No abstract

The median survival of patients with idiopathic pulmonary fibrosis (IPF) continues to be approximately 3 years from the time of diagnosis, underscoring the lack of effective medical therapies for this disease. In the United States alone, approximately 40,000 patients die of this disease annually. In November 2012, the NHLBI held a workshop aimed at coordinating research efforts and accelerating the development of IPF therapies. Basic, translational, and clinical researchers gathered with representatives from the NHLBI, patient advocacy groups, pharmaceutical companies, and the U.S. Food and Drug Administration to review the current state of IPF research and identify priority areas, opportunities for collaborations, and directions for future research. The workshop was organized into groups that were tasked with assessing and making recommendations to promote progress in one of the following six critical areas of research: (1) biology of alveolar epithelial injury and aberrant repair; (2) role of extracellular matrix; (3) preclinical modeling; (4) role of inflammation and immunity; (5) genetic, epigenetic, and environmental determinants; (6) translation of discoveries into diagnostics and therapeutics. The workshop recommendations provide a basis for directing future research and strategic planning by scientific, professional, and patient communities and the NHLBI.

Animal heterotrimeric G proteins are activated by guanine nucleotide exchange factors (GEF), typically seven transmembrane receptors that trigger GDP release and subsequent GTP binding. In contrast, the Arabidopsis thaliana G protein (AtGPA1) rapidly activates itself without a GEF and is instead regulated by a seven transmembrane Regulator of G protein Signaling (7TM-RGS) protein that promotes GTP hydrolysis to reset the inactive (GDP-bound) state. It is not known if this unusual activation is a major and constraining part of the evolutionary history of G signaling in eukaryotes. In particular, it is not known if this is an ancestral form or if this mechanism is maintained, and therefore constrained, within the plant kingdom. To determine if this mode of signal regulation is conserved throughout the plant kingdom, we analyzed available plant genomes for G protein signaling components, and we purified individually the plant components encoded in an informative set of plant genomes in order to determine their activation properties in vitro. While the subunits of the heterotrimeric G protein complex are encoded in vascular plant genomes, the 7TM-RGS genes were lost in all investigated grasses. Despite the absence of a Gα-inactivating protein in grasses, all vascular plant Gα proteins examined rapidly released GDP without a receptor and slowly hydrolyzed GTP, indicating that these Gα are self-activating. We showed further that a single amino acid substitution found naturally in grass Gα proteins reduced the Gα-RGS interaction, and this amino acid substitution occurred before the loss of the RGS gene in the grass lineage. Like grasses, non-vascular plants also appear to lack RGS proteins. However, unlike grasses, one representative non-vascular plant Gα showed rapid GTP hydrolysis, likely compensating for the loss of the RGS gene. Our findings, the loss of a regulatory gene and the retention of the “self-activating” trait, indicate the existence of divergent Gα regulatory mechanisms in the plant kingdom. In the grasses, purifying selection on the regulatory gene was lost after the physical decoupling of the RGS protein and its cognate Gα partner. More broadly these findings show extreme divergence in Gα activation and regulation that played a critical role in the evolution of G protein signaling pathways.

Objective: Our enhanced recovery after cardiac surgery (ERAS Cardiac) program is an evidence-based interdisciplinary process, which has not previously been systematically applied to cardiac surgery in the United States.Methods: The Knowledge-to-Action Framework synthesized evidence-based enhanced recovery interventions and implementation of a designated ERAS Cardiac program. Standardized processes included (1) preoperative patient education, (2) carbohydrate loading 2 hours before general anesthesia, (3) multimodal opioid-sparing analgesia, (4) goal-directed perioperative insulin infusion, and (5) a rigorous bowel regimen. All cardiac anesthesiologists and surgeons agreed to follow the standardized pathway for adult cardiac surgery cases. The 1-year outcomes were compared between the 9 months pre-and post-ERAS Cardiac implementation using prospectively collected, retrospectively reviewed data.Results: Comparing the pre-(N ¼ 489) with the post-(N ¼ 443) ERAS Cardiac groups, median postoperative length of stay was decreased from 7 to 6 days (P <.01). Total intensive care unit hours were decreased from a mean of 43 to 28 hours (P <.01). The incidence of gastrointestinal complications was 6.8% pre-ERAS versus 3.6% post-ERAS implementation (P <.05). Opioid use was reduced by a mean of 8 mg of morphine equivalents per patient in the first 24 hours postoperatively (P <.01). Reintubation rate and intensive care unit readmission rate were reduced by 1.2% and 1.5%, respectively (P ¼ not significant). The incidence of hyperglycemic episodes was no different after ERAS Cardiac initiation. Patient satisfaction was 86.3% pre-ERAS versus 91.8% post-ERAS Cardiac implementation and work culture domain scores revealed increases in satisfaction across all measured indices, including patient focus, culture, and engagement.Conclusions: Initial clinical and survey data after the first year of a system-wide ERAS Cardiac program were associated with significantly improved perioperative outcomes. We believe this value-based approach to cardiac surgery can consistently result in earlier recovery, cost reductions, and increased patient/staff satisfaction.

Rocky Mountain spotted fever and other related diseases are systemic infections caused by rickettsiae. These obligatory intracellular bacteria target the endothelium, offering an appealing model to study the interactions between endothelial cells and T lymphocytes. We investigated the mRNA expression of chemokines known to target CD8+ T cells and CD4(+) T-helper 1 cells in the lungs of C3H/HeN mice infected with Rickettsia conorii with the purpose of identifying evidence for a role of chemokines in the immune clearance of rickettsiae from the vasculature. The expression of the CXCR3 ligands CXCL9 and CXCL10 was significantly higher than the other chemokines investigated. We validated the relevance of these results in the animal model through the analysis of tissues from humans with Rocky Mountain spotted fever. We then characterized the kinetics and localization of expression of CXCL9 and CXCL10 in lungs, brain, and liver of mice infected with lethal or sublethal doses of R. conorii by a combination of quantitative real-time polymerase chain reaction and immunohistochemistry. Interestingly, the peak of expression of these chemokines occurred 4 days before CD8+ T cells infiltrated the infected tissues. Our results suggest that CXCL9 and CXCL10 may play a role early during the immune response against rickettsial infections.