Behçet disease presenting with neurological complications immediately after conversion from conventional cyclosporin A to microemulsion formulation

A 53-year-old man with Beh?et disease was treated with conventional cyclosporin A (CyA), because of refractory bilateral uveitis. Immediately following the conversion from conventional CyA to a microemulsion formulation, he presented with neurological complications. The neurological findings, pleocytosis of the cerebrospinal fluid (CSF) and brainstem lesions revealed by brain magnetic resonance imaging (MRI) suggested neuro-Beh?et disease. After discontinuing CyA and introducing oral prednisolone, the neurological symptoms, pleocytosis of CSF and brainstem lesions on MRI improved. Although the microemulsion formulation, which can maintain a stable level of blood CyA, is a useful agent for the control of ocular lesions in Beh?et disease, the resulting abrupt increase in blood CyA level may have induced neuro-Beh?et disease.     

Dopamine exerts no acute effects on Kv1.3 in activated encephalitogenic T cells

Apart from a central function in the extrapyramidal motor system, dopamine has been suggested to play a role in neuroimmune interactions. Particularly in diseases of the central nervous system, such as multiple sclerosis, alterations in dopamine homeostasis might have immunological consequences. We investigated potential effects of dopamine stabilized by ascorbic acid on specifically activated encephalitogenic T cells at the peak of activation. Those cells exhibited an upregulation of voltage-sensitive K+ channels which play a role in many neurotransmitter responses of lymphocytes and fulfilled a prerequisite to respond to dopamine, i.e. stable expression of mRNA for dopamine receptors DRD1, DRD2 and DRD3. However, whole-cell and perforated whole-cell recordings revealed no change in voltage-sensitive K+ currents. Moreover, T cell proliferation was not changed in the presence of dopamine. Previously reported dopamine effects on T cells may be explained by a comparatively lower activation of the cells under investigation, suggesting an activation dependence of dopamine effects that may not be mediated by K+ channels. Alternatively, the occurrence of dopamine degradation products under unprotected conditions may account for the changes reported. Nevertheless, care should be taken when using the dopamine-protecting anti-oxidant ascorbic acid, since we found that it markedly inhibited both K+ currents and lymphocyte proliferation at higher concentrations.     

Immunocytochemical localization of a neuron-specific diacylglycerol kinase beta and gamma in the developing rat brain

Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to produce phosphatidic acid (PA) and is, therefore, a potential terminator of DG signaling. DG and PA are important intracellular second messengers. DG directly binds protein kinase C (PKC) then activates this multifunctional enzyme. Ca2+-dependent and brain-specific DGKs, alpha, beta, and gamma, are suggested to play pivotal roles in the central nervous system. To elucidate the DGK function in neuronal development, we studied the developmental changes of DGKalpha, beta, and gamma in the postnatal rat brain. By immunoblot analysis, DGKalpha and gamma subtypes were present at birth and then gradually increased, while DGKbeta was not present at birth or postnatal day 3, then increased rapidly from day 14 to reach maximum at day 28. Immunohistochemically, DGKbeta and gamma were distributed in different brain regions. In most brain regions, DGKgamma showed sustained expression throughout the postnatal developmental periods. Interestingly, a temporal expression of DGKgamma was observed in the medial geniculate nucleus during day 3 to 14, and a delay of DGKgamma expression was seen in Purkinje cells, which was coincident with dendritic growth of Purkinje cells. In the hippocampal pyramidal cell, both DGKbeta and gamma were abundant but subcellular localization was different. DGKgamma localized in the cytosol while DGKbeta localized along the membrane structure. These findings suggest that each DGK subtype has a spatio-temporally different function in the developmental neurons.     

A prostate stem cell antigen-derived peptide immunogenic in HLA-A24- prostate cancer patients

BACKGROUND: We attempted to identify prostate stem cell antigen (PSCA)-derived peptides immunogenic in HLA-A24+ prostate cancer patients. METHODS: Peripheral blood mononuclear cells (PBMCs) were stimulated in vitro with each of three different PSCA-derived peptides, which were prepared based on the HLA-A24 binding motif, and their peptide-specific and HLA-A24-restricted anti-tumor responses were examined. Plasma levels of immunoglobulin G (IgG) against PSCA peptides were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Among three PSCA peptides, the PSCA 76-84 peptide most effectively induced peptide-specific cytotoxic T lymphocytes (CTLs) from PBMCs of HLA-A24+ prostate cancer patients. Cytotoxicity was dependent on peptide-specific and CD8+ T cells. The PSCA 76-84 peptide-stimulated PBMCs showed a significant level of cytotoxicity against prostate cancer cells in an HLA-A24-restricted manner. IgG reactive to the PSCA 76-84 peptide was detected in half of patients. CONCLUSIONS: The PSCA 76-84 peptide should be considered for use in clinical trials of immunotherapy for HLA-A24+ patients.     

Automatic time perception in the human brain for intervals ranging from milliseconds to seconds

Time perception in everyday life deals with various intervals. Here we investigated whether an automatic duration-discrimination mechanism in audition operates even for intervals of an order of seconds, by using the mismatch negativity (MMN), an index of automatic change detection in audition. In Experiment 1, occasional decrements of the duration of a repetitive "standard" tone elicited an MMN in subjects ignoring auditory stimulation, even with the standard-stimulus durations over a second. Nevertheless, the MMN amplitude was significantly diminished with standard-stimulus durations of 800 ms and above, despite the fact that a constant deviant versus standard duration ratio was used. Complementary experiments varying the interstimulus interval (Experiment 2) and the magnitude of duration change (Experiment 3) yielded corroborating results. The present results suggest that automatic duration discrimination in audition operates even for durations of the order of seconds; yet its optimum time scale might be of the order of milliseconds.     

Effects of perinatal simultaneous exposure to tributyltin (TBT) and p,p'-DDE [1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene) on male offspring of Wistar rats

p,p'-DDE [1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene; DDE] and tributyltin (TBT) are ubiquitous in the environment and in Japan were shown to bioaccumulate in marine products. Thus these chemicals serve as a source of contaminant in the mammalian food chain. Fetuses and neonates through maternal ingestion may be exposed to DDE and TBT. Therefore, the effects of concurrent exposure to DDE and TBT were investigated in male Wistar rat offspring of dams ingesting these two contaminants. In this study, TBT suppressed the growth and delayed eye opening. However, both growth retardation and delayed eye opening produced by TBT failed to occur in the presence of DDE. Unexpectedly, the prostate weight of male rat offspring was significantly reduced with the administration of TBT but restored in the presence of DDE. These results indicate that TBT and DDE affected the development of male rat offspring following maternal exposure, and simultaneous administration of DDE prevented some of the observed effects of TBT, especially of an antagonistic nature, through a mechanism, still to be determined.     

An impaired neocortical Ih is associated with enhanced excitability and absence epilepsy

Neuronal subthreshold excitability and firing behaviour are markedly influenced by the activation and deactivation of the somato-dendritic hyperpolarization-activated cation current (Ih). Here, we evaluated possible contributions of Ih to hyperexcitability in an animal model of absence seizures (WAG/Rij rats). We investigated pyramidal neurons of the somatosensory neocortex, the site of generation of spike-wave discharges. Ih-mediated functions in neurons from WAG/Rij rats, Wistar rats (sharing the same genetic background with WAG/Rij, but less epilepsy-prone) and ACI rats (an inbred strain, virtually free of seizures) were compared. We complemented whole-cell recordings from layer 2-3 pyramidal neurons with immunohistochemistry, Western blot and RT-PCR analysis of the h-channel subunits HCN1-4. The fast component of Ih activation in WAG/Rij neurons was significantly reduced (50% reduction in the h-current density) and four times slower than in neurons from nonepileptic Wistar or ACI rats. The results showing decreases in currents corresponded to a 34% reduction in HCN1 protein in the WAG/Rij compared to the Wistar neocortex, but HCN1 mRNA showed stable expression. The other three Ih subunit mRNAs and proteins (HCN2-4) were not affected. The alterations in Ih magnitude and kinetics of gating in WAG/Rij neurons may contribute to augmented excitatory postsynaptic potentials, the increase in their temporal summation and the facilitation of burst firing of these neurons because each of these effects could be mimicked by the selective Ih antagonist ZD 7288. We suggest that the deficit in Ih-mediated functions may contribute to the development and onset of spontaneously occurring hyperexcitability in a rat model of absence seizures.