Masato Hojo

Milrinone for the treatment of cerebral vasospasm after subarachnoid hemorrhage: report of seven cases.

OBJECTIVEThe intra-arterial infusion of papaverine has been used for dilation of spastic cerebral vessels after aneurysmal subarachnoid hemorrhage, although its efficacy is controversial. Milrinone is an inotropic drug that dilates vessels by phosphodiesterase inhibition in a mechanism similar to that of papaverine. We examined the effects of intra-arterial and subsequent intravenous administration of milrinone on patients with symptomatic cerebral vasospasm. METHODSSeven patients with cerebral vasospasm were enrolled in this study. Milrinone was delivered intra-arterially via catheter at a rate of 0.25 mg/min. The total delivered dose was between 2.5 and 15 mg. Radiological measurement of the middle cerebral artery diameter and cerebral blood flow was carried out before and after arterial infusion. Intravenous treatment followed at 0.50 or 0.75 &mgr;g/kg/min for up to 2 weeks from the onset of subarachnoid hemorrhage. RESULTSDilation of the vasospastic vessels occurred in all patients. The rate of cerebral blood flow was calculated in six patients and was increased in all. Subsequent intravenous infusion was effective in preventing a recurrence of symptomatic vasospasm in four of the seven patients. CONCLUSIONIt is suggested that milrinone was effective and safe for the treatment of cerebral vasospasm after subarachnoid hemorrhage in the patients in this series. Intra-arterial infusion with adjunctive intravenous infusion holds promise as a clinically advantageous treatment regimen.

Evaluation of primary brain tumors with FLT-PET: usefulness and limitations.

Purpose of the Report: The purpose of this report was to investigate the potential of positron emission tomography using F-18 fluorodeoxythymidine (FLT-PET) in evaluating primary brain tumors. Materials and Methods: FLT-PET was performed in 25 patients with primary brain tumors. FLT uptake in the lesion was semiquantitatively evaluated by measuring the maximal standardized uptake value (SUVmax) and the tumor-to-normal tissue ratio (TNR). SUVmax and TNR were compared with the histologic grade and the expression of the proliferation marker (Ki-67). Results: FLT uptake in normal brain parenchyma was very low, resulting in the visualization of brain tumors with high contrast. Both SUVmax and TNR significantly correlated with the malignant grade of brain gliomas, in which high SUVmax/TNR was obtained for high-grade gliomas. Patients with primary lymphoma also showed SUVmax/TNR equivalent to glioblastoma. There was a positive correlation between SUVmax/TNR and the Ki-67 index. In contrast, spuriously high SUVmax and TNR were obtained in 3 of 6 patients with suspected recurrent tumors (2 patients with recurrent grade 2 glioma and one patient with postoperative granuloma), all of which showed lesion enhancement on MRI after Gd administration. Conclusions: FLT-PET can be used to evaluate the malignant grade and proliferation activity of primary brain tumors, especially malignant brain tumors. However, the presence of benign lesions showing blood–brain barrier disruption cannot be distinguished from malignant tumors and needs to be carefully evaluated.

Neuronal differentiation of adult rat hippocampus-derived neural stem cells transplanted into embryonic rat explanted retinas with retinoic acid pretreatment.

The purpose of this study was to evaluate the effects of the retinal environment and retinoic acid (RA) pretreatment on the differentiation of transplanted adult rat hippocampus-derived neural stem cells (AHSCs). AHSCs were transplanted into embryonic (E18) or neonatal (P6) rat retinal explants and the mixture was cultured for 2 weeks. Other AHSCs were stimulated by 0.5 microM all-trans RA for 6 days before transplantation. Immunofluorescent double staining showed that a larger number of AHSCs became beta-tubulin III-positive neurons in the E18 than in P6 retinas. In addition, many AHSCs became MAP2ab-positive and MAP5-positive neurons following RA pretreatment and transplantation. Only a few AHSCs became HPC-1-, calbindin-, PKC- or rhodopsin-positive cells under these conditions. We conclude that the microenvironment supplied by embryonic retinas is conductive to neuronal differentiation in general. RA stimulation before transplantation was also effective in stimulating differentiation.

P53 gene mutation in an atypical corticotroph adenoma with Cushing's disease.

© 2009 The Authors Journal compilation

Regulated expression of neurogenic basic helix-loop-helix transcription factors during differentiation of the immortalized neuronal progenitor cell line HC2S2 into neurons

Abstract Expression of nine neurogenic basic helix-loop-helix (bHLH) transcription factors was examined in an immortalized neuronal progenitor cell line HC2S2, which differentiates into neurons after suppression of the v-myc expression with tetracycline. Expression of MASH-1, NeuroD, NeuroD-related factor (NDRF) and HES-1 was demonstrated in HC2S2 cells by Northern blot analysis using total RNA. Expression of MASH-1 mRNA was downregulated upon differentiation of HC2S2 cells into mature neurons. In contrast, NeuroD and NDRF mRNA expression was maintained all through the differentiation. The expression of HES-1, a negative regulator of the neuronal differentiation, was upregulated temporarily in accordance with the suppression of the v-myc expression and was downregulated upon the differentiation of HC2S2 cells into neurons. The reduced expression of HES-1 mRNA in undifferentiated HC2S2 cells may be explained by the transcriptional suppression of HES-1 by the myc oncoprotein. The above data imply that both HES-1 and MASH-1 need to be downregulated at the time of accomplishment of the terminal differentiation into mature neurons and that NeuroD and NDRF participate in the regulatory process of the terminal differentiation in combination.

Hes1 and Hes5 regulate vascular remodeling and arterial specification of endothelial cells in brain vascular development.

The vascular system is the first organ to form in the developing mammalian embryo. The Notch signaling pathway is an evolutionarily conserved signaling mechanism essential for proper embryonic development in almost all vertebrate organs. The analysis of targeted mouse mutants has demonstrated essential roles of the Notch signaling pathway in embryonic vascular development. However, Notch signaling-deficient mice have so far not been examined in detail in the head region. The bHLH genes Hes1 and Hes5 are essential effectors for Notch signaling, which regulate the maintenance of progenitor cells and the timing of their differentiation in various tissues and organs. Here, we report that endothelial-specific Hes1 and Hes5 mutant embryos exhibited defective vascular remodeling in the brain. In addition, arterial identity of endothelial cells was partially lost in the brain of these mutant mice. These data suggest that Hes1 and Hes5 regulate vascular remodeling and arterial fate specification of endothelial cells in the development of the brain. Hes1 and Hes5 represent critical transducers of Notch signals in brain vascular development.

A cerebrospinal fluid protein associated with moyamoya disease: report of three cases.

OBJECTIVE The pathogenesis of moyamoya disease is unknown. The purpose of this study was to detect proteins associated with the pathogenesis of moyamoya disease. CLINICAL PRESENTATION Cerebrospinal fluid (CSF) samples from three patients with moyamoya disease and four control patients who had cervical lesions but no intracranial lesion were studied. INTERVENTION CSF proteins separated by two-dimensional polyacrylamide gel electrophoresis were analyzed with the SWISS-2DPAGE and SWISS-PROT databases. In the CSF samples from all three patients with moyamoya disease, a polypeptide spot (Mr = 12,000, pI = 5.35) was observed. This spot was not evident in samples from the four control patients and has not been reported in the SWISS-2DPAGE and SWISS-PROT databases. CONCLUSION A CSF protein, which is possibly novel and associated with moyamoya disease, has been detected. The analysis of CSF by two-dimensional polyacrylamide gel electrophoresis may reveal a clue by which the molecular mechanism of moyamoya disease may be elucidated.

Induction of the N-methyl-D-aspartate receptor subunit 1 in the immortalized neuronal progenitor cell line HC2S2 during differentiation into neurons

Conditionally immortalized neuronal progenitor cell line HC2S2 differentiates into mature neurons after suppression of the v‐myc expression with tetracycline. Reverse transcription‐polymerase chain reaction analyses were used to measure expression levels of N‐metyl‐D‐aspartate receptor subunit 1 (NMDAR1) mRNAs encoding splice variants (NMDAR1a, −exon 5; NMDAR1b, +exon 5) in HC2S2 cells during the differentiation. Differential induction of NMDAR1a and NMDAR1b mRNAs was observed during the differentiation. Very low expression of NMDAR1 was observed in undifferentiated HC2S2 cells. NMDAR1a mRNA was induced coincidentally with the emergence of neurites, whereas NMDAR1b mRNA was induced at the time of network formation. Immunohistochemistry also demonstrated induction of NMDAR1 immunoreactivity in differentiated HC2S2 cells. In addition, expression of NMDAR2 mRNA and immunoreactivity was observed in undifferentiated and differentiated HC2S2 cells, suggesting that functional NMDA receptors are present in differentiated HC2S2 cells. While exposure to NMDA resulted in almost no cell death in undifferentiated HC2S2 cells, NMDA induced cell death in differentiated HC2S2 cells in a dose‐dependent fashion. These findings suggest that the expression of NMDAR1 mRNA may be regulated by myc or its counterpart during neuronal terminal differentiation and that the splicing choice between NMDAR1a and NMDAR1b may vary according to the formation of neuronal network. J. Neurosci. Res. 52:699–708, 1998. © 1998 Wiley‐Liss, Inc.

Hes1 and Hes5 are required for differentiation of pituicytes and formation of the neurohypophysis in pituitary development

The pituitary gland is a critical endocrine organ regulating diverse physiological functions, including homeostasis, metabolism, reproduction, and growth. It is composed of two distinct entities: the adenohypophysis, including the anterior and intermediate lobes, and the neurohypophysis known as the posterior lobe. The neurohypophysis is composed of pituicytes (glial cells) and axons projected from hypothalamic neurons. The adenohypophysis derives from Rathkes pouch, whereas the neurohypophysis derives from the infundibulum, an evagination of the ventral diencephalon. Molecular mechanisms of adenohypophysis development are much better understood, but little is known about mechanisms that regulate neurohypophysis development. Hes genes, known as Notch effectors, play a crucial role in specifying cellular fates during the development of various tissues and organs. Here, we report that the ventral diencephalon fails to evaginate resulting in complete loss of the posterior pituitary lobe in Hes1(-/-); Hes5(+/-) mutant embryos. In these mutant mice, progenitor cells are differentiated into neurons at the expense of pituicytes in the ventral diencephalon. In the developing neurohypophysis, the proliferative zone is located at the base of the infundibulum. Thus, Hes1 and Hes5 modulate not only maintenance of progenitor cells but also pituicyte versus neuron fate specification during neurohypophysis development.

3D dynamic pituitary MR imaging with CAIPIRINHA: initial experience and comparison with 2D dynamic MR imaging.

OBJECTIVES To evaluate the validity of 3D dynamic pituitary MR imaging with controlled aliasing in parallel imaging results in higher acceleration (CAIPIRINHA), with special emphasis on demarcation of pituitary posterior lobe and stalk. METHODS Participants comprised 32 patients who underwent dynamic pituitary MR imaging due to pituitary or parasellar lesions. 3D dynamic MR with CAIPIRINHA was performed at 3T with 20-s-interval, precontrast, 1st to 5th dynamic images. Normalized values and enhanced ratios (dynamic postcontrast image values divided by precontrast ones) were compared between 3D and 2D dynamic MR imaging for patients with visual identification of posterior lobe and stalk. RESULTS In 3D, stalk was identified in 29 patients and unidentified in 3, and posterior lobe was identified in 28 and unidentified in 4. In 2D, stalk was identified in 26 patients and unidentified in 6 patients, and posterior lobe was identified in 15 and unidentified in 17. Normalized values of pituitary posterior lobe and stalk were higher in 3D than 2D (P<0.001). No significant difference in enhancement ratio was seen between 3D and 2D. CONCLUSIONS 3D dynamic pituitary MR provided better identification and higher normalized values of pituitary posterior lobe and stalk than 2D.