Karyn L. Butler

Regulating RISK: a role for JAK-STAT signaling in postconditioning?

Postconditioning (POC), a novel strategy of cardioprotection against ischemia-reperfusion injury, is clinically attractive because of its therapeutic application at the predictable onset of reperfusion. POC activates several intracellular kinase signaling pathways, including phosphatidylinositol 3-kinase (PI3K)-Akt (RISK). The regulation of POC-induced survival kinase signaling, however, has not been fully characterized. JAK-STAT activation is integral to cardiac ischemic tolerance and may provide upstream regulation of RISK. We hypothesized that POC requires the activation of both JAK-STAT and RISK signaling. Langendorff-perfused mouse hearts were subjected to 30 min of global ischemia and 40 min of reperfusion, with or without POC immediately after ischemia. A separate group of POC hearts was treated with AG 490, a JAK2 inhibitor, Stattic, a specific STAT3 inhibitor, or LY-294002, a PI3K inhibitor, at the onset of reperfusion. Cardiomyocyte-specific STAT3 knockout (KO) hearts were also subjected to non-POC or POC protocols. Myocardial performance (+dP/dt(max), mmHg/s) was assessed throughout each perfusion protocol. Phosphorylated (p-) STAT3 and Akt expression was analyzed by Western immunoblotting. POC enhanced myocardial functional recovery and increased expression of p-STAT3 and p-Akt. JAK-STAT inhibition abrogated POC-induced functional protection. STAT3 inhibition decreased expression of both p-STAT3 and p-Akt. PI3K inhibition also attenuated POC-induced cardioprotection and reduced p-Akt expression but had no effect on STAT3 phosphorylation. Interestingly, STAT3 KO hearts undergoing POC exhibited improved ischemic tolerance compared with KO non-POC hearts. POC induces myocardial functional protection by activating the RISK pathway. JAK-STAT signaling, however, is insufficient for effective POC without PI3K-Akt activation.

The impact of preinjury antiplatelet and anticoagulant pharmacotherapy on outcomes in elderly patients with hemorrhagic brain injury

BACKGROUND More elderly trauma patients are identified with preinjury use of clopidogrel, aspirin, or warfarin (CAW). The purpose of this study was to determine whether preinjury CAW use was an important predictor of mortality in patients aged >or=50 years with blunt, hemorrhagic brain injury (HBI). METHODS A retrospective review of patients with blunt, HBI aged >or=50 years with subgroup analysis for older (>70 years) and younger (50-70 years) patients was performed. CAW use was analyzed for differences in age, gender, hospital length of stay (LOS), Injury Severity Score (ISS), Glasgow Coma Score (GCS), mechanism of injury (MOI), platelet transfusion therapy (PLT), disposition at discharge, and in-hospital mortality. RESULTS From January 2003 to October 2005, 416 patients were identified. The mean age was 69+/-1 years. No differences were found for ISS (24 +/- 0.5), GCS (12 +/- 0.2), or LOS (8 +/- 0.4 days). CAW use was present in 40% of patients and significantly higher in older patients. Mortality was not different between older and younger CAW(+) patients, but it significantly increased for older CAW(-) patients. Significant predictors of death included age, ISS, and GCS (P<.02). CONCLUSIONS Preinjury CAW use in older blunt, HBI patients is not associated with increased mortality. Age was a significant predictor of mortality independent of CAW use.

Risk factors for relapse of ventilator-associated pneumonia in trauma patients.

BACKGROUND Our goal was to define risk factors for ventilator-associated pneumonia (VAP) relapse and examine the implications, if any, for initial therapy in trauma patients. METHODS Trauma patients cared for in the surgical intensive care unit during a 48-month period with confirmed VAP recurrence were evaluated. Recurrent VAP was defined as a positive quantitative culture (> or = 10(4) colony-forming units/mL in a bronchoalveolar lavage or protected catheter lavage specimen) > or = 4 days after initiation of antibiotics for the primary episode. Recurrence with at least one of the initial causative pathogens was defined as a relapse. Initial causal pathogen, Acute Physiology and Chronic Health Evaluation II score, injury severity score, Glasgow Coma Score (GCS), age, white blood cell count (WBC), and duration of hospital stay before diagnosis were analyzed in univariate and multivariate regression models. RESULTS A total of 55 patients met the criteria of recurrent VAP. Of these 55 recurrences, 19 (35%) were relapses. Acute Physiology and Chronic Health Evaluation II score, injury severity score, and GCS were not associated with VAP relapse by univariate analyses. Patients who relapsed had primary VAP involving nonfermenting gram-negative bacilli (NFGNB) (Acinetobacter, Pseudomonas, and Stenotrophomonas species) more frequently than other organisms (68% vs. 32%, p = 0.001). Primary VAP with NFGNB was found to be a significant predictor of VAP relapse by univariate and multivariate logistic regression analysis (OR = 5.1, p = 0.003; OR = 4.63, p = 0.005, respectively). CONCLUSIONS There is a high rate of VAP relapse associated with primary infection by NFGNB, suggesting initial treatment failure. Trauma patients with primary VAP involving these organisms may benefit from increased surveillance for relapse.

Equine-related injury: a retrospective analysis of outcomes over a 10-year period

BACKGROUND Morbidity and financial loss caused by equine-related injuries may be significant. The purposes of this study were to determine the patterns of equine-related injury and the impact on outcomes. METHODS A 10-year retrospective review of equine-related injuries was performed. Age, gender, mechanism, injury severity score, Glasgow Coma Score, length of stay, surgical interventions, and mortality were assessed. RESULTS Of 80 emergency department evaluations, 76 patients were admitted and form the basis of this study. The most frequent mechanism of injury was fall (68%), followed by crush injuries (15%), kicks (8%), and trampling (5%). Musculoskeletal injuries were most common (64%). Thirty-eight (50%) patients required surgical intervention. Thirty-seven (52%) patients were discharged home; 34% required outpatient physical therapy, and 14% required inpatient rehabilitation. The mortality rate was 7%. CONCLUSIONS Equine-related injuries resulted in significant morbidity; most victims required outpatient or inpatient rehabilitation. The use of preventive strategies may minimize mortality and reduce the financial impact of postinjury morbidity.

AT1-receptor blockade enhances ischemic preconditioning in hypertrophied rat myocardium

The purpose of this study was to determine whether ischemic preconditioning protects contractile function in hypertrophied rat myocardium from ischemia-reperfusion (I/R) injury. Male salt-sensitive rats were fed a high-salt diet for 2 wk to induce myocardial hypertrophy. Nonhypertrophied hearts were obtained from age-matched Sprague-Dawley (SD) rats fed a regular diet. Heart weight-to-body weight ratios were higher in salt-sensitive rats than in SD rats (6.9 ± 0.2 vs. 4.7 ± 0.2 g/kg, P < 0.01). A second group of salt-sensitive and SD rats was administered losartan (10 mg ⋅ kg-1 ⋅ day-1), an AT1-receptor blocker, for 1 wk before the study. Isolated hearts were preconditioned with transient ischemia before global I/R. After I/R, preconditioned hypertrophied hearts exhibited greater recovery of left ventricular developed pressure compared with that of preconditioned normal hearts (73 ± 8 vs. 18 ± 8%, P < 0.01). Left ventricular developed pressure was further enhanced by losartan in both hypertrophied and normal myocardium (99 ± 5 vs. 73 ± 8%, P < 0.05 and 97 ± 15 vs. 18 ± 8%, P < 0.01). Hypertrophied rat myocardium can be protected from I/R-induced contractile dysfunction by ischemic preconditioning. Losartan improves the ischemic tolerance of normal and hypertrophied myocardium.The purpose of this study was to determine whether ischemic preconditioning protects contractile function in hypertrophied rat myocardium from ischemia-reperfusion (I/R) injury. Male salt-sensitive rats were fed a high-salt diet for 2 wk to induce myocardial hypertrophy. Nonhypertrophied hearts were obtained from age-matched Sprague-Dawley (SD) rats fed a regular diet. Heart weight-to-body weight ratios were higher in salt-sensitive rats than in SD rats (6.9 +/- 0.2 vs. 4.7 +/- 0.2 g/kg, P < 0.01). A second group of salt-sensitive and SD rats was administered losartan (10 mg. kg(-1). day(-1)), an AT(1)-receptor blocker, for 1 wk before the study. Isolated hearts were preconditioned with transient ischemia before global I/R. After I/R, preconditioned hypertrophied hearts exhibited greater recovery of left ventricular developed pressure compared with that of preconditioned normal hearts (73 +/- 8 vs. 18 +/- 8%, P < 0.01). Left ventricular developed pressure was further enhanced by losartan in both hypertrophied and normal myocardium (99 +/- 5 vs. 73 +/- 8%, P < 0.05 and 97 +/- 15 vs. 18 +/- 8%, P < 0.01). Hypertrophied rat myocardium can be protected from I/R-induced contractile dysfunction by ischemic preconditioning. Losartan improves the ischemic tolerance of normal and hypertrophied myocardium.

The devil is in the details: Maximizing revenue for daily trauma care

BACKGROUND Falling reimbursement rates for trauma care demand a concerted effort of charge capture for the fiscal survival of trauma surgeons. We compared current procedure terminology code distribution and billing patterns for Subsequent Hospital Care (SHC) before and after the institution of standardized documentation. METHODS Standardized SHC progress notes were created. The note was formulated with an emphasis on efficiency and accuracy. Documentation was completed by residents in conjunction with attendings following standard guidelines of linkage. Year-to-year patient volume, length of stay (LOS), injury severity, bills submitted, coding of service, work relative value units (wRVUs), revenue stream, and collection rate were compared with and without standardized documentation. RESULTS A 394% average revenue increase was observed with the standardization of SHC documentation. Submitted charges more than doubled in the first year despite a 14% reduction in admissions and no change in length of stay. Significant increases in level II and level III billing and billing volume (P < .05) were sustainable year to year and resulted in an average per patient admission SHC income increase from

Unusual complications of long-term percutaneous gastrostomy tubes

91.85 to

STAT subtype specificity and ischemic preconditioning in mice: is STAT-3 enough?

362.31. CONCLUSIONS Use of a standardized daily progress note dramatically increases the accuracy of coding and associated billing of subsequent hospital care for trauma services.

Is bilateral protected specimen brush sampling necessary for the accurate diagnosis of ventilator-associated pneumonia?

Percutaneous endoscopic gastrostomy (PEG) has been popular since it was introduced in 1980. Gastrostomy tubes left in place for long periods often result in unusual complications. Complications may also result from simply replacing a long-term indwelling tube. Five patients who had gastrostomy tubes in place for as long as 4 years are presented and their complications reviewed. Various methods used in treating these complications are discussed, and suggestions for their prevention are given. Gastrointestinal erosion and jejunal perforation following migration of the gastrostomy tube, persistent abdominal wall sinus tracts, and separation of the flange head with small bowel obstruction were encountered. Reinsertion of a gastrostomy tube through a tract prior to adequate maturation was also noted to lead to complications. Complications may result from gastrostomy tubes left in place for extended periods of time and during replacement procedures. Awareness of such complications along with education of caregivers and timely intervention by the endoscopist may prevent such occurrences. In some cases one can only hope to minimize morbidity.

Heart Function Challenged with β-Receptor Agonism or Antagonism in a Heart Failure Model

The role of other STAT subtypes in conferring ischemic tolerance is unclear. We hypothesized that in STAT-3 deletion alternative STAT subtypes would protect myocardial function against ischemia-reperfusion injury. Wild-type (WT) male C57BL/6 mice or mice with cardiomyocyte STAT-3 knockout (KO) underwent baseline echocardiography. Langendorff-perfused hearts underwent ischemic preconditioning (IPC) or no IPC before ischemia-reperfusion. Following ex vivo perfusion, hearts were analyzed for STAT-5 and -6 phosphorylation by Western blot analysis of nuclear fractions. Echocardiography and postequilibration cardiac performance revealed no differences in cardiac function between WT and KO hearts. Phosphorylated STAT-5 and -6 expression was similar in WT and KO hearts before perfusion. Contractile function in WT and KO hearts was significantly impaired following ischemia-reperfusion in the absence of IPC. In WT hearts, IPC significantly improved the recovery of the maximum first derivative of developed pressure (+dP/dtmax) compared with that in hearts without IPC. IPC more effectively improved end-reperfusion dP/dtmax in WT hearts compared with KO hearts. Preconditioned and nonpreconditioned KO hearts exhibited increased phosphorylated STAT-5 and -6 expression compared with WT hearts. The increased subtype activation did not improve the efficacy of IPC in KO hearts. In conclusion, baseline cardiac performance is preserved in hearts with cardiac-restricted STAT-3 deletion. STAT-3 deletion attenuates preconditioning and is not associated with a compensatory upregulation of STAT-5 and -6 subtypes. The activation of STAT-5 and -6 in KO hearts following ischemic challenge does not provide functional compensation for the loss of STAT-3. JAK-STAT signaling via STAT-3 is essential for effective IPC.