A murine model of mild traumatic brain injury exhibiting cognitive and motor deficits

Background

Mild traumatic brain injury (TBI) is a serious public health concern affecting more than 1.7 million people in the United States annually. Mild TBI is difficult to diagnose and is clinically associated with impaired motor coordination and cognition.

Methods

We subjected mice to a mild TBI (mTBI-1 or mTBI-2) induced by a weight drop model. We assessed brain injury histologically and biochemically, the latter by serum neuron-specific enolase and glial fibrillary acidic protein. Systemic and brain inflammation were measured by cytokine array. We determined blood–brain barrier integrity by cerebral vascular leakage of micromolecular and macromolecular fluorescent molecules. We evaluated mice using a rotarod device and novel object recognition to measure motor coordination and cognition, respectively.

Results

Mice undergoing mTBI-1 or mTBI-2 had significant deficits in motor coordination and cognition for several days after injury compared with controls. Furthermore, both mTBI-1 and mTBI-2 caused micromolecular leakage in the blood–brain barrier, whereas only mTBI-2 caused macromolecular leakage. Serum neuron-specific enolase and glial fibrillary acidic protein were elevated acutely and corresponded to the degree of injury, but returned to baseline within 24 h. Serum cytokines interleukin-6 and keratinocyte-derived chemokine were significantly increased within 90 min of TBI. Interleukin-6 levels correlated with the degree of injury.

Conclusions

The current study provides a reproducible model of mild TBI in mice that exhibits pathologic features of mild TBI in humans. Furthermore, our data suggest that serum cytokines, such as IL-6, may be effective biomarkers for severity of head injury.     

Relationship between personality change and the onset and course of alcohol dependence in young adulthood

Aims To examine the reciprocal effects between the onset and course of alcohol use disorder (AUD) and normative changes in personality traits of behavioral disinhibition and negative emotionality during the transition between adolescence and young adulthood. Design Longitudinal–epidemiological study assessing AUD and personality at ages 17 and 24 years. Setting Participants were recruited from the community and took part in a day‐long, in‐person assessment. Participants Male (n = 1161) and female (n = 1022) twins participating in the Minnesota Twin Family Study. Measurements The effects of onset (adolescent versus young adult) and course (persistent versus desistent) of AUD on change in personality traits of behavioral disinhibition and negative emotionality from ages 17 to 24 years. Findings Onset and course of AUD moderated personality change from ages 17 to 24 years. Adolescent onset AUD was associated with greater decreases in behavioral disinhibition. Those with an adolescent onset and persistent course failed to exhibit normative declines in negative emotionality. Desistence was associated with a ‘recovery’ towards psychological maturity in young adulthood, while persistence was associated with continued personality dysfunction. Personality traits at age 11 predicted onset and course of AUD, indicating personality differences were not due to active substance abuse. Conclusions Personality differences present prior to initiation of alcohol use increase risk for alcohol use disorder, but the course of alcohol use disorder affects the rate of personality change during emerging adulthood. Examining the reciprocal effects of personality and alcohol use disorder within a developmental context is necessary to improve understanding for theory and intervention.     

Monocytes and γδ T cells control the acute‐phase response to intravenous zoledronate: Insights from a phase IV safety trial

Aminobisphosphonates (NBPs) are used widely against excessive bone resorption in osteoporosis and Paget's disease as well as in metastatic bone disease and multiple myeloma. Intravenous NBP administration often causes mild to severe acute‐phase responses (APRs) that may require intervention with analgesics and antipyretics and lead to treatment noncompliance and nonadherence. We here undertook a phase IV safety trial in patients with osteoporosis to investigate the APR of otherwise healthy individuals to first‐time intravenous treatment with the NBP zoledronate. This study provides unique insight into sterile acute inflammatory responses in vivo, in the absence of confounding factors such as infection or cancer. Our data show that both peripheral γδ T cells and monocytes become rapidly activated after treatment with zoledronate, which ultimately determines the clinical severity of the APR. Our study highlights a key role for IFN‐γ in the zoledronate‐induced APR and identifies pretreatment levels of monocytes and central/memory Vγ9/Vδ2 T cells as well as their responsiveness to zoledronate in vitro as predictive risk factors for the occurrence of subclinical and clinical symptoms. These findings have diagnostic and prognostic implications for patients with and without malignancy and are relevant for Vγ9/Vδ2 T‐cell–based immunotherapy approaches. © 2012 American Society for Bone and Mineral Research. © 2013 American Society for Bone and Mineral Research.     

Progressive amnestic dementia, hippocampal sclerosis, and mutation in C9ORF72

The most common cause of familial frontotemporal lobar degeneration with TAR DNA-binding protein-43 pathology (FTLD-TDP) has been found to be an expansion of a hexanucleotide repeat (GGGGCC) in a noncoding region of the gene C9ORF72. Hippocampal sclerosis (HpScl) is a common finding in FTLD-TDP. Our objective was to screen for the presence of C9ORF72 hexanucleotide repeat expansions in a pathologically confirmed cohort of “pure” hippocampal sclerosis cases (n = 33), outside the setting of FTLD-TDP and Alzheimer’s disease (AD). Using a recently described repeat-associated non-ATG (RAN) translation (C9RANT) antibody that was found to be highly specific for c9FTD/ALS, we identified a single “pure” HpScl autopsy case with a repeat expansion in C9ORF72 (c9HpScl). Mutation screening was also performed with repeat-primed polymerase chain reaction and further confirmed with Southern blotting. The c9HpScl patient had a 14-year history of a slowly progressive amnestic syndrome and a clinical diagnosis of probable AD. Neuropsychological testing revealed memory impairment, but no deficits in other cognitive domains. Autopsy showed hippocampal sclerosis with TDP-43 immunoreactive neuronal inclusions relatively limited to limbic lobe structures. Neuritic pathology immunoreactive for p62 was more frequent than TDP-43 in amygdala and hippocampus. Frequent p62-positive neuronal inclusions were present in cerebellar granule neurons as is typical of C9ORF72 mutation carriers. There was no significant FTLD or motor neuron disease. C9RANT was found to be sensitive and specific in this autopsy-confirmed series of HpScl cases. The findings in this patient suggest that the clinical and pathologic spectrum of C9ORF72 repeat expansion is wider than frontotemporal dementia and motor neuron disease, including cases of progressive amnestic dementia with restricted TDP-43 pathology associated with HpScl.     

Emergency Department Utilization of Adolescents and Young Adults with Autism Spectrum Disorder

Journal of Autism and Developmental Disorders - This study examined emergency department (ED) utilization by adolescents and young adults, 12–30 years of age (AYA) with autism...     

Human pancreatic secretory trypsin inhibitor stabilizes intestinal mucosa against noxious agents

Pancreatic secretory trypsin inhibitor (PSTI) is a serine protease inhibitor, expressed in gut mucosa, whose function is unclear. We, therefore, examined the effects of PSTI on gut stability and repair. Transgenic mice overexpressing human PSTI within the jejunum (FABPi(-1178 to +28) hPSTI construct) showed no change in baseline morphology or morphometry but reduced indomethacin-induced injury in overexpressing hPSTI region by 42% (P < 0.01). Systemic recombinant hPSTI did not affect baseline morphology or morphometry but truncated injurious effects in prevention and recovery rat models of dextran-sodium-sulfate-induced colitis. In vitro studies showed PSTI stimulated cell migration but not proliferation of human colonic carcinoma HT29 or immortalized mouse colonic YAMC cells. PSTI also induced changes in vectorial ion transport (short-circuit current) when added to basolateral but not apical surfaces of polarized monolayers of Colony-29 cells. Restitution and vectorial ion transport effects of PSTI were dependent on the presence of a functioning epidermal growth factor (EGF) receptor because cells with a disrupted (EGFR(-/-) immortalized cells) or neutralized (EGFR blocking antibodies or tyrosine kinase inhibitor) receptor prevented these effects. PSTI also reduced the cytokine release of lipopolysaccharide-stimulated dendritic cells. We conclude that administration of PSTI may provide a novel method of stabilizing intestinal mucosa against noxious agents and stimulating repair after injury.     

The long history of health inequality in New Zealand: occupational class and lifespan in the late 1800s and early 1900s

Objective: As relatively little is known about how socioeconomic position might have affected health prior to the Second World War, we aimed to study lifespan by occupational class in two cohorts in New Zealand. Methods: The first study included men on the electoral rolls in Dunedin in the period 1893 to 1902. The second study used an established cohort of male military personnel who were recruited for the First World War. Linear regression was used to estimate lifespan by occupational class. Results: The first study of 259 men on the electoral rolls found no substantive lifespan differences between the high and low occupational class groups. But the second study of 2,406 military personnel found that men in the three highest occupational classes lived 3.5 years longer (95%CI: 0.3–6.8 years) than the three lowest classes (in the multivariable analysis adjusting for age in 1918 and rurality of occupation). Conclusions: We found no significant lifespan differences in one cohort, but a second cohort is the earliest demonstration to our knowledge of substantial differences in mortality by socioeconomic position in this country prior to the 1960s. Implications for public health: This study provides historical context to the long‐term efforts to address health inequalities in society.     

Pilot Randomized Trial of a Family Management Efficacy Intervention for Caregivers of African American Adolescents with Disruptive Behaviors

Background

Caregivers of adolescents diagnosed with Oppositional Defiant Disorder and/or Conduct Disorder (ODD/CD) experience unique challenges when interacting with child service systems involved in their adolescents’ care. Absent from the literature are interventions to improve these interactions, which in the long term may improve adolescent behavioral health outcomes.

Objective

To examine feasibility/acceptability of Family Management Efficacy (FAME) intervention content, structure, delivery, and appropriateness of selected measures for caregivers of African American adolescents with ODD/CD. Secondary aim was to explore changes in FAME caregivers’ interaction self-efficacy, stress, quality of life, and family functioning scores relative to caregivers receiving treatment as usual (TAU).

Method

A pilot two-group randomized trial was conducted with caregivers of African American adolescents (ages 12–18 years) diagnosed with ODD/CD receiving FAME (n?=?11) or TAU (n?=?9). Feasibility outcomes of enrollment/attrition, measurement completion, session attendance, and homework completion were assessed using tracking logs and field notes, and acceptability through caregiver satisfaction scores and interviews. Preliminary outcomes were assessed at baseline, post- and 2-months post intervention.

Results

FAME was highly acceptable and met a priori thresholds for feasibility in enrollment (56%), attrition (35%), caregiver attendance (55%), and homework completion (50%), with lower than anticipated kin attendance (42%) and measurement completion (55%). Preliminary outcomes suggest FAME may benefit caregivers in areas of family communication, cohesion, and quality of life, but lacked observed benefit for self-efficacy and problem solving indicating need for refinement.

Conclusion

Results inform changes to FAME content, measurement, and delivery schedule in preparation for a fully powered randomized controlled trial.