Involvement of the endocannabinoid system in the physiological response to transient common carotid artery occlusion and reperfusion

Background: The transient global cerebral hypoperfusion/reperfusion achieved by induction of Bilateral Common Carotid Artery Occlusion followed by Reperfusion (BCCAO/R) may trigger a physiological response in an attempt to preserve tissue and function integrity. There are several candidate molecules among which the endocannabinoid system (ECS) and/or peroxisome-proliferator activated receptor-alpha (PPAR-alpha) may play a role in modulating oxidative stress and inflammation. The aims of the present study are to evaluate whether the ECS, the enzyme cyclooxygenase-2 (COX-2) and PPAR-alpha are involved during BCCAO/R in rat brain, and to identify possible markers of the ongoing BCCAO/R-induced challenge in plasma. Methods: Adult Wistar rats underwent BCCAO/R with 30 min hypoperfusion followed by 60 min reperfusion. The frontal and temporal-occipital cortices and plasma were analyzed by high performance liquid chromatography-mass spectrometry (HPLC-MS) to determine concentrations of endocannabinoids (eCBs) and related molecules behaving as ligands of PPAR-alpha, and of oxidative-stress markers such as lipoperoxides, while Western Blot and immunohistochemistry were used to study protein expression of cannabinoid receptors, COX-2 and PPAR-alpha. Unpaired Student's t-test was used to evaluate statistical differences between groups. Results: The acute BCCAO/R procedure is followed by increased brain tissue levels of the eCBs 2-arachidonoylglycerol and anandamide, palmitoylethanolamide, an avid ligand of PPAR-alpha, lipoperoxides, type 1 (CB1) and type 2 (CB2) cannabinoid receptors, and COX-2, and decreased brain tissue concentrations of docosahexaenoic acid (DHA), one of the major targets of lipid peroxidation. In plasma, increased levels of anandamide and lipoperoxides were observed. Conclusions: The BCCAO/R stimulated early molecular changes that can be easily traced in brain tissue and plasma, and that are indicative of the tissue physiological response to the reperfusion-induced oxidative stress and inflammation. The observed variations suggest that the positive modulation of the ECS and the increase of proinflammatory substances are directly correlated events. Increase of plasmatic levels of anandamide and lipoperoxides further suggests that dysregulation of these molecules may be taken as an indicator of an ongoing hypoperfusion/reperfusion challenge

KCNK3 mutation causes altered immune function in pulmonary arterial hypertension patients and mouse models

Loss of function KCNK3 mutation is one of the gene variants driving hereditary pulmonary arterial hypertension (PAH). KCNK3 is expressed in several cell and tissue types on both membrane and endoplasmic reticulum and potentially plays a role in multiple pathological process associated with PAH. However, the role of various stressors driving the susceptibility of KCNK3 mutation to PAH is unknown. Hence, we expose

pretreatment with the monoacylglycerol lipase inhibitor urb602 protects from the long term consequences of neonatal hypoxic ischemic brain injury in rats

Pretreatment with the monoacylglycerol lipase inhibitor URB602 protects from the long-term consequences of neonatal hypoxic–ischemic brain injury in rat

Clinical implications of a possible role of vitamin D in multiple sclerosis

Hypovitaminosis D is currently one of the most studied environmental risk factors for multiple sclerosis (MS) and is potentially the most promising in terms of new clinical implications. These practical consequences, which could be applied to MS patients without further delay, constitute the main purpose of this review. Vitamin D is involved in a number of important general actions, which were not even suspected until quite recently. In particular, this vitamin could play an immunomodulatory role in the central nervous system. Many and varied arguments support a significant role for vitamin D in MS. In animal studies, vitamin D prevents and improves experimental autoimmune encephalomyelitis. Epidemiologically, latitude, past exposure to sun and the serum level of vitamin D influence the risk of MS, with, furthermore, significant links existing between these different factors. Clinically, most MS patients have low serum levels of vitamin D and are in a state of insufficiency or even deficiency compared to the international norm, which has been established on a metabolic basis. Large therapeutic trials using vitamin D are still lacking but the first results of phase I/II studies are promising. In the meantime, while awaiting the results of future therapeutic trials, it can no longer be ignored that many MS patients have a lack of vitamin D, which could be detected by a serum titration and corrected using an appropriate vitamin D supplementation in order to restore their serum level to within the normal range. From a purely medical point of view, vitamin D supplementation appears in this light to be unavoidable in order to improve the general state of these patients. Furthermore, it cannot currently be ruled out that this supplementation could also be neurologically beneficial

Effects of CB1 cannabinoid receptor activation on cerebellar granule cell nitric oxide synthase activity

AbstractCerebellar granule cells (CGCs) express the CB1 subtype of cannabinoid receptor. CB1 receptor agonists Win 55212-2, CP55940 and HU210 inhibit KCl-induced activation of nitric oxide synthase (NOS) in CGCs. Win 55212-2 has no effect on either basal NOS activity or on activation by N-methyl-D-aspartate and its effect is abolished by pre-treatment of the cells with pertussis toxin. The CB1 receptor antagonist/inverse agonist SR141716A both reverses the effects of Win 55212-2 and produces an increase in NOS activity that is additive with KCl. These results support the hypothesis that activation of the CB1 receptor in CGCs results in a decreased influx of calcium in response to membrane depolarization, resulting in a decreased activation of neuronal NOS

Gross morphological study of the renal pelvicalyceal patterns in human cadaveric kidneys

Introduction: The knowledge of detailed calyceal anatomy is essential for performing urologic procedures such as percutaneous nephrolithotomy, percutaneous nephrostomy, flexible ureterorenoscopy, endopyelotomy, and retrograde renal surgery. This study was performed to analyze the various patterns of pelvicalyceal system in the South Indian population, and compare these with previously published studies in different populations. Methods: The study was conducted in 100 kidney specimens. Morphologically undamaged kidneys belonging to both sexes were removed en bloc from cadavers and autopsy cases of the Departments of Anatomy and Forensic Medicine, respectively. The specimens were carefully dissected, and the percentage of various patterns was compared with previous studies. Results: The renal pelvis was found to be intrarenal in 79% of the specimens. The most common type of anatomy was a bicalyceal system with two major calyces, one each from the upper and lower poles, with the middle zone drainage dependent on any one or both of them. An interesting and rare variation of extrarenal calyces with the absence of renal pelvis was observed in 1% of the specimens. In addition, the presence of minor calyces opening directly into the renal pelvis was seen in 8% of the specimens. Conclusion: A biclayceal system of drainage with intrarenal pelvis is the most common calyceal pattern in the kidneys. The patterns must be borne in mind while examining a radiological report involving the kidneys

Visualization of Endocannabinoids in the Cell

A still unsolved, although critical, issue in endocannabinoid research is the mechanism by which the lipophilic compound anandamide (AEA) moves from its site of synthesis, crosses the aqueous milieu, and reaches the different intracellular compartments, where its metabolic and signaling pathways take place. The difficulty of studying intracellular AEA transport and distribution results from the lack of specific probes and techniques to track and visualize this bioactive lipid within the cell. Here, we describe the use of a biotinylated, non-hydrolyzable derivative of AEA (biotin-AEA, b-AEA) for visualizing the subcellular distribution of this endocannabinoid by means of confocal fluorescence microscopy

INSTalytics

We present the design, implementation, and evaluation of INSTalytics , a co-designed stack of a cluster file system and the compute layer, for efficient big-data analytics in large-scale data centers. INSTalytics amplifies the well-known benefits of data partitioning in analytics systems; instead of traditional partitioning on one dimension, INSTalytics enables data to be simultaneously partitioned on four different dimensions at the same storage cost, enabling a larger fraction of queries to benefit from partition filtering and joins without network shuffle. To achieve this, INSTalytics uses compute-awareness to customize the three-way replication that the cluster file system employs for availability. A new heterogeneous replication layout enables INSTalytics to preserve the same recovery cost and availability as traditional replication. INSTalytics also uses compute-awareness to expose a new sliced-read API that improves performance of joins by enabling multiple compute nodes to read slices of a data block efficiently via co-ordinated request scheduling and selective caching at the storage nodes. We have built a prototype implementation of INSTalytics in a production analytics stack, and we show that recovery performance and availability is similar to physical replication, while providing significant improvements in query performance, suggesting a new approach to designing cloud-scale big-data analytics systems. </jats:p