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In cross-platform analyses of 174 metabolites, we identify 499 associations (P

Background The Children’s Sleep Habits Questionnaire (CSHQ) is a parent-report questionnaire used to examine sleep behavior in children. Linguistic adaptation of CSHQ into several languages and/or psychometric analysis of reliability have been published. Main text Our aim was to translate the original 33-items CSHQ from English to Italian and to examine its reliability for use in 4–10 years-old children of Italy. After translation and back-translation procedure of the original CSHQ, the Italian CSHQ (CSHQ-IT) was administered to 69 mothers of healthy children. Reliability of CSHQ-IT was examined by the internal consistency of the scale (using the Cronbach’s alpha coefficient), and by the test-retest analysis obtained by asking mothers who had completed the CSHQ-IT at baseline to re-complete it after a two-week interval (measured with the Lin’s Concordance Correlation Coefficient, CCC). The CSHQ-IT showed adequate internal consistency (Cronbach’s alpha = 0.81 for the total scale). The total CSHQ-IT score showed a strong correlation in retests (CCC 0.87; 95% Confidence Interval, 0.80; 0.92). Conclusion CSHQ-IT is a valuable tool for evaluating sleep behavior in children 4–10 years-old in Italy. Future research should be implemented to provide definitive validity of CSHQ-IT in children with sleep-disordered breathing.

AIMS/HYPOTHESIS: This study aimed to: (1) identify metabolite patterns during late childhood that differ with respect to exposure to maternal gestational diabetes mellitus (GDM); (2) examine the persistence of GDM/metabolite associations 5 years later, during adolescence; and (3) investigate the associations of metabolite patterns with adiposity and metabolic biomarkers from childhood through adolescence. METHODS: This study included 592 mother–child pairs with information on GDM exposure (n = 92 exposed), untargeted metabolomics data at age 6–14 years (T1) and at 12–19 years (T2), and information on adiposity and metabolic risk biomarkers at T1 and T2. We first consolidated 767 metabolites at T1 into factors (metabolite patterns) via principal component analysis (PCA) and used multivariable regression to identify factors that differed by GDM exposure, at α = 0.05. We then examined associations of GDM with individual metabolites within factors of interest at T1 and T2, and investigated associations of GDM-related factors at T1 with adiposity and metabolic risk throughout T1 and T2 using mixed-effects linear regression models. RESULTS: Of the six factors retained from PCA, GDM exposure was associated with greater odds of being in quartile (Q)4 (vs Q1–3) of ‘Factor 4’ at T1 after accounting for age, sex, race/ethnicity, maternal smoking habits during pregnancy, Tanner stage, physical activity and total energy intake, at α = 0.05 (OR 1.78 [95% CI 1.04, 3.04]; p = 0.04). This metabolite pattern comprised phosphatidylcholines, diacylglycerols and phosphatidylethanolamines. GDM was consistently associated with elevations in a subset of individual compounds within this pattern at T1 and T2. While this metabolite pattern was not related to the health outcomes in boys, it corresponded with greater adiposity and a worse metabolic profile among girls throughout the follow-up period. Each 1-unit increment in Factor 4 corresponded with 0.17 (0.08, 0.25) units higher BMI z score, 8.83 (5.07, 12.59) pmol/l higher fasting insulin, 0.28 (0.13, 0.43) units higher HOMA-IR, and 4.73 (2.15, 7.31) nmol/l higher leptin. CONCLUSIONS/INTERPRETATION: Exposure to maternal GDM was nominally associated with a metabolite pattern characterised by elevated serum phospholipids in late childhood and adolescence at α = 0.05. This metabolite pattern was associated with greater adiposity and metabolic risk among female offspring throughout the late childhood-to-adolescence transition. Future studies are warranted to confirm our findings.

Stop–start vehicles (SSVs) represent a potential alternative for improving internal combustion engine (ICE) efficiency. SSVs provide ICEs with the functionality of turning the engine off during traffic halts and restarting it without intervention by the driver. This strategy reduces fuel consumption, especially in dense urban traffic areas, and contributes to emissions reduction to meet green emissions targets. The most widely adopted SSV system has a mechanical interface to connect the electric starter motor to the ICE, which requires increased robustness compared with standard starting motors. This requirement allows the motor to withstand a higher number of engine start cycles compared with a standard starting motor. Nevertheless, it is a critical problem for wider adoption of SSVs. As SSV systems usually are based on the conventional starting system, its durability and noise remains a critical issue to be addressed by automakers. The typical pinion–ring gear interface uses intermittent gear meshing to form a transient coupling interface. The research reported here presents the development of an innovative mechanical interface for starting systems, called the permanent coupling (PC)-type interface, which reduces noise and increases durability compared with the existing design. The results obtained by a functional prototype of the PC-type mechanical interface confirm the feasibility of the proposed concept. The methodology is based on a product development process integrated with lumped-parameter modeling and virtual simulation aimed at reducing failures during prototype testing. The new mechanical interface was proven to be a good candidate for increasing the use of SSVs in the automotive market.

PURPOSE: The aim was to evaluate the role of tumor-infiltrating lymphocytes (TIL) in predicting molecular response after preoperative endocrine or cytotoxic treatment for HR+/HER2- patients who do not achieve a pathological complete response. METHODS: Stromal (Str) TIL were centrally evaluated on samples from diagnostic core-biopsies of HR+/HER2- patients included in two prospective randomized trials: the LETLOB trial (neoadjuvant endocrine-based treatment) and the GIOB trial (neoadjuvant chemotherapy-based treatment). Pre- and post-treatment Ki67 was centrally assessed. RESULTS: StrTIL were evaluable in 111 cases (n = 73 from the LETLOB trial and n = 38 from the GIOB trial). Median StrTIL was 2%. Patients with high StrTIL (StrTIL ≥10%, n = 28) had more frequently breast cancer of ductal histology (p = 0.02), high grade (p = 0.049), and high Ki67 (p = 0.02). After neoadjuvant endocrine treatment (LETLOB cohort), a significant Ki67 suppression (p < 0.01) from pre- to post-treatment was observed in both the low and high StrTIL groups. High StrTIL patients achieve more frequently a relative Ki67 suppression ≥50% from baseline as compared to low StrTIL patients (55 vs. 35%, p non significant). After neoadjuvant chemotherapy (GIOB cohort), a significant Ki67 suppression was observed only for low StrTIL patients (Wilcoxon p = 0.001) and not in the high StrTIL group (p = 0.612). In this cohort, the rate of patients achieving a relative Ki67 suppression ≥50% from baseline was significantly higher in the low vs high StrTIL group (64% vs 10%, p = 0.003). Geometric mean Ki67 suppression was evaluated in each cohort according to StrTIL: the lowest value (-41%) was observed for high StrTIL cases treated with chemotherapy. CONCLUSIONS: This hypothesis-generating study suggests that in HR+/HER2- breast cancer StrTIL at baseline may influence the achievement of a molecular response after neoadjuvant treatment. Further evaluation in large studies is needed, and interaction with the type of treatment warrants to be explored.

This study aims at merging the therapeutic effects associated to the inhibition of Carbonic Anhydrase IX (CAIX), an essential enzyme overexpressed by cancer cells including mesothelioma and breast cancer, with those ones brought by the application of Boron Neutron Capture Therapy (BNCT). This task was pursued by designing a sulfonamido-functionalised-carborane (CA-SF) that acts simultaneously as CAIX inhibitor and boron delivery agent. The CAIX expression, measured by Western blot analysis, resulted high in both mesothelioma and breast tumours. This finding was exploited for the delivery of a therapeutic dose of boron (> 20 μg/g) to the cancer cells. The synergic cytotoxic effects operated by the enzymatic inhibition and neutron irradiation was evaluated in vitro on ZL34, AB22 and MCF7 cancer cells. Next, an in vivo model was prepared by subcutaneous injection of AB22 cells in Balb/c mice and CA-SF was administered as inclusion complex with a β-cyclodextrin oligomer. After irradiation with thermal neutrons tumour growth was evaluated for 25 days by MRI. The obtained results appear very promising as the tumour growth was definitively markedly lower in comparison to controls and the CAIX inhibitor alone. This approach appears promising and it call consideration for the design of new therapeutic routes to cure patients affected by this disease.

Several clinically successful tumor-targeting mAbs induce NK cell effector functions. Human NK cells exclusively recognize tumor-bound IgG by the FcR CD16A (FcγRIIIA). Unlike other NK cell activating receptors, the cell surface density of CD16A can be rapidly downregulated in a cis manner by the metalloproteinase ADAM17 following NK cell stimulation in various manners. CD16A downregulation takes place in cancer patients and this may affect the efficacy of tumor-targeting mAbs. We examined the effects of MEDI3622, a human mAb and potent ADAM17 inhibitor, on NK cell activation by antibody-bound tumor cells. MEDI3622 effectively blocked ADAM17 function in NK cells and caused a marked increase in their production of IFNγ. This was observed for NK cells exposed to different tumor cell lines and therapeutic antibodies, and over a range of effector/target ratios. The augmented release of IFNγ by NK cells was reversed by a function-blocking CD16A mAb. In addition, NK92 cells, a human NK cell line that lacks endogenous FcγRs, expressing a recombinant non-cleavable version of CD16A released significantly higher levels of IFNγ than NK92 cells expressing equivalent levels of wildtype CD16A. Taken together, our data shows that MEDI3622 enhances the release of IFNγ by NK cells engaging antibody-bound tumor cells by blocking the shedding of CD16A. These findings support ADAM17 as a dynamic inhibitory checkpoint of the potent activating receptor CD16A, which can be targeted by MEDI3622 to potentially increase the efficacy of anti-tumor therapeutic antibodies.

The combined application of humic substances and mycorrhizal inocula under increased CO in the air is a promising horticultural technique for improving the quality of greenhouse-grown onion seedlings. The objective of this study was to evaluate if the development and qualitative characteristics of bulbs from the yellow onion Allium cepa L. Alfa São Francisco improved with the application of the abovementioned agronomic, biotic, and environmental factors. The lowest dry matter was achieved in bulbs of onions not inoculated with mycorrhizal fungi, non-amended with humic acids (HA), and grown at ambient CO. Mycorrhizal inoculation significantly increased bulb biomass in plants cultivated at ambient CO, and not fertilized with HA, which may be a consequence of the enhanced acid phosphatase activity in roots. The application of HA always increased bulb dry matter, which were more evident at elevated rather than ambient CO conditions and correlated with improved acid phosphatase activity in the plants at elevated CO. Mycorrhizal inoculation, HA supplementation, and elevated CO in the air had an additive effect of increasing the content of soluble sugars, proteins, and phenolics in bulbs. While high levels of sugars and proteins enhanced the energetic value of onions, the increase in phenolics improved their antioxidant properties. The triple interaction between mycorrhization, HA fertilization, and elevated CO also increased the ratio between soluble solids and total titratable acidity, which may enhance the perception of sweetness and make onions more pleasant for consumption., This study has been supported by the ‘Ministerio de Ciencia e Innovación’ (Spain) (BFU2011-26989). Marcelle M. Bettoni received a grant from ‘Los CAPES y Coordenação do Programa de Pós-graduação em Agronomia - Produção Vegetal’ from the Brazilian Government.

Probiotic ingestion is recommended as a preventive approach to maintain the balance of the intestinal microbiota and to enhance the human well-being. During the whole life of each individual, the gut microbiota composition could be altered by lifestyle, diet, antibiotic therapies and other stress conditions, which may lead to acute and chronic disorders. Hence, probiotics can be administered for the prevention or treatment of some disorders, including lactose malabsorption, acute diarrhoea, irritable bowel syndrome, necrotizing enterocolitis and mild forms of inflammatory bowel disease. The probiotic-mediated effect is an important issue that needs to be addressed in relation to strain-specific probiotic properties. In this work, the probiotic properties of new Lactobacillus and Bifidobacterium strains were screened, and their effects in vitro were evaluated. They were screened for probiotic properties by determining their tolerance to low pH and to bile salts, antibiotic sensitivity, antimicrobial activity and vitamin B8, B9 and B12 production, and by considering their ability to increase the antioxidant potential and to modulate the inflammatory status of systemic-miming cell lines in vitro. Three out of the examined strains presenting the most performant probiotic properties, as Lactobacillus plantarum PBS067, Lactobacillus rhamnosus PBS070 and Bifidobacterium animalis subsp. lactis PBSO75, were evaluated for their effects also on human intestinal HT-29 cell line. The obtained results support the possibility to move to another level of study, that is, the oral administration of these probiotical strains to patients with acute and chronic gut disorders, by in vivo experiments.

Background Breast cancer related lymphoedema (BCRL) occurs in a substantial proportion of breast cancer survivors and is a major contributor to patients’ disability. Regrettably, there are no validated predictive biomarkers, diagnostic tools, and strong evidence-supported therapeutic strategies for BCRL. Here, we provide an integrative characterization of a large series of women with node-positive breast cancers and identify new bona fide predictors of BCRL occurrence. Methods Three hundred thirty-two cases of surgically-treated node-positive breast cancers were retrospectively collected (2–10.2 years of follow-up). Among them, 62 patients developed BCRL. To identify demographic and clinicopathologic features related to BCRL, Fisher’s exact test or Chi-squared test were carried out for categorical variables; the Wilcoxon rank-sum was employed for continuous variables. Factors associated with BCRL occurrence were assessed using a Cox proportional hazards regression model. Results En-bloc dissection of the axillary lymph nodes but not the type of breast surgery impacted on BCRL development. Most of BCRL patients had a Luminal A-like neoplasm. The median number of lymph nodes involved by metastatic deposits was significantly higher in BCRL compared to the control group (p = 0.04). Both peritumoral lymphovascular invasion (LVI) and extranodal extension (ENE) of the metastasis had a negative impact on BCRL-free survival (p = 0.01). Specifically, patients with LVI and left side localization harboured 4-fold higher risk of developing BCRL, while right axillary nodes metastases with ENE increased the probability of BCRL compared to ENE-negative patients. Conclusions Assessment of LVI and ENE should be integrated with clinical and surgical data to improve BCRL risk stratification. Electronic supplementary material The online version of this article (10.1186/s12885-018-4851-2) contains supplementary material, which is available to authorized users.

Internal combustion engines inherently demand startup assistance to perform its autonomous functioning. Nevertheless, the common solution over more than one century has been the electric starter motor, for both Otto and diesel cycles. The dynamic coupling system defined herein as the mechanical connection between the internal combustion engine and the starter motor has not evolved considerably since the intermittent pinion–ring gear interface has been adopted. This paper reviews the conceptual design behind the starting systems developed so far, focusing on their functional analysis, and proposes an innovative concept. Preliminary study on dynamic simulation using lumped parameters model, implemented in AMESim, is also discussed as potential aid for the proposed design. Based on decision matrix method, it is possible to evaluate the proposed design against state-of-the-art and promising alternatives to find a real cost-effective alternative to the existing concepts to couple the electric motor and the internal combustion engine. The patented dynamic coupling system proposed herein demonstrates potential to evolve as a cost-effective solution to implement start–stop systems worldwide, contributing to reduction of pollution caused by automotive vehicle emissions.

Background Obesity is associated with multiple diseases, but it is unclear how obesity promotes progressive tissue damage. Recovery from injury requires repair, an energy-expensive process that is coupled to energy availability at the cellular level. The satiety factor, leptin, is a key component of the sensor that matches cellular energy utilization to available energy supplies. Leptin deficiency signals energy depletion, whereas activating the Hedgehog pathway drives energy-consuming activities. Tissue repair is impaired in mice that are obese due to genetic leptin deficiency. Tissue repair is also blocked and obesity enhanced by inhibiting Hedgehog activity. We evaluated the hypothesis that loss of leptin silences Hedgehog signaling in pericytes, multipotent leptin-target cells that regulate a variety of responses that are often defective in obesity, including tissue repair and adipocyte differentiation. Results We found that pericytes from liver and white adipose tissue require leptin to maintain expression of the Hedgehog co-receptor, Smoothened, which controls the activities of Hedgehog-regulated Gli transcription factors that orchestrate gene expression programs that dictate pericyte fate. Smoothened suppression prevents liver pericytes from being reprogrammed into myofibroblasts, but stimulates adipose-derived pericytes to become white adipocytes. Progressive Hedgehog pathway decay promotes senescence in leptin-deficient liver pericytes, which, in turn, generate paracrine signals that cause neighboring hepatocytes to become fatty and less proliferative, enhancing vulnerability to liver damage. Conclusions Leptin-responsive pericytes evaluate energy availability to inform tissue construction by modulating Hedgehog pathway activity and thus, are at the root of progressive obesity-related tissue pathology. Leptin deficiency inhibits Hedgehog signaling in pericytes to trigger a pericytopathy that promotes both adiposity and obesity-related tissue damage. Electronic supplementary material The online version of this article (doi:10.1186/s12860-017-0135-y) contains supplementary material, which is available to authorized users.

An emerging body of literature has highlighted a gap in our understanding of the extent to which the salience attached to human rights is likely to influence the extent to which an individual takes account of Corporate Social Responsibility (CSR) in decision making. The primary aim of this study is to begin to address this gap by understanding how individuals attribute different emphasis on specific aspects of human rights when making decisions to purchase, work, invest or support the community operations for socially responsible organisations. In order to achieve this objective, a survey instrument was administered to professionals in Russia and Bulgaria. Our data indicate that there is a significant correlation between individuals’ sensitivity towards different components of human rights and their perceptions of the importance of CSR in decision making. Specifically, the recognition of political rights was strongly associated with the willingness to purchase, invest, seek employment and support socially responsible firms. Our analysis also outlines significant differences between the Russian and the Bulgarian samples with regard to the manners in which individuals rate the importance of civil, political and economic human rights.

The Antarctic continent is one of the most protected areas on the planet, but is dynamically responding to environmental change on a global scale. Change in the air temperature may affect the organic matter production in the area. Biomarkers such as sterols, n-alkanols and phytol in three sediment cores from Admiralty Bay, Antarctica, were determined to identify the type of organic matter, variation in input and possible relationship with general temperature changes over the past decades. The concentrations ranged from 0.91 to 13.99 μg g−1 (dry weight) of total sterols, 0.20–2.14 μg g−1 of total n-alkanols and 0.13–2.38 μg g−1 of phytol. Cholest-5-en-3β-ol was the most abundant sterol. The fecal sterols, 5β-cholestan-3β-ol and 5β-cholestan-3α-ol, occurred at low concentration (

Smoking is associated with increased morbidity and mortality in cardiac patients. However, data on the prognostic impact of smoking in heart failure (HF) patients on cardiac resynchronization therapy with defibrillator (CRT-D) are absent. We investigated the effects of smoking on all-cause mortality and on a composite endpoint (all-cause death/appropriate device therapy), appropriate and inappropriate device therapy, in 649 patients with HF who underwent CRT-D between January 2003 and October 2011 in 6 Centers (4 in Italy and 2 in USA). 68 patients were current smokers, 396 previous-smokers (patients who had smoked in the past but who had quit before the CRT-D implant), and 185 had never smoked. The risk of each endpoint by smoking status was evaluated with both Kaplan–Meier and Cox proportional-hazard analysis. After adjusting for age, left ventricular ejection fraction, QRS width and ischemic etiology, both current and previous smoking were independent predictors of all-cause death [HR = 5.07 (95 % CI 2.68–9.58), p

RrS1-like sequences of water frogs (genus Pelophylax) display varied genomic organization, whereas the centromeric hybridization pattern reveals species-specific differences. Using fluorescent in situ hybridization, Pelophylax cf. bedriagae, Pelophylax kurtmuelleri, and Pelophylax ridibundus showed a hybridization signal at centromeres of chromosomes 1-5, but in P. kurtmuelleri the medium-small chromosome labeled was 10 rather than 8. Pelophylax cretensis had almost 16 of 26 centromeres labeled, as did Pelophylax lessonae from Poland when its chromosomes are hybridized with a homologous probe. When StuI-digested genomic DNA was hybridized with RrS1 probe, hybridization ladders for P. ridibundus from Poland have evenly spaced steps (about 100 bp) of uniform intensity from about 200 bp upward. Steps in hybridization ladders from circum-Aegean taxa vary in intensity: larger, odd-numbered steps are often fainter. A strong double band (800/900 bp) in Anatolian P. cf. bedriagae, emphasized by a weak 700 bp band, distinguishes them from P. kurtmuelleri from the Peloponnisos, in which the 900 bp band is almost absent. The ladder in P. cretensis lacks odd-numbered steps. A and B repeats, observed originally within the RrS1 satellite of P. ridibundus, occur also in the circum-Aegean frogs and in P. lessonae, Pelophylax epeiroticus, Pelophylax saharicus, and Pelophylax shqipericus. It is plausible that AB dimers or ABB trimers rather than A or B monomers correspond to functional/evolutionary units. The presence of regions similar to yeast CDEs and mammalian CENP-B boxes suggests a role for RrS1 sequences in centromere organization.

Second harmonic generation coefficients of GaN and AlxGa1–xN (x=0.08) thin films deposited by MOCVD on a sapphire 0001 substrate were deduced through the standard Maker fringes method. Measurements were performed at λ=1064 nm using a Nd:YAG Q-Switched laser. The measured ratio between the d33 and d31 coefficients allowed one to retrieve information on the degree of crystallinity of the thin film samples that was found to be higher in thicker films. The presence of tiny oscillations in the SHG detected signal as a function of the incidence angle of the fundamental beam on the samples is discussed and related to the reflectance at the sample-air interfaces. Finally, nonlinear coefficients for three AlxGa1–xN/GaN multiple quantum well (MQW) samples (x=0.08 and x=0.15) were determined and compared to the values obtained for GaN crystalline thin films.

Although alpha(1)AR antagonists have been used for more than two decades to treat lower urinary tract symptoms (LUTS), we have little understanding of the mechanistic basis of their efficacy and their role in the development of LUTS. It is clear that alpha(1)ARs play a critical role in bladder dysfunction and recent data suggest that alpha(1)AR subtype switching may play a key role in this pathophysiology, providing support for use of alpha(1)(d)AR-selective antagonists in treating irritative symptoms. This review seeks to summarize current levels of understanding in this field and discusses new concepts that suggest increased levels of complexity involving cross-talk in multiple receptor systems. Effective therapeutic modalities likely will involve increased subtype selective alpha(1)AR antagonists and other pharmacodynamic factors.