VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment

Tandem mass spectrometry-based newborn screening correctly identifies individuals with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD). However, a great number of healthy individuals present with identical acylcarnitine profiles during catabolism in the first three days of life. We routinely perform an enzyme activity assay as confirmation analysis in newborns identified by screening. Whereas VLCAD residual activities of less than 10% are clearly diagnostic and indicate patients at risk of clinical disease, the clinical relevance of higher residual activities is unclear. In this study we assess the molecular basis in 34 individuals with residual activities of 10-50%. We identify two pathogenic mutations in patients that result in residual activities as high as 22%, while individuals with residual activities of 25-50% either present with a heterozygous or no mutation in the VLCAD gene. In addition, confirmed heterozygous parents present with residual activities as low as 32%.     

Neurocognitive outcome in patients with hypertyrosinemia type I after long-term treatment with NTBC

Objective  

The implementation of NTBC into treatment of hypertyrosinemia type I (HT I) greatly improved survival by prevention of acute liver failure and hepatocellular carcinoma. However, there are first reports of cognitive impairment in patients with elevated plasma tyrosine concentrations.     

Three-dimensional,three-vector-component velocimetry of cilia-driven fluid flow using correlation-based approaches in optical coherence tomography

Microscale quantification of cilia-driven fluid flow is an emerging area in medical physiology, including pulmonary and central nervous system physiology. Cilia-driven fluid flow is most completely described by a three-dimensional, three-component (3D3C) vector field. Here, we generate 3D3C velocimetry measurements by synthesizing higher dimensional data from lower dimensional measurements obtained using two separate optical coherence tomography (OCT)-based approaches: digital particle image velocimetry (DPIV) and dynamic light scattering (DLS)-OCT. Building on previous work, we first demonstrate directional DLS-OCT for 1D2C velocimetry measurements in the sub-1 mm/s regime (sub-2.5 inch/minute regime) of cilia-driven fluid flow in Xenopus epithelium, an important animal model of the ciliated respiratory tract. We then extend our analysis toward 3D3C measurements in Xenopus using both DLS-OCT and DPIV. We demonstrate the use of DPIV-based approaches towards flow imaging of Xenopus cerebrospinal fluid and mouse trachea, two other important ciliary systems. Both of these flows typically fall in the sub-100 μm/s regime (sub-0.25 inch/minute regime). Lastly, we develop a framework for optimizing the signal-to-noise ratio of 3D3C flow velocity measurements synthesized from 2D2C measures in non-orthogonal planes. In all, 3D3C OCT-based velocimetry has the potential to comprehensively characterize the flow performance of biological ciliated surfaces.OCIS codes: (110.4500) Optical coherence tomography, (120.7250) Velocimetry, (170.3340) Laser Doppler velocimetry, (170.6480) Spectroscopy, speckle     

Lentiviral Gene Therapy Using Cellular Promoters Cures Type 1 Gaucher Disease in Mice

Gaucher disease is caused by an inherited deficiency of the enzyme glucosylceramidase. Due to the lack of a fully functional enzyme, there is progressive build-up of the lipid component glucosylceramide. Insufficient glucosylceramidase activity results in hepatosplenomegaly, cytopenias, and bone disease in patients. Gene therapy represents a future therapeutic option for patients unresponsive to enzyme replacement therapy and lacking a suitable bone marrow donor. By proof-of-principle experiments, we have previously demonstrated a reversal of symptoms in a murine disease model of type 1 Gaucher disease, using gammaretroviral vectors harboring strong viral promoters to drive glucosidase β-acid (GBA) gene expression. To investigate whether safer vectors can correct the enzyme deficiency, we utilized self-inactivating lentiviral vectors (SIN LVs) with the GBA gene under the control of human phosphoglycerate kinase (PGK) and CD68 promoter, respectively. Here, we report prevention of, as well as reversal of, manifest disease symptoms after lentiviral gene transfer. Glucosylceramidase activity above levels required for clearance of glucosylceramide from tissues resulted in reversal of splenomegaly, reduced Gaucher cell infiltration and a restoration of hematological parameters. These findings support the use of SIN-LVs with cellular promoters in future clinical gene therapy protocols for type 1 Gaucher disease.     

Why Do Patients with Partial Epilepsy Improve Their IQ After Training to Self-Regulate Slow Cortical Potentials?

In patients with epilepsy, not only seizures but also cognitive, emotional, and social functioning are of increasing interest in research (Kelley, Jacobs, &; Lowenstein, 2009 Kelley , M. S. , Jacobs , M. P. , &; Lowenstein , D. H. , for the NINDS Epilepsy Benchmark Stewards . ( 2009 ). The NINDS epilepsy research benchmarks . Epilepsia , 50 , 579 – 582 . doi: doi:10.1111/j.1528-1167.2008.01813.x  [Google Scholar]). As a decrease in cognitive functions over the course of the illness is usually reported, we wanted to explore changes in Intelligence Scores observed after a neurofeedback treatment in patients with drug-resistant epilepsies. In a controlled study that compared the outcome of three different interventions (training to regulate slow cortical potentials, N = 34; training to regulate breath rate and the amount of carbon dioxide in the end tidal volume of the exhaled air, N = 11; modification of drug regime, N = 25), pre- and postmeasurements of a short version of the Wechsler Intelligence Scale were applied. The interval between the two assessments was more than 12 months, with a mean of 61 weeks. Mean age of the patients was 35, with a range from 17 to 57. The highly significant 7-point increment of IQ only after training of slow cortical potentials was not related to clinical (e.g., seizure reduction) or neuropsychological (e.g., attention and memory) variables. Instead, it was related to psychophysiological measures: IQ change was inversely related to the Latency of the P300 component of event-related brain potentials and directly related to the Latency of the P2 component and the increase of N2 Amplitude during training. We conclude that regulation training of slow cortical potentials improves IQ in patients with refractory partial epilepsy, which might be related to an improved ability for controlled allocation of cognitive resources.