Application of machine learning to automated analysis of cerebral edema in large cohorts of ischemic stroke patients

Cerebral edema contributes to neurological deterioration and death after hemispheric stroke but there remains no effective means of preventing or accurately predicting its occurrence. Big data approaches may provide insights into the biologic variability and genetic contributions to severity and time course of cerebral edema. These methods require quantitative analyses of edema severity across large cohorts of stroke patients. We have proposed that changes in cerebrospinal fluid (CSF) volume over time may represent a sensitive and dynamic marker of edema progression that can be measured from routinely available CT scans. To facilitate and scale up such approaches we have created a machine learning algorithm capable of segmenting and measuring CSF volume from serial CT scans of stroke patients. We now present results of our preliminary processing pipeline that was able to efficiently extract CSF volumetrics from an initial cohort of 155 subjects enrolled in a prospective longitudinal stroke study. We demonstrate a high degree of reproducibility in total cranial volume registration between scans (R = 0.982) as well as a strong correlation of baseline CSF volume and patient age (as a surrogate of brain atrophy, R = 0.725). Reduction in CSF volume from baseline to final CT was correlated with infarct volume (R = 0.715) and degree of midline shift (quadratic model, p < 2.2 × 10−16). We utilized generalized estimating equations (GEE) to model CSF volumes over time (using linear and quadratic terms), adjusting for age. This model demonstrated that CSF volume decreases over time (p < 2.2 × 10−13) and is lower in those with cerebral edema (p = 0.0004). We are now fully automating this pipeline to allow rapid analysis of even larger cohorts of stroke patients from multiple sites using an XNAT (eXtensible Neuroimaging Archive Toolkit) platform. Data on kinetics of edema across thousands of patients will facilitate precision approaches to prediction of malignant edema as well as modeling of variability and further understanding of genetic variants that influence edema severity

International Stroke Genetics Consortium recommendations for studies of genetics of stroke outcome and recovery

Numerous biological mechanisms contribute to outcome after stroke, including brain injury, inflammation, and repair mechanisms. Clinical genetic studies have the potential to discover biological mechanisms affecting stroke recovery in humans and identify intervention targets. Large sample sizes are needed to detect commonly occurring genetic variations related to stroke brain injury and recovery. However, this usually requires combining data from multiple studies where consistent terminology, methodology, and data collection timelines are essential. Our group of expert stroke and rehabilitation clinicians and researchers with knowledge in genetics of stroke recovery here present recommendations for harmonizing phenotype data with focus on measures suitable for multicenter genetic studies of ischemic stroke brain injury and recovery. Our recommendations have been endorsed by the International Stroke Genetics Consortium

Indole and 3-indolylacetonitrile inhibit spore maturation in Paenibacillus alvei

<p>Abstract</p> <p>Background</p> <p>Bacteria use diverse signaling molecules to ensure the survival of the species in environmental niches. A variety of both Gram-positive and Gram-negative bacteria produce large quantities of indole that functions as an intercellular signal controlling diverse aspects of bacterial physiology.</p> <p>Results</p> <p>In this study, we sought a novel role of indole in a Gram-positive bacteria <it>Paenibacillus alvei </it>that can produce extracellular indole at a concentration of up to 300 μM in the stationary phase in Luria-Bertani medium. Unlike previous studies, our data show that the production of indole in <it>P. alvei </it>is strictly controlled by catabolite repression since the addition of glucose and glycerol completely turns off the indole production. The addition of exogenous indole markedly inhibits the heat resistance of <it>P. alvei </it>without affecting cell growth. Observation of cell morphology with electron microscopy shows that indole inhibits the development of spore coats and cortex in <it>P. alvei</it>. As a result of the immature spore formation of <it>P. alvei</it>, indole also decreases <it>P. alvei </it>survival when exposed to antibiotics, low pH, and ethanol. Additionally, indole derivatives also influence the heat resistance; for example, a plant auxin, 3-indolylacetonitrile dramatically (2900-fold) decreased the heat resistance of <it>P. alvei</it>, while another auxin 3-indoleacetic acid had a less significant influence on the heat resistance of <it>P. alvei</it>.</p> <p>Conclusions</p> <p>Together, our results demonstrate that indole and plant auxin 3-indolylacetonitrile inhibit spore maturation of <it>P. alvei </it>and that 3-indolylacetonitrile presents an opportunity for the control of heat and antimicrobial resistant spores of Gram-positive bacteria.</p

Enzyme Attached on Polymeric Micelles as a Nanoscale Reactor

Similar to what lipase does, a surface-active enzyme was developed by attaching peroxidase on combshaped polymaleic anhydride-alt-1-tetradecene (PMA-TD) in a microemulsion system composed of n-butyl acetate and buffer solution, and its catalytic characteristics of polyphenol synthesis were investigated in an aqueous solution. The modified peroxidase with PMA-TD tended to form self-assembled aggregates like micelles in the aqueous solution and could be concentrated at solvent/water interfaces without unfolding of the enzyme. The efficiency of conversion of 2,4-dichlorophenol to phenolic oligomers was approximately 2-fold improved with the modified peroxidase compared to native peroxidase. The K m and V max values for the modified peroxidase were 1.5-fold lower and 2-fold higher, respectively. The hydrodynamic diameter of the micelle on the modified peroxidase increased with the reaction time, indicating that phenolic products were accumulated in the hydrophobic interior of micelles. In addition, the molecular weight (MW) of phenolic polymers was much larger in the system with the modified peroxidase. These observations implied that the modified peroxidase with hydrophobic side chains formed micellar structures by solubilization of phenolic products and further polymerization reaction could occur in the hydrophobic interior of the micelles

Enzyme Attached on Polymeric Micelles as a Nanoscale Reactor

Similar to what lipase does, a surface-active enzyme was developed by attaching peroxidase on combshaped polymaleic anhydride-alt-1-tetradecene (PMA-TD) in a microemulsion system composed of n-butyl acetate and buffer solution, and its catalytic characteristics of polyphenol synthesis were investigated in an aqueous solution. The modified peroxidase with PMA-TD tended to form self-assembled aggregates like micelles in the aqueous solution and could be concentrated at solvent/water interfaces without unfolding of the enzyme. The efficiency of conversion of 2,4-dichlorophenol to phenolic oligomers was approximately 2-fold improved with the modified peroxidase compared to native peroxidase. The K m and V max values for the modified peroxidase were 1.5-fold lower and 2-fold higher, respectively. The hydrodynamic diameter of the micelle on the modified peroxidase increased with the reaction time, indicating that phenolic products were accumulated in the hydrophobic interior of micelles. In addition, the molecular weight (MW) of phenolic polymers was much larger in the system with the modified peroxidase. These observations implied that the modified peroxidase with hydrophobic side chains formed micellar structures by solubilization of phenolic products and further polymerization reaction could occur in the hydrophobic interior of the micelles

Optical-resolution photoacoustic microscopy of amyloid-β deposits in vivo

Advances in high-resolution imaging have permitted microscopic observations within the brains of living animals. Applied to Alzheimer's disease (AD) mouse models, multiphoton microscopy has opened a new window to study the real-time appearance and growth of amyloid plaques. Here, we report an alternative technology-optical-resolution photoacoustic microscopy (OR-PAM)-for in vivo imaging of amyloid plaques in a transgenic AD mouse model. In vivo validation using multiphoton microscopy shows that OR-PAM has sufficient sensitivity and spatial resolution to identify amyloid plaques in living brains. In addition, with dual-wavelength OR-PAM, the three-dimensional morphology of amyloid plaques and the surrounding microvasculature are imaged simultaneously through a cranial window. In vivo transcranial OR-PAM imaging of amyloid plaques is highly likely once the imaging parameters are optimized

Dichroism optical-resolution photoacoustic microscopy

We have developed dichroism optical-resolution photoacoustic microscopy, capable of imaging polarization-dependent optical absorption (i.e., dichroism) with excellent specificity. This technical innovation enriches molecular photoacoustic contrasts and holds particular potential for detecting amyloid-associated neurodegenerative and cardiovascular diseases

Mechanisms of Cross-protection by Influenza Virus M2-based Vaccines

Current influenza virus vaccines are based on strain-specific surface glycoprotein hemagglutinin (HA) antigens and effective only when the predicted vaccine strains and circulating viruses are well-matched. The current strategy of influenza vaccination does not prevent the pandemic outbreaks and protection efficacy is reduced or ineffective if mutant strains emerge. It is of high priority to develop effective vaccines and vaccination strategies conferring a broad range of cross protection. The extracellular domain of M2 (M2e) is highly conserved among human influenza A viruses and has been utilized to develop new vaccines inducing cross protection against different subtypes of influenza A virus. However, immune mechanisms of cross protection by M2e-based vaccines still remain to be fully elucidated. Here, we review immune correlates and mechanisms conferring cross protection by M2e-based vaccines. Molecular and cellular immune components that are known to be involved in M2 immune-mediated protection include antibodies, B cells, T cells, alveolar macrophages, Fc receptors, complements, and natural killer cells. Better understanding of protective mechanisms by immune responses induced by M2e vaccination will help facilitate development of broadly cross protective vaccines against influenza A virus

A case-control study of the effectiveness of tissue plasminogen activator on 6 month patients -- reported outcomes and health care utilization

none5siWe examined the benefit of tissue plasminogen activator (tPA), delivered as part of usual stroke management, on patient-reported outcomes and health care utilization. Using a case control design, patients who received tPA as part of usual stroke management were compared with patients who would have received tPA had they arrived to the hospital within the therapeutic time window. Data were collected from surveys 6 months after stroke using standardized patient-reported outcome measures and questions about health care utilization. Demographic and medical data were acquired from hospital records. Patients were matched on stroke severity, age, race, and gender. Matching was done with 1:2 ratio of tPA to controls. Results were compared between groups with 1-tailed tests because of a directionally specific hypothesis in favor of the tPA group. The tPA (n = 78) and control (n = 156) groups were matched across variables, except for stroke severity, which was better in the control group; subsequent analyses controlled for this mismatch. The tPA group reported better physical function, communication, cognitive ability, depressive symptomatology, and quality of life/participation compared with the control group. Fewer people in the tPA group reported skilled nursing facility stays, emergency department visits, and rehospitalizations after their stroke compared with controls. Reports of other postacute services were not different between groups. Although it is known that tPA reduces disability, this is the first study to demonstrate the effectiveness of tPA in improving meaningful, patientreported outcomes. Thus, use of tPA provides a large benefit to the daily lives of people with ischemic stroke.mixedLang, Catherine E.; Bland, Marghuretta D.; Cheng, Nuo; Corbetta, Maurizio; Lee, Jin-MooLang, Catherine E.; Bland, Marghuretta D.; Cheng, Nuo; Corbetta, Maurizio; Lee, Jin Mo