Cannabinoid-mediated modulation of neuropathic pain and microglial accumulation in a model of murine type I diabetic peripheral neuropathic pain

Background

Despite the frequency of diabetes mellitus and its relationship to diabetic peripheral neuropathy (DPN) and neuropathic pain (NeP), our understanding of underlying mechanisms leading to chronic pain in diabetes remains poor. Recent evidence has demonstated a prominent role of microglial cells in neuropathic pain states. One potential therapeutic option gaining clinical acceptance is the cannabinoids, for which cannabinoid receptors (CB) are expressed on neurons and microglia. We studied the accumulation and activation of spinal and thalamic microglia in streptozotocin (STZ)-diabetic CD1 mice and the impact of cannabinoid receptor agonism/antagonism during the development of a chronic NeP state. We provided either intranasal or intraperitoneal cannabinoid agonists/antagonists at multiple doses both at the initiation of diabetes as well as after establishment of diabetes and its related NeP state.

Results

Tactile allodynia and thermal hypersensitivity were observed over 8 months in diabetic mice without intervention. Microglial density increases were seen in the dorsal spinal cord and in thalamic nuclei and were accompanied by elevation of phosphorylated p38 MAPK, a marker of microglial activation. When initiated coincidentally with diabetes, moderate-high doses of intranasal cannabidiol (cannaboid receptor 2 agonist) and intraperitoneal cannabidiol attenuated the development of an NeP state, even after their discontinuation and without modification of the diabetic state. Cannabidiol was also associated with restriction in elevation of microglial density in the dorsal spinal cord and elevation in phosphorylated p38 MAPK. When initiated in an established DPN NeP state, both CB1 and CB2 agonists demonstrated an antinociceptive effect until their discontinuation. There were no pronociceptive effects demonstated for either CB1 or CB2 antagonists.

Conclusions

The prevention of microglial accumulation and activation in the dorsal spinal cord was associated with limited development of a neuropathic pain state. Cannabinoids demonstrated antinociceptive effects in this mouse model of DPN. These results suggest that such interventions may also benefit humans with DPN, and their early introduction may also modify the development of the NeP state.     

Whole cell‐catalyzed transesterification of waste vegetable oil

Enzymatic transesterification of waste cooking oil, comprising fats, oil and grease (FOG), to produce fatty acid methyl esters (FAME) i.e. biodiesel, was investigated using a novel strain of the fungus Aspergillus niger, immobilized as a whole‐cell biocatalyst. Response surface methodology (RSM), with a five‐level‐three‐factor central composite rotatable design, was used to optimize the reaction and analyze the relationship of reaction variables and their coinfluent on the response i.e. FAME yield. Independent variables that affect the transesterification reaction include temperature, feedstock water content and enzyme amount. Using RSM, a second‐order polynomial equation was derived for FAME yield using multiple regression analysis. The second‐order polynomial regression model was highly significant (P<0.001) in predicting the actual relationship between the response and the variables, where a linear relationship was apparent between observed and predicted values (R²=0.9651). In addition, the predicted determination coefficient q² i.e. 0.7723, also proved that the model has a high predictive ability. The validation experiments, under optimized conditions, showed that the predicted value of maximum FAME yield (i.e. 91.3%) was in close agreement with the experimental value (i.e. 91.8%).     

A randomized, rater-blinded, crossover study comparing the clinical efficacy of Ritalin® LA (methylphenidate) treatment in children with attention-deficit hyperactivity disorder under different breakfast conditions over 2 weeks

Several extended-release methylphenidate medications are available for treatment of children with ADHD. Pharmacokinetic investigations suggest that the serum levels of methylphenidate are partially altered when the medication is taken without breakfast. Clinical data comparing different breakfast situations are missing. In this study, different breakfast compositions and their influence on treatment with Ritalin LA are investigated. A total of 150 patients were enrolled in a rater-blinded, randomized crossover trial that compared a minimal breakfast with a standard breakfast in patients under stable treatment with Ritalin LA. Ratings for clinical efficacy were carried out after 1 week by teachers and parents (FBB-ADHS), as well as physicians (CGI). Additionally, a math test was administered to the patients. Of the total patients, 144 finished the trial with a breakfast compliance of 93%. All of the clinical rating scales showed consistently no difference between the two breakfast conditions. Non-inferiority of minimal breakfast versus standard breakfast was shown to be statistically significant (FBB-AHDS(Teacher): 0.97 with minimal breakfast, 1.01 with standard breakfast, P < 0.0001). The clinical efficacy of Ritalin LA is not influenced by breakfast and works independently of food intake.     

Population dynamics of a pathogen: the conundrum of vivax malaria

Building a mathematical model of population dynamics of pathogens within their host involves considerations of factors similar to those in ecology, as pathogens can prey on cells in the host. But within the multicellular host, attacked cell types are integrated with other cellular systems, which in turn intervene in the infection. For example, immune responses attempt to sense and then eliminate or contain pathogens, and homeostatic mechanisms try to compensate for cell loss. This review focuses on modeling applied to malarias, diseases caused by single-cell eukaryote parasites that infect red blood cells, with special concern given to vivax malaria, a disease often thought to be benign (if sometimes incapacitating) because the parasite only attacks a small proportion of red blood cells, the very youngest ones. However, I will use mathematical modeling to argue that depletion of this pool of red blood cells can be disastrous to the host if growth of the parasite is not vigorously check by host immune responses. Also, modeling can elucidate aspects of new field observations that indicate that vivax malaria is more dangerous than previously thought.     

Your worst enemy could be your best friend: predator contributions to invasion resistance and persistence of natives

Native predators are postulated to have an important role in biotic resistance of communities to invasion and community resilience. Effects of predators can be complex, and mechanisms by which predators affect invasion success and impact are understood for only a few well-studied communities. We tested experimentally whether a native predator limits an invasive species’ success and impact on a native competitor for a community of aquatic insect larvae in water-filled containers. The native mosquito Aedes triseriatus alone had no significant effect on abundance of the invasive mosquito Aedes albopictus. The native predatory midge Corethrella appendiculata, at low or high density, significantly reduced A. albopictus abundance. This effect was not caused by trait-mediated oviposition avoidance of containers with predators, but instead was a density-mediated effect caused by predator-induced mortality. The presence of this predator significantly reduced survivorship of the native species, but high predator density also significantly increased development rate of the native species when the invader was present, consistent with predator-mediated release from interspecific competition with the invader. Thus, a native predator can indirectly benefit its native prey when a superior competitor invades. This shows the importance of native predators as a component of biodiversity for both biotic resistance to invasion and resilience of a community perturbed by successful invasion.     

The role of resource dispersion in promoting the co‐occurrence of dominant and subordinate ant species

Dominant competitors govern resource use in many communities, leading to predictions of local exclusion and lower species diversity where dominant species are abundant. However, subordinate and dominant species frequently co‐occur. One mechanism that could facilitate resource sharing and co‐occurrence of dominant and subordinate competitors is fine‐scale resource dispersion. Here, we distributed 6 g of a food resource into 1, 2, 8, 32 or 64 units in small 0.40 m² areas centred on nests of the dominant ant Monomorium sydneyense. We tested three hypotheses. First, we hypothesized that the species richness and abundance of foraging ants would increase with increasing resource dispersion. Accordingly, species richness doubled and total ant abundance was two orders of magnitude higher in high resource dispersion treatments. Secondly, we hypothesized that increasing resource dispersion would reduce competitive interactions such as resource turnover events and lower the probability of food resources being occupied. Substantial support for this hypothesis was observed. Finally, we tested the hypothesis that the foraging time of each species would be proportional to the relative abundance of each species solely in high resource dispersion treatments. Expected and observed foraging times were statistically similar for only the dominant ant M. sydneyense. The subdominant Pheidole rugosula increased its foraging time much more than was expected, while two subordinate ants showed no relationship between observed and expected times. Thus, while increasing resource dispersion significantly increased overall species richness, this increase in co‐occurrence did not correlate with a significant increase in foraging time for the two subordinate species. Rather, changes in resource dispersion appeared to benefit only the subdominant species. Inter‐site variation appeared more important for other subordinate species indetermining co‐occurrence and foraging time. Multiple mechanisms facilitate co‐occurrence and resource sharing in this community, and probably in most other communities.     

Plant genotypic diversity does not beget root-fungal species diversity

The number of genetically distinct individuals within a community is a key component of biodiversity and yet its impact at different trophic levels, especially upon the diversity of functionally important soil microorganisms is poorly understood. Here, we test the hypothesis that plant communities that are genetically impoverished will support fewer species of root-associated fungi. We used established grassland mesocosms comprising non-sterile natural soil supporting defined communities of 11 clonally-propagated plant species. Half of the mesocosms contained one genotype per species and half 16 genotypes per species. After 8 years growth, we sampled roots from the mesocosms and measured root-associated fungal richness and diversity using terminal restriction fragment length polymorphism (T-RFLP). Contrary to our hypothesis, we found that the roots of genetically impoverished communities contained more species of fungi and had greater diversity compared to genetically rich communities. Analysis of the plant species composition of the mesocosm communities indicated that genotypic diversity affects root-fungal diversity indirectly through its influence upon plant species diversity. Our findings highlight the need to include feedbacks with plant intraspecific diversity into existing models describing the maintenance of soil biodiversity.     

Stem cell fate in proliferating tissues: equal odds in a game of chance

Quantitative lineage tracing reveals stem cell fate in?vivo. A new study in a recent issue of Cell shows intestinal crypt stem cells are functionally equivalent, with equal odds of differentiation. Differentiating stem cells are replaced by the symmetric division of adjacent stem cells.