Protein carbamylation renders high-density lipoprotein dysfunctional

Carbamylation of proteins through reactive cyanate has been demonstrated to predict an increased cardiovascular risk. Cyanate is formed in vivo by breakdown of urea and at sites of inflammation by the phagocyte protein myeloperoxidase. Because myeloperoxidase (MPO) associates with high-density lipoprotein (HDL) in human atherosclerotic intima, we examined in the present study whether cyanate specifically targets HDL. Mass spectrometry analysis revealed that protein carbamylation is a major posttranslational modification of HDL. The carbamyllysine content of lesion-derived HDL was more than 20-fold higher in comparison with 3-chlorotyrosine levels, a specific oxidation product of MPO. Notably, the carbamyllysine content of lesion-derived HDL was five- to eightfold higher when compared with lesion-derived low-density lipoprotein (LDL) or total lesion protein and increased with lesion severity. The carbamyllysine content of HDL, but not of LDL, correlated with levels of 3-chlorotyrosine, suggesting that MPO mediated carbamylation in the vessel wall. Remarkably, one carbamyllysine residue per HDL-associated apolipoprotein A-I was sufficient to induce cholesterol accumulation and lipid-droplet formation in macrophages through a pathway requiring the HDL-receptor scavenger receptor class B, type I. The present results raise the possibility that HDL carbamylation contributes to foam cell formation in atherosclerotic lesions.     

Post-resuscitation care at the emergency department with critical care facilities--a length-of-stay analysis

Aim of the study

An emergency department providing critical care will have an effect on outcome and intensive-care-units’ resources by avoiding unnecessary or futile intensive-care admissions and thereby save hospital expenses. The study focussed on this result.

Methods

The study employed a retrospective analysis of prospectively collected data of out-of-hospital cardiac arrest patients with return of spontaneous circulation, comatose on arrival. Outcomes and length of stay of patients who either stayed at the ‘emergency department only’ or were ‘transferred in addition to an intensive care unit’ were compared. Linear regression with log length of stay as outcome and ‘emergency department only’ as predictor with covariates was used for modelling.

Results

From 1991 to 2008, out of 1236 patients (age 57 ± 15 years, female 31%), the ‘emergency department only’ group (n = 349 (28%)) survived to discharge in 81(23%) cases, with a median length-of-stay in critical care of 1.7 (interquartile range 0.8; 3.1) days. The patients ‘transferred in addition to an intensive care unit’ (n = 887 (72%)), with a survival rate of 55% (n = 486, p < 0.001) stayed 10 (5; 18) days (p < 0.001). The length-of-stay in hospital was significantly shorter if patients were treated in the ‘emergency department only’ independent of other cardiac-arrest-related factors (regression coefficient −1.42, confidence interval −1.60 to −1.24).

Conclusions

An emergency department with critical care prevents admissions to intensive care units in 28% of patients with out-of-hospital cardiac arrest. It saves intensive-care-unit resources and shortens length of stay for comatose out-of-hospital cardiac-arrest survivors, regardless of their outcome.     

CECOG experts’ recommendations on the use of denosumab in the prevention of skeletal-related events in bone metastases of lung cancer

Purpose

Skeletal-related events represent a substantial burden for patients with advanced cancer. Randomized, controlled studies suggested superiority of denosumab over zoledronic acid in the prevention of skeletal-related events in metastatic cancer patients, with a favorable safety profile. Experts gathered at the 2012 Skeletal Care Academy in Istanbul to bring forward practical recommendations, based on current evidence, for the use of denosumab in patients with bone metastases of lung cancer.

Recommendations

Based on current evidence, use of denosumab in lung cancer patients with confirmed bone metastases is recommended. It is important to note that clinical judgment should take into consideration the patient’s general performance status, overall prognosis, and live expectancy. Currently, the adverse event profile reported for denosumab includes hypocalcemia and infrequent occurrence of osteonecrosis of the jaw. Therefore, routine calcium and vitamin D supplementation, along with dental examination prior to denosumab initiation are recommended. There is no evidence for renal function impairment due to denosumab administration. At present, there is no rationale to discourage concomitant use of denosumab and surgery or radiotherapy.     

Femoro-iliacal artery versus pulmonary artery core temperature measurement during therapeutic hypothermia: An observational study

Aim of the study

Therapeutic hypothermia after cardiac arrest improves neurologic outcome. The temperature measured in the pulmonary artery is considered to best reflect core temperature, yet is limited by invasiveness. Recently a femoro-arterial thermodilution catheter (PiCCO-Pulse Contour Cardiac Output) has been introduced in clinical practice as a safe and accurate haemodynamic monitoring system, which is also able to measure blood temperature. The aim of the study was to investigate, if the temperature measured with the PiCCO catheter reflects pulmonary artery temperature better than other sites during therapeutic hypothermia.

Methods

In this observational study twenty patients after cardiac arrest and successful resuscitation were cooled with various cooling methods to 33 ± 1 °C for 24 h, followed by rewarming. Temperatures were recorded continuously in the pulmonary artery (Tpa), femoro-iliacal artery (Tpicco), ear canal (Tear), oesophagus (Toeso) and urinary bladder (Tbla). We assessed agreement of methods using the Bland Altman approach including bias and limits of agreement (LA).

Results

All other sites differed significantly from Tpa with the bias varying from 0.4 °C (Tbla) to −0.6 °C (Tear). Standard deviations varied from 0.1 °C (Tpicco, Toeso) to 0.5 °C (Tear). For all sites bias was closer to zero with increasing average temperatures. Bias tended to be larger in the cooling phase compared to overall measurements.

Conclusions

Temperature measurement in the femoro-iliacal artery (Tpicco) reflects the gold standard of pulmonary artery temperature most accurately, especially during the cooling phase. Tpicco is easily accessible and might be used for monitoring core temperature without the need for additional temperature probes.     

The small molecule specific EphB4 kinase inhibitor NVP-BHG712 inhibits VEGF driven angiogenesis

EphB4 and its cognitive ligand ephrinB2 play an important role in embryonic vessel development and vascular remodeling. In addition, several reports suggest that this receptor ligand pair is also involved in pathologic vessel formation in adults including tumor angiogenesis. Eph/ephrin signaling is a complex phenomena characterized by receptor forward signaling through the tyrosine kinase of the receptor and ephrin reverse signaling through various protein–protein interaction domains and phosphorylation motifs of the ephrin ligands. Therefore, interfering with EphR/ephrin signaling by the means of targeted gene ablation, soluble receptors, dominant negative mutants or antisense molecules often does not allow to discriminate between inhibition of Eph/ephrin forward and reverse signaling. We developed a specific small molecular weight kinase inhibitor of the EphB4 kinase, NVP-BHG712, which inhibits EphB4 kinase activity in the low nanomolar range in cellular assays showed high selectivity for targeting the EphB4 kinase when profiled against other kinases in biochemical as well as in cell based assays. Furthermore, NVP-BHG712 shows excellent pharmacokinetic properties and potently inhibits EphB4 autophosphorylation in tissues after oral administration. In vivo, NVP-BHG712 inhibits VEGF driven vessel formation, while it has only little effects on VEGF receptor (VEGFR) activity in vitro or in cellular assays. The data shown here suggest a close cross talk between the VEGFR and EphR signaling during vessel formation. In addition to its established function in vascular remodeling and endothelial arterio-venous differentiation, EphB4 forward signaling appears to be an important mediator of VEGF induced angiogenesis since inhibition of EphB4 forward signaling is sufficient to inhibit VEGF induced angiogenesis.     

Student learning preferences and the impact of a multimedia learning tool in the dissection course at the University of Munich

How do students use multimedia tools to support their learning during a gross anatomy dissection course? We investigated this question in the anatomic dissection course for first year medical students at the University of Munich (n=850) by giving all participating students access to an anatomical multimedia CD-ROM. The use of this multimedia learning tool was voluntary and it was not essential for the end-of-course examination.After the examination, two questionnaires (return rate first questionnaire n₁=347, 41%; return rate second questionnaire n₂=644, 76%) were given to the surveyed students with the following content: evaluation of the multimedia learning tool, details about the usage of different kinds of available learning media, and finally an evaluation of the media used for teaching during the course. Furthermore we collected personal data from participants such as age, gender and the score achieved in the examination.Classical textbooks and anatomical atlases were used by 84% of students for preparation. The multimedia learning tool was used by 34% as an additional media for learning. The multimedia learning tool was not used alone. The data showed differences with regard to gender and performance of students, but not relating to age. Students rated the computer-specific features, e.g. three-dimensional (3D) models, virtual simulations, and an interactive quiz module, as major reasons for using the multimedia learning tool.Our results show that medical students use anatomic multimedia learning tools primarily as an additional medium for learning, and thus lead to the conclusion that the main learning media are still textbooks and anatomic atlases.