Fast absolute 3D CGO-based electrical impedance tomography on experimental tank data.

Objective.To present the first 3D CGO-based absolute EIT reconstructions from experimental tank data.Approach.CGO-based methods for absolute EIT imaging are compared to traditional TV regularized non-linear least squares reconstruction methods. Additional robustness testing is performed by considering incorrect modeling of domain shape.Main Results.The CGO-based methods are fast, and show strong robustness to incorrect domain modeling comparable to classic difference EIT imaging and fewer boundary artefacts than the TV regularized non-linear least squares reference reconstructions.Significance.This work is the first to demonstrate fully 3D CGO-based absolute EIT reconstruction on experimental data and also compares to TV-regularized absolute reconstruction. The speed (1-5 s) and quality of the reconstructions is encouraging for future work in absolute EIT.

iRFP (near-infrared fluorescent protein) imaging of subcutaneous and deep tissue tumours in mice highlights differences between imaging platforms.

BACKGROUND: In vivo imaging using fluorescence is used in cancer biology for the detection, measurement and monitoring of tumours. This can be achieved with the expression of fluorescent proteins such as iRFP, which emits light at a wavelength less attenuated in biological tissues compared to light emitted by other fluorescent proteins such as GFP or RFP. Imaging platforms capable of detecting fluorescent tumours in small animals have been developed but studies comparing the performance of these platforms are scarce. RESULTS: Through access to three platforms from Xenogen, Bruker and Li-Cor, we compared their ability to detect iRFP-expressing subcutaneous tumours as well as tumours localised deeper within the body of female NSG mice. Each platform was paired with proprietary software for image analyse, but the output depends on subjective decisions from the user. To more objectively compare platforms, we developed an 'in house' software-based approach which results in lower measured variability between mice. CONCLUSIONS: Our comparisons showed that all three platforms allowed for reliable detection and monitoring of subcutaneous iRFP tumour growth. The biggest differences between platforms became apparent when imaging deeper tumours with the Li-Cor platform detecting most tumours and showing the highest dynamic range.

3D ELECTRICAL IMPEDANCE TOMOGRAPHY RECONSTRUCTIONS FROM SIMULATED ELECTRODE DATA USING DIRECT INVERSION texp AND CALDERÓN METHODS.

The first numerical implementation of a t exp method in 3D using simulated electrode data is presented. Results are compared to Calderón's method as well as more common TV and smoothness regularization-based methods. The t exp method for EIT is based on tailor-made non-linear Fourier transforms involving the measured current and voltage data. Low-pass filtering in the non-linear Fourier domain is used to stabilize the reconstruction process. In 2D, t exp methods have shown great promise for providing robust real-time absolute and time-difference conductivity reconstructions but have yet to be used on practical electrode data in 3D, until now. Results are presented for simulated data for conductivity and permittivity with disjoint non-radially symmetric targets on spherical domains and noisy voltage data. The 3D t exp and Calderón methods are demonstrated to provide comparable quality to their 2D counterparts, and hold promise for real-time reconstructions due to their fast, non-optimized, computational cost.

The cytoskeleton adaptor protein ankyrin-1 is upregulated by p53 following DNA damage and alters cell migration.

The integrity of the genome is maintained by a host of surveillance and repair mechanisms that are pivotal for cellular function. The tumour suppressor protein p53 is a major component of the DNA damage response pathway and plays a vital role in the maintenance of cell-cycle checkpoints. Here we show that a microRNA, miR-486, and its host gene ankyrin-1 (ANK1) are induced by p53 following DNA damage. Strikingly, the cytoskeleton adaptor protein ankyrin-1 was induced over 80-fold following DNA damage. ANK1 is upregulated in response to a variety of DNA damage agents in a range of cell types. We demonstrate that miR-486-5p is involved in controlling G1/S transition following DNA damage, whereas the induction of the ankyrin-1 protein alters the structure of the actin cytoskeleton and sustains limited cell migration during DNA damage. Importantly, we found that higher ANK1 expression correlates with decreased survival in cancer patients. Thus, these observations highlight ANK1 as an important effector downstream of the p53 pathway.

Estimating a regional ventilation-perfusion index.

This is a methods paper, where an approximation to the local ventilation-perfusion ratio is derived. This approximation, called the ventilation-perfusion index since it is not exactly the physiological ventilation-perfusion ratio, is calculated using conductivity reconstructions obtained using electrical impedance tomography. Since computation of the ventilation-perfusion index only requires knowledge of the internal conductivity, any conductivity reconstruction method may be used. The method is explained and results are presented using conductivities obtained from two EIT systems, one using an iterative method and the other a linearization method.

Functional interplay between MDM2, p63/p73 and mutant p53.

Many cancers express mutant p53 proteins that have lost wild-type tumor suppressor activity and, in many cases, have acquired oncogenic functions that can contribute to tumor progression. These activities of mutant p53 reflect interactions with several other proteins, including the p53 family members p63 and p73. Mutations in p53 that affect protein conformation (such as R175H) show strong binding to p63 and p73, whereas p53 mutants that only mildly affect the conformation (such as R273H) bind less well. A previously described aggregation domain of mutant p53 is not required for p63 or p73 binding; indeed, mutations within this region lead to the acquisition of a mutant p53 phenotype-including a conformational shift, p63/p73 binding and the ability to promote invasion. The activity of wild-type p53 is regulated by an interaction with MDM2 and we have investigated the potential role of MDM2 in the mutant p53/p63/p73 interactions. Both mutant p53 and p73 bind MDM2 well, whereas p63 binds much more weakly. We found that MDM2 can inhibit p63 binding to p53R175H but enhances the weaker p53R273H/p73 interaction. These effects on the interactions are reflected in an ability of MDM2 to relieve the inhibition of p63 by p53R175H, but enhance the inhibition of p73 activity by p53R175H and R273H. We propose a model in which MDM2 competes with p63 for binding to p53R175H to restore p63 activity, but forms a trimeric complex with p73 and p53R273H to more strongly inhibit p73 function.

Functions of TAp63 and p53 in restraining the development of metastatic cancer.

Many tumours harbour mutations in the p53 tumour-suppressor gene that result in the expression of a mutant p53 protein. This mutant p53 protein has, in most cases, lost wild-type transcriptional activity and can also acquire novel functions in promoting invasion and metastasis. One of the mechanisms underlying these novel functions involves the ability of the mutant p53 to interfere with other transcription factors, including the p53 family protein TAp63. To investigate whether simultaneous depletion of both p53 and TAp63 can recapitulate the effect of mutant p53 expression in vivo, we used a mouse model of pancreatic cancer in which the expression of mutant p53 resulted in the rapid appearance of primary tumours and metastases. As shown previously, loss of one allele of wild-type (WT) p53 accelerated tumour development. A change of one WT p53 allele into mutant p53 did not further accelerate tumour development, but did promote the formation of metastasis. By contrast, loss of TAp63 did not significantly accelerate tumour development or metastasis. However, simultaneous depletion of p53 and TAp63 led to both rapid tumour development and metastatic potential, although the incidence of metastases remained lower than that seen in mutant p53-expressing tumours. TAp63/p53-null cells derived from these mice also showed an enhanced ability to scatter and invade in tissue culture as was observed in mutant p53 cells. These data suggest that depletion of TAp63 in a p53-null tumour can promote metastasis and recapitulate-to some extent-the consequences of mutant p53 expression.

Calderón's method on an elliptical domain.

One possible application for electrical impedance tomography is in medical imaging where lung and heart function may be monitored. One drawback of current algorithms is that they are implemented for use in a circular domain, but a human thorax is more elliptical than circular. In this paper, a reconstruction algorithm based on the work of Calderón (1980 Seminar on Numerical Analysis and its Applications to Continuum Physics (Rio de Janeiro) pp 65-75) on the inverse conductivity problem is derived for an elliptical domain. It is explained how this reconstruction algorithm uses a transformed Dirichlet-to-Neumann map. Experimental results from an elliptical tank are given to show how correct domain modelling reduces the artefacts produced by this version of Calderón's reconstruction algorithm.

Mutant p53 enhances MET trafficking and signalling to drive cell scattering and invasion.

Tumour-derived mutant p53 proteins promote invasion, in part, by enhancing Rab coupling protein (RCP)-dependent receptor recycling. Here we identified MET as an RCP-binding protein and showed that mutant p53 promoted MET recycling. Mutant p53-expressing cells were more sensitive to hepatocyte growth factor, the ligand for MET, leading to enhanced MET signalling, invasion and cell scattering that was dependent on both MET and RCP. In cells expressing the p53 family member TAp63, inhibition of TAp63 also lead to cell scattering and MET-dependent invasion. However, in cells that express very low levels of TAp63, the ability of mutant p53 to promote MET-dependent cell scattering was independent of TAp63. Taken together, our data show that mutant p53 can enhance MET signalling to promote cell scattering and invasion through both TAp63-dependent and -independent mechanisms. MET has a predominant role in metastatic progression and the identification of mechanisms through which mutations in p53 can drive MET signalling may help to identify and direct therapy.

Adjuvant treatment of recalcitrant bullous pemphigoid with immunoadsorption.

Elimination of pathogenic autoantibodies by immunoadsorption (IA) has been described as an effective adjuvant treatment in severe bullous autoimmune diseases, especially in pemphigus. There is much less experience in the treatment of bullous pemphigoid (BP). BP was diagnosed in a 62-year-old Caucasian woman presenting a pruritic rash with multiple tense blisters. Standard treatments with topical and oral corticosteroids, steroid-sparing agents including dapsone, azathioprine, mycophenolate mofetil (MMF) and intravenous immunoglobulins were ineffective or had to be discontinued due to adverse events. An immediate clinical response could be achieved by two treatment cycles of adjuvant protein A immunoadsorption (PA-IA) in addition to continued treatment with MMF (2 g/day) and prednisolone (1 mg/kg/day). Tolerance was excellent. Clinical improvement remained stable after discontinuation of IA and went along with sustained reduction of circulating autoantibodies. Our data demonstrate that PA-IA might be a safe and effective adjuvant treatment in severe and recalcitrant BP.

[Maculo-papular exanthem with acute renal failure. Drug-induced hypersensitivity syndrome]. / Makulopapulöses Exanthem mit akuter Niereninsuffizienz. Arzneimittelinduziertes Hypersensitivitätssyndrom.

Acute renal failure caused by interstitial nephritis as part of a drug hypersensitivity syndrome constitutes a rare, but potentially life-threatening adverse drug reaction. We describe a patient with a mild maculo-papular rash accompanied by eosinophilia after prolonged treatment with meropenem, vancomycin, and moxifloxacin. Subsequently, a rapidly progressing renal failure developed which dominated the clinical picture. Upon cessation of all suspected drugs and therapy with high-dose steroids for 6 weeks, the renal function slowly returned to normal.

Change, conflict, and coping.

Managing in a health care organization requires the ability to cope with a constantly changing environment in which the manager is often caught in a situation of conflict. Developing a broader perspective on the problem and reframing one's thought process allows more opportunity to deal with the issues through logical rather than crisis management.

Leadership versus management: a matter of focus.

The manager's role is changing due to the changes in the environment. The major change in this role is a move from process management to ensuring outcomes. Assisting staff to achieve outcomes in a constantly changing environment may now be the major contribution of the manager. Five ideas are presented to assist the manager make a successful transition to the role of leader-manager.