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The aim of this study was to elucidate the characteristics, pathogenesis and treatment strategy of hypertrophic pachymeningitis that is associated with myeloperoxidase anti-neutrophil cytoplasmic antibody (ANCA). We retrospectively investigated clinical, radiological, immunological and pathological profiles of 36 patients with immune-mediated or idiopathic hypertrophic pachymeningitis, including 17 patients with myeloperoxidase-ANCA, four patients with proteinase 3-ANCA, six patients with other immune-mediated disorders, and nine patients with 'idiopathic' variety. Myeloperoxidase-ANCA-positive hypertrophic pachymeningitis was characterized by: (i) an elderly female predominance; (ii) 82% of patients diagnosed with granulomatosis with polyangiitis (previously known as Wegener's granulomatosis) according to Watts' algorithm; (iii) a high frequency of patients with lesions limited to the dura mater and upper airways, developing headaches, chronic sinusitis, otitis media or mastoiditis; (iv) a low frequency of patients with the 'classical or generalized form' of granulomatosis with polyangiitis involving the entire upper and lower airways and kidney, or progressing to generalized disease, in contrast to proteinase 3-ANCA-positive hypertrophic pachymeningitis; (v) less severe neurological damage according to the modified Rankin Scale and low disease activity according to the Birmingham Vasculitis Activity Score compared with proteinase 3-ANCA-positive hypertrophic pachymeningitis; (vi) increased levels of CXCL10, CXCL8 and interleukin 6 in cerebrospinal fluids, and increased numbers of T cells, neutrophils, eosinophils, plasma cells and monocytes/macrophages in autopsied or biopsied dura mater with pachymeningitis, suggesting TH1-predominant granulomatous lesions in hypertrophic pachymeningitis, as previously reported in pulmonary or renal lesions of granulomatosis with polyangiitis; and (vii) greater efficacy of combination therapy with prednisolone and cyclophosphamide compared with monotherapy with prednisolone. Proteinase 3-ANCA may be considered a marker for more severe neurological damage, higher disease activity and a higher frequency of the generalized form compared with myeloperoxidase-ANCA-positive hypertrophic pachymeningitis. However, categorization into 'granulomatosis with polyangiitis' according to Watts' algorithm and immunological or pathological features were common in both proteinase 3- and myeloperoxidase-ANCA-positive hypertrophic pachymeningitis. These data indicate that most patients with myeloperoxidase-ANCA-positive hypertrophic pachymeningitis should be categorized as having the central nervous system-limited form of ANCA-associated vasculitis, consistent with the concept of ophthalmic-, pulmonary- or renal-limited vasculitis.

Objectives: There have been several previous studies showing that ciclosporin, a ligand for cyclophilin D (CypD), reduces mitochondrial permeability transition (mPT) and ameliorates delayed neuronal death. NIM811 is a non-immunosuppressive ciclosporin derivative that also inhibits mPT, but has significantly less cytotoxicity than ciclosporin. Actually, in animal experiments, several investigators have reported that NIM811 ameliorates central nervous system disorders, such as traumatic brain injury, transient focal cerebral ischaemia and spinal cord injury. Therefore, we evaluated whether the ciclosporin derivative, NIM811 reduces mPT and ameliorates delayed neuronal death in the hippocampal CA1 sectors in mice when subjected to transient forebrain ischaemia., Methods: Male C57BL/6 mice were treated with 50 mg/kg ciclosporin, 10, 50 or 100 mg/kg NIM811 or phosphate-buffered saline. At 30 min post-injection, all mice were subjected to 20 min bilateral common carotid artery occlusion (BCCAO). To estimate delayed neuronal death, the sections were prepared for HE staining and terminal deoxynucleotidyl transferase-mediated dUTP end-labelling (TUNEL) staining at 72 h after 20 min BCCAO. Furthermore, using 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine iodide (JC-1) staining technique, we evaluated whether NIM811 (1, 10, 100 or 1000 microm) inhibited mPT in the neurons exposed to 100 microm glutamate., Results: Both delayed neuronal injury and apoptosis in the hippocampal CA1 sectors were significantly ameliorated at 72 h after transient forebrain ischaemia in the mice treated with 100 mg/kg NIM811 or 50 mg/kg ciclosporin. The treatments with 100 microm and 1,000 microm NIM811 significantly inhibited the reduction of mitochondrial membrane potential in the neurons exposed to 100 microm glutamate., Conclusions: These findings strongly suggest that NIM811 inhibits mPT and ameliorates delayed neuronal death in mice subjected to transient forebrain ischaemia.

The effect of commercial purified soybean saponin on renin activity and blood pressure was investigated. Soybean saponin significantly inhibited human renin in vitro with IC(50)=59.9 µg/ml. Orally administered soybean saponin at 80 mg/kg of body weight per day to spontaneously hypertensive rats for 8 weeks significantly decreased the blood pressure.

We found renin inhibitory activity in rice. The physico-chemical data on the isolated inhibitors were identical to those of oleic acid and linoleic acid. Oleic acid and linoleic acid competitively inhibited renin activity, with K(i) values of 15.8 and 19.8 microM respectively. Other unsaturated free fatty acids also inhibited renin activity, but saturated fatty acids had no effect on it.

The pharmacokinetics, cerebrovascular permeability, and tissue distribution of the neurotoxic plasticizer N-butylbenzenesulfonamide (NBBS) were determined in rats. A stable isotope-labeled form ([(13)C(6)]NBBS) was used to circumvent ubiquitous contamination that was evident whenever the native form was measured. Plasticizer decline in plasma, following an iv dose of 1 mg/kg, was described by a triexponential decay function. NBBS was cleared from plasma at a rate of 25 ml/min/kg, and 24 h after administration, plasma concentrations represented 0.04% of the administered dose. These data suggest rapid elimination and uptake into tissue; however, NBBS was not accumulated by any of the tissues studied (i.e., liver, kidney, muscle, adipose tissue, and brain). Given the critical interest in NBBS neurotoxicity, the brain uptake of [(13)C(6)]NBBS was further explored in experiments using the in situ brain perfusion technique. During perfusion with protein-free saline for 15-30 s, the single-pass brain extraction for free [(13)C(6)]NBBS was very high (73-100%) with a unidirectional blood-brain barrier transfer constant (K(in)) of > 0.08 ml/s/g. No significant differences were found in [(13)C(6)]NBBS content among the measured brain regions. Plasma protein binding (70%) only slightly lowered the single-pass brain extraction to 48%. In summary, the results demonstrate that NBBS distributes rapidly to tissues, including brain. Though highly lipophilic with a Log octanol/water partition coefficient of 2.17 +/- 0.09, brain:blood ratios (2:1) for NBBS were consistent throughout the experimental duration, with little indication of accumulation.