ATP-Sensitive Potassium Channel Opener Diazoxide Reduces Myocardial Stunning in a Porcine Regional With Subsequent Global Ischemia Model.

Background ATP-sensitive potassium channels are inhibited by ATP and open during metabolic stress, providing endogenous myocardial protection. Pharmacologic opening of ATP potassium channels with diazoxide preserves myocardial function following prolonged global ischemia, making it an ideal candidate for use during cardiac surgery. We hypothesized that diazoxide would reduce myocardial stunning after regional ischemia with subsequent prolonged global ischemia, similar to the clinical situation of myocardial ischemia at the time of revascularization. Methods and Results Swine underwent left anterior descending occlusion (30 minutes), followed by 120 minutes global ischemia protected with hyperkalemic cardioplegia±diazoxide (N=6 each), every 20 minutes cardioplegia, then 60 minutes reperfusion. Cardiac output, time to wean from cardiopulmonary bypass, left ventricular (LV) function, caspase-3, and infarct size were compared. Six animals in the diazoxide group separated from bypass by 30 minutes, whereas only 4 animals in the cardioplegia group separated. Diazoxide was associated with shorter but not significant time to wean from bypass (17.5 versus 27.0 minutes; P=0.13), higher, but not significant, cardiac output during reperfusion (2.9 versus 1.5 L/min at 30 minutes; P=0.05), and significantly higher left ventricular ejection fraction at 30 minutes (42.5 versus 15.8%; P<0.01). Linear mixed regression modeling demonstrated greater left ventricular developed pressure (P<0.01) and maximum change in ventricular pressure during isovolumetric contraction (P<0.01) in the diazoxide group at 30 minutes of reperfusion. Conclusions Diazoxide reduces myocardial stunning and facilitates separation from cardiopulmonary bypass in a model that mimics the clinical setting of ongoing myocardial ischemia before revascularization. Diazoxide has the potential to reduce myocardial stunning in the clinical setting.

Low Back Pain, Psychiatric Disorders, and a Combination of Both Negatively Affect Hip Arthroscopy Outcomes in Servicemembers.

BACKGROUND: Hip arthroscopy for femoroacetabular impingement (FAI) in athletes, including military servicemembers, has resulted in variable outcomes. The prevalence of low back pain (LBP) and psychiatric disorders (PSYs) is high among patients undergoing hip arthroscopy. PURPOSE: To determine the effect of LBP, PSYs, and the combination of both on outcomes in servicemembers treated arthroscopically for FAI. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Between April 2016 and June 2020, a total of 108 consecutive active-duty servicemembers underwent hip arthroscopy by a single surgeon at a single military medical center. Servicemembers were grouped according to the presence of preoperative LBP (Group LBP), a PSY (Group PSY), or both (Group Both), and outcomes were compared with those of servicemembers without these comorbidities (Group None). The minimum follow-up was 6 months. The primary outcome measure was return to duty (RTD). Secondary outcomes included the Nonarthritic Hip Score (NAHS), Hip Outcome Score-Activities of Daily Living (HOS-ADL) subscale, and Hip Outcome Score-Sports (HOS-S) subscale. RESULTS: All servicemembers' final duty status was confirmed, with a mean follow-up of 2 years (range, 6 months-4.3 years). The prevalence of preoperative LBP and PSY was 27% and 39%, respectively. RTD was 59% (10/17) in Group LBP, 10% (3/30) in Group PSY, 0% (0/12) in Group Both, and 47% (23/49) in Group None. Compared with Group None, the risk of discontinuing military service was statistically higher in Group PSY (relative risk [RR], 1.70 [95% CI, 1.41-1.99]) and Group Both (RR, 1.88 [95% CI, 1.62-2.15]) but not in Group LBP (RR, 0.78 [95% CI, 0.15-1.40]). The mean preoperative secondary outcomes all significantly improved postoperatively in Group None (NAHS, 58 to 75 [P < .001]; HOS-ADL, 63 to 74 [P < .001]; HOS-S, 44 to 57 [P < .001]). Among the comorbid groups, the mean HOS-S did not significantly improve (Group LBP, 45 to 48 [P = .71]; Group PSY, 36 to 44 [P = .22]; Group Both 43 to 45 [P = .75]), and <50% of these servicemembers achieved HOS-S meaningful clinical benefit metrics. CONCLUSION: Preoperative LBP, PSY, and a combination of both negatively affected outcomes after hip arthroscopy. Preoperative counseling is crucial in setting realistic outcome expectations.

Diazoxide preserves myocardial function in a swine model of hypothermic cardioplegic arrest and prolonged global ischemia.

OBJECTIVE: Adenosine triphosphate potassium sensitive channels provide endogenous myocardial protection via coupling of cell membrane potential to myocardial metabolism. Adenosine triphosphate potassium sensitive channel openers, such as diazoxide, mimic ischemic preconditioning, prevent cardiomyocyte swelling, preserve myocyte contractility after stress, and provide diastolic protection. We hypothesize that diazoxide combined with hyperkalemic cardioplegia provides superior myocardial protection compared with cardioplegia alone during prolonged global ischemia in a large animal model. METHODS: Twelve pigs were randomized to global ischemia for 2 hours with a single dose of cold blood (4:1) hyperkalemic cardioplegia alone (n = 6) or with diazoxide (500 µmol/L) (n = 6) and reperfused for 1 hour. Cardiac output, myocardial oxygen consumption, left ventricular developed pressure, left ventricular ejection fraction, diastolic function, myocardial troponin, myoglobin, markers of apoptosis, and left ventricular infarct size were compared. RESULTS: Four pigs in the cardioplegia alone group could not be weaned from cardiopulmonary bypass. There were no differences in myoglobin, troponin, or apoptosis between groups. Diazoxide preserved cardiac output versus control (74.5 vs 18.4 mL/kg/min, P = .01). Linear mixed regression modeling demonstrated that the addition of diazoxide to cardioplegia preserved left ventricular developed pressure by 36% (95% confidence interval, 9.9-61.5; P < .01), dP/dt max by 41% (95% confidence interval, 14.5-67.5; P < .01), and dP/dt min by 33% (95% confidence interval, 8.9-57.5; P = .01). It was also associated with higher (but not significant) myocardial oxygen consumption (3.7 vs 1.4 mL O2/min, P = .12). CONCLUSIONS: Diazoxide preserves systolic and diastolic ventricular function in a large animal model of prolonged global myocardial ischemia. Diazoxide as an adjunct to hyperkalemic cardioplegia may allow safer prolonged ischemic times during increasingly complicated cardiac procedures.

WIDECARS multi-parameter measurements in premixed ethylene-air flames using a wavelength stable ultrabroadband dye laser.

Width-increased dual-pump enhanced coherent anti-Stokes Raman spectroscopy (WIDECARS) measurements were used to determine the temperature and major species mole fractions in laminar, premixed, ethylene-air flames operating at atmospheric pressure. Conventional ultrabroadband dye lasers for WIDECARS, which use Pyrromethene dyes, have historically suffered from day-to-day wavelength shifting. To overcome this problem, a new ultrabroadband dye laser was developed in this study to provide a stable wavelength and power generation. A new dye laser pumping scheme and a mixture of Sulforhodamine 640, Kiton Red 620, and Rhodamine 640, was used to generate the desired FWHM ${\sim}{15}\;{\rm nm}$∼15nm (${410}\;{{\rm cm}^{ - 1}}$410cm-1) bandwidth. The WIDECARS measured mole fraction ratios of ${{\rm CO}_2}$CO2, CO, and ${{\rm H}_2}$H2 with ${{\rm N}_2}$N2 agreed well with chemical equilibrium calculations.

A non-human primate model of radiation-induced cachexia.

Cachexia, or muscle wasting, is a serious health threat to victims of radiological accidents or patients receiving radiotherapy. Here, we propose a non-human primate (NHP) radiation-induced cachexia model based on clinical and molecular pathology findings. NHP exposed to potentially lethal partial-body irradiation developed symptoms of cachexia such as body weight loss in a time- and dose-dependent manner. Severe body weight loss as high as 20-25% was observed which was refractory to nutritional intervention. Radiographic imaging indicated that cachectic NHP lost as much as 50% of skeletal muscle. Histological analysis of muscle tissues showed abnormalities such as presence of central nuclei, inflammation, fatty replacement of skeletal muscle, and muscle fiber degeneration. Biochemical parameters such as hemoglobin and albumin levels decreased after radiation exposure. Levels of FBXO32 (Atrogin-1), ActRIIB and myostatin were significantly changed in the irradiated cachectic NHP compared to the non-irradiated NHP. Our data suggest NHP that have been exposed to high dose radiation manifest cachexia-like symptoms in a time- and dose-dependent manner. This model provides a unique opportunity to study the mechanism of radiation-induced cachexia and will aid in efficacy studies of mitigators of this disease.

Increased Expression of Connective Tissue Growth Factor (CTGF) in Multiple Organs After Exposure of Non-Human Primates (NHP) to Lethal Doses of Radiation.

Exposure to sufficiently high doses of ionizing radiation is known to cause fibrosis in many different organs and tissues. Connective tissue growth factor (CTGF/CCN2), a member of the CCN family of matricellular proteins, plays an important role in the development of fibrosis in multiple organs. The aim of the present study was to quantify the gene and protein expression of CTGF in a variety of organs from non-human primates (NHP) that were previously exposed to potentially lethal doses of radiation. Tissues from non-irradiated NHP and NHP exposed to whole thoracic lung irradiation (WTLI) or partial-body irradiation with 5% bone marrow sparing (PBI/BM5) were examined by real-time quantitative reverse transcription PCR, western blot, and immunohistochemistry. Expression of CTGF was elevated in the lung tissues of NHP exposed to WTLI relative to the lung tissues of the non-irradiated NHP. Increased expression of CTGF was also observed in multiple organs from NHP exposed to PBI/BM5 compared to non-irradiated NHP; these included the lung, kidney, spleen, thymus, and liver. These irradiated organs also exhibited histological evidence of increased collagen deposition compared to the control tissues. There was significant correlation of CTGF expression with collagen deposition in the lung and spleen of NHP exposed to PBI/BM5. Significant correlations were observed between spleen and multiple organs on CTGF expression and collagen deposition, respectively, suggesting possible crosstalk between spleen and other organs. These data suggest that CTGF levels are increased in multiple organs after radiation exposure and that inflammatory cell infiltration may contribute to the elevated levels of CTGF in multiple organs.

A MALDI-MSI Approach to the Characterization of Radiation-Induced Lung Injury and Medical Countermeasure Development.

Radiation-induced lung injury is highly complex and characterized by multiple pathologies, which occur over time and sporadically throughout the lung. This complexity makes biomarker investigations and medical countermeasure screenings challenging. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) has the ability to resolve differences spatially in molecular profiles within the lung following radiation exposure and can aid in biomarker identification and pharmaceutical efficacy investigations. MALDI-MSI was applied to the investigation of a whole-thorax lung irradiation model in non-human primates (NHP) for lipidomic analysis and medical countermeasure distribution.

Dietary microbes modulate transgenerational cancer risk.

Environmental factors are suspected in the increase of obesity and cancer in industrialized countries but are poorly understood. Here, we used animal models to test how future generations may be affected by Westernized diets. We discover long-term consequences of grandmothers' in utero dietary exposures, leading to high rates of obesity and frequent cancers of lung and liver in two subsequent generations of mice. Transgenerational effects were transplantable using diet-associated bacteria communities alone. Consequently, feeding of beneficial microbes was sufficient to lower transgenerational risk for cancer and obesity regardless of diet history. Targeting microbes may be a highly effective population-based approach to lower risk for cancer.

Microbial symbionts accelerate wound healing via the neuropeptide hormone oxytocin.

Wound healing capability is inextricably linked with diverse aspects of physical fitness ranging from recovery after minor injuries and surgery to diabetes and some types of cancer. Impact of the microbiome upon the mammalian wound healing process is poorly understood. We discover that supplementing the gut microbiome with lactic acid microbes in drinking water accelerates the wound-healing process to occur in half the time required for matched control animals. Further, we find that Lactobacillus reuteri enhances wound-healing properties through up-regulation of the neuropeptide hormone oxytocin, a factor integral in social bonding and reproduction, by a vagus nerve-mediated pathway. Bacteria-triggered oxytocin serves to activate host CD4+Foxp3+CD25+ immune T regulatory cells conveying transplantable wound healing capacity to naive Rag2-deficient animals. This study determined oxytocin to be a novel component of a multi-directional gut microbe-brain-immune axis, with wound-healing capability as a previously unrecognized output of this axis. We also provide experimental evidence to support long-standing medical traditions associating diet, social practices, and the immune system with efficient recovery after injury, sustained good health, and longevity.

Preparedness of orthopaedic surgeons for modern battlefield surgery.

Over 220 U.S. Army orthopaedic surgeons have deployed during the Global War on Terrorism (GWOT). This study documents the orthopaedic procedures performed during the GWOT and identifies training that prepared surgeons for deployment. It reveals deficiencies in surgeons' preparedness and intends to improve predeployment training. All surgeons deployed during the GWOT from 2001 to 2007 were surveyed. Questions fit 4 general categories: deployment demographics, medical and surgical experiences, predeployment preparation, and self-perceived preparedness during deployment. Response rate was 70%. Surgeons averaged 138 adult operative cases and 26 pediatric cases per deployment. All surgeons performed irrigation and debridement, 94% external fixation, 93% amputations, 89% arthrotomies, 86% open reduction and internal fixation, and 76% soft-tissue coverage procedures. Residency and fellowship contributed most to surgeon preparedness for deployment. Surgeons generally reported high levels of preparedness, but nearly 1 in 6 reported low levels of medical, surgical and physical preparedness. More reported low levels of mental preparedness. Soft-tissue coverage was the most frequently reported surgical deficiency. This study documents the number and types of orthopaedic procedures performed during the GWOT and identifies the self-perceived preparedness deficiencies of surgeons in a combat environment. Improvements in predeployment training are needed to better prepare surgeons for managing battlefield causalities.

Laser-induced incandescence measurements of soot in turbulent pool fires.

We present what we believe to be the first application of the laser-induced incandescence (LII) technique to large-scale fire testing. The construction of an LII instrument for fire measurements is presented in detail. Soot volume fraction imaging from 2 m diameter pool fires burning blended toluene/methanol liquid fuels is demonstrated along with a detailed report of measurement uncertainty in the challenging pool fire environment. Our LII instrument relies upon remotely located laser, optical, and detection systems and the insertion of water-cooled, fiber-bundle-coupled collection optics into the fire plume. Calibration of the instrument was performed using an ethylene/air laminar diffusion flame produced by a Santoro-type burner, which allowed for the extraction of absolute soot volume fractions from the LII images. Single-laser-shot two-dimensional images of the soot layer structure are presented with very high volumetric spatial resolution of the order of 10(-5) cm3. Probability density functions of the soot volume fraction fluctuations are constructed from the large LII image ensembles. The results illustrate a highly intermittent soot fluctuation field with potentially large macroscale soot structures and clipped soot probability densities.