Heme oxygenase-1 (HO-1) plays a crucial role in oxidative stress processes, apoptosis and cell differentiation. Further, some proteins related to cell cycle including cyclins and p21 are important markers of astrocyte cultures. Aim of investigation was to study the effects of cholinergic precursors (choline, CDP-choline, Acetylcholine and α-Glyceril-Phosphorylcholine) on HO-1 and p21 expression during astroglial cell proliferation and differentiation in primary cultures at 14 and 35 days in vitro (DIV) treated for 24 h with choline metabolites. Our results showed a slight reduction of HO-1 expression (data not statistical significant) in astroglial cell cultures treated with CDP-choline at 14 DIV and 35 DIV. On the contrary, ACh and choline induced a significant increase of HO-1 expression in 14 DIV astrocyte cultures. Surprisingly, choline and ACh dramatically reduced HO-1 expression at 35 DIV. A slight decrease not statistical significant was detectable for α-GPC at 14 DIV and particularly significant at 35 DIV. Data concerning p21 expression, a well known protein inhibiting cell cycle, evidenced a significant increase at 14 and 35 DIV after α-GPC treatment. CDP-choline treatment caused a high increase of p21 expression in 14 DIV astrocyte cultures, but no modification at 35 DIV. Instead, ACh treatment induced a marked increment of p21 expression at 35 DIV. Our data suggest that cholinergic precursors modulate HO-1 and p21 expression during astroglial cell proliferation and differentiation in culture and could be considered a tool to study the induced effects of ischemia and hypoxia diseases in some in vitro models to prevent and reduce its effects after treatment with cholinergic drugs.

Excitatory neurotransmission mediated by NMDA (N-methyl-D-aspartic acid) receptors plays a key role in both healthy and diseased processes in the brain. Therefore, bioactive compounds that can interact selectively with these receptors have been the aim of extensive research in the search of effective therapeutic agents or, at least, useful pharmacological tools. NMDA receptors are heteromeric ion channels that contain different modulatory sites capable to bind subunit-selective ligands. In particular, the activation of NMDA receptors requires two distinct ligands: glutamate (the endogenous agonist) and glycine (the co-agonist). In view of the renewed interest in this research area and the high therapeutic potential of this target, this review presents an updated survey of ligands which interact with the glutamate binding-site of the NMDA receptors, their rational development, and data on the structure-activity relationship which are of utmost importance for the design of novel lead compounds.

The present study was designed to assess the balance between antioxidant and prooxidant components and the oxidative stability of beef from cattle fed exclusively grazed pasture (PAS) or a barley-based concentrate offered indoors (CONC) for 11 mo, or fed grass silage indoors for a 5-mo winter period, followed for the remaining 6-mo summer period by grazed pasture (SiP) or by grazed pasture plus concentrate at 50% of the dietary DM (SiPC). Muscle prooxidant and antioxidant components were determined by measuring fatty acids and α-tocopherol concentration of LM, respectively. Lipid oxidation and color stability were monitored in ground LM, packaged in a high-oxygen modified atmosphere, over 11 d of refrigerated storage. Vitamin E concentration decreased (P < 0.0005) with an increasing proportion of concentrate in the diet (2.59, 2.45, 1.76, and 1.15 μg/g for PAS, SiP, SiPC, and CONC, respectively). A greater proportion of PUFA was found in LM from cattle in the PAS, SiP, and SiPC groups compared with animals in the CONC group (9.62, 11.04, 8.96, and 6.94%, respectively; P < 0.0005). A greater concentration of highly peroxidizable PUFA was found in LM from heifers in the PAS, SiP, and SiPC groups compared with those in the CONC group (0.84, 0.85, 0.87, and 0.65 mg/g of muscle, respectively; P = 0.02). Dietary treatment affected lipid oxidation (P < 0.0005), with greater 2-thiobarbituric acid reactive substance values in beef from heifers in the SiPC group than in beef from those in the PAS, SiP, and CONC groups. Dietary treatment affected myoglobin oxidation (P = 0.002) during storage, with greater metmyoglobin accumulation in beef from animals receiving concentrate (CONC and SiPC treatments) than in beef from cattle in the PAS and SiP groups. Consequently, feeding concentrate impaired meat color stability over the storage duration, with greater H*(hue angle) values (P < 0.0005) in meat from heifers in the SiPC and CONC groups compared with meat from those in the PAS and SiP groups. The results of the present study confirm a positive effect of grass-based feeding systems on meat color stability compared with concentrate-based dietary strategies. It appears that vitamin E in muscle alone does not explain the resistance of meat to oxidative deterioration because a clear interaction with highly peroxidizable PUFA exists.

Additional pulmonary surgery in a previously pneumonectomized patient requires apnea during surgical manipulation of the surviving lung. We report on a novel approach to manage the intraoperative apnea period, combining apneic oxygenation and minimally invasive, low flow extracorporeal CO2 removal. A 69-year-old man previously submitted to left pneumonectomy was scheduled for wedge resection of a single right upper lobe lesion. During the intraoperative apnea period, oxygenation was maintained through apneic oxygenation with continuous positive airway pressure (CPAP) of 5 cmH2O and inspiratory oxygen fraction (FiO2) of 1 and respiratory acidosis was prevented through extracorporeal CO2 removal, performed with the Decap® system (Hemodec, Salerno, Italy), a veno¬venous pump-driven extracorporeal circuit including a neonatal membrane lung. The extracorporeal circuit was connected to the right femoral vein, accessed via a 14 Fr double lumen catheter. The blood flow through the circuit was 350 mL/min and the sweep flow of oxygen through the membrane lung was 8 L/min. The intraoperative apnea period lasted 13 minutes. Our approach allowed maintaining normocapnia (PaCO2 38,5 and 40 mmHg before and at the end of the apnea period, respectively), preserving oxygenation (P/F ratio 378, 191, 198 and 200 after 3, 6, 9 and 12 min of apnea, respectively). Our report suggests that the minimally invasive CO2 removal associated with apneic oxygenation is an useful technique for managing anesthesiological situations requiring moderate apnea periods.

BACKGROUND: One-lung ventilation (OLV) affects respiratory mechanics and ventilation/perfusion matching, reducing functional residual capacity of the ventilated lung. While the application of a lung-recruiting manoeuvre (RM) on the ventilated lung has been shown to improve oxygenation, data regarding the impact of RM on respiratory mechanics are not available. METHODS: Thirteen patients undergoing lung resection in lateral decubitus were studied. During OLV, a lung-recruiting strategy consisting in a RM lasting 1 min followed by the application of positive end-expiratory pressure 5 cmH(2)O was applied to the ventilated lung. Haemodynamics, gas exchange and respiratory mechanics parameters were recorded on two-lung ventilation (TLV(baseline)), OLV before and 20 min after the RM (OLV(pre-RM), OLV(post-RM), respectively) and TLV(end). Haemodynamics parameters were also recorded during the RM. RESULTS: The PaO(2)/FiO(2) ratio was 358+/-126 on TLV(baseline); it decreased to 235+/-113 on OLV(pre-RM)(P<0.01) increased to 351+/-120 on OLV(post-RM)(P<0.01 vs. OLV(pre-RM)), and remain stable thereafter. During the RM, CI decreased from 3.04+/-0.7 l/m(2) OLV(pre-RM) to 2.4+/-0.6 l/m(2)(P<0.05), and returned to baseline on OLV(post-RM)(3.1+/-0.7 l/m(2), NS vs. OLV(pre-RM)). The RM resulted in alveolar recruitment and caused a significant decrease in static elastance of the dependent lung (16.6+/-8.9 cmH(2)O/ml OLV(post-RM) vs. 22.3+/-8.1 cmH(2)O/ml OLV(pre-RM))(P<0.01). CONCLUSIONS: During OLV in lateral decubitus for thoracic surgery, application to the dependent lung a recruiting strategy significantly recruits the dependent lung, improving arterial oxygenation and respiratory mechanics until the end of surgery. However, the transient haemodynamic derangement occurring during the RM should be taken into account.

ABSTRACT: BACKGROUND: Polycystic Ovary Syndrome (PCOS) is a multifactorial pathology that affects 10% of the women in reproductive age being the main cause of infertility due to menstrual dysfunction. Since 1980, it is known that PCOS is associated with insulin resistance (IR). The recognition of this association has prompted extensive investigation on the relationship between insulin and gonadal function, and has turned insulin sensitizer agent as the main therapeutic choice. In particular two different polyalcohol myo-inositol and D-chiro-inositol have been shown to improve insulin resistance, hyperandrogenism and to induce ovulation in PCOS women. In particular, while data on myo-inositol and restored ovulation were consistent, data on Dchiro- inositol were not once the dosage was increased. Recently, a comparative study, proposed a D-chiro-inositol paradox in the ovary of PCOS patients hypothesizing that only myo-inositol has a specific ovarian action. In the present study we aim to further study the role played by D-chiro-inositol at ovarian lavel. METHODS: A total of 54 women, aged <40 years and diagnosed with PCOS were enrolled in this study. Patients with insulin resistance and/or hyperglycaemia were excluded from the study. Patients were randomly divided into 5 groups (n=10-12): a placebo group, and 4 groups (A-D) that received 300-600-1200-2400 mg of DCI daily respectively. All treatments were carried out for 8 weeks before follicle stimulating hormone (rFSH) administration. RESULTS: Total r-FSH units increased significantly in the two groups that received the higher doses of DCI. The number of immature oocytes was significantly increased in the three groups that received the higher doses of DCI. Concurrently, the number of MII oocytes was significantly lower in the D group compared to placebo group. Noteworthy, the number of grade I embryos was significantly reduced by DCI supplementation. CONCLUSIONS: Indeed, increasing DCI dosage progressively worsens oocyte quality and ovarian response.

There is no clear acceptance of specific follicular fluid biomarker and its correlation with oocyte quality or related embryo variable till now. Most of the studies analyze correlation between certain biomolecules and the oocyte quality using single variable, instead of multivariate analysis algorithms. Our hypothesis is not based on single biomarker discovery, but attempts to explain oocyte quality in terms of energy metabolic pathways by considering its various intermediates. Reduced availability of glucose in the oocytes and follicular cells caused by defective transportation of glucose is expected in polycystic ovary syndrome (PCOS). This initiates alternative pathways to utilize fatty acid, amino acids etc. for energy as a compensatory mechanism to deal with the energy requirement. These compensations can be reflected by altered levels of various biomolecules in follicular fluid (e.g. ketone bodies, lipids, amino acids, lactate, pyruvate etc.). The amount of compensation, in order to meet the energy requirement can be directly correlated to quality of oocytes and better outcome after in vitro fertilization (IVF) in PCOS cases. This can be predicted with fair accuracy by doing a multivariate analysis of altered levels of various biomolecules in follicular fluid. Various supervised and unsupervised classification techniques based on spectroscopic data, obtained from follicular fluid samples may certainly prove to be an important tool to predict oocytes quality and IVF outcome with better accuracy in women with PCOS.

Our aim is to investigate the follicular fluid concentrations of antimullerian hormone and its effect on assisted reproductive technology (ART) outcome in non-obese, non-hyperandrogenemic polycystic ovary syndrome patients. Subjects were categorized according to in vitro fertilization (IVF) indications: Group 1 PCOS (n:16), Group 2 male factor infertility (n:19) and Group 3 unexplained infertiliy patients (n:19). Follicular fluid antimullerian hormone levels (FF AMH) on the day of oocyte retrieval were analysed and ART outcome was studied. FF AMH levels in group 1, 2 and 3 were 35.70 ng/ml (median); 17.90 ng/ml (median); 17.90 ng/ml (median), respectively (p = 0.18). There were correlations between the FF AMH levels and follicle, oocyte, 2PN and embryo numbers in pathophysiology of polycystic ovary syndrome (PCOS) patients (p = 0.012; 0.024; 0.027; 0.013 respectively). There were no correlations between the FF AMHand ART outcome parameters in group 2 and 3. FF AMH levels were not different between the groups who were pregnant or not (p = 0.06). In conclusion there were no significant differences in terms of FF AMH levels in the three groups. FF AMH levels can predict the recovery of oocytes but not oocyte quality, embryo quality or pregnancy in non-obese non-hyperandrogenemic PCOS patient.

Aromatase inhibitors (AIs) were originally developed for the treatment of advanced breast cancer in postmenopausal women. Their use in reproductive medicine has been extensively studied in the past decade. We reviewed the current strategies for ovulation induction for anovulatory women, mostly women with polycystic ovarian syndrome (PCOS), and the scientific basis for use of AIs in reproductive medicine. The AI, letrozole, is effective in ovulation induction in women with PCOS resistant to clomifene citrate and ovarian stimulation for intrauterine insemination and in vitro fertilization (IVF). Letrozole is an attractive option with its oral route of administration, cost, safety profile and effectiveness in ovulation induction and ovarian stimulation. Letrozole has the potential to be the first-line treatment option for ovulation induction in PCOS women, while its use in ovarian stimulation for IVF deserves further study.

In an attempt to evaluate the role of inositol supplementation in insulin-resistant patients with polycystic ovary syndrome (PCOS), undergoing gonadotropin ovulation induction using the low-dose step-down regimen, we conducted a prospective longitudinal study comparing the stimulation characteristics of 15 patients treated with inositol, to a cohort, matched by age and body mass index (BMI), without inositol. Inositol nutritional supplementation produced very good clinical results with a significant reduction in cancellation rate (0 vs. 40%) and the consequent improvement in clinical pregnancy rate (PR)(33.3% vs. 13.3%).

Metabolic syndrome affects one in four women in the USA, and the incidence is rising every year. Metabolic syndrome is strongly associated with development of coronary artery disease and diabetes. Women of reproductive age are not spared from the complications of metabolic syndrome, which overlaps with obesity and polycystic ovary syndrome (PCOS), both of which are linked to infertility and poor reproductive outcome. Therefore, the relationship between the metabolic syndrome and reproductive dysfunction is an active area of study. In this review, we discuss the animal and human data available to determine if the abnormality is at the level of the ovary and/or endometrium, and discuss the underlying mechanisms causing the associated poor reproductive outcomes.

Polycystic ovary syndrome (PCOS) is the most frequent endocrinopathy in reproductive-aged women, mainly characterized by oligoanovulation and hyperandrogenism. Insulin resistance represents a major pathophysiological feature of the syndrome and, therefore, insulin-sensitizing agents (metformin and thiazolidinediones) have been applied in PCOS women. However, the clinical use of insulin sensitizers in PCOS has been debated. The aim of the current review was to update the knowledge regarding the role of metformin and thiazolidinediones in PCOS treatment, focusing on recently published studies. Several clinical trials examined metformin effectiveness on lipids, atherosclerosis and inflammatory markers, hormone levels, menstrual irregularities, ovulation induction, fertility, hirsutism, obesity parameters and quality of life in PCOS women. Metformin treatment was shown to improve these features, although conflicting results were also reported. Only one study investigated pioglitazone effect on PCOS, reporting an improved IVF outcome in clomiphene citrate-resistant PCOS patients. Finally, both metformin and pioglitazone, as a part of a low-dose polytherapy, exerted beneficial effects on lipids, androgen levels, hirsutism and markers of atherosclerosis in nonobese PCOS women. Further research, including larger randomized controlled trials and meta-analyses, is needed to clarify the role of metformin and thiazolidinediones in the treatment of clinical and biochemical PCOS characteristics.

HASH(0x2189efd0)

HASH(0x20482080)

To compare different oral ovulation induction agents in treating infertile women with polycystic ovary syndrome (PCOS). Decision-analytic model comparing three treatment strategies using probability estimates derived from literature review and sensitivity analyses performed on the baseline assumptions. Outpatient reproductive medicine and gynecology practices. Infertile women with PCOS. Metformin, clomiphene citrate, or metformin with clomiphene citrate. Live birth. Within the baseline assumptions, combination therapy with metformin and clomiphene citrate was the preferred therapy for achieving live birth in women with PCOS. Sensitivity analysis revealed the model to be robust over a wide range of probabilities. Combination therapy with metformin and clomiphene citrate should be considered as first-line treatment for infertile women with PCOS.