Effects of lipids and lipid-lowering therapy on hemostatic factors in patients with myocardial infarction.

BACKGROUND: The risk of cardiovascular disease (CVD) is associated with specific hemostatic markers and lipid profiles, and evidence indicates that there are associations between lipid profiles and the levels of certain hemostatic factors. The disturbances in hemostasis and the risk of CVD can be ameliorated by lipid-lowering therapy. OBJECTIVE: We investigated the associations of lipid profiles with factor (F)VIIa, von Willebrand factor (VWF), D-dimer and plasminogen activator inhibitor-1 (PAI-1), and examined whether lipid-lowering statin therapy would affect the levels of these hemostatic markers. PATIENTS AND METHODS: This cross-sectional study analyzed 1045 postmyocardial infarction patients. RESULTS: In multivariate regression analyses (without adjusting for clinical covariates) HDL-cholesterol (HDL-C) and HDL size were independent and significant predictors of FVIIa; HDL size was a predictor of VWF; HDL size, HDL-C and LDL size were predictors of D-dimer; and triglyceride and HDL size were predictors of PAI-1. After adjusting for clinical covariates, HDL-C, lipoprotein (Lp)(a), apolipoprotein B (apoB) and warfarin were independent and significant predictors of FVIIa; HDL size, age, diabetes mellitus, insulin, race and warfarin were predictors of VWF; HDL-C, HDL size, LDL size, age, warfarin, hypertension and gender were predictors of D-dimer; and triglyceride, HDL size, body mass index, insulin and hypertension were predictors of PAI-1. Patients on statin therapy had significantly lower levels of D-dimer than those who were not on this therapy. CONCLUSION: There are significant associations of lipid profiles with hemostatic factors, the directions of which suggest novel pathways by which dyslipidemia may contribute to coronary heart disease.

Tracking sexual contacts of HIV patients: a study of physician practices.

Notification of sexual partners of HIV-infected individuals has become a focus of debate at local, state, and national levels. Issues of confidentiality and ethical concerns continue to pose challenges to state and local health departments addressing this issue. We conducted a telephone survey with physicians in Syracuse, New York to ascertain opinions about HIV partner notification and the role of public health agencies in that notification process. In general, physicians mostly relied upon the HIV-infected individuals to notify their own partners but were supportive of enhanced efforts regarding partner notification.

Use of stage of change (SOC) to develop an STD/HIV behavioral intervention: phase 1. A system to classify SOC for STD/HIV sexual risk behaviors--development and reliability in an STD clinic.

This paper reports on the initial phase in the development, program implementation, and inter-rater reliability of an application of Stage of Change (SOC) behavioral theory for use in STD/HIV risk reduction. SOC was adapted to assess readiness for sexual behavior change in an urban STD clinic in Rochester, New York. A standardized staging grid and protocol were developed and implemented as part of HIV pre- and post-test counseling. A "client instructor" methodology was used to assess standardization and staff inter-rater reliability. Percent agreement for stage assessment for target behaviors was calculated. The Rochester STD/HIV Behavioral Counseling (RoSHBeC) Staging Grid and Protocol was used to train staff and this staging system was implemented in the STD clinic. After training, staff identified the correct behavioral target and stage 90% of the time. Inter-rater agreement for SOC classification was greater than 70%. Our experience demonstrates that it is possible to develop, implement, and sustain an integrated provider-delivered STD/HIV behavioral intervention in a busy urban STD Clinic. This staging system has the potential for use in other settings and for other health-related behaviors.

Physical activity, obesity, and diabetes in pregnancy.

Gestational diabetes mellitus (GDM) is the most common medical complication of pregnancy. Women with GDM are at elevated for numerous maternal health complications, and their infants are at elevated risk for death and morbidity. Management of GDM has traditionally been through diet and close monitoring of glucose levels, with initiation of insulin therapy when diet alone fails to maintain euglycemia. Recently, however, it has been suggested that alternative treatment modalities, such as exercise, may overcome a peripheral resistance to insulin, thus preventing GDM or controlling hyperglycemia in women with GDM. In this study, conducted from October 1995 to July 1996, the authors used a population-based birth registry to determine whether exercise has a preventive role in the development of GDM in women living in central New York State. They used contingency tables and chi-square statistics to examine bivariate differences among maternal and demographic variables and the occurrence of GDM. When stratified by prepregnancy body mass index category, exercise was associated with reduced rates of GDM only among women with a body mass index greater than 33 (odds ratio = 1.9, 95% confidence interval 1.2-3.1). The effect of exercise in obese women was further complicated by insurance status. When the data were stratified by insurance status, it appeared that women of higher socioeconomic status who were obese and did not exercise were at a significantly elevated risk of GDM compared with their counterparts of lower socioeconomic status. The results of this study suggest that for some women exercise may play a role in reducing the risk that they will develop GDM during pregnancy.

The antiprogestins RU486 and ZK98299 affect follicle-stimulating hormone secretion differentially on estrus, but not on proestrus.

Previous in vivo studies from our laboratory indicated that administration of the antiprogestin RU486 on proestrus suppresses both the preovulatory gonadotropin surges and the secondary FSH surge, suggesting a role for the progesterone receptor (PR) in the generation of these surges. The present study was designed to test the effects of another antiprogestin, ZK98299, which has been reported to block the PR through a mechanism different from that of RU486, on gonadotropin secretion in vivo. RU486 and ZK98299 (2 and 6 mg/kg) were administered s.c. at 1230 h on proestrus; uterine intraluminal fluid content, serum gonadotropins, and gonadotropin subunit messenger RNAs (mRNAs) were determined at 1830 h on proestrus and at 0900 h on estrus. At 1830 h on proestrus, both RU486 and ZK98299 at both doses caused equal suppression of the preovulatory FSH surge and FSHbeta mRNA. Both antiprogestins also equally attenuated the preovulatory LH surge at this time, with the higher doses causing greater suppression. In contrast, at 0900 h on estrus, the antiprogestins affected serum FSH differentially; only RU486 suppressed the secondary FSH surge despite the fact that both drugs prevented the release of uterine intraluminal fluid, confirming blockade of progesterone action at the level of the uterus. Neither drug had a significant effect on FSHbeta mRNA at 0900 h on estrus. ZK98299 at the higher dose caused a small, but significant, increase in serum LH. In a subsequent experiment, we compared the effects of RU486 and ZK98299 (6 mg/kg, s.c.), administered at 1230 h on proestrus, on serum FSH raised above the natural secondary FSH surge on the morning of estrus by passive immunization with an antiserum to inhibin-alpha (anti-I) at 1700 h on proestrus. Consistent with the results of the first experiment, both antiprogestins blocked the release of uterine intraluminal fluid, but only RU486 lowered serum FSH in both the normal sheep serum-treated controls and anti-I-treated rats; in contrast, ZK98299 actually increased serum FSH in the normal sheep serum-treated control animals. ZK98299 also increased FSHbeta mRNA in the control group; RU486, on the other hand, reduced FSHbeta mRNA only in the anti-I group. The results demonstrate unequivocally that whereas the effects of the two antiprogestins on serum FSH and FSHbeta mRNA are similar on proestrus, they are divergent on estrus. The data suggest that the functional state of the PR/transcriptional activation complex in the gonadotrope on the morning of estrus is different from that on the evening of proestrus.

RU486 on an estrogen background blocks the rise in serum follicle-stimulating hormone induced by antiserum to inhibin or ovariectomy.

We used passive immunization with an antiserum to the alpha-subunit of inhibin (anti-I) or acute ovariectomy to investigate the relationship between serum inhibin levels and FSH secretion in the presence of the progesterone/glucocorticoid antagonist RU486. We demonstrated previously that 1) anti-I administered at 1700 h causes serum FSH to rise on the morning of estrus, even in the presence of a GnRH antagonist, when the two treatments are delivered on proestrus; and that 2) RU486 given on proestrus (1230 h), a time when serum estradiol levels are high, not only blocks the natural secondary FSH surge, but also suppresses the anti-I-induced rise in serum FSH on the morning of estrus. We have now extended our studies of the relationship between inhibin and RU486 to investigate treatment with RU486 and anti-I on a different day of the cycle, estrus, when serum estradiol levels are low. When both RU486 and anti-I were given on estrus (1230 and 1700 h, respectively), RU486 failed to block the anti-I-induced rise in serum FSH on the next morning of metestrus, in contrast to the blockade seen with RU486 treatment on the day of proestrus. However, pretreatment with estradiol benzoate (50 microgram) on the evening of proestrus, before the RU486 and anti-I treatment on estrus, caused RU486 to suppress the effects of anti-I on serum FSH, as it does when given on proestrus. We then repeated the study, using ovariectomy on proestrus or estrus (1700 h) to raise serum FSH, and assessed the effects of RU486 treatment at proestrus and estrus and estradiol benzoate treatment on proestrus. Our results indicate that treatment with RU486 can block the postovariectomy rise in serum FSH only in the presence of high circulating estradiol levels. We conclude that the inhibitory action of RU486 on FSH secretion after a fall in serum inhibin depends on a precedent estradiol background, probably due to induction of progesterone receptors by estradiol.

Mechanism of the inhibitory action of RU486 on the secondary follicle-stimulating hormone surge.

Recent evidence utilizing RU486 has implicated progesterone (P) and glucocorticoids, in addition to a drop in serum inhibin, in the development of the secondary FSH surge on the morning of estrus. To assess the role of these steroids, we treated proestrous female rats with the antiprogestin/antiglucocorticoid RU486 (6 mg/kg sc) at 1230 h, and with dexamethasone (dex; 8.4 or 16.2 mg/kg sc), or with the steroid biosynthesis inhibitor aminoglutethimide (AG; 150 mg/kg ip) at 1030 h, alone or in combination with RU486. The effects of these treatments on uterine ballooning and intraluminal fluid content (an index of P action), ovulation, and serum levels of P, corticosterone (B), FSH, LH, and inhibin-alpha at 1830 h proestrus and 0900 h estrus were examined. In accord with previous work from our laboratory, RU 486 caused uterine intraluminal fluid retention on the morning of estrus and significantly suppressed the preovulatory surges of both FSH and LH, and the secondary surge of FSH without affecting the fall in inhibin-alpha. Treatment with dex alone raised serum FSH at both 1830 h proestrus and 0900 h estrus, coincident with suppression of serum inhibin-alpha. When administered in combination with RU486, dex partially reversed the increased uterine intraluminal fluid retention at 0900 h estrus, but did not modify the inhibitory effect of RU486 on the primary gonadotropin surges or the secondary surge of FSH. AG alone significantly suppressed serum P, B, and gonadotropins (LH to a greater extent than FSH) at 1830 h proestrus and blocked ovulation and uterine intraluminal fluid release at 0900 h estrus; it did not, however, suppress the secondary FSH surge or prevent the fall in serum inhibin-alpha. When administered 2 h before RU486, AG did not prevent the RU486-induced inhibition of the primary gonadotropin surges or the secondary FSH surge. We conclude from these results that development of the secondary FSH surge does not require P or glucocorticoid action and that RU486 suppression of the secondary FSH surge does not involve blockade of binding of these steroids to their receptors. Our data are compatible with ligand-independent activation of the P receptor, susceptible to blockade by RU486, as the mechanism underlying the enhanced secretion of FSH from the gonadotrope on the morning of estrus.

Unmasking of neuropeptide-Y inhibitory effects on in vitro gonadotropin secretion from pituitaries of metestrous, but not proestrous, rats.

We have recently demonstrated that GnRH-stimulated gonadotropin secretion is augmented by coadministration with neuropeptide-Y (NPY) in anterior pituitaries removed in the afternoon from proestrous, but not metestrous, rats. To test the hypothesis that these effects of NPY are due to an interaction with progesterone (P4), we conducted another cycle stage experiment using NPY, adding an in vitro treatment with P4. Pituitaries were taken from rats at 0900 h (before the rise of P4 on proestrus) on proestrus or metestrus and were perifused for 8 h, with and without GnRH pulses. P4 was given continuously in half of each of the basal or GnRH-stimulated perifusions. Pulsatile NPY was administered in half of the basal or GnRH-stimulated runs in the presence or absence of P4. P4 alone had a stimulatory effect on GnRH-induced LH secretion only on the day of metestrus. P4 did not confer responsiveness to NPY stimulation on either day. Unexpectedly, NPY reversed the P4 augmentation of GnRH-stimulated LH release on metestrus. With respect to FSH secretion, NPY or P4 alone had a striking suppressive effect on GnRH-stimulated FSH secretion rates from pituitaries of metestrous, but not proestrous, donors. These data suggest that the previous endogenous endocrine environment may be crucial in determining the divergent and interrelated effects of P4 and NPY on gonadotropin secretion. In particular, the metestrous environment appears to promote a suppressive role for NPY.

Estrous cycle stage-dependent effects of neuropeptide-Y on luteinizing hormone (LH)-releasing hormone-stimulated LH and follicle-stimulating hormone secretion from anterior pituitary fragments in vitro.

We recently demonstrated that neuropeptide Y (NPY) potentiates LH-releasing hormone (LHRH)-stimulated LH secretion in vivo, and that these actions of NPY are exerted only under the endocrine conditions leading to preovulatory LH surges, viz. the proestrous or estrogen- and progesterone-primed ovariectomized animal. The present experiments tested the hypothesis that NPY's facilitatory actions are exerted directly at the level of the anterior pituitary gland and depend on in vivo exposure of gonadotropes to the preovulatory endocrine milieu. Animals were killed at 1600 h on either metestrus or proestrus. Anterior pituitary glands (APs) were rapidly removed, cut into eighths, and placed into perifusion chambers. APs were perifused with medium 199 for a total of 8 h, and perfusate samples were collected every 5 min. After 30 min of equilibration, APs received hourly pulses of LHRH alone (10(-8) M), NPY alone (10(-6) M), or LHRH plus NPY. Basal runs consisted of perifusion with medium 199 for 8 h with no peptide treatments. Calculations of total hourly LH and FSH responses revealed that whereas LHRH significantly stimulated gonadotropin secretion from both metestrous and proestrous pituitaries, NPY significantly enhanced LHRH-stimulated LH and FSH secretion only from proestrous pituitaries, i.e. from tissue exposed to the endogenous endocrine milieu under which preovulatory gonadotropin surges are generated. NPY had no facilitatory effect on LHRH-induced gonadotropin secretion from metestrous APs. These results are consistent with our previous in vivo findings and demonstrate that the facilitatory actions of NPY on LHRH-stimulated gonadotropin secretion in vitro are limited to the endocrine conditions under which preovulatory gonadotropin surges are generated.

RU486 blocks the effects of inhibin antiserum or luteinizing hormone on the secondary follicle-stimulating hormone surge.

Previous work in this laboratory has shown that when the antiprogesterone RU486 is administered at 1230 h on proestrus, the primary surges of LH and FSH are significantly attenuated, and the secondary FSH surge is abolished. This suppression of the secondary FSH surge occurs in RU486-treated rats despite a drop in serum inhibin, which is presumably due to the partial primary LH surge. The experiments described investigated the interrelationships among the primary LH surge, the rising proestrous levels of progesterone, and the falling levels of inhibin on proestrus on the selective secretion of FSH during the night of proestrus and the morning of estrus. Exogenous LH given to rats treated first with RU486 cannot restore the secondary surge of FSH, as it does in GnRH antagonist-blocked rats, and progesterone alone cannot restore the secondary FSH surge in an animal in which the surges are blocked with GnRH antagonist. Antiserum to inhibin superimposed on GnRH antagonist causes an enhancement of FSH levels beyond that of the secondary FSH surge, but antiserum to inhibin superimposed on RU486 does not induce a similar elevation of FSH secretion. The failure of antiserum to inhibin to increase FSH in the face of RU486 suggests that either a small amount of progesterone, or perhaps another hormone blocked by RU486, is needed to facilitate FSH secretion in response to the drop in inhibin or RU486 is acting through nonprogesterone-mediated effects to block pituitary FSH secretion.

RU486 blocks the secondary surge of follicle-stimulating hormone in the rat without blocking the drop in serum inhibin.

The stimulatory effect of progesterone on the release of the primary surges of serum LH and FSH is well characterized. Less is known about the relationship of progesterone to the secondary FSH surge. We used the antiprogesterone, RU486, to block the action of progesterone and studied the effects on the primary surges of LH and FSH, and especially on the secondary surge of FSH. Proestrous rats were treated with RU486 at 1,200 h. Rats were killed on proestrus and estrus, and serum levels of LH, FSH, and inhibin were measured. In all RU486-treated rats, the primary surges of LH and FSH were significantly attenuated, and the secondary FSH surge was completely abolished, despite a drop in inhibin levels following the primary surges. A high replacement dose of progesterone, delivered immediately after RU486 treatment, did not restore the primary surges of LH and FSH, or the secondary surge of FSH. These data suggest that other factors in addition to a drop in inhibin are responsible for producing the secondary FSH surge.

Rat testes interstitial cell nuclei exhibit three distinct receptors for retinoic acid.

Purified nuclei from rat testes interstitial cells were incubated with an equimolar complex of [3H]retinoic acid and purified cellular retinoic acid-binding protein (cRABP) and with ATP. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and radiofluorographic analysis of the nuclear fractions indicated the presence of 3 highly labeled receptors for retinoic acid which were distinct from cRABP. These data demonstrate that retinoic acid binds to 3 novel nuclear acceptors of which cRABP does not appear to be a part.

Recurrent squamous cell carcinoma of the skin.

A retrospective analysis of all patients having the diagnosis of squamous cell carcinoma of the skin at a single hospital over a ten-year period was performed. These lesions are less common than both basal cell carcinomas and malignant melanomas. Noninvasive squamous cell carcinomas were not observed to recur. There was a 20% incidence of recurrence in 86 patients with invasive squamous cell carcinoma. The presence of solar changes in the skin did not obviate recurrence. The larger, less differentiated lesions had a greater probability of recurrence. When the depth of invasion of the lesions were determined, it was found that only the lesions that penetrated to Clark's Level IV or V recurred. Squamous cell carcinomas that penetrate to this depth have the potential to recur and metastasize to regional lymph nodes and should be considered malignant lesions, even if they are associated with actinic skin changes.

Follow-up adjuvant chemotherapy and chemoimmunotherapy for stage II and III carcinoma of the breast.

Patients with stage II or III carcinoma of the breast were assigned to one of three adjuvant chemotherapy and chemoimmunotherapy treatment groups following radical or modified radical mastectomy. This study compares the efficacy of single drug treatment (melphalan) versus multiple drug regimens (CFP and CFP + BCG). In the initial phase of the project participants in the melphalan group showed a higher recurrence rate than those in the CFP and CFP + BCG groups. The recurrence rate of the melphalan group was 4.4 times higher than the recurrence rate of the combined polychemotherapy arms. However, after the initial phase, the recurrence rates for the polychemotherapy arms steadily increased and approached the dropping rate of the melphalan group. Currently (247 weeks after the beginning of the study and nine months after the last patient accrual), 194 patients have been treated (median follow-up time of 101 weeks), and no significant differences can be detected between the three treatment arms using any of the following criteria: disease-free interval, proportion of recurrence and recurrence rate. The only factors which are significant with respect to recurrence are the two prognostic factors: tumor size and degree of nodal involvement. The two chemotherapy groups, CFP and CFP + BCG, show no significant difference with respect to recurrence rate along the entire span of the study.