Hypothalamic-Ovarian axis and Adiposity Relationship in Polycystic Ovary Syndrome: Physiopathology and Therapeutic Options for the Management of Metabolic and Inflammatory Aspects.

PURPOSE OF REVIEW: The goal of the present review is to address the main adiposity-related alterations in Polycystic Ovary Syndrome (PCOS) focusing on hypothalamic-pituitary-ovarian (H-P-O) axis and to provide an overview of nutraceutical and pharmacological therapeutic strategies. RECENT FINDINGS: Female reproduction is a complex and delicate interplay between neuroendocrine signals involving the H-P-O axis. Elements that disrupt the balance of these interactions can lead to metabolic and reproductive disorders, such as PCOS. This disorder includes menstrual, metabolic, and biochemical abnormalities as well as hyperandrogenism, oligo-anovulatory menstrual cycles, insulin resistance, and hyperleptinemia which share an inflammatory state with other chronic diseases. Moreover, as in a self-feeding cycle, high androgen levels in PCOS lead to visceral fat deposition, resulting in insulin resistance and hyperinsulinemia, further stimulating ovarian and adrenal androgen production. In fact, regardless of age and BMI, women with PCOS have more adipose tissue and less lean mass than healthy women. Excessive adiposity, especially visceral adiposity, is capable of affecting female reproduction through direct mechanisms compromising the luteal phase, and indirect mechanisms as metabolic alterations able to affect the function of the H-P-O axis. The intricate crosstalk between adiposity, inflammatory status and H-P-O axis function contributes to the main adiposity-related alterations in PCOS, and alongside currently available hormonal treatments, nutraceutical and pharmacological therapeutic strategies can be exploited to treat these alterations, in order to enable a more comprehensive synergistic and tailored treatment.

Effects of physical exercise associated with a diet enriched with natural antioxidants on cerebral hypoperfusion and reperfusion injury in spontaneously hypertensive rats.

Oxidative stress is implicated in the pathogenesis of arterial hypertension. The reduction in the bioavailability of nitric oxide (NO) causes endothelial dysfunction, altering the functions of cerebral blood vessels. Physical exercise and intake of antioxidants improve the redox state, increasing the vascular NO production and/or the decrease in NO scavenging by reactive oxygen species (ROS). The present study was aimed at assessing the effects of physical exercise associated with a diet enriched with antioxidants from the Annurca apple in preventing the microvascular damage due to cerebral hypoperfusion and reperfusion injury in spontaneously hypertensive rats (SHRs). The rat pial microcirculation was investigated by intravital fluorescence microscopy through a parietal closed cranial window. As expected, SHRs subjected to physical exercise or an antioxidants-enriched diet showed a reduction of microvascular permeability, ROS formation, and leukocyte adhesion to venular walls, with a major effect of the antioxidants-enriched diet, when compared to untreated SHRs. Moreover, capillary perfusion was preserved by both treatments in comparison with untreated SHRs. Unexpectedly, the combined treatments did not induce higher effects than the single treatment. In conclusion, our results support the efficacy of physical activity or antioxidant supplement in reducing the microvascular alterations due to hypertension and ascribe to an antioxidants-enriched diet effective microvascular protection in SHRs.

The Emerging Role of c-Met in Carcinogenesis and Clinical Implications as a Possible Therapeutic Target.

BACKGROUND: c-MET is a receptor tyrosine kinase receptor (RTK) for the hepatocyte growth factor (HGF). The binding of HGF to c-MET regulates several cellular functions: differentiation, proliferation, epithelial cell motility, angiogenesis, and epithelial-mesenchymal transition (EMT). Moreover, it is known to be involved in carcinogenesis. Comprehension of HGF-c-MET signaling pathway might have important clinical consequences allowing to predict prognosis, response to treatment, and survival rates based on its expression and dysregulation. Discussion. c-MET represents a useful molecular target for novel engineered drugs. Several clinical trials are underway for various solid tumors and the development of new specific monoclonal antibodies depends on the recent knowledge about the definite c-MET role in each different malignance. Recent clinical trials based on c-MET molecular targets result in good safety profile and represent a promising therapeutic strategy for solid cancers, in monotherapy or in combination with other target drugs. CONCLUSION: The list of cell surface receptors crosslinking with the c-MET signaling is constantly growing, highlighting the importance of this pathway for personalized target therapy. Research on the combination of c-MET inhibitors with other drugs will hopefully lead to discovery of new effective treatment options.

The Effects of Angiotensin II or Angiotensin 1-7 on Rat Pial Microcirculation during Hypoperfusion and Reperfusion Injury: Role of Redox Stress.

Renin-angiotensin systems produce angiotensin II (Ang II) and angiotensin 1-7 (Ang 1-7), which are able to induce opposite effects on circulation. This study in vivo assessed the effects induced by Ang II or Ang 1-7 on rat pial microcirculation during hypoperfusion-reperfusion, clarifying the mechanisms causing the imbalance between Ang II and Ang 1-7. The fluorescence microscopy was used to quantify the microvascular parameters. Hypoperfusion and reperfusion caused vasoconstriction, disruption of blood-brain barrier, reduction of capillary perfusion and an increase in reactive oxygen species production. Rats treated with Ang II showed exacerbated microvascular damage with stronger vasoconstriction compared to hypoperfused rats, a further increase in leakage, higher decrease in capillary perfusion and marker oxidative stress. Candesartan cilexetil (specific Ang II type 1 receptor (AT1R) antagonist) administration prior to Ang II prevented the effects induced by Ang II, blunting the hypoperfusion-reperfusion injury. Ang 1-7 or ACE2 activator administration, preserved the pial microcirculation from hypoperfusion-reperfusion damage. These effects of Ang 1-7 were blunted by a Mas (Mas oncogene-encoded protein) receptor antagonist, while Ang II type 2 receptor antagonists did not affect Ang 1-7-induced changes. In conclusion, Ang II and Ang 1-7 triggered different mechanisms through AT1R or MAS receptors able to affect cerebral microvascular injury.

Tratamiento con brace termoplástico para fracturas de húmero / Thermoplastic brace treatment for humerus fractures

Objetivo: Evaluar la satisfacción con el uso del brace termoplástico y el resultado funcional del tratamiento conservador en pacientes con fracturas de la diáfisis del húmero. Materiales y métodos: Estudio retrospectivo de pacientes con fracturas de húmero cerradas, tratados con brace termoplástico hasta su consolidación y un seguimiento mínimo de 12 meses. Se registraron los siguientes datos: tipo de fractura y localización, mecanismo de lesión, miembro lesionado, tiempo de inmovilización con yeso y uso del brace, complicaciones y tiempo de consolidación. Se evaluaron el dolor mediante la escala analógica visual, la satisfacción con la escala de Likert, el balance articular con la escala de Constant y la funcionalidad según el puntaje QuickDASH. Resultados: Se incluyó a 17 pacientes (16 mujeres, 1 hombre; edad promedio 67 años). La inmovilización inicial con yeso fue de 13 días (rango 0-32). Los pacientes usaron el brace por 8.6 semanas (rango 3-16) hasta la consolidación radiográfica en la décima semana. El seguimiento promedio fue de 24 meses (rango 12-60) y el puntaje de dolor, de 0,5 (rango 1-3). El 59% estuvo muy satisfecho con los resultados y el 41%, satisfecho. El 59% logró una flexión del hombro >150°, el 47%, una abducción >150°, el 41%, una rotación interna con pulgar entre escápulas y el 47%, una rotación externa de 70°. El puntaje QuickDASH promedio fue de 9. Conclusiones: Los pacientes se mostraron muy satisfechos con el uso del brace termoplástico para el tratamiento incruento de las fracturas de húmero y los resultados funcionales fueron aceptables. Nivel de Evidencia: IV

Purpose: To evaluate the satisfaction with the use of a thermoplastic brace and the functional outcomes in the conservative treatment of patients with humeral shaft fractures. Materials and methods: Retrospective study of patients with closed humerus fractures, treated with a thermoplastic brace until union and with a minimum follow-up of 12 months. We recorded the type and location of the fracture, mechanism of injury, injured limb, time of immobilization with plaster and use of brace, complications, and time of consolidation. The evaluation was performed using the visual analog scale (VAS) for pain, the Likert scale for patient satisfaction, the Constant scale for joint balance, and the QuickDash score for functionality. Results: 17 patients were included (16 female, 1 male), with an average age of 67 years. The initial plaster immobilization lasted 13 days (range 0-32). The patients wore the brace for 8.6 weeks (range 3-16) until radiographic consolidation in the 10th week. The average follow-up was 24 months (range 12-60) and the pain score was 0.5 (range 1-3). 59% were very satisfied with the results and 41% were satisfied. 59% achieved a shoulder flexion >150°; 47%, an abduction >150°; 41%, an internal rotation with thumb between scapulae; and 47%, an external rotation of 70°. The average QuickDASH score was 9. Conclusion: The use of a thermoplastic brace in the conservative treatment of humerus fractures presented high patient satisfaction and acceptable functional outcomes for the affected limb.Keywords: Humerus; fractures; thermoplastic brace; conservative treatment. Level of Evidence:IV

Therapy with probiotics and synbiotics for polycystic ovarian syndrome: a systematic review and meta-analysis.

OBJECTIVE: Several randomized controlled trials (RCTs) have investigated the use of probiotic/synbiotic in PCOS patients, without clarifying the real use in clinical practice. The aim of this meta-analysis was to evaluate the effectiveness of probiotics and synbiotics on metabolic, hormonal and inflammatory parameters of PCOS. METHODS: Electronic databases (MEDLINE, Scopus, EMBASE, ScienceDirect, The Cochrane Database of Systematic Reviews and ClinicalTrials.gov) were searched from their inception until May 2019. The study protocol was registered in PROSPERO with number CRD42018111534. Randomized controlled trials (RCTs) of PCOS's women undergoing therapy at least 8 weeks with probiotics or synbiotics or without therapy were included. The primary outcomes were changes in anthropometric parameters, glucose/insulin metabolism, lipid profile, sex hormones profile, inflammation markers. RESULTS: 587 patients were included in nine RCT. The administration of probiotic/synbiotic were associated with a significant improvement in FPG, FBI, HOMA I-R, BMI. It also modified Ferriman-Gallway, serum triglycerides, serum testosterone, hs-CRP, NO, TAC, GSH, and MDA. Subgroup analysis of the type of intervention showed that probiotics were associated with greater testosterone and FPG reduction; synbiotics administration resulted in a more pronounced decrease of the FBI. Subgroup analyses on the duration of therapy showed that, probiotic/synbiotic administration had a significantly greater effect on QUICK-I in the case of women with 12-weeks of therapy than in the 8-weeks therapy group. Nevertheless, we did not observe any significant difference was observed in terms of FBI, HOMA-IR, and FPG. CONCLUSIONS: Probiotics and synbiotics seem to either an effect on/influence metabolic, hormonal and inflammatory parameters, or can influence them. Consequently, it could lead to an improvement of fertility in PCOS.