Elevated BAFF levels in the cerebrospinal fluid of patients with neuro-Behçet's disease: BAFF is correlated with progressive dementia and psychosis.

Neuro-Behçet's disease (NBD) is a serious complication of Behçet's disease. Generally, NBD patients with a chronic course are refractory to immunosuppressive treatment, resulting in the deterioration of personality. In this study, levels of B cell-activating factor belonging to the TNF family (BAFF) were measured in the cerebrospinal fluid (CSF) from 18 patients with NBD, 27 patients with epidemic aseptic meningitis (AM), 24 patients with multiple sclerosis (MS) and 34 healthy controls. BAFF levels in patients with NBD were significantly elevated compared with healthy controls, but showed no statistically significant elevation compared with either of the disease controls. In contrast, CSF IL-6 levels were slightly elevated in patients with NBD and significantly elevated in patients with AM and MS compared with healthy controls. Patients with NBD were subdivided into two groups according to their clinical course (eight patients with a slowly progressive course presenting with psychosis and dementia and 10 patients with an acute course including aseptic meningitis, brainstem involvement and myelopathy). BAFF levels were significantly increased in those with a slowly progressive course compared with those with an acute course. CSF BAFF levels did not correlate with serum BAFF levels, CSF cell counts or CSF IL-6 levels in patients with NBD. These data suggested that BAFF was produced within the central nervous system and may be associated with the development of NBD, particularly with a progressive course.

Effect of alendronate on bone metabolic indices and bone mineral density in patients treated with high-dose glucocorticoid: a prospective study.

SUMMARY: This prospective study, in the very early phase after initiation of glucocorticoid (GC) treatment, showed that alendronate was effective in suppressing accelerated bone resorption and subsequent decrease in bone mineral density (BMD) at the lumbar spine of patients with high-dose GC treatment. INTRODUCTION: How bisphosphonates affect bone metabolism and BMD of patients with high-dose GC in the early phase, especially within 1 month is unclear. METHODS: We examined the prospective effects of daily 5 mg alendronate on bone metabolism and BMD in 20 patients with high-dose GC (at least 40 mg prednisolone/day) and compared them to 34 high-dose GC-treated patients without alendronate. RESULTS: Serum levels of calcium decreased at day 28 in the alendronate group. Urinary calcium excretion significantly increased after day 7 in both groups. The increase in serum parathyroid hormone (PTH) level at day 7 in the control group was not observed in the alendronate group, but PTH levels increased at day 28 and month 3 in the alendronate group. As for the bone turnover markers, the serum osteocalcin level decreased in both alendronate and control groups, but serum bone-type alkaline phosphatase levels did not show significant changes. Although the urinary type I collagen cross-linked N-telopeptide (NTX) level showed significant increases on days 7 and 28 in the control group; such early increases in urinary NTX were not observed in the alendronate group. Thereafter, the urinary NTX levels fell slowly in the alendronate group significantly. BMD at the lumbar spine significantly decreased from month 1 in the control group, whereas in the alendronate group, BMD at the lumbar spine maintained almost the same level at all time points observed. CONCLUSION: Alendronate was effective in suppressing bone resorption and subsequent BMD decrease at the lumbar spine in patients with high-dose GC treatment.

Bone fragility in male glucocorticoid-induced osteoporosis is not defined by bone mineral density.

UNLABELLED: Eighty-seven male Japanese subjects taking prednisolone > or = 5 mg for more than 6 months and 132 age- and body mass index (BMI)-matched control subjects were examined. Multiple regression analysis adjusted for age and BMI showed that spinal bone mineral density (BMD) in the prednisolone group was not associated with prevalent vertebral fractures (VFs). INTRODUCTION: Glucocorticoid (GC) treatment is known to increase the risk for bone fractures. However, the association between VFs and BMD in GC-treated male patients remains unclear. METHODS: Eighty-seven male subjects taking prednisolone > or = 5 mg for more than 6 months and 132 age- and BMI-matched control subjects were examined using lateral thoracic and lumbar spine radiographs and spine dual energy X-ray absorptiometry. RESULTS: The presence of GC use was an independent risk factor for VFs adjusted for age and BMI (odds ratio 10.93, P < 0.001). By receiver operating characteristic analysis, the absolute BMD values for detecting VFs were higher and the sensitivity and specificity were lower in the GC group than in the control group (0.936 vs 0.825 g/cm(2) and 53.5% vs 74.0%, respectively). Multiple regression analysis adjusted for age and BMI showed that spinal BMD in the GC group was not associated with prevalent VFs, even after adding current and past maximum GC doses as independent variables. CONCLUSIONS: These results show that lumbar BMD values are not associated with prevalent VFs in GC-treated male patients, suggesting that bone fragility in male GC users is affected by bone quality rather than by BMD.

Genetic polymorphisms in the surfactant proteins in systemic sclerosis in Japanese: T/T genotype at 1580 C/T (Thr131Ile) in the SP-B gene reduces the risk of interstitial lung disease.

OBJECTIVES: To investigate the association between single-nucleotide polymorphisms (SNPs) in the pulmonary surfactant protein (SP) genes and the presence or absence of interstitial lung disease (ILD) in SSc patients. METHODS: We studied 127 Japanese patients with SSc and 206 normal subjects. Investigated SNPs were C/T within amino acid (aa) 219, Arg219Trp in the SP-A1 gene (rs4253527), C/T within aa 131 (at nucleotide 1580) and Thr131Ile of the SP-B gene (rs1130866). Genotypes were determined by the TaqMan method. RESULTS: Genotype frequencies were not different between the SSc patients and normal controls for both loci. The patients were subsequently divided into two groups based on presence or absence of ILD. In the SNP in the SP-B gene, the frequency of the T/T genotype was significantly lower in the patients with ILD than in those without ILD. Limited in the patients who were positive for anti-Scl-70 antibody, the difference in the frequency of the T/T genotype between the ILD-positive and ILD-negative groups became more apparent. On the other hand, in the SNP in the SP-A1 gene, there was no significant skewing for a certain genotype. CONCLUSION: In SSc, where massive fibrosis occurs, possession of the T/T genotype in the SP-B gene would reduce the risk of ILD in Japanese.

Chemokine-like factor expression in the idiopathic inflammatory myopathies.

OBJECTIVES: We evaluated the expression of chemokine-like factor (CKLF) in biopsied muscle fibers in inflammatory myopathies, non-inflammatory myopathies and neurologically diseased controls. MATERIALS AND METHODS: We studied the expression of CKLF in 15 polymyositis (PM), five dermatomyositis (DM), 15 non-inflammatory myopathies and nine neurologically diseased patients by immunohistochemistry. RESULTS: Chemokine-like factor was mostly expressed in small diameter muscle fibers surrounded by infiltrated lymphocytes of inflammatory myopathies patients. Parts of them were also positive for the staining of the developmental form of myosin heavy chain, a maker of regenerating muscle fibers. Thrombin immunoreactivity was observed in endomysium in PM and perimysium in DM. In vitro differentiation study showed a constitutive expression of CKLF in myoblasts that was abolished in myotubes during differentiation process and was induced again by thrombin. Thrombin regulates CKLF expression through protease-activated receptor-1 in myotubes. Treatment of a protein kinase C inhibitor partially blocked CKLF expression in myoblasts, while it remarkably inhibited that in myotubes. CONCLUSION: Chemokine-like factor expression is differentially regulated in myoblasts and myotubes. Thrombin could be a strong regulator for its expression. As CKLF is immunohistochemically positive in regenerating muscle fibers, we postulate here that CKLF is a useful marker for regenerating muscle fibers in inflammatory myopathies.

The preventive and therapeutic effects of GCPII (NAALADase) inhibition on painful and sensory diabetic neuropathy.

Excitotoxic glutamate release occurs in several neurological disorders. One source is derived from the hydrolysis of the neuropeptide N-acetyl aspartyl glutamate (NAAG) by glutamate carboxypeptidase II (GCPII, also known as NAALADase). Drugs that attenuate glutamate transmission have been shown to relieve neuropathic pain, however side effects have limited their clinical use. It appears that GCPII is exclusively recruited to provide a glutamate source in hyperglutamatergic, excitotoxic conditions and therefore would be devoid of such side effects. Here we report on the therapeutic effects of an orally bio-available GCP II inhibitor on established painful and sensory neuropathy in the spontaneously diabetic BB/Wor rat. It significantly improved hyperalgesia, nerve conduction velocity and underlying myelinated fiber atrophy. The data suggest that GCP II inhibition may provide a meaningful and effective approach to the treatment of painful diabetic neuropathy.

Hemophagocytosis associated with MPO-ANCA positive vasculitis in systemic sclerosis.

Hemophagocytosis is a histiocytic proliferative condition associated with underlying disorders such as infection, lymphoma and autoimmune disease. We describe here a patient with systemic sclerosis who developed MPO-ANCA positive necrotizing vasculitis and hemophagocytosis concomitantly. Vasculitis supervened on a prior systemic sclerosis, and no causative disorder of hemophagocytosis could be found other than active vasculitis, suggesting that an occurrence of hemophagocytosis is associated with underlying vasculitis. Immunosuppressive therapy resulted in excellent improvement of both the hemophagocytosis and vasculitis. On the other hand, this case shows the elevated serum levels of IL-1beta, IL-6 and M-CSF which may be involved in the pathogenesis of hemophagocytosis. To our knowledge, this is the first demonstration indicating the possibility of vasculitis-associated hemophagocytosis.

GCPII (NAALADase) inhibition prevents long-term diabetic neuropathy in type 1 diabetic BB/Wor rats.

AIMS/HYPOTHESIS: Hyperglutamatergic activity induced by ischemia is believed to underlie neuronal damage in a variety of neurological disorders, including neuropathic pain. Since ischemia is believed to be a prominent mechanism involved in diabetic polyneuropathy (DPN), we investigated the effect of the glutamate carboxypeptidase II (GCPII, EC #3.4-17.21; previously termed NAALADase), an enzyme responsible for the hydrolysis of the neuropeptide NAAG to NAA and glutamate, on the development of DPN in type 1 diabetic BB/Wor rats. METHODS: Diabetic animals were treated with 10 mg/kg/day i.p. of the selective GCPII inhibitor GPI-5232 from onset of diabetes for 6 months. Hyperalgesia to thermal stimulation and nerve conduction velocity (NCV) were measured monthly. The effect on structural DPN was assessed by scoring of single, teased myelinated fibers, myelinated fiber morphometry and ultrastructural examination of C-fibers at 6 months. RESULTS: GCPII inhibition showed significant but partial effects on hyperalgesia (p<0.001), nerve conduction slowing (p<0.01) axonal and nodal structural changes (p<0.001), small myelinated fiber atrophy, and degenerative changes of C-fibers. CONCLUSIONS: GCPII inhibition has beneficial effects on hyperalgesia, nerve function, and structural degenerative changes in DPN, which are likely mediated by inhibition of ischemia-induced glutamate release.

His-bundle parasystole masquerading as exercise-induced 2:1 atrioventricular block.

We describe a case of symptomatic pseudo-AV block due to His-bundle parasystole masquerading as exercise-induced 2:1 AV block. Electrophysiologic study revealed the presence of His-bundle parasystole, and the fluctuation of parasystolic cycle length could be explained by the concept of modulated parasystole. Modulated parasystole is a possible explanation for maintenance of stable 2:1 AV conduction at an atrial rate of specific range during exercise.

Nicotinamide-N-methyltransferase is higher in the lumbar cerebrospinal fluid of patients with Parkinson's disease.

Parkinson's disease (PD) may be initiated or precipitated by endogenous toxins with a structure similar to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in genetically-predisposed individuals. Nicotinamide N-methyltransferase (NNMT) catalyzes N-methylation of nicotinamide and other pyridines to form pyridinium ions. The protein amount of NNMT was measured in the lumbar cerebrospinal fluid of PD patients by immunoblot analysis using anti-human NNMT antibody. In younger (65 years old or younger) PD patients, the relative level of NNMT protein was significantly higher than that in younger controls. The NNMT protein was significantly affected by aging: the amount decreased along with aging in PD patients. These findings suggested that excess NNMT in the central nervous system might be implicated in the PD pathogenesis.

Human C-peptide dose dependently prevents early neuropathy in the BB/Wor-rat.

In order to explore the neuroprotective and cross-species activities of C-peptide on type 1 diabetic neuropathy, spontaneously diabetic BB/W-rats were given increasing doses of human recombinant C-peptide (hrC-peptide). Diabetic rats received 10, 100, 500, or 1000 microg of hrC-peptide/kg body weight/day from onset of diabetes. After 2 months of hrC-peptide administration, 100 microg and greater doses completely prevented the nerve conduction defect, which was associated with a significant but incomplete prevention of neural Na+/K+-ATPase activity in diabetic rats with 500 microg or greater C-peptide replacement. Increasing doses of hrC-peptide showed increasing prevention of early structural abnormalities such as paranodal swelling and axonal degeneration and an increasing frequency of regenerating sural nerve fibers. We conclude that hrC-peptide exerts a dose dependent protection on type 1 diabetic neuropathy in rats and that this effect is probably mediated by the partially conserved sequence of the active C-terminal pentapeptide.

Time- and subunit-dependent differential mRNA expression of L-type Ca2+ channel during progression of right ventricular hypertrophy.

To clarify the molecular basis for changes in L-type calcium channel (VLCC) density in ventricular hypertrophy, we analyzed the mRNA expression of all the subunits including the main subunit alpha1c and auxiliary subunits (alpha2delta, beta2 and beta3) composing VLCC in rat right ventricular hypertrophy (RVH) induced by monocrotaline injection. To test the hypothesis that the expression of each subunit might change differently during progression of RVH, leading to an altered electrophysiologic outcome for VLCC, we investigated the ratio of the mRNA level of each auxiliary subunit to the main subunit. After monocrotaline injection, alpha1c mRNA showed a transient decrease on the 14th day and thereafter significantly increased to reach approximately 1.8 fold that of the control level on the 21st day. The auxiliary subunit alpha2delta mRNA showed a pattern similar to that of alpha1c. The beta3 mRNA increased rapidly after monocrotaline injection and increased approximately 4.1 fold. On the other hand, beta2 mRNA showed no significant changes. Accordingly, only the mRNA ratio of beta3 to alpha1c showed a significant increase among the auxiliary subunits after the monocrotaline injection. The ratio increased to a maximum of approximately 5.7 fold on the 14th day and thereafter decreased. These results suggest that VLCC density may be modified not only by alpha1c but also by its auxiliary subunit expression in ventricular hypertrophy, and provide a clue for understanding the controversial electrophysiologic results on VLCC density in hypertrophied hearts.

Diabetic neuropathy--a continuing enigma.

In this article we will review the clinical signs and symptoms of diabetic somatic polyneuropathy (DPN), its prevalence and clinical management. Staging and classification of DPN will be exemplified by various staging paradigms of varied sophistication. The results of therapeutic clinical trials will be summarized. The pathogenesis of diabetic neuropathy reviews an extremely complex issue that is still not fully understood. Various recent advances in the understanding of the disease will be discussed, particularly with respect to the differences between neuropathy in the two major types of diabetes. The neuropathology and natural history of diabetic neuropathy will be discussed pointing out the heterogeneities of the disease. Finally, the various prospective therapeutic avenues will be dealt with and discussed.

Insulin receptor in rat peripheral nerve: its localization and alternatively spliced isoforms.

BACKGROUND: Diabetic neuropathy accompanies both Type 1 and Type 2 diabetes, although it shows in both humans and animal models distinct differences between the two types of diabetes. Progressive paranodal degenerations occurring in Type 1, but not in Type 2, diabetes is believed to account for the more severe functional deficits in Type 1 diabetic rats. This suggests that factors other than hyperglycemia, such as insulin deficiency, may play a pathogenetic role. In this study, we investigated the immunolocalization of the insulin receptor (IR) and the expression of its two alternatively spliced isoforms in adult rat peripheral nerve. METHODS: Adult male Wistar rats 6-8 months of age were examined. Both light and ultrastructural immunohistochemistry was employed for localization of IR. The antibody was a mouse monoclonal antibody raised against the beta-subunit of human IR. Reverse transcription polymerase chain reaction (RT-PCR) was used to identify the two IR isoforms in peripheral nerve and seven other organs. Localization of the mRNA message was assessed by in situ hybridization. RESULTS: IR was localized to paranodal terminal Schwann cell loops and microvilli and to the paranodal axolemma. Furthermore, IR immunoreactivity was also present in Schmidt-Lantermann incisures. Endoneurial vessels showed IR localization on plasma membranes and in endocytotic vesicles of endothelial cells and pericytes. A high intensity of immunostained IR was found in close proximity to interendothelial tight junctions. Peripheral nerve showed, like the brain, predominantly the high affinity IR lacking exon 11. The mRNA message was localized to Schwann cells, endothelial cells and pericytes. CONCLUSION: Peripheral nerve expresses predominantly the high affinity IR, which is localized to strategic structures associated with the blood-nerve barrier and the paranodal ion-channel barrier.