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Background The Kingston Allergy Birth Cohort (KABC) is a prenatally recruited cohort initiated to study the developmental origins of allergic disease. Kingston General Hospital was chosen for recruitment because it serves a population with notable diversity in environmental exposures relevant to the emerging concept of the exposome. Objective To establish a profile of the KABC using the exposome framework and examine parentally reported respiratory symptoms to 2 years of age. Methods Data on phase 1 of the cohort (n = 560 deliveries) were compiled, and multivariate Cox proportional hazards regression models were used to determine associations with respiratory symptoms. Results The KABC exhibits diversity within the 3 exposome domains of general external (socioeconomic status, rural or urban residence), specific external (cigarette smoke, breastfeeding, mold or dampness), and internal (respiratory health, gestational age), as well as significant associations between exposures from different domains. Significant associations emerged between parental reports of wheeze or cough without a cold and prenatal cigarette smoke exposure, mold or dampness in the home, and the use of air fresheners in the early-life home environment. Breastfeeding, older siblings, and increased gestational age were associated with decreased respiratory symptoms. Conclusion The KABC is a unique cohort with diversity that can be leveraged for exposomics-based studies. This study found that all 3 domains of the exposome had effects on the respiratory health of KABC children. Ongoing studies using phase 1 of the KABC continue to explore the internal exposome through allergy skin testing and epigenetic analyses and the specific external domain through in-home environmental analyses, air pollution modeling, and ultimately potential convergences within and among domains.

The Kingston Allergy Birth Cohort (KABC) is a prenatally recruited cohort initiated to study the developmental origins of allergic disease. Kingston General Hospital was chosen for recruitment because it serves a population with notable diversity in environmental exposures relevant to the emerging concept of the exposome.To establish a profile of the KABC using the exposome framework and examine parentally reported respiratory symptoms to 2 years of age.Data on phase 1 of the cohort (n = 560 deliveries) were compiled, and multivariate Cox proportional hazards regression models were used to determine associations with respiratory symptoms.The KABC exhibits diversity within the 3 exposome domains of general external (socioeconomic status, rural or urban residence), specific external (cigarette smoke, breastfeeding, mold or dampness), and internal (respiratory health, gestational age), as well as significant associations between exposures from different domains. Significant associations emerged between parental reports of wheeze or cough without a cold and prenatal cigarette smoke exposure, mold or dampness in the home, and the use of air fresheners in the early-life home environment. Breastfeeding, older siblings, and increased gestational age were associated with decreased respiratory symptoms.The KABC is a unique cohort with diversity that can be leveraged for exposomics-based studies. This study found that all 3 domains of the exposome had effects on the respiratory health of KABC children. Ongoing studies using phase 1 of the KABC continue to explore the internal exposome through allergy skin testing and epigenetic analyses and the specific external domain through in-home environmental analyses, air pollution modeling, and ultimately potential convergences within and among domains.

There is growing evidence that repeated brain concussion can result in cumulative and long-term behavioral symptoms, neuropathological changes, and neurodegeneration. Little is known about the factors and mechanisms that contribute to these effects. The current study addresses the need to investigate and better understand the effects of repeated concussion through the development of an animal model. Male Long-Evans rats received 1, 3, or 5 mild lateral fluid percussion injuries or sham injuries spaced 5 days apart. After the final injury, rats received either a short (24 h) or long (8 weeks) post-injury recovery period, followed by a detailed behavioral analysis consisting of tests for rodent anxiety-like behavior, cognition, social behavior, sensorimotor function, and depression-like behavior. Brains were examined immunohistochemically to assess neuroinflammation and cortical damage. Rats given 1, 3, or 5 mild percussion injuries displayed significant short-term cognitive impairments. Rats given repeated mild percussion injuries displayed significantly worse short- and long-term cognitive impairments. Rats given 5 mild percussion injuries also displayed increased anxiety- and depression-like behaviors. Neuropathological analysis revealed short-term neuroinflammation in 3-injury rats, and both short- and long-term neuroinflammation in 5-injury rats. There was also evidence that repeated injuries induced short- and long-term cortical damage. These cumulative and long-term changes are consistent with findings in human patients suffering repeated brain concussion, provide support for the use of repeated mild lateral fluid percussion injuries to study repeated concussion in the rat, and suggest that neuroinflammation may be important for understanding the cumulative and chronic effects of repeated concussion.

Traumatic brain injury (TBI) is an international health concern often resulting in chronic neurological abnormalities, including cognitive deficits, emotional disturbances, and motor impairments. An anti-CD11d monoclonal antibody that blocks the CD11d/CD18 integrin and vascular cell adhesion molecule (VCAM)-1 interaction following experimental spinal cord injury improves functional recovery, while reducing the intraspinal number of neutrophils and macrophages, oxidative activity, and tissue damage. Since the mechanisms of secondary injury in the brain and spinal cord are similar, we designed a study to evaluate fully the effects of anti-CD11d treatment after a moderate lateral fluid percussion TBI in the rat. Rats were treated at 2 h after TBI with either the anti-CD11d antibody or an isotype-matched control antibody 1B7, and both short (24-to 72-h) and long (4-week) recovery periods were examined. The anti-CD11d integrin treatment reduced neutrophil and macrophage levels in the injured brain, with concomitant reductions in lipid peroxidation, astrocyte activation, amyloid precursor protein accumulation, and neuronal loss. The reduced neuroinflammation seen in anti-CD11d-treated rats correlated with improved performance on a number of behavioral tests. At 24 h, the anti-CD11d group performed significantly better than the 1B7 controls on several water maze measures of spatial cognition. At 4 weeks post-injury the anti-CD11d-treated rats had better sensorimotor function as assessed by the beam task, and reduced anxiety-like behaviors, as evidenced by elevated-plus maze testing, compared to 1B7 controls. These findings suggest that neuroinflammation is associated with behavioral deficits after TBI, and that anti-CD11d antibody treatment is a viable strategy to improve neurological outcomes after TBI. © 2012, Mary Ann Liebert, Inc.

The systemic inflammatory response syndrome (SIRS) follows spinal cord injury (SCI) and causes damage to the lungs, kidney, and liver due to an influx of inflammatory cells from the circulation. After SCI in rats, the SIRS develops within 12 h and is sustained for at least 3 days. We have previously shown that blockade of CD11d/CD18 integrin reduces inflammation-driven secondary damage to the spinal cord. This treatment reduces the SIRS after SCI. In another study we found that blockade of α4β1 integrin limited secondary cord damage more effectively than blockade of CD11d/CD18. Therefore we considered it important to assess the effects of anti-α4β1 treatment on the SIRS in the lung, kidney, and liver after SCI. An anti-α4 antibody was given IV at 2 h after SCI at the fourth thoracic segment and the effects on the organs were evaluated at 24 h post-injury. The migration of neutrophils into the lungs and liver was markedly reduced and all three organs contained fewer macrophages. In the lungs and liver, the activation of the oxidative enzymes myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and gp91 phox, the production of free radicals, lipid peroxidation, and cell death were substantially and similarly reduced. Treatment effects were less robust in the kidney. Overall, the efficacy of the anti-α4β1 treatment did not differ greatly from that of the anti-CD11d antibody, although details of the results differed. The SIRS after SCI impedes recovery, and attenuation of the SIRS with an anti-integrin treatment is an important, clinically-relevant finding. © Mary Ann Liebert, Inc. 2012.

Traumatic injury to the spinal cord triggers a systemic inflammatory response syndrome (SIRS), in which inflammatory cells from the circulation invade organs such as the liver, lung and kidney, leading to damage of these organs. Our previous study (Gris, et al, Exp. Neurol, 2008) demonstrated that spinal cord injury (SCI) activates circulating neutrophils that then invade the lung and kidney from 2 to 24. h after injury, increasing myeloperoxidase activity, cyclooxygenase-2 and matrix metalloproteinase-9 expression and lipid peroxidation in these organs. The present study was designed to ascertain whether a treatment that limits the influx of leukocytes into the injured spinal cord would also be effective in reducing the SIRS after SCI. This treatment is intravenous delivery of a monoclonal antibody (mAb) against the CD11d subunit of the CD11d/CD18 integrin expressed by neutrophils and monocytes. We delivered the anti-CD11d mAb at 2. h post moderate clip compression SCI at the 4th or 12th thoracic segments and assessed inflammation, oxidative activity and cellular damage within the lung, kidney and liver at 12. h post-injury. In some analyses we compared high and low thoracic injuries to evaluate the importance of injury level on the intensity of the SIRS. After T4 injury, treatment with the anti-integrin mAb reduced the presence of neutrophils and macrophages in the lung, with associated decreases in expression of NF-κB and oxidative enzymes and in the concentration of free radicals in this organ. The treatment also reduced lipid peroxidation, protein nitration and cell death in the lung. The anti-CD11d treatment also reduced the inflammatory cells within the kidney after T4 injury, as well as the free radical concentration and amount of lipid peroxidation. In the liver, the mAb treatment reduced the influx of neutrophils but most of the other measures examined were unaffected by SCI. The inflammatory responses within the lung and kidney were often greater after T4 than T12 injury. Clinical studies show that SIRS, with its associated organ failure, contributes significantly to the morbidity and mortality of SCI patients. This anti-integrin treatment may block the onset of SIRS after SCI. © 2011 Elsevier Inc.