Makoto Shibuya

Alzheimer's disease with spastic paresis and cotton wool type plaques.

We reviewed Alzheimers cases with spastic paresis and cotton wool type plaques in five Japanese and nine Caucasian cases. Most were early onset familial Alzheimers disease with presenilin 1 mutations. The cotton wool type plaques were related to extremely high production of Aβ42, due mainly to presenilin 1 mutations and low immune responses. Cotton wool plaques were numerous in the entire central nervous system, including basal ganglia, brainstem and even in spinal cord. Cotton wool type plaques were composed of slightly electron dense synaptic structures, but amyloid fibrils were rarely found. Such a high accumulation of Aβ42 may cause degeneration of the pyramidal tract and basal ganglia from an early stage of Alzheimers disease.

A distinct pattern of Olig2-positive cellular distribution in papillary glioneuronal tumors: a manifestation of the oligodendroglial phenotype?

Mixed neuronal-glial tumors of the central nervous system display a wide spectrum of differentiation. Among them, the papillary glioneuronal tumor (PGNT) is characterized by pseudopapillary structures composed of astroglial cells covering hyalinized vessels, and by neurocytic, ganglioid and ganglion cells. In addition, a “nonspecific” cell type, not similar to either astrocytes or neurocytes, has been recognized since the initial reports. Recently, minigemistocytic cells and a population immunostained by anti-Olig2 antibody have also been recognized in PGNT. Olig2 is a transcription factor that is specific for the cellular phenotype of oligodendrocytes. The aim of this study was to further investigate the histological diversity of PGNT. We examined six cases of PGNT, each of which showed Olig2 immunopositivity. Minigemistocytes were encountered in three cases at close proximity to the Olig2-positive area. Olig2-positive cells were negative for glial fibrillary acidic protein (GFAP) and neuronal nuclear antigen by double immunostaining, and mainly occupied the interpapillary area laterally adjacent to the GFAP-positive cells. They had relatively small, round and vesicular nuclei, and were formerly regarded as neurocytic cells or nonspecific cellular elements. Fluorescence in situ hybridization targeting chromosome 1p failed to demonstrate any deletion. This study disclosed an additional cellular component of PGNT that is characterized by Olig2 positivity, suggestive of oligodendroglial phenotype, and the results also encourage us to investigate oligodendroglial participation in various glioneuronal tumors.

Post-ischemic delayed expression of hepatocyte growth factor and c-Met in mouse brain following focal cerebral ischemia.

We investigated long-term changes in the expression of protein and mRNA of hepatocyte growth factor (HGF) and its receptor c-Met in mouse brain after permanent occlusion of the middle cerebral artery, by using immunohistochemistry and quantitative reverse transcription-polymerase chain reaction. HGF-immunopositive cells were observed in the periinfarct region from 4 days after occlusion, peaking at 14-28 days. The area containing HGF-immunopositive cells continued to expand until 28 days after occlusion. c-Met-immunopositive cells were observed exclusively at the periinfarct region at 7 and 14 days after occlusion. At 28 days after occlusion, there were many c-Met-immunopositive cells in the widespread periinfarct region. Triple immunohistochemical staining by using confocal laser scanning microscopy (CLSM) demonstrated that most of the HGF-immunopositive cells were localized to reactive astrocytes. The c-Met-immunopositive cells were also localized to reactive astrocytes. HGF mRNA was upregulated exclusively in the periinfarct region at 14 days. c-Met mRNA was upregulated in the periinfarct region from as late as 28 days after occlusion. Thus, HGF and c-Met show delayed expression in the periinfarct region at both protein and mRNA levels after induction of ischemia. Because HGF was recently shown to play critical roles in angiogenesis and neurotrophic activities, the temporal profiles of their expression may imply the involvement of HGF in the process of post-ischemic brain tissue repair.

TYPE VI COLLAGEN IMMUNOREACTIVITY IN SKEINOID FIBERS IN SMALL INTESTINAL STROMAL TUMORS

By immunoperoxidase analysis for types I to VI collagen, elastin, cytoskeletal components and some glycoproteins, we found type VI collagen immunoreactivity in amorphous eosinophilic deposits (skeinoid fibers) in three small intestinal stromal tumors. Negative results were obtained for types I, II, III, IV and V collagen, elastin, laminin, ubiquitin, intracellular filaments such as actin, desmin, vimentin, calponin and caldesmon, and glycoprotein such as lysozyme, factor XIIIa, β2‐microglobulin, α1‐antitrypsin and α1‐antichymotrypsin. In two lesions, the periodic acid‐Schiff‐positive skeinoid fibers were also focally labeled for amyloid P component.

Cerebellopontine calcification: a new entity of idiopathic intracranial calcification?

We report the autopsy case of a 40-year-old woman with severe intellectual and motor disabilities, who showed calcification in the cerebellum and pons but not in the basal ganglia on CT scan, and died of intracranial hemorrhage due to intractable hypertension. At autopsy, numerous calcium deposits were noted in the cerebellar cortex, the dentate nucleus, the cerebellar white matter and the ventral pons. These deposits were distributed both in the neuropil and the white matter, but rarely within the arterial walls or in contact with capillaries. This weak relationship between calcification and the blood vessels, in addition to the paucity of basal ganglia calcification, is in contrast to the findings with other disorders involving intracranial calcification, including Fahr’s disease and calcium metabolism disorders. Immunohistochemistry revealed intense staining of calbindin-D28K and parvalbumin at sites of calcium deposits both in the present case and in a case of pseudohypoparathyroidism, whereas these proteins were not localized to calcium deposits in the cerebellum of a Fahr’s disease brain. We propose that the present case may represent a distinct entity among diseases characterized by idiopathic intracranial calcification. In addition, calcium-binding proteins may be involved in the calcification process in some cases with intracranial calcification.

Indicators of the need for insulin treatment and the effect of treatment for gestational diabetes on pregnancy outcomes in Japan.

This study assessed indicators of the need for insulin therapy and the effect of treatment on pregnancy outcomes in Japanese patients with gestational diabetes mellitus (GDM). All patients diagnosed with GDM were hospitalized for three days. Plasma glucose profiles in patients under strict dietary management and the characteristics of GDM patients with high daily glucose levels were investigated. Patients who failed to achieve glycemic targets were treated with insulin. Indicators of the need for insulin treatment were investigated. Pregnancy outcomes in patients prescribed dietary management and patients prescribed insulin treatment were compared. The study included 112 patients with GDM. GDM patients with high daily glucose levels in the hospital exhibited significantly higher 1-h and 2-h plasma glucose levels in oral glucose tolerance tests (OGTTs) at diagnosis. In our hospital, 102 GDM patients with singleton pregnancies were followed until delivery; 32 (31.3%) were treated with insulin. Univariate analysis identified significant associations of insulin requirement with family history of diabetes and with 1-h and 2-h OGTT values at diagnosis. Multivariate analysis showed that the 1-h OGTT plasma glucose level at diagnosis was an independent predictor of the need for insulin. In perinatal outcomes, insulin treatment was associated with low birth weight.

Hemophagocytic syndrome in ileum-origin B-cell lymphoma

A 56 year-old-man was admitted due to upper abdominal tumor and was diagnosed as having stage IVb diffuse B-cell malignant lymphoma that originally developed in the terminal ileum. The first and the second administrations of CHOP (cyclophosphamide, 750 mg/m2; adriamycin, 50 mg/m2; vincristine, 1.4 mg/m2; and prednisolone, 100 mg/day) therapy were effective; however, the third course of therapy was postponed because of an episode of massive hematochezia. After this episode, lymph nodes began to enlarge and progressive pancytopenia occurred. Bone marrow smear showed the proliferation of reactive histiocytic cells which phagocytized red blood cells, white blood cells, and platelets. B-cell lymphoma-associated hemophagocytic syndrome (B-LAHS) was diagnosed. This case is extremely rare because: (1) LAHS occurred in an ileum-origin B-cell lymphoma, and (2) LAHS developed during an interval after chemotherapy.

Clinical and Histological Prognostic Factors in Axillary Node-Negative Breast Cancer: Univariate and Multivariate Analysis with Relation to 5-Year Recurrence

In the recent years several studies have shown that about 30% of cases with axillary node-nagative breast cancer suffer relapse of the disease. Our attempt was made to evaluate the most significant prognostic factors to predict this high risk group which may be benefited from adjuvant treatment. For this purpose, we selected 9 patients out of 80 cases of node-negative breast cancer who had been followed up at least for 5 years and had the recurrence of the disease. For comparison, 16 patients from the same group who did not have relapse were selected on a random basis. Histology, receptor status, AgNOR, DNA flow cytometry and various immunohistochemical parameters were compared between the groups with recurrence and that without recurrence.On univariate analysis, tumor size, immunohistochemical expressions of PCNA, MIB-1, c-erbB-2 and S-phase fraction were significantly different between the above two groups. By multivariate analysis, immunohistochemicalc-erbB-2 expression (more than 50% of cancer cells) was an independent parameter.As a summary from our studies, c-erbB-2 immunohistochemical staining on paraffin sections might be the best independent prognostic factor in axillary node-negative breast cancers.