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Purpose This study was conducted to evaluate the prevalence of perineal trauma during childbirth and to assess the correlations of the pelvic floor dimensions and fetal head station with obstetric trauma in a prospectively recruited cohort of women. Methods The study included women with a gestational age of at least 37 weeks, who were carrying a single fetus in a cephalic presentation. Transperineal ultrasound (TPU) was performed prior to the onset of labor or labor induction. The purpose was to measure the anteroposterior diameter (APD) of the levator ani muscle (LAM) and the angle of progression, at both rest and maximum Valsalva maneuver. The head-perineum distance was assessed only at rest. Results A total of 296 women were included. Of the 253 women who delivered vaginally, 19% (48/253) experienced no perineal trauma, 18.2% (46/253) received an episiotomy during childbirth, 34.4% (87/253) sustained a first-degree laceration, 25.3% (64/253) had a second-degree laceration, and 3.2% had a third- or fourth-degree laceration (8/253). Women with episiotomy had a significantly shorter median APD under Valsalva than women without perineal trauma. Furthermore, women with LAM coactivation (identified by a negative difference between the APD at Valsalva and the APD at rest) were approximately three times more likely to undergo an operative vaginal delivery and over five times more likely to sustain a third- or fourth-degree tear during childbirth than women who exhibited normal relaxation of the LAM during the Valsalva maneuver. Conclusion TPU may predict the risk of perineal trauma in women with term pregnancy during childbirth.

Simultaneous carotid artery stenosis (CS) and coronary artery disease (CAD) is a common condition among patients with several cardiovascular risk factors; however, its optimal management still remains under investigation, such as the assumption that carotid disease is causally related to perioperative stroke and that preventive carotid revascularization decrease the risk of this complication. Synchronous surgical approach to both conditions, performing carotid endarterectomy (CEA) before coronary artery bypass graft (CABG) during the same procedure, should still be considered in selective patients, in order to reduce the risk of perioperative stroke during coronary cardiac surgery. For the same purpose, staged approaches, such as CEA followed by CABG or CABG followed by CEA during the same hospitalization or a few weeks later have been described. Hybrid approach with carotid artery stenting (CAS) and CABG can also be an option in selected cases, offering a minimally invasive procedure to treat CS among patients whom CABG cannot be postponed. When carotid intervention is indicated in patients with concomitant CAD requiring CABG, a personalized and tailored approach is mandatory, especially in asymptomatic patients, in order to define the ideal surgical strategy. The aim of this paper is to summarize the current “state of the art” of the different approaches to carotid artery diseases in patients undergoing CABG.

Summary: In pancreatic ductal adenocarcinomas (PDAC), the KRASG12D-NRF2 axis controls cellular functions such as redox homeostasis and metabolism. Disruption of this axis through suppression of NRF2 leads to profound reprogramming of metabolism. Unbiased transcriptome and metabolome analyses showed that PDAC cells with disrupted KRASG12D-NRF2 signaling (NRF2−/− cells) shift from aerobic glycolysis to metabolic pathways fed by amino acids. Metabolome, RNA-seq and qRT-PCR analyses revealed a blockade of the urea cycle, making NRF2−/− cells dependent on exogenous arginine for survival. Arginine is channeled into anabolic pathways, including the synthesis of phosphocreatine, which generates an energy buffer essential for cell growth. A similar switch was observed in tumor clones that had survived FOLFIRINOX therapy or blockade of KRAS signaling. Inhibition of the creatine pathway with cyclocreatine reduced both ATP and invasion rate in 3D spheroids from NRF2-deficient PDAC cells. Our study provides basis for the rational development of combination therapies for pancreatic cancer.

The refractoriness of tumor cells to apoptosis represents the main mechanism of resistance to chemotherapy. Smac/DIABLO mimetics proved to be effective in overcoming cancer-acquired resistance to apoptosis as a consequence of overexpression of the anti-apoptotic proteins XIAP, cIAP1, and cIAP2. In this work, we describe a dual-targeting peptide capable of selectively activating apoptosis in cancer cells. The complex consists of a fluorescent periodic mesoporous organosilica nanoparticle that carries the short sequences of Smac/DIABLO bound to the αvβ3–integrin ligand. The dual-targeting peptide @PMO shows significantly higher toxicity in αvβ3-positive HeLa cells with respect to αvβ3-negative Ht29 cells. @PMO exhibited synergistic effects in combination with oxaliplatin in a panel of αvβ3-positive cancer cells, while its toxicity is overcome by XIAP overexpression or integrin β3 silencing. The successful uptake of the molecule by αvβ3-positive cells makes @PMO promising for the re-sensitization to apoptosis of many cancer types.

Abstract Background Monochorionic dizygotic twins are a rare condition, mostly related to assisted reproductive technology. This type of twinning is burdened by the same risk of pregnancy complications found in monochorionic monozygotic pregnancies. Case presentation We report a case of spontaneous monochorionic dizygotic twins sharing situs inversus abdominalis and isolated levocardia, with only one twin affected by biliary atresia with splenic malformation syndrome. We also conducted a literature review of the 14 available documented monochorionic dizygotic twin gestations spontaneously conceived. Conclusions It is still unclear how this unusual type of twinning can occur in spontaneous conception. The evidence so far suggest the importance to timely diagnose the chorionicity, in order to adequately manage the typical complications associated with monochorionicity.

Severe maternal and newborn morbidity and mortality associated with pre-eclampsia, which are caused partly by premature delivery, affect a factual proportion of pregnancies. Despite its prevalence, the underlying causes of pre-eclampsia remain elusive, with emerging evidence implicating the aryl hydrocarbon receptor (AhR) in its pathogenesis. This study sought to elucidate the involvement of the AhR and its associated pathway in pre-eclampsia by comparing placental components of the AhR pathway in pregnant individuals with and without pre-eclampsia. This case–control investigation was conducted at the University Hospital of Udine from May 2021 to February 2023. The AhR was assessed using immunohistochemistry and immunofluorescence, and its mRNA was evaluated using a Real-Time Quantitative Reverse Transcription PCR. Levels of mRNA expression were also estimated for other components of the AhR pathway (CYP1B1, IDO1, ARNT, TIPARP, S100A4, and AHRR). Our findings show decreased levels of expression of AhR, IDO1, ARNT, TiPARP, and S100A4 in the placental tissues of individuals with pre-eclampsia compared to controls (p < 0.05). The AhR exhibited a distinct localization within the syncytiotrophoblast (nuclei and cytoplasm) and CD45-positive cells (nuclei and cytoplasm). Furthermore, a significant positive correlation between the AhR and S100A4 (rho = 0.81) was observed in normal placentas, while CYP1B1 displayed a significant negative correlation with the AhR (rho = −0.72), within addition to its negative correlation with TiPARP (rho = −0.83). This study illuminates pre-eclampsia’s molecular aberrations, suggesting new diagnostic, therapeutic, and mechanistic approaches. This study emphasizes the need for more research to validate and broaden these findings to improve the management of this complex pregnancy condition.

IntroductionThis study aimed to compare the outcomes of preterm infants given 12 vs. 24mg of betamethasone prophylaxis to understand whether a partial course of antenatal corticosteroids (CCS) could prevent or mitigate the major preterm birth complications.MethodsThis is a retrospective single-center cohort study including neonates born between 24 and 34 weeks of gestation from 2001 to 2019 at the University Hospital of Udine. The study population was divided into two groups: one group received 12mg, and another received a 24mg dose of betamethasone before the delivery. A separate analysis was performed for single and multiple pregnancies. The two groups were evaluated for various neonatal outcomes.ResultsThe study population included a total of 1,258 pregnancies and 1,543 neonates delivered between 24 and 34 weeks of gestation, of which 1,022 (803 single and 219 multiple pregnancies) were exposed to the complete CCS prophylaxis, whereas 236 (192 single and 44 multiple pregnancies) received the incomplete CCS prophylaxis. In single pregnancies, as for maternal characteristics, the most significant differences observed between the two groups are the following: a higher prevalence of spontaneous vaginal deliveries in the incomplete CCS prophylaxis (36.46 vs. 23.91%) and, by contrast, a higher prevalence of cesarean deliveries in the complete CCS prophylaxis group (75.72 vs. 63.02%). As for neonatal outcomes, the low Apgar score in the first and fifth min was significantly more prevalent in the incomplete CCS prophylaxis group compared with the complete CCS prophylaxis group. The group of incomplete CCS prophylaxis reported a higher occurrence of the following outcomes: IVH grade 3-4 (7.81 vs. 3.74%, p < 0.05), PVL (7.29 vs. 1.99% p < 0.05), ROP (23.96 vs. 18.06% p = 0.062), and RDS (84.38 vs. 78.83% p = 0.085). After adjusting for covariates, the complete CCS prophylaxis group in single pregnancies was significantly protective for IVH grade 3-4, PVL, and low Apgar's scores. Similar results were found in multiple pregnancies except for RDS.DiscussionThis retrospective single-center cohort study found that, compared with preterm infants treated with 24mg betamethasone in utero, those given half course of betamethasone had a significantly higher prevalence of IVH grade 3-4, PVL, RDS, and lower Apgar scores at 1 and 5 min. In conclusion, the evidence from this single-center retrospective study supports the preference for the complete CCS prophylaxis in women at risk of preterm birth because of its beneficial effect on the main adverse outcomes.

In contemporary societies merit, one of the cornerstones of our Constitution, is losing its original moral connotation. The economy of the global market, which now tends to disregard politics, actually supports a kind of meritocratic ideology whose perspective, extensively discussed in these pages, fades over time to obtain the opposite effect. This article highlights the contradictions of meritocracy, without endorsing the incompatibility between democracy and merit that it raises as an opportunity for each and everyone through education.

Bi-directional transcription of Human Endogenous Retroviruses (hERVs) is a common feature of autoimmunity, neurodegeneration and cancer. Higher rates of cancer incidence, neurodegeneration and autoimmunity but a lower prevalence of autoimmune diseases characterize elderly people. Although the re-expression of hERVs is commonly observed in different cellular models of senescence as a result of the loss of their epigenetic transcriptional silencing, the hERVs modulation during aging is more complex, with a peak of activation in the sixties and a decline in the nineties. What is clearly accepted, instead, is the impact of the re-activation of dormant hERV on the maintenance of stemness and tissue self-renewing properties. An innate cellular immunity system, based on the RLR-MAVS circuit, controls the degradation of dsRNAs arising from the transcription of hERV elements, similarly to what happens for the accumulation of cytoplasmic DNA leading to the activation of cGAS/STING pathway. While agonists and inhibitors of the cGAS–STING pathway are considered promising immunomodulatory molecules, the effect of the RLR-MAVS pathway on innate immunity is still largely based on correlations and not on causality. Here we review the most recent evidence regarding the activation of MDA5-RIG1-MAVS pathway as a result of hERV de-repression during aging, immunosenescence, cancer and autoimmunity. We will also deal with the epigenetic mechanisms controlling hERV repression and with the strategies that can be adopted to modulate hERV expression in a therapeutic perspective. Finally, we will discuss if the RLR-MAVS signalling pathway actively modulates physiological and pathological conditions or if it is passively activated by them.

Simultaneous carotid artery stenosis (CS) and coronary artery disease (CAD) is a common condition among patients with several cardiovascular risk factors; however, its optimal management still remains under investigation, such as the assumption that carotid disease is causally related to perioperative stroke and that preventive carotid revascularization decrease the risk of this complication. Synchronous surgical approach to both conditions, performing carotid endarterectomy (CEA) before coronary artery bypass graft (CABG) during the same procedure, should still be considered in selective patients, in order to reduce the risk of perioperative stroke during coronary cardiac surgery. For the same purpose, staged approaches, such as CEA followed by CABG or CABG followed by CEA during the same hospitalization or a few weeks later have been described. Hybrid approach with carotid artery stenting (CAS) and CABG can also be an option in selected cases, offering a minimally invasive procedure to treat CS among patients whom CABG cannot be postponed. When carotid intervention is indicated in patients with concomitant CAD requiring CABG, a personalized and tailored approach is mandatory, especially in asymptomatic patients, in order to define the ideal surgical strategy. The aim of this paper is to summarize the current "state of the art" of the different approaches to carotid artery diseases in patients undergoing CABG. [ABSTRACT FROM AUTHOR]

Abstract Since sexual health education (SHE) is not mandatory in Italian schools, we conducted a survey on freshmen of four Italian university campuses in 2012 to investigate the respective level of sexual health knowledge (SHK) in relation to birth control, with the aim to inform public health policy makers. A convenience strategy was employed to sample 4,552 freshmen registered with various undergraduate courses at four Italian universities: Padua university (Veneto Region); university of Milan (Lombardy Region); university of Bergamo (Lombardy Region); university of Palermo (Sicily Region). We investigated the level of SHK on birth control using 6 proxy indicators: (1) the average length of a woman’s period [outcome with 3 levels: wrong (base) vs. acceptable vs. correct]; (2) the most fertile interval within a woman’s period (binary outcome: correct vs. wrong answer); (3) the event between the end of a period and the beginning of the next cycle (binary outcome: correct vs. wrong answer); (4) the average survival of spermatozoa in the womb (binary outcome: correct vs. wrong answer); (5) the concept of contraception (binary outcome: correct vs. wrong answer); (6) the efficacy of various contraceptives to prevent unintended pregnancies (linear score: 0–17). We fitted 6 separate models of multiple regression: multinomial for outcome 1; logistic for outcomes 2, 3, 4, 6; linear for outcome 6. Statistical estimates were adjusted for a number of socio-demographic factors. Results were expressed as odds ratios (OR) for the 4 multiple logistic regression models, linear coefficients (RC) for the linear regression model and relative risk ratio (RRR) for the multinomial logistic regression model. The level of significance of each risk estimate was set at 0.05. The level of SHK of freshmen sampled was rather low, as 60% interviewees did not know the average length of a woman’s period, the average survival of spermatozoa in the womb and the concept of contraception, whilst the most fertile interval within a woman’s period was known only to 55% of interviewees. The mean score of SHK on the efficacy of various contraceptive methods was only 5 (scale 0–17). Some categories of students were consistently and significantly less knowledgeable on birth control at multivariable analysis: males; students from the university of Palermo; those with vocational secondary school education and those not in a romantic relationship at the time the survey was conducted. The results of this survey clearly call for the introduction of SHE programs in Italian schools, as already done in several European countries. School SHE should start as early as possible, ideally even before secondary school. SHE should be holistic and delivered with a multiple agency coordinated approach involving the Ministry of Health, the Ministry of Education, University and Scientific Research (MIUR), families, schools, public health departments, primary health care providers, pharmacists, media, other.

Background: Recently, the literature suggested that placental transfusion facilitated by delayed cord clamping (DCC), besides having benefits on hematological parameters, might improve the infants' brain development.Objective: The present review primarily evaluates the Ages and Stages Questionnaire (ASQ) total score mean difference (MD) at long-term follow-up (≥4 months) comparing DCC (>90 or >180 s) to early cord clamping (ECC). Secondary aims consisted of evaluating the ASQ domains' MD and the results obtained from other methods adopted to evaluate the infants' neurodevelopment.Methods: MEDLINE, Scopus, Cochrane, and ClinicalTrials.gov databases were searched (up to 2nd November 2020) for systematic review and meta-analysis. All randomized controlled trials (RCTs) of term singleton gestations received DCC or ECC. Multiple pregnancies, pre-term delivery, non-randomized studies, and articles in languages other than English were excluded. The included studies were assessed for bias and quality. ASQ data were pooled stratified by time to follow up.Results: This meta-analysis of 4 articles from 3 RCTs includes 765 infants with four-month follow-up and 672 with 12 months follow-up. Primary aim (ASQ total score) pooled analysis was possible only for 12 months follow-up, and no differences were found between DCC and ECC (MD 1.1; CI 95: −5.1; 7.3). DCC approach significantly improves infants' communication domains (MD 0.6; CI 95: 0.1; 1.1) and personal-social assessed (MD 1.0; CI 95: 0.3; 1.6) through ASQ at 12 months follow-up. Surprisingly, the four-month ASQ personal social domain (MD −1.6; CI 95: −2.8; −0.4) seems to be significantly lower in the DCC group than in the ECC group.Conclusions: DCC, a simple, non-interventional, and cost-effective approach, might improve the long-term infants' neurological outcome. Single-blinding and limited studies number were the main limitations. Further research should be performed to confirm these observations, ideally with RCTs adopting standard methods to assess infants' neurodevelopment.Trial registration: NCT01245296, NCT01581489, NCT02222805, NCT01620008, IRCT201702066807N19, and NCT02727517

Historically, fetal heart rate (FHR) decelerations were classified into “early”, “late”, and “variable” based on their relationship with uterine contractions. So far, three different putative etiologies were taken for granted. Recently, this belief, passed down through generations of birth attendants, has been questioned by physiologists. This narrative review aimed to assess the evidence on pathophysiology behind intrapartum FHR decelerations. This narrative review is based on information sourced from online peer-reviewed articles databases and recommendations from the major scientific societies in the field of obstetrics. Searches were performed in MEDLINE/PubMed, EMBASE, and Scopus and selection criteria included studies in animals and humans, where the physiology behind FHR decelerations was explored. The greater affinity for oxygen of fetal hemoglobin than the maternal, the unicity of fetal circulation, and the high anaerobic reserve of the myocardium, ensure adequate oxygenation to the fetus, under basal conditions. During acute hypoxic stress the efficiency of these mechanisms are increased because of the peripheral chemoreflex. This reflex, activated at each uterine contraction, is characterized by the simultaneous activation of two neural arms: the parasympathetic arm, which reduces the myocardial consumption of oxygen by decreasing the FHR and the sympathetic component, which promotes an intense peripheric vasoconstriction, thus centralizing the fetal blood volume. This review summarizes the evidence supporting the hypoxic origin of FHR decelerations, therefore archiving the historical belief that FHR decelerations have different etiologies, according to their shape and relationship with uterine contractions. The present review suggests that it is time to welcome the new scientific evidence and to update the CTG classification systems.

Purpose: To demonstrate the feasibility and outcomes of using the microvascular plug (MVP) for intentional occlusion of directional branches (DB) during complex endovascular aortic procedures. Case Report: Two patients were treated with the off-the-shelf four-branched Zenith t-Branch thoracoabdominal stent-graft (Cook Medical, Bloomington, Ind). In both cases, the renal arteries (on one side in patient #1 and on both sides in patient #2, respectively) were occluded at time of index intervention. Preoperative planning included the intentional occlusion of each DB with one 7Q-MVP. Technical success was achieved in all cases and maintained at mid-term follow-up (12 months and 36 months, respectively). Conclusions: Use of the MVP appears to be feasible and effective for intentional occlusion of DB during complex endovascular aortic repair. This novel and simple technique may present some unique technical advantages, allowing precise placement of the device while avoiding extension using a bridging stent and DB cannulation with larger sheaths. [ABSTRACT FROM AUTHOR]

Purpose: This study was conducted to evaluate the prevalence of perineal trauma during childbirth and to assess the correlations of the pelvic floor dimensions and fetal head station with obstetric trauma in a prospectively recruited cohort of women. Methods: The study included women with a gestational age of at least 37 weeks, who were carrying a single fetus in a cephalic presentation. Transperineal ultrasound (TPU) was performed prior to the onset of labor or labor induction. The purpose was to measure the anteroposterior diameter (APD) of the levator ani muscle (LAM) and the angle of progression, at both rest and maximum Valsalva maneuver. The head-perineum distance was assessed only at rest. Results: A total of 296 women were included. Of the 253 women who delivered vaginally, 19.0% (48/253) experienced no perineal trauma, 18.2% (46/253) received an episiotomy during childbirth, 34.4% (87/253) sustained a first-degree laceration, 25.3% (64/253) had a second-degree laceration, and 3.2% had a third- or fourth-degree laceration (8/253). Women with episiotomy had a significantly shorter median APD under Valsalva than women without perineal trauma. Furthermore, women with LAM coactivation (identified by a negative difference between the APD at Valsalva and the APD at rest) were approximately three times more likely to undergo an operative vaginal delivery and over five times more likely to sustain a third- or fourth-degree tear during childbirth than women who exhibited normal relaxation of the LAM during the Valsalva maneuver. Conclusion: TPU may predict the risk of perineal trauma in women with term pregnancy during childbirth. [ABSTRACT FROM AUTHOR]

The advent and refinement of complex endovascular techniques in the last two decades has revolutionized the field of vascular surgery. This has allowed an effective minimally invasive treatment of extensive disease involving the pararenal and the thoracoabdominal aorta. Fenestrated-branched EVAR (F/BEVAR) now represents a feasible technical solution to address these complex diseases, moving the proximal sealing zone above the renal-visceral vessels take-off and preserving their patency. The aim of this paper was to provide a narrative review on the peri-operative management of patients undergoing F/BEVAR procedures for juxtarenal abdominal aortic aneurysm (JAAA), pararenal abdominal aortic aneurysm (PRAA) or thoracoabdominal aortic aneurism (TAAA). It will focus on how to prevent, diagnose, and manage the complications ensuing from these complex interventions, in order to improve clinical outcomes. Indeed, F/BEVAR remains a technically, physiologically, and mentally demanding procedure. Intraoperative adverse events often require prolonged or additional procedures and complications may significantly impact a patient’s quality of life, health status, and overall cost of care. The presence of standardized preoperative, perioperative, and postoperative pathways of care, together with surgeons and teams with significant experience in aortic surgery, should be considered as crucial points to improve clinical outcomes. Aggressive prevention, prompt diagnosis and timely rescue of any major adverse events following the procedure remain paramount clinical needs.

Background: Pregnancy in Parkinson's disease is a rare occurrence, and to date, clinical experience with its management is rather limited. In clinical practice, doubts concern mainly the impact of PD on gestation, labor, and delivery as well as the safety of dopaminergic drugs.Case and review of the literature: We report the case of a 40-year-old woman with an 8-year history of PD. In the first trimester of her pregnancy, her motor status was similar to the pre-conceptional period. In gestation week 16, her motor status dramatically worsened and she complained of predictable “off” periods in the afternoon. For this reason, her dose of L-DOPA/carbidopa was increased up to 500/125 mg per day. At 39 gestational weeks, she gave birth to a healthy girl with an Apgar score of 9 by an uncomplicated cesarean delivery. The child was not breast fed to avoid exposure to antiparkinsonian drugs. The L-DOPA/carbidopa dosage remained constant during the postpartum period. We performed a systematic review of the literature using Ovid Medline, Scopus, and PubMed (including Cochrane database). We used the search terms “Parkinson disease” AND “pregnancy.” We identified 20 studies of PD in pregnancy with a total of 37 pregnant women with PD. The most important available data concern the safety of L-DOPA therapy during pregnancy. There seems to be some risk of worsening of the condition or upcoming of new PD symptoms during or shortly after pregnancy.Conclusion: More data concerning the safety of antiparkinsonian drugs in PD treatment, as well as the effect of pregnancy on parkinsonian symptoms are needed. According to the current state of the art, L-DOPA therapy should be considered preferable to other drugs during pregnancy.

Severe maternal and newborn morbidity and mortality associated with pre-eclampsia, which are caused partly by premature delivery, affect a factual proportion of pregnancies. Despite its prevalence, the underlying causes of pre-eclampsia remain elusive, with emerging evidence implicating the aryl hydrocarbon receptor (AhR) in its pathogenesis. This study sought to elucidate the involvement of the AhR and its associated pathway in pre-eclampsia by comparing placental components of the AhR pathway in pregnant individuals with and without pre-eclampsia. This case–control investigation was conducted at the University Hospital of Udine from May 2021 to February 2023. The AhR was assessed using immunohistochemistry and immunofluorescence, and its mRNA was evaluated using a Real-Time Quantitative Reverse Transcription PCR. Levels of mRNA expression were also estimated for other components of the AhR pathway (CYP1B1, IDO1, ARNT, TIPARP, S100A4, and AHRR). Our findings show decreased levels of expression of AhR, IDO1, ARNT, TiPARP, and S100A4 in the placental tissues of individuals with pre-eclampsia compared to controls (p < 0.05). The AhR exhibited a distinct localization within the syncytiotrophoblast (nuclei and cytoplasm) and CD45-positive cells (nuclei and cytoplasm). Furthermore, a significant positive correlation between the AhR and S100A4 (rho = 0.81) was observed in normal placentas, while CYP1B1 displayed a significant negative correlation with the AhR (rho = −0.72), within addition to its negative correlation with TiPARP (rho = −0.83). This study illuminates pre-eclampsia's molecular aberrations, suggesting new diagnostic, therapeutic, and mechanistic approaches. This study emphasizes the need for more research to validate and broaden these findings to improve the management of this complex pregnancy condition. [ABSTRACT FROM AUTHOR]

Background and Objectives: This observational study aims to determine the correlation between glycemic control with the HbA1c value and adverse obstetric outcome in women affected by pre-gestational diabetes. Materials and Methods: A retrospective analysis has been performed at the University Hospital of Udine. Only patients with a singleton pregnancy, pre-gestational diabetes, and known level of Hb A1c throughout pregnancy were included in the study. Results: According to the HbA1c level, at the beginning of pregnancy, 49 patients with HbA1c ≤ 7.0% were compared with 45 patients with HbA1c > 7.0%. Maternal age at diagnosis of the disease was significantly higher in the group with HbA1c ≤ 7% than in the group with HbA1c > 7%, 26.00 (18.00–32.00) vs. 20.00 (12.50–27.00). Women with HbA1c ≤ 7.0% reached, at term of pregnancy, significantly lower levels of HbA1c, 5.8% (5.7–6.0) vs. 6.7% (6.3–7.3). Daily insulin units were statistically different between the two groups at the end of pregnancy (47.92 (39.00–67.30) vs. 64.00 (48.00–82.00)). Proteinuria was significantly higher in the group with HbA1c > 7.0%, who delivered at earlier gestational age (37.57 (35.57–38.00) vs. 38.14 (38.00–38.43). Moreover, women with HbA1c > 7.0% had a significantly higher prevalence of an adverse composite outcome. Of note, in multivariate logistic regression analysis, pregnancy complications were significantly correlated to pre-pregnancy HbA1c > 7.0% (OR 2.95 CI.95 1.16–7.48, p < 0.05) independently of age, insulin treatment, and type of diabetes. Conclusions: Our data, obtained from a single-center cohort study, suggest that starting pregnancy with poor glycemic control might predict more complex management of diabetes in the following trimesters.

Information concerning the mechanisms underlying oxidative stress and low-grade inflammation in young healthy women predisposing eventually to future diseases is scarce. We investigated the relationship of oxidative stress and high-sensitivity C-reactive protein (hsCRP) in fertile-age women by oral combined contraceptive (OC) use. Caucasian Italian healthy non-obese women (n = 290; 100 OC-users; 190 non-OC-users; mean age 23.2 ± 4.7 years) were analyzed. Blood hydroperoxides, as oxidative stress biomarkers, were assessed by Free Oxygen Radical Test (FORT). Serum hsCRP was determined by an ultra-sensitive method (hsCRP). Markedly elevated oxidative stress (≥400 FORT Units) was found in 77.0% of OC-users and 1.6% of non-OC-users, odds ratio (OR) = 209, 95% CI = 60.9–715.4, p < 0.001. Elevated hsCRP levels ≥ 2.0 mg/L, considered risky for cardiovascular diseases (CVDs), were found in 41.0% of OC-users and 9.5% of non-OC-users, OR = 6.6, 95%CI 3.5–12.4, p < 0.001. Hydroperoxides were strongly positively correlated to hsCRP in all women (rs = 0.622, p < 0.001), in OC-users (rs = 0.442, p < 0.001), and in non-OC-users (rs = 0.426, p < 0.001). Women with hydroperoxides ≥ 400 FORT Units were eight times as likely to have hsCRP ≥ 2 mg/L. In non-OC-users only, hydroperoxides values were positively correlated with weight and body mass index, but negatively correlated with red meat, fish and chocolate consumption. Our research is the first finding a strong positive correlation of serum hydroperoxides with hsCRP, a marker of low-grade chronic inflammation, in young healthy women. Further research is needed to elucidate the potential role of these two biomarkers in OC-use associated side-effects, like thromboembolism and other CVDs.

The promoter of the Kirsten ras (KRAS) proto-oncogene contains, upstream of the transcription start site, a quadruplex-forming motif called 32R with regulatory functions. As guanine under oxidative stress can be oxidized to 8-oxoguanine (8OG), we investigated the capacity of glycosylases 8-oxoguanine glycosylase (OGG1) and endonuclease VIII-like 1 (Neil1) to excise 8OG from 32R, either in duplex or G-quadruplex (G4) conformation. We found that OGG1 efficiently excised 8OG from oxidized 32R in duplex but not in G4 conformation. By contrast, glycosylase Neil1 showed more activity on the G4 than the duplex conformation. We also found that the excising activity of Neil1 on folded 32R depended on G4 topology. Our data suggest that Neil1, besides being involved in base excision repair pathway (BER), could play a role on KRAS transcription.

The herpes simplex virus 1 (HSV-1) genome is extremely rich in guanine tracts that fold into G-quadruplexes (G4s), nucleic acid secondary structures implicated in key biological functions. Viral G4s were visualized in HSV-1 infected cells, with massive virus cycle-dependent G4-formation peaking during viral DNA replication. Small molecules that specifically interact with G4s have been shown to inhibit HSV-1 DNA replication. We here investigated the antiviral activity of TMPyP4, a porphyrin known to interact with G4s. The analogue TMPyP2, with lower G4 affinity, was used as control. We showed by biophysical analysis that TMPyP4 interacts with HSV-1 G4s, and inhibits polymerase progression in vitro; in infected cells, it displayed good antiviral activity which, however, was independent of inhibition of virus DNA replication or entry. At low TMPyP4 concentration, the virus released by the cells was almost null, while inside the cell virus amounts were at control levels. TEM analysis showed that virus particles were trapped inside cytoplasmatic vesicles, which could not be ascribed to autophagy, as proven by RT-qPCR, western blot, and immunofluorescence analysis. Our data indicate a unique mechanism of action of TMPyP4 against HSV-1, and suggest the unprecedented involvement of currently unknown G4s in viral or antiviral cellular defense pathways.

The refractoriness of tumor cells to apoptosis represents the main mechanism of resistance to chemotherapy. Smac/DIABLO mimetics proved to be effective in overcoming cancer-acquired resistance to apoptosis as a consequence of overexpression of the anti-apoptotic proteins XIAP, cIAP1, and cIAP2. In this work, we describe a dual-targeting peptide capable of selectively activating apoptosis in cancer cells. The complex consists of a fluorescent periodic mesoporous organosilica nanoparticle that carries the short sequences of Smac/DIABLO bound to the αvβ3--integrin ligand. The dual-targeting peptide @PMO shows significantly higher toxicity in αvβ3-positive HeLa cells with respect to αvβ3-negative Ht29 cells. @PMO exhibited synergistic effects in combination with oxaliplatin in a panel of αvβ3-positive cancer cells, while its toxicity is overcome by XIAP overexpression or integrin β3 silencing. The successful uptake of the molecule by αvβ3-positive cells makes @PMO promising for the re-sensitization to apoptosis of many cancer types. [ABSTRACT FROM AUTHOR]