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Background Exposure to brain injury via blast or blunt mechanisms disrupts multiple sensorimotor systems simultaneously. Large numbers of US Gulf War era and Operation Iraqi/Enduring Freedom veterans with traumatic brain injury (TBI) are suffering the symptom of dizziness - presumed due to "Multi-Sensory Impairment", a clinical pattern of damage to the auditory, visual and vestibular sensorimotor systems. Objective To describe the oculomotor response to rapid head rotation in a population of veterans with dizziness. We also describe the reliability of using the video head impulse test (vHIT) in a veteran population. Methods We used the vHIT to evaluate the vestibular-ocular reflex (VOR) gain and presence of compensatory saccades (CS) in each semicircular canal of 81 veterans (31% TBI) with dizziness. Data was collected using the ICS Otometric™ vHIT. Data was processed using both the Otometric™ software and custom software written in MATLAB™. This data was evaluated through Kruskal-Wallis rank-sum test and analysis of regression. Results Veterans with dizziness recruit CS in all semicircular canal planes even though their VOR gain is normal. The vHIT is a reliable clinical test to quantify the metrics of the VOR and CS in veterans. Conclusion Veterans with dizziness symptoms use compensatory saccades in all planes of semicircular canal rotation, despite having normal peripheral VOR gain during rapid head rotation. The video head impulse test is a stable measure of vestibular slow phase and metrics of compensatory saccades in veterans with dizziness.

Primary hyperparathyroidism (PHPT) is a common endocrine disorder characterized by dysregulation of parathyroid hormone release. The large majority of PHPT cases are attributable to sporadic, single-gland parathyroid adenoma, in which MEN1 and CCND1/cyclin D1 are the most well-established drivers of tumorigenesis. Sporadic parathyroid carcinoma, which appears to mostly arise through molecular pathways distinct from those causing benign parathyroid tumors, is rare and is most frequently driven by mutational inactivation of the CDC73 (HRPT2) tumor suppressor gene. Targeted investigation of suspected tumor driver genes, as well as unbiased whole-genome or exome sequencing of small cohorts, have revealed additional novel candidate tumor genes in sporadic parathyroid neoplasia, generally at modest or low mutational frequencies consistent with marked molecular genetic heterogeneity from tumor to tumor. The ability of these additional candidates to participate in the pathogenic process of driving parathyroid tumorigenesis in vivo largely remains to be demonstrated experimentally. This review will summarize the molecular genetic abnormalities identified to date in sporadic PHPT and discuss the strength of evidence for their proposed roles in parathyroid tumor formation.

Objective Primary hyperparathyroidism is most often caused by a sporadic single-gland parathyroid adenoma (PTA), a tumor type for which cyclin D1 is the only known and experimentally validated oncoprotein. However, the molecular origins of its frequent overexpression have remained mostly elusive. In this study, we explored a potential tumorigenic mechanism that could increase cyclin D1 stability through a defect in molecules responsible for its degradation. Methods We examined two tumor suppressor genes known to modulate cyclin D1 ubiquitination, PRKN and FBXO4 (FBX4), for evidence of classic two-hit tumor suppressor inactivation within a cohort of 82 PTA cases. We examined the cohort for intragenic inactivating and splice site mutations by Sanger sequencing and for locus-associated loss of heterozygosity (LOH) by microsatellite analysis. Results We identified no evidence of bi-allelic tumor suppressor inactivation of PRKN or FBXO4 via inactivating mutation or splice site perturbation, neither in combination with nor independent of LOH. Among the 82 cases, we encountered previously documented benign single nucleotide polymorphisms (SNPs) in 35 tumors at frequencies similar to those reported in the germlines of the general population. Eight cases exhibited intragenic LOH at the PRKN locus, in some cases extending to cover at least an additional 1.7 Mb of chromosome 6q25-26. FBXO4 was not affected by LOH. Conclusion: The absence of evidence for specific bi-allelic inactivation in PRKN and FBXO4 in this sizeable cohort suggests that these genes only rarely, if ever, serve as classic driver tumor suppressors responsible for the growth of PTAs.

Objective Deficits in vestibular function increase the risk for falls while turning. However, the clinical assessment of turning in patients with vestibular dysfunction is lacking, and evidence is limited that identifies the effectiveness of vestibular physical therapy in improving turning performance. The purpose of this study was to quantify walking and turning performance during the instrumented Timed “Up & Go” (TUG) test using body-worn inertial measurement units (IMUs). Novel instrumented TUG parameters were investigated for ability to distinguish patients with unilateral vestibular deafferentation (UVD) from control groups and discriminate the differences in turning parameters of patients with UVD following vestibular physical therapy. Methods Thirty-eight individuals were recruited following UVD surgery: 26 age-matched veteran controls with reports of dizziness not from a peripheral vestibular origin, and 12 age-matched healthy controls. Participants were donned with IMUs and given verbal instructions to complete the TUG test as fast as safely possible. The IMU-instrumented and automated assessment of the TUG test provided component-based TUG parameters, including the novel walk:turn ratio. Among the participants with UVD, 19 completed an additional instrumented TUG testing after vestibular physical therapy. Results The walk:turn time ratio showed that turning performance in patients with UVD before rehabilitation is significantly more impaired than both the individuals with nonperipheral conditions and healthy controls. Vestibular rehabilitation significantly improved turning performance and “normalized” their walk:turn time ratio compared with healthy controls. The duration of the straight walking component in individuals with UVD before vestibular physical therapy, however, was not significantly different compared with that component in people after vestibular physical therapy and in healthy controls. Conclusion The IMU-instrumented TUG test can be used to distinguish individuals with vestibular deafferentation and to objectively quantify the change in their turning performance after vestibular physical therapy. Impact The IMU-based instrumented TUG parameters have the potential to quantify the efficacy of vestibular physical therapy and be adopted in the clinic.

Mechanisms underlying the propensity of latent lung adenocarcinoma (LUAD) to relapse are poorly understood. In this study, we show how differential expression of a network of extracellular matrix (ECM) molecules and their interacting proteins contributes to risk of relapse in distinct LUAD subtypes. Overexpression of the hyaluronan receptor HMMR in primary LUAD was associated with an inflammatory molecular signature and poor prognosis. Attenuating HMMR in LUAD cells diminished their ability to initiate lung tumors and distant metastases. HMMR upregulation was not required for dissemination in vivo, but enhanced ECM-mediated signaling, LUAD cell survival, and micrometastasis expansion in hyaluronan-rich microenvironments in the lung and brain metastatic niches. Our findings reveal an important mechanism by which disseminated cancer cells can coopt the inflammatory ECM to persist, leading to brain metastatic outgrowths. Cancer Res; 77(8); 1905–17. ©2017 AACR.

To examine inter-rater, intra-rater and test-re-test reliability of the Community Balance and Mobility Scale (CBM) and compare reliability in live vs videotape rating contexts for children with acquired brain injury (ABI).Repeated measures design.Seven physiotherapists (PTs) were trained as assessors. The primary assessor administered and scored baseline CBM while the second assessor observed and scored independently (inter-rater reliability). Re-assessment occurred 3-10 days later by primary assessor (test-re-test reliability). Assessments were videotaped.There were 32 participants with ABI (mean age = 14 years 1 month (SD = 2 years 1 month)). Baseline mean scores were 67.4% (18.2) and 66.7% (18.3) for primary and second assessor, respectively. Primary assessors' re-test mean score was 69.3%. Inter-rater reliability ICC was 0.93 (95% confidence interval (CI) = 0.87-0.97). Test-re-test ICC was 0.90 (95%CI = 0.81-0.95) and Bland-Altman plot indicated greatest test-re-test differences for mid-range CBM scores. Minimum detectable change (MDC₉₀) was 13.5% points.The CBM showed excellent reliability in youth. Reliability was comparable for live and videotape rating approaches, meaning that the easier and less expensive live-rating can be recommended. Future work should focus on evaluation of responsiveness to change in rehabilitation centre and community intervention contexts.

The purpose of our study was to obtain a clear understanding of the various diagnoses within the closed neural tube defect (NTD) groups included in the large database of clients in our Spina Bifida Clinic and a clear picture of the outcomes for the various NTD groups.One hundred and four clients with closed NTD were categorized using a classification system devised by Tortori-Donati et al. Various clinical markers were investigated, including ambulation and the need for orthoses and wheelchairs.Most clients are ambulatory, requiring an orthoses, but not a wheelchair, despite the high incidence of ankle/foot abnormalities.This classification system has enhanced our knowledge of this group of clients, provided a greater understanding of the varied outcomes of these children and clinical management required.

Collaborative goal setting between clinicians and clients/families is considered a fundamental component of the pediatric rehabilitation process. However, truly client-centered goal setting is not without its challenges. The purpose of this paper is to highlight theoretical concepts relevant to rehabilitation goal setting, review clinical studies directly evaluating relationships between goal setting and pediatric rehabilitation outcomes, and provide recommendations to facilitate collaborative goal processes. Four theoretical frameworks were identified that may lie behind and help explain the effectiveness of collaborative goal setting. The four relevant outcome studies found in the review revealed that individualized goal setting is an important component of the intervention, engages families more actively in therapy, and is associated to some extent with positive outcomes. The evidence suggests that the impact of fully collaborative goal setting is sufficiently positive to support investment of organizational and individual time, energy, and resources to make it an integral part of the rehabilitation process.

The molecular mechanisms underlying the pathogenesis of sporadic parathyroid adenomas are incompletely understood. The oncoprotein cyclin D1 is overexpressed in 20-40% of sporadic parathyroid adenomas; however, known aberrations in the gene that encodes cyclin D1, CCND1, account for less than half of these cases. Genetic alterations of PARK2, which encodes the E3 ubiquitin ligase responsible for targeting cyclin D1 for degradation, have been identified as a frequent finding in a variety of human tumors. Interestingly, genetic abnormalities of PARK2 were mutually exclusive of cyclin D1 gene alterations, suggesting a common pathway in tumorigenesis. We postulate that inactivating mutations in PARK2 lead to increased stability of cyclin D1 and thereby may contribute to the development of sporadic parathyroid adenoma. We therefore sought to identify PARK2 coding region mutations in a series of sporadic parathyroid adenomas by direct DNA sequencing. The entire coding region and intron-exon boundaries of PARK2 were examined in a cohort of eighty typically presenting, sporadic parathyroid adenomas. Six known polymorphisms were identified in several of the adenomas in this series; however, none of the polymorphisms are associated with cancer, and no other cancer-associated mutations were found. The absence of intragenic mutations in PARK2 suggests that such mutations do not commonly contribute to the development of sporadic parathyroid adenoma. However, because such intragenic mutations could be rare and limited to only those samples in which overexpression of cyclin D1 cannot be explained by genetic abnormalities in the CCND1 gene, a significant role for cyclin D1 accumulation in parathyroid tumor formation due intragenic inactivating mutations of PARK2 cannot be ruled out. Further research must be conducted in order to elucidate the mechanism(s) of cyclin D1 accumulation in parathyroid adenomas in which CCND1 aberrations are not present. . Citation Format: Kelly Brewer, Jessica Costa-Guda, Andrew Arnold. Mutational analysis of PARK2, a regulator of cyclin D1 stability, in sporadic parathyroid adenoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3653.