Containment of simian immunodeficiency virus infection in vaccinated macaques: correlation with the magnitude of virus-specific pre- and postchallenge CD4+ and CD8+ T cell responses.
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Macaques infected with the SIV strain SIVmac251 develop a disease closely resembling human AIDS characterized by high viremia, progressive loss of CD4(+) T cells, occurrence of opportunistic infection, cachexia, and lymphomas. We report in this study that vaccination with the genetically attenuated poxvirus vector expressing the structural Ags of SIVmac (NYVAC-SIV-gag, pol, env) in combination with priming with DNA-SIV-gag, env resulted in significant suppression of viremia within 2 mo after mucosal exposure to the highly pathogenic SIVmac251 in the majority of vaccinated macaques. The control of viremia in these macaques was long lasting and inversely correlated to the level of both pre- and postchallenge Gag-specific lymphoproliferative responses, as well as to the level of total SIV-specific CD4(+) T lymphocyte responses at the peak of acute viremia as detected by intracellular cytokine-staining assay. Viremia containment also correlated with the frequency of the immunodominant Gag(181-189)CM9 epitope-specific CD8(+) T cells present before the challenge or expanded during acute infection. These data indicate, for the first time, the importance of vaccine-induced CD4(+) Th cell responses as an immune correlate of viremia containment. The results presented in this work also further demonstrate the potential of a DNA-prime/attenuated poxvirus-boost vaccine regimen in an animal model that well mirrors human AIDS. (+info)
Observations on experimental colonisation of mice by ureaplasmas of human origin.
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Three serovars (5, 8 and 10) of Ureaplasma urealyticum were inoculated intravaginally into groups of oestradiol-treated young adult BALB/c strain mice. Hormone treatment was essential for vaginal colonisation. The proportion of mice colonised initially and the persistence of colonisation were different with the three serovars; half of those given serovar 8 were still colonised after 84 days. A strain of serovar 5 after a further 50 subcultures in vitro was a little less persistent than it was before such subculture, but not in a way to suggest that subculturing was the main reason for differences in the behaviour of the serovars. At autopsy of six mice that were still colonised vaginally 158 days after inoculation of serovar 8, spread to the upper genital tract was shown to have occurred in three of them and dissemination to the liver and kidney in one. Compared with immunocompetent mice of strain CB20, such dissemination was not a feature in genetically related mice with severe combined immunodeficiency. This is not in keeping with the situation in hypogammaglobulinaemic patients in whom ureaplasmas and other mycoplasmas are known to disseminate. However, differences in the proportion of immunocompetent mice colonised or in ureaplasmal persistence with different serovars may act as a marker for differences in human pathogenicity and is worthy of further study. (+info)
Uterine first pass effect in postmenopausal women.
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BACKGROUND: Vaginally administered drugs distribute preferentially to the uterus; counter-current transfer from the vaginal veins to the uterine artery probably plays a pivotal role. In each side, the ovarian and uterine arteries form arterial anastomoses and controversy exists regarding the origin of the arterial supply to the Fallopian tube and tubal part of the uterus, and consequently whether these tissues can be reached through vaginal administration. METHODS: A thermocatheter with four measurement points, each separated by 5 mm, was inserted under endoscopic control into the tubal corner of uterus in 10 conscious, menopausal women and the temperatures registered every 2 s. The vagina was then flushed for 15 min with 1.5 l of saline at room temperature, after which the probe position was re-assessed by the endoscope. RESULTS: The lowest measurement point (15 mm from the tip) cooled significantly more than the other points (P < 0.0001). At 15 min, mean temperature reduction at point 4 was significantly greater than at all other measurement points (P < 0.05) due to local transfer of cold from vaginal vein blood to the uterine arterial blood (but not the ovarian artery). CONCLUSIONS: The results support the theory that, at least in postmenopausal women, the uterine artery supplies most of the uterus while the corneal part of cavity (up to 5-10 mm from the ostium) receives the blood supply from the ovarian artery. This finding represents a rationale for vaginal administration of drugs when a local effect on the uterus (e.g. progestational or relaxation) in postmenopausal women is requested. (+info)
Early pregnancy termination with vaginal misoprostol before and after 42 days gestation.
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BACKGROUND: Misoprostol is a prostaglandin E(1) analogue that has been used for medical abortion. We conducted this prospective study to compare the efficacy of vaginal misoprostol for abortion in women at a gestational age of <42 days and in women at a gestational age of 42-56 days. METHODS: A total of 160 women seeking medical termination of a pregnancy of <56 days were enrolled in the study. Medical termination was performed using 800 micro g of vaginal misoprostol, repeated every 24 h for a maximum of three doses. RESULTS: The overall complete abortion rate was 91.3%. In group A (gestation <42 days) complete abortion occurred in 96.3% of women, whereas in group B (gestation = 42-56 days) complete abortion occurred in 86.3% of women (P < 0.025). The two groups did not differ significantly with respect to side-effects (incidence of pain, bleeding, nausea, diarrhoea, fever and headache). Women who had aborted successfully were significantly more satisfied with the method compared with women who did not (P < 0.001). CONCLUSIONS: The vaginal misoprostol-alone regimen is highly effective for women seeking medical abortion of pregnancies of +info)
A 13-week subchronic intravaginal toxicity study of the novel broad-spectrum anti-HIV and spermicidal agent, N-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (PHI-346) in mice.
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The nonnucleoside inhibitor (NNI) of HIV-1 reverse transcriptase, PHI-346 (N-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea), is a dual-function spermicidal agent with potent anti-HIV activity against drug-sensitive as well as drug-resistant HIV-1 strains with genotypic and phenotypic NNI resistance. PHI-346 was formulated via a lipophilic gel-microemulsion for intravaginal use as a potential dual-function microbicide. To evaluate the toxicity potential of short-term intravaginal exposure to PHI-346, groups of 15 female B6C3F1 and CD-1 mice were exposed intravaginally to a gel-microemulsion containing 0, 0.5, 1.0, or 2.0% PHI-346, 5 days per week for 13 consecutive weeks. On a molar basis, these concentrations of PHI-346 are 350 to 1,400-times higher than its spermicidal EC50 and nearly 5 x 10(6) to 2 x 10(7) times higher than its in vitro anti-HIV IC50. After 13 weeks of intravaginal treatment, B6C3F1 mice were evaluated for survival, body weight gain, absolute and relative organ weights. Blood was analyzed for hematology and clinical chemistry profiles. Microscopic examination was performed on hematoxylin and eosin-stained tissue sections from each study animal. Placebo control and PHI-346 dosed female CD-1 mice were mated with untreated males in order to evaluate if PHI-346 has any deleterious effects on the reproductive performance. There were no treatment-related mortalities. Mean body weight gain during the dosing period was not reduced by PHI-346 treatment. The hemogram or blood chemistry profiles revealed lack of systemic toxicity following daily intravaginal instillation of PHI-346 for 13 weeks. No clinically significant changes in absolute and relative organ weights were noted in PHI-346 dose groups. Extensive histopathological examination of tissues revealed no treatment-related abnormalities in any of the three PHI-346 dose groups. Repeated intravaginal exposure of CD-1 mice to increasing concentrations of PHI-346 for 13 weeks had no adverse effect on their subsequent reproductive capability, perinatal outcome, growth, and development of offspring. Collectively, these findings demonstrate that repetitive intravaginal administration of PHI-346 at concentrations as high as 1,400-times its spermicidal EC50 and 2 x 10(7) times its in vitro anti-HIV IC50 was not associated with local or systemic toxicity and did not adversely affect the reproductive performance in mice. PHI-346 may be useful as an active ingredient of a safe vaginal microbicide for prevention of the sexual transmission of multidrug-resistant HIV-1. (+info)
A prospective randomized study to compare the use of repeated doses of vaginal with sublingual misoprostol in the management of first trimester silent miscarriages.
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BACKGROUND: A randomized controlled trial comparing sublingual with vaginal administration of misoprostol for medical management of silent miscarriages. METHODS: Eighty women who had silent miscarriages (<13 weeks) were randomized to receive 600 micro g of misoprostol every 3 h for a maximum of three doses either sublingually or vaginally. RESULTS: The success rates of medical management were the same in both groups (87.5%; 95% CI: 74-95%). There were no serious complications. The incidence of diarrhoea was higher in the sublingual (70%) than the vaginal route (27.5%) (P < 0.005). Other side effects were similar in each group, although fatigue was experienced by more women in the sublingual group than in the vaginal group (65 versus 40%: P = 0.043). The overall acceptability of medical management was good. Most women would choose the medical method if they were allowed to choose again and would recommend the method to others. CONCLUSION: The current regimen of misoprostol is useful for the management of silent miscarriage in terms of complete miscarriage rate and patient acceptability. Sublingual misoprostol may offer an alternative for women who do not like repeated vaginal administration of the drug. (+info)
Simian-human immunodeficiency virus SHIV89.6-induced protection against intravaginal challenge with pathogenic SIVmac239 is independent of the route of immunization and is associated with a combination of cytotoxic T-lymphocyte and alpha interferon responses.
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Attenuated primate lentivirus vaccines provide the most consistent protection against challenge with pathogenic simian immunodeficiency virus (SIV). Thus, they provide an excellent model to examine the influence of the route of immunization on challenge outcome and to study vaccine-induced protective anti-SIV immune responses. In the present study, rhesus macaques were immunized with live nonpathogenic simian-human immunodeficiency virus (SHIV) 89.6 either intravenously or mucosally (intranasally or intravaginally) and then challenged intravaginally with pathogenic SIVmac239. The route of immunization did not affect mucosal challenge outcome after a prolonged period of systemic infection with the nonpathogenic vaccine virus. Further, protection from the SIV challenge was associated with the induction of multiple host immune effector mechanisms. A comparison of immune responses in vaccinated-protected and vaccinated-unprotected animals revealed that vaccinated-protected animals had higher frequencies of SIV Gag-specific cytotoxic T lymphocytes and gamma interferon (IFN-gamma)-secreting cells during the acute phase postchallenge. Vaccinated-protected animals also had a more pronounced increase in peripheral blood mononuclear cell IFN-alpha mRNA levels than did the vaccinated-unprotected animals in the first few weeks after challenge. Thus, innate as well as cellular anti-SIV immune responses appeared to contribute to the SHIV89.6-induced protection against intravaginal challenge with pathogenic SIVmac239. (+info)
Changes in circulating concentrations of inhibins A and pro-alpha C during first trimester medical termination of pregnancy.
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BACKGROUND: Both inhibin A and inhibin pro-alpha C are detectable in the circulation in increasing amounts during establishment of pregnancy. However, their origins and functions remain to be elucidated. We have studied levels of inhibin A and inhibin pro-alpha C in serum samples collected at various stages during medical termination of pregnancy with consecutive use of mifepristone and misoprostol. METHODS: Samples were collected from three groups of patients at different weeks of gestation (group A: 6-7 weeks, n = 6; group B: 7-8 weeks, n = 6; group C: 8-9 weeks, n = 6) at the time of administration of oral mifepristone, 48 h later just before administration of vaginal misoprostol and again soon after expulsion of the products of conception. Plasma concentrations of inhibin A and pro-alpha C were assayed using specific and sensitive enzyme-linked immunosorbent assays. Results were correlated with concentrations of hCG and progesterone. RESULTS: We observed a significant fall in plasma concentration of inhibin pro-alpha C following administration of mifepristone, which continued after administration of misoprostol. In contrast mifepristone had no effect on plasma levels of inhibin A, which fell steeply only after administration of misoprostol. CONCLUSIONS: These results suggest dissociation between major sources of inhibin A and inhibin pro-alpha C in early pregnancy. Treatment with mifepristone, a competitive antagonist of the progesterone receptor, resulted in a significant and rapid fall in concentrations of inhibin pro-alpha C, identifying a link between production of pro-alpha C and luteal steroidogenesis. In contrast, concentrations of inhibin A did not fall after mifepristone, identifying a predominantly feto-placental origin in early human pregnancy. (+info)