‐mediated mitotic checkpoint signaling, and suggest that >50% decrease in expression (or activity) of BubR1 is involved in the PCS syndrome.

Post-stroke affective or apathetic depression and lesion location: left frontal lobe and bilateral basal ganglia

This study was designed to examine the correlation between damage to the basal ganglia or frontal lobe and depression status (both affective and apathetic dimensions) in 243 stroke patients. We assessed the affective dimension in post-stroke depression (PSD) using the Zung Self-rating Depression Scale (SDS) and the apathetic dimension in PSD using the apathy scale (AS). We classified basal ganglia or frontal lobe damage into four groups: no damage, damage to the left side only, damage to the right side only, and damage to both sides. Affective and/or apathetic PSD was found in 126 patients (51.9%). The severity of affective depression (SDS score) was associated with left frontal lobe (but not basal ganglia) damage, and that of apathetic depression (AS score) was related to damage to the bilateral basal ganglia (but not to the frontal lobe). The anatomical correlates of PSD differ depending on the PSD dimension (affective or apathetic) and may explain interstudy differences regarding the association between lesion location and type of PSD.

Post-stroke depression and apathy: Interactions between functional recovery, lesion location, and emotional response.

Depression and apathy are often observed after stroke and are often confused with one another. In the present review, we argue that the current concept of ‘post‐stroke depression’ (PSD) in fact consists of two core symptoms or syndromes: (i) affective (depressive) PSD; and (ii) apathetic PSD. We argue that these two core symptoms are each associated with a different underlying neuroanatomical mechanism, a pattern that influences functional recovery. Post‐stroke disabilities can provoke several distinct emotional responses, some of which are associated with severe depression. We examined one of these emotional responses previously, namely ‘insistence on recovery’, which was believed to be a negative indicator of functional improvement in disabled stroke patients. However, an appropriate level of insistence on recovery may, in fact, be associated with reduced depression and apathy, resulting in enhanced recovery from stroke‐related disabilities. Improvements in physical disabilities (trunk stability or activities of daily living, such as walking) also reduce depression and apathy. Therefore, the experience of PSD/apathy may be intertwined with various initial emotional responses and improvements in physical functioning. Effective treatment of PSD/apathy requires a multidisciplinary approach, such that neuroanatomical/neurobiological, emotional, and physical (rehabilitation) domains are all addressed.

Centrosome amplification induced by survivin suppression enhances both chromosome instability and radiosensitivity in glioma cells

Glioblastoma is characterised by invasive growth and a high degree of radioresistance. Survivin, a regulator of chromosome segregation, is highly expressed and known to induce radioresistance in human gliomas. In this study, we examined the effect of survivin suppression on radiosensitivity in malignant glioma cells, while focusing on centrosome aberration and chromosome instability (CIN). We suppressed survivin by small interfering RNA transfection, and examined the radiosensitivity using a clonogenic assay and a trypan blue exclusion assay in U251MG (p53 mutant) and D54MG (p53 wild type) cells. To assess the CIN status, we determined the number of centrosomes using an immunofluorescence analysis, and the centromeric copy number by fluorescence in situ hybridisation. As a result, the radiosensitisation differed regarding the p53 status as U251MG cells quickly developed extreme centrosome amplification (=CIN) and enhanced the radiosensitivity, while centrosome amplification and radiosensitivity increased more gradually in D54MG cells. TUNEL assay showed that survivin inhibition did not lead to apoptosis after irradiation. This cell death was accompanied by an increased degree of aneuploidy, suggesting mitotic cell death. Therefore, survivin inhibition may be an attractive therapeutic target to overcome the radioresistance while, in addition, proper attention to CIN (centrosome number) is considered important for improving radiosensitivity in human glioma.

Vulnerable carotid arterial plaque causing repeated ischemic stroke can be detected with B-mode ultrasonography as a mobile component: Jellyfish sign

Mobile plaque is associated with increased risk of ischemic stroke, but definitions have remained unclear. We have previously reported that carotid ultrasonography can detect the mobile component of the carotid plaque surface, which rises and falls in a manner inconsistent with arterial pulsatile wall motion (Jellyfish sign). However, clinical and pathological features of Jellyfish sign remain unclear. The subjects comprised of 165 patients with carotid plaque and degree of area stenosis ≥50% on ultrasonography. Using magnetic resonance imaging, we quantified intraplaque hemorrhage (IPH) and defined ischemic stroke in each patient. Fifteen surgical specimens were obtained by carotid endarterectomy, and pathological features (area of fibrous cap and intraplaque atheromatous lesion) were compared with ultrasonographic plaque surface movement rate. Carotid plaques with IPH were seen in 78 cases, with Jellyfish sign in 31 cases. Jellyfish sign was not detected in patients without IPH. In these 15 patients, the fibrous cap covered the atheromatous lesion, and cap thickness correlated negatively with Jellyfish-positive plaque surface movement rate. Kaplan–Meier and Cox multiple regression analysis demonstrated that the most important predictor of ischemic stroke during follow-up is Jellyfish sign, not IPH. Stroke events in patients with Jellyfish sign repeated within a short interval after diagnosis. Jellyfish sign on ultrasonography is a sign of high-risk plaque vulnerability, suggesting rupture of the fibrous cap associated with the release of thrombogenic factors into the arterial lumen, and resulting in repeated ischemic stroke during a short interval after diagnosis.

Neuroanatomic Pathways Associated with Poststroke Affective and Apathetic Depression

OBJECTIVES Our goal was to localize lesions in poststroke depression patients using magnetic resonance imaging, based on the statistical parametric maps image analysis technique that can be used to combine image data from multiple participants and correlate these images with other data sets. METHODS Magnetic resonance imaging acquisitions were obtained from 149 poststroke patients, who were assessed for affective and apathetic symptoms using the Hospital Anxiety and Depression Scale and the Apathy Scale, respectively. We created a statistical parametric map that displayed an association between lesion location and affective and apathetic symptoms. RESULTS Among the patients with higher depressive scores, the lesion overlap centered on the brainstem, left basal ganglia, and left frontal cortex. Among the patients with higher apathy scores, the lesion overlap centered on the brainstem and bilateral striatum. The overlap lesion for both affective and apathetic depression centered mainly on the brainstem; however, the two types of depression often did not overlap. CONCLUSIONS Two core symptoms that can occur after stroke, affective and apathetic symptoms, appear to be associated with different monoaminergic neuroanatomic pathways (serotonergic and dopaminergic).

Geminin: A good prognostic factor in high‐grade astrocytic brain tumors

Geminin is a nuclear protein that belongs to the DNA replication inhibitor group. It inhibits DNA replication by preventing Cdt1 from loading minichromosome maintenance protein onto chromatin, as is required for DNA replication. For this study, the authors investigated geminin expression in high‐grade astrocytic tumors, including anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM), with a view to predicting clinical outcomes on this basis in patients with these malignant brain tumors.

Cytoplasmic, but not nuclear, p16 expression may signal poor prognosis in high-grade astrocytomas.

SummaryBackgroundThe negative consequences of the cytoplasmic localization of p16 in patients with high-grade astrocytomas, on their prognosis, was investigated.Methodsp16 Expression was examined in 20 anaplastic astrocytoma and 42 glioblastoma patients by immunohistochemical analysis, and the relationship between both cytoplasmic and nuclear p16 expression and prognosis analyzed.ResultsThe cytoplasmic expression of p16 statistically correlated with poor prognosis. On the other hand, no correlation was observed between p16 nuclear expression and patient survival.ConclusionThe cytoplasmic immunoreactivity of p16 appears to be an unfavorable prognostic indicator in high-grade astrocytoma patients. The localization of p16 expression should be determined when evaluating the prognosis of these patients.