Field potential recording in the ventral tegmental area: pharmacological and toxicological evaluations of postsynaptic dopaminergic neuron activity

Addictive drugs and psychologic stress influence the input strength of ventral tegmental area (VTA) neurons, which implies the involvement of synaptic plasticity in dopaminergic neurons. Properties of excitatory synaptic transmission to the dopaminergic neurons have been analyzed using intracellular and patch-clamp recording methods. In the present study, we attempted to establish the field recording procedure in VTA slice preparations to monitor excitatory synaptic transmission. We evaluated this procedure using slice preparations from 6-hydroxydopamine (6-OHDA)-treated animals. In horizontal slices containing the VTA, electrical stimulation of anterior afferent fibers produced two distinct negative field potentials, presumably a fiber volley component and a transsynaptic component. Pharmacological analysis revealed that the transsynaptic component was composed of bicuculline-sensitive and CNQX-sensitive components. Neonatal 6-OHDA administration reduced approximately 90% of tyrosine hydroxylase expression in the VTA and eliminated more than 50% of the transsynaptic components. This result suggests that at least 50% of the observed transsynaptic component reflected the postsynaptic responses of the dopaminergic neurons.     

(Pro)renin receptor promotes choroidal neovascularization by activating its signal transduction and tissue renin-angiotensin system

The receptor-associated prorenin system (RAPS) refers to pathogenic mechanisms whereby prorenin binding to its receptor activates both the tissue renin-angiotensin system (RAS) and RAS-independent intracellular signaling pathways. Although we found significant involvement of angiotensin II type 1 receptor (AT1-R)-mediated inflammation in choroidal neovascularization (CNV), a central abnormality of vision-threatening age-related macular degeneration, the association of receptor-associated prorenin system with CNV has not been defined. Here, (pro)renin receptor blockade in a murine model of laser-induced CNV led to the significant suppression of CNV together with macrophage infiltration and the up-regulation of intercellular adhesion molecule-1, (ICAM-1) monocyte chemotactic protein-1, (MCP-1) vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)-1, and VEGFR-2. To clarify the role of signal transduction via the (pro)renin receptor in CNV, we used mice in which renin-angiotensin system was deactivated by either the pharmacological blockade of AT1-R with losartan or the genetic ablation of AT1-R or angiotensinogen. Compared with wild-type controls, these mice exhibited significant reduction of CNV and macrophage infiltration, both of which were further suppressed by (pro)renin receptor blockade. The (pro)renin receptor and phosphorylated extracellular signal-regulated kinases (ERK) were co-localized in vascular endothelial cells and macrophages in CNV. (Pro)renin receptor blockade suppressed ERK activation and the production of MCP-1 and VEGF, but not ICAM-1, VEGFR-1, or VEGFR-2, in AT1-R-deficient mice with CNV and in losartan-treated microvascular endothelial cells and macrophages. These results indicate the significant contribution of RAPS to CNV pathogenesis.     

Lung toxicity of 16 fine particles on intratracheal instillation in a bioassay model using f344 male rats

We have developed a bioassay model to estimate toxicity of fine particles in the lungs at an early stage after intratracheal instillation (Yokohira et al. 2005; Yokohira et al. 2007). The present experiment was conducted to improve the model by estimating appropriate doses based on dose-dependent toxicity of instilled quartz (4 mg to 0 mg) as a positive control and assessing the impact of powdered particles without suspension (Experiment 1). In addition, examination of the toxicity of a series of particles was performed with the developed bioassay (Experiments 2A, 2B, and 2C). The materials chosen were sixteen particles, including nanoparticles and diesel powder. Histopathological and immunohistochemical analysis of bromodeoxyuridine (BrdU) incorporation and inducible nitric oxide synthase (iNOS) were performed after exposure of the lungs. A dose of 2 mg quartz suspended in 0.2 mL saline was suggested to be most appropriate for sensitive detection of acute and subchronic inflammatory changes. Although some materials, including nanoparticles, demonstrated toxicity that was too strong for sensitive assessment, the ranking order could be given as follows: CuO > quartz > neutralized Na2PdCl4 > NiO > hydrotalcite > MnO2 > diesel > titanium dioxide (in Experiment 2B) > beta-cyclodextrin > diesel standard > titanium dioxide (in Experiment 2A) > CaCO3.     

Successful Treatment with Infliximab for Inflammatory Colitis in a Patient with X-linked Anhidrotic Ectodermal Dysplasia with Immunodeficiency

X-linked anhidrotic ectodermal dysplasia with immunodeficiency (X-EDA-ID) is caused by hypomorphic mutations in the gene encoding nuclear factor-κB essential modulator protein (NEMO). Patients are susceptibile to diverse pathogens due to insufficient cytokine and frequently show severe chronic colitis. An 11-year-old boy with X-EDA-ID was hospitalized with autoimmune symptoms and severe chronic colitis which had been refractory to immunosuppressive drugs. Since tumor necrosis factor (TNF) α is responsible for the pathogenesis of NEMO colitis according to intestinal NEMO and additional TNFR1 knockout mice studies, and high levels of TNFα-producing mononuclear cells were detected in the patient due to the unexpected gene reversion mosaicism of NEMO, an anti-TNFα monoclonal antibody was administered to ameliorate his abdominal symptoms. Repeated administrations improved his colonoscopic findings as well as his dry skin along with a reduction of TNFα-expressing T cells. These findings suggest TNF blockade therapy is of value for refractory NEMO colitis with gene reversion.     

The effects of clonidine on arterial baroreflex sensitivity and cardiopulmonary baroreflex control of sympathetic nerve activity in patients with left ventricular dysfunction

Background: Clonidine is a potent sympatholytic drug with central neural effects. The aim of this study was to evaluate the effects of clonidine on arterial baroreflex sensitivity (BRS) and cardiopulmonary (CP) baroreflex control of muscle sympathetic nerve activity (MSNA) in patients with left ventricular (LV) dysfunction. Method: Twenty patients were randomly assigned to either clonidine or placebo groups (10 in each group). BRS (by phenylephrine method) and CP baroreflex (by lower body negative pressure) effects on sympathetic nerve activity (circulating norepinephrine and MSNA recordings) were measured before and after a 4‐week treatment period. Results: Clonidine lowered blood pressure and heart rate. Clonidine was accompanied not only by a decrease in plasma noradrenaline (from 444 ± 196 to 260 ± 144 pg ml^?1) but also by a reduction in directly measured MSNA (from 47 ± 16 to 36 ± 16 bursts min^?1). BRS increased significantly from 3·01 ± 1·19 to 6·86 ± 2·84 ms mmHg^?1 after clonidine. When expressed as per cent change in MSNA during CP baroreceptor stimulation, CP baroreflex control of MSNA was significantly increased from 9·26 ± 8·93% to 28·83 ± 11·96% after clonidine. However, there were no significant changes in the measured variables in the control group. Conclusion: Clonidine enhanced BRS and CP baroreflex control of MSNA while reducing baseline sympathetic activity in patients with LV dysfunction.     

A case report of bilateral spermatocytic seminoma

Spermatocytic seminoma is a rare germ cell tumor which was first described by Masson in 1946. We experienced a case of bilateral spermatocytic seminoma. A 56-year-old man presented with painless swelling of left scrotal contents. This patient was diagnosed with bilateral testicular tumor after various image examinations (ultrasonography/computerized tomography/magnetic resonance imaging) and bilateral high orchidectomy was performed. Histological diagnosis was bilateral spermatocytic seminoma, pT1. After the operation, this patient was followed closely without adjuvant therapy. There has been no sign of recurrence at five months after the operation.     

Efficacy of naftopidil in patients with overactive bladder associated with benign prostatic hyperplasia: prospective randomized controlled study to compare differences in efficacy between morning and evening medication

A total of 100 patients with benign prostatic hyperplasia (BPH) and overactive bladder (OAB) symptoms (BPH/OAB), enrolled between June 2006 to March 2008, were randomly divided into 2 groups of morning medication (M) and evening medication (E) groups, then 50 mg of naftopidil was given once a day after breakfast or supper for 8 weeks. Data were available for efficacy analysis on 80 patients (M group ; 43, E group ; 37). Naftopidil significantly improved the overall international prostatic symptom score ; from 19.2±7.9 to 11.7±5.8 in the M group and from 19.4±6.4 to 12.3±6.8 in the E group (p<0.0001), QOL score from 4.9±0.8 to 3.2±1.4 in the M group and from 5.0±0.8 to 3.6±1.3 in the E group (p<0.0001), and OAB symptom score from 7.8±2.6 to 5.0±2.5 in the M group (p<0.0001) and from 8.6±2.9 to 5.8± 3.3 in the E group (p<0.0001). There was no significant difference in the incidence of adverse effects between the M group (6.1%) and E group (2.2%). These results suggest that naftopidil improves storage symptoms as well as voiding symptoms regardless of timing of administration.     

Schizosaccharomyces pombe taf1 + is required for nitrogen starvation-induced sexual development and for entering the dormant G0 state

Environmental change, such as nutritional starvation, induces physiological and morphological alterations that enable fission yeast cells to survive. We isolated a novel gene, taf1 ⁺ , required for the response to nitrogen starvation in the fission yeast Schizosaccharomyces pombe. taf1 disruptants could not mate upon nitrogen starvation, but could upon carbon starvation. taf1 disruptants had a defect in inducing ste11 ⁺ expression under nitrogen starvation conditions. Furthermore, they lost viability quickly in nitrogen-depleted medium. Unlike wild-type cells, starved taf1 ⁻ cells had nuclear chromatin that were flat and adhered to the cell periphery. These results indicate that taf1 ⁺ is required for nitrogen starvation-induced sexual development and entering the dormant G0 state. Received: 30 May 2000 / Accepted: 21 August 2000     

In situ expression of connective tissue growth factor in human crescentic glomerulonephritis

Connective tissue growth factor (CTGF) has recently been recognized as an important profibrotic factor and is up-regulated in various renal diseases with fibrosis. The present study describes the sequential localization of CTGF mRNA and its association with transforming growth factor (TGF)-1 in human crescentic glomerulonephritis (CRGN). Furthermore, we examined the phenotype of CTGF-expressing cells using serial section analysis. Kidney biopsy specimens from 18 CRGN patients were examined using in situ hybridization and immunohistochemistry. CTGF mRNA was expressed in the podocytes and parietal epithelial cells (PECs) in unaffected glomeruli. In addition, it was strongly expressed in the cellular and fibrocellular crescents, particularly in pseudotubule structures. Serial sections revealed that the majority of CTGF mRNA-positive cells in the crescents co-expressed the epithelial marker cytokeratin, but not a marker for macrophages. Moreover, TGF-1, its receptor TGF- receptor-I, and extracellular matrix molecules (collagen type I and fibronectin) were co-localized with CTGF mRNA-positive crescents. Our results suggest that CTGF is involved in extracellular matrix production in PECs and that it is one of the mediators promoting the scarring process in glomerular crescents.