A controlled study of mianserin in moderately to severely depressed outpatients.

Following a 1-week, single-blind placebo washout, 150 patients were randomized to double-blind treatment with daily doses of either mianserin, 30 mg to 150 mg; amitriptyline, 60 mg to 300 mg; or placebo, 1 to 5 capsules taken at bedtime (qhs). Mianserin and amitriptyline were found to be comparable in efficacy, and both significantly more effective than placebo in the treatment of major depressive illness. Rating instruments, all of which showed significant improvement in the active drug groups over the placebo, included the 17- and 21-item Hamilton Rating Scale for Depression (HAM-D), Montgomery and Asberg Depression Rating Scale (MADRS), Self-rating Depression Scale (SDS) index, and the Clinical Global Impressions (CGI) Severity of Illness and Improvement rating scales. Furthermore, for most efficacy parameters in the efficacy-evaluable group, the earliest statistically significant difference vs. placebo could be observed at Visit 1 for the mianserin patients and at Visit 3 for the amitriptyline patients. The safety profile for mianserin was comparable with placebo with respect to laboratory values, electrocardiogram changes, vital signs, ophthalmologic evaluations, and most adverse clinical experiences. Complaints of somnolence and weight gain were comparable in the amitriptyline and mianserin groups. Mianserin was superior to amitriptyline in terms of vital signs; anticholinergic effects; and complaints of dizziness, dyspepsia, and tremor.

Effects of prolonged estrogen-progesterone treatment and hypophysectomy on the stimulation of short-latency maternal behavior and aggression in female rats.

Two experiments were undertaken to examine the stimulation of home-cage and/or maternal aggressiveness by a hormonal treatment stimulating short-latency maternal behavior. Nonpregnant ovariectomized rats were treated with a 16-day regimen providing pregnancy levels of estrogen (E, 5-mm Silastic capsule) and progesterone (P, daily injection of 4 mg) followed by E and P withdrawal, with or without a terminal injection of estradiol benzoate (EB, 5 micrograms/kg). In Experiment 1, hormonally treated and control females were exposed continuously to pups and tested for aggression toward male intruders on the fifth day of pup exposure. Females receiving E/P/Oil and E/P/EB were highly aggressive whether or not they had yet shown maternal behavior, whereas vehicle-treated females were nonaggressive. In Experiment 2, hypophysectomized (HYPX) and Sham-HYPX females received either E/P/EB or a control treatment and were tested with male intruders (a) immediately preceding and (b) on the fifth day of continuous pup exposure. HYPX and Sham-HYPX females treated with E/P/EB were almost equally aggressive both preceding and following pup exposure (during which they initiated maternal care), whereas HYPX and Sham-HYPX vehicle-treated females were nonaggressive at both tests. In contrast, maternal behavior latencies were reduced by E/P/EB only among Sham-HYPX females. The results establish that an E/P/EB-treatment which elicits short-latency maternal responses also increases aggressiveness toward intruders. Pituitary products, although involved in the mediation of maternal responsiveness, do not contribute significantly to the stimulation of female aggressiveness by ovarian hormones.

Cytosol and nuclear estrogen receptor binding in the preoptic area and hypothalamus of female rats during pregnancy and ovariectomized, nulliparous rats after steroid priming: correlation with maternal behavior.

In a previous study, high nuclear estrogen receptor concentrations in the preoptic area (POA) were found on Day 16 of pregnancy to prime females to respond to a subsequent low dose of estradiol benzoate (EB) after hysterectomy-ovariectomy by exhibiting maternal behavior in 48 hr. Receptor concentrations in the POA were found to be higher than those in the hypothalamus (HYP). The present study investigated when nuclear estrogen receptors increase during pregnancy in POA and when the difference in receptor concentrations between POA and HYP occurs. An attempt was made to reproduce these pregnancy changes with a 16-day treatment of estrogen and progesterone in ovariectomized (OVX), nulliparous rats. In Experiment 1, we measured cytosol and nuclear estrogen receptor concentrations in the POA and HYP of female rats during pregnancy. Nuclear receptor concentrations in the POA increased beginning on Day 10, increased again on Day 16, and continued at this high level for the remainder of pregnancy. Nuclear estrogen receptor concentrations in the HYP remained at a lower level throughout most of pregnancy until Day 22 when they increased significantly. In Experiment 2, we tested the maternal behavior and measured estrogen receptor concentrations in OVX, steroid-primed, nulliparous rats after hysterectomy (H) and EB treatment. While 90% of estradiol (E) + progesterone (P)-primed females displayed short-latency maternal behavior 48 hr after H and EB treatment, 46% of E + vehicle (V)-treated controls were maternal. At 0 hr (prior to H and EB treatment), there was a significantly larger nuclear receptor accumulation in the POA but significantly attenuated receptor binding in the HYP. P treatment significantly affected cytosol and nuclear estrogen receptor dynamics. Differences in nuclear estrogen receptor concentrations were shown to be based on the number of available binding sites and not to changes in receptor affinity for estradiol.

Sexual receptivity in hamsters: brain nuclear estrogen and cytosolic progestin receptors after single and multiple steroid treatments and during the estrous cycle.

This series of experiments investigated the relationship between various treatments consisting of estradiol benzoate (EB) and progesterone (P) on sexual receptivity and on concentrations of nuclear estrogen receptors (NER) and cytosolic progestin receptors (CPR) in the hypothalamus-preoptic area in female hamsters. The injection of 1 microgram EB at 0 and 24 hr resulted in higher levels of receptivity (after 0.25 or 0.5 mg P), NER and CPR compared to those obtained after a single injection of 2 micrograms EB. Animals treated with 5 micrograms EB at 0 and 24 hr displayed greater levels of receptivity (after 0.5 mg P) and had higher NER concentrations than animals given a single injection of 10 micrograms EB. Groups treated with either 1 microgram EB at 0 hr or 0.5 microgram EB at 0 and 24 hr did not differ and showed low levels of receptivity, NER and CPR, NER and CPR were also measured on each day of the estrous cycle. NER levels rose between Days 1 and 2, again between Days 2 and 3, and remained elevated on Day 4. CPR levels increased between Days 2 and 3, and there was no difference between Days 3 and 4. Taken together, these data suggest that receptivity in hamsters after estrogen exposure is correlated with the accumulation and maintenance of relatively high NER levels and on the induction of CPR. This can be accomplished by a single large injection of EB or by smaller split doses.

Sex differences in nuclear androgen receptors in guinea pig brain and the effects of an alpha 2 noradrenergic blocker on androgen receptors.

The binding of the synthetic androgen, [3H]methyltrienolone (R1881) to nuclear androgen receptors (NAR) was studied in various brain areas of gonadectomized male and female guinea pigs treated for 3 days with 2 mg testosterone propionate. The Scatchard analysis of salt-extracted NAR showed a single, high-affinity receptor with a Kd of 0.152 nM and maximum binding sites (Bmax) of 161.9 fmol/mg DNA. The concentration of NAR was highest in the hypothalamus (HYPO) and preoptic area (POA) in both males and females. Lower receptor levels were detected in the amygdala and cortex. NAR levels were significantly lower in the POA of females than in males. Systemic injection of prazosin, an alpha 1-adrenergic antagonist had no effect on NAR concentrations, but an alpha 2-antagonist, idazoxan, significantly reduced the binding of [3H]R1881 to NAR in both HYPO and POA. The reduction in binding of the ligand to receptor was not due to alterations in affinity of NAR, but rather to the decline in the number of receptors.

Effects of brain antiestrogen implants on maternal behavior and on postpartum estrus in pregnant rats.

To test the hypothesis that the onset of maternal behavior is stimulated by estrogen, we examined the effects of medial preoptic area (MPOA) or ventromedial hypothalamus (VMH) implants of the antiestrogen 4-hydroxytamoxifen (OH-TAM) on pre- and postpartum maternal behavior and on postpartum estrus in rats. On day 20 of pregnancy, animals were implanted bilaterally with OH-TAM or cholesterol cannulae into MPOA or VMH. Unilateral cannulae of OH-TAM were also placed into MPOA. Females were tested with newborn pups for the onset of immediate retrieval, prepartum, at noon on day 21, at midnight of the day 21, and 1 day following parturition (which occurred on day 22). On the evening of parturition, implanted animals were tested with stimulus males for the occurrence of postpartum estrus. In order to examine the influence of estrogen on maternal behavior in the absence of parturitional experience, antiestrogen-implanted animals were delivered surgically (cesarean section) and were observed for the display of maternal behavior at various times after surgery. At noon of day 21, only a few animals in any group retrieved pups. However, 12 h later, females that received bilateral OH-TAM implants into MPOA remained nonresponsive, while over 80% animals in other groups retrieved and gathered pups. The antiestrogen did not disrupt the display of postpartum maternal behavior in those females that were allowed to undergo normal parturition, but it significantly reduced the number of cesarean-delivered animals showing maternal behavior. Bilateral implants of OH-TAM into VMH, but not into MPOA, effectively blocked postpartum estrus. The MPOA implants of OH-TAM resulted in a significant reduction in cytoplasmic estrogen receptor levels and an increase in nuclear estrogen receptor concentrations. The results of these experiments lend support to the current hypothesis that estrogen acts most effectively in the MPOA to stimulate maternal behavior and in the VMH to facilitate sexual receptivity.

Effects of human growth hormone on immune functions: in vitro studies on cells of normal and growth hormone-deficient children.

We have studied the in vitro effects of human growth hormone on cell surface markers and mitogenic responses of peripheral blood lymphocytes (PBL) of normal and growth hormone-deficient children before, during and after treatment with growth hormone. Growth hormone resulted in a decrease in B cell expression but it did not affect expression of T cell subsets. Growth hormone depressed the proliferation of PBL of normal and untreated growth hormone-deficient children. The proliferative responses to phytohemagglutinin (PHA) versus PHA with growth hormone were not statistically different, though the responses of most normal and on treatment children were diminished by the addition of growth hormone. PBL derived from growth hormone-deficient children during treatment with human growth hormone exhibited significantly greater spontaneous proliferation then the PBL of normal children. Growth hormone further significantly enhanced their proliferation. PHA and PHA with growth hormone resulted in significantly greater proliferation of these patients' PBL when compared to those of normal children. We demonstrated that human growth hormone had substantial in vitro effects on immune functions. These effects, some of which depend on the treatment status of the children, may need to be considered in the clinical use of human growth hormone.

Cytosol androgen receptors in guinea pig brain and pituitary.

Cytosol androgen receptors were assayed in guinea pig brain and pituitary tissues, using [3H]R1881 as ligand. These receptors had an apparent Kd of 0.04 nM and were androgen-specific (R1881 greater than dihydrotestosterone greater than testosterone = estradiol greater than progesterone). Concentrations of cytosol androgen receptors in castrated adult male guinea pigs were 12.2, 11.6, 6.9, 2.6 and 1.3 fmol per mg protein in anterior pituitary, hypothalamus, medial preoptic area, amygdala and cortex, respectively. No significant differences in receptor levels were observed between castrated adult males and females. The concentration of androgen receptors was significantly lower in the hypothalamus, medial preoptic area and anterior pituitary of castrated neonatal males than in castrated adult male guinea pigs. The systemic injection of the alpha 1-adrenergic antagonist, prazosin, had no significant influence on androgen receptor levels in castrated males in any brain area.

Suppression of immune function in growth hormone-deficient children during treatment with human growth hormone.

Inasmuch as growth hormone is known to interact with the immune system, we studied immune functions including immunoglobulins, cell surface markers, mitogen responses, and polymorphonuclear cell function in eight children with growth hormone deficiency, ages 1 to 17 years, before and during treatment with human growth hormone for 12 to 16 months. Before treatment immune functions were normal in all children. Treatment with human growth hormone did not significantly affect serum immunoglobulins, polymorphonuclear cell function, or percent T cells. However, percent B cells decreased to subnormal levels in seven of seven patients. T helper/suppressor ratios decreased in all patients, to subnormal values in seven of eight patients; and mitogen responses decreased to below normal in all. The decline of percent B cells was transient in all patients, of T helper/suppressor ratios in seven of eight, and mitogen responses in five of eight patients. In vitro incubation of lymphocytes with growth hormone resulted in no changes in cell surface markers or mitogen responses. Although the depression of immune functions resulted in no increased rate of infections during the observation period, we do not know the possible effects of prolonged treatment and therefore caution against the indiscriminate use of human growth hormone. The effects of biosynthetically obtained growth hormone on immune function remain to be determined.

Hypothalamic nuclear estrogen receptors and lordosis behavior in hamsters.

These experiments examined the effects of a high and a low dose of estradiol benzoate (EB) in enhancing lordosis behavior and correlated these effects with the retention of hypothalamic nuclear estrogen receptors (NER) in female hamsters. Ten micrograms EB was significantly more effective in facilitating sexual receptivity in hamsters when it was followed 36 or 48 hr later by 0.5 mg progesterone (P), but not when P was given 24 hr after EB. Low levels of behavioral responses were observed in animals that received P at 24, 36 or 48 hr after 2 micrograms EB. Correspondingly, although the hypothalamic NER levels were equally elevated 24 hr after either a low or a high dose of EB, these receptor concentrations remained high at 36 and 48 hr post EB, only in those animals that received the high estrogen dose. The results of these experiments suggest that the long-term retention of NERs (which is maintained by a single high EB dose) may play an important role in the enhancement of sexual receptivity in hamsters.

Hypothalamic nuclear progestin receptors and the duration of sexual receptivity in ovariectomized and ovariectomized-hysterectomized rats.

In order to determine if the enhancement of sexual behavior in hysterectomized rats is associated with an increased level of hypothalamic nuclear progestin receptors, ovariectomized (OVX) and ovariectomized-hysterectomized (OVHX) rats were injected with 2 micrograms estradiol benzoate. Twenty-four hr later, animals were injected with 0.5 mg progesterone and were tested for sexual receptivity every 4 hr. Hysterectomy had an overall facilitatory effect on lordosis and increased the duration of the period of sexual receptivity by about 4 hr. In a second experiment, similarly-treated animals were killed 4, 8, or 12 hr after progesterone injection, and hypothalamic nuclear progestin receptor levels were measured. In contrast to what has been reported for guinea pigs, nuclear progestin receptor levels decreased to baseline 8-12 hr before the termination of sexual receptivity. Nuclear progestin receptor concentrations were higher in OVHX rats than in OVX rats at 4 hr after progesterone injection, and there was a trend toward higher receptor concentrations in OVHX rats at 8 hr. These results demonstrate that hysterectomy-induced facilitation of sexual receptivity is associated with an increased level of hypothalamic nuclear progestin receptors. Furthermore, they suggest a fundamental difference in the regulation of nuclear progestin receptor retention between rats and guinea pigs.

The role of the uterus in regulation of heat duration in cycling rats.

These experiments examined the effects of hysterectomy on heat duration and on the reinduction of estrous behavior by progesterone (P) following the termination of spontaneous heat in 4-day cycling rats. Hysterectomy did not affect the onset of estrus but prolonged heat duration. The average duration of sexual receptivity for hysterectomized (H) and sham-hysterectomized (SH) rats was 18.2 and 13.0 hr, respectively. Furthermore, H animals injected with either 0.5 mg P within 2 hr, or 4.0 mg P 24 hr following the termination of natural estrus showed significantly higher lordosis and solicitation responses than SH rats similarly treated. These behavioral findings were correlated with the level of hypothalamic progestin receptors. That is, H animals had a significantly higher concentration of progestin receptors than SH rats immediately following the termination of spontaneous heat and also 24 hr later. Both in estrous-cycling rats and in gonadectomized animals treated with estradiol benzoate (EB), hysterectomy resulted in higher serum estradiol (E2) levels. The results of these experiments suggest that prolongation of the period of sexual receptivity and the facilitated behavioral responses to P following the cessation of estrus in hysterectomized animals may be due to a lowered clearance rate of circulating estradiol which presumably enhances the estrogen conditioning of the neural substrates.

The role of the uterus in reproductive behavior.

The uterus plays a major role in reproductive physiology. Numerous studies have shown that estradiol and progesterone exert their effects by binding to receptors within the cytoplasm of uterine cells and translocating these receptors to the nuclei where they presumably alter genomic activity. The extent of the steroid-receptor interaction in the cytoplasm and the nucleus is well correlated with uterine growth. Other physiological changes that take place in the uterus are also correlated with variations in the cytoplasmic and nuclear steroid receptor levels observed during different stages of reproductive cycle. In the rat, the uterus also exerts an inhibitory effect on the hormone-induced maternal and copulatory behaviors. Hysterectomy shortens the latency for the induction of maternal behavior and enhances sexual receptivity and proceptivity in ovariectomized, hormone treated rats. The mechanism of this inhibitory effect is not fully understood; however, it seems that the steroid binding capacity of the uterus mediates its behavioral influence. Thus when this capacity is reduced, as evidenced by lower levels of cytoplasmic estrogen receptors in long-term gonadectomized animals, the uterus loses its inhibitory effect on copulatory behavior.

Effects of antibiotics on polymorphonuclear leukocyte chemiluminescence and chemotaxis.

Polymorphonuclear leukocyte chemiluminescence and chemotaxis assays were performed on cells obtained from normal individuals and patients with defined defects in chemotaxis or chemiluminescence. After in-vitro pre-incubation with trimethoprim/sulphamethoxazole, its separate components, clindamycin and cefotaxime, normal cells showed some enhancement in chemotaxis and significant increase in chemiluminescence. There was an even more marked increase in chemotaxis when these antibiotics were incubated with cells from patients with leukocyte chemotaxic defects. When the cells from patients with chemiluminescence defects were pre-incubated with these antibiotics, there was also substantial enhancement in chemiluminescence.

Progesterone-induced sequential inhibition of copulatory behavior in hysterectomized rats: relationship to neural cytoplasmic progestin receptors.

The inhibitory effects of progesterone on the copulatory behavior and on neural cytoplasmic progestin receptors were examined in ovariectomized (DV) and ovariectomized-hysterectomized (OH) rats. Ovariectomized and OH rats were given 2.0 micrograms of estradiol benzoate (EB) followed 24 hr later by 0.1, 0.5, 0.1 or 2.0 mg of progesterone (P) and were tested for lordosis 6 hr later (30 hr). Twenty four hr after the first P treatment, all animals received 0.5 mg of P and were tested again (54 hr). The initial doses of 1.0 and 2.0 mg of P significantly reduced lordosis quotients in response to the subsequent P treatment in OV animals but only the 2.0 mg dose of P effectively suppressed lordosis in OH animals. In order to determine whether the priming dose of EB influences the inhibitory effects of progesterone, OV and OH rats were injected with 1.0 microgram of EB followed by 1.0 mg of P, or 6.0 micrograms of EB followed by 2.0 mg of P and were tested for receptivity under the same schedule. Treatment with 1.0 microgram of EB permitted, and 6.0 micrograms of EB prevented sequential inhibition of sexual behavior by progesterone in both OV and OH rats. Hypothalamic cytoplasmic progestin [( 3H]R5020) receptors were then measured 48 hr after EB injection in OV or OH rats given the same treatments with EB and P. Hypothalamic progestin receptors were significantly lower in OV animals given 2.0 micrograms of EB followed by 1.0 or 2.0 mg of P than oil-treated controls, but only the 2.0 mg dose of P significantly reduced receptors in OH rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Copulatory behavior and hypothalamic estrogen and progestin receptors in chronically insulin-deficient female rats.

The effects of relatively short- or long-term diabetes on sexual receptivity and and proceptivity and on hypothalamic estrogen and progestin receptors were examined in rats fed regular chow or high fat diet. Ovariectomized, streptozotocin-induced chronically insulin deficient and normal rats received sequential treatments with 2 micrograms estradiol benzoate (EB) and 1 mg progesterone (P) 10 days following the induction of diabetes and were tested for lordosis and soliciting behaviors. Nondiabetic rats fed either diet displayed significantly higher lordosis and solicitation behaviors than chow-fed diabetics, and fat-fed diabetic animals displayed behavior levels intermediate to those of nondiabetic and chow-fed rats. Ten days after the induction of diabetes, the levels of hypothalamic estrogen receptors of chow-fed diabetics were significantly lower than nondiabetics with the fat-fed diabetic group showing intermediate levels. However, 70 days after streptozotocin treatment diabetic rats had significantly lower estrogen receptors than nondiabetics regardless of the diet. Treatment of long-term (70 days) diabetic rats with 1-2 U of U-100 Lente insulin for 24 hr or 7 days was ineffective in restoring the hypothalamic estrogen receptor concentrations to those of nondiabetics. Three weeks following induction of diabetes, induction of cytoplasmic progestin receptors by EB treatment was significantly impaired in diabetic animals fed either chow or high fat diet. Although the reproductive dysfunctions present in short-term diabetic female rats may be due in part to chronic fuel deprivation, it appears that the long-term maintenance of cytosol estrogen receptor level is dependent on other actions of insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Immune deficiency syndrome in children.

The present epidemic of acquired immune deficiency syndrome (AIDS) was originally described in homosexual men and subsequently in intravenous drug abusers, Haitians, and hemophiliacs. Profound defects in cell-mediated immunity (CMI) are associated with Kaposi's sarcoma and a variety of serious opportunistic infections. Recently, we and others have encountered a group of children with an otherwise unexplained immune deficiency syndrome and infections of the type found in adults with AIDS. In this report, we describe eight children from the Newark, NJ, metropolitan area born into families with recognized risks for AIDS. These patients have had recurrent febrile illnesses, failure to thrive, hypergammaglobulinemia, and depressed CMI. Four of these children have died. Our experience suggests that children living in high-risk households are susceptible to AIDS and that sexual contact, drug abuse, or exposure to blood products is not necessary for disease transmission.

Hysterectomy facilitates proceptive behavior in rats.

The effects of hysterectomy on proceptive behavior were investigated using several doses of estradiol benzoate (EB) and progesterone (P) in female rats. One week after surgery, ovariectomized (OV) and ovariectomized-hysterectomized (OH) rats were given three daily injections of 1.0 or 2.0 micrograms EB followed by 0.5 mg P or oil on the fourth day and were tested for solicitation 4 hr later. The same animals received 1.0 or 2.0 micrograms EB plus 0.1 mg P, or 4.0 micrograms EB plus oil on the same schedule a week following the first test and were tested again. Ovariectomized-hysterectomized animals receiving 0.5 mg P, regardless of the EB dose, showed significantly higher solicitation scores than OV animals, but the scores of the EB-primed OV and OH rats receiving 0.1 mg P or oil vehicle did not differ.