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Gulf War illness (GWI) is an important exemplar of environmentally-triggered chronic multisymptom illness, and a potential model for accelerated aging. Inflammation is the main hypothesized mechanism for GWI, with mitochondrial impairment also proposed. No study has directly assessed mitochondrial respiratory chain function (MRCF) on muscle biopsy in veterans with GWI (VGWI). We recruited 42 participants, half VGWI, with biopsy material successfully secured in 36. Impaired MRCF indexed by complex I and II oxidative phosphorylation with glucose as a fuel source (CI&CIIOXPHOS) related significantly or borderline significantly in the predicted direction to 17 of 20 symptoms in the combined sample. Lower CI&CIIOXPHOS significantly predicted GWI severity in the combined sample and in VGWI separately, with or without adjustment for hsCRP. Higher-hsCRP (peripheral inflammation) related strongly to lower-MRCF (particularly fatty acid oxidation (FAO) indices) in VGWI, but not in controls. Despite this, whereas greater MRCF-impairment predicted greater GWI symptoms and severity, greater inflammation did not. Surprisingly, adjusted for MRCF, higher hsCRP significantly predicted lesser symptom severity in VGWI selectively. Findings comport with a hypothesis in which the increased inflammation observed in GWI is driven by FAO-defect-induced mitochondrial apoptosis. In conclusion, impaired mitochondrial function-but not peripheral inflammation-predicts greater GWI symptoms and severity.

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The obesity epidemic has increased type II diabetes mellitus (T2DM) across developed countries. Cardiac T2DM risks include ischemic heart disease, heart failure with preserved ejection fraction, intolerance to ischemia-reperfusion (I-R) injury, and refractoriness to cardioprotection. While opioids are cardioprotective, T2DM causes opioid receptor signaling dysfunction. We tested the hypothesis that sustained opioid receptor stimulus may overcome diabetes mellitus-induced cardiac dysfunction via membrane/mitochondrial-dependent protection. In a murine T2DM model, we investigated effects of morphine on cardiac function, I-R tolerance, ultrastructure, subcellular cholesterol expression, mitochondrial protein abundance, and mitochondrial function. T2DM induced 25% weight gain, hyperglycemia, glucose intolerance, cardiac hypertrophy, moderate cardiac depression, exaggerated postischemic myocardial dysfunction, abnormalities in mitochondrial respiration, ultrastructure and Ca2+ -induced swelling, and cell death were all evident. Morphine administration for 5 days: (1) improved glucose homeostasis; (2) reversed cardiac depression; (3) enhanced I-R tolerance; (4) restored mitochondrial ultrastructure; (5) improved mitochondrial function; (6) upregulated Stat3 protein; and (7) preserved membrane cholesterol homeostasis. These data show that morphine treatment restores contractile function, ischemic tolerance, mitochondrial structure and function, and membrane dynamics in type II diabetic hearts. These findings suggest potential translational value for short-term, but high-dose morphine administration in diabetic patients undergoing or recovering from acute ischemic cardiovascular events.

Jan M Schilling,1 Chloe G Hughes,1 Mark S Wallace,2 Michelle Sexton,2 Miroslav Backonja,1,3 Tobias Moeller-Bertram1 1Clinical Research, Vitamed Research, Palm Desert, CA, USA; 2Department of Anesthesiology, University of California San Diego, San Diego, CA, USA; 3Department of Neurology, University of Washington, Seattle, WA, USACorrespondence: Jan M Schilling; Tobias Moeller-BertramClinical Research, Vitamed Research, LLC, 44630 Monterey Ave, Suite 100, Palm Desert, CA, 92260, USAEmail jan@vitamedresearch.com; toby@vitamedresearch.comIntroduction: Cannabis products have become easily available and accessible after decriminalization of cannabis for recreational and medicinal use in many states. Cannabidiol (CBD) has been of increasing interest to patients and is being used to self-medicate a variety of ailments. However, very limited information is available to patients and providers to form an educated opinion regarding its indicated use to treat the many conditions this substance has been implied to be helpful for. The aim of this survey was to learn about participants’ attitudes and views towards cannabis-based medicine (CBM) with a focus on perception of “CBD” and its potential role for pain management.Materials and Methods: We recruited survey participants from seven pain management clinics in Southern California to learn about their knowledge, beliefs, and personal experience with CBD products. After Institutional Review Board (IRB) review, an internet survey platform was utilized to administer the survey online.Results: A total of 253 participants answered the survey. Participants were 45.4 ± 13.8 (Mean ± SD) years of age, the majority identified as white (56.1%), had an annual household income of less than $20,000, and were primarily insured by Medicare (22.5%) or Medicaid (43.9%). Among participants, 62.0% reported trying a CBD product [including products containing delta-9-tetrahydrocannabinol (THC)]. The

Caveolins have been recognized over the past few decades as key regulators of cell physiology. They are ubiquitously expressed and regulate a number of processes that ultimately impact efficiency of cellular processes. Though not critical to life, they are central to stress adaptation in a number of organs. The following review will focus specifically on the role of caveolin in stress adaptation in the heart, brain, and eye, three organs that are susceptible to acute and chronic stress and that show as well declining function with age. In addition, we consider some novel molecular mechanisms that may account for this stress adaptation and also offer potential to drive the future of caveolin research.

The handling-induced dark neuron is a histological artifact observed in brain samples handled before fixation with aldehydes. To explore associations between dark neurons and immunohistochemical alterations in mouse brains, we examined protein products encoded by Cav3 (neuronal perikarya/neurites), Rbbp4 (neuronal nuclei), Gfap (astroglia), and Aif1 (microglia) genes in adjacent tissue sections. Here, dark neurons were incidental findings from our prior project, studying the effects of age and high-fat diet on metabolic homeostasis in male C57BL/6N mice. Available were brains from 4 study groups: middle-aged/control diet, middle-aged/high-fat diet, old/control diet, and old/high-fat diet. Young/control diet mice were used as baseline. The hemibrains were immersion-fixed with paraformaldehyde and paraffin-embedded. In the hippocampal formation, we found negative correlations between dark neuron hyperbasophilia and immunoreactivity for CAV3, RBBP4, and glial fibrillary acidic protein (GFAP) using quantitative image analysis. There was no significant difference in dark neuron hyperbasophilia or immunoreactivity for any protein examined among all groups. In contrast, in the hippocampal fimbria, old age seemed to be associated with higher immunoreactivity for GFAP and allograft inflammatory factor-1. Our findings suggest that loss of immunohistochemical reactivity for CAV3, RBBP4, and GFAP in the hippocampal formation is an artifact associated with the occurrence of dark neurons. The unawareness of dark neurons may lead to misinterpretation of immunohistochemical reactivity alterations.

The handling-induced dark neuron is a histological artifact observed in brain samples handled before fixation with aldehydes. To explore associations between dark neurons and immunohistochemical alterations in mouse brains, we examined protein products encoded by Cav3 (neuronal perikarya/neurites), Rbbp4 (neuronal nuclei), Gfap (astroglia), and Aif1 (microglia) genes in adjacent tissue sections. Here, dark neurons were incidental findings from our prior project, studying the effects of age and high-fat diet on metabolic homeostasis in male C57BL/6N mice. Available were brains from 4 study groups: middle-aged/control diet, middle-aged/high-fat diet, old/control diet, and old/high-fat diet. Young/control diet mice were used as baseline. The hemibrains were immersion-fixed with paraformaldehyde and paraffin-embedded. In the hippocampal formation, we found negative correlations between dark neuron hyperbasophilia and immunoreactivity for CAV3, RBBP4, and glial fibrillary acidic protein (GFAP) using quantitative image analysis. There was no significant difference in dark neuron hyperbasophilia or immunoreactivity for any protein examined among all groups. In contrast, in the hippocampal fimbria, old age seemed to be associated with higher immunoreactivity for GFAP and allograft inflammatory factor-1. Our findings suggest that loss of immunohistochemical reactivity for CAV3, RBBP4, and GFAP in the hippocampal formation is an artifact associated with the occurrence of dark neurons. The unawareness of dark neurons may lead to misinterpretation of immunohistochemical reactivity alterations.

Cirrhotic cardiomyopathy is a clinical syndrome in patients with liver cirrhosis characterized by blunted cardiac contractile responses to stress and/or heart rate-corrected QT (QTc) interval prolongation. Caveolin-3 (Cav-3) plays a critical role in cardiac protection and is an emerging therapeutic target for heart disease. We investigated the protective role of cardiac-specific overexpression (OE) of Cav-3 in cirrhotic cardiomyopathy. Biliary fibrosis was induced in male Cav-3 OE mice and transgene negative (TGneg) littermates by feeding a diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC; 0.1%) for 3 wk. Liver pathology and blood chemistries were assessed, and stress echocardiography, telemetry, and isolated heart perfusion studies to assess adrenergic responsiveness were performed. Cav-3 OE mice showed a similar degree of hyperdynamic contractility, pulmonary hypertension, and QTc interval prolongation as TGneg mice after 3 wk of DDC diet. Blunted systolic responses were shown in both DDC-fed Cav-3 OE and TGneg hearts after in vivo isoproterenol challenge. However, QTc interval prolongation after in vivo isoproterenol challenge was significantly less in DDC-fed Cav-3 OE hearts compared with DDC-fed TGneg hearts. In ex vivo perfused hearts, where circulatory factors are absent, isoproterenol challenge showed hearts from DDC-fed Cav-3 OE mice had better cardiac contractility and relaxation compared with DDC-fed TGneg hearts. Although Cav-3 OE in the heart did not prevent cardiac alterations in DDC-induced biliary fibrosis, cardiac expression of Cav-3 reduced QTc interval prolongation after adrenergic stimulation in cirrhosis.NEW & NOTEWORTHY Prevalence of cirrhotic cardiomyopathy is up to 50% in cirrhotic patients, and liver transplantation is the only treatment. However, cirrhotic cardiomyopathy is associated with perioperative morbidity and mortality after liver transplantation; therefore, management of cirrhotic cardiomyopathy is crucial for suc

People heterozygous for an activating mutation in protein kinase G1 (PRKG1, p.Arg177Gln) develop thoracic aortic aneurysms and dissections (TAAD) as young adults. Here we report that mice heterozygous for the mutation have a three-fold increase in basal protein kinase G (PKG) activity, and develop age-dependent aortic dilation. Prkg1R177Q/+ aortas show increased smooth muscle cell apoptosis, elastin fiber breaks, and oxidative stress compared to aortas from wild type littermates. Transverse aortic constriction (TAC)-to increase wall stress in the ascending aorta-induces severe aortic pathology and mortality from aortic rupture in young mutant mice. The free radical-neutralizing vitamin B12-analog cobinamide completely prevents age-related aortic wall degeneration, and the unrelated anti-oxidant N-acetylcysteine ameliorates TAC-induced pathology. Thus, increased basal PKG activity induces oxidative stress in the aorta, raising concern about the widespread clinical use of PKG-activating drugs. Cobinamide could be a treatment for aortic aneurysms where oxidative stress contributes to the disease, including Marfan syndrome.

The noble gas helium (He) induces cardioprotection in vivo through unknown molecular mechanisms. He can interact with and modify cellular membranes. Caveolae are cholesterol and sphingolipid-enriched invaginations of the plasma-membrane-containing caveolin (Cav) proteins that are critical in protection of the heart. Mice (C57BL/6J) inhaled either He gas or adjusted room air. Functional measurements were performed in the isolated Langendorff perfused heart at 24 h post He inhalation. Electron paramagnetic resonance spectrometry (EPR) of samples was carried out at 24 h post He inhalation. Immunoblotting was used to detect Cav-1/3 expression in whole-heart tissue, exosomes isolated from platelet free plasma (PFP) and membrane fractions. Additionally, transmission electron microscopy analysis of cardiac tissue and serum function and metabolomic analysis were performed. In contrast to cardioprotection observed in in vivo models, the isolated Langendorff perfused heart revealed no protection after He inhalation. However, levels of Cav-1/3 were reduced 24 h after He inhalation in whole-heart tissue, and Cav-3 was increased in exosomes from PFP. Addition of serum to muscle cells in culture or naïve ventricular tissue increased mitochondrial metabolism without increasing reactive oxygen species generation. Primary and lipid metabolites determined potential changes in ceramide by He exposure. In addition to direct effects on myocardium, He likely induces the release of secreted membrane factors enriched in caveolae. Our results suggest a critical role for such circulating factors in He-induced organ protection.

Mild traumatic brain injury is an all-too-common outcome from modern warfare and sport, and lacks a reproducible model for assessment of potential treatments and protection against it. Here we consider the use of surface acoustic wave (SAW) irradiation of C. elegans worms-without cavitation-as a potential, ethically reasonable animal-on-a-chip model for inducing traumatic brain injury in an animal, producing significant effects on memory and learning that could prove useful in a model that progress from youth to old age in but a few weeks. We show a significant effect by SAW on the ability of worms to learn post-exposure through associative learning chemotaxis. At higher SAW intensity, we find immediate, thorough, but temporary paralysis of the worms. We further explore the importance of homogeneous exposure of the worms to the SAW-driven ultrasound, an aspect poorly controlled in past efforts, if at all, and demonstrate the absence of cavitation through a change in fluids from a standard media for the worms to the exceedingly viscous polyvinyl alcohol. Likewise, we demonstrate that acoustic streaming, when present, is not directly responsible for paralysis nor learning disabilities induced in the worm, but is beneficial at low amplitudes to ensuring homogeneous ultrasound exposure.

ObjectiveCongenital heart disease (CHD) is the most frequent birth defect worldwide. The number of adult patients with CHD, now referred to as ACHD, is increasing with improved surgical and treatment interventions. However the mechanisms whereby ACHD predisposes patients to heart dysfunction are still unclear. ACHD is strongly associated with metabolic syndrome, but how ACHD interacts with poor modern lifestyle choices and other comorbidities, such as hypertension, obesity, and diabetes, is mostly unknown.MethodsWe used a newly characterized mouse genetic model of ACHD to investigate the consequences and the mechanisms associated with combined obesity and ACHD predisposition. Metformin intervention was used to further evaluate potential therapeutic amelioration of cardiac dysfunction in this model.ResultsACHD mice placed under metabolic stress (high fat diet) displayed decreased left ventricular ejection fraction. Comprehensive physiological, biochemical, and molecular analysis showed that ACHD hearts exhibited early changes in energy metabolism with increased glucose dependence as main cardiac energy source. These changes preceded cardiac dysfunction mediated by exposure to high fat diet and were associated with increased disease severity. Restoration of metabolic balance by metformin administration prevented the development of heart dysfunction in ACHD predisposed mice.ConclusionsThis study reveals that early metabolic impairment reinforces heart dysfunction in ACHD predisposed individuals and diet or pharmacological interventions can be used to modulate heart function and attenuate heart failure. Our study suggests that interactions between genetic and metabolic disturbances ultimately lead to the clinical presentation of heart failure in patients with ACHD. Early manipulation of energy metabolism may be an important avenue for intervention in ACHD patients to prevent or delay onset of heart failure and secondary comorbidities. These interactions raise the prospe

Mild traumatic brain injury is an all-too-common outcome from modern warfare and sport, and lacks a reproducible model for assessment of potential treatments and protection against it. Here we consider the use of surface acoustic wave (SAW) irradiation of C. elegans worms-without cavitation-as a potential, ethically reasonable animal-on-a-chip model for inducing traumatic brain injury in an animal, producing significant effects on memory and learning that could prove useful in a model that progress from youth to old age in but a few weeks. We show a significant effect by SAW on the ability of worms to learn post-exposure through associative learning chemotaxis. At higher SAW intensity, we find immediate, thorough, but temporary paralysis of the worms. We further explore the importance of homogeneous exposure of the worms to the SAW-driven ultrasound, an aspect poorly controlled in past efforts, if at all, and demonstrate the absence of cavitation through a change in fluids from a standard media for the worms to the exceedingly viscous polyvinyl alcohol. Likewise, we demonstrate that acoustic streaming, when present, is not directly responsible for paralysis nor learning disabilities induced in the worm, but is beneficial at low amplitudes to ensuring homogeneous ultrasound exposure.

ObjectiveCongenital heart disease (CHD) is the most frequent birth defect worldwide. The number of adult patients with CHD, now referred to as ACHD, is increasing with improved surgical and treatment interventions. However the mechanisms whereby ACHD predisposes patients to heart dysfunction are still unclear. ACHD is strongly associated with metabolic syndrome, but how ACHD interacts with poor modern lifestyle choices and other comorbidities, such as hypertension, obesity, and diabetes, is mostly unknown.MethodsWe used a newly characterized mouse genetic model of ACHD to investigate the consequences and the mechanisms associated with combined obesity and ACHD predisposition. Metformin intervention was used to further evaluate potential therapeutic amelioration of cardiac dysfunction in this model.ResultsACHD mice placed under metabolic stress (high fat diet) displayed decreased left ventricular ejection fraction. Comprehensive physiological, biochemical, and molecular analysis showed that ACHD hearts exhibited early changes in energy metabolism with increased glucose dependence as main cardiac energy source. These changes preceded cardiac dysfunction mediated by exposure to high fat diet and were associated with increased disease severity. Restoration of metabolic balance by metformin administration prevented the development of heart dysfunction in ACHD predisposed mice.ConclusionsThis study reveals that early metabolic impairment reinforces heart dysfunction in ACHD predisposed individuals and diet or pharmacological interventions can be used to modulate heart function and attenuate heart failure. Our study suggests that interactions between genetic and metabolic disturbances ultimately lead to the clinical presentation of heart failure in patients with ACHD. Early manipulation of energy metabolism may be an important avenue for intervention in ACHD patients to prevent or delay onset of heart failure and secondary comorbidities. These interactions raise the prospe

The noble gas helium (He) induces cardioprotection in vivo through unknown molecular mechanisms. He can interact with and modify cellular membranes. Caveolae are cholesterol and sphingolipid-enriched invaginations of the plasma-membrane-containing caveolin (Cav) proteins that are critical in protection of the heart. Mice (C57BL/6J) inhaled either He gas or adjusted room air. Functional measurements were performed in the isolated Langendorff perfused heart at 24 h post He inhalation. Electron paramagnetic resonance spectrometry (EPR) of samples was carried out at 24 h post He inhalation. Immunoblotting was used to detect Cav-1/3 expression in whole-heart tissue, exosomes isolated from platelet free plasma (PFP) and membrane fractions. Additionally, transmission electron microscopy analysis of cardiac tissue and serum function and metabolomic analysis were performed. In contrast to cardioprotection observed in in vivo models, the isolated Langendorff perfused heart revealed no protection after He inhalation. However, levels of Cav-1/3 were reduced 24 h after He inhalation in whole-heart tissue, and Cav-3 was increased in exosomes from PFP. Addition of serum to muscle cells in culture or naïve ventricular tissue increased mitochondrial metabolism without increasing reactive oxygen species generation. Primary and lipid metabolites determined potential changes in ceramide by He exposure. In addition to direct effects on myocardium, He likely induces the release of secreted membrane factors enriched in caveolae. Our results suggest a critical role for such circulating factors in He-induced organ protection.

People heterozygous for an activating mutation in protein kinase G1 (PRKG1, p.Arg177Gln) develop thoracic aortic aneurysms and dissections (TAAD) as young adults. Here we report that mice heterozygous for the mutation have a three-fold increase in basal protein kinase G (PKG) activity, and develop age-dependent aortic dilation. Prkg1R177Q/+ aortas show increased smooth muscle cell apoptosis, elastin fiber breaks, and oxidative stress compared to aortas from wild type littermates. Transverse aortic constriction (TAC)-to increase wall stress in the ascending aorta-induces severe aortic pathology and mortality from aortic rupture in young mutant mice. The free radical-neutralizing vitamin B12-analog cobinamide completely prevents age-related aortic wall degeneration, and the unrelated anti-oxidant N-acetylcysteine ameliorates TAC-induced pathology. Thus, increased basal PKG activity induces oxidative stress in the aorta, raising concern about the widespread clinical use of PKG-activating drugs. Cobinamide could be a treatment for aortic aneurysms where oxidative stress contributes to the disease, including Marfan syndrome.

To understand the health impact of long-duration spaceflight, one identical twin astronaut was monitored before, during, and after a 1-year mission onboard the International Space Station; his twin served as a genetically matched ground control. Longitudinal assessments identified spaceflight-specific changes, including decreased body mass, telomere elongation, genome instability, carotid artery distension and increased intima-media thickness, altered ocular structure, transcriptional and metabolic changes, DNA methylation changes in immune and oxidative stress-related pathways, gastrointestinal microbiota alterations, and some cognitive decline postflight. Although average telomere length, global gene expression, and microbiome changes returned to near preflight levels within 6 months after return to Earth, increased numbers of short telomeres were observed and expression of some genes was still disrupted. These multiomic, molecular, physiological, and behavioral datasets provide a valuable roadmap of the putative health risks for future human spaceflight.

Caveolin-3 (Cav-3) plays a critical role in organizing signaling molecules and ion channels involved in cardiac conduction and metabolism. Mutations in Cav-3 are implicated in cardiac conduction abnormalities and myopathies. Additionally, cardiac-specific overexpression of Cav-3 (Cav-3 OE) is protective against ischemic and hypertensive injury, suggesting a potential role for Cav-3 in basal cardiac electrophysiology and metabolism involved in stress adaptation. We hypothesized that overexpression of Cav-3 may alter baseline cardiac conduction and metabolism. We examined: (1) ECG telemetry recordings at baseline and during pharmacological interventions, (2) ion channels involved in cardiac conduction with immunoblotting and computational modeling, and (3) baseline metabolism in Cav-3 OE and transgene-negative littermate control mice. Cav-3 OE mice had decreased heart rates, prolonged PR intervals, and shortened QTc intervals with no difference in activity compared to control mice. Dobutamine or propranolol did not cause significant changes between experimental groups in maximal (dobutamine) or minimal (propranolol) heart rate. Cav-3 OE mice had an overall lower chronotropic response to atropine. The expression of Kv1.4 and Kv4.3 channels, Nav1.5 channels, and connexin 43 were increased in Cav-3 OE mice. A computational model integrating the immunoblotting results indicated shortened action potential duration in Cav-3 OE mice linking the change in channel expression to the observed electrophysiology phenotype. Metabolic profiling showed no gross differences in VO2, VCO2, respiratory exchange ratio, heat generation, and feeding or drinking. In conclusion, Cav-3 OE mice have changes in ECG intervals, heart rates, and cardiac ion channel expression. These findings give novel mechanistic insights into previously reported Cav-3 dependent cardioprotection.

Translation of preclinical treatments for ischaemia-reperfusion injury into clinical therapies has been limited by a number of factors. This review will focus on a single mode of cardiac protection related to a membrane scaffolding protein, caveolin, which regulates protective signalling as well as myocyte ultrastructure in the setting of ischaemic stress. Factors that have limited the clinical translation of protection will be considered specifically in terms of signalling and structural defects. The potential of caveolin to overcome barriers to protection with the ultimate hope of clinical translation will be discussed.

Studies in vitro and in vivo demonstrate that membrane/lipid rafts (MLR) and caveolin (Cav) organize pro-growth receptors, and when over-expressed specifically in neurons, Cav-1 augments neuronal signaling and growth, and improves cognitive function in adult and aged mice. However, whether Cav-1 overexpression can preserve motor and cognitive function in the setting of brain trauma is unknown. Here, we engineered a neuron-targeted Cav-1 overexpressing transgenic (Tg) mouse (via synapsin promoter, SynCav1 Tg) and subjected it to a controlled cortical impact (CCI) model of brain trauma and measured biochemical, anatomical, and behavioral changes. SynCav1 Tg mice exhibited increased hippocampal expression of Cav-1 and MLR-localization of PSF-95, NMDAR, and TrkB. When subjectd to CCI, SynCav1 Tg mice demonstrated preserved hippocampal-dependent fear learning and memory, motor function recovery on inverted grid, and decreased brain lesion volume. Conclusion: Neuron-targeted overexpression of Cav-1 in the adult brain preserves hippocampal-dependent learning and memory, restores motor function after brain trauam, and decreases brain lesion size. Our findings suggest neuron-targeted Cav-1 as a novel therapeutic strategy to restore nerve function and prevent trauma-associated neurodegeneration.

Studies in vitro and in vivo demonstrate that membrane/lipid rafts (MLR) and caveolin (Cav) organize pro-growth receptors, and when over-expressed specifically in neurons, Cav-1 augments neuronal signaling and growth, and improves cognitive function in adult and aged mice. However, whether Cav-1 overexpression can preserve motor and cognitive function in the setting of brain trauma is unknown. Here, we engineered a neuron-targeted Cav-1 overexpressing transgenic (Tg) mouse (via synapsin promoter, SynCav1 Tg) and subjected it to a controlled cortical impact (CCI) model of brain trauma and measured biochemical, anatomical, and behavioral changes. SynCav1 Tg mice exhibited increased hippocampal expression of Cav-1 and MLR-localization of PSF-95, NMDAR, and TrkB. When subjectd to CCI, SynCav1 Tg mice demonstrated preserved hippocampal-dependent fear learning and memory, motor function recovery on inverted grid, and decreased brain lesion volume. Conclusion: Neuron-targeted overexpression of Cav-1 in the adult brain preserves hippocampal-dependent learning and memory, restores motor function after brain trauam, and decreases brain lesion size. Our findings suggest neuron-targeted Cav-1 as a novel therapeutic strategy to restore nerve function and prevent trauma-associated neurodegeneration.

The impact of volatile anesthetics on cancer progression has been observed for decades, but sex differences have not been described. Male and female immune systems vary considerably, and the immune system plays an important role in limiting cancer growth. Currently, mouse models describing the impact of volatile anesthetics on cancer growth are limited to same-sex models. In this brief report, we describe a sex-specific impact of isoflurane on melanoma growth observed in wild-type but not in immune-deficient mice. Future experimental designs related to anesthesia and cancer should evaluate the biological variable of sex in a systematic manner.

BackgroundStudies in vitro demonstrate that neuronal membrane/lipid rafts (MLRs) establish cell polarity by clustering progrowth receptors and tethering cytoskeletal machinery necessary for neuronal sprouting. However, the effect of MLR and MLR-associated proteins on neuronal aging is unknown.MethodsHere, we assessed the impact of neuron-targeted overexpression of an MLR scaffold protein, caveolin-1 (Cav-1) (via a synapsin promoter, SynCav1), in the hippocampus in vivo in adult (6-month-old) and aged (20-month-old) mice on biochemical, morphologic, and behavioral changes.ResultsSynCav1 resulted in increased expression of Cav-1, MLRs, and MLR-localization of Cav-1 and tropomyosin-related kinase B receptor independent of age and time post gene transfer. Cav-1 overexpression in adult mice enhanced dendritic arborization within the apical dendrites of hippocampal cornu ammonis 1 and granule cell neurons, effects that were also observed in aged mice, albeit to a lesser extent, indicating preserved impact of Cav-1 on structural plasticity of hippocampal neurons with age. Cav-1 overexpression enhanced contextual fear memory in adult and aged mice demonstrating improved hippocampal function.ConclusionsNeuron-targeted overexpression of Cav-1 in the adult and aged hippocampus enhances functional MLRs with corresponding roles in cell signaling and protein trafficking. The resultant structural alterations in hippocampal neurons in vivo are associated with improvements in hippocampal-dependent learning and memory. Our findings suggest Cav-1 as a novel therapeutic strategy in disorders involving impaired hippocampal function.

BackgroundPost-traumatic stress disorder (PTSD) and pain have a well-documented high comorbidity; however, the underlying mechanisms of this comorbidity are currently poorly understood. The aim of this psychophysical study was to investigate the behavioral response to a prolonged suprathreshold pain stimulus in subjects with combat-related PTSD and combat controls (CC) for clinical evidence of central sensitization.MethodsTen male subjects with current PTSD related to combat and 11 CC male subjects underwent baseline quantitative sensory testing (QST), temporal pain summation, and psychological profiling followed by an intramuscular injection of capsaicin into the quadriceps muscle.ResultsThere was no significant between-group difference for the initial maximal pain response or an initial pain reduction for the first 15 minutes postinjection on QST or pain ratings. However, we observed significantly higher scores in the PTSD group for the second 15 minutes postinjection on both pain intensity and pain unpleasantness ratings. Assessment of temporal summation to repetitive pressure stimuli showed significantly higher subjective pain in the PTSD group.ConclusionThese findings are consistent with a significantly higher degree of acute central sensitization in individuals with PTSD. Increased acute central sensitization may underlie increased vulnerability for developing pain-related conditions following combat trauma.

BackgroundPost-traumatic stress disorder (PTSD) and pain have a well-documented high comorbidity; however, the underlying mechanisms of this comorbidity are currently poorly understood. The aim of this psychophysical study was to investigate the behavioral response to a prolonged suprathreshold pain stimulus in subjects with combat-related PTSD and combat controls (CC) for clinical evidence of central sensitization.MethodsTen male subjects with current PTSD related to combat and 11 CC male subjects underwent baseline quantitative sensory testing (QST), temporal pain summation, and psychological profiling followed by an intramuscular injection of capsaicin into the quadriceps muscle.ResultsThere was no significant between-group difference for the initial maximal pain response or an initial pain reduction for the first 15 minutes postinjection on QST or pain ratings. However, we observed significantly higher scores in the PTSD group for the second 15 minutes postinjection on both pain intensity and pain unpleasantness ratings. Assessment of temporal summation to repetitive pressure stimuli showed significantly higher subjective pain in the PTSD group.ConclusionThese findings are consistent with a significantly higher degree of acute central sensitization in individuals with PTSD. Increased acute central sensitization may underlie increased vulnerability for developing pain-related conditions following combat trauma.

Urocortin-2 (UCn2) peptide infusion increases cardiac function in patients with heart failure, but chronic peptide infusion is cumbersome, costly, and provides only short-term benefits. Gene transfer would circumvent these shortcomings. Here we ask whether a single intravenous injection of adeno-associated virus type 8 encoding murine urocortin-2 (AAV8.UCn2) could provide long-term elevation in plasma UCn2 levels and increased left ventricular (LV) function. Normal mice received AAV8.UCn2 (5×10¹¹ genome copies, intravenous). Plasma UCn2 increased 15-fold 6 weeks and >11-fold 7 months after delivery. AAV8 DNA and UCn2 mRNA expression was persistent in LV and liver up to 7 months after a single intravenous injection of AAV8.UCn2. Physiological studies conducted both in situ and ex vivo showed increases in LV +dP/dt and in LV -dP/dt, findings that endured unchanged for 7 months. SERCA2a mRNA and protein expression was increased in LV samples and Ca²⁺ transient studies showed an increased rate of Ca²⁺ decline in cardiac myocytes from mice that had received UCn2 gene transfer. We conclude that a single intravenous injection of AAV8.UCn2 increases plasma UCn2 and increases LV systolic and diastolic function for at least 7 months. The simplicity of intravenous injection of a long-term expression vector encoding a gene with paracrine activity to increase cardiac function is a potentially attractive strategy in clinical settings. Future studies will determine the usefulness of this approach in the treatment of heart failure.

Urocortin-2 (UCn2) peptide infusion increases cardiac function in patients with heart failure, but chronic peptide infusion is cumbersome, costly, and provides only short-term benefits. Gene transfer would circumvent these shortcomings. Here we ask whether a single intravenous injection of adeno-associated virus type 8 encoding murine urocortin-2 (AAV8.UCn2) could provide long-term elevation in plasma UCn2 levels and increased left ventricular (LV) function. Normal mice received AAV8.UCn2 (5×10¹¹ genome copies, intravenous). Plasma UCn2 increased 15-fold 6 weeks and >11-fold 7 months after delivery. AAV8 DNA and UCn2 mRNA expression was persistent in LV and liver up to 7 months after a single intravenous injection of AAV8.UCn2. Physiological studies conducted both in situ and ex vivo showed increases in LV +dP/dt and in LV -dP/dt, findings that endured unchanged for 7 months. SERCA2a mRNA and protein expression was increased in LV samples and Ca²⁺ transient studies showed an increased rate of Ca²⁺ decline in cardiac myocytes from mice that had received UCn2 gene transfer. We conclude that a single intravenous injection of AAV8.UCn2 increases plasma UCn2 and increases LV systolic and diastolic function for at least 7 months. The simplicity of intravenous injection of a long-term expression vector encoding a gene with paracrine activity to increase cardiac function is a potentially attractive strategy in clinical settings. Future studies will determine the usefulness of this approach in the treatment of heart failure.

Benjamin Beal,1 Tobias Moeller-Bertram,1,2 Jan M Schilling,1 Mark S Wallace11Division of Pain Medicine, Department of Anesthesiology, University of California, 2VA San Diego Healthcare System, San Diego, CA, USAAbstract: Post-herpetic neuralgia is a neuropathic pain syndrome resulting from an insult to the peripheral and central nervous systems caused by the varicella zoster virus. Spontaneous pain may result in the persistent sensation of burning, tingling, or aching and may be associated with thermally or mechanically provoked pain, resulting in hyperalgesia or allodynia. The majority of cases occur in patients over the age of 50 years. Gabapentin is a structural analog of gamma aminobutyric acid that binds to the α2-δ site of voltage-dependent calcium channels and modulates the influx of calcium, with a resulting reduction in excitatory neurotransmitter release. Gabapentin is effective in reducing neuropathic pain due to post-herpetic neuralgia when given at least three times per day, due to its short half-life, resulting in demonstrable fluctuations in plasma levels. Gabapentin has dose-limiting side effects that prevent some patients from achieving therapeutic plasma levels, such as somnolence (27.4%), dizziness (23.9%), and ataxia (7.1%). Gralise™ is a once-daily extended-release formulation of gabapentin that has been developed using AcuForm™ technology. AcuForm is a polymer-based drug delivery system that retains the tablet in the stomach and upper gastrointestinal tract for a sustained period of time. Once-daily dosing has been shown to provide comparable drug exposure with an identical daily dose of the immediate-release formulation when administered three times daily. Participants given Gralise 1800 mg daily had a statistically significant reduction in average daily pain intensity scores compared with placebo, reduced sleep interference due to pain, and a greater percent of participants reporting being much or very