Parent-reported measure of repetitive behavior in Phelan-McDermid syndrome.

BACKGROUND: Phelan McDermid syndrome (PMS) is a neurogenetic condition associated with a high prevalence of intellectual disability (ID) and autism spectrum disorder (ASD). This study provides a more comprehensive and quantitative profile of repetitive behaviors within the context of ID seen with the condition. METHODS: Individuals age 3-21 years with a confirmed PMS diagnosis participated in a multicenter observational study evaluating the phenotype and natural history of the disorder. We evaluated data collected from this study pertaining to repetitive behaviors from the Repetitive Behavior Scales-Revised (RBS-R). RESULTS: There were n = 90 participants who were part of this analysis. Forty-seven percent (n = 42/90) were female, and the average age at baseline evaluation was 8.88 ± 4.72 years. The mean best estimate IQ of the cohort was 26.08 ± 17.67 (range = 3.4-88), with n = 8 with mild ID (or no ID), n = 20 with moderate ID, and n = 62 with severe-profound ID. The RBS-R total overall score was 16.46 ± 13.9 (compared to 33.14 ± 20.60 reported in previous studies of ASD) (Lam and Aman, 2007), and the total number of items endorsed was 10.40 ± 6.81 (range = 0-29). After statistical correction for multiple comparisons, IQ correlated with the RBS-R stereotypic behavior subscale score (rs = - 0.33, unadjusted p = 0.0014, adjusted p = 0.01) and RBS-R stereotypic behavior total number of endorsed items (rs = - 0.32, unadjusted p = 0.0019, adjusted p = 0.01). IQ did not correlate with any other RBS-R subscale scores. CONCLUSIONS: The RBS-R total overall score in a PMS cohort appears milder compared to individuals with ASD characterized in previous studies. Stereotypic behavior in PMS may reflect cognitive functioning.

The effects of child anxiety and depression on concordance between parent-proxy and self-reported health-related quality of life for pediatric liver transplant patients.

BACKGROUND: HRQOL is a key outcome following pediatric LT. Parent-proxy reports may substitute for patients unable to report their own HRQOL. This study compared parent-proxy and self-reported HRQOL in children who have undergone LT. METHODS: Pediatric LT recipients between the ages of 8 and 18 years, and a parent, completed self and proxy versions of the PeLTQL questionnaire, PedsQL Generic and Transplant modules, and standardized measures of depression and anxiety. RESULTS: Data from 129 parent-patient dyads were included. Median parent age was 44 years, and most (89%) were mothers. Median patient age was 2.5 years at LT and 13.6 years at the time of study participation. Parents had significantly lower scores than patients on PedsQL total generic (70.8 ± 18.5 and 74.3 ± 19.0, p = .01), PeLTQL coping and adjustment (63.0 ± 15.6 and 67.3 ± 16.2, p < .01), and social-emotional (66.3 ± 14.9 and 71.9 ± 15.6, p < .001) domains. Higher patient anxiety and depression were related to larger absolute differences between parent-proxy and self-reported scores on all HRQOL measures (all p < .05). In this disparity, parents reported higher HRQOL scores than their child as self-reported anxiety and depression scores increased. CONCLUSIONS: Differences in concordance between parent-proxy and self-reported HRQOL scores can be more prominent when children have more symptoms of anxiety and depression. Children's mental health symptoms should be queried, if feasible, when interpreting differences in parent and child reports of HRQOL.

Gastrokine-1, an anti-amyloidogenic protein secreted by the stomach, regulates diet-induced obesity.

Obesity and its sequelae have a major impact on human health. The stomach contributes to obesity in ways that extend beyond its role in digestion, including through effects on the microbiome. Gastrokine-1 (GKN1) is an anti-amyloidogenic protein abundantly and specifically secreted into the stomach lumen. We examined whether GKN1 plays a role in the development of obesity and regulation of the gut microbiome. Gkn1-/- mice were resistant to diet-induced obesity and hepatic steatosis (high fat diet (HFD) fat mass (g) = 10.4 ± 3.0 (WT) versus 2.9 ± 2.3 (Gkn1-/-) p < 0.005; HFD liver mass (g) = 1.3 ± 0.11 (WT) versus 1.1 ± 0.07 (Gkn1-/-) p < 0.05). Gkn1-/- mice also exhibited increased expression of the lipid-regulating hormone ANGPTL4 in the small bowel. The microbiome of Gkn1-/- mice exhibited reduced populations of microbes implicated in obesity, namely Firmicutes of the class Erysipelotrichia. Altered metabolism consistent with use of fat as an energy source was evident in Gkn1-/- mice during the sleep period. GKN1 may contribute to the effects of the stomach on the microbiome and obesity. Inhibition of GKN1 may be a means to prevent obesity.

Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia.

Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0-49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2-5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1-46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an 'AP-4 deficiency syndrome'. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.

Optimization of Protocols for Detection of De Novo Protein Synthesis in Whole Blood Samples via Azide-Alkyne Cycloaddition.

Aberrant protein synthesis and protein expression are a hallmark of many conditions ranging from cancer to Alzheimer's. Blood-based biomarkers indicative of changes in proteomes have long been held to be potentially useful with respect to disease prognosis and treatment. However, most biomarker efforts have focused on unlabeled plasma proteomics that include nonmyeloid origin proteins with no attempt to dynamically tag acute changes in proteomes. Herein we report a method for evaluating de novo protein synthesis in whole blood liquid biopsies. Using a modification of the "bioorthogonal noncanonical amino acid tagging" (BONCAT) protocol, rodent whole blood samples were incubated with l-azidohomoalanine (AHA) to allow incorporation of this selectively reactive non-natural amino acid within nascent polypeptides. Notably, failure to incubate the blood samples with EDTA prior to implementation of azide-alkyne "click" reactions resulted in the inability to detect probe incorporation. This live-labeling assay was sensitive to inhibition with anisomycin and nascent, tagged polypeptides were localized to a variety of blood cells using FUNCAT. Using labeled rodent blood, these tagged peptides could be consistently identified through standard LC/MS-MS detection of known blood proteins across a variety of experimental conditions. Furthermore, this assay could be expanded to measure de novo protein synthesis in human blood samples. Overall, we present a rapid and convenient de novo protein synthesis assay that can be used with whole blood biopsies that can quantify translational change as well as identify differentially expressed proteins that may be useful for clinical applications.

In-Hospital Feeding Practices of Infants Born to Mothers With Gestational Diabetes Mellitus or Type 2 Diabetes Mellitus: Evaluating Policy Implementation Effectiveness.

OBJECTIVES: Women with diabetes in pregnancy may experience unique breastfeeding challenges. Few studies have examined the effectiveness of hospital policy to support breastfeeding in this patient population. This study aimed 1) to describe infant feeding practices of mother-infant pairs with gestational diabetes mellitus (GDM) or type 2 diabetes in pregnancy before and after introduction of an in-hospital policy and, 2) to compare feeding practices before and after policy introduction. METHODS: A retrospective chart audit of mother-infant pairs (n=120) was performed: 60 at 1 year before and 60 after policy introduction. The primary outcome was provision of breast milk at discharge; a chi-square test was completed to compare pre- and postpolicy groups. Secondary outcomes included participant and infant feeding characteristics. RESULTS: There was no significant difference in the number of infants receiving breast milk at discharge between pre- (58% [35 of 60]) and postpolicy (58% [35 of 60]) groups (p=0.64). The number of infants receiving breast milk exclusively throughout the hospital stay also did not differ by group (37% [22 of 60] before; and 43% [26 of 60] after; p=0.39). Information for each feed was infrequently recorded in charts for the method of feeding (34% [704 of 2,064]), infant state (96% [1,991 of 2,064]) and feeding description (96% [1,987 of 2,064]). CONCLUSIONS: This practice-based research has highlighted a need for continuation of this work, examining an in-hospital policy to support breastfeeding in those with GDM or type 2 diabetes in pregnancy. Initially, feedback could be collected from health-care providers to understand perceived facilitators and barriers to policy application and the use of job aids (e.g. record keeping tools).

Reproducibility of Structural and Diffusion Tensor Imaging in the TACERN Multi-Center Study.

BACKGROUND: Multi-site MRI studies are often necessary for recruiting sufficiently sized samples when studying rare conditions. However, they require pooling data from multiple scanners into a single data set, and therefore it is critical to evaluate the variability of quantitative MRI measures within and across scanners used in multi-site studies. The aim of this study was to evaluate the reproducibility of structural and diffusion weighted (DW) MRI measurements acquired on seven scanners at five medical centers as part of the Tuberous Sclerosis Complex Autism Center of Excellence Research Network (TACERN) multisite study. METHODS: The American College of Radiology (ACR) phantom was imaged monthly to measure reproducibility of signal intensity and uniformity within and across seven 3T scanners from General Electric, Philips, and Siemens vendors. One healthy adult male volunteer was imaged repeatedly on all seven scanners under the TACERN structural and DW protocol (5 b = 0 s/mm2 and 30 b = 1000 s/mm2) over a period of 5 years (age 22-27 years). Reproducibility of inter- and intra-scanner brain segmentation volumes and diffusion tensor imaging metrics fractional anisotropy (FA) and mean diffusivity (MD) within white matter regions was quantified with coefficient of variation. RESULTS: The American College of Radiology Phantom signal intensity and uniformity were similar across scanners and changed little over time, with a mean intra-scanner coefficient of variation of 3.6 and 1.8%, respectively. The mean inter- and intra-scanner coefficients of variation of brain structure volumes derived from T1-weighted (T1w) images of the human phantom were 3.3 and 1.1%, respectively. The mean inter- and intra-scanner coefficients of variation of FA in white matter regions were 4.5 and 2.5%, while the mean inter- and intra-scanner coefficients of variation of MD in white matter regions were 5.4 and 1.5%. CONCLUSION: Our results suggest that volumetric and diffusion tensor imaging (DTI) measurements are highly reproducible between and within scanners and provide typical variation amplitudes that can be used as references to interpret future findings in the TACERN network.

Honey promotes lower weight gain, adiposity, and triglycerides than sucrose in rats.

Various dietary carbohydrates have been linked to obesity and altered adipose metabolism; however, the influences of honey vs common sweeteners have not been fully explored. We hypothesized that in comparison with sucrose, a honey-based diet would promote lower weight gain, adiposity, and related biomarkers (leptin, insulin, and adiponectin) as well as a better blood lipid profile. Thirty-six male Sprague-Dawley rats (228.1 ± 12.5 g) were equally divided by weight into 2 groups (n = 18) and provided free access to 1 of 2 diets of equal energy densities differing only in a portion of the carbohydrate. Diets contained 20% carbohydrate (by weight of total diet) from either clover honey or sucrose. After 33 days, epididymal fat pads were excised and weighed, and blood was collected for analyses of serum concentrations of lipids, glucose, and markers of adiposity and inflammation. Body weight gain was 14.7% lower (P ≤ .05) for rats fed honey, corresponding to a 13.3% lower (P ≤ .05) consumption of food/energy, whereas food efficiency ratios were nearly identical. Epididymal fat weight was 20.1% lower (P ≤ .05) for rats fed honey. Serum concentrations of triglycerides and leptin were lower (P ≤ .05) by 29.6% and 21.6%, respectively, and non-high-density lipoprotein cholesterol was higher (P ≤ .05) by 16.8% for honey-fed rats. No significant differences in serum total cholesterol, high-density lipoprotein cholesterol, adiponectin, C-reactive protein, monocyte chemoattractant protein-1, glucose, or insulin were detected. These results suggest that in comparison with sucrose, honey may reduce weight gain and adiposity, presumably due to lower food intake, and promote lower serum triglycerides but higher non-high-density lipoprotein cholesterol concentrations.