Acute Cellular Rejection and Infection Rates in Alemtuzumab vs Traditional Induction Therapy Agents for Lung and Heart Transplantation: A Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVES: Heart and lung transplantation is a high-risk procedure requiring intensive immunosuppressive therapy for preventing organ rejection. Alemtuzumab, a CD52-specific monoclonal antibody, is increasingly used for induction therapy compared with conventional agents. However, there has been no systematic review comparing its efficacy with traditional therapeutic drugs. METHODS: PubMed and EMBASE were searched to October 1, 2017, for articles on alemtuzumab in cardiothoracic transplant surgery. Of the 433 studies retrieved, 8 were included in the final meta-analysis. RESULTS: In lung transplantation, alemtuzumab use was associated with lower odds of acute cellular rejection compared with antithymocyte globulin (odds ratio [OR], 0.21; 95% CI, 0.11-0.40; P < .001), lower acute rejection rates (OR, 0.12; 95% CI, 0.03-0.55; P < .01), and infection rates (OR, 0.69; 95% CI, 0.35-1.36; P = .33) when compared with basiliximab. Multivariate meta-regression analysis found that mean age, male sex, single lung transplant, double lung transplant, cytomegalovirus or Epstein-Barr virus status, idiopathic pulmonary fibrosis, cystic fibrosis, and mean ischemic time did not significantly influence acute rejection outcomes. For heart transplantation, alemtuzumab use was associated with lower acute rejection rates when compared with tacrolimus (OR, 0.44; 95% CI, 0.30-0.66; P < .001). CONCLUSIONS: Alemtuzumab use was associated with lower rejection rates when compared with conventional induction therapy agents (antithymocyte globulin, basiliximab, and tacrolimus) in heart and lung transplantation. However, this was based on observational studies. Randomized controlled trials are needed to verify its clinical use.

WITHDRAWN: Acute Cellular Rejection and Infection Rates in Alemtuzumab vs Traditional Induction Therapy Agents for Lung and Heart Transplantation: A Systematic Review and Meta-analysis.

The Publisher regrets that this article is an accidental duplication of an article that has already been published in Transplant Proc. 2018; 50 (10):3739-3747, https://doi.org/10.1016/j.transproceed.2018.08.018. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Targeting of nucleotide-binding proteins by HAMLET--a conserved tumor cell death mechanism.

HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells) kills tumor cells broadly suggesting that conserved survival pathways are perturbed. We now identify nucleotide-binding proteins as HAMLET binding partners, accounting for about 35% of all HAMLET targets in a protein microarray comprising 8000 human proteins. Target kinases were present in all branches of the Kinome tree, including 26 tyrosine kinases, 10 tyrosine kinase-like kinases, 13 homologs of yeast sterile kinases, 4 casein kinase 1 kinases, 15 containing PKA, PKG, PKC family kinases, 15 calcium/calmodulin-dependent protein kinase kinases and 13 kinases from CDK, MAPK, GSK3, CLK families. HAMLET acted as a broad kinase inhibitor in vitro, as defined in a screen of 347 wild-type, 93 mutant, 19 atypical and 17 lipid kinases. Inhibition of phosphorylation was also detected in extracts from HAMLET-treated lung carcinoma cells. In addition, HAMLET recognized 24 Ras family proteins and bound to Ras, RasL11B and Rap1B on the cytoplasmic face of the plasma membrane. Direct cellular interactions between HAMLET and activated Ras family members including Braf were confirmed by co-immunoprecipitation. As a consequence, oncogenic Ras and Braf activity was inhibited and HAMLET and Braf inhibitors synergistically increased tumor cell death in response to HAMLET. Unlike most small molecule kinase inhibitors, HAMLET showed selectivity for tumor cells in vitro and in vivo. The results identify nucleotide-binding proteins as HAMLET targets and suggest that dysregulation of the ATPase/kinase/GTPase machinery contributes to cell death, following the initial, selective recognition of HAMLET by tumor cells. The findings thus provide a molecular basis for the conserved tumoricidal effect of HAMLET, through dysregulation of kinases and oncogenic GTPases, to which tumor cells are addicted.

Assessment of the Pediatric Index of Mortality (PIM) and the Pediatric Risk of Mortality (PRISM) III score for prediction of mortality in a paediatric intensive care unit in Hong Kong.

OBJECTIVE: To compare two models (The Pediatric Risk of Mortality III score and Pediatric Index of Mortality) for prediction of mortality in a paediatric intensive care unit in Hong Kong. DESIGN: Prospective case series. SETTING: A five-bed paediatric intensive care unit in a general hospital in Hong Kong. PATIENTS: All patients consecutively admitted to the unit between April 2001 and March 2003. MAIN OUTCOME MEASURES: Scores for both models compared with observed mortality. RESULTS: A total of 303 patients were admitted to the paediatric intensive care unit during the study period. The median age was 2 years, with an interquartile range of 7 months to 7 years. The male to female ratio was 169:134 (55.8%:44.2%). The median length of hospital stay was 3 days. The overall predicted number of deaths using The Pediatric Risk of Mortality III score was 10.2 patients whereas that by Pediatric Index of Mortality was 13.2 patients. The observed mortality was eight patients. The area under the receiver operating characteristics curve for the two models was 0.910 and 0.912, respectively. CONCLUSION: The predicted mortality using both prediction models correlated well with the observed mortality.

Bacteriological screening of expressed breast milk revealed a high rate of bacterial contamination in Chinese women.

A screening programme for expressed breast milk (EBM) revealed the alarming fact that our study group had the highest rate of contamination ever reported. The programme started in July 2002 and involved a group of Chinese women whose premature babies were in the neonatal intensive care unit. EBM was considered to be contaminated if there was any growth of pathogens, including Gram-negative bacteria, enterococci or Staphylococcus aureus, or if the total bacterial count was >10(5) cfu/mL. Of 59 samples from 23 mothers, 63% were contaminated. This high contamination rate could be due to the Chinese tradition of avoiding bathing for one month after childbirth. Previous studies have shown that feeding EBM rather than premature infant formula milk has advantages in terms of decreased incidence of necrotizing enterocolitis and neonatal sepsis. However, in this population, with such a high incidence of contaminated EBM, this may not be the case. Further studies to compare EBM with premature infant formula in this population are required.

Clinical risk factors for obstructive sleep apnoea in children.

OBJECTIVE: To identify the clinical factor(s) that identify obstructive sleep apnoea syndrome (OSAS) in children. METHODS: A prospective study of children referred to the sleep clinic of the paediatric department was conducted in a public non-teaching regional hospital in Hong Kong. A standard questionnaire was administered and overnight sleep polysomnography was performed in a consecutive series of patients. Logistic regression analysis was performed to obtain significant risk factors for prediction of OSAS in this series of patients. RESULTS: Sixty-two children were enrolled into the study and 22 were diagnosed to have OSAS. Logistic regression analysis showed that, among all the answers, 'snoring every night' is the single most significant risk factor (p<0.0001) to predict OSAS. 'Snoring every night' has a sensitivity of 91% and specificity of 75% for OSAS patients. It also has a positive predictive value of 67% and negative predictive value of 94%. CONCLUSION: Snoring every night is an important risk factor in identifying OSAS in children. Priority for an overnight sleep polysomnogram should be given to those with this symptom.

Effects of pharmacological preconditioning with U50488H on calcium homeostasis in rat ventricular myocytes subjected to metabolic inhibition and anoxia.

1. The effects of pharmacological preconditioning with U50488H (U(50)), a selective kappa-opioid receptor agonist, on Ca(2+) homeostasis in rat ventricular myocytes subjected for 9 min to metabolic inhibition (MI) and anoxia (A), consequences of ischaemia, were studied and compared with those of preconditioning with brief periods of MI/A. 2. Precondition with 30 micro M of U(50) for three cycles of 1 min each cycle separated by 3 min of recovery (UP) significantly increased the percentage of non-blue cells following MI/A. The effect of UP is the same as that of preconditioning with an inhibitor of glycolysis and an oxygen scavenger for three 1-min cycles separated by three-minute recovery (MI/AP). The results indicate that like MI/AP, UP also confers cardioprotection. 3. MI/A increased intracellular Ca(2+) ([Ca(2+)](i)) and reduced the amplitude of caffeine-induced [Ca(2+)](i) transients, an indication of Ca(2+) content in the sarcoplasmic reticulum (SR). MI/A also reduced the electrically-induced [Ca(2+)](i) transient, that indicates Ca(2+)-release during excitation-contraction coupling, and Ca(2+) sparks in unstimulated myocytes, that indicates spontaneous Ca(2+)-release from SR. It also prolonged the decline of the electrically-induced [Ca(2+)](i) transient and slowed down the recovery of the electrically-induced [Ca(2+)](i) transient after administration of caffeine. In addition, MI/A prolonged the decline of caffeine induced [Ca(2+)](i) transient, an indication of Na(+)-Ca(2+) exchange activity, and UP prevented it. So UP, that confers cardioprotection, prevented the changes induced by MI/A. With the exception of Ca(2+)-spark, which was not studied, the effects of MI/AP are the same as those of UP. 4. It is concluded that pharmacological preconditioning with U(50), that confers immediate cardioprotection, prevents changes of Ca(2+) homeostasis altered by MI/A in the rat heart. This may be responsible, at least partly, for the cardioprotective action. 5. The study also provided evidence that MI/A causes mobilization of Ca(2+) from SR to cytoplasm causing Ca(2+)-overload which may be due to reduced Ca(2+)-uptake by SR. MI/A also reduces spontaneous and electrically induced Ca(2+) release from SR.

Review of children with severe trauma or thermal injury requiring intensive care in a Hong Kong hospital: retrospective study.

OBJECTIVE: To study the injury pattern of children admitted for management of severe trauma or thermal injury. DESIGN: Retrospective review. SETTING: Paediatric intensive care unit of a regional hospital, Hong Kong. PATIENTS: Twenty-eight children were admitted under this category from July 1996 to December 1999. MAIN OUTCOME MEASURES: Mechanisms, severity, and circumstances of injury. RESULTS: Road traffic accident was the most common cause of admission, followed by thermal injury, accidental fall, and non-accidental injury. However, children with non-accidental injury were admitted in a significantly more severe condition, as measured by the paediatric risk of mortality score, than those admitted for the other three reasons. Non-accidental injury was also associated with significantly higher morbidity and mortality than the other causes of admission. CONCLUSIONS: During the 42-month study period, trauma and thermal injury accounted for 7% of all admissions to the paediatric intensive care unit. Road traffic accident was the most common reason, while non-accidental injury accounted for the most serious injury. Detailed analysis of these cases identified certain preventable risk factors.