The effects of therapeutic sulfide on myocardial apoptosis in response to ischemia–reperfusion injury

Objective: Ischemia–reperfusion (I/R) injury, often encountered clinically, results in myocardial apoptosis and necrosis. Hydrogen sulfide (H₂S) is produced endogenously in response to ischemia and thought to be cardioprotective, although its mechanism of action is not fully known. This study investigates cardioprotection provided by exogenous H₂S, generated as sodium sulfide on apoptosis following myocardial I/R injury. Methods: The mid-LAD coronary artery in Yorkshire swine (n = 12) was occluded for 60 min, followed by reperfusion for 120 min. Controls (n = 6) received placebo, and treatment animals (n = 6) received sulfide 10 min prior to and throughout reperfusion. Hemodynamic, global, and regional functional measurements were obtained. Evans blue/TTC staining identified the area-at-risk (AAR) and infarction. Serum CK-MB, troponin I, and FABP were assayed. Tissue expression of bcl-2, bad, apoptosis-inducing-factor (AIF), total and cleaved caspase-3, and total and cleaved PARP were assessed. PAR and TUNEL staining were performed to assess apoptotic cell counts and poly-ADP ribosylation, respectively. Results: Pre-I/R hemodynamics were similar between groups. Post-I/R, mean arterial pressure (mmHg) was reduced by 30.2 ± 4.3 in controls vs 8.2 ± 6.9 in treatment animals (p = 0.01). +LV dP/dt (mmHg/s) was reduced by 1308 ± 435 in controls vs 403 ± 283 in treatment animals (p = 0.001). Infarct size (% of AAR) in controls was 47.4 ± 6.2% vs 20.1 ± 3.3% in the treated group (p = 0.003). In treated animals, CK-MB and FABP were lower by 47.0% (p = 0.10) and 45.1% (p = 0.01), respectively. AIF, caspase-3, and PARP expression was similar between groups, whereas cleaved caspase-3 and cleaved PARP was lower in treated animals (p = 0.04). PAR staining was significantly reduced in sulfide treated groups (p = 0.04). TUNEL staining demonstrated significantly fewer apoptotic cells in sulfide treated animals (p = 0.02). Conclusions: Sodium sulfide is efficacious in reducing apoptosis in response to I/R injury. Along with its known effects on reducing necrosis, sulfide's effects on apoptosis may partially contribute to providing myocardial protection. Exogenous sulfide may have therapeutic utility in clinical settings in which I/R injury is encountered.     

A Pilot Study of Body Composition and Bone Mineral Density in Healthy Men From Argentina

A precise assessment of bone mineral density (BMD) and body composition can be performed using dual-energy X-ray absorptiometry (DXA). Values of body composition for males would be useful to evaluate the occurrence of alterations in body composition in a number of diseases. The objectives of this study were to establish BMD and body composition values in healthy men and to analyze age-related changes. BMD and body composition of total body and subareas were determined in 116 healthy men (aged 20–79 yr) using DXA. Comparison between 20–29- and 70–79-yr-old men showed that older subjects were shorter (p < 0.03), and had a higher body mass index (p < 0.01). Fat mass increased (+46.7%; p < 0.001) especially in the trunk. Lean mass (LM) decreased (−9.4%; p < 0.05) mainly in the arms and legs. Bone mineral content (BMC) and BMD decreased (−15.3% [p < 0.001], −6.3% [p < 0.05], respectively). Correlation was observed between BMC and LM (r = 0.7, p < 0.01). Values of BMD and body composition in healthy men were obtained. A relation was observed between bone mass and body composition, suggesting that the age-related decrease in LM may be associated to bone mass loss. Further studies should be conducted to elucidate the role of body composition in the occurrence of osteoporosis in men.     

Comparison of on pump and off pump coronary surgery: risk factors for neurological outcome

Objective: Cerebrovascular accidents (CVA) are devastating complications after coronary artery bypass grafting (CABG). The reported incidence of neurological complications after conventional CABG (CCABG) is 3–6%. Off-pump coronary bypass grafting (OPCAB) has been associated in recent studies to a decreased morbidity and risk of perioperative stroke. Nevertheless, uncertainty still surrounds the relative benefits of OPCAB. We investigated whether, in our experience, OPCAB was associated with lower neurological morbidity than conventional CABG approach. Methods: Eight thousand and two patients underwent isolated CABG at our institution between January 1998 and January 2005. OPCAB operation was performed on 1415 patients. Data were prospectively collected. A multiple logistic regression analysis was used to evaluate the influence of the two different surgical techniques on the neurological outcomes. Results: Patients in the OPCAB group were significantly older (66.2 vs 63.5%, p < 0.0001), had a higher incidence of renal injury (5.4 vs 2.4%, p < 0.0001), and were more redo interventions (6.95 vs 1.53%, p < 0.0001). The CCABG patients were more urgent at operation (5.46 vs 3.26, p = 0.0007), were less hypertensive (57.6 vs 63% of the patients, p = 0.0003) more diabetics (22 vs 20.6%, NS), and had an ejection fraction less than 0.40 (10.4 vs 9.6%, NS). CVA incidence was similar in both groups (Type I outcome: OPCAB = 0.70% vs CCABG = 0.68%, p = 0.91; Type II outcome OPCAB = 0.70% vs CCABG = 0.83%, p = 0.63). Conclusions: In our experience patients undergoing CCABG were not exposed to a grater risk of neurological adverse events when compared to OPCAB patients.     

Mortality and risk factors for surgical lung biopsy in patients with idiopathic interstitial pneumonia

Background: The overall safety of surgical lung biopsy in patients with idiopathic interstitial pneumonia (IIP) remains controversial. This study was performed to investigate the mortality and complication rate and identify the risk factors for surgical lung biopsy in patients with IIP. Methods: A total of 200 patients with IIP who underwent surgical lung biopsy at the Asan Medical Center, Korea, from April 1990 to August 2003, were enrolled. Complications and mortality were analyzed retrospectively. Results: (1) The mortality rate 30 days after the surgical lung biopsy was 4.3%, which was significantly higher than the control group. Biopsy performed at the time of acute exacerbation (AE) resulted in higher 30-day mortality (28.6%) compared to non-AE (3.0%; p < 0.05). AE was followed by biopsy itself in three cases. (2) Univariate analysis indicated that lower FVC, lower DL_CO, and presence of AE were significant risk factors for 30-day mortality (p < 0.05). However, multivariate analysis revealed that only AE (OR: 11.334, 95% CI: 1.727–74.365, p = 0.011) was an independent risk factor. (3) The patients with low DL_CO (<50% predicted) had higher mortality and complication rate than high DL_CO group. Conclusion: Our data suggested that the presence of acute exacerbation at the time of biopsy and lower DL_CO were predictors of higher mortality after the surgical lung biopsy.     

Immunohistochemistry-detected microscopic tumor spread affects outcome in en-bloc resection for T3-chest wall lung cancer

Objective: This study is aimed at analyzing the effect of immunohistochemistry-detected microscopic tumor spread on long-term survival after en-bloc lung and chest wall resection for T3-chest wall non-small cell lung cancer (NSCLC). Methods: We retrospectively reviewed 47 patients (mean age 64.4 ± 7.1 years, range 48–77) who underwent radical en-bloc lung and chest wall resection for NSCLC between 1987 and 2000. Resection margins, invasion depth, and lymph nodes were re-assessed by immunohistochemistry with AE1/AE3 anti-cytokeratin and anti-CEA monoclonal antibodies. Results: Operative mortality and morbidity were 2.1% and 34%, respectively. At immunohistochemistry analysis, five patients (10.6%) revealed microinfiltration of the resection margins that was significantly correlated with the development of local recurrence (p < 0.005). Nodal micrometastases were found in 4 out of 33 N0 patients (12.1%), and correlated with distant relapse (p < 0.001). Overall and disease-free survivals were significantly influenced by N-status (p < 0.001), especially after re-evaluation of micrometastases (p < 0.0001), and resection margins microinfiltration (p < 0.0001) being these last two the only significant prognostic factors at Cox regression analysis. Five-year overall survival in radically resected patients was 73%. Conclusions: In this study immunohistochemical analysis allowed to identify patients at higher risk of recurrence following en-bloc resection for T3-chest wall NSCLC.     

Clinical advantages of using mini-bypass systems in terms of blood product use, postoperative bleeding and air entrainment: an in vivo clinical perspective

Objective: In an effort to minimize the effect of extracorporeal circulation (ECC), mini-bypass is gaining clinical acceptance in routine coronary artery bypass grafting (CABG). These small circuits target combine the clinical advantages of reduced prime, 100% bio-coating and suction blood separation. We demonstrate that the use of mini-bypass in routine CABG reduces homologous blood product use and postoperative bleeding. Our goal was to also demonstrate that these small systems are effective in gaseous microemboli (GME) management as compared to a conventional extracorporeal system. Methods: Prospective, randomized study comparing 30 mini-bypass (Dideco ECC.O™) to 30 conventional systems (n = 30, Dideco 903 Avant™). Study included CABG cases only, independent of preoperative coagulative status; clinic ethical committee approval and informed patient consent was obtained before initiating study. Results: There were no statistical differences in terms of patient demographics. Statistically significant differences were seen in transfusion frequency (27% of the study group vs 43% in the control group, p = 0.05), transfused volume (133.3 ± 244.5 ml vs 325 ± 483.1 ml, p < 0.05), fresh frozen plasma (0 unit vs 3 units, p < 0.001), postoperative bleeding (301.8 ± 531.9 ml vs 785.5 ± 1000.4 ml, p < 0.05) and GME activity post-arterial filter (0.14 μl vs 5.32 μl, p < 0.05). Conclusions: The adoption of mini-bypass significantly potentially reduces hemodilution, donor blood usage, postoperative bleeding and exposure to GME in routine CABG patients as compared to the use of conventional extracorporeal circulation circuits.     

A three decade analysis of factors affecting burn mortality in the elderly

This study's objective was to identify variables that affect the mortality of elderly burn patients and to assess their changes over time. A retrospective review was conducted on all patients 75 or older (n = 201) admitted to a university-based burn center between 1972 and 2000. Variables examined were age, sex, TBSA, ABSI, inhalation injury, timing from burn to operative intervention, the number of surgical procedures, the number of pre-morbid conditions, and mortality. There were 95 fatalities. TBSA strongly correlated with mortality (p < 0.0001). Adjusting for TBSA and inhalation injury, mortality significantly decreased (p = 0.04, odds ratio = 0.58). Mortality significantly increased with inhalation injury (p < 0.01). Fatality risk increased by 400% with inhalation injury. Absence of inhalation injury was not significant with respect to mortality in the 1970s, however there was a significant decrease (p = 0.02) in mortality without an inhalation injury in the 1980s and 1990s. ABSI was strongly predictive of mortality (p < 0.0001). On average there was a 200% increase in mortality per unit increase of ABSI. The elderly are 58% less likely to die from burns now as compared to the 1970s. Although mortality rose with increasing TBSA equally in each decade, the absolute risk of mortality decreased over time. This data suggests major strides have been made in burn care, however similar success has not been achieved with inhalation injuries.     

Lymph node isolated tumor cells and micrometastases in pathological stage I non-small cell lung cancer: prognostic significance

Objective: To determine the prevalence and prognostic significance of lymph node micrometastases and isolated tumor cells (ITC) in patients submitted for radical resection for pathological stage I non-small cell lung cancer (NSCLC). Methods: From January 1998 through December 2005, 87 consecutive pT1-2, pN0 NSCLC patients were enrolled. Surgical specimens were submitted to pathological routine examinations to define histotype, grade, stage, vascular invasion, necrosis and tumor proliferative index. A total of 694 regional lymph nodes were examined by means of serial sections stained with hematoxylin and eosin and labelled by immunohistochemistry (antibody AE1/AE3, DAKO). Relationships between these parameters and patients’ prognosis were investigated. Results: By histological examination, there were 36 squamous-cell carcinoma, 38 adenocarcinoma and 13 large-cell carcinoma. Micrometastases and ITC were detected in 19 lymph nodes (2.7%) of 14 patients (16%). Significant correlation was observed between micrometastases or ITC and adenocarcinoma (p = 0.03) and the absence of necrosis (p = 0.05). No relationship was demonstrated between micrometastases or ITC and T-status, vascular invasion or proliferative index (p > 0.05). Median follow-up was 3.2 (range 0.25–8.6) years. Two- and 5-year disease-free survival was similar for patients with and without micrometastases or ITC (79% and 64% vs 81% and 64%, respectively). Recurrence occurred in three patients with (two local, 66%) and in 21 patients without micrometastases or ITC (three local, 14%) (p = 0.186). By multivariate analysis only T-status was demonstrated to be a significant prognostic factor. Discussion: Micrometastases or ITC to regional lymph nodes are demonstrated to be not a rare aspect of pathological stage I resected lung cancer. In our series, the presence of lymph nodes micrometastases does not affect long-term disease-free survival.     

Factors affecting early and long-term outcomes after completion pneumonectomy

Objective: To identify factors that affect operative mortality and morbidity and long-term survival after completion pneumonectomy. Methods: We retrospectively reviewed the charts of consecutive patients who underwent completion pneumonectomy at our cardiothoracic surgery department from January 1996 to December 2005. Results: We identified 69 patients, who accounted for 17.8% of all pneumonectomies during the study period; 22 had benign disease and 47 malignant disease (second primary lung cancer, n = 19; local recurrence, n = 17; or metastasis, n = 11). There were 50 males and 19 females with a mean age of 60 years (range, 29–80 years). Postoperative mortality was 12% and postoperative morbidity 41%. Factors associated with postoperative mortality included obesity (p = 0.005), coronary artery disease (p = 0.03), removal of the right lung (p = 0.02), advanced age (p = 0.02), and renal failure (p < 0.0001). Preoperative renal failure was the only significant risk factor for mortality by multivariate analysis (p = 0.036). Bronchopleural fistula developed in seven patients (10%), with risk factors being removal of the right lung (p = 0.04) and mechanical stump closure (p = 0.03). Overall survival was 65% after 3 years and 46% after 5 years. Long-term survival was not affected by the reason for completion pneumonectomy. Conclusion: Although long-term survival was acceptable, postoperative mortality and morbidity rates remained high, confirming the reputation of completion pneumonectomy as a challenging procedure. Significant comorbidities and removal of the right lung were the main risk factors for postoperative mortality. Improved patient selection and better management of preoperative renal failure may improve the postoperative outcomes of this procedure, which offers a chance for prolonged survival.     

Prognostic value of FDG uptake in early stage non-small cell lung cancer

Background: Non-small cell lung cancer (NSCLC) has a poor prognosis even for early stages of the disease (stage I and II). We studied the prognostic value of PET FDG in patients with completely resected stage I and II NSCLC. Methods: Retrospective study of 96 patients with NSCLC whose staging included ¹⁸F-FDG PET (fluoro deoxy glucose positron emission tomography). Histopathological stage was either stage I (75) or stage II (n = 21). FDG uptake was measured as maximal standardized uptake value for body weight (SUVmax). Mean follow-up was 45 ± 30 months (1–142 months). Overall and cancer-free survival rates were recorded. Results: SUVmax were higher for stage II than for stage I (10.5 ± 4.5 vs 8.5 ± 5, p = 0.04). Mean tumor volumes were equivalent for both stages (33 cm³, p = 0.18), excluding a partial volume effect. The median SUVmax in the whole study population was 7.8. The median survival was significantly longer in patients with a lower (SUVmax ≤ 7.8) FDG uptake (127 months vs 69 months, p = 0.001). For stage I tumors (n = 75), high FDG uptake was significantly associated with reduced median survival: 127 months if SUVmax ≤ 7.8 and 69 months if SUVmax > 7.8 (p = 0.001). For stage II tumors (n = 21), no statistical difference was observed: 72 months vs 40 months for SUVmax ≤ 7.8 and for SUVmax > 7.8, respectively (p = 0.11), although there was a clear trend towards reduced survival for highly metabolic tumors. Disease-free survival was also significantly better for lower metabolic tumors: 96.1 months vs 87.7 months (p = 0.01). Conclusion: High FDG uptake is associated with reduced overall survival and disease-free survival of patients with completely resected stage I–II NSCLC. Whether patients with highly metabolic tumors should undergo a closer postoperative surveillance or adjuvant chemotherapy has to be addressed in a properly designed prospective trial.     

Ulinastatin attenuates lung ischemia-reperfusion injury in rats by inhibiting tumor necrosis factor alpha

Ischemia-reperfusion (I/R) injury may influence graft function following transplantation. Ulinastatin, a urinary trypsin inhibitor has been shown to attenuate I/R injury in various organs such as intestine, heart, and kidney in animals. The present experiment was designed to evaluate the effect of pretreatment with ulinastatin on I/R-induced lung injury. METHODS: After establishing a constant left lung warm ischemia-reperfusion model in rats, 45 animals were randomly divided into three experimental groups: sham group (n = 15), IR group (n = 15), and ulinastatin (5000 U/kg pre-ischemia) + IR group (n = 15). The lung injury was evaluated by tissue myeloperoxidase activity, with simultaneous estimation of the serum concentration of TNFalpha. RESULTS: The ulinastatin-pretreated animals exhibited markedly decreased lung tissue myeloperoxidase activity (P < .05). Blood gas analysis demonstrated, that the treated animals had significantly ameliorated pulmonary oxygenation (P < .05). The serum concentration of TNF-alpha in the ulinastatin-pretreated group was markedly decreased compared with that of the I/R group (P < .05). CONCLUSIONS: Ulinastatin attenuated I/R-induced lung injury. This function is partly related to the capacity of the agent to inhibit myeloperoxidase activity in lung tissue and decrease systemic expression to TNF-alpha.     

Genetic background influences fluoride's effects on osteoclastogenesis

Excessive fluoride (F) can lead to abnormal bone biology. Numerous studies have focused on the anabolic action of F yet little is known regarding any action on osteoclastogenesis. Little is known regarding the influence of an individual's genetic background on the responses of bone cells to F. Four-week old C57BL/6J (B6) and C3H/HeJ (C3H) female mice were treated with NaF in the drinking water (0 ppm, 50 ppm and 100 ppm F ion) for 3 weeks. Bone marrow cells were harvested for osteoclastogenesis and hematopoietic colony-forming cell assays. Sera were analyzed for biochemical and bone markers. Femurs, tibiae, and lumbar vertebrae were subjected to microCT analysis. Tibiae and femurs were subjected to histology and biomechanical testing, respectively. The results demonstrated new actions of F on osteoclastogenesis and hematopoietic cell differentiation. Strain-specific responses were observed. The anabolic action of F was favored in B6 mice exhibiting dose-dependent increases in serum ALP activity (p < 0.001); in proximal tibia trabecular and vertebral BMD (tibia at 50&100 ppm, p = 0.001; vertebrae at 50 and 100 ppm, p = 0.023&0.019, respectively); and decrease in intact PTH and sRANKL (p = 0.045 and p < 0.001, respectively). F treatment in B6 mice also resulted in increased numbers of CFU-GEMM colonies (p = 0.025). Strain-specific accumulations in bone [F] were observed. For C3H mice, dose-dependent increases were observed in osteoclast potential (p < 0.001), in situ trabecular osteoclast number (p = 0.007), hematopoietic colony forming units (CFU-GEMM: p < 0.001, CFU-GM: p = 0.006, CFU-M: p < 0.001), and serum markers for osteoclastogenesis (intact PTH: p = 0.004, RANKL: p = 0.022, TRAP5b: p < 0.001). A concordant decrease in serum OPG (p = 0.005) was also observed. Fluoride treatment had no significant effects on bone morphology, BMD, and serum PYD cross-links in C3H suggesting a lack of significant bone resorption. Mechanical properties were also unaltered in C3H. In conclusion, short term F treatment at physiological levels has strain-specific effects in mice. The expected anabolic effects were observed in B6 and novel actions hallmarked by enhanced osteoclastogenesis shifts in hematopoietic cell differentiation in the C3H strain.     

Antithrombin III pretreatment reduces neutrophil recruitment into the lung and skeletal muscle tissues in the rat model of bilateral lower limb ischemia and reperfusion: a pilot study

BACKGROUND: Anti-inflammatory action of Antithrombin III (AT III) is still not well understood in ischemia/reperfusion (I/R) injury. In the present study, we aimed to investigate the anti-inflammatory action of AT III on remote lung and local skeletal muscle tissue injury in a rat model of bilateral lower limb I/R model. METHODS: Bilateral lower limb ischemia and reperfusion were produced by means of tourniquets occlusions and releases, respectively. Three groups of rats were used in this controlled study: sham group (sham, n=3) underwent 5 h of anesthesia only; control group (I/R, n=7) underwent 3 h of bilateral lower limb ischemia followed by 2 h of reperfusion; and AT III pretreated group (I/R-AT III, n=6) underwent the same procedure as the control group, but also received i.v. 250 U kg-1 AT III 30 min before ischemia induction under midazolam and fentanyl anesthesia. MEASUREMENTS AND RESULTS: Lung and muscle tissue accumulation of polymorphonuclear leukocytes (PMN) were assessed by measuring tissue myeloperoxidase (MPO) activity. Histopathological changes in tissues were assessed by PMN counts in the lung, and muscle tissues and by histological lung injury score. Plasma 6-keto prostaglandin F(1alpha) and tumor necrosis factor alpha levels were measured by an enzyme immunoassay technique. Myeloperoxidase activity could not be detected in the muscle tissues of all groups. The lung and muscle tissue PMN counts in the I/R group were significantly higher compared with the I/R-AT III group (P<0.05). CONCLUSIONS: Data from the present study provides some evidence that AT III pretreatment attenuates remote lung and local skeletal muscle tissue injury caused by lower limb I/R.     

Effects of atorvastatin on arterial endothelial function in coronary bypass surgery

Objective: Endothelial dysfunction represents a critical early component of organ injury following cardiopulmonary bypass. Recent studies demonstrate that the treatment with atorvastatin is associated with a significant improvement of endothelial function independently of its efficacy on cholesterol levels. Therefore, we investigated the effects of preoperative atorvastatin treatment on endothelium function after coronary surgery. Methods: Forty patients undergoing coronary surgery were randomized to treatment with atorvastatin (20 mg/die; N = 20) or placebo (N = 20) 3 weeks before surgery. Twenty normal patients served as control group. The flow-mediated dilations (FMD) of the brachial artery after both reactive hyperemia (endothelium dependent) and nitroglycerin administration (endothelium independent) were evaluated at baseline, at 48 h, and 5 days postoperatively. Results: At baseline, the endothelium-dependent FMD was significantly attenuated in coronary versus normal patients (normal 10.3 ± 1.8% vs coronary 4.1 ± 1.6%, p < 0.01). At 48 h postoperatively all patients exhibited a reduced FMD compared with baseline values: the endothelium-dependent dilatation showed a drop of 60.1 + 15% in the patients of the placebo group compared with 45.8 + 16.6% (p < 0.05) those in the atorvastatin group. At the univariate analysis, no significant correlation was found between serum levels of either total cholesterol or HDL cholesterol and FMD. The nitroglycerin-induced dilation was not significantly influenced by extracorporeal circulation as well as by atorvastatin treatment. Conclusions: The endothelial dysfunction following cardiopulmonary bypass is improved by the treatment with atorvastatin, by a mechanism unrelated to the drug efficacy of controlling serum cholesterol levels.     

Intestinal ischaemia following cardiac surgery: a multivariate risk model

Objective: Intestinal ischaemia following cardiac surgery is a serious complication, which carries a high mortality rate. Several studies have examined pre-operative and intra-operative risk factors. We aimed to develop a multivariate risk model to identify those patients at highest risk of intestinal ischaemia. Methods: Data was prospectively collected for 10,976 consecutive cardiac surgery patients from our institution between April 1997 and March 2004. Fifty (0.5%) patients developed post-operative intestinal ischaemia. A forward stepwise multivariate logistic regression analysis was undertaken to identify predictors of developing intestinal ischaemia. Intra-operative and post-operative variables were censored at the time of onset of intestinal ischaemia. Results: The predictors of post-operative intestinal ischaemia were: post-op inotrope and dialysis support (OR 6.7; p < 0.001), post-op ventilation >48 h (OR 5.1; p < 0.001), age at operation (OR 1.06 [for each additional year]; p < 0.001), post-op atrial fibrillation (OR 2.3; p = 0.014) and blood loss in intensive care unit (ICU) >700 ml (OR 2.0; p = 0.037). The predictive ability of this model was very good with an area under the receiver operating characteristic curve of 0.93. In-hospital mortality for the patients who developed intestinal ischaemia was 94% (47/50) compared to 3.6% (390/10,926) for the other patients (p < 0.001). Conclusions: Although the incidence of intestinal ischaemia following cardiac surgery is low, the prognosis for these patients is very poor. We have identified several risk factors, and developed a multivariate prediction tool, which may be useful in identifying patients at high-risk of developing intestinal ischaemia.     

Assessment of Spine Bone Mineral Density in Juvenile Idiopathic Arthritis: Impact of Scan Projection

Although children with juvenile idiopathic arthritis (JIA) are at risk for vertebral fractures, recent conventional posterior-anterior (PA) spine dual-energy X-ray absorptiometry studies reported minimal areal bone mineral density (aBMD, g/cm²) deficits. Width-adjusted BMD (WA-BMD, g/cm³) represents the bone mineral content (BMC) from the lateral projection, excluding the dense cortical spinous processes, divided by the estimated vertebral body volume based on paired PA-lateral bone dimensions. Therefore, WA-BMD may be more sensitive to JIA effects on the predominantly trabecular vertebral body. Age- and sex-specific Z-scores for spine aBMD and WA-BMD were generated in 84 JIA subjects compared with healthy controls, aged 5–21 yr. JIA was associated with lower mean WA-BMD Z-scores (−0.78, 95% CI: −1.03, −0.53; p < 0.001) and aBMD Z-scores (−0.26, 95% CI: −0.49, −0.02; p < 0.05), compared with controls. WA-BMD Z-scores were significantly lower than aBMD Z-scores in JIA (p < 0.001). A significant JIA by age interaction (p < 0.001) indicated that the magnitude of the difference between WA-BMD and aBMD Z-scores was greater in younger subjects. In conclusion, WA-BMD may be more sensitive to disease effects in children because it selectively measures the trabecular-rich vertebral body and is independent of growth-related changes in BMC of the dense spinous processes.     

A Mac-1 antibody reduces liver and lung injury but not neutrophil sequestration after intestinal ischemia-reperfusion.

BACKGROUND. Intestinal ischemia and reperfusion (I/R) result in leukosequestration and injury to the liver and lungs. The adherence-dependent oxidative burst of neutrophils requires cell adhesion through the Mac-1 integrin. Neutrophil-mediated tissue injury may depend on this specific cell adhesion event. This study tests the effect of a Mac-1 (CD 11b) monoclonal antibody (MAb) (R17) on liver and lung injury after intestinal I/R. METHODS. After collaterals were ligated in anesthetized rats, the superior mesenteric artery was clamped for 60 minutes followed by 3 hours of reperfusion. Animals were treated with saline solution, R17, or nonspecific immunoglobulin M. Another nonischemic group of rats were sham controls. Lung and intestinal polymorphonuclear leukocyte sequestration was assessed by measurement of myeloperoxidase and lung permeability by bronchoalveolar lavage blood concentration ratio of 125I-labeled bovine serum albumin. RESULTS. At 3 hours of reperfusion lung and intestinal myeloperoxidase and lung permeability were increased. Treatment with R17 MAb did not reduce intestinal or lung myeloperoxidase but prevented increased lung permeability. Similarly, after treatment with saline solution, liver polymorphonuclear leukocyte sequestration increased after 3 hours of reperfusion, and serum alanine aminotransferase level rose eightfold. R17 MAb did not significantly reduce liver neutrophil sequestration; however, it reduced alanine aminotransferase level more than 50% when compared to saline solution controls. At 3 hours of reperfusion there was a leukocytosis (white blood cell count, 14.9 +/- 1.0 x 10(3)/mm3 vs 6.0 +/- 0.8 in sham [p less than 0.05]). The white blood cell count was unaffected by R17 MAb. CONCLUSIONS. These data indicate that a MAb to the neutrophil Mac-1 integrin reduces lung and liver injury after intestinal I/R but does not reduce lung or intestinal leukosequestration.     

The "lively" cytokines network in beta-Thalassemia Major-related osteoporosis

Osteoporosis affects approximately 40–50% of adult patients with β-Thalassemia Major (βTM). Recent data have implicated an altered modulation of the osteoprotegerin (OPG)/receptor activator of NFkB ligand (RANKL) system in the pathogenesis of βTM-osteoporosis. OPG/RANKL system acts downstream from IL-1, IL-6 and TNF- and it may be the final actor mediating the effects of these cytokines on the regulation of both postmenopausal and metabolic bone resorption. However, to date, there are no data on circulating levels of these pro-resorptive cytokines in βTM patients. We investigated the potential relationships among these cytokines, several markers of bone turnover and bone mineral density (BMD) in βTM patients.

IL-1, IL-6 and TNF-, OPG and RANKL serum levels, hemato-urinary bone remodeling markers and bone mineral density (BMD) at L2L4 and femoral neck as well as erythropoietin (EPO), 17β-estradiol, and free-testosterone levels were measured in 30 well treated βTM patients and in 20 healthy subjects, matched for age, sex and BMI with the patients.

βTM patients showed an altered bone turnover, with increased deoxypyridinoline (D-PYR) levels (P < 0.0001), decreased osteocalcin (BGP) concentrations (< 0.0001) and significantly lower lumbar (P = 0.001) and femoral (P < 0.05) BMD values as compared to controls. Circulating levels of IL-1 (P < 0.0001), TNF- (P < 0.0001) and IL-6 (P < 0.05) were all increased in βTM patients as compared with controls. In βTM patients, IL-1 was significantly related with D-PYR (r = 0.5; P < 0.05), RANKL (r = 0.7; P = 0.03) and IL-6 (r = 0.3; P = 0.006); IL-6 was also significantly correlated with D-PYR (r = 0.5; P < 0.05) and EPO levels (r = 0.3; P = 0.03); TNF- showed a negative correlation with L2L4 BMD (r = − 0.4; P < 0.05).

Our data demonstrate, for the first time, an association between increased circulating levels of pro-resorptive cytokines and an altered bone turnover in βTM-patients, suggesting their involvement in the pathogenesis of βTM-osteoporosis.     

Effect of risk-adjusted, non-dialysis-dependent renal dysfunction on mortality and morbidity following coronary artery bypass surgery: a multi-centre study

Objective: As little is known about the impact of non-dialysis-dependent renal dysfunction on short- and mid-term outcomes following coronary surgery we have conducted a large multi-centre study comparing patients with no history of renal dysfunction to those with preoperative renal dysfunction. Methods: Data was prospectively collected on 19,625 consecutive patients undergoing isolated coronary surgery between 1997 and 2003 from four institutions. Sixty-seven patients had a history of dialysis support prior to coronary surgery, and were excluded from the main analysis of the study. The remaining 19,558 patients were divided into two groups based on preoperative serum creatinine level, patients with preoperative renal dysfunction with serum creatinine levels >200 μmol/L without dialysis support and control patients with preoperative serum creatinine levels <200 μmol/L. Case-mix was accounted for by developing a propensity score, which was the probability of belonging to the non-dialysis-dependent renal dysfunction group, and included in the multivariable analyses. Results: There were 19,172 patients with preoperative serum creatinine levels <200 μmol/L and 386 patients with serum creatinine levels >200 μmol/L without dialysis support. The propensity score included sex, body mass index, co-morbidity factors (respiratory disease, diabetes, cerebrovascular disease, hypertension, and hypercholesterolemia), ejection fraction, left main stem stenosis, emergency status, prior cardiac surgery, off-pump surgery, and the logistic EuroSCORE. After adjusting for the propensity score, patients with preoperative non-dialysis-dependent renal dysfunction had significantly higher in-hospital mortality (adjusted odds ratio 3.0, p < 0.001), stroke (adjusted odds ratio 2.0, p = 0.033), atrial arrhythmia (adjusted odds ratio 1.5, p = 0.003), prolonged ventilation (adjusted odds ratio 2.1, p < 0.001), and post-op stay > 6 days (adjusted odds ratio 2.6, p < 0.001). One thousand one hundred and eighty-three (6.1%) deaths occurred during 58,062 patient-years follow-up. After adjusting for the propensity score, the adjusted hazard ratio of mid-term mortality for non-dialysis-dependent renal dysfunction was 2.7 (p < 0.001). Conclusions: Patients undergoing coronary surgery with non-dialysis-dependent renal dysfunction have significantly increased perioperative morbidity and mortality. Mid-term survival is also significantly reduced at 5-years.     

Retrograde flush following topical cooling is superior to preserve the non-heart-beating donor lung

Objective: The use of non-heart-beating donors (NHBD) has been propagated as an alternative to overcome the scarcity of pulmonary grafts. Formation of microthrombi after circulatory arrest, however, is a major concern for the development of reperfusion injury. We looked at the effect and the best route of pulmonary flush following topical cooling in NHBD. Methods: Non-heparinized pigs were sacrificed by ventricular fibrillation and divided into three groups (n = 6 per group). After 1 h of in situ warm ischaemia and 2.5 h of topical cooling, lungs in group I were retrieved unflushed (NF). In group II, lungs were explanted following an anterograde flush (AF) through the pulmonary artery with 50 ml/kg Perfadex^® (6 °C). Finally, in group III, lungs were retrieved after an identical but retrograde flush (RF) via the left atrium. Flush effluent was sampled at intervals to measure haemoglobin concentration. Performance of the left lung was assessed during 60 min in our ex vivo reperfusion model. Wet-to-dry weight ratio (W/D) of both lungs was calculated as an index of pulmonary oedema. IL-1ß and TNF- protein levels in bronchial lavage fluid from both lungs were compared between groups. Results: Haemoglobin concentration (g/dl) was higher in the first effluent in RF versus AF (3.4 ± 1.1 vs 0.6 ± 0.1; p < 0.05). Pulmonary vascular resistance (dynes × s × cm⁻⁵) was 975 ± 85 RF versus 1567 ± 98 AF and 1576 ± 88 NF at 60 min of reperfusion (p < 0.001). Oxygenation (mmHg) and compliance (ml/cmH₂O) were higher (491 ± 44 vs 472 ± 61 and 430 ± 33 NS, 22 ± 3 vs 19 ± 3 and 14 ± 1 NS, respectively) and plateau airway pressure (cmH₂O) was lower (11 ± 1 vs 13 ± 1 and 13 ± 1 NS) after RF versus AF and NF, respectively. No differences in cytokine levels or in W/D ratios were observed between groups after reperfusion. Histology demonstrated microthrombi more often present after AF and NF compared to RF. Conclusion: Retrograde flush of the lung following topical cooling in the NHBD results in a better washout of residual blood and microthrombi and subsequent reduced pulmonary vascular resistance upon reperfusion.