Chronic Fibrotic Changes in Experimental Pulmonary Embolization in the Rat Model

Comparative Medicine - OneHealth and Comparative Medicine Poster SessionIntroduction: Fat embolism, a subclinical event, occurs in many clinical settings, such as long bones fractures, liposuction and during cardiopulmonary bypass. Some cases, especially with trauma, result in fat embolism syndrome (FES), a serious manifestation of fat embolism. FES is reported to occur in 5-10% of major trauma cases and can produce profound respiratory problems that may culminate in adult respiratory distress syndrome (ARDS). Embolized fat is hydrolyzed by lipase into free fatty acids which have been shown by previous histological studies to be toxic to the lung. An animal model of fat embolism has been developed utilizing triolein given intravenously (i.v.) to rats. We hypothesized that i.v. triolein will produce histological changes in the lung that are similar to the changes seen in human FES. Methods: Following University animal care approval, unanesthetized Sprague Dawley rats (study n=13, control n=12) were injected with either triolein, 0.2 mL (study) or saline, 0.2 mL (control). Weights were recorded until necropsy at 3 weeks (n=13) and 6 weeks (n=12). Morphometric measurements were made on both H&E and fat-stained tissues from the lungs, heart, kidneys and spleen. All vessels were examined using high magnification fields. Arterial wall thickness (lumen patency) was calculated by vessel luminal and external diameters. The medial-adventitial ratio was calculated from the outer medial diameter divided by the outer adventitial diameter. These values were keyed into statistical software and analysis as a function of time and treatment was calculated using t-tests with significance noted at a p<0.05. Results: Gross pathological changes were seen in lung, heart, kidneys, liver and spleen of the triolein group. Pulmonary histological examination revealed diffuse intra-alveolar hemorrhages and edema with peri-bronchial inflammation. Vasculitis was more prominent in the peri-bronchial areas as well. Pulmonary arteries revealed significant medial thickening as compared with the control groups with lumen patency p=0.004. Adventitia/media ratio, with large variability in the triolein group, was not statistically significant. Conclusions: Our data showed that injected triolein remains in the rat lung after 3 and 6 weeks with associated vascular and septal damage in the lung tissue compared to controls. Discussion: This study is a continuation of our previous study showing an increase of severe pulmonary damage within 3-6 hours following triolein induced fat embolism in the rat, reaching a peak at 96 hrs post injection. Despite unmedicated recovery of general condition and body weight and reopening of the pulmonary arteries and arterioles, collagen and vasculitis persisted up to 6 weeks. Further studies are needed to verify the eventual recovery or the organ evolution toward chronic fibrosis

Determinants of Mosaic Chromosomal alteration Fitness

Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI toPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (

Determinants of mosaic chromosomal alteration fitness

Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (R2 = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using population-level distributions of clonal fraction. Among individuals with JAK2 V617F clonal hematopoiesis of indeterminate potential or mCAs affecting the JAK2 gene on chromosome 9, PACER score was strongly correlated with erythrocyte count. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified a TCL1A locus variant associated with mCA clonal expansion rate, with suggestive variants in NRIP1 and TERT

13C-phenylalanine breath test detects altered phenylalanine kinetics in schizophrenia patients

Phenylalanine is an essential amino acid required for the synthesis of catecholamines including dopamine. Altered levels of phenylalanine and its metabolites in blood and cerebrospinal fluid have been reported in schizophrenia patients. This study attempted to examine for the first time whether phenylalanine kinetics is altered in schizophrenia using L-[1-13C]phenylalanine breath test (13C-PBT). The subjects were 20 chronically medicated schizophrenia patients (DSM-IV) and the same number of age- and sex-matched controls. 13C-phenylalanine (99 atom% 13C; 100 mg) was administered orally and the breath 13CO2 /12CO2 ratio was monitored for 120 min. The possible effect of antipsychotic medication (risperidone (RPD) or haloperidol (HPD) treatment for 21 days) on 13C-PBT was examined in rats. Body weight (BW), age and diagnostic status were significant predictors of the area under the curve of the time course of Δ13CO2 (‰) and the cumulative recovery rate (CRR) at 120 min. A repeated measures analysis of covariance controlled for age and BW revealed that the patterns of CRR change over time differed between the patients and controls and that Δ13CO2 was lower in the patients than in the controls at all sampling time points during the 120 min test, with an overall significant difference between the two groups. Chronic administration of RPD or HPD had no significant effect on 13C-PBT indices in rats. Our results suggest that 13C-PBT is a novel laboratory test that can detect altered phenylalanine kinetics in chronic schizophrenia patients. Animal experiments suggest that the observed changes are unlikely to be attributable to antipsychotic medication

Genetic analyses of diverse populations improves discovery for complex traits

Genome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development and clinical guidelines. However, the majority of discovery efforts are based on data from populations of European ancestry1–3. In light of the differential genetic architecture that is known to exist between populations, bias in representation can exacerbate existing disease and healthcare disparities. Critical variants may be missed if they have a low frequency or are completely absent in European populations, especially as the field shifts its attention towards rare variants, which are more likely to be population-specific4–10. Additionally, effect sizes and their derived risk prediction scores derived in one population may not accurately extrapolate to other populations11,12. Here we demonstrate the value of diverse, multi-ethnic participants in large-scale genomic studies. The Population Architecture using Genomics and Epidemiology (PAGE) study conducted a GWAS of 26 clinical and behavioural phenotypes in 49,839 non-European individuals. Using strategies tailored for analysis of multi-ethnic and admixed populations, we describe a framework for analysing diverse populations, identify 27 novel loci and 38 secondary signals at known loci, as well as replicate 1,444 GWAS catalogue associations across these traits. Our data show evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts and insights into clinical implications. In the United States—where minority populations have a disproportionately higher burden of chronic conditions13—the lack of representation of diverse populations in genetic research will result in inequitable access to precision medicine for those with the highest burden of disease. We strongly advocate for continued, large genome-wide efforts in diverse populations to maximize genetic discovery and reduce health disparities. © 2019, The Author(s), under exclusive licence to Springer Nature Limited