Inhibition of transforming growth factor-β restores endothelial thromboresistance in vein grafts

BackgroundThrombosis is a major cause of the early failure of vein grafts (VGs) implanted during peripheral and coronary arterial bypass surgeries. Endothelial expression of thrombomodulin (TM), a key constituent of the protein C anticoagulant pathway, is markedly suppressed in VGs after implantation and contributes to local thrombus formation. While stretch-induced paracrine release of transforming growth factor-β (TGF-β) is known to negatively regulate TM expression in heart tissue, its role in regulating TM expression in VGs remains unknown.MethodsChanges in relative mRNA expression of major TGF-β isoforms were measured by quantitative polymerase chain reaction (qPCR) in cultured human saphenous vein smooth muscle cells (HSVSMCs) subjected to cyclic stretch. To determine the effects of paracrine release of TGF-β on endothelial TM mRNA expression, human saphenous vein endothelial cells (HSVECs) were co-cultured with stretched HSVSMCs in the presence of 1D11, a pan-neutralizing TGF-β antibody, or 13C4, an isotype-control antibody. Groups of rabbits were then administered 1D11 or 13C4 and underwent interpositional grafting of jugular vein segments into the carotid circulation. The effect of TGF-β inhibition on TM gene expression was measured by qPCR; protein C activating capacity and local thrombus formation were measured by in situ chromogenic substrate assays; and VG remodeling was assessed by digital morphometry.ResultsCyclic stretch induced TGF-β1 expression in HSVSMCs by 1.9 ± 0.2-fold (P < .001) without significant change in the expressions of TGF-β2 and TGF-β3. Paracrine release of TGF-β1 by stretched HSVSMCs inhibited TM expression in stationary HSVECs placed in co-culture by 57 ± 12% (P = .03), an effect that was abolished in the presence of 1D11. Similarly, TGF-β1 was the predominant isoform induced in rabbit VGs 7 days after implantation (3.5 ± 0.4-fold induction; P < .001). TGF-β1 protein expression localized predominantly to the developing neointima and coincided with marked suppression of endothelial TM expression (16% ± 2% of vein controls; P < .03), a reduction in situ activated protein C (APC)-generating capacity (53% ± 9% of vein controls; P = .001) and increased local thrombus formation (3.7 ± 0.8-fold increase over vein controls; P < .01). External stenting of VGs to limit vessel distension significantly reduced TGF-β1 induction and TM downregulation. Systemic administration of 1D11 also effectively prevented TM downregulation, preserved APC-generating capacity, and reduced local thrombus in rabbit VGs without observable effect on neointima formation and other morphometric parameters 6 weeks after implantation.ConclusionTM downregulation in VGs is mediated by paracrine release of TGF-β1 caused by pressure-induced vessel stretch. Systemic administration of an anti-TGF-β antibody effectively prevented TM downregulation and preserved local thromboresistance without negative effect on VG remodeling.Clinical RelevanceVein grafts (VGs) are commonly used conduits for coronary and peripheral arterial bypass surgeries. Thrombosis is a major cause of early VG failure. Trombomodulin (TM), a key component of the anticoagulant protein C pathway, is downregulated early after VG implantation and facilitates local thrombus formation. We found that paracrine release of transforming growth factor-β1 (TGF-β1), caused by pressure-induced stretch, was a potent negative regulator of TM in rabbit VGs. Administration of a neutralizing anti-TGF-β antibody effectively prevented TM downregulation and reduced local thrombus generation without adversely affecting long-term VG remodeling. This may represent a novel strategy to improve patency in patients undergoing arterial bypass procedures

Acute Trauma Factor Associations With Suicidality Across the First 5 Years After Traumatic Brain Injury

AbstractObjectiveTo determine whether severity of head and extracranial injuries (ECI) is associated with suicidal ideation (SI) or suicide attempt (SA) after traumatic brain injury (TBI).DesignFactors associated with SI and SA were assessed in this inception cohort study using data collected 1, 2, and 5 years post-TBI from the National Trauma Data Bank and Traumatic Brain Injury Model Systems (TBIMS) databases.SettingLevel I trauma centers, inpatient rehabilitation centers, and the community.ParticipantsParticipants with TBI from 15 TBIMS Centers with linked National Trauma Data Bank trauma data (N=3575).InterventionsNot applicable.Main Outcome MeasuresSI was measured via the Patient Health Questionnaire 9 (question 9). SA in the last year was assessed via interview. ECI was measured by the Injury Severity Scale (nonhead) and categorized as none, mild, moderate, or severe.ResultsThere were 293 (8.2%) participants who had SI without SA and 109 (3.0%) who had SA at least once in the first 5 years postinjury. Random effects logit modeling showed a higher likelihood of SI when ECI was severe (odds ratio=2.73; 95% confidence interval, 1.55–4.82; P=.001). Drug use at time of injury was also associated with SI (odds ratio=1.69; 95% confidence interval, 1.11–2.86; P=.015). Severity of ECI was not associated with SA.ConclusionsSevere ECI carried a nearly 3-fold increase in the odds of SI after TBI, but it was not related to SA. Head injury severity and less severe ECI were not associated with SI or SA. These findings warrant additional work to identify factors associated with severe ECI that make individuals more susceptible to SI after TBI

Damage control operations in non-trauma patients: defining criteria for the staged rapid source control laparotomy in emergency general surgery

Abstract Background The staged laparotomy in the operative management of emergency general surgery (EGS) patients is an extension of trauma surgeons operating on this population. Indications for its application, however, are not well defined, and are currently based on the lethal triad used in physiologically-decompensated trauma patients. This study sought to determine the acute indications for the staged, rapid source control laparotomy (RSCL) in EGS patients. Methods All EGS patients undergoing emergent staged RSCL and non-RSCL over 3 years were studied. Demographics, physiologic parameters, perioperative variables, outcomes, and survival were compared. Logistic regression models determined the influence of physiologic parameters on mortality and postoperative complications. EGS-RSCL indications were defined. Results 215 EGS patients underwent emergent laparotomy; 53 (25 %) were staged RSCL. In the 53 patients who underwent a staged RSCL based on the lethal triad, adjusted multivariable regression analysis shows that when used alone, no component of the lethal triad independently improved survival. Staged RSCL may decrease mortality in patients with preoperative severe sepsis / septic shock, and an elevated lactate (≥3); acidosis (pH ≤ 7.25); elderly (≥70); male gender; and multiple comorbidities (≥3). Of the 162 non-RSCL emergent laparotomies, 27 (17 %) required unplanned re-explorations; of these, 17 (63 %) had sepsis preoperatively and 9 (33 %) died. Conclusions The acute physiologic indicators that help guide operative decisions in trauma may not confer a similar survival advantage in EGS. To replace the lethal triad, criteria for application of the staged RSCL in EGS need to be defined. Based on these results, the indications should include severe sepsis / septic shock, lactate, acidosis, gender, age, and pre-existing comorbidities. When correctly applied, the staged RSCL may help to improve survival in decompensated EGS patients

A genomic storm in critically injured humans

Critical injury in humans induces a genomic storm with simultaneous changes in expression of innate and adaptive immunity genes

Mutations in Zebrafish lrp2 Result in Adult-Onset Ocular Pathogenesis That Models Myopia and Other Risk Factors for Glaucoma

The glaucomas comprise a genetically complex group of retinal neuropathies that typically occur late in life and are characterized by progressive pathology of the optic nerve head and degeneration of retinal ganglion cells. In addition to age and family history, other significant risk factors for glaucoma include elevated intraocular pressure (IOP) and myopia. The complexity of glaucoma has made it difficult to model in animals, but also challenging to identify responsible genes. We have used zebrafish to identify a genetically complex, recessive mutant that shows risk factors for glaucoma including adult onset severe myopia, elevated IOP, and progressive retinal ganglion cell pathology. Positional cloning and analysis of a non-complementing allele indicated that non-sense mutations in low density lipoprotein receptor-related protein 2 (lrp2) underlie the mutant phenotype. Lrp2, previously named Megalin, functions as an endocytic receptor for a wide-variety of bioactive molecules including Sonic hedgehog, Bone morphogenic protein 4, retinol-binding protein, vitamin D-binding protein, and apolipoprotein E, among others. Detailed phenotype analyses indicated that as lrp2 mutant fish age, many individuals—but not all—develop high IOP and severe myopia with obviously enlarged eye globes. This results in retinal stretch and prolonged stress to retinal ganglion cells, which ultimately show signs of pathogenesis. Our studies implicate altered Lrp2-mediated homeostasis as important for myopia and other risk factors for glaucoma in humans and establish a new genetic model for further study of phenotypes associated with this disease

Multi-omic analysis in injured humans: Patterns align with outcomes and treatment responses

Trauma is a leading cause of death and morbidity worldwide. Here, we present the analysis of a longitudinal multi-omic dataset comprising clinical, cytokine, endotheliopathy biomarker, lipidome, metabolome, and proteome data from severely injured humans. A "systemic storm" pattern with release of 1,061 markers, together with a pattern suggestive of the "massive consumption" of 892 constitutive circulating markers, is identified in the acute phase post-trauma. Data integration reveals two human injury response endotypes, which align with clinical trajectory. Prehospital thawed plasma rescues only endotype 2 patients with traumatic brain injury (30-day mortality: 30.3 versus 75.0%; p = 0.0015). Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) was identified as the most predictive circulating biomarker to identify endotype 2-traumatic brain injury (TBI) patients. These response patterns refine the paradigm for human injury, while the datasets provide a resource for the study of critical illness, trauma, and human stress responses

Geographic distribution of trauma centers and injury-related mortality in the United States

BackgroundRegionalized trauma care improves outcomes; however, access to care is not uniform across the United States. The objective was to evaluate whether geographic distribution of trauma centers correlates with injury mortality across state trauma systems.MethodsLevel I or II trauma centers in the contiguous United States were mapped. State-level age-adjusted injury fatality rates per 100,000 people were obtained and evaluated for spatial autocorrelation. Nearest neighbor ratios (NNRs) were generated for each state. A NNR less than 1 indicates clustering, while a NNR greater than 1 indicates dispersion. NNRs were tested for difference from random geographic distribution. Fatality rates and NNRs were examined for correlation. Fatality rates were compared between states with trauma center clustering versus dispersion. Trauma center distribution and population density were evaluated. Spatial-lag regression determined the association between fatality rate and NNR, controlling for state-level demographics, population density, injury severity, trauma system resources, and socioeconomic factors.ResultsFatality rates were spatially autocorrelated (Moran's I = 0.35, p &lt; 0.01). Nine states had a clustered pattern (median NNR, 0.55; interquartile range [IQR], 0.48-0.60), 22 had a dispersed pattern (median NNR, 2.00; IQR, 1.68-3.99), and 10 had a random pattern (median NNR, 0.90; IQR, 0.85-1.00) of trauma center distribution. Fatality rate and NNR were correlated (ρ = 0.34, p = 0.03). Clustered states had a lower median injury fatality rate compared with dispersed states (56.9 [IQR, 46.5-58.9] vs. 64.9 [IQR, 52.5-77.1]; p = 0.04). Dispersed compared with clustered states had more counties without a trauma center that had higher population density than counties with a trauma center (5.7% vs. 1.2%, p &lt; 0.01). Spatial-lag regression demonstrated that fatality rates increased by 0.02 per 100,000 persons for each unit increase in NNR (p &lt; 0.01).ConclusionGeographic distribution of trauma centers correlates with injury mortality, with more clustered state trauma centers associated with lower fatality rates. This may be a result of access relative to population density. These results may have implications for trauma system planning and require further study to investigate underlying mechanisms.Level of evidenceTherapeutic/care management study, level IV

Data from: Variation in individual temperature preferences, not behavioural fever, affects susceptibility to chytridiomycosis in amphibians

The ability of wildlife populations to mount rapid responses to novel pathogens will be critical for mitigating the impacts of disease outbreaks in a changing climate. Field studies have documented that amphibians preferring warmer temperatures are less likely to be infected with the fungal pathogen Batrachochytrium dendrobatidis (Bd). However, it is unclear whether this phenomenon is driven by behavioural fever or natural variation in thermal preference. Here, we placed frogs in thermal gradients, tested for temperature preferences and measured Bd growth, prevalence, and the survival of infected animals. Although there was significant individual- and species-level variation in temperature preferences, we found no consistent evidence of behavioural fever across five frog species. Interestingly, for species that preferred warmer temperatures, the preferred temperatures of individuals were negatively correlated with Bd growth on hosts, while the opposite correlation was true for species preferring cooler temperatures. Our results suggest that variation in thermal preference, but not behavioural fever, might shape the outcomes of Bd infections for individuals and populations, potentially resulting in selection for individual hosts and host species whose temperature preferences minimize Bd growth and enhance host survival during epidemics

Incompatible plasma transfusion is not associated with increased mortality in civilian trauma patients

ABSTRACTBackground The introduction of low titer group O whole blood (LTOWB) that contains potentially ABO-incompatible plasma and the increasing use of group A plasma, due to shortages of AB plasma, in trauma patients whose ABO group is unknown could put the recipients of incompatible plasma at risk of increased morbidity and mortality. This study evaluated civilian trauma patient outcomes following receipt of incompatible plasma.Methods One trauma center’s patient contributions to three multicenter studies of different trauma resuscitation strategies was analyzed; these patients were separated into two groups based on receipt of only compatible plasma versus receipt of any quantity of incompatible plasma. Multivariate analysis was performed to determine if receipt of incompatible plasma was associated with 24-hour or 30-day mortality.Results There were 347 patients eligible for this secondary analysis with 167 recipients of only compatible plasma and 180 recipients of incompatible plasma. The two groups were well matched demographically and on both prehospital and hospital arrival vital signs. The median (IQR) volume of incompatible plasma received by these patients was 684 ml (342, 1229). There was not a significant difference between the groups in 24-hour and 30-day mortality, nor in in-hospital or intensive care unit lengths of stay. In the Cox proportional-hazards regression model for both 24-hour and 30-day survival, receipt of incompatible plasma was not independently predictive of either mortality endpoint.Conclusion Receipt of incompatible plasma was not independently associated with increased mortality in trauma patients. Prospective studies are needed to confirm these findings