The vagina as source and target of androgens: implications for treatment of GSM/VVA, including DHEA.

The vagina is traditionally thought of as a passive organ in the female reproductive system, serving primarily as a passageway for menstrual blood, sexual intercourse and childbirth. However, recent research has shed light on the vagina's role as an endocrine organ that plays a crucial role in female hormonal balance and overall health. Particularly, growing evidence shows that the human vagina can be considered both as source and target of androgens, in view of the novel concept of 'intracrinology'. Besides the well-known role of estrogens, androgens are also crucial for the development and maintenance of healthy genitourinary tissues in women. As androgen levels decline with age, and estrogen levels fall during the menopausal transition, the tissues in the vagina, together with those in the urinary tract, become thinner, drier and less elastic, leading to a variety of uncomfortable and sometimes painful symptoms, clustered in the genitourinary syndrome of menopause (GSM). Given the lack of testosterone-based or androstenedione-based products approved by regulatory agencies to treat GSM, the possibility of using intravaginal prasterone, which works by providing a local source of dehydroepiandrosterone (DHEA) to the vaginal tissues, appears to be a targeted treatment. Further studies are needed to better assess its safety and efficacy.

Testosterone does not affect lower urinary tract symptoms while improving markers of prostatitis in men with benign prostatic hyperplasia: a randomized clinical trial.

PURPOSE: Benign Prostatic Hyperplasia (BPH) is a result of prostate inflammation, frequently occurring in metabolic syndrome (MetS). Low testosterone is common in MetS. A randomized clinical trial was designed to evaluate if 24 weeks of testosterone therapy (TTh) in BPH men with MetS and low testosterone improve urinary symptoms and prostate inflammation. METHODS: One-hundred-twenty men with MetS waitlisted for BPH surgery were enrolled. They were categorized into normal testosterone (TT ≥ 12 nmol/L and cFT ≥ 225 pmol/L; n = 48) and testosterone deficient (TD) (TT < 12 nmol/L and/or cFT < 225 pmol/L; n = 72) then randomized to testosterone gel 2% (5 g/daily) or placebo for 24 weeks. At baseline and follow-up, questionnaires for urinary symptoms and trans-rectal ultrasound were performed. Prostate tissue was collected for molecular and histopathological analyses. RESULTS: No differences in the improvement of urinary symptoms were found between TTh and placebo (OR [95% CI] 0.96 [0.39; 2.37]). In TD + TTh, increase in prostate but not adenoma volume was observed (2.64 mL [0.07; 5.20] and 1.82 mL [- 0.46; 0.41], respectively). Ultrasound markers of inflammation were improved. In a subset of 61 men, a hyper-expression of several pro-inflammatory genes was found in TD + placebo when compared with normal testosterone. TTh was able to counteract this effect. For 80 men, the inflammatory infiltrate was higher in TD + placebo than in normal testosterone (0.8 points [0.2; 1.4]) and TD + TTh men (0.9 points [0.2; 1.5]). CONCLUSIONS: Twenty-four weeks of TTh in TD men with BPH and MetS improves ultrasound, molecular and histological proxies of prostate inflammation. This does not result in symptom improvement.

Testosterone positively regulates vagina NO-induced relaxation: an experimental study in rats.

PURPOSE: Female sexual response involves a complex interplay between neurophysiological mechanisms and the nitric oxide (NO)-mediated relaxation of clitoris and vagina. The aim of this study was to evaluate sex steroids regulation of the relaxant pathway in vagina, using a validated animal model. METHODS: Subgroups of OVX Sprague-Dawley rats were treated with 17ß-estradiol, testosterone, or testosterone and letrozole, and compared with a group of intact animals. Masson's trichrome staining was performed for morphological evaluation of the distal vaginal wall, in vitro contractility studies investigated the effect of OVX and in vivo treatments on vaginal smooth muscle activity. RNA from vaginal tissue was analyzed by semi-quantitative RT-PCR. RESULTS: Immunohistochemical analysis showed that OVX induced epithelial and smooth muscle structural atrophy, testosterone and testo + letrozole increased the muscle bundles content and organization without affecting the epithelium while 17ß-estradiol mediated the opposite effects. In vitro contractility studies were performed on noradrenaline pre-contracted vaginal strips from each experimental group. Acetylcholine (0.001-10 µM) stimulation induced a concentration-dependent relaxation, significantly reduced by NO-synthase inhibitor L-NAME and by guanylate cyclase inhibitor ODQ. OVX resulted in a decreased responsiveness to acetylcholine, restored by testosterone, with or without letrozole, but not by 17ß-estradiol. OVX sensitivity to the NO-donor SNP was higher than in the control. Vardenafil, a PDE5 inhibitor, enhanced SNP effect in OVX + testosterone as well as in control, as supported by RNA expression analysis. CONCLUSIONS: Our study demonstrates that testosterone improves the NO-mediated smooth muscle vaginal cells relaxation confirming its role in maintaining the integrity of muscular relaxant machinery.

Effects of testosterone treatment on clitoral haemodynamics in women with sexual dysfunction.

PURPOSE: To explore the effects of 6-month systemic testosterone (T) administration on clitoral color Doppler ultrasound (CDU) parameters in women with female sexual dysfunction (FSD). METHODS: 81 women with FSD were retrospectively recruited. Data on CDU parameters at baseline and after 6 months with four different treatments were available and thus further longitudinally analyzed: local non-hormonal moisturizers (NH group), n = 37; transdermal 2% T gel 300 mcg/day (T group), n = 23; local estrogens (E group), n = 12; combined therapy (T + E group), n = 9. Patients underwent physical, laboratory, and genital CDU examinations at both visits and completed different validated questionnaires, including the Female Sexual Function Index (FSFI). RESULTS: At 6-month visit, T therapy significantly increased clitoral artery peak systolic velocity (PSV) when compared to both NH (p < 0.0001) and E (p < 0.0001) groups. A similar increase was found in the T + E group (p = 0.039 vs. E). In addition, T treatment was associated with significantly higher FSFI desire, pain, arousal, lubrication, orgasm, and total scores at 6-month visit vs. baseline. Similar findings were observed in the T + E group. No significant differences in the variations of total and high-density lipoprotein-cholesterol, triglycerides, fasting glycemia, insulin and glycated hemoglobin levels were found among the four groups. No adverse events were observed. CONCLUSION: In women complaining for FSD, systemic T administration, either alone or combined with local estrogens, was associated with a positive effect on clitoral blood flow and a clinical improvement in sexual function, showing a good safety profile. TRIAL REGISTRATION NUMBER: NCT04336891; date of registration: April 7, 2020.

Biochemical predictors of structural hypothalamus-pituitary abnormalities detected by magnetic resonance imaging in men with secondary hypogonadism.

PURPOSE: Organic conditions underlying secondary hypogonadism (SH) may be ascertained by magnetic resonance imaging (MRI) of the hypothalamic-pituitary region that could not be systematically proposed to each patient. Based upon limited evidence, the Endocrine Society (ES) guidelines suggest total testosterone (T) < 5.2 nmol/L to identify patients eligible for MRI. The study aims to identify markers and their best threshold value predicting pathological MRI findings in men with SH. METHODS: A consecutive series of 609 men seeking medical care for sexual dysfunction and with SH (total T < 10.5 nmol/L and LH ≤ 9.4 U/L) was retrospectively evaluated. An independent cohort of 50 men with SH was used as validation sample. 126 men in the exploratory sample and the whole validation sample underwent MRI. RESULTS: In the exploratory sample, patients with pathological MRI findings (n = 46) had significantly lower total T, luteinizing hormone (LH), follicle stimulating hormone (FSH) and prostate specific antigen (PSA) than men with normal MRI (n = 80). Receiver Operating Characteristics analysis showed that total T, LH, FSH and PSA are accurate in identifying men with pathologic MRI (accuracy: 0.62-0.68, all p < 0.05). The Youden index was used to detect the value with the best performance, corresponding to total T 6.1 nmol/L, LH 1.9 U/L, FSH 4.2 U/L and PSA 0.58 ng/mL. In the validation cohort, only total T ≤ 6.1 nmol/L and LH ≤ 1.9 U/L were confirmed as significant predictors of pathologic MRI. CONCLUSION: In men with SH, total T ≤ 6.1 nmol/L or LH ≤ 1.9 U/L should arise the suspect of hypothalamus/pituitary structural abnormalities, deserving MRI evaluation.

The European Academy of Andrology (EAA) ultrasound study on healthy, fertile men: Scrotal ultrasound reference ranges and associations with clinical, seminal, and biochemical characteristics.

BACKGROUND: Scrotal color Doppler ultrasound (CDUS) still suffers from lack of standardization. Hence, the European Academy of Andrology (EAA) has promoted a multicenter study to assess the CDUS characteristics of healthy fertile men (HFM) to obtain normative parameters. OBJECTIVES: To report and discuss the scrotal organs CDUS reference ranges and characteristics in HFM and their associations with clinical, seminal, and biochemical parameters. METHODS: A cohort of 248 HFM (35.3 ± 5.9years) was studied, evaluating, on the same day, clinical, biochemical, seminal, and scrotal CDUS following Standard Operating Procedures. RESULTS: The CDUS reference range and characteristics of the scrotal organs of HFM are reported here. CDUS showed a higher accuracy than physical examination in detecting scrotal abnormalities. Prader orchidometer (PO)- and US-measured testicular volume (TV) were closely related. The US-assessed TV with the ellipsoid formula showed the best correlation with the PO-TV. The mean TV of HFM was ~ 17 ml. The lowest reference limit for right and left testis was 12 and 11 ml, thresholds defining testicular hypotrophy. The highest reference limit for epididymal head, tail, and vas deferens was 12, 6, and 4.5 mm, respectively. Mean TV was associated positively with sperm concentration and total count and negatively with gonadotropins levels and pulse pressure. Subjects with testicular inhomogeneity or calcifications showed lower sperm vitality and concentration, respectively, than the rest of the sample. Sperm normal morphology and progressive motility were positively associated with epididymal head size/vascularization and vas deferens size, respectively. Increased epididymis and vas deferens sizes were associated with MAR test positivity. Decreased epididymal tail homogeneity/vascularization were positively associated with waistline, which was negatively associated with intratesticular vascularization. CDUS varicocele was detected in 37.2% of men and was not associated with seminal or hormonal parameters. Scrotal CDUS parameters were not associated with time to pregnancy, number of children, history of miscarriage. CONCLUSIONS: The present findings will help in better understanding male infertility pathophysiology, improving its management.

The prevalence of midline prostatic cysts and the relationship between cyst size and semen parameters among infertile and fertile men.

STUDY QUESTION: When is the investigation and treatment of midline prostatic cysts (MPC) of clinical value in the work-up of males of infertile couples? SUMMARY ANSWER: With a prevalence of 10.2% in infertile men, MPC should be investigated according to a seminal algorithm detecting a MPC volume >0.117 ml, which may impair semen parameters, and could be treated to improve sperm count and achieve natural pregnancy. WHAT IS KNOWN ALREADY: MPC are frequent and are considered a correctable cause of male infertility. However, they have been poorly investigated in an infertility setting. In addition, no study has investigated clinical and ultrasound (US) characteristics of men with MPC. STUDY DESIGN, SIZE, DURATION: A cross-sectional analysis was carried out of 693 consecutive subjects consulting for couple infertility from September 2012 to March 2017. As a control group, 103 age-matched healthy, fertile men were studied. Furthermore, a longitudinal evaluation of 11 infertile men undergoing trans-rectal ultrasonically-guided cyst aspiration (TRUCA), semen analyses 1 and 3 months after TRUCA and a follow-up 1 year after TRUCA to assess natural pregnancy were performed. PARTICIPANTS/MATERIALS, SETTING, METHODS: All subjects underwent, in our outpatient clinic, clinical, hormonal, scrotal and transrectal US evaluation and semen analysis within the same day. Of 693 males of infertile couples, 648 (37.1 ± 7.9 years, mean+SD) without genetic abnormalities were studied, along with 103 fertile men (36.6 ± 5.0 years). Eleven infertile men underwent TRUCA and were followed-up as reported above. MAIN RESULTS AND THE ROLE OF CHANCE: A MPC was present in 66/648 (10.2%) males of infertile couples and in 6/103 (5.8%) fertile men. MPC occurrence and volume were higher in patients with severe oligo- or azoospermia than in fertile men (all P < 0.05). Infertile men with a MPC showed a lower seminal volume and sperm count and a higher prevalence of azoospermia than the rest of the infertile sample or fertile men, and a higher frequency of US signs suggestive of ejaculatory duct obstruction. MPC volume was negatively associated with total sperm count (r = -0.452, P < 0.0001). In fertile men, the highest MPC volume was 0.117 ml, suggesting it as a biological threshold not compromising semen quality. In infertile men, using receiver operating characteristic curve analyses, a MPC volume >0.117 ml identified subjects with severe oligo- or azoospermia with an overall accuracy of ~75% (both P < 0.005). Eleven men with infertility, semen abnormalities and large MPC (>0.250 ml) underwent TRUCA, which led to sperm count improvement in all patients 1 month after surgery. Three months after TRUCA a lower sperm count and a higher MPC volume than 2 months before were observed (P < 0.005 and P < 0.05, respectively), although improved when compared to baseline. After TRUCA a natural pregnancy occurred in four couples. Finally, we propose an algorithm, based on semen parameters, useful in identifying a MPC in males of infertile couples. LIMITATIONS, REASONS FOR CAUTION: Although in line with the sample size of previous studies (n = 7-20), the number of infertile men with MPC evaluated longitudinally after treatment is limited (n = 11). In addition, although a MPC volume >0.117 ml can negatively affect the sperm count, only MPC > 0.250 ml have been treated in this study. WIDER IMPLICATIONS OF THE FINDINGS: First, the algorithm proposed is easy to use and useful for selecting patients who can benefit from a prostate US in the infertility work-up. Second, a MPC volume ≤0.117 ml may not impair semen quality, while a larger volume can lead to severe oligo- or azoospermia and could be treated. Third, TRUCA is effective, and simpler and less invasive than other surgical techniques for MPC treatment. Finally, since the MPC can increase in size and sperm count decrease over time after TRUCA, semen cryopreservation should be considered 1 month after TRUCA. STUDY FUNDING/COMPETING INTEREST(S): Grants from the Ministry of University and Scientific Research (SIR project to F.L., protocol number: RBSI14LFMQ). No conflicts of interest.

Alcohol intake and semen variables: cross-sectional analysis of a prospective cohort study of men referring to an Italian Fertility Clinic.

BACKGROUND: The association between alcohol intake and male reproductive function is still controversial. In the frame of a prospective cohort study, designed to investigate the relation between life style and fertility, we performed a cross-sectional analysis of semen quality. METHODS: Men of subfertile couples, referring to an Italian Infertility Unit and eligible for assisted reproductive techniques (ARTs), were asked about their lifestyle: BMI, smoking, caffeine intake, occupational and leisure physical activity (PA) and alcohol intake in the last year before ART procedure. Semen volume, sperm concentration, total sperm count and sperm motility were determined. Age, risk factors for impaired male fertility, caffeine, smoking, leisure PA, days of abstinence and daily calories intake were accounted for in the analyses. RESULTS: Between September 2014 and December 2016, we enrolled 323 male patients, mean age 39.3 years. Thirty-one (9.6%) were abstainers, 97 (30.0%) drank <1-3, 98 (30.3%) 4-7 and 97 (30.0%) ≥8 alcohol units per week. As compared to men drinking <1-3 units per week, median semen volume was higher in the 4-7 units/week group (3.0 mL, interquartile range, IQR, 2.0-4.0 vs. 2.4 mL, IQR 1.7-3.5), as well as total sperm count (87.9 mil/mL, IQR 20.2-182.1 vs. 51.5 mil/mL, IQR 15.2-114.7). Association with sperm concentration was also significant, with a U-shaped trend in groups of alcohol intake. After adjusting for potential confounders, these relations were confirmed. Similar patterns were observed in subgroups of leisure PA and risk factors for impaired male fertility, although these estimates often lacked statistical significance, presumably because of low sample size. CONCLUSIONS: Moderate alcohol intake appears positively associated to semen quality in male partners of infertile couples undergoing ARTs.

Premenstrual syndrome and beyond: lifestyle, nutrition, and personal facts.

AIM: The aim was to study prevalence of menstrual symptoms and their presenting patterns, and to assess nutrition and behaviours correlates. METHODS: The study enrolled 108 women, who were prospectively assessed for menstrual symptoms; a 212 items questionnaire about lifestyle and nutrition was administered. Diagnosis and intensity of symptoms were separately compared for dietary and other factors. The χ2 test or Fisher exact test as required and a multivariate analysis were performed. RESULTS: Seventeen percent of the sample reported no symptoms; core PMD was diagnosed in 14%, and related to symptoms of moderate intensity, to late menarche, irregular, long cycles, dysmenorrhoea, and to lower intake of complex carbohydrates, fibers, calcium; non-cyclical pattern in 27%, and related to symptoms of severe intensity, to young age, unemployed, to poor health, stress, traumatic events, abnormal BMI, to long, heavy menses, to lower intake of fibers, magnesium, vitamin B6, and to higher intake of fat, proteins, sodium, caffeine; variant PMD-premenstrual exacerbation in 42%, and related to symptoms of severe - moderate intensity, to young age, students, unemployed, sedentary work, abnormal BMI, stress, to cycle irregularities, heavy menses, to higher intake of simple sugars and sodium, and to lower intake of calcium, magnesium, and vitamin B6. Regardless of diagnosis, severe intensity of symptoms was associated with young age /students (P<0.001), lower education, unemployed, smoke, sedentary work, poor health, stress, heavy menses (P<0.01), dysmenorrhea, more unfavorable and less favorable nutrients. CONCLUSION: Lifestyle, nutrition, and general health considerations seem to be important issues in the management of menstrual symptoms, prospective symptoms chart being mandatory for diagnosis.

Protection by inosine in a cellular model of Parkinson's disease.

Inosine (hypoxanthine 9-beta-D-ribofuranoside), a purine nucleoside with multiple intracellular roles, also serves as an extracellular modulatory signal. On neurons, it can produce anti-inflammatory and trophic effects that confer protection against toxic influences in vivo and in vitro. The protective effects of inosine treatment might also be mediated by its metabolite urate. Urate in fact possesses potent antioxidant properties and has been reported to be protective in preclinical Parkinson's disease (PD) studies and to be an inverse risk factor for both the development and progression of PD. In this study we assessed whether inosine might protect rodent MES 23.5 dopaminergic cell line from oxidative stress in a cellular model of PD, and whether its effects could be attributed to urate. MES 23.5 cells cultured alone or in presence of enriched murine astroglial cultures MES 23.5-astrocytes co-cultures were pretreated with inosine (0.1-100 µM) for 24 h before addition of the oxidative stress inducer H2O2 (200 µM). Twenty-four hours later, cell viability was quantified by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay or immunocytochemistry in pure and MES 23.5-astrocytes co-cultures, respectively. H2O2-toxic effect on dopaminergic cells was reduced when they were cultured with astrocytes, but not when they were cultured alone. Moreover, in MES 23.5-astrocytes co-cultures, indicators of free radical generation and oxidative damage, evaluated by nitrite (NO2(-)) release and protein carbonyl content, respectively, were attenuated. Conditioned medium experiments indicated that the protective effect of inosine relies on the release of a protective factor from inosine-stimulated astrocytes. Purine levels were measured in the cellular extract and conditioned medium using high-performance liquid chromatography (HPLC) method. Urate concentration was not significantly increased by inosine treatment however there was a significant increase in levels of other purine metabolites, such as adenosine, hypoxanthine and xanthine. In particular, in MES 23.5-astrocytes co-cultures, inosine medium content was reduced by 99% and hypoxanthine increased by 127-fold. Taken together these data raise the possibility that inosine might have a protective effect in PD that is independent of any effects mediated through its metabolite urate.

Pregnancy outcome in women with peritoneal, ovarian and rectovaginal endometriosis: a retrospective cohort study.

We retrospectively assessed pregnancy outcome in 419 women who achieved a first spontaneous singleton pregnancy after surgery for endometriosis. A miscarriage was observed in 87 of 419 women (20.8%) and an ectopic pregnancy in eight (1.9%). Among the remaining 324 women, 14 (4.3%) experienced gestational hypertension/pre-eclampsia, 38 (11.7%) had a preterm delivery, five (1.5%) had placental abruption and 12 (3.7%) had placenta praevia. The incidence of placenta praevia was 7.6% in 150 women with rectovaginal lesions, 2.1% in 69 with ovarian endometriomas plus peritoneal implants, and 2.4% in 100 women with peritoneal implants only, whereas no case was observed in 100 women with ovarian endometriomas only.

Ten years survival of FIGO stage IIIC epithelial ovarian cancer cases due to lymph node metastases only.

PURPOSE OF INVESTIGATION: In this paper the authors have analyzed the long-term survival of women with Stage III ovarian cancer due to lymph node metastasis. MATERIALS AND METHODS: This retrospective study included 27 patients with FIGO Stage IIIC epithelial ovarian carcinoma due to lymph node metastases observed consecutively at the Mangiagalli Clinic of Milan from 1982 to 2008. RESULTS: Two cases had Fallopian tube carcinoma. A total of ten recurrences were observed. Median time to recurrence was 158 months. The five-year disease-free survival (DFS) was 57.7%. The ten-year corresponding value was 53.2%. Median survival time was 158 months, with median follow-up time of 169 months. The five-year (overall survival) OS rate was 77.1%; the ten-year rate was 55.4%. CONCLUSION: Women with ovarian cancer Stage IIIC due to nodal involvement have a five-year OS of about 80% and a ten-year OS of about 50%.

[Effects of folic acid supplementation on pregnancy outcomes: a review of randomized clinical trials]. / Revisione narrativa dei risultati degli studi clinici controllati sull'efficacia della supplementazione con folati nel migliorare l'esito della gravidanza.

Despite the causal association between defects of the metabolism of the folate (hyperhomocysteinemia) and risk of neural tube defects are both well documented, the association between folate deficiency and other pregnancy pathologies is still not entirely clear. The present article aims to gather the data published about the relationship between serum folate and pregnancy pathologies, distinguishing between the evidences emerged from the observational studies and the results of the clinical trials. We carried out a brief examination of the relationships between folate metabolism and homocysteine. Observational studies have suggested that a good level of folate in pregnancy is associated with higher birthweight, increased placental weight and fewer preterm birth. These results were not entirely consistent with findings from clinical trials. We have identified 12 randomized clinical studies with folate supplementation versus placebo. In the clinical studies where folic acid (FA) could improve pregnancy outcomes, its effect was not statistically significant, except for three studies where FA showed a significant decrease of low birthweight. With regard to preterm birth, pre-eclampsia and abruptio placentae, although in some observational studies AF was found to be associated with a reduction of these adverse outcomes, in currently available controlled clinical trials, FA supplementation had no statistically significant effects.

The adenosine A2A receptor antagonist ZM241385 enhances neuronal survival after oxygen-glucose deprivation in rat CA1 hippocampal slices.

BACKGROUND AND PURPOSE: Activation of adenosine A(2A) receptors in the CA1 region of rat hippocampal slices during oxygen-glucose deprivation (OGD), a model of cerebral ischaemia, was investigated. EXPERIMENTAL APPROACH: We made extracellular recordings of CA1 field excitatory postsynaptic potentials (fepsps) followed by histochemical and immunohistochemical techniques coupled to Western blots. KEY RESULTS: OGD (7 or 30 min duration) elicited an irreversible loss of fepsps invariably followed by the appearance of anoxic depolarization (AD), an unambiguous sign of neuronal damage. The application of the selective adenosine A(2A) receptor antagonist, ZM241385 (4-(2-[7-amino-2-{2-furyl}{1,2,4}triazolo{2,3-a}{1,3,5}triazin-5-ylamino]ethyl)phenol; 100-500 nmolxL(-1)) prevented or delayed AD appearance induced by 7 or 30 min OGD and protected from the irreversible fepsp depression elicited by 7 min OGD. Two different selective adenosine A(2A) receptor antagonists, SCH58261 and SCH442416, were less effective than ZM241385 during 7 min OGD. The extent of CA1 cell injury was assessed 3 h after the end of 7 min OGD by propidium iodide. Substantial CA1 pyramidal neuronal damage occurred in untreated slices, exposed to OGD, whereas injury was significantly prevented by 100 nmolxL(-1) ZM241385. Glial fibrillary acid protein (GFAP) immunostaining showed that 3 h after 7 min OGD, astrogliosis was appreciable. Western blot analysis indicated an increase in GFAP 30 kDa fragment which was significantly reduced by treatment with 100 nmolxL(-1) ZM241385. CONCLUSIONS AND IMPLICATIONS: In the CA1 hippocampus, antagonism of A(2A) adenosine receptors by ZM241385 was protective during OGD (a model of cerebral ischaemia) by delaying AD appearance, decreasing astrocyte activation and improving neuronal survival.

Determinants of adenomyosis in women who underwent hysterectomy for benign gynecological conditions: results from a prospective multicentric study in Italy.

OBJECTIVE: We conducted a cross-sectional study on the frequency and risk factors for adenomyosis in women who underwent hysterectomy for benign gynecological conditions. STUDY DESIGN: All women who consecutively underwent hysterectomy during the study period for benign gynecological conditions at 18 gynecological departments were eligible for the study. A total of 820 women entered the study. Pathological data were collected prospectically. RESULTS: Adenomyosis was identified in 231 women (28.2%, 95% confidence interval, CI, 24.6-32.5). The frequency of adenomyosis was similar in women with indication for surgery fibroids/menorrhagia (143 cases, 28.5%) or genital prolapse (69 cases, 28.2%). The rate ratio (RR) of adenomyosis was 1.9 (95% CI 1.2-2.8) in women reporting one or more induced abortions, in comparison with those reporting no induced abortion. Women with adenomyosis reported more frequently dysmenorrhoea and chronic pelvic pain, but not dyspareunia. CONCLUSIONS: This study shows that adenomyosis is common in women who undergo hysterectomy and that it is more frequent among women reporting induced abortions dysmenorrhoea and chronic pelvic pain.

High-dose calcitriol therapy and progression of cardiac vascular calcifications.

BACKGROUND: Dialysis patients show a very high prevalence of cardiovascular complications, affected as they are with abnormal and accelerated vascular calcifications and, eventually, calcium and phosphorous metabolism disorders. Multislice computed tomography (MSCT) provides a reproducible, high-resolution imaging of calcium contained in cardiac arteries, measured by Agatston score. The aim of the present study was to evaluate the influence of high-dose and low-dose calcitriol therapy on the progression of cardiac vascular calcifications in dialyzed patients. METHODS: We enrolled 36 dialyzed patients in a prospective study, including an interventional period of 12 months and a follow-up period of 12 months. Eighteen protocol patients received intravenous pulses of high-doses calcitriol at the end of dialytic treatment and sevelamer hydrochloride therapy. Control patients received low-dose calcitriol and sevelamer hydrochloride as well. Two MSCT scans were performed: 1 at the start of the study and 1 at the end of follow-up, and Agatston score was calculated at both examinations. RESULTS: At first examination, protocol patients showed almost the same level of cardiac vascular calcification as control patients. At the second MSCT, statistically significantly higher values of Agatston score were recorded for all patients. Indeed, patients who showed higher baseline values developed worse calcifications as recorded at the end of follow-up, both in the protocol and control group. CONCLUSIONS: Our data show that baseline level is strongly predictive of vascular calcification progression, and, moreover, there is no association between calcitriol administered doses and the progression of cardiac vascular calcification.

Adenosine A2A receptor antagonism increases nNOS-immunoreactive neurons in the striatum of Huntington transgenic mice.

Medium spiny GABAergic projection neurons are progressively lost in Huntington's disease (HD), whereas there is preferential sparing of the few interneurons co-expressing NPY, somatostatin and neuronal nitric oxide synthase. We investigated the effect of the selective adenosine A(2A) receptor antagonist SCH58261 (0.01 mg/kg, acutely and chronically administered i.p.) on nNOS striatal expression and motor impairment in R6/2 transgenic mice in clearly symptomatic phase (10-11-week old). SCH58261 chronically administered increased the number of nNOS-immunoreactive neurons (nNOS-IR) in the striatum of R6/2 mice. No glial activation was detected in the striatum or cortex. SCH58261 also improved walking in the inclined plane test but not motor capability evaluated by the rotarod test. These findings demonstrate for the first time a role of adenosine A(2A) receptors in regulating nNOS expression in the striatum. We suggest that the protective effect of A(2A) antagonism in HD is related to the increase in striatal nNOS-IR neurons.

Induced abortion and risk of small-for-gestational-age birth.

OBJECTIVE: To investigate the possibility of an association between previous induced abortion and subsequent birth of a small-for-gestational-age (SGA) infant. DESIGN: Case-control study. SETTING: General and university hospitals. METHODS: Cases were 555 women who delivered SGA babies. Controls were 1966 women who gave birth at term (>37 weeks of gestation) to healthy infants of normal weight on randomly selected days at the hospital where cases had been identified. All women in the case and control categories were interviewed on the obstetric wards by one of a team of six interviewers. During the interviews, information was obtained regarding general socio-demographic factors, personal characteristics and habits, gynaecological and obstetric history, general anamnesis, family history of obstetric and gynaecological diseases, and the age of the father of the child. Further information on current pregnancy and delivery was also collected. We used conditional multiple logistic regression (with age as the matching variable), with maximum likelihood fitting, to obtain odds ratios and their corresponding 95% CIs. Included in the regression equations were terms for education, plus terms significantly associated in this data set with the risk of SGA birth (smoking in pregnancy, history of SGA, gestational hypertension and parity). POPULATION: Women admitted to a general and a university hospital. RESULTS: No significant increase in the risk of SGA birth was observed in women with a previous induced abortion [odds ratio (OR) 1.0; 95% CI 0.6-1.7]. The OR for SGA birth was 1.2 (95% CI 0.7-2.1) for preterm and 1.0 (95% CI 0.7-1.4) for term SGA births. CONCLUSION: This study found no association between risk of SGA birth and induced abortion.

The role of ATP and adenosine in the brain under normoxic and ischemic conditions.

By taking advantage of some recently synthesized compounds that are able to block ecto-ATPase activity, we demonstrated that adenosine triphosphate (ATP) in the hippocampus exerts an inhibitory action independent of its degradation to adenosine. In addition, tonic activation of P2 receptors contributes to the normally recorded excitatory neurotransmission. The role of P2 receptors becomes critical during ischemia when extracellular ATP concentrations increase. Under such conditions, P2 antagonism is protective. Although ATP exerts a detrimental role under ischemia, it also exerts a trophic role in terms of cell division and differentiation. We recently reported that ATP is spontaneously released from human mesenchymal stem cells (hMSCs) in culture. Moreover, it decreases hMSC proliferation rate at early stages of culture. Increased hMSC differentiation could account for an ATP-induced decrease in cell proliferation. ATP as a homeostatic regulator might exert a different effect on cell trophism according to the rate of its efflux and receptor expression during the cell life cycle. During ischemia, adenosine formed by intracellular ATP escapes from cells through the equilibrative transporter. The protective role of adenosine A(1) receptors during ischemia is well accepted. However, the use of selective A(1) agonists is hampered by unwanted peripheral effects, thus attention has been focused on A(2A) and A(3) receptors. The protective effects of A(2A) antagonists in brain ischemia may be largely due to reduced glutamate outflow from neurones and glial cells. Reduced activation of p38 mitogen-activated protein kinases that are involved in neuronal death through transcriptional mechanisms may also contribute to protection by A(2A) antagonism. Evidence that A(3) receptor antagonism may be protective after ischemia is also reported.

Infectious complications in renal transplant recipients.

Renal transplantation has become a well-established therapeutic option for end-stage renal disease, but infectious diseases remain a significant cause of morbidity and mortality. Although a wide variety of pathogens may cause infection, viral ones must be regarded as the single most important class of infections. Progress has been made both in the prevention and the early recognition treatment of infections that are closely linked to rejection. Immunosuppressive therapy is central to the pathogenesis of both. Because of the particular characteristics of transplant recipients, it is desirable to establish a close collaboration between nephrologists, surgeons, and infectious disease specialists for the management of these patients. In this article, we describe the different kinds of infectious disease that may affect patients with kidney transplant and the fundamental principles of clinical management, particularly our experience in Polyoma virus (BK) infection.