Cardiovascular Responsiveness to Vasopressin and α1-Adrenergic Receptor Agonists After Burn Injury.

The effects of burn injury on cardiovascular responsiveness to vasoactive agents are not well understood. The aims of this study were to determine whether burn injury alters cardiovascular reactivity to vasoactive drugs in vivo and intrinsic function of isolated mesenteric resistance arteries. Anesthetized Sprague-Dawley rats were subjected to sham procedure or 30% TBSA dorsal scald burn, followed by crystalloid resuscitation (Parkland Formula). At 24, 72, 96, and 168 hours post burn, rats were reanesthetized, and the mean arterial blood pressure (MAP) responses to various doses of the α1-adrenergic receptor agonist phenylephrine and arginine vasopressin were tested. Mesenteric arteries were harvested from uninjured animals and at 24 and 168 hours post burn. The responsiveness of arteries to phenylephrine and arginine vasopressin was tested by pressure myography. Dose response curves were generated and EC50 concentrations, Hill slopes, and maximal effects were compared. The potency of phenylephrine to increase MAP was reduced 2-fold 24 hours post burn (P < .05 vs sham) and gradually normalized at later time points. The reactivity of isolated arteries to phenylephrine was not significantly altered after burns. The potency of arginine vasopressin to increase MAP and to constrict isolated arteries was increased 2- to 3-fold at 24 hours post burn (P < .05) and normalized at later time points. Our findings suggest that burn injury differentially regulates vasopressor and blood pressure effects of α-adrenergic and vasopressin receptor agonists. Intrinsic vasopressin receptor reactivity of resistance arteries is sensitized early after burns. These findings will help to optimize resuscitation strategies and vasopressor use in difficult to resuscitate burn patients.

Ubiquitin Urine Levels in Burn Patients.

The objective of this study was to determine whether urine ubiquitin levels are elevated after burns and to assess whether urine ubiquitin could be useful as a noninvasive biomarker for burn patients. Forty burn patients (%TBSA: 20 ± 22; modified Baux scores: 73 ± 26) were included (control: 11 volunteers). Urine was collected in 2-hour intervals for 72 hours, followed by 12-hour intervals until discharge from the intensive care unit. Ubiquitin concentrations were analyzed by enzyme linked immunosorbent assay and Western blot. Total protein was determined with a Bradford assay. Patient characteristics and clinical parameters were documented. Urine ubiquitin concentrations, renal ubiquitin excretion, and excretion rates were correlated with patient characteristics and outcomes. Initial urine ubiquitin concentrations were 362 ± 575 ng/ml in patients and 14 ± 18 ng/ml in volunteers (P < .01). Renal ubiquitin excretion on day 1 was 292.6 ± 510.8 µg/24 hr and 21 ± 27 µg/24 hr in volunteers (P < .01). Initial ubiquitin concentrations correlated with modified Baux scores (r = .46; P = .02). Ubiquitin levels peaked at day 6 postburn, whereas total protein concentrations and serum creatinine levels remained within the normal range. Total renal ubiquitin excretion and excretion rates were higher in patients with %TBSA ≥20 than with %TBSA <20, in patients who developed sepsis/multiple organ failure than in patients without these complications and in nonsurvivors vs survivors. These data suggest that ubiquitin urine levels are significantly increased after burns. Renal ubiquitin excretion and/or excretion rates are associated with %TBSA, sepsis/multiple organ failure, and mortality. Although these findings may explain previous correlations between systemic ubiquitin levels and outcomes after burns, the large variability of ubiquitin urine levels suggests that urine ubiquitin will not be useful as a noninvasive disease biomarker.

Characterizing the role of a high-volume cancer resection ecosystem on low-volume, high-quality surgical care.

BACKGROUND: Our objective was to determine the hospital resources required for low-volume, high-quality care at high-volume cancer resection centers. METHODS: Patients who underwent esophageal, pancreatic, and rectal resection for malignancy were identified using Healthcare Cost and Utilization Project State Inpatient Database (Florida and California) between 2007 and 2011. Annual case volume by procedure was used to identify high- and low-volume centers. Hospital data were obtained from the American Hospital Association Annual Survey Database. Procedure risk-adjusted mortality was calculated for each hospital using multilevel, mixed-effects models. RESULTS: A total of 24,784 patients from 302 hospitals met the inclusion criteria. Of these, 13 hospitals were classified as having a high-volume, oncologic resection ecosystem by being a high-volume hospital for ≥2 studied procedures. A total of 11 of 31 studied hospital factors were strongly associated with hospitals that performed a high volume of cancer resections and were used to develop the High Volume Ecosystem for Oncologic Resections (HIVE-OR) score. At low-volume centers, increasing HIVE-OR score resulted in decreased mortality for rectal cancer resection (P = .038). HIVE-OR was not related to risk-adjusted mortality for esophagectomy (P = .421) or pancreatectomy (P = .413) at low-volume centers. CONCLUSION: Our study found that in some settings, low-volume, high-quality cancer surgical care can be explained by having a high-volume ecosystem.

New Insights into Mechanisms and Functions of Chemokine (C-X-C Motif) Receptor 4 Heteromerization in Vascular Smooth Muscle.

Recent evidence suggests that C-X-C chemokine receptor type 4 (CXCR4) heteromerizes with α1A/B-adrenoceptors (AR) and atypical chemokine receptor 3 (ACKR3) and that CXCR4:α1A/B-AR heteromers are important for α1-AR function in vascular smooth muscle cells (VSMC). Structural determinants for CXCR4 heteromerization and functional consequences of CXCR4:α1A/B-AR heteromerization in intact arteries, however, remain unknown. Utilizing proximity ligation assays (PLA) to visualize receptor interactions in VSMC, we show that peptide analogs of transmembrane-domain (TM) 2 and TM4 of CXCR4 selectively reduce PLA signals for CXCR4:α1A-AR and CXCR4:ACKR3 interactions, respectively. While both peptides inhibit CXCL12-induced chemotaxis, only the TM2 peptide inhibits phenylephrine-induced Ca(2+)-fluxes, contraction of VSMC and reduces efficacy of phenylephrine to constrict isolated arteries. In a Cre-loxP mouse model to delete CXCR4 in VSMC, we observed 60% knockdown of CXCR4. PLA signals for CXCR4:α1A/B-AR and CXCR4:ACKR3 interactions in VSMC, however, remained constant. Our observations point towards TM2/4 of CXCR4 as possible contact sites for heteromerization and suggest that TM-derived peptide analogs permit selective targeting of CXCR4 heteromers. A molecular dynamics simulation of a receptor complex in which the CXCR4 homodimer interacts with α1A-AR via TM2 and with ACKR3 via TM4 is presented. Our findings further imply that CXCR4:α1A-AR heteromers are important for intrinsic α1-AR function in intact arteries and provide initial and unexpected insights into the regulation of CXCR4 heteromerization in VSMC.

Food entrainment of circadian gene expression altered in PPARalpha-/- brown fat and heart.

The circadian clock is subject to food entrainment. Since PPARalpha exhibits a circadian expression profile, we hypothesized that PPARalpha deficiency would alter the food entrainable response of adipose, cardiac, and liver tissues. Wild-type and PPARalpha null mice were compared under ad libitum or restricted food access for the expression of circadian transcription factor-encoding mRNAs. Temporally restricted food access caused between a mean 5.8-11.5 h phase shift in the expression profiles of the circadian genes Bmal1, Per3, and Rev-erbalpha in all tissues of control mice. In contrast, these same conditions phase shifted the circadian genes in tissues of PPARalpha null mice between a mean of 10.8-14.2 h with amplitude attenuation. The food entrained phase shifts in the brown adipose and cardiac tissue circadian transcription factors of the PPARalpha null mice were prolonged significantly relative to wild-type controls. Likewise, PPARalpha responsive genes in the livers of PPARalpha null mice exhibited a significantly prolonged phase shift relative to control mice. These findings confirm and extend recent observations in the literature.