Glial Cells as a Target for the Development of New Therapies for Treating Parkinson's Disease

Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease. This disease is mainly characterized by tremor, bradykinesia, rigidity and postural instability that results primarily from a loss of dopaminergic neurons of the nigrostriatal pathway. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is well known to damage the nigrostriatal dopaminergic pathway, as seen in Parkinson's disease. Recent evidence shows that glial-related response plays a key role in the MPTP neurotoxic process, and the blockade of glial activation may be a new therapeutic approach to treating Parkinson's disease. In view of these new insights, this article suggests that the overexpression of S100beta protein secreted by glial cells may be an exacerbating factor in the neurodegeneration of dopaminergic cells in MPTP-treated animals. (c) 2002 Prous Science. All rights reserved.     

Recombinant adeno-associated viral vectors bring gene therapy for Parkinson's disease closer to reality

The recombinant adeno-associated viral (rAAV) vector is a powerful tool for delivering therapeutic genes into mammalian brains. In rodents and non-human primates, a substantial number of striatal neurons can be transduced with high titer rAAV vectors by simple stereotaxic injection. Efficient and long-term expression of genes for dopamine (DA)-synthesizing enzymes in the striatum restored local DA production and achieved behavioral recovery in animal models of Parkinson's disease (PD). Moreover, sustained expression of a glial cell line-derived neurotrophic factor gene in the striatum rescued nigral neurons and led to functional recovery in a rat model of PD, even when treatment was delayed until after the onset of progressive degeneration. These results suggest that gene therapy using rAAV vectors may become a novel and feasible treatment for PD.     

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.     

Anterior interosseous nerve palsy after cardiopulmonary resuscitation in a resuscitator with undiagnosed muscle anomaly

IMPLICATIONS: We present a case of nerve palsy after cardiopulmonary resuscitation in a resuscitator with undiagnosed muscle anomaly. Effort-related nerve palsy may occur after prolonged performance of CPR.     

The effect of heat-treated human bone morphogenetic protein on clinical implantation

For the clinical usage of human-derived bones, it is necessary to treat bones to reduce the risk of contamination by microorganisms. Bone morphogenetic protein is vulnerable to chemicals, but shows resistance to thermal heat to 70 degrees C in a short time. In this experiment, crude human bone morphogenetic protein was extracted from heat-treated bones at 60 degrees C for 10 hours and from nonheated bones. Sodium dodecyl sulfate polyacrylamide gel electrophoresis for these specimens was done. Gelatin capsules containing 5 mg of crude human bone morphogenetic protein extracted from heated and nonheated bones were implanted into thigh muscle pouches of five mice. At 20 days after implantation, the heterotopic bone formation was compared by evaluating the radiographic and histologic analyses. The sodium dodecyl sulfate polyacrylamide gel electrophoresis pattern of the human bone morphogenetic proteins showed five main bands (16, 22, 28, 35, and 67 kDa) that were almost identical. Heterotopic bone formation observed on the radiograph was induced by crude human bone morphogenetic protein from heated bones in a manner similar to that used for nonheated bones. The results from this study show that heat-treated bone preserves osteoinduction.     

A case of mosaic Klinefelter syndrome associated with isodicentric Yp

We describe a case of mosaic Klinefelter syndrome demonstrating an isodicentric Y chromosome. A 70-year-old man visited our outpatient clinic complaining of dysuria resulting from atrophy of the penis. His height was 170 cm and his weight was 60 kg. A serum hormonal analysis revealed hypergonadotropic hypogonadism. A chromosomal analysis with fluorescence in situ hybridization revealed four cell lines in which the karyotypes were 47,XXY, 46,XY, 46,XX and 47,XX,idic(Y) (q11.2). To the best of our knowledge this is the first case of mosaic Klinefelter syndrome bearing an isodicentric Y chromosome. The origin of the isodicentric Y is discussed.     

Endometrium-myometrium Ratio: A Newly Proposed Diagnostic Parameter on Magnetic Resonance Imaging Assessment of Myometrial Invasion by Endometrial Cancer

In order to improve the accuracy of magnetic resonance (MR)imaging assessment of myometrial invasion by endometrial cancer,the usefulness of a new diagnostic parameter, the endometriummyometrium(EM) ratio has been evaluated. EM ratio is the proportion ofthe widest length of endometrium to the length of myometriummeasured at the same line, this being vertical to the parallelof the long axis of the uterine body in the sagittal plane ofthe MR images. Myometrial invasion was defined as a value ofthe EM ratio > 1 , and the tumor was limited to the endometriumfor values < 1 . In 25 consecutive patients, both the EMratio-based assessment and the well-established junctional zone-basedasessment with T2-weighted MR imaging and enhanced MR imagingwith gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA)were compared with the results from pathological examinationsof postoperative specimens. In identifying moymetrial invasionby endometrial cancer, the sensitivity of the EM ratio-basedassessment was better than that of the junctional zone-basedassessment. The overall sensitivity of the former was 96% inboth the T2-weighted and enhanced MR imaging with Cd-OTPA, whereasthat of the latter was 84% in the T2-weighted MR imaging and72% (P<0.05) in the enhanced MR imaging. The use of the EMratio with MR imaging improves the ability to assess myometrialinvasion by endometrial cancer.     

A role for the fyn oncogene in metastasis of methylcholanthrene-induced fibrosarcoma a cells

Expression of various oncogenes (ras, myc, erbB2, src, fyn, yes and sis) in a high-metastatic clone (MH-02) derived from a murine methylcholanthrene-induced fibrosarcoma A (Meth A) was compared with those of its parent clone (ML-01) by Northern blot analysis. Two oncogenes, fyn, belonging to the tyrosine-kinase family, and sis, belonging to the cellular-growth-factor family, were found to have higher signals (3.6-fold and 1.8-fold respectively) in MH-02 than in ML-01 cells. To explore the possibility that higher expression of these oncogenes is involved in enhanced metastasis of the MH-02 clone, ML-01 was transfected by a fyn vector and the metastatic potential of the transfectant was examined. Mice administered fyn-transfected ML-01 cells had significantly increased metastatic nodules in the lung, as compared with those whose ML-01 cells were transfected with control vector without the fyn gene. The result indicates that the fyn gene is one of the factors governing the metastatic potential of Meth A cells.