Potent and selective inhibitors of histone deacetylase-3 containing chiral oxazoline capping groups and a N-(2-Aminophenyl)-benzamide binding unit

A novel series of potent chiral inhibitors of histone deacetylase (HDAC) is described that contains an oxazoline capping group and a N-(2-aminophenyl)-benzamide unit. Among several new inhibitors of this type exhibiting Class I selectivity and potent inhibition of HDAC3-NCoR2, in vitro assays for the inhibition of HDAC1, HDAC2, and HDAC3-NCoR2 by N-(2-aminophenyl)-benzamide 15k gave respective IC50 values of 80, 110, and 6 nM. Weak inhibition of all other HDAC isoforms (HDAC4, 5, 6, 7, and 9: IC50 > 100 000 nM; HDAC8: IC50 = 25 000 nM; HDAC10: IC50 > 4000 nM; HDAC11: IC50 > 2000 nM) confirmed the Class I selectivity of 15k. 2-Aminoimidazolinyl, 2-thioimidazolinyl, and 2-aminooxazolinyl units were shown to be effective replacements for the pyrimidine ring present in many other 2-(aminophenyl)-benzamides previously reported, but the 2-aminooxazolinyl unit was the most potent in inhibiting HDAC3-NCoR2. Many of the new HDAC inhibitors showed higher solubilities and lower binding to human serum albumin than that of Mocetinostat. Increases in histone H3K9 acetylation in the human cell lines U937 and PC-3 was observed for all three oxazolinyl inhibitors evaluated; those HDAC inhibitors also lowered cyclin E expression in U937 cells but not in PC-3 cells, indicating underlying differences in the mechanisms of action of the inhibitors on those two cell lines

A repeat cross-sectional study examining the equitable impact of nutritional standards for school lunches in England in 2008 on the diets of 4-7y olds across the socio-economic spectrum

BACKGROUND: The 2008 nutritional standards for primary school lunch in England improved nutritional content. The impact on socio-economic inequalities is unknown. We examine the impact of the nutritional standards on children’s nutrient intake at lunchtime and in total diet by level of deprivation. METHODS: We conducted cross-sectional studies in 12 English primary schools before and after legislation. Dietary intake was recorded for 4-7y olds using a validated, prospective four-day food diary. Socio-economic status was estimated using the Index of Multiple Deprivation; three groups of approximately equal sizes were created. Linear, mixed-effect models explored the effect of year, lunch type (school or home-packed lunch), level of deprivation and the interaction(s) between these factors on children’s diets. RESULTS: 368 and 624 children participated in 2003–4 and 2008–9 respectively. At lunchtime, between 2003–4 and 2008–9, the increase in non-starch polysaccharide (NSP) intake was larger in the least compared to the most deprived group (difference in mean change 0.8 mg; 95% CI 0.4, 1.3). There were similar differences in mean changes for iron (0.3 mg; 0.2, 0.4) and zinc (0.3 mg; 0.1, 0.5). In total diet, differential effects were observed for NSP, iron and zinc; we found no evidence these changes were associated with lunch type. Lunch type was associated with changes in per cent energy from non-milk-extrinsic sugars (NMES) and vitamin C. Per cent energy from NMES was lower and vitamin C intake higher in school lunches in 2008–9 compared with 2003–4. The corresponding differences in home-packed lunches were not as marked and there were subtle but statistically significant effects of the level of deprivation. CONCLUSIONS: By 2008–9, NMES at lunchtime and in total diet was lower for children consuming a school lunch; this change was equitable across the deprivation groups. Vitamin C intake increased more for children in the most deprived group, narrowing the socio-economic inequality. A range of significant differential effects of the nutritional standards were observed and important socio-economic inequalities in dietary intake remain. Additional interventions to promote equitable nutrition in children are needed to support legislative measures and maximise their impact

Experiments on Multidimensional Solitons

This article presents an overview of experimental efforts in recent years related to multidimensional solitons in Bose-Einstein condensates. We discuss the techniques used to generate and observe multidimensional nonlinear waves in Bose-Einstein condensates with repulsive interactions. We further summarize observations of planar soliton fronts undergoing the snake instability, the formation of vortex rings, and the emergence of hybrid structures.Comment: review paper, to appear as Chapter 5b in "Emergent Nonlinear Phenomena in Bose-Einstein Condensates: Theory and Experiment," edited by P. G. Kevrekidis, D. J. Frantzeskakis, and R. Carretero-Gonzalez (Springer-Verlag

Evaluating Active U: an Internet-mediated physical activity program.

Background: Engaging in regular physical activity can be challenging, particularly during the winter months. To promote physical activity at the University of Michigan during the winter months, an eight-week Internet-mediated program (Active U) was developed providing participants with an online physical activity log, goal setting, motivational emails, and optional team participation and competition. Methods: This study is a program evaluation of Active U. Approximately 47,000 faculty, staff, and graduate students were invited to participate in the online Active U intervention in the winter of 2007. Participants were assigned a physical activity goal and were asked to record each physical activity episode into the activity log for eight weeks. Statistics for program reach, effectiveness, adoption, and implementation were calculated using the Re-Aim framework. Multilevel regression analyses were used to assess the decline in rates of data entry and goal attainment during the program, to assess the likelihood of joining a team by demographic characteristics, to test the association between various predictors and the number of weeks an individual met his or her goal, and to analyze server load. Results: Overall, 7,483 individuals registered with the Active U website (≈16% of eligible), and 79% participated in the program by logging valid data at least once. Staff members, older participants, and those with a BMI < 25 were more likely to meet their weekly physical activity goals, and average rate of meeting goals was higher among participants who joined a competitive team compared to those who participated individually (IRR = 1.28, P < .001). Conclusion: Internet-mediated physical activity interventions that focus on physical activity logging and goal setting while incorporating team competition may help a significant percentage of the target population maintain their physical activity during the winter months

Physical activity and clustered cardiovascular disease risk factors in young children: a cross-sectional study (the IDEFICS study)

&lt;p&gt;Background The relevance of physical activity (PA) for combating cardiovascular disease (CVD) risk in children has been highlighted, but to date there has been no large-scale study analyzing that association in children aged &#8804;9 years of age. This study sought to evaluate the associations between objectively-measured PA and clustered CVD risk factors in a large sample of European children, and to provide evidence for gender-specific recommendations of PA.&lt;/p&gt; &lt;p&gt;Methods Cross-sectional data from a longitudinal study in 16,224 children aged 2 to 9 were collected. Of these, 3,120 (1,016 between 2 to 6 years, 2,104 between 6 to 9 years) had sufficient data for inclusion in the current analyses. Two different age-specific and gender-specific clustered CVD risk scores associated with PA were determined. First, a CVD risk factor (CRF) continuous score was computed using the following variables: systolic blood pressure (SBP), total triglycerides (TG), total cholesterol (TC)/high-density lipoprotein cholesterol (HDL-c) ratio, homeostasis model assessment of insulin resistance (HOMA-IR), and sum of two skinfolds (score CRFs). Secondly, another CVD risk score was obtained for older children containing the score CRFs + the cardiorespiratory fitness variable (termed score CRFs + fit). Data used in the current analysis were derived from the IDEFICS (‘Identification and prevention of Dietary- and lifestyle-induced health EFfects In Children and infantS’) study.&lt;/p&gt; &lt;p&gt;Results In boys &#60;6 years, the odds ratios (OR) for CVD risk were elevated in the least active quintile of PA (OR: 2.58) compared with the most active quintile as well as the second quintile for vigorous PA (OR: 2.91). Compared with the most active quintile, older children in the first, second and third quintiles had OR for CVD risk score CRFs + fit ranging from OR 2.69 to 5.40 in boys, and from OR 2.85 to 7.05 in girls.&lt;/p&gt; &lt;p&gt;Conclusions PA is important to protect against clustering of CVD risk factors in young children, being more consistent in those older than 6 years. Healthcare professionals should recommend around 60 and 85 min/day of moderate-to-vigorous PA, including 20 min/day of vigorous PA.&lt;/p&gt

Hepatitis B infection and immunity in Migrant Children and Pregnant Persons in Europe: A Systematic Review and Meta-Analysis.

BACKGROUND: The WHO's global hepatitis strategy aims to achieve viral hepatitis elimination by 2030. Migrant children and pregnant persons represent an important target group for prevention strategies. However, evidence on the burden of chronic hepatitis B (CHB) infection, and the factors affecting incidence, is lacking. METHODS: EMBASE, Global Health, Global Index Medicus, Web of Science and Medline were searched for articles in any language from 1/1/2012 to 8/6/2022. Studies reporting CHB prevalence, disease severity, complications and/or prevention strategies including vaccination, prevention of vertical transmission, and access to care/treatment in migrant children and pregnant migrants were included. Pooled estimates of CHB prevalence and Hepatitis B vaccination (HBV) coverage among migrant children were calculated using random effects meta-analysis. FINDINGS: 42 studies were included, 27 relating to migrant children and 15 to pregnant migrants across 12 European countries, involving data from 64 773 migrants. Migrants had a higher incidence of CHB than host populations. Among children, the pooled prevalence of CHB was higher for unaccompanied minors (UAM) (5%, [95% CI: 3-7%]) compared to other child migrants including internationally adopted children (IAC) and refugees (1%, [95% CI: 1-2%]). Region of origin was identified as a risk factors for CHB, with children from Africa and pregnant migrants from Africa, Eastern Europe and China at highest risk. Pooled estimates of HBV vaccine coverage were lower among UAM (12%, [95% CI: 3-21%]) compared to other child migrants (50%, [95% CI: 37-63%]). CONCLUSION: A range of modifiable determinants of HBV prevalence in migrant children and pregnant persons were identified including sub-optimal screening, prevention, and continuum of care. There is a need to develop evidence-based approaches in hepatitis care for these groups, thereby contributing towards global viral hepatitis elimination goals

Wnt signalling in adenomas of familial adenomatous polyposis patients

BACKGROUND: Epigenetic silencing of Wnt antagonists and expression changes in genes associated with Wnt response pathways occur in early sporadic colorectal tumourigenesis, indicating that tumour cells are more sensitive to Wnt growth factors and respond differently. In this study, we have investigated whether similar changes occur in key markers of the Wnt response pathways in the genetic form of the disease, familial adenomatous polyposis (FAP). METHODS: We investigated epigenetic and expression changes using pyrosequencing and real-time RT-PCR in samples from seven patients without neoplasia, and matched normal and tumour tissues from 22 sporadic adenoma and 14 FAP patients. RESULTS: We found that 17 out of 24 (71%) FAP adenomas were hypermethylated at sFRP1, compared with 20 out of 22 (91%) of sporadic cases. This was reflected at the level of sFRP1 transcription, where 73% of FAP and 100% of sporadic cases were downregulated. Increased expression levels of c-myc and FZD3 were less common in FAP (35 and 46% respectively) than sporadic tumours (78 and 67% respectively). CONCLUSION: Overall, the changes in expression and methylation were comparable, although the degree of change was generally lower in the FAP adenomas. Molecular heterogeneity between multiple adenomas from individual FAP patients may reflect different developmental fates for these premalignant tumours

Pattern and levels of spending allocated to HIV prevention programs in low- and middle-income countries

<p>Abstract</p> <p>Background</p> <p>AIDS continues to spread at an estimated 2.6 new million infections per year, making the prevention of HIV transmission a critical public health issue. The dramatic growth in global resources for AIDS has produced a steady scale-up in treatment and care that has not been equally matched by preventive services. This paper is a detailed analysis of how countries are choosing to spend these more limited prevention funds.</p> <p>Methods</p> <p>We analyzed prevention spending in 69 low- and middle-income countries with a variety of epidemic types, using data from national domestic spending reports. Spending information was from public and international sources and was analyzed based on the National AIDS Spending Assessment (NASA) methods and classifications.</p> <p>Results</p> <p>Overall, prevention received 21% of HIV resources compared to 53% of funding allocated to treatment and care. Prevention relies primarily on international donors, who accounted for 65% of all prevention resources and 93% of funding in low-income countries. For the subset of 53 countries that provided detailed spending information, we found that 60% of prevention resources were spent in five areas: communication for social and behavioral change (16%), voluntary counselling and testing (14%), prevention of mother-to-child transmission (13%), blood safety (10%) and condom programs (7%). Only 7% of funding was spent on most-at-risk populations and less than 1% on male circumcision. Spending patterns did not consistently reflect current evidence and the HIV specific transmission context of each country.</p> <p>Conclusions</p> <p>Despite recognition of its importance, countries are not allocating resources in ways that are likely to achieve the greatest impact on prevention across all epidemic types. Within prevention spending itself, a greater share of resources need to be matched with interventions that approximate the specific needs and drivers of each country's epidemic.</p

Dimensional analysis of MINMOD leads to definition of the disposition index of glucose regulation and improved simulation algorithm

BACKGROUND: Frequently Sampled Intravenous Glucose Tolerance Test (FSIVGTT) together with its mathematical model, the minimal model (MINMOD), have become important clinical tools to evaluate the metabolic control of glucose in humans. Dimensional analysis of the model is up to now not available. METHODS: A formal dimensional analysis of MINMOD was carried out and the degree of freedom of MINMOD was examined. Through re-expressing all state variable and parameters in terms of their reference scales, MINMOD was transformed into a dimensionless format. Previously defined physiological indices including insulin sensitivity, glucose effectiveness, and first and second phase insulin responses were re-examined in this new formulation. Further, the parameter estimation from FSIVGTT was implemented using both the dimensional and the dimensionless formulations of MINMOD, and the performances were compared utilizing Monte Carlo simulation as well as real human FSIVGTT data. RESULTS: The degree of freedom (DOF) of MINMOD was found to be 7. The model was maximally simplified in the dimensionless formulation that normalizes the variation in glucose and insulin during FSIVGTT. In the new formulation, the disposition index (Dl), a composite parameter known to be important in diabetes pathology, was naturally defined as one of the dimensionless parameters in the system. The numerical simulation using the dimensionless formulation led to a 1.5–5 fold gain in speed, and significantly improved accuracy and robustness in parameter estimation compared to the dimensional implementation. CONCLUSION: Dimensional analysis of MINMOD led to simplification of the model, direct identification of the important composite factors in the dynamics of glucose metabolic control, and better simulations algorithms

Cardiometabolic risk factors and quality of life in severely obese children and adolescents in the Netherlands

BACKGROUND: The prevalence of severe obesity in children and adolescents is increasing. However, little is known about cardiometabolic risk factors and quality of life of children with severe obesity.Therefore, the aim of this study was to assess the demographic characteristics and the prevalence of cardiometabolic risk factors and quality of life in severely obese children and adolescents undergoing intensive inpatient treatment for obesity. METHODS: Data were collected between August 2009 and April 2011 on 16 children (8-13y) and 64 adolescents (13-19y) with severe obesity (SDS-BMI >= 3.0 or SDS-BMI >= 2.3 and comorbidity) participating in an RCT evaluating two intensive inpatient treatment programs for obesity. Demographic, anthropometric, clinical characteristics and two components of the EuroQol for the assessment of quality of life are described. RESULTS: Eighty percent of participants in this study had at least one cardiometabolic risk factor in addition to severe obesity. Low HDL-cholesterol and hypertension were most prevalent (65.0% respectively 31.2%). The highest significant correlations were found between SDS-BMI and SDS-waist circumference, fasting plasma insulin and HOMA-IR (correlation coefficients respectively 0.80, 0.49, and 0.48). With regard to quality of life, the mean utility score of the participants was 0.79 on a scale of 0.0 to 1.0 on the EuroQol questionnaire and their mean individual valuation was 69.1 on a scale of 0 to100. CONCLUSION: Cardiometabolic risk factors are already highly prevalent in this group of severely obese children and adolescents. The score of 69.1 found for quality of life in this study suggests that participants experience important limitations in their quality of life. However, quality of life is not associated with the prevalence of cardiometabolic risk factors. TRIAL REGISTRATION: Netherlands Trial Register (NTR1678, registered 20-Feb-2009)