The influence of voxelotor on cerebral blood flow and oxygen extraction in pediatric sickle cell disease.

ABSTRACT: Voxelotor is an inhibitor of sickle hemoglobin polymerization that is used to treat sickle cell disease. Although voxelotor has been shown to improve anemia, the clinical benefit on the brain remains to be determined. This study quantified the cerebral hemodynamic effects of voxelotor in children with sickle cell anemia (SCA) using noninvasive diffuse optical spectroscopies. Specifically, frequency-domain near-infrared spectroscopy combined with diffuse correlation spectroscopy were used to noninvasively assess regional oxygen extraction fraction (OEF), cerebral blood volume, and an index of cerebral blood flow (CBFi). Estimates of CBFi were first validated against arterial spin-labeled magnetic resonance imaging (ASL-MRI) in 8 children with SCA aged 8 to 18 years. CBFi was significantly positively correlated with ASL-MRI-measured blood flow (R2 = 0.651; P = .015). Next, a single-center, open-label pilot study was completed in 8 children with SCA aged 4 to 17 years on voxelotor, monitored before treatment initiation and at 4, 8, and 12 weeks (NCT05018728). By 4 weeks, both OEF and CBFi significantly decreased, and these decreases persisted to 12 weeks (both P < .05). Decreases in CBFi were significantly correlated with increases in blood hemoglobin (Hb) concentration (P = .025), whereas the correlation between decreases in OEF and increases in Hb trended toward significance (P = .12). Given that previous work has shown that oxygen extraction and blood flow are elevated in pediatric SCA compared with controls, these results suggest that voxelotor may reduce cerebral hemodynamic impairments. This trial was registered at www.ClinicalTrials.gov as #NCT05018728.

Effect of a Low Free Sugar Diet vs Usual Diet on Nonalcoholic Fatty Liver Disease in Adolescent Boys: A Randomized Clinical Trial.

Importance: Pediatric guidelines for the management of nonalcoholic fatty liver disease (NAFLD) recommend a healthy diet as treatment. Reduction of sugary foods and beverages is a plausible but unproven treatment. Objective: To determine the effects of a diet low in free sugars (those sugars added to foods and beverages and occurring naturally in fruit juices) in adolescent boys with NAFLD. Design, Setting, and Participants: An open-label, 8-week randomized clinical trial of adolescent boys aged 11 to 16 years with histologically diagnosed NAFLD and evidence of active disease (hepatic steatosis >10% and alanine aminotransferase level ≥45 U/L) randomized 1:1 to an intervention diet group or usual diet group at 2 US academic clinical research centers from August 2015 to July 2017; final date of follow-up was September 2017. Interventions: The intervention diet consisted of individualized menu planning and provision of study meals for the entire household to restrict free sugar intake to less than 3% of daily calories for 8 weeks. Twice-weekly telephone calls assessed diet adherence. Usual diet participants consumed their regular diet. Main Outcomes and Measures: The primary outcome was change in hepatic steatosis estimated by magnetic resonance imaging proton density fat fraction measurement between baseline and 8 weeks. The minimal clinically important difference was assumed to be 4%. There were 12 secondary outcomes, including change in alanine aminotransferase level and diet adherence. Results: Forty adolescent boys were randomly assigned to either the intervention diet group or the usual diet group (20 per group; mean [SD] age, 13.0 [1.9] years; most were Hispanic [95%]) and all completed the trial. The mean decrease in hepatic steatosis from baseline to week 8 was significantly greater for the intervention diet group (25% to 17%) vs the usual diet group (21% to 20%) and the adjusted week 8 mean difference was -6.23% (95% CI, -9.45% to -3.02%; P < .001). Of the 12 prespecified secondary outcomes, 7 were null and 5 were statistically significant including alanine aminotransferase level and diet adherence. The geometric mean decrease in alanine aminotransferase level from baseline to 8 weeks was significantly greater for the intervention diet group (103 U/L to 61 U/L) vs the usual diet group (82 U/L to 75 U/L) and the adjusted ratio of the geometric means at week 8 was 0.65 U/L (95% CI, 0.53 to 0.81 U/L; P < .001). Adherence to the diet was high in the intervention diet group (18 of 20 reported intake of <3% of calories from free sugar during the intervention). There were no adverse events related to participation in the study. Conclusions and Relevance: In this study of adolescent boys with NAFLD, 8 weeks of provision of a diet low in free sugar content compared with usual diet resulted in significant improvement in hepatic steatosis. However, these findings should be considered preliminary and further research is required to assess long-term and clinical outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02513121.

Effect of repetition time on metabolite quantification in the human brain in 1 H MR spectroscopy at 3 tesla.

PURPOSE: To examine the effects of repetition time (TR) on metabolite concentration measurements in the human brain in 1 H magnetic resonance spectroscopy at 3 Tesla (T). MATERIALS AND METHODS: Spectra were acquired from the posterior cingulate of five healthy adults at repetition times of 1.5 s, 3.0 s, 4.0 s, 6.0 s, and 8.0 s on a 3T MRI system. Relaxation data were also acquired for the water signal in the voxel of interest to separate tissue water and cerebrospinal fluid signal contributions. All data were quantified relative to total creatine and relative to the tissue water signal. RESULTS: On average, the variance for absolute metabolite concentrations was smaller than that of ratio concentrations (P = 0.003). Metabolite ratio concentrations calculated from a short TR of 1.5 s significantly differed (P < 0.05) from their "true" ratios, i.e., ratios corrected for T1 -weighting. In comparison, absolute metabolite concentrations exhibited significant differences (P < 0.05) up to a 4-s TR. CONCLUSION: To minimize potential TR-dependent concentration differences at 3T, a minimum TR of 2.5 s is suggested for ratio concentration measurements, and a 5-s TR for absolute concentrations. When possible, preference should be to perform absolute concentration measurements. LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017;45:710-721.

Lake Nutrient Responses to Integrated Conservation Practices in an Agricultural Watershed.

Watershed-scale management efforts to reduce nutrient loads and improve the conservation of lakes in agricultural watersheds require effective integration of a variety of agricultural conservation best management practices (BMPs). This paper documents watershed-scale assessments of the influence of multiple integrated BMPs on oxbow lake nutrient concentrations in a 625-ha watershed of intensive row-crop agricultural activity during a 14-yr monitoring period (1996-2009). A suite of BMPs within fields and at field edges throughout the watershed and enrollment of 87 ha into the Conservation Reserve Program (CRP) were implemented from 1995 to 2006. Total phosphorus (TP), soluble reactive phosphorus (SRP), ammonium, and nitrate were measured approximately biweekly from 1996 to 2009, and total nitrogen (TN) was measured from 2001 to 2009. Decreases in several lake nutrient concentrations occurred after BMP implementation. Reductions in TP lake concentrations were associated with vegetative buffers and rainfall. No consistent patterns of changes in TN or SRP lake concentrations were observed. Reductions in ammonium lake concentrations were associated with conservation tillage and CRP. Reductions in nitrate lake concentrations were associated with vegetative buffers. Watershed simulations conducted with the AnnAGNPS (Annualized Agricultural Non-Point Source) model with and without BMPs also show a clear reduction in TN and TP loads to the lake after the implementation of BMPs. These results provide direct evidence of how watershed-wide BMPs assist in reducing nutrient loading in aquatic ecosystems and promote a more viable and sustainable lake ecosystem.

Engineered zinc-finger transcription factors activate OCT4 (POU5F1), SOX2, KLF4, c-MYC (MYC) and miR302/367.

Artificial transcription factors are powerful tools for regulating gene expression. Here we report results with engineered zinc-finger transcription factors (ZF-TFs) targeting four protein-coding genes, OCT4, SOX2, KLF4 and c-MYC, and one noncoding ribonucleic acid (RNA) gene, the microRNA (miRNA) miR302/367 cluster. We designed over 300 ZF-TFs whose targets lie within 1 kb of the transcriptional start sites (TSSs), screened them for increased messenger RNA or miRNA levels in transfected cells, and identified potent ZF-TF activators for each gene. Furthermore, we demonstrate that selected ZF-TFs function with alternative activation domains and in multiple cell lines. For OCT4, we expanded the target range to -2.5 kb and +500 bp relative to the TSS and identified additional active ZF-TFs, including three highly active ZF-TFs targeting distal enhancer, proximal enhancer and downstream from the proximal promoter. Chromatin immunoprecipitation (FLAG-ChIP) results indicate that several inactive ZF-TFs targeting within the same regulatory region bind as well as the most active ZF-TFs, suggesting that efficient binding within one of these regulatory regions may be necessary but not sufficient for activation. These results further our understanding of ZF-TF design principles and corroborate the use of ZF-TFs targeting enhancers and downstream from the TSS for transcriptional activation.

MRI and Blood-based Biomarkers Are Associated With Surgery in Children and Adults With Ileal Crohn's Disease.

BACKGROUND: Despite advances in medical therapy, many children and adults with ileal Crohn's disease (CD) progress to fibrostenosis requiring surgery. We aimed to identify MRI and circulating biomarkers associated with the need for surgical management. METHODS: This prospective, multicenter study included pediatric and adult CD cases undergoing ileal resection and CD controls receiving medical therapy. Noncontrast research MRI examinations measured bowel wall 3-dimensional magnetization transfer ratio normalized to skeletal muscle (normalized 3D MTR), modified Look-Locker inversion recovery (MOLLI) T1 relaxation, intravoxel incoherent motion (IVIM) diffusion-weighted imaging metrics, and the simplified magnetic resonance index of activity (sMaRIA). Circulating biomarkers were measured on the same day as the research MRI and included CD64, extracellular matrix protein 1 (ECM1), and granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies (Ab). Associations between MRI and circulating biomarkers and need for ileal resection were tested using univariate and multivariable LASSO regression. RESULTS: Our study sample included 50 patients with CD undergoing ileal resection and 83 patients with CD receiving medical therapy; mean participant age was 23.9 ±â€…13.1 years. Disease duration and treatment exposures did not vary between the groups. Univariate biomarker associations with ileal resection included log GM-CSF Ab (odds ratio [OR], 2.87; P = .0009), normalized 3D MTR (OR, 1.05; P = .002), log MOLLI T1 (OR, 0.01; P = .02), log IVIM perfusion fraction (f; OR, 0.38; P = .04), and IVIM apparent diffusion coefficient (ADC; OR, 0.3; P = .001). The multivariable model for surgery based upon corrected Akaike information criterion included age (OR, 1.03; P = .29), BMI (OR, 0.91; P = .09), log GM-CSF Ab (OR, 3.37; P = .01), normalized 3D MTR (OR, 1.07; P = .007), sMaRIA (OR, 1.14; P = .61), luminal narrowing (OR, 10.19; P = .003), log C-reactive protein (normalized; OR, 2.75; P = .10), and hematocrit (OR, 0.90; P = .13). CONCLUSION: After accounting for clinical and MRI measures of severity, normalized 3D MTR and GM-CSF Ab are associated with the need for surgery in ileal CD.

Despite advances in medical therapy, many patients with ileal Crohn's disease progress to fibrostenosis requiring surgery. Our study has shown that GM-CSF autoantibodies and MRI biomarker sequences are associated with the need for ileal resection and may help guide management decisions.

Impact of Smart Snacks Intervention on College Students' Vending Selections.

OBJECTIVES: To place Smart Snacks in vending machines and determine if different sales strategies affect Smart Snack selection. PARTICIPANTS: University students living in resident halls. METHODS: Vending machines included 50% Smart Snacks and 50% non compliant snacks. Three sales strategies targeted student selection of Smart Snacks: Reduced price, signage, and nutrition education activities. Three-way ANOVA was used for analysis. RESULTS: There was a statistically significant three-way interaction on snack selection between sales strategy, study period, and snack type, F(4, 77) = 3.33, P = .01. There were no statistically significant simple two-way interaction between study period and sales strategy for either Smart Snack, F(1, 77) = 1.62, P = 0.18, or NC snack types, F(1, 77) = 2.02, P = 0.07. CONCLUSIONS: Sales strategies did not affect Smart Snack selections. Advocates for healthier snacks in vending machines can align with university administrations to establish nutrient guidelines.

Diagnostic Excellence in Pediatric Spine Imaging: Using Contextualized Imaging Protocols.

Contextual design and selection of MRI protocols is critical for making an accurate diagnosis given the wide variety of clinical indications for spine imaging in children. Here, we describe our pediatric spine imaging protocols in detail, tailored to specific clinical questions.

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.

RNA interference in marine and freshwater sponges: actin knockdown in Tethya wilhelma and Ephydatia muelleri by ingested dsRNA expressing bacteria.

BACKGROUND: The marine sponge Tethya wilhelma and the freshwater sponge Ephydatia muelleri are emerging model organisms to study evolution, gene regulation, development, and physiology in non-bilaterian animal systems. Thus far, functional methods (i.e., loss or gain of function) for these organisms have not been available. RESULTS: We show that soaking developing freshwater sponges in double-stranded RNA and/or feeding marine and freshwater sponges bacteria expressing double-stranded RNA can lead to RNA interference and reduction of targeted transcript levels. These methods, first utilized in C. elegans, have been adapted for the development and feeding style of easily cultured marine and freshwater poriferans. We demonstrate phenotypic changes result from 'knocking down' expression of the actin gene. CONCLUSION: This technique provides an easy, efficient loss-of-function manipulation for developmental and gene regulatory studies in these important non-bilaterian animals.

Very short echo time improves the precision of glutamate detection at 3T in 1H magnetic resonance spectroscopy.

PURPOSE: To examine the precision of glutamate detection using a very short echo time (TE) phase rotation STEAM (PR-STEAM) sequence. MATERIALS AND METHODS: Spectrosopic data were acquired from the anterior cingulate gyrus in nine healthy adults using 6.5-msec TE PR-STEAM, 40-msec TE PRESS, 72-msec TE STEAM, and TE-Averaging with an effective TE of 105 msec on a clinical 3T magnetic resonance imaging (MRI) system. All data were quantified using LCModel and reported as ratios relative to total creatine. RESULTS: Glutamate Cramer-Rao lower bounds were less than 8% for all sequences. The 6.5-msec TE PR-STEAM identified glutamate with the greatest precision (coefficient of variation [CV] of 7.1%), followed by TE-Averaging (CV of 8.9%), 40-msec TE PRESS (CV of 11.9%), and 72-msec TE STEAM (CV of 13.8%). CONCLUSION: In the absence of spectral editing, glutamate is best detected in the human brain at 3T using very short TEs.

Dietary sugar restriction reduces hepatic de novo lipogenesis in adolescent boys with fatty liver disease.

BACKGROUNDHepatic de novo lipogenesis (DNL) is elevated in nonalcoholic fatty liver disease (NAFLD). Improvements in hepatic fat by dietary sugar reduction may be mediated by reduced DNL, but data are limited, especially in children. We examined the effects of 8 weeks of dietary sugar restriction on hepatic DNL in adolescents with NAFLD and correlations between DNL and other metabolic outcomes.METHODSAdolescent boys with NAFLD (n = 29) participated in an 8-week, randomized controlled trial comparing a diet low in free sugars versus their usual diet. Hepatic DNL was measured as percentage contribution to plasma triglyceride palmitate using a 7-day metabolic labeling protocol with heavy water. Hepatic fat was measured by magnetic resonance imaging-proton density fat fraction.RESULTSHepatic DNL was significantly decreased in the treatment group (from 34.6% to 24.1%) versus the control group (33.9% to 34.6%) (adjusted week 8 mean difference: -10.6% [95% CI: -19.1%, -2.0%]), which was paralleled by greater decreases in hepatic fat (25.5% to 17.9% vs. 19.5% to 18.8%) and fasting insulin (44.3 to 34.7 vs. 35.5 to 37.0 µIU/mL). Percentage change in DNL during the intervention correlated significantly with changes in free-sugar intake (r = 0.48, P = 0.011), insulin (r = 0.40, P = 0.047), and alanine aminotransferase (ALT) (r = 0.39, P = 0.049), but not hepatic fat (r = 0.13, P = 0.532).CONCLUSIONOur results suggest that dietary sugar restriction reduces hepatic DNL and fasting insulin, in addition to reductions in hepatic fat and ALT, among adolescents with NAFLD. These results are consistent with the hypothesis that hepatic DNL is a critical metabolic abnormality linking dietary sugar and NAFLD.TRIAL REGISTRYClinicalTrials.gov NCT02513121.FUNDINGThe Nutrition Science Initiative (made possible by gifts from the Laura and John Arnold Foundation, Ambrose Monell Foundation, and individual donors), the UCSD Altman Clinical and Translational Research Institute, the NIH, Children's Healthcare of Atlanta and Emory University's Children's Clinical and Translational Discovery Core, Children's Healthcare of Atlanta and Emory University Pediatric Biostatistical Core, the Georgia Clinical and Translational Science Alliance, and the NIH National Institute of Diabetes, Digestive, and Kidney Disease.

Toxicity evaluation of a conservation effects assessment program watershed, Beasley Lake, in the Mississippi Delta, USA.

Beasley Lake was assessed monthly in 2005 for biological impairment from 17 historic and current-use pesticides in water and leaf litter using Hyalella azteca (Saussure). Sixteen pesticides were detected in both water and leaf litter with peak detections in spring and summer. Detections ranged from 1-125 ng L(-1) in water and 1-539 ng g(-1) OC in leaf litter. Ten-day H. azteca survival and growth (mg dw) bioassay results indicated no adverse effects on survival or growth in H. azteca exposed to water or leaf litter. Rather, enhanced growth occurred in both lake water and leaf litter exposures for 8 and 6 months, respectively.

Agricultural pesticides in Mississippi Delta oxbow lake sediments during autumn and their effects on Hyalella azteca.

Agricultural pesticide contamination of sediments from five Mississippi Delta oxbow lakes and their effects and bioavailablity to Hyalella azteca were assessed during a low-application season-autumn. Three reference oxbow lakes were located in the White River National Wildlife Refuge (WRNWR), Arkansas and two impaired lakes, according to the US Environmental Agency Sect. 303 (d) Clean Water Act, were located in Mississippi. Surface sediment (top 5 cm) was collected at three sites within each lake and analyzed for 17 current and historic-use pesticides and metabolites. Chronic 28-day H. azteca sediment bioassays and pesticide body residue analyses were completed to determine the degree of biological responses and bioavailability. The greatest number of detectable pesticides in WRNWR and 303 (d) sediment samples was 9 and 12, respectively, with historic-use pesticide metabolite, p,p'-DDE [1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene] ubiquitous. No significant (p > 0.05) differences in animal survival were observed among sites. Animal growth was significantly (p < 0.05) less at only one site in a 303 (d)-listed lake (Macon Lake). Only six pesticides were observed in H. azteca with current-use pesticides detected at three sites; historic-use pesticides and metabolites detected at 11 sites. Animal body residues of a historic-use pesticide (dieldrin) and metabolite (p,p'-DDE) were associated with observed growth responses. Results show limited current-use pesticide contamination of sediments and H. azteca body tissues during autumn and that historic-use pesticides and metabolites are the primary contributors to observed biological responses.

Hyalella azteca (Saussure) responses to Coldwater River backwater sediments in Mississippi, USA.

Sediment from three Coldwater River, Mississippi backwaters was examined using 28 day Hyalella azteca bioassays and chemical analyses for 33 pesticides, seven metals and seven PCB mixtures. Hydrologic connectivity between the main river channel and backwater varied widely among the three sites. Mortality occurred in the most highly connected backwater while growth impairment occurred in the other two. Precopulatory guarding behavior was not as sensitive as growth. Fourteen contaminants (seven metals, seven pesticides) were detected in sediments. Survival was associated with the organochlorine insecticide heptachlor.

Effects of an atrazine, metolachlor and fipronil mixture on Hyalella azteca (Saussure) in a modified backwater wetland.

We examined the toxicity mitigation efficiency of a hydrologically modified backwater wetland amended with a pesticide mixture of atrazine, metolachlor, and fipronil, using 96 h survival bioassays with Hyalella azteca. Significant H. azteca 96 h mortality occurred within the first 2 h of amendment at the upstream amendment site but not at any time at the downstream site. H. azteca survival varied spatially and temporally in conjunction with measured pesticide mixture concentrations. Hyalella azteca 96 h survival pesticide mixture effects concentrations ranges were 10.214­11.997, 5.822­6.658, 0.650­0.817, and 0.030­0.048 µg L−1 for atrazine, metolachlor, fipronil, and fipronil-sulfone, respectively.

Development of a Plasma Screening Panel for Pediatric Nonalcoholic Fatty Liver Disease Using Metabolomics.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children, but diagnosis is challenging due to limited availability of noninvasive biomarkers. Machine learning applied to high-resolution metabolomics and clinical phenotype data offers a novel framework for developing a NAFLD screening panel in youth. Here, untargeted metabolomics by liquid chromatography-mass spectrometry was performed on plasma samples from a combined cross-sectional sample of children and adolescents ages 2-25 years old with NAFLD (n = 222) and without NAFLD (n = 337), confirmed by liver biopsy or magnetic resonance imaging. Anthropometrics, blood lipids, liver enzymes, and glucose and insulin metabolism were also assessed. A machine learning approach was applied to the metabolomics and clinical phenotype data sets, which were split into training and test sets, and included dimension reduction, feature selection, and classification model development. The selected metabolite features were the amino acids serine, leucine/isoleucine, and tryptophan; three putatively annotated compounds (dihydrothymine and two phospholipids); and two unknowns. The selected clinical phenotype variables were waist circumference, whole-body insulin sensitivity index (WBISI) based on the oral glucose tolerance test, and blood triglycerides. The highest performing classification model was random forest, which had an area under the receiver operating characteristic curve (AUROC) of 0.94, sensitivity of 73%, and specificity of 97% for detecting NAFLD cases. A second classification model was developed using the homeostasis model assessment of insulin resistance substituted for the WBISI. Similarly, the highest performing classification model was random forest, which had an AUROC of 0.92, sensitivity of 73%, and specificity of 94%. Conclusion: The identified screening panel consisting of both metabolomics and clinical features has promising potential for screening for NAFLD in youth. Further development of this panel and independent validation testing in other cohorts are warranted.

Glia maturation factor overexpression in neuroblastoma cells activates glycogen synthase kinase-3beta and caspase-3.

In the present study we report that a replication-defective adenovirus construct of GMF cDNA (GMF-V) induced overexpression of GMF protein in neuroblastoma (N18) cells caused cytotoxicity and loss of cell viability. A significant increase in activation of GSK-3beta occurred after infection with GMF-V when compared with mock and lacZ controls. Overexpression of GMF also increased caspase-3 activity, an early marker of apoptosis. Depletion of GMF gene by introducing GMF-specific siRNA (GsiRNA) completely blocked both activation of GSK-3beta and caspase-3 activation whereas a control scrambled siRNA (CsiRNA) had no effect. A cell-permeable peptide inhibitor of GSK-3beta, and lithium completely prevented GMF-dependent activation of caspase-3. These results demonstrate that GSK-3 mediates activation of the death domain caspase by GMF overexpression. We also show that the phosphorylation of GSK-3-dependent site of Tau was a consequence of GMF-overexpression in N18 cells. Taken together our results imply that GMF is involved in the signaling leading to the activation of GSK-3beta and caspase-3 in N18 cells and strongly suggest its involvement in neurodegeneration since GSK-3beta is known to hyperphosphorylate tau which is associated with the neurotoxicity of neurofibrillary tangles in Alzheimer's disease.

Physical activity in the Families in Transformation (FIT) weight management program for children.

Background: The purpose was to determine if an 8-week nutrition education and exercise program for families could influence health and fitness parameters, and retention of nutrition knowledge. Methods: Eighteen children (mean age: 10.52 ± 1.26 year; 50% boys, 50% girls; 56% white, 25% black, 19% multiracial) participated in the Families in Transformation (FIT) program. Preand post-study anthropocentric, blood pressure, fitness, and nutrition knowledge data was collected. Results: Diastolic blood pressure decreased for the total group (66.63 ± 8.81 to 63.75 ± 11.81mm Hg). Significant (P < 0.05) increases were seen for the group for push-ups (14.31 ± 7.62 to 19.63 ± 6.62) and chair squats (30.50 ± 10.21 to 34.44 ± 7.39). The reinforcing physical activity group performed significantly better on nutrition knowledge quizzes. Conclusion: Although, body mass index (BMI) z-scores did not change, there was a decrease in diastolic blood pressure, increase in fitness parameters, and increased retention of nutrition knowledge.

Increased glucose concentration in the hippocampus in early Alzheimer's disease following oral glucose ingestion.

Glucose is the primary source of energy for brain cells. Because energy storage in the brain is limited, an uninterrupted supply of glucose and its rapid metabolism are essential for normal cognitive function. This study utilized an oral glucose load to examine hippocampal glucose metabolism in early Alzheimer's disease (AD) - a disease characterized by progressive deterioration of cognitive function and glucose hypometabolism. Short echo time 1H MR spectra (20 ms) from the right hippocampus of 8 patients with probable AD, 14 healthy elderly and 14 healthy young adults were compared pre- and post-glucose loading. In contrast to the healthy adults, the AD patients exhibited significantly elevated hippocampal glucose concentrations post-glucose ingestion relative to baseline (P < .01). These results suggest that cerebral glucose hypometabolism in AD leads to an increased steady-state concentration of cerebral glucose. This research demonstrates the feasibility of studying cerebral glucose metabolism in AD with 1H MR spectroscopy.