Multi-system neurological disease is common in patients with OPA1 mutations

Additional neurological features have recently been described in seven families transmitting pathogenic mutations in OPA1, the most common cause of autosomal dominant optic atrophy. However, the frequency of these syndromal 'dominant optic atrophy plus' variants and the extent of neurological involvement have not been established. In this large multi-centre study of 104 patients from 45 independent families, including 60 new cases, we show that extra-ocular neurological complications are common in OPA1 disease, and affect up to 20% of all mutational carriers. Bilateral sensorineural deafness beginning in late childhood and early adulthood was a prominent manifestation, followed by a combination of ataxia, myopathy, peripheral neuropathy and progressive external ophthalmoplegia from the third decade of life onwards. We also identified novel clinical presentations with spastic paraparesis mimicking hereditary spastic paraplegia, and a multiple sclerosis-like illness. In contrast to initial reports, multi-system neurological disease was associated with all mutational subtypes, although there was an increased risk with missense mutations [odds ratio = 3.06, 95% confidence interval = 1.44-6.49; P = 0.0027], and mutations located within the guanosine triphosphate-ase region (odds ratio = 2.29, 95% confidence interval = 1.08-4.82; P = 0.0271). Histochemical and molecular characterization of skeletal muscle biopsies revealed the presence of cytochrome c oxidase-deficient fibres and multiple mitochondrial DNA deletions in the majority of patients harbouring OPA1 mutations, even in those with isolated optic nerve involvement. However, the cytochrome c oxidase-deficient load was over four times higher in the dominant optic atrophy + group compared to the pure optic neuropathy group, implicating a causal role for these secondary mitochondrial DNA defects in disease pathophysiology. Individuals with dominant optic atrophy plus phenotypes also had significantly worse visual outcomes, and careful surveillance is therefore mandatory to optimize the detection and management of neurological disability in a group of patients who already have significant visual impairment

Interactive histogenesis of axonal strata and proliferative zones in the human fetal cerebral wall

Development of the cerebral wall is characterized by partially overlapping histogenetic events. However, little is known with regards to when, where, and how growing axonal pathways interact with progenitor cell lineages in the proliferative zones of the human fetal cerebrum. We analyzed the developmental continuity and spatial distribution of the axonal sagittal strata (SS) and their relationship with proliferative zones in a series of human brains (8-40 post-conceptional weeks; PCW) by comparing histological, histochemical, and immunocytochemical data with magnetic resonance imaging (MRI). Between 8.5 and 11 PCW, thalamocortical fibers from the intermediate zone (IZ) were initially dispersed throughout the subventricular zone (SVZ), while sizeable axonal "invasion" occurred between 12.5 and 15 PCW followed by callosal fibers which "delaminated" the ventricular zone-inner SVZ from the outer SVZ (OSVZ). During midgestation, the SS extensively invaded the OSVZ, separating cell bands, and a new multilaminar axonal-cellular compartment (MACC) was formed. Preterm period reveals increased complexity of the MACC in terms of glial architecture and the thinning of proliferative bands. The addition of associative fibers and the formation of the centrum semiovale separated the SS from the subplate. In vivo MRI of the occipital SS indicates a "triplet" structure of alternating hypointense and hyperintense bands. Our results highlighted the developmental continuity of sagittally oriented "corridors" of projection, commissural and associative fibers, and histogenetic interaction with progenitors, neurons, and glia. Histogenetical changes in the MACC, and consequently, delineation of the SS on MRI, may serve as a relevant indicator of white matter microstructural integrity in the developing brain

Tuning and validation of a diesel spray model

A spray model has been implemented in the OpenFOAM CFD toolkit. A set of constant volume chamber injection simulations has been performed in order to analyze the influence of the spray model constants. In the performed analysis, a set of model constants was selected and the simulation results were compared to the experimental results obtained in the Sandia constant volume combustion chamber. The implemented model showed very good agreement with the experimental results with respect to the vapour penetration and spray shape. The simulated liquid penetration did not match the experimental results, but this is considered less important for combustion simulations

LNG carrier main steam turbine reliability in the exploatation period of time

In this paper the LNG carrier with steam turbine propulsion plant maintenance records has been analysed. Actual observed data from the ship, built in 2001, are from ship maintenance history data from September 2002 until August 2010. During the analysed period, main propulsion turbine had one major failure and several minor failures. The ship had three dry docks and one was prolonged due to increased requirements for cargo transport. Total running hours of the main propulsion turbine in the observed period of time were 63204 hours. The list of failures and influence of each mentioned failure of main turbine propulsion machinery is discussed and analysed in respect to the propulsion autonomy of the vessel

PET molecular imaging of phosphodiesterase 10A: An early biomarker of Huntington's disease progression

Background Changes in phosphodiesterase 10A enzyme levels may be a suitable biomarker of disease progression in Huntington's disease. Objectives To evaluate phosphodiesterase 10A PET imaging as a biomarker of HD progression using the radioligand, [F-18]MNI-659. Methods The cross-sectional study (NCT02061722) included 45 Huntington's disease gene-expansion carriers stratified into four disease stages (early and late premanifest and Huntington's disease stages 1 and 2) and 45 age- and sex-matched healthy controls. The primary analysis compared striatal and pallidal phosphodiesterase 10A availability between Huntington's disease gene-expansion carriers and healthy controls as assessed by [F-18]MNI-659 binding. We assessed changes in phosphodiesterase 10A expression using several PET methodologies and compared with previously proposed measures of Huntington's disease progression (PET imaging of D-2/3 receptors and anatomical volume loss on MRI). The longitudinal follow-up study (NCT02956148) continued evaluation of phosphodiesterase 10A availability in 35 Huntington's disease gene-expansion carriers at a mean of 18 months from baseline of the cross-sectional study. Results Primary analyses revealed that phosphodiesterase 10A availability in caudate, putamen, and globus pallidus was significantly lower in Huntington's disease gene-expansion carriers versus healthy controls across all stages. Striatal and pallidal phosphodiesterase 10A availability progressively declined in the premanifest stages and appeared to plateau between stages 1 and 2. The percentage decline of phosphodiesterase 10A availability measured cross-sectionally between Huntington's disease gene-expansion carriers and healthy controls was greater than that demonstrated by D-2/3 receptor availability or volumetric changes. Annualized rates of phosphodiesterase 10A change showed a statistically significant decline between the cross-sectional study and follow-up. Conclusions [F-18]MNI-659 PET imaging is a biologically plausible biomarker of Huntington's disease progression that is more sensitive than the dopamine-receptor and volumetric methods currently used. (c) 2020 International Parkinson and Movement Disorder SocietyNeurological Motor Disorder