Summary Major burns provoke a profound stress response, which is unrivalled in terms of its magnitude and duration. Evidence suggests that the pathophysiological stress response to severe burn trauma ...persists for several years after injury. Thus, there is a pressing need for novel strategies that mitigate this response and restore normal metabolic function in patients with burns. This is the first in a Series of three papers about the care of people with burns. In this paper, we review the current knowledge of the stress response to burn trauma, with a focus on hypermetabolism, muscle wasting, and stress-induced diabetes. We highlight recent developments and important knowledge gaps that need to be pursued to develop novel therapeutic strategies to improve outcomes in burn survivors.
Under laminar flow conditions, when no external forces are applied, particles are generally thought to follow fluid streamlines. Contrary to this perspective, we observe that flowing particles ...migrate across streamlines in a continuous, predictable, and accurate manner in microchannels experiencing laminar flows. The migration is attributed to lift forces on particles that are observed when inertial aspects of the flow become significant. We identified symmetric and asymmetric channel geometries that provide additional inertial forces that bias particular equilibrium positions to create continuous streams of ordered particles precisely positioned in three spatial dimensions. We were able to order particles laterally, within the transverse plane of the channel, with >80-nm accuracy, and longitudinally, in regular chains along the direction of flow. A fourth dimension of rotational alignment was observed for discoidal red blood cells. Unexpectedly, ordering appears to be independent of particle buoyant direction, suggesting only minor centrifugal contributions. Theoretical analysis indicates the physical principles are operational over a range of channel and particle length scales. The ability to differentially order particles of different sizes, continuously, at high rates, and without external forces in microchannels is expected to have a broad range of applications in continuous bioparticle separation, high-throughput cytometry, and large-scale filtration systems.
This review explores the series of published analyses from Massachusetts General Hospital to better understand how changes in medical specialization of burn medicine likely enabled the most important ...increase in survival from burns in the past 70 years.
Seventy years ago, survival from the most serious burn injuries was not possible even in the most advanced countries until critical advances were introduced. Insights into those few medical advances that actually impacted survival might be better understood from the consideration of a continuous series of survival analyses over 7 decades at Massachusetts General Hospital.
Mortality data from previously reported probit and logit analyses from thousands of patients treated at Massachusetts General Hospital were reviewed. A comparison of mortality from these prior mortality analyses from a more recent multicenter study and a national data set was performed.
The only giant leap forward in survival occurred during the 1970s, with no improvement during either the preceding or subsequent 30-year intervals. Despite the many modern advances that have been added to the care of these patients since 1984, although these may have represented medical progress, these advances did not impact survival.
Survival rates from burn injury may have been maximized by current treatment approaches within medical centers of excellence in burn medicine. Further efforts to improve the quality of life of survivors of burn injury should ultimately have very favorable impact upon the long-term outcomes in these patients who now survive such devastating injuries.
Inflammation and apoptosis develop in skeletal muscle after major trauma, including burn injury, and play a pivotal role in insulin resistance and muscle wasting. We and others have shown that ...inducible nitric oxide synthase (iNOS), a major mediator of inflammation, plays an important role in stress (e.g., burn)-induced insulin resistance. However, it remains to be determined how iNOS induces insulin resistance. Moreover, the interrelation between inflammatory response and apoptosis is poorly understood, although they often develop simultaneously. Nuclear factor (NF)-κB and p53 are key regulators of inflammation and apoptosis, respectively. Sirt1 inhibits p65 NF-κB and p53 by deacetylating these transcription factors. Recently, we have shown that iNOS induces S-nitrosylation of Sirt1, which inactivates Sirt1 and thereby increases acetylation and activity of p65 NF-κB and p53 in various cell types, including skeletal muscle cells. Here, we show that iNOS enhances burn-induced inflammatory response and apoptotic change in mouse skeletal muscle along with S-nitrosylation of Sirt1. Burn injury induced robust expression of iNOS in skeletal muscle and gene disruption of iNOS significantly inhibited burn-induced increases in inflammatory gene expression and apoptotic change. In parallel, burn increased Sirt1 S-nitrosylation and acetylation and DNA-binding capacity of p65 NF-κB and p53, all of which were reversed or ameliorated by iNOS deficiency. These results indicate that iNOS functions not only as a downstream effector but also as an upstream enhancer of burn-induced inflammatory response, at least in part, by Sirt1 S-nitrosylation-dependent activation (acetylation) of p65 NF-κB. Our data suggest that Sirt1 S-nitrosylation may play a role in iNOS-mediated enhanced inflammatory response and apoptotic change, which, in turn, contribute to muscle wasting and supposedly to insulin resistance after burn injury.
Mice are not men Warren, H. Shaw; Tompkins, Ronald G.; Moldawer, Lyle L. ...
Proceedings of the National Academy of Sciences - PNAS,
01/2015, Volume:
112, Issue:
4
Journal Article
Trauma patients are at risk of repeated hospital-acquired infections, however predictive scores aiming to identify susceptibility to such infections are lacking. The objective of this study was to ...investigate whether commonly employed disease-severity scores can successfully predict susceptibility to multiple independent infectious episodes (MIIEs) among trauma patients. A secondary analysis of data derived from the prospective, longitudinal study "Inflammation and the Host Response to Injury" ("Glue Grant") was performed. 1,665 trauma patients, older than 16, were included. Patients who died within seven days from the time of injury were excluded. Five commonly used disease-severity scores Denver, Marshall, Acute Physiology and Chronic Health Evaluation II (APACHE II), Injury Severity Score (ISS), and New Injury Severity Score (NISS) were examined as independent predictors of susceptibility to MIIEs. The latter was defined as two or more independent infectious episodes during the index hospital stay. Multivariable logistic regression was used for the statistical analysis. 22.58% of the population was found to be susceptible to MIIEs. Denver and Marshall scores were highly predictive of the MIIE status. For every 1-unit increase in the Denver or the Marshall score, there was a respective 15% (Odds Ratio:1.15; 95% CI: 1.07-1.24; p < 0.001) or 16% (Odds Ratio:1.16; 95% CI: 1.09-1.24; p < 0.001) increase in the odds of MIIE occurrence. APACHE II, ISS, and NISS were not independent predictors of susceptibility to MIIEs. In conclusion, the Denver and Marshall scores can reliably predict which trauma patients are prone to MIIEs, prior to any clinical sign of infection. Early identification of these individuals would potentially allow the implementation of rapid, personalized, preventative measures, thus improving patient outcomes and reducing healthcare costs.
Characterizing the genome-wide dynamic regulation of gene expression is important and will be of much interest in the future. However, there is currently no established method for identifying ...differentially expressed genes in a time course study. Here we propose a significance method for analyzing time course microarray studies that can be applied to the typical types of comparisons and sampling schemes. This method is applied to two studies on humans. In one study, genes are identified that show differential expression over time in response to in vivo endotoxin administration. By using our method, 7,409 genes are called significant at a 1% false-discovery rate level, whereas several existing approaches fail to identify any genes. In another study, 417 genes are identified at a 10% false-discovery rate level that show expression changing with age in the kidney cortex. Here it is also shown that as many as 47% of the genes change with age in a manner more complex than simple exponential growth or decay. The methodology proposed here has been implemented in the freely distributed and open-source EDGE software package.
Rapid separation and filtration of particles in solution has a wide range of applications including blood cell separation, ultrasound contrast agent preparation, and purification of fermentation ...products. However, current techniquesthat provide quick processing rates are high in complexity. We present a rapid microfluidic filtration technology capable of separating particles based on size, with purities from 90 to 100% and high-volume throughputs of 1 mL/min. Data for separation of rigid particles, deformable emulsions, and platelets from whole blood are presented. The system is based upon differential inertial focusing of particles of varying sizes and allows continuous separation based only on intrinsic hydrodynamic forces developed in a flow through an asymmetrically curved channel. A theoretical description of the underlying forces is developed, and in combination with data determining a size cutoff for separation, a semiempirical relationship describing how channel geometry is related to this cutoff is shown. Cascading separations in series is shown to be useful for increasing purity and yield. This type of microfluidic system can filter deformable particles, is largely independent of particle density, and can provide throughputs typical of macroscale filtration in a compact format, enabling applications in blood filtration and particle concentration.
Severe burn causes metabolic disturbances that can last for a year after injury; persistent and profound catabolism hampers rehabilitative efforts and delays the meaningful return of individuals to ...society. The simplest, effective anabolic strategies for severe burn injuries are: early excision and grafting of the wound; prompt treatment of sepsis; maintenance of environmental temperature at 30–32°C; continuous feeding of a high carbohydrate, high protein diet, preferably by the enteral route; and early institution of vigorous and aerobic resistive exercise programmes. To further keep erosion of lean body mass to a minimum, administration of anabolic agents, recombinant human growth hormone, insulin, oxandrolone, or anticatabolic drugs such as propranolol are alternative approaches. Exogenous continuous low-dose insulin infusion, β blockade with propranolol, and use of the synthetic testosterone analogue oxandrolone are the most cost effective and least toxic pharmacological treatments to date.
PDF
