Fiber-Flux Diffusion Density for White Matter Tracts Analysis: Application to Mild Anomalies Localization in Contact Sports Players

We present the concept of fiber-flux density for locally quantifying white matter (WM) fiber bundles. By combining scalar diffusivity measures (e.g., fractional anisotropy) with fiber-flux measurements, we define new local descriptors called Fiber-Flux Diffusion Density (FFDD) vectors. Applying each descriptor throughout fiber bundles allows along-tract coupling of a specific diffusion measure with geometrical properties, such as fiber orientation and coherence. A key step in the proposed framework is the construction of an FFDD dissimilarity measure for sub-voxel alignment of fiber bundles, based on the fast marching method (FMM). The obtained aligned WM tract-profiles enable meaningful inter-subject comparisons and group-wise statistical analysis. We demonstrate our method using two different datasets of contact sports players. Along-tract pairwise comparison as well as group-wise analysis, with respect to non-player healthy controls, reveal significant and spatially-consistent FFDD anomalies. Comparing our method with along-tract FA analysis shows improved sensitivity to subtle structural anomalies in football players over standard FA measurements

Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios

Purpose: Despite the recognized clinical value of exome-based diagnostics, methods for comprehensive genomic interpretation remain immature. Diagnoses are based on known or presumed pathogenic variants in genes already associated with a similar phenotype. Here, we extend this paradigm by evaluating novel bioinformatics approaches to aid identification of new gene–disease associations. Methods: We analyzed 119 trios to identify both diagnostic genotypes in known genes and candidate genotypes in novel genes. We considered qualifying genotypes based on their population frequency and in silico predicted effects we also characterized the patterns of genotypes enriched among this collection of patients. Results: We obtained a genetic diagnosis for 29 (24%) of our patients. We showed that patients carried an excess of damaging de novo mutations in intolerant genes, particularly those shown to be essential in mice (P = 3.4 × 10−8). This enrichment is only partially explained by mutations found in known disease-causing genes. Conclusion: This work indicates that the application of appropriate bioinformatics analyses to clinical sequence data can also help implicate novel disease genes and suggest expanded phenotypes for known disease genes. These analyses further suggest that some cases resolved by whole-exome sequencing will have direct therapeutic implications

The Functional DRD3 Ser9Gly Polymorphism (rs6280) Is Pleiotropic, Affecting Reward as Well as Movement

Abnormalities of motivation and behavior in the context of reward are a fundamental component of addiction and mood disorders. Here we test the effect of a functional missense mutation in the dopamine 3 receptor (DRD3) gene (ser9gly, rs6280) on reward-associated dopamine (DA) release in the striatum. Twenty-six healthy controls (HCs) and 10 unmedicated subjects with major depressive disorder (MDD) completed two positron emission tomography (PET) scans with [11C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition) and on another occasion subjects completed a gambling task (reward condition). A linear regression analysis controlling for age, sex, diagnosis, and self-reported anhedonia indicated that during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding (i.e., increased reward-related DA release) in the middle (anterior) caudate (p<0.01) and the ventral striatum (p<0.05). The possible functional effect of the ser9gly polymorphism on DA release is consistent with previous work demonstrating that the glycine allele yields D3 autoreceptors that have a higher affinity for DA and display more robust intracellular signaling. Preclinical evidence indicates that chronic stress and aversive stimulation induce activation of the DA system, raising the possibility that the glycine allele, by virtue of its facilitatory effect on striatal DA release, increases susceptibility to hyperdopaminergic responses that have previously been associated with stress, addiction, and psychosis

Designer receptors show role for ventral pallidum input to ventral tegmental area in cocaine seeking.

The ventral pallidum is centrally positioned within mesocorticolimbic reward circuits, and its dense projection to the ventral tegmental area (VTA) regulates neuronal activity there. However, the ventral pallidum is a heterogeneous structure, and how this complexity affects its role within wider reward circuits is unclear. We found that projections to VTA from the rostral ventral pallidum (RVP), but not the caudal ventral pallidum (CVP), were robustly Fos activated during cue-induced reinstatement of cocaine seeking--a rat model of relapse in addiction. Moreover, designer receptor-mediated transient inactivation of RVP neurons, their terminals in VTA or functional connectivity between RVP and VTA dopamine neurons blocked the ability of drug-associated cues (but not a cocaine prime) to reinstate cocaine seeking. In contrast, CVP neuronal inhibition blocked cocaine-primed, but not cue-induced, reinstatement. This double dissociation in ventral pallidum subregional roles in drug seeking is likely to be important for understanding the mesocorticolimbic circuits underlying reward seeking and addiction

The Impact of the Laterality on Radiographic Outcomes of the Bernese Periacetabular Osteotomy

The purpose of this study was to compare the pre and postoperative radiographic findings and analyze the complication rate with respect to the laterality in periacetabular osteotomy in right-handed surgeons. Satisfaction rate and radiographic findings were prospectively collected between 2017 and 2019 and retrospectively reviewed. For analysis, all measurements of the CT scans were performed by a musculoskeletal fellowship-trained radiologist. Complications were classified into two categories: perioperative or postoperative. All surgeries were performed by three right-hand dominant hip surgeons. A total of 41 dysplastic hips (25 right and 16 left hips) in 33 patients were included. Postoperatively, a significantly lower acetabular index angle on the left side was observed at -2.6 +/- 4.3 as compared to the right side at 1.6 +/- 6.5 (p < 0.05). The change in Center edge (CE) angle was significantly lower for the left side 13.7 +/- 5.5 degrees than on the right side, measured at 18.4 +/- 7.3 (p < 0.001); however, the overall CE angle was comparable at 38.5 +/- 8.9 degrees without any significant difference between the operated hips (left side at 37.8 +/- 6.1 degrees versus right side at 39.0 +/- 10.3; p = 0.340). No significant differences in other radiographic measurements or surgical time were observed. For complications, the right side was more commonly affected, which may also explain a higher satisfaction rate in patients who were operated on the left hip with 92.3%. The change in lateral CE angle was significantly lower for the left side and the right hip seems to be predisposed to complications, which correlate with a lower satisfaction rate in right-handed surgeons

The Impact of the Laterality on Radiographic Outcomes of the Bernese Periacetabular Osteotomy

The purpose of this study was to compare the pre and postoperative radiographic findings and analyze the complication rate with respect to the laterality in periacetabular osteotomy in right-handed surgeons. Satisfaction rate and radiographic findings were prospectively collected between 2017 and 2019 and retrospectively reviewed. For analysis, all measurements of the CT scans were performed by a musculoskeletal fellowship-trained radiologist. Complications were classified into two categories: perioperative or postoperative. All surgeries were performed by three right-hand dominant hip surgeons. A total of 41 dysplastic hips (25 right and 16 left hips) in 33 patients were included. Postoperatively, a significantly lower acetabular index angle on the left side was observed at -2.6 +/- 4.3 as compared to the right side at 1.6 +/- 6.5 (p < 0.05). The change in Center edge (CE) angle was significantly lower for the left side 13.7 +/- 5.5 degrees than on the right side, measured at 18.4 +/- 7.3 (p < 0.001); however, the overall CE angle was comparable at 38.5 +/- 8.9 degrees without any significant difference between the operated hips (left side at 37.8 +/- 6.1 degrees versus right side at 39.0 +/- 10.3; p = 0.340). No significant differences in other radiographic measurements or surgical time were observed. For complications, the right side was more commonly affected, which may also explain a higher satisfaction rate in patients who were operated on the left hip with 92.3%. The change in lateral CE angle was significantly lower for the left side and the right hip seems to be predisposed to complications, which correlate with a lower satisfaction rate in right-handed surgeons

Rotational abnormalities in dysplastic hips and how to predict acetabular torsion

Objectives: The aim of this study was to investigate the degree to which conventional radiography can represent the acetabular and femoral rotational alignment profile between dysplastic and borderline-dysplastic hips. Methods: A retrospective trial was conducted including 56 borderline-dysplastic and dysplastic hips at a mean age of 28.9 years (range from 18 to 46). Inclusion criteria consisted of symptomatic patients with hip dysplasia undergoing 2-dimensional radiography as well as computed tomography. On radiography, the lateral center edge angle, acetabular hip index, hip lateralization index, acetabular index angle, and the Sharp angle were measured, and the presence of a crossover sign was noted. In computed tomography, the full rotational profile of the lower limb was measured. Results: Significant correlations were observed in the overall analysis between the anteversion of the acetabulum and the hip lateralization index (mean 0.56, coefficient of regression (CoR) -32.35, p = 0.011) as well as the acetabular index angle with a mean of 11.50 (CoR 0.544, p = 0.018). Similar results were found in the subgroup of dysplastic hips with an acetabular index angle of 13.9 (p = 0.013, CoR 0.74). For the borderline-dysplastic group, no significant correlations between the pelvis radiography and rotational CT were seen. Conclusion: Although the femoral and acetabular torsion cannot be predicted from x-rays, the anteversion of the acetabulum correlates with the acetabular index angle, the hip lateralization index, and eventually the beta angle in dysplastic hips. For borderline-dysplastic hips, such results did not show up, which strongly illustrates the need for computed tomography in these cases

Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination.

Axon pathfinding and synapse formation are essential processes for nervous system development and function. The assembly of myelinated fibres and nodes of Ranvier is mediated by a number of cell adhesion molecules of the immunoglobulin superfamily including neurofascin, encoded by the NFASC gene, and its alternative isoforms Nfasc186 and Nfasc140 (located in the axonal membrane at the node of Ranvier) and Nfasc155 (a glial component of the paranodal axoglial junction). We identified 10 individuals from six unrelated families, exhibiting a neurodevelopmental disorder characterized with a spectrum of central (intellectual disability, developmental delay, motor impairment, speech difficulties) and peripheral (early onset demyelinating neuropathy) neurological involvement, who were found by exome or genome sequencing to carry one frameshift and four different homozygous non-synonymous variants in NFASC. Expression studies using immunostaining-based techniques identified absent expression of the Nfasc155 isoform as a consequence of the frameshift variant and a significant reduction of expression was also observed in association with two non-synonymous variants affecting the fibronectin type III domain. Cell aggregation studies revealed a severely impaired Nfasc155-CNTN1/CASPR1 complex interaction as a result of the identified variants. Immunofluorescence staining of myelinated fibres from two affected individuals showed a severe loss of myelinated fibres and abnormalities in the paranodal junction morphology. Our results establish that recessive variants affecting the Nfasc155 isoform can affect the formation of paranodal axoglial junctions at the nodes of Ranvier. The genetic disease caused by biallelic NFASC variants includes neurodevelopmental impairment and a spectrum of central and peripheral demyelination as part of its core clinical phenotype. Our findings support possible overlapping molecular mechanisms of paranodal damage at peripheral nerves in both the immune-mediated and the genetic disease, but the observation of prominent central neurological involvement in NFASC biallelic variant carriers highlights the importance of this gene in human brain development and function

The Impact of Hip Dysplasia on CAM Impingement

Predisposing factors for CAM-type femoroacetabular impingement (FAI) include acetabular protrusion and retroversion; however, nothing is known regarding development in dysplastic hips. The purpose of this study was to determine the correlation between CAM-type FAI and developmental dysplastic hips diagnosed using X-ray and rotational computed tomography. In this retrospective study, 52 symptomatic hips were included, with a mean age of 28.8 +/- 7.6 years. The inclusion criteria consisted of consecutive patients who suffered from symptomatic dysplastic or borderline dysplastic hips and underwent a clinical examination, conventional radiographs and rotational computed tomography. Demographics, standard measurements and the rotational alignments were recorded and analyzed between the CAM and nonCAM groups. Among the 52 patients, 19 presented with CAM impingement, whereas, in 33 patients, no signs of CAM impingement were noticed. For demographics, no significant differences between the two groups were identified. On conventional radiography, the acetabular hip index as well as the CE angle for the development of CAM impingement were significantly different compared to the nonCAM group with a CE angle of 21.0 degrees +/- 5.4 degrees vs. 23.7 degrees +/- 5.8 degrees (p = 0.050) and an acetabular hip index of 25.6 +/- 5.7 vs. 21.9 +/- 7.3 (p = 0.031), respectively. Furthermore, a crossing over sign was observed to be more common in the nonCAM group, which is contradictory to the current literature. For rotational alignment, no significant differences were observed. In dysplastic hips, the CAM-type FAI correlated to a lower CE angle and a higher acetabular hip index. In contrast to the current literature, no significant correlations to the torsional alignment or to crossing over signs were observed