Identification and interpretation of longitudinal gene expression changes in trauma

Rationale

The relationship between leukocyte gene expression and recovery of respiratory function after injury may provide information on the etiology of multiple organ dysfunction.

Objectives

To find a list of genes for which expression after injury predicts respiratory recovery, and to identify which networks and pathways characterize these genes.

Methods

Blood was sampled at 12 hours and at 1, 4, 7, 21 and 28 days from 147 patients who had been admitted to the hospital after blunt trauma. Leukocyte gene expression was measured using Affymetrix oligonucleotide arrays. A linear model, fit to each probe-set expression value, was used to impute the gene expression trajectory over the entire follow-up period. The proportional hazards model score test was used to calculate the statistical significance of each probe-set trajectory in predicting respiratory recovery. A list of genes was determined such that the expected proportion of false positive results was less than 10%. These genes were compared to the Gene Ontology for ‘response to stimulus’ and, using Ingenuity software, were mapped into networks and pathways.

Measurements and Main Results

The median time to respiratory recovery was 6 days. There were 170 probe-sets representing 135 genes that were found to be related to respiratory recovery. These genes could be mapped to nine networks. Two known pathways that were activated were antigen processing and presentation and JAK- signaling.

Conclusions

The examination of the relationship of gene expression over time with a patient''s clinical course can provide information which may be useful in determining the mechanism of recovery or lack of recovery after severe injury.     

Selection of disease-specific biomarkers by integrating inflammatory mediators with clinical informatics in AECOPD patients: a preliminary study

Systemic inflammation is a major factor influencing the outcome and quality of patient with chronic obstructive pulmonary disease (COPD) and acute exacerbations (AECOPD). Because of the inflammatory complexity, a great challenge is still confronted to optimize the identification and validation of disease-specific biomarkers. This study aimed at developing a new protocol of specific biomarker evaluation by integrating proteomic profiles of inflammatory mediators with clinical informatics in AECOPD patients, understand better their function and signal networks. Plasma samples were collected from healthy non-smokers or patients with stable COPD (sCOPD) or AECOPD on days 1 and 3 of the admission and discharging day (day 7-10). Forty chemokines were measured using a chemokine multiplex antibody array. Clinical informatics was achieved by a Digital Evaluation Score System (DESS) for assessing severity of patients. Chemokine data was compared among different groups and its correlation with DESS scores was performed by SPSS software. Of 40 chemokines, 30 showed significant difference between sCOPD patients and healthy controls, 16 between AECOPD patients and controls and 13 between AECOPD patients and both sCOPD and controls, including BTC, IL-9, IL-18Bpa, CCL22,CCL23, CCL25, CCL28, CTACK, LIGHT, MSPa, MCP-3, MCP-4 and OPN. Of them, some had significant correlation with DESS scores. There is a disease-specific profile of inflammatory mediators in COPD and AECOPD patients which may have a potential diagnostics together with clinical informatics of patients. Our preliminary study suggested that integration of proteomics with clinical informatics can be a new way to validate and optimize disease-special biomarkers.     

Cognitive changes and quality of life in neurocysticercosis: a longitudinal study

Background

Few studies have focused on the cognitive morbidity of neurocysticercosis (NCC), one of the most common parasitic infections of the central nervous system. We longitudinally assessed the cognitive status and quality of life (QoL) of patients with incident symptomatic NCC cases and matched controls.

Methodology/Principal Findings

The setting of the study was the Sabogal Hospital and Cysticercosis Unit, Department of Transmissible Diseases, National Institute of Neurological Sciences, Lima, Peru. The design was a longitudinal study of new onset NCC cases and controls. Participants included a total of 14 patients with recently diagnosed NCC along with 14 healthy neighborhood controls and 7 recently diagnosed epilepsy controls. A standardized neuropsychological battery was performed at baseline and at 6 months on NCC cases and controls. A brain MRI was performed in patients with NCC at baseline and 6 months. Neuropsychological results were compared between NCC cases and controls at both time points. At baseline, patients with NCC had lower scores on attention tasks (p<0.04) compared with epilepsy controls but no significant differences compared to healthy controls. Six months after receiving anti-parasitic treatment, the NCC group significantly improved on tasks involving psychomotor speed (p<0.02). QoL at baseline suggested impaired mental function and social function in both the NCC and epilepsy group compared with healthy controls. QoL gains in social function (p = 0.006) were noted at 6 months in patients with NCC.

Conclusions/Significance

Newly diagnosed patients with NCC in this sample had mild cognitive deficits and more marked decreases in quality of life at baseline compared with controls. Improvements were found in both cognitive status and quality of life in patients with NCC after treatment.     

Metacarpophalangeal length changes in humans during adulthood: a longitudinal study.

Total lengths of the 19 diaphyseal hand bones were measured from standardized radiographs of healthy American whites as young adults (ca. 21 years) and again at ca. 55 years of age. The four hand-bone rows exhibit distinctive length changes: Distal and middle phalanges continue to increase significantly in length, proximal phalanges constitute a transition zone of little change, and metacarpals uniformly decrease in length. Clear-cut sex differences are noteworthy: Males change more (lose more in some bone rows, gain more in others) than females. Progressive elongation was greatest in the distal phalanges where apposition around the distal aspect ("tufting") is not constrained by a joint or epiphysis. Loss of bone length in the metacarpals by subchondral resorption is consistent with documented reductions in activity levels and grip strength with age, as well as diminished joint spaces which alter loading of the joints.     

Mapping determinants of gene expression plasticity by genetical genomics in C. elegans

Recent genetical genomics studies have provided intimate views on gene regulatory networks. Gene expression variations between genetically different individuals have been mapped to the causal regulatory regions, termed expression quantitative trait loci. Whether the environment-induced plastic response of gene expression also shows heritable difference has not yet been studied. Here we show that differential expression induced by temperatures of 16 °C and 24 °C has a strong genetic component in Caenorhabditis elegans recombinant inbred strains derived from a cross between strains CB4856 (Hawaii) and N2 (Bristol). No less than 59% of 308 trans-acting genes showed a significant eQTL-by-environment interaction, here termed plasticity quantitative trait loci. In contrast, only 8% of an estimated 188 cis-acting genes showed such interaction. This indicates that heritable differences in plastic responses of gene expression are largely regulated in trans. This regulation is spread over many different regulators. However, for one group of trans-genes we found prominent evidence for a common master regulator: a transband of 66 coregulated genes appeared at 24 °C. Our results suggest widespread genetic variation of differential expression responses to environmental impacts and demonstrate the potential of genetical genomics for mapping the molecular determinants of phenotypic plasticity.     

Evolution of a microbial nitrilase gene family: a comparative and environmental genomics study

Background  

Completed genomes and environmental genomic sequences are bringing a significant contribution to understanding the evolution of gene families, microbial metabolism and community eco-physiology. Here, we used comparative genomics and phylogenetic analyses in conjunction with enzymatic data to probe the evolution and functions of a microbial nitrilase gene family. Nitrilases are relatively rare in bacterial genomes, their biological function being unclear.     

Radiographic changes in alveolar bone height on overdenture abutments: a longitudinal study

Objective: Stabilisation of partial dentures is an important part of prosthodontic treatment, particularly in patients with an excessive reduction in alveolar bone supporting their abutment teeth. In these cases, overdenture prostheses are one possible treatment choice. Background: The aim of this study was to evaluate the effects of overdentures on the condition of alveolar bone of the remaining teeth, and to evaluate the overdenture concept in the prosthetic treatment of partially edentulous patients. Materials and methods: The investigation was conducted on 22 patients during observation periods of 6 and 10 years. After preparation, all abutment teeth were provided with either amalgam restorations or gold copings. An overdenture in the lower jaw was fabricated for every patient. A special film holder was used to repeat the X‐ray procedure in every patient in the same manner. The radiographs were evaluated using the grid scale. The alveolar bone level of all remaining teeth was evaluated on dental films by measuring the distance between the root apex and coronal border of the alveolar bone. Results: A statistically significant difference (p < 0.01) was calculated 6 years after delivery stage between distal alveolar bone levels of experimental abutments under overdentures and the remaining teeth of the control group. Alveolar bone of abutment teeth was considerably preserved, particularly in seven patients observed 10 years after provision of their dentures. Conclusion: Within the limitation of this study, the validity of the overdenture treatment in partially edentulous patients is concluded. Good oral hygiene was crucial for the success of treatment with overdentures.     

Developing a gene expression model for predicting ventilator-associated pneumonia in trauma patients: a pilot study

Background

Ventilator-associated pneumonia (VAP) carries significant mortality and morbidity. Predicting which patients will become infected could lead to measures to reduce the incidence of VAP.

Methodology/Principal Findings

The goal was to begin constructing a model for VAP prediction in critically-injured trauma patients, and to identify differentially expressed genes in patients who go on to develop VAP compared to similar patients who do not. Gene expression profiles of lipopolysaccharide stimulated blood cells in critically injured trauma patients that went on to develop ventilator-associated pneumonia (n = 10) was compared to those that never developed the infection (n = 10). Eight hundred and ten genes were differentially expressed between the two groups (ANOVA, P<0.05) and further analyzed by hierarchical clustering and principal component analysis. Functional analysis using Gene Ontology and KEGG classifications revealed enrichment in multiple categories including regulation of protein translation, regulation of protease activity, and response to bacterial infection. A logistic regression model was developed that accurately predicted critically-injured trauma patients that went on to develop VAP (VAP+) and those that did not (VAP−). Five genes (PIK3R3, ATP2A1, PI3, ADAM8, and HCN4) were common to all top 20 significant genes that were identified from all independent training sets in the cross validation. Hierarchical clustering using these five genes accurately categorized 95% of patients and PCA visualization demonstrated two discernable groups (VAP+ and VAP−).

Conclusions/Significance

A logistic regression model using cross-validation accurately predicted patients that developed ventilator-associated pneumonia and should now be tested on a larger cohort of trauma patients.     

The modulation of inflammatory gene expression by lipids: mediation through Toll-like receptors

Toll-like receptors (TLRs) were evolved to detect invading pathogens and to induce innate immune responses in order to mount host defense mechanisms. It becomes apparent that the activation of certain TLRs is also modulated by endogenous molecules including lipid components, fatty acids. Results from epidemiological and animal studies demonstrated that saturated and polyunsaturated dietary fatty acids can differentially modify the risk of development of many chronic diseases. Inflammation is now recognized as an important underlying etiologic condition for the pathogenesis of many chronic diseases. Therefore, if the activation of TLRs and consequent inflammatory and immune responses are differentially modulated by types of lipids in vivo, this would suggest that the risk of the development of chronic inflammatory diseases and the host defense against microbial infection may be modified by the types of dietary fat consumed.     

Salmonella carrier-state in hens: study of host resistance by a gene expression approach

Salmonellosis is one of the main causes of food-borne poisoning due to the consumption of contaminated poultry products. In the flocks, Salmonella is able to persist in the digestive tract of birds for weeks without triggering any symptom. In order to identify molecules and genes involved in the mechanism of host resistance to intestinal carrier-state, two different inbred lines of laying hens were orally inoculated with Salmonella Enteritidis. Bacterial colonization and host gene expression were measured in the caecum and its sentinel lymphoid tissue, respectively. Significantly increased expression of chemokine, anti-infectious cytokine, bacterial receptor, antimicrobial mediator and particularly, defensin genes was observed in the line carrying a lower level of bacteria in the caecum. These innate immunity molecules were either constitutively or inductively highly expressed in resistant adult birds and thus present candidate genes to play an important role in the host defence against Salmonella colonization.     

Different statins produce highly divergent changes in gene expression profiles of human hepatoma cells: a pilot study

Statins are inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), the key enzyme of the sterol biosynthesis pathway. Statin therapy is commonly regarded as well tolerated. However, serious adverse effects have also been reported, especially during high-dose statin therapy. The aim of our study was to investigate the effect of statins on gene expression profiles in human hepatoma HepG2 cells using Affymetrix Human Genome U133 Plus 2.0 arrays. Expression of 102, 857 and 1091 genes was changed substantially in HepG2 cells treated with simvastatin, fluvastatin and atorvastatin, respectively. Pathway and gene ontology analysis showed that many of the genes with changed expression levels were involved in a broad range of metabolic processes. The presented data clearly indicate substantial differences between the tested statins.     

Inflammatory mediators and cartilage biomarkers in synovial fluid after a single inflammatory insult: a longitudinal experimental study

Introduction  

Inflammation is an important feature of many joint diseases, and levels of cartilage biomarkers measured in synovial fluid may be influenced by local inflammatory status. Little is known about the magnitude and time course of inflammation-induced changes in cartilage tissue turnover as measured in vivo by synovial fluid markers. We aimed to study temporal changes in concentrations of inflammatory mediators, matrix metalloproteinase activity and cartilage biomarkers over 1 week in joints with experimentally induced inflammation.     

Quantitative evolutionary genomics: differential gene expression and male reproductive success in Drosophila melanogaster

We combined traditional quantitative genetics and oligonucleotide microarrays to examine within-population genetic variation in a trait closely related to fitness. The trait, male reproductive success under competitive conditions (MCRS), is of central importance to both life-history and sexual-selection theory. We identified 27 candidate genes whose expression levels were associated with within-population variation in MCRS. "High" MCRS was associated with low expression of a cytochrome P450 that causes pesticide resistance, suggesting a fitness cost to resistance. Two groups of metabolic proteins (glutathione transferases and phosphatases) were significantly over-represented, and a large portion of the candidates are genes involved in oxidative stress resistance, energy acquisition or energy storage. Genes expressed in accessory glands and testes were not over-represented among differentially expressed genes, but testis-expressed genes were significantly more likely to be upregulated in high MCRS genotypes. Finally, nine candidate genes that we identified had no previous functional annotation, and this experiment suggests that they play a role in male reproductive success.     

Analysis of longitudinal changes in dyspnea of patients with chronic obstructive pulmonary disease: an observational study

Background

Guidelines recommend that symptoms as well as lung function should be monitored for the management of patients with chronic obstructive pulmonary disease (COPD). However, limited data are available regarding the longitudinal change in dyspnea, and it remains unknown which of relevant measurements might be used for following dyspnea.

Methods

We previously consecutively recruited 137 male outpatients with moderate to very severe COPD, and followed them every 6 months for 5 years. We then reviewed and reanalyzed the data focusing on the relationships between the change in dyspnea and the changes in other clinical measurements of lung function, exercise tolerance tests and psychological status. Dyspnea with activities of daily living was assessed with the Oxygen Cost Diagram (OCD) and modified Medical Research Council dyspnea scale (mMRC), and two dimensions of disease-specific health status questionnaires of the Chronic Respiratory Disease Questionnaire (CRQ) and the St. George’s Respiratory Questionnaire (SGRQ) were also used. Dyspnea at the end of exercise tolerance tests was measured using the Borg scale.

Results

The mMRC, CRQ dyspnea and SGRQ activity significantly worsened over time (p < 0.001), but the OCD did not (p = 0.097). Multiple regression analyses revealed that the changes in the OCD, mMRC, CRQ dyspnea and SGRQ activity were significantly correlated to changes in forced expiratory volume in one second (FEV₁) (correlation of determination (r²) = 0.05-0.19), diffusing capacity for carbon monoxide (r² = 0.04-0.08) and psychological status evaluated by Hospital Anxiety and Depression Scale (r² = 0.14-0.17), although these correlations were weak. Peak Borg score decreased rather significantly, but was unrelated to changes in clinical measurements.

Conclusion

Dyspnea worsened over time in patients with COPD. However, as different dyspnea measurements showed different evaluative characteristics, it is important to follow dyspnea using appropriate measurements. Progressive dyspnea was related not only to progressive airflow limitation, but also to various factors such as worsening of diffusing capacity or psychological status. Changes in peak dyspnea at the end of exercise may evaluate different aspects from other dyspnea measurements.