Impact of oral melatonin on the electroretinogram cone response

<p>Abstract</p> <p>Background</p> <p>In the eye, melatonin plays a role in promoting light sensitivity at night and modulating many aspects of circadian retinal physiology. It is also an inhibitor of retinal dopamine, which is a promoter of day vision through the cone system. Consequently, it is possible that oral melatonin (an inhibitor of retinal dopamine) taken to alleviate circadian disorders may affect cone functioning. Our aim was to assess the impact of melatonin on the cone response of the human retina using electroretinography (ERG).</p> <p>Methods</p> <p>Twelve healthy participants aged between 18 to 52 years old were submitted to a placebo-controlled, double-blind, crossover, and counterbalanced-order design. The subjects were tested on 2 sessions beginning first with a baseline ERG, followed by the administration of the placebo or melatonin condition and then, 30 min later, a second ERG to test the effect.</p> <p>Results</p> <p>Following oral melatonin administration, a significant decrease of about 8% of the cone maximal response was observed (mean 6.9 μV ± SEM 2.0; P = 0.0065) along with a prolonged b-wave implicit time of 0.4 ms ± 0.1, 50 minutes after ingestion.</p> <p>Conclusion</p> <p>Oral melatonin appears to reach the eye through the circulation. When it is administered at a time of day when it is not usually present, melatonin appears to reduce input to retinal cones. We believe that the impact of melatonin on retinal function should be taken into consideration when used without supervision in chronic self-medication for sleep or circadian disorder treatment.</p

Caracterização morfológica, mineralógica e química dos níveis de alteração da Formação Marília (Membro Serra da Galga) do Neocretáceo da Bacia Bauru, no Triângulo Mineiro (MG)

In the flat plateaus of the Triângulo Mineiro, the sediments of Marília Formation (Neo Cretaceous) are intensively altered and pedogenised, developing thick profiles, strongly clayey with high concentrations of kaolinite and gibbsite. The objective of this paper is to characterize the major changes of petrography (optical microscopy), mineralogical (XRD and DTA-TG) and geochemical (XRF Geochemical Transport and function) in an alteration profile involving the sandstone, the saprolite and the superficial plinthic horizons and with aluminous clays. The results have shown that the kaolinite and gibbsite are the dominant secondary paragenesis of the profile. The concentrations are accentuated in the saprolite on account of the weathering of feldspars and micaceous minerals, and it is most present in the plinthite and in the aluminous clay. In the superficial horizons, the gibbsite concentration is higher than the kaolinite. The geochemical data and the transport function have shown that there is an increase of iron oxides in saprolite (1.45%) and in the plinthite (2.66%) due to the absolute concentration in the nodules. In saprolite there are absolute gains of Si, Al and Fe. There was loss of Si in the plinthite and in the aluminous clay. Regarding the Al, it is noticed gains in the saprolite, plinthite and aluminous clay. There is a relative increase in the proportion of kaolinite and gibbsite from the base to the top of the profile, from ~ 72% of kaolinite and ~ 3% of gibbsite in the sandstone and from to ~ 28% of kaolinite and ~ 71% of gibbsite in aluminous clay, indicating strong loss of silica in the soil solution. The results obtained show strong similarity between the analyzed samples, suggesting a possible mineralogical relationship among them.Nos planaltos tabulares do Triângulo Mineiro, os sedimentos da Formação Marília (Neocretáceo) são intensamente alterados e pedogeneizados formando perfis espessos, muito argilosos com elevada concentração de caulinita e gibbsita. O objetivo deste trabalho é caracterizar as principais alterações petrográficas (microscopia ótica), mineralógicas (DRX e ATD-TG) e geoquímicas (FRX e Função de Transporte Geoquímico) em um perfil de alteração envolvendo o arenito, o saprolito e os horizontes superficiais plínticos e com argilas aluminosas. Os resultados mostraram que a caulinita e a gibbsita são a paragênese secundária dominante no perfil. As concentrações se acentuam na alterita, devido à alteração de feldspatos e minerais micáceos e, mais acentuadamente na plintita e na argila aluminosa. Nos horizontes superficiais, a concentração de gibbsita é maior que a da caulinita. A geoquímica e a função de transporte mostraram aumento dos óxidos de ferro na alterita (1,45%) e na plintita (2,66%) devido à concentração absoluta nos nódulos. Na alterita ocorrem ganhos absolutos de Si, Al e Fe. Houve perda de Si na plintita e na argila aluminosa. Em relação ao Al, observa-se ganhos na alterita, plintita e na argila aluminosa. A proporção de gibbsita em relação à caulinita aumenta da base para o topo do perfil, passando de ~72% de caulinita e ~3% de gibbsita no arenito para ~28% de caulinita e ~71% de gibbsita na argila aluminosa, indicando meio fortemente dessilicificado. Os resultados obtidos mostram estreita similaridade entre os materiais analisados, sugerindo possível filiação mineralógica

The role of mercury, selenium and the Se-Hg antagonism on cognitive neurodevelopment: A 40-month follow-up of the Italian mother-child PHIME cohort

Despite a 15-year long effort to define the \u201csafety\u201d of fish intake during pregnancy, there remains still uncertainty on this important public health issue. The evaluation of the toxic effects of contaminants, particularly mercury (Hg) in fish-eating populations is complicated by the fact that sea-food is also rich in beneficial nutrients, such as selenium (Se). There is toxicological plausibility of an antagonistic effects between Se and Hg, and some theoretical support for the inclusion of the Se\u2013Hg interaction to better assess the risk linked with fish intake. To assess the effects of exposure to low-level Hg through fish consumption on the developing brain and the interaction between Hg and Se, we conducted an analysis at age 40 months in Italian children, enrolled in a prospective mother-child cohort, comparing additive and multiplicative models. Participant subjects were the 470 children born within the Northern Adriatic Cohort II (NAC-II) cohort who were tested by using the Bayley Scales of Infant and Toddler Development third edition (Bayley-III) (BSID-III) at age 40. Family demographic and socioeconomic information, pregnancy and delivery history, parental and child medical history and food consumption were assessed through questionnaires. Maternal blood samples were collected during pregnancy, cord blood at birth and maternal milk 1 month after delivery. As other exposures of interest, we considered the level of Se in maternal and cord blood and in breast milk and the potential Se\u2013Hg antagonism. Se and inverse of THg (1:THg) concentrations were categorized according to the tertiles of their distributions, in low, medium and high levels of exposure. The lower end of the composite cognitive score distribution closest to 20% was defined as suboptimal development. Multiple logistic regression were applied to assess the association between the dichotomized composite cognitive score and the categorized exposure to Se and 1:THg, and the antagonism between Se and 1:THg. In the recruiting period, 900 pregnant women were enrolled in the cohort; 767 of these remained in the study at delivery and 470 children at 40 months. After excluding preterm births, 456 children were used in the final analyses. The larger difference in risk for suboptimal neurodevelopment was observed for the category with High THg and Low Se with OR = 2.55 (90% CI 1.02; 6.41) under the multiplicative and OR = 1.33 (90% CI 0.80; 1.87) under the additive model. The category High THg and High Se showed a very slightly better fit of the additive model (OR = 1.07, 90% CI 0.65; 1.50) versus the multiplicative (OR = 1.66, 90% CI 0.73; 1.77). A negative \u2013 antagonistic \u2013 interaction term for this category was estimated under the multiplicative model giving an OR = 1.17 (90% CI 0.42; 3.28). Although this evidence of the effects of the Se\u2013Hg antagonism on the children neuro-development needs to be confirmed, if Se can counterbalance Hg toxicity, the evaluation of the effect on human health of fish consumption, should also consider the diverse ratios between Se and Hg concentration in different fish species

Current use and performance of the different fetal growth charts in the Italian population

Objectives: The choice of growth charts impacts on screening, diagnosis and clinical management of fetal growth abnormalities. The objectives of the study were to evaluate: 1) the clinical practice at a national level among tertiary referral centers in the use of fetal biometric growth charts; and 2) the impact on fetal growth screening of existing national and international growth charts. Study design: A questionnaire was sent to 14 Italian tertiary referral centers to explore biometric reference growth charts used in clinical practice. National and international (Intergrowth-21st and World Health Organization) fetal growth charts were tested on a large national cohort of low risk women with singleton uneventful pregnancy derived from a retrospective cross-sectional multicenter study (21 centers). The percentage of fetuses with biometric measurements below and above the 10th and 90th percentile for each biometric parameter and gestational week were calculated for each growth chart. The percentile curves of the study population were calculated by non-linear quantile regressions. Results: Twelve Italian centers (86 %) answered to the questionnaire showing a wide discrepancy in the use of growth charts for fetal biometry. The cohort included 7347 pregnant women. By applying Intergrowth-21st growth charts the percentage of fetuses with head circumference, abdominal circumference and femur length below the 10th centile was 3.9 %, 3.6 % and 2.3 %, and above the 90th centile 29.9 %, 32.5 % and 46 %, respectively. The percentages for the World Health Organization growth charts for head and abdominal circumferences and femur length were: below the 10th centile 6.3 %, 7.2 % and 5.3 %, and above 90th centile 22.8 %, 21.3 % and 31.9 %, respectively. Conclusions: The wide discrepancy in clinical use of fetal growth charts in Italian centers warrants the adoption of an uniform set of charts. Our data suggest that immediate application into clinical practice of international growth charts might result into an under-diagnosis of small for gestational age fetuses and, especially, in an over-diagnosis of large for gestational age fetuses with major consequences for clinical practice. On these grounds, there is an urgent need for a nationwide study for the prospective evaluation of international growth charts and, if needed, the construction and adoption of methodologically robust national growth charts

Impact of the COVID-19 epidemic in Friuli Venezia Giulia Region (Northern Italy): assessment of factors associated with the risk of death by competing risks analysis

OBJECTIVES: to investigate the role of gender, age, province of residence, and nursing home residency on the risk of death for residents in the Friuli Venezia Giulia (FVG) Region (Northern Italy) tested positive for Covid-19, considering recovery as a competing event. The secondary objective is to describe the impact of the Covid-19 epidemic in FVG and in the Regions of Northern and Central Italy in terms of incidence and mortality compared to the national data. DESIGN: retrospective cohort study. SETTING AND PARTICIPANTS: resident population in FVG in the period between 29 February and 25 June 2020. MAIN OUTCOME MEASURES: in order to describe the impact of the Covid-19 outbreak in FVG, in terms of incidence and mortality compared to the national data, the standardized incidence (SIR) and mortality (SMR) ratios and their respective 95% confidence intervals (95%CI) were calculated compared to the Italian population for the northern and central Regions of Italy and the autonomous Provinces (PA) of Trento and Bolzano. A retrospective cohort study was conducted on subjects residing in FVG to whom at least one naso-oropharyngeal swab (hereafter, named swab) resulted positive for Covid-19. For each subject included in the cohort, the observation period started with the first positive swab and ended with the first of the following events: death, recovery or censored, which means that at the end of the observation period the subject was still alive and positive. The cause of death was assigned to Covid-19 if a subject had not yet recovered at the time when the event occurred. Cohort members were considered recovered after two negative consecutive swabs. The sub-hazard ratio (SHR) was estimated by applying the regression model of competing risks by Fine and Gray, in which the event of interest was the death caused by Covid-19 and the competing event was recovery. The explanatory variables included in the multiple models are: gender, age at the beginning of the observation period, the Province of residence, and nursing home residency. The cause-specific hazard was estimated using Cox proportional hazard regression. RESULTS: during the observation period, 3,305 cases and 345 deaths were recorded in FVG; SIR and SMR resulted, respectively, equal to 0.64 (95%CI 0.61-0.68) and 0.43 (95%CI 0.37-0.50). The FVG was the Northern Region one with the lowest incidence and mortality. The cohort consisted of 3,121 residents in FVG with at least one swab with a positive Covid-19 result during the study period. The SHR of dying for Covid-19 is equal to 16.13 (95%CI 9.73-26.74) for people with age 70-79 years and 35.58 (95%CI 21.77-58.15) with age >=80 years respect those with age <70 years. It is higher in males (SHR 1.71; 95%CI 1.34-2.17). There is no evidence that being resident in a nursing home affects the SHR (SHR 0.91 and 95%CI 0.69-1.20). As regards the province as an explanatory variable, the sub-hazard of death in the province of Trieste appears to overlap to the sub-hazard of Pordenone used as a reference; for the provinces of Udine and Gorizia the sub-hazards seem lower than the reference. CONCLUSIONS: while other Northern Regions and autonomous Provinces show higher standardized incidence and mortality compared with Italy, FVG and Veneto do not. In FVG, male gender and age are important determinants of death while there is no evidence that the condition of guest in a nursing home increases the sub-hazard of death

Evaluation of tolerance to lentiviral LV-RPE65 gene therapy vector after subretinal delivery in non-human primates.

Several approaches have been developed for gene therapy in RPE65-related Leber congenital amaurosis. To date, strategies that have reached the clinical stages rely on adeno-associated viral vectors and two of them documented limited long-term effect. We have developed a lentiviral-based strategy of RPE65 gene transfer that efficiently restored protein expression and cone function in RPE65-deficient mice. In this study, we evaluated the ocular and systemic tolerances of this lentiviral-based therapy (LV-RPE65) on healthy nonhuman primates (NHPs), without adjuvant systemic anti-inflammatory prophylaxis. For the first time, we describe the early kinetics of retinal detachment at 2, 4, and 7 days after subretinal injection using multimodal imaging in 5 NHPs. We revealed prolonged reattachment times in LV-RPE65-injected eyes compared to vehicle-injected eyes. Low- (n = 2) and high-dose (n = 2) LV-RPE65-injected eyes presented a reduction of the outer nuclear and photoreceptor outer segment layer thickness in the macula, that was more pronounced than in vehicle-injected eyes (n = 4). All LV-RPE65-injected eyes showed an initial perivascular reaction that resolved spontaneously within 14 days. Despite foveal structural changes, full-field electroretinography indicated that the overall retinal function was preserved over time and immunohistochemistry identified no difference in glial, microglial, or leucocyte ocular activation between low-dose, high-dose, and vehicle-injected eyes. Moreover, LV-RPE65-injected animals did not show signs of vector shedding or extraocular targeting, confirming the safe ocular restriction of the vector. Our results evidence a limited ocular tolerance to LV-RPE65 after subretinal injection without adjuvant anti-inflammatory prophylaxis, with complications linked to this route of administration necessitating to block this transient inflammatory event

ALAD and APOE polymorphisms are associated with lead and mercury levels in Italian pregnant women and their newborns with adequate nutritional status of zinc and selenium

The impacts of single-nucleotide polymorphisms (SNPs) in ALAD and VDR genes on Pb health effects and/or kinetics are inconclusive at low exposure levels, while studies including APOE SNPs are rare. In this study, we examined the associations of ALAD, VDR and APOE SNPs with exposure biomarkers of Pb and other trace elements (TEs) in Italian pregnant women (N = 873, aged 18–44 years) and their newborns (N = 619) with low-level mixed-element exposure through diet, the environment or endogenously. DNA from maternal peripheral venous blood (mB), sampled during the second and third trimesters, was genotyped for ALAD (rs1800435, rs1805313, rs1139488, rs818708), VDR (rs2228570, rs1544410, rs7975232, rs731236) and APOE (rs429358, rs7421) using TaqMan SNP assays. Personal and lifestyle data and TE levels (mB, maternal plasma, hair and mixed umbilical cord blood [CB]) from the PHIME project were used. Multiple linear regression models, controlling for confounding variables, were performed to test the associations between SNPs and TEs. The geometric means of mB-Pb, mB-Hg, mB-As and mB-Cd (11.0 ng/g, 2.16 ng/g, 1.38 ng/g and 0.31 ng/g, respectively) indicated low exposure levels, whereas maternal plasma Zn and Se (0.72 μg/mL and 78.6 ng/g, respectively) indicated adequate micronutritional status. Variant alleles of ALAD rs1800435 and rs1805313 were negatively associated with mB-Pb levels, whereas a positive association was observed for rs1139488. None of the VDR SNPs or their haplotypes had any association with Pb levels. Regarding APOE, the ϵ4 allele was associated with lower mB-Hg and CB-Hg, while a positive association was found with the ϵ2 allele and CB-Pb when the model included only newborn girls. The observed associations indicate possible modification effects of ALAD and APOE SNPs on Pb or Hg kinetics in women and their newborns with low exposure to non-essential TEs, as well as an adequate nutritional status of Zn and Se

Non-Hodgkin Lymphoma in Children and Adolescents: Progress Through Effective Collaboration, Current Knowledge, and Challenges Ahead

Non-Hodgkin lymphoma is the fourth most common malignancy in children, has an even higher incidence in adolescents, and is primarily represented by only a few histologic subtypes. Dramatic progress has been achieved, with survival rates exceeding 80%, in large part because of a better understanding of the biology of the different subtypes and national and international collaborations. Most patients with Burkitt lymphoma and diffuse large B-cell lymphoma are cured with short intensive pulse chemotherapy containing cyclophosphamide, cytarabine, and high-dose methotrexate. The benefit of the addition of rituximab has not been established except in the case of primary mediastinal B-cell lymphoma. Lymphoblastic lymphoma is treated with intensive, semi-continuous, longer leukemia-derived protocols. Relapses in B-cell and lymphoblastic lymphomas are rare and infrequently curable, even with intensive approaches. Event-free survival rates of approximately 75% have been achieved in anaplastic large-cell lymphomas with various regimens that generally include a short intensive B-like regimen. Immunity seems to play an important role in prognosis and needs further exploration to determine its therapeutic application. ALK inhibitor therapeutic approaches are currently under investigation. For all pediatric lymphomas, the intensity of induction/consolidation therapy correlates with acute toxicities, but because of low cumulative doses of anthracyclines and alkylating agents, minimal or no long-term toxicity is expected. Challenges that remain include defining the value of prognostic factors, such as early response on positron emission tomography/computed tomography and minimal disseminated and residual disease, using new biologic technologies to improve risk stratification, and developing innovative therapies, both in the first-line setting and for relapse

High IGFBP2 expression correlates with tumor severity in pediatric rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is the most common childhood sarcoma and is identified as either the embryonal or alveolar (ARMS) subtype. In approximately 75% of cases, ARMSs are characterized by specific chromosomal translocations that involve PAX and FKHR genes. ARMS gene expression signatures vary, depending on the presence or absence of the translocations. Insulin-like growth factor-binding protein 2 (IGFBP2) is strongly overexpressed in translocation-negative RMS. Because IGFBP2 is associated with tumorigenesis, we investigated its functional role in RMS. An analysis of IGFBP2 distribution in RMS cell lines revealed a strong accumulation in the Golgi complex, in which morphological characteristics appeared peculiarly modified. After silencing IGFBP2 expression, our microarray analysis revealed mostly cell cycle and actin cytoskeleton gene modulations. In parallel, IGFBP2-silenced cells showed reduced cell cycle and rates of invasion and decreased seeding in the lungs after tail vein injections in immunodeficient mice. An analysis of IGFBP2 mRNA and protein localization in human tumors showed abnormal protein accumulation in the Golgi complex, mostly in PAX/FKHR-negative RMS. Moreover, an analysis of patients with RMS revealed the presence of conspicuous circulating levels of IGFBP2 proteins in children with highly aggressive RMS tumors. Taken together, our data provide evidence that IGFBP2 contributes to tumor progression and that it could be used as a marker to better classify clinical and biological risks in RMS

Nutrient intake during pregnancy and adherence to dietary recommendations: The mediterranean phime cohort

Few studies provide a detailed description of dietary habits during pregnancy, despite the central role of nutrition for the health of the mother and offspring. This paper describes the dietary habits, energy and nutrient intake in pregnant women from four countries belonging to the Mediterranean PHIME cohort (Croatia, Greece, Italy and Slovenia) and evaluates their adherence to the European Food Safety Authority (EFSA) recommendations. A total of 1436 women were included in the present analysis. Maternal diet was assessed using a food frequency questionnaire (FFQ). The mean macro and micronutrient intakes were estimated and compared with the dietary reference values (DRVs). The percentage distribution of the 16 food groups in the total intake of each macronutrient was estimated. All women shared a similar diet during pregnancy; almost all the women in the four countries exceeded the DRV for sugars, and the total fat intake was above the DRV in most women in all the countries, as was the contribution of saturated fatty acids (SFAs) to the total energy intake. In all four countries, we observed an increased risk of micronutrient deficiency for iron, folate and vitamin D. Shared guidelines, implemented at both the national and European level, are essential to improve the maternal nutritional status during pregnancy