Turning Over a New Leaf: Cannabinoid and Endocannabinoid Modulation of Immune Function

Cannabis is a complex substance that harbors terpenoid-like compounds referred to as phytocannabinoids. The major psychoactive phytocannabinoid found in cannabis ∆9-tetrahydrocannabinol (THC) produces the majority of its pharmacological effects through two cannabinoid receptors, termed CB1 and CB2. The discovery of these receptors as linked functionally to distinct biological effects of THC, and the subsequent development of synthetic cannabinoids, precipitated discovery of the endogenous cannabinoid (or endocannabinoid) system. This system consists of the endogenous lipid ligands N- arachidonoylethanolamine (anandamide; AEA) and 2-arachidonylglycerol (2-AG), their biosynthetic and degradative enzymes, and the CB1 and CB2 receptors that they activate. Endocannabinoids have been identified in immune cells such as monocytes, macrophages, basophils, lymphocytes, and dendritic cells and are believed to be enzymatically produced and released “on demand” in a similar fashion as the eicosanoids. It is now recognized that other phytocannabinoids such as cannabidiol (CBD) and cannabinol (CBN) can alter the functional activities of the immune system. This special edition of the Journal of Neuroimmune Pharmacology (JNIP) presents a collection of cutting edge original research and review articles on the medical implications of phytocannabinoids and the endocannabinoid system. The goal of this special edition is to provide an unbiased assessment of the state of research related to this topic from leading researchers in the field. The potential untoward effects as well as beneficial uses of marijuana, its phytocannabinoid composition, and synthesized cannabinoid analogs are discussed. In addition, the role of the endocannabinoid system and approaches to its manipulation to treat select human disease processes are addressed

Segment and track neurons in 3D by repulsive snake method

We present a snake (active contour) model based on repulsive force to segment neurons obtained from microscopy. Based on these segmentation results, we track the neurons in 3D image to look for its branch structure. These segmentation results allow user to study morphology of neurons to further investigate neuronal function and connectivity. This repulsive snake model can successfully segment two or multiple neurons that are close to each other by some alternating repulsive force generated from the neighboring objects. We apply our results on real data to demonstrate the performance of our method. © 2005 IEEE.published_or_final_versio

Cannabinoids Occlude the HIV-1 Tat-Induced Decrease in GABAergic Neurotransmission in Prefrontal Cortex Slices

In the era of combined antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV-1) is now considered a chronic disease that specifically targets the brain and causes HIV-1-associated neurocognitive disorders (HAND). Endocannabinoids exhibit neuroprotective and anti-inflammatory properties in several central nervous system (CNS) disease models, but their effects in HAND are poorly understood. To address this issue, whole-cell recordings were performed on young (14 – 21 day old) C57BL/6J mice. We investigated the actions of the synthetic cannabinoid WIN55,212-2 (1 μM) and the endocannabinoid N-arachidonoyl ethanolamine (anandamide; AEA, 1 μM) in the presence of HIV-1 Tat on GABAergic neurotransmission in mouse prefrontal cortex (PFC) slices. We found a Tat concentration dependent (5 – 50 nM) decrease in the frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs). The cannabinoid 1 receptor (CB1R) antagonist rimonabant (1 μM) and zero extracellular calcium prevented the significant Tat-induced decrease in mIPSCs. Further, bath-applied WIN55,212-2 or AEA by itself, significantly decreased the frequency, but not amplitude of mIPSCs and/or spontaneous IPSCs (sIPSCs), and occluded a further down-regulation of IPSCs by Tat. Pretreatment with rimonabant but not the CB2R antagonist AM630 (1 μM) prevented the WIN55,212-2- and AEA-induced decrease in IPSCs frequency without any further Tat effect. Results indicated a Tat-induced decrease in GABAergic neurotransmission, which was occluded by cannabinoids via a CB1R-related mechanism. Understanding the relationship between Tat toxicity and endocannabinoid signaling has the potential to identify novel therapeutic interventions to benefit individuals suffering from HAND and other cognitive impairments

Age Differences in the Association of Obstructive Sleep Apnea Risk with Cognition and Quality of Life

Using a sample of 2925 stroke-free participants drawn from a national population-based study, we examined cross-sectional associations of obstructive sleep apnea risk (OSA) with cognition and quality of life and whether these vary with age, while controlling for demographics and co-morbidities. Included participants from the REasons for Geographic And Racial Differences in Stroke Study were aged 47-93. OSA risk was categorized as high or low based on responses to the Berlin Sleep Questionnaire. Cognitive function was assessed with standardized fluency and recall measures. Depressive symptoms were assessed with the four-item Center for Epidemiologic Studies Depression Scale. Health-related Quality of Life (HRQoL) was assessed with the Medical Outcomes Study Short Form-12 (SF-12). MANCOVA statistics were applied separately to the cognitive and quality of life dependent variables while accounting for potential confounders (demographics, co-morbidities). In fully adjusted models, those at high risk for OSA had significantly lower cognitive scores (Wilks’ Lambda = 0.996, F(3, 2786) = 3.31, p < .05) and lower quality of life (depressive symptoms and HRQoL) (Wilks’ Lambda = 0.989, F(3, 2786) = 10.02, p < .0001). However, some of the associations were age-dependent. Differences in cognition and quality of life between those at high and low obstructive sleep apnea risk were most pronounced during middle age, with attenuated effects after age 70

Interactions between sediment microbial ecology and physical dynamics drive heterogeneity in contextually similar depositional systems

This study focuses on the interactions between sediment stability and biological and physical variables that influence the erodibility across different habitats. Sampling at short‐term temporal scales illustrated the persistence of the microphytobenthos (MPB) biomass even during periods of frequent, high physical disturbance. The role of MPB in biological stabilization along the changing sedimentary habitat was also assessed. Key biological and physical properties, such as the MPB biomass, composition, and extracellular polymeric substances, were used to predict the sediment stability (erosion threshold) of muddy and sandy habitats within close proximity to one another over multiple days, and within emersion periods. The effects of dewatering, MPB growth, and productivity were examined as well as the resilience and recovery of the MPB community after disturbance from tidal currents and waves. Canonical analysis of principal components (CAP) ordinations were used to visualize and assess the trends observed in biophysical properties between the sites, and marginal and sequential distance‐based linear models were used to identify the key properties influencing erodibility. While the particle size of the bed was important for differences between sites in the CAP analysis, it contributed less to the variability in sediment erodibility than key biological parameters. Among the biological predictors, MPB diversity explained very little variation in marginal tests but was a significant predictor in sequential tests when MPB biomass was also considered. MPB diversity and biomass were both key predictors of sediment stability, contributing 9% and 10%, respectively, to the final model compared to 2% explained by grain size

Degradation of endogenous bacterial cell wall polymers by the muralytic enzyme mutanolysin prevents hepatobiliary injury in genetically susceptible rats with experimental intestinal bacterial overgrowth.

Jejunal self-filling blind loops with subsequent small bowel bacterial overgrowth (SBBO) induce hepatobiliary injury in genetically susceptible Lewis rats. Lesions consist of portal tract inflammation, bile duct proliferation, and destruction. To determine the pathogenesis of SBBO-induced hepatobiliary injury, we treated Lewis rats with SBBO by using several agents with different mechanisms of activity. Buffer treatment, ursodeoxycholic acid, prednisone, methotrexate, and cyclosporin A failed to prevent SBBO-induced injury as demonstrated by increased plasma aspartate aminotransferase (AST) and elevated histology scores. However, hepatic injury was prevented by mutanolysin, a muralytic enzyme whose only known activity is to split the beta 1-4 N-acetylmuramyl-N-acetylglucosamine linkage of peptidoglycan-polysaccharide (PG-PS), a bacterial cell wall polymer with potent inflammatory and immunoregulatory properties. Mutanolysin therapy started on the day blind loops were surgically created and continued for 8 wk significantly diminished AST (101 +/- 37 U/liter) and liver histology scores (2.2 +/- 2.7) compared to buffer-treated rats (228 +/- 146 U/liter, P < 0.05, 8.2 +/- 1.9, P < 0.001 respectively). Mutanolysin treatment started during the early phase of hepatic injury, 16-21 d after surgery, decreased AST in 7 of 11 rats from 142 +/- 80 to 103 +/- 24 U/liter contrasted to increased AST in 9 of 11 buffer-treated rats from 108 +/- 52 to 247 +/- 142 U/liter, P < 0.05. Mutanolysin did not change total bacterial numbers within the loop, eliminate Bacteroides sp., have in vitro antibiotic effects, or diminish mucosal PG-PS transport. However, mutanolysin treatment prevented elevation of plasma anti-PG antibodies and tumor necrosis factor-alpha (TNF alpha) levels which occurred in buffer treated rats with SBBO and decreased TNF alpha production in isolated Kupffer cells stimulated in vitro with PG-PS. Based on the preventive and therapeutic activity of this highly specific muralytic enzyme, we conclude that systemic uptake of PG-PS derived from endogenous enteric bacteria contributes to hepatobiliary injury induced by SBBO in susceptible rat strains

Pervasive Synaptic Branch Removal in the Mammalian Neuromuscular System at Birth

SummaryUsing light and serial electron microscopy, we show profound refinements in motor axonal branching and synaptic connectivity before and after birth. Embryonic axons become maximally connected just before birth when they innervate ∼10-fold more muscle fibers than in maturity. In some developing muscles, axons innervate almost every muscle fiber. At birth, each neuromuscular junction is coinnervated by approximately ten highly intermingled axons (versus one in adults). Extensive die off of terminal branches occurs during the first several postnatal days, leading to much sparser arbors that still span the same territory. Despite the extensive pruning, total axoplasm per neuron increases as axons elongate, thicken, and add more synaptic release sites on their remaining targets. Motor axons therefore initially establish weak connections with nearly all available postsynaptic targets but, beginning at birth, massively redistribute synaptic resources, concentrating many more synaptic sites on many fewer muscle fibers. Analogous changes in connectivity may occur in the CNS.Video Abstrac

Effect of low perceived social support on health outcomes in young patients with acute myocardial infarction: results from the VIRGO (variation in recovery: role of gender on outcomes of young AMI patients) study

Background: Social support is an important predictor of health outcomes after acute myocardial infarction (AMI), but social support varies by sex and age. Differences in social support could account for sex differences in outcomes of young patients with AMI. Methods and Results: Data from the Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients (VIRGO) study, an observational study of AMI patients aged ≤55 years in the United States and Spain, were used for this study. Patients were categorized as having low versus moderate/high perceived social support using the ENRICHD Social Support Inventory. Outcomes included health status (Short Form-12 physical and mental component scores), depressive symptoms (Patient Health Questionnaire), and angina-related quality of life (Seattle Angina Questionnaire) evaluated at baseline and 12 months. Among 3432 patients, 21.2% were classified as having low social support. Men and women had comparable levels of social support at baseline. On average, patients with low social support reported lower functional status and quality of life and more depressive symptoms at baseline and 12 months post-AMI. After multivariable adjustment, including baseline health status, low social support was associated with lower mental functioning, lower quality of life, and more depressive symptoms at 12 months (all P<0.001). The relationship between low social support and worse physical functioning was nonsignificant after adjustment (P=0.6). No interactions were observed between social support, sex, or country. Conclusion: Lower social support is associated with worse health status and more depressive symptoms 12 months after AMI in both young men and women. Sex did not modify the effect of social support.Emily M. Bucholz, Kelly M. Strait, Rachel P. Dreyer, Mary Geda, Erica S. Spatz, Hector Bueno, Judith H. Lichtman, Gail D'Onofrio, John A. Spertus, Harlan M. Krumhol