Study protocol for a randomized, controlled trial using a novel, family-centered diet treatment to prevent nonalcoholic fatty liver disease in Hispanic children.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the leading liver disorder among U.S. children and is most prevalent among Hispanic children with obesity. Previous research has shown that reducing the consumption of free sugars (added sugars + naturally occurring sugars in fruit juice) can reverse liver steatosis in adolescents with NAFLD. This study aims to determine if a low-free sugar diet (LFSD) can prevent liver fat accumulation and NAFLD in high-risk children. METHODS: In this randomized controlled trial, we will enroll 140 Hispanic children aged 6 to 9 years who are ≥50th percentile BMI and without a previous diagnosis of NAFLD. Participants will be randomly assigned to either an experimental (LFSD) or a control (usual diet + educational materials) group. The one-year intervention includes removal of foods high in free sugars from the home at baseline, provision of LFSD household groceries for the entire family (weeks 1-4, 12, 24, and 36), dietitian-guided family grocery shopping sessions (weeks 12, 24, and 36), and ongoing education and motivational interviewing to promote LFSD. Both groups complete assessment measures at baseline, 6, 12, 18, and 24 months. Primary study outcomes are percent hepatic fat at 12 months and incidence of clinically significant hepatic steatosis (>5%) + elevated liver enzymes at 24 months. Secondary outcomes include metabolic markers potentially mediating or moderating NAFLD pathogenesis. DISCUSSION: This protocol describes the rationale, eligibility criteria, recruitment strategies, analysis plan as well as a novel dietary intervention design. Study results will inform future dietary guidelines for pediatric NAFLD prevention. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05292352.

Metabolic and cardiovascular effects of TX-001HR in menopausal women with vasomotor symptoms.

Objective: This study aimed to evaluate the effects of TX-001HR (17ß-estradiol [E2] and progesterone [P4] in a single oral capsule) on cardiometabolic markers and outcomes. Methods: Four E2/P4 doses (1 mg/100 mg, 0.5 mg/100 mg, 0.5 mg/50 mg, 0.25 mg/50 mg) were compared with placebo in menopausal women with vasomotor symptoms (VMS) and a uterus in the phase 3 REPLENISH (ClinicalTrials.gov, NCT01942668) trial. Changes in lipid and coagulation parameters and blood glucose from baseline at 6, 9, and 12 months as well as cardiovascular events are summarized. Results: A total of 1835 participants took ≥1 capsule of daily E2/P4; 1684 received E2/P4 and 151 received placebo. No clinically significant changes in lipid parameters, coagulation factors, or glucose were observed between treatment groups. Minimal increases of potential clinical importance were observed in total cholesterol, triglycerides, and glucose at month 12 with E2/P4 (1-4%, 6-11%, and 1%, respectively) and placebo (3%, 7%, and 2%, respectively). One episode of deep venous thrombosis and three cases of cardiovascular disease were observed, similar to expected rates of these events in the general population. Conclusions: In the REPLENISH trial, postmenopausal women with VMS treated with E2/P4 had no clinically meaningful effects on lipids, glucose, or coagulation parameters compared with placebo.

Traffic-related air pollution associations with cytokeratin-18, a marker of hepatocellular apoptosis, in an overweight and obese paediatric population.

INTRODUCTION: Traffic-related air pollution causes fatty liver, inflammation and fibrosis in animal models, but there have been few studies in humans. OBJECTIVES: To test the hypothesis that traffic-related air pollution causes non-alcoholic fatty liver disease (NAFLD) and increased markers for non-alcoholic steatohepatitis (NASH); and that NAFLD increases liver susceptibility to increased NASH risk. METHODS: Data collected prospectively from 74 overweight or obese children were obtained from the Yale Pediatric Obesity Clinic. Traffic-related air pollution was characterized as vehicle traffic volume on major roads within a 1 km residential buffer, and as residential nitrogen dioxide (NO2 ) exposure. Outcomes were hepatic fat fraction (HFF) measured by magnetic resonance imaging, liver enzymes using standard assays and plasma cytokeratin-18 (CK-18) by immunosorbent assays. RESULTS: Significant non-linear relationships with air pollution and CK-18 were found. Plasma CK-18 at follow-up increased from approximately 150 U/L to almost 200 U/L as residential traffic volume increased from 220 000 vehicle-km to 330 000 vehicle-km, after adjustment for baseline CK-18, age and gender. Among patients with NAFLD at baseline, CK-18 increased from 140 U/L to 200 U/L (a 1.5 standard deviation increase in CK-18) as NO2 increased from 8 to 10 ppb. CONCLUSIONS: Traffic-related air pollution was associated with CK-18. Effects were larger in children with pre-existing NAFLD at study entry.

Anti-TNF-α and risk of infections: the experience in one center.

AIM: In the last years there is an increasing interest for the question of whether patients treated with antitumour necrosis factor-α (TNF-α) agents are at increased risk of infections. We aim to assess the possible role of anti-TNF-α treatment in the increase of the risk of infections in a population of patients affected by rheumatoid arthritis or psoriatic arthritis. METHODS: We analyzed data of patients affected by chronic arthritis treated with anti-TNF-α to investigate the risk of infections. Statistical analysis was done using STATA software. RESULTS: The odds ratio for patients treated with anti-TNF-α who developed infections was 1.61 (CI: 0.88, 2.92, P<0.11). We found an odds ratio of 1.41 (CI: 0.74, 2.68, P<0.29) in patients treated with anti-TNF-α who developed urinary tract infection, and an odds ratio of 2.63 (CI: 0.31, 22.19, P<0.37) in patients treated with anti-TNF-α who developed herpes zoster. DISCUSSION: These results seems to indicate a role of anti-TNF-α treatment in the risk of infection. Nevertheless, our results are not statistically significant probably because the sample sizes are too small and the time of observation among patients is variable. Moreover, other confounding factors may be gender, age and the different degrees of disease activity and comorbidity. In conclusion, limitations in the study size and design preclude definitive conclusions about the question of whether patients treated with anti-TNF-α agents are at increased risk of infections. The performance of additional research are needed to answer this question.

Melkersson-Rosenthal syndrome in a patient with psoriatic arthritis receiving etanercept.

Melkersson-Rosenthal syndrome is a rare granulomatous neuro-mucocutaneous systemic disease that is characterized by relapsing peripheral facial paralysis, orofacial edema and fissured tongue. The disease etiology is still not well known, but it has been hypothesized that a possible role is played by various causal agents such as infectious diseases, genetic causes, allergic conditions, benign lymphogranulomatosis, various associations with other pathological conditions, particularly with immune-mediated diseases and food contact allergies. In this report we describe the case of a woman, 42 years old, with psoriatic arthritis who developed neurological episodes related to MRS after treatment with anti-TNF therapy. This finding further supports the hypothesis that TNF-alpha blockade, and particularly the use of the TNF-alpha receptor, could trigger the development of granulomatous lesions in predisposed patients. The case we report further sustains the importance for the clinician to take into account this potential adverse event in patients receiving anti-TNF-alpha therapies.

Endocrinology of the ageing female; the hypothalamic-pituitary-ovarian axis.

The hypothalamic-pituitary-ovarian (HPO) axis goes through a series of complicated, but well coordinated changes as a women enters the menopausal transition. The reproductive consequences of these changes are obvious, but there are also a number of general health consequences as well. As our understanding of the complex inter-workings of the HPO axis evolves, we will be better able to predict menopausal events and create strategies and treatments to optimize women's health as the progress through the menopausal transition.

Magnetic resonance imaging screening of cerebral thromboembolic events in children with acute lymphoblastic leukemia: a pilot study.

BACKGROUND: Thromboembolism is a complication of acute lymphoblastic leukemia therapy in children. The majority of thromboembolic events are cerebral thromboses and deep venous thromboses; many asymptomatic deep venous thromboses are detected in children with acute lymphoblastic leukemia by instrumental screening. The aim of this study was to assess the incidence of asymptomatic cerebral thromboembolic events in children with acute lymphoblastic leukemia (ALL) screened by magnetic resonance imaging and magnetic resonance venography. METHODS: 46 children with acute lymphoblastic leukemia, during the induction phase of the AIEOP ALL 2000 protocol, were stratified into 2 groups. In group "A" cerebral thromboembolic events were suspected following the appearance of suggestive signs and symptoms and confirmed by cerebral magnetic resonance imaging and magnetic resonance venography; in group "B" children underwent a screening by cerebral magnetic resonance imaging and magnetic resonance venography, at set times, in absence of symptoms. RESULTS: We observed one cerebral thromboembolic event in both groups; we found no differences between early detecting asymptomatic cerebral thromboembolic events among monitored and not monitored patients. CONCLUSIONS: Our study does not seem to suggest a screening for asymptomatic cerebral thromboembolic events in children with ALL during the induction phase.

A simple scoring system for outcome prediction of ischemic stroke.

OBJECTIVES: According to most existing models, a computer is usually needed for predicting stroke outcome. Our purpose was to construct a simple and reliable prognostic scale not requiring the use of a calculating machine. MATERIALS AND METHODS: The scale [the Bologna Outcome Algorithm for Stroke (BOAS)] was obtained in 221 patients with ischemic stroke not undergoing thrombolysis and was then validated in a test group of 100 different patients. Outcome was assessed at 9 months as the number of dependent or dead patients (modified Rankin scale - mRS > 2). RESULTS: By a preliminary systematic univariate analysis, 25 of 415 baseline variables were found to be associated with a mRS > 2 independently of stroke severity and age. Subsequent multivariable analyses led to a final model based on five dichotomous risk factors (RF): National Institutes of Health Stroke Scale score ≥10, age ≥78, need of urinary catheter, oxygen administration, and persistence of upper limb paralysis at discharge from stroke unit. The patients with two or more RF (53%) had a mRS > 2 in 91% of cases and were dead in 42% of cases. With 0-1 RF, the two percentages were 24% and 2%, respectively (overall accuracy of prediction 83.9%, area under ROC curve [AUC] 0.891). In the test group, the accuracy was 79.0% and the AUC was 0.839. CONCLUSIONS: The need of urinary catheter, oxygen administration, and persistence of upper limb paralysis, together with stroke severity and advanced age, allow a simple and accurate prediction of dependency or death after ischemic stroke.

Effect of body mass index reduction on serum hepcidin levels and iron status in obese children.

Iron deficiency has been linked to obesity. Hepcidin is the main regulator of iron homeostasis and is higher in obese children compared to controls. To gain insight into the link between obesity and hepcidin, we performed an intervention study in 15 obese children. These children were subjected to a 6-month weight loss program and underwent physical examination and iron status and absorption as well as hepcidin, interleukin-6 and leptin serum levels evaluation at baseline and after the weight loss program. After the program all children reduced their body mass index standard deviation score (BMI SDS) of at least 0.5. We observed a significant decrease in hepcidin (P=0.003) and leptin levels (P=0.005), and a significant increase in iron absorption (P=0.02). A direct correlation between the measure of hepcidin and leptin reduction was observed and this correlation appeared significant (r²=0.33, P=0.003) when adjusted for interleukin-6 and BMI SDS variations. In conclusion, we have shown that, in obese children, BMI reduction is associated with hepcidin reduction, potentially improving iron status and absorption. Implications of these findings could be considered in the management of obese children with poor iron status.

High normal fasting glucose level in obese youth: a marker for insulin resistance and beta cell dysregulation.

AIMS/HYPOTHESIS: A high but normal fasting plasma glucose level in adults is a risk factor for future development of type 2 diabetes mellitus and cardiovascular disease. We investigated whether normal fasting plasma glucose levels (<5.60 mmol/l) are associated with decreases in insulin sensitivity and beta cell function, as well as an adverse cardiovascular profile in obese youth. METHODS: We performed a cross-sectional analysis in a multiethnic sample of 1,020 obese youth (614 girls and 406 boys; mean age 12.9 years [CI 95% 12.7-13.1], BMI z score 2.34 [CI 95% 2.31-2.38]) with normal fasting plasma glucose. All participants had a standard OGTT, with calculation of indices of insulin sensitivity and beta cell function. For the analysis, prepubertal and pubertal participants were stratified into quartiles of normal fasting plasma glucose. RESULTS: We observed a significant increase in fasting insulin and AUC 2 h glucose across quartiles. Pronounced changes were observed in insulin sensitivity and secretion, particularly in the pubertal group. Moreover, the odds of presenting with impaired glucose tolerance increased by 4.5% with each 0.06 mmol/l increase in fasting plasma glucose. No significant differences in cardiovascular indices were seen across quartiles. CONCLUSIONS/INTERPRETATION: These data suggest that in obese youth, independent of age, BMI z score, sex, family history and ethnicity, insulin sensitivity and secretion decline when moving from low to high normal fasting plasma glucose. The simple measure of fasting plasma glucose could assist clinicians in identifying children for targeted diabetes screening and subsequent lifestyle management.

The relationship between psychosocial status, acculturation and country of origin in mid-life Hispanic women: data from the Study of Women's Health Across the Nation (SWAN).

METHOD: To test the hypothesis that psychosocial symptomatology differs by country of origin and acculturation among Hispanic women, we examined 419 women, aged 42-52 years at baseline, enrolled in the New Jersey site of the Study of Women's Health Across the Nation (SWAN). Women were categorized into six groups: Central (CA, n = 29) or South American (SA, n = 106), Puerto Rican (PR, n = 56), Dominican (D, n = 42), Cuban (Cu, n = 44) and non-Hispanic Caucasian (NHC, n = 142). Acculturation, depressive symptoms, hostility/cynicism, mistreatment/discrimination, sleep quality, social support, and perceived stress were assessed at baseline. Physical functioning, trait anxiety and anger were assessed at the fourth annual follow-up. Comparisons between Hispanic and non-Hispanic Caucasians used χ², t test or non-parametric alternatives; ANOVA or Kruskal-Wallis testing examined differences among the five Hispanic sub-groups. Multivariable regression models used PR women as the reference group. RESULTS: Hispanic women were overall less educated, less acculturated (p < 0.001 for both) and reported more depressive symptoms, cynicism, perceived stress, and less mistreatment/discrimination than NHCs. Along with D women, PR women reported worse sleep than Cu women (p < 0.01) and more trait anxiety than SA and Cu women (p < 0.01). Yet, PR women were most acculturated (21.4% highly acculturated vs. CA (0.0%), D (4.8%), SA (4.8%) and Cu (2.3%) women; p < 0.001). In regression models, PR women reported depressive symptoms more frequently than D, Cu, or SA women, and reported trait anxiety more frequently than Cu or SA women. Greater acculturation was associated with more favorable psychosocial status, but PR ethnicity was negatively related to psychosocial status. CONCLUSION: Psychosocial symptomatology among Hispanic women differs by country of origin and the relatively adverse profile of Puerto Rican women is not explained by acculturation.

Menopausal symptoms within a Hispanic cohort: SWAN, the Study of Women's Health Across the Nation.

INTRODUCTION: Since the designation of people as Hispanic involves the amalgamation of a number of different cultures and languages, we sought to test the hypothesis that menopausal symptoms would differ among Hispanic women, based upon country of origin and degree of acculturation. METHODS: A total of 419 women, aged 42-52 years at baseline, were categorized as: Central American (CA, n = 29) or South American (SA, n = 106), Puerto Rican (PR, n = 56), Dominican (D, n = 42), Cuban (Cu, n = 44) and non-Hispanic Caucasian (n = 142). We assessed vasomotor symptoms, vaginal dryness and trouble in sleeping. Hispanics and non-Hispanic Caucasians were compared using the chi(2) test, t test or non-parametric alternatives; ANOVA or Kruskal-Wallis testing examined differences among the five Hispanic sub-groups. Multivariable regression models used PR women as the reference group. RESULTS: Hispanic women were overall less educated, less acculturated (p < 0.001 for both) than non-Hispanic Caucasians and more of them reported vasomotor symptoms (34.1-72.4% vs. 38.3% among non-Hispanic Caucasians; p = 0.0293) and vaginal dryness (17.9-58.6% vs. 21.1% among non-Hispanic Caucasians, p = 0.0287). Among Hispanics, more CA women reported vasomotor symptoms than D, Cu, SA, or PR women (72.4% vs. 45.2%, 34.1%, 50.9%, and 51.8%, respectively). More CA (58.6%) and D women (38.1%) reported vaginal dryness than PR (17.9%), Cu (25.0%) and SA (31.4%) women. More PR and D women reported trouble in sleeping (66.1 and 64.3%, respectively) compared to CA (51.7%), Cu (36.4%), and SA (45.3%) women. CONCLUSION: Symptoms associated with menopause among Hispanic women differed by country of origin but not acculturation. Central American women appear to be at greatest risk for both vasomotor symptoms and vaginal dryness.

A nosocomial outbreak of 2009 pandemic influenza A(H1N1) in a paediatric oncology ward in Italy, October-November 2009.

A nosocomial outbreak of 2009 pandemic influenza A(H1N1), with eight confirmed cases, occurred in a paediatric oncology ward in Italy, in October/November 2009. The fact that one case was infected despite being isolated and without contact to a symptomatic patient, hints towards potential transmission through a health care worker (HCW) and underlines the importance of vaccination of HCW who are involved in the care of critically ill patients.

Thyroid function and thyroid autoimmunity in childhood acute lymphoblastic leukemia off-therapy patients treated only with chemotherapy.

OBJECTIVE: Scanty data are available about the thyroid function in childhood acute lymphoblastic leukemia (ALL) off-therapy patients treated only with chemotherapy. We aimed to assess the prevalence of thyroid autoimmunity and thyroid dysfunction in such patients. DESIGN: Case-control cross-sectional study. METHODS: Eighty-four patients diagnosed with ALL and treated only with chemotherapy. Mean age at diagnosis 5.9+/-3.6 yr, at recruitment 12.1+/-4.3 yr. The treatment had been stopped 4.3+/-3.2 yr before recruitment. A control group of 60 subjects was recruited. Free T4, TSH, anti-thyroperoxidase, and anti-thyroglobulin antibodies were measured. RESULTS: Anti-thyroglobulin and anti-thyroperoxidase antibodies were negative in all patients. TSH was increased in 7 patients (8.3%) and 3 controls (5.0%). Free T4 was within the normal limits in all patients and controls.Mean TSH and free T4 levels did not statistically differ between controls and ALL offtherapy patients. TSH was negatively correlated with the age at the diagnosis (p=0.01) and the age at the end of therapy (p=0.008). Anti-thyroglobulin and/or anti-thyroperoxidase antibodies were detected in 3 controls (5%; vs study group: p=0.038), 1 of them with increased TSH. CONCLUSIONS: Some patients present hyperthyrotropinemia, without anti-thyroid antibodies, with a prevalence comparable to the control group. The thyroid gland seems more prone to be damaged by chemotherapy at a younger age. We think that a thyroid follow- up in ALL off-therapy patients may be advisable and should be differentiated on the basis of the age at the end of treatment, with more frequent tests for younger patients.

Long-term results of the Italian Association of Pediatric Hematology and Oncology (AIEOP) Studies 82, 87, 88, 91 and 95 for childhood acute lymphoblastic leukemia.

We analyzed the long-term outcome of 4865 patients treated in Studies 82, 87, 88, 91 and 95 for childhood acute lymphoblastic leukemia (ALL) of the Italian Association of Pediatric Hematology and Oncology (AIEOP). Treatment was characterized by progressive intensification of systemic therapy and reduction of cranial radiotherapy. A progressive improvement of results with reduction of isolated central nervous system relapse rate was obtained. Ten-year event-free survival increased from 53% in Study 82 to 72% in Study 95, whereas survival improved from 64 to 82%. Since 1991, all patients were treated according to Berlin-Frankfurt-Muenster (BFM) ALL treatment strategy. In Study 91, reduced treatment intensity (25%) yielded inferior results, but intensification of maintenance with high-dose (HD)-L-asparaginase (randomized) allowed to compensate for this disadvantage; in high-risk patients (HR, 15%), substitution of intensive polychemotherapy blocks for conventional BFM backbone failed to improve results. A marked improvement of results was obtained in HR patients when conventional BFM therapy was intensified with three polychemotherapy blocks and double delayed intensification (Study 95). The introduction of minimal residual disease monitoring and evaluation of common randomized questions by AIEOP and BFM groups in the protocol AIEOP-BFM-ALL 2000 are expected to further ameliorate treatment of children with ALL.

Variations of retinol binding protein 4 levels are not associated with changes in insulin resistance during puberty.

Retinol binding protein 4 (RBP4) is an adipokine involved in the pathogenesis of insulin resistance in obese adults and children. Since insulin resistance occurs during puberty, independently of adiposity, a role for RBP4 in the onset of this phenomenon may be hypothesized. In order to verify our hypothesis, we studied 90 subjects (45 obese and 45 lean controls). A complete physical examination was assessed, the z-score body mass index (BMI) was calculated, fat mass was assessed by bioelectric impedance analysis, and pubertal stage was assessed according to Tanner. Serum insulin and serum RBP4 levels were assayed. Obese and lean children differed for z-score BMI, fat mass, homeostasis model assessment of insulin resistance (HOMA-IR) and RBP4 levels. z-score BMI and HOMA-IR showed a direct correlation with RBP4 in the total population. When the subjects were divided in lean and obese, this correlation was evident only in obese (r2: 0.2; p=0.009 and r2: 0.2; p=0.01), but not in lean subjects (r2: 0.09; p=0.1 and r2: 0.03; p=0.4). Both in obese and lean HOMA-IR values were higher in pubertal subjects than in pre-pubertal (p<0.001), while serum RBP4 levels were similar in pubertal and in pre-pubertal subjects (>0.1). We conclude that RBP4 is correlated with adiposity and insulin resistance in obese children, but it is not involved in the insulin resistance occurring during puberty.

Using basic science to design a clinical trial: baseline characteristics of women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS).

Observational and epidemiological studies suggest that menopausal hormone therapy (MHT) reduces cardiovascular disease (CVD) risk. However, results from prospective trials showed neutral or adverse effects most likely due to differences in participant demographics, such as age, timing of initiation of treatment, and preexisting cardiovascular disease, which reflected in part the lack of basic science information on mechanisms of action of hormones on the vasculature at the time clinical trials were designed. The Kronos Early Estrogen Replacement Study (KEEPS) is a prospective, randomized, controlled trial designed, using findings from basic science studies, to test the hypothesis that MHT when initiated early in menopause reduces progression of atherosclerosis. KEEPS participants are younger, healthier, and within 3 years of menopause thus matching more closely demographics of women in prior observational and epidemiological studies than women in the Women's Health Initiative hormone trials. KEEPS will provide information relevant to the critical timing hypothesis for MHT use in reducing risk for CVD.

The insulin gene variable number of tandemrepeats (INS VNTR) genotype and sleep disordered breathing in childhood obesity.

Aim of our study is to verify the association between the genetic predisposition to hyperinsulinism due to the presence of the insulin gene (INS) I/I genotype and the development of sleep-related breathing disorders (SRBD) in obese children and adolescents. Two hundred and fifty-six obese children and adolescents (125 girls) have been investigated. As initial screening all subjects' mothers filled out the Sleep Disturbances Scale for Children (SDSC). The Sleep-Disordered Breathing (SDB) scale has been taken into account. Successively, a subgroup of 34 patients belonging to the first (14 children) and the last (20 children) SDB score quintiles underwent an overnight polysomnography and the apnea-hypopnea index (AHI) was evaluated. All subjects were genotyped for the INS VNTR and fasting insulin levels were evaluated. The population was divided into two groups according to the genotype: the first group was comprehensive of patients homozygotes for class I allele and the second group was composed by class III allele heterozygotes and homozygotes patients. Subjects I/I showed statistically signifIcant higher insulin levels (p<0.001) and SDB scores (p<0.001). Moreover, in the subgroup of patients investigated with polysomnography, class I homozygous subjects showed higher AHI compared to those patients carrying class III allele (p<0.001). Our data support the hypothesis that INS VNTR is associated with the development of SDB among obese children and adolescents.