Antagonistic effects of selective alpha1-adrenoceptor antagonists MDL73005EF and tamsulosin and partial agonists clonidine and tizanidine in rat thoracic aorta and rabbit iliac artery

The antagonistic effects of MDL73005EF and tamsulosin and partial agonists clonidine and tizanidine at rat thoracic aorta and rabbit iliac artery alpha1-adrenoceptors were investigated in this study. Selective alpha1-adrenoceptor antagonists MDL73005EF and tamsulosin dose-dependently shifted the concentration-response curves for noradrenaline to the right. Schild plots of the results obtained from the inhibition by MDL73005EF (pA2 8.30 +/- 0.04) and tamsulosin (pA2 10.51 +/- 0.06) of noradrenaline yielded a straight line with a slope of unity in rat thoracic aorta. The slopes of Schild plots obtained from the inhibition by MDL73005EF and tamsulosin of noradrenaline were significantly different from unity in rabbit iliac artery. Schild plots of the results obtained from the inhibition by clonidine and tizanidine of noradrenaline yielded a straight line with a slope of unity in rat thoracic aorta (pA2 7.08 +/- 0.04 and 7.32 +/- 0.04, respectively). These results suggest that alpha1D-adrenoceptors play a significant role in the alpha1-adrenoceptor-agonist-induced contraction of rat thoracic aorta and rabbit iliac artery, and that clonidine and tizanidine interact with the alpha1D-adrenoceptor subtype as competitive antagonists in rat thoracic aorta.     

Cell type-specific involvement of RIG-I in antiviral response

Toll-like receptors (TLRs) play an important role in antiviral response by recognizing viral components. Recently, a RNA helicase, RIG-I, was also suggested to recognize viral double-stranded RNA. However, how these molecules contribute to viral recognition in vivo is poorly understood. We show by gene targeting that RIG-I is essential for induction of type I interferons (IFNs) after infection with RNA viruses in fibroblasts and conventional dendritic cells (DCs). RIG-I induces type I IFNs by activating IRF3 via IkappaB kinase-related kinases. In contrast, plasmacytoid DCs, which produce large amounts of IFN-alpha, use the TLR system rather than RIG-I for viral detection. Taken together, RIG-I and the TLR system exert antiviral responses in a cell type-specific manner.     

Vertical spread of neuronal activity within the cat motor cortex investigated with epicortical stimulation and intracellular recording

In the encéphale isolé cat preparation the surface of precruciate cortex was electrically stimulated. Intracellular responses underneath the stimulated site were recorded to assess the vertical spread of activities across the cortical layers. To the epicortical stimulation (EPICS) with intensity adjusted to evoke a pure negative wave in the direct cortical response (DCR), only some neurons in relatively superficial layers responded with excitatory postsynaptic potentials (EPSPs). Stimuli intensified to evoke both the negative and subsequent positive waves in DCR produced in all tested cells either EPSPs, inhibitory postsynaptic potentials (IPSPs), or both. Direct or axonal antidromic excitation of the cell was observed only infrequently. Cells with EPSPs distributed through all the layers with two peak populations in laminae II and V-VI. Those with IPSPs were located mainly in the upper half of lamina III with a few in more superficial as well as in deeper layers. Both EPSPs and IPSPs showed mono- or oligosynaptic latencies (0.6-10 msec) that tended to become longer in deep than in superficial layers. Some deep layer cells including fast and slow pyramidal tract cells showed slowly rising monosynaptic EPSPs of dendritic origin. Further late responses consisted of EPSPs, IPSPs, disfacilitation (DF), and disinhibition (DI). DF or DI occurred in some deep layer cells. Two modes of vertical spread of activities were postulated: one the cascade transmissions which increased response repertoire toward the depths, and the other the electrotonic spread of EPSPs along dendrites.     

Monitoring CD4+ T cell responses against viral and tumor antigens using T cells as novel target APC

CD4+ T cells play an important role in the induction and maintenance of an effective antiviral and antitumor immune response. However, standardized monitoring of antigen-specific CD4+ T cells has not been established at the single-cell level. We now present a sensitive, specific, and simple methodology in which purified memory CD4+ T cells are expanded from PBMC in a single cycle of antigen-driven stimulation and quantitatively assayed by interferon-gamma ELISPOT. Issues of nonspecific background in assays were resolved with the use of innovative target cells, autologous PHA-expanded CD4+ T cells (T-APC). Remarkably, T-APC could not only present peptide epitopes from model antigens NY-ESO-1 and influenza nucleoprotein, but could also process full-length antigen endogenously expressed from recombinant fowlpox vector. This approach makes it possible to monitor CD4+ T cells in large series of patients, regardless of HLA haplotype, against the full peptide repertoire of a given antigen.     

ADRENAL PHEOCHROMOCYTOMA WITH BOTH BENIGN AND MALIGNANT COMPONENTS

A case of adrenal pheochromocytoma Is reported characterized by polygonal basophilic granular cells of benign type, plump eosinophilic granular cells of transitional type, and spindle-shaped cells of malignant type. In the primary tumor the neoplastic cells of each type revealed a distinctive topographical distribution. All gradations between the latter two varieties of cells were found, especially in the vicinity of the transitional cell area. Multiple metastases were present in the liver and lungs, where only anaplastic spindle-shaped cells could be found. Ultrastructurally, the benign cells contained predominantly large, rather light, secretory granules with a coarsely granulated core. In the malignant cells, the number, size, and intensity of granules varied considerably from cell to cell or even within a single cell. In general, the malignant cells had a higher frequency of smaller granules with electron-dense homogeneous cores. Moderate amounts of noradrenalin but not significant dopamine or adrenalin could be demonstrated from a metastatic nodule In liver. We postulate that this adrenal medullary pheochromocytoma was benign originally and underwent malignant transformation shortly before the patient's death. This is based upon the patient's clinical features and the peculiar structures of the primary tumor.     

Clinicopathologic and immunogenetic analysis of mucosa-associated lymphoid tissue lymphomas arising in conjunctiva.

PURPOSE: To identify mucosa-associated lymphoid tissue (MALT) type lymphoma in conjunctival infiltrates. METHODS: Clinical, histopathologic, immunophenotypic, and immunogenotypic studies were performed on 14 patients with conjunctival lymphoid infiltrates. Surgical biopsy specimens were subjected to histopathologic, immunohistochemical, and gene rearrangement analysis. RESULTS: Thirteen of the 14 patients (92.9%) met the diagnostic criteria for MALT lymphoma, and the remaining patient showed morphologic features of diffuse, small lymphocytic lymphoma. Genotypic analysis confirmed immunoglobulin heavy chain gene rearrangement in all of the 12 patients on whom the analysis was performed. Two patients with bilateral lesions exhibited identical immunoglobulin rearrangement patterns in each pair of lesions. All patients were alive at the last follow-up (mean: 39.9 months). Nine of the 14 patients were alive without disease, 4 had localized recurrences, and 1 had a residual tumor. CONCLUSIONS: These findings indicate that conjunctival lymphoid infiltrates usually have the features of MALT lymphoma with genotypic B lymphocytic monoclonality and a favorable prognosis.     

Reduction in formation of 2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine (PhIP)-induced aberrant crypt foci in the rat colon by docosahexaenoic acid (DHA)

Docosahexaenoic acid (DHA), a major component of fish oil, suppresses the formation and growth of aberrant crypt foci induced by 1,2- dimethylhydrazine and azoxymethane. In the present study we examined the effects of intragastric gavage administration of DHA on the yield of rat colonic aberrant crypt foci due to treatment with a heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), which induces colon cancer in male F344 rats and is considered to be a possible human colon carcinogen. Male F344 rats were given a standard diet (AIN-76A) and received 10 doses of PhIP (75 mg/kg body wt, by intragastric intubation, on days 1-5 and 8-12) with or without intragastric application of 1 ml DHA 4 h prior to each carcinogen treatment, followed by further DHA dosing. The numbers of PhIP-induced aberrant crypt foci per colon after 4 and 12 weeks DHA administration were significantly reduced to 47 and 38% respectively of the values obtained when PhIP alone was used. The mean number of aberrant crypts per focus was also decreased by DHA treatment. At week 4 the PhIP-DNA adduct levels in the colon of rats from the PhIP+DHA group were approximately two thirds of the PhIP group value. The results thus suggest that DHA exerts a preventive effect on PhIP-induced colon carcinogenesis.