A pilot study investigating the effects of remote ischemic preconditioning in high-risk cardiac surgery using a randomised controlled double-blind protocol

The efficacy of remote ischemic preconditioning (RIPC) in high-risk cardiac surgery is uncertain. In this study, 96 adults undergoing high-risk cardiac surgery were randomised to RIPC (3 cycles of 5 min of upper-limb ischemia induced by inflating a blood pressure cuff to 200 mmHg with 5 min of reperfusion) or control. Main endpoints were plasma high-sensitivity troponin T (hsTNT) levels at 6 and 12 h, worst post-operative acute kidney injury (AKI) based on RIFLE criteria, and noradrenaline duration. hsTNT levels were log-normally distributed and higher with RIPC than control at 6-h post cross-clamp removal [810 ng/ml (IQR 527-1,724) vs. 634 ng/ml (429-1,012); ratio of means 1.41 (99.17% CI 0.92-2.17); P=0.04] and 12 h [742 ng/ml (IQR 427-1,700) vs. 514 ng/ml (IQR 356-833); ratio of means 1.56 (99.17% CI 0.97-2.53); P=0.01]. After adjustment for baseline confounders, the ratio of means of hsTNT at 6 h was 1.23 (99.17% CI 0.88-1.72; P=0.10) and at 12 h was 1.30 (99.17% CI 0.92-1.84; P=0.05). In the RIPC group, 35/48 (72.9%) had no AKI, 5/48 (10.4%) had AKI risk, and 8/48 (16.7%) had either renal injury or failure compared to the control group where 34/48 (70.8%) had no AKI, 7/48 (14.6%) had AKI risk, and 7/48 (14.6%) had renal injury or failure (Chi-squared 0.41; two degrees of freedom; P = 0.82). RIPC increased post-operative duration of noradrenaline support [21 h (IQR 7-45) vs. 9 h (IQR 3-19); ratio of means 1.70 (99.17% CI 0.86-3.34); P=0.04]. RIPC does not reduce hsTNT, AKI, or ICU-support requirements in high-risk cardiac surgery.     

ABT-737 increases tyrosine kinase inhibitor-induced apoptosis in chronic myeloid leukemia cells through XIAP downregulation and sensitizes CD34(+) CD38(-) population to imatinib

Chronic myeloid leukemia (CML) tumorigenicity is driven by the oncogenic BCR-ABL tyrosine kinase. Specific tyrosine kinase inhibitors (TKI) have been designed and are now used for the treatment of CML. These TKI induce apoptosis in leukemic cells in a BIM-dependent mechanism. We hypothesized that an increase in BIM activity could sensitize CML cells to TKI. We blocked the anti-apoptotic proteins of the Bcl-2 family by using ABT-737, a Bcl-2 and Bcl-XL inhibitor. ABT-737 modified Bcl-2 protein interactions toward a pro-apoptotic phenotype. Its combination with TKI resulted in a strong synergism in CML cell lines. The association also induced a large decrease in X-linked inhibitor of apoptosis (XIAP), followed by caspase-3 activation. This XIAP decrease was due to post-translational events. The mitochondrial serine protease HtrA2/Omi was identified as being responsible for this off-target effect. Then, ABT-737 and TKI cooperate at several levels to induce apoptosis of CML cells lines, and the benefit of this association was also observed in CML hematopoietic progenitors. Interestingly, a lethal effect was also observed in the more immature CD34(+)CD38(-) TKI-insensitive population. Combination therapy might by an interesting strategy for the treatment of CML patients.     

Effect of source of funding on weight loss up to 3 years after gastric banding

Background

Laparoscopic adjustable gastric banding (LAGB) is a popular choice for patients seeking weight loss surgery. Since behavioural change appears to play a role in weight loss outcomes we postulated that publicly funded patients might not do as well as self-payers. This series examines the effect of public funding versus self-pay on patients undergoing LAGB over 1, 2 and 3 years.

Methods

Consecutive non-randomised cohort series of patient undergoing LAGB over 5 years (September 2003 to December 2008) in a single unit. Age, sex, funding route, body mass index (BMI) and complications were recorded. Per cent excess weight loss (EWL) and the Reinhold criterion for success (proportion achieving 50 % EWL) were assessed.

Results

Ninety-nine patients were publicly funded, and 250 patients were self-payers. Initial BMI was significantly higher in publicly funded patients (46.6 vs. 42.3 kg/m², p < 0.001) with a higher proportion of males (22.2 vs. 6.0 %, p < 0.001). Mean % EWL was significantly less for publicly funded patients at 1 year (38.1 vs. 53.5 %, p < 0.001) and 2 years (49.6 vs. 64.1 %, p < 0.001), but not at 3 years (59.7 vs. 61.8 %, p = 0.784). Fewer publicly funded patients achieved 50 % EWL at 1 year (24.5 vs. 50.2 %, p < 0.001), but with no significant difference at 2 years (54.8 vs. 67.0 %, p = 0.140) or 3 years (55.2 vs. 66.0 %, p = 0.349).

Conclusions

Self-pay patients initially achieved more % EWL and greater success in reaching 50 % EWL after LAGB, but this difference was not maintained. The results suggest that patient motivation, using self-pay as a surrogate marker, may affect early results, but the operation itself is the main determinant of weight loss at 3 years.     

Role of Pretransplant Echocardiographic Evaluation in Predicting Outcomes Following Liver Transplantation

Maintenance of cardiac function is critical to the survival of patients with end‐stage liver disease after liver transplantation (LT). We sought to determine whether pre‐LT echocardiographic indices of right heart structure and function were independently predictive of morbidity and mortality post‐LT. We retrospectively studied 216 consecutive patients who underwent pre‐LT 2‐dimensional/Doppler echocardiography with subsequent LT from 2007 to 2010. A blinded reader analyzed multiple echocardiographic parameters, including right ventricular structure and function, pulmonary artery systolic pressure (PASP) and the presence and severity of tricuspid regurgitation (TR). On univariate analysis, Model of End‐Stage Liver Disease (MELD) score, PASP, presence of ≥mild TR, post–operative renal replacement therapy (RRT) and spontaneous bacterial peritonitis were found to be significant predictors of adverse outcomes. On multivariate analysis, only ≥mild TR was found to predict both patient mortality (p = 0.0024, HR = 3.91, 95% CI: 1.62–9.44) and graft failure (p = 0.0010, HR = 3.70, 95% CI: 1.70–8.06). PASP and MELD correlated with post‐LT intensive care unit length of stay (LOS) and, along with hemodialysis, were associated with hospital LOS and time on ventilator. In conclusion, pre‐LT echocardiographic assessments of the right heart may be useful in predicting post‐LT morbidity and mortality and guiding the selection of appropriate LT candidates.     

Neuropeptide Y Attenuates Stress‐Induced Bone Loss Through Suppression of Noradrenaline Circuits

Chronic stress and depression have adverse consequences on many organ systems, including the skeleton, but the mechanisms underlying stress‐induced bone loss remain unclear. Here we demonstrate that neuropeptide Y (NPY), centrally and peripherally, plays a critical role in protecting against stress‐induced bone loss. Mice lacking the anxiolytic factor NPY exhibit more anxious behavior and elevated corticosterone levels. Additionally, following a 6‐week restraint, or cold‐stress protocol, Npy‐null mice exhibit three‐fold greater bone loss compared to wild‐type mice, owing to suppression of osteoblast activity. This stress‐protective NPY pathway acts specifically through Y2 receptors. Centrally, Y2 receptors suppress corticotropin‐releasing factor expression and inhibit activation of noradrenergic neurons in the paraventricular nucleus. In the periphery, they act to control noradrenaline release from sympathetic neurons. Specific deletion of arcuate Y2 receptors recapitulates the Npy‐null stress response, coincident with elevated serum noradrenaline. Importantly, specific reintroduction of NPY solely in noradrenergic neurons of otherwise Npy‐null mice blocks the increase in circulating noradrenaline and the stress‐induced bone loss. Thus, NPY protects against excessive stress‐induced bone loss, through Y2 receptor‐mediated modulation of central and peripheral noradrenergic neurons. © 2014 American Society for Bone and Mineral Research.