The clinical significance of ABCB1 overexpression in predicting outcome of CML patients undergoing first-line imatinib treatment.

Tyrosine kinase inhibitor (TKI) therapy results in excellent responses in the majority of patients with chronic myeloid leukaemia. First-line imatinib treatment, with selective switching to nilotinib when patients fail to meet specific molecular targets or for imatinib intolerance, results in excellent overall molecular responses and survival. However, this strategy is less effective in cases of primary imatinib resistance; moreover, 25% of patients develop secondary resistance such that 20-35% of patients initially treated with imatinib will eventually experience treatment failure. Early identification of these patients is of high clinical relevance. Since the drug efflux transporter ABCB1 has previously been implicated in TKI resistance, we determined if early increases in ABCB1 mRNA expression (fold change from diagnosis to day 22 of imatinib therapy) predict for patient response. Indeed, patients exhibiting a high fold rise (⩾2.2, n=79) were significantly less likely to achieve early molecular response (BCR-ABL1IS ⩽10% at 3 months; P=0.001), major molecular response (P<0.0001) and MR4.5 (P<0.0001). Additionally, patients demonstrated increased levels of ABCB1 mRNA before the development of mutations and/or progression to blast crisis. Patients with high fold rise in ABCB1 mRNA were also less likely to achieve major molecular response when switched to nilotinib therapy (49% vs 82% of patients with low fold rise). We conclude that early evaluation of the fold change in ABCB1 mRNA expression may identify patients likely to be resistant to first- and second-generation TKIs and who may be candidates for alternative therapy.

Graft durability and fatigue after in situ fenestration of endovascular stent grafts using radiofrequency puncture and balloon dilatation.

OBJECTIVES: In situ fenestration of endovascular stent grafts is a technique that is becoming more common, as it has the advantages of decreased cost, increased availability, and more anatomic configuration than other methods of branch revascularization. However, a significant concern is the short- and long-term durability of the stent graft fabric during and after fenestration. METHODS: This study utilizes the textiles analysis techniques of macro- and microscopic imaging, tear strength testing, burst strength testing, and accelerated cyclic fatigue testing on the fabrics of the Cook Zenith, Medtronic Talent, and Medtronic Endurant stent grafts (three polyester grafts), as well as two different expanded polytetrafluoroethylene (ePTFE) membranes. Specimens were punctured using radiofrequency, and serially dilated with angioplasty balloons (3, 5, and 7 mm). For each type of fabric, three groups were analyzed: control, radiofrequency (RF) puncture only, and balloon dilated. RESULTS: A total of 110 specimens were analyzed, with 80 of them having been fenestrated. The Zenith fabric had the greatest strength after fenestration, but was limited by the inability to fully dilate the fenestration with the conventional balloons, which only achieved 26-29% of their nominal balloon diameter. While the Talent and Endurant grafts could be dilated with balloons, the orifices were markedly elliptical not circular. After accelerated fatigue testing, there was an increase in the size of fenestrations of the Talent fabric. There was no increase in fenestration size for the Endurant fabric, Zenith fabric, or the ePTFE fabrics, after fatigue testing. CONCLUSIONS: While the Zenith fabric was the strongest both before and after fenestration, it requires further study with cutting balloons to achieve full-sized fenestrations. All fenestrations remained stable during fatigue testing except for the Talent fabric. This study serves as the baseline for future studies that will include stent grafts, branch stents, and cutting balloons.

Interaction of the efflux transporters ABCB1 and ABCG2 with imatinib, nilotinib, and dasatinib.

The efflux transporters adenosine triphosphate (ATP)-binding cassette (ABC)B1 and ABCG2 have been demonstrated to interact with the tyrosine kinase inhibitors (TKIs) imatinib, nilotinib, and dasatinib. However, although some studies conclude that TKIs are substrates of one or both transporters, other studies demonstrate only an inhibitory function. This variation is probably due to differences in the concentration of TKIs assayed and the experimental systems used. This article examines the evidence for clinically relevant interactions between three currently approved TKIs and ABCB1/ABCG2.

A comparison of headnet electrode arrays for electrical impedance tomography of the human head.

Three types of commercially available headnet electrode arrays, designed for use in EEG, and conventional EEG Ag/AgCl cup electrodes were tested on human subjects, and a realistic, saline-filled head-shaped tank was prepared with vegetable skin to simulate human skin in order to determine the optimum electrode system for electrical impedance tomography (EIT) of the human head. Impedance changes during EIT acquisition were produced in healthy volunteers during a finger-thumb apposition task and in tanks by the insertion of a Perspex rod. Signal-to-baseline noise, measured from raw EIT data, was 2.3 +/- 0.3 and 2.3 +/- 0.2 for the human and tank data, respectively. In both the human and tank experiments, a commercial hydrogel elasticated electrode headnet produced the least amount of baseline noise, and was the only headnet in the human data with noise levels acceptable for EIT imaging. Image quality measured in the tank was similar for most of the headnets tested, except that the EEG electrodes produced a higher positional error and electrodes in a geodesic elasticated net produced images with worse subjective image quality. Overall, the hydrogel elasticated headnet was judged to be the most suitable for human neuroimaging with EIT.

Telemedicine in surgery.

BACKGROUND: Telemedicine is influencing surgical training, allows mentoring, proctoring and teleconferencing, and is increasingly being applied to carry out remote surgical procedures. A systematic review of the telemedicine systems available, along with a critical appraisal of their application, potential and limitations in the surgical field, has been undertaken. METHOD: Medline, Ovid and internet searches were carried out using the keywords 'telesurgery', 'telepresence surgery' and 'telemedicine and surgery', along with hand searches of the two peer-reviewed telesurgery journals. RESULTS: Telementoring and teleconferencing have been used widely for surgical teaching and training. Two clinical telesurgery systems are currently available and have been a trial in patients undergoing a variety of operations including cholecystectomy, coronary artery bypass, prostatectomy and gastroplasty. Most studies have reported successful outcomes but with prolonged operating times. In 2002 the first long-distance telesurgery procedure was successfully performed. CONCLUSION: Telemedicine has huge potential to alter surgical practice but improvements are required in telesurgical technology with respect to tactile feedback, instrumentation, telecommunication speed and availability. Issues of liability, legislation, cost and benefit require clarification. The future of telemedicine in surgery may lie in facilitating complex minimally invasive techniques.

A comparison of techniques to optimize measurement of voltage changes in electrical impedance tomography by minimizing phase shift errors.

In electrical impedance tomography, errors due to stray capacitance may be reduced by optimization of the reference phase of the demodulator. Two possible methods, maximization of the demodulator output and minimization of reciprocity error have been assessed, applied to each electrode combination individually, or to all combinations as a whole. Using an EIT system with a single impedance measuring circuit and multiplexer to address the 16 electrodes, the methods were tested on resistor-capacitor networks, saline-filled tanks and humans during variation of the saline concentration of a constant fluid volume in the stomach. Optimization of each channel individually gave less error, particularly on humans, and maximization of the output of the demodulator was more robust. This method is, therefore, recommended to optimize systems and reduce systematic errors with similar EIT systems.

Development of the ultrastructural features of neuropeptide Y-immunoreactive neurons in the rat visual cortex.

Immunohistochemical studies have localized neuropeptide Y into a small population of non-pyramidal neurons in the mammalian cerebral cortex. In the rat, these cells are distributed in layers II-VI and are characterized at the ultrastructural level by an abundance of cytoplasm containing a plethora or organelles, most conspicuous of which are cisternae of granular endoplasmic reticulum stacked in parallel arrays. In the present study, we used electron microscopic immunocytochemistry to examine the ultrastructural development of neuropeptide Y-labelled neurons in the rat visual cortex from birth, when they first appear in this cortical area, until postnatal day 32. At birth and in the subsequent few days, neuropeptide Y neurons, found exclusively in layers V and VI, often show a deeply infolded nucleus and little cytoplasm containing few organelles. At the end of the first postnatal week, labelled cells are still restricted to layers V and VI and display immature features. However, at this stage, cells often show irregularly enlarged proximal dendrites filled with organelles. During the second postnatal week, neuropeptide Y-immunoreactive cell bodies appear for the first time in layers II and III, and at the end of this week they have a distribution similar to that observed in the adult. Labelled cells are overall more differentiated than at earlier ages showing some of the ultrastructural features which distinguish them in the adult. No differences in maturation are evident between immunoreactive neurons located in the superficial layers and those in the deep layers, suggesting that the neuropeptide Y neurons in the more superficial layers express the peptide after having completed their migration and have acquired their characteristic ultrastructural features. Maturation proceeds during the third postnatal week. At the end of this stage, neuropeptide Y-containing cells acquired their mature nuclear and cytoplasmic features and an adult complement of synapses.

The development of basal forebrain projections to the rat visual cortex.

The development of the basal forebrain projections to the visual cortex of the rat were studied using retrograde tracer techniques. Injections of wheat germ agglutinin-horseradish peroxidase placed in the visual cortex of newborn animals resulted in labelling of neurons throughout the basal forebrain nuclei. Although at this time the overall distribution of retrogradely labelled cells within the basal forebrain appeared similar to that seen in the adult, cells were smaller and weakly stained. It was only at the end of the second postnatal week that the somata of stained neurons showed sizes and staining intensity comparable to the adult. This precedes or coincides with the reported significant increases in cortical and basal forebrain ChAT activity and the first detection of ChAT-labelled fibres in this cortical area. These data suggest an important developmental point around the end of the second postnatal week that may correspond to the time when a significant number of cholinergic axons first appear within the visual cortex. They also suggest that the cholinergic projections to the visual cortex develop late in comparison with the thalamic and other subcortical afferents in this cortical area.

Development of the ultrastructural features of somatostatin-immunoreactive neurons in the rat visual cortex.

The peroxidase-antiperoxidase immunocytochemical technique has been used to examine the development of the ultrastructural features of somatostatin (SRIF)-immunoreactive neurons in the visual cortex of the rat between embryonic day 17 and postnatal day 32. In the adult, stained neurons are distributed in layers II through VI and characterized by an abundance of cytoplasm containing a plethora of organelles, most conspicuous of which are cisternae of granular endoplasmic reticulum organized in parallel arrays. In embryonic tissue, SRIF-positive cells are present in the subplate and in the border between the cortical plate and marginal zone. These cells possess scanty cytoplasm containing a few organelles; synapses onto immunoreactive perikarya and dendrites are evident at this stage. At birth and in early postnatal life, labelled cells are confined to the subplate region. Already at this age a number of cells display signs of ultrastructural features which characterize them in adult life. At the end of the first postnatal week, SRIF-immunoreactive neurons span a considerable spectrum of maturity. At one extreme are a few cells with little cytoplasm surrounding a large nucleus and at the other are the majority of labelled neurons showing abundant cytoplasm including prominent arrays of granular endoplasmic reticulum. Labelled cells first appear in the more superficial layers at the beginning of the second postnatal week and attain a distribution similar to that observed in adult animals at the end of this week. At this time their ultrastructural features closely resemble those of their adult counterparts, and differences in cytoplasmic maturity between superficial and deep labelled cells are not evident. This suggests that the SRIF-producing neurons in the superficial layers begin to express this peptide after they complete their migration and have acquired their morphological features. Maturation proceeds during the third postnatal week; at this stage most cells acquire their mature nuclear and cytoplasmic features and an adult complement of synapses. However, a number of SRIF-immunoreactive cells contain a particularly prominent accumulation of cytoplasmic organelles and appear hypertrophic.