Region-specific associations between sex, social status, and oxytocin receptor density in the brains of eusocial rodents.

Naturally occurring variations in neuropeptide receptor distributions in the brain contribute to numerous mammalian social behaviors. In naked mole-rats, which live in large social groups and exhibit remarkable reproductive skew, colony-related social behaviors vary with reproductive status. Here we examined whether variation in social status is associated with variations in the location and/or density of oxytocin binding in this species. Autoradiography was performed to assess forebrain oxytocin receptor (OTR) densities in breeding and non-breeding naked mole-rats of both sexes. Overall, males exhibited higher OTR binding in the medial amygdala in comparison to females. While there were no main effects of reproductive status in any region, a sex difference in OTR binding in the nucleus accumbens was mediated by status. Specifically, breeding males tended to have more OTR binding than breeding females in the nucleus accumbens, while no sex difference was observed in subordinates. These effects suggest that oxytocin may act in a sex- and region-specific way that corresponds to reproductive status and associated social behaviors.

Social regulation of adult neurogenesis in a eusocial mammal.

The present study examined the effects of social status on adult neurogenesis in an extreme cooperative breeder: the naked mole rat. These animals live in large colonies of up to 300 individuals, with a strict reproductive dominance hierarchy; one female and one to three males breed, and all other members are socially subordinate and reproductively suppressed. We examined the effects of social and gonadal cues on doublecortin (DCX; a marker for immature neurons) immunoreactivity in the dentate gyrus (DG), piriform cortex (PCx) and basolateral amygdala (BLA) by comparing dominant breeding animals to non-breeding subordinates from intact colonies. We also examined DCX expression in subordinate animals that had been removed from their colony and paired with an opposite- or same-sex conspecific for 6months. Compared to subordinates, dominant breeders had significantly reduced DCX immunoreactivity in all brain areas, with BLA effects confined to females. By contrast, the effects of same- versus opposite-sex housing were region-specific. In the DG and PCx, more DCX immunoreactivity was observed for opposite- than same-sex-paired subordinates. Conversely, same-sex-paired females had more DCX immunoreactivity than opposite-sex-paired females in the BLA. Gonadectomy did not affect DCX expression in opposite-sex-paired animals, and no significant relationships between gonadal steroids and DCX immunoreactivity were detected, suggesting that group differences in neurogenesis are independent of gonadal hormones. The apparent lower neurogenic capacity displayed by breeders contrasts previous reports on neurogenesis and social rank, challenging the conventional view that subordination is stressful and impairs neurogenesis. Future work will clarify whether the present findings can be attributed to status-dependent differences in stress, behavioral plasticity, or life stage.

Social condition and oxytocin neuron number in the hypothalamus of naked mole-rats (Heterocephalus glaber).

The naked mole-rat is a subterranean colonial rodent. In each colony, which can grow to as many as 300 individuals, there is only one female and 1-3 males that are reproductive and socially dominant. The remaining animals are reproductively suppressed subordinates that contribute to colony survival through their cooperative behaviors. Oxytocin is a peptide hormone that has shown relatively widespread effects on prosocial behaviors in other species. We examined whether social status affects the number of oxytocin-immunoreactive neurons in the paraventricular nucleus and the supraoptic nucleus by comparing dominant breeding animals to subordinate non-breeding workers from intact colonies. We also examined these regions in subordinate animals that had been removed from their colony and paired with an opposite- or same-sex conspecific for 6 months. Stereological analyses indicated that subordinates had significantly more oxytocin neurons in the paraventricular nucleus than breeders. Animals in both opposite- and same-sex pairs showed a decreased oxytocin neuron number compared to subordinates suggesting that status differences may be due to social condition rather than the reproductive activity of the animal per se. The effects of social status appear to be region specific as no group differences were found for oxytocin neuron number in the supraoptic nucleus. Given that subordinate naked mole-rats are kept reproductively suppressed through antagonism by the queen, we speculate that status differences are due either to oxytocin's anxiolytic properties to combat the stress of this antagonism or to its ability to promote the prosocial behaviors of subordinates.

Sex differences in NeuN- and androgen receptor-positive cells in the bed nucleus of the stria terminalis are due to Bax-dependent cell death.

The principal nucleus of the bed nucleus of the stria terminalis (BNSTp) is larger in males than in females of several species. We previously demonstrated that in mice lacking the pro-death gene, bax, total BNSTp cell number is increased and sex differences in cell number are eliminated. This suggests that Bax-dependent cell death underlies sexual differentiation of the BNSTp. However, it is not known what cells in the BNSTp are affected by bax deletion. Here we used immunohistochemistry and stereological techniques to quantify phenotypically-identified cells in the BNSTp of adult male and female bax -/- and bax +/+ mice. Sections were thionin-stained, or double-labeled for antigen expressed in neuronal nuclei (NeuN) and glial fibrillary acidic protein (GFAP) to identify mature neurons and astrocytes, respectively; an additional series was labeled for androgen receptor (AR). As previously demonstrated, sex differences in BNSTp area and overall cell number were seen in wild-type mice, but absent in bax -/- animals. In addition, sex differences (favoring males) were present in the number of NeuN+ and AR+ cells in wild-type mice. Bax gene deletion significantly increased the number of NeuN+ and AR+ cells and reduced or eliminated the sex differences in these cell types. The number of astrocytes in the BNSTp was not sexually dimorphic, nor significantly affected by bax gene status, although there was a trend for more GFAP+ cells in bax -/- mice. Overall brain weight was also greater in bax -/- animals compared with controls. We conclude that the sex differences in neuron and AR+ cell number are due at least in part to Bax-mediated cell death. Increased NeuN+ and AR+ cell number in bax -/- mice suggests that supernumerary cells in bax knockouts differentiate similarly to those in wild-type mice, and retain the capacity to respond to androgens.

Testosterone regulates androgen receptor immunoreactivity in the copulatory, but not courtship, neuromuscular system in adult male green anoles.

Androgens regulate the expression of male reproductive behaviour in diverse vertebrate species, often acting on androgen receptors (AR) to induce structural or functional changes in the nervous system and periphery. Male green anoles possess two sexually dimorphic neuromuscular systems, one controlling throat fan (dewlap) extension, which occurs during courtship, and the other mediating copulatory organ function. Although androgens are required for behavioural activation in both systems, testosterone has differential effects on the neuromuscular morphology. It increases the size of copulatory muscle fibres during the breeding season, but significant effects on dewlap muscle fibre size and motoneurone soma size in either system have not been detected. Corresponding to the lack of testosterone-induced morphological effects in the courtship system, relatively low levels of AR are expressed in the associated motoneurones. The present experiment had two goals, aiming to determine whether: (i) the other courtship and copulatory neuromuscular tissues express AR and (ii) testosterone and/or seasonal environmental changes regulate AR expression. The percentage of AR+ nuclei was evaluated in both the breeding and nonbreeding seasons in gonadally intact adult males (Experiment 1) and in castrated males treated with either testosterone or vehicle (Experiment 2). AR was extensively expressed in the dewlap and copulatory muscles, and in a high percentage of the copulatory motoneurones, but immunoreactivity did not vary across season. Testosterone increased the percentage of AR+ nuclei in the copulatory muscles of both breeding and nonbreeding males but not in the dewlap muscle or copulatory motoneurones. Finally, the target structures for both systems (cartilages and hemipenes) expressed AR in all animals. Therefore, the effects of testosterone on AR immunoreactivity suggest that up-regulation of the receptors may be important for morphological change. However, because all structures investigated in the present experiment expressed AR, the data also indicate that the receptors are involved with other functions.

High levels of estradiol disrupt conditioned place preference learning, stimulus response learning and reference memory but have limited effects on working memory.

The present study investigated the effects of high levels of estradiol in female rats on four different radial arm maze tasks: the hippocampus-dependent spatial working-reference memory task; the prefrontal cortex-hippocampus dependent delayed win-shift task; the striatum-dependent cued win-stay task; and the amygdala-dependent conditioned place preference task. Ovariectomized female rats were injected daily with either 10 microg of estradiol benzoate or sesame oil vehicle approximately 4 h prior to testing. In Experiment 1, treatment with estradiol disrupted learning on the spatial working-reference memory task by increasing the number of reference memory errors to reach criterion. In Experiment 2, treatment with estradiol had no significant effect on the delayed win-shift task. In Experiment 3, treatment with estradiol resulted in impaired performance on a striatum-dependent cued win-stay task. In Experiment 4, treatment with estradiol impaired the acquisition of a conditioned place-preference task. Taken together these findings suggest that high levels of estradiol inhibit reference memory, stimulus response learning, and amygdala-dependent appetitive conditioning while having little effect on working memory.

Predictors of post-rape medical care in a national sample of women.

BACKGROUND: Rape has a negative impact on physical and mental health, health-related behaviors, and health service utilization. Timely medical care is important for preventive services. METHODS: Cross-sectional data were obtained from a larger 2-year longitudinal study, the National Women's Study (NWS). A total of 3006 adult women participated in the final data collection wave of the NWS. During a structured telephone interview, women who reported a most-recent or only rape incident during adulthood were asked about rape characteristics, reporting to authorities, medical care, and rape-related concerns. The main outcome measures were receipt and timing of medical care received after an adult rape, and factors influencing whether or not medical care was received. RESULTS: Of the sample, 214 (7.1%) had experienced a most-recent or only rape as an adult (aged >/=18), and 56 (26.2%) received rape-related medical care following that incident. The final model multivariable logistic regression indicated that reporting the crime to police or other authorities (odds ratio [OR], 9.45; 95% confidence interval [CI]=3. 34-26.70) and fear of sexually transmitted diseases (OR, 8.61; 95% CI=3.12-23.72) were significant predictors of receipt of post-rape medical care. CONCLUSIONS: One in five victims reported an adult rape to police or other authorities; these women were nine times more likely to receive medical care than those who did not. Public health efforts are needed to increase the proportion of rape victims who receive immediate post-rape medical care.

Behavioral feedback regulation of circadian rhythm phase angle in light-dark entrained mice.

Induced and spontaneous wheel running can alter the phase and period (tau) of circadian rhythms in rodents. The relationship between spontaneous running and the phase angle (psi) of entrainment to 24-h light-dark (LD) cycles was evaluated in C57BL/6j mice. With a wheel freely available, psi was significantly correlated with the absolute (r = 0.32) and relative (r = 0.44) amount of activity during the first 2 h of the activity period. When wheels were locked during the first half of the night in LD and then unlocked in constant dark (DD), mice exhibited a delayed psi and lengthened tau compared with mice that had wheels locked during the second half of the night. In DD, tau correlated negatively with total daily activity. To evaluate if wheel running modulates the phase-resetting actions of LD, phase shifts to light pulses were measured at two time points in DD, when daily activity levels differed by 40%. Phase delays to light were 56% greater when activity levels were lower. However, in a counterbalanced follow-up experiment, phase advances and delays to light pulses were not affected by the availability of wheels, although an effect of time in DD was replicated. Spontaneous activity can regulate psi and tau without altering the response of the pacemaker to light.

Food anticipatory activity and photic entrainment in food-restricted BALB/c mice.

The BALB/c mouse was evaluated as a model for the study of entrainment of circadian rhythms by feeding schedules. Mice were housed in a 12:12-h light-dark (LD) environment with food available for 3-5 h/day (5 h before dark onset). Food anticipatory activity (FAA) rhythms were evident in all mice, ranging from robust in some to weak and variable in others. Advancing transients of the end of nocturnal activity were evident in many cases, culminating in a significant shortening of the main bout of nocturnal activity. Transients and contraction of nocturnal activity were not dependent on the expression of FAA. Following restricted feeding, nocturnal activity expanded by a series of delaying transients. On the first day of constant dark (DD) with ad libitum food access following restricted feeding in LD, the phase from which activity free-ran was advanced by comparison with control tests. Transients, compressed nocturnal activity, and advanced phase of free-run suggest that feeding schedules cause phase advancement of light-entrained rhythms in BALB/c mice. When restricted feeding was imposed in DD, several mice expressed robust FAA concurrent with a free-running activity component. In some cases, free-running rhythms entrained to feeding time, and in other cases, the period of the free run lengthened toward 24 h. These data show that restricted feeding in BALB/c mice can engage a circadian mechanism driving FAA rhythms and can also modulate the phase of photic entrainment, possibly by a direct entraining effect on the light-entrained rhythm. The BALB/c mouse strain, in several respects, appears to be a useful model for the study of scheduled feeding and circadian rhythms.

Adolescents and sexually transmissible diseases.

Sexually transmitted infections are alarmingly common among adolescents in the United States. Behavioral, biologic, and health care access factors place adolescent girls at high risk for many common infections. This population also experiences a disproportionate burden related to the sequelae of STDs. The costs are high for the individual adolescent and for society. Clinicians treating adolescent girls should address the general lack of knowledge about the risks and consequences of STDs. They should be prepared to offer confidential and comprehensive counseling, screening, and treatment according to established guidelines. Office policies that protect adolescent confidentiality are an important component in providing effective care. Adolescence is a period during which lifelong health behaviors are established. It provides a critical opportunity for promoting responsible behaviors and reducing risks through health promotion and prevention strategies.

A randomized, double-blind, placebo-controlled trial of 5-fluorouracil for the treatment of cervicovaginal human papillomavirus.

OBJECTIVE: To compare intravaginal 5-fluorouracil (5-FU) and placebo for the treatment of cervical and/or vaginal human papillomavirus (HPV). METHODS: A randomized, placebo-controlled trial was performed. Women with HPV detected visually or by Papanicolaou (Pap) test and confirmed by colposcopic biopsy were randomized to receive either intravaginal 5-FU cream or an intravaginal placebo cream. Women with cervical or vaginal intraepithelial neoplasia were excluded. The primary outcome measure was cytologic regression of HPV as determined by Pap test screening 4 to 6 months after treatment. The secondary outcome was cytologic evidence of disease progression at both the 4-6-month and 12-month follow-up evaluations. Data were analyzed using the Chi square test with significance established at P < 0.05. RESULTS: A total of forty patients were randomized, and thirty patients had a follow-up Pap test 4 to 6 months after treatment. Of those patients treated with 5-FU, 28% demonstrated regression of HPV on cytologic evaluation, compared with 69% of those treated with placebo (P < 0.05). Twelve-month follow-up cytology was available from 18 of the study participants. There were no significant differences in the frequency of cytologic progression or regression between groups at 12 months. CONCLUSION: Four to six months post treatment, the use of intravaginal 5-FU for the treatment of cervical or vaginal HPV is associated with a lower rate of regression than the use of placebo.

Morphine-induced activity attenuates phase shifts to light in C57BL/6J mice.

Circadian rhythms can be phase shifted and entrained by daily schedules of light and by non-photic stimuli such as locomotor activity. Relatively little is known of how photic and non-photic stimuli interact to regulate circadian phase. Morphine injections were used to examine the effects of locomotor activity on phase shifts to light pulses in mice free-running in constant dark. Morphine injections scheduled early or late in the active period (subjective night) induced hyperactivity, but did not induce phase shifts. Light pulses late in the subjective night induced phase advance shifts that were significantly attenuated (63% smaller, p<0. 01) by pretreatment with morphine. This inhibitory effect of morphine on light-induced phase advances was blocked by preventing mice from running for 6 h after the injections. Light pulses early in the subjective night induced phase delay shifts that were only weakly attenuated (15% smaller, p=0.06) by morphine. These results demonstrate behavioral inhibition of light-induced phase resetting of circadian rhythms in mice, and suggest that the strength of this effect may be phase dependent, although other interpretations are possible.

Treating health concerns within the context of childhood sexual assault: a case study.

A cognitive-behavioral treatment package used to treat physical health concerns and fears in a young adult woman with a history of child sexual assault is described. Treatment targeting health concerns was used as an adjunct to treatment for posttraumatic stress disorder (PTSD). Treatment included psychoeducation, systematic desensitization, and stress-innoculation training. The treatment helped reduce the patient's health concerns, including stomach cramps and fear of medical examinations. Theoretical issues underlying treatment of health concerns as related to PTSD avoidance behavior are discussed.

Serotonin and feedback effects of behavioral activity on circadian rhythms in mice.

Wheel running activity can shorten the period (tau) of circadian rhythms in rats and mice. The role of serotonin (5HT), in this effect of behavior on circadian pacemaker function, was assessed by measuring tau during wheel-open and wheel-locked conditions in mice sustaining neurotoxic 5HT lesions directed at the suprachiasmatic nucleus (SCN). Intact mice exhibited a significant lengthening of tau (approximately 10 min) within 3 weeks when running wheels were locked. Mice with immunocytochemically confirmed 5HT depletion showed significantly longer tau than intact mice during wheel access, and did not show a significant change in tau up to 6 weeks after wheels were locked. In these mice, variability of tau across wheel access conditions was similar in magnitude to tau variability in intact mice at two time points without wheel access (+/- 3 min). 5HT-depleted mice also exhibited significantly longer activity periods (alpha), and a significantly delayed peak of activity within alpha. Previous studies show that a delayed peak of activity within alpha is associated with longer tau. Group differences in tau, and apparent failure of wheel-locking to lengthen tau in mice with 5HT lesions, may thus be due to loss of a serotonergic behavioral input pathway to the SCN, or to a lesion-induced change in the waveform of the activity rhythm.

Follow-up of sexual assault victims.

OBJECTIVES: Our goal was to describe medical findings and health-related concerns of sexual assault victims who returned for follow-up and to assess demographic and assault characteristics of victims who used follow-up services compared to those who did not. STUDY DESIGN: This study is a retrospective cohort analysis involving records from two sources: the acute sexual assault evidentiary examination and the SAFE (Sexual Assault Follow-up Evaluation) Clinic visit. Data were extracted from the records of 389 adolescent and adult victims who reported an acute sexual assault and underwent a complete evidentiary examination between January 1, 1995, and June 30, 1997. Descriptive statistics were generated on demographic and historical information, assault characteristics, and medical and laboratory findings. For the subgroup that presented for follow-up, additional descriptive statistics were generated to describe their interim history, concerns, medical outcomes, treatments, and psychosocial functioning. Chi2 analyses were used to identify differences in the group that returned for follow-up compared with the group that did not. Statistical significance was defined as P < .05. RESULTS: There were no differences in age, race, or perpetrator factors between patients who used follow-up services and patients who did not return to the SAFE Clinic. Similarly, there were no other assault characteristics, relationships, or physical examination findings that were associated with follow-up patterns. A total of 31% (n = 122) of all sexual assault victims returned for a follow-up visit. Physical complaints were reported by 42.6%, but 98.0% had normal findings at a general examination, and 94.8% had a normal result of gynecologic examination. Pregnancy and sexually transmitted diseases, including human immunodeficiency virus, were identified through the follow-up clinic. Since the assault, 49.2% had been sexually active, 10% with multiple partners and 73.3% without consistent condom use. Disturbances in sleep, sexual function, and appetite were commonly reported among victims at follow-up. Numerous assault-related fears were reported. CONCLUSIONS: Among recent rape victims, follow-up rates are low, and there are no factors that correlate with the use of follow-up services. Those who do come in for follow-up have physical complaints and health-related concerns that are related to their recent assault, but most have normal physical findings. Efforts to reach sexual assault victims will require aggressive and innovative strategies to remain in contact with women and girls after rape.

Rape-related pregnancy: estimates and descriptive characteristics from a national sample of women.

OBJECTIVE: We attempted to determine the national rape-related pregnancy rate and provide descriptive characteristics of pregnancies that result from rape. STUDY DESIGN: A national probability sample of 4008 adult American women took part in a 3-year longitudinal survey that assessed the prevalence and incidence of rape and related physical and mental health outcomes. RESULTS: The national rape-related pregnancy rate is 5.0% per rape among victims of reproductive age (aged 12 to 45); among adult women an estimated 32,101 pregnancies result from rape each year. Among 34 cases of rape-related pregnancy, the majority occurred among adolescents and resulted from assault by a known, often related perpetrator. Only 11.7% of these victims received immediate medical attention after the assault, and 47.1% received no medical attention related to the rape. A total 32.4% of these victims did not discover they were pregnant until they had already entered the second trimester; 32.2% opted to keep the infant whereas 50% underwent abortion and 5.9% placed the infant for adoption; an additional 11.8% had spontaneous abortion. CONCLUSIONS: Rape-related pregnancy occurs with significant frequency. It is a cause of many unwanted pregnancies and is closely linked with family and domestic violence. As we address the epidemic of unintended pregnancies in the United States, greater attention and effort should be aimed at preventing and identifying unwanted pregnancies that result from sexual victimization.

Subdermal contraceptive implant (Norplant) continuation rates among adolescents and adults in a family planning clinic.

STUDY OBJECTIVE: The purpose of this study was to prospectively evaluate the continuation rate of subdermal contraceptive implants (Norplant) among adolescent (< 20 years) and adult (> or = 20 years) women in the clinic population of a tertiary care medical center. DESIGN: Adolescents and adults desiring contraception for greater than a 6-month period were eligible for Norplant insertion. Prior to insertion, personal counseling and extensive education were provided. Following insertion, rapid access, personal counseling, and prompt treatment were provided for complications that occurred. Device removal was available to all individuals at any time upon patient request or if side effects could not be ameliorated. Patient demographic, historical, physical, and follow-up data were entered into a computer data base. RESULTS: Since February 1991, 1800 subdermal contraceptive implants were inserted. Of these 1688 patients were prospectively followed, providing 45,576 women-months of data for analysis. Adolescents comprised 40% of the study population. Over a 50-month period, the cumulative continuation rate for adolescents was 93.6%, and for adults it was 91.1%. The mean duration of use among adolescents was 26.5 months and for adults was 27.6 months. CONCLUSIONS: There was no significant difference between adolescent and adult subdermal contraceptive implant continuation rates for up to 50 months of use. In this patient population, high continuation rates may result from a combination of extensive patient education and intensive surveillance by a well-trained and dedicated multidisciplinary staff. When all patients are enrolled in a program that provides aggressive education and supportive follow-up, age is not a significant factor in continuation rates.

Quantitative increases in surgical house officer clinical activity as the basis for increased work loads in a university hospital.

BACKGROUND: House officer (HO) work loads, particularly work hours, have been the subject of considerable controversy. The hypothesis of this study was that a disproportionate work burden has been placed on HOs in teaching hospitals because of increased obligatory clinical activities and increased educational expectations. METHODS: Factors directly and indirectly affecting care of surgical patients were related to individual HO efforts at the University of Michigan from 1981 to 1991. Data regarding clinical activity and support services were abstracted for analysis from hospital year-end reports, personnel rosters, and educational logs and correlated with the number of surgical HOs. RESULTS: The total numbers of HOs in the Department of Surgery were relatively constant (122 +/- 4) throughout the study interval. Increases that occurred in annual hospital admissions (7615 to 10,651), discharges (7909 to 11,176), clinic visits (53,251 to 86,111), total operations (6789 to 16,526), and operating room hours (24,175 to 62,429) were significant (r greater than 0.9; p less than 0.001 in each category). The acuity of inpatient hospital care increased twofold, as measured by a case mix index, and was accompanied by a 125% increase in the number of surgical intensive care unit beds. During the study period, department of surgery faculty increased 49% (59 to 88), clinical nursing staff increased 118% (821 to 1794), hospital administrative staff increased 59% (2086 to 3320), and hospital support staff increased 53% (4134 to 6342). The number of students in each University of Michigan Medical School class, a group that might defray certain HO work loads, decreased significantly by 16% (226 to 189) during this time (r = -0.76; p less than 0.02). CONCLUSIONS: Disproportionate increases in work demands have been placed on surgical HOs compared with other health care team members during the past decade. Calculated work loads increased from 91.2 hr/wk/HO in 1981 to 110.9 hr/wk/HO in 1991. Balancing the increasing service activities with educational needs of surgical HOs remains a substantial challenge to be addressed by educators.