Bacteremias in liver transplant recipients: shift toward gram-negative bacteria as predominant pathogens.

During the 1990s, gram-positive bacteria emerged as major pathogens after liver transplantation. We sought to determine whether the pathogens associated with bacteremias in liver transplant recipients have changed. Patients included 233 liver transplant recipients transplanted between 1989 and 2003. The proportion of all infections due to bacteremias increased significantly over time (P <.0001). Of other major infections, a trend toward a decrease in fungal infections (P =.089) and a significant decrease in cytomegalovirus (CMV) disease (P =.0004) were documented. Whereas the proportion of bacteremias due to gram-negatives increased from 25% in the period of 1989-1993 to 51.8% in 1998-03, that of gram-positive bacteria decreased from 75% in the period of 1989-93 to 48.2% in the period of 1998-2003. Methicillin-resistant Staphylococcus aureus (MRSA), Klebsiella pneumoniae, and Pseudomonas aeruginosa were the most frequent pathogens in bacteremic patients. The incidence of bacteremias due to MRSA and Pseudomonas aeruginosa has remained unchanged (P <.20); however, that due to enteric gram-negative bacteria, particularly Klebsiella pneumoniae has increased (P =.02). Klebsiella pneumoniae isolates in the current quartile were not clonally related. In conclusion, bacteremias as a proportion of all infections in liver transplant recipients have increased significantly over time, due in part to a decline in infections due to other major pathogens, e.g., fungi, primarily Candida species, and CMV. Gram-negative bacteria have emerged as predominant pathogens in bacteremic liver transplant recipients.     

One-stage repair of cardiac and arch anomalies without circumlatory arrest

Indian Journal of Thoracic and Cardiovascular Surgery -     

Timely bolus insulin for glucose control during cardiopulmonary bypass

Hyperglycemia during cardiopulmonary bypass (CPB) with glucose containing cardioplegia is common; normoglycemia is difficult to maintain and failure to do so may result in worse outcomes. The purpose of this quality improvement initiative was to show that a simple timely insulin bolus is more effective for glucose control during CPB with glucose containing cardioplegia than conventional (not standardized) glucose management in historical case-matched controls. A single bolus of insulin (.2 international units per kilogram; iu/kg) was administered, at the time of aortic cannulation, to 211 consecutive patients undergoing cardiac surgery with CPB and glucose containing cardioplegia. A further .1 iu/kg bolus of insulin was given for blood glucose (BG) measurements greater than 10.0 mmol/L (180 mg/dL) during CPB. The control group of 211 historical case-matched patients had glucose management according to anesthesiologist preference (insulin as a bolus, bolus plus infusion, infusion only, or no insulin). The frequency of hyperglycemia (BG > 11.0 mmol/L; 198 mg/dL) during CPB was significantly less in the study group (22; 10.5%) than in the control group (117; 55.5%) (p < .0001). Hyperglycemia in the first 6 hours in the intensive care unit was also significantly less frequent in the study group (5; 2.4%) than in the control group (14; 6.6%) (p = .03). Severe hypoglycemia (BG < 2.8 mmol/L; 50.4 mg/dL) occurred in one patient (.47%) in the timely bolus insulin group and five patients (2.3%) in the control group (p = .09). The timely bolus insulin method is more efficacious, but equally safe, in preventing hyperglycemia during CPB with glucose containing cardioplegia, compared with conventional (not standardized) insulin treatment in historical case-matched controls.     

Initial experience with laparoscopic bypass for upper gastrointestinal malignancy: a new option for palliation of patients with advanced upper gastrointestinal tumors

BACKGROUND: The majority of patients with upper gastrointestinal (UGI) tract malignancy present at a stage where cure of disease is not possible. The aim of treatment in these patients is effective palliation. Various interventions have been described for the palliation of biliary and gastric outlet obstruction including open surgery, endoscopic and transparietal stent placement. Laparoscopic bypass appears to have the advantage of decreased postoperative pain and shorter hospital stay as well as offer effective palliation. The aim of this study was to assess the safety and efficacy of laparoscopic bypass in patients with incurable UGI tract malignancy. PATIENTS AND METHODS: Between August 2000 and April 2002 laparoscopic gastric and biliary bypass concurrently or alone was attempted in 19 consecutive patients with unresectable carcinoma of the head of the pancreas, adenocarcinoma of the stomach, cholangiocarcinoma of the distal common bile duct, or adenocarcinoma of the duodenum. The operative time, length of postoperative stay, complications, and the effectiveness of the procedure in terms of the ability to sustain oral nutrition and or the relief of obstructive jaundice were recorded and used as outcome measures. RESULTS: Laparoscopic bypass was successful in 18 out of 19 cases. The mean operative time for a single bypass was 164 minutes while the average postoperative hospital stay was 11 days. All patients were able to sustain oral nutrition during the course of their hospital stay and or had effective relief from their obstructive jaundice. Two patients died from procedure unrelated causes within 30 days of the operation. CONCLUSION: Laparoscopic bypass appears to be a safe and effective means of palliation for patients with unresectable UGI tract tumors and should replace open surgical palliation in this group of patients.     

Involvement of IL-8 in COX-2-mediated bone metastases from breast cancer

BACKGROUND: Cyclooxygenase-2 (COX-2) overexpression by a primary tumor correlates with poor prognosis in breast cancer, including early spread to bone. Interleukin-8 (IL-8) stimulates osteoclastogenesis and resorption of bone, and elevated IL-8 levels predict early metastatic spread of breast cancer. The purpose of this study was to test our hypothesis that tumors that overexpress COX-2 induce IL-8 production. MATERIALS AND METHODS: We cotransfected MCF-10A (nonmalignant breast epithelial) cells, as well as MDA-231 (highly metastatic human breast cancer) cell lines with a pSG5-COX-2 vector and pEF1a-Luc-IRES-Neo vector (luciferase reporter). COX-2 overexpression was confirmed by Western blot and PGE2 (a product of the COX-2 pathway) immunoassay. IL-8 production was measured by immunoassay. In vivo testing used a nude mouse model to measure COX-2 and IL-8 production from breast cancer cells that had metastasized to bone (bone-seeking clones (BSCs)). Long bone metastases were localized and quantified by luciferase imaging (Xenogen IVIS system) and X-ray. BSCs were isolated and cultured and then tested for the production of PGE2 and IL-8. RESULTS: COX-2 overexpression caused a 4- to 5-fold increase in IL-8 production in both MCF-10A and MDA-231 cells in vitro. In vivo, we observed that the MDA-231-BSC (metastatic cells isolated from bone metastases) produced significantly greater levels of both PGE2 and IL-8 compared to the parental MDA-231 cells (P < 0.01). In contrast to the results obtained with these estrogen receptor-negative cell lines, COX-2 expression failed to induce IL-8 in the MCF-7 estrogen receptor-positive breast cancer cell line. Treatment with the COX-2 inhibitor NS-398 at a low 1-mu[scap]M dose reduced the production of IL-8 in COX-2-transfected MDA-231 cells by 30%, thus confirming the involvement of COX-2 in IL-8 induction. CONCLUSION: COX-2 expression induced formation of PGE2 and IL-8 in breast cancer cells. Since PGE2 and IL-8 stimulate osteoclasts to resorb bone, COX-2 inhibition is a potential target for treatment to prevent bone metastases.     

Patterns of expression of cell cycle/apoptosis genes along the spectrum of thyroid carcinoma progression

BACKGROUND: Genetic screening studies suggest that genetic changes underlie progression from well differentiated to anaplastic thyroid cancers. The aim of this study is to determine to what extent cell cycle/apoptosis regulators contribute to cancer progression. METHODS: Tissue microarrarys (TMAs) were constructed from well-differentiated papillary thyroid carcinoma (WDPTC; n = 41), poorly differentiated thyroid carcinoma (PDTC; n = 43), and anaplastic thyroid carcinoma (ATC; n = 22). TMAs were immunostained for 7 different cell cycle/apoptosis-related genes (p53, Ki-67, bcl-2, mdm-2, cyclin D1, p21, and p27). RESULTS: p53 (0%, 12%, 32%) and Ki-67 (5%, 49%, 82%) were expressed with increasing frequency, and bcl-2 (68%, 42%, 0%) and p21 (40%, 7%, 0%) with decreasing frequency in WDPTC to PDTC and ATC, respectively (P < .001). Interestingly, mdm-2 (54%, 5%, 0%) showed decreased expression along the progression axis (P < .001). p27 and cyclin D1 were expressed in <15% of cases, with a trend toward decreasing expression from WDPTC to PDTC to ATC. CONCLUSIONS: These data confirm the presence of increasing genetic complexity with progressive dedifferentiation in thyroid cancer, with aberrant tumor suppressor activity and increased proliferative activity being most prevalent in ATC. The data also confirm the intermediate position of PDTC in the classification scheme of thyroid carcinomas.     

Serum 25‐Hydroxyvitamin D Levels: Variability,Knowledge Gaps,and the Concept of a Desirable Range

Hypovitaminosis D is prevalent worldwide but proportions vary widely between regions, depending on genetic and lifestyle factors, the threshold to define deficiency, and accuracy of 25‐hydroxyvitamin D (25OHD) assays used. Latitude, pollution, concealing clothing, sun exposure, gender, dietary habits, and lack of government regulation account for up to 50% in variations in serum 25OHD levels, whereas genetic polymorphisms in the vitamin D pathway account for less than 5%. Organizations/societies have developed guidelines for recommended desirable 25OHD levels and vitamin D doses to reach them, but their applicability across age groups and populations are still debated. This article and the accompanying online Supporting Information highlight sources of variations in circulating 25OHD levels, uncertainties and knowledge gaps, and analytical problems facing 25OHD assays, while keeping efficacy and safety data as the dominant factors when defining a desirable range for 25OHD levels. We propose a desirable range of 20 to 40 ng/mL (50 to 100 nmol/L), provided precise and accurate assays are used. Although slightly lower levels, 15 to 20 ng/mL, may be sufficient for some infants and adults, higher levels, 40 to 60 ng/mL, may still be safe. This desirable range allows physicians to tailor treatment while taking season, lifestyle, vitamin D intake, and other sources of variation into account. We reserve 25OHD measurements for at‐risk patients, defined by disease or lifestyle, and the use of 25OHD assays calibrated against the recommended international standards. Most target groups reach desirable target levels by a daily intake of 400 to 600 IU for children and 800 IU for adults. A total daily allowance of vitamin D of up to 1000 IU in the pediatric age groups, and up to 2000 IU in adults, tailored to an individual patient risk profile, is probably safe over long durations. Additional data are needed to validate the proposed range and vitamin D doses, especially in children, pregnant women, and non‐white populations. © 2015 American Society for Bone and Mineral Research.     

Evidence for Kidney Rejection After Combined Bone Marrow and Renal Transplantation Despite Ongoing Whole‐Blood Chimerism in Rhesus Macaques

Although there is evidence linking hematopoietic chimerism induction and solid organ transplant tolerance, the mechanistic requirements for chimerism‐induced tolerance are not clearly elucidated. To address this, we used an MHC‐defined primate model to determine the impact of impermanent, T cell‐poor, mixed‐chimerism on renal allograft survival. We compared two cohorts: one receiving a bone marrow and renal transplant (“BMT/renal”) and one receiving only a renal transplant. Both cohorts received maintenance immunosuppression with CD28/CD40‐directed costimulation blockade and sirolimus. As previously demonstrated, this transplant strategy consistently induced compartmentalized donor chimerism, (significant whole‐blood chimerism, lacking T cell chimerism). This chimerism was not sufficient to prolong renal allograft acceptance: the BMT/renal mean survival time (MST, 76 days) was not significantly different than the renal transplant alone MST (85 days, p = 0.46), with histopathology documenting T cell mediated rejection. Flow cytometric analysis revealed significant enrichment for CD28–/CD95+ CD4+ and CD8+ Tem cells in the rejected kidney, suggesting a link between CD28‐negative Tem and costimulation blockade‐resistant rejection. These results suggest that in some settings, transient T cell‐poor chimerism is not sufficient to induce tolerance to a concurrently placed renal allograft and that the presence of this chimerism per se is not an independent biomarker to identify tolerance.