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1.
Hum Mol Genet ; 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31504550

RESUMO

Although hundreds of GWAS-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity, and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of thirty studies consisting of up to 13,005 cases (≥95th percentile of BMI achieved 2-18 years old) and 15,599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1,888 cases and 4,689 controls from seven cohorts of European and North/South American ancestry. In addition to observing eighteen previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene: METTL15). The variant was nominally associated in only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than ten SNPs (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci.

2.
PLoS One ; 14(9): e0221829, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31479473

RESUMO

Mitochondrial DNA (mtDNA) genome integrity is essential for proper mitochondrial respiratory chain function to generate cellular energy. Nuclear genes encode several proteins that function at the mtDNA replication fork, including mitochondrial single-stranded DNA-binding protein (SSBP1), which is a tetrameric protein that binds and protects single-stranded mtDNA (ssDNA). Recently, two studies have reported pathogenic variants in SSBP1 associated with hearing loss, optic atrophy, and retinal degeneration. Here, we report a 14-year-old Chinese boy with severe and progressive mitochondrial disease manifestations across the full Pearson, Kearns-Sayre, and Leigh syndromes spectrum, including infantile anemia and bone marrow failure, growth failure, ptosis, ophthalmoplegia, ataxia, severe retinal dystrophy of the rod-cone type, sensorineural hearing loss, chronic kidney disease, multiple endocrine deficiencies, and metabolic strokes. mtDNA genome sequencing identified a single large-scale 5 kilobase mtDNA deletion (m.8629_14068del5440), present at 68% and 16% heteroplasmy in the proband's fibroblast cell line and blood, respectively, suggestive of a mtDNA maintenance defect. On trio whole exome blood sequencing, the proband was found to harbor a novel de novo heterozygous mutation c.79G>A (p.E27K) in SSBP1. Size exclusion chromatography of p.E27K SSBP1 revealed it remains a stable tetramer. However, differential scanning fluorimetry demonstrated p.E27K SSBP1 relative to wild type had modestly decreased thermostability. Functional assays also revealed p.E27K SSBP1 had altered DNA binding. Molecular modeling of SSBP1 tetramers with varying combinations of mutant subunits predicted general changes in surface accessible charges, strength of inter-subunit interactions, and protein dynamics. Overall, the observed changes in protein dynamics and DNA binding behavior suggest that p.E27K SSBP1 can interfere with DNA replication and precipitate the introduction of large-scale mtDNA deletions. Thus, a single large-scale mtDNA deletion (SLSMD) with manifestations across the clinical spectrum of Pearson, Kearns-Sayre, and Leigh syndromes may result from a nuclear gene disorder disrupting mitochondrial DNA replication.

3.
Pediatr Neurol ; 99: 31-39, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31303369

RESUMO

BACKGROUND: Revised diagnostic criteria for pseudotumor cerebri syndrome require three of four neuroimaging findings in the absence of papilledema. We examined the sensitivity and specificity of three or more of four of these magnetic resonance imaging (MRI) findings for pseudotumor cerebri syndrome in children. METHODS: As part of clinical care, patients in whom there was suspicion for pseudotumor cerebri syndrome underwent neurological and fundoscopic examinations, lumbar puncture, MRI, or magnetic resonance venogram. For this retrospective study, we used this information to classify 119 subjects into definite (n = 66) or probable pseudotumor cerebri syndrome (n = 12), elevated opening pressure without papilledema (n = 23), or controls who had normal opening pressure without papilledema (n = 24). A neuroradiologist, unaware of the clinical findings or original MRI report, reviewed MRIs for pituitary gland flattening, flattening of the posterior sclera, optic nerve sheath distention, and transverse venous sinus stenosis. RESULTS: The presence of three or more MRI findings has a sensitivity of 62% (95% confidence interval: 47% to 75%) and a specificity of 95% (95% confidence interval: 77% to 100%), compared with controls. Two of three (transverse venous sinus stenosis, pituitary gland flattening, flattening of the posterior sclera) had a similar sensitivity and specificity. Transverse venous sinus stenosis alone had a slightly higher sensitivity (74%, 95% confidence interval: 60% to 85%) and specificity (100%, 95% confidence interval: 80% to 100%). CONCLUSIONS: In children, three of four of the proposed neuroimaging criteria and transverse venous sinus stenosis alone have a moderate sensitivity and robust specificity for pseudotumor cerebri syndrome. MRIs should be reviewed for these criteria, and their presence should raise suspicion for pseudotumor cerebri syndrome in children, particularly if the presence of papilledema is uncertain.

4.
Ann Clin Transl Neurol ; 6(3): 546-553, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30911578

RESUMO

Objective: In vitro, in vivo, and open-label studies suggest that interferon gamma (IFN-γ 1b) may improve clinical features in Friedreich Ataxia through an increase in frataxin levels. The present study evaluates the efficacy and safety of IFN-γ 1b in the treatment of Friedreich Ataxia through a double-blind, multicenter, placebo-controlled trial. Methods: Ninety-two subjects with FRDA between 10 and 25 years of age were enrolled. Subjects received either IFN-γ 1b or placebo for 6 months. The primary outcome measure was the modified Friedreich Ataxia Rating Scale (mFARS). Results: No difference was noted between the groups after 6 months of treatment in the mFARS or secondary outcome measures. No change was noted in buccal cell or whole blood frataxin levels. However, during an open-label extension period, subjects had a more stable course than expected based on natural history data. Conclusions: This study provides no direct evidence for a beneficial effect of IFN-γ1b in FRDA. The modest stabilization compared to natural history data leaves open the possibility that longer studies may demonstrate benefit.

5.
J Clin Endocrinol Metab ; 104(7): 2961-2970, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30811542

RESUMO

CONTEXT: Mutations in melanocortin receptor (MC4R) are the most common cause of monogenic obesity in children of European ancestry, but little is known about their prevalence in children from the minority populations in the United States. OBJECTIVE: This study aims to identify the prevalence of MC4R mutations in children with severe early-onset obesity of African American or Latino ancestry. DESIGN AND SETTING: Participants were recruited from the weight management clinics at two hospitals and from the institutional biobank at a third hospital. Sequencing of the MC4R gene was performed by whole exome or Sanger sequencing. Functional testing was performed to establish the surface expression of the receptor and cAMP response to its cognate ligand α-melanocyte-stimulating hormone. PARTICIPANTS: Three hundred twelve children (1 to 18 years old, 50% girls) with body mass index (BMI) >120% of 95th percentile of Centers for Disease Control and Prevention 2000 growth charts at an age <6 years, with no known pathological cause of obesity, were enrolled. RESULTS: Eight rare MC4R mutations (2.6%) were identified in this study [R7S, F202L (n = 2), M215I, G252D, V253I, I269N, and F284I], three of which were not previously reported (G252D, F284I, and R7S). The pathogenicity of selected variants was confirmed by prior literature reports or functional testing. There was no significant difference in the BMI or height trajectories of children with or without MC4R mutations in this cohort. CONCLUSIONS: Although the prevalence of MC4R mutations in this cohort was similar to that reported for obese children of European ancestry, some of the variants were novel.

6.
Bone ; 121: 221-226, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30711642

RESUMO

Over the past two decades, a low frequency variant (rs1800012) within the first intron of the type I collagen alpha 1 (COLIA1) gene has been implicated in lower areal BMD (aBMD) and increased risk of osteoporotic fracture. This association is particularly strong in postmenopausal women, in whom net bone loss arises in the context of high bone turnover. High bone turnover also accompanies childhood linear growth; however, the role of rs1800012 in this stage of net bone accretion is less well understood. Thus, we assessed the association between rs1800012 and aBMD and bone mineral content (BMC) Z-scores for the 1/3 distal radius, lumbar spine, total hip, and femoral neck total body less head in the Bone Mineral Density in Childhood Study, a mixed-longitudinal cohort of children and adolescents (total n = 804 girls and 771 boys; n = 19 girls and 22 boys with the TT genotype). Mixed effects modeling, stratified by sex, was used to test for associations between rs1800012 and aBMD or BMC Z-scores and for pubertal stage interactions. Separately, SITAR growth modeling of aBMD and BMC in subjects with longitudinal data reduced the complex longitudinal bone accrual curves into three parameters representing a-size, b-timing, and c-velocity. We tested for differences in these three parameters by rs1800012 genotype using t-tests. Girls with the TT genotype had significantly lower aBMD and BMC Z-scores prior to puberty completion (e.g. spine aBMD-Z P-interaction = 1.0 × 10-6), but this association was attenuated post-puberty. SITAR models revealed that TT girls began pubertal bone accrual later (b-timing; e.g. total hip BMC, P = 0.03). BMC and aBMD Z-scores also increased across puberty in TT homozygous boys. Our data, along with previous findings in post-menopausal women, suggest that rs1800012 principally affects female bone density during periods of high turnover. Insights into the genetics of bone gain and loss may be masked during the relatively quiescent state in mid-adulthood, and discovery efforts should focus on early and late life.

7.
J Med Genet ; 56(3): 123-130, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30683676

RESUMO

Primary genetic mitochondrial diseases are often difficult to diagnose, and the term 'possible' mitochondrial disease is used frequently by clinicians when such a diagnosis is suspected. There are now many known phenocopies of mitochondrial disease. Advances in genomic testing have shown that some patients with a clinical phenotype and biochemical abnormalities suggesting mitochondrial disease may have other genetic disorders. In instances when a genetic diagnosis cannot be confirmed, a diagnosis of 'possible' mitochondrial disease may result in harm to patients and their families, creating anxiety, delaying appropriate diagnosis and leading to inappropriate management or care. A categorisation of 'diagnosis uncertain', together with a specific description of the metabolic or genetic abnormalities identified, is preferred when a mitochondrial disease cannot be genetically confirmed.

8.
J Bone Miner Res ; 2018 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-30372552

RESUMO

Annual gains in BMC and areal bone mineral density (aBMD) in children vary with age, pubertal status, height-velocity, and lean body mass accrual (LBM velocity). Evaluating bone accrual in children with bone health-threatening conditions requires consideration of these determinants. The objective of this study was to develop prediction equations for calculating BMC/aBMD velocity SD scores (velocity-Z) and to evaluate bone accrual in youth with health conditions. Bone and body compositions via DXA were obtained for up to six annual intervals in healthy youth (n = 2014) enrolled in the Bone Mineral Density in Childhood Study (BMDCS) . Longitudinal statistical methods were used to develop sex- and pubertal-status-specific reference equations for calculating velocity-Z for total body less head-BMC and lumbar spine (LS), total hip (TotHip), femoral neck, and 1/3-radius aBMD. Equations accounted for (1) height velocity, (2) height velocity and weight velocity, or (3) height velocity and LBM velocity. These equations were then applied to observational, single-center, 12-month longitudinal data from youth with cystic fibrosis (CF; n = 65), acute lymphoblastic leukemia (ALL) survivors (n = 45), or Crohn disease (CD) initiating infliximab (n = 72). Associations between BMC/aBMD-Z change (conventional pediatric bone health monitoring method) and BMC/aBMD velocity-Z were assessed. The BMC/aBMD velocity-Z for CF, ALL, and CD was compared with BMDCS. Annual changes in the BMC/aBMD-Z and the BMC/aBMD velocity-Z were strongly correlated, but not equivalent; LS aBMD-Z = 1 equated with LS aBMD velocity-Z = -3. In CF, BMC/aBMD velocity-Z was normal. In posttherapy ALL, BMC/aBMD velocity-Z was increased, particularly at TotHip (1.01 [-.047; 1.7], p < 0.0001). In CD, BMC/aBMD velocity-Z was increased at all skeletal sites. LBM-velocity adjustment attenuated these increases (eg, TotHip aBMD velocity-Z: 1.13 [0.004; 2.34] versus 1.52 [0.3; 2.85], p < 0.0001). Methods for quantifying the BMC/aBMD velocity that account for maturation and body composition changes provide a framework for evaluating childhood bone accretion and may provide insight into mechanisms contributing to altered accrual in chronic childhood conditions. © 2018 American Society for Bone and Mineral Research.

9.
J Pediatr ; 2018 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-30268397

RESUMO

OBJECTIVE: To assess whether body mass index (BMI) provides a better assessment of measured adiposity at age 1 month compared with weight-for-length (WFL). STUDY DESIGN: Participants were healthy term-born infants in the Infant Growth and Microbiome (n = 146) and the Baby Peas (n = 147) studies. Length, weight, and body composition by air displacement plethysmography were measured at 1 month. World Health Organization-based WFL and BMI z-scores were calculated. Within-cohort z-scores of percent fat-Z, fat mass-Z, fat mass/length2-Z, fat mass/length3-Z, fat-free mass-Z, and fat-free mass/length2-Z were calculated. Correlation and multiple linear regression (adjusted for birth weight) analyses tested the associations between body composition outcomes and BMI-Z vs WFL-Z. Quantile regression was used to test the stability of these associations across the distribution of body compositions. RESULTS: The sample was 52% female and 56% African American. Accounting for birth weight, both BMI-Z and WFL-Z were strongly associated with fat mass-Z (coefficients 0.56 and 0.35, respectively), FM/L2-Z (0.73 and 0.51), and FM/L3-Z (0.79 and 0.58), with stronger associations for BMI-Z compared with WFL-Z (P < .05). Even after accounting statistically for birth weight, BMI-Z was persistently more strongly associated than WFL-Z with body composition outcomes across the distribution of body composition outcomes. CONCLUSIONS: We demonstrate in 2 distinct cohorts that BMI is a better indicator of adiposity in early infancy compared with WFL. Our findings support the preferred use of BMI for growth and nutritional status assessment in infancy.

10.
Headache ; 58(9): 1339-1346, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30137653

RESUMO

BACKGROUND: Certain headache characteristics and associated symptoms are commonly attributed to increased intracranial pressure, but they have not been systematically studied among children in the context of revised diagnostic criteria for pseudotumor cerebri syndrome (PTCS). METHODS: We performed a retrospective cohort study of patients treated for suspected or confirmed PTCS. Charts were reviewed for PTCS and headache diagnostic criteria and associated characteristics. Chi-squared or Fisher's exact tests were used to compare the frequency of headache characteristics between groups. RESULTS: One hundred and twenty-seven individuals were identified: 61 had definite PTCS, 10 had probable PTCS, 31 had elevated opening pressure (OP) without papilledema, and 25 had normal OP without papilledema. Eleven children had no headache (6 with definite PTCS, 5 with probable PTCS). Headache pattern was episodic in 49% (95% CI: 34-64%) of those with definite PTCS, 18% (95% CI 6-37%) of those with elevated OP without papilledema, and 16% (5-36%) of those with normal OP without papilledema. Headache location was more likely to involve the head along with neck or shoulders in those with definite PTCS compared with elevated OP without papilledema (OR = 7.2, 95% CI: 1.9-27.6) and normal OP (OR = 4.5, 95% CI: 1.3-15.6) groups. DISCUSSION: While missing data and small cohort size are limitations, this study suggests that headache in PTCS is more likely to involve the head along with neck/shoulders, and that headache in PTCS may be episodic or constant. Headache is occasionally absent in PTCS.

12.
Pediatr Neurol ; 83: 50-55, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29753572

RESUMO

BACKGROUND: The purpose of this study was to determine the prognostic utility of closing pressure and volume of cerebrospinal fluid removed with respect to papilledema resolution and headache improvement in pediatric pseudotumor cerebri syndrome. METHODS: This is a retrospective observational study of 93 children with definite pseudotumor cerebri syndrome. The primary outcome measure was time to resolution of papilledema, and the secondary outcome measure was time to resolution of headache. RESULTS: There were no significant differences in gender, age, or body mass index z score observed between subjects with (N = 35) and without (N = 58) documented closing pressure. The median time to resolution of papilledema was not statistically different between children above or equal to and those below the median closing pressure (170 mm of cerebrospinal fluid, n = 31, P = 0.391) or the volume of median cerebrospinal fluid removed (16 mL, n = 19, P = 0.155). There was no statistically significant difference detected in days of headache between the children with opening pressure above and equal to the median (400 mm of cerebrospinal fluid) and the children with opening pressure below the median (n = 44, P = 0.634). CONCLUSIONS: No significant association between closing pressure, amount of cerebrospinal fluid removed, and time to resolution of papilledema due to pseudotumor cerebri syndrome was detected. The diagnostic and therapeutic purposes of either measuring the closing pressure or maximizing the volume of cerebrospinal fluid removed were not evident in these analyses.

13.
PLoS One ; 13(5): e0197513, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29771953

RESUMO

BACKGROUND: Clinical treatment trials are increasingly being designed in primary mitochondrial disease (PMD), a phenotypically and genetically heterogeneous collection of inherited multi- system energy deficiency disorders that lack effective therapy. We sought to identify motivating factors and barriers to clinical trial participation in PMD. METHODS: A survey study was conducted in two independent mitochondrial disease subject cohorts. A discovery cohort invited subjects with well-defined biochemical or molecularly- confirmed PMD followed at a single medical center (CHOP, n = 30/67 (45%) respondents). A replication cohort included self-identified PMD subjects in the Rare Disease Clinical Research Network (RDCRN) national contact registry (n = 290/1119 (26%) respondents). Five-point Likert scale responses were analyzed using descriptive and quantitative statistics. Experienced and prioritized symptoms for trial participation, and patient attitudes toward detailed aspects of clinical trial drug features and study design. RESULTS: PMD subjects experienced an average of 16 symptoms. Muscle weakness, chronic fatigue, and exercise intolerance were the lead symptoms encouraging trial participation. Motivating trial design factors included a self-administered study drug; vitamin, antioxidant, natural or plant-derivative; pills; daily treatment; guaranteed treatment access during and after study; short travel distances; and late-stage (phase 3) participation. Relative trial participation barriers included a new study drug; discontinuation of current medications; disease progression; daily phlebotomy; and requiring participant payment. Treatment trial type or design preferences were not influenced by population age (pediatric versus adult), prior research trial experience, or disease severity. CONCLUSIONS: These data are the first to convey clear PMD subject preferences and priorities to enable improved clinical treatment trial design that cuts across the complex diversity of disease. Partnering with rare disease patient communities is essential to effectively design robust clinical trials that engage patients and enable meaningful evaluation of emerging treatment interventions.

14.
J Neuroophthalmol ; 2018 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-29608535

RESUMO

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a condition characterized by increased intracranial pressure of unknown cause. IIH has been shown to be associated with female sex as well as obesity. This genome-wide association study was performed to determine whether genetic variants are associated with this condition. METHODS: We analyzed the chromosomal DNA of 95 patients with IIH enrolled in the Idiopathic Intracranial Hypertension Treatment Trial and 95 controls matched on sex, body mass index, and self-reported ethnicity. The samples were genotyped using Illumina Infinium HumanCoreExome v1-0 array and analyzed using a generalized linear mixed model that accounted for population stratification using multidimensional scaling. RESULTS: A total of 301,908 single nucleotide polymorphisms (SNPs) were evaluated. The strongest associations observed were for rs2234671 on chromosome 2 (P = 4.93 × 10), rs79642714 on chromosome 6 (P = 2.12 × 10), and rs200288366 on chromosome 12 (P = 6.23 × 10). In addition, 3 candidate regions marked by multiple associated SNPs were identified on chromosome 5, 13, and 14. CONCLUSIONS: This is the first study to investigate the genetics of IIH in a rigorously characterized cohort. The study was limited by its modest size and thus would have only been able to demonstrate highly significant association on a genome-wide scale for relatively common alleles exerting large effects. However, several variants and loci were identified that might be strong candidates for follow-up studies in other well-phenotyped cohorts.

15.
J Endocr Soc ; 2(4): 361-373, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29594260

RESUMO

Context: Endocrine disorders are common in individuals with mitochondrial disease. To develop evidence-based screening practices in this high-risk population, updated age-stratified estimates of the prevalence of endocrine conditions are needed. Objective: To measure the point prevalence of selected endocrine disorders in individuals with mitochondrial disease. Design Setting and Patients: The North American Mitochondrial Disease Consortium Patient Registry is a large, prospective, physician-curated cohort study of individuals with mitochondrial disease. Participants (n = 404) are of any age, with a diagnosis of primary mitochondrial disease confirmed by molecular genetic testing. Main Outcome Measures: Age-specific prevalence of diabetes mellitus (DM), abnormal growth and sexual maturation (AGSM), hypoparathyroidism, and hypothyroidism. Results: The majority of our sample was pediatric (<18 years; 60.1%), female (56.9%), and white (85.9%). DM affected 2% of participants aged <18 years [95% confidence interval (CI): 0.4% to 5.7%] and 24.4% of adult participants (95% CI: 18.6% to 30.9%). DM prevalence was highest in individuals with mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes syndrome (MELAS; 31.9%, of whom 86.2% had the m.3243A>G mutation). DM occurred more often with mitochondrial DNA defects (point mutations and/or deletions) than with nuclear DNA mutations (23.3% vs 3.7%, respectively; P < 0.001). Other prevalence estimates were 44.1% (95% CI: 38.8% to 49.6%) for AGSM; 0.3% (95% CI: 0% to 1.6%) for hypoparathyroidism; and 6.3% (95% CI: 4% to 9.3%) for hypothyroidism. Conclusion: DM and AGSM are highly prevalent in primary mitochondrial disease. Certain clinical mitochondrial syndromes (MELAS and Kearns-Sayre/Pearson syndrome spectrum disorders) demonstrated a higher burden of endocrinopathies. Clinical screening practices should reflect the substantial prevalence of endocrine disorders in mitochondrial disease.

16.
Mol Genet Metab ; 123(4): 449-462, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29526616

RESUMO

Oxidative stress is a known contributing factor in mitochondrial respiratory chain (RC) disease pathogenesis. Yet, no efficient means exists to objectively evaluate the comparative therapeutic efficacy or toxicity of different antioxidant compounds empirically used in human RC disease. We postulated that pre-clinical comparative analysis of diverse antioxidant drugs having suggested utility in primary RC disease using animal and cellular models of RC dysfunction may improve understanding of their integrated effects and physiologic mechanisms, and enable prioritization of lead antioxidant molecules to pursue in human clinical trials. Here, lifespan effects of N-acetylcysteine (NAC), vitamin E, vitamin C, coenzyme Q10 (CoQ10), mitochondrial-targeted CoQ10 (MS010), lipoate, and orotate were evaluated as the primary outcome in a well-established, short-lived C. elegans gas-1(fc21) animal model of RC complex I disease. Healthspan effects were interrogated to assess potential reversal of their globally disrupted in vivo mitochondrial physiology, transcriptome profiles, and intermediary metabolic flux. NAC or vitamin E fully rescued, and coenzyme Q, lipoic acid, orotic acid, and vitamin C partially rescued gas-1(fc21) lifespan toward that of wild-type N2 Bristol worms. MS010 and CoQ10 largely reversed biochemical pathway expression changes in gas-1(fc21) worms. While nearly all drugs normalized the upregulated expression of the "cellular antioxidant pathway", they failed to rescue the mutant worms' increased in vivo mitochondrial oxidant burden. NAC and vitamin E therapeutic efficacy were validated in human fibroblast and/or zebrafish complex I disease models. Remarkably, rotenone-induced zebrafish brain death was preventable partially with NAC and fully with vitamin E. Overall, these pre-clinical model animal data demonstrate that several classical antioxidant drugs do yield significant benefit on viability and survival in primary mitochondrial disease, where their major therapeutic benefit appears to result from targeting global cellular, rather than intramitochondria-specific, oxidative stress. Clinical trials are needed to evaluate whether the two antioxidants, NAC and vitamin E, that show greatest efficacy in translational model animals significantly improve the survival, function, and feeling of human subjects with primary mitochondrial RC disease.

17.
Aging Dis ; 9(1): 17-30, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29392078

RESUMO

TCF7L2 is located at one of the most strongly associated type 2 diabetes loci reported to date. We previously reported that the most abundant member of a specific protein complex to bind across the presumed causal variant at this locus, rs7903146, was poly [ADP-ribose] polymerase type 1 (PARP-1). We analyzed the impact of PARP-1 inhibition on C. elegans health in the setting of hyperglycemia and on glucose-stimulated GLP-1 secretion in human intestinal cells. Given that high glucose concentrations progressively shorten the lifespan of C. elegans, in part by impacting key well-conserved insulin-modulated signaling pathways, we investigated the effect of PARP-1 inhibition with Olaparib on the lifespan of C. elegans nematodes under varying hyperglycemic conditions. Subsequently, we investigated whether Olaparib treatment had any effect on glucose-stimulated GLP-1 secretion in the human NCI-H716 intestinal cell line, a model system for the investigation of enteroendocrine function. Treatment with 100uM Olaparib in nematodes exposed to high concentrations of glucose led to significant lifespan rescue. The beneficial lifespan effect of Olaparib appeared to require both PARP-1 and TCF7L2, since treatment had no effect in hyperglycemic conditions in knock-out worm strains for either of these homologs. Further investigation using the NCI-H716 cells revealed that Olaparib significantly enhanced secretion of the incretin, GLP-1, plus the gene expression of TCF7L2, GCG and PC1. These data from studies in both C. elegans and a human cell line suggest that PARP-1 inhibition offers a novel therapeutic avenue to treat type 2 diabetes.

18.
Med Sci Sports Exerc ; 50(5): 977-986, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29465475

RESUMO

PURPOSE: This study aimed to determine if replacing time spent in high- and low-impact physical activity (PA) predicts changes in pediatric bone mineral density (BMD) and content (BMC). METHODS: We analyzed data from the longitudinal Bone Mineral Density in Childhood Study (N = 2337 with up to seven visits). The participants were age 5-19 yr at baseline, 51.2% were female, and 80.6% were nonblack. Spine, total hip, and femoral neck areal BMD and total body less head (TBLH) BMC Z-scores were calculated. Hours per day spent in high- and low-impact PA were self-reported. Standard covariate-adjusted (partition model) and time allocation-sensitive isotemporal substitution modeling frameworks were applied to linear mixed models. Statistical interactions with sex, self-reported ancestry, age, and bone fragility genetic scores (percentage of areal BMD-lowering alleles carried) were tested. RESULTS: In standard models, high-impact PA was positively associated with bone Z-score at all four skeletal sites (e.g., TBLH-BMC Z-score: beta = 0.05, P = 2.0 × 10), whereas low-impact PA was not associated with any of the bone Z-scores. In isotemporal substitution models, replacing 1 h·d of low- for high-impact PA was associated with higher bone Z-scores (e.g., TBLH-BMC Z-score: beta = 0.06, P = 2.9 × 10). Conversely, replacing 1 h·d of high- for low-impact PA was associated with lower bone Z-scores (e.g., TBLH-BMC Z-score: beta = -0.06, P = 2.9 × 10). The substitution associations were similar for each sex and ancestry group, and for those with higher and lower genetic scores for bone fragility (P-interactions > 0.05), but increased in strength among the older adolescents (P-age interactions < 0.05). CONCLUSIONS: Time-sensitive models suggest that replacing low-impact PA for high-impact PA would be beneficial for the growing skeleton in the majority of children.

19.
JAMA Pediatr ; 172(2): 196-197, 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29228153
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