Estimating Potency for the E max-Model Without Attaining Maximal Effects

The most widely applied model relating drug concentrations to effects is the E_max model. In practice, concentration–effect relationships often deviate from a simple linear relationship but without reaching a clear maximum because a further increase in concentration might be associated with unacceptable or distorting side effects. The parameters for the E_max model can only be estimated with reasonable precision if the curve shows sign of reaching a maximum, otherwise both EC₅₀ and E_max estimates may be extremely imprecise. This paper provides a solution by introducing a new parameter (S₀ ) equal to E_max/EC₅₀ that can be used to characterize potency adequately even if there are no signs of a clear maximum. Simulations are presented to investigate the nature of the new parameter and published examples are used as illustration.     

Effects of androgens and estrogens on the vasopressin and oxytocin innervation of the adult rat brain

Recently we reported that castration of rats eliminates vasopressin immunoreactivity in the lateral septum and other areas that appear to receive vasopressin innervation from the bed nucleus of the stria terminalis. Testosterone treatment counteracts this effect of castration. In the present study, we investigated whether this action of testosterone depends on its androgenic or estrogenic metabolites by treating long-term castrated rats with estradiol (E) and/or 5 alpha-dihydrotestosterone (DHT) or testosterone. The brains were then processed for immunocytochemistry or radioimmunoassay. DHT did not increase vasopressin staining in the lateral septum, although it fully restored the size of the seminal vesicles. E did restore the original fiber density, but individual fibers stained more weakly than in sham-operated males. Only treatment with both E and DHT fully restored the vasopressin innervation. This pattern was also reflected in the radioimmunoassay data. The vasopressin content of the lateral septum decreased about 90% after castration but was fully restored by either testosterone or E + DHT treatment. E alone, however, was only half as effective as E + DHT. The treatments had no effect on the oxytocin content of the septum, or on the vasopressin or oxytocin content of the dorsal vagal complex. The results suggest that E mediates most of the effects of testosterone on the vasopressin innervation of the lateral septum. DHT enhances the response to E but has little effect on its own.     

Alpha-methyldopa induces a naltrexone-insensitive antinociception and hypomotility in rats.

1. This study served to investigate whether endogenous opioid peptides play a role in the putative antinociceptive and the sedative actions of alpha-methyldopa. 2. In conscious normotensive rats, alpha-methyldopa induced hypotension, starting around 1 h and reaching a maximum 3-4 h after administration. Pretreatment with naltrexone resulted in an inhibition of alpha-methyldopa-induced hypotension. 3. alpha-Methyldopa dose-dependently increased hot plate latency which became evident after a 4 h lag period and reaching a maximum effect at 6 h. The antinociceptive effect of alpha-methyldopa was not affected by naltrexone. 4. In a small open field, alpha-methyldopa dose-dependently suppressed locomotion and sniffing behaviour. These effects of alpha-methyldopa were apparent 1 h after administration and were naltrexone-insensitive. 5. No changes in the level of beta-endorphin-like immunoreactivity in plasma and cerebrospinal fluid were observed after administration of alpha-methyldopa. 6. The results indicate that endogenous opioid peptides are involved in the hypotensive action of alpha-methyldopa but not in alpha-methyldopa-induced hypomotility and antinociception.     

Changes in anti-Müllerian hormone serum concentrations over time suggest delayed ovarian ageing in normogonadotrophic anovulatory infertility

BACKGROUND: Anti-Müllerian hormone (AMH), produced by growing pre-antral and early antral ovarian follicles, has been shown to be a useful marker for ovarian ageing. Serum AMH concentrations are elevated during reproductive life in anovulatory women, especially in those patients exhibiting polycystic ovaries (PCO). The current study was designed to investigate whether the decrease in AMH serum concentrations over time is different comparing women with normogonadotrophic anovulation [World Health Organization (WHO) group 2 (including polycystic ovary syndrome (PCOS)] and normo-ovulatory controls. METHODS AND RESULTS: AMH serum levels were assessed on two occasions in 98 patients suffering from WHO 2 anovulatory infertility as well as in 41 normo-ovulatory premenopausal women. Median time interval between both visits was 2.6 years (range 0.3-9.0) for WHO 2 patients compared with 1.6 years (range 1.0-7.3) in controls. Serum AMH concentrations were significantly (P < 0.0001) elevated on both occasions in WHO 2 patients (AMH1, median = 7.5 microg/l, range 0.1-35.8; and AMH2, median = 6.7 microg/l, range 0.0-30.6) compared with controls (AMH1, median = 2.1 microg/l, range 0.1-7.4; and AMH2, median = 1.3 microg/l, range 0.0-5.0). Regression analysis, corrected for age, indicated a significant relative decrease in serum AMH concentrations over time for both groups (P < 0.001). However, the decline in serum AMH in WHO 2 patients was significantly less compared with controls (P = 0.03). CONCLUSION: The present longitudinal study shows that serum AMH concentrations decrease over time both in women presenting with WHO 2 anovulatory infertility and in normo-ovulatory controls. The decrease in WHO 2 patients is less pronounced despite distinctly elevated concentrations. This observation may suggest retarded ovarian ageing and hence a sustained reproductive life span in these patients.     

The proximal border of the human respiratory unit,as shown by scanning and transmission electron microscopy and light microscopical cytochemistry

The muscles of the pectoral girdle in domestic animals attach the forelimbs to the trunk and function as the suspensory apparatus. In the present study the composition of the pectoral girdle musculature of sheep by myofiber types was examined. Myofibers showing a strong reaction for alkali-stable myosin ATPase were classified into fast-twitch/glycolytic (FG) myofibers with a weak activity for NADH tetrazolium reductase (NADH-TR) and fast-twitch/oxidative/glycolytic (FOG) myofibers with a moderate and strong NADH-TR activity. Myofibers showing a weak reaction for alkali-stable myosin ATPase and a strong activity for NADH-TR were classified as slow-twitch/oxidative (SO) myofibers. The SO myofibers that showed a granular and striped pattern of diformazan deposits in NADH-TR activity were classified as SO-1 myofibers, whereas the SO myofibers characterized by a reticular pattern of diformazan deposits were classified as SO-2 myofibers. The trapezius, rhomboideus cervicis, and pectoralis descendens muscles situated superficially in the cranial regions of the back and chest had about 50% SO (SO-1 plus SO-2) myofibers. The deeply situated serratus ventralis cervicis and thoracis muscles had 37.5% SO myofibers. These five muscles included more SO-2 myofibers with large diameters than did all other muscles, and had about 50% and more cross-sectional area of SO myofibers. The other muscles had less than 32% SO myofibers and fewer SO-2 myofibers. The FOG and FG myofibers accounted for 50% or less in the muscles examined. Many muscles of the pectoral girdle had many fast-twitch (FOG plus FG) myofibers; they seem to meet locomotory requirements. In the pectoral girdle musculature, the SO myofibers were not necessarily distributed more in the deep regions than in the superficial regions. The distribution of SO myofibers appears to meet postural requirements for stabilizing the shoulder and brachium and for supporting the trunk.     

Follicle stimulating hormone measured in unextracted urine throughout the menstrual cycle correlates with age and ovarian reserve

BACKGROUND: A method was previously described to measure FSH reliably in unextracted urine. The aim of the current study was to establish the course of FSH measured in urine throughout the cycle. METHOD: Daily urinary FSH (uFSH) concentrations were determined in 14 regularly menstruating volunteers aged 23-39 years during one complete menstrual cycle. RESULTS: In each subject, mean daily uFSH measured in urine, as gold standard for FSH tone, correlated significantly with FSH in early follicular phase fixed to menstruation on cycle day 3 (r = 0.75, P = 0.002), or fixed to ovulation 9 days before the pre-ovulatory FSH surge (r = 0.87, P = 0.0001), or when selected as being the highest follicular phase value (r = 0.91, P = 0.0001). Age correlated significantly with mean daily uFSH (r = 0.67, P = 0.009), highest follicular phase uFSH (r = 0.60, P = 0.024), uFSH on cycle day 3 (r = 0.80, P = 0.0006), and uFSH 9 days before FSH surge (r = 0.65, P = 0.0016). The uFSH was also measured on cycle day 3 in 104 IVF patients in a cycle prior to pituitary down-regulation. The uFSH correlated significantly with numbers of follicles (P = 0.02) and oocytes (P = 0.024). CONCLUSION: It is concluded that cycle day 3 uFSH is a good reflection of the mean uFSH of the complete cycle, and there is a highly significant correlation between uFSH and age and ovarian reserve. Measurement of FSH in urine on cycle day 3 seems to be a reliable and non-invasive tool for determining ovarian reserve in IVF.     

Colonic mucosal changes in nude mice associated with orthotopic xenografts of human colon cancer cells

Summary We used the nude mouse tumour xenograft model to study the pathogenesis of mucosa alterations in the large bowel surrounding a carcinoma. In mouse colonic mucosa overlying HT-29 colonic carcinoma xenografts in the caecum, the crypts were elongated in comparison with those in distant mucosa and also frequently showed a shift towards sialomucin production. These features, which are comparable with socalled transitional mucosa (TM) in man, were absent in control animals inoculated with Indian Ink instead of HT-29 cells. Although the localization of the proliferative cell compartment in mouse colonic mucosa overlying HT-29 xenografts appeared to be confined to the lower half of the crypt as in normal mucosa, the relative length of the DNA synthesizing cell compartment along the crypts was slightly elongated. These data strongly suggest that TM should be regarded as a secondary phenomenon rather than a premalignant change in large intestinal epithelium and that higher proliferative activity of epithelial cells contributes little to the elongation of crypts in TM.     

Simultaneous mapping of human papillomavirus integration sites and molecular karyotyping in short-term cultures of cervical carcinomas by using 49-color combined binary ratio labeling fluorescence in situ hybridization

Infection with high-risk type human papillomavirus (HPV) is a necessary causal factor in the pathogenesis of cervical carcinoma. In most invasive cervical cancers, HPV is integrated in the host cell genome, and additional genetic aberrations are observed among which are chromosomal aberrations. To analyze in detail such often complex chromosomal changes and simultaneously map HPV integration sites, we extended the multiplicity of the combined binary ratio labeling fluorescence in situ hybridization (COBRA-FISH) technique to 49 by inclusion of a large Stokes' shift fluorochrome as the third binary label. The technique allows mapping of the integrated HPV genome in the context of p- and q-arm COBRA-FISH, with a sensitivity of one copy of the HPV genome as tested for HPV 16 in SiHa cells. We investigated the molecular karyotypes and integration patterns of HPV types 16 and 18 in metaphase spreads from short-term cultures of primary cervical carcinomas (n=5). Of the tested cervical carcinomas, two contained integrated HPV at 8q24, one of which in addition harbored the integrated virus near a translocation breakpoint. Two carcinomas had integrated HPV at 17q21 through 23 in a morphologically normal chromosome 17. One carcinoma contained HPV at 1q42 in a morphologically normal chromosome 1. Our data illustrate the efficacy of 49-color COBRA-FISH to resolve complex karyotypes and simultaneously map specific sequences in metaphases obtained from short-term solid tumor cultures.     

Trying to stop smoking: Effects of perceived addiction,attributions for failure,and expectancy of success

This paper reports the results of a postal questionnaire completed by 2343 smokers who had contacted a television company for help with stopping smoking. Of these, 1848 (78.9%) completed a follow-up questionnaire 1 year later. This indicated that 797 had tried to stop, 709 had tried to cut down, and 164 had become abstinent. Analyses show that the intention to try to stop smoking was dependent not only on the perceived health benefit, but also on the subjects' confidence that they would succeed if they tried to stop. As predicted by Weiner's [(1979). J. Educ. Psychol.71: 3–25] model of achievement motivation, those who attributed other smokers' failures at quitting to stable factors had lower expectancies of success, as had those who saw themselves as more addicted. When the follow-up data are considered, reported attempts at quitting were strongly related to previously declared intentions, and reported abstinence was related to previous confidence (expectancy of success) and perceived addiction. There is no support for hypotheses concerning self-other differences in attribution, or defensive attribution, in subjects' attributions for their own failures at cessation. Implications for antismoking interventions are discussed.This research was facilitated to various extents by grants from the British Council, the Department of Health and Social Security, the Medical Research Council, and the Social Science Research Council, London. When the data were collected, all authors were at the Addiction Research Unit, Institute of Psychiatry, University of London.