Allelic contribution of Nrxn1α to autism-relevant behavioral phenotypes in mice.

Copy number variations (CNVs) in the Neurexin 1 (NRXN1) gene, which encodes a presynaptic protein involved in neurotransmitter release, are some of the most frequently observed single-gene variants associated with autism spectrum disorder (ASD). To address the functional contribution of NRXN1 CNVs to behavioral phenotypes relevant to ASD, we carried out systematic behavioral phenotyping of an allelic series of Nrxn1 mouse models: one carrying promoter and exon 1 deletion abolishing Nrxn1α transcription, one carrying exon 9 deletion disrupting Nrxn1α protein translation, and one carrying an intronic deletion with no observable effect on Nrxn1α expression. We found that homozygous loss of Nrxn1α resulted in enhanced aggression in males, reduced affiliative social behaviors in females, and significantly altered circadian activities in both sexes. Heterozygous or homozygous loss of Nrxn1α affected the preference for social novelty in male mice, and notably, enhanced repetitive motor skills and motor coordination in both sexes. In contrast, mice bearing an intronic deletion of Nrxn1 did not display alterations in any of the behaviors assessed. These findings demonstrate the importance of Nrxn1α gene dosage in regulating social, circadian, and motor functions, and the variables of sex and genomic positioning of CNVs in the expression of autism-related phenotypes. Importantly, mice with heterozygous loss of Nrxn1, as found in numerous autistic individuals, show an elevated propensity to manifest autism-related phenotypes, supporting the use of models with this genomic architecture to study ASD etiology and assess additional genetic variants associated with autism.

Cannabidiol attenuates seizure susceptibility and behavioural deficits in adult CDKL5R59X knock-in mice.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is caused by a loss-of-function mutation in CDKL5 gene, encoding a serine-threonine kinase highly expressed in the brain. CDD manifests with early-onset epilepsy, autism, motor impairment and severe intellectual disability. While there are no known treatments for CDD, the use of cannabidiol has recently been introduced into clinical practice for neurodevelopmental disorders. Given the increased clinical utilization of cannabidiol, we examined its efficacy in the CDKL5R59X knock-in (R59X) mice, a CDD model based on a human mutation that exhibits both lifelong seizure susceptibility and behavioural deficits. We found that cannabidiol pre-treatment rescued the increased seizure susceptibility in response to the chemoconvulsant pentylenetetrazol (PTZ), attenuated working memory and long-term memory impairments, and rescued social deficits in adult R59X mice. To elucidate a potential mechanism, we compared the developmental hippocampal and cortical expression of common endocannabinoid (eCB) targets in R59X mice and their wild-type littermates, including cannabinoid type 1 receptor (CB1R), transient receptor potential vanilloid type 1 (TRPV1) and 2 (TRPV2), G-coupled protein receptor 55 (GPR55) and adenosine receptor 1 (A1R). Many of these eCB targets were developmentally regulated in both R59X and wild-type mice. In addition, adult R59X mice demonstrated significantly decreased expression of CB1R and TRPV1 in the hippocampus, and TRPV2 in the cortex, while TRPV1 was increased in the cortex. These findings support the potential for dysregulation of eCB signalling as a plausible mechanism and therapeutic target in CDD, given the efficacy of cannabidiol to attenuate hyperexcitability and behavioural deficits in this disorder.

Incomplete partition type II in its various manifestations: isolated, in association with EVA, syndromic, and beyond; a multicentre international study.

PURPOSE: Incomplete partition type II (IP-II) is characterized by specific histological features and radiological appearance. It may occur in isolation or in association with an enlarged vestibular aqueduct (EVA). Among those with IP-II and EVA, a subset has a diagnosis of Pendred syndrome. This study aimed to explore the prevalence of isolated IP-II, IP-II with EVA, and cases with a genetic or syndromic basis in our cohort. METHODS: From a large, multicentre database of dysplastic cochleae (446 patients, 892 temporal bones), those with imaging features of IP-II were examined in detail, including whether there was a genetic or syndromic association. RESULTS: A total of 78 patients with IP-II were identified. Among these, 55 patients had bilateral IP-II and EVA (only 12 with typical Mondini triad), 8 with bilateral IP-II and normal VA, 2 with bilateral IP-II and unilateral EVA, and 13 with unilateral IP-II (9 with unilateral EVA). Among the group with bilateral IP-II and bilateral EVA in whom genetic analysis was available, 14 out of 29 (48%) had SLC26A4 mutations and a diagnosis of Pendred syndrome, 1 had a FOXI1 mutation, and a few other genetic abnormalities; none had KCNJ10 pathogenic variants. CONCLUSION: Bilateral IP-II-bilateral EVA may be seen in the context of Pendred syndrome (SLC26A4 or FOXI1 mutations) but, in the majority of our cohort, no genetic abnormalities were found, suggesting the possibility of unknown genetic associations. IP-II in isolation (without EVA) is favored to be genetic when bilateral, although the cause is often unknown.

R-8 Dispersion Interaction: Derivation and Application to the Effective Fragment Potential Method.

The anisotropic and isotropic R-8 dispersion contributions (disp8) are derived and implemented within the framework of the effective fragment potential (EFP) method formulated with imaginary frequency-dependent Cartesian polarizability tensors distributed at the centroids of the localized molecular orbitals (LMOs). Two forms of damping functions, intermolecular overlap-based and Tang-Toennies, are extended for disp8. To obtain LMO polarizability tensors centered at LMO centroids, an origin-shifting transformation is derived and implemented for the dipole-octopole polarizability tensor and the quadrupole-quadrupole polarizability tensor. The analytic gradient is derived and implemented for the isotropic disp8 contribution. Relative to the previously implemented empirical EFP disp8 energy, the isotropic disp8 component of the interaction energy improves the overall agreement of the EFP dispersion energies with the symmetry-adapted perturbation theory (SAPT) benchmarks, reducing the mean absolute errors (MAEs) and mean absolute percentage errors for most of the databases examined in this work. While the anisotropic disp8 can further enhance the accuracy of the EFP dispersion energy and yield smaller MAEs, significantly overbound dispersion energies are predicted by the anisotropic disp8 when the maximum element in the intermolecular overlap matrix is greater than 0.1, possibly due to the breakdown of the approximations made in the EFP dispersion derivation at a short range. For potential energy scan databases, the newly developed EFP dispersion model with isotropic disp8 yields the overall correct curvature and good agreement with SAPT benchmarks around equilibrium and longer but overestimates the dispersion interactions at a short range. While the overlap-based dispersion-damping functions produce better MAEs than Tang-Toennies damping functions, further improvement is needed to better screen the large attractive dispersion energies at a short range (overlap >0.1).

Monitoring the acute and subacute recovery of cognitive ocular motor changes after a sports-related concussion.

Identifying when recovery from a sports-related concussion (SRC) has occurred remains a challenge in clinical practice. This study investigated the utility of ocular motor (OM) assessment to monitor recovery post-SRC between sexes and compared to common clinical measures. From 139 preseason baseline assessments (i.e. before they sustained an SRC), 18 (12 males, 6 females) consequent SRCs were sustained and the longitudinal follow-ups were collected at 2, 6, and 13 days post-SRC. Participants completed visually guided, antisaccade (AS), and memory-guided saccade tasks requiring a saccade toward, away from, and to a remembered target, respectively. Changes in latency (processing speed), visual-spatial accuracy, and errors were measured. Clinical measures included The Sports Concussion Assessment Tool, King-Devick test, Stroop task, and Digit span. AS latency was significantly longer at 2 days and returned to baseline by 13-days post-SRC in females only (P < 0.001). Symptom numbers recovered from 2 to 6 days and 13 days (P < 0.05). Persistently poorer AS visual-spatial accuracy was identified at 2, 6 and 13 days post-SRC (P < 0.05) in both males and females but with differing trajectories. Clinical measures demonstrated consistent improvement reminiscent of practice effects. OM saccade assessment may have improved utility in tracking recovery compared to conventional measures and between sexes.

Evaluation of Scatterer Parameters From Ultrasound Scattering Models Taking Into Account Scattering From Nuclei and Cells of Cell-Pellet Biophantoms and Ex Vivo Tumors.

The Quantitative Ultrasound backscatter coefficient provides the capability to evaluate tissue microstructure parameters. Tissue-based scatterer parameters are extracted using ultrasound scattering models. It is challenging to correlate ultrasound scatterer parameters of tissue structures from optical-measured histology, possibly because of inappropriate scattering models or the presence of multiple scatterers. The objective of this study is to pursue the quantification of pertinent scatterer parameters with scattering models that consider ultrasound scattering from nuclei and cells. The concentric sphere model (CSM) and the structure factor model adapted for two types of scatterers (SFM2) are evaluated for cell-pellet biophantoms and ex vivo tumors of four cell lines: 4T1, JC, LMTK, and MAT. The structure factor model (SFM) was used for comparison. CSM and SFM2 provided scatterer parameters closer to histology (lower relative errors) for nucleus and cell radii and volume fractions than SFM but were not always accompanied by lower dispersion of the scatterer distribution (lower coefficient of variation). CSM and SFM2 quantified cell and nucleus radius and volume fraction parameters with lower relative error compared to SFM. For tumors, CSM provided better results than SFM2.

Psychological flexibility prospectively predicts COVID-19 PPE use across a two-month interval.

Perceived susceptibility, psychological flexibility and health behaviors (PPE use, social distancing) were measured at two time points spaced 2 months apart during the height of the COVID-19 pandemic and lockdown in the U.S.A (Time 1 April 2020; Time 2 June 2020). Demographic variables were also collected. Data from 151 Mturk workers indicated that Time 1 psychological flexibility significantly predicted PPE use and social distancing. The effect sizes were substantial. Perceived susceptibility was not a significant predictor. Psychological flexibility messaging and interventions could be an important way to increase the likelihood of people performing health protective behaviors to better constrain the continuing COVID-19 outbreak.

The role of mTORC1 activation in seizure-induced exacerbation of Alzheimer's disease.

The risk of seizures is 10-fold higher in patients with Alzheimer's disease than the general population, yet the mechanisms underlying this susceptibility and the effects of these seizures are poorly understood. To elucidate the proposed bidirectional relationship between Alzheimer's disease and seizures, we studied human brain samples (n = 34) from patients with Alzheimer's disease and found that those with a history of seizures (n = 14) had increased amyloid-ß and tau pathology, with upregulation of the mechanistic target of rapamycin (mTOR) pathway, compared with patients without a known history of seizures (n = 20). To establish whether seizures accelerate the progression of Alzheimer's disease, we induced chronic hyperexcitability in the five times familial Alzheimer's disease mouse model by kindling with the chemoconvulsant pentylenetetrazol and observed that the mouse model exhibited more severe seizures than the wild-type. Furthermore, kindled seizures exacerbated later cognitive impairment, Alzheimer's disease neuropathology and mTOR complex 1 activation. Finally, we demonstrated that the administration of the mTOR inhibitor rapamycin following kindled seizures rescued enhanced remote and long-term memory deficits associated with earlier kindling and prevented seizure-induced increases in Alzheimer's disease neuropathology. These data demonstrated an important link between chronic hyperexcitability and progressive Alzheimer's disease pathology and suggest a mechanism whereby rapamycin may serve as an adjunct therapy to attenuate progression of the disease.

Functional outcomes of patients with ischaemic stroke with known atrial fibrillation not on therapeutic anticoagulation.

BACKGROUND: Anticoagulation significantly reduces the risk of ischaemic stroke in patients with atrial fibrillation (AF). There are a proportion of patients with known AF who remain off anticoagulation. Aims This study aims to retrospectively compare the baseline characteristics, treatments and functional outcomes between patients with ischaemic stroke and known AF based on their anticoagulation status. METHODS: A single-centre, retrospective review of consecutive patients with an ischaemic stroke and a known history of AF was conducted. RESULTS: Two hundred four patients with an ischaemic stroke had documented AF prior to the index admission, of which 126 were anticoagulated. Median admission National Institutes of Health Stroke Scale score was lower for anticoagulated patients, though not statistically significant (5.1 vs 7.0, P = 0.09). Median baseline modified Rankin score (mRS) did not significantly differ. Nonanticoagulated patients were more likely to have large vessel occlusions (37.2% vs 23.8%, P = 0.04) and more likely to receive intravenous thrombolysis (15.4% vs 1.6%, P < 0.01). There was no difference in rates of endovascular clot retrieval between groups (P > 0.05). Unfavourable functional outcome at 90 days (mRS ≥ 3) did not significantly differ between groups (P = 0.51). A total of 38.5% of nonanticoagulated patients had no documented reason for this. Of the patients who survived the index admission, 81.5% of patients who were not anticoagulated on admission received anticoagulation. CONCLUSIONS: Baseline anticoagulation was associated with milder stroke severity in ischaemic stroke patients with known AF. There was no significant difference in functional outcomes at 90 days between groups. Larger observational studies are required to further assess this cohort.

Mitigating the negative impact of new buildings on existing buildings' user comfort-a case study analysis.

Campus master plans are released every few years for developing and implementing its physical infrastructure. Open spaces, compactness, connectivity, greenness, and environmental impact have often been the focus on its framework. In particular, the effect of new building development on existing buildings' occupant comfort and design intent is mostly ignored. Providing guidelines to retain existing users' comfort for stakeholders involved in design decision making will result in improved design decisions. Hence, this research aims to provide a work methodology to mitigate the adverse effects of new buildings on existing buildings' user comfort through a case study at Carleton University. The case study shows a methodology to retain the existing users' comfort by analyzing Carleton University's master plan on massing studies, occupant survey to understand their comfort needs, performance analysis of the impact of the new building on the existing building user comfort. The analysis reveals the key parameters to consider in design for occupants' comfort. Finally, the research reinforces the generative design and the need for dynamic modeling in campus master plans to mitigate the negative implications of new development on occupants' comfort.

Diagnostic Utility of Computed Tomography Perfusion in the Telestroke Setting.

BACKGROUND: Definitive diagnosis of acute ischemic stroke is challenging, particularly in telestroke settings. Although the prognostic utility of CT perfusion (CTP) has been questioned, its diagnostic value remains under-appreciated, especially in cases without an easily visible intracranial occlusion. We assessed the diagnostic accuracy of routine CTP in the acute telestroke setting. METHODS: Acute and follow-up data collected prospectively from consecutive suspected patients with stroke assessed by a state-wide telestroke service between March 2020 and August 2021 at 12 sites in Australia were analyzed. All patients in the final analysis had been assessed with multimodal CT, including CTP, which was post-processed with automated volumetric software. Diagnostic sensitivity and specificity were calculated for multimodal CT and each individual component (noncontrast CT [NCCT], CT angiogram [CTA], and CTP). Final diagnosis determined by consensus review of follow-up imaging and clinical data was used as the reference standard. RESULTS: During the study period, complete multimodal CT examination was obtained in 831 patients, 457 of whom were diagnosed with stroke. Diagnostic sensitivity for ischemic stroke increased by 19.5 percentage points when CTP was included with NCCT and CTA compared with NCCT and CTA alone (73.1% positive with NCCT+CTA+CTP [95% CI, 68.8-77.1] versus 53.6% positive with NCCT+CTA alone [95% CI, 48.9-58.3], P<0.001). No difference was observed between specificities of NCCT+CTA and NCCT+CTA+CTP (98.7% [95% CI, 98.5-100] versus 98.7% [95% CI, 96.9-99.6], P=0.13). Multimodal CT, including CTP, demonstrated the highest negative predictive value (75.0% [95% CI, 72.1-77.7]). Patients with stroke not evident on CTP had small volume infarcts on follow-up (1.2 mL, interquartile range 0.5-2.7mL). CONCLUSIONS: Acquisition of CTP as part of a telestroke imaging protocol permits definitive diagnosis of cerebral ischemia in 1 in 5 patients with normal NCCT and CTA.

Direct Comparison of Quantitative US versus Controlled Attenuation Parameter for Liver Fat Assessment Using MRI Proton Density Fat Fraction as the Reference Standard in Patients Suspected of Having NAFLD.

Background MRI-derived proton density fat fraction (PDFF) is an accurate, reliable, and safe biologic marker for use in the noninvasive diagnosis of hepatic steatosis in patients with nonalcoholic fatty liver disease (NAFLD). Because of the cost and limited availability of MRI, it is necessary to develop an accurate method to diagnose NAFLD with potential point-of-care access. Purpose To compare the diagnostic accuracy of the quantitative US (QUS) fat fraction (FF) estimator with that of the controlled attenuation parameter (CAP) in the diagnosis of NAFLD using contemporaneous MRI-derived PDFF as the reference standard. Materials and Methods Participants with or suspected of having NAFLD were prospectively recruited at the NAFLD Research Center between July 2015 and July 2019. All participants underwent MRI-derived PDFF measurement, transient elastography with CAP measurement, and QUS. QUS FF was derived using computed QUS parameters from the acquired radiofrequency US data using a calibrated reference phantom. The area under the receiver operating characteristic curve (AUC) was calculated to assess the accuracy of QUS FF and CAP in the diagnosis of hepatic steatosis (defined as MRI-derived PDFF ≥ 5%). AUCs were compared using the DeLong test. Results A total of 123 participants were included (mean age, 52 years ± 13 [SD]; 67 [54%] women). Of these participants, 100 (81%) had MRI-derived PDFF of 5% or more. QUS FF had a significantly higher AUC for diagnosis of NAFLD than did CAP (0.92 [95% CI: 0.87, 0.98] vs 0.79 [95% CI: 0.67, 0.90], P = .03). QUS FF had a sensitivity of 98% (98 of 100) and a specificity of 48% (11 of 23). CAP had a sensitivity of 87% (87 of 100) and a specificity of 57% (13 of 23). Conclusion The quantitative US fat fraction estimator is more accurate than the controlled attenuation parameter in the diagnosis of hepatic steatosis in patients with or suspected of having nonalcoholic fatty liver disease. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Ito in this issue.

Diffusion Imaging Reveals Sex Differences in the White Matter Following Sports-Related Concussion.

Sports-related concussion (SRC) is a serious health concern. However, the temporal profile of neuropathophysiological changes after SRC and how these relate to biological sex are still poorly understood. This preliminary study investigated whether diffusion-weighted magnetic resonance imaging (dMRI) was sensitive to neuropathophysiological changes following SRC; whether these changes were sex-specific; and whether they persisted beyond the resolution of self-reported symptoms. Recently concussed athletes (n = 14), and age- and education-matched nonconcussed control athletes (n = 16), underwent MRI 24-48-h postinjury and again at 2-week postinjury (i.e., when cleared to return-to-play). Male athletes reported more symptoms and greater symptom severity compared with females. dMRI revealed white matter differences between athletes with SRC and their nonconcussed counterparts at 48-h postinjury. These differences were still present at 2-week postinjury, despite SRC athletes being cleared to return to play and may indicate increased cerebral vulnerability beyond the resolution of subjective symptoms. Furthermore, we identified sex-specific differences, with male SRC athletes having significantly greater white matter disruption compared with female SRC athletes. These results have important implications for the management of concussion, including guiding return-to-play decisions, and further improve our understanding regarding the role of sex in SRC outcomes.

White and Gray Matter Abnormalities in Australian Footballers With a History of Sports-Related Concussion: An MRI Study.

Sports-related concussion (SRC) is a form of mild traumatic brain injury that has been linked to long-term neurological abnormalities. Australian rules football is a collision sport with wide national participation and is growing in popularity worldwide. However, the chronic neurological consequences of SRC in Australian footballers remain poorly understood. This study investigated the presence of brain abnormalities in Australian footballers with a history of sports-related concussion (HoC) using multimodal MRI. Male Australian footballers with HoC (n = 26), as well as noncollision sport athletes with no HoC (n = 27), were recruited to the study. None of the footballers had sustained a concussion in the preceding 6 months, and all players were asymptomatic. Data were acquired using a 3T MRI scanner. White matter integrity was assessed using diffusion tensor imaging. Cortical thickness, subcortical volumes, and cavum septum pellucidum (CSP) were analyzed using structural MRI. Australian footballers had evidence of widespread microstructural white matter damage and cortical thinning. No significant differences were found regarding subcortical volumes or CSP. These novel findings provide evidence of persisting white and gray matter abnormalities in Australian footballers with HoC, and raise concerns related to the long-term neurological health of these athletes.

High-rise residential building ventilation in cold climates: A review of ventilation system types and their impact on measured building performance.

Ventilation system performance in high-rise multi-unit residential buildings (MURBs) has a significant impact on resident wellbeing. While the importance of ventilation is well established, it is commonly overlooked since underperformance often goes undetected. This article presents a review and synthesis of ventilation system performance in high-rise MURBs located in cold climates as it relates to the three pillars of sustainability: economic (capital and operational cost), social (airflow control, indoor environmental quality, and occupant behavior and interactions), and ecological (energy and carbon). A meta-analysis revealed previous ventilation system designs generally prioritized economic sustainability, specifically, capital cost. However, priorities have recently shifted toward social and ecological sustainability. While this shift is positive, there is insufficient empirical evidence showing which ventilation system most effectively supports it. The decentralized heat/energy recovery ventilator (HRV/ERV) system shows the potential to improve upon the social and ecological sustainability of previous designs, such as the centralized pressurized corridor system, but the interconnected nature of performance metrics can cause improvements to one to negatively impact others. Therefore, further research is required to enhance ventilation system performance in cold climate, high-rise MURBs, and facilitate decision-making while designing and retrofitting these systems.

Liver Fat Assessment in Multiview Sonography Using Transfer Learning With Convolutional Neural Networks.

OBJECTIVES: To develop and evaluate deep learning models devised for liver fat assessment based on ultrasound (US) images acquired from four different liver views: transverse plane (hepatic veins at the confluence with the inferior vena cava, right portal vein, right posterior portal vein) and sagittal plane (liver/kidney). METHODS: US images (four separate views) were acquired from 135 participants with known or suspected nonalcoholic fatty liver disease. Proton density fat fraction (PDFF) values derived from chemical shift-encoded magnetic resonance imaging served as ground truth. Transfer learning with a deep convolutional neural network (CNN) was applied to develop models for diagnosis of fatty liver (PDFF ≥ 5%), diagnosis of advanced steatosis (PDFF ≥ 10%), and PDFF quantification for each liver view separately. In addition, an ensemble model based on all four liver view models was investigated. Diagnostic performance was assessed using the area under the receiver operating characteristics curve (AUC), and quantification was assessed using the Spearman correlation coefficient (SCC). RESULTS: The most accurate single view was the right posterior portal vein, with an SCC of 0.78 for quantifying PDFF and AUC values of 0.90 (PDFF ≥ 5%) and 0.79 (PDFF ≥ 10%). The ensemble of models achieved an SCC of 0.81 and AUCs of 0.91 (PDFF ≥ 5%) and 0.86 (PDFF ≥ 10%). CONCLUSION: Deep learning-based analysis of US images from different liver views can help assess liver fat.

Wireless Communications for Smart Manufacturing and Industrial IoT: Existing Technologies, 5G and Beyond.

Smart manufacturing is a vision and major driver for change in today's industry. The goal of smart manufacturing is to optimize manufacturing processes through constantly monitoring, controlling, and adapting processes towards more efficient and personalised manufacturing. This requires and relies on technologies for connected machines incorporating a variety of computation, sensing, actuation, and machine to machine communications modalities. As such, understanding the change towards smart manufacturing requires knowledge of the enabling technologies, their applications in real world scenarios and the communication protocols and their performance to meet application requirements. Particularly, wireless communication is becoming an integral part of modern smart manufacturing and is expected to play an important role in achieving the goals of smart manufacturing. This paper presents an extensive review of wireless communication protocols currently applied in manufacturing environments and provides a comprehensive review of the associated use cases whilst defining their expected impact on the future of smart manufacturing. Based on the review, we point out a number of open challenges and directions for future research in wireless communication technologies for smart manufacturing.

Acculturation Mitigates the Negative Impact of Perceived Stress on Depressive Symptoms Among U.S. Chinese Older Adults.

The present study aimed to examine the role of acculturation in mitigating the negative impact of perceived stress on depressive symptoms among U.S. Chinese older adults. Data of 3,159 Chinese adults over 60 years old were drawn from the Population Study of Chinese Elderly in Chicago (PINE). In addition to socio-demographic variables, participants' acculturation levels, perceived stress, and depressive symptoms were assessed. Perceived stress was positively related to depressive symptoms among Chinese older adults. However, no significant association was found between acculturation level and depressive symptoms. Regression analysis supported the moderation hypothesis of acculturation level on the relationship between perceived stress on depressive symptoms. The negative impact of perceived stress on depressive symptoms was mitigated for Chinese older adults who had higher levels of acculturation than for those who had lower levels of acculturation. The findings have implications in minority aging and mental health policies during the on-going pandemic era.

Behavioral, axonal, and proteomic alterations following repeated mild traumatic brain injury: Novel insights using a clinically relevant rat model.

A history of mild traumatic brain injury (mTBI) is linked to a number of chronic neurological conditions, however there is still much unknown about the underlying mechanisms. To provide new insights, this study used a clinically relevant model of repeated mTBI in rats to characterize the acute and chronic neuropathological and neurobehavioral consequences of these injuries. Rats were given four sham-injuries or four mTBIs and allocated to 7-day or 3.5-months post-injury recovery groups. Behavioral analysis assessed sensorimotor function, locomotion, anxiety, and spatial memory. Neuropathological analysis included serum quantification of neurofilament light (NfL), mass spectrometry of the hippocampal proteome, and ex vivo magnetic resonance imaging (MRI). Repeated mTBI rats had evidence of acute cognitive deficits and prolonged sensorimotor impairments. Serum NfL was elevated at 7 days post injury, with levels correlating with sensorimotor deficits; however, no NfL differences were observed at 3.5 months. Several hippocampal proteins were altered by repeated mTBI, including those associated with energy metabolism, neuroinflammation, and impaired neurogenic capacity. Diffusion MRI analysis at 3.5 months found widespread reductions in white matter integrity. Taken together, these findings provide novel insights into the nature and progression of repeated mTBI neuropathology that may underlie lingering or chronic neurobehavioral deficits.

A 10% Tomato Diet Selectively Reduces Radiation-Induced Damage in TRAMP Mice.

BACKGROUND: Tomatoes contain carotenoids that have the potential to alter the effects of external beam radiation therapy (EBRT). OBJECTIVES: We hypothesized that dietary lyophilized tomato paste (TP) would reduce apoptosis within carotenoid-containing nonneoplastic tissues in EBRT-treated TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice. METHODS: Male TRAMP mice (n = 73) were provided an AIN-93G diet or a modified AIN-93G diet containing 10% TP (wt:wt) at 4 wk of age. Prostate tumor growth was monitored by ultrasound. The caudal half of the mouse was irradiated with 7.5 Gy (Rad) or 0 Gy (sham) at 24 wk of age or after the tumor volume exceeded 1000 mm3 with a Cobalt-60 source. Mice were euthanized 24 h postradiation. Carotenoids and α-tocopherol were measured by HPLC and compared by a t test. Tissues were assessed for radiation-induced changes (hematoxylin and eosin) and apoptosis [cleaved caspase-3 (CC3)] and compared by Kruskal-Wallis test or Freedman-Lane's permutation test. RESULTS: Serum concentrations of lycopene (52% lower), phytoene (26% lower), and α-tocopherol (22% lower) were decreased in TP-fed irradiated mice (TP-Rad) compared with TP-fed sham mice (P < 0.05). CC3 scores increased within the prostate tumor with radiation treatments (P < 0.05), but were not affected by tomato consumption. In nonneoplastic tissues, TP-Rad had a lower percentage of CC3-positive cells within the cranial (67% lower) and caudal (75% lower) duodenum than irradiated mice on the control diet (Rad) (P < 0.005). Likewise, CC3 scores within the dorsolateral prostate of TP-Rad trended toward lower scores than for Rad (P = 0.07). CONCLUSIONS: TP selectively reduces radiation-induced apoptosis in extratumoral tissues without decreasing radiation-induced apoptosis within the prostate tumor in TRAMP mice. Additional studies are needed to confirm and expand upon these findings.