Little is known about the use of medical services by children who have autism (ASD). Provide nationally representative data for health service utilization and expenditures of children with ASD. Cross-sectional survey using the Medical Expenditure Panel (MEPS), and National (Hospital) Ambulatory Medical Care Surveys (N(H)AMCS). A total of 80 children with ASD were identified from N(H)AMCS (weighted sample size (wss) 186,281), and 31 (wss 340,158) from MEPS. They had more outpatient visits, physician visits, and medications prescribed than children in general. They spent more time during physician visits than other children. Annual expenses for children with autism spectrum disorder (6,132 dollars) were more than for other children (860 dollars). Children with ASD have a substantial burden of medical illness.
NRTIs deplete mtDNA and polypeptides, cause mitochondrial structural and functional defects in vivo, follow inhibition kinetics with DNA pol gamma in vitro, and are corroborated by molecular models. Disrupted pools of nucleotide precursors and inhibition of DNA pol gamma by specific NRTIs are mechanistically important in mitochondrial toxicity.
The placenta is metabolically active and supports the growth of the fetus. We hypothesize that deficits in the capacity of the placenta to maintain bioenergetic and metabolic stability during pregnancy may result in spontaneous preterm birth (SPTB). To explore this hypothesis, we performed a nested cased control study of metabolomic signatures in placentas from women with SPTB (<36 weeks gestation) compared to normal pregnancies (≥38 weeks gestation). To control for the effects of gestational age on placenta metabolism, we also studied a subset of metabolites in non-laboring preterm and term Rhesus monkeys. Comprehensive quantification of metabolites demonstrated a significant elevation in the levels of amino acids, prostaglandins, sphingolipids, lysolipids, and acylcarnitines in SPTB placenta compared to term placenta. Additional quantification of placental acylcarnitines by tandem mass spectrometry confirmed the significant elevation in SPTB human, with no significant differences between midgestation and term placenta in Rhesus macaque. Fatty acid oxidation as measured by the flux of 3H-palmitate in SPTB placenta was lower than term. Collectively, significant and biologically relevant alterations in the placenta metabolome were identified in SPTB placenta. Altered acylcarnitine levels and fatty acid oxidation suggest that disruption in normal substrate metabolism is associated with SPTB.
Mitochondrial toxicity limits nucleoside reverse transcriptase inhibitors (NRTIs) for acquired immune deficiency syndrome. NRTI triphosphates, the active moieties, inhibit human immunodeficiency virus reverse transcriptase and eukaryotic mitochondrial DNA polymerase pol-␥. NRTI phosphorylation seems to correlate with mitochondrial toxicity, but experimental evidence is lacking. Transgenic mice (TGs) with cardiac overexpression of thymidine kinase isoforms (mitochondrial TK2 and cytoplasmic TK1) were used to study NRTI mitochondrial toxicity. Echocardiography and nuclear magnetic resonance imaging defined cardiac performance and structure. TK gene copy and enzyme activity, mitochondrial (mt) DNA and polypeptide abundance, succinate dehydrogenase and cytochrome oxidase histochemistry, and electron microscopy correlated with transgenesis, mitochondrial structure, and biogenesis. Antiretroviral combinations simulated therapy. Untreated hTK1 or TK2 TGs exhibited normal left ventricle mass. In TK2 TGs, cardiac TK2 gene copy doubled, activity increased 300-fold, and mtDNA abundance doubled. Abundance of the 17-kd subunit of complex I, succinate dehydrogenase histochemical activity, and cristae density increased. NRTIs increased left ventricle mass 20% in TK2 TGs. TK activity increased 3 logs in hTK1 TGs, but no cardiac phenotype resulted. NRTIs abrogated functional effects of transgenically increased TK2 activity but had no effect on TK2 mtDNA abundance. Thus, NRTI mitochondrial phosphorylation by TK2 is integral to clinical NRTI mitochondrial toxicity.
Maternal obesity is associated with an increased risk of obesity and metabolic disease in offspring. Increasing evidence suggests that the placenta plays an active role in fetal programming. In this study, we used a mouse model of diet-induced obesity to demonstrate that the abnormal metabolic milieu of maternal obesity sets the stage very early in pregnancy by altering the transcriptome of placenta progenitor cells in the preimplantation (trophectoderm [TE]) and early postimplantation (ectoplacental cone [EPC]) placenta precursors, which is associated with later changes in placenta development and function. Sphingolipid metabolism was markedly altered in the plasma of obese dams very early in pregnancy as was expression of genes related to sphingolipid processing in the early placenta. Upregulation of these pathways inhibits angiogenesis and causes endothelial dysfunction. The expression of many other genes related to angiogenesis and vascular development were disrupted in the TE and EPC. Other key changes in the maternal metabolome in obese dams that are likely to influence placenta and fetal development include a marked decrease in myo and chiro-inositol. These early metabolic and gene expression changes may contribute to phenotypic changes in the placenta, as we found that exposure to a high-fat diet decreased placenta microvessel density at both mid and late gestation. This is the first study to demonstrate that maternal obesity alters the transcriptome at the earliest stages of murine placenta development.
Nucleoside reverse transcriptase inhibitors (NRTIs) are antiretrovirals for AIDS with limiting mitochondrial side effects. The mitochondrial deoxynucleotide carrier (DNC) transports phosphorylated nucleosides for mitochondrial DNA replication and can transport phosphorylated NRTIs into mitochondria. Transgenic mice (TG) that exclusively overexpress DNC in the heart tested DNC's role in mitochondrial dysfunction from NRTIs. Two TG lines were created that overexpressed the human DNC gene in murine myocardium. Cardiac and mitochondrial structure and function were examined by magnetic resonance imaging, echocardiography, electrocardiography, transmission electron microscopy, and plasma lactate. Antiretroviral combinations (HAART) that contained NRTIs (stavudine (2 0 , 3 0 -didehydro-2 0 , 3 0 -deoxythymidine or d4T)/lamivudine/indinavir; or zidovudine (3 0 azido-3 0 -deoxythymidine or AZT)/lamivudine/indinavir; 35 days) were administered to simulate AIDS therapy. In parallel, a HAART combination without NRTIs (nevirapine/efavirenz/indinavir; 35 days) served as an NRTI-sparing, control regimen. Untreated DNC TGs exhibited normal cardiac function but abnormal mitochondrial ultrastructure. HAART that contained NRTIs caused cardiomyopathy in TGs with increased left ventricle mass and volume, heart rate variability, and worse mitochondrial ultrastructural defects. In contrast, treatment with an NRTI-sparing HAART regimen caused no cardiac changes. Data suggest the DNC is integral to mitochondrial homeostasis in vivo and may relate mechanistically to mitochondrial dysfunction in patients treated with HAART regimens that contain NRTIs. Keywords: deoxynucleotide; NRTI; AIDS; antiretroviral; mitochondrial import; DNC; cardiac; HIV The inner mitochondrial membrane contains transport proteins to move molecules into and out of the matrix. Members of the mitochondrial carrier family of proteins contain three conserved tandemrepeated sequences (B100 residues with two hydrophobic transmembrane a-helices and a hydrophilic segment thought to be an extramembranous loop 1 ). One of these proteins functions as a deoxynucleotide carrier (DNC) to import phosphorylated precursors of mitochondrial (mt-) DNA synthesis and has been characterized. 1-3 Toxicity to mitochondria from antiretroviral nucleoside reverse transcriptase inhibitors (NRTI) is an established side effect of AIDS therapy that limits effective treatment (reviewed in Lewis et al 4 ). Alternative combinations that are NRTI-sparing may be effective if toxicity is a significant clinical problem (reviewed in Joly et al 5 ).Since DNC provides a route for mitochondrial uptake of NRTIs including zidovudine (3 0 azido-3 0 -deoxythymidine or AZT) and stavudine (2 0 , 3 0 -didehydro-2 0 , 3 0 -deoxythymidine or d4T), its role in mitochondrial NRTI import and toxicity was addressed in vivo using transgenic mice (TG) and HAART treatment. One HAART regimen included NRTIs (with either an AZT or D4T 'backbone'). A second NRTI-sparing regimen was administered in parallel as a control.DNC ov...
Neu-Laxova syndrome is a rare autosomal recessive disorder characterized by severe intra-uterine growth restriction, extreme microcephaly, marked edema with skin restriction, ichthyosis, craniofacial anomalies, limb deformities, and a spectrum of central nervous system malformations. Less than 70 cases have been described since the first report in 1971. To this day the etiology and genetic basis remains unknown. Consanguinity has been reported. Some authors have postulated the syndrome to be a form of neuro-ectodermal dysplasia, while others suggest that it is a malformation syndrome secondary to severe skin restriction. Although the outcome of this syndrome is lethal, a single case of longer survival (6 months) has been reported. The majority of cases are stillborn or die shortly after birth. Thus, it is clear that Neu-Laxova exhibits a spectrum of disease, with varying degrees of phenotypic expression. We are presenting three new cases of Neu-Laxova syndrome; two were stillbirths and one lived for eleven weeks. Our microscopic and post-mortem findings in these three cases display the vast spectrum of this rare syndrome.
Historically, congenital pulmonary lymphangiectasia (CPL) has had poor treatment outcomes despite aggressive therapy. There are recent reports of ethiodized oil (Lipiodol) lymphangiography successfully treating lymphatic leakage in adults. In this report, we describe two infants with CPL complicated by chylothoraces successfully treated by instillation of ethiodized oil into the lymphatic system. Congenital atresia of the thoracic duct was demonstrated on the lymphangiogram in both patients before treatment. Both patients have shown good short-term outcomes without supplemental oxygen or fat restricted diets at 9 months of age. Ethiodized oil lymphangiography represents a new treatment modality for some patients with CPL.
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