Adolescence is the starting point of sex-dichotomous COMT genetic effects.

The catechol-o-methyltransferase (COMT) genetic variations produce pleiotropic behavioral/neuroanatomical effects. Some of these effects may vary among sexes. However, the developmental trajectories of COMT-by-sex interactions are unclear. Here we found that extreme COMT reduction, in both humans (22q11.2 deletion syndrome COMT Met) and mice (COMT-/-), was associated to cortical thinning only after puberty and only in females. Molecular biomarkers, such as tyrosine hydroxylase, Akt and neuronal/cellular counting, confirmed that COMT-by-sex divergent effects started to appear at the cortical level during puberty. These biochemical differences were absent in infancy. Finally, developmental cognitive assessment in 22q11DS and COMT knockout mice established that COMT-by-sex-dichotomous effects in executive functions were already apparent in adolescence. These findings uncover that genetic variations severely reducing COMT result in detrimental cortical and cognitive development selectively in females after their sexual maturity. This highlights the importance of taking into account the combined effect of genetics, sex and developmental stage.

Visual perception skills: a comparison between patients with Noonan syndrome and 22q11.2 deletion syndrome.

Ventral and dorsal streams are visual pathways deputed to transmit information from the photoreceptors of the retina to the lateral geniculate nucleus and then to the primary visual cortex (V1). Several studies investigated whether one pathway is more vulnerable than the other during development, and whether these streams develop at different rates. The results are still discordant. The aim of the present study was to understand the functionality of the dorsal and the ventral streams in two populations affected by different genetic disorders, Noonan syndrome (NS) and 22q11.2 deletion syndrome (22q11.2DS), and explore the possible genotype-phenotype relationships. 'Form coherence' abilities for the ventral stream and 'motion coherence' abilities for the dorsal stream were evaluated in 19 participants with NS and 20 participants with 22q11.2DS. Collected data were compared with 55 age-matched controls. Participants with NS and 22q11.2DS did not differ in the form coherence task, and their performance was significantly lower than that of controls. However, in the motion coherence task, the group with NS and controls did not differ, and both obtained significantly higher scores than the group with 22q11.2DS. Our findings indicate that deficits in the dorsal stream are related to the specific genotype, and that in our syndromic groups the ventral stream is more vulnerable than the dorsal stream.

[GnRH agonists and antagonists in the preoperative therapy of uterine fibroids: literature review]. / Agonisti e antagonisti del GnRH nella terapia pre-chirurgica della fibromiomatosi uterina.

Uterine leiomyomas are the most frequent gynecological benign tumors. Their growth is regulated by ovarian steroids, therefore a hypoestrogenic state, like menopause or pharmacologically induced pseudo-menopause by GnRH-agonists or GnRH-antagonists, is associated with the decrease of their volume. This volume reduction allows a less invasive surgical procedure and may reduce the amount of blood loss during surgery. Therefore, GnRH-agonists and antagonists are used in presurgical treatment of uterine fibromatosis. This review analyses the effects of GnRH-agonists and GnRH-antagonists therapies. GnRH-agonists produce a down-regulation of GnRH receptor, while GnRH-antagonists compete with endogenous GnRH for pituitary binding sites. Due to the lack of any intrinsic activity of GnRH-antagonists, the characteristic initial flare-up observed with GnRH-agonist treatment is absent. So, GnRH-antagonists rapidly suppress gonadotropin release within 4-8 h, while GnRH-agonists show clinical effects after 2 or 3 weeks of treatment. GnRH-antagonist activity is dose-dependent so it is possible to adjust the dose to obtain the proper levels of inhibition. The GnRH-agonist presurgical treatment usually is a short-term therapy (3-6 months), because it causes side-effects like menopause symptoms. GnRH-antagonist clinical effects can be achieved with a short-time therapy too. Their side-effects include flushes and head-ache. After stopping therapy with both drugs, leiomyomas rapidly achieve their original size while side-effects disappear. Further studies are necessary to establish the use of GnRH-antagonists in leiomyomas therapy, but in Italy this is not possible because their use is not approved.

Effects of gonadotropin-releasing hormone agonists on uterine volume and vasculature and on the immunohistochemical expression of basic fibroblast growth factor (bFGF) in uterine leiomyomas.

We investigated the effect of the GnRH agonist (GnRH-a) on the uterine volume and on the immunohistochemical expression of basic fibroblast growth factor (bFGF) and the vasculature of leiomyomas. Twenty-five women were treated with leuprorelin acetate for 3 months; 46 untreated patients were enrolled as a control group. The uterine volume was measured by ultrasonography. After myomectomy or hysterectomy, the immunoexpression of bFGF and the endothelial marker, CD34, was studied and compared in treated and untreated leiomyomas. Uterine volume decreased after therapy. The number of cells expressing bFGF and the vascularity were diminished in treated leiomyomas. Reduction in the blood supply might be responsible, in part, for uterine-volume shrinkage after GnRH-a therapy.

[Prenatal telemedicine and teledidactic networking. A report on the TOCOMAT project]. / Telemedicina prenatale e teledidattica. Esperienza nel progetto TOCOMAT.

Telemedicine originates with the combined use of electromedical equipment, information technologies and telecommunication systems designed to improve healthcare by overcoming the limitations of time and space. Moreover, telemedicine also possesses greater didactic potential than instruction by traditional means. Teledidactic networking, both as e-learning and e-teaching, represents a new integrated system of computer-aided education for the development and management of distance learning programs. Our study evaluated the effectiveness of teledidactic applications in the first Italian project in conventional and computerized telecardiotocography (TOCOMAT). Five cardiotocography outpatient monitoring facilities were linked telematically to a university central operating unit to obtain computerized analysis of telecardiotocographic (CTG) tracings and specialist consulting. The peripheral site operators received theoretical-practical training in the function and use of the system, the guidelines for CTG tracing interpretation and the diagnostic-therapeutic protocols. Improvement in learning progress was observed in the reduction of technical errors in CTG recording and in the increased ability of the outpatient clinic staff to select, analyze and interpret test RESULTS. Results from the feedback questionnaires on the didactic impact of the project indicated objective improvement in the specific skills acquired by the physicians at these facilities. The findings also show that a well-structured distance learning course can improve clinical, technical and managerial skills and behavior of healthcare operators by promoting the kind of professional continuing education a modern medical school should provide.

Plasma levels of metalloproteinases-3 and -9 as markers of successful abdominal aortic aneurysm exclusion after endovascular graft treatment.

BACKGROUND: Structural alterations of aortic wall resulting from degradation of matrix proteins by matrix metalloproteinases (MMPs) characterize abdominal aortic aneurysms (AAAs). No studies have compared circulating levels of MMPs after endovascular graft (EVG) exclusion in comparison with open surgical repair (OSR) in patients affected by AAA. METHODS AND RESULTS: An abdominal angiography and CT scan were performed in all patients at the time of enrollment. A spiral CT scan was performed at 6 months to detect presence of endoleaks. MMP-3 and MMP-9 levels were measured before EVG (n=30) and OSR (n=15) treatments and at 1, 3, and 6 months of follow-up by a sandwich ELISA technique. Healthy volunteers (n=10) were used as control subjects. Immunohistochemical staining for MMP-9 and MMP-3 was performed on tissue samples from surgical cases. Both MMP-9 and MMP-3 mean basal levels were significantly higher in patients affected by AAA than in control subjects (32.3+/-20.7 ng/mL for EVG and 28+/-9.9 ng/mL for OSR versus 8.9+/-2.5 ng/mL, 2P<0.05; 18.3+/-9.7 ng/mL and 26.7+/-10.8 ng/mL versus 8.2+/-5.3 ng/mL, 2P<0.001). In the OSR group, both MMP-9 and MMP-3 mean levels decreased after surgery (28+/-9.9 ng/mL at basal versus 14.7+/-6.6 ng/mL at 6 months, 2P<0.001; 26.7+/-10.8 versus 12+/-5.3 ng/mL; 2P<0.001). In the EVG group, a statistically significant difference at 6-month follow-up in MMP-9 and MMP-3 mean plasma values was detected in patients who had endoleakage in comparison with patients without endoleakage (44.3+/-20.7 versus 14.6+/-7.0 ng/mL, 2P<0.005; 25+/-11.5 versus 10.3+/-5.4 ng/mL, 2P<0.005). CONCLUSIONS: After EVG exclusion, MMP-9 and MMP-3 levels decreased to a level similar to that of patients undergoing OSR. In addition, a lack of decrease in MMP levels after EVG exclusion may help in identifying patients who will have endoleakage and consequent aneurysm expansion caused by continuous sac pressurization during follow-up.

Homocysteinaemia during pregnancy and placental disease.

OBJECTIVE: Hyperhomocysteinaemia, due to enzymatic defects or to the lack of some vitamin cofactors (vit. B6, vit. B12, folic acid), could be associated with obstetric disease. The aim of this study was to investigate placental disease in women with mild-moderate hyperhomocysteinaemia. MATERIALS AND METHODS: Blood samples of seven pregnant women with severe early onset preeclampsia were assessed for hyperhomocysteinaemia. The obtained values were compared with those of a control group. In all cases, tissue samples obtained from the placenta, umbilical cord and membranes were studied. One of the patients was treated empirically with folic acid during a subsequent pregnancy. RESULTS: Patient homocysteine plasma levels were higher than in the control group. In all cases several placental abnormalities were found. The patient treated with folic acid had a good pregnancy outcome. CONCLUSION: Hyperhomocysteinaemia during pregnancy could be responsible for placental abnormalities. Treatment with folic acid could improve pregnancy outcome in women with homocysteine metabolism abnormalities.

[Modifications in diagnosis and therapy of osteoporosis after bone densitometry]. / Modifica di diagnosi e terapia per l'osteoporosi dopo esecuzione di un esame densitometrico.

The cost-benefit ratio of diagnostic procedures has become a major problem: in particular, the expense of computerized bone mineral densitometry for osteoporosis diagnosis has brought this issue to public attention. To avoid a procedure considered costly, non-specialists often rely on standard radiography alone for diagnosis. In this study, we evaluated the percent of cases in which densitometry modified diagnosis and therapy based solely on radiographic findings. Over a 10-month period, we recruited 133 consecutive post-menopausal patients (average age 58.3 years, average time since menopause 12 years) who had never undergone densitometry. Bone density at the lumbar (L1-L4) or femoral (non-dominant) level was measured with dual energy X-ray absorptiometry. The average time between densitometry and the last radiographic examination was 13.6 months. Ninety-one patients (68.4%) had a change in diagnosis following densitometry. In 42 cases (31.6%), the previous diagnosis remained unchanged (prevalence ratio 2.2; 95% confidence interval 1.6 to 2.7). Therapy was changed in 75.2% of the cases (100 patients) and remained the same in 24.8% (33 patients; prevalence ratio 3.0; 95% confidence interval 2.3 to 3.7). Our data underscore the importance of densitometry in yielding quantitative data that are utilizable during follow-up and able to support osteoporosis diagnosis and therapy.

Influence of goserelin depot therapy on epidermal growth factor receptor expression in pelvic endometriosis.

We have studied epidermal growth factor (EGF) receptor expression in endometrium and in endometriotic implants, testing a group of 36 women before and after a 4-month gonadotropin-releasing hormone (GnRH) analog (GnRH-a) goserelin depot treatment. Each woman underwent laparoscopy twice. At the initial laparoscopy, before starting treatment, the disease was staged according to the American Fertility Society (AFS) classification and biopsies of endometriotic implants were undertaken. The follow-up laparoscopy was performed within 5 weeks of the last GnRH-a administration. Biopsies were taken from areas of previously noted disease, both visually persistent and visually free of disease. At the time of each laparoscopy, photographs of all areas of disease were taken. Specimens of eutopic endometrium were collected from each patient at the time of laparoscopy by a Novak curette. Endometrial and endometriotic samples were processed for immunohistochemical detection of EGF receptor, using anti-EGF receptor monoclonal antibody Ab-3. After treatment, the marked improvement of AFS score was associated with a dramatic reduction of EGF receptor immunostaining, but the exact meaning of this finding is still not completely understood. The dramatic reduction of EGF receptor expression in eutopic and ectopic endometrium samples after treatment is not obviously related to the hypoestrogenism induced by the drug. It has been suggested that steroid hormones and EGF play a role in regulation of EGF receptor expression, so that drugs such as goserelin depot could act directly at local peripheral level influencing the EGF receptor expression via the production of its ligand.

Cirrhosis negatively affects the efficiency of serologic diagnosis of Helicobacter pylori infection.

In cirrhosis, Helicobacter pylori infection may be implicated, together with portal hypertension, bile reflux and alcohol abuse, in damage to gastric mucosa. Aim of this study was to define the influence of non-alcoholic liver disease on the incidence of Helicobacter pylori infection and on the diagnostic accuracy of specific serology. Enrolled in the study were 232 individuals, 105 also had cirrhosis. Infection by Helicobacter pylori, diagnosed by a positive concordance of quick urease test and histology, was detected in 97 (48 with cirrhosis) out of 184 patients. Severe gastritis was more frequent in patients with Helicobacter pylori infection than in patients without. Cirrhosis did not significantly affect the prevalence of Helicobacter pylori infection or the histological features of gastritis. Specific anti-Helicobacter pylori IgG and IgA assay (Bio-Rad GAP test) was used for serological diagnosis. Anti-Helicobacter pylori IgG showed a high sensitivity (85% in cirrhotics, 89% in non-cirrhotics) and low specificity being more evident in cirrhotics (38% vs 56% non-cirrhotics). Serum specific IgA showed low sensitivity (approximately 25% in both groups) and specificity of 79% in cirrhotics vs 84% in non-cirrhotics. In conclusion, non-alcoholic cirrhosis does not affect the incidence of Helicobacter pylori infection and the histological features of chronic gastritis but does decrease diagnostic efficiency of serological tests for Helicobacter pylori.

[Retrospective study of postoperative infectious morbidity following cesarean section]. / Studio retrospettivo della morbilità infettiva postoperatoria nel taglio cesareo.

The increase of cesarean sections produced more postoperative infections. Several authors assessed the effectiveness of chemioantibiotic prophylaxis to reduce the postoperative infective morbidity. Although the family of antibiotics more frequently used is that of cephalosporin, the best single agent has not been found yet. The aim of our study, made in the Department of Obstetrics and Gynecology of University of Naples "Federico II", is to propose a retrospective analysis concerning the incidence of cesarean section (CS), the postoperative infective morbidity and the employment of antibiotic prophylaxis. Our sample is a group of 13285 pregnant women, 3171 (23.9%) of these patients underwent to CS from 1st January 1985 to 31st December 1994. The group of 3171 women was divided in two subgroups, the first of 2748 patients un-derwent to antibiotic prophylaxis, the second of 423 was untreated due to their previous experience of allergy towards antibiotics or because there was no evidence of risk factors. The women we treated with antibiotics underwent a three days prophylactic therapy with cefazolin or ampicillin soon after the CS. The incidence of infective complications had a 21.2% rate over a total of 3171 women. Endometritis was the most common infectious complication following cesarean delivery. The rate was 53.3% in the case of primary cesarean section and 52.3% in the case of iterative cesarean section. The use of antibiotic prophylaxis gave us the opportunity to reduce the postoperative morbidity in the primary CS (23.4%) as well in the iterative CS (16.6%). On the contrary the untreated group had an infective incidence with a 33.8% rate in the case of primary CS and with a 27.4% rate in the case of iterative CS. Our opinion is that the administration of antibiotics as cefazolin and ampicillin is able to reduce in a significant way the incidence of postoperative infective morbidity as well the period of hospitalization.

EGF/EGF-R system and benign breast disease during and following the treatment of gynaecological pathologies with an analogue of LH-RH.

Clinical and pathological changes of the mammary gland have been studied in 64 women affected by symptomatic Benign Breast Disease (BBD) coexisting with endometriosis or uterine leiomyomata. These patients were rendered hypoestrogenic by subcutaneous administration of the LH-RH analogue Goserelin depot [D-ser (tBu)6 Aza-Gly10-GnRH (ICI118630)] performed every 28 days, for six months. They were evaluated clinically and ultrasonographically before and after treatment to find possible changes of BBD as well as of endometriosis or uterine leiomyomata. Mammary biopsies were performed before and after treatment in all the patients to study the changes of EGF-R expression. Results showed that clinical improvement is accompanied with a reduction of EGF-R expression.

Growth hormone and insulin-like growth factor I in athletes performing a marathon at 4000 m of altitude.

Human growth hormone (hGH) characteristically increases during physical exercise. In sports medicine, hGH changes have mostly been described in short-term performances under standardized laboratory procedures. We studied hGH and insulin-like growth factor I (IGF-I) under field conditions in 7 runners performing a marathon at 4000 m of altitude, to study the hormonal changes under extreme endurance effort and to evaluate the release of 22 kDa and 20 kDa monomers under these conditions, in comparison with a control group. The blood samples were taken at sea level, after 1 week of acclimatization, immediately after the run, and after a recovery of 24 h from the marathon. hGH was quantified by using a polyclonal method, a 22 kDa specific monoclonal method and a monoclonal method recognizing both 22 kDa and 20 kDa isoforms. A significant increase in hGH was noted using all methods after the marathon, followed by a significant decrease after recovery. Significant differences between athletes and controls were found only for the measurement after the marathon. No statistically reliable decrease of IGF-I was observed in athletes and controls. We obtained more limited hGH rises than previously described in athletes; the importance of lactate levels indicates that the use of physical exercise as a stimulation test for hGH should be closely standardized. The 20 kDa monomer and other hGH molecular forms played a limited role in the hormone increase: in our experience, elevation of hGH in heavy exercise corresponds mostly to the 22 kDa isoform. We suggest that the evaluation of hGH elevation in sports medicine could be accurately performed using specific 22 kDa monoclonal assays.

Desogestrel versus gestodene in oral contraceptives: influence on the clinical and histomorphological features of benign breast disease.

Forty-four female volunteers asking for oral contraception, affected by symptomatic benign breast disease (BBD) were evaluated to compare the effects on mastalgia and breast nodularity of two different low dose oral contraceptives (OCs), containing 20 micrograms [corrected] ethinylestradiol + 150 micrograms desogestrel (EE+D) and 30 micrograms ethinylestradiol + 75 micrograms gestodene (EE+G), respectively. Physical examination, bilateral thermography, X-ray and/or ultrasonography of breast, and needle and screw-needle biopsies of mammary tissue were performed in all patients before OCs administration and after six cycles of treatment. OCs administration caused an overall improvement of mastalgia in 53%. Breast nodularity improved only in 8% of patients in both groups. Epithelial tissue modifications in mammary biopsies were observed, with involutive and/or secretory histomorphological and ultrastructural changes, frequently coexisting in different areas of the same breast.

PIP: In Italy, researchers compared data on 22 women who used the low-dose oral contraceptive (OC) containing 20 mcg ethinyl estradiol and 150 mcg desogestrel (EE+D) with data on 22 other women who used the low-dose OC containing 30 mcg ethinyl estradiol and 75 mcg gestodene (EE+G) to determine the pharmacological effects of the 2 OCs on women affected by mastalgia and breast nodularity. Clinicians performed physical exams, bilateral thermography, X-ray and/or ultrasonography of breast and needle and screw-needle biopsies of mammary tissue before OC administration and after 6 cycles of OC treatment. An overall improvement of mastalgia and breast nodularity occurred in 53% and 8% of all patients, respectively. There were no significant differences between groups. Among EE+D treated women, a marked secretory attitude in breast epithelial cells occurred, probably due to a prominent progestin effect. Both OCs increased the number of cytoplasmatic organules and intraluminal secretory material without any apparent increase of cell proliferation. The observed involutive and/or secretory histomorphological and ultrastructural changes often occurred in different areas of the same breast. These results suggest that low dose OC use by women affected by benign breast disease improves mastalgia but not breast nodularity.

Standardization with synthetic 22-kDa monomer human growth hormone reduces discrepancies between two monoclonal immunoradiometric assay kits.

Discrepancies among different methods for assaying human growth hormone have been described in various studies. The two major sources of discordant results are the heterogeneity of the antibodies and the different standardization bases used by the assay manufacturers. We propose standardizing assays with 22-kDa biosynthetic monomer human growth hormone diluted with the diluents supplied by the kit manufacturers. In a study of two monoclonal immunoradiometric assays (Hybritech, specific for the 22-kDa monomer; Sorin, recognizing also a 20-kDa variant hormone), standardization with 22-kDa monomer human growth hormone reduced by 63% the differences in results for 44 serum samples from children. The use of 22-kDa human growth hormone as a common standard, highly pure and easily available in large quantities, could help limit the interpretative problems in growth diagnostics.

Uterine motility and cervical ripening in second trimester elective abortion by two different PGE analogues.

The clinical effects were studied of two different PGE analogues on the uterine motility and cervical ripening of eighty pregnant women asking for a second trimester elective abortion for fetal abnormalities. Forty women received vaginal suppositories each containing 1 milligram of 16, 16-dimethyl-trans-s2-PGE1 (Gemeprost) every 3 hours (5 mg max). Intramuscular injections of 500 micrograms of 16-phenoxy-w 17, 18, 19, 20 tetranor PGE2 methyl-sulphonylamide (Sulprostone) were administered every four hours (2000 mcg max.) to the remaining forty patients. Thirty-three Gemeprost treated patients (82.5%) and 34 Sulprostone treated patients (85%) experienced a complete abortion in the mean of 12.92 +/- 6.95 hours and 11.88 +/- 6.8 hours respectively. The histological and ultrastructural findings of cervical ripening were similar in both groups, while the tocographic patterns showed different characteristics. Side effects occurred in 16 Sulprostone (40%), but only in 9 (22.5%) Gemeprost treated patients, demonstrating that Gemeprost, although equally effective, is better tolerated.

PIP: Researchers analyzed data on 80 pregnant women seeking a 2nd trimester abortion due to fetal abnormalities at the Federico II Medical School at the University of Naples in Italy to determine the effectiveness and side effects of 2 different prostaglandin analogues and their ability to bring about cervical ripening and uterine contractions. 40 women received 1 mg Gemeprost every 3 hours up to 5 mg in vaginal suppository form while the other 40 women who tended to be primigravidae received an intramuscular injection of 500 mcg Sulprostone every 4 hours up to 2000 mcg. Sulprostone achieved an 85% success rate and Gemeprost achieved an 82.5% success rate. Complete abortion occurred more quickly for multigravidae patients than it did for primigravidae patients (in hours, 10.6 vs. 16.5 for Gemeprost, p.1; 9.83 vs. 15.65 for Sulprostone, p.01). There was no statistically significant difference between the 2 treatment groups, however. Side effects were more common among Sulprostone patients than among Gemeprost patients (40% vs. 22.5%). The most common side effects among Sulprostone patients were, in descending order, abdominal pain (75%), diarrhea (50%), and nausea (50%). For Gemeprost patients, they were abdominal pain (55.5%) and headache (44.4%). In terms of uterine contractility, Sulprostone brought about hypertone more quickly than did Gemeprost (in minutes, 18.32 vs. 36.75; range 10-30 vs. 25-50). Gemeprost treatment was more like physiological labor than was Sulprostone treatment. Both prostaglandin analogues produced similar histological and ultrastructural findings of cervical ripening. These results indicated that the women were better able to tolerate Gemeprost.