HIV-1tat induced apoptosis of T-cells is not mediated by TGF-β

Recent reports have demonstrated that the HIV-1 transactivator protein,tat, induces apoptosis in T-lymphocyte cell lines, as well as in peripheral blood mononuclear cells, and stimulates a cascade of events resulting in up-regulation of the potent immunosuppressive cytokine, transforming growth factor-β (TGF-β). In this study we evaluated the ability of TGF-β to mediatetat induced apoptosis in T-lymphocyte cell lines. T-cells treated exogenously with either TGF-β1 or a combination of tat and pan-specific TGF-β neutralizing antibodies showed little change in the amount of apoptosis. When treated with pan-specific TGF-β neutralizing antibodies, Jurkat cells that stably expresstat protein (Jurkat-tat) showed only a modest decrease in apoptosis, while CEM-TART cells (CEM T-cells expressing both HIV-1tat andrev) demonstrated little change in the amount of apoptosis. In conclusion, we have demonstrated that TGF-β does not play a significant role in mediatingtat induced T-cell apoptosis.     

Myoglobin: an evaluation of its role as a marker of rhabdomyosarcomas

Tumour markers now have an established role in tumour diagnosis and patient management. However, antibodies used to detect these tumour markers have in some instances proved unreliable, with a low rate of sensitivity and specificity. In this study we wished to evaluate the role of a commercial antibody to myoglobin as a marker of rhabdomyosarcomas. The purpose of this investigation was to assess the sensitivity and specificity of myoglobin antiserum as a marker of rhabdomyosarcomas. This was performed by reacting a large number of tumours (sarcomas, carcinomas and melanomas) with a polyclonal anti human myoglobin antiserum. Staining was demonstrated in 60% of rhabdomyosarcomas. Only two tumours from a total of 226 non-skeletal muscle tumours showed a positive reaction (0.88%). One was a leiomyosarcoma and the other had been classified as an undifferentiated sarcoma but a rhabdomyosarcoma was included in its differential diagnosis. It is of interest that both had been earlier irradiated. This antiserum was therefore a specific but not a very sensitive tumor marker. Its rate of staining of rhabdomyosarcomas is compared with the results in the literature. A great disparity is found and the reasons for this are discussed.     

Successful first trimester abortion with 15(S) 15-methyl-prostaglandin F2alpha-methyl ester vaginal suppositories.

First trimester abortion was successfully performed in 58 women by the serial self-administration of vaginal suppositories containing 15(S)15-methyl PGF_2α-methyl ester. A total of 4 or 6 mg of the compound was given over a 12-hour period and vacuum aspiration was performed 18 hours after the start of therapy. Cervical dilatation, operative bleeding and the presence of the products of conception were noted. All patients aborted prior to vacuum aspiration and cervical dilatation was sufficient to perform easy curettage. The major side effect was pain; this was easily controlled. Based on the microscopic examination of the aspirated material, 36 per cent of the patients who received the lower dose aborted completely, while 57 per cent of those who received a total of 6 mg of the compound, aborted completely. A greater proportion of women in the 8–9th week than those in the 11–12th week aborted completely. There was no significant relationship between the parity of the patients and the completeness of the abortion. The results of this study suggest that the compound may be a safe, effective and easily administered method of inducing complete abortion through the 9th week of pregnancy. In the 10–12th week, pre-treatment with this prostaglandin facilitates the evacuation of the uterus by surgical means.     

Delayed disease progression after allogeneic cell vaccination in hormone-resistant prostate cancer and correlation with immunologic variables.

PURPOSE: There are a significant number of patients with asymptomatic hormone-resistant prostate cancer who have increasing prostate-specific antigen (PSA) levels but little or no evaluable disease. The immunogenicity and minimal toxicity associated with cell-based vaccine therapy makes this approach attractive for these patients. EXPERIMENTAL DESIGN: We have evaluated a vaccine comprising monthly intradermal injection of three irradiated allogeneic prostate cell lines (8 x 10(6) cells each) over 1 year. The first two doses were supplemented with bacille Calmette-Guérin as vaccine adjuvant. Twenty-eight hormone-resistant prostate cancer patients were enrolled. Patients were assessed clinically and PSA levels were measured monthly. Radiologic scans (X-ray, computed tomography, and bone scan) were taken at baseline and at intervals throughout the treatment period. Comprehensive monthly immunologic monitoring was undertaken including proliferation studies, activation markers, cytokine protein expression, and gene copy number. This longitudinal data was analyzed through predictive modeling using artificial neural network feed-forward/back-propagation algorithms with multilayer perceptron architecture.RESULTS: Eleven of the 26 patients showed statistically significant, prolonged decreases in their PSA velocity (PSAV). None experienced any significant toxicity. Median time to disease progression was 58 weeks, compared with recent studies of other agents and historical control values of around 28 weeks. PSAV-responding patients showed a titratable T(H)1 cytokine release profile in response to restimulation with a vaccine lysate, while nonresponders showed a mixed T(H)1 and T(H)2 response. Furthermore, immunologic profile correlated with PSAV response by artificial neural network analysis. We found predictive power not only in expression of cytokines after maximal stimulation with phorbol 12-myristate 13-acetate, but also the method of analysis (qPCR measurement of IFN-gamma > qPCR measurement tumor necrosis factor-alpha > protein expression of IFN-gamma > protein expression of interleukin 2). CONCLUSIONS: Whole cell allogeneic vaccination in hormone-resistant prostate cancer is nontoxic and improves the natural history of the disease. Longitudinal changes in immunologic function in vaccinated patients may be better interpreted through predictive modeling using tools such as the artificial neural network rather than periodic "snapshot" readouts.     

Effect of oral misoprostol after second-trimester delivery: a randomized,blinded study

OBJECTIVE: To determine whether serial oral misoprostol shortens the third stage of labor in second-trimester pregnancy loss. METHODS: This was a randomized, double-blind, placebo-controlled study of women between 13 and 28 weeks' gestation admitted for spontaneous or induced pregnancy termination. Subjects were randomized to receive either misoprostol (200 microg) or placebo orally every hour for a maximum of three doses if the placenta had not delivered spontaneously within 10 minutes of the fetus. A dilute oxytocin infusion was given to women in both groups. The patients were managed expectantly until intervention was required or up to 6 hours when curettage was scheduled. RESULTS: One hundred eighteen women were randomized to misoprostol and 119 randomized to placebo. Fifty-eight (49%) and 55 (46%) of the misoprostol and placebo groups, respectively, did not receive their medication (P =.65, chi(2) test). There was no difference between the groups with regard to demographic features, method of pregnancy termination, or gestational age. Sixty-seven (57%) and 62 (52%) of the misoprostol and placebo groups, respectively, completed the third stage of labor within 2 hours (P =.47, chi(2) test). There was no statistically significant difference in the median time from fetus to placenta (60 versus 91 minutes in the misoprostol versus placebo group, P =.57, Mann-Whitney U test). There was no difference between the groups in the incidence of hemorrhage, need for transfusion, or curettage rate. CONCLUSION: The therapeutic use of oral misoprostol in the third stage of labor in second-trimester pregnancy loss does not reduce the time to complete spontaneous placental delivery.     

Expression of CD44 in uterine cervical squamous neoplasia: a predictor of microinvasion?

OBJECTIVE: CD44, an integral membrane glycoprotein, may have an important role in early tumorigenesis, specifically, facilitating early tumor progression. Reports of the expression of CD44 in early uterine cervical squamous carcinogenesis are conflicting. We examined the expression of CD44 in microinvasive carcinoma of the cervix (MIC), as yet unreported, and compared it to that in cervical intraepithelial neoplasia (CIN) 1 and CIN 3 to further elucidate its role in early squamous carcinogenesis. METHODS: Seventeen cases of CIN 1, 24 cases of CIN 3, and 20 cases of MIC were stained with antibodies to CD44s, CD44v5, and CD44v6. Only membranous staining was considered positive. RESULTS: Positive membranous staining (>50% cells) was observed in 97% of cases of CIN 1 using all three antibodies. In CIN 3, positive staining was seen more often with CD44v6 (18/24) and CD44v5 (19/24) than with CD44s (6/24). Expression of CD44v6 was retained more often in MIC (16/20) compared with CD44s (3/20) and CD44v5 (9/20). Those cases of CIN 3 and MIC that failed to meet our criteria for positive staining showed either heterogeneous or absent staining. CONCLUSION: There is a qualitative and quantitative reduction in expression of CD44 in MIC and CIN 3 compared with CIN 1. Down-regulation of CD44 variants may occur later in neoplastic progression than CD44s. This pattern may reflect their important biological function in early progression by cervical cancer cells. Patchy and heterogeneous staining in more advanced lesions limits the usefulness of CD44 and its variants in the assessment of microinvasion.     

Maternal stress and obstetric and infant outcomes: epidemiological findings and neuroendocrine mechanisms

This review examines the associations between antenatal maternal stress and obstetric and infant outcomes using preterm delivery as the key outcome indicator. This was done by means of a Medline search focusing predominantly on prospective, controlled studies which investigated both the associated epidemiological factors and putative neuroendocrine mechanisms. There is evidence from a number of United States studies in economically deprived African American women for an association between perceived maternal life event (LE) stress and preterm delivery. The findings from the European studies are conflicting, partly because they combine outcome measures ie. preterm delivery and low birth weight. However the three largest Scandinavian epidemiological studies examining preterm delivery and controlling for confounders such as smoking, age and obstetric history, have confirmed this association. These studies taken together suggest that this may be a robust finding not limited to socioeconomically deprived African American samples and independent of other significant risk factors. Two small prospective studies examining the relationship between the hypothalamic-pituitary-adrenal (HPA) axis, psychosocial status and premature delivery have reported a significant association between a set of adverse psychosocial factors on the one hand, and levels of adrenocorticotrophic hormone (ACTH), corticotrophin releasing hormone (CRH) and cortisol levels, and on the other hand, a significant correlation between CRH levels and premature delivery. Clearly, these findings remain preliminary and indicate a complex relationship between perceived stress in pregnancy, the HPA axis and premature delivery. The impact of antenatal maternal stress on infant temperament and psychopathology remains to be examined more fully in prospective controlled trials.