James Yang

Early lactate clearance is associated with biomarkers of inflammation, coagulation, apoptosis, organ dysfunction and mortality in severe sepsis and septic shock

BackgroundLactate clearance, a surrogate for the magnitude and duration of global tissue hypoxia, is used diagnostically, therapeutically and prognostically. This study examined the association of early lactate clearance with selected inflammatory, coagulation, apoptosis response biomarkers and organ dysfunction scores in severe sepsis and septic shock.MethodsMeasurements of serum arterial lactate, biomarkers (interleukin-1 receptor antagonist, interleukin-6, interleukin-8, interleukin-10, tumor necrosis factor-alpha, intercellular adhesion molecule-1, high mobility group box-1, D-Dimer and caspase-3), and organ dysfunction scores (Acute Physiology and Chronic Health Evaluation II, Simplified Acute Physiology Score II, Multiple Organ Dysfunction Score, and Sequential Organ Failure Assessment) were obtained in conjunction with a prospective, randomized study examining early goal-directed therapy in severe sepsis and septic shock patients presenting to the emergency department (ED). Lactate clearance was defined as the percent change in lactate levels after six hours from a baseline measurement in the ED.ResultsTwo-hundred and twenty patients, age 65.0 +/- 17.1 years, were examined, with an overall lactate clearance of 35.5 +/- 43.1% and in-hospital mortality rate of 35.0%. Patients were divided into four quartiles of lactate clearance, -24.3 +/- 42.3, 30.1 +/- 7.5, 53.4 +/- 6.6, and 75.1 +/- 7.1%, respectively (p < 0.01). The mean levels of all biomarkers and organ dysfunction scores over 72 hours were significantly lower with higher lactate clearance quartiles (p < 0.01). There was a significant decreased in-hospital, 28-day, and 60-day mortality in the higher lactate clearance quartiles (p < 0.01).ConclusionsEarly lactate clearance as a surrogate for the resolution of global tissue hypoxia is significantly associated with decreased levels of biomarkers, improvement in organ dysfunction and outcome in severe sepsis and septic shock.

The kinin B1 receptor contributes to the cardioprotective effect of angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers in mice

Recent studies have shown that inhibition of angiotensin‐converting enzyme (ACE) or angiotensin II receptors causes upregulation of the B1 receptor (B1R). Here we tested the hypothesis that activation of the B1R partly contributes to the cardiac beneficial effect of ACE inhibitor (ACEi) and angiotensin II receptor blockers (ARB). B1R knockout mice (B1R−/−) and C57Bl/6J (wild‐type control animals, WT) were subjected to myocardial infarction (MI) by ligating the left anterior descending coronary artery. Three weeks after MI, each strain of mice was treated with vehicle, ACEi (ramipril, 2.5 mg kg−1 day−1 in drinking water) or ARB (valsartan, 40 mg kg−1 day−1 in drinking water) for 5 weeks. We found that: (1) compared with WT mice, B1R−/− mice that underwent sham surgery had slightly but significantly increased left ventricular (LV) diastolic dimension, LV mass and myocyte size, whereas systolic blood pressure, cardiac function and collagen deposition did not differ between strains; (2) MI leads to LV hypertrophy, chamber dilatation and dysfunction similarly in both WT and B1R−/− mice; and (3) ACEi and ARB improved cardiac function and remodelling in both strains; however, these benefits were significantly diminished in B1R−/− mice. Our data suggest that kinins, acting via the B1R, participate in the cardioprotective effects of ACEi and ARB.

Investigation of the location effect of external markers in respiratory‐gated radiotherapy

In 7 lung and breast cancer patients, we investigated the location effect of external markers on the correlation between the motions of external markers and of an internal target under various breathing patterns. Our department developed a tumor tracking system consisting of two infrared cameras and a medical simulator. Using the system, we monitored the simultaneous motions of tumor and external markers placed at various locations on a patients skin and saved the results for offline analysis. We then used a cross‐covariance approach to analyze the correlation between the motions of individual markers and of the tumor. Based on the additive model, we evaluated the predictability of tumor motion from the motions of the external markers. The effect of marker location on the correlation between the motions of the tumor and of the external markers varied widely from patient to patient. At no specific marker location did the surrogate signal consistently present superior correlation with tumor motion in 3 breathing sessions with 7 patients. When the composite external signal generated from multiple external motion signals was correlated with tumor motion, the quality of the correlation improved significantly. In most cases, the composite signal provided the best surrogate signal for correlating with tumor motion. Correlation between the motions of external markers and of a tumor may be affected by several factors, including patient characteristics, marker locations, and breathing pattern. A single external marker cannot provide sufficient and reliable tracking information for tumor motion. A composite signal generated from the motions of multiple external makers provides an excellent surrogate signal, which in this study demonstrated superior correlation with tumor motion as compared with the signal provided by an individual marker. A composite signal would be a more reliable way to track tumor motion during respiratory‐gated radiotherapy. PACS numbers: 87.53.Jw

Gene expression profiling of dilated cardiomyopathy in older male EP4 knockout mice

Using a line of mice with cardiac-specific knockout (KO) of the EP4 receptor gene, experiments were designed to determine whether a cardiac phenotype developed with age. Cardiac function was assessed by echocardiography in 23- to 33-wk-old male and female KO and littermate controls (WT) mice. After echocardiography, hearts were removed to assess weight, and then some were further processed for histology [myocyte cross-sectional area (MCSA), interstitial collagen fraction (ICF), and macrophage infiltration] and some for extraction of total RNA and protein. Older male KO mice had reduced ejection fraction (EF) coupled with left ventricular dilatation. MCSA and infiltrating macrophages were not different between groups, but ICF increased by 39% in KO mice. In contrast to male KO mice, 30- to 32-wk-old female KO mice had only a slight reduction in EF. To understand gene expression differences between male WT and KO mice, we performed whole genome gene expression profiling (Illumina BeadChips) on hearts of 30-to 32-wk-old mice. Data indicated that 156 genes were overexpressed in the KO hearts more than twofold, including genes involved in remodeling, inflammation, and oxidative stress. Overexpressed chemokines/cytokines were further examined in hearts of 10- to 12-wk-old male KO mice, and we found that growth differentiation factor-15 (GDF-15) expression was higher in KO than in WT hearts. In conclusion, EP4 knockdown in cardiac myocytes in aged male KO mice is in part associated with increased fibrosis, reduced EF, and dilated cardiomyopathy. Early overexpression of GDF-15 in hearts of male KO mice may contribute to or be a marker of the disease phenotype. The absence of serious cardiac dysfunction in aged female mice suggests a sexual dimorphism in the phenotype.

The incidence and significance of bacteremia in out of hospital cardiac arrest

BACKGROUND The most common etiology of cardiac arrest is presumed of myocardial origin. Recent retrospective studies indicate that preexisting pneumonia, a form of sepsis, is frequent in patients who decompensate with abrupt cardiac arrest without preceding signs of septic shock, respiratory failure or severe metabolic disorders shortly after hospitalization. The contribution of pre-existing infection on pre and post cardiac arrest events remains unknown and has not been studied in a prospective fashion. We sought to examine the incidence of pre-existing infection in out-of hospital cardiac arrest (OHCA) and assess characteristics associated with bacteremia, the goal standard for presence of infection. METHODS AND RESULTS We prospectively observed 250 OHCA adult patients who presented to the Emergency Department (ED) between 2007 and 2009 to an urban academic teaching institution. Bacteremia was defined as one positive blood culture with non-skin flora bacteria or two positive blood cultures with skin flora bacteria. 77 met pre-defined exclusion criteria. Of the 173 OHCA adults, 65 (38%) were found to be bacteremic with asystole and PEA as the most common presenting rhythms. Mortality in the ED was significantly higher in bacteremic OHCA (75.4%) compared to non-bacteremic OHCA (60.2%, p<0.05). After adjustment for potential confounders, predictive factors associated with bacteremic OHCA were lower initial arterial pH, higher lactate, WBC, BUN and creatinine. CONCLUSIONS Over one-third of OHCA adults were bacteremic upon presentation. These patients have greater hemodynamic instability and significantly increased short-term mortality. Further studies are warranted to address the epidemiology of infection as possible cause of cardiac arrest.

Dose-dependent toxic effects of high-dose estrogen on renal and cardiac injury in surgically postmenopausal mice.

AIMS We previously found that in mice with experimental myocardial infarction (MI), 17β-estradiol (E2) increased mortality and worsened cardiac remodeling and these deleterious effects were associated with renal enlargement and hydronephrosis in a dose-dependent manner. In the present study we questioned whether E2-induced renal damage predisposes to rather than results from its adverse effects on the heart. MAIN METHODS Ovariectomized (ovx) mice received either placebo (P) or E2 at 0.02 (E2-L, low dose), 0.42 (E2-M, moderate dose) or 4.2 μg/d (E2-H, high dose) for 8 weeks. KEY FINDINGS E2-L partially restored uterine weight and plasma estrogen levels without affecting heart, lung and liver weight, hemodynamic parameters, or heart and kidney morphology and function. E2-M restored normal uterine weight, but this was accompanied by a significant increase in kidney weight, albuminuria, glomerular matrix formation and markers for oxidative stress. E2-H increased uterine weight 4.5-fold and resulted in higher plasma creatinine levels, severe albuminuria, renal tubular dilatation, tubulointerstitial injury, hydronephrosis, glomerulosclerosis and oxidative stress. E2-H also caused ascites, hepatomegaly and fluid retention in the uterine horns but had no significant effect on blood pressure or heart function. SIGNIFICANCE Our data demonstrated that an excessive dose of E2 that raises uterine weight beyond physiological levels adversely affects the kidney even before it damages the heart. We believe estrogen dosage should be taken into account when considering hormonal replacement therapy, since inappropriate doses of E2 may damage not only the heart but also the kidney.

Cilengitide-induced temporal variations in transvascular transfer parameters of tumor vasculature in a rat glioma model: identifying potential MRI biomarkers of acute effects.

Increased efficacy of radiotherapy (RT) 4-8 h after Cilengitide treatment has been reported. We hypothesized that the effects of Cilengitide on tumor transvascular transfer parameters might underlie, and thus predict, this potentiation. Athymic rats with orthotopic U251 glioma were studied at ~21 days after implantation using dynamic contrast-enhanced (DCE)-MRI. Vascular parameters, viz: plasma volume fraction (v p), forward volume transfer constant (K trans) and interstitial volume fraction (v e) of a contrast agent, were determined in tumor vasculature once before, and again in cohorts 2, 4, 8, 12 and 24 h after Cilengitide administration (4 mg/kg; N = 31; 6-7 per cohort). Perfusion-fixed brain sections were stained for von Willebrand factor to visualize vascular segments. A comparison of pre- and post-treatment parameters showed that the differences between MR indices before and after Cilengitide treatment pivoted around the 8 h time point, with 2 and 4 h groups showing increases, 12 and 24 h groups showing decreases, and values at the 8 h time point close to the baseline. The vascular parameter differences between group of 2 and 4 h and group of 12 and 24 h were significant for K trans (p = 0.0001 and v e (p = 0,0271). Vascular staining showed little variation with time after Cilengitide. The vascular normalization occurring 8 h after Cilengitide treatment coincided with similar previous reports of increased treatment efficacy when RT followed Cilengitide by 8 h. Pharmacological normalization of vasculature has the potential to increase sensitivity to RT. Evaluating acute temporal responses of tumor vasculature to putative anti-angiogenic drugs may help in optimizing their combination with other treatment modalities.