Myopathy phenotype of transgenic mice expressing active site-mutated inactive p94 skeletal muscle-specific calpain, the gene product responsible for limb girdle muscular dystrophy type 2A.

A defect of the gene for p94 (calpain 3), a skeletal muscle-specific calpain, is responsible for limb girdle muscular dystrophy type 2A (LGMD2A), or 'calpainopathy', which is an autosomal recessive and progressive neuromuscular disorder. To study the relationships between the physiological functions of p94 and the etiology of LGMD2A, we created transgenic mice that express an inactive mutant of p94, in which the active site Cys129 is replaced by Ser (p94:C129S). Three lines of transgenic mice expressing p94:C129S mRNA at various levels showed significantly decreased grip strength. Sections of soleus and extensor digitorum longus (EDL) muscles of the aged transgenic mice showed increased numbers of lobulated and split fibers, respectively, which are often observed in limb girdle muscular dystrophy muscles. Centrally placed nuclei were also frequently found in the EDL muscle of the transgenic mice, whereas wild-type mice of the same age had almost none. There was more p94 protein produced in aged transgenic mice muscles and it showed significantly less autolytic degradation activity than that of wild-type mice. Although no necrotic-regenerative fibers were observed, the age and p94:C129S expression dependence of the phenotypes strongly suggest that accumulation of p94:C129S protein causes these myopathy phenotypes. The p94:C129S transgenic mice could provide us with crucial information on the molecular mech-anism of LGMD2A.

[An autopsy case of Alzheimer's disease associated with Parkinson's disease, compared to 2 autopsy cases of diffuse Lewy body disease].

A 68 year old male, diagnosed as Alzheimer's disease clinically, pathologically showed both findings of Alzheimer's disease and Parkinson's disease. The brain weight was 940 g. Macroscopically, severe cortical brain atrophy and depigmentation of the substantia nigra was noted. Microscopic examination showed marked appearance of senile plaque and a large number of neurofibrillary tangle with sever neuronal loss of the cerebral cortex. Additionally, the loss of neuron with many Lewy bodies was found in the substantia nigra. Lewy bodies were also found in the locus ceruleus and the dorsal vagal nucleus, but few in the cerebral cortical neurons. We compared this case neuropathologically with two autopsy cases of diffuse Lewy body disease (DLBD). There was no distinction concerning the lesions of the brain stem between this case and the cases of DLBD. In all three cases, the nucleus of basalis of Meynert showed marked neuronal loss. However, the brain was lighter than those of the cases of DLBD. Senile changes such as senile plaque and neurofibrillary tangles were more marked in this cases than in the cases of DLBD. Furthermore a large number of cortical Lewy bodies were found in the cases of DLBD, but few in this case. The distribution and number of Lewy bodies did not correspond with those of senile changes in the cases of DLBD. Also the cerebral cortical structure was better preserved in the cases of DLBD than in this case. In conclusion, from the clinicopathological findings, we considered that this case is Alzheimer's disease associated with Parkinson's disease. According to Kosaka's study, this case seemed to correspond with a transitional type of the Lewy body disease.

[Five cases of Parkinson disease with the past history of hand injury].

Incidental occurrence of Parkinson disease following to the history of peripheral trauma was reported in 1932 by Naville and Morsier. So far as we know not more than 50 cases with such an interesting outbreaks have been reported. In Japan no report has been published. We happened to have opportunities to observe five cases of Parkinson disease with similar past history of peripheral trauma comprising two males and three females. Their age at onset ranged from 40 to 74 years and all the five cases had histories of finger injury, including amputation in four cases, followed by insidious onset of tremulous movement at the same site of the trauma during the period between two months and 36 years. So far as we know, no evident explanation is made concerning to the etiological interrelation between onset of Parkinson disease and trauma of the fingers. It appears to be suggestive of the possible mechanism, in which chronic persistent facilitation from the site of trauma up to the diencephalospinal dopamine system, recently advocated by Lindvall and others, result in Parkinson disease beginning at the homolateral site of the previous peripheral trauma.

Heavy metal concentrations in blood cells in patients with amyotrophic lateral sclerosis.

Manganese (Mn) and selenium (Se) concentrations in blood cells were measured by neutron activation analysis. Blood was obtained from patients with amyotrophic lateral sclerosis (ALS), patients with other neurological diseases and control subjects. Dried blood cells were activated by neutron irradiation. Mn was determined after chemical separation and Se was determined nondestructively. Mn concentrations in blood cells from ALS patients were significantly lower (P less than 0.01) than those from the other groups. The Mn concentrations were also significantly lower (P less than 0.01) in late than in earlier stages of ALS. Se concentrations in blood cells from ALS patients were significantly higher (P less than 0.01) than those from the other two groups. A generalized abnormal distribution of these metals may play a role in the pathogenesis of this disorder. Bromine, zinc, rubidium, and iron concentrations of erythrocytes were the same in all groups.