Prakash K. Pandalai

Traumatic diaphragmatic injury: Experience from a level I trauma center

OBJECTIVE Traumatic diaphragmatic injuries (TDI) are uncommon but associated with substantial morbidity and mortality. We sought to analyze patients with TDI at a large trauma center and associated county coroner to identify characteristics predictive of increased mortality. METHODS We queried a level I university trauma center and associated county coroner databases containing >20,000 patients to identify patients with ICD-9 diagnoses pertaining to TDI from January 1992 through May 2005. Once identified, hospital records, operative details, and autopsy reports were reviewed to determine injury characteristics, treatment provided, and outcome. Statistical analyses were performed using the Student t-test, chi-square analysis, analysis of variance, and multiple logistic regression. RESULTS TDI were identified in 254 individuals. Two hundred (79%) survived to undergo operation. Of the 81 (32%) deaths, 33 (41%) occurred before arrival at the trauma center. Survivors were younger, had lesser injury severity scores (ISS), were more likely to be female, and had more bilateral injuries (P < or = .002 all) than nonsurvivors. By multiple logistic regression analyses, increased age (odds ratio [OR], 1.044; 95% confidence interval [CI], 1.015-1.074; P = .0029) and greater ISS (OR, 1.145; 95% CI, 1.103-1.188; P < .0001) were predictors of the probability of death in all patients. CONCLUSION Although TDI may indicate substantive trauma burden in any patient, those with greater ISS and advanced age are at the greatest risk of death.

Can lung cancer screening by computed tomography be effective in areas with endemic histoplasmosis

OBJECTIVE Low-dose chest computed tomography (CT) is being evaluated in several national trials as a screening modality for the early detection of lung cancer. The goal of the present study was to determine whether lung cancer screening could be done while minimizing the number of benign biopsy specimens taken in an area endemic for histoplasmosis. METHODS The subjects were recruited by letters mailed to area physicians and local advertisement. The inclusion criteria were age older than 50 years and at least a 20 pack-year smoking history. The exclusion criteria were symptoms suggestive of lung cancer or a history of malignancy in the previous 5 years. The participants completed a questionnaire and underwent a chest CT scan at baseline and annually for 5 years. The management of positive screening results was determined using a defined algorithm: annual follow-up CT scan for nodules less than 5 mm; 6-month follow-up CT scan for nodules 5 to 7 mm; review by our multidisciplinary tumor board for nodules 8 to 12 mm; and biopsy for nodules greater than 12 mm. RESULTS A total of 132 patients were recruited. Of the 132 patients, 61% had positive baseline CT findings and 22% had positive findings on the annual CT scans. Six cancers were detected. Of these 6 patients, 5 had stage I disease and underwent lobectomy, and 1 had stage IIIA disease and underwent induction chemotherapy and radiotherapy followed by lobectomy. All patients were alive and disease free at a mean follow-up of 41.7 ± 18.6 months. No biopsies were performed for benign lesions. Also, no cancers were missed when the protocol was followed. CONCLUSIONS Screening with CT can be done effectively in an area endemic for histoplasmosis while minimizing benign biopsies.

Activation of JAK-STAT and nitric oxide signaling as a mechanism for donor heart dysfunction

BACKGROUND Donor heart dysfunction (DHD) precluding procurement for transplantation occurs in up to 25% of brain-dead (BD) donors. The molecular mechanisms of DHD remain unclear. We investigated the potential role of myocardial interleukin (IL)-6 signaling through the JAK2-STAT3 pathway, which can lead to the generation of nitric oxide (NO) and decreased cardiac myocyte contractility. METHODS Hearts were procured using standard technique with University of Wisconsin (UW) solution from 14 donors with a left ventricular (LV) ejection fraction of <35% (DHD). Ten hearts with normal function (NF) after BD served as controls. LV IL-6 was quantitated by enzyme-linked immunoassay (ELISA) and JAK2-STAT3 signaling was assessed by expression of phosphorylated STAT3. Inducible NO synthase (iNOS) and caspase-3 were measured by activity assays. RESULTS Myocardial IL-6 expression was 8-fold greater in the DHD group vs NF controls. Phosphorylated STAT3 expression was 5-fold higher in DHD than in NF, indicating increased JAK2-STAT3 signaling. LV activity of iNOS was 2.5-fold greater in DHD than in NF. LV expression of the pro-apoptotic gene Bnip3 and caspase-3 activity were 3-fold greater in the DHD group than in the NF group. CONCLUSIONS Myocardial IL-6 expression is significantly higher in the setting of DHD compared with hearts procured with normal function. This may lead to increased JAK2-STAT3 signaling and upregulation of iNOS, which has been shown to decrease cardiac myocyte contractility. Increased NO production may also lead to increased apoptosis through upregulation of Bnip3 gene expression. Increased iNOS signaling may be an important mechanism of DHD and represents a novel therapeutic target to improve cardiac function after BD.

Uncoupling of Myocardial β-Adrenergic Receptor Signaling During Coronary Artery Bypass Grafting: The Role of GRK2

BACKGROUND Cardiopulmonary bypass (CPB) and cardioplegic arrest during cardiac surgery leads to desensitization of myocardial beta-adrenergic receptors (beta-ARs). Impaired signaling through this pathway can have a detrimental effect on ventricular function and increased need for inotropic support. The mechanism of myocardial beta-AR desensitization during cardiac surgery has not been defined. This study investigates the role of G protein-coupled receptor kinase-2 (GRK2), a serine-threonine kinase which phosphorylates and desensitizes agonist-occupied beta-ARs, as a primary mechanism of beta-AR uncoupling during coronary artery bypass grafting (CABG) with CPB and cardioplegic arrest. METHODS Forty-eight patients undergoing elective CABG were enrolled in this study. Myocardial beta-AR signaling was assessed by measuring total beta-AR density and adenylyl cyclase activity in right atrial biopsies obtained before CPB and just before weaning from CPB. Myocardial GRK2 expression and activity were also measured before CPB and just before weaning from CPB. RESULTS Myocardial beta-AR signaling was significantly impaired after CPB and cardioplegic arrest during CABG. Cardiac GRK2 expression was not altered; however, there was a twofold increase in GRK2 activity during CABG. There was an even greater elevation in cardiac GRK2 activity in patients with severely depressed ventricular function. CONCLUSIONS Increased myocardial GRK2 activity appears to be the primary mechanism of impaired beta-AR signaling during CABG with CPB and cardioplegic arrest. This may contribute to the greater need for inotropic support in patients with severe ventricular dysfunction. Strategies to inhibit activation of GRK2 during CABG may decrease morbidity in this patient population.

Acute β-blockade prevents myocardial β-adrenergic receptor desensitization and preserves early ventricular function after brain death

OBJECTIVE Beta-adrenergic receptor desensitization through activation of the G protein-coupled receptor kinase 2 is an important mechanism of early cardiac dysfunction after brain death. We hypothesized that acute beta-blockade can prevent myocardial beta-adrenergic receptor desensitization after brain death through attenuation of G protein-coupled receptor kinase 2 activity, resulting in improved cardiac function. METHODS Adult pigs underwent either sham operation, induction of brain death, or treatment with esmolol (beta-blockade) for 30 minutes before and 45 minutes after brain death (n = 8 per group). Cardiac function was assessed at baseline and for 6 hours after the operation. Myocardial beta-adrenergic receptor signaling was assessed 6 hours after operation by measuring sarcolemmal membrane adenylate cyclase activity, beta-adrenergic receptor density, and G protein-coupled receptor kinase 2 expression and activity. RESULTS Baseline left ventricular preload recruitable stroke work was similar among sham, brain death, and beta-blockade groups. Preload recruitable stroke work was significantly decreased 6 hours after brain death versus sham, and beta-blockade resulted in maintenance of baseline preload recruitable stroke work relative to brain death and not different from sham. Basal and isoproterenol-stimulated adenylate cyclase activities were preserved in the beta-blockade group relative to the brain death group and were not different from the sham group. Left ventricular G protein-coupled receptor kinase 2 expression and activity in the beta-blockade group were markedly decreased relative to the brain death group and similar to the sham group. Beta-adrenergic receptor density was not different among groups. CONCLUSION Acute beta-blockade before brain death attenuates beta-adrenergic receptor desensitization mediated by G protein-coupled receptor kinase 2 and preserves early cardiac function after brain death. These data support the hypothesis that acute beta-adrenergic receptor desensitization is an important mechanism in early ventricular dysfunction after brain death. Future studies with beta-blocker therapy immediately after brain death appear warranted.