Spatial distribution of human arachnoid trabeculae

Traumatic brain injury (TBI) is a common injury modality affecting a diverse patient population. Axonal injury occurs when the brain experiences excessive deformation as a result of head impact. Previous studies have shown that the arachnoid trabeculae (AT) in the subarachnoid space significantly influence the magnitude and distribution of brain deformation during impact. However, the quantity and spatial distribution of cranial AT in humans is unknown. Quantification of these microstructural features will improve understanding of force transfer during TBI, and may be a valuable dataset for microneurosurgical procedures. In this study, we quantify the spatial distribution of cranial AT in seven post-mortem human subjects. Optical coherence tomography (OCT) was used to conduct in situ imaging of AT microstructure across the surface of the human brain. OCT images were segmented to quantify the relative amounts of trabecular structures through a volume fraction (VF) measurement. The average VF for each brain ranged from 22.0% to 29.2%. Across all brains, there was a positive spatial correlation, with VF significantly greater by 12% near the superior aspect of the brain (p < .005), and significantly greater by 5%−10% in the frontal lobes (p < .005). These findings suggest that the distribution of AT between the brain and skull is heterogeneous, region-dependent, and likely contributes to brain deformation patterns. This study is the first to image and quantify human AT across the cerebrum and identify region-dependencies. Incorporation of this spatial heterogeneity may improve the accuracy of computational models of human TBI and enhance understanding of brain dynamics.     

Whole MYBPC3 NGS sequencing as a molecular strategy to improve the efficiency of molecular diagnosis of patients with hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiomyopathy, historically believed to affect 1 of 500 people. MYBPC3 pathogenic variations are the most frequent cause of familial HCM and more than 90% of them introduce a premature termination codon. The current study aims to determine the prevalence of deep intronic MYBPC3 pathogenic variations that could lead to splice mutations. To improve molecular diagnosis, a next‐generation sequencing (NGS) workflow based on whole MYBPC3 sequencing of a cohort of 93 HCM patients, for whom no putatively causative point mutations were identified after NGS sequencing of a panel of 48 cardiomyopathy‐causing genes, was performed. Our approach led us to reconsider the molecular diagnosis of six patients of the cohort (6.5%). These HCM probands were carriers of either a new large MYBPC3 rearrangement or splice intronic variations (five cases). Four pathogenic intronic variations, including three novel ones, were detected. Among them, the prevalence of one of them (NM_000256.3:c.1927+ 600 C>T) was estimated at about 0.35% by the screening of 1,040 unrelated HCM individuals. This study suggests that deep MYBPC3 splice mutations account for a significant proportion of HCM cases (6.5% of this cohort). Consequently, NGS sequencing of MYBPC3 intronic sequences have to be performed systematically.     

Elucidating the clinical spectrum and molecular basis of HYAL2 deficiency

PurposeWe previously defined biallelic HYAL2 variants causing a novel disorder in 2 families, involving orofacial clefting, facial dysmorphism, congenital heart disease, and ocular abnormalities, with Hyal2 knockout mice displaying similar phenotypes. In this study, we better define the phenotype and pathologic disease mechanism.MethodsClinical and genomic investigations were undertaken alongside molecular studies, including immunoblotting and immunofluorescence analyses of variant/wild-type human HYAL2 expressed in mouse fibroblasts, and in silico modeling of putative pathogenic variants.ResultsTen newly identified individuals with this condition were investigated, and they were associated with 9 novel pathogenic variants. Clinical studies defined genotype–phenotype correlations and confirmed a recognizable craniofacial phenotype in addition to myopia, cleft lip/palate, and congenital cardiac anomalies as the most consistent manifestations of the condition. In silico modeling of missense variants identified likely deleterious effects on protein folding. Consistent with this, functional studies indicated that these variants cause protein instability and a concomitant cell surface absence of HYAL2 protein.ConclusionThese studies confirm an association between HYAL2 alterations and syndromic cleft lip/palate, provide experimental evidence for the pathogenicity of missense alleles, enable further insights into the pathomolecular basis of the disease, and delineate the core and variable clinical outcomes of the condition.     

Taking a Broad Approach to Public Health Program Adaptation: Adapting a Family-Based Diabetes Education Program

Diabetes health disparities among Hispanic populations have been countered with federally funded health promotion and disease prevention programs. Dissemination has focused on program adaptation to local cultural contexts for greater acceptability and sustainability. Taking a broader approach and drawing on our experience in Mexican American communities at the U.S.–Mexico Border, we demonstrate how interventions are adapted at the intersection of multiple cultural contexts: the populations targeted, the community- and university-based entities designing and implementing interventions, and the field team delivering the materials. Program adaptation involves negotiations between representatives of all contexts and is imperative in promoting local ownership and program sustainability.     

Reelin immunoreactivity in the adult sea lamprey brain

The expression of reelin, a large extracellular matrix glycoprotein, was studied in the brain of pre-spawning adult sea lampreys by immunohistochemistry using two monoclonal antibodies against this protein. Reelin immunoreactive (reln-ir) neurons were observed in the olfactory bulb, and pallial and subpallial regions in the telencephalon. In the diencephalon, reln-ir cells were observed in some hypothalamic nuclei, in the nucleus of Bellonci, and in the habenula. In the mesencephalon, this protein was detected in several nuclei related with the centrifugal visual system, although the optic tectum was devoid of immunoreactivity. The hindbrain showed several nuclei with immunopositive neurons, including the branchiomeric nerve motor nuclei and also some groups of non-giant cells of the reticular formation. The rostral spinal cord showed some immunopositive neurons mainly located in lateral and ventral positions. Overall, the pattern of distribution of reelin in the adult sea lamprey correlates with the previously reported in other adult vertebrates. Furthermore, the wide distribution of reelin in the adult lamprey brain is consistent with a possible existence of different roles for this protein not related with development in the central nervous system (CNS) of vertebrates (i.e. neuronal plasticity and/or maintenance).