Variant progesterone receptor mRNAs are co-expressed with the wild-type progesterone receptor mRNA in human endometrium during all phases of the menstrual cycle.

Progesterone receptor (PR) variant mRNAs in human endometrium could encode proteins with the potential to alter progesterone action in states of normal and abnormal endometrial development. We have assessed the expression levels of mRNA for the wild-type PR and splice variants of PR mRNA lacking exon 4 (del-4 PR), exon 6 (del-6 PR), exons 4 and 6 (del-4&6 PR), and part of exon 4 (del-p4 PR) or part of exon 6 (del-p6 PR) in the human endometrium throughout menstrual cycle development. Eighty-eight endometrial specimens (47 proliferative, 41 secretory) were collected from patients undergoing hysterectomy for benign gynaecologic causes. Measurements by RT-PCR indicated that mRNAs for wild-type PR, and splice variants del-4 PR, del-6 PR, del-4&6 PR, del-p6 PR, and a novel del-p4 PR were detected in all endometrial specimens throughout the menstrual cycle. Higher levels of wild-type PR and all PR variant mRNAs were found in the early and mid-proliferative endometrial phases than in secretory endometrium. The relative expression of mRNA for all PR variants compared to wild-type PR mRNA, however, did not change through all stages of endometrial development. We, therefore, found no evidence of differential co-expression of the PR variants compared with wild-type PR during normal menstrual development. Future studies will determine if the expression profile of PR variant mRNAs will be different in the endometrium of patients with infertility, recurrent pregnancy loss, or endometrial adenocarcinoma.

Uterine artery embolization for symptomatic uterine myomas.

OBJECTIVE: To evaluate the role of uterine artery embolization as treatment for symptomatic uterine myomas. DESIGN: Medline literature review, cross-reference of published data, and review of selected meeting abstracts. RESULT(S): Results from clinical series have shown a consistent short-term reduction in uterine size, subjective improvement in uterine bleeding, and reduced pain following treatment. Posttreatment hospitalization and recovery tend to be shorter after uterine artery embolization compared with hysterectomy. Randomized controlled trials have not been conducted, and long-term efficacy has not been studied. A limited number of deliveries have been reported following uterine artery embolization for uterine myomas. CONCLUSION(S): Uterine artery embolization is a unique new treatment for symptomatic uterine myomas. Even without controlled studies, demand for this procedure has increased rapidly. Uterine artery embolization may be considered an alternative to hysterectomy, or perhaps myomectomy, in well-selected cases. At the present time, however, uterine artery embolization should not be routinely recommended for women who desire future fertility.

Cardiovascular effects of clenbuterol are beta 2-adrenoceptor-mediated in steers.

The mechanism through which the repartitioning agent clenbuterol increases heart rate was investigated. First, the relative importance of the beta 1- and beta 2-adrenoceptors was established in rat and bovine right atria in vitro. The positive chronotropic and inotropic effects of (+/-)isoproterenol in rat and bovine right atria, respectively, were markedly antagonized (P < .001) by the beta 1-adrenoceptor antagonist CGP 20712A but were antagonized less by the beta 2-adrenoceptor antagonist ICI 118 551 in rat (P < .01), but not in bovine atria, indicating a major role of the beta 1-adrenoceptors. Clenbuterol was only a partial agonist in rat right atria, increasing heart rate at high concentrations through stimulation of beta 1-adrenoceptors. In studies in vivo, clenbuterol decreased the plasma potassium concentration (P < .05) and increased the plasma glucose concentration (P < .05). Clenbuterol also reduced diastolic blood pressure (P < .01) and increased heart rate (P < .001). The increase in heart rate was not due to direct stimulation of cardiac beta 1-adrenoceptors by clenbuterol but was consistent with a reflex response to beta 2-adrenoceptor-mediated hypotension. This would have caused the activation of baroreceptors, which in turn would have resulted in both the release of norepinephrine to stimulate cardiac beta 1-adrenoceptors and the inhibition of cholinergic input to the heart. Thus, the effects of clenbuterol could be eliminated completely by ICI 118 551 or reduced by approximately 50% using CGP 20712A. The combination of treatment of clenbuterol and CGP 20712A could be useful. It may allow the full repartitioning effects seen with the beta 2-agonist alone, but with a markedly attenuated effect on the heart. Such a treatment regimen may also help reduce the increased energy expenditure and loss of appetite seen following the initial administration of clenbuterol.

Effects of BRL-47672 on growth, beta 2-adrenoceptors, and adenylyl cyclase activation in female rats.

The morpholine compound BRL-47672 has a chemical structure similar to that of clenbuterol and causes similar anabolic effects in rats but has no actions on beta 2-adrenoceptors in vitro. It has been argued therefore that beta 2-adrenoceptors do not mediate the anabolic effects of this family of compounds. In the present study BRL-47672 was shown to bind to rat beta 2-adrenoceptors with low affinity (dissociation constant 16 microM) relative to clenbuterol (48 nM) and to be a very weak activator of adenylyl cyclase activity in rat skeletal muscle membranes in vitro. In contrast, acute administration of the drug to anesthetized rats in vivo caused an increase in muscle adenosine 3',5'-cyclic monophosphate output, and chronic treatment of conscious rats for > 6 days caused a significant increase in weight gain (69%) accounted for by increased muscle growth. The anabolic effects of BRL-47672 were not counteracted by daily injections of the drug ICI-118551 (2 mg/day) but were prevented when the same beta 2-antagonist was administered in the diet (200 mg/kg feed, equivalent to 4.3 mg/day). The beta 1-adrenoceptor selective antagonist CGP-20712A fed in the diet (200 mg/kg feed) failed to attenuate the response to BRL-47672. These results support the conclusion that BRL-47672 has little direct action on beta 2-adrenoceptors but suggest that the compound is metabolized rapidly in vivo to a potent beta 2-agonist. Thus the stimulation of muscle growth by BRL-47672 is via beta 2-adrenoceptors, with no contribution to this response from beta 1- or beta 3-adrenoceptor activation.

Classical and atypical binding sites for beta-adrenoceptor ligands and activation of adenylyl cyclase in bovine skeletal muscle and adipose tissue membranes.

1. The radioligand [125I]-iodocyanopindolol ([125I]-ICYP) was used under standard ligand binding conditions, to detect beta 1- and beta 2-adrenoceptors in membrane preparations from bovine skeletal muscle and adipose tissue. High concentrations of [125I]-ICYP were also used, to identify an 'atypical' binding site in skeletal muscle. Finally, adenosine 3':5'-cyclic monophosphate (cyclic AMP) production was measured in the same membrane preparations, to determine the relationship between the beta-adrenoceptor sub-types present and the production of this second-messenger. 2. According to the results of radioligand binding studies, both skeletal muscle and adipose tissue membranes have beta 2-adrenoceptors, characterized by a high affinity for the beta 2-selective antagonist, ICI 118551 (pK 8.3 and 8.6 respectively); and a low affinity for the beta 1-selective antagonist CGP 20712A (pK 5.2 in both tissues). Antagonism of (-)-isoprenaline-stimulated cyclic AMP production by low concentrations of ICI 118551, yielded pseudo pA2 values in muscle and adipose tissue of 7.6 and 8.7 respectively, confirming that beta 2-adrenoceptors in these tissues are linked to the production of the second-messenger. 3. Although beta 1-adrenoceptors could not be detected in either skeletal muscle or adipose tissue membranes by use of ligand binding techniques, high pseudo pA2 values were obtained (8.0 and 8.2 respectively), when CGP 20712A was used to block the stimulation of cyclic AMP production by (-)-isoprenaline. This finding is consistent with the presence in both tissues of a population of beta 1-adrenoceptors which is small, but efficiently coupled to the second-messenger. 4.In addition to identifying standard beta 1- and beta 2-adrenoceptors, it was also established that skeletal muscle membranes have an 'atypical' binding site which has a relatively low affinity for [125]-ICYP(pK8.84), but which exists in abundance. At high concentrations of radioligand, the 'atypical' site accounted for 89% of the total [125I]-ICYP binding sites present.5. The results of second-messenger studies do not support the hypothesis that skeletal muscle or adipose tissue membranes contain functional beta 3-adrenoceptors: based on the failure of a beta 3-adrenoceptor-selective agonist (BRL 37344) to stimulate cyclic AMP production, the absence of a biphasic response to (-)-isoprenaline, and the observation that cyclic AMP production was not resistant to blockade by either ICI 118551 or CGP20712A.6. It is concluded that data from radioligand binding studies do not accurately reflect the contribution made by beta 1- and beta 2-adrenoceptors to cyclic AMP production in bovine skeletal muscle and adipose tissue membranes. Furthermore, the 'atypical' [125I]-ICYP binding site identified in bovine skeletal muscle does not represent a functional bovine beta 3-adrenoceptor.

Growth, nitrogen metabolism, and cardiac responses to clenbuterol and ketoclenbuterol in rats and underfed cattle.

Two beta-adrenoceptor agonists, clenbuterol and ketoclenbuterol, were examined for their effects on growth and cardiac tissue. In female rats, clenbuterol caused a 48% increase in weight gain (P < .05), with improved feed efficiency (26%; P < .1) and increased muscle mass (9%; P < .1). Ketoclenbuterol had less effect on weight gain (30%) and feed efficiency (16%) and did not increase muscle mass. Next we studied the adverse cardiovascular effects of these compounds. Neither drug increased the force of contraction of isolated rat ventricular papillary muscle. Clenbuterol was potent at causing an increase in the rate of contraction of isolated rat atria, and when fed to cattle over 2 d, the drug caused heart rate to increase by 92 to 117%. In contrast, ketoclenbuterol was not a potent stimulator of atrial rate in the rat, and in cattle it caused a smaller increase in heart rate than clenbuterol (12 to 27%). Finally, cattle that were underfed to simulate dry-season tropical pasture conditions were treated with clenbuterol or ketoclenbuterol for 35 d. Ketoclenbuterol caused no beneficial changes in N metabolism. The results obtained with clenbuterol were equivocal, and might have been confounded partly by the refusal of some treated animals to eat all the feed offered. Although clenbuterol did not cause a reduction in total urinary N output relative to control animals, marked reductions in plasma urea concentrations and in urea synthesis were observed (23 to 53%; P < .001). We conclude that ketoclenbuterol is not effective for attenuation of dry-season protein loss in cattle. Clenbuterol seems to be less effective in underfed cattle than in well-fed cattle, and further evidence is required to judge whether compounds of this nature are likely to benefit tropical cattle under harsh grazing conditions.

Effects of the alpha 2-adrenoceptor agonist guanfacine on growth and thermogenesis in mice.

Guanfacine is an alpha 2-adrenoceptor agonist with antithermogenic properties. A single treatment of guanfacine caused a dose-related reduction in metabolic rate. The maximum reduction was 40%, and a dose of .5 mg/kg was close to that required to produce half this effect. It was determined whether the antithermogenic action of guanfacine would result in increased growth rate in mice. In animals treated once daily for 10 d (0, .125, .5, or 2 mg/kg), the drug caused dose-related reductions in feed intake, weight gain, and feed conversion efficiency. In a further experiment, mice were fed a restricted quantity of feed and treated for 14 d with guanfacine (.5 mg/kg twice daily). Because of repeated dosing, the antithermogenic effect of the drug was attenuated, so that metabolic rate was not lower in treated mice at the end of the experiment. Control and treated mice ate all the feed offered, but the guanfacine-treated group gained 2.9 g less weight (P < .01) than the controls. Half this difference in BW was accounted for by body water (P < .1), whereas body energy content was also reduced by the drug (P < .05). In a final experiment we sought possible sources of energy loss. Mice were treated with guanfacine (.5 mg/kg) three times over 24 h. Severe glucosuria was observed in the guanfacine-treated mice, with a tendency also toward increased output of fecal energy. We have confirmed that guanfacine has a powerful, if short-term, antithermogenic action. However, in mice, other effects of the drug on energy metabolism result in weight loss rather than growth stimulation.

Effects of clenbuterol, ICI118551 and sotalol on the growth of cardiac and skeletal muscle and on beta 2-adrenoceptor density in female rats.

The aim of the present study was to determine whether the anabolic effects of clenbuterol in rat skeletal muscle are mediated by beta 2-adrenoceptor stimulation. Female rats were treated with clenbuterol, alone or in combination with either the nonselective beta 1/beta 2-adrenoceptor antagonist sotalol, or the beta 2-adrenoceptor-selective antagonist ICI118551. Clenbuterol caused an increase in muscle growth, accompanied by a reduction in beta 2-adrenoceptor density in the rat hind-limb. Both actions were attenuated by sotalol. However, at the dose tested ICI118551 was the more effective antagonist of the muscle growth response, and when given alone, ICI118551 caused significant muscle atrophy. An increase in the weight of the heart was also observed in clenbuterol-treated rats, and again while this effect was attenuated by sotalol, it was reversed by ICI118551. It is concluded that beta 2-adrenoceptors mediate the anabolic effects of clenbuterol in cardiac and skeletal muscle, and that they play an important physiological role in the growth and maintenance of muscle mass in the rat hind-limb.

Visual performance and subjective discomfort in prolonged viewing of chromatic displays.

Visual search and decision-making performance together with subjective fatigue were investigated over a 4-hr time block as a function of display foreground and background chromaticity using colors matched for brightness. Although some small differences in performance related to chromaticity were observed, these were not exacerbated over time. On the basis of the performance data obtained and the subjective reports, there was no support for the general recommendation to avoid the use of red and blue stimuli, either alone or in combination, in CRT displays.

Neural, optical, and search performance in prolonged viewing of chromatic displays.

The effect of prolonged cathode ray tube (CRT) work on the afferent visual neural and focusing system of the human eye was examined by visually evoked potentials (VEPs) and laser optometer techniques, respectively. These measures were compared with parallel measurements of search performance. Ten volunteers performed three 4-hr sessions of a search/decision task on a high-resolution-red/green/blue (RGB) monitor. Stimuli were numbers and symbols presented in a blue/black, red/black, or red/green foreground/background combination. Results showed minimal changes in the neural and focusing responses to each foreground/background combination over time on task. Weak correlations were found between neural-optical and search performance measurements. These data suggest that the use of chromatic stimuli in the color combinations examined do not have a detrimental effect on visual performance.

The influence of colour on CRT reading performance and subjective comfort under operational conditions.

Performance and reports of comfort when proof-reading text displayed on a CRT were investigated as a function of the text/background colour. Luminances were those typically produced by commercially available hardware and software, and task conditions were designed to simulate those experienced by typical users. Colours from the extremes of the spectrum (red, blue) were shown to produce poorer reading performance, higher ratings of discomfort and a higher incidence of reported symptoms of discomfort than those from mid-spectrum and white stimulus conditions.

Age differences in male drivers' perception of accident risk: the role of perceived driving ability.

Young (18-25) and older (35-50) male drivers were compared in their perception of driving risk and confidence in driving ability. Both groups provided responses a questionnaire on accident risk and driving ability and further generated subjective ratings of risk to a series of videotaped sequences depicting various elements of driving behavior. Although young drivers' estimates of accident involvement in the next year were higher than those of older drivers, young drivers gave lower ratings of accident risk for specific driving situations which demanded fast driving reflexes or substantial vehicle-handling skills. Young drivers rated their own risk of an accident and driving abilities as being the same as for older drivers. However, they saw their peers as being significantly higher at risk and having poorer abilities than themselves. Young drivers were more confident in their driving abilities than the older drivers. Evidence is provided to suggest that perceived risk and self-perceived driving abilities are interrelated. Further, the data from young drivers showed two disturbing characteristics: first, a notable dissociation between perceived and actual ability and, second, a tendency to view themselves as immune from the effects of higher levels of risk, which they are prepared to ascribe to their peers but not to themselves.

A comparison of the actual and expected pain response following insertion of an intrauterine contraceptive device.

The expected, immediate, and three-minute pain response following IUCD insertion was evaluated in 84 nulliparous women undergoing a first IUCD insertion. Expected pain was significantly higher than immediate pain and both were significantly higher than three-minute pain. Immediate pain following IUCD insertion was positively related to expected pain but the relationship was not strong enough to be of clinical value. The pain was significantly related to the degree of cervical resistance and this relationship was made much more obvious by the use of the expected pain parameter which is a valuable additional clinical measurement in pain research. IUCD insertion pain consists of a short cervical (less than 3 minutes) and longer fundal component. Avoiding excessive uterine manipulation during device insertion results in lower immediate and later pain response scores for a given device when comparisons are made with other studies, where standard techniques were used.

PIP: This study was aimed at evaluating actual versus expected pain levels associated with an IUD insertion technique developed by the authors. This technique eliminates prior uterine sounding and use of local anesthesia or oral analgesia. It was tested in 84 nulliparous women ages 18-40 years who were undergoing their 1st IUD insertion. Expected pain before IUD insertion, immediate pain, and 3-minute pain following insertion were evaluated on a visual analog scale recorder. Expected pain was significantly higher than immediate pain, and both were significantly higher than 3-minute pain. Immediate postinsertion pain was independent of age, gravidity, or day of cycle but dependent on expected pain and cervical resistance; however, the relationship was not strong enough to be of clinical value. The relationship between cervical resistance and the difference in expected and immediate pain scores was highly significant (p0.001). The 3-minute pain score was significantly different from the immediate pain score but was not related to the expected pain score. Follow-up ratings were obtained from 44 study participants; the relationship between 3-minute pain score and follow-up symptoms was significant. These results confirm the clinical observation that IUD insertion without prior uterine sounding results in immediate and 3-minute pain levels that are lower than those expected by patients. IUD insertion pain appears to consist of a short cervical component and a longer (more than 3 minutes) fundal component. The cervical pain response can be abolished through use of local anesthesia whereas fundal pain should be treated with antiprostaglandin analgesics.

A comparison of the actual and expected response following removal of an IUD.

The expected pain before insertion and immediate and 3 minutes pain response following IUD insertion was evaluated in 38 nulliparous women undergoing a 1st IUD removal. Expected pain was significantly greater than immediate pain and both were significantly greater than 3 minute pain. Immediate pain after IUD removal was positively related to expected pain, but the relationship was not strong enough to be clinically useful. IUD removal was highly significantly related to cervical resistance, and this relationship was made very much greater by the use of expected pain as a clinical parameter. IUD removal pain is probably related to IUD retention forces, and this relationship should be investigated.

Interpersonal linkage among Hodgkin's disease patients and controls in Western Australia.

Interpersonal linkages were studied in 178 Hodgkin's disease patients, aged 60 years or younger, who lived in Western Australia between 1964 and 1975, and in their matched controls. Eighty-nine living subjects were interviewed about places and periods of residence, school attendance and employment, and possible linkages were computed based on concurrence of these events. Subjects were also shown the names of all patients and controls and asked to mark the names they recognized, giving details of acquaintanceships. The acquaintanceship method yielded more and the concurrence method fewer case-case links than expected. Little overlap occurred in linkages identified by the two methods. The acquaintanceship method is thought to be the more reliable. Risk factors suggested in the literature were also investigated. Increased risk of Hodgkin's disease in living patients was associated with being unmarried, being born outside Western Australia, smoking cigarettes, and having lived and worked on a farm and worked with animals. These effects did not explain the excess of case-case linkages found by the acquaintanceship method.

Inter-observer variation in the histopathological reporting of Hodgkin's disease: an analysis of diagnostic subcomponents using kappa statistics.

Levels of agreement between nine pathologists on the Rye classification of Hodgkin's disease and on diagnostic subcomponents used in applying the classification, were analysed by kappa statistics. Pathologists experienced comparatively little difficulty in agreeing on the presence of nodules and lacunar cells and hence best agreement was achieved on the nodular sclerosis category. Poorer agreement levels on the lymphocytic predominance, mixed cellularity and lymphocytic depletion categories were explained mainly by problems in the assessment of numbers of lymphocytes and abnormal reticulum cells other than Reed-Sternberg cells. Identification of the Reed-Sternberg cell, although of paramount importance to a diagnosis of Hodgkin's disease, appeared to have no great practical relevance to use of the Rye classification in this series of cases.

The effect of diagnostic review on the estimated incidence of lymphatic and hematopoietic neoplasms in Western Australia.

Diagnoses of 1443 patients from a population-based leukemia and allied disorders registry in Western Australia were subjected to diagnostic review, resulting in 235 deletions, 120 changes in diagnosis, and 23 undecided diagnoses. Deletions occurred mainly in lymphoma registrations, most of these being reclassified as other cancers. Among the patients whose names were deleted, 196 deaths occurred of whom 67 had leukemia or an allied disorder as the certified cause of death. Lymphoma incidence rates in Western Australia were lower than those reported from another Australian registry. Quality control of registration and special interests in diagnosis or classification of particular tumors may affect their reported incidence rates.

The Rye classification of a population based series of Hodgkin's disease patients in Western Australia.

Data are presented on the incidence in Western Australia of subtypes of Hodgkin's disease which were obtained by review of all cases of the disease notified between 1960 and 1974. Observations were also made on within- and between-observer agreement on the use of the Rye classification by a group of 9 surgical pathologists, all in the day-to-day practice of pathology. Although many consensus diagnoses were made only after spirited discussion by the Group, the results suggested that general surgical pathologists can perform nearly as well as lymphoma experts. A comparison of the incidence of Hodgkin's disease and distribution of Rye subtypes in Western Australia with 4 other populations showed a similar overall incidence but appreciable variation in the relative frequency of the subtypes--mainly in the proportions of nodular sclerosing and mixed cellularity.