OBESITY AND GUT-BRAIN AXIS.

Epidemic of obesity is ongoing and did not slow down. Causes of obesity are numerous and very complex. Among them, the concept of bidirectional signaling within the brain-gut-microbiome axis was recently proposed as possible pathophysiological mechanism and become a hot topic in the explanations for the control of food intake. Discoveries of new anti-obesity drugs that are analogs for the receptors for some hormones derived from gastrointestinal tract contribute to the investigations in this area. The human gut microbiota plays a fundamental role in human health and disease and it is considered that it represent an endocrine organ that participate in energy homeostasis and host immunity. Role of gut microbiome has been investigated in metabolic diseases such as obesity, type 2 diabetes and non-alcoholic fatty liver disease. Gut microbiome participate in regulation of various mechanisms inside the gastrointestinal tract due to its production of different bacterial metabolites. In our manuscript we present current knowledge about microbiota in the gut; the relation between gut microbiota and brain; neuroendocrine system and gut-brain axis; immune system and gut-brain axis; endocrine system and gut-brain axis; the role of gut microbiota in obesity development and possible use of gut microbiota for the treatment of obesity.

THE EFFECTS OF ENDOCRINE DISRUPTORS ON FEMALE GONADAL AXIS: AN UPDATE.

Endocrine disruptors (EDs) are considered to have an impact on the function of reproductive axis at different levels as well on reproductive organs in both sexes. Complexity of female reproductive system influenced with various stressors including EDs lead to morphological and functional alterations. This is resulting in modulation of neuroendocrine regulation with consequent developmental irregularities and derangements, causative infertility, endometriosis as well as premature ovarian insufficiency or polycystic ovary syndrome. A number of experimental clues was obtained on female animal models using various EDs such as synthetic estrogens and phytoestrogens, neurotransmitters, pesticides or various chemicals. These substances lead towards consequent derangement of the neuroendocrine control of reproduction from early phases of reproductive development towards different phases of adult reproductive period. This text will address some novel insights into the effects of EDs on neuroendocrine regulation of gonadal axis, effects on ovaries as well on endometrium during implantation period.

A non-invasive method for estimating the severity of liver steatosis and the risk of fibrosis in non-obese type 2 diabetes patients with NAFLD.

Context: Prognostic considerations include assessing the risk of liver fibrosis in people with non-alcoholic fatty liver disease (NAFLD). Objectives: This study evaluates the use of hematologic and metabolic parameters regarding liver steatosis and fibrosis scores (FLI and Fib-4) in non-obese type 2 diabetes mellitus (t2DM) patients with NAFLD. Methods: Subjects underwent abdominal ultrasound examinations, and FLI and Fib-4 scores were calculated to evaluate liver steatosis and the risk of liver fibrosis non-invasively: 61 non-obese NAFLD subjects with t2DM were included in the cohort study and were divided into 2 groups depending on the t2DM treatment regimen. Results: Fib-4 and WBC count demonstrated a significant inverse correlation (OR = 0.509, p = 0.007). WBC count had an R2 of 0.237, indicating that this marker could account for up to 23.7% of a variation in Fib-4. Fib-4 and FFA had positive correlation which did not achieve statistically significant prediction (OR=7.122, p=0.062). Additionally, a significant prediction of HbA1c (OR=1.536, p=0.016) and haemoglobin (OR=1.071, p=0.020) for FLI was revealed. Conclusion: HbA1c and other haematological and metabolic parameters, such as haemoglobin and WBC, may be another non-invasive tool for determining whether non-obese NAFLD patients with t2DM are at risk of developing liver steatosis and fibrosis.

The effect of metformin and myoinositol on metabolic outcomes in women with polycystic ovary syndrome: role of body mass and adiponectin in a randomized controlled trial.

PURPOSE: To compare the effects of insulin sensitizers metformin (MET) and myo-inositol (MI) on adiponectin levels and metabolic characteristics in women with polycystic ovary syndrome (PCOS) with respect to their body mass index (BMI). METHODS: In this open label, parallel randomized clinical trial, 66 women with PCOS (33 normal-weight and 33 overweight/obese) were randomized to either MI (4 g/day) or MET (1500 mg/day) for a period of 6 months. Serum concentration of adiponectin, hormonal and metabolic laboratory outcomes and clinical assessment of BMI, body composition and Ferriman-Gallwey score (FG score) were evaluated before and after treatment. RESULTS: After the 6-month intervention, comparison between MET and MI in time to treatment analysis showed no significant differences between the two treatments for all analyzed parameters. Only borderline significantly lower AUC glucose was found in the MET group in comparison to the MI group (p = 0.071). The main effect of treatment was shown for glucose concentration at 120 min OGTT (p = 0.032) and testosterone (p = 0.002). The main effect of time was shown for body mass (p = 0.004), waist circumference (p < 0.001), BMI (p = 0.003), body fat mass (p = 0.001), adiponectin (p = 0.020), fasting glucose (p = 0.001), testosterone (p = 0.015), SHBG (p = 0.013), 17OH progesterone (p = 0.008), LH (p = 0.004) and estradiol (p = 0.014). CONCLUSION: Our study showed similar effects of MET and MI on BMI, body composition, hormonal profile, metabolism of glucose and insulin, and adiponectin level. The two insulin sensitizers, MET and MI, were useful in reducing BMI and improving body composition without significant differences between the two treatments in PCOS women. TRIAL REGISTRATION: ISRCTN13199265. Trial registration date: 14.04.2021. (ISRCTN Registry), retrospectively registered.

THE EFFECT OF MYOINOSITOL AND METFORMIN ON CARDIOVASCULAR RISK FACTORS IN WOMEN WITH POLYCYSTIC OVARY SYNDROME: A RANDOMIZED CONTROLLED TRIAL.

CONTEXT: Cardiovascular risk is increased in women with polycystic ovary syndrome (PCOS). Do insulin sensitizing agents such as metformin (MET) and myoinositol (MI) ameliorate biomarkers of cardiovascular risk? OBJECTIVE: To compare the effects of MET and MI on blood pressure, lipid profile and high sensitive C-reactive protein (hs-CRP) in women with PCOS in respect to their body mass index (BMI). DESIGN: Open label, parallel randomized, single center study. SUBJECTS AND METHODS: Sixty six women with PCOS (33 normal-weight and 33 overweight/obese) were randomized to either MI (4 g/day) or MET (1500 mg/day) for a period of 6 months. Serum concentration of hormones, lipid profile, oxidized LDL (ox-LDL), hs-CRP, blood pressure measurement and clinical assessment of BMI, waist circumference (WC) and Ferriman Gallwey score (FG score) were performed before and after treatment. RESULTS: Thirty patients in each group completed the trial. Compared with MET, MI significantly decreased diastolic blood pressure (DBP) (p=0.036) and significantly increased serum hs-CRP (p=0.043). No differences between groups in total cholesterol (TC), HDL-cholesterol, LDL-cholesterol, ox-LDL and triglycerides were reported after 6 months. Treatment with MI reduced BMI (p=0.037), WC (p=0.005), DBP (p=0.021) and TC (p=0.008). During MET treatment a significant decrease in BMI (p=0.005), WC (p=0.004), FG score (p=0.001), testosterone (p=0.013) and free androgen index (FAI) (p=0.006) was observed. CONCLUSIONS: Our study showed an advantage of MI in reduction of DBP and TC thus predicting favorable metabolic and cardiovascular outcomes in PCOS women. MET more effectively decrease indices of hyperandrogenism.

ENDOCRINE DISRUPTING CHEMICALS AND OBESITY: THE EVOLVING STORY OF OBESOGENS.

Increase in obesity pandemic all over the world consequently leads to the investigation of possible causes. In addition to the traditional explanation using the so-called caloric model, the field of endocrine disruptors (EDs), especially subgroup called obesogens, offered more light on the pathogenetic mechanisms involved. After the Second World War a correlation between an increased production of exogenous pollutants and actual obesity epidemic was suggested. "Obesogen hypothesis" implies that molecules called obesogens inadequately stimulate the development of adipose cells and lipid accumulation in existing adipose cells, as well as change metabolic balance or hormonal control of appetite and satiety, leading to an increase in body fat mass. The list of obesogens includes some industrial chemicals, biocides, pharmaceuticals, pollutants, and smoke. EDs from the group of obesogens may exert their effects by the impairment in the programming development of adipocytes, by an increase in energetic depot in the adipose tissue, and by influencing neuroendocrine control of appetite and satiety. Increased scientific evidence on obesogens and their mechanisms of action may help to prevent obesity and mitigate deleterious effects of the environment on human life and development. New translational studies are needed to explain the possible mechanism proposed.

Insulin resistance, androgens, and lipids are gradually improved in an age-dependent manner in lean women with polycystic ovary syndrome: insights from a large Caucasian cohort.

PURPOSE: Polycystic ovary syndrome (PCOS), considered a lifelong condition, manifests mainly as a cluster of hyperandrogenic symptoms during the early reproductive years, with the affected woman gradually developing an adverse cardiometabolic profile over the years. However, some data point to the possibility of differences in the evolution of PCOS according to a woman's weight. The aim of the present study was to evaluate the metabolic and hormonal profiles of women with PCOS over time. METHODS: A total of 763 lean women with PCOS (BMI 20-25 kg/m2) and 376 controls were included. The study group was further divided into three age groups representing women post-adolescence, of reproductive age, and of late reproductive age. All subjects were assessed clinically, biochemically, and hormonally. RESULTS: Waist circumference, lipids, androgens, and insulin resistance index (homeostasis model assessment of IR index (HOMA-IR)) were significantly higher in the PCOS group compared with controls. Age subgroup analysis showed a progressive decrease of HOMA-IR and waist circumference, and lipid levels were comparable between PCOS and controls in all age groups. Androgens remained significantly higher in PCOS, but they gradually decreased through time. A significant negative association of age with waist circumference, androgens, insulin, and HOMA-IR was revealed. Univariate and multivariate regression analysis disclosed a strong correlation of HOMA-IR with age (p = 0.014, ß - 0.19, SE coefficient 0.008) as a single parameter or in combination with total cholesterol (TC) (p < 0.001, age: ß - 0.023, SE 0.10; TC: ß 0.084, SE 0.027). CONCLUSION: Insulin resistance, androgens, and lipids are gradually improved in an age-dependent manner in lean PCOS women. We hypothesize that if these women do not gain weight with the passage of time, there is a high probability that their cardiometabolic risk will be attenuated.

Peripartum cardiomyopathy: a case of patient with triplet pregnancy.

Peripartum cardiomyopathy (PPCM) is a rare but potentially devastating complication of pregnancy associated with heart failure due to left ventricular systolic dysfunction occurring within the last month of pregnancy and five month postpartum with no obvious other cause of heart failure and no pre-existing heart disease. In the present case report the authors present a woman who developed PPCM on the day after she delivered by cesarean section in 35th weeks of gestation of triplet pregnancy conceived after ovarian stimulation and insemination. A treatment with diuretics, ACE inhibitors, antiarrhythmics, low weight heparin, antibiotics and bromocriptine was applied and resulted in complete recovery. In conclusion, timely detection and initiation of treatment are important factors for complete recovery of patients with PPCM.

Non-alcoholic fatty liver disease is associated with insulin resistance and lipid accumulation product in women with polycystic ovary syndrome.

STUDY QUESTION: What are the most relevant factors associated with non-alcoholic fatty liver disease (NAFLD) in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Insulin resistance (IR) and lipid accumulation product (LAP) are independently associated with NAFLD in PCOS. WHAT IS KNOWN ALREADY: Obesity and IR are frequently present in both women with PCOS and subjects having NAFLD. The coexistence of PCOS and NAFLD might synergistically increase the risk for both type 2 diabetes (T2DM) and cardiovascular disease (CVD). LAP, calculated from waist circumference (WC) and triglycerides (TGs) concentrations [(WC-58) × TGs], has been shown to represent an integrated marker of cardiometabolic risk in women with PCOS. STUDY DESIGN, SIZE, DURATION: This cross-sectional study included 600 Caucasian women diagnosed with PCOS by the Rotterdam criteria between May 2008 and May 2013. PARTICIPANTS, SETTINGS, METHODS: The study was done at the university hospitals in Belgrade, Serbia and Thessaloniki, Greece. All subjects underwent anthropometric measurements and analyses of fasting blood glucose, insulin, lipids, total testosterone and SHBG, as well as liver tests (transaminases, γ-glutamyltransaminase, total bilirubin and alkaline phosphatase). Calculations for a NAFLD liver fat score (NAFLD-LFS) (with, accordingly, determination of metabolic syndrome and testing for T2DM) as well as homeostasis model assessment of IR (HOMA-IR), LAP as a marker of visceral adiposity, and free androgen index (FAI) were performed. We evaluated the prevance of NAFLD and analyzed associations of the above variables with NAFLD. MAIN RESULTS AND THE ROLE OF CHANCE: NAFLD was more prevalent in patients with PCOS than in controls (50.6 versus 34.0%, respectively). Women with PCOS had higher readings for WC, LAP, insulin and HOMA-IR, total cholesterol and TGs than controls (P < 0.001). In PCOS women, the NAFLD-LFS significantly (P < 0.001) correlated with WC, BMI, glucose, HOMA-IR, TGs, LAP and FAI. In multivariate logistic regression, HOMA-IR and LAP were independently associated with NAFLD (P ≤ 0.001). LIMITATIONS, REASONS FOR CAUTION: A possible weakness of the study may be the absence of structural confirmation of liver status. Hovewer, liver biopsy is invasive, difficult to perform in large populations and carries some risk of complications while magnetic resonance spectroscopy does not provide any information regarding the presence of fibrosis and is not routinely available. Another possible limitation could be the measurement of total testosterone by radioimmunoassay, which can be inaccurate when determining low levels of testosterone. Finally, fewer controls than subjects in the study group could have affected the significance of the results. WIDER IMPLICATIONS OF THE FINDINGS: There is a debate on the most accurate clinical method for diagnosing liver disease as an early predictor of T2DM and CVD in general population and in PCOS women. There current study provided data on this issue from a cohort of Caucasian women with PCOS. STUDY FUNDING/COMPETING INTERESTS: The study was supported by a research grant by the Serbian Ministry of Science and Education (grant nos 41009 and 175032). All authors have no competing interests.

Cardiac Nitric Oxide Synthases and Na⁺/K⁺-ATPase in the Rat Model of Polycystic Ovary Syndrome Induced by Dihydrotestosterone.

Nitric oxide synthases (NOSs) and Na(+)/K(+)-ATPase are enzymes essential for regular functioning of the heart. Since both enzymes are under insulin and androgen regulation and since insulin action and androgen level were disturbed in polycystic ovary syndrome (PCOS), we hypothesized that cardiac nitric oxide (NO) production and sodium/potassium transport would be deteriorated in PCOS. To test our hypothesis we introduced animal model of PCOS based on dihydrotestosterone (DHT) treatment of female Wistar rats and analyzed protein expression, phosphorylation or subcellular localization of endothelial NOS (eNOS), inducible NOS (iNOS) and alpha subunits of Na(+)/K(+)-ATPase in the heart. Obtained results indicate that DHT treatment significantly decreased cardiac eNOS protein level and activating phosphorylation at serine 1,177, while inhibitory phosphorylation at threonine 495 was increased. In contrast to expression of eNOS, iNOS protein level in the heart of DHT-treated rats was significantly elevated. Furthermore, cardiac protein level of alpha 1 subunit of the ATPase, as well as its plasma membrane content, were decreased in rats with PCOS. In line with this, alpha 2 subunit protein level in fraction of plasma membranes was also significantly below control level. In conclusion, DHT treatment impaired effectiveness of NOSs and Na(+)/K(+)-ATPase in the female rat heart. Regarding the importance of NO production and sodium/potassium transport in the cardiac contraction and blood flow regulation, it implicates strong consequences of PCOS for heart functioning.

Cardiovascular risk factors and events in women with androgen excess.

Androgen excess (AE) was approximated to be present in 7% of the adult population of women. Polycystic ovary syndrome (PCOS) is the most prevalent among them, followed by idiopathic hirsutism (IH), congenital adrenal hyperplasia (CAH), hyperandrogenic insulin-resistant acanthosis nigricans (HAIRAN) syndrome, and androgen-secreting neoplasms (ASNs). Increased cardiovascular risk was implicated in women with AE. Serum testosterone independently increases risk for cardiovascular disease (CVD), and correlates even with indices of subclinical atherosclerosis in various populations of postmenopausal women. Hyperandrogenism in PCOS is closely related to the aggravation of abdominal obesity, and together with insulin resistance forming the metabolic core for the development of CVD. However, phenotypic variability of PCOS generates significant influence on the cardiometabolic risks. Numerous risk factors in PCOS lead to 5-7 times higher risk for CVD and over 2-fold higher risk for coronary heart disease and stroke. However, issue on the cardiometabolic risk in postmenopausal women with hyperandrogenic history is still challenging. There is a significant overlapping in the CVD characteristics of women with PCOS and variants of CAH. Relevant clinical data on the prevalence and cardiometabolic risk and events in women with IH, HAIRAN syndrome or ASNs are scarce. The effects of various oral contraceptives (OCs) and antiandrogenic compounds on metabolic profile are varying, and could be related to the selected populations and different therapy regiments mainly conducted in women with PCOS. It is assumed relation of OCs containing antiandrogenic progestins to the increased risk of cardiovascular and thromboembolic events.

Homocysteine thiolactone-induced seizures in adult rats are aggravated by inhibition of inducible nitric oxide synthase.

Homocysteine and its metabolites (homocysteine thiolactone (HT)) induce seizures via different but still not well-known mechanisms. The role of nitric oxide (NO) in epileptogenesis is highly contradictory and depends on, among other factors, the source of NO production. The aim of the present study was to examine the effects of aminoguanidine, selective inhibitor of inducible NO synthase (iNOS), on HT-induced seizures. Aminoguanidine (50, 75, and 100 mg/kg, intraperitoneally (i.p.)) was injected to rats 30 min prior to inducing HT (5.5 mmol/kg, i.p.). Seizure behavior was assessed by seizure incidence, latency time to first seizure onset, number of seizure episodes, and their severity during observational period of 90 min. Number and duration of spike and wave discharges (SWDs) were determined in electroencephalogram (EEG). Seizure latency time was significantly shortened, while seizure incidence, number, and duration of HT-induced SWD in EEG significantly increased in rats receiving aminoguanidine 100 mg/kg before subconvulsive dose of HT. Aminoguanidine in a dose-dependent manner also significantly increased the number of seizure episodes induced by HT and their severity. It could be concluded that iNOS inhibitor (aminoguanidine) markedly aggravates behavioral and EEG manifestations of HT-induced seizures in rats, showing functional involvement of iNOS in homocysteine convulsive mechanisms.

Exercise decreases susceptibility to homocysteine seizures: the role of oxidative stress.

The aim of the study was to examine the effects of chronic exercise training on seizures induced by homocysteine thiolactone (HCT) in adult rats. Rats were assigned to: sedentary control; exercise control; sedentary+HCT; exercise+HCT group. Animals in the exercise groups ran 30 min daily on a treadmill for 30 consecutive days (belt speed 20 m/min), while sedentary rats spent the same time on the treadmill (speed 0 m/min). On the 31st day, the HCT groups received HCT (8.0 mmol/kg), while the control groups received vehicle. Afterwards, convulsive behavior and EEG activity were registered. Lipid peroxidation, superoxide dismutase (SOD) and catalase (CAT) activity were ascertained in the rat hippocampus. No signs of seizures were registered in sedentary and exercise control rats. Seizure latency was increased, while number of seizure episodes and spike-and-wave discharges (SWD) in EEG were decreased in the exercise+HCT compared to the sedentary+HCT group. Seizure incidence, the severity thereof and duration of SWDs were not significantly different between these groups. Exercise partly prevented increase of lipid peroxidation and decrease of the SOD and CAT activity after HCT administration. These results indicate beneficial effects of exercise in model of HCT-induced seizures in rats, what could be, at least in part, a consequence of improved antioxidant enzymes activity.

Hypothalamic-pituitary-adrenocortical axis hypersensitivity and glucocorticoid receptor expression and function in women with polycystic ovary syndrome.

INTRODUCTION: Molecular mechanisms underlying pathophysiology of polycystic ovary syndrome (PCOS), especially those related to cortisol signaling, are poorly understood. We hypothesized that modulation of glucocorticoid receptor (GR) expression and function, may underlie possible PCOS-related impairment of feedback inhibition of hypothalamic-pituitary-adrenocortical (HPA) axis activity and thus contribute to increased adrenal androgen production in women with PCOS. MATERIALS AND METHODS: 24 normal-weight and 31 obese women with PCOS were compared to 25 normal-weight controls. Fasting blood samples were collected for measurements of serum concentrations of dehydroepiandrosterone sulfate, testosterone, sex hormone-binding globulin, insulin, basal cortisol and cortisol after oral administration of 0.5 mg dexamethasone. Concentrations of GR mRNA, GR protein, mineralocorticoid receptor (MR) protein and heat shock proteins (Hsps), as well as the number of GR per cell (B(max)) and its equilibrium dissociation constant (K(D)) were measured in isolated peripheral blood mononuclear cells. RESULTS: An increase in HPA axis sensitivity to dexamethasone, an elevation of the GR protein concentration, and unaltered receptor functional status were found in both normal-weight and obese women with PCOS vs. healthy controls. Lymphocyte MR, Hsp90 and Hsp70 concentrations, and MR/GR ratio were similar in all groups. Correlation between B(max) and K(D) was weaker in the group of obese women with PCOS than in the other 2 groups. CONCLUSIONS: The results did not confirm the initial hypothesis, but imply that PCOS is associated with increased GR protein concentration and HPA axis sensitivity to dexamethasone.

Insulin resistance in non-obese women with polycystic ovary syndrome: relation to byproducts of oxidative stress.

To get more insight into molecular mechanisms underlying oxidative stress and its link with insulin resistance, oxidative stress parameters, as well as, antioxidant enzyme activities were studied in young, non-obese women with polycystic ovary syndrome (PCOS). Study was performed in 34 PCOS women and 23 age and body mass index (BMI)-matched healthy controls. Plasma nitrotyrosine and malondialdehyde (MDA), representative byproducts of protein and lipid oxidative damage, were determined by enzyme immunoassay. Antioxidant enzyme activities, superoxide dismutase (SOD) and glutathione peroxidase (GPX) were studied spectrophotometrically. Insulin resistance was calculated using homeostasis assessment model (HOMA-IR). Plasma nitrotyrosine and MDA were increased, but only nitrotyrosine was significantly higher (p < 0.05) in PCOS women compared to controls. Uric acid (surrogate marker of × antine oxidase) was also significantly elevated in PCOS (p < 0.05). Both plasma SOD and GPX activity showed no statistically significant difference between PCOS and controls. Indices of insulin resistance (insulin and HOMAIR) were significantly higher in PCOS group and positively correlated with level of MDA (r = 0.397 and r = 0.523, respectively; p < 0.05) as well as GPX activity (r = 0.531 and r = 0.358, respectively; p < 0.05). Our results indicate that insulin resistance could be responsible for the existence of subtle form of oxidative stress in young, nonobese PCOS women. Hence, presence of insulin resistance, hyperinsulinemia and oxidative damage are likely to accelerate slow development of cardiovascular disease in PCOS.

The effect of N-methyl-D-aspartate receptor antagonists on D,L-homocysteine thiolactone induced seizures in adult rats.

The aim of our study was to investigate the effects of ifenprodil and MK-801 on D,L-homocysteine thiolactone induced seizures in adult rats.Male Wistar rats were divided into following groups: 1. Saline-treated (C, n=10); 2. D,L-homocysteine thiolactone 8 mmol/kg, i.p. (H, n=7); 3. Ifenprodil 20 mg/kg i.p. (IF, n=8); 4. MK-801 0.5 mg/kg, i.p. (MK, n=8) and 5. Groups that received IF or MK 30 minutes prior to H (IFH, n=8 and MKH, n=8). Seizure behavior was assessed by incidence, latency, number and intensity of seizure episodes. Seizure severity was described by a descriptive scale with grades 0-4. Lethality in experimental group was recorded 90 min and 24 h upon D,L-homocysteine thiolactone administration.There were no behavioral signs of seizure activity in groups C, IF and MK.Pre-treatment with MK-801 (MKH) showed tendency to reduced incidence of convulsions, latency to the first seizure onset and the severity of seizure episodes, but statistical significance was not attained comparing to the H group. However, median number of seizure episodes was significantly decreased in MKH (p<0.05), comparing to the H group. On the other hand, ifenprodil (IFH) decreased the latency to the first seizure onset and increased the median number of seizure episodes (p<0.05). The majority of seizure episodes in IFH (72.1%, p<0.05) and MKH (73.1%, p<0.05) groups was grade 2 and significantly different comparing to the H (36.0%). Our findings suggest that MK-801 has a mild anticonvulsive effect on D,L-homocysteine thiolactone induced seizures in adult rats.

Pure red-cell aplasia as the presenting feature of the carcionoid tumor of the thymus: case report.

Acquired pure red-cell aplasia (PRCA) is an uncommon disorder of erythrocytopoiesis that can develop in association with thymic tumors. We present the very rare case of a severely anemic 62-year-old man with PRCA and a concurrent neuroendocrine carcinoid tumor of the thymus. The anterior mediastinal thymus tumor was completely excised, and following histological and immunohistochemical analyses (showing positive staining for cytokeratin, chromogranin A, synaptophysin, and neuron-specific enolase) the diagnosis of a (grade I; T(1)N(0)M(0)) typical carcinoid tumor of the thymus was made. Postoperatively the anemia persisted despite no signs of residual tumor on CT chest. A hematological work up found: normocellularity with <0.5% erythroblasts and preserved megakaryocytopoiesis and granulocytopoiesis in a trephine biopsy; reduced numbers of Colony Forming Unit Erythroid (CFU-E) and normal numbers of Burst-Forming Unit Erythroid (BFU-E) in bone marrow colony-forming assays; a markedly increased level of serum erythropoietin; normal T and B-cell numbers with a normal CD4/CD8 ratio; and no clonal T-cell receptor -gamma and -delta gene rearrangement) The patient responded favorably to a therapeutic trial of glucocorticoid immunosuppressive treatment (prednisone 1 mg/kg/day) with a normalization of the reticulocyte count and hematocrit, suggesting an immunologic mechanism for the PRCA. Though the exact mechanisms underlying the association between the PRCA and the carcinoid tumor of the thymus remain unknown.

Cardiovascular risk in adolescent and young adult obese females with polycystic ovary syndrome (PCOS).

Women with polycystic ovary syndrome (PCOS) could have associated risk for cardiovascular disease. The aim of the present study was to investigate the relationship between age and metabolic factors on cardiovascular risk in obese women with PCOS. Obese patients with PCOS were divided into an adolescent group (n=11; age 16.90 +/- 0.45 yr; BMI 35.04 +/- 1.70 kg/m2), and an adult group (n=18; age 29.66 +/- 1.31; BMI 34.57 +/- 1.46). We determined basal values of glucose, insulin, lipid and fibrinolytic parameters from blood samples taken in all patients and matched controls. Significantly different concentrations between the groups with PCOS were obtained for glucose, total cholesterol, triglycerides, LDL-cholesterol and Apo-B. Elevated concentrations of insulin (20.63 mU/l), both insulin sensitivity indexes--G:I ratio (7.52 mg/10(-4) U) and HOMA model (4.11 mmol/l x U/l(2))--and PAI-1 (5.49 U/ml) were obtained in the adolescent group with PCOS compared to controls, with further increase in the adult group with PCOS. It seems that the youngest obese population with PCOS represents a cohort with potential cardiovascular disease in adulthood.