[Aggregatibacter segnis endocarditis mimicking antineutrophil cytoplasmic antibody-associated vasculitis presenting with cerebral hemorrhage: a case report].

A 56-year-old man who underwent a tooth extraction in the previous year presented with weakness of the right upper extremity. Brain CT and MRI scans showed subcortical hemorrhage in the left frontal lobe. His body temperature was 37.5°C. Blood examination revealed anemia, elevated levels of C-reactive protein, and a positive result for PR3-ANCA. Aggregatibacter segnis was identified in the incubated blood cultures, and transesophageal echocardiograms showed infectious growth in the anterior mitral leaflet. He was diagnosed with infectious endocarditis. After treatment with ceftriaxione, the clinical symptoms were improved. We concluded that infectious endocarditis caused cerebral hemorrhage and that the positive result for PR3-ANCA was a false positive. Infectious endocarditis can mimic ANCA-associated vasculitis. When ANCA-associated vasculitis is suspected, infectious endocarditis must be ruled out.

Effects of interferon-beta on microglial functions as inflammatory and antigen presenting cells in the central nervous system.

Interferon-beta (IFNbeta) reduces exacerbations of the relapsing-remitting form of multiple sclerosis (MS), but the exact mechanisms by which it exerts its beneficial effects are unknown. In this study, we examined the effects of IFNbeta on microglial functions, as either antigen presenting cells or effector cells for inflammatory demyelination. IFNbeta significantly suppressed the expression of class II MHC antigen and the co-stimulatory molecule B7-1 in microglia. It also suppressed microglial IL-12 production and differentiation of myelin oligodendrocyte glycoprotein (MOG)-sensitized T cells into the T helper 1 phenotype, which use microglia as antigen presenting cells. However, IFNbeta significantly and dose-dependently enhanced the production of inflammatory mediators for demyelination, such as TNFalpha, IL-1beta, IL-6, and nitric oxide (NO). The upregulation of inflammatory mediators was effectively suppressed with a phosphodiesterase inhibitor. Thus, IFNbeta may exert its suppressive effects in the induction phase, but not in the effector phase of MS. Side effects of IFNbeta treatment may be due to elevation of pro-inflammatory cytokines, and may be reduced by co-treatment with phosphodiesterase inhibitors.

Neuroprotective role of phosphodiesterase inhibitor ibudilast on neuronal cell death induced by activated microglia.

The phosphodiesterase inhibitor, ibudilast, has many effects on lymphocytes, endothelial cells, and glial cells. We examined the neuroprotective role of ibudilast in neuron and microglia co-cultures. Ibudilast significantly suppressed neuronal cell death induced by the activation of microglia with lipopolysaccharide (LPS) and interferon (IFN)-gamma. To examine the mechanisms by which ibudilast exerts a neuroprotective role against the activation of microglia, we examined the production of inflammatory and anti-inflammatory mediators and trophic factors following ibudilast treatment. In a dose-dependent manner, ibudilast suppressed the production of nitric oxide (NO), reactive oxygen species, interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha and enhanced the production of the inhibitory cytokine, IL-10, and additional neurotrophic factors, including nerve growth factor (NGF), glia-derived neurotrophic factor (GDNF), and neurotrophin (NT)-4 in activated microglia. Thus, ibudilast-mediated neuroprotection was primarily due to the inhibition of inflammatory mediators and the upregulation of neurotrophic factor. In the CA1 region of hippocampal slices, long-term potentiation (LTP) induced by high frequency stimulation (HFS) could be inhibited with LPS and interferon-gamma stimulation. Ibudilast returned this LTP inhibition to the levels observed in controls. These results suggest that ibudilast may be a useful neuroprotective and anti-dementia agent counteracting neurotoxicity in activated microglia.

Pain-related differential expression of NGF, GDNF, IL-6, and their receptors in human vasculitic neuropathies.

OBJECTIVE: Pain-related differential expressions of nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF) and interleukin-6 (IL-6), and their receptors were investigated in human vasculitic neuropathies. MATERIALS AND METHODS: The mRNA levels of pain-related neurotrophic factors, NGF, GDNF and IL-6, were examined in the sural nerves of 22 painful and non-painful patients with acute necrotizing vasculitic neuropathies, together with their concomitant soluble receptors (p75, GFR(alpha)-1 and IL-6R(alpha)). RESULTS: The mRNAs for these factors and receptors in the lesioned nerves were up-regulated to a variable extent in both groups. NGF mRNA expression was more closely correlated with that of p75 in painful neuropathy with relatively preserved large fiber density, compared with non-painful neuropathy, though the NGF mRNA level in painful neuropathy was lower than that in non-painful neuropathy. GDNF was closely associated with GFR(alpha)-1 in mRNA levels regardless of the pain state, but IL-6 was not associated with IL-6R(alpha). CONCLUSION: The differential expression of neurotrophic factors and their cognate soluble receptors in human vasculitic neuropathy suggests that NGF, which was effectively transferred to sensory axons with p75, may induce pain.

Loss of Bardet Biedl syndrome proteins causes defects in peripheral sensory innervation and function.

Reception and interpretation of environmental stimuli is critical for the survival of all organisms. Here, we show that the ablation of BBS1 and BBS4, two genes mutated in Bardet-Biedl syndrome and that encode proteins that localize near the centrioles of sensory neurons, leads to alterations of s.c. sensory innervation and trafficking of the thermosensory channel TRPV1 and the mechanosensory channel STOML3, with concomitant defects in peripheral thermosensation and mechanosensation. The thermosensory phenotype is recapitulated in Caenorhabditis elegans, because BBS mutants manifest deficient thermosensory responses at both physiological and nociceptive temperatures and defective trafficking of OSM-9, a polymodal sensory channel protein and a functional homolog of TRPV1 or TRPV4. Our findings suggest a hitherto unrecognized, but essential, role for mammalian basal body proteins in the acquisition of mechano- and thermosensory stimuli and highlight potentially clinical features of ciliopathies in humans.

The ciliopathies: an emerging class of human genetic disorders.

Cilia and flagella are ancient, evolutionarily conserved organelles that project from cell surfaces to perform diverse biological roles, including whole-cell locomotion; movement of fluid; chemo-, mechano-, and photosensation; and sexual reproduction. Consistent with their stringent evolutionary conservation, defects in cilia are associated with a range of human diseases, such as primary ciliary dyskinesia, hydrocephalus, polycystic liver and kidney disease, and some forms of retinal degeneration. Recent evidence indicates that ciliary defects can lead to a broader set of developmental and adult phenotypes, with mutations in ciliary proteins now associated with nephronophthisis, Bardet-Biedl syndrome, Alstrom syndrome, and Meckel-Gruber syndrome. The molecular data linking seemingly unrelated clinical entities are beginning to highlight a common theme, where defects in ciliary structure and function can lead to a predictable phenotypic pattern that has potentially predictive and therapeutic value.

Interferon-gamma induces microglial-activation-induced cell death: a hypothetical mechanism of relapse and remission in multiple sclerosis.

Relapse and remission are characteristics of multiple sclerosis (MS). The underlying mechanisms, however, remain uncertain. Interferon-gamma (IFN-gamma) disturbs the immunological privilege of the central nervous system (CNS) by inducing major histocompatibility complex antigen expression in CNS cells and activating microglia to become antigen-presenting and effector cells. Thus, IFN-gamma and microglia are thought to play important roles in the initiation and development of MS. Here, we show that IFN-gamma induces microglial apoptosis as the activation-induced cell death. This microglial apoptosis was associated with the up-regulation of pro-apoptosis proteins, especially Bax. Microglial apoptosis was also observed in peak EAE mice, but not in early EAE mice. Therefore, IFN-gamma may act on microglia as part of a self-limiting negative feedback system. The activation and subsequent death of microglia induced by IFN-gamma may play pivotal roles in the mechanism of MS relapse and remission.

Parallel expression of neurotrophic factors and their receptors in chronic inflammatory demyelinating polyneuropathy.

The mRNA levels of nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), and interleukin-6 (IL-6) were examined in sural nerves of 22 patients with chronic inflammatory demyelinating polyneuropathy (CIDP). The mRNAs for NGF, GDNF, LIF, and IL-6 were upregulated, whereas CNTF mRNA was downregulated significantly in the nerves. The NGF, GDNF, and CNTF, but not LIF mRNA expressions were parallel to those of the cognate receptors, suggesting that these cognate soluble receptors effectively present these factors to maintain and regenerate the axons. Furthermore, IL-6 mRNA expression was significantly parallel to both binding and signal-transducing receptor expression, implying a role of the IL-6 signal for non-neuronal cells in CIDP. These findings indicate that multiple neurotrophic growth factors and cytokines are expressed cooperatively with their concomitant receptors in the nerve lesions of CIDP and play an important role particularly in nerve repair.