Pediatric Research Center

Zürich, Switzerland

Pediatric Research Center

Zürich, Switzerland
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Mosquera R.A.,University of Texas Health Science Center at Houston | Samuels C.L.,Comprehensive Care | Harris T.S.,Comprehensive Care | Yadav A.,University of Texas Health Science Center at Houston | Hashmi S.S.,Pediatric Research Center
Open Respiratory Medicine Journal | Year: 2013

Background: Nitric oxide (NO) deficiency may occur in mitochondrial disorders (MD) and can contribute to the pathogenesis of the disease. It is difficult and invasive to measure systemic nitric oxide. NO is formed in the lungs and can be detected in expired air. Currently, hand-held fractional exhaled nitric oxide (FeNO) measurement devices are available enabling a fast in-office analysis of this non-invasive test. It was postulated that FeNO levels might be reduced in MD. Methods: Sixteen subjects with definite MD by modified Walker criteria (4 to 30 years of age) and sixteen healthy control subjects of similar age, race and body mass index (BMI) underwent measurement of FeNO in accordance with the American Thoracic Society guidelines. Results: Sixteen patient-control pairs were recruited. The median FeNO level was 6.5 ppm (IQR: 4-9.5) and 10.5 ppm (IQR: 8-20.5) in the MD and control groups, respectively. In 13 pairs (81%), the FeNO levels were lower in the MD cases than in the matched controls (p=0.021). Eleven (69%) cases had very low FeNO levels (≤7ppm) compared to only 1 control (p=0.001). All cases with enzymatic deficiencies in complex I had FeNO ≤7ppm. Conclusions: Single-breath exhaled nitric oxide recordings were decreased in patients with MD. This pilot study suggests that hand-held FeNO measurements could be an attractive non-invasive indicator of MD. In addition, measurement of FeNO could be used as a parameter to monitor therapeutic response in this population. © Mosquera et al.

Kundu B.K.,University of Virginia | Hashmi S.S.,Pediatric Research Center | Locke L.W.,University of Virginia | Roy R.J.,University of Virginia | And 10 more authors.
Journal of the American Heart Association | Year: 2013

Background-Changes in energy substrate metabolism are first responders to hemodynamic stress in the heart. We have previously shown that hexose-6-phosphate levels regulate mammalian target of rapamycin (mTOR) activation in response to insulin. We now tested the hypothesis that inotropic stimulation and increased afterload also regulate mTOR activation via glucose 6-phosphate (G6P) accumulation. Methods and Results- We subjected the working rat heart ex vivo to a high workload in the presence of different energy-providing substrates including glucose, glucose analogues, and noncarbohydrate substrates. We observed an association between G6P accumulation, mTOR activation, endoplasmic reticulum (ER) stress, and impaired contractile function, all of which were prevented by pretreating animals with rapamycin (mTOR inhibition) or metformin (AMPK activation). The histone deacetylase inhibitor 4-phenylbutyrate, which relieves ER stress, also improved contractile function. In contrast, adding the glucose analogue 2-deoxy-Dglucose, which is phosphorylated but not further metabolized, to the perfusate resulted in mTOR activation and contractile dysfunction. Next we tested our hypothesis in vivo by transverse aortic constriction in mice. Using a micro-PET system, we observed enhanced glucose tracer analog uptake and contractile dysfunction preceding dilatation of the left ventricle. In contrast, in hearts overexpressing SERCA2a, ER stress was reduced and contractile function was preserved with hypertrophy. Finally, we examined failing human hearts and found that mechanical unloading decreased G6P levels and ER stress markers. Conclusions-We propose that glucose metabolic changes precede and regulate functional (and possibly also structural) remodeling of the heart. We implicate a critical role for G6P in load-induced mTOR activation and ER stress. © 2013 The Authors.

Kretz R.,Pediatric Research Center | Bozorgmehr B.,Kariminejad Najmabadi Pathology and Genetic Center | Kariminejad M.H.,Kariminejad Najmabadi Pathology and Genetic Center | Rohrbach M.,Pediatric Research Center | And 6 more authors.
Journal of Inherited Metabolic Disease | Year: 2011

Pyrroline-5-carboxylate reductase 1 (PYCR1) catalyzes the last step in proline synthesis. Deficiency of PYCR1, caused by a defect in PYCR1, was recently described in patients with cutis laxa, intrauterine growth retardation, developmental dysplasia of the hips and mental retardation. In this paper, we describe additional six patients (ages ranging from 4 months to 55 years) from four Iranian families with clinical manifestations of a wrinkly skin disorder. All patients have distinct facial features comprising triangular face, loss of adipose tissue and thin pointed nose. Additional features are short stature, wrinkling over dorsum of hand and feet, visible veins over the chest and hyperextensible joints. Three of the patients from a large consanguineous family do not have mental retardation, while the remaining three patients from three unrelated families have mental and developmental delay. Mutation analysis revealed the presence of disease-causing variants in PYCR1, including a novel deletion of the entire PYCR1 gene in one family, and in each of the other patients the homozygous missense mutations c.616G > A (p.Gly206Arg), c.89T > A (p.Ile30Lys) and c.572G > A (p.Gly191Glu) respectively, the latter two of which are novel. Light- and electron microscopy investigations of skin biopsies showed smaller and fragmented elastic fibres, abnormal morphology of the mitochondria and their cristae, and slightly abnormal collagen fibril diameters with irregular outline and variable size. In conclusion, this study adds information on the natural course of PYCR1 deficiency and sheds light on the pathophysiology of this disorder. However, the exact pathogenesis of this new disorder and the role of proline in the development of the clinical phenotype remain to be fully explained. © 2011 SSIEM and Springer.

Dobrowolski S.F.,University of Utah | Heintz C.,University of Zürich | Miller T.,Idaho Technology Inc. | Ellingson C.,Pennsylvania State University | And 11 more authors.
Molecular Genetics and Metabolism | Year: 2011

Background: The prevalence of phenylalanine hydroxylase (PAH)-deficient phenylketonuria (PKU) in Turkey is high (1 in 6500 births), but data concerning the genotype distribution and impact of the genotype on tetrahydrobiopterin (BH4) therapy are scarce. Objective: To characterize the phenotypic and genotypic variability in the Turkish PKU population and to correlate it with physiological response to BH4 challenge. Methods: We genotyped 588 hyperphenylalaninemic patients and performed a BH4 loading test (20mg/kg bw) in 462 patients. Residual PAH activity of mutant proteins was calculated from available in vitro expression data. Data were tabulated in the BIOPKU database ( Results: Eighty-eight mutations were observed, the most common missense mutations being the splice variant c.1066-11G>A (24.6%). Twenty novel mutations were detected (11 missense, 4 splice-site, and 5 deletion/insertions). Two mutations were observed in 540/588 patients (91.8%) but in 9 patients atypical genotypes with >2 mutations were found (8 with p.R155H in cis with another variant) and in 19 patients mutations were found in BH4-metabolizing genes. The most common genotype was c.1066-11G>A/c.1066-11G>A (15.5%). Approximately 22% of patients responded to BH4 challenge. A substantial in vitro residual activity (average >25% of the wild-type enzyme) was associated with response to BH4. In homozygous genotypes (n=206), both severity of the phenotype (r=0.83) and residual PAH activity (r=0.85) correlate with BH4 responsiveness. Conclusion: Together with the BH4 challenge, these data enable the genotype-based classification of BH4 responsiveness and document importance of residual PAH activity. This first report of a large-scale genotype assessment in a population of Turkish PKU patients also documents a high prevalence (47%) of the severe classic phenotype. © 2010 Elsevier Inc.

Adamsen D.,University of Zürich | Adamsen D.,Center for Neuroscience | Adamsen D.,Pediatric Research Center | Meili D.,University of Zürich | And 8 more authors.
Molecular Genetics and Metabolism | Year: 2011

The known Gly56Ala mutation in the serotonin transporter SERT (or 5-HTT), encoded by the SLC6A4 gene, causes increased serotonin reuptake and has been associated with autism and rigid-compulsive behavior. We report a patient with macrocephaly from birth, followed by hypotonia, developmental delay, ataxia and a diagnosis of atypical autism (PDD-NOS) in retrospect at the age of 4 1/2. years. Low levels of the serotonin end-metabolite 5-hydroxyindolacetic acid (5HIAA) in CSF were detected, and SLC6A4 gene analysis revealed the heterozygous Gly56Ala alteration and the homozygous 5-HTTLPR L/L promoter variant. These changes are reported to be responsible for elevated SERT activity and expression, suggesting that these alterations were responsible in our patient for low serotonin turnover in the central nervous system (CNS). Daily treatment with 5-hydroxytryptophan (and carbidopa) led to clinical improvement and normalization of 5HIAA, implying that brain serotonin turnover normalized. We speculate that the mutated 56Ala SERT transporter with elevated expression and basal activity for serotonin re-uptake is accompanied with serotonin accumulation within pre-synaptic axons and their vesicles in the CNS, resulting in a steady-state of lowered serotonin turnover and degradation by monoamine-oxidase (MAO) enzymes in pre-synaptic or neighboring cells. © 2010 Elsevier Inc.

Dhamne C.,National University Hospital Singapore | Chung Y.,Institute of Molecular Medicine | Alousi A.M.,University of Texas M. D. Anderson Cancer Center | Cooper L.J.N.,University of Texas M. D. Anderson Cancer Center | Tran D.Q.,Pediatric Research Center
Frontiers in Immunology | Year: 2013

Over the past decade, much has been learnt and much more to discover about Foxp3+ regulatory T cells (Tregs). Initially, it was thought that Tregs were a unique entity that originates in the thymus. It is now recognized that there is a fraternal twin sibling that is generated in the periphery. Th difficulty is in the distinction between these two subsets. The ability to detect, monitor, and analyze these two subsets in health and disease will provide invaluable insights into their functions an purposes. The plasticity and mechanisms of action can be unique and not overlapping within these subsets. Therefore, the therapeutic targeting of a particular subset of Tregs might be more efficacious. In the past couple of years, a vast amount of data have provided a better understanding of the cellular and molecular components essential for their development and stability. Many studies are implicating their preferential involvement in certain diseases and immunologic tolerance. However, it remain controversial as to whether any phenotypic markers have been identified that can differentiate thymic versus peripheral Tregs. This review will address the validity and controversy regarding Helios, Lap/Garp and Neuropilin-1 as markers of thymic Tregs. It also will discuss updated information on distinguishing features of these two subsets and their critical roles in maternal-fetal tolerance and transplantation. © 2013 Dhamne, Chung, Alousi, Cooper and Tran.

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