Metabotropic glutamate receptor 5 antagonist-induced stimulation of hypothalamic-pituitary-adrenal axis activity: interaction with serotonergic systems.

The mGluR5 antagonist 2-methyl-6-(phenylethynyl) pyridine (MPEP) produces anxiolytic or antidepressant effects in several rodent models through incompletely described mechanisms. Anxiolytics and antidepressants share several neuroendocrine features, including acute activation of the hypothalamic-pituitary-adrenal (HPA)-axis, desensitization of neuroendocrine responses with repeated dosing, and desensitization of the HPA axis to 5-HT1A agonist stimulation. We characterized these neuroendocrine parameters in rats treated systemically with MPEP and compared them to those induced by the anxiolytic buspirone. Acutely, MPEP dose-dependently (0.1-10 mg/kg i.p.) increased plasma corticosterone concentrations. These responses were blocked by 50% with the 5-HT1A antagonist WAY100635. The corticosterone responses to both 3 mg/kg MPEP and buspirone were decreased by 80% after 5 days of twice-daily injections. Repeated injection with MPEP decreased HPA-axis sensitivity to buspirone challenge by 75%. This desensitization was not associated with changes in mGluR5 or 5-HT1A receptor binding properties, expression of G-protein subunits coupled to these receptors, or in 5-HT-stimulated binding of [(3)H]-GTPgammaS to membranes. We conclude that MPEP acutely disinhibits the HPA axis, in part through uncharacterized changes in serotonergic signaling. Desensitization of 5-HT1A responses after repeated MPEP administration may indicate that, like other anxiolytics and antidepressants, plasticity in 5-HT signal transduction pathways has occurred.

Reduced cerebrospinal fluid levels of alpha-secretase-cleaved amyloid precursor protein in aged rats: correlation with spatial memory deficits.

The amyloid precursor protein undergoes proteolysis at several sites to yield a number of functionally relevant peptides, including beta-amyloid and the soluble amyloid precursor protein derivatives alpha-soluble amyloid precursor protein and beta-soluble amyloid precursor protein. beta-Amyloid is the primary constituent of senile plaques associated with Alzheimer's disease, while a-soluble amyloid precursor protein promotes synaptogenesis and plays a role in neuroprotective processes. We tested for age-related alterations in these amyloid precursor protein proteolytically derived peptides by measuring the levels of alpha-soluble amyloid precursor protein, total soluble amyloid precursor proteins (alpha- and beta-soluble amyloid precursor protein combined) and beta-amyloid in cerebrospinal fluid from three-, 13- and 23-month-old Fischer-344 rats. Western blot analysis using selective antibodies revealed 50% less total soluble amyloid precursor protein and a-soluble amyloid precursor protein in cisternal cerebrospinal fluid from 23-month-old rats compared with three- and 13-month-old animals. Mass spectrometric analysis indicated, however, that beta-amyloid in cerebrospinal fluid was not different between the three age groups. In a second group of young (five to six months of age) and aged (24-25 months of age) rats, spatial working and reference memory were assessed in a water maze followed by collection of cerebrospinal fluid. As a group, the aged rats consistently performed below the young rats in both working and reference memory tests. The aged rats also had 49% less cerebrospinal fluid alpha-soluble amyloid precursor protein than did their younger counterparts. There was a positive correlation (r= 0.52-0.57, P < 0.001) between performance in spatial memory tasks and cerebrospinal fluid alpha-soluble amyloid precursor protein in these young and aged rats. These results suggest that there is a positive association between cerebrospinal fluid levels of alpha-soluble amyloid precursor protein and cognitive performance in rats, and that alpha-soluble amyloid precursor protein may be involved in the spatial learning and memory changes that accompany ageing.

Ascorbic acid inhibits the squamous metaplasia that results from treatment of tracheal explants with asbestos or benzo[a]pyrene-coated asbestos.

Hamster tracheal explants were maintained in culture in the presence or absence of benzo[a]pyrene (BP), crocidolite asbestos, or BP-coated crocidolite. Dose-dependent squamous metaplasia was observed in the treated samples. L-Ascorbic acid and DL-alpha-tocopherol were able to partially protect the tracheal explants from the metaplastic response induced by crocidolite. Furthermore, ascorbic acid reduced the extent of metaplasia observed in hamster tracheal explants that were exposed to BP-crocidolite.

Laparoscopy in the massively obese female.

Fifteen women weighing more than 250 pounds (113.6 kg) underwent laparoscopy. The open technique was used in two patients electively because of repeated pelvic laparotomies through periumbilical incisions. Of the remainder, four had used the closed technique and in nine it was necessary to adopt an open technique. Use of the latter effectively "lengthened" the instruments. Visualization was excellent in all but one subject, and the only complication was a single case of wound cellulitis.

Primary pure insular ovarian carcinoids.

Ovarian carcinoids are generally found in association with teratomatous elements. Reported are the 23rd and 24th primary pure insular ovarian carcinoids. One of the cases presented initially with carcinoid heart disease.

Paraneoplastic hypercalcemia in ovarian tumors.

Two cases of paraneoplastic hypercalcemia secondary to ovarian tumors are presented. Both cases were secondary to ectopic parathormone (PTH) production. Other mediators postulated to cause this syndrome are prostaglandins, vitamin D-like sterols, non-vitamin D sterols, vitamin A, cortisol, and "osteoclast-activating factor.' The key treatment modalities for acute hypercalcemia are hydration and diuresis with furosemide; phosphates, steroids, antiprostaglandins, and hemodialysis may also be of value. Calcitonin is theoretically the most attractive treatment modality, but the rapid development of resistance limits its use to acute management. Mithramycin is most effective for long-term palliation of hypercalcemia if tumor-directed therapy is unsuccessful. Review of the literature confirms the previously made observation that mesonephromas are disproportionaately represented in association with this syndrome.

Effect of surgical technique on peritoneal adhesion reformation after lysis.

The effectiveness of macrosurgical and microsurgical techniques for adhesion management was evaluated in nonpregnant female baboons that had significant pelvic adhesions as a sequela of previous surgery. Two weeks after the initial laparotomy the animals were reoperated upon and adhesion reformation assessed. Mean adhesion scores were not significantly different between the macrosurgery and microsurgery groups before or after lysis. However, the reduction in the mean adhesion score following lysis approached significance (P less than 0.1) in the microsurgical group, whereas it did not in the macrosurgical group. This study does not confirm that the use of microsurgery in adhesion management is clearly superior but does suggest it may be slightly more effective in reducing adhesion reformation.

Effect of thirty-two per cent dextran 70 on peritoneal adhesion formation and re-formation after lysis.

Thirty-two per cent dextran 70 in dextrose (Hyskon) has been reported effective in limiting adhesion formation following a peritoneal injury when employed in doses larger than that known to be safe for intraperitoneal use in humans. The effectiveness of a lower dosage believed to be safe for human use was investigated. Female rabbits received a standardized injury to their uterine horns and proximal fallopian tubes. Following the injury, Hyskon (2.5 ml/kg of body weight) was dripped over the sites of injury in the treatment group. Animals were reoperated upon 2 weeks later, and adhesions were scored. Hyskon significantly reduced adhesion formation. In a second experiment the effect of Hyskon on adhesion re-formation was evaluated. Adhesions were induced in the same manner. Two weeks later, the animals were reoperated upon, and adhesions were scored and lysed. Hyskon was instilled in the treatment group as in the first experiment. No significant difference was noted between adhesion scores in control and treatment groups after adhesion induction or when re-evaluated 2 weeks after lysis.

Isthmic ectopic pregnancy and salpingitis isthmica nodosa.

Two hundred eighty-five charts were reviewed from patients who underwent surgery for ectopic pregnancy. Excluded were patients with previous tubal reparative surgery, linear salpingotomy, or failed sterilization. The incidence of isthmic ectopic pregnancy in the remaining 255 cases was 15.3%. The association of salpingitis isthmica nodosa (SIN) and isthmic ectopic pregnancy was determined by review of resected tubal segments. SIN was noted in 17 of 37 cases (45.9%) of isthmic ectopic pregnancy. SIN places the patient at risk for recurrent ectopic pregnancy or infertility. Recommended conservative management of isthmic ectopic pregnancy is segmental resection with postoperative emphasis on documentation of SIN when present. Postoperative hysterosalpingography is recommended with an abnormal contralateral tube or when SIN is noted in the resected tubal segment. Management options after an isthmic ectopic pregnancy when future fertility is desired are presented.

An endometrial antibody assay in the clinical diagnosis and management of endometriosis.

Coded serum samples from 11 normal fertile men and 17 fertile women without endometriosis (control groups) and 41 women with endometriosis were tested blindly for the presence of endometrial antibodies by use of a passive hemagglutination assay. Endometrial antibodies were either absent or present in low baseline titers in the serum samples from the control group. In contrast, 17 of the 23 (74%) patients with untreated endometriosis had elevated titers of endometrial antibodies in their serum. Of the 18 patients treated with danazol, endometrial antibodies were absent in 7 women who showed a good response at repeat laparoscopy, whereas 4 of 5 women with a poor response had significantly positive titers of antibodies. Six patients treated with danazol did not have repeat laparoscopy, but were found to have endometrial antibody titers in the baseline control range. Endometrial antibody titers in women with a good response to danazol were significantly lower than those in women with untreated endometriosis or with a poor response to danazol (P = 0.003). No correlation was observed between the antibody titers and the stage of endometriosis. The results suggest that the assay for serum endometrial antibodies may prove to be a clinically useful, noninvasive aid in the diagnosis of endometriosis. Sequential determination of endometrial antibody titers may be helpful in assessing the efficacy of pharmacologic therapy for endometriosis and evaluating the cases of patients with possible recurrence of the disease.

Interleukin-1: a possible role in the infertility associated with endometriosis.

Increased numbers of activated macrophages are associated with mild endometriosis. Interleukin-1 (IL-1) is a protein produced by macrophages and is believed to be a primary mediator of host responses. IL-1 induces prostaglandin and fibrinogen synthesis and stimulates fibroblast proliferation. This study was undertaken to evaluate the role of IL-1 in the infertility associated with mild endometriosis. Peritoneal fluid (PF) was obtained at laparoscopy from 11 patients with minimal or mild endometriosis and from 7 women undergoing tubal ligation. Peritoneal macrophages were isolated and cultured for 24 hours. Peritoneal and macrophage culture fluids were studied for IL-1 activity, which was measured with the EL-4 assay. IL-1 activity was present in the PF of 10 of the 11 patients with endometriosis and 11 of the 11 macrophage culture fluids and was absent in the PF and macrophage culture fluid of the tubal ligation patients. The effect of recombinant alpha-IL-1 on the in vitro growth of 2-cell mouse embryos was also studied. IL-1 in concentrations similar to those present in the PF (greater than 1 U/ml) was toxic to mouse embryo development. We conclude that the IL-1 may play a role in the infertility associated with endometriosis.

Sperm motility on postcoital testing correlates with male autoimmunity to sperm.

To assess whether or not immunologic factors in husbands, wives, or both, influence the motility of sperm in the female reproductive tract, hemagglutination and cytotoxicity sperm antibody (Ab) assays and postcoital tests (PCTs) were performed in 293 infertile couples. More couples without male autoimmunity to sperm (64% of 66; P less than 0.001) had greater than or equal to 10 motile sperm per high power field (adequate PCT), as compared with 26% of 122 couples with untreated male autoimmunity, 19% of 77 couples with corticosteroid-treated male autoimmunity without a pregnancy, and 36% of 28 couples with successfully treated male autoimmunity to sperm. Good correlation was obtained among pregnancy achievement, lack of sperm antibodies, and adequate sperm motility in the PCT (P less than 0.0001). Sperm motility in the PCT correlated positively with sperm motility in the semen and inversely with cytotoxic sperm Ab in the serum and seminal plasma of men and women and hemagglutinating sperm Ab in the cervical mucus samples. Sperm motility in the PCT has a predictive value of 72% for male autoimmunity and 57% for female isoimmunity to sperm in the presence of normal cervical mucus and in the absence of infections.

Plasma androgens, 17 beta-estradiol, and sex hormone-binding globulin in patients with hirsutism and/or clitoromegaly.

Plasma androgen, 17 beta-estradiol, and sex hormone-binding globulin (SHBG) levels were measured in 11 normal subjects (group 1), 18 hirsute patients with no clitoromegaly (group 2), 13 hirsute patients with clitoromegaly (group 3), and 8 patients with clitoromegaly but no hirsutism (group 4). Significantly elevated levels of testosterone (T) and dihydrotestosterone (DHT) were found in groups 2 and 3 but not in group 4 when compared with group 1. In contrast, levels of dehydroepiandrosterone (DHEA) in groups 1 and 2 were comparable but significantly lower than those in group 3 and 4; the levels in the latter two groups were not significantly different from each other. In groups 2, 3, and 4, levels of androstenedione (delta 4A) and the factor T/SHBG were significantly elevated whereas SHBG levels were significantly suppressed when compared with those of group 1. The clitoral index correlated (P less than 0.01) with DHEA levels in group 3. It is concluded that clitoromegaly without hirsutism is associated with increased plasma levels of DHEA and delta 4A. In contrast, hirsutism without clitoromegaly is associated with elevated levels of T, DHT, and delta 4A but normal DHEA levels.

Prevention of postoperative adhesions.

PIP: Recent laboratory and clinical studies concerning the pathogenesis and prophylaxis of postoperative peritoneal adhesions are reviewed. Since the late 19th century there have been several clinical and experimental observations demonstrating that peritoneal defects usually fail to heal with adhesion formation. Instead, mesothelization takes place, producing a surface indistinguishable from the original. This occurs from the base of the defect, meaning large defects heal as quickly as smaller defects. In a study conducted in rats (Ellis), it was noted that areas reperitonealized under tension developed adhesions while similar peritoneal defects left unrepaired and suture controls placed loosely in peritoneum usually healed without adhesions. These findings were confirmed by Buckman and coworkers who discovered that plasminogen activator activity was normally present in the mesothelium and submesothelial blood vessels of peritoneum. 2 other peritoneal insults known to induce adhesion formation are infection and foreign body contamination. Theoretically, it seems possible to reduce adhesion formation by taking the following steps: 1) reducing the initial inflammatory reaction and subsequent exudate release; 2) inhibiting coagulation of this exudate; 3) promoting the removal of fibrin deposition; 4) mechanically separating fibrin-covered surfaces; and 5) inhibiting fibroplastic proliferation. Adhesions continue to be a frequent sequelae of pelvic surgery despite the use of meticulous surgical technique. Although dextran solutions appear promising, their clinical value is unconfirmed.^ieng

Galactorrhea in oral contraceptive users.

One hundred women who had been employing combination estrogen/progestin oral contraceptives (OCs) for a minimum of six consecutive months were evaluated for the presence of galactorrhea. It was found in 9%. The incidence did not vary significantly with age, gravidity, duration of OC use of estrogen content. Only six subjects had breast fed previously, preventing assessment of the effect this may have on the incidence of galactorrhea. Twelve OC users with galactorrhea were evaluated for the presence of pituitary microadenomas. Two had radiologic and hormonal findings consistent with the presence of prolactinomas, one had functional hyperprolactinemia, one had an empty sella, one had a partially empty sella, and two with normal basal prolactin levels had both polytomography and computerized axial tomography findings suggestive of pituitary microadenomas. Galactorrhea in OC users who have not breast fed is frequently associated with significant intrasellar pathology and should be an indication for further evaluation.

Luteinized unruptured follicle syndrome in mild endometriosis. Assessment with biochemical parameters.

Failure to extrude an ovum, with subsequent luteinization of the unruptured follicle (LUF), has been proposed as a cause of infertility in women with mild endometriosis. To assess the incidence of this process we performed laparoscopies in the early luteal phase on 16 women with mild endometriosis and 8 control subjects. Peritoneal fluid was aspirated and a plasma sample obtained concurrently. Estradiol (E2) and progesterone (P) concentrations were determined. A review of the literature suggested that the following hormonal criteria correlated with follicular rupture: fluid E2 greater than or equal to 500 pg/ml, E2 fluid/plasma ratio greater than or equal to 3.1, fluid P greater than or equal to 3,000 ng/dl and P fluid/plasma ratio greater than or equal to 5:1. All control subjects met at least one E2 and one P criterion: 75% met all. In contrast, less than one-third with mild endometriosis met all, and three (19%) met none. Five met only E2 criteria. These findings suggest that LUF occurs occasionally in association with mild endometriosis. Additionally, ovarian steroidogenesis, particularly P secretion, was impaired frequently in the absence of LUF in women with endometriosis.

Dual-image video endoscopy.

The use of a digital audio-video mixer is advocated when concurrent endoscopic procedures, such as laparoscopy and hysteroscopy, are performed. The device can also assist in postproduction work.