THE EFFICACY OF SCHOOL WELLNESS POLICIES IN KENTUCKY

With the passage of the Child Nutrition and WIC Reauthorization Act of 2004, all schools that participate in the National School Lunch Program are required to establish local wellness policies to address childhood obesity. In the state of Kentucky, Senate Bill 172 requires all elementary schools to adopt a local wellness policy addressing competitive foods, healthy choices, and daily physical activity. This study measured federal and state compliance among schools that responded to the 2008 Kentucky School Nutrition Survey. This study analyzed differences in the school nutrition environment among policies based on data from the 2002 and 2008 Kentucky School Nutrition surveys. The majority of school wellness policies were compliant with both federal and state guidelines. Significant differences in the school environment include a reduction in the availability of vending machines, decreased percentage of teachers using food as a reward, and increased use by teachers of non food items as a reward. Significant differences were not found among foods offered in vending machines, snack bars, and classroom parties. In 2008, elementary schools provided an average of 174 minutes of physical activity weekly, which is above the recommended guideline of 150 minutes per week

The Role of Exercise in Polychlorinated Biphenyl Induced Cardiovascular Disease

Cardiovascular disease remains the leading cause of death in Western societies. Endothelial dysfunction is one of the initiating steps in the development of atherosclerosis. While there is a strong correlation with a person’s genetics, lifestyle factors including smoking, physical activity, and diet can significantly increase a person’s susceptibility to the development of atherosclerosis. In addition to these lifestyle factors, there is a strong body of evidence linking exposure to environmental pollutants including persistent organic pollutants such as polychlorinated biphenyls to increased cardiovascular disease and mortality. It has been well-established that exercise protects against cardiovascular disease, but whether exercise can modulate PCB-induced cardiovascular inflammation and dysfunction is unknown. To investigate the effects of exercise on PCB-induced cardiovascular disease, two murine models of atherosclerosis, the ApoE-/- and the LDLr-/- mouse were utilized. Risk factors for cardiovascular disease including adiposity, glucose intolerance, hyperlipidemia, hypertension, oxidative stress, and inflammation, were assessed in these two models as well as mean atherosclerotic lesion size. Exercise positively modulates several risk factors associated with cardiovascular disease including hypertension, hyperlipidemia, adiposity and obesity, systemic levels of oxidative stress, inflammation, and glucose tolerance. Exercise significantly reduced mean lesion size in vehicle-treated animals. To assess the mechanism of protection of exercise in chapter 4, vascular reactivity studies were performed to measure endothelial function after exposure to PCB 77. Exercise prevented PCB-impaired endothelial function implicating the role of superoxide as a cause of impairment. Exercise upregulated phase II antioxidant enzymes. The work in this dissertation demonstrates several protective properties of exercise against PCB-induced cardiovascular disease; however, additional studies are needed to determine if exercise enhances metabolism and excretion of these environmental pollutants

Developmental Origins of Cardiovascular Disease: Impact of Early Life Stress in Humans and Rodents

The Developmental Origins of Health and Disease (DOHaD) hypothesizes that environmental insults during childhood programs the individual to develop chronic disease in adulthood. Emerging epidemiological data strongly supports that early life stress (ELS) given by the exposure to adverse childhood experiences is regarded as an independent risk factor capable of predicting future risk of cardiovascular disease. Experimental animal models utilizing chronic behavioral stress during postnatal life, specifically maternal separation (MatSep) provides a suitable tool to elucidate molecular mechanisms by which ELS increases the risk to develop cardiovascular disease, including hypertension. The purpose of this review is to highlight current epidemiological studies linking ELS to the development of cardiovascular disease and to discuss the potential molecular mechanisms identified from animal studies. Overall, this review reveals the need for future investigations to further clarify the molecular mechanisms of ELS in order to develop more personalized therapeutics to mitigate the long-term consequences of chronic behavioral stress including cardiovascular and heart disease in adulthood

Impact of Pediatric Obesity on Diurnal Blood Pressure Assessment and Cardiovascular Risk Markers

Background: The prevalence of hypertension is increasing particularly among obese children and adolescents. Obese children and adolescents with hypertension are likely to remain hypertensive as they reach adulthood and hypertension is linked to an increased risk for cardiovascular disease. Twenty-four-hour ambulatory blood pressure monitoring (ABPM) has become one of the most important tools in diagnosing hypertension in children and adolescents and circadian patterns of blood pressure may be important disease-risk predictors. Methods: A retrospective chart review was conducted in patients aged 6–21 years who underwent 24-h ABPM at Kentucky Children\u27s Hospital (KCH) from August 2012 through June 2017. Exclusion criteria included conditions that could affect blood pressure including chronic kidney disease and other renal abnormalities, congenital heart disease, cancer, and thyroid disease. Subjects were categorized by body mass index into normal (below 85th percentile), overweight (85th−95th percentile), stage I obesity (95th−119th percentile), stage II obesity (120th−139th) and stage III obesity (\u3e 140th). Non-dipping was defined as a nocturnal BP reduction of \u3c 10%. Results: Two hundred and sixty-three patients (156 male patients) were included in the analysis, of whom 70 were normal weight, 33 overweight, 55 stage I obesity, 53 stage II, and 52 stage III obesity. Although there was no significant difference between normal weight and obese groups for prevalence of hypertension, there was a greater prevalence of SBP non-dipping in obese patients as BMI increased (p = 0.008). Furthermore, non-dippers had a significantly elevated LVMI as well as abnormal lab values for uric acid, blood lipid panel, creatinine, and TSH (p \u3c 0.05). Conclusions: These findings demonstrate that obese children and adolescents constitute a large proportion of hypertensive children and adolescents and the severity of pediatric obesity is associated with nocturnal BP non-dipping. Additionally, obesity in children is linked to several cardiovascular risk factors including left ventricular hypertrophy, dyslipidemia, and elevated uric acid levels. Further studies utilizing ABPM measures on risk stratification in this very high-risk population are warranted

Chlamydia Screening in Ireland: a pilot study of opportunistic screening for genital Chlamydia trachomatis infection in Ireland (2007-2009). Summary Integrated Report

Genital Chlamydia trachomatis (CT) infection is the most common curable, bacterial sexually transmitted infection (STI) worldwide [1, 2]. The number of cases notified in Ireland increased from 3,353 in 2005 to 5,781 in 2009 [3]. Notifications have increased since 2004 when legislation requiring laboratory notification came into effect. Chlamydia is usually a ‘silent’ asymptomatic infection, spread without the knowledge of those transmitting and contracting it: most cases remain undetected and thus untreated. It is a major public health problem because it causes pelvic inflammatory disease (PID) in up to 30% of infected women who are not treated, which can lead to ectopic pregnancy and tubal factor infertility, and it also facilitates the transmission of HIV in both women and men [1, 4]. Prevalence studies in Ireland have detected chlamydia in 4–11% of young people [5, 6, 7], with positivity rates of over 10% in some settings [8]. Similar rates have been found in large studies in the United Kingdom (UK) [9], elsewhere in Europe [10] and North America [11]. A 2004 review estimated UK rates of 4–5% for women under 20 years in the general population, and 8–17% in women under 20 years attending sexual health services [9]. The authors of the review assumed, in the absence of data, that males had similar rates. Age under 25 years is considered a risk factor for infection in England [12]. In the English National Chlamydia Screening Programme (NCSP) overall chlamydia positivity rates have averaged 7.6% in men and 9.3% in women, based on a total of 370,012 screening tests reported [13]. Chlamydia screening has become more feasible due to the development of urinebased laboratory tests, which can be used in clinical and non-clinical settings, instead of more invasive and uncomfortable methods such as endocervical and urethral swabs. Urine testing is now the norm for screening men for chlamydia. For these reasons and because most cases are asymptomatic and undetected, especially in women, several countries have introduced chlamydia screening interventions [1]. A 2005 report prepared by the Health Protection Surveillance Centre (HPSC) [14] concluded that an investigation of the feasibility, acceptability and likely uptake of chlamydia screening in various settings in Ireland should be prioritised. It also concluded that agreement on best practice for the management of identified infections and partner notification was urgently needed. Following a competitive tendering process in late 2006, the HPSC, supported by the Health Research Board (HRB), contracted a team of population health and other specialists from the Royal College of Surgeons in Ireland (RCSI), the National University of Ireland Galway (NUIG) and the Health Service Executive (HSE) to conduct a pilot study of chlamydia screening.The study ran from 2007 to 2009. Since 2009, several articles and reports have been published internationally, including reviews and the results of screening studies, which question the case for chlamydia screening in the general population. A systematic review of screening programmes concluded that the available evidence did not justify the establishment of opportunistic chlamydia screening programmes in under-25 year olds in the general population, given methodological weaknesses in the trials cited as justification for screening [4]. A review of the three phases of the English National Chlamydia Screening Programme (NCSP) reported screening coverage levels in the target population of only 4.8% in 2007–2008 [13]; although by 2009–2010, 47% of sexually active young women and 25% of men had been tested [15]. A review by the English National Audit Office [16] concluded that the NCSP had not demonstrated value for money, citing lack of efficiencies in purchasing and logistics. Also, models had shown that annual testing rates of young people of between 26% and 43% would be needed in order to significantly reduce the prevalence of chlamydia [17]. The recent higher coverage levels achieved by the NCSP in reaching these recommended levels is a cause for optimism, and valuable lessons will be learned from the English national programme. However, the potential of opportunistic chlamydia screening to prevent serious morbidity (chiefly pelvic inflammatory disease in women) has been challenged by the results of an important randomised control trial of screening among young female students in London [18]. The trial found that most episodes of PID (30 of 38) would not have been prevented by annual screening as they occurred in women who had tested negative for chlamydia at the start of the 12 months

Chlamydia Screening in Ireland: a pilot study of opportunistic screening for genital Chlamydia trachomatis infection in Ireland (2007-2009). Screening Intervention Report

This report summarises the findings of the Pilot Screening Intervention conducted in Ireland between 2008 and 2009 as part of the Chlamydia Screening in Ireland Pilot study. The studies aimed to pilot screening models and to evaluate their feasibility and effectiveness. The study was commissioned by the Health Protection Surveillance Centre (HPSC) and overseen by the Health Research Board (HRB). It was carried out by a team from the Division of Population Health Sciences at the Royal College of Surgeons (RSCI) in Ireland, the College of Medicine, Nursing and Health Sciences at the National University of Ireland Galway, and Consultants in Public Health Medicine from the Health Service Executive (HSE). ² Ethical approval for study components was provided by Research Ethics Committees of the RCSI, NUI Galway and the Irish College of General Practitioners (ICGP)

Chlamydia Screening in Ireland: a pilot study of opportunistic screening for genital Chlamydia trachomatis infection in Ireland (2007-2009). Economic evaluation

Economic Evaluation The aim of the economic evaluation was to examine the cost effectiveness of the two screening models tested in the Chlamydia Screening in Ireland Pilot (CSIP) study: (a) Clinical Setting screening, and (b) ’Pee-in-a-pot’ periodic screening in third level institution/college settings. The methodological approach comprised of a dynamic transmission model paired with an economic model. In both analyses, screening was compared to a control strategy of no organised screening, that is existing care in Ireland. A public health system or provider perspective was adopted with respect to costs. The analysis considered the cost of screening to the health service, and the costs of infection and complications, not any additional costs reported by young people in accepting a chlamydia screening test. Health outcomes were assessed in terms of major outcomes (MOs) averted and quality adjusted life years (QALYs) gained. The costs of Clinical Setting screening were presented in terms of the cost per offer (€26 ), the cost per negative case (€66), the cost per positive case (€152), and the cost per partner notified and treated (€74). The costs of ’Pee-in-a-pot’ screening were presented in terms of the cost per negative case (€39), the cost per positive case (€125), and the cost per partner notified and treated (€74). In both analyses, screening was estimated to result in fewer major outcomes, fewer QALYs lost, and higher healthcare costs compared to the control strategy. The incremental cost effectiveness analyses indicated that screening in the Clinical Setting would result in an incremental cost per MO averted of €6,093 and an incremental cost per QALY gained of €94,717. ’Pee-in-a-pot’ screening was estimated to result in incremental cost effectiveness ratios of €2,294 per MO averted and €34,486 per QALY gained respectively. In Ireland, there is no fixed and generally agreed cost effectiveness threshold below which health care technologies would be considered by policy makers to be costeffective. Nonetheless, on the basis of other technologies that are currently funded, it is not likely that screening delivered in the Clinical Setting, given an incremental cost per QALY in the region of the €94,717 found in this study, would be considered cost effective. ’Pee-in-a-pot’ screening in third level institution/college settings may be considered cost effective if a cost effectiveness threshold in the region of €45,000 per QALY gained is used. This is open to question, however, given the current economic climate and its resulting impact in terms of imposing further constraints on future healthcare budgets. It is also important to note that this strategy would have minimal in impact in reducing overall chlamydia prevalence in the population, if not supported by general population screening and prevention strategy

D-cycloserine augmentation of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders: a systematic review and meta-analysis of individual participant data

Importance: Whether and under which conditions D-cycloserine (DCS) augments the effects of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders is unclear. Objective: To clarify whether DCS is superior to placebo in augmenting the effects of cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders and to evaluate whether antidepressants interact with DCS and the effect of potential moderating variables. Data Sources: PubMed, EMBASE, and PsycINFO were searched from inception to February 10, 2016. Reference lists of previous reviews and meta-analyses and reports of randomized clinical trials were also checked. Study Selection: Studies were eligible for inclusion if they were (1) double-blind randomized clinical trials of DCS as an augmentation strategy for exposure-based cognitive behavior therapy and (2) conducted in humans diagnosed as having specific phobia, social anxiety disorder, panic disorder with or without agoraphobia, obsessive-compulsive disorder, or posttraumatic stress disorder. Data Extraction and Synthesis: Raw data were obtained from the authors and quality controlled. Data were ranked to ensure a consistent metric across studies (score range, 0-100). We used a 3-level multilevel model nesting repeated measures of outcomes within participants, who were nested within studies. Results: Individual participant data were obtained for 21 of 22 eligible trials, representing 1047 of 1073 eligible participants. When controlling for antidepressant use, participants receiving DCS showed greater improvement from pretreatment to posttreatment (mean difference, -3.62; 95% CI, -0.81 to -6.43; P = .01; d = -0.25) but not from pretreatment to midtreatment (mean difference, -1.66; 95% CI, -4.92 to 1.60; P = .32; d = -0.14) or from pretreatment to follow-up (mean difference, -2.98, 95% CI, -5.99 to 0.03; P = .05; d = -0.19). Additional analyses showed that participants assigned to DCS were associated with lower symptom severity than those assigned to placebo at posttreatment and at follow-up. Antidepressants did not moderate the effects of DCS. None of the prespecified patient-level or study-level moderators was associated with outcomes. Conclusions and Relevance: D-cycloserine is associated with a small augmentation effect on exposure-based therapy. This effect is not moderated by the concurrent use of antidepressants. Further research is needed to identify patient and/or therapy characteristics associated with DCS response.2018-05-0

Inhibition of Transforming Growth Factor ␤ Signaling Reduces Pancreatic Adenocarcinoma Growth and Invasiveness □ S

ABSTRACT Transforming growth factor ␤ (TGF␤) is a pleiotropic factor that regulates cell proliferation, angiogenesis, metastasis, and immune suppression. Dysregulation of the TGF␤ pathway in tumor cells often leads to resistance to the antiproliferative effects of TGF␤ while supporting other cellular processes that promote tumor invasiveness and growth. In the present study, SD-208, a 2,4-disubstituted pteridine, ATP-competitive inhibitor of the TGF␤ receptor I kinase (TGF␤RI), was used to inhibit cellular activities and tumor progression of PANC-1, a human pancreatic tumor line. SD-208 blocked TGF␤-dependent Smad2 phosphorylation and expression of TGF␤-inducible proteins in cell culture. cDNA microarray analysis and functional gene clustering identified groups of TGF␤-regulated genes involved in metastasis, angiogenesis, cell proliferation, survival, and apoptosis. These gene responses were inhibited by SD-208. Using a Boyden chamber motility assay, we demonstrated that SD-208 inhibited TGF␤-stimulated invasion in vitro. An orthotopic xenograft mouse model revealed that SD-208 reduced primary tumor growth and decreased the incidence of metastasis in vivo. Our findings suggest mechanisms through which TGF␤ signaling may promote tumor progression in pancreatic adenocarcinoma. Moreover, they suggest that inhibition of TGF␤RI with a small-molecule inhibitor may be effective as a therapeutic approach to treat human pancreatic cancer

Targeting succinate dehydrogenase with malonate ester prodrugs decreases renal ischemia reperfusion injury

Renal ischemia reperfusion (IR) injury leads to significant patient morbidity and mortality, and its amelioration is an urgent unmet clinical need. Succinate accumulates during ischemia and its oxidation by the mitochondrial enzyme succinate dehydrogenase (SDH) drives the ROS production that underlies IR injury. Consequently, compounds that inhibit SDH may have therapeutic potential against renal IR injury. Among these, the competitive SDH inhibitor malonate, administered as a cell-permeable malonate ester prodrug, has shown promise in models of cardiac IR injury, but the efficacy of malonate ester prodrugs against renal IR injury have not been investigated. Here we show that succinate accumulates during ischemia in mouse, pig and human models of renal IR injury, and that its rapid oxidation by SDH upon reperfusion drives IR injury. We then show that the malonate ester prodrug, dimethyl malonate (DMM), can ameliorate renal IR injury when administered at reperfusion but not prior to ischemia in the mouse. Finally, we show that another malonate ester prodrug, diacetoxymethyl malonate (MAM), is more potent than DMM because of its faster esterase hydrolysis. Our data show that the mitochondrial mechanisms of renal IR injury are conserved in the mouse, pig and human and that inhibition of SDH by ‘tuned’ malonate ester prodrugs, such as MAM, is a promising therapeutic strategy in the treatment of clinical renal IR injury