[Hypertrophic pachymeningitis: three adult cases and a review of the literature].

Hypertrophic pachymeningitis (HP) is thought to have an autoimmune etiology but its precise cause and treatment remains to be elucidated. Here, we report the clinical details and therapeutic responses of 3 patients with HP and reviewed 66 previously reported cases in the literature. Among these patients, headache was the most frequent complaint. Cranial nerve involvement was also frequently observed, with the optic nerve being the most frequently impaired followed by the oculomotor, trochlear, and abducens nerves in frequency. Elevated C-reactive protein levels and erythrocyte sedimentation rates were found in approximately 97% of the patients. Steroids were the most commonly prescribed therapy, but no definite protocols for the standard dose and duration in HP have been proposed thus far. The average initial dose of prednisolone (PSL) was 42.7 mg/day, and the average maintenance dose was 12.4 mg/day in the chronic stage. Recurrence occurred in many patients when the dose of PSL was reduced to under 20 mg/day. Therefore, steroids should be tapered extremely slowly.

Neurotrophin levels in cerebrospinal fluid of adult patients with meningitis and encephalitis.

BACKGROUND: The data on cerebrospinal fluid (CSF) levels of neurotrophins (NTs) in patients with meningoencephalitis are scarce, especially in adult patients. METHODS: We measured CSF levels of NTs such as nerve growth factor (NGF), brain-derived neurotrophic factor, and neurotrophin-3 (NT-3) in adult patients with various meningitis (n = 10) and encephalitis (n = 10) in both acute phase and recovery phase and adult control subjects (n = 21) by the enzyme-linked immunosorbent assay for NTs. RESULTS: Data show that NGF and NT-3 CSF levels were markedly elevated in the patient group in the acute phase compared with non-neurological controls (p < 0.001 and p < 0.05, respectively) and later returned to the levels of controls. Most intriguingly, we only recognized a significant correlation between NGF and NT-3 CSF levels in the patients in the acute phase. CONCLUSION: Such strong correlation of NGF and NT-3 CSF levels strongly suggests that in adult patients, some common regulatory mechanism(s) might be present among various kinds of NTs to cope with central nervous system infection.

Clioquinol inhibits NGF-induced Trk autophosphorylation and neurite outgrowth in PC12 cells.

Clioquinol is considered to be a causative agent of subacute myelo-optico neuropathy (SMON), although the pathogenesis of SMON is yet to be elucidated. To investigate the mechanism of neurotoxicity of clioquinol, we used PC12 cell line and focused on nerve growth factor (NGF) signaling through Trk receptor, which is essential for survival and differentiation of neuronal cells. Clioquinol inhibited NGF-induced Trk autophosphorylation in a dose-dependent manner. This inhibitory activity was further confirmed by the data of the inhibition of NGF-induced mitogen-activated protein kinase (MAPK) phosphorylation, which is located in the down stream of NGF-Trk intracellular signaling pathway. Clioquinol also caused neurite retraction induced by NGF and cell death. NGF-stimulated (differentiated) cells were more vulnerable than naïve cells. These results strongly suggest that clioquinol may cause the perturbation of the intracellular survival pathway by inhibiting Trk-initiated signaling pathway.

Acute autonomic, sensory and motor neuropathy: successful treatment with IVIg.

Acute autonomic, sensory and motor neuropathy (AASMN) is a rare peripheral nerve disorder characterized by prominent dysautonomia with somatic sensory and motor impairment. Dysautonomia in AASMN is intractable even with corticosteroid therapy or plasmapheresis. Here we report a case of AASMN with severe orthostatic hypotension. Although the effectiveness of corticosteroid was insufficient, high dose intravenous immunoglobulin therapy (IVIg) was effective for not only sensorimotor symptoms but also autonomic symptoms. This is the first case of AASMN showing favorable responses to IVIg treatment, suggesting that IVIg should be considered when corticosteroid therapy or plasmapheresis is ineffective or insufficient.

[A case of acute disseminated encephalomyelitis (ADEM) following treatment for pneumococcal meningoencephalitis].

A 58-year-old man was admitted to our hospital with fever, vomiting and disturbance of consciousness after common cold-like symptoms for 2 days. Physical examination showed high fever, moderate hypertension and tachycardia. There were no superficial lymph nodes swelling nor skin rashes. Cerebrospinal fluid (CSF) examination revealed increased protein level (467 mg/dl) and pleocytosis (508 cells/mm3), but no glucose was detected. CSF smear test detected the pneumococcus. Intravenous cefotaxime was administered along with intravenous immunoglobulins and steroid pulse therapy. However, DIC developed, so FOY therapy was started. With these treatments, level of consciousness gradually improved and he became able to eat. At 11th days after the onset, the patient suddenly developed left facial palsy and paresis of the left arm. Head T2-weighted magnetic resonance imaging demonstrated tumor-like hyperintensity signal lesions (28 x 16.6 mm) with ring enhancements in the right frontal lobe. Acute disseminated encephalomyelitis (ADEM) was diagnosed based on MRI and CSF findings, and then additional corticosteroid pulse therapy was administered twice. Herpes simplex virus and herpes zoster virus DNA in the CSF were undetectable by PCR. After 6 days of treatment with corticosteroid pulse therapy, left facial palsy and paresis of the left arm gradually improved and MRI showed the disappearance of tumor-like hyperintense signals. Although ADEM usually develops as a complication after viral infection such as measles, rubella, mumps and herpes zoster, this case suggests that ADEM complication should be considered even after pneumococcal meningoencephalitis.

Growth inhibition and differentiation of cultured smooth muscle cells depend on cellular crossbridges across the tubular lumen of type I collagen matrix honeycombs.

Although rabbit vascular smooth muscle cells (SMCs) showed a differentiated phenotype in three-dimensional type I collagen matrices (honeycombs, diameter of pores=200-500 microm), mouse vascular SMCs proliferated in honeycombs having the same pore size. Here we investigated the relationship between pore sizes of honeycombs and differentiation of SMCs using various pore sizes of honeycombs. Rabbit SMCs (length: 200+/-32 microm) and mouse SMCs (49+/-10 microm) formed crossbridges in honeycombs with 200-300 microm and less than 200 microm of pores, respectively. Both SMCs spread on the inner wall but did not form crossbridges in honeycombs with larger pores. [(3)H]Thymidine incorporation and cell number of both SMCs were decreased when the crossbridges were formed in honeycombs. Because proliferation inhibition and crossbridge formation were observed in the culture of rabbit and mouse SMCs using 200-300 microm and less than 200 microm pore sized honeycombs, respectively, these data suggested that forming crossbridges was important for the inhibition of proliferation of SMCs. Rabbit SMCs differentiation was accompanied by the expression of caldesmon heavy chain when cultured in honeycombs having less than 300 microm pores. Proliferation of mouse SMCs stopped in honeycombs having less than 200 microm pores, but caldesmon heavy chain was not detected despite the expression of its mRNA. Proliferation of SMCs stopped on plates when cells reached confluent state, however, caldesmon heavy chain was not expressed. These data suggested that an appropriate structure and suitable honeycomb pore size are important for the differentiation of SMCs.

Role of glycosphingolipids and therapeutic perspectives on Alzheimer's disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder dividing into two forms, early onset familial and late onset sporadic forms. Early onset genetic cases (familial AD (FAD)) constitute about 10% of all AD cases. Heretofore, highly fibrillinogenic and pathological Abeta peptide formation is regarded as the fundamental molecular basis for this disorder. Recent enormous efforts to find out a pathogenesis, however, have revealed that this disorder has a multiplicity of causes such as glycosphingolipids abnormalities, impairment of neurotrophin signaling, protein trafficking, and protein turnover. Most of these aspects were disclosed by the studies on FAD-related presenilin. In this review, we will focus on the current knowledge of many abnormal aspects of cellular lipids, especially glycosphingolipids other than a pathogenic Abeta production caused by the mutant presenilins as a model system. Moreover, we will discuss how these glycosphingolipids abnormalities cause the pathological conditions found in this disorder.

A novel variant allele of OATP-C (SLCO1B1) found in a Japanese patient with pravastatin-induced myopathy.

We have recently found that the frequency of OATP-C*15 is significantly higher in patients who experienced myopathy after receiving pravastatin or atorvastatin than in patients without myopathy. However, there were two patients who experienced pravastatin-induced myopathy despite the fact that they did not possess OATP-C*15 or other known mutations of OATP-C that have been reported to decrease the function of OATP-C. In this study, we sequenced all of the exons and exon-intron junctions of OATP-C of the two patients and found a novel mutation in exon 12 of OATP-C in one of the patients. In this mutation (1628T>G), there is a substitution of Leu to Trp at position 543 in transmembrane-spanning domain 10 of OATP-C. However, the frequency of this mutation in the Japanese population appears to be very low (<1%).