Thermoneutral Housing Enables Studies of Vertical Transmission of Obesogenic Diet-Driven Metabolic Diseases.

Vertical transmission of obesity is a critical contributor to the unabated obesity pandemic and the associated surge in metabolic diseases. Existing experimental models insufficiently recapitulate "human-like" obesity phenotypes, limiting the discovery of how severe obesity in pregnancy instructs vertical transmission of obesity. Here, via utility of thermoneutral housing and obesogenic diet feeding coupled to syngeneic mating of WT obese female and lean male mice on a C57BL/6 background, we present a tractable, more "human-like" approach to specifically investigate how maternal obesity contributes to offspring health. Using this model, we found that maternal obesity decreased neonatal survival, increased offspring adiposity, and accelerated offspring predisposition to obesity and metabolic disease. We also show that severe maternal obesity was sufficient to skew offspring microbiome and create a proinflammatory gestational environment that correlated with inflammatory changes in the offspring in utero and adulthood. Analysis of a human birth cohort study of mothers with and without obesity and their infants was consistent with mouse study findings of maternal inflammation and offspring weight gain propensity. Together, our results show that dietary induction of obesity in female mice coupled to thermoneutral housing can be used for future mechanistic interrogations of obesity and metabolic disease in pregnancy and vertical transmission of pathogenic traits.

Nutrition for critically ill children with congenital heart disease.

Children with congenital heart disease often require admission to the cardiac intensive care unit at some point in their lives, either after elective surgical or catheter-based procedures or during times of acute critical illness. Meeting both the macronutrient and micronutrient needs of children in the cardiac intensive care unit requires complex decision-making when considering gastrointestinal perfusion, vasoactive support, and fluid balance goals. Although nutrition guidelines exist for critically ill children, these cannot always be extrapolated to children with congenital heart disease. Children with congenital heart disease may also suffer unique circumstances, such as chylothoraces, heart failure, and the need for mechanical circulatory support, which greatly impact nutrition delivery. Guidelines for neonates and children with heart disease continue to be developed. We provide a synthesized narrative review of current literature and considerations for nutrition evaluation and management of critically ill children with congenital heart disease.

Presence of Alpha 1 Antitrypsin Risk Variants is Not Associated With Histologic Severity of Pediatric NAFLD.

BACKGROUND: Among adults with nonalcoholic fatty liver disease (NAFLD), alpha-1-antitrypsin (A1AT) heterozygosity has been linked to advanced liver disease; pediatric data remain unclear. OBJECTIVE: The objective of this study is to determine whether A1AT PiZ or PiS variants are associated with liver disease severity in youth with NAFLD. METHODS: Retrospective study of youth with confirmed NAFLD. Multivariable logistic regression used to determine independent associations between A1AT risk variants and histologic severity [NAFLD activity score (NAS) ≥5 and/or significant fibrosis (stage ≥2)]. RESULTS: The cohort included 269 patients, mean age 12 [±3] years with NAFLD and A1AT phenotyping (n = 260) and/or A1AT levels (n = 261). The mean NAS of the cohort was 4.2 [±1.5]; 50% had any, and 18% had significant fibrosis. Most (86%) had the MM A1AT phenotype, while 7% had the MS and 3% the MZ phenotype (the rest had other, nonpathogenic variants). Mean A1AT level was 123 mg/dL [±20]. A1AT levels did not differ by low versus high NAS (122 ± 2 vs 126 ± 19 mg/dL, P = 0.12) or by no/mild versus significant fibrosis (123 ± 20 vs 126 ± 20 mg/dL, P = 0.23, respectively). Carriers and noncarriers of the PiS or PiZ variants had similar NAS (mean NAS 3.8 ± 1.6 vs 4.2 ± 1.4; P = 0.25, respectively). Fibrosis severity did not differ by carrier vs noncarrier group: 38% versus 52% had any fibrosis ( P = 0.17) and 14% versus 18% had significant fibrosis ( P = 0.80, respectively). Multivariable modeling showed no association between A1AT risk variants and histologic severity. CONCLUSION: While not uncommon, carriage of the A1AT PiZ or PiS risk variants was not associated with histologic severity in children with NAFLD.

Pediatric formulas: Categories, composition, and considerations.

Formulas, liquid nutrition, may be consumed orally or via a feeding tube to provide partial or complete nutrition that a given individual could not obtain using natural food stuffs in their native form. A wide range of commercially available formulas exist, which may be used as sole-source nutrition or in conjunction with other foods. Physicians and dietitians must understand the nature of and indications for specific formulas to treat diseases, provide complete nutrition to patients, and avoid harm. Products vary in macronutrient and micronutrient content and calorie concentration among many other factors. They are formulated specifically for patients of specific ages, correlating to nutritional needs and medical diagnoses. Additionally, formula availability, insurance coverage, mode of consumption, physiologic tolerance, and caregiver preference influence formula selection. Caregivers may also make their own pediatric formulas. We review commercial and homemade pediatric formulas.

BMI Metrics Are Poor Predictors of Pediatric Nonalcoholic Fatty Liver Disease Severity.

Background: Alternative BMI metrics are superior to BMI z score (BMIz) in tracking obesity but have not been evaluated in patients with nonalcoholic fatty liver disease (NAFLD). Our objective was to evaluate whether BMI-adjusted z score (BMIaz) or BMI expressed as a percentage of the 95th percentile (%BMIp95) are better predictors of degree of alanine aminotransferase (ALT) elevation, a surrogate for NAFLD severity, compared with BMIz in patients with NAFLD. Methods: A retrospective study of 776 subjects aged 2-18 years with BMIz > 1.0 followed in a NAFLD subspecialty clinic was conducted. Regression analysis was used to determine predictors of elevated ALT. Results: There was no association between BMIz, BMIaz, or %BMIp95 and degree of ALT elevation using linear or logistic regression. Conclusion: These results do not support the use of alternative BMI metrics for evaluating NAFLD severity. Future studies should investigate longitudinal assessments and correlation with histology.

Nonalcoholic Fatty Liver Disease in Young Children with Obesity.

Background: To evaluate the prevalence of suspected nonalcoholic fatty liver disease (NAFLD) in young children with obesity and determine associated risk factors. Methods: Retrospective single-center study of children with obesity, ages 2-6 years. Suspected NAFLD was defined as an alanine aminotransferase (ALT) >30 U/L. Multivariable analyses were performed to determine predictors of elevated ALT. Results: Among 237 children 2-6 years old, 35% had elevated ALT. Multivariable analysis showed that higher BMI z score [odds ratio (OR): 1.5 confidence interval (95% CI: 1.04-1.92)] and higher gamma-glutamyl transferase (GGT) [OR: 21.3 (95% CI: 3.7-121.1)] predicted elevated ALT. Of those with ≥2 ALT levels, 38% (n = 33/86) had a persistently elevated ALT (median ALT >30 U/L). Only 7% of patients with ALT >30 U/L underwent further testing to evaluate for alternative causes of liver disease. Conclusion: Suspected NAFLD is common in young children with obesity and predicted by obesity severity and GGT. Other cardiometabolic markers were equivalent between those with normal vs. elevated ALT, suggesting NAFLD onset may precede development of comorbidities. Earlier screening will enable prompt diagnosis and intervention, which may prevent or delay the onset of cardiometabolic diseases commonly associated with NAFLD in adolescence and adulthood.

Clinically Meaningful Body Mass Index Change Impacts Pediatric Nonalcoholic Fatty Liver Disease.

OBJECTIVE: To investigate the prevalence and characteristics of children with nonalcoholic fatty liver disease (NAFLD) who reduce their body mass index (BMI) z-score (BMIz) by >.25, a goal in obesity medicine, and to determine the BMIz decrease needed for serum aminotransferase normalization. STUDY DESIGN: This retrospective, single-center study included patients aged <18 years followed for NAFLD. Patients who had undergone weight loss surgery or had other reasons for weight loss/gain were excluded. Logistic regression was used to determine the odds of achieving a BMIz change of >-.25, as well as predictors of this outcome. RESULTS: Of the 784 children who met the study criteria (median age, 13 years; 66% male; 24% Hispanic), 541 had a lowest BMIz at >90 days following the baseline clinic visit. Of these children, 168 (31%) had a BMIz change of >-.25 from baseline over a median of 367 days (IQR, 201-678 days). Decreases in serum aminotransferase and lipid levels were seen in both groups (with and without a BMIz change of >-.25); however, these decreases were more pronounced in children who achieved a BMIz drop of >.25. Hemoglobin A1c concentration did not change in either group. Young age (OR, .861; 95% CI, .81-.92; P < .01) and non-Hispanic ethnicity (OR of non-Hispanic vs Hispanic, .61; 95% CI, .38-.97; P < .04) were predictors of a BMIz change >-.25. The BMIz decrease associated with normalization of serum alanine aminotransferase was .27. CONCLUSIONS: A BMIz reduction of >.25 is associated with significant changes in serum aminotransferase levels. These findings can further guide the clinical management of children with NAFLD.

Impact of adenoviral stool load on adenoviremia in pediatric hematopoietic stem cell transplant recipients.

BACKGROUND: Adenoviremia adversely affects prognosis in the post-hematopoietic stem cell transplant setting. METHODS: We sought to determine retrospectively the cutoff load of adenovirus in the stool as a predictor of adenoviremia, in children who underwent an allogeneic hematopoietic stem cell transplant. The prevalence of sapovirus, norovirus and astrovirus in the stool was also studied. RESULTS: The study cohort consisted of 117 patients, of which 71 (60%) had diarrhea. Adenovirus was detected in the stool in 39 of 71 (55%) patients. Age ≤10 years (P = 0.05; odds ratio: 2.57; 95% confidence interval: 0.98-6.75) and male sex (P = 0.04; odds ratio: 2.67; 95% confidence interval: 1.02-6.99) increased risk for detection of adenovirus in stool on univariate analysis. Coinfections with enteric pathogens were infrequent. Viral load >10 copies/g stool predicted adenoviremia with a sensitivity and specificity of 82%. Sapovirus, norovirus and astrovirus were detected in 3, 4 and 1 patient, respectively. CONCLUSIONS: Quantitative detection of adenovirus in stool may have implications for preemptive therapy. Testing for other enteric viruses may have implications for infection control.

Reduced susceptibility of DNA methyltransferase 1 hypomorphic (Dnmt1N/+) mice to hepatic steatosis upon feeding liquid alcohol diet.

BACKGROUND: Methylation at C-5 (5-mdC) of CpG base pairs, the most abundant epigenetic modification of DNA, is catalyzed by 3 essential DNA methyltransferases (Dnmt1, Dnmt3a and Dnmt3b). Aberrations in DNA methylation and Dnmts are linked to different diseases including cancer. However, their role in alcoholic liver disease (ALD) has not been elucidated. METHODOLOGY/PRINCIPAL FINDINGS: Dnmt1 wild type (Dnmt1(+/+)) and hypomorphic (Dnmt1(N/+)) male mice that express reduced level of Dnmt1 were fed Lieber-DeCarli liquid diet containing ethanol for 6 weeks. Control mice were pair-fed calorie-matched alcohol-free liquid diet, and Dnmtase activity, 5-mdC content, gene expression profile and liver histopathology were evaluated. Ethanol feeding caused pronounced decrease in hepatic Dnmtase activity in Dnmt1(+/+) mice due to decrease in Dnmt1 and Dnmt3b protein levels and upregulation of miR-148 and miR-152 that target both Dnmt1 and Dnmt3b. Microarray and qPCR analysis showed that the genes involved in lipid, xenobiotic and glutathione metabolism, mitochondrial function and cell proliferation were dysregulated in the wild type mice fed alcohol. Surprisingly, Dnmt1(N/+) mice were less susceptible to alcoholic steatosis compared to Dnmt1(+/+) mice. Expression of several key genes involved in alcohol (Aldh3b1), lipid (Ppara, Lepr, Vldlr, Agpat9) and xenobiotic (Cyp39a1) metabolism, and oxidative stress (Mt-1, Fmo3) were significantly (P<0.05) altered in Dnmt1(N/+) mice relative to the wild type mice fed alcohol diet. However, CpG islands encompassing the promoter regions of Agpat9, Lepr, Mt1 and Ppara were methylation-free in both genotypes irrespective of the diet, suggesting that promoter methylation does not regulate their expression. Similarly, 5-mdC content of the liver genome, as measured by LC-MS/MS analysis, was not affected by alcohol diet in the wild type or hypomorphic mice. CONCLUSIONS/SIGNIFICANCE: Although feeding alcohol diet reduced Dnmtase activity, the loss of one copy of Dnmt1 protected mice from alcoholic hepatosteatosis by dysregulating genes involved in lipid metabolism and oxidative stress.