Differential effects of tyrosine kinase inhibitors in haemostasis, thrombosis and inflammation

The detection of the Bcr-Abl gene in chronic myeloid leukaemia (CML) has resulted in the development of novel tyrosine kinase inhibitors (TKIs), such as imatinib that particularly interfere with the ATP binding pocket of the Abl kinase domain of the Bcr-Abl protein. Imatinib is currently used as a frontline therapy, with impressive outcomes at producing long-term clinical remission among many CML patients; however, resistance to imatinib has been reported in patients due to the development of Bcr-Abl mutations and/or intolerance to the drug. Potent second generation TKIs, namely nilotinib and dasatinib, have since been developed and approved to address this therapeutic challenge. With their prompt and noticeable deep molecular and haematological remission properties, dasatinib and nilotinib have provided a significant effect and efficiency against leukaemic cells. However, due to the side effects and challenges linked to dasatinib, imatinib, and nilotinib, ponatinib which is a new third generation TKI inhibitor multi-kinase drug has been developed to be effective against leukemic cells containing the Bcr-Abl resistance mutation T315I. Nevertheless, ponatinib can inhibit T315I Bcr-Abl mutant enzymes selectively especially the ones which are not sensitive to new Bcr-Abl inhibitors obtainable at clinics. The management of malignancy in a significant proportion of patients and their survival is improved using these later generation drugs, therefore, recent studies have concentrated on their toxicity. For instance, in the case of ponatinib and nilotinib, clinical studies have revealed excessive and unnecessarily severe vascular problems, such as peripheral arterial occlusive disease (PAOD) and arterial occlusive events compared with other TKIs. Consequently, this had led to an increased desire to limit the pathophysiology of cardiovascular risk factors. Cardiovascular disease is a major clinical issue and a leading cause of illness, disability and mortality in the world, specifically in industrialised countries. Platelets are essential in normal haemostasis as they prevent blood loss following trauma by blood clot formation and they sustain vascular integrity. They also play a crucial role in the pathophysiological processes of atherosclerotic plaque and arterial thrombotic disease by contributing to vaso-occlusive thrombotic mechanisms that generate ischaemic traumatic damage in cardiovascular and peripheral blood vessel disease. Platelets¿ attachment under some extreme conditions of excessive flow shear forces in stenotic blood arteries enhances the reaction of platelets leading to increased in vivo arterial coagulation. In the context of vasculature, the pro-atherothrombotic role of platelets is presently well defined and involves pro-incendiary viscid particles in the interface between endothelium and platelets at sites of ruptured atherosclerosis plaques. This promotes the recruitment and adhesion of leukocytes, thereby leading to enhancement of atherosclerotic plaque formation and development of arterial thrombosis. The anti-leukaemic therapies, such as TKIs, are commonly associated with modifications of platelets and endothelial function that lead to the production of pathological thrombi. The primary purpose of this study was to determine the effect of ponatinib, nilotinib, dasatinib and imatinib on the function of platelets and thrombus growth in mouse and human arteries by in vitro, ex vivo and in vivo methods. The overarching goal was to provide a comprehensive analysis that would improve the understanding of potential mechanisms by which the TKI, ponatinib, potentiates a prothrombotic state. In vitro experiments demonstrated that dasatinib and imatinib, but not ponatinib or nilotinib, inhibited ADP-, CRP-, and collagen-induced platelet aggregation. Ponatinib also potentiated PAR-1-mediated alpha granule release, whilst imatinib and dasatinib showed inhibitory effects on platelet alpha granule exocytosis following agonist stimulation. In this study, we demonstrated using intravital microscopy of vascular injury of mesenteric arterioles and carotid arteries induced by ferric chloride (FeCl3) that there was a significant increase in in vivo thrombus formation over time in mice treated with ponatinib (3 mg/kg), nilotinib (25 mg/kg), but not with imatinib (25 mg/kg) or dasatinib (5 mg/kg). In addition, the effect of ponatinib was independent of platelet glycoprotein surface expression. Ponatinib potentiated alpha granule exocytosis in humans and mice. The data presented in this thesis confirmed the prothrombotic effects of ponatinib and nilotinib in humans where it was shown that in whole blood from drug-treated CML patients there was increased ex vivo platelet adhesion under flow conditions and increased plasma levels of soluble P-selectin (sP-selectin) and pro-inflammatory cytokines. The results from this study also demonstrated that ponatinib and nilotinib TKIs have a prothrombotic effect that can be reversed by pretreatment with the L-type calcium channel blocker, diltiazem and the COX-2 inhibitor, diclofenac, and to a lesser extent by the eNOS synthase inhibitor, L-NNA. However, the study suggested that nilotinib or ponatinib-treated CML patients who develop vascular complications of coronary artery vasospasm or cerebrovascular accident (CVA) could potentially be treated with L-type calcium channel blockers to reduce arterial occlusive events. Further clinical trials are indicated to examine the efficacy and safety of using calcium channel blockers in the clinical setting of ponatinib and nilotinib-treated CML patients

Cultural contingency on the antecedents of the complexity of management accounting systems: Evidence from a meta-analysis of individual data

The purpose of this study is to test the hypothesis that there is a cultural contingency on the antecedents of the complexity of management accounting systems. After briefly reviewing the theoretical debate on this hypothesis, we present our results which provide support for cultural contingency on these antecedents. However, the data studied could be criticized. Thus, further research will be needed to explore this cultural contingency.Cultural contingency ; complexity of management accounting systems ; meta-analysis of individual data ; small and medium sized enterprise

Some larval morphological characteristics of Camelostrongylus mentulatus and Nematodirus spathiger

Monitoring of gastrointestinal nematode parasites in ruminants (domestic and wild) is often based on fecal examination techniques, looking for excreted eggs and larval forms using morphological keys. These, are more available in domestic ruminants, in which helminths are widely studied, than in wild ruminants.  This study tried to provide certain morphological elements that will help to recognize the L3 larvae of Camelostrongylus mentulatus and Nematodirus spathiger that could parasite either domestic or wild ruminants. For that, we resorted first to the culture of L3 larvae from fecal samples taken from African antelopes, and second by the microscopic characterization of each isolated larval morphological pattern previously identified by sequencing of its internal transcribed spacer (ITS-2) regions of the ribosomal DNA. The results of different microscopic captured images showed that Camelostrongylus mentulatus larva is 16 intestinal cells that measuring approximately 820 µm length, ‎≈ 25 µm wide, and ‎≈ 47 µm for its sheath tail extension and by this be closer to Teladorsagia circumcincta characteristics.  For Nematodirus spathiger, it possesses 8 gut cells and measuring about 1020 µm long, ‎≈ 25 µm wide, and‎ ≈ 143 µm for its sheath tail extension with specific tail appendages. Have done this, we were able to get some clarifications on the morphology of the studied larvae, and we believe thus that this study will contribute to the establishment of morphological identification keys especially for parasitic nematodes of wild ruminants

Towards Robust and Unconstrained Full Range of Rotation Head Pose Estimation

Estimating the head pose of a person is a crucial problem for numerous applications that is yet mainly addressed as a subtask of frontal pose prediction. We present a novel method for unconstrained end-to-end head pose estimation to tackle the challenging task of full range of orientation head pose prediction. We address the issue of ambiguous rotation labels by introducing the rotation matrix formalism for our ground truth data and propose a continuous 6D rotation matrix representation for efficient and robust direct regression. This allows to efficiently learn full rotation appearance and to overcome the limitations of the current state-of-the-art. Together with new accumulated training data that provides full head pose rotation data and a geodesic loss approach for stable learning, we design an advanced model that is able to predict an extended range of head orientations. An extensive evaluation on public datasets demonstrates that our method significantly outperforms other state-of-the-art methods in an efficient and robust manner, while its advanced prediction range allows the expansion of the application area. We open-source our training and testing code along with our trained models: https://github.com/thohemp/6DRepNet360

The Study of Electrical Properties and Photocurrent of Polyaniline/ fluorescein films

Electrical conductivity and visible photo current (PC) measurements have been performed on thick film (10 ?m) of polyaniline modified with (1x10-4) fluorescein organic dye were all measurements have been made using Sandwich structure of aluminum and semitransparent aluminum with area (0.03 cm2) circular electrode. The D.C. conductivity was measured as a function of doping ratio with iodine using the technique of two probes.All current measurements have been made at steady state conditions were the obtained results showed that the domain conduction mechanisms was identified as space charge limited current (SCLC) and the D.C. bulk conductivity of pure films was 6.6x10-9S.cm-172mole) content of ,and this conductivity is increased by 5.4 times of films with doping ratio equal to 2% . Photocurrent (PC) was measured with specified wave length as a function of applied voltage were the intensity of the incident light was 295 lux/m for each case. The obtained results of PC showed that the observed photons form excites, and the caste films have poor photoconductivity while maximum peak of D.C. conductivity under illumination was obtained near Yellow region of visible light were the absorption of incident light is high and free carriers are available. Also the obtained results showed that the cut-off wave length is near red region, and the recombination process is bulk finally Another noticeable remark, that the photocurrent is increased by amount of 800 times & D.C conductivity is increased by 1300 comapred to magnitude at darkness

Study of the Active Compound in the Essential Oil of Myrtus communis L.

This study appears of the major volatile compounds in the essential oil of myrtle leaves because of its significant medical and economic benefits. The essential oil composition of Myrtus communis leaves during its flowering stage was determined. six volatile compounds were identified in leaves essential oils, α-Pinene 308 µg/ml, linalool (23.83 µg/ml), Eucalyptol or 1,8-cineole (41.46 µg/ml), Limonene (45.22 µg/ml), α-terpineol (41.73 µg/ml), Geranyl acetate (18.28 µg/ml) were the main monoterpene compounds. α-Pinene was Represents the bulk of the other compounds in the myrtle leave Keywords: Myrtus communis L., myrtle, flowering stage, essential oil, chemical compounds

The Study of Electrical Properties and Photocurrent of Polyaniline/ fluorescein films

Electrical conductivity and visible photo current (PC) measurements have been performed on thick film (10 μm) of polyaniline modified with (1x10-4) fluorescein organic dye were all measurements have been made using Sandwich structure of aluminum and semitransparent aluminum with area (0.03 cm2) circular electrode. The D.C. conductivity was measured as a function of doping ratio with iodine using the technique of two probes.All current measurements have been made at steady state conditions were the obtained results showed that the domain conduction mechanisms was identified as space charge limited current (SCLC) and the D.C. bulk conductivity of pure films was 6.6x10-9S.cm-172mole) content of ,and this conductivity is increased by 5.4 times of films with doping ratio equal to 2% . Photocurrent (PC) was measured with specified wave length as a function of applied voltage were the intensity of the incident light was 295 lux/m for each case. The obtained results of PC showed that the observed photons form excites, and the caste films have poor photoconductivity while maximum peak of D.C. conductivity under illumination was obtained near Yellow region of visible light were the absorption of incident light is high and free carriers are available. Also the obtained results showed that the cut-off wave length is near red region, and the recombination process is bulk finally Another noticeable remark, that the photocurrent is increased by amount of 800 times & D.C conductivity is increased by 1300 comapred to magnitude at darkness

Composition, properties and application of the medicinal sage in veterinary and human medicine

veterinary medicine, human medicine, medicinal sage, composition, properties, application, английский язык, лекарственные растения, шалфей лекарственный, состав, свойств