Spinal transient receptor potential ankyrin 1 channel induces mechanical hypersensitivity, increases cutaneous blood flow, and mediates the pronociceptive action of dynorphin A.

We characterized pain behavior and cutaneous blood flow response induced by activation of the spinal transient receptor potential ankyrin 1 (TRPA1) channel using intrathecal drug administrations in the rat. Additionally, we assessed whether the pronociceptive actions induced by intrathecally administered dynorphin A, cholecystokinin or prostaglandin F(2α) are mediated by the spinal TRPA1 channel. Cinnamaldehyde, a TRPA1 agonist, produced a dose-related (3-10 µg) cutaneous blood flow increase and mechanical hypersensitivity effect. These effects at the currently used doses were of short duration and attenuated, although not completely, by pretreatment with A-967079, a TRPA1 antagonist. The cinnamaldehyde-induced hypersensitivity was also reduced by pretreatment with minocycline (an inhibitor of microglial activation), but not by carbenoxolone (a gap junction decoupler). In vitro study, however, indicated that minocycline only poorly blocks the TRPA1 channel. The mechanical hypersensitivity effect induced by dynorphin A, but not that by cholecystokinin or prostaglandin F(2α), was attenuated by a TRPA1 antagonist Chembridge-5861528 as well as A-967079. The cinnamaldehyde-induced cutaneous blood flow increase was not suppressed by MK-801, an NMDA receptor antagonist, or bicuculline, a GABA(A) receptor antagonist. The results indicate that spinal TRPA1 channels promote mechanical pain hypersensitivity and due to antidromic activation of nociceptive nerve fibers increase cutaneous blood flow. The attenuation of the cinnamaldehyde-induced hypersensitivity effect by minocycline may be explained by action other than block of the TRPA1 channel. Moreover, the spinal TRPA1 channel is involved in mediating the pronociceptive action of dynorphin A, but not that of the spinal cholecystokinin or prostaglandin F(2α).

Immunohistochemical studies on the expression and estrogen dependency of EGF and its receptor and C-fos proto-oncogene in the uterus and vagina of normal and neonatally estrogen-treated mice.

BACKGROUND: The final target cell response to estrogen is dependent not only on the estrogen receptor, but also on autocrine/paracrine interactions with growth factors (e.g., EGF) and proto-oncogenes (e.g., c-fos). Because neonatal estrogen treatment results in permanent changes in the female mouse genital tract (permanent vaginal cornification, cervical adenosis and tumors, changed growth control mechanisms in uterus), it was of interest to study possible acute and permanent effects of such treatment on distribution and levels of EGF, its receptor (EGF-r), and c-fos and to relate such changes to morphological development and appearance of epithelial abnormalities. METHODS: Immunohistochemical techniques using frozen sections from the uterus and vagina of neonatal and adult (ovariectomized, estradiol-treated) females, treated with olive oil or diethylstilbestrol in neonatal life. RESULTS: A difference in stromal-epithelial distribution of EGF was demonstrated with respect to region studied (uterus, vagina) and age (neonatal, adult). EGF was localized mainly in the uterine stroma but in both vaginal epithelium and stroma (with a different pattern compared to uterus). In neonatal females, EGF occurred in both tissue components in both regions, and the distribution pattern was quite different from that in adult females. The EGF level was increased by estrogen in adult but not in neonatal females. EGF-r and c-fos occurred in both uterine epithelium and stroma and in the vaginal epithelium; levels and distribution pattern were affected by estrogen. Neonatal estrogen treatment increased the levels of uterine EGF and c-fos in adult life. CONCLUSIONS: There are distinct developmental changes in the distribution and estrogen sensitivity of EGF. Only further studies can prove or disprove the association between the earlier reported disturbed growth control mechanisms in the uterus of adult but neonatally estrogen-treated females and the increased levels of uterine EGF and c-fos. The present results do not seem to explain mechanisms involved in the origin of neonatally estrogen-induced cervicovaginal epithelial abnormalities, nor do they explain the earlier described difference in estrogen-induced proliferative response between the uterine cervix and uterus proper.

Continuity and discontinuity in the anti-V3 IgG response of human immunodeficiency virus type 1-infected persons in a cross-sectional and longitudinal study using synthetic peptides.

The principal neutralization domain (PND) of the V3 region of human immunodeficiency virus type 1 (HIV-1) gp120 is central to HIV pathogenesis. The IgG antibody response to PND was followed in 15 HIV-1-infected persons from southern Sweden over 2-5 years using 32 synthetic V3 peptides. Five peptides had amino acid sequences derived from isolates from each of 5 patients. Sera obtained simultaneously with isolate almost always reacted strongly with these cognate peptides; however, reactivity was undetectable in 1 patient's serum and short lived in the sera of another, indicating inducible holes in the antibody repertoire, which would facilitate dissemination of the corresponding virus strains. Reactivity to other V3 peptides correlated with sequence similarity to the cognate peptide. Strong, stable reactivity to peptides with sequences similar to a south Swedish V3-consensus was accompanied by transient activity to less similar ones. The latter may reflect viral variation, B lymphocyte clonal depletion, or both. Certain IgG responses appeared to preclude others, suggesting clonal dominance.

Norfloxacin versus trimethoprim-sulfamethoxazole. A study in patients with known bacteriuria undergoing transurethral resection of the prostate.

Three hundred and forty-three patients with suspected bacteriuria undergoing transurethral resection of the prostate (TUR-P) were randomized to treatment with either trimethoprim-sulfamethoxazole (TMP-SMX) or norfloxacin (NF) for 5 1/2 days beginning the evening prior to operation. It was possible to analyse 165 patients for efficacy. Elimination of bacteria on days 10 to 20 was achieved in 78.1% and 78.3% in the TMP-SMX and NF group, respectively. The accumulated elimination rates for the follow up period (days 10-42) were 68.5% for the TMP-SMX group and 76.2% for the NF group. The differences were not statistically significant. No patient had any clinical signs of upper urinary tract infection or septicemia. Three hundred and twelve patients were analysed for safety. Twenty-six patients reported 32 adverse drug events (ADEs). Four reactions in the TMP-SMX group were considered severe while in the NF group all the ADEs were of mild or moderate intensity. In this study NF seems to be at least as effective and safe as TMP-SMX.