CDDO-Im is a stimulator of megakaryocytic differentiation

Although the triterpene CDDO and its potent derivatives, CDDO-Im and CDDO-Me, are now in phase I/II studies in the treatment of some pathological conditions, their effects on normal hematopoiesis are not known. In the present study we provide evidence that CDDO-Im exerts in vitro a potent inhibitory effect on erythroid cell proliferation and survival and a stimulatory action on megakaryocytic differentiation.The effect of CDDO-Im on erythroid and megakaryocytic differentiation was evaluated both on normal hemopoietic progenitor cells (HPCs) induced to selective erythroid (E) or megakaryocytic (Mk) differentiation and on erythroleukemic cell lines HEL and TF1.The inhibitory effect of CDDO-Im on erythroid cell survival and proliferation is mainly related to a reduced GATA-1 expression. This conclusion is supported by the observation that GATA-1 overexpressing TF1 cells are partially protected from the inhibitory effect of CDDO-Im on cell proliferation and survival. The stimulatory effect of CDDO-Im on normal megakaryopoiesis is seemingly related to upmodulation of GATA2 expression and induction of mitogen-activated protein kinases ERK1/2.     

Indocyanine green kinetics to assess liver function: Ready for a clinical dynamic assessment in major liver surgery?

Indocyanine green(ICG) kinetics(PDR/R15) used to quantitatively assess hepatic function in the perioperative period of major resective surgery and liver transplantation have been the object of an extensive, updated and critical review. New, non invasive bedside monitors(pulse dye densitometry technology) make this opportunity widely available in clinical practice. After having reviewed basic concepts of hepatic clearance, we analysed the most common indications ICG kinetic parameters have nowadays in clinical practice, focusing in particular on the diagnostic and prognostic role of PDR and R15 in the perioperative period of major liver surgery and liver transplantation. As recently pointed out, even if of extreme interest, ICG clearance parameters have still some limitations, to be considered when using these tests.     

The importance of pre-trauma centre treatment of life-threatening events on the mortality of patients transferred with severe trauma

Aim

The benefit of a well organised trauma system is acknowledged but doubts remain concerning the optimal pre-hospital trauma care model. We hypothesise that the treatment of life-threatening events before arrival at trauma centre - either pre-hospital or first hospital - may be more relevant to decreasing mortality than shortening the time to trauma centre.

Methods

A cohort of 727 trauma patients with life-threatening events - identified as airway, breathing, circulation or neurological disability - requiring transfer to a trauma centre were studied. Data on patient's characteristics, trauma features, and mortality were taken from a trauma registry. Patients were divided into 3 groups depending on the place of treatment of life-threatening events: pre-hospital, first hospital or trauma centre. Survival Kaplan-Meier curves and logistic regression were used to assess the effect of place of treatment of life-threatening events on mortality.

Results

Patients from the pre-hospital and first hospital groups had 20% and 27% mortality respectively, compared to 38% among those whose life-threatening events were corrected only at the trauma centre. Logistic regression showed that patients whose life-threatening events were corrected only at the trauma centre had an odds of death 3.3 times greater than those from the pre-hospital group, adjusted for patient and trauma characteristics and time to trauma centre.

Conclusion

In trauma patients requiring transfer to a trauma centre, pre-hospital interventions to treat life-threatening events may significantly decrease mortality when compared to similar interventions performed later at the trauma centre.     

A model-based approach to the in vitro evaluation of anticancer activity

Purpose  The use of in vitro screening tests for characterizing the activity of anticancer agents is a standard practice in oncology research and development. In these studies, human A2780 ovarian carcinoma cells cultured in plates are exposed to different concentrations of the compounds for different periods of time. Their anticancer activity is then quantified in terms of EC₅₀ comparing the number of metabolically active cells present in the treated and the control arms at specified time points. The major concern of this methodology is the observed dependency of the EC₅₀ on the experimental design in terms of duration of exposure. This dependency could affect the efficacy ranking of the compounds, causing possible biases especially in the screening phase, when compound selection is the primary purpose of the in vitro analysis. To overcome this problem, the applicability of a modeling approach to these in vitro studies was evaluated. Methods  The model, consisting of a system of ordinary differential equations, represents the growth of tumor cells using a few identifiable and biologically relevant parameters related to cell proliferation dynamics and drug action. In particular, the potency of the compounds can be measured by a unique and drug-specific parameter that is essentially independent of drug concentration and exposure time. Parameter values were estimated using weighted nonlinear least squares. Results  The model was able to adequately describe the growth of tumor cells at different experimental conditions. The approach was validated both on commercial drugs and discovery candidate compounds. In addition, from this model the relationship between EC₅₀ and the exposure time was derived in an analytic form. Conclusions  The proposed approach provides a new tool for predicting and/or simulating cell responses to different treatments with useful indications for optimizing in vitro experimental designs. The estimated potency parameter values obtained from different compounds can be used for an immediate ranking of anticancer activity.     

Cerebrolysin and morphine decrease glutathione and 5-hydroxyindole acetic acid levels in fasted rat brain

Purpose

The aim was to evaluate if morphine sulphate combined with cerebrolysin enhances the risk of oxidative damage in the presence of moderate hypoglycaemia.

Methods

Wistar rats under starvation for 48 h received a single dose of 215 mg/kg cerebrolysin or 4 mg/kg morphine sulphate. Glutathione (GSH) and 5-hydroxyindoleacetic acid (5-HIAA) levels were measured in brain tissue, as well as lipid peroxidation, Na⁺–K⁺ ATPase and total ATPase enzymatic activities, by fluorescence and spectrophotometric methods.

Results

GSH and 5-HIAA levels decreased significantly (p < 0.05) in animals which received cerebrolysin and morphine alone or combined. TBARS levels increased in all groups, but the values were statistically significant only in those animals that received cerebrolysin combined with morphine (p < 0.05). Na⁺–K⁺ ATPase and total ATPase activities decreased significantly in rats treated only with morphine, but the cerebrolysin and morphine groups showed a significant increase in these enzymatic activities.

Conclusions

Results suggest that cerebrolysin as well as morphine induced changes in cellular regulation and biochemical responses to oxidative stress induced by moderate hypoglycaemia in brain.     

Cost of abortions in Zambia: A comparison of safe abortion and post abortion care

Unsafe abortion is a significant but preventable cause of maternal mortality. Although induced abortion has been legal in Zambia since 1972, many women still face logistical, financial, social, and legal obstacles to access safe abortion services, and undergo unsafe abortion instead. This study provides the first estimates of costs of post abortion care (PAC) after an unsafe abortion and the cost of safe abortion in Zambia. In the absence of routinely collected data on abortions, we used multiple data sources: key informant interviews, medical records and hospital logbooks. We estimated the costs of providing safe abortion and PAC services at the University Teaching Hospital, Lusaka and then projected these costs to generate indicative cost estimates for Zambia. Due to unavailability of data on the actual number of safe abortions and PAC cases in Zambia, we used estimates from previous studies and from other similar countries, and checked the robustness of our estimates with sensitivity analyses. We found that PAC following an unsafe abortion can cost 2.5 times more than safe abortion care. The Zambian health system could save as much as US$0.4 million annually if those women currently treated for an unsafe abortion instead had a safe abortion.