The effects of the selective progesterone receptor modulator asoprisnil on the morphology of uterine tissues after 3 months treatment in patients with symptomatic uterine leiomyomata.

BACKGROUND: Asoprisnil is a selective progesterone receptor modulator with mixed progesterone agonist/antagonist activity which controls uterine bleeding via an endometrial effect. This study examined full-thickness endometrial, leiomyoma and myometrial morphology in hysterectomy specimens from patients with uterine leiomyomata, after treatment with asoprisnil for 3 months. METHODS: In this double-blind, randomized, placebo-controlled study, 33 subjects with uterine leiomyomata were randomized to receive asoprisnil 10, 25 mg or placebo for an average of 95 days prior to hysterectomy. Samples of endometrium, myometrium and leiomyoma tissue were subjected to systematic morphological assessment with quantification of mitotic activity. RESULTS: In patients treated with 10 or 25 mg asoprisnil, a unique pattern called 'non-physiologic secretory effect' was evident in endometrium, recognizable through partially developed secretory glandular appearances and stromal changes. Endometrial thickness was decreased, and there were low levels of mitotic activity in endometrial glands and stroma. Unusual thick-walled muscular arterioles and prominent aggregations of thin-walled vessels were present in endometrial stroma, but not in myometrium or non-endometrial vascular beds. Mitotic activity was decreased in leiomyomata. CONCLUSIONS: Asoprisnil induces unique morphological changes and is associated with low levels of glandular and stromal proliferation in endometrium, and in leiomyomata. These changes are likely to contribute to the amenorrhoea experienced after exposure to the medication.

Endometriosis: a continuing enigma?

Endometriosis is a common gynaecological disease but remains a poorly understood condition. Fundamental questions about the aetiology, pathophysiology, diagnosis, natural history and treatment are still unanswered by the extensive research into endometriosis. This article will outline present understanding of endometriosis and the advances provided by recent research.

The influence of psychiatric hospital and community residence labels on social rejection of the mentally ill.

In order to identify some of the variables influencing public level of acceptance and attitudes towards people with a mental illness, a social distance scale accompanying a case vignette was sent to 488 postal respondents. The vignette contained systematically varied residence labels (psychiatric hospital/community) and behaviours (disturbed/control). There was a 43 per cent response rate. The results showed that social rejection was influenced by the behaviour described in the vignette, the respondents' judgement about the behaviour, and the respondents' previous contact with people with mental illness. The given residence label had an impact on only one component of social rejection and only for those presented with the control vignette. The findings are discussed in relation to current community care policies.

Endometrial progesterone receptor expression during the human menstrual cycle.

The human endometrium undergoes regular cyclical changes under the endocrine control of oestrogens and progesterone acting via specific nuclear receptors. The molecular and cellular events mediating these changes are not understood. The present study examined the changes in the endometrial progesterone receptor and its mRNA during the menstrual cycle. Forty-four endometrial samples obtained from women with normal menstrual cycles were divided into four categories: early proliferative (days 6-9), late proliferative (days 10-14), early secretory (days 15-21) and late secretory (days 22-28). The progesterone receptor protein was determined using a human progesterone receptor enzyme-linked immunoassay kit. Total RNA was extracted using RNAzol and the abundance of mRNA encoding the progesterone receptor was determined by reverse transcriptase-polymerase chain reaction and by northern blot analysis. The concentration of the progesterone receptor in the endometrium was highest during the late proliferative phase and was lowest in the late secretory phase. Significant differences were observed between the menstrual cycle phases (P < 0.003). No cyclical variation was observed in the concentration of mRNA encoding for the progesterone receptor in the endometrium when analysed by reverse transcriptase polymerase chain reaction or by northern analysis. There appears to be no association between the amounts of mRNA encoding the progesterone receptor and progesterone receptor protein during the menstrual cycle suggesting that the control of the expression of the progesterone receptor may not occur solely at the transcriptional level.

Gastroschisis and reduced fetal heart-rate variability.

Most liveborn babies with gastroschisis do well after surgical repair, although about one-eighth of affected cases die late in utero. Our practice is to use weekly computerised cardiotocograph (CTG) analysis after week 34 of gestation in cases of gastroschisis. In a look-back at the records in 18 such singleton pregnancies, CTG showed 7 to be highly abnormal or preterminal. All but 1 of these 7 had a normal fetal heart rate. In all 7 cases, delivery was expedited. Only 1 infant had neurological sequelae, and in all the abdominal defect was successfully repaired. Monitoring of these high-risk pregnancies with serial computerised CTG may be helpful in timing delivery.

Cooperative mixtures of bispecific F(ab')2 antibodies for delivering saporin to lymphoma in vitro and in vivo.

We report that selected combinations of two or more monoclonal bispecific F(ab')2 antibodies (BsAbs) far outperform single derivatives in the delivery of the ribosome-inactivating protein, saporin, to guinea pig L2C leukemic cells. Throughout the work, BsAbs were constructed by thioether-linking the hinges of two Fab'gamma, one from monoclonal anti-L2C-idiotype antibody and the other from anti-saporin antibody. The latter was either affinity-purified rabbit polyclonal or one of a panel of five mouse monoclonal antibodies. In vitro cytotoxicity studies showed that, though all derivatives were effective, the BsAb made with the polyclonal antibody was always 10 to 20 times more potent than those made with a monoclonal antibody in yielding 50% inhibition of [3H]leucine uptake. This superior activity could be matched by selective mixtures of two or more of the monoclonal derivatives. Furthermore, in immunotherapeutic delivery of saporin to tumor, a pair of BsAbs performed significantly better than did either individually. Binding and uptake studies with radiolabeled saporin demonstrated a 20-fold increase in functional affinity when saporin was held at the cell surface by an appropriate BsAb mixture rather than by a single BsAb. In contrast, only small differences were recorded in the rate at which saporin was internalized as a result of the same maneuver. We conclude that the improved performance of combinations of BsAbs arises from their ability to provide multiple linkages between saporin molecules and cell surfaces, significantly increasing the functional affinity with which saporin is tethered to the cell, but, in this system at least, having only a minor effect on the rate at which it is internalized. Cocktails of two or more BsAbs, selected to bind to multiple epitopes on ribosome-inactivating proteins and perhaps also on unwanted cells, could provide an important new strategy in immunotherapy.