Control by tachykinin NK(2) receptors of CRF(1) receptor-mediated activation of hippocampal acetylcholine release in the rat and guinea-pig.

In vivo microdialysis was employed to explore the effects of different selective non-peptides NK(1),NK(2) and NK(3) receptor antagonists on the corticotropin releasing factor (CRF)-induced release of acetylcholine (ACh) in the hippocampus of rats and guinea-pigs. In both species, the intracerebroventricular (i.c.v.) administration of CRF produced a time- and dose-dependent increase in hippocampal ACh release that was totally suppressed by an intraperitoneally (i.p.) pretreatment with the selective non-peptide CRF(1) receptor antagonist antalarmin (30 mg/kg). Pretreatment with the selective NK(2) receptor antagonist SR48968 (1mg/kg, i.p.) significantly reduced the increase of ACh induced by CRF. In contrast, its low-affinity enantiomer SR48965 (1mg/kg, i.p.) or the NK(1) receptor antagonist, GR205171 (1mg/kg, i.p.) did not exert any antagonist effect. Moreover, administration of the selective NK(3) receptor antagonist SR142801 (1mg/kg, i.p.) did not significantly reduce the CRF-induced hippocampal ACh release in guinea-pigs (the only species studied). The selective activity of SR48968 versus GR205171 or SR142801 indicates that NK(2) receptors play a major role in the control of CRF-induced hippocampal ACh release. Moreover, in freely moving rats, two sessions of stroking of the neck and back of the rat for 30 min, at 90 min intervals, known to be a stressful stimulus, produced a marked and reproducible increase in hippocampal ACh release. This effect was prevented by the administration of the two selective non-peptide CRF1 and NK(2) receptor antagonists antalarmin (30 mg/kg, i.p.) and SR48968 (1mg/kg, i.p.), respectively. This suggests that stress-induced activation of the hippocampal ACh system may be under the control of both endogenously released CRF and NKA, and opens the possibility of the existence of a functional interplay between the pathways containing these peptides as we observed in our experiments on anaesthetized animals.

Expression and presence of septal neurokinin-2 receptors controlling hippocampal acetylcholine release during sensory stimulation in rat.

We examined the expression and presence of NK2 receptors in the septal area of rat brain, and investigated their functional role in the regulation of the septohippocampal cholinergic system. Using reverse transcription-polymerase chain reaction (RT-PCR) analysis, we showed the presence of NK2 receptor mRNA expression in the septal area, and detected septal NK2 binding sites by using a fluorescent-tagged neurokinin A (NKA) derivative. In vivo microdialysis was employed to explore the functional role of NK2 receptors in the release of hippocampal acetylcholine evoked by tactile stimulation in freely moving rats. Two sessions of stroking of the neck and back of the rat for 30 min, at 90 min intervals, produced a marked and reproducible increase in hippocampal acetylcholine release. This effect was dose-dependently prevented by intraperitoneal administration of the two selective non-peptide tachykinin NK2 receptor antagonists SR144190 (0.03-0.3 mg/kg, i.p.) and SR48968 (0.3 and 1 mg/kg, i.p.), but not by the inactive enantiomer of SR48968 (SR48965, 1 mg/kg) nor by the two non-peptide NK1 receptor antagonists SR140333 (3 mg/kg, i.p.) and GR205171 (1 mg/kg, i.p.). Furthermore, the intraseptal application of SR144190 (10(-8) M) reduced the sensory response. Finally, intraseptal perfusion of neurokinin A (0.01-10 microM) in anaesthetized rats produced a concentration-dependent increase in hippocampal acetylcholine release. The response to neurokinin A (0.1 microM) was prevented by SR144190 (0.03-0.3 mg/kg, i.p.) and SR48968 (0.3-1 mg/kg, i.p.). In conclusion, this study provides direct evidence for the role of endogenous NKA/substance P, through the activation of NK2 receptors, in regulating the septohippocampal cholinergic function.

Environmental endocrine disruption: an effects assessment and analysis.

This report is an overview of the current state of the science relative to environmental endocrine disruption in humans, laboratory testing, and wildlife species. Background information is presented on the field of endocrinology, the nature of hormones, and potential sites for endocrine disruption, with specific examples of chemicals affecting these sites. An attempt is made to present objectively the issue of endocrine disruption, consider working hypotheses, offer opposing viewpoints, analyze the available information, and provide a reasonable assessment of the problem. Emphasis is placed on disruption of central nervous system--pituitary integration of hormonal and sexual behavioral activity, female and male reproductive system development and function, and thyroid function. In addition, the potential role of environmental endocrine disruption in the induction of breast, testicular, and prostate cancers, as well as endometriosis, is evaluated. The interrelationship of the endocrine and immune system is documented. With respect to endocrine-related ecological effects, specific case examples from the peer-reviewed literature of marine invertebrates and representatives of the five classes of vertebrates are presented and discussed. The report identifies some data gaps in our understanding of the environmental endocrine disruption issue and recommends a few research needs. Finally, the report states the U.S. Environmental Protection Agency Science Policy Council's interim position on endocrine disruption and lists some of the ongoing activities to deal with this matter.

Facilitation of striatal acetylcholine release by dopamine D1 receptor stimulation: involvement of enhanced nitric oxide production via neurokinin-2 receptor activation.

The regulation of striatal cholinergic function by dopamine D1 receptor activation was examined in vivo in urethane-anaesthetized rats with microdialysis probes. Extracellular acetylcholine levels were enhanced by activation of D1 receptors either directly by a striatal application of the D1 receptor agonist (+)-SKF-38393 (3 microM) or indirectly by the release of dopamine evoked by striatal application of neurotensin (0.1 microM) under D2 receptor blockade. SR 144190, a new potent and selective non-peptide neurokinin-2 receptor antagonist (0.03-1 mg/kg, i.p.), dose-dependently reduced the acetylcholine release induced by (+)-SKF-38393 or neurotensin. Furthermore, intrastriatal application of SR 144190 (1 nM) blocked the increase in acetylcholine release induced by the local application of (+)-SKF-38393 (3 microM), neurokinin A (1 microM) or substance P (1 microM). Finally, a role for nitric oxide in mediating the effects of D1 neurokinin-2 receptor activation on acetylcholine release is proposed since local infusion of the competitive inhibitor of nitric oxide synthase, N(G)-monomethyl-L-arginine (0.01-10 microM), blocked the increase in acetylcholine release induced by (+)-SKF-38393 (3 microM), neurotensin (0.1 microM) or neurokinin A (1 microM) without affecting the enhancing effect of the neurokinin-1 agonist septide (0.1 microM).

Pharmacological characterization of tachykinin receptors controlling acetylcholine release from rat striatum: an in vivo microdialysis study.

The regulation of striatal cholinergic function by tachykinins was examined in urethane-anesthetized rats by using microdialysis. Substance P (0.01-1 microM), [Sar9, Met (O2)11]substance P (1-10 microM), septide (0.1-3 microM), neurokinin (NK) A (0.1-10 microM), and senktide (0.1-10 microM) produced concentration-dependent increases in striatal acetylcholine (ACh) release. Septide was the most potent agonist for inducing release of ACh, whereas the stimulating effect of senktide was less pronounced and more progressive in onset. The response to septide was prevented by intraperitoneal administration of the nonpeptide NK1 antagonist SR 140333 (1-3 mg/kg) but not by the nonpeptide NK2 receptor antagonist SR 48968, indicating that the effect was mediated specifically by NK1 receptors. ACh release caused by NKA was reduced by SR 48968 (1-3 mg/kg) and slightly affected by SR 140333, indicating a principal role for NK2 receptors in the peptide response. The similar efficacy of SR 140333 and SR 48968 in blocking substance P-induced ACh release suggested that the effect of this peptide involves the stimulation of both NK1 and NK2 receptors. Finally, our results indicate that the increase in striatal ACh release induced by the D1 agonist (+)-SKF-38393 (3 microM) may be mediated indirectly through local release of NKA or substance P acting at NK2 receptors.

SR 48692-sensitive neurotensin receptors modulate acetylcholine release in the rat striatum.

The effects of stimulation and blockade of neurotensin receptors on striatal acetylcholine release were examined in anaesthetized rats using microdialysis. Local perfusion with neurotensin (100 nM) did not influence the release of acetylcholine. Application of neurotensin (100 nM) 30 min after haloperidol (125 micrograms/kg, i.p.) increased acetylcholine levels to 188% compared to 120% when haloperidol was administered alone. SR 48692 (3-100 micrograms/kg, i.p.) dose-dependently reduced the stimulatory effect of neurotensin in the presence of haloperidol. Comparable antagonism was observed with SR 48527, a chemically-related compound with high affinity for neurotensin receptors, but not with SR 49711, its low-affinity antipode. These results indicate that high affinity neurotensin receptors regulate acetylcholine release, when D2-dopaminergic inhibitory input is suppressed.

SR 48692, a non-peptide neurotensin receptor antagonist differentially affects neurotensin-induced behaviour and changes in dopaminergic transmission.

Unilateral microinjection of neurotensin in the ventral tegmental area of the rat (2.5 micrograms/0.5 microliter) produced behavioural excitation illustrated by contralateral circling. Given orally, SR 48692, a selective and potent non-peptide neurotensin receptor antagonist, significantly reduced these rotations with a triphasic dose-effect relationship. Inhibition occurred at 0.12 mg/kg; further increases in dose up to 2.5 mg/kg produced no significant antagonism, then at doses > or = 5 mg/kg, a second phase of antagonism was observed. Bilateral injection of neurotensin (0.5 microgram each side) into the nucleus accumbens antagonized the increase in locomotor activity following intraperitoneal injection of amphetamine. Given orally, SR 48692 reduced dose-dependently (0.1-1 mg/kg) these intra-accumbens neurotensin effects. Using high pressure liquid chromatography with electrochemical detection, we showed that microgram amounts of neurotensin injected into the ventral tegmental area increased dihydroxyphenylacetate/dopamine ratios in the nucleus accumbens. Using in vivo voltammetry techniques, we found that the injection of nanogram and picogram amounts of neurotensin in the ventral tegmental area stimulated dopamine efflux in the nucleus accumbens. None of these biochemical changes were affected by SR 48692 (0.1-10 mg/kg). These results indicate complex interactions between neurotensin and the mesolimbic dopamine system. More particularly, the differential ability of SR 48692 to affect neurotensin-evoked behavioural versus biochemical changes supports the concept of neurotensin receptor heterogeneity.

[Role of pelvic exenterations in the treatment of cervix cancers. Apropos of 41 surgically treated cases]. / La place des exentérations pelviennes dans le traitement des récidives des cancers du col utérin. A propos de 41 cas opérés.

The Department of surgical oncology of the Paul-Strauss Cancer Center of Strasbourg (France) reports its experience about pelvic exenterations in recurrent cervix carcinomas. Based on a series of 41 cases (median age: 48.5 years), all patients, but one, have been primarily treated by sole external beam irradiation or surgery combined with radiotherapy. Salvage ultraradical surgical procedures were total (25 cases), anterior (7 cases) and posterior exenterations (9 cases). Overall 5 and 10 years crude survival were 39 and 27.5%, respectively. Advances in surgical procedures, new developments in techniques of pelvic floor reconstruction and improvement in devices of urinary diversions have mainly contributed to a decrease of postoperative morbidity associated with the obtaining of long survivals in selected patients previously treated, in a curative intent, by other therapeutic modalities. The current place of palliative pelvic exenterations and the support of intraoperative radiotherapy are discussed according to recent literature data.

Influence of mastectomy techniques on estrogen and progesterone receptor analysis in carcinoma of the breast.

Gradual tumor tissue devascularization during mastectomy is thought to decrease estrogen (ER) and progesterone (PgR) receptor activity. To determine whether or not hormone receptor values could be influenced by different mastectomy techniques, 62 patients with carcinoma of the breast had a Tru-cut needle (Baxter Healthcare Corporation) biopsy (premastectomy sample) and underwent modified radical mastectomy (postmastectomy sample) either before (group 1, 40 patients) or after (group 2, 22 patients) axillary lymph node dissection. When the two surgical procedures were compared in 33 patients in whom it could be assessed, no significant tendency (p = 0.51 for ER and p = 0.36 for PgR) for the postmastectomy sample to have hormone receptors levels less than samples taken at biopsy was detected. Overall, in the two groups (44 assessable patients), comparison with respect of each patient, between premastectomy and postmastectomy samples showed that the variations in either ER or PgR receptor values, determined by immunoenzymatic assays, were not statistically significant (p = 0.32 for ER and p = 0.21 for PgR). The current results indicated the relative stability of steroid receptors during the two modified radical mastectomy procedures and suggested that a systematic reference determination of hormone receptors on biopsy before modified radical mastectomy is unnecessary.

Use of polyglactin 910 mesh (Vicryl) in pelvic oncologic surgery.

Various synthetic materials have been shown to be useful surgical adjuncts in shielding the small intestine from pelvic radiation or in creating a new pelvic floor after major radical resections. Promising preliminary results with a polyglactin 910 (Vicryl) mesh in preventing radiation enteropathy prompted the authors to evaluate its clinical usefulness in reconstruction of the pelvic floor. Use of this mesh in pelvic exenterations (five total, one posterior) for advanced or recurrent gynecologic malignancies was associated with one enteroperineal fistula but no pelvic infection. In comparison with other pelvic reconstruction devices, this absorbable mesh significantly reduced intestinal morbidities in pelvic exenterations. This procedure appears to be feasible, reproducible, and safe, especially in patients who have undergone previous irradiation or those with an unsuitable omentum.

[Latissimus dorsi myocutaneous flap closure in mastectomies after chemotherapy of advanced and progressive breast cancers]. / Fermeture par lambeau myocutané de grand dorsal dans les mastectomies après chimiothérapie pour cancers avancés et évolutifs du sein.

A latissimus dorsi myocutaneous flap now appears to be the best solution to closing large carcinological exeresis of the breast. After an analysis of a series of 14 cases of advanced cancer (T3 or T4) or of progressive cancers (PeV3) of the breast treated by inductive chemotherapy and which underwent surgery at the Strasbourg CRLCC (France), the authors stress the simplicity and reliability of the method, which can make it possible to carry out an extensive and complete exeresis, which is of primordial importance in the control of the local tumor. Its excellent trophic quality made it possible to start radiochemotherapeutic adjuvant treatments rapidly. The other methods (myocutaneous flap of the rectus abdominis, Kiricuta's epiploic flap, neighboring autoplasties) now persist only in cases of advanced breast tumor in which the greater dorsal flap is contraindicated.

[Ovarian metastases from colorectal cancers. Current place of prophylactic bilateral ovariectomy]. / Métastases ovariennes des cancers colo-rectaux. Place actuelle de l'ovariectomie bilatérale prophylactique.

Ovarian metastases occur in the course of colorectal adenocarcinomas on 3 to 14% of cases. They are bilateral in 50-70% of cases and frequently occult (6 to 25%) and constitute a factor of poor short-term prognosis (median survival: 18 months). After analysing the features of ovarian metastases from colorectal cancers, the authors discuss the current place of prophylactic bilateral oophorectomy in terms of its indications and results. Although this procedure should clearly be performed routinely in postmenopausal patients, it is more controversial in women of reproductive age who, according to some authors, nevertheless constitute a group at high risk of ovarian metastases. The contribution of this prophylactic oophorectomy to the improvement in the prognosis of colorectal neoplasms has not been statistically established to date and needs to be demonstrated by means of prospective studies.

[Treatment of the pelvis after total pelvic exenteration. Experience of the Regional Paul Strauss Cancer Center of Strasbourg]. / Traitement du pelvis après exentération pelvienne totale. Expérience du Centre Régional de Lutte contre le Cancer Paul Strauss de Strasbourg.

Intestinal morbidity after total pelvic exenteration presents usually as fistulae. These appear particularly if irradiation has been carried out in the pelvis or the abdomen before surgery, and particularly as a result of the types of surgery carried out in the emptied pelvis. An analysis of 92 exenterations of the pelvis of which 52 were total exenterations led us to look at how treatments in the pelvis have evolved technically and to analyse the contribution they have made to reducing the number of fistulae and obstructions found as a result of this major surgery. Making a "sac" by packing the pelvis as suggested by the pioneer of this exceptionally extensive pelvic surgery gradually has been replaced by the use of endogenous material such as the omentum and more recently by the use of absorbable synthetic materials (vicryl) which give rise to progressive reperitonealisation. The authors approve of this last way of dealing with the emptied pelvic cavity because the synthetic material is very well tolerated clinically and the polyglactine 910 mesh is not predisposed to infection when it is used to make a hammock to prevent chronic radiation enteritis by holding the small intestines out of the pelvis.

Prevention of radiation enteritis by an absorbable polyglycolic acid mesh sling. A 60-case multicentric study.

Radiation-induced small bowel injury is a limiting factor to postoperative tumoricidal pelvic doses exceeding 4500 to 5000 cGy. Data from a review of the literature showed the inadequacy of medical measures and the bad reproducibility of radiation therapeutic attempts to decrease small intestine damage. Recent studies cited the benefit of a polyglycolic acid mesh to create an absorbable intestinal sling and suspend the loops above the pelvic radiation field. In 60 cases of gynecologic and rectal malignancies with a surgical intestinal morbidity of 8.3% (5 cases), the rate of radiation enteritis was 7% (4 cases) with an average follow-up of 17.8 months (range, 1 to 57 months). The quality of small intestinal elevation and the absence of loop herniation were demonstrated by the barium index. Magnetic resonance imaging was used for checking the polymer polyglycolic acid mesh position and its complete resorption at the third to fifth postoperative month. The authors conclude that this new procedure is safe in selected patients with high pelvic recurrence risk after optimal surgery, in residual disease after debulking surgery, or at the time of exploration for unresectable pelvic tumors. Clinical studies are ongoing to evaluate the long-term efficacy of this surgical technique to prevent chronic radiation enteropathy and improve locoregional control in advanced pelvic carcinomas.

[Role of total thyroidectomy in the treatment of multinodular goiter]. / Place de la thyroïdectomie totale dans le traitement des goitres multihétéronodulaires.

Although it may seem to be excessive, total thyroidectomy has recently been advocated by several authors for the treatment of diffuse multiheteronodular goiters. As a complement to a recent study on the thyroid function following thyroidectomy for benign goiters, the authors specify the role of this surgical technique, which had been reserved for the sole thyroid neoplasms for a long time. On the occasion of the presentation of a series of 75 cases gathered from 1989 to 1990, the justification of glandular resection is based on the publication of new pathogenetic data and on the absence of any increase in morbidity, subject to precise indications and to a strict technique aimed at preserving recurrents and locating the parathyroid glands while maintaining their vasculature. When aimed at reducing the frequency of recurrence of euthyroid and toxic diffuse multinodular goiters, total thyroidectomy might also contribute in reducing the morbidity of second surgery, at the expense of a permanent substitution therapy. While the choice of its indications must remain eclecty, thelong-term consequences of initial surgery with too restricted glandular exeresis must be recognized.

[The value of peritoneal cytology in invasive uterine cancers. Analysis of 80 cases]. / Intérêt de la cytologie péritonéale dans les cancers utérins invasifs. Analyse d'une série de 80 cas.

When they analysed 80 cancers of the uterus, the authors showed how valuable it was both for diagnosis and prognosis to carry out cytological lavage of the peritoneum, particularly in cases of endometrial adenocarcinoma. The results of this study are compared with recent extracts appearing in the international literature. This technique makes it possible to identify groups of patients of high risk for recurrences in the pelvis and abdomen who would benefit from adjuvant therapies, demonstrating that this technique is applicable to the diagnosis of gynaecological cancers with intraperitoneal spread which have long been failed to be recognised. The procedure is innocuous and simple and therefore should be carried out widely in the management of uterine cancers.

[Surgical removal of diaphragmatic metastasis of advanced ovarian cancer. Review of the literature]. / Chirurgie d'exérèse des métastases diaphragmatiques des cancers avancés de l'ovaire. Revue de la littérature.

Many studies have established the close relationship between the survival and the residual tumoral volume after a first maximal cyto-reducing surgery. In that light, the surgical exeresis of the metastatic lesions should facilitate the response to chemotherapy. In this respect, the diaphragm metastases of ovarian cancers prove to be worthy of the highest interest due to the difficulty of their surgical approach. Several techniques for the exeresis of these secondary peritoneal localizations have been reported, using various processes (electrocoagulation, laser vaporization, classic surgical exeresis) and more recently, the ultrasound dissector. After a review of the literature on 43 cases, the authors draw the attention on the approach and surgical exeresis methods for these metastases. If these techniques prove to be quite feasible, with an acceptable morbidity rate, only a great hindsight, together with more observations, will enable the assessment of the benefit in terms of survival.