Rat estrous cycle influences the sexual diergism of HPA axis stimulation by nicotine

We previously reported that female rats had significantly greater hypothalamic-pituitary-adrenal (HPA) axis responses to cholinergic stimulation by nicotine (NIC) than did male rats. Females in defined estrous cycle stages, however, were not studied because of sample size limitations. We further explored this finding by determining HPA axis responses to two doses of NIC in female rats (N = 101) during different estrous cycle stages, and in males (N = 69). NIC doses were: 0.3 mg/kg, which provided the greatest female-male difference in the earlier study, and 0.5 mg/kg, which stimulated the HPA axis similarly in the two sexes. Plasma AVP, ACTH, and corticosterone were measured. Proestrous and estrous females had higher ACTH responses to NIC (0.3 mg/kg) compared to metestrous and diestrous females, and compared to males. ACTH responses to NIC (0.5 mg/kg) were similar, regardless of estrous cycle stage or sex. Males had higher AVP responses to both NIC doses compared to females in all estrous cycle stages. Corticosterone responses followed the ACTH responses, except that females in all estrous stages started from a higher corticosterone baseline compared to males. These results are similar to our earlier findings across the estrous cycle with non-specific cholinergic stimulation by physostigmine and suggest that the nicotinic system contributes to the differential HPA axis responses to cholinergic challenge across the estrous cycle.     

Successive depth variations in microvascular distribution of rat somatosensory cortex

Although hemodynamic-based functional brain imaging techniques are powerful tools to explore the brain functions noninvasively, hemodynamic-based signal is strongly affected by spatial configuration of microvessels. Understanding the quantitative relations between microvascular structure and functional activity is therefore significant to make a valid signal interpretation for the imaging techniques. In the present study, we evaluated depth profiles of microvascular distributions in rat somatosensory subfields (barrel field, forelimb region, trunk region and hindlimb region) and characterized depth variations in microvascular structures, such as locations, lengths and directions of microvessels, throughout the cortical layers (I-VI). To obtain the accurate microvascular structure, we made a customized casting method by using confocal laser scanning microscope. We observed that microvascular distribution successively varied throughout the cortical layers (I-VI) and that the maximum number density of microvessels was consistently found in middle layers (III-V). In addition, superficial layers had relatively long microvessels, almost perpendicular to the cortical surface, whereas middle layers had short microvessels propagating in all directions. These regional differences in microvascular structures were closely related to the somatosensory subfields, e.g., barrel field was the greatest number density of microvessels among the investigated subfields. Based on these observations, we compared microvascular profiles with previously reported distribution patterns of tissue partial pressure of oxygen (pO2). The results showed that tissue pO2 was correlated with microvascular distribution in some but not all of the subfields. This finding shows that detailed microvascular profiles are helpful to investigate causal relationships between microvascular structure and functional activities in cerebral cortex.     

Sex and estrus cycle differences in the modulatory effects of morphine on seizure susceptibility in mice

PURPOSE: To evaluate the effects of sex and estrus cycle on biphasic anticonvulsant and proconvulsant modulation of seizure threshold by morphine. METHODS: The threshold for the clonic seizures (CST) induced by acute intravenous administration of gamma-aminobutyric acid (GABA)-antagonist pentylenetetrazole (PTZ) was assessed in male and female mice. Estrus cycle was assessed by vaginal smears. The effect of removing circulating sex hormones was assessed by gonadectomy. RESULTS: At baseline, diestrus females had a higher CST compared with males and estrus females. Morphine at lower doses (0.5-3 mg/kg) had a significant anticonvulsant effect in males and estrus females compared with that in vehicle-treated controls, whereas female mice in diestrus phase showed a relative subsensitivity to this effect. Morphine at higher doses (30 and 60 mg/kg) significantly decreased CST in males and diestrus females, with less relative effect in estrus mice. In both phases, morphine exerted stronger effects in males compared with females. Ovariectomy brought the baseline CST to the male level and resulted in significant expression of both phases of morphine effect but did not abolish the sex difference in responsiveness to morphine. CONCLUSIONS: The biphasic modulation of seizure threshold is subject to both constitutive sex differences in sensitivity to morphine and hormonal fluctuations during the estrus cycle.     

The juvenile three-spined stickleback (Gasterosteus aculeatus L.) as a model organism for endocrine disruption II--kidney hypertrophy, vitellogenin and spiggin induction

This study investigated the suitability of juvenile three-spined sticklebacks, Gasterosteus aculeatus L., for detecting both androgen- and oestrogen-induced endocrine disruption. The investigated endpoints were kidney hypertrophy and the induction of the protein markers spiggin and vitellogenin. Juveniles were exposed to steroid hormones 17β-oestradiol (E2: nominal 0.01, 1.0 and 10 μg/L), 17-ethinylestradiol (EE2: nominal 0.05 μg/L) and 17-methyltestosterone (MT: nominal 1.0 μg/L) from the day of hatching until the termination of the experiments between 39 and 58 days after hatching. E2 (10 μg/L) and MT were applied during different time windows: (a) 14 days after hatching only and (b) continuously with start 14 days after hatching.

Kidney hypertrophy is an androgen-dependent secondary sexual character in adult male sticklebacks and corresponds to the production of the glue protein spiggin during the breeding season. The kidneys were hypertrophied and spiggin levels were elevated in juvenile sticklebacks after treatment with MT. Paradoxically, slightly elevated spiggin levels and kidney hypertrophy were observed also in fish treated with high dose E2. Levels of vitellogenin, the oestrogen-inducible yolk precursor protein, were elevated in juvenile sticklebacks after E2 medium and high dose and EE2 treatment.

The tested endpoints are suitable for the study of endocrine disruption in juvenile sticklebacks, a fish species that is easy to handle in laboratory and relevant for temperate geographical regions.     

A cost-related approach for evaluating drug development programs

Most pharmaceutical statisticians make a contribution to drug development at the study level by designing and analysing clinical studies. There is less involvement at the drug project level, especially when it comes to making a strategic decision for a drug development program. Motivated by the assessment of drug safety, this paper presents a new decision rule on whether or not to continue developing a new drug based on a cost function. The cost function takes into account both type I and type II errors in a decision making problem. It also incorporates both the cost and benefit from a drug development program. This cost-benefit approach enables company senior management to evaluate a drug program objectively and make decisions in a quantitative and rational manner. The probabilities of making correct decisions are illustrated by using a real data example.     

Impact of a course on human sexuality and adolescence

Obective: This study was conducted as part of a course on Human Sexuarity and Adodescence for school childrenmèt/ to ascertain the prior knowledge of children, source of their knowledge and whether the course was a felt need of the childrenMethod : Students were given a questionnaire before the course. Few selected questions were asked again after the last session. The course was conducted in a private co-educational. English medium school in urban Bangalore involving 392 students 13–15 years of age. The course was designed by the authors and dealt with anatomy, physiology, social and psychological aspects of growing up, HIV and contraception.Results : 55–70% of class VIII; IX and X students had learnt about sex from friends, 30% from movies, 15% from text books and only 10% from parents. Misconceptions about anatomy, childbirth, HIV were common. 90% of tenth class students felt that education in human sexuality was necessary.Conclusion: In spite of chapters on reproduction in textbooks, children turn to peers or media to gather information on sexuality. Education in human sexuality is nequired in our schools, as this need is currently not being addressed adequately in our society.     

Relation of intra-abdominal fat distribution to metabolic disorders in nonobese patients with polycystic ovary syndrome

OBJECTIVE: To investigate the relation between intra-abdominal fat distribution and metabolic disorders in nonobese patients with the polycystic ovary syndrome (PCOS). DESIGN: Prospective case-control study. SETTING: University-based hospital. PATIENT(S): Thirty nonobese patients with PCOS and 30 lean women with regular menstrual cycles (controls). All participants had a body mass index < 25kg/m(2). MAIN OUTCOME MEASURES: Subcutaneous and intra-abdominal visceral and preperitoneal fat thicknesses were assessed by ultrasonography. Glucose tolerance and insulin sensitivity were evaluated by standard 75-g oral glucose tolerance test and area-under-the-curve analysis. Serum hormones and lipid profile were measured. RESULT(S): The mean preperitoneal and visceral fat thicknesses were significantly greater in nonobese patients with PCOS. Subcutaneous fat mass was similar between the PCOS and control groups. Nonobese patients with PCOS had glucose intolerance, hyperinsulinemia, and dyslipidemia, manifested by high serum levels of triglyceride, total cholesterol, and high-density lipoprotein (HDL) levels and low serum low-density lipoprotein (LDL) levels. No correlation existed between subcutaneous fat thickness and the metabolic variables in nonobese patients with PCOS. However, serum triglyceride levels correlated with visceral fat and preperitoneal fat thickness. The mean HDL level correlated negatively with visceral fat and preperitoneal fat thickness. The area under the curve for insulin and mean fasting insulin levels correlated positively with visceral fat thickness. In multiple regression analysis, visceral fat thickness contributed significantly to high serum triglyceride and fasting insulin levels. CONCLUSION(S): Intra-abdominal preperitoneal and visceral fat accumulation may contribute to the development of glucose and lipid metabolism disorders in nonobese patients with PCOS.     

Headache following cervical sympathectomy and results of a blood flow study in the cat

BACKGROUND: A patient developed severe, continuous, unilateral headache that was "vascular" in nature, following cervical sympathectomy. OBJECTIVE: To determine the changes in cranial blood flow in the cat following lesioning and stimulation of the cervical sympathetic nerve. METHOD: Carotid blood flow was determined by electromagnetic flowmetry and its tissue distribution by intra-arterial injection of 15-microm radioactive microspheres. RESULTS: Following sympathetic lesioning, an increase in carotid blood flow was observed and reversed with stimulation. The distribution of carotid blood flow changed for the brain only, maintaining relatively constant tissue perfusion. CONCLUSION: An increase in cerebral blood flow could not have accounted for the sympathectomy-induced headache. Dilation of major cerebral arteries and cranial noncerebral vasodilation probably constitutes its mechanism.     

Tissue distribution of a new photosensitizer ATX-S10Na(II) and effect of a diode laser (670 nm) in photodynamic therapy

The aims of the present study were to analyse the quantitative tissue distribution of ATX-S10Na(II) and to investigate the maximal effect of a diode laser and the irradiation conditions required to obtain this effect in photodynamic therapy (PDT) with ATX-S10Na(II). Spectrofluorometry was used to obtain quantitative tissue distribution of ATX-S10Na(II) in Colon 26 carcinoma-bearing mice as a function of time following administration. Next, transplanted tumours of mice with or without ATX-S10Na(II) were treated with the diode laser under conditions in which power density and irradiation time were varied. Tumour tissue concentrations of ATX-S10Na(II) were higher than in all tissues at all intervals following administration. The uptake of ATX-S10Na(II) by most tissues was rapid, with maximal concentrations occurring 1 h after i.v. injection, and ATX-S10Na(II) was almost excreted within 24 h after administration. The maximal depth of necrosis induced by PDT in the treated tumour was 7.9 mm under conditions in which power density was 160 mW/cm² and total dose was above 100 J/cm². PDT with ATX-S10Na(II) and the diode laser is useful for the treatment of superficial cancers.     

Androgen and estrogen receptors in the human corpus cavernosum penis: immunohistochemical and cell culture results

Despite the central and peripheral effects of androgens on the nervous system, the local effects of androgens in the corpus cavernosum penis and their importance for erectile function is still unclear. In this study corpus cavernosum biopsies of eight adult potent patients, aged 19–63 years, undergoing penile deviation surgery (group A) and 12 patients undergoing male-to-female transsexual surgery (group B) were immunostained for nuclear androgen and estrogen-alpha receptors. Additionally, primary corpus cavernosum endothelial cell cultures were obtained from six transsexual patients and exposed to testosterone, dihydrotestosterone, estradiol and progesterone likewise for 7 days. Total cell count was performed and cell metabolic activity was measured by a tetrazolium salt-based assay. Androgen and estrogen-alpha receptors were detected in stromal as well as in endothelial cells. Of all cell nuclei, 74.9% (SD 16.4) in group A and 63.5% (SD 17.1) in group B were positively stained for androgen receptors. The respective percentage of estrogen receptors was 11% (SD 9.5) and 21.2% (SD 12.6). An age-dependent difference in receptor distribution was not observed in either group. In the cell culture system only cultures exposed to testosterone and dihydrotestosterone showed a dose-dependent increase of cell metabolic activity compared to the cultures supplemented with estradiol and progesterone. The significant and age-independent high androgen and low estrogen-alpha receptor distribution found in both groups suggests a possible peripheral effect of androgens at the level of the corpus cavernosum penis in adult humans. This is supported by the observed effect of testosterone and dihydrotestosterone on cell count and endothelial cell metabolism in our cell culture system. The role of estrogens remains unclear.