Carbon monoxide controls microglial erythrophagocytosis by regulating CD36 surface expression to reduce the severity of hemorrhagic injury

Microglial erythrophagocytosis is crucial in injury response to hemorrhagic stroke. We hypothesized that regulation of microglial erythrophagocytosis via HO-1/CO depends on a pathway involving reactive oxygen species (ROS) and CD36 surface-expression. The microglial BV-2 cell line and primary microglia (PMG) were incubated +/−blood and +/−CO-exposure. PMG isolated from tissue-specific HO-1-deficient (LyzM-Cre-Hmox1 ^fl/fl) and CD36 ^−/− mice or siRNA against AMPK (AMP-activated protein kinase) were used to test our hypothesis. In a murine subarachnoid hemorrhage (SAH) model, we compared neuronal injury in wild-type and CD36 ^−/− mice. Readouts included vasospasm, microglia activation, neuronal apoptosis, and spatial memory. We observed increased microglial HO-1-expression after blood-exposure. A burst in ROS-production was seen after CO-exposure, which led to increased amounts of phosphorylated AMPK with subsequently enhanced CD36 surface-expression. Naïve PMG from LyzM-Cre-Hmox1 ^fl/fl mice showed reduced ROS-production and CD36 surface-expression and failed to respond to CO with increased CD36 surface-expression. Lack of HO-1 and CD36 resulted in reduced erythrophagocytosis that could not be rescued with CO. Erythrophagocytosis was enhanced in BV-2 cells in the presence of exogenous CO, which was abolished in cells treated with siRNA to AMPK. CD36 ^−/− mice subjected to SAH showed enhanced neuronal cell death, which resulted in impaired spatial memory function. We demonstrate that microglial phagocytic function partly depends on a pathway involving HO-1 with changes in ROS-production, phosphorylated AMPK, and surface expression of CD36. CD36 was identified as a crucial component in blood clearance after hemorrhage that ultimately determines neuronal outcome. These results demand further investigations studying the potential neuroprotective properties of CO.     

Living donor liver transplantation in patients with portal vein thrombosis: a survey and review of technical issues

BACKGROUND: Unlike cadaveric liver transplantation, current attitudes in living donor liver transplantation (LDLT) quote increased risk factors in the potential recipient such as retransplantation, multiple previous surgeries, or preexisting recipient portal vein thrombosis (PVT) as absolute or relative contraindications to this procedure. METHODS: An international survey was performed to examine the attitude of transplant teams relative to LDLT in the setting of preexisting PVT in the potential recipient. A questionnaire was sent to a total of 80 transplant centers performing LDLT in the United States, Europe, Canada, Japan, Southeast Asia, and Australia. RESULTS: A response was obtained from 47 transplant centers (59% response rate). This included 2146 LDLT procedures that combined both left and right lobe allografts. The incidence of acute preexisting recipient PVT was 18 (0.8%) and of chronic PVT was 26 (1.2%). Thrombectomy was performed in 28 (64%), a jump graft in 13 (29.5%), and a combination of both thrombectomy and a jump graft in 2 (4.5%) cases. With reference to the presence of preexisting PVT in the potential recipient, 5 centers considered this to be an absolute contraindication (10.7%), 24 centers as a relative contraindication (51%), and 18 as not being a contraindication (38.3%) to LDLT. CONCLUSIONS: The overall response to our questionnaire reflected a cautious attitude within the transplant community. Ethical criteria pertaining to risk undertaken by a healthy donor in situations of higher recipient morbidity risk does seem to impact on the decision to undertake LDLT in this group of patients.     

Application of Poisson kriging to the mapping of cholera and dysentery incidence in an endemic area of Bangladesh

Background  

Disease maps can serve to display incidence rates geographically, to inform on public health provision about the success or failure of interventions, and to make hypothesis or to provide evidences concerning disease etiology. Poisson kriging was recently introduced to filter the noise attached to rates recorded over sparsely populated administrative units. Its benefit over simple population-weighted averages and empirical Bayesian smoothers was demonstrated by simulation studies using county-level cancer mortality rates. This paper presents the first application of Poisson kriging to the spatial interpolation of local disease rates, resulting in continuous maps of disease rate estimates and the associated prediction variance. The methodology is illustrated using cholera and dysentery data collected in a cholera endemic area (Matlab) of Bangladesh.     

Independent association of insulin resistance with larger amounts of intermuscular adipose tissue and a greater acute insulin response to glucose in African American than in white nondiabetic women

BACKGROUND: African Americans (AAs) have a higher prevalence of obesity and type 2 diabetes than do whites. Higher insulin resistance and hyperinsulinemia have been reported in adult AAs than in whites. Differences in adipose tissue and its distribution may account for these findings. OBJECTIVE: The objective was to ascertain whether differences between AA and white women in adipose tissue (AT) and skeletal muscle (SM) volumes account for ethnic differences in insulin resistance. DESIGN: We used whole-body magnetic resonance imaging to measure AT and SM volumes and used the intravenous-glucose-tolerance test to measure insulin resistance. RESULTS: AAs (n = 32) were 29-42% more insulin resistant than were whites (n = 28) after adjustment for weight and height or any AT volumes (P < 0.05). After adjustment for SM volume, the difference decreased to 19% and became nonsignificant. AAs had a 163% greater acute insulin response to glucose than did whites; this difference was significant even after adjustment for insulin sensivitity index, weight, height, and any magnetic resonance imaging measures. With respect to regional AT volumes, an association independent of race, weight, height, and SM volume was found only between increased intermuscular AT and lower insulin sensitivity index. CONCLUSIONS: Premenopausal AA women had significantly higher insulin resistance and acute insulin response to glucose than did their white counterparts. Whereas the difference in insulin resistance was partially accounted for by a greater SM volume in the AAs than in the whites, the difference in the acute insulin response to glucose was independent of any AT and SM measures and was disproportionately larger than expected according to the difference in insulin resistance. In addition, whole-body intermuscular AT was an important independent correlate of insulin resistance.     

Optimal peritoneal dialysis catheter type and exit site location: an anthropometric analysis

An anthropometric analysis of 200 adult patients was performed to provide better guidance in catheter selection and placement. Height, weight, various abdominal wall measurements, and gender effects were analyzed. Suitability of Tenckhoff catheters with straight and preformed bends in the intercuff segment was evaluated regarding ability to produce deep pelvic position of the catheter tip and ideal exit site location. Conflicts with belt line and with skin creases and folds were recorded. Results showed that abdominal wall measurements varied widely by height and weight. Swan neck catheters with a downwardly directed external limb and exit site were significantly better suited for females (62% versus 27%, p < 0.0001). Tenckhoff catheters with straight intercuff segments with a laterally directed tunnel tract and exit site were significantly better matched to males (78% versus 30%, p < 0.0001). Neither catheter was suitable in 25% of subjects, emphasizing the need for an extended catheter system capable of remotely locating the exit site to the upper abdomen or chest without compromising pelvic position of the catheter tip. Appropriate preoperative evaluation with selection of the best suited catheter should replace the substandard practice of using a pet catheter to fit all patients and rigidly placing the insertion incision at a set location irrespective of body habitus.     

A prospective randomized study in 100 consecutive patients undergoing major liver resection with versus without ischemic preconditioning

OBJECTIVE: To evaluate the protective effects of ischemic preconditioning in a prospective randomized study involving a large population of unselected patients and to identify factors affecting the protective effects. SUMMARY BACKGROUND DATA: Ischemic preconditioning is an effective protective strategy in several animal models. Protection has also been suggested in a small series of patients undergoing a hemihepatectomy with 30 minutes of inflow occlusion. Whether preconditioning confers protection in other types of liver resection and longer periods of ischemia is unknown. Therefore, we conducted a prospective randomized study to evaluate the impact of ischemic preconditioning in liver surgery. METHODS: A total of 100 unselected patients undergoing major liver resection (> bisegmentectomy) under inflow occlusion for at least 30 minutes were randomized during surgery to either receive or not receive an ischemic preconditioning protocol (10 minutes of ischemia followed by 10 minutes of reperfusion). Univariate and multivariate analyses were performed to identify independent factors affecting the protective effects of ischemic preconditioning. ATP contents in liver were measured as a possible mechanism of protection. RESULTS: Both groups (n = 50 in each) were comparable regarding age, gender, duration of inflow occlusion, and resected liver volumes. Postoperative serum transaminase levels were significantly lower in preconditioned than in control patients (median peak AST 364 U/L vs. 520 U/L, P = 0.028; ALT 406 vs. 519 U/L, P = 0.049). Regression multivariate analysis revealed an increased benefit of ischemic preconditioning in younger patients, in patients with longer duration of inflow occlusion (up to 60 minutes), and in cases of lower resected liver volume (<50%). Patients with steatosis were also particularly protected by ischemic preconditioning. ATP content in liver tissue was preserved by ischemic preconditioning in young but not older patients. CONCLUSIONS: This study establishes ischemic preconditioning as a protective strategy against hepatic ischemia in humans. The strategy is particularly effective in young patients requiring a prolonged period of inflow occlusion, and in the presence of steatosis, and is possibly related to preservation of ATP content in liver tissue. Other strategies are needed in older patients.     

Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancer

Dysfunction in the physiological pathways of programmed cell death may promote proliferation of malignant cells, and correction of such defects may selectively induce apoptosis in cancer cells. We measured the levels of ceramide, a candidate lipid mediator of apoptosis, in human metastatic colorectal cancer and tested in vitro and in vivo effects of various ceramide analogues in inducing apoptosis in metastatic colon cancer. Human colon cancer showed a > 50% decrease in the cellular content of ceramide when compared with normal colon mucosa. Application of ceramide analogues and ceramidase inhibitors induced rapid cell death through activation of various proapoptotic molecules, such as caspases and release of cytochrome c. Ceramidase inhibition increases the ceramide content of tumor cells, resulting in maximum activation of the apoptotic cascade. Normal liver cells were completely resistant to inhibitors of ceramidases. Treatment of nude mice with B13, the most potent ceramidase inhibitor, completely prevented tumor growth using two different aggressive human colon cancer cell lines metastatic to the liver. Therefore, B13 and related analogues of ceramide and inhibitors of ceramidases offer a promising therapeutic strategy with selective toxicity toward malignant but not normal cells. These studies also suggest that the ceramide content in cancer cells might be involved in the pathogenesis of tumor growth in vitro and in vivo.