The mechanisms underlying the complications of mild traumatic brain injury, including post-concussion syndrome, post-impact catastrophic death, and delayed neurodegeneration, remain poorly understood. This limited pathophysiological understanding has hindered the development of diagnostic and prognostic biomarkers and has prevented the advancement of treatments for the sequelae of mild traumatic brain injury. We aimed to characterize the early electrophysiological and neurovascular alterations following repetitive mild traumatic brain injury and sought to identify new targets for the diagnosis and treatment of individuals at risk of severe post-impact complications. We combined behavioural, electrophysiological, molecular, and neuroimaging techniques in a rodent model of repetitive mild traumatic brain injury. In humans, we used dynamic contrast-enhanced MRI to quantify blood-brain barrier dysfunction after exposure to sport-related concussive mild traumatic brain injury. Rats could clearly be classified based on their susceptibility to neurological complications, including life-threatening outcomes, following repetitive injury. Susceptible animals showed greater neurological complications and had higher levels of blood-brain barrier dysfunction, transforming growth factor β signaling, and neuroinflammation compared to resilient animals. Cortical spreading depolarizations were the most common electrophysiological events immediately following mild traumatic brain injury and were associated with longer recovery from impact. Triggering cortical spreading depolarizations in mild traumatic brain injured rats (but not in controls) induced blood-brain barrier dysfunction. Treatment with a selective transforming growth factor β receptor inhibitor prevented blood-brain barrier opening and reduced injury complications. Consistent with the rodent model, blood-brain barrier dysfunction was found in a subset of human athletes following concussive mild traumatic brain injury. We provide evidence that cortical spreading depolarization, blood-brain barrier dysfunction, and pro-inflammatory transforming growth factor β signaling are associated with severe, potentially life-threatening outcomes, following repetitive mild traumatic brain injury. Diagnostic-coupled targeting of transforming growth factor β signaling may be a novel strategy in treating mild traumatic brain injury.

The gene RUNX1 at chromosome 21q22 encodes the alpha subunit of Core binding factor (CBF), a heterodimeric transcription factor involved in the development of normal hematopoiesis. Translocations of RUNX1 are seen in several types of leukemia with at least 21 identified partner genes. The cryptic t(7;21)(p22;q22) rearrangement involving the USP42 gene appears to be a specific and recurrent cytogenetic abnormality. Eight of the 9 cases identified in the literature with this translocation were associated with acute myeloid leukemia (AML), with the remaining case showing refractory anemia with excess blasts, type 2. Herein, we present a patient with two preceding years of leukopenia and one year of anemia prior to the diagnosis of AML, NOS with monocytic differentiation (myelomonocytic leukemia) whose conventional cytogenetics showed an abnormal clone with 5q deletion. Interphase FISH using LSI RUNX1/RUNXT1 showed three signals for RUNX1. FISH studies on previously G-banded metaphases showed the extra RUNX1 signal on the short arm of chromosome 7. Further characterization using the subtelomeric 7p probe showed a cryptic 7;21 translocation. Our case and eight previously reported leukemic cases with the t(7;21)(p22;q22) appear to share similar features including monocytic differentiation, immunophenotypic aberrancies (often with CD56 and/or CD7), and a generally poor response to standard induction chemotherapy. About 80% of these cases had loss of 5q material as an additional abnormality at initial diagnosis or relapse. These findings suggest that t(7;21) may represent a distinct recurrent cytogenetic abnormality associated with AML. The association between the t(7;21) and 5q aberrancies appears to be non-random, however the pathogenetic connection remains unclear. Additional studies to evaluate for RUNX1 partner genes may be considered for AML patients with RUNX1 rearrangement and 5q abnormalities; however knowledge of the prognostic implications of this rearrangement is still limited.

Objectives The dynamic bone-periodontal ligament (PDL)-tooth fibrous joint consists of two adaptive functionally graded interfaces (FGI), the PDL-bone and PDL-cementum that respond to mechanical strain transmitted during mastication. In general, from a materials and mechanics perspective, FGI prevent catastrophic failure during prolonged cyclic loading. This review is a discourse of results gathered from literature to illustrate the dynamic adaptive nature of the fibrous joint in response to physiologic and pathologic simulated functions, and experimental tooth movement. Methods Historically, studies have investigated soft to hard tissue transitions through analytical techniques that provided insights into structural, biochemical, and mechanical characterization methods. Experimental approaches included two dimensional to three dimensional advanced in situ imaging and analytical techniques. These techniques allowed mapping and correlation of deformations to physicochemical and mechanobiological changes within volumes of the complex subjected to concentric and eccentric loading regimes respectively. Results Tooth movement is facilitated by mechanobiological activity at the interfaces of the fibrous joint and generates elastic discontinuities at these interfaces in response to eccentric loading. Both concentric and eccentric loads mediated cellular responses to strains, and prompted self-regulating mineral forming and resorbing zones that in turn altered the functional space of the joint. Significance A multiscale biomechanics and mechanobiology approach is important for correlating joint function to tissue-level strain-adaptive properties with overall effects on joint form as related to physiologic and pathologic functions. Elucidating the shift in localization of biomolecules specifically at interfaces during development, function, and therapeutic loading of the joint is critical for developing “functional regeneration and adaptation” strategies with an emphasis on restoring physiologic joint function.

This novel approach illustrates the importance of 3D-imaging and analysing 3D alveolar socket subjected to OTM otherwise omitted by 2D micrographs. A measured force on the crown elicits a response related to narrowed and widened regions in the 3D complex. OTM that exceeds PDL-space can illicit biological responses that attempt to restore physiologic PDL-space via remodelling of the periodontium. Regenerated weaker bone due to aseptic inflammation caused by orthodontics could leave patients at a higher risk of bone loss or root resorption if they later develop periodontitis, a form of septic inflammation.

Traumatic brain injury (TBI) is the leading cause of death in young individuals, and is a major health concern that often leads to long-lasting complications. However, the electrophysiological events that occur immediately after traumatic brain injury, and may underlie impact outcomes, have not been fully elucidated. To investigate the electrophysiological events that immediately follow traumatic brain injury, a weight-drop model of traumatic brain injury was used in rats pre-implanted with epidural and intracerebral electrodes. Electrophysiological (near-direct current) recordings and simultaneous alternating current recordings of brain activity were started within seconds following impact. Cortical spreading depolarization (SD) and SD-induced spreading depression occurred in approximately 50% of mild and severe impacts. SD was recorded within three minutes after injury in either one or both brain hemispheres. Electrographic seizures were rare. While both TBI- and electrically induced SDs resulted in elevated oxidative stress, TBI-exposed brains showed a reduced antioxidant defense. In severe TBI, brainstem SD could be recorded in addition to cortical SD, but this did not lead to the death of the animals. Severe impact, however, led to immediate death in 24% of animals, and was electrocorticographically characterized by non-spreading depression (NSD) of activity followed by terminal SD in both cortex and brainstem.

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The novel aspect of this study was to contextualize the co‐localization of biomolecular expression in widened and narrowed periodontal ligament (PDL)‐space within a mechanically activated periodontal complex. The PDL is unique as it is the only ligament with both innervation and vascularization. Maxillary molars in 6‐week‐old male C57BL/6 mice (N = 5) were experimentally translated for 2 weeks using an elastic spacer. Contralateral teeth were used as controls. Mechanical testing of the periodontal complex of a mouse in situ and imaging using X‐ray micro‐computed tomography (micro‐XCT) illustrated deformations within blood vessels (BV) of the PDL. PDL‐bone and PDL‐cementum entheses at the widened and narrowed PDL‐spaces following experimental tooth movement (ETM) illustrated osterix (OSX), bone sialoprotein (BSP), cluster of differentiation 146 (CD146), and protein gene product 9.5 (PGP9.5), indicating active remodeling at these sites. PGP9.5 positive nerve bundles (NBs) were co‐localized with multinucleated cells (MCs), Howship's resorption lacunae, and CD146 positive BVs. Association between nerves and MC was complemented by visualizing the proximity of osmium tetroxide stained NBs with the ultrastructure of MCs by performing scanning transmission electron microscopy. Spatial association of NB with BV, and NB with MC, provided insights into the plausible co‐activation of NBs to initiate osteoclastic activity. Resorption of mineral occurred as an attempt to restore PDL‐space of the load‐bearing complex, specifically at the PDL‐entheses. Mapping of anatomy‐specific structural elements and their association with regenerative molecules by correlating light and electron micrographs provided insights into the use of these extracellular matrix molecules as plausible targets for pharmacological interventions related to tooth movement. Within the realm of tissue regeneration, modulation of load can reverse naturally occurring mineral formation to experimentally induced resorption, and naturally occurring mineral resorption to experimentally induced formation at the enthesial sites to permit tooth translation.

BackgroundThe t(1;19)(q23;p13), which can result in the TCF3-PBX1 chimeric gene, is one of the most frequent translocations in B-acute lymphoblastic leukemia (B-ALL) and is observed in both adult and pediatric populations at an overall frequency of 6%. It can occur in a balanced or unbalanced form and as a sole abnormality is associated with an intermediate prognosis. Additionally, this translocation is observed in the context of hyperdiploid B-ALL, in which case it is associated with a poor prognosis. However, due to different translocation partner genes at chromosomes 1 and 19, distinct subtypes of hyperdiploid B-ALL with t(1;19)/der(19)t(1;19) are recognized based on the presence or absence of the TCF3-PBX1 fusion gene, but the cytogenetic and etiologic differences between the two remain understudied.FindingsWe report a case of an adult with a history of relapsed precursor B-ALL whose conventional cytogenetics showed an abnormal female karyotype with both hyperdiploidy and a t(1;19)(q23;p13). Fluorescence in situ hybridization (FISH) on previously G-banded metaphases using the LSI TCF3/PBX1 Dual Color, Dual Fusion Translocation Probe confirmed the presence of the TCF3-PBX1 gene fusion.ConclusionsThis particular pattern with a TCF3-PBX1 fusion within the context of a hyperdiploid karyotype is seen in B-ALL and is usually associated with a poor outcome. This case is one of only a few cases with both hyperdiploidy and a confirmed TCF3-PBX1 fusion, demonstrating the importance of using FISH for proper molecular classification of these cases in order to distinguish them from those with hyperdiploidy but no TCF3-PBX1 fusion gene. Such molecular studies may provide insight into the precise differences between TCF3-PBX1 positive and negative hyperdiploid B-ALL bearing the t(1;19)(q23;p13).