Complement in the homeostatic and ischemic brain

The complement system is a component of the immune system involved in both recognition and response to pathogens, and it is implicated in an increasing number of homeostatic and disease processes. It is well documented that reperfusion of ischemic tissue results in complement activation and an inflammatory response that causes post-reperfusion injury. This occurs following cerebral ischemia and reperfusion and triggers secondary damage that extends beyond the initial infarcted area, an outcome that has rationalized the use of complement inhibitors as candidate therapeutics after stroke. In the central nervous system, however, recent studies have revealed that complement also has essential roles in synaptic pruning, neurogenesis, and neuronal migration. In the context of recovery after stroke, these apparent divergent functions of complement may account for findings that the protective effect of complement inhibition in the acute phase after stroke is not always maintained in the subacute and chronic phases. The development of effective stroke therapies based on modulation of the complement system will require a detailed understanding of complement-dependent processes in both early neurodegenerative events and delayed neuro-reparatory processes. Here, we review the role of complement in normal brain physiology, the events initiating complement activation after cerebral ischemia-reperfusion injury, and the contribution of complement to both injury and recovery. We also discuss how the design of future experiments may better characterize the dual role of complement in recovery after ischemic stroke

Reperfusion injury following cerebral ischemia: pathophysiology, MR imaging, and potential therapies

INTRODUCTION: Restoration of blood flow following ischemic stroke can be achieved by means of thrombolysis or mechanical recanalization. However, for some patients, reperfusion may exacerbate the injury initially caused by ischemia, producing a so-called “cerebral reperfusion injury”. Multiple pathological processes are involved in this injury, including leukocyte infiltration, platelet and complement activation, postischemic hyperperfusion, and breakdown of the blood–brain barrier. METHODS/RESULTS AND CONCLUSIONS: Magnetic resonance imaging (MRI) can provide extensive information on this process of injury, and may have a role in the future in stratifying patients’ risk for reperfusion injury following recanalization. Moreover, different MRI modalities can be used to investigate the various mechanisms of reperfusion injury. Antileukocyte antibodies, brain cooling and conditioned blood reperfusion are potential therapeutic strategies for lessening or eliminating reperfusion injury, and interventionalists may play a role in the future in using some of these therapies in combination with thrombolysis or embolectomy. The present review summarizes the mechanisms of reperfusion injury and focuses on the way each of those mechanisms can be evaluated by different MRI modalities. The potential therapeutic strategies are also discussed

Imaging of activated complement using ultrasmall superparamagnetic iron oxide particles (USPIO) - conjugated vectors: an in vivo in utero non-invasive method to predict placental insufficiency and abnormal fetal brain development.

In the current study, we have developed a magnetic resonance imaging-based method for non-invasive detection ofcomplement activation in placenta and foetal brain in vivo in utero. Using this method, we found that anti-complementC3-targeted ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles bind within the inflamed placenta and foetal braincortical tissue, causing a shortening of the T2* relaxation time. We used two mouse models of pregnancy complications: a mousemodel of obstetrics antiphospholipid syndrome (APS) and a mouse model of preterm birth (PTB). We found that detection of C3deposition in the placenta in the APS model was associated with placental insufficiency characterised by increased oxidative stress,decreased vascular endothelial growth factor and placental growth factor levels and intrauterine growth restriction. We alsofound that foetal brain C3 deposition was associated with cortical axonal cytoarchitecture disruption and increasedneurodegeneration in the mouse model of APS and in the PTB model. In the APS model, foetuses that showed increased C3in their brains additionally expressed anxiety-related behaviour after birth. Importantly, USPIO did not affect pregnancyoutcomes and liver function in the mother and the offspring, suggesting that this method may be useful for detecting complementactivation in vivo in utero and predicting placental insufficiency and abnormal foetal neurodevelopment that leads toneuropsychiatric disorders

A Computational Model of Vortex Ring Formation in Hydrogels

Duo An, a PhD student at Cornell University, is developing a method that uses electrospray technique to expel clay hydrogel droplets into an ion solution. Upon contact, the droplets crosslink and form various solid geometries, including spheres and toroids. Depending on a few factors, including composition of the hydrogel, volume, viscosity, and speed of falling, the hydrogel will form a variety shapes. Toroidal shapes have many applications because they have a greater surface area to volume ratio than spheres. Therefore, clay hydrogels in the shape of a torus have a greater diffusive capacity than spherically shaped hydrogel formations. This allows for greater mass transfer and thus more efficient drug treatment therapies. The current problem is that the specific conditions that cause micro-toroid formation are not well understood. The majority of An’s data has used a larger scale droplet size diameter. This project aimed to elucidate the formation of a toroid shape by creating a COMSOL® simulation that can model the fluid flow and physics on a smaller scale. A pseudo three-phase model was designed to represent the three parts: the droplet of hydrogel, the air, and the ion solution. However, the model had to be implemented as a two-phase problem, due to the three-phase restraints in COMSOL. This was accomplished by implementing the solution and hydrogel as a single phase by defining an initial ion concentration for both the hydrogel and water bath. Additionally, the particle-tracing feature was used in COMSOL to help track the hydrogel species during the simulation. A larger scale model with a diameter of 3.0 mm was first developed to demonstrate toroid formation on a larger scale. Performing a sensitivity analysis on particle number, density, diameter and initial velocity showed that initial velocity had the largest impact on formation of the final product. This reflects An’s findings that varying initial velocities of the hydrogel droplet leads to different spreading and shape formation. In order to further evaluate the model, simulations with different initial velocities were run and their shape formations were qualitatively compared to images and descriptions from An's data. Success in obtaining vortex formation at the large scale indicated that a smaller scale model could be useful in predicting and understanding micro-toroid formation of these hydrogels. Next, the model was scaled down to a 500 μm diameter droplet and the results were compared to the larger droplet. When compared, the small model had similar vorticity trends to the large model at a faster rate. In order to compare the model’s results to An’s, the Reynolds and Weber numbers were calculated and final shape formation images were compared with experimental images for models that matched these numbers. Two of the models showed a similar mushroom shape formation to experimental data. The use of COMSOL to create a scaled down model of An's work helps to provide a better understanding of the underlying physics behind toroid formation of these clay hydrogels. This understanding will lead to better control of the process, in order to produce hydrogels of desired geometries and dimensions, which could give promise for production in future biomedical applications

Dental caries experience in high risk soft drinks factory workers of South India: A comparative study

Background: The consumption of soft-drinks has been associated with dental caries development. Objective: The aim was to evaluate dental caries experience amongst the workers working in soft-drink industries located in South India and compare it with other factory workers. To evaluate the validity of specific caries index (SCI), which is newer index for caries diagnosis. Materials and Methods: This was a cross-sectional study carried out among 420 workers (210 in soft-drinks factory and 210 in other factories), in the age group of 20-45 years of Udupi district, Karnataka, India. Index used for clinical examination was decayed, missing, filled surfaces (DMFS) index and SCI. Results: The mean and standard deviation (SD) of decayed surface (5.8 ± 1.8), missing surface (4.3 ± 2) and filled surface (1.94 ± 1.95) and total DMFS score (12.11 ± 3.8) in soft-drinks factory workers were found to be significantly higher than the other factory workers. The total SCI score (mean and SD) was found to be significantly higher in soft-drinks factory workers (5.83 ± 1.80) compared with other factory workers (4.56 ± 1.45). There was a high correlation obtained between SCI score and DMFS score. The regression equation given by DMFS = 1.178 + 1.866 (SCI scores). Conclusion: The caries experience was higher in workers working in soft-drinks factory and this study also showed that specific caries index can be used as a valid index for assessing dental caries experience

The impact of lifestyles on the periodontal health of adults in Udupi district: A cross sectional study

Objectives: (1) To assess the impact of different lifestyle factors on periodontal health of adults. (2) To assess the impact of overall/combined lifestyle variable (calculated by health practice index [HPI]) on periodontal health of adults. Materials and Methods: A cross-sectional study consisting of a structured questionnaire on HPI, oral health-related behavior, and personal habits as well as sociodemographic variables was conducted on 800 subjects aged 20–50 years attending dental outreach set-ups of Manipal College of Dental Sciences, Manipal. Clinical examination for periodontal status was done by recording loss of attachment scores using community periodontal index (FDI/WHO-1982). Statistical analysis was done by bivariate analysis using Chi-square followed by multivariate analysis to obtain adjusted odds ratio with 95% confidence interval. Results: After adjusting for all the confounding variables in multivariate logistic regression analysis, the variables that showed an independent association with periodontitis were age, location, marital status, smoking, hours of sleep per night, physical activity, and overall poor lifestyles. Conclusion: Our results support studying a combined approach using various lifestyle behaviors for controlling chronic periodontitis. Necessary public health action on conditions which determine unhealthy lifestyle behaviors across population is needed which is possible by patient's involvement in self-care by promoting healthy lifestyles