Biomedical subjects
Publications and source records attributed to K Eto.
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We describe MR findings in patients with Minamata disease who have been followed for a long time. All patients examined were affected after daily eating of a large quantity of methylmercury-contaminated seafood, from 1955 to 1958, and showed typical neurological findings. On MR images, the visual cortex, the cerebellar vermis and hemispheres, and the postcentral cortex are significantly atrophic in Minamata disease. The visual cortex is slightly hypointense on T1-weighted images and hyperintense on T2-weighted images, probably representing the pathologic changes of status spongiosus. MRI can demonstrate the lesions located in the calcarine area, cerebellum, and postcentral gyri, which are probably related to three of the characteristic manifestations of this disease: the constriction of the visual fields, ataxia, and sensory disturbance, respectively.
Our knowledge concerning the pathology of fetal cases of human Minamata disease (methylmercury poisoning) is relatively limited. We report here a case with description of the distribution of mercury in the systemic organs, and the ultrastructural changes of the nervous system after a survival of 29 yr. The patient was a female born in 1957, with a body wt of 3000 g, who died in 1987. She carried a diagnosis of cerebral palsy, and had a convulsion at age 3 yr. Mercury levels in her mother's hair were 101 micrograms/g at the time of examination in 1959. At autopsy, the body measured 43 cm and weighed 23 kg. The brain weighed 920 g and showed marked cerebral atrophy, mild neuronal loss in the calcarine, postcentral and precentral cortices, cerebellar atrophy, and segmental demyelination of peripheral nerves. Mercury granules were present in the brain, kidney, and liver. Ultrastructural examination of the calcarine, post- and precentral cortices, and cerebellar cortices, showed severe atrophy of nerve cells, with a decrease in rough ER and an increase in nuclear chromatin and preservation of mitochondria. Autophagosomes were increased in number. In addition, high electron density, globular and dense bodies, measuring 0.3-1.8 microns in diameter, were found, surrounded by limited membrane, within both cerebral and cerebellar neurons. In the cellebellum, synapses were well-preserved.
Tacrolimus and rapamycin both belong to a new family of immunosuppressants, immunophilin ligands, but the mechanisms by which they inhibit T cell activation are different. Therefore, we tested the immunosuppressive effects of combination therapy with low doses of tacrolimus and rapamycin on experimental autoimmune uveoretinitis (EAU) in rats. Male Lewis rats, immunized with S-antigen (S-Ag) were given intraperitoneal injection of the combined drugs for 14 days after the immunization with S-Ag. Effects were evaluated by clinical observations, histological examination and immune response. The combination therapy with tacrolimus (0.1 mg/kg per day) and rapamycin (0.03 mg/kg per day) achieved 100% suppression of clinical EAU and 66.7% suppression of histological EAU; tacrolimus combined with a higher dose of rapamycin (0.1 mg/kg per day) caused 100% suppression clinically and histologically. Therapy with either drug alone achieved only partial suppression: tacrolimus alone (0.1 or 0.2 mg/kg per day) or rapamycin alone (0.03-0.2 mg/kg per day). Doubling the dose of either drug produced only 16.7% suppression with rapamycin or 50% suppression with tacrolimus. The serum antibody levels to S-Ag and proliferative response of lymphocytes to S-Ag were also significantly suppressed by the combination therapy with low doses of tacrolimus and rapamycin.
Neuropathological lesions found in chronic human Minamata disease tend to be localized in the calcarine cortex of occipital lobes, the pre- and postcentral lobuli, and the temporal gyri. The mechanism for the selective vulnerability is still not clear, though several hypotheses have been proposed. One hypothesis is vascular and postulates that the lesions are the result of ischemia secondary to compression of sulcal arteries from methylmercury-induced cerebral edema. To test this hypothesis, we studied common marmosets because the cerebrum of marmosets has 2 distinct deep sulci, the calcarine and Sylvian fissures. MRI analysis, mercury assays of tissue specimens, histologic and histochemical studies of the brain are reported and discussed. Brains sacrificed early after exposure to methylmercury showed high contents of methylmercury and edema of the cerebral white matter. These results may explain the selective cortical degeneration along the deep cerebral fissures or sulci.
Minamata disease, or methylmercury poisoning, was first discovered in 1956 around Minamata Bay, Kumamoto Prefecture, Japan. A similar epidemic occurred in 1965 along the Agano River, Niigata Prefecture, Japan. The neuropathology of Minamata disease has been well studied; this review focuses on human cases of Minamata disease in Kumamoto Prefecture. Nervous system lesions associated with Minamata disease have a characteristic distribution. In the cerebral cortex, the calcarine cortex was found to be involved in all cases of Minamata disease, particularly along the calcarine fissure. The destruction of nerve tissue was prominent in the anterior portions of the calcarine cortex. Occasionally, the centrifugal route from the visual and visual association areas (internal sagittal stratum) showed secondary degeneration in prolonged cases after acute onset. Postcentral, precentral, and temporal transverse cortices showed similar changes, though they were less severe. Intense lesions in the precentral cortex caused the development of secondary bilateral degeneration of the pyramidal tracts. In the cerebellum, the lesions occurred deeper in the hemisphere. The granule cell population was most affected. In the peripheral nerves, sensory nerves were more affected than motor nerves. Secondary degeneration of Goll's tracts was occasionally seen in prolonged or chronic cases.
Differences in pathology were found between acute and chronic exposure to methylmercury, mercury vapor, and inorganic mercury. Characteristic pathologic changes produced by organic mercury in the brain have previously been described in patients with Minamata disease. The brains of patients who presented with acute onset of symptoms and died within 2-mo showed loss of neurons with reactive proliferation of glial cells, microcavitation, vascular congestion, petechial hemorrhage, and edema in the cerebral cortices, predominantly in the calcarine, pre- and postcentral, and transverse temporal cortices and in the cerebellar cortex. The neuropathologic changes in the patients with acute onset of symptoms who survived for a long period (>10 yr) were also included neuronal loss with reactive proliferation of glial cells in similar anatomic locations. The neuropathologic changes in patients with inorganic mercury poisoning are quite different. Autopsies performed on 3 individuals with fatal cases of acute inorganic mercury poisoning who were exposed to mercury vapor for about 2 wk revealed diffuse organized pneumonia, renal cortical necrosis, disseminated intravascular coagulopathy, and infarctions in the brain and kidneys. In 2 other patients who worked in mercury mines for about 10 yr and who suffered from chronic inorganic poisoning, no specific lesions were demonstrated in the brain. However, the assay and the histochemistry of mercury revealed that inorganic mercury was present in the brain in all 3 groups irrespective of the brain lesions and the duration of clinical signs.
BACKGROUND AND PURPOSE: Although abnormal hyperintensities are frequently observed at or around the optic radiation in elderly subjects, no previous reports have mentioned the clinical significance and pathologic changes of these hyperintensities. We evaluated the hyperintensity patterns of the optic radiation and its surrounding structures on T2-weighted MR images and compared these findings with pathologic observations and visual field measurements. METHODS: High-resolution coronal T2-weighted MR images of 102 consecutive patients (51-84 years old) were evaluated retrospectively for the presence and morphology of hyperintensities of the optic radiation (204 sides) and its surrounding structures. Pathologic specimens were obtained from 25 other patients (60-91 years old) who had died of nonneurologic causes. The histopathologic changes of the optic radiation and its surrounding structures were evaluated and correlated with the MR findings. Finally, MR findings and visual field measurements were correlated in 46 elderly volunteers (70-91 years old). RESULTS: Hyperintensities of the optic radiation or its surrounding structures or both were observed on 125 sides (93%) of 67 patients (61%), and linear/laminar hyperintensity of the optic radiation and the tapetum was the characteristic finding. Eleven (44%) of 25 pathologic specimens exhibited pallor of three anatomic layers (the external sagittal stratum or the optic radiation, the internal sagittal stratum, and the tapetum). No subjects with hyperintensity of the optic radiation had visual field abnormalities. CONCLUSION: Linear/laminar hyperintensity of the optic radiation and tapetum on T2-weighted images is common in elderly subjects, and may reflect differences in the internal structures and in the water content of three anatomic structures. Hyperintensities of this region did not cause visual field abnormalities in a group of elderly volunteers.
Histological and experimental studies were performed in mouse embryos to elucidate possible roles of actin filaments in the nasal epithelium during facial morphogenesis. C57BL/6 mouse embryos (8.5-11.5 days of gestation) were fixed and frozen sections were stained with rhodamine-phalloidin. Before formation of the nasal placode, there was no specific localization of F-actin. After the nasal placode was formed, intense staining of F-actin was observed at the apical side of the placode. Conversely, it was located at the basal side of the epithelium of developing nasal prominences. By using the whole embryo culture system, perturbation experiments were conducted with cytochalasin D (CD), which inhibits the polymerization of actin filaments. When day-10 embryos were exposed to CD at several concentrations for 24 hr, fusion of nasal prominences was inhibited in a dose-dependent manner. Treatment with a high dose of CD for 2 hr also prevented the same development irreversibly. In contrast, when day-9 embryos were exposed to CD at several concentrations for 24 hr, invagination of the nasal placode was not perturbed at all. The results suggest that apical F-actin plays an essential role in maintaining the close apposition state of the nasal prominences and in the following fusion. During the invagination stage, F-actin might be important in maintaining the epithelial structure, but is not crucial to the initiation of placode invagination.
Proliferation of nasal epithelial and mesenchymal cells in mouse embryos was analyzed during primary palate formation using immunohistochemical demonstration of the thymidine analogue, 5-bromodeoxyuridine. Pulse labeling was employed to determine cell proliferation rates, with cell density of the nasal mesenchyme also being measured. To represent the entire nasal groove and prominences, four levels along the superior-inferior direction of three regions were utilized, i.e., the lateral and medial nasal prominences (LNP and MNP) and the bottom of the nasal groove. During the formation period, the labeling indices of the LNP and MNP epithelium decreased with respect to the development stage, whereas those of the bottom epithelium only slightly did. The epithelial cells in the prospective fusion area particularly showed decreased DNA synthesis in comparison with those in the nonfusing areas. In addition, the corresponding activity in the presumptive fusion area of the LNP epithelium was less than that in the MNP epithelium. The time at which a definitive decrease in the labeling index of the presumptive fusion area is believed to occur between tail somite (TS) stages TS5-7. A similar yet smaller decreasing tendency was observed in the labeling indices of the nasal mesenchyme. The cell density of the mesenchyme, however, slightly increased in all examined regions. Our results suggest that epithelial cell proliferation converts to a differentiation-type pattern, especially in the presumptive fusion area.(ABSTRACT TRUNCATED AT 250 WORDS)