Dopamine agonists and valvular heart disease in Japanese patients with Parkinson's disease

Journal of Neurology - A high incidence of valvular heart disease in Parkinson's disease (PD) patients treated with ergot-derived dopamine agonists, such as cabergoline and pergolide, has been...     

Clinical significance of serum cardiac myosin light chain I in patients with Duchenne muscular dystrophy]

The cardiac myosin light chain I (LCI) is one of the cardiac muscle structural proteins. A sensitive immunoradiometric assay kit for LCI by using LCI monoclonal antibodies is developed. We estimated LCI in the patients with Duchenne muscular dystrophy (DMD) and Kugelberg-Welander disease (KW). The results suggested that LCI has close relationships with the functional disturbances of skeletal muscles, especially disturbances of pulmonary ventilation. Therefore we studied properties and localizations of LCI in the skeletal muscles by Western blotting and immunohistochemical methods. In Western blotting method LCI monoclonal antibodies have a band of 27 KD proteins of skeletal muscles. LCI has also found to be localized in type 1 fibers in frozen sections of biopsied of human skeletal muscles. LCI was measured from 47 patients with DMD and 8 patients with KW. The average serum LCI levels in the patients with DMD were 11.79 ng/dl and its levels in the patients with KW were in the normal range (under 2.5 ng/dl). Among 12 patients receiving negative pressure chest respirator, the levels of LCI were also under 2.5 ng/dl. Serum LCI decreased with increasing age and reduced physical activity. The levels of LCI has obvious positive correlations with CK and myoglobin. These results suggested that the measurements of serum LCI are useful as one of the markers of disease severity and the determination of suitable time of using respirator.     

Intraventricular administration of the neurotrophic factor midkine ameliorates hippocampal delayed neuronal death following transient forebrain ischemia in gerbils

Midkine (MK) is a growth factor with neurotrophic activities, and is expressed during the early stages of experimental cerebral infarction in rats in the zone surrounding the infarct. To evaluate in vivo activity of MK in preventing neuronal death, MK produced in yeast (Pichia pastoris) was administered into the brain ventricle immediately before occlusion of the bilateral common carotid artery of Mongolian gerbils. MK administration at the dose of 0.5-2 microg immediately before occlusion was found to ameliorate delayed neuronal death in the hippocampal CA1 region caused by transient ischemia 7 days after the insult. The hippocampal neurons of the MK-administered gerbils tended to degenerate 14 and 21 days after the insult, but their numbers remained higher than those in saline-administered controls; however, the hippocampal neurons were degenerated 28 days after the insult. MK administration at 2 h after occlusion did not ameliorate the neuronal death. These findings suggested that the therapeutic time window was narrow. The two to four times repeated administration of 2 microg MK immediately before and at 1, 2, or 3 weeks after the occlusion were not significantly different for the hippocampal neuronal death at 28 days after the insult compared with a single injection, but were significantly effective compared with vehicle administration alone. These findings suggested that the therapeutic time window was relatively narrow. The potent neuroprotective activity of MK observed in vivo suggested that MK might be useful as a therapeutic reagent for prevention of neuronal death in neurodegenerative diseases.     

T-cell malignant lymphoma with hemophagocytic histiocytosis, hyperferritinemia and disseminated intravascular coagulation syndrome

A 57-year-old man was admitted to our hospital with high fever and nasal obstruction. The diagnosis of T cell type malignant lymphoma (T-ML) was made by the biopsy of left nasal cavity tumor. After admission, his general condition was improved by chemotherapy and radiotherapy, but relapsed a month later. He was then treated with chemotherapy, and the partial remission was obtained. During the clinical course, he had a high fever again without any significant infections or exacerbation of T-ML. The data of coagulation system showed DIC. The levels of serum ferritin and LDH were extremely elevated. Bone marrow aspiration showed markedly increased hemophagocytic histiocytes. These data suggested that he was complicated by DIC and hyperferritinemia closely associated with hemophagocytic histiocytosis a part from the underlying T-ML. Causes of DIC and hyperferritinemia associated with hemophagocytic histiocytosis in the present case were discussed.     

Phenotypic Duchenne muscular dystrophy with C-terminal domain.

We report a patient with X-linked muscular dystrophy who had rapidly progressive muscle weakness and became wheelchair-bound at age 10 years. Clinically, he was diagnosed as having Duchenne muscular dystrophy; however, he was diagnosed as having Becker muscular dystrophy by dystrophin tests using a C-terminal monoclonal antibody. No immunolabelling was observed with a monoclonal antibody against the N-terminal domain. Multiplex polymerase chain reaction analysis revealed the deletion of exons 3-19. The data suggest that the deletion of the N-terminal domain of dystrophin can cause a severe phenotype even when the C-terminus of the protein is well preserved.     

A family of Machado-Joseph disease with a patient having frequent apnea in all day

One male and two female cases in a family of Machado-Joseph disease were reported. Two cases showed typical symptoms that are characterized by bulging eyes, ophthalmoplegia, dystonia, ataxia, spasticity of extremities and amyotrophy, and were consistent with Type II (Rosenberg et al). But another one lacked diversity of the symptoms, showing mainly progressive cerebellar ataxia for over 10 years. We pointed out the existence of a new type of MJD case exhibiting only progressive cerebellar ataxia over a long period. A female patient had dyspnea and insomnia after 20 years in her clinical course, and central sleep apnea was revealed by respiratory monitor. But, the apnea and irregular respiration appeared in both awake and sleep stages. We described the importance of attention to the apnea as a new complication of Machado-Joseph disease.     

Human T-lymphotropic virus type I-associated myelopathy and tax gene expression in CD4+ T lymphocytes

Infection by human T-lymphotropic virus type I (HTLV-I) is associated with adult T-cell leukemia and a slowly progressive disease of the central nervous system (CNS), HTLV-I-associated myelopathy/tropical spastic paraparesis, characterized pathologically by inflammation and white matter degeneration in the spinal cord. One of the explanations for the tissue destruction is that HTLV-I infects cells in the CNS, or HTLV-I-infected CD4⁺ T lymphocytes enter the CNS, and this drives local expansion of virus-specific CD8⁺ cytotoxic T lymphocytes, which along with cytokines cause the pathological changes. Because both in the circulation and in the cerebrospinal fluid, CD8⁺ cytotoxic T lymphocytes are primarily reactive to the product of the HTLV-I tax gene, we sought evidence of expression of this gene within cells in the inflammatory lesions. After using double-label in situ hybridization techniques, we now report definitive localization of HTLV-I tax gene expression in CD4⁺ T lymphocytes in areas of inflammation and white matter destruction. These findings lend support to a hypothetical scheme of neuropathogenesis in which HTLV-I tax gene expression provokes and sustains an immunopathological process that progressively destroys myelin and axons in the spinal cord.     

A rat model of human T lymphocyte virus type I (HTLV-I) infection: in situ detection of HTLV-I provirus DNA in microglia/macrophages in affected spinal cords of rats with HTLV-I-induced chronic progressive myeloneuropathy

To investigate the pathogenetic role of human T lymphocyte virus type I (HTLV-I) in central nervous system disease, a rat model for HTLV-I-associated myelopathy/tropical spastic paraparesis, designated as HAM rat disease, has been established. Wistar-King-Aptekman-Hokudai strain rats with induced HTLV-I infection develop a chronic progressive myeloneuropathy with paraparesis of hind limbs after an incubation period of 15 months. In the affected spinal cord in these rats, white matter degeneration, demyelination and vacuolar change with microglia/macrophage infiltration are present as are the provirus DNA and the virus mRNA. To identify infected cells in the affected lesions, we carried out in situ hybridization of amplified fragments of the provirus DNA by polymerase chain reaction on thin sections, plus immunohistochemistry on the same sections. The provirus DNA was localized in some microglia/macrophages in the spinal cord lesion. In addition, the HTLV-I provirus was clearly evident not only in ED-1-negative lymphoid cells but also in ED-1-positive macrophages from lymph nodes. These observations suggest that cells of microglia/macrophage lineage may be one of dominant viral reservoirs in the spinal cords and lymph nodes in HAM rat disease. These infected microglia/macrophages may relate to cause the myeloneuropathy through neurotoxic cytokine synthesis. Received: 14 January 1998 / Revised, accepted: 30 July 1998     

Effect of renal impairment on the pharmacokinetics of memantine

The effect of renal impairment on the pharmacokinetics of a single oral dose of memantine (10 mg) was determined in Japanese subjects. Subjects were assigned to four groups based on baseline creatinine clearance (CL(CR)): normal renal function (> 80 mL/min, n = 6), and mild (50 to ≤ 80 mL/min, n = 6), moderate (30 to < 50 mL/min, n = 6), and severe renal impairment (5 to < 30 mL/min, n = 7). Mean memantine maximum plasma concentration (C(max)) was similar in the groups (12.66, 17.25, 15.75, and 15.83 ng/mL, respectively), as was mean time to C(max) (6.2, 5.2, 4.3, and 5.4 h, respectively). However, exposure to memantine determined from mean area under the plasma concentration-time curve was 1.62-, 1.97-, and 2.33-times higher in subjects with mild, moderate, and severe renal impairment, respectively, as compared to controls with normal renal function. Mean memantine plasma elimination half-life increased according to increasing renal impairment (61.15, 83.00, 100.13, and 124.31 h, respectively), while mean cumulative urinary recovery of unchanged memantine in 72 h after dosing decreased according to increasing renal impairment (33.68%, 33.47%, 23.60%, and 16.17%, respectively). These results are the same as those in the previous study on caucasian individuals, when compared per body weight. It is suggested that the dose of memantine should be halved in patients with renal impairment.     

Histopathological analysis of four autopsy cases of HTLV-I-associated myelopathy/tropical spastic paraparesis: inflammatory changes occur simultaneously in the entire central nervous system

Although brain lesions have been described in some cases with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), little is known about the nature of brain lesion and its relation to the spinal cord lesion. In the present study, we performed histopathological analysis of the brain and the spinal cord of four autopsied cases with HAM/TSP to clarify the relationship between the brain and the spinal cord lesions. In two cases with active-chronic inflammation in the spinal cord, perivascular inflammatory infiltration was also seen in the brain, and the composition of cell subsets was similar both in the spinal cord and in the brain. No active inflammatory change was seen in the brain in two cases with inactive-chronic spinal cord lesions. Inflamed vessels were distributed mainly in the deep white matter and in the area between cerebral cortex and white matter of the brain. In the spinal cord inflamed vessels were mainly seen in the bilateral lateral and the ventral posterior columns. Parenchymal infiltration was diffused in the spinal cord but very sparse in the brain, suggesting the importance of parenchymal infiltration in the destruction of tissues. These results suggest that inflammatory changes occurred simultaneously in the spinal cord and in the brain, and that distribution of inflamed vessels closely correlated with the characteristics of vascular architecture of the brain and the spinal cord, which lead to a slow blood flow. This study may help promote a better understanding of the pathogenesis of HAM/TSP. Received: 9 July 1999 / Revised, accepted: 9 November 1999