Impact of pulmonary exposure to gold core silver nanoparticles of different size and capping agents on cardiovascular injury

Background:The uses of engineered nanomaterials have expanded in biomedical technology and consumer manufacturing. Furthermore, pulmonary exposure to various engineered nanomaterials has, likewise, demonstrated the ability to exacerbate cardiac ischemia reperfusion (I/R) injury. However, the influence of particle size or capping agent remains unclear. In an effort to address these influences we explored response to 2 different size gold core nanosilver particles (AgNP) with two different capping agents at 2 different time points. We hypothesized that a pulmonary exposure to AgNP induces cardiovascular toxicity influenced by inflammation and vascular dysfunction resulting in expansion of cardiac I/R Injury that is sensitive to particle size and the capping agent. Methods: Male Sprague–Dawley rats were exposed to 200 μg of 20 or 110 nm polyvinylprryolidone (PVP) or citrate capped AgNP. One and 7 days following intratracheal instillation serum was analyzed for concentrations of selected cytokines; cardiac I/R injury and isolated coronary artery and aorta segment were assessed for constrictor responses and endothelial dependent relaxation and endothelial independent nitric oxide dependent relaxation. Results: AgNP instillation resulted in modest increase in selected serum cytokines with elevations in IL-2, IL-18, and IL-6. Instillation resulted in a derangement of vascular responses to constrictors serotonin or phenylephrine, as well as endothelial dependent relaxations with acetylcholine or endothelial independent relaxations by sodium nitroprusside in a capping and size dependent manner. Exposure to both 20 and 110 nm AgNP resulted in exacerbation cardiac I/R injury 1 day following IT instillation independent of capping agent with 20 nm AgNP inducing marginally greater injury. Seven days following IT instillation the expansion of I/R injury persisted but the greatest injury was associated with exposure to 110 nm PVP capped AgNP resulted in nearly a two-fold larger infarct size compared to naïve. Conclusions: Exposure to AgNP may result in vascular dysfunction, a potentially maladaptive sensitization of the immune system to respond to a secondary insult (e.g., cardiac I/R) which may drive expansion of I/R injury at 1 and 7 days following IT instillation where the extent of injury could be correlated with capping agents and AgNP size.This work was supported by the National Institute of Environmental Health Sciences U19ES019525, U01ES020127, U19ES019544 and East Carolina Universit

Aerosol and cloud feedbacks on surface energy balance over selected regions of the Indian subcontinent

We investigate aerosol and cloud forcing on the surface energy balance over selected regions in India. Four regions were selected with different surface characteristics and have considerable differences in the long-term trends and seasonal distribution of clouds and aerosols. These regions are described as (1) northern semiarid, (2) humid subtropical, (3) populated central peninsula, and (4) northeast monsoon impacted. Modern Era Retrospective-analysis for Research and Applications (MERRA) data and Climate Forecast System Reanalysis version 2 (CFSR) data are used in this study. An intercomparison of cloud fractions from both data sets shows that CFSR systematically underestimates high-cloud fraction during premonsoon and monsoon seasons. However, there are fewer low-cloud fraction biases. The positive temporal trend over 31 years (1979-2009) from MERRA in high clouds is greater than that of low clouds. This is due to positive anomalies in the cloud ice and supercooled liquid water content in MERRA. Biases in the radiative fluxes and surface fluxes show a strong relationship (correlations exceeding 0.8) with cloud fraction biases, more so for the high clouds. During the premonsoon season, aerosol forcing causes a change in surface shortwave radiation of -24.5, -25, -19, and -16 W m<SUP>-2</SUP> over regions 1 -4, respectively. The corresponding longwave radiation decrease is -9.8, -6.8, -4.5, and -1.9 W m<SUP>-2</SUP> over these same regions, respectively. The maximum surface shortwave reduction due to clouds, which is observed during the monsoon season, is -86, -113, -101, and -97 W m<SUP>-2</SUP> for these same regions, respectively. A decreasing trend in the boundary layer height is noticed both in MERRA and CFSR. The variation in the Bowen ratio and its relation to aerosol and cloud effect anomalies are also discussed

Phenotype of CNTNAP1: a study of patients demonstrating a specific severe congenital hypomyelinating neuropathy with survival beyond infancy.

CHN is genetically heterogeneous and its genetic basis is difficult to determine on features alone. CNTNAP1 encodes CASPR, integral in the paranodal junction high molecular mass complex. Nineteen individuals with biallelic variants have been described in association with severe congenital hypomyelinating neuropathy, respiratory compromise, profound intellectual disability and death within the first year. We report 7 additional patients ascertained through exome sequencing. We identified 9 novel CNTNAP1 variants in 6 families: three missense variants, four nonsense variants, one frameshift variant and one splice site variant. Significant polyhydramnios occurred in 6/7 pregnancies. Severe respiratory compromise was seen in 6/7 (tracheostomy in 5). A complex neurological phenotype was seen in all patients who had marked brain hypomyelination/demyelination and profound developmental delay. Additional neurological findings included cranial nerve compromise: orobulbar dysfunction in 5/7, facial nerve weakness in 4/7 and vocal cord paresis in 5/7. Dystonia occurred in 2/7 patients and limb contractures in 5/7. All had severe gastroesophageal reflux, and a gastrostomy was required in 5/7. In contrast to most previous reports, only one patient died in the first year of life. Protein modelling was performed for all detected CNTNAP1 variants. We propose a genotype-phenotype correlation, whereby hypomorphic missense variants partially ameliorate the phenotype, prolonging survival. This study suggests that biallelic variants in CNTNAP1 cause a distinct recognisable syndrome, which is not caused by other genes associated with CHN. Neonates presenting with this phenotype will benefit from early genetic definition to inform clinical management and enable essential genetic counselling for their families