Stress e nutrizione materna: quale effetto su gravidanza e programming fetale?

Lo stress \ue8 una sindrome generale di adattamento (SGA) atta a ristabilire un nuovo equilibrio interno (omeostasi) in seguito a fattori di stress (stressors). Le alterazioni dell'equilibrio interno possono avvenire a livello endocrino, umorale, organico, biologico. Gli agenti stressanti possono essere stimoli di diversa natura, spesso interconnessi tra loro. Molti fattori che determinano la salute materna e quella fetale, possono rappresentare degli agenti stressanti. Tra di essi la nutrizione materna, laddove non equilibrata. La nutrizione materna ha infatti un ruolo centrale nel determinare la salute nel corso dell\u2019intero ciclo della vita e attraverso le generazioni. Nei \u201cprimi 1000 giorni\u201d, dal concepimento ai due anni di vita, l\u2019organismo umano \ue8 soggetto ad una vera e propria programmazione del suo sviluppo (\u201cdevelopmental programming\u201d), grazie alla quale uno specifico genotipo produrr\ue0 fenotipi differenti in base agli stimoli esterni ricevuti. Questo \ue8 quanto descritto dalla teoria DOHaD (Developmental Origin of Health and Disease), confermata negli ultimi anni da innumerevoli studi, secondo la quale il rischio di patologie nell\u2019adulto \ue8 modulato da fattori che agiscono sin da prima del concepimento sui genitori, e poi in utero e nei primi due anni di vita del bambino. Negli ultimi anni, un numero sempre maggiore di studi scientifici ha dimostrato che la nutrizione materna \ue8 uno dei fattori principali attraverso cui il developmental programming si attua. Questo ha portato ad una progressiva sensibilizzazione da parte degli studiosi e degli operatori del Sistema Sanitario, per promuovere una corretta nutrizione nei primi 1000 giorni, che rappresentano una opportunit\ue0 per la salute futura del nascituro. La nutrizione della donna \ue8 dunque una delle maggiori sfide della Sanit\ue0 Pubblica, in quanto non coinvolge solo la salute della donna, ma anche quella delle future generazioni. Risulta quindi di grande importante ottimizzare il BMI della donna sin da prima della gravidanza, un corretto controllo dell\u2019incremento ponderale durante la gestazione, una equilibrata alimentazione e stile di vita della madre nel periodo periconcezionale, unitamente ad una supplementazione adeguata, in base a linee guida, grazie ad una valutazione nutrizionale e dello stile di vita sin dalla prima visita in gravidanza, condotta da pi\uf9 figure professionali coinvolte nel percorso della gravidanza della donna

Obese infertili non PCOS trattate con acido alfa lipoico

L\u2019obesit\ue0 si associa ad un aumento di infertilit\ue0 femminile (Sim et al, 2014; Robker et al., 2011 ), un minore tasso di concepimento (Van Der Steeg et al., 2008; Wise et al., 2010; Wu et al, 2010), ed una modifica della qualit\ue0 ovocitaria; donne obese sottoposte a fecondazione assistita presentano infatti minore maturazione ovocitaria, minore fertilizzazione, minore capacit\ue0 di sviluppo dell\u2019ovocita verso la blastocisti (Esinler et al., 2008; Zhang et al., 2010; Metwally et al., 2007). Lo stato di obesit\ue0 nella donna pu\uf2 dunque compromettere la funzionalit\ue0 ovarica, ma ancora non sono stati chiariti i meccanismi molecolari nell\u2019essere umano che sottintendono a tali disfunzioni. La maggior parte degli studi riportati in letteratura sono infatti condotti su modelli murini di obesit\ue0, che hanno evidenziato come l\u2019accumulo intracellulare di lipidi provochi risposte infiammatorie e danneggi la struttura della membrana mitocondriale, inducendo la produzione di ROS e dunque stress ossidativo; questi fenomeni si esacerbano vicendevolmente (Robker et al., 2011). Lo STRESS OSSIDATIVO \ue8 un eccessivo rilascio a livello dei mitocondri di Reactive Oxygen Species (ROS), che se non inattivati da enzimi endogeni antiossidanti portano all\u2019ossidazione di proteine e lipidi, al danno a membrane intracellulari e DNA, e ad apoptosi (morte cellulare). I MITOCONDRI hanno una funzione fondamentale nella maturazione dell\u2019ovocita e nello sviluppo embrionale. Un recente studio su topi mostra un ruolo chiave dei mitocondri dell\u2019ovocita nello sviluppo di difetti riproduttivi legati all\u2019obesit\ue0: viene infatti riportata una maggiore quantit\ue0 di DNA mitocondriale (mtDNA), marker di stress ossidativo, nell\u2019ovocita di topi obesi (Glinder and Moley, 2013). Nostri dati recenti mostrano inoltre un aumento di DNA mitocondriale in placente di donne obese rispetto alle normopeso. Per questo, ci siamo chiesti se tali alterazioni siano gi\ue0 presenti nell\u2019ovocita di donne obese, e se una supplementazione adeguata possa aiutare a contrastare queste possibili alterazioni. I dati preliminari, mostrano livelli di DNA mitocondriale significativamente pi\uf9 alti nelle donne obese supplementate con acido folico, rispetto alle normopeso che avevano seguito la stessa supplementazione. Le pazienti obese supplementate con Sinopol invece, presentano livelli di DNA mitocondriale non diversi significativamente dalle normopeso, ed inferiori a quelli delle pazienti obese supplementate con solo acido folico. L\u2019azione dell\u2019acido \u3b1-lipoico, in sinergia con il mio-inositolo, potrebbe dunque avere effetti positivi nella riduzione dei livelli di mtDNA, marker di stress ossidativo, delle cellule della granulosa di donne obese infertili

Effetti dell’acido lipoico sull’ovocita di donne infertili

L\u2019obesit\ue0 si associa ad un aumento di infertilit\ue0 femminile (Sim et al, 2014; Robker et al., 2011 ), un minore tasso di concepimento (Van Der Steeg et al., 2008; Wise et al., 2010; Wu et al, 2010), ed una modifica della qualit\ue0 ovocitaria; donne obese sottoposte a fecondazione assistita presentano infatti minore maturazione ovocitaria, minore fertilizzazione, minore capacit\ue0 di sviluppo dell\u2019ovocita verso la blastocisti (Esinler et al., 2008; Zhang et al., 2010; Metwally et al., 2007). Lo stato di obesit\ue0 nella donna pu\uf2 dunque compromettere la funzionalit\ue0 ovarica, ma ancora non sono stati chiariti i meccanismi molecolari nell\u2019essere umano che sottintendono a tali disfunzioni. La maggior parte degli studi riportati in letteratura sono infatti condotti su modelli murini di obesit\ue0, che hanno evidenziato come l\u2019accumulo intracellulare di lipidi provochi risposte infiammatorie e danneggi la struttura della membrana mitocondriale, inducendo la produzione di ROS e dunque stress ossidativo; questi fenomeni si esacerbano vicendevolmente (Robker et al., 2011). Lo STRESS OSSIDATIVO \ue8 un eccessivo rilascio a livello dei mitocondri di Reactive Oxygen Species (ROS), che se non inattivati da enzimi endogeni antiossidanti portano all\u2019ossidazione di proteine e lipidi, al danno a membrane intracellulari e DNA, e ad apoptosi (morte cellulare). I MITOCONDRI hanno una funzione fondamentale nella maturazione dell\u2019ovocita e nello sviluppo embrionale. Un recente studio su topi mostra un ruolo chiave dei mitocondri dell\u2019ovocita nello sviluppo di difetti riproduttivi legati all\u2019obesit\ue0: viene infatti riportata una maggiore quantit\ue0 di DNA mitocondriale (mtDNA), marker di stress ossidativo, nell\u2019ovocita di topi obesi (Glinder and Moley, 2013). Nostri dati recenti mostrano inoltre un aumento di DNA mitocondriale in placente di donne obese rispetto alle normopeso. Per questo, ci siamo chiesti se tali alterazioni siano gi\ue0 presenti nell\u2019ovocita di donne obese, e se una supplementazione adeguata possa aiutare a contrastare queste possibili alterazioni. I dati preliminari, mostrano livelli di DNA mitocondriale significativamente pi\uf9 alti nelle donne obese supplementate con acido folico, rispetto alle normopeso che avevano seguito la stessa supplementazione. Le pazienti obese supplementate con Sinopol invece, presentano livelli di DNA mitocondriale non diversi significativamente dalle normopeso, ed inferiori a quelli delle pazienti obese supplementate con solo acido folico. L\u2019azione dell\u2019acido \u3b1-lipoico, in sinergia con il mio-inositolo, potrebbe dunque avere effetti positivi nella riduzione dei livelli di mtDNA, marker di stress ossidativo, delle cellule della granulosa di donne obese infertili

Effects of Alpha-Lipoic Acid and Myoinositol Supplementation on the Oocyte Enviroment of Obese Infertile Women

INTRODUCTION Obesity is characterized by increased inflammation and oxidative stress, resulting in adverse effects on women reproductive potential. Antioxidant supplementation may exert a positive effect on the obese ovarian environment. Indeed, we preliminarily observed a reduction of mitochondrial (mt) DNA content, a marker of oxidative stress, in granulosa cells of obese infertile women supplemented with Sinopol\uae (Laborest SpA), composed by alpha-lipoic acid (ALA) 800 mg, myoinositol (MYO) 2 g, folic acid (FA) 400 ug. This suggested a potential role of Sinopol\uae in reducing oxidative stress in the obese ovarian environment. Here we analyzed Total Antioxidant Capacity (TAC) in follicular fluid and mtDNA levels in granulosa cells, in a larger population of infertile women undergoing in vitro fertilization (IVF). METHODS 19 normal weight (NW) and 24 obese (OB) infertile women were enrolled in our IVF center. Infertility was investigated and a non-ovarian diagnosis was made. Patients did not present any additional pathology. All women were provided with FA and among them 15 OB (OB-SIN) were also supplemented with ALA and MYO, for 2 months before ovarian stimulation. Follicular fluid (FF) and granulosa cells (GC) were collected after oocyte retrieval. TAC was measured in FF by enzymatic assay, mtDNA levels evaluated in GC by Real-time PCR. Results were compared by ANOVA and correlations assessed by Pearson\u2019s correlation (SPSS; IBM). RESULTS OB groups had similar BMI (OB patients supplemented with only folic acid (OB-F): 30.2 \ub1 0.7; OB-SIN: 32.7 \ub1 1.1 kg/m2). Women age was similar in all groups (NW: 36.7 \ub1 0.6; OB-F: 37.6 \ub1 1.7; OB-SIN: 35.9 \ub1 1.1 years). Among OB women, antioxidant capacity was significantly higher in OB-SIN than in OB-F. mtDNA levels showed an opposite trend, being decreased in OB-SIN and increased in OB-F compared to NW, though not reaching statistical significance. mtDNA levels were significantly and inversely correlated with the number of total oocytes and metaphase II (mature) oocytes. Pregnancy rate was similar in NW (36.8%) and OB-SIN (33.3%) women, while it was lower in OB-F patients (11.1%). CONCLUSION We analyzed molecular markers in granulosa cells and follicular fluid as indicators of oocytes oxidative state. Our results suggest that supplementation with a compound of ALA -a natural antioxidant, cofactor in the mt respiratory chain- and MYO -an insulin-sensitizer- might increase antioxidant defenses and reduce oxidative stress in the obese ovarian environment, possibly contributing at restoring physiological conditions. This might improve IVF pregnancy rates in obese infertile women. Further studies are needed to clarify the synergic action of ALA, MYO and FA on the oocyte oxidative environment. Supported by Laborest Sp

Micro-beam and pulsed laser beam techniques for the micro-fabrication of diamond surface and bulk structures

Micro-fabrication in diamond is involved in a wide set of emerging technologies, exploiting the exceptional characteristics of diamond for application in bio-physics, photonics, radiation detection. Micro ion-beam irradiation and pulsed laser irradiation are complementary techniques, which permit the implementation of complex geometries, by modification and functionalization of surface and/or bulk material, modifying the optical, electrical and mechanical characteristics of the material. In this article we summarize the work done in Florence (Italy) concerning ion beam and pulsed laser beam micro-fabrication in diamond.Comment: 14 pages, 5 figure

Placental ERRγ-CYP19 expressions and circulating 17-Beta Estradiol in IUGR pregnancies

Introduction: Sex steroids are regulating factors for intrauterine growth. 17- f Estradiol (E2) is particularly critical to a physiological pregnancy, as increased maternal E2 was correlated to lower birth weight. The placenta itself is a primary source of estrogens, synthetized from cholesterol precursors. Cytochrome P450 aromatase (encoded by CYP19 gene) is a rate-limiting enzyme for E2 biosynthesis. CYP19 transcription is supported by Estrogen Related-Receptor Gamma (ERR\u3b3), thus having an indirect role in placental steroidogenesis. Here we investigated maternal E2 levels and placental CYP19 and ERR expressions in pregnancies with intrauterine growth restriction (IUGR). Methods: Singleton pregnancies were studied. E2 was measured in maternal plasma by electrochemiluminescence in 16 term controls and 11 IUGR (classified by umbilical artery doppler Pulsatility Index) at elective cesarean section, and also in 13 controls during pregnancy at a gestational age comparable to IUGR. CYP19 and ERR\u3b3 expressions were analyzed in placental tissue. Maternal/fetal characteristics, placental and molecular data were compared among study groups and tested for correlations. Results: Maternal E2 plasma concentrations were significantly decreased in IUGR compared to controls at delivery. When analyzing normal pregnancies at the same IUGR gestational age, E2 levels were not different to IUGR. However, E2 levels at delivery positively correlated with placental efficiency. Placental CYP19 was significantly higher in IUGR placental tissue versus controls, with levels specifically increased in female IUGR placentas. ERR\u3b3 expression was not different among groups. Discussion: We report a positive correlation between 17- f Estradiol levels and placental efficiency, that might indicate a disrupted steroidogenesis in IUGR pregnancies. Moreover, we showed alterations of CYP19 in IUGR placentas, possibly indicating a compensatory effect to the adverse IUGR intrauterine environment, also depending on fetal sex. Further studies are needed to deeper investigate IUGR alterations in the complex interaction among molecules involved in placental steroidogenesis

Permeability of matrix-fracture systems under mechanical loading – constraints from laboratory experiments and 3-D numerical modelling

The permeability of single fractures is commonly approximated by the cubic law assumption, which is however only valid under the condition of a single phase laminar flow between parallel plates. Departure from cubic law are related to many features like aperture fluctuations due to fracture surface roughness, relative shear displacement, the amount of flow exchange between the matrix and the fracture itself, etc. In order to quantify constitutive relationships among the aforementioned aspects, we have conducted a flow-through experiment with a porous rock sample (Flechtinger sandstone) containing a single macroscopic fracture. Based on this experiment, we obtained range of variations of intrinsic rock parameters, permeability and stress-strain relationships of the combined matrix-fracture system under hydrostatic loading. From the measured deformation of the matrixfracture system, we derived the evolution in the mechanical aperture of the fracture. In order to quantify the processes behind the laboratory observations, we carried out coupled hydro-mechanical simulations of the matrix-fracture system. Navier–Stokes flow was solved in the 3-dimensional open rough fracture domain, and back-coupled to the Darcy flow and the poroelastic behaviour of the rock matrix. The results demonstrate that the elastic behaviour and the related permeability alteration of the fracture domain could be captured by the numerical simulation. Furthermore, the stress-strain values obtained in the vicinity of the fracture asperities suggest that inelastic deformation develops at low mechanical load. An attempt was made to quantify the inelastic deformation by using the failure envelope obtained by laboratory experiments (whether tensile, shear, compaction, or a combination of those). However, change in permeability observed in the experiments are significantly larger than that in the simulation showing the importance of plastic deformation during opening and closure of the fracture and its impact on the cubic law approximation

Detection of breast cancer precursor lesions by autofluorescence ductoscopy

Purpose: Autofluorescence is an image enhancement technique used for the detection of cancer precursor lesions in pulmonary and gastrointestinal endoscopy. This study evaluated the feasibility of addition of autofluorescence to ductoscopy for the detection of intraductal breast cancer precursor lesions. Methods: An autofluorescence imaging system, producing real-time computed images combining fluorescence intensities, was coupled to a conventional white light ductoscopy system. Prior to surgery, ductoscopy with white light and autofluorescence was evaluated under general anaesthesia in women scheduled for therapeutic or prophylactic mastectomy. Endoscopic findings in both modes were compared, marked and correlated with histology of the surgical specimen. Results: Four breast cancer patients and five high-risk women, with a median age of 47 years (range 23–62) were included. In autofluorescence mode, two intraductal lesions were seen in two breast cancer patients, which had an increase in the red-to-green fluorescence intensity compared with the surrounding tissue. One lesion had initially been missed by white light ductoscopy but was clearly visible in subsequent autofluorescence mode. One endoscopic finding was classified as suspicious by white light, but was negative in autofluorescence mode and showed normal histology. Conclusions: This study demonstrates for the first time the in vivo feasibility of autofluorescence ductoscopy to detect pathologically confirmed breast cancer precursor lesions in both breast cancer patients and high-risk women that were occult under white light

Effect of the COVID-19 Pandemic on Surgical Breast Cancer Care in the Netherlands: A Multicenter Retrospective Cohort Study

BACKGROUND: Coronavirus disease 2019 (COVID-19) has put a strain on regular healthcare worldwide. In the Netherlands, the national screening programs, including for breast cancer, were halted temporarily. This posed a challenge to breast cancer care, because ∼40% of cases are detected through national screening. Therefore, the aim of the present study was to evaluate the effects of the COVID-19 pandemic on the surgical care of patients with breast cancer in the Netherlands. MATERIALS AND METHODS: The present multicenter retrospective cohort study investigated the effects of COVID-19 on patients with breast cancer who had undergone surgery from March 9 to May 17, 2020. The primary endpoints were the number of surgical procedures performed during the study period, tumor characteristics, surgery type, and route of referral. The secondary endpoint was the incidence of postoperative complications during the study period. RESULTS: A total of 217 consecutive patients with breast cancer requiring surgery were included. We found an overall decrease in the number of patients with breast cancer who were undergoing surgery. The most significant decline was seen in surgery for T1-T2 and N0 tumors. A decline in the number of referrals from both the national screening program and general practitioners was observed. The incidence of postoperative complications remained stable during the study period. CONCLUSIONS: The temporary halt of the national screening program for breast cancer resulted in fewer surgical procedures during the study period and a pronounced decrease in surgery of the lower tumor stages