Crosstalk in transition: the translocation of Akt

Journal of Mathematical Biology - Akt/PKB is an important crosstalk node at the junction between a number of major signalling pathways in the mammalian cell. As a significant nutrient sensor, Akt...     

The effect of pressure on the electrical breakdown in the membranes of Valonia utricularis

The interpretation of electrical breakdown in terms of electro-mechanical instabilities, predicts that the breakdown potential should decrease with increasing cell turgor pressure.Experiments were conducted to test this hypothesis on cells of Valonia utricularis over a turgor pressure range of 0.5 · 10⁵–5.0 · 10⁵ N/m². Electrical breakdown was measured using intracellular electrodes and 500 μs current pulses. The pressure was monitored by an intracellular micropipette pressure transducer. The results obtained show a linear decrease in the critical breakdown potential with pressure. The effective compressive modulus of the cell membrane, γ, is calculated from the slope of this line to 69 ± 10 · 10⁵N/m² (average value of seven measurements). This is consistent with the theoretical prediction of the electromechanical model using our previously determined values of the elastic modulus of the membrane.A theoretical analysis is given of the effects of pressure on the breakdown. This includes also considerations of the indirect effect of pressure on the membrane via stretching of the cell wall with a possible coupling of such strains to the cell membrane. The results and analysis presented allow us to conclude on the basis of the experimentally determined breakdown P.D. of 959 mV that the region of membrane where electrical breakdown occurs is a dielectric with one of the following combinations of parameters: (A) a thickness δ = 7–9 nm with a dielectric constant ? = >10, e.g. a hydrated protein spanning the whole membrane. (B) δ = 4–5 nm with ? = 3–8, e.g. a lipoprotein of lipid bilayer dimensions. (C) δ ≈ 2 nm with ? = 2–3, e.g. a half lipid bilayer.If we assume that the breakdown P.D. of the tonoplast and plasmalemma are identical, that is 480 mV, then there is only one reasonable choice for the membrane thickness and the dielectric constant: δ = 2nm, ? = 3–8, e.g. a (lipo-)proteinaceous module facing a half lipid bilayer.     

Determination of parameters of the survival curve of the stem cells of the intestinal crypts by LD50 and the regenerated crypt count. Determination of the RBE of p(65) + Be neutrons

The early effects of an irradiation on the intestinal epithelium have been evaluated, at the tissular level, by LD50 after single and multifraction irradiation, and, at the cellular level, by numeration of the regenerated intestinal crypts (Withers technique) after a single fraction irradiation. From the set of informations provided by both criteria, one derived the values of the parameters defining the survival curve of the intestinal clonogenic crypt cells after irradiation by gamma-rays (two component model): D0 = 1.5 Gy, 1D0 = 4.5 Gy, nD0 = 2.25 Gy and n = 20. In other respects, the p(65) + Be neutrons RBE (ref. 60-Cobalt) after a single fraction irradiation is equal to 1.75 +/- 0.2 and 1.64 +/- 0.25 for the LD50 at the 5th day and for the regeneration of 50 crypts after 3.5 days respectively.     

Proposed follow up programme after curative resection for lower third oesophageal cancer

Cyclins are indispensable elements of the cell cycle and derangement of their function can lead to cancer formation. Recent studies have also revealed more mechanisms through which cyclins can express their oncogenic potential. This review focuses on the aberrant expression of G1/S cyclins and especially cyclin D and cyclin E; the pathways through which they lead to tumour formation and their involvement in different types of cancer. These elements indicate the mechanisms that could act as targets for cancer therapy.     

Combination of chemotherapy and radiotherapy. I. Differential effect on the intestinal syndrome of irradiation combined with the drug administered in fractional doses and at various times]

We have studied the different effects on the intestinal syndrome between the administration of fractional doses of 5-Fu before and after irradiation. There is no difference between the diverse modalities and we obtain the same result when the 5-Fu is administered, fractionated or not, before or after the irradiation.     

Strategies to Improve Survival from Surgery for Heart Valve Implantation in Sheep

Sheep are a commonly used and validated model for cardiovascular research and, more specifically, for heart valve research. Implanting a heart valve on the arrested heart in sheep is complex and is often complicated by difficulties in restarting the heart, causing significant on-table mortality. Therefore, optimal cardioprotective management during heart valve implantation in sheep is essential. However, little is known about successful cardioprotective management techniques in sheep. This article reports our experience in the cardioprotective management of 20 female sheep that underwent surgical aortic valve replacement with a stented tissue-engineered heart valve prosthesis. During this series of experiments, we modified our cardioprotection protocol to improve survival. We emphasize the importance of total body hypothermia and external cooling of the heart. Furthermore, we recommend repeated cardioplegia administration at 20 min intervals during surgery, with the final dosage of cardioplegia given immediately before the de-clamping of the aorta. To reduce the number of defibrillator shocks during a state of ventricular fibrillation (VF), we have learned to restart the heart by reclamping the aorta, administering cardioplegia until cardiac arrest, and de-clamping the aorta thereafter. Despite these encouraging results, more research is needed to finalize a protocol for this procedure.

Sheep are a commonly used and well-validated model for cardiovascular research, particularly for heart valve research, as blood pressure, heart rate, cardiac output, and intracardiac pressures are similar between sheep and humans. Sheep are particularly useful for heart valve research because observable changes in implanted heart valve bioprostheses that would take several years to develop in humans are apparent after only a few months in sheep.^3,11 This feature allows the ovine model to provide relevant and important information about heart valve prostheses in a relatively short time span. The first preclinical step in developing novel heart valves is to test the valve in the pulmonary position in sheep. This surgical technique is relatively easy, as the procedure can be performed on a beating heart in a low-pressure circulation. However, aortic valve surgery is the most frequently performed valvular surgical intervention in human patients.¹² Thus, an important next step is to prove the clinical applicability of a new valve by testing the valve in-vivo in the aortic position in an animal model. In contrast to pulmonary valve replacement, aortic valve replacement must be performed on an arrested heart, which makes the surgical procedure significantly more complex. The sheep is a difficult model for aortic valve replacements due to its narrow annulus, short distance between the annulus and coronary ostia, a short ascending aorta, and difficulty in de-airing of the heart prior to suturing the aortotomy.¹⁹ Consequently, high on-table mortality rates, ranging from 9% to 33%, have been reported.^1,18,21,24 Furthermore, the incidence of mortality during the first 30 d after surgery, directly related to the surgical procedure, is often high, ranging from 17% to 50%.^1,2,16,18,21 Therefore, optimizing cardioprotective strategies during surgery would improve postoperative survival. However, little is known about protective strategies in sheep. In the current series of experiments, we implanted stented, tissue engineered, aortic heart valve prostheses in 20 adult domestic sheep and developed cardioprotective techniques to increase survival rates. In this observational study, we share our experience and insights regarding cardioprotective management to potentially improve the outcome of future surgeries that require an arrested heart in sheep.