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The objective of this study was to assess the association between vitamin D and cardiometabolic markers in 2 indigenous communities from similar ethnic backgrounds, but living at different altitudes. A cross-sectional study compared 152 (72 females) indigenous schoolchildren from San Antonio de los Cobres (SAC), 3750 m above sea level, with 175 (86 females) from Chicoana (CH), 1400 m above sea level, mean age 9 years. Anthropometry, blood pressure, lipids, glucose, insulin, and vitamin D were assessed in spring season. The prevalence of children's overweight/obesity was significantly lower in SAC, 9.2% (13), than in CH, 41.5% (71). There was a significantly higher prevalence of vitamin D deficiency (<20 ng/mL) in SAC (n = 103, 67.7%) than in CH (n = 62, 36.3%). SAC showed an inverse correlation between vitamin D and insulinemia ( r = -0.17, P < .05), whereas CH showed an inverse correlation between vitamin D and systolic blood pressure ( r = -0.19, P < .05), z -BMI (body mass index; r = -0.25, P < .01), triglycerides ( r = -0.15, P < .05), glucose ( r = -0.35, P < .05), and insulinemia ( r = -0.24, P < .01). Multiple linear regression analysis showed that vitamin D (β = -.47; R 2 = .21) was significantly associated with SAC location, adjusted for confounding variables. Vitamin D levels were significantly and directly associated with altitude and inversely with metabolic markers, suggesting that populations living at high altitudes are at higher risk for future cardiovascular diseases., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Over the past decades, operator splitting methods have become ubiquitous for non-smooth optimization owing to their simplicity and efficiency. In this paper, we consider the Forward-Douglas-Rachford splitting method and study both global and local convergence rates of this method. For the global rate, we establish a sublinear convergence rate in terms of a Bregman divergence suitably designed for the objective function. Moreover, when specializing to the Forward-Backward splitting, we prove a stronger convergence rate result for the objective function value. Then locally, based on the assumption that the non-smooth part of the optimization problem is partly smooth, we establish local linear convergence of the method. More precisely, we show that the sequence generated by Forward-Douglas-Rachford first (i) identifies a smooth manifold in a finite number of iteration and then (ii) enters a local linear convergence regime, which is for instance characterized in terms of the structure of the underlying active smooth manifold. To exemplify the usefulness of the obtained result, we consider several concrete numerical experiments arising from applicative fields including, for instance, signal/image processing, inverse problems and machine learning.

High inter-patient variability and high spatial heterogeneity are features of colorectal cancer (CRC). This may influence the molecular characterization of tumor tissue, now mandatory for patients with metastatic CRC who are candidates for treatment with an anti-EGFR mAb, as false-negative results can occur, leading to non optimal therapy. Moreover, temporal molecular heterogeneity during treatment is known to influence the response to therapy and prognosis. We present a literature overview of advances made in characterizing molecular heterogeneity in CRC, underlining that the analysis of liquid biopsy could represent an efficient non-invasive tool to overcome the problem. We believe that understanding CRC heterogeneity is fundamental for a more accurate diagnosis, for selecting the best targets to ensure prolonged antitumor response, and for monitoring minimal residual disease and the onset of resistance to therapy, all essential components of successful personalized treatment.

Background: Exposure to hypoxia at high altitude is increasingly being recognized as a risk factor for metabolic diseases., Objective: To determine the association between Type 2 diabetes (T2D) risk factors and altitude in two groups of Argentinean indigenous schoolchildren who live permanently at different altitudes., Methods: This cross-sectional study compared 142 schoolchildren from San Antonio de los Cobres (SAC), 3750 m above sea level, with 171 from Chicoana (CH), 1400 m. Data for children's anthropometry, blood pressure and lipids, as well as mothers' height and weight were assessed., Results: There was not a significant difference in age between SAC (9.0 + 2y) and CH (9.4 + 2y) children. However, mean children's weight (29 vs. 38 kg), height (130 vs. 138 cm), BMI (17 vs. 19 kg/m 2 ), and HDL-C (46 vs. 48 mg/dL) were significantly lower in SAC than in CH, respectively. In contrast, systolic blood pressure (87 vs. 70 mmHg), cholesterol (157 vs. 148 mg/dL), and triglycerides (104 vs. 88 mg/dL) were significantly higher in SAC than in CH, respectively. There was not a significant difference in age (33.2 + 7y vs. 34.4 + 8y) and BMI (26.2 + 4y vs. 28 + 5y) between SAC and CH mothers. Multiple linear regression analyses showed that children's blood pressure (R 2 = 0.38), triglycerides (R 2 = 0.21), and HDL-C (R 2 = 0.16) were significantly associated with altitude, adjusted for confounding variables., Conclusion: This study shows that indigenous Argentinean children living at 3750 meters have higher T2D risk compared with those living at 1400 meters above sea level., Competing Interests: Conflict of interest: No competing financial interests exist.

The influence of different drivers on changes in North American and European boreal forests biomass burning (BB) during the Holocene was investigated based on the following hypotheses: land use was important only in the southernmost regions, while elsewhere climate was the main driver modulated by changes in fuel type. BB was reconstructed by means of 88 sedimentary charcoal records divided into six different site clusters. A statistical approach was used to explore the relative contribution of (a) pollen-based mean July/summer temperature and mean annual precipitation reconstructions, (b) an independent model-based scenario of past land use (LU), and (c) pollen-based reconstructions of plant functional types (PFTs) on BB. Our hypotheses were tested with: (a) a west-east northern boreal sector with changing climatic conditions and a homogeneous vegetation, and (b) a north-south European boreal sector characterized by gradual variation in both climate and vegetation composition. The processes driving BB in boreal forests varied from one region to another during the Holocene. However, general trends in boreal biomass burning were primarily controlled by changes in climate (mean annual precipitation in Alaska, northern Quebec, and northern Fennoscandia, and mean July/summer temperature in central Canada and central Fennoscandia) and, secondarily, by fuel composition (BB positively correlated with the presence of boreal needleleaf evergreen trees in Alaska and in central and southern Fennoscandia). Land use played only a marginal role. A modification towards less flammable tree species (by promoting deciduous stands over fire-prone conifers) could contribute to reduce circumboreal wildfire risk in future warmer periods., (© 2018 John Wiley & Sons Ltd.)

The potentially harmful nature of electromagnetic fields (EMF) and static magnetic fields (SMF) has become a major problem in recent years. All these elements could be combined to produce cellular responses. For example, the orientation of molecules of water or other complex molecules, growth and cell viability, cell morphology, and intracellular metabolic pathways have demonstrated binding to magnetic fields. The effect of EMF and SMF on humans is a topic of great importance, especially because modern technology has introduced artificial magnetic fields such as those generated by power lines, mobile communications, and medical imaging equipment. A relevant problem is certainly that of professional exposure. The aim of this study was the evaluation of the effectiveness of a commercially available device, Skudo® patches (Edil Natura S.r.l., Novara, Italy), in protecting magnetic resonance operators from the influence of magnetic fields such as those present in the workplace. Skudo® patches are designed to protect microareas of the body from external electromagnetic disturbances. In this study, 10 male Italian volunteers aged between 50 and 60 were enrolled in the hospital. All participants were subjected to measurements at 4 specific time points to evaluate the effectiveness of Skudo® to counteract both EMF and SMF magnetic fields by evaluating the level of bioenergetic reactivity. To perform the measurements, a variant of the Ryodoraku method has been used, based upon the assessment of electropermeability. In particular, 12 acupoints were measured, one for each of the main meridians. This study shows that both SMF and EMF cause an alteration of the body's water system. The application of Skudo® patches determines a regularization of bioenergetic levels related to the water system. The application of Skudo® on the EMF source has suppressed the imbalance effect of the water system found in the subject without any protection.

Recent advances in the care of von Willebrand's disease (vWD) have allowed the majority of patients to be managed adequately. Even in the more severe forms, it is now possible to control recurrent bleeding through secondary long-term prophylaxis with von Willebrand factor-containing concentrates. Moreover, in the setting of surgical prophylaxis, the combination of interdisciplinary management and close patient monitoring yields a positive outcome in nearly all cases, although safety concerns remain. In clinical practice, the effectiveness of therapy is hindered by the difficulties in making a rapid, yet accurate diagnosis, in identifying the subgroup of bleeders who may benefit most from a specific strategy, and in selecting the optimal product and regimen.Since specific guidelines for heavy bleeders requiring short- and long-term prophylaxis are still lacking, sharing the experience of experts dealing with vWD patients on a daily basis is crucial to fill gaps in information relating to patient management. To address this important issue, 13 Italian haematologists met in Milan on April, 2, 2016 and in Florence on July, 9, 2016. A 30-question survey constituted the input to discuss (i) optimisation of the diagnostic workflow for vWD, (ii) the characteristics of patients who may benefit from secondary long-term prophylaxis (in particular with the purified von Willebrand factor concentrate with a low content of factor VIII), (iii) the key elements to consider when selecting a concentrate and (iv) the pre-operative and post-operative management of vWD patients. A summary of the main points covered is provided in this report.

Background: In chronic lymphocytic leukemia (CLL) disease onset and progression are influenced by the behavior of specific CD4 + T cell subsets, such as T regulatory cells (Tregs). Here, we focused on the phenotypic and functional characterization of Tregs in CLL patients to improve our understanding of the putative mechanism by which these cells combine immunosuppressive and effector-like properties., Methods: Peripheral blood mononuclear cells were isolated from newly diagnosed CLL patients (n = 25) and healthy volunteers (n = 25). The phenotypic and functional characterization of Tregs and their subsets was assessed by flow cytometry. In vitro analysis of TH1, TH2, TH17 and Tregs cytokines was evaluated by IFN-γ, IL-4, IL-17A and IL-10 secretion assays. The transcriptional profiling of 84 genes panel was evaluated by RT 2 Profiler PCR Array. Statistical analysis was carried out using exact non parametric Mann-Whitney U test., Results: In all CLL samples, we found a significant increase in the frequency of IL-10-secreting Tregs and Tregs subsets, a significant rise of TH2 IL-4 + and TH17 IL-17A + cells, and a higher percentage of IFN-γ/IL-10 and IL-4/IL-10 double-releasing CD4 + T cells. In addition, we also observed the up-regulation of innate immunity genes and the down-regulation of adaptive immunity ones., Conclusions: Our data show that Tregs switch towards an effector-like phenotype in CLL patients. This multifaceted behavior is accompanied by an altered cytokine profiling and transcriptional program of immune genes, leading to a dysfunction in immune response in the peripheral blood environment of CLL patients.

Objective: Wound healing is a dynamic, interactive, and complex process that involves a series of events, including inflammation, migration, proliferation, granulation tissue formation, and matrix remodeling. Despite the high frequency of serious slow-healing wounds, there is still no adequate therapy. The aim of this study is to evaluate a new highly diluted acetylcholine (Ach) formulation obtained through a sequential kinetic activation (SKA) method applied to a wound healing in vivo model to verify the hypothesis that a low dose of Ach could be a more physiological stimulus for healing, by stimulating muscarinic and nicotinic receptors and their related intracellular pathways. Approach: Two different concentrations (10 fg/mL and 1 pg/mL) and two formulations (either kinetically or nonkinetically activated) of Ach were used to verify the wound healing process. Area closure, histological aspect, and nicotinic and muscarinic receptors, matrix metalloproteinase 9 (MMP-9), Nestin, and von Willebrand's factor have been assessed by Western blot or ELISA and compared to 147 ng/mL Ach, used as positive control. Moreover, the systemic effect through plasmatic radical oxygen species (ROS) production and Ach concentration has been evaluated. Results: Ach SKA 1 pg/mL revealed a significant capacity to restore the integrity of tissue compared to other formulation and this effect was more evident after a single administration. Innovation: Topical application on skin of Ach SKA 1 pg/mL accelerates wound closure stimulating non-neuronal cholinergic system. Conclusion: Our results demonstrate for the first time the importance in an in vivo model of highly diluted SKA Ach during wound healing, suggesting a potential use in skin disease.

CDH1a, a non-canonical transcript of the CDH1 gene, has been found to be expressed in some gastric cancer (GC) cell lines, whereas it is absent in normal gastric mucosa. Recently, we detected CDH1a transcript variant in fresh-frozen tumor tissues obtained from patients with GC. The expression of this variant in tissue samples was investigated by the chip-based digital PCR (dPCR) approach presented here. dPCR offers the potential for an accurate, robust, and highly sensitive measurement of nucleic acids and is increasingly utilized for many applications in different fields. dPCR is capable of detecting rare targets; in addition, dPCR offers the possibility for absolute and precise quantification of nucleic acids without the need for calibrators and standard curves. In fact, the reaction partitioning enriches the target from the background, which improves amplification efficiency and tolerance to inhibitors. Such characteristics make dPCR an optimal tool for the detection of the CDH1a rare transcript.

Aim: To describe characteristics relevant in case of an unplanned pregnancy for T1D or T2D women of childbearing age., Methods: We analyzed the 2011 AMD-Annals dataset, compiling information from 300 clinics (28,840 T1D patients and 532,651 T2D patients). A risk score of unfavorable conditions for pregnancy included HbA1c > 8.0%; BMI ≥ 35; systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg; microalbuminuria/proteinuria; use of statins, ACE inhibitors, ARB; use of diabetes drugs other than metformin/insulin., Results: The proportion of T2D cases increased from 30.8% (95% CI 29.9-32.4) at age 18-30 years to 67.5% (66.6-68.5) at age 36-45 years. The proportion of women with HbA1c < 7.0% was 20.4% (20.0-20.8) in T1D and 43.4% (42.8-43.9) in T2D women. Furthermore, 47.6% (47.0-48.3) of T1D women and 34.5% (33.9-35.0) of T2D women had HbA1c ≥ 8.0%. The prevalence of obesity (BMI ≥ 30) was sevenfold higher among T2D than T1D women [49.9% (49.4-50.5) and 7.4% (7.2-7.5), respectively]. T2D women were more likely to have hypertension or microalbuminuria than T1D women. Almost half of the T2D women were taking drugs not approved during pregnancy. At least one unfavorable condition for starting a pregnancy was present in 51% of T1D women of childbearing age and in 66.7% of T2D women., Conclusions: Women with either T1D or T2D of childbearing age in Italy were far from the ideal medical condition for conception. Our data strongly support the need for counseling all women with diabetes about pregnancy planning.

Shigella spp. is the most frequent micro-biological isolation in bacterial diarrhea in Argentina. It causes a watery diarrhea or dysenteric disease. It rarely causes extraintestinal problems. It has an incidence of bacteremia of 0,4-7,3%, and its appearance compels us to look for associated risk factors, as children under one year of age and immunodeficiency, among others. We describe two children with Shigella flexneri bacteremia. They presented with fever and diarrhea. One of them had primary immune deficiency.

This work demonstrates the cooperative effect of Q10, vitamin D3, and L-arginine on both cardiac and endothelial cells. The effects of Q10, L-arginine, and vitamin D3 alone or combined on cell viability, nitric oxide, and reactive oxygen species productions in endothelial and cardiac cells were studied. Moreover, the involvement of PI3K/Akt and ERK/MAPK pathways leading to eNOS activation as well as the involvement of vitamin D receptor were also investigated. The same agents were tested in an animal model to verify vasodilation, nitric oxide, and reactive oxygen species production. The data obtained in this work demonstrate for the first time the beneficial and cooperative effect of stimulation with Q10, L-arginine, and vitamin D3. Indeed, in cardiac and endothelial cells, Q10, L-arginine, and vitamin D3 combined were able to induce a nitric oxide production higher than the that induced by the 3 substances alone. The effects on vasodilation induced by cooperative stimulation have been confirmed in an in vivo model as well. The use of a combination of Q10, L-arginine, and vitamin D to counteract increased free radical production could be a potential method to reduce myocardial injury or the effects of aging on the heart., (© 2018 S. Karger AG, Basel.)

Background: Exposure to hypoxia at high altitude is increasingly being recognized as a risk factor for hypertension., Objective: To compare the prevalence of hypertension in Indigenous Argentinean children living at high altitude with that reported in the 2011-2012 National Health and Nutrition Examination Survey (NHANES) of US children., Methods: A cross-sectional study of 811 (400 females) Argentinean Indigenous school children (8-14 years) from San Antonio de los Cobres (SAC) was performed between 2011-2014. SAC is located in the Andean foothills 3,750 m above sea level. 98% of its population is Indigenous. Anthropometric, BP, and biochemical data were obtained from SAC and compared with those of 1279 (625 females) US children. Pre-hypertension and hypertension were defined by BP≥90th to <95th percentile or ≥95th percentile, respectively., Results: The prevalence of obesity was significantly lower in SAC (22; 2.7%) than in the US (310; 24.3%). However, the prevalence of hypertension was significantly higher in SAC (129; 15.9%) than in US children (35; 2.9%). Multiple logistic regression analyses showed that SAC children had four times the odds of having pre-hypertension compared with US children (OR 4.47; 95% CI 3.29-6.08), and eight times the odds of presenting hypertension (OR 8.36; 95% CI 5.36-13.05), adjusted for age, gender, and BMI., Conclusions: This study shows a higher prevalence of hypertension in Indigenous Argentinean children living at high altitude compared with US children. Various factors such as high hemoglobin levels, lifestyle behavior, and genetics may have an influence on BP in high altitude Indigenous SAC children., Abbreviations: BP: Blood pressure; SAC: San Antonio de los Cobres; CDC: Centers for Disease Control and Prevention; NHANES: National Health and Nutrition Examination Survey.

Objective: The study aims to determine the association between apo B levels in mothers and their pre-school offspring., Methods: Anthropometric measurement (e.g. BMI), lipids, lipoproteins, and apolipoproteins (e.g. apo B) levels in mothers and their children were obtained in November 2015 in Buenos Aires., Results: Eighty-four children (42M) aged 5.3±1.6 years and their mothers aged 33.8±7.2 years were examined. The prevalence of overweight was 39.2 % (33) in mothers and 22.6 % (19) in children, and the prevalence of obesity was 38.1% (32) in mothers and 10.7% (9) in children. Multiple linear regression analysis showed that maternal apo B levels were associated with apo B levels in their offspring, adjusted for confounding variables (Beta=0.29; p=0.03; R2=0.25). Furthermore, offspring born to mothers with high apo B levels were six times likelier to have high apo B levels (OR), 5.7; (95% CI 1.3-25.5)., Conclusion: This study suggests that maternal apo B levels were significantly associated with apo B concentration in their pre-school age children., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Botulinum toxin type A is a valid and safe treatment for focal spasticity, with documented effects on both sympathetic and parasympathetic systems. Heart rate variability can provide detailed information about the control of the autonomic nervous system on cardiovascular activities. Previous studies in literature showed no significant changes in Heart Rate Variability with doses >600 U of incobotulinumtoxinA in chronic post stroke spastic patients; however, at present time, these results have not been confirmed with doses >600 U of onabotulinumtoxinA., Aim: To evaluate changes in Heart Rate Variability induced by high doses (>600 U) of incobotulinumtoxinA or onabotulinumtoxinA in spastic stroke patients over a 1-year period., Design: single blind randomized controlled crossover study design., Setting: Rehabilitation Unit of the University Hospital in Novara., Population: 10 stroke survivors with spastic hemiplegia (Modified Ashworth Scale ≥ 2) were recruited and randomly divided in two groups (A and B)., Methods: In the first part of the study, patients in Group A were injected with incobotulinumtoxinA while patients in Group B with onabotulinumtoxinA; after 6 months, a crossover intervention was performed. All patients were blinded to Botulinum toxin type A type, and performed an ECG registration in the 24 h before injection (t0) and 10 days after treatment (t1), both in the first and in the second part of the study. Functional status was evaluated with Barthel Index, Motricity Index and Functional Ambulation Category scores., Results: Heart Rate Variability analysis showed no significant changes after each Botulinum toxin type A injection in both groups at any evaluation time. Moreover, no statistically significant differences were found regarding each variable between the two groups., Conclusions: Our data show that high doses (>600 U) of incobotulinumtoxinA and onabotulinumtoxinA do not influence the cardiovascular activity of the autonomic nervous system in chronic hemiplegic spastic stroke survivors., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a natural antioxidant polyphenol able to exert a wide range of biological effect on several tissues. Despite its important beneficial properties, it has a low water solubility, which limits its therapeutic applications in humans. Resveratrol also acts as a phytoestrogen that modulates estrogen receptor (ER)-mediated transcription. In addition, it has been shown that ovarian tissues benefit greatly from vitamin D3, which exerts its beneficial effects through VDR receptors. The aim was to evaluate the cooperative effects of resveratrol combined with vitamin D3 on ovarian cells and tissues and some other organs as well. Moreover, the modulation of specific intracellular pathways involving ER and VDR receptors has been studied., Methods: The experiments were performed both in vitro and in vivo, to analyze cell viability, radical oxygen species production, signal transductions through Western Blot, and resveratrol quantification by HPLC., Results: Cell viability, radical oxygen species production, and intracellular pathways have been studied on CHO-K1 cells. Also, the relative mechanism activated following oral intake in female Wistar rats as animal model was investigated, evaluating bioavailability, biodistribution and signal transduction in heart, kidney, liver and ovarian tissues. Both in in vitro and in vivo experiments, resveratrol exerts more evident effects when administered in combination with vitD in ovarian cells, showing a common biphasic cooperative effect: The role of vitamin D3 in maintaining and supporting the biological activity of resveratrol has been clearly observed. Moreover, resveratrol plus vitamin D3 blood concentrations showed a biphasic absorption rate., Conclusions: Such results could be used as a fundamental data for the development of new therapies for gynecological conditions, such as hot-flashes.

This study compares the absorption characteristics of two iron-based dietary supplements and their biocompatibility to bisglycinate iron, a common chelated iron form. The Caco-2 cell line-a model of human intestinal absorption-and GTL-16 cell line-a model of gastric epithelial cells-were used to perform the experiments; in the first experiments, the kinetics of absorption have been evaluated analyzing the divalent metal transporter 1 (DMT1) expression. Three different iron combinations containing 50 µM iron (named Fisioeme ® , Sideral ® and bisglycinate) were used for different stimulation times (1-24 h). After this, the effects of the three iron formulations were assessed in both a short and a long time, in order to understand the extrusion mechanisms. The effects of the three different formulations were also analyzed at the end of stimulation period immediately after iron removal, and after some time in order to clarify whether the mechanisms were irreversibly activated. Findings obtained in this study demonstrate that Fisioeme ® was able to maintain a significant beneficial effect on cell viability compared to control, to Sideral ® , and to iron bisglycinate. This observation indicates that Fisioeme ® formulation is the most suitable for gastric and intestinal epithelial cells., Competing Interests: The authors declare no conflict of interest.

Sirtuins (SIRT), first described as nicotinamide adenine dinucleotide (NAD + )-dependent type III histone deacetylases, are produced by cells to support in the defense against chronic stress conditions such as metabolic syndromes, neurodegeneration, and cancer. SIRT-3 is one of the most studied members of the mitochondrial sirtuins family. In particular, its involvement in metabolic diseases and its dual role in cancer have been described. In the present review, based on the evidence of SIRT-3 involvement in metabolic dysfunctions, we aimed to provide an insight into the multifaceted role of SIRT-3 in many solid and hematological tumors with a particular focus on hepatocellular carcinoma (HCC). SIRT-3 regulatory effect and involvement in metabolism dysfunctions may have strong implications in HCC development and treatment. Research literature widely reports the relationship between metabolic disorders and HCC development. This evidence suggests a putative bridge role of SIRT-3 between metabolic diseases and HCC. However, further studies are necessary to demonstrate such interconnection.

Objective: To determine the association between nontraditional risk factors such as magnesium and uric acid with blood pressure (BP) in Indigenous children., Methods: A total of 263 school-aged indigenous children living at high altitude were enrolled in a cross-sectional study in November 2011. Prehypertension (preHTN) and hypertension (HTN) were defined by systolic and/or diastolic BP ≥ 90th to <95th percentile or ≥95th percentile respectively, according to age, sex, and height., Results: The prevalence of preHTN and HTN was 13.7 and 8.3%, respectively. Low magnesium levels were identified in 21.7% (57/263): 28.1% (16/57) of the children with low magnesium levels had preHTN versus 9.7% (20/206) with normal magnesium values. Furthermore, 21.8% (12/57) of the children with low magnesium levels had HTN versus 4.5% (20/206) with normal magnesium values. There was a significant association between mean arterial pressure and magnesium (r = -026), uric acid (r = 0.20), phosphorus (r = -0.17), z-BMI (r = 0.22), potassium (r = -0.10), HOMA-IR (r = 0.17), calcium (r = -0.10), and sodium (r = -0.13). Multiple linear regression analysis showed that mean arterial pressure was associated significantly and directly with BMI, age, gender, and uric acid; and inversely with magnesium, adjusted for sodium, calcium, phosphorus, potassium, and HOMA-IR (R 2  = 0.43). Furthermore, multiple logistic regression analyses showed that magnesium (OR = 0.015) and uric acid (OR = 2.95) were significantly associated with preHTN. Similar results were obtained when preHTN was replaced by HTN., Conclusion: Our results indicate that HTN was associated inversely with magnesium and positively with uric acid in indigenous school children., (© 2017 Wiley Periodicals, Inc.)

Various hindbrain nuclei have been demonstrated to be involved in the control of the cardiovascular reflexes elicited by both non-noxious and noxious gastric distension, through parasympathetic and sympathetic activation. The different role played by the branches of autonomic nervous system in exerting these effects and their crosstalk in relation to low-/high-pressure distension rate has not been examined yet. Therefore, in the present work, monolateral and bilateral vagotomy and splanchnicotomy were performed in anesthetised rats to analyse the involvement of hindbrain nuclei in haemodynamic changes caused by gastric distension at high (80 mmHg) and low (15 mmHg) pressure. The analysis of c-Fos expression in neuronal areas involved in cardiovascular control allowed us to examine their recruitment in response to various patterns of gastric distension and the crosstalk between vagal and splanchnic systems. The results obtained show that the low-pressure (non-noxious) gastric distension increases both heart rate and arterial blood pressure. In addition, the vagus nerve and hindbrain nuclei, such as nucleus ambiguous, ventrolateral medulla and lateral reticular nucleus, appear to be primarily involved in observed responses. In particular, we have found that although vagus nerve plays a central role in exerting those cardiovascular reflex changes at low gastric distension, for its functional expression an intact splanchnic system is mandatory. Hence, the absence of splanchnic input attenuates pressor responses or turns them into depressor responses. Instead at high-pressure (noxious) gastric distension, the splanchnic nerve represents the primary component in regulating the reflex cardiovascular effects.

E-cadherin is a cell-cell adhesion protein encoded by CDH1 tumor-suppressor gene. CDH1 inactivating mutations, leading to loss of protein expression, are common in gastric cancer of the diffuse histotype, while alternative mechanisms modulating E-cadherin expression characterize the more common intestinal histotype. These mechanisms are still poorly understood. CDH1 intron 2 has recently emerged as a cis-modulator of E-cadherin expression, encoding non-canonical transcripts. One in particular, CDH1a, proved to be expressed in gastric cancer cell lines, while being absent in the normal stomach. For the first time, we evaluated by digital PCR the expression of CDH1 and CDH1a transcripts in cancer and normal tissue samples from 32 patients with intestinal-type gastric cancer. We found a significant decrease in CDH1 expression in tumors compared to normal counterparts (P = 0.001), which was especially evident in 76% of cases. CDH1a was detected at extremely low levels in 47% of tumors, but not in normal mucosa. A trend was observed of having less CDH1 in tumors expressing CDH1atranscript. The majority of tumors with both a decrease in CDH1 and presence of CDH1a also showed a decrease in miR-101 expression levels. On the whole, the decrease of CDH1 transcript, corresponding to the canonical protein, and the presence of CDH1a, corresponding to an alternative isoform, are likely to perturb E-cadherin-mediated signaling and cell-cell adhesion, thus contributing to intestinal-type gastric carcinogenesis.

The physiological effects of acetylcholine on keratinocytes depend on the presence of nicotinic and muscarinic receptors. The role of nonneuronal acetylcholine in keratinocytes could have important clinical implications for patients with various skin disorders such as nonhealing wounds. In order to evaluate the efficacy of highly diluted acetylcholine solutions obtained by sequential kinetic activation, we aimed to investigate the effects of these solutions on normal human keratinocytes. Two different concentrations (10 fg/mL and 1 pg/mL) and formulations (kinetically activated and nonkinetically activated) of acetylcholine were used to verify keratinocyte viability, proliferation, and migration and the intracellular pathways involved using MTT, crystal violet, wound healing, and Western blot compared to 147 ng/mL acetylcholine. The activated formulations (1 pg/mL and 10 fg/mL) revealed a significant capacity to increase migration, cell viability, and cell proliferation compared to 147 ng/mL acetylcholine, and these effects were more evident after a single administration. Sequential kinetic activation resulted in a statistically significant decrease in reactive oxygen species production accompanied by an increase in mitochondrial membrane potential and a decrease in oxygen consumption compared to 147 ng/mL acetylcholine. The M1 muscarinic receptor was involved in these effects. Finally, the involvement of ERK/mitogen-activated protein kinases (MAPK) and KI67 confirmed the effectiveness of the single treatment on cell proliferation. The intracellular pathways of calcium were investigated as well. Our results indicate for the first time that highly diluted and kinetically activated acetylcholine seems to play an active role in an in vitro model of wound healing. Moreover, the administration of acetylcholine within the physiological range may not only be effective but is also likely to be safe., (© 2016 S. Karger AG, Basel.)

Purpose: An observational retrospective study was conducted by 2 diabetes clinics in Italy to assess patterns of use and long-term effectiveness of liraglutide on established and emerging parameters., Methods: Data from 261 patients with type 2 diabetes who started treatment with liraglutide between 2010 and 2014 were collected. Hierarchical linear regression models were applied to assess trends over time of clinical parameters. Factors associated with higher likelihood of dropout were identified through multivariate logistic analysis., Findings: Liraglutide was initiated as a switch in 42.5% of patients and as an add-on in 49.8%; in 7.7% of the patients initiation of liraglutide was associated with a reduction in the number of pharmacologic agents. A statistically significant reduction after 36 months was found for the following parameters (mean change [95% CIs]): glycosylated hemoglobin (HbA 1c ; -1.01% [1.34% to -0.68%]), fasting blood glucose (-27.5 [-40.6 to -14.4] mg/dL), weight (-2.9 [-4.5 to -1.3] kg), body mass index (-1.13 [-1.76 to -0.50] kg/m 2 ), waist circumference (-1.74 [-3.85 to -0.37] cm), and LDL-C (-24.7 [-36.67 to -12.8] mg/dL). Improvements in systolic (-3.5 mm Hg) and diastolic (-2.3 mm Hg) blood pressures were observed at 24 months. Albuminuria was reduced by -16.6 mg/L during 36 months, although statistical significance was not reached. Glomerular filtration rate and heart rate were unchanged. Reductions in HbA 1c between -0.6% and -1.3% were obtained in specific subgroups. Treatment was effective also in patients with >20 years of diabetes duration, although the likelihood of dropout was 6% higher for each additional year of disease duration (RR = 1.06; 95% CI, 1.01-1.12). The likelihood of dropout was almost four times higher for subjects treated with insulin (RR = 3.82; 95% CI, 1.22-11.96) and more than twice for those treated with sulfonylureas (RR = 2.39; 95% CI, 1.16-4.94) compared with patients not treated with these agents., Implications: Liraglutide used in routine clinical conditions maintains its effectiveness on metabolic control and weight after 3 years. Improvements in terms of metabolic control were found when liraglutide was used as both switch and add-on treatment. In addition, improvements were sustained when liraglutide replaced sulfonylureas or insulin. Diabetes duration had no impact on drug efficacy. Long-term benefits relative to blood pressure and LDL-C were also found, which could not be entirely explained by antihypertensive/lipid-lowering treatment intensification. No major effect on renal parameters was documented. Diabetes duration and some concomitant treatments were associated with a higher likelihood of liraglutide discontinuation. These data can contribute to improve appropriateness and cost-effectiveness profile of liraglutide., (Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.)

Introduction: Although the role of circulating cell free DNA in cancer has been widely demonstrated, less is known about the role of urine cell free DNA (UcfDNA). UcfDNA can serve as a 'liquid biopsy' for urological and non-urological tumors, as it carries information on DNA from cells exfoliated in urine and from circulation. Areas covered: We review the studies on UcfDNA as a source of biomarkers for cancer, focusing on the new techniques and the differences between urological and non-urological tumors. We searched Pubmed for articles published between 1998 and 2016 with the following key words and phrases: 'urine' and 'cell free DNA' or 'liquid biopsy' or 'cancer'. Expert commentary: Despite the few papers published on this topic, UcfDNA is an important component of 'liquid biopsy', a useful and non-invasive tool for cancer diagnosis, prognosis and treatment monitoring, containing a wide range of genetic information.

Background: Studies in adults show that central obesity increases the likelihood of Type 2 diabetes (T2DM)., Objective: To determine the association between waist circumference (WC) and non-traditional risk factors such as magnesium (Mg), phosphorus, and uric acid in indigenous children living at high altitudes., Methods: A total of 354 (166 M) indigenous school children, aged 9.6 + 2.3 years, were enrolled in a cross-sectional study in November 2011. Central obesity was defined as WC &gt; 90th percentile according to age and sex. Low Mg and phosphorus levels were defined as serum Mg &lt;1.8 mg/dL and phosphorus &lt;2.4 mg/dL . Hyperuricemia was defined as serum uric acid &gt; 7 mg/dL., Results: The prevalence of central obesity was 6.8% (24/354). None of the children had hyperuricemia or low P levels. HypoMg was identified in 21.7% (57/263). There was a significant association between WC (z-score) and Mg (r-015), uric acid (r0.28), phosphorus (r-0.30), HOMA-IR (r0.49), Triglycerides (r0.24), and HDL-C (r0.24). However, calcium, sodium, and potassium were not significantly associated with WC. As z-WC quartiles increased Mg and phosphorus levels significantly decreased, whereas uric acid levels increased. Multiple linear regression analysis showed that z-WC was associated significantly and directly with uric acid (B0.31), triglycerides (B0.004), and HOMA-IR (B0.35); and inversely with Mg (B-0.83) and phosphorus (B-0.25), adjusted for confounding variables (R2 0.34)., Conclusion: Our results indicate that central obesity was significantly and inversely associated with Mg and phosphorus and directly with uric acid in indigenous school children. Supplementation with Mg and/or phosphorus could prevent future cardiovascular disease. Prospective and randomized studies should be performed to confirm these findings.

Background: Gastric diseases are a worldwide problem in modern society, as reported in the USA, in the range of 0.5-2 episodes/year/person and an incidence of 5-100 episodes/1000/week according to seasons and age. There is convincing evidence that oxidative stress is involved in the pathogenesis of acute gastric injury. Acid secreted from gastric parietal cells determines mucosal injuries which in turn cause inflammation and oxidative stress. Consequent inflammation produces free radicals by mitochondria thus causing lipid peroxidation, oxidative and acidic stress, which can lead to cell apoptosis. Vitamin D 3, the active form of vitamin D, may counteract intracellular cell death and improve epithelial regeneration., Methods: This study was planned to assess whether vitamin D 3 is a protective factor against acid injury and oxidative stress in gastric epithelial cells. Primary epithelial cells and GTL-16 cells have been used to test the effects of Grisù® alone or in combination with vitamin D 3 during oxidative stress or high acid exposition measuring cell viability, ROS production, cellular adhesion time along with apoptotic, autophagic and survival pathways. The combined effect of Grisù® and vitamin D 3 was found more effective in counteracting the negative consequences of oxidative stress and acidity conditions than some other gastroprotective agents, such as Maalox® or Gaviscon®., Results: In case of oxidative stress or acidity condition the stimulation with Grisù® alone caused an improvement of cell viability and a reduction of ROS production on epithelial gastric cells. In addition, the adhesion time of the cells was improved. All these effects were increased by the presence of vitamin D 3 . Similar data were also observed in primary gastric epithelial cells confirming the results obtained in GTL-16 cells., Conclusions: These results suggest that Grisù® in combination with vitamin D 3 may exert a gastroprotective effect to maintain or restore the integrity of gastric epithelium through an antioxidant pathway, inhibiting apoptosis and activating survival kinases. Moreover, the combination of Grisù® and vitamin D 3 improves cell viability and decreases ROS production compared to other gastroprotective agents combined with vitamin D 3 . All these data were validated using primary cells isolated from gastric tissue.

Background: Recently, vitamin D3 (1alpha, 25-dihydroxyvitamin D) has shown its capability to take part in many extraskeletal functions and its serum levels have been related to patient survival rate and malignancy of many types of neoplasms, including ovarian cancers. Catalytic iron is a free circulating form of iron that is able to generate reactive oxygen species and consequently to promote a number of cellular and tissutal dysfunctions including tumorigenesis. In fertile women an important source of catalytic iron is derived from retrograde menstruation. Epithelial secretory cells from fimbriae of fallopian tubes are greatly exposed to catalytic iron derived from menstrual reflux and so represent the site of origin for most serous ovarian cancers. The aim of this study was to assess whether vitamin D3 can play a role in counteracting catalytic iron-induced oxidative stress in cells from fimbriae of fallopian tubes., Methods: The cells, isolated from women undergoing isteroannessiectomy, were treated with catalytic iron 50-75-100 mM and vitamin D3 at a concentration ranging from 0.01 to 10 nM to study cell viability, radical oxygen species production, p53, pan-Ras, Ki67 and c-Myc protein expressions through Western Blot, and immunocytochemistry or immunofluorescence analysis., Results: The pre-treatment with vitamin D3 1 nM showed its beneficial effects that consists in a significant decrease in ROS production. In addition a novel finding is represented by the demonstration that pre-treatment with vitamin D3 is also able to significantly counteract tumoral biomarkers activation, such as p53, pan-Ras, Ki67 and c-Myc, and consequently the catalytic iron-induced cellular injury., Conclusions: This study demonstrates for the first time that vitamin D3 plays an important role in preventing catalytic iron-dependent oxidative stress in cultured fimbrial cells. These results support the hypothesis that vitamin D3 could counteract carcinogenic changes induced by catalytic iron.

Des-acyl ghrelin (DAG), the most abundant form of ghrelin in humans, has been found to reduce arterial blood pressure and prevent cardiac and endothelial cell apoptosis. Despite this, data regarding its direct effect on cardiac function and coronary blood flow, as well as the related involvement of autonomic nervous system and nitric oxide (NO), are scarce. We therefore examined these issues using both in vivo and in vitro studies. In 20 anesthetized pigs, intracoronary 100 pmol/mL DAG infusion with a constant heart rate and aortic blood pressure, increased coronary blood flow and NO release, whereas reducing coronary vascular resistances (P < .05). Dose responses to DAG were evaluated in five pigs. No effects on cardiac contractility/relaxation or myocardial oxygen consumption were observed. Moreover, whereas the blockade of muscarinic cholinoceptors (n = 5) or α- and β-adrenoceptors (n = 5 each) did not abolish the observed responses, NO synthase inhibition (n = 5) prevented the effects of DAG on coronary blood flow and NO release. In coronary artery endothelial cells, DAG dose dependently increased NO release through cAMP signaling and ERK1/2, Akt, and p38 MAPK involvement as well as the phosphorylation of endothelial NO synthase. In conclusion, in anesthetized pigs, DAG primarily increased cardiac perfusion through the involvement of NO release. Moreover, the phosphorylation of ERK1/2 and Akt appears to play roles in eliciting the observed NO production in coronary artery endothelial cells.

Recent studies have postulated a role for vitamin D and its receptor on cerebral function, and anti-inflammatory, immunomodulatory and neuroprotective effects have been described; vitamin D can inhibit proinflammatory cytokines and nitric oxide synthesis during various neurodegenerative insults, and may be considered as a potential drug for the treatment of these disorders. In addition, iron is crucial for neuronal development and neurotransmitter production in the brain, but its accumulation as catalytic form (Fe(3+)) impairs brain function and causes the dysregulation of iron metabolism leading to tissue damage due to the formation of toxic free radicals (ROS). This research was planned to study the role of vitamin D to prevent iron damage in neuroblastoma BE(2)M17 cells. Mechanisms involved in neurodegeneration, including cell viability, ROS production, and the most common intracellular pathways were studied. Pretreatment with calcitriol (the active form of vitamin D) reduced cellular injury induced by exposure to catalytic iron., (© 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

Neoadjuvant chemoradiotherapy (NCRT) followed by surgery is the gold standard for the treatment of patients with locally advanced rectal cancer (LARC). However, response is variable, and no predictive markers have been validated. The amplification of 13q31-34 seemed to distinguish between nonresponders and responders to NCRT. The miR-17-92a-1 cluster host gene (MIR17HG), which is involved in the development, progression, and aggressiveness of colorectal cancer, and the ABCC4 gene, an ATP-binding cassette transporter, are located at this region. Moreover, the transcription factor c-Myc is closely related to MIR17HG. The aim of this study was to examine the role of MIR17HG, ABCC4, and CMYC gene copy numbers (CNs) in determining response to NCRT. We analyzed DNA CN of pretherapy biopsies from 108 LARC patients and the expression of microRNA (miR)-17, miR-18a, miR-19a, miR-19b-1, miR-20a, and miR-92a-1 in 34 biopsies. MIR17HG, CMYC, and ABCC4 gene CNs were frequently altered in pretreatment tumors, amplification being the most frequent alteration. With regard to response to therapy, 41% of responders showed MIR17HG deletion, while MIR17HG amplification was observed in 41% of nonresponders. With regard to pathological T stage (ypT), a higher percentage of ypT3-4 than ypT0-2 tumors showed MIR17HG amplification. Finally, a higher, albeit nonsignificant, variability in the expression of MIR17HG cluster members was detected in nonresponders compared to responders. No association was observed between clinical pathological parameters and ABCC4 or CMYC CN. Our data did not highlight a significant association between MIR17HG, CMYC, and ABCC4 gene CNs and response to NCRT in LARC. However, MIR17HG gene amplification would seem to be related to a lack of response. Evaluation of the expression of MIR17HG cluster members is warranted in a larger case series, together with functional studies, to evaluate the potential of this gene as a new predictive marker.

Background: Studies have shown low levels of high-density lipoprotein cholesterol (HDL-C) in indigenous children versus urban children from Argentina. We hypothesized that indigenous children living at high altitudes might have lower HDL-C levels compared with U.S. children, probably due to ambient hypoxia, lifestyle conditions, or ethnicity. This study was designed (1) to compare HDL-C levels in Argentinean indigenous children with those reported in the 2011-2012 National Health and Nutrition Examination Survey (NHANES) for U.S. children and (2) to determine the association between HDL-C and adiposity in both groups., Subjects and Methods: A cross-sectional study of 1,232 (631 females) Argentinean indigenous schoolchildren (4-14 years old) from San Antonio de los Cobres (SAC) was performed between November 2011 and November 2014. Anthropometric measures were performed in the whole group and compared with those of 2,151 U.S. children (1,034 females). However, HDL-C concentrations were measured in 905 SAC children and compared with those of 1,451 U.S. children. Analyses were done incorporating sampling weights for age in both samples to obtain unbiased estimates. In the case of NHANES the weights provided by each individual in the 2011-2012 NHANES demographic file were used, whereas in the SAC sample the weights were obtained using the census data provided by the 2010 National Statistics and Censuses Institute of Argentina., Results: The prevalence of overweight/obesity was significantly lower in SAC (135/1,232; 11%) than in the United States (759/2,151; 35%). However, the prevalence of low levels of HDL-C was significantly higher in SAC (298/905; 33%) than in the United States (142/1,451; 10%). The prevalence of low levels of HDL-C increased significantly in both groups as body mass index categories increased. Multiple logistic regression analysis showed that SAC children had nine and a half times the odds of having low levels of HDL-C compared with U.S. children, adjusted for confounding variables (odds ratio = 9.55; 95% confidence interval, 7.18-12.71)., Conclusions: This study shows a high prevalence of low levels of HDL-C in indigenous Argentinean children 4-14 years of age living at high altitudes compared with U.S. children.

Background: Central obesity is associated with increased risk of type 2 diabetes., Objectives: The study objectives were to develop waist circumference (WC) percentiles, to determine if WC is associated with metabolic risk, and to compare our WC percentiles with those reported in the 2007-2010 National Health and Nutrition Examination Survey (NHANES)., Methods: A cross-sectional study of 1232 children (606 boys ) 5-14 years was performed from 2011 to 2014 in indigenous Koya children from northwestern Argentina. Anthropometric characteristics, glucose, lipids, and insulin levels were measured. Sex-specific reference percentiles were computed using the Lambda-Mu-Sigma (LMS) method. We obtained 2007-2010 NHANES data for comparison with our results., Results: Compared with the NHANES 90th percentile, WC values for children in this study were lower by an average of 11.05 cm for girls and 12.66 cm for boys. The prevalence of low high-density lipoprotein cholesterol (HDL-C) was 11.8% in children with WC ≤50th percentile, 10.3% in children with WC >50th-70th percentile, 17.5% in children with WC >70th-90th percentile, and 21.3% in children with WC >90th percentile. The prevalence of high triglycerides (TG) was 19.5% in children with WC ≤50th percentile, 19.9% in children with WC >50th-70th percentile, 28.8% in children with WC >70th-90th percentile, and 39.7% in children with WC >90th percentile. Multiple logistic regression analyses showed that high TG values (>150 mg/dL) were significantly associated with WC [odds ratio (OR)] 1.05; 95% confidence interval (CI) 1.03-1.08; and low HDL-C values (<35 mg/dL) were significantly associated with WC (OR 1.04; 95% CI 1.01-1.06), adjusted for age and gender., Conclusion: We present for the first time WC reference data for indigenous Koya children ages 5-14 years. There was a significant association between WC and dyslipidemia in this community. Compared with the NHANES WC percentiles, our WC values were lower. These differences possibly reflect ethnicity or the lower prevalence of obesity.

Objective: to explore changes in lipid levels in two groups of children of different ethnicities who were able to access vitamin D supplementation versus those who were not., Methods: A prospective one-year study evaluated 87 San Antonio de los Cobres (SAC) Indigenous and 36 Buenos Aires (BA) urban schoolchildren aged 9.7 + 2.1 years between October 2013 and October 2014. SAC children included 70 (80.5%) treated with 100,000 IU/year of vitamin D and 17 (19.5%) untreated; and BA children included 25 (69,5%) treated and 11(30.5%) untreated. BMI, lipids, and 25-hydroxyvitamin D (25(OH)D) concentrations were measured at baseline and after one year., Results: There was a significantly lower prevalence of overweight/obesity in SAC (n = 7; 8%) versus BA (n = 7; 36.4%) children. There was a significant association between changes in (25(OH)D) and changes in HDL-C levels in SAC (r0.44;p < 0.01) and in BA (r0.34;p < 0.05). Multiple linear regression analyses showed that changes in (25(OH)D ) were significantly associated with changes in HDL-C in SAC (Beta = 0.55, p = 0.02; R20.11) and BA children (Beta = 0.42, p = 0.04; R2 0.21) adjusted for age, gender, and BMI. Furthermore, multiple logistic regression analysis showed that children in the treated group had a likelihood six times greater of having HDL-C >40 mg/dL than the untreated group, adjusted for age, gender, and BMI (OR 6.3: CI 2.0 - 19.8; p < 0.01)., Conclusion: These results suggest that children who had received vitamin D supplementation had significantly higher vitamin D status and HDL-C, as compared with non-supplemented children in both communities.

Study Design Case report. Objective There is a paucity of literature describing the use of bone graft substitutes to achieve fusion in the pediatric cervical spine. The outcomes and complications involving the off-label use of bone morphogenetic protein (BMP)-2 in the pediatric cervical spine are not clearly defined. The purpose of this article is to report successful fusion without complications in two pediatric patients who had instrumented occipitocervical fusion using low-dose BMP-2. Methods A retrospective review of the medical records was performed, and the patients were followed for 5 years. Two patients under 10 years of age with upper cervical instability were treated with occipitocervical instrumented fusion using rigid occipitocervical fixation techniques along with conventionally available low-dose BMP-2. A Medline and PubMed literature search was conducted using the terms "bone morphogenetic protein," "BMP," "rh-BMP2," "bone graft substitutes," and "pediatric cervical spine." Results Solid occipitocervical fusion was achieved in both pediatric patients. There were no reported perioperative or follow-up complications. At 5-year follow-up, radiographs in both patients showed successful occipital cervical fusion without evidence of instrumentation failure or changes in the occipitocervical alignment. To date, there are few published reports on this topic. Complications and the appropriate dosage application in the pediatric posterior cervical spine remain unknown. Conclusions We describe two pediatric patients with upper cervical instability who achieved successful occipital cervical fusion without complication using off-label BMP-2. This report underscores the potential for BMP-2 to achieve successful arthrodesis of the posterior occipitocervical junction in pediatric patients. Use should be judicious as complications and long-term outcomes of pediatric BMP-2 use remain undefined in the existing literature.

Purpose of Investigation: Hydatidiform mole (HM) is an abnormal pregnancy characterized by proliferation of cytotrophoblast and syncytiotrophoblast and vesicular swelling of placental villi. The fetus or embryo can be absent or abnormal. HMs can be complete or partial., Case Report: A case of diginyc partial HM at 12 weeks of gestational age was referred to the present center of prenatal diagnosis. The patient showed ovarian hyperstimulation syndrome. At ultrasonography, increased fetal nuchal translucency (NT) with fetal anomaly was evident, without sonographic signs of placental mole. Pregnancy was terminated with legal abortion., Results: Partial HM (PHM) was suspected by ultrasonographic fetal markers with ovarian hyperstimulation syndrome, but the diagnosis was performed only with fluorescent in situ hybridization. In particular fetal NT appeared increased also in diginyc mole., Conclusion: In order to improve the detection rate of PHM, routine histological examinations may be associated to fluorescent in situ hybridization in all cases of fetal anomalies.

Standard treatment of patients with locally advanced rectal cancer (LARC) includes neoadjuvant chemoradiotherapy (NCRT) followed by surgery. Tumor regression after NCRT varies substantially among individuals and pathological complete response is a known prognostic factor for LARC. The identification of a predictive model for response to chemoradiotherapy would help clinicians to identify patients who would probably benefit from multimodal treatment and to perform an early assessment of individual prognosis. Carcinoembryonic antigen has proven to be a good predictor of response in several clinical trials. Other widely studied predictive models in LARC include molecular biomarkers, analyzed at various levels and by different techniques, and molecular imaging, in particular magnetic resonance imaging and positron emission tomography/computed tomography. Although none of the studied markers have been approved in clinical practice, their evaluation in larger, prospective trials and in combined predictive models could be of use to define tailored therapeutic strategies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

A 7-year-old patient exhibited gingival recession of tooth #41 and severe plaque accumulation after 3 months of face mask therapy. The recession improved only slightly after appropriate oral hygiene instructions and motivation. Decisive improvement began when the vertical chin pad extension was reduced to avoid pressure on the affected area.

Study Design Case report. Objectives Symptomatic triple-region spinal stenosis (TRSS), defined as spinal stenosis in three different regions of the spine, is extremely rare. To our knowledge, treatment with simultaneous decompressive surgery is not described in the literature. We report a case of a patient with TRSS who was treated successfully with simultaneous decompressive surgery in three separate regions of the spine. Methods A 50-year-old man presented with combined progressive cervical and thoracic myelopathy along with severe lumbar spinal claudication and radiculopathy. He underwent simultaneous decompressive surgery in all three regions of his spine and concomitant instrumented fusion in the cervical and thoracic regions. Results Estimated blood loss for the procedure was 600 mL total (250 mL cervical, 250 mL thoracic, 100 mL lumbar) and operative time was ∼3.5 hours. No changes were noted on intraoperative monitoring. The postoperative course was uncomplicated. The patient was discharged to inpatient rehabilitation on postoperative day (POD) 7 and discharged home on POD 11. At 6-month follow-up, his gait and motor function was improved and returned to normal in all extremities. He remains partially disabled due to chronic back pain. Conclusions This report is the first of symptomatic TRSS treated with simultaneous surgery in three different regions of the spine. Simultaneous triple region stenosis surgery appears to be an effective treatment option for this rare condition, but may be associated with prolonged hospital stay after surgery.

Study Design Literature review and case report. Objective Review the existing literature and report the successful nonoperative management of a two-level craniocervical ligamentous distraction injury. Methods A PubMed and Medline review revealed only three limited reports involving the nonoperative management of patients with craniocervical distraction injury. This article reviews the existing literature and reports the case of a 27-year-old man who was involved in a motorcycle accident and sustained multiple systemic injuries and ligamentous distraction injuries to both occipitocervical joints and both C1-C2 joints. The patient's traumatic brain injury and bilateral pulmonary contusions precluded safe operative management of the two-level craniocervical distraction injury. Therefore, the patient was placed in a halo immobilization device. Results The literature remains unclear as to the specific indications for nonoperative management of ligamentous craniocervical injuries. Nonoperative management was associated with poor outcomes in the majority of reported patients. We report a patient who was managed for 6 months in a halo device. Posttreatment computed tomography and flexion-extension radiographs demonstrated stable occipitocervical and C1-C2 joints bilaterally. The patient reported minimal neck pain and had excellent functional outcome with a Neck Disability Index score of 2 points at 41 months postoperatively. He returned to preinjury level of employment without restriction. Conclusions Further study is needed to determine which craniocervical injuries may be managed successfully with nonoperative measures.

Purpose: To evaluate whether the variation of the apparent diffusion coefficient (ADC) values obtained with DWI can predict elevated levels of Ki67 proliferation index and aggressive subtypes in patients with breast cancer., Materials and Methods: Breast MRI studies of 115 patients (mean age 57.3 years, range 36-81 years) with a biopsy-proven breast cancers were evaluated in this retrospective IRB-approved study. Examinations were performed on a 1.5 T magnet and included a Single-Shot Echoplanar DWI sequence with b values of 0 and 1000 s/mm(2). For each target lesion, ADC was measured. ADC values were compared considering Ki67 status (≥20 % or <20 %), histology, grade (G1, G2 or G3) and clinical-pathological classification (Luminal A, Luminal B HER2-positive, Luminal B HER-2 negative, HER-2 enriched and Triple Negative). Mann-Whitney U test and Kruskal-Wallis test were used for comparisons and receiver operating characteristic (ROC) curves were obtained. Inter- and intra-reader variability was evaluated in a subset of 40 patients, using interclass correlation coefficient (ICC) and Bland-Altman plots., Results: Of 115 lesions, 53 (46.1 %) were assessed as Ki67 positive and 62 (53.9 %) as Ki67 negative. ADC values were significantly (p < 0.0001) lower in Ki67-positive patients (median 0.86 × 10(-3) mm(2)/s; interquartile range 0.75-0.92) compared to Ki67-negative (median 1.03 × 10(-3) mm(2)/s; interquartile range 0.92-1.13). Median ADC was also lower in G2 and G3 cancer and in the Luminal B Her2-negative subtype (p = 0.0015). No differences were found when evaluating histology. ROC curve showed a sensitivity and specificity of 83.0 and 66.1 %, respectively, when using a cutoff of 0.95 s/mm(2) to differentiate Ki67-positive from Ki67-negative cancers. Inter- and intra-reader variability was moderate (ICC = 0.623; ICC = 0.548, respectively). No systematic differences were identified with Bland-Altman plots., Conclusions: Lower ADC values are associated with elevated Ki67 proliferation index and more aggressive pathologic features. Moderate agreement in ADC measurement could be a limitation.

Aim: We conducted a pilot study to evaluate the effectiveness of resveratrol absorbed orally, conveyed through a new patented technology that increases the absorption through the oral mucosa in treatment of hot flushes (HF) during menopause., Methods: This is a randomized controlled double-blind study with crossover design. From October 2012 to July 2014 we considered the first 50 patients enrolled at the Center for Menopause Maggiore Hospital of Charity of Novara, with diagnosis of physiological or surgical menopause. Each woman received a diary in which she indicated the weekly number of HF and the perceived intensity, in a 0-10 Scale (Visual Analogue Scale, VAS)., Results: Reduction of the monthly number of vasomotor episodes. Resveratrol 16/28 (57.1%); P2/22 placebo (9.1%) <0.001. The resveratrol group gets a positive result 6.28 times more compared to the placebo arm (95% CI: 1.61-24.49). Improvement of the intensity of symptoms and improving quality of life: resveratrol 22/28 (78.6%); placebo 4/22 P (18.2%) <0.001. Resveratrol group obtained a positive result 4:32 times more than the placebo arm (95% CI: 1.74-10.71)., Conclusion: Resveratrol is effective in reducing the number of episodes vasomotor and the intensity of HF, with the transition from moderate/severe to mild symptoms in 78.6% of patients. Resveratrol has the characteristics to be an alternative therapy in the treatment of HF in menopause.

Aim: As the treatment of hyperglycaemia during pregnancy with diet or insulin reduces the risk of adverse maternal outcomes and perinatal complications, screening for gestational diabetes mellitus (GDM) is included, albeit to variable extents, in all guidelines of care for pregnant women. The aim of the present investigation was to estimate the proportion of pregnancies screened for GDM in Lombardy between 2007 and 2010, and to identify predictors of screening., Methods: A retrospective cross-sectional study using regional healthcare utilization databases of Lombardy was conducted. The study included all residents of Lombardy without pregestational diabetes who delivered between 1 January 2007 and 31 December 2010. The proportion of pregnancies with at least one screening test for GDM was calculated, along with the odds ratios and 95% confidence intervals associated with selected covariates for GDM screening., Results: Of the 362,818 pregnancies included in the sample, 30% were screened for GDM. The proportion of pregnancies screened increased slightly from 2007 (27%) to 2010 (33%) and with maternal age (from 28% among women<25 years to 32% among those ≥35 years), and varied widely across local health management organizations (HMOs) of residence (range: 20% to 68%). Socioeconomic indicators (education, immigrant status), obstetric history and prepregnancy hypertension were independent predictors of GDM screening., Conclusion: The study finding of a low rate of pregnant women screened for GDM among residents of Lombardy supports the need for programmes to improve training of healthcare professionals, to raise women's awareness of GDM and to eliminate barriers to GDM screening., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Background: The most important adverse effect of BoNT-A is the systemic diffusion of the toxin. There is some evidence that the administration of high doses can increase the risk of systemic diffusion and the development of clinically evident adverse effects, however an international consensus does not exist about its maximum dose., Aim: The aim of this study was to evaluate changes in autonomic heart drive induced by high doses (higher than 600 units) of incobotulinumtoxinA injection in spastic stroke patients. Moreover, the treatment safety by monitoring adverse events occurrence was assessed., Design: Case control study., Population: Eleven stroke survivors with spastic hemiplegia., Methods: Patients were treated with intramuscular focal injections of IncobotulinumtoxinA (NT 201; Xeomin®, Merz Pharmaceuticals GmbH, Frankfurt, Germany). Doses were below 12 units/Kg. Each patient underwent an ECG recording before injection and 10 days after treatment. Linear and non-linear Heart Rate variability (HRV) measures were derived from ECGs with a dedicated software., Results: None of the variable considered showed statistically significant changes after BoNT-A injection., Conclusion: The use of incobotulinumtoxinA in adult patients at doses up to 12 units/kg seems to be safe regarding autonomic heart drive., Clinical Rehabilitation Impact: The use of IncobotulinumtoxinA up to 600 units could be a safe therapeutic option in spastic hemiplegic stroke survivors.

Recently, Vitamin D (Vit. D) has gained importance in cellular functions of a wide range of extraskeletal organs and target tissues, other than bone. In particular, Vit. D has displayed important beneficial effects in the cardiovascular system. Although little is known about the mechanism by which this response is exerted, a Vit. D-induced eNOS-dependent nitric oxide (NO) production in endothelial cells (EC) has been reported. The aim of this study was to evaluate whether Vit. D administration could affect human EC proliferation and/or migration through NO production. For this purpose, HUVEC (human umbilical vein endothelial cells) were used to evaluate Vit. D effects on cell proliferation and migration in a 3D matrix. Experiments were also performed in the presence of the specific VDR ligand ZK159222 and eNOS inhibitor L-NAME. This study demonstrated that Vit. D can promote both HUVEC proliferation and migration in a 3D matrix. These effects were NO dependent, since HUVEC proliferation and migration were abrogated along with Vit. D induced MMP-2 expression by inhibiting eNOS activity by L-NAME. These findings support the role of Vit. D in the angiogenic process, suggesting new applications for Vit. D in tissue repair and wound healing., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: To compare the prevalence of misperception between 2 groups of mothers towards their children's weight status from an indigenous population in San Antonio de los Cobres (SAC) and a Buenos Aires (BA) mixed population., Methods: Questionnaires regarding mothers' perceptions about their children's shape were performed during 2014., Results: Overall, 152 SAC children (80 males) aged 9.0+2.1 years and 119 BA children (59 males) aged 8.1+1.7 years were evaluated. There was a significant difference in the prevalence of maternal misperception of normal weight vs overweight children in both ethnicities: SAC (38.8% vs 66.7%) and BA (33.3% vs 62.9%)., Conclusion: These results suggest that maternal misperception of children's overweight was poor in both communities despite having different socio-economic and ethnic backgrounds.

Objective: Recent evidence strongly suggests that the fallopian tube is a site of origin of ovarian cancer. Although histological data show iron deposition in the fallopian tubes, its role remains unclear. To establish whether catalytic iron has a possible role in ovarian carcinogenesis, we isolated human fimbrial secretory epithelial cells (FSECs)., Methods: Fimbrial secretory epithelial cells, isolated from women undergoing isteroannessiectomy, were treated with different doses of catalytic iron (0.05-100 mM) to study cell viability; NO production; p53, Ras, ERK/MAPK, PI3K/Akt, Ki67, and c-Myc protein expressions through Western blot analysis; and immunocytochemistry or immunofluorescence., Results: In FSECs treated with catalytic iron for up to 6 days, we observed an increase in cell viability, NO production, and p53, pan-Ras, ERK/MAPK, PI3K/Akt, Ki67, and c-Myc activations (P < 0.05) in a dose-dependent and time-dependent manner. These same results were also observed in FSECs maintained for respectively 2 and 4 weeks in the absence of catalytic iron after 6 days of stimulation., Conclusions: Our model aimed at studying the main nongenetic risk factor for ovarian cancer, providing an alternative interpretation for the role of menstruation in increasing risk of this pathology. This in vitro model mimics several features of the precursor lesions and opens new scenarios for further investigations regarding the correlation between damages produced by repeated retrograde menstruation carcinogenic stimuli.

Objective: To determine whether vitamin D supplementation improves non-traditional cardiovascular risk factors such as Apo B levels among indigenous children., Methods: A prospective two-year study evaluated a treated cohort of 190 children (104 males) aged 9.4+ 2.2 years. Children were divided into group A (n=104; 54.7%) and group B (n=86; 45.3%). Both groups received vitamin D supplementation with 100,000 u/year; group B was treated in 2013 and group A in 2014. All subjects were evaluated at the end of each treatment and anthropometric measures, lipids and vitamin D levels between the two groups were compared., Results: Changes in vitamin D levels were significantly higher in Group A, which was supplied in 2014, than in group B, which was not supplied in 2014 (6.8 vs 0.96 ng/dL; respectively). Levels of LDL-C and Apo B were improved in group A versus B: LDL-C (-5.7 vs 6.9 mg/dL respectively) and Apo B (-0.9 vs 11. mg/dL respectively). Several multiple regression linear analyses showed that changes in vitamin D were significantly associated with lower LDL-C levels (Beta- 0.41, p<0.01; R2 0.07); and with lower Apo B levels (Beta-0.37, p<0.01; R2 0.17)., Conclusion: Vitamin D supplementation among indigenous children could improve Apo B levels.

Background: Epidemiological studies have suggested an inverse association between circulating levels of vitamin D and cardiovascular disease risk biomarkers, including an atherogenic lipid profile., Objective: To compare the prevalence and the distribution of lipid levels among vitamin D supplemented Argentinean indigenous San Antonio de los Cobres (SAC) children with a nonsupplemented Buenos Aires (BA) mixed population group., Methods: A group of indigenous children from SAC with hypovitaminosis D supplemented with vitamin D; and a nonsupplemented group from a BA mixed population were compared via a cross sectional study. Anthropometric measures, glucose, lipids, vitamin D, and insulin were measured., Results: The mean ages were 10.3 + 2.3 in SAC and 8.7 ± 1.8 years in BA children. There was a lower prevalence of overweight 7.9%(15/192) vs 17.8% (23/129); and of obesity 1.6% (3/192) vs 30.2% (39/129) in SAC vs. BA respectively. Approximately half of the SAC children versus 30% from BA had optimal vitamin D levels (≥30ng/mL). There was a significantly higher prevalence of high triglycerides (TG) (27.6%vs 4.6%) and low HDL-C (21.3% vs 5.4%) in SAC vs BA children, respectively. In separate linear regression models, we found that despite effective vitamin D repletion, SAC children had higher TG and TG/HDL-C values, whereas HDL-C levels were lower than those of BA children adjusted for age, gender, BMI, and insulin levels., Conclusion: Indigenous Argentinean children have a higher risk for dyslipidemia in comparison with BA children, even after vitamin D treatment, suggesting that dyslipidemia could be related to diet or ethnic backgrounds.