A Look Into How the "Blue Zone" Lifestyle May Affect Patients' Lives Before and After Hip Fracture: A Propensity-Matched Cohort Study.

INTRODUCTION: Hip fractures are life-changing injuries with associated one-year mortality up to 30%. Five locations in the world have been termed "blue zones," where the longevity of the population is markedly higher than that of surrounding areas and there are 10 times more centenarians. The United States has one blue zone (Loma Linda, California), which is believed to be because of the lifestyle of the Seventh-day Adventist population living there. We hypothesized that patients from the blue zone experience low-energy, frailty-driven, osteoporotic hip fractures later in life and an increased postinjury longevity relative to non-blue zone control subjects. METHODS: A review of patients treated for hip fracture between January 2010 and August 2020 from a single institution was conducted. Demographic data were collected, and the end point of mortality was assessed using death registry information, queried in April 2024. Groups were divided into blue zone and non-blue zone. Statistical analysis was conducted with P < 0.05 considered significant. RESULTS: Complete data were available for 1,032 patients. The blue zone cohort sustained low-energy hip fractures 12 years later in life (83.2 versus 71.1, P < 0.01). Propensity score matching was used to account for this difference. After propensity score matching, age, body mass index, American Society of Anesthesiologists score, surgery performed, sex, mechanism, ethnicity, diabetes, chronic obstructive pulmonary disease, CHF, chronic kidney disease grade, dementia, surgical time, and drug/tobacco/marijuana use were similar between groups. Blue zone patients had lower mortality at both 1 and 2 years postoperatively (12% versus 24%, P = 0.03 and 20% versus 33%, P = 0.03, respectively), had more hypertension (76% versus 62%, P = 0.03), reported lower alcohol use (7% versus 20%, P < 0.01), and included more Seventh-day Adventists (64% versus 15%, P < 0.01). CONCLUSION: The blue zone lifestyle affected the onset of frailty and delayed osteoporotic hip fracture by 12 years in this propensity-matched cohort study. Postoperative mortality was also markedly lower in the blue zone cohort.

Wildfires Increase Concentrations of Hazardous Air Pollutants in Downwind Communities.

Due in part to climate change, wildfire activity is increasing, with the potential for greater public health impact from smoke in downwind communities. Studies examining the health effects of wildfire smoke have focused primarily on fine particulate matter (PM2.5), but there is a need to better characterize other constituents, such as hazardous air pollutants (HAPs). HAPs are chemicals known or suspected to cause cancer or other serious health effects that are regulated by the United States (US) Environmental Protection Agency. Here, we analyzed concentrations of 21 HAPs in wildfire smoke from 2006 to 2020 at 309 monitors across the western US. Additionally, we examined HAP concentrations measured in a major population center (San Jose, CA) affected by multiple fires from 2017 to 2020. We found that concentrations of select HAPs, namely acetaldehyde, acrolein, chloroform, formaldehyde, manganese, and tetrachloroethylene, were all significantly elevated on smoke-impacted versus nonsmoke days (P < 0.05). The largest median increase on smoke-impacted days was observed for formaldehyde, 1.3 µg/m3 (43%) higher than that on nonsmoke days. Acetaldehyde increased 0.73 µg/m3 (36%), and acrolein increased 0.14 µg/m3 (34%). By better characterizing these chemicals in wildfire smoke, we anticipate that this research will aid efforts to reduce exposures in downwind communities.

Effects of Air Pollutants from Wildfires on Downwind Ecosystems: Observations, Knowledge Gaps, and Questions for Assessing Risk.

Wildfires have increased in frequency and area burned, trends expected to continue with climate change. Among other effects, fires release pollutants into the atmosphere, representing a risk to human health and downwind terrestrial and aquatic ecosystems. While human health risks are well studied, the ecological impacts to downwind ecosystems are not, and this gap may present a constraint on developing an adequate assessment of the ecological risks associated with downwind wildfire exposure. Here, we first screened the scientific literature to assess general knowledge about pathways and end points of a conceptual model linking wildfire generated pollutants and other materials to downwind ecosystems. We found a substantial body of literature on the composition of wildfire derived pollution and materials in the atmosphere and subsequent transport, yet little observational or experimental work on their effects on downwind ecological end points. This dearth of information raises many questions related to adequately assessing the ecological risk of downwind exposure, especially given increasing wildfire trends. To guide future research, we pose eight questions within the well-established US EPA ecological risk assessment paradigm that if answered would greatly improve ecological risk assessment and, ultimately, management strategies needed to reduce potential wildfire impacts.

Wildfires in the western United States are mobilizing PM2.5-associated nutrients and may be contributing to downwind cyanobacteria blooms.

Wildfire activity is increasing in the continental U.S. and can be linked to climate change effects, including rising temperatures and more frequent drought conditions. Wildfire emissions and large fire frequency have increased in the western U.S., impacting human health and ecosystems. We linked 15 years (2006-2020) of particulate matter (PM2.5) chemical speciation data with smoke plume analysis to identify PM2.5-associated nutrients elevated in air samples on smoke-impacted days. Most macro- and micro-nutrients analyzed (phosphorus, calcium, potassium, sodium, silicon, aluminum, iron, manganese, and magnesium) were significantly elevated on smoke days across all years analyzed. The largest percent increase was observed for phosphorus. With the exception of ammonium, all other nutrients (nitrate, copper, and zinc), although not statistically significant, had higher median values across all years on smoke vs. non-smoke days. Not surprisingly, there was high variation between smoke impacted days, with some nutrients episodically elevated >10 000% during select fire events. Beyond nutrients, we also explored instances where algal blooms occurred in multiple lakes downwind from high-nutrient fires. In these cases, remotely sensed cyanobacteria indices in downwind lakes increased two to seven days following the occurrence of wildfire smoke above the lake. This suggests that elevated nutrients in wildfire smoke may contribute to downwind algal blooms. Since cyanobacteria blooms can be associated with the production of cyanotoxins and wildfire activity is increasing due to climate change, this finding has implications for drinking water reservoirs in the western United States, and for lake ecology, particularly alpine lakes with otherwise limited nutrient inputs.

Home-Cage Sipper Devices Reveal Age and Sex Differences in Ethanol Consumption Patterns.

Free-choice paradigms such as two-bottle choice (2BC) are commonly used to characterize ethanol consumption and preference of rodent models used to study alcohol use disorder (AUD). However, these assays are limited by low temporal resolution that misses finer patterns of drinking behavior, including circadian drinking patterns that are known to vary with age and sex and are affected in AUD pathogenesis. Modern, cost-effective tools are becoming widely available that could elucidate these patterns, including open-source, Arduino-based home-cage sipper devices. We hypothesized that adaptation of these home-cage sipper devices would uncover distinct age- and sex-related differences in temporal drinking patterns. To test this hypothesis, we used the sipper devices in a continuous 2BC paradigm using water and ethanol (10%; v/v) for 14 days to measure drinking patterns of male and female adolescent (3-week), young adult (6-week), and mature adult (18-week) C57BL/6J mice. Daily grams of fluid consumption were manually recorded at the beginning of the dark cycle, while home-cage sipper devices continuously recorded the number of sips. Consistent with prior studies, females consumed more ethanol than males, and adolescent mice consumed the most out of any age group. Correlation analyses of manually recorded fluid consumption versus home-cage sipper activity revealed a statistically significant prediction of fluid consumption across all experimental groups. Sipper activity was able to capture subtle circadian differences between experimental groups, as well as distinct individual variation in drinking behavior among animals. Blood ethanol concentrations were significantly correlated with sipper data, suggesting that home-cage sipper devices can accurately determine individual timing of ethanol consumption. Overall, our studies show that augmenting the 2BC drinking paradigm with automated home-cage sipper devices can accurately measure ethanol consumption across sexes and age groups, revealing individual differences and temporal patterns of ethanol drinking behavior. Future studies utilizing these home-cage sipper devices will further dissect circadian patterns for age and sex relevant to the pathogenesis of AUD, as well as underlying molecular mechanisms for patterns in ethanol consumption. Highlights: Female mice consume more ethanol than males in a continuous access paradigmAdolescent male and female mice consume more ethanol than young or mature adult miceAutomated home-cage sipper devices accurately measure ethanol consumptionDevices reveal sex- and age-dependent differences in circadian drinking patternsDevices reveal distinct individual variation in circadian drinking patterns.

Rolling out a mindfulness-based stress reduction intervention for parents of children with ADHD: a feasibility study.

BACKGROUND: Attention-deficit/Hyperactivity Disorder (ADHD) is the single most frequent reason for attendance at Child and Adolescent Mental Health Services (CAMHS) in Ireland. Research has suggested that parents of children with ADHD experience more parenting stress than parents of non-clinical controls, yet routine treatment for ADHD rarely addresses parental well-being. Mindfulness-based interventions (MBIs) have been found to result in a reduction in parental stress. METHOD: An adapted Mindfulness-Based Stress Reduction (MBSR) intervention was delivered to parents (n = 23) of children with ADHD recruited from CAMHS and ADHD Ireland. RESULTS: Following the intervention a significant improvement was documented within the social relationships domain of quality of life (WHOQOL-BREF) and a significant reduction on the child hyperactivity scale of the Strengths and Difficulties (SDQ) questionnaire. CONCLUSION: This pilot study suggests that an MBSR intervention is both feasible and effective for parents whose children have ADHD. Larger scale studies need to be conducted before inclusion in routine CAMHS.

Do All-terrain or Recreational Off-highway Vehicle Crashes Have a Higher Odds of Amputation?

BACKGROUND: Riding off-road vehicles is associated with the risk of injury to the extremities. There are two main types of four-wheel recreational off-road vehicles: quads or all-terrain vehicles (ATVs), which are essentially four-wheel off-road motorcycles, and recreational off-highway vehicles (ROVs), also colloquially referred to as utility terrain vehicles, which have side-by-side seating, higher maximum speeds, and a roll cage. There are multiple orthopaedic society position statements on ATVs, but none on ROVs. Perhaps this is because the injury patterns and differences between the two vehicles have not been elucidated. QUESTIONS/PURPOSES: (1) What patient, vehicle (ROVs versus ATVs), and injury factors are associated with amputation? (2) What are the anatomic location distributions of fractures and amputations by vehicle type? METHODS: Records of all patients in our hospital's billing system who had both a diagnostic code indicating an accident related to an off-road vehicle and one indicating an extremity or pelvic fracture between February 2014 and January 2020 were screened; this resulted in the identification of 328 patients with fractures resulting from off-road vehicle collisions. A total of 16% (51 of 328) of patients were excluded from the analysis because their injury did not involve either an ATV or an ROV; 277 patients were included in the final analysis. The following variables were collected: age at time of the injury, gender, BMI, vehicle type, Gustilo-Anderson type if applicable, amputation level if applicable, anatomic locations of injuries, ethanol level, and drug screen. ATV crashes accounted for 52% (145 of 277) of patients, and ROV crashes accounted for 48% (132 of 277). Patients from ATV crashes did not differ from those in ROV crashes in terms of mean age (24 ± 16 years versus 24 ± 13 years; p = 0.82), BMI (25 ± 7 kg/m 2 versus 26 ± 6 kg/m 2 ; p = 0.18), or gender (79% [114 of 145] men/boys versus 77% [102 of 132]; p = 0.79). Among patients who had a drug or ethanol screen, there was a higher percent of ATV riders who used marijuana (39% [19 of 49] versus 17% [7 of 42]; p = 0.04), but there were no differences in abnormal blood alcohol screen or abnormal nonmarijuana drug screen; however, these results were available in only about one-third of patients (99 of 277 for ethanol and 91 of 277 for drug screen). Statistical analysis was performed using logistic regression analysis for factors associated with amputation, with p values < 0.05 considered significant. RESULTS: After controlling for differences in demographic factors, the stepwise increase in Gustilo-Anderson grade of open fracture (OR 9.8 [95% CI 3.6 to 27.0]; p < 0.001) and ROV vehicle type (OR 15.7 [95% CI 3.6 to 68.5]; p < 0.001) were both associated with amputation. There was no increase in the odds of amputation associated with age (OR 1.0 [95% CI 0.9 to 1.1]; p = 0.81), gender (OR 1.4 [95% CI 0.3 to 5.8]; p = 0.68), or BMI (OR 1.1 [95% CI 0.9 to 1.2]; p = 0.37). The most frequent ATV fractures occurred in the forearm and wrist (22% [45 of 203]), whereas most ROV injuries occurred through the metacarpals (41% [107 of 262] of fractures and 58% [18 of 31] of amputations). CONCLUSION: ROV crashes are associated with a higher odds of amputation when compared with ATV crashes. Because most ROV injuries were in the forearm and below, this likely occurs when upper extremities are crushed and mangled under the roll cage in rollover ROV crashes. Because of this danger, we urge our orthopaedic societies to either update current ATV position statements to include ROVs or release separate statements on ROVs. LEVEL OF EVIDENCE: Level III, prognostic study.

Beyond Particulate Matter Mass: Heightened Levels of Lead and Other Pollutants Associated with Destructive Fire Events in California.

As the climate warms, wildfire activity is increasing, posing a risk to human health. Studies have reported on particulate matter (PM) in wildfire smoke, yet the chemicals associated with PM have received considerably less attention. Here, we analyzed 13 years (2006-2018) of PM2.5 chemical composition data from monitors in California on smoke-impacted days. Select chemicals (e.g., aluminum and sulfate) were statistically elevated on smoke-impacted days in over half of the years studied. Other chemicals, mostly trace metals harmful to human health (e.g., copper and lead), were elevated during particular fires only. For instance, in 2018, lead was more than 40 times higher on smoke days on average at the Point Reyes monitoring station, due mostly to the Camp Fire, burning approximately 200 km away. There was an association between these metals and the combustion of anthropogenic material (e.g., the burning of houses and vehicles). Although still currently rare, these infrastructure fires are likely becoming more common and can mobilize trace metals in smoke far downwind, at levels generally unseen except in the most polluted areas of the country. We hope a better understanding of the chemicals in wildfire smoke will assist in the communication and reduction of public health risks.

Ozone exposure-response relationships parametrized for sixteen tree species with varying sensitivity in the United States.

It is well known that exposure to ambient O3 can decrease growth in many tree species in the United States (US). Our study reports experimental data from outdoor open-top chamber (OTC) studies that quantify total biomass response changes for seedlings of 16 species native to western and eastern North America, which were exposed to several levels of elevated O3 for one or more years. The primary objective of this study is to establish a reference set of parameters for these seedling exposure-response relationships using a 3-month (92 day) 12-hr W126 O3 metric used by US Environmental Protection Agency and other agencies to assess risk to trees from O3 exposure. We classified the 16 species according to their sensitivity, based on the biomass loss response functions to protect from a 5% biomass loss. The three-month 12-h W126 estimated to result in a 5% biomass loss was 2.5-9.2 ppm-h for sensitive species, 20.8-25.2 ppm-h for intermediate species, and > 28.7 ppm-h for insensitive species. The most sensitive tree species include black cherry, ponderosa pine, quaking aspen, red alder, American sycamore, tulip poplar and winged sumac. These species are ecologically important and widespread across US. The effects of O3 on whole-plant biomass depended on exposure duration and dynamics and on the number of successive years of exposure. These species-specific exposure-response relationships will allow US agencies and other groups to better estimate biomass losses based on ozone exposures in North America and can be used in risk assessment and scenario analyses.

Do Current Stability Scores After MPFL Reconstruction Correlate With Patient Satisfaction Postoperatively?

Background: Patellar dislocation can lead to instability, pain, limited function, and recurrent dislocations. Medial patellofemoral ligament (MPFL) reconstruction leads to favorable patient reported outcomes, but many patients fail to return to previous activity levels. The purpose of this study is to determine how well patients do after MPFL reconstruction and to determine the most important factors for evaluation of patellar instability following MPFL reconstruction. Methods: After IRB approval, a retrospective chart review was performed on all patients who underwent MPFL reconstruction from January 2006 to January 2014 by two board-certified sports orthopaedic surgeons. Patients were then contacted to complete a follow-up questionnaire about satisfaction, functional status, pain, and patellar stability. Patients with at least one-year of follow-up data, a complete data set, and a completed questionnaire were included in the final analysis. Charts of 100 patients were reviewed and 54 patients met all criteria for inclusion in the study. Chi-square analysis, t-tests, and multivariate and univariate logistic regression models were used to estimate the effects of multiple variables on return to activity, satisfaction, and function while controlling for covariates with p<0.05 considered significant. Results: When asked about subluxation, 20% (11/54) reported recurrent patellar subluxation (without re-dislocation). Of the 11 patients who reported re-subluxation, 54% (6/11) reported being highly satisfied (rating of 9-10/10) with the outcome of their knee. Of the 54 patients, 54% (29/54) did not return to previous levels of activity, nevertheless, 31% (9/29) of these 29 patients reported being highly satisfied with the outcome of their knee. Conclusion: Patients report high levels of satisfaction even if they have recurrent instability or are unable to return to prior activity levels. Current scoring systems do not accurately depict patients' post-operative outcomes after MPFL Reconstruction. Level of Evidence: III.

The prevention of obesity starting from the kindergarten by means of peer educator mothers and WhatsApp messages.

BACKGROUND: Early-life diet plays a crucial role in the development of body weight issues. We therefore investigated the effectiveness of a peer-education intervention, aiming at encouraging the intake of fruits and vegetables and of a healthy mid-morning snack, targeting the mothers of 3-8 years old children attending kindergarten and primary school. STUDY DESIGN: Experimental approach. METHODS: The study involved 924 children (intervention group) and 450 children (control group). The intervention was carried out by organizing three meetings at school with the participation of healthcare professionals, mothers and teachers in a maieutic way. The meetings focused on i) discussing the issues that mothers face with their children's nutrition; ii) possible solutions; iii) identification of "leading mothers" playing as peer-educators. As control a similar intervention targeting only the teachers, without involving the mothers, was also carried out. The effectiveness of such interventions was evaluated by external evaluators, before, the interventions and 3 and 9 months after the interventions. RESULTS: The check, carried out 3 months after the intervention, showed a significant improvement with respect to the mid-morning snack, and the consumption of the main dishes as well as fruits; the check carried out 9 months after the intervention, showed that such improvements were maintained in the case of the mid-morning snack and the fruit intake. No improvement was observed in relation to the control group. CONCLUSIONS: This is the first example of an intervention promoting a healthy diet involving mothers of children attending kindergarten and primary school as peer educators and it actually improved the dietary habits.

Ozone exposure during early pregnancy and preterm birth: A systematic review and meta-analysis.

Exposure to ozone has been linked to reproductive outcomes, including preterm birth. In this systematic review, we summarize published epidemiologic cohort and case-control studies examining ozone exposures (estimated on a continuous scale) in early pregnancy (1st and 2nd trimesters (T1, T2)) and preterm birth using ratio measures, and perform a meta-analysis to evaluate the potential relationship between them. Studies were identified by searching PubMed and Web of Science, screened according to predefined inclusion/exclusion criteria, and evaluated for study quality. We extracted study data including effect estimates, confidence limits, study location, study years, ozone exposure assessment method, and mean or median ozone concentrations. Nineteen studies were identified and included, of which 18 examined T1 exposure (17 reported effect estimates), and 15 examined T2 exposure. Random effects meta-analysis was performed in the metafor package, R 3.5.3. The pooled OR (95% CI) for a 10 ppb increase in ozone exposure in T1 was 1.06 (1.03, 1.10) with a 95% prediction interval of 0.95, 1.19; for T2 it was 1.05 (1.02, 1.08) with a 95% prediction interval of 0.95, 1.16. Effect estimates for both exposure periods showed high heterogeneity. In meta-regression analyses of study characteristics, study location (continent) explained some (~20%) heterogeneity for T1 exposure studies, but no characteristic explained a substantial amount of heterogeneity for T2 exposure studies. Increased ozone exposure during early pregnancy is associated with preterm birth across studies.

The general populations' understanding of first trimester miscarriage: a cross sectional survey.

OBJECTIVES: Miscarriage is a common, yet for many, devastating adverse pregnancy outcome. However, despite this the level of public knowledge on the topic is sub-optimal. We aimed to examine the general public's knowledge of miscarriage as well as their health information seeking behaviours associated with this topic. STUDY DESIGN: We commissioned a national cross-sectional telephone survey of adults in the Republic of Ireland. 967 members of the general public consented to participate to this anonymised telephone survey. Sampling procedures ensured proportionality as per national standards. We examined respondents' definitions of miscarriage, its incidence and clinical findings, as well as the information seeking behaviours of the general population surrounding miscarriage. RESULTS: 699 (72%) of respondents provided an estimate of miscarriage frequency, with 28% of respondents correctly estimating that miscarriage occurs in 21-30% of pregnancies, with 61% under-estimating the incidence. Men were three times more likely than women to under-estimate (aOR3.5; 95% CI 2.4-4.9), as were those without children (aOR 1.7; 95% CI 1.2-2.6), or those living in urban areas (aOR 1.6; 95%CI 1.0-2.4. One third of respondents (33%) believed that the risk of miscarriage was higher following only one miscarriage. While 83% of respondents knew someone who had experienced a miscarriage, just over one third had discussed the topic of miscarriage with a family member/friend. CONCLUSIONS: The general populations' knowledge of miscarriage, its incidence and associated factors is concerning, as are their health information seeking behaviours. Improving the level of knowledge of the general public could be achieved by adopting the topic into existing public health and education strategies. This will allow those experiencing miscarriage to frame their experience and expectations.

Optimizing T Cell Expansion in a Hollow-Fiber Bioreactor.

PURPOSE OF REVIEW: Recent developments in regenerative medicine have precipitated the need to expand gene-modified human T cells to numbers that exceed the capacity of well-plate-based, and flask-based processes. This review discusses the changes in process development that are needed to meet the cell expansion requirements by utilizing hollow-fiber bioreactors. Maintenance of cell proliferation over long periods can become limited by unfilled demands for nutrients and oxygen and by the accumulation of waste products in the local environment. RECENT FINDINGS: Perfusion feeding, improved gas exchange, and the efficient removal of lactate can increase the yield of T cells from an average of 10.8E +09 to more than 28E +09 in only 10 days. SUMMARY: Aggressively feeding cells and actively keeping cells in the bioreactor improves gas exchange and metabolite management over semi-static methods. The ability to remove the environmental constraints that can limit cell expansion by using a two-chamber hollow-fiber bioreactor will be discussed.

Perforated esophageal intervention focus (PERF) study: a multi-center examination of contemporary treatment.

The treatment of esophageal perforation (EP) remains a significant clinical challenge. While a number of investigators have previously documented efficient approaches, these were mostly single-center experiences reported prior to the introduction of newer technologies: specifically endoluminal stents. This study was designed to document contemporary practice in the diagnosis and management of EP at multiple institutions around the world and includes early clinical outcomes. A five-year (2009-2013) multicenter retrospective review of management and outcomes for patients with thoracic or abdominal esophageal perforation was conducted. Demographics, etiology, diagnostic modalities, treatments, subsequent early outcomes as well as morbidity and mortality were captured and analyzed. During the study period, 199 patients from 10 centers in the United States, Canada, and Europe were identified. Mechanisms of perforation included Boerhaave syndrome (60, 30.1%), iatrogenic injury (65, 32.6%), and penetrating trauma (25, 12.6%). Perforation was isolated to the thoracic segment alone in 124 (62.3%), with 62 (31.2%) involving the thoracoabdominal esophagus. Mean perforation length was 2.5 cm. Observation was selected as initial management in 65 (32.7%), with only two failures. Direct operative intervention was initial management in 65 patients (32.6%), while 29 (14.6%) underwent esophageal stent coverage. Compared to operative intervention, esophageal stent patients were significantly more likely to be older (61.3 vs. 48.3 years old, P < 0.001) and have sustained iatrogenic mechanisms of esophageal perforation (48.3% vs.15.4%). Secondary intervention requirement for patients with perforation was 33.7% overall (66). Complications included sepsis (56, 28.1%), pneumonia (34, 17.1%) and multi-organ failure (23, 11.6%). Overall mortality was 15.1% (30). In contemporary practice, diagnostic and management approaches to esophageal perforation vary widely. Despite the introduction of endoluminal strategies, it continues to carry a high risk of mortality, morbidity, and need for secondary intervention. A concerted multi-institutional, prospectively collected database is ideal for further investigation.

Rescue of impaired sociability and anxiety-like behavior in adult cacna1c-deficient mice by pharmacologically targeting eIF2α.

CACNA1C, encoding the Cav1.2 subunit of L-type Ca2+ channels, has emerged as one of the most prominent and highly replicable susceptibility genes for several neuropsychiatric disorders. Cav1.2 channels play a crucial role in calcium-mediated processes involved in brain development and neuronal function. Within the CACNA1C gene, disease-associated single-nucleotide polymorphisms have been associated with impaired social and cognitive processing and altered prefrontal cortical (PFC) structure and activity. These findings suggest that aberrant Cav1.2 signaling may contribute to neuropsychiatric-related disease symptoms via impaired PFC function. Here, we show that mice harboring loss of cacna1c in excitatory glutamatergic neurons of the forebrain (fbKO) that we have previously reported to exhibit anxiety-like behavior, displayed a social behavioral deficit and impaired learning and memory. Furthermore, focal knockdown of cacna1c in the adult PFC recapitulated the social deficit and elevated anxiety-like behavior, but not the deficits in learning and memory. Electrophysiological and molecular studies in the PFC of cacna1c fbKO mice revealed higher E/I ratio in layer 5 pyramidal neurons and lower general protein synthesis. This was concurrent with reduced activity of mTORC1 and its downstream mRNA translation initiation factors eIF4B and 4EBP1, as well as elevated phosphorylation of eIF2α, an inhibitor of mRNA translation. Remarkably, systemic treatment with ISRIB, a small molecule inhibitor that suppresses the effects of phosphorylated eIF2α on mRNA translation, was sufficient to reverse the social deficit and elevated anxiety-like behavior in adult cacna1c fbKO mice. ISRIB additionally normalized the lower protein synthesis and higher E/I ratio in the PFC. Thus this study identifies a novel Cav1.2 mechanism in neuropsychiatric-related endophenotypes and a potential future therapeutic target to explore.

Design and testing of a controlled electromagnetic spinal cord impactor for use in large animal models of acute traumatic spinal cord injury.

BACKGROUND: Spinal cord injury (SCI) causes debilitating neurological dysfunction and has been observed in warfighters injured in IED blasts. Clinical benefit of SCI treatment remains elusive and better large animal models are needed to assess treatment options. Here, we describe a controlled electromagnetic spinal cord impactor for use in large animal models of SCI. METHODS: A custom spinal cord impactor and platform were fabricated for large animals (e.g., pig, sheep, dog, etc.). Impacts were generated by a voice coil actuator; force and displacement were measured with a load cell and potentiometer respectively. Labview (National Instruments, Austin, TX) software was used to control the impact cycle and import force and displacement data. Software finite impulse response (FIR) filtering was employed for all input data. Silicon tubing was used a surrogate for spinal cord in order to test the device; repeated impacts were performed at 15, 25, and 40 Newtons. RESULTS: Repeated impacts demonstrated predictable results at each target force. The average duration of impact was 71.2 ±6.1ms. At a target force of 40N, the output force was 41.5 ±0.7N. With a target of 25N, the output force was 23.5 ±0.6N; a target of 15Newtons revealed an output force of 15.2 ±1.4N. The calculated acceleration range was 12.5-21.2m/s2. CONCLUSIONS: This custom spinal cord impactor reliably delivers precise impacts to the spinal cord and will be utilized in future research to study acute traumatic SCI in a large animal.

Enhancing VTA Cav1.3 L-type Ca2+ channel activity promotes cocaine and mood-related behaviors via overlapping AMPA receptor mechanisms in the nucleus accumbens.

Genetic factors significantly influence susceptibility for substance abuse and mood disorders. Rodent studies have begun to elucidate a role of Cav1.3 L-type Ca2+ channels in neuropsychiatric-related behaviors, such as addictive and depressive-like behaviors. Human studies have also linked the CACNA1D gene, which codes for the Cav1.3 protein, with bipolar disorder. However, the neurocircuitry and the molecular mechanisms underlying the role of Cav1.3 in neuropsychiatric phenotypes are not well established. In the present study, we directly manipulated Cav1.3 channels in Cav1.2 dihydropyridine insensitive mutant mice and found that ventral tegmental area (VTA) Cav1.3 channels mediate cocaine-related and depressive-like behavior through a common nucleus accumbens (NAc) shell calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (CP-AMPAR) mechanism that requires GluA1 phosphorylation at S831. Selective activation of VTA Cav1.3 with (±)-BayK-8644 (BayK) enhanced cocaine conditioned place preference and cocaine psychomotor activity while inducing depressive-like behavior, an effect not observed in S831A phospho-mutant mice. Infusion of the CP-AMPAR-specific blocker Naspm into the NAc shell reversed the cocaine and depressive-like phenotypes. In addition, activation of VTA Cav1.3 channels resulted in social behavioral deficits. In contrast to the cocaine- and depression-related phenotypes, GluA1/A2 AMPARs in the NAc core mediated social deficits, independent of S831-GluA1 phosphorylation. Using a candidate gene analysis approach, we also identified single-nucleotide polymorphisms in the CACNA1D gene associated with cocaine dependence in human subjects. Together, our findings reveal novel, overlapping mechanisms through which VTA Cav1.3 mediates cocaine-related, depressive-like and social phenotypes, suggesting that Cav1.3 may serve as a target for the treatment of neuropsychiatric symptoms.