Pitfalls in the use of lead nitrate for the histochemical demonstration of adenylate cyclase activity.

The biochemistry of the lead histochemical technique for demonstrating adenylate cyclase was studied. The enzyme activity of fat cell plasma membranes, using 5'-adenylyl-imidodiphosphate (AMP-PNP) as substrate, was completely inhibited at 1 times 10- minus 4 M Pb(NO3)2 and yet at 4 times 10- minus 3 M Pb(NO3)2 precipitate could be demonstrated by electron microscopy on both sides of plasma membrane vesicles. No lead-diphosphoimide or lead-phosphate precipitate could be visualized by electron microscopy when the lead was reduced to a level (2 times 10- minus 5 M) which caused only 50% inhibition of the enzyme. A solubility product coefficient of 1 times 10- minus 10 M was found necessary to allow precipitation of lead-phosphate complex in the adenylate cyclase medium. Varying the ratio of substrate or dextran relative to the lead failed to protect the inhibition of the enzyme. Increasing concentrations of beta-mercaptoethanol restored the basal and stimulated activity of adenylate cyclase but also prevented the precipitation reaction. Lead at 2 times 10- minus 3 M caused the nonenzymatic hydrolysis of AMP-PNP, resulting in the production of small but significant quantities of cyclic AMP and substantial amounts of AMP. This hydrolysis was inhibited by alloxan but unaffected by dextran of NaF. The adenylate cyclase activity of pancreatic islet homogenates and of fat pad capillaries was completely inhibited by lead concentrations equal to or less than those used in histochemical studies (Howell, S. L., and M. Whitfield. 1972. J. Histochem. Cytochem. 20:873-879. and Wagner, R. C., P. Kreiner, R. J. Barrnett, and M. W. Bitensky. 1972. Proc. Natl. Acad. Sci. U.S.A. 69:3175-3179.). The present study shows that the lead histochemical method cannot be used for localization of adenylate cyclase because of the inhibition of the enzyme and artifacts produced by high lead concentrations and the inability to produce a visible precipitate at low lead concentrations which only partially inhibit the enzyme.

Replacing an inpatient electronic medical record. Lessons learned from user satisfaction with the former system.

OBJECTIVE: Since it is important to develop strategies for the successful implementation of electronic clinical information systems, the aim of this study is to explore where, and to what extent, users' attitudes toward the former system that is being replaced may vary. METHODS: A cross-sectional survey of 346 nurses and physicians practicing in two Canadian teaching hospitals resulted in a total response rate of 63%. User attitudes were measured in three dimensions: a) user satisfaction with the system's quality attributes, b) perceived system usefulness, and c) perceived impact on quality of care and patient safety. The current system (the one being replaced) was analyzed as a dual system composed of both paper-based and electronic records. RESULTS: The results on user satisfaction demonstrate a wide variation in opinions, with satisfaction ranging from 4.2 to 7.7 on a 10-point disagree-agree, Likert scale. The quality attributes varied by record type, with differences that were systematically in favor of the electronic record component, which received higher scores. The results also highlighted large differences by user group. Physicians and nurses systematically rated the two record formats differently. The nurses were more satisfied with the attributes of the paper-based record. Multivariate regression analyses results also revealed strong interdependencies among the three dimensions of user attitudes, to the extent that perceived system usefulness was strongly correlated with system quality attributes and the system outcomes were also correlated, although less strongly, with the two former system dimensions. CONCLUSION: Understanding users' attitudes toward a clinical information system in use, both in its paper and electronic aspects, is crucial for developing more successful implementation strategies for electronic record systems.

[Child tuberculosis at the teaching hospital of Brazzaville from 1995 to 2003]. / La tuberculose chez l'enfant au CHU de Brazzaville de 1995 à 2003.

In the paediatric service of the teaching hospital of Brazzaville, 582 files of children hospitalized were studied from January 1995 to December 2003. To determine tuberculosis frequency among sickle cell children and estimate the clinical and paraclinical aspects, a case-control study of tubercular patients with HIV negative serology was carried out by comparing at the same time a cohort of 75 sickle cell patients versus 125 patients without sickle cell disease. The results of these studies are as follows. The main assessment is the high frequency of tuberculosis. In 1995 the tuberculosis rate reaches 8%, in 2003 it was up to 13.6%, and 20.6% in 2000 due to the serious consequences of the recurrent wars between 1993 and 1999. Another cause of that high frequency is the rate of HIV/aids patients with a frequency of 2.5% of hospitalization ranging from 1.6 to 3.2%, among them 35% of the tubercular patients were seropositive. The tuberculosis prevalence was 7.4% among sickle cell patients versus 14.2% among control patients. Infection was more often identified in control patients (51.2%) than in sickle cell patients (24%). 68% of the parents were really poor and 18.5% of the children were evicted from their home by war. The pulmonary localizations were prevailing in groups of patients with sickle cell disease as well as in group of control patients. Pleuritis was observed in 8% of the patients with sickle cell disease versus 16.8% for control patients (P = 0.02). No patient with sickle cell disease had a miliary. Anergia to tuberculin test was reported in 35.8% sickle cell patients versus 10.4% for the control patients (P = 0.001). Tuberculosis prevalence is higher among control patients than in sickle cell patients. The high proportion of clinical and paraclinical data of tuberculosis did not significantly differ from the two groups. Evolution was good for 98% of the patients, 1.4% of them died; 74% of deceased patients were affected by HIV/aids.

A sphingosine-1-phosphate receptor 1 agonist inhibits tertiary lymphoid tissue reactivation and hypersensitivity in the lung.

Hypersensitivity pneumonitis is characterized by pulmonary accumulation of B-cell-rich tertiary lymphoid tissues (TLTs), which are alleged sites of amplification for antigen-specific responses. The sphingosine-1-phosphate receptor 1 (S1P1) regulates key mechanisms underlying lymphoid tissue biology and its chemical modulation causes lymphocyte retention in lymph nodes. Given the putative immunopathogenic impact of lymphocyte accumulation in TLTs, we investigated whether or not chemical modulation of S1P1 caused lymphocyte retention within TLTs in a model of hypersensitivity pneumonitis. Mice were exposed subchronically to Methanosphaera stadtmanae (MSS) in order to induce an hypersensitivity pneumonitis-like disease. MSS exposure induced B-cell-rich TLTs surrounded by S1P1-positive microvessels. Upon MSS rechallenge, the S1P1 agonist RP001 prevented the pulmonary increase of CXCL13, a chief regulator of B-cell recruitment in lymphoid tissues. This was associated with a complete inhibition of MSS rechallenge-induced TLT enlargement and with a 2.3-fold reduction of MSS-specific antibody titers in the lung. Interference with TLT reactivation was associated with a 77% reduction of neutrophil accumulation and with full inhibition of protein-rich leakage in the airways. Thus, an S1P1 agonist hinders TLT enlargement upon antigenic rechallenge and inhibits key pathognomonic features of experimental hypersensitivity pneumonitis.

[Tuberculosis and HIV/AIDS co-infection in children: experience carried out in paediatric service of the teaching hospital of Brazzaville, Republic of Congo (1995-2004)]. / Tuberculose et infection dues au VIH/sida chez l'enfant: expérience du service de pédiatrie du CHU de Brazzaville, Congo (1995-2004).

Epidemiologic, clinical and paraclinical data of 126 children with tuberculosis whose HIV status was known, have been compared. Among them, 65% were HIV positive, the co-infection tuberculosis HIV/AIDS was observed in all social categories. The source of contamination was discovered for 72% of the patients. The mother was involved in 47.5% of cases. The main reasons of consultation were a long standing fever a chronic cough and a weight loss. Diarrhea was mainly observed in positive HIV patients (p = 0.00). The general condition was influenced by a weight loss which was more important in positive patients with a IMC lower than 10 in 12.8% of cases. There was no significant difference between all clinical forms. Digital hippocratism, chronic otitis and parotiditis were only observed in positive HIV patients with skin illness ten times more frequent (p = 0.00). Anergia to tuberculin tests (78.4%) and a sedimentation speed up to 100 mm at the first hour were observed in more than 60% of the positive HIV patients (p = 0.001). Evolution was favorable under treatment for 84% of positive HIV patients with an increasing weight becoming weaker after one month of treatment. All deaths happened among that population.

[Recurrent quadric paralysis in an 11-year-old girl with spinal tuberculosis]. / Tétraplégie récidivante chez une enfant de 11 ans présentant un mal de Pott cervical.

The authors report a recurring quadric paralysis in a 11-year-old girl with cervical, pulmonary and mediastinal tuberculosis. The diagnosis was belated. After the first treatment with anti tuberculosis drugs and immobilization with a surgical collar, an improvement has been obtained; but at the 8th month of this treatment, a partial paralysis of superior members and total paralysis of inferior members appeared. A treatment with streptomycin, ethambutol, rifampicin, pyrazinamide, isoniazide, and prednisone was undertaken. The spontaneous motility was observed at 37 days of treatment. However, at the 8th months of this treatment, quadric paralysis happened again after a fall down. After immobilization with a new surgical collar and prednisone, the spontaneous motility came back again 3 months later.

Electrophysiological and molecular identification of hepatocellular volume-activated K+ channels.

Although K+ channels are essential for hepatocellular function, it is not known which channels are involved in the regulatory volume decrease (RVD) in these cells. We have used a combination of electrophysiological and molecular approaches to describe the potential candidates for these channels. The dialysis of short-term cultured rat hepatocytes with a hypotonic solution containing high K+ and low Cl- concentration caused the slow activation of an outward, time-independent current under whole-cell configuration of the patch electrode voltage clamp. The reversal potential of this current suggested that K+ was the primary charge carrier. The swelling-induced K+ current (IKvol) occurred in the absence of Ca2+ and was inhibited with 1 microM Ca2+ in the pipette solution. The activation of IKvol required both Mg2+ and ATP and an increasing concentration of Mg-ATP from 0.25 through 0.5 to 0.9 mM activated IKvol increasingly faster and to a larger extent. The KCNQ1 inhibitor chromanol 293B reversibly depressed IKvol with an IC50 of 26 microM. RT-PCR detected the expression of members of the KCNQ family from KCNQ1 to KCNQ5 and of the accessory proteins KCNE1 to KCNE3 in the rat hepatocytes, but not KCNQ2 and KCNE2 in human liver. Western blotting showed KCNE3 expression in a plasma membrane-enriched fraction from rat hepatocytes. The results suggest that KCNQ1, probably with KCNE2 or KCNE3 as its accessory unit, provides a significant fraction of IKvol in rat hepatocytes.

Specific fragmentation of human erythrocyte spectrin by chemical cleavage at cysteine residues.

Spectrin, isolated from human erythrocyte membrane, was specifically cleaved at the amino side of its cysteine residues by reacting it with 2-nitro-5-thiocyanobenzoic acid at pH 8.0 and incubating the product at pH 9.0. Conditions were developed to obtain quantitative cleavage, with virtually no side reactions due to exposure to the alkaline pH. The solubility and aggregation state of the spectrin fragments in 0.2 M sodium chloride, in 7 M guanidine hydrochloride or in 10 M urea, at pH 8.0, allow separation and partial purification of the fragments by gel filtration or by ion-exchange chromatography. Our results strongly suggest that various parts of the spectrin molecules have similar amino acid compositions. Due to the relatively limited number of fragments, this cleavage method is a promising tool for further elucidation of the structure of spectrin and for understanding its role in the erythrocyte membrane.

The effects of flaxseed dietary supplement on lipid profile, bone mineral density, and symptoms in menopausal women: a randomized, double-blind, wheat germ placebo-controlled clinical trial.

Phytoestrogens are increasingly incorporated into the diet of menopausal women. However, there are limited data on the efficacy of flaxseed on the consequences of estrogen deficiency in menopausal women. The purpose of the study was to assess the effects of flaxseed incorporation into the diet of healthy menopausal women. One hundred and ninety-nine menopausal women were randomly assigned to consume 40 g flaxseed/d (n = 101) or wheat germ placebo (n = 98) for 12 months. At baseline and at month 12, serum levels of lipids, bone mineral density (BMD), and menopausal symptoms were evaluated. Statistical analysis was performed under the intention to treat principle. Flaxseed reduced serum total (-0.20 +/- 0.51 mmol/liter; P = 0.012) and high-density lipoprotein (-0.08 +/- 0.24 mmol/liter; P = 0.031) cholesterol concentrations compared with wheat germ placebo. BMD did not differ significantly between the two arms. Both flaxseed and wheat germ reduced (P < 0.0001) the severity scores of menopausal symptoms, but no statistical difference was found between the two arms. Our findings suggest that 1-yr incorporation of flaxseed into the diet produced a favorable, but not clinically significant, effect on blood cholesterol and caused no significant change in BMD or symptoms in healthy menopausal women.

Sequential estrogen-progestin addition to gonadotropin-releasing hormone agonist suppression for the chronic treatment of ovarian hyperandrogenism: a pilot study.

The purpose of the study was to evaluate the efficacy and safety of a sequential regimen of estrogen-progestin addition to GnRH agonist suppression in ovarian hyperandrogenism. Eight patients presenting with a polycystic ovary syndrome were treated with an sc implant of GnRH agonist every 4 weeks for 48 weeks. Starting at week 9, patients were replaced with 100 micrograms transdermal estradiol patches continuously and sequentially combined with 10 mg oral medroxyprogesterone acetate the last 2 weeks of each 4-week period. The rapid down-regulation of the pituitary-ovarian axis led to significant reduction of testosterone and androstenedione to 48.9% and 67.4% of baseline, respectively. During steroid replacement, testosterone and androstenedione continued to decrease gradually. The baseline hirsutism score (18.7 +/- 1.3) progressively fell to 9.7 +/- 2.0 at the end of treatment. The mean hair diameter was significantly reduced (0.097 +/- 0.004 vs. 0.081 +/- 0.005 mm). A withdrawal bleeding was obtained in 63.6% of the artificial cycles, but breakthrough bleeding occurred during 48% of the sequential replacements. The incidence of menopausal symptoms was low. There was a nonsignificant decrease in bone mineral content of the lumbar spine and the femoral neck but no trend in Ca2+/creatinine and OH-proline (OH-P)/creatinine ratios or in serum triglycerides and cholesterol fractions. There was a nonsignificant increase in hirsutism score in five patients followed up for 24 weeks after cessation of treatment, although there was a rapid return of hormones toward baseline and recurrence of irregular bleeding. Transdermal estradiol addition periodically combined with medroxyprogesterone acetate is effective in reducing hirsutism and is safe in minimizing side effects and bone loss. A regimen allowing a better bleeding control would make this approach a valuable alternative for prolonged or repeated palliative treatment of excessive hair growth and irregular bleeding in polycystic ovary syndrome.

Fourteen-day versus twenty-one-day regimens of intermittent intranasal luteinizing hormone-releasing hormone agonist combined with an oral progestogen as antiovulatory contraceptive approach.

This study was designed to determine the effect of discontinuous administration of a LHRH agonist on pituitary-ovarian function in normal women. The LHRH agonist buserelin (200 micrograms/12 h or 400 micrograms/24 h) was given intranasally for four consecutive cycles for 14 or 21 days in 26 normally cycling women. Five milligrams of medroxyprogesterone acetate were given orally twice daily from days 15-21. There was a 7-day pause between each medication cycle. Blood samples were drawn every other day for RIA of LH, FSH, estradiol (E2), and progesterone (P). Serum FSH increased for only a few days at the beginning of each cycle, whereas sustained elevation of serum LH occurred during LHRH agonist administration. Serum E2 increased rapidly and remained elevated during the administration of buserelin. Serum P remained in the follicular phase range or increased briefly after the initiation of buserelin occasionally in the 14-day regimens. After discontinuation of buserelin, E2 fell rapidly, and uterine withdrawal bleeding occurred. During the pause, FSH increased progressively. The patterns of gonadotropin response to buserelin were similar in the four cycles. Based on measurement of the areas of the response curves, serum LH and E2 levels were higher during the administration of 200 micrograms/12 h compared to 400 micrograms/24 h buserelin. However, down-regulation of the pituitary-ovarian axis, as evaluated by the acute gonadotropin response to buserelin on day 14, was more pronounced with 200 micrograms/12 h than with 400 micrograms/24 h. Breakthrough bleeding occurred in the 14-day schedules, whereas withdrawal bleeding occurred during the pause in the 21-day schedules. The immediate cycles following buserelin administration were normal ovulatory cycles. Intermittent LHRH agonist administration for 21 days avoided constant down-regulation of the pituitary-ovarian axis and allowed regular uterine bleeding. Combined with an appropriate P complement, it could be a useful contraceptive approach.

Attenuation of mild hyperandrogenic activity in postpubertal acne by a triphasic oral contraceptive containing low doses of ethynyl estradiol and d,l-norgestrel.

The effect of a low dose triphasic oral contraceptive (OC) was evaluated during a 6-month treatment period in 41 patients (mean age, 25.4 +/- 0.7 yr) who had grade I-IV postpubertal acne and normal menses. The OC contained three dose levels of ethynyl estradiol and dl-norgestrel. Acne lesions were assessed, and serum androgen levels were measured during a control cycle and between days 17-21 of treatment cycles 1, 2, 3, and 6. Four patients dropped out after 3 months of treatment. Acne was significantly improved after the first OC cycle. After six cycles, the number of comedones had decreased by 79.6 +/- 3.2% (range, 50-100%) in 69.4% of the patients. Mean baseline levels of testosterone, 17-hydroxyprogesterone, and dehydroepiandrosterone sulfate were in the upper third of the normal range, with elevated individual values in 18.9%, 36.5%, and 26.8% of the women, respectively. Mean baseline levels of androstenedione, free testosterone (T), and 3 alpha-androstanediol glucuronide (3 alpha-diol-G) were above the normal range, with elevated individual values in 51.2%, 75.0%, and 85.4% of the patients, respectively. Sex hormone-binding globulin (SHBG) levels were below the normal range in 26.8% of the cases. At the end of the first OC cycle, there was a significant (P less than 0.01) decrease in all androgen precursors and a 2-fold increase in SHBG. Androstenedione and free T decreased into the normal range during OC intake. Serum 3 alpha-diol-G levels remained elevated, but had decreased by 34.5% at cycle 6 (P less than 0.05). These results show that the triphasic OC has significantly improved acne in postpubertal women for whom acne was the main manifestation of mild hyperandrogenic activity. The improvement in acne corresponded to a decrease in adrenal/ovarian androgens and free T, which led to a decreased metabolism to 3 alpha-diol-G, presumably by the sebaceous glands. The increase in SHBG is considered an estrogenic effect, and the triphasic formulation containing low dose dl-norgestrel is not androgenic but, rather, an estrogen-dominant formulation; as such, this product is recommended in women requiring contraception who also have idiopathic acne.

Effect of finasteride, a 5 alpha-reductase inhibitor, on serum gonadotropins in normal men.

Testosterone exerts negative feedback control on gonadotropin secretion either directly, after aromatization to estradiol, or after 5 alpha-reduction to dihydrotestosterone (DHT). Conflicting data exist as to the role of DHT in the modulation of this negative feedback. To determine whether suppression of endogenous DHT alters gonadotropin secretion, we gave the selective 5 alpha-reductase inhibitor finasteride (5 mg daily), or placebo, to 20 healthy men for 28 days. Basal and GnRH-stimulated LH, bioactive LH, FSH, testosterone, and DHT levels were measured before and after 14 and 28 days of treatment. Basal DHT fell from 1.1 +/- 0.2 to 0.15 +/- 0.04 nmol/L after 28 days of finasteride treatment. A significant rise in baseline testosterone from 17.6 +/- 2.0 to 18.3 +/- 2.3 nmol/L was seen at 14 days (P = 0.046), but not at 28 days. No significant changes were seen in either basal or GnRH-stimulated gonadotropin levels on any day. We conclude that suppression of serum DHT levels with 5 mg finasteride daily in healthy young men has no discernible effect on serum gonadotropin levels.

Melatonin-and serotonin-stimulated release of vasopressin from rat neurohypophysis in vitro.

In order to study the control of vasopressin-release, the effect of a series of potential agents was studied in an in vitro perifusion system of rat neurohypophysis after in vivo treatment with nialamide, a monoamine oxidase inhibitor. In this system, metlatonin stimulated vasopressin-release in a dose-dependent manner (1 x 10-8 to 1 x 10-3 M). Serotonin (1 x 10-3 M) also led to a significant increase of vasopressin-release whereas quipazine (1 x 10-3 M), a putative serotonin agonist and monoamine oxidase inhibitor, caused a 3-fold stimulation of the release of the neurohormone. The stimulatory effects of melatonin and serotonin were prevented by omission of Ca2+ combined to an excess of Mg2+ (12mM) in the perifusion medium. 1 x 10-6 M somatostatin did not affect basal or melatonin-stimulated vasopressin-release. These results show that melatonin and serotonin can have a direct stimulatory effect on vasopressin release at the neurohypophyseal level.

Decreased amounts of antibodies to 22 and 18 kDa antigens in the peritoneal fluid of patients with endometriosis

Accumulated evidence implicates immunological alterations in endometriosis. The purpose of this study was to look for variations in antibodies to distinct antigens in peritoneal fluid of women with and without endometriosis. Peritoneal fluid was aspirated from 17 women undergoing laparoscopy for tubal ligation and 37 patients complaining of symptoms of pain and/or infertility. Peritoneal fluid antibodies to a standard preparation of peritoneal fluid antigens were detected by Western blot analysis using peroxidase-labelled anti-human immunoglobulin G antibodies specific to the Fc region. Antibodies to distinct antigens were quantified by estimating the ratio of the relative optical density between samples and a standard amount of antibodies. Marked changes were found in the antibody detection to two antigens having apparent molecular weights of 22 and 18 kDa. The intensity of the antibody signal was significantly weaker in the peritoneal fluid from endometriosis patients (0.36 ± 0.06 and 0.46 ± 0.06) compared with that in women without endometriosis (0.62 ± 0.08 and 0.75 ± 0.06). It was also weaker in patients without endometriosis presenting with infertility (0.36 ± 0.07 and 0.47 ± 0.08), but only the 18 kDa antigen result was significant. After adjusting for infertility, the P values for the 18 and 22 kDa bands were 0.03 and 0.28 (not significant) respectively in the group of endometriosis patients. These changes were not related to the phase of the menstrual cycle. These data suggest an alteration in the immune response to two distinct antigens in the peritoneal fluid from women with endometriosis and infertility. Further evaluation of these two antigens and their antibodies would be of interest to help understand endometriosis and its associated infertility. Keywords: antibodies/antigens/endometriosis/peritoneal fluid/Western blot analysis

Reference values for the oral glucose tolerance test at each trimester of pregnancy.

A 100-gram oral glucose tolerance test (OGTT) was performed on a selected group of normal women at each trimester of pregnancy to establish reference values for hyperglycemia and hypoglycemia. Ninety three OGTT were performed in the first trimester, 121 in the second trimester, and 98 in the last trimester. The fasting serum glucose did not differ significantly between the trimesters. The values at 60 and 120 minutes were significantly different for the fifth, fiftieth, and ninety-fifth percentiles between each trimester of pregnancy. For the 180-minute readings, the fifth and fiftieth percentiles were not significantly different between the first and second trimester of pregnancy, but the results of the third trimester were significantly higher than those of the other trimesters. The mean fasting insulinemia remained relatively constant during pregnancy. Insulin response to OGTT increased during the progression of the pregnancy. The interpretation of the glucose tolerance tests during pregnancy, either to detect gestational diabetes or hypoglycemia, should take these physiologic changes into account.

Bone mass in endometriosis patients treated with GnRH agonist implant or danazol.

Before treatment, the trabecular bone mineral content of the lumbar spine and femoral neck was not significantly different between endometriosis patients and age-matched controls (N = 26). In 17 subjects treated with a monthly goserelin implant, serum estradiol (E2) levels were suppressed into the menopausal range. Mean decreases from pre-treatment values in the lumbar spine and femoral neck were -5.7 and -3.8% at 3 months and -8.2 and -7.7% at 6 months of treatment, respectively; lumbar spine values were significantly different (P less than .05) from those of the control group, whose values changed little during the same period. Significant increases over baseline values were also observed in urinary calcium-creatinine ratio and serum alkaline phosphatase. In nine danazol-treated subjects, serum E2 levels were generally within the early follicular-phase range. There were no significant changes in bone assessments. Normal menses returned within 2 months after cessation of either medication. Six months after goserelin treatment, the lumbar spine and femoral neck bone mineral content was still reduced but to values not significantly different from the pre-treatment and control values; urinary calcium-creatinine ratio was decreased, whereas serum alkaline phosphatase was still elevated. The rapid and deep suppression of ovarian steroidogenesis by a monthly goserelin implant induced significant bone loss compared with the control and danazol groups. This loss was not reversed completely 6 months after cessation of treatment, but bone densities at that time were not different from those of controls. Studies of larger numbers of patients followed for longer periods will be required to resolve the question of complete reversibility.

Biological markers in major psychosis and alcoholism: phenotypic and genotypic markers.

Some basic concepts and trends which appear to be essential in the search for biological markers in mental disorders are discussed. Comments related to major psychosis and alcoholism are presented under three headings: (i) heterogeneity of disorders (ii) multifactoriality of disorders and (iii) mental disorders as genetically influenced disorders. Tentative classification and terminology of biological markers are given. Various types of phenotypic markers are discussed and alcoholism is taken as a model for a more detailed discussion of available putative phenotypic markers and of research strategies to be used, namely the pharmacological challenge in high risk subjects (e.g. ethanol and TRH challenge). Some highlights from the field of DNA markers are described, mainly the basic procedures which may be used to investigate genetic aspects of mental disorders by recombinant DNA technology.

Potential new treatment of endometriosis: reversible inhibition of pituitary-ovarian function by chronic intranasal administration of a luteinizing hormone-releasing hormone (LH-RH) agonist.

PIP: This paper reports on the case of a 30 year old woman suffering from pelvic endometriosis, dyspareunia, and postcoital bleeding. The patient was treated for 173 days, starting on the 7th day of the cycle, with intranasal administration of 300 mcg of Buserelin, a luteinizing hormone-releasing hormone (LH-RH) agonist, every 12 hours. During the treatment period basal luteinizing hormone (LH) and estradiol (E2) levels were measured at various time intervals. Buserelin caused a marked inhibition of pituitary and ovarian function 2 weeks after inception of treatment. Basal LH levels were low, and serum E2 levels were decreased below those usually found in the early follicular phase. The hormonal inhibition lasted for the entire treatment period, and the only side effects were hot flashes. After 2 months of treatment dyspareunia and postcoital bleeding had almost disappeared; laparoscopy at the end of treatment showed a marked regression of endometrial lesions. Ovulation returned spontaneously after only 43 days of treatment, and regular menstrual cycles appeared shortly after termination of treatment. This prompt return to normal ovarian function should be particularly advantageous for patients seeking pregnancy. This study shows that LH-RH treatment could be a valuable approach for the medical treatment of endometriosis; however, this is only a preliminary report, and further investigation is needed before it can be safely stated that LH-RH agonist is an effective drug for the longterm treatment of endometriosis.^ieng

Ovarian sonographic findings during intermittent intranasal luteinizing hormone-releasing hormone agonist sequentially combined with an oral progestogen as antiovulatory contraceptive approach.

Ovarian ultrasounds were performed in four groups of six or seven women taking intranasal luteinizing hormone-releasing hormone agonist Buserelin (200 micrograms twice daily or 400 micrograms once daily) for periods of 14 or 21 days. Medroxyprogesterone acetate (5 mg by mouth twice daily) was added on days 15 to 21. A pause of 7 days followed each of the four treatment periods. Between days 12 to 15 of the first Buserelin cycle, sonograms showed in 17 cases (68%) various degrees of follicular stimulation ranging from numerous 4- to 10-mm follicles (24%), to 10- to 27-mm developing follicle(s) (24%), to greater than 27-mm ovarian cysts (20%). At the fourth Buserelin cycle, the predominant observation was large follicle(s) in the 14-day schedules, whereas ovarian scans did not reveal follicular stimulation in 66% of the 21-day schedules. The area under estradiol (E2) curves was above control in cycles with induced large follicles mainly in the 14-day schedules at the 200 micrograms/12 hour dose. Occasional brief and low elevation of progesterone was compatible with luteinized follicles. In the 21-day schedules at 400 micrograms/24 hours, absence of follicular development was frequently associated with serum E2 in the early follicular phase range. The most appropriate dosage regimen for potential contraception was 200 micrograms/12 hours for 21 days because it was associated with small follicles and serum E2 was in the range of control cycles.

PIP: This study was aimed at evaluating the ovarian changes during intermittent luteinizing hormone-releasing hormone agonist (LH-RH-A) administration. Ovarian ultrasonic findings were analyzed during 4 successive cycles of LH-RH-A administration in 4 groups of subjects treated with 400 mcg once daily or 200 mcg twice daily of Buserelin and for periods of 14 or 21 days. Intermittent LH-RH-A administration was associated with stimulation of ovarian follicles to various stages of development. After 2 weeks of Buserelin in a 1st treatment cycle, ovarian scans revealed follicular development in 68% of cases--4-10 mm follicles in 24%, 10-27 mm developing follicles in another 24%, and ovarian cysts greater than 27 mm in 20%. At the 4th Buserelin cycle, the predominant finding was large follicles in the 14-day schedules, whereas ovarian scans failed to reveal follicular stimulation in 66% of the 21-day schedules. The most appropriate dosage regimen for potential contraception is 200 mcg/12 hours for 21 days. This regimen was associated with small follicles and serum estradiol was in the range of control cycles.