28 research outputs found
Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal encephalopathy
This is the author accepted manuscript. The final version is available from Oxford University Press via the DOI in this record.The corrigendum to this article is in ORE: http://hdl.handle.net/10871/33588Cellular distribution and dynamics of mitochondria are regulated by several motor proteins and a microtubule network. In neurons, mitochondrial trafficking is crucial because of high energy needs and calcium ion buffering along axons to synapses during neurotransmission. The trafficking kinesin proteins (TRAKs) are well characterized for their role in lysosomal and mitochondrial trafficking in cells, especially neurons. Using whole exome sequencing, we identified homozygous truncating variants in TRAK1 (NM_001042646:c.287-2A > C), in six lethal encephalopathic patients from three unrelated families. The pathogenic variant results in aberrant splicing and significantly reduced gene expression at the RNA and protein levels. In comparison with normal cells, TRAK1-deficient fibroblasts showed irregular mitochondrial distribution, altered mitochondrial motility, reduced mitochondrial membrane potential, and diminished mitochondrial respiration. This study confirms the role of TRAK1 in mitochondrial dynamics and constitutes the first report of this gene in association with a severe neurodevelopmental disorder.D.M.E. and J.K. are supported by the Office of Naval Research (ONR) Grant N000141410538. M.S. is supported by the BBSRC (BB/K006231/1), a Wellcome Trust Institutional Strategic Support Award (WT097835MF, WT105618MA), and a Marie Curie Initial Training Network (ITN) action PerFuMe (316723). M.C.V.M., J.S., H.P., C.F., T.V. and W.A.G. are supported by the NGHRI Intramural Research Program. G.R. is supported by the Kahn Family Foundation and the Israeli Centers of Excellence (I-CORE) Program (ISF grant no. 41/11)
1941 Ovarian Dermoid Cyst as the Cause of Anti-Nmda Receptor Encephalitis: A Case Series
Fetal urine production rate in preterm premature rupture of membranes is associated with adverse neonatal outcome: A pilot study.
Introduction In this study we evaluated the associations between fetal urinary production rate (FUPR), measured by ultrasound, and adverse neonatal outcome in women with preterm premature rupture of membranes (PPROM). Material and Methods We conducted a prospective cohort of singleton pregnancies complicated by PPROM occurring at gestational week 24 or later in a single center. Women with PPROM and conservative management until spontaneous labor (after 48 hours of admission), chorioamnionitis, or induction by protocol at 35+0 weeks. FUPR was evaluated by 2D sonography at admission, and corrected for gestational age. Attending physicians were blinded to FUPR results. The main neonatal outcome measures were chorioamnionitis, placental inflammatory grading, first neonatal creatinine value, first neonatal dextrose value, length of neonatal intensive care unit (NICU) stay, necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH) (grades I-IV), blood transfusions, reduced neonatal urine production rate (<4mL/kg/h), and early neonatal sepsis. Samples of maternal (at admission) and umbilical cord blood were analyzed for interleukin-6 (IL-6) level. Results The study included 38 women. Low FUPR was associated with chorioamnionitis, longer NICU hospitalization (p=0.01), and higher rates of NEC or IVH (p=0.008), and blood transfusion (p=0.004). There were no significant associations between antenatal FUPR and placental histologic inflammation grading, neonatal creatinine, neonatal dextrose, or early neonatal sepsis. IL-6 levels did not correlate with chorioamnionitis, FUPR, or early sepsis. Conclusion A finding of FUPR on in utero ultrasound examination in pregnancies complicated by PPROM may be indicative of an inflammatory process and predictive of adverse neonatal outcome.</p
Fetal urine production rate in preterm premature rupture of membranes is associated with adverse neonatal outcome: A pilot study.
Introduction
In this study we evaluated the associations between fetal urinary production rate (FUPR), measured by ultrasound, and adverse neonatal outcome in women with preterm premature rupture of membranes (PPROM).
Material and Methods
We conducted a prospective cohort of singleton pregnancies complicated by PPROM occurring at gestational week 24 or later in a single center. Women with PPROM and conservative management until spontaneous labor (after 48 hours of admission), chorioamnionitis, or induction by protocol at 35+0 weeks. FUPR was evaluated by 2D sonography at admission, and corrected for gestational age. Attending physicians were blinded to FUPR results. The main neonatal outcome measures were chorioamnionitis, placental inflammatory grading, first neonatal creatinine value, first neonatal dextrose value, length of neonatal intensive care unit (NICU) stay, necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH) (grades I-IV), blood transfusions, reduced neonatal urine production rate (
Results
The study included 38 women. Low FUPR was associated with chorioamnionitis, longer NICU hospitalization (p=0.01), and higher rates of NEC or IVH (p=0.008), and blood transfusion (p=0.004). There were no significant associations between antenatal FUPR and placental histologic inflammation grading, neonatal creatinine, neonatal dextrose, or early neonatal sepsis. IL-6 levels did not correlate with chorioamnionitis, FUPR, or early sepsis.
Conclusion
A finding of FUPR on in utero ultrasound examination in pregnancies complicated by PPROM may be indicative of an inflammatory process and predictive of adverse neonatal outcome.</p
Cannabinoid receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease without effective treatment, highlighting the need for identifying new targets and treatment modalities. The pathogenesis of IPF is complex, and engaging multiple targets simultaneously might improve therapeutic efficacy. To assess the role of the endocannabinoid/cannabinoid receptor 1 (endocannabinoid/CBR) system in IPF and its interaction with inducible nitric oxide synthase (iNOS) as dual therapeutic targets, we analyzed lung fibrosis and the status of the endocannabinoid/CBR system and iNOS in mice with bleomycin-induced pulmonary fibrosis (PF) and in lung tissue and bronchoalveolar lavage fluid (BALF) from patients with IPF, as well as controls. In addition, we investigated the antifibrotic efficacy in the mouse PF model of an orally bioavailable and peripherally restricted CBR/iNOS hybrid inhibitor. We report that increased activity of the endocannabinoid/CBR system parallels disease progression in the lungs of patients with idiopathic PF and in mice with bleomycin-induced PF and is associated with increased tissue levels of interferon regulatory factor-5. Furthermore, we demonstrate that simultaneous engagement of the secondary target iNOS by the hybrid CBR/iNOS inhibitor has greater antifibrotic efficacy than inhibition of CBR alone. This hybrid antagonist also arrests the progression of established fibrosis in mice, thus making it a viable candidate for future translational studies in IPF