MRI and pathological findings of rheumatoid meningitis.

Rheumatoid meningitis (RM) is one of the most severe complications of rheumatoid arthritis. The mortality rate of RM is relatively high and diagnosis can be difficult. We present an 80-year-old woman who was diagnosed with microscopic findings of RM after analysis of biopsy specimens taken from a brain lesion. MRI scanning revealed meningeal enhancement in the brain, and the pathological findings were those of meningeal lymphocytic infiltration, vasculitis and rheumatoid nodules. RM is a treatable disease and in this patient RM was diagnosed on the basis of biopsy findings.

[Reliability of blood gas analyzers for measuring lactate levels in cerebrospinal fluid].

The lactate levels in the cerebrospinal fluid (CSF) can be used to distinguish bacterial meningitis from aseptic meningitis. However, it is usually difficult to promptly measure the lactate levels. There are certain blood gas analyzers that can be used to easily and promptly obtain glucose and lactose data. We ascertained whether the lactate and glucose levels from CSF samples can be analyzed by blood gas analyzers, and we subsequently compared the data obtained with that measured at the laboratory. In this study, we measured the cell counts and the protein, glucose, and lactate levels in 62 CSF samples obtained from 51 patients. Of these 62 samples, lactate and glucose of 17 samples were also measured by a blood gas analyzer. There were no significant differences in the lactate and glucose levels between the data measured at the laboratory and that measured by the blood gas analyzer. In conclusion, we consider that rapid measurement of the lactate and glucose levels in CSF samples by blood gas analyzers can be considerably reliable in clinical practice.

Bone marrow stromal cells promote neurite extension in organotypic spinal cord slice: significance for cell transplantation therapy.

OBJECTIVE: Recent reports have indicated that bone marrow stromal cells (BMSCs) have the potential to improve neurological function when transplanted into models of central nervous system (CNS) disorders, including traumatic spinal cord injury. In this study, the authors aimed to clarify the underlying mechanism through which BMSCs supported CNS regeneration in the spinal cord. METHODS: The authors topically applied mouse BMSCs expressing green fluorescence protein (0.4-4 x 10(4) cells) on the organotypic spinal cord slice culture prepared from 6-day-old rat pups (n = 17). They were co-cultured for 3 weeks after the slice culture started, and the behavior of the applied BMSCs was serially observed using a fluorescence bioimaging technique. The authors completed a histological analysis at the end of the co-cultures and evaluated the profiles of the cultured BMSCs using microarray and immunocytochemistry techniques. RESULTS: The fluorescence bioimaging showed that the BMSCs survived and made a cluster on the slice during the experiments. They also induced a morphological change in the slice within 48 hours of co-culture. Immunohistochemistry analysis showed that the BMSCs promoted a marked neurite extension toward their cluster and some of the BMSCs expressed Tuj-1, an early neuronal marker. Analysis by microarray and immunocytochemistry revealed that BMSCs highly expressed the matrix metalloproteinases (MMPs), stromal cell-derived factor-1, and its specific receptor CXCR4. CONCLUSIONS: These findings suggest that the donor BMSCs can support CNS regeneration due to their acquisition of a suitable environment for differentiation and promotion of neurite extension via MMPs and chemokines.

[Idiopathic intracranial hypertension without headache detected during a routine health check].

A 47-year-old woman was admitted to our hospital with an optic disc edema detected during a routine health check. On admission, she exhibited bilateral optic disc edema without headache and no visual disturbance. Her cerebrospinal pressure was 440 mmH2O, but we detected no abnormalities in the CSF, blood tests, brain MRI or MRV. Therefore, she was diagnosed with idiopathic intracranial hypertension (IIH). Treatment with acetazolamide reduced the cerebrospinal pressure. We suggest that examination of the optic fundi is sufficient to diagnose both IIH without headache and IIH with atypical symptoms.

Transient subacute cerebellar ataxia in a patient with Lambert-Eaton myasthenic syndrome after intracranial aneurysm surgery.

Several reports have presented patients with subacute cerebellar ataxia (CA) and Lambert-Eaton myasthenic syndrome (LEMS). Some clinical features of those patients have been described in the previous reports, manifestation of subacute CA prior to LEMS or a co-existence of both diseases, a high incidence of malignancy, and less efficacy of the treatment for subacute CA compared with that for LEMS. Cerebellar ataxia in some patients with LEMS has been suggested to be caused by antibodies to P/Q-type voltage-gated calcium channels (VGCCs). We report herein a patient with subacute CA and LEMS. Cerebellar ataxia appeared 15 months after the occurrence of LEMS, and the onset of CA was thought to be due to serum anti-P/Q-type VGCC antibodies. The clinical course of this patient was atypical, as follows: (1) LEMS preceded subacute CA, which developed after intracranial aneurysm surgery, (2) no malignancy was detected when both diseases co-existed, (3) symptoms of LEMS did not progress with the onset of CA, and (4) there was a definite improvement in symptoms of CA and (123)I-IMP SPECT imaging findings after steroid administration. In addition, it is remarkable that LEMS became aggravated in electrophysiologic examinations, in contrast to subacute CA. We suggest that these atypical features of subacute CA and the changes in LEMS may be associated with a balance between the amount of serum anti-P/Q-type VGCC antibodies and the susceptibility of the cerebellum and presynaptic nerve terminals to the antibodies. More cases are needed to investigate the mechanisms involved. The subacute CA and LEMS in this patient have remained comparatively silent after the withdrawal of steroids, and we are continuing to observe her condition.

Secretion of DJ-1 into the serum of patients with Parkinson's disease.

DJ-1 was initially identified by us as a novel oncogene and has later been found to be a causative gene for familial Parkinson's disease PARK7. DJ-1 plays role in transcriptional regulation and in oxidative stress function, and loss of its function is thought to be related to onset age, mode of progression and clinical severity of both familial and sporadic forms of Parkinson's disease (PD). DJ-1 is localized both in the cytoplasm and nucleus, and it has been reported to be secreted into the serum or plasma of patients with breast cancer, melanoma, familial amyloidotic polyneuropathy and stroke. In this study, levels of DJ-1 secreted into the serum of healthy controls and patients with sporadic PD were examined by using a DJ-1 ELISA kit, and the level of oxidative stress in the serum was also measured. The results showed that DJ-1 was secreted into the serum of both healthy controls and PD patients. There was no significant difference between the levels of secreted DJ-1 in two groups, and correlations of levels of secreted DJ-1 with age, clinical severity of PD and level of oxidative stress were not found.

Role of p53 in neurotoxicity induced by the endoplasmic reticulum stress agent tunicamycin in organotypic slice cultures of rat spinal cord.

The endoplasmic reticulum (ER) is important for maintaining the quality of cellular proteins. Various stimuli can disrupt ER homeostasis and cause the accumulation of unfolded or misfolded proteins, i.e., a state of ER stress. Recently, ER stress has been reported to play an important role in the pathogenesis of neurological disorders such as cerebral ischemia and neurodegenerative diseases, but its involvement in the spinal cord diseases has not been fully discussed. We conducted this study using tunicamycin (Tm) as an ER stress inducer for rat spinal cord in organotypic slice culture, a system that we have recently established. Tm was shown to induce ER stress by increased expression of GRP78. The viability rate of spinal cord neurons decreased in a dose-dependent manner with Tm treatment, and dorsal horn interneurons were more vulnerable to Tm-induced neurotoxicity. A p53 inhibitor significantly increased the viability of dorsal horn interneurons, and immunofluorescence studies showed nuclear accumulation of p53 in the dorsal horns of Tm-treated spinal cord slices. These findings suggest that p53 plays an important role in the killing of dorsal horn interneurons by Tm. In contrast, motor neurons were not protected by the p53 inhibitor, suggesting that the role of p53 may vary between different cell types. This difference might be a clue to the mechanism of the stress-response pathway and might also contribute to the potential application of p53 inhibitors for the treatment of spinal cord diseases, including amyotrophic lateral sclerosis.

Proteasome inhibition induces selective motor neuron death in organotypic slice cultures.

A dysfunctional ubiquitin-proteasome system recently has been proposed to play a role in the pathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). We have shown previously that spinal motor neurons are more vulnerable to proteasome inhibition-induced neurotoxicity, using a dissociated culture system. To confirm this toxicity, we used organotypic slice cultures from rat neonatal spinal cords, which conserve the structure of the spinal cord in a horizontal plane, enabling us to identify motor neurons more accurately than in dissociated cultures. Furthermore, such easy identifications make it possible to follow up the course of the degeneration of motor neurons. When a specific proteasome inhibitor, lactacystin (5 microM), was applied to slice cultures, proteasome activity of a whole slice was suppressed below 30% of control. Motor neurons were selectively damaged, especially in neurites, with the increase of phosphorylated neurofilaments. They were eventually lost in a dose-dependent manner (1 microM, P < 0.05; 5 microM, P < 0.01). The low capacity of Ca(2+) buffering is believed to be one of the factors of selectivity for damaged motor neurons in ALS. In our system, negative staining of Ca(2+)-binding proteins supported this notion. An intracellular Ca(2+) chelator, BAPTA-AM (10 microM), exerted a significant protective effect when it was applied with lactacystin simultaneously (P < 0.01). We postulate that proteasome inhibition is an excellent model for studying the mechanisms underlying selective motor neuron death and searching for new therapeutic strategies in the treatment of ALS.

Effect of proteasome inhibitor on cultured mesencephalic dopaminergic neurons.

Proteasomal dysfunction has been implicated in the pathogenesis of Parkinson's disease (PD). We examined the effect of a selective proteasomal inhibitor, epoxomicin, on primary cultured mesencephalic neurons. Exposing rat cultured mesencephalic neurons to epoxomicin for 24 h resulted in neurotoxicity in a dose-dependent manner. Epoxomicin caused mitochondrial dysfunction, reduction in reduced glutathione (GSH), and increased generation of free radicals. Neuronal damage was significantly blocked by antioxidative/GSH-augmenting agents. Epoxomicin also increased the expression of Bax and decreased that of Bcl-2, which may cause mitochondrial dysfunction and release of free radicals. Dopaminergic neurons were preferentially resistant to the toxicity of epoxomicin. Inhibiting the synthesis of tetrahydrobiopterin (BH(4)), which has been reported to have antioxidative function, increased the susceptibility of dopaminergic neurons, whereas increasing BH(4) levels protected non-dopaminergic neurons. These findings suggest that BH(4) is at least in part a contributing factor to grand the resistance to dopaminergic neurons against epoxomicin neurotoxicity. Our results suggest that proteasome inhibition causes the neurotoxicity in mesencephalic neurons, but that is not sufficient to reproduce the selective damage to dopaminergic neurons, such as that seen in PD.

Effect of geranylgeranylaceton on cellular damage induced by proteasome inhibition in cultured spinal neurons.

We investigated the effect of two proteasome inhibitors, lactacystin and epoxomicin, on cultured spinal cord neurons. The incubation of spinal neurons with proteasome inhibitors for 24 hr induced neurotoxicity in a dose-dependent manner. We found motor neurons to be more vulnerable to proteasome-induced neurotoxicity than nonmotor neurons. The staining of cell bodies in treated motor neurons was markedly disrupted and showed characteristic granular patterns. Proteasome-induced neurotoxicity is accompanied by apoptotic nuclear changes, posttranslational modification of the cellular proteins, generation of intracellular free radicals, reduction in the amount of reduced glutathione, and mitochondrial dysfunction. Neurotoxicity was reduced by the administration of low concentrations (1-100 nM) of geranylgeranylacetone (GGA), which is widely used as an antiulcer drug, although higher concentrations of this drug produced neurotoxicity in spinal cord neurons. GGA was found to induce the expression of heat shock protein 70 as well as thioredoxin, which may partly contribute to the protective effect of GGA. These data suggest that the inhibition of proteasome may play a role in the mechanism of neurodegenerative diseases of the spinal cord, such as amyotrophic lateral sclerosis, and that the use of GGA may be effective in the treatment of these conditions.