RARS2 mutations in a sibship with infantile spasms

Pontocerebellar hypoplasia is a group of heterogeneous neurodevelopmental disorders characterized by reduced volume of the brainstem and cerebellum. We report two male siblings who presented with early infantile clonic seizures, and then developed infantile spasms associated with prominent isolated cerebellar hypoplasia/atrophy on magnetic resonance imaging (MRI). Using whole exome sequencing techniques, both were found to be compound heterozygotes for one previously reported and one novel mutation in the gene encoding mitochondrial arginyl-tRNA synthetase 2 (RARS2). Mutations in this gene have been classically described in pontocerebellar hypoplasia type six (PCH6), a phenotype characterized by early (often intractable) seizures, profound developmental delay, and progressive pontocerebellar atrophy. The electroclinical spectrum of PCH6 is broad and includes a number of seizure types: myoclonic, generalized tonic-clonic, and focal clonic seizures. Our report expands the characterization of the PCH6 disease spectrum and presents infantile spasms as an associated electroclinical phenotype

Oxygen dependency of mitochondrial metabolism indicates outcome of newborn brain injury

There is a need for a method of real-time assessment of brain metabolism during neonatal hypoxic-ischaemic encephalopathy (HIE). We have used broadband near-infrared spectroscopy (NIRS) to monitor cerebral oxygenation and metabolic changes in 50 neonates with HIE undergoing therapeutic hypothermia treatment. In 24 neonates, 54 episodes of spontaneous decreases in peripheral oxygen saturation (desaturations) were recorded between 6 and 81 h after birth. We observed differences in the cerebral metabolic responses to these episodes that were related to the predicted outcome of the injury, as determined by subsequent magnetic resonance spectroscopy derived lactate/N-acetyl-aspartate. We demonstrated that a strong relationship between cerebral metabolism (broadband NIRS-measured cytochrome-c-oxidase (CCO)) and cerebral oxygenation was associated with unfavourable outcome; this is likely to be due to a lower cerebral metabolic rate and mitochondrial dysfunction in severe encephalopathy. Specifically, a decrease in the brain tissue oxidation state of CCO greater than 0.06 µM per 1 µM brain haemoglobin oxygenation drop was able to predict the outcome with 64% sensitivity and 79% specificity (receiver operating characteristic area under the curve = 0.73). With further work on the implementation of this methodology, broadband NIRS has the potential to provide an early, cotside, non-invasive, clinically relevant metabolic marker of perinatal hypoxic-ischaemic injury

HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenase

Background: Deficiency of 3-hydroxy-isobutyryl-CoA hydrolase (HIBCH) caused by HIBCH mutations is a rare cerebral organic aciduria caused by disturbance of valine catabolism. Multiple mitochondrial respiratory chain (RC) enzyme deficiencies can arise from a number of mechanisms, including defective maintenance or expression of mitochondrial DNA. Impaired biosynthesis of iron-sulphur clusters and lipoic acid can lead to pyruvate dehydrogenase complex (PDHc) deficiency in addition to multiple RC deficiencies, known as the multiple mitochondrial dysfunctions syndrome. Methods: Two brothers born to distantly related Pakistani parents presenting in early infancy with a progressive neurodegenerative disorder, associated with basal ganglia changes on brain magnetic resonance imaging, were investigated for suspected Leigh-like mitochondrial disease. The index case had deficiencies of multiple RC enzymes and PDHc in skeletal muscle and fibroblasts respectively, but these were normal in his younger brother. The observation of persistently elevated hydroxy-C4-carnitine levels in the younger brother led to suspicion of HIBCH deficiency, which was investigated by biochemical assay in cultured skin fibroblasts and molecular genetic analysis. Results: Specific spectrophotometric enzyme assay revealed HIBCH activity to be below detectable limits in cultured skin fibroblasts from both brothers. Direct Sanger sequence analysis demonstrated a novel homozygous pathogenic missense mutation c.950G <A; p.Gly317Glu in the HIBCH gene, which segregated with infantile-onset neurodegeneration within the family. Conclusions: HIBCH deficiency, a disorder of valine catabolism, is a novel cause of the multiple mitochondrial dysfunctions syndrome, and should be considered in the differential diagnosis of patients presenting with multiple RC deficiencies and/or pyruvate dehydrogenase deficiency

Novel surface features for automated detection of focal cortical dysplasias in paediatric epilepsy

Focal cortical dysplasia is a congenital abnormality of cortical development and the leading cause of surgically remediable drug-resistant epilepsy in children. Post-surgical outcome is improved by presurgical lesion detection on structural MRI. Automated computational techniques have improved detection of focal cortical dysplasias in adults but have not yet been effective when applied to developing brains. There is therefore a need to develop reliable and sensitive methods to address the particular challenges of a paediatric cohort. We developed a classifier using surface-based features to identify focal abnormalities of cortical development in a paediatric cohort. In addition to established measures, such as cortical thickness, grey-white matter blurring, FLAIR signal intensity, sulcal depth and curvature, our novel features included complementary metrics of surface morphology such as local cortical deformation as well as post-processing methods such as the "doughnut" method - which quantifies local variability in cortical morphometry/MRI signal intensity, and per-vertex interhemispheric asymmetry. A neural network classifier was trained using data from 22 patients with focal epilepsy (mean age = 12.1 ± 3.9, 9 females), after intra- and inter-subject normalisation using a population of 28 healthy controls (mean age = 14.6 ± 3.1, 11 females). Leave-one-out cross-validation was used to quantify classifier sensitivity using established features and the combination of established and novel features. Focal cortical dysplasias in our paediatric cohort were correctly identified with a higher sensitivity (73%) when novel features, based on our approach for detecting local cortical changes, were included, when compared to the sensitivity using only established features (59%). These methods may be applicable to aiding identification of subtle lesions in medication-resistant paediatric epilepsy as well as to the structural analysis of both healthy and abnormal cortical development

Seizure and cognitive outcomes after resection of glioneuronal tumors in children

Objective: Glioneuronal tumors (GNTs) are well‐recognized causes of chronic drug‐resistant focal epilepsy in children. Our practice involves an initial period of radiological surveillance and antiepileptic medications, with surgery being reserved for those with radiological progression or refractory seizures. We planned to analyze the group of patients with low‐grade GNTs, aiming to identify factors affecting seizure and cognitive outcomes. / Methods: We retrospectively reviewed the medical records of 150 children presenting to Great Ormond Street Hospital with seizures secondary to GNTs. Analysis of clinical, neuroimaging, neuropsychological, and surgical factors was performed to determine predictors of outcome. Seizure outcome at final follow‐up was classified as either seizure‐free (group A) or not seizure‐free (group B) for patients with at least 12‐months follow‐up postsurgery. Full‐scale intelligence quotient (FSIQ) was used as a measure of cognitive outcome. / Results: Eighty‐six males and 64 females were identified. Median presurgical FSIQ was 81. One hundred twenty‐one patients (80.5%) underwent surgery. Median follow‐up after surgery was 2 years, with 92 patients (76%) having at least 12 months of follow‐up after surgery. Seventy‐four patients (80%) were seizure‐free, and 18 (20%) continued to have seizures. Radiologically demonstrated complete tumor resection was associated with higher rates of seizure freedom (P = .026). Higher presurgical FSIQ was related to shorter epilepsy duration until surgery (P = .012) and to older age at seizure onset (P = .043). / Significance: A high proportion of children who present with epilepsy and GNTs go on to have surgical tumor resection with excellent postoperative seizure control. Complete resection is associated with a higher chance of seizure freedom. Higher presurgical cognitive functioning is associated with shorter duration of epilepsy prior to surgery and with older age at seizure onset. Given the high rate of eventual surgery, early surgical intervention should be considered in children with continuing seizures associated with GNTs

The Effect of Corporate Social Responsibility on Financial Performance with Real Manipulation as a Moderating Variable

This study aimed to obtain empirical evidence about the effect of real manipulation practices on Corporate Social Responsibility (CSR), and further examined the impact of real manipulation on relationship between CSR and the financial performance of companies in the future. 27 companies listed on Indonesian Stock Exchange during the years 2006 - 2008 were selected as sample for this study. Data were collected by purposive sampling method and statistical method used for analysis was ordinary least square regression. The study provided empirical evidence that companies engaged in the practice of real manipulation had no influence on CSR activities. The results showed that the higher level of real manipulation on operation cash flow leads to negative effect on the relationship between CSR and financial performance

Proton Magnetic Resonance Spectroscopy Lactate/N-Acetylaspartate within 2 weeks of birth accurately predicts 2-year motor, cognitive and language outcomes in Neonatal Encephalopathy after Therapeutic Hypothermia

OBJECTIVE: Brain proton (1H) magnetic resonance spectroscopy (MRS) lactate/N-Acetylaspartate (Lac/NAA) peak area ratio is used for prognostication in Neonatal Encephalopathy (NE). At 3-Tesla in NE babies, the objectives were to assess: (i) sensitivity and specificity of basal ganglia and thalamus (BGT) 1H MRS Lac/NAA for prediction of Bayley III outcomes at 2-years using optimized metabolite fitting (Tarquin) with threonine and total NAA; (ii) prediction of motor outcome with diffusion-weighted MRI; iii) BGT Lac/NAA correlation with the NICHD MRI score. MATERIALS AND METHODS: 55 (16 inborn, 39 outborn) NE infants at 39w+5d (35w+5d-42w+0d) admitted between February 2012 and August 2014 to UCH for therapeutic hypothermia underwent MRI and 1H MRS at 3T on day 2-14 (median day 5). MRIs were scored. Bayley III was assessed at 24 (22-26) months. RESULTS: Sixteen babies died (1 inborn, 15 outborn); 20, 19 and 21 babies had poor motor, cognitive and language outcomes. Using a threshold of 0.39, sensitivity and specificity of BGT Lac/NAA for 2-year motor outcome was 100% and 97%, cognition 90% and 97% and language 81% and 97% respectively. Sensitivity and specificity for motor outcome of mean diffusivity (MD; threshold 0.001 mm2 /s) up to day 9 was 72% and 39% and fractional anisotropy (FA; threshold 0.198) was 100%, and 94% respectively. Lac/NAA correlated with BGT injury on NICHD scores (2A, 2B, 3). CONCLUSIONS: BGT Lac/NAA on 1H MRS at 3T within 14 days accurately predicts 2-year motor, cognitive and language outcome and may be a marker directing decisions for therapies after cooling

Multimodal computational neocortical anatomy in pediatric hippocampal sclerosis

Objective: In contrast to adult cohorts, neocortical changes in epileptic children with hippocampal damage are not well characterized. Here, we mapped multimodal neocortical markers of epilepsy-related structural compromise in a pediatric cohort of temporal lobe epilepsy and explored how they relate to clinical factors. Methods: We measured cortical thickness, gray–white matter intensity contrast and intracortical FLAIR intensity in 22 patients with hippocampal sclerosis (HS) and 30 controls. Surface-based linear models assessed between-group differences in morphological and MR signal intensity markers. Structural integrity of the hippocampus was measured by quantifying atrophy and FLAIR patterns. Linear models were used to evaluate the relationships between hippocampal and neocortical MRI markers and clinical factors. Results: In the hippocampus, patients demonstrated ipsilateral atrophy and bilateral FLAIR hyperintensity. In the neocortex, patients showed FLAIR signal hyperintensities and gray–white matter boundary blurring in the ipsilesional mesial and lateral temporal neocortex. In contrast, cortical thinning was minimal and restricted to a small area of the ipsilesional temporal pole. Furthermore, patients with a history of febrile convulsions demonstrated more pronounced FLAIR hyperintensity in the ipsilesional temporal neocortex. Interpretation: Pediatric HS patients do not yet demonstrate the widespread cortical thinning present in adult cohorts, which may reflect consequences of a protracted disease process. However, pronounced temporal neocortical FLAIR hyperintensity and blurring of the gray–white matter boundary are already detectable, suggesting that alterations in MR signal intensities may reflect a different underlying pathophysiology that is detectable earlier in the disease and more pervasive in patients with a history of febrile convulsions

Use of green solvents as pre-treatment of dissolving pulp to decrease CS2 consumption from viscose production

Choline chloride-based deep eutectic solvents are widely used in biomass processing. In this work, four different green solvent mixtures were used as pre-treatment of acid sulphite dissolving pulp with the hypothesis of increasing the possibilities to produce viscose fibres and decreasing the use of the harmful and toxic carbon disulphide in the process. The experiments were performed at two different pulp to solvent mass ratios. Pulp quality parameters were also measured to determine the suitability of the pretreatment: a-cellulose, viscosity, lignin and pentosan content. In addition, X-ray diffraction analysis of pulps at the best solid to liquid ratio was performed to obtain the influence of the crystallinity index. Best results were obtained with the use of lactic acid, with reactivity values close to 94%, giving a reduction of CS2 usage of 15.83%. Furthermore, a linear relationship between the crystallinity index calculated by the XRD and reactivity with a regression factor of 0.87 was found