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Obesity is becoming pandemic and is associated with impaired reproductive potential. Oxidative stress, low-grade chronic inflammation and mitochondrial dysfunctions, which characterize obesity, strongly affect oocyte environment and function. Supplementation with antioxidant and anti-inflammatory compounds has been suggested to improve fertility. Here we evaluated the effect of α-lipoic acid and myo-inositol supplementation on the oocyte environment of infertile obese women. Nineteen normal-weight and twenty-three obese women, infertile for non-ovarian reasons, were recruited. For two months before ovarian stimulation, all women received 400 μg/die folic acid, whereas 15 obese were additionally supplemented with 800 mg α-lipoic acid, 2 g myo-inositol/die. Antioxidant capacity was measured in follicular fluid by enzymatic assay; mitochondrial DNA (mtDNA) content and mRNA levels of two respiratory chain subunits were analyzed in granulosa cells by Real-time PCR. Pregnancy rate was similar between normal-weight and treated obese, and lower in untreated obese patients. Supplemented women showed significantly higher antioxidant levels in follicular fluid compared to the two groups taking only folic acid. Conversely, granulosa cells mtDNA content was decreased in treated and higher in untreated obese patients compared to normal-weight women, suggesting mtDNA increases to compensate for oxidative-stress damages. Reduced expression of respiratory subunits in untreated obese may confirm mitochondria impairment. Interestingly, mtDNA levels inversely correlated to both total and metaphase II oocyte number. In this preliminary study, combined supplementation of α-lipoic acid and myo-inositol in infertile obese women was associated with amelioration in the oxidative status of the oocyte environment, possibly contributing to a higher pregnancy rate.

Invasive aspergillosis in hematologic pediatric patients is an opportunistic infection that is difficult to treat, with a high mortality rate when localized in the central nervous system. We are describing a 3-year-old girl who was affected by acute lymphoblastic leukemia who developed cerebral and pulmonary aspergillosis during induction chemotherapy. The patient failed first-line voriconazole treatment because of being a CYP2C19 ultrarapid metabolizer and received effective isavuconazole therapy with no notable side effects.

Background Childhood acute lymphoblastic leukaemia (ALL) survivors have an increased risk of metabolic and cardiovascular disease. We aimed to assess the presence of non-alcoholic fatty liver disease (NAFLD) in childhood ALL and if it is associated with early cardiovascular dysfunction. Methods In total, 53 childhood ALL survivors and 34 controls underwent auxological evaluation, biochemical assay, liver, heart and vascular ultrasound study. Results NAFLD was more frequent in ALL patients than in controls (39.6% vs 11.7%, P P P = 0.011). In ALL survivors, BMI-SDS and subcutaneous fat were the strongest predictors of NAFLD, whereas preperitoneal adipose tissue and C-reactive protein were the strongest predictors of left ventricular ejection fraction. Conclusions Childhood ALL survivors had higher prevalence of NAFLD than healthy controls, which is associated with early left ventricular impairment. In the case of fatty liver, a comprehensive heart evaluation is mandatory. We strongly recommend to prevent visceral adiposity in ALL survivors, to search for metabolic syndrome or its components and to reinforce the need of intervention on diet and lifestyle during the follow-up of these patients.

Introduction: Sex steroids are regulating factors for intrauterine growth. 17-β Estradiol (E2) is particularly critical to a physiological pregnancy, as increased maternal E2 was correlated to lower fetal weight at delivery. The placenta itself is a primary source of estrogens, synthetized from cholesterol precursors. Cytochrome P450 aromatase (encoded by CYP19A1 gene) is a rate-limiting enzyme for E2 biosynthesis. CYP19A1 transcription is supported by Estrogen Related-Receptor Gamma (ERRγ- ESRRG gene), which thus has an indirect role in placental steroidogenesis. Here we investigated maternal E2 levels and placental CYP19A1 and ESRRG 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. CYP19A1 and ESRRG 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 a gestational age similar to IUGR, E2 levels were not different to pathological cases. However, E2 levels at delivery positively correlated with placental efficiency. Placental CYP19A1 levels were significantly higher in IUGR placental tissue vs. controls, and specifically increased in female IUGR placentas. ESRRG expression was not different among groups. Discussion: We report a positive correlation between 17-β Estradiol levels and placental efficiency, that might indicate a disrupted steroidogenesis in IUGR pregnancies. Moreover, we show alterations of CYP19A1 expression 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.

Vitamin D (25-OHD) has a role in bone health after treatment for cancer. 25-OHD deficiency has been associated with risk factors for cardiovascular disease, but no data focusing on this topic in childhood cancer survivors have been published. We investigated the 25-OHD status in children treated for acute lymphoblastic leukemia (ALL), and evaluated its influence on vascular function. 25-OHD levels were evaluated in 52 ALL survivors and 40 matched healthy controls. Patients were grouped according to 25-OHD level (

Maternal dietary intake during pregnancy needs to meet increased nutritional demands to maintain metabolism and to support fetal development. Docosahexaenoic acid (DHA) is essential for fetal neuro-/visual development and in immunomodulation, accumulating rapidly within the developing brain and central nervous system. Levels available to the fetus are governed by the maternal diet. In this multicenter, parallel, randomized controlled trial, we evaluated once-daily supplementation with multiple micronutrients and DHA (i.e., multiple micronutrient supplementation, MMS) on maternal biomarkers and infant anthropometric parameters during the second and third trimesters of pregnancy compared with no supplementation. Primary efficacy endpoint: change in maternal red blood cell (RBC) DHA (wt% total fatty acids) during the study. Secondary variables: other biomarkers of fatty acid and oxidative status, vitamin D, and infant anthropometric parameters at delivery. Supplementation significantly increased RBC DHA levels, the omega-3 index, and vitamin D levels. Subscapular skinfold thickness was significantly greater with MMS in infants. Safety outcomes were comparable between groups. This first randomized controlled trial of supplementation with multiple micronutrients and DHA in pregnant women indicated that MMS significantly improved maternal DHA and vitamin D status in an industrialized setting&mdash, an important finding considering the essential roles of DHA and vitamin D.

Background: Maternal obesity is related to immunologic and inflammatory systemic modifications that may worsen the pregnancy inflammatory status. Hormonal changes during pregnancy can adversely affect oral biofilms and oral health initiating or worsening periodontal diseases, with enhanced local and systemic oxidative stress and inflammation. Objective: The aim of this study was to examine the relationship between local salivary and systemic parameters of oxidative stress and inflammation in relation to obesity and periodontal diseases. Study Design: Sixty-two women with singleton pregnancies were enrolled. Twenty-seven women were normal weight (NW; 18.5< body mass index [BMI] 0.59), to maternal BMI (P =.000; r > 0.52), and fasting glycemia (P 0.47). Periodontal disease was more frequent in obese groups (80%) versus NW (52%; P =.04), particularly when GDM was diagnosed (P =.009). A significant interaction effect between maternal BMI and oral condition was found for s-TAC levels. Obese with periodontitis showed significant increase in local and systemic parameters versus NW. Conclusion: Obesity and periodontal disease could synergistically amplify the inflammatory and oxidative status, resulting in increased local and systemic biomarkers particularly when GDM is diagnosed.

A lipotoxic placental environment is recognized in maternal obesity, with increased inflammation and oxidative stress. These changes might alter mitochondrial function, with excessive production of reactive oxygen species, in a vicious cycle leading to placental dysfunction and impaired pregnancy outcomes. Here, we hypothesize that maternal pregestational body mass index (BMI) and glycemic levels can alter placental mitochondria. We measured mitochondrial DNA (mtDNA, real-time PCR) and morphology (electron microscopy) in placentas of forty-seven singleton pregnancies at elective cesarean section. Thirty-seven women were normoglycemic: twenty-one normal-weight women, NW, and sixteen obese women, OB/GDM(−). Ten obese women had gestational diabetes mellitus, OB/GDM(+). OB/GDM(−) presented higher mtDNA levels versus NW, suggesting increased mitochondrial biogenesis in the normoglycemic obese group. These mitochondria showed similar morphology to NW. On the contrary, in OB/GDM(+), mtDNA was not significantly increased versus NW. Nevertheless, mitochondria showed morphological abnormalities, indicating impaired functionality. The metabolic response of the placenta to impairment in obese pregnancies can possibly vary depending on several parameters, resulting in opposite strains acting when insulin resistance of GDM occurs in the obese environment, characterized by inflammation and oxidative stress. Therefore, mitochondrial alterations represent a feature of obese pregnancies with changes in placental energetics that possibly can affect pregnancy outcomes.

Maternal obesity is characterized by systemic low-grade inflammation and oxidative stress (OxS) with the contribution of fetal sex dimorphism. We recently described increased mitochondrial content (mtDNA) in placentas of obese pregnancies. Here, we quantify mtDNA and hepcidin as indexes of OxS and systemic inflammation in the obese maternal circulation.Forty-one pregnant women were enrolled at elective cesarean section: 16 were normal weight (NW) and 25 were obese (OB). Obese women were further classified according to the presence/absence of maternal gestational diabetes mellitus (GDM); [OB/GDM(-)]: n = 15, [OB/GDM(+)]: n = 10. mtDNA and hepcidin were evaluated in blood (real-time PCR) and plasma (ELISA).mtDNA and hepcidin levels were significantly increased in OB/GDM(-) versus NW, significantly correlating with pregestational BMI. Male/female (M/F) ratio was equal in study groups, and overall F-carrying pregnancies showed significantly higher mtDNA and hepcidin levels than M-carrying pregnancies both in obese and normal weight mothers.Our results indicate a potential compensatory mechanism to increased obesity-related OxS and inflammation, indicated by the higher hepcidin levels found in obese mothers. Increased placental mitochondrial biogenesis, due to lipotoxic environment, may account for the greater mtDNA amount released in maternal circulation. This increase is namely related to F-carrying pregnancies, suggesting a gender-specific placental response.

Introduction Placental biometry at birth has been shown to predict chronic disease in later life. We hypothesized that maternal overweight/obesity, a state of low-grade inflammation and risk factor for adverse pregnancy outcome, could negatively influence placental development and that differences would be sex-specific. Methods 696 women (537 normal-weight, NW; 112 overweight, OW; 47 obese, OB) with singleton uncomplicated pregnancies were prospectively enrolled at term delivery. Gestational age, maternal (age, height, pre-pregnancy BMI, gestational weight gain -GWG, hemoglobin, hematocrit and glycemia), fetal (weight, length, ponderal index, cranial circumference) and placental (weight, diameters) data were collected. Placental area, thickness and efficiency (fetal/placental weight ratio, F/P) were calculated. Results GWG was within standard recommendations in OB, while OW exceeded it. Placental weight was significantly higher in OW versus NW, but not in OB, leading to significantly higher placental thickness and lower F/P in this group. In the total population, a significant interaction effect between maternal BMI and fetal sex on placental weight and efficiency was found. Indeed, differences in placental parameters were present only in female offspring. Discussion In our population of OW and OB uncomplicated pregnancies only OW women, presenting GWG over standard recommendations, had thicker and less efficient placentas. We also reported different placental adaptation depending on fetal sex, with significant changes only in female fetuses. This may be part of a female-specific strategy aiming to ensure survival if another adverse event occurs. Customized counseling according to maternal BMI and fetal sex should be evaluated in clinical care.

Polyclonal hypergammaglobulinemia (PHG) associated with hematological malignancies is a rare occurrence. We reviewed our series of 47 children with AML in order to define the prevalence of PHG and its prognostic value in achieving complete remission (CR) after induction treatment. Patients were stratified by immunoglobulin levels into two groups: with PHG and without PHG. CR reached after induction chemotherapy was considered a positive response. Conditional exact tests were used for the statistical analysis; conditional maximum likelihood estimates of the odds ratio (OR) were obtained. Significance levels (p) were determined from two-tailed tests. Twenty-two of 38 (57.9%) evaluable children showed PHG. Children with PHG and AML were more likely to be in CR after first induction treatment (OR=6.25, p=0.021), independent of sex, age at diagnosis, white blood cell count, percentage of blasts in the bone marrow, FAB phenotype, and treatment protocol. Infections seemed to positively influence early treatment response (p=0.038). PHG and infections were not statistically associated (p=0.16). PHG may result from the uncontrolled stimulation of B lymphocytes by cytokines. Infections or transfusions may act as triggers for the immune system, leading to the antileukemic effect seen in patients with AML and PHG going into spontaneous remission. It could be that this activation caused the larger number of CRs observed in our series. Clarification of why PHG exerts a positive influence on children with AML could help us to understand the ways by which the organism is able to control a malignant disease.

Human gliomas are the most frequent tumours of the central nervous system (Kleihues & Cavenee, 2000). They are of neuroectodermal origin and present as different histological types and malignancy grades (Louis et al., 2007). According to the WHO (world health organization) system, astrocytoma, oligodendroglioma and mixed oligoastrocytoma are classified as differentiated gliomas, while anaplastic glioma and glioblastoma show increasing grades of malignancy (Box 1).

Background Radiotherapy of the head region in children is known to cause long-term sequelae, such as facial, dental, and ocular abnormalities. We investigated whether a decreased nasal mucociliary function occurs after radiotherapy of the head in children. Methods A saccharin/charcoal test was performed in 20 children treated with radiotherapy of the head and in 20 controls, age-matched and gender-matched. Results We found a decreased nasal mucociliary clearance (lower percentage of responses (p = 0083) and longer mucociliary transport times (p = .0001) in the patients compared with the controls. The radiotherapy dosage influenced the response to the test (p = .0046). Conclusions Irradiation of the head in children may cause impairment of mucociliary function, even permanently, which may predispose children to upper respiratory infections. We would suggest careful monitoring of such patients to detect as early as possible the clinical effects of the functional changes and to prevent the evolution to chronic diseases. © 2001 John Wiley & Sons, Inc. Head Neck 23: 461–466, 2001

Background Ear involvement (EI) in Langerhans' cell histiocytosis (LCH) occurs quite often. We reviewed the Italian pediatric population of 251 children with LCH diagnosed between 1982 and 1995, focusing on EI, to highlight the prevalence, the clinical presentation, the outcome during follow-up, and the prognostic impact of otologic LCH. Methods EI was defined by chronic otorrhea and/or mastoid infiltration, external auditory meatus lesions, and middle/internal EI. The age at diagnosis, sex, system involved, organ dysfunction, treatment, disease control, and outcome were recorded. Results EI was noted at presentation in 34 children (13.5%). They had a younger age at diagnosis (p= .0013) and near totality of multisystem disease (93.8% of patients with EI). Among patients with multisystem disease, children with EI seemed to have a higher risk of poor response and a higher percentage of second line treatment (p= .003). Conclusions EI seems to identify patients with a particular disease behavior, which requires a more accurate evaluation at diagnosis, staging and treatment, and a strict follow-up, considering the possibility of an unfavorable outcome. © 2000 John Wiley & Sons, Inc. Head Neck 22: 42–47, 2000.

Background Human gliomas are a heterogeneous group of primary malignant brain tumors whose molecular pathogenesis is not yet solved. In this regard, a major research effort has been directed at identifying novel specific glioma-associated genes. Here, we investigated the effect of TRIM8 gene in glioma. Methods TRIM8 transcriptional level was profiled in our own glioma cases collection by qPCR and confirmed in the independent TCGA glioma cohort. The association between TRIM8 expression and Overall Survival and Progression-free Survival in TCGA cohort was determined by using uni-multivariable Cox regression analysis. The effect of TRIM8 on patient glioma cell proliferation was evaluated by performing MTT and clonogenic assays. The mechanisms causing the reduction of TRIM8 expression were explored by using qPCR and in vitro assays. Results We showed that TRIM8 expression correlates with unfavorable clinical outcome in glioma patients. We found that a restored TRIM8 expression induced a significant reduction of clonogenic potential in U87MG and patient’s glioblastoma cells. Finally we provide experimental evidences showing that miR-17 directly targets the 3′ UTR of TRIM8 and post-transcriptionally represses the expression of TRIM8. Conclusions Our study provides evidences that TRIM8 may participate in the carcinogenesis and progression of glioma and that the transcriptional repression of TRIM8 might have potential value for predicting poor prognosis in glioma patients. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1449-9) contains supplementary material, which is available to authorized users.