Masakuni Mukoyama

Gracile Axonal Dystrophy (GAD), a New Neurological Mutant in the Mouse

Abstract A new neurological mutant has been found in the F2 offspring of CBA/Nga and RFM/Nga mice. Affected mice exhibited ataxia beginning at about 80 days of age, followed by tremor, difficulty in moving, and muscular atrophy of the hind limbs. The neurological signs became progressively severe, and death occurred by 5 to 6 months of age. Since the animals could be distinguished from normal mice by the abnormal positions of the hind limbs when the mouse was hung by the tail after 1 month of age, they could be bred until onset of the signs. Pathological examination revealed neuroaxonal dystrophy and degeneration in the gracile nucleus of the medulla oblongata and the gracile fascicules of the spinal cord, which could be the main cause of the clinical signs. The mutation is inherited as an autosomal recessive trait. It was, therefore, named gracile axonal dystrophy (GAD) with the gene symbol gad. The mice could be a new pathological model for the study of neuroaxonal dystrophy.

Life spans of Duchenne muscular dystrophy patients in the hospital care program in Japan

Analysis of 176 autopsy cases of Duchenne muscular dystrophy (DMD) demonstrated that (1) hospitalized patients showed longer life spans than their non-hospitalized affected maternal uncles, (2) patients hospitalized recently lived longer than those hospitalized in the past, and (3) pulmonary infection has become a less frequent cause of death in recent years, whereas dystrophic changes of the cardiac and respiratory muscles are more closely related with recent fatal cases. These results indicate the changing life span expectancy of patients with DMD and the changes in cause of death over the last decade, probably owing to the benefits of a hospital care program.

Action‐induced rhythmic dystonia An autopsy case

We studied a patient with action-induced rhythmic dystonia that followed a stroke. Postmortem studies showed an infarct in the right posterolateral ventral part of the thalamus. Electrophysiologic analysis indicated that the eliciting factor of the involuntary movement was an impulse, promoting voluntary contraction of muscle. CSF 5-HIAA content was low, and HVA was high. Administration of 5-HTP and clonazepam abolished the involuntary movements.

Demonstration of slow acetylator genotype of N-acetyltransferase in isoniazid neuropathy using an archival hematoxylin and eosin section of a sural nerve biopsy specimen

The genotype for N-acetyltransferase was analyzed in five Japanese patients with isoniazid neuropathy by using the allele specific polymerase chain reaction for a single slice of the 30-year-old paraffin-embedded and hematoxylin-eosin stained sural nerve biopsy specimens. We found slow acetylator genotypes for N-acetyltransferase in all isoniazid neuropathy patients. This result confirmed that patients with the slow acetylator genotype tend to develop neuropathy after administration of isoniazid.

Determination of manganese concentrations in the spinal cords from amyotrophic lateral sclerosis patients by inductively coupled plasma emission spectroscopy

Continuing analytical studies on environmental factors in the foci of amyotrophic lateral sclerosis (ALS) in the Kii Peninsula of Japan and Guam, and metal analysis using neutron activation analysis in central nervous system (CNS) tissues from ALS cases indicate that chronic exposure to metals such as aluminum and manganese, together with a deficiency of minerals such as calcium and magnesium, may play a causative role in the neurodegeneration seen in ALS. An accurate and simple method for detecting minerals and trace metals in small, fresh samples of CNS tissue is necessary in order to follow the pathogenetic behavior of these elements. In this paper, we describe a method for measuring manganese (Mn) content in CNS tissue samples taken from mouse brain using inductively coupled plasma (ICP) spectroscopy and present results of the determination of Mn contents in spinal cord samples from ALS cases using the same method. ICP emission spectroscopy is considered to have great advantage for the simultaneous determination of elements in small, fresh CNS samples because of its simplicity and convenience, and the elimination of the necessity to use potentially dangerous acids. Results showed that the mean concentration of Mn in a mouse brain (0.56 microgram/g) and in human spinal cords (0.39 microgram/g wet weight in the anterior horn, 0.37 in the lateral fasciculus, 0.39 in the posterior horn and 0.28 in the posterior fasciculus) were compatible with results previously reported using other methods. In ALS spinal cords, the mean content of Mn was similar to that of controls, but the distribution differed. In the ALS cases, Mn contents were higher in the anterior horn and lateral fasciculus than in the posterior horn.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of change in indoleamine metabolism in spinal cord of patients with amyotrophic lateral sclerosis

Indoleamine metabolism was determined by high-performance liquid chromatography with electrochemical detection in the cervical spinal cord of patients with amyotrophic lateral sclerosis (ALS) and controls with non-neurological diseases. The concentrations of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were the highest in the ventral horn compared with other regions of the spinal cord both in ALS and controls. There was no significant change in the concentration of 5-HT in any region of the spinal cord between ALS and controls. In addition, the concentration of 5-HIAA in ALS was lower than that in controls, however, no statistical significance was observed.

Hyperbaric oxygen therapy for peripheral nerve damage induced in rabbits with clioquinol

Abstract The effect of hyperbaric oxygen therapy on the peripheral nerve disorder produced by administration of clioquinol to rabbits was studied. The damage of myelin and axons, which was apparent after administration of clioquinol, decreased in grade with hyperbaric oxygen, in contrast with animals without hyperbaric oxygen treatment. Nerve fibers were teased and examined individually; statistical analysis of regression coefficient (a) and variance (R) was performed. These values were improved in the group treated with hyperbaric oxygen, and the difference from the untreated group was statistically significant. Monthly improvement of these values was also more prominent in the treated group. From these results the effect of hyperbaric oxygen therapy in peripheral nerve damage was confirmed.

Concentrations of thyrotropin-releasing hormone in the brain of patients with amyotrophic lateral sclerosis

Concentrations of thyrotropin-releasing hormone (TRH) were measured by a specific radioimmunoassay in the brain of 11 patients with amyotrophic lateral sclerosis (ALS) and 6 controls (myocardial infarction, gastric cancer, multiple myeloma, cerebrovascular disease, amyloid neuropathy). TRH was found in all parts of the dissected brain tissues (pedunculus cerebri, corpus callosum, capsula interna, motor area) in patients with ALS and controls. The TRH concentrations in the brain of patients with ALS were significantly lower in the pedunculus cerebri, compared with controls, and tended to decrease in the motor area and corpus callosum, but not significantly. Changes in TRH concentrations did not always correlate with pathohistological changes. These findings suggest that TRH is widely distributed in the human brain and decreases in some part of the ALS brain.

The Absence of Synergism between the Effects of an Aldose Reductase Inhibitor, Epalrestat, and a Vasodilator, Cilostazol, on the Nerve Conduction Slowing and the Myelinated Fiber Atrophy in Streptozotocin-Induced Diabetic Rats

The preventive effects of combined or separate treatment for 10 weeks with an aldose reductase inhibitor, epalrestat (50 mg/kg/day), and a vasodilator, cilostazol (30 mg/kg/day), on nerve conduction deficits and morphometric alterations were examined in streptozotocin-induced diabetic rats. The average motor nerve conduction velocities (MNCV) in the tail nerve of the untreated diabetic (DM) group, the group treated with epalrestat (ES), the group treated with cilostazol (CZ), the group with both agents together (ES&CZ), and the normal control group were 34.7, 37.7, 39.3, 39.0 and 42.1 m/s, respectively. All treatments partially but significantly prevented a reduction in MNCV. The MNCV in the ES&CZ group was almost the same as in the CZ group. In a morphometric study of the sural nerve, the DM group showed a reduction in the average diameter of myelinated fiber and in occupancy (percentage of the fascicular area occupied by myelinated fibers), and a shift in the diameter-frequency histogram to smaller diameters. Only the CZ group showed evidence of a partial but significant preventive effect on the decrease in occupancy. In the CS and ES&CZ groups, there was a significant tendency away from the shift of histograms to smaller diameters. The ES&CZ group did not show any fewer morphometric changes than the CZ group. Thus, there was no synergism between the effects of epalrestat and cilostazol on the development of experimental diabetic neuropathy. This finding may provide a useful clue to the mechanisms of action of ES and CZ in diabetic neuropathy.

Concentrations of thyrotropin-releasing hormone and substance P are increased in several areas of the central nervous system of shambling mutant mice

The concentrations of thyrotropin-releasing hormone (TRH) and substance P (SP) in the brain of shambling mouse, a mutant mouse which is neurologically defective showing trunk instability and hind limb incoordination, were measured by radioimmunoassay. The TRH concentrations were significantly higher in the pons, medulla oblongata and spinal cord. The SP concentrations were also significantly higher in the thalamus, pons, thoracic and lumbar spinal cord. The findings suggest that changes in TRH and SP concentration in the brain might be relevant to the motor dysfunction of shambling mouse.