Ubiquitination and cysteine nitrosylation during aging and Alzheimer's disease.

Protein oxidation and ubiquitination of brain proteins are part of mechanisms that modulate protein function or that inactivate proteins and target misfolded proteins to degradation. In this study, we focused on brain aging and on mechanism involved in neurodegeneration such as events occurring in Alzheimer's disease (AD). The goal was to identify differences in nitrosylated proteins - at cysteine residues, and in the composition of ubiquinated proteins between aging and Alzheimer's samples by using a proteomic approach. A polyclonal anti-S-nitrosyl-cysteine, a mono- and a polyclonal anti-ubiquitin antibody were used for the detection of modified or ubiquitinated proteins in middle-aged and aged human entorhinal autopsy brains tissues of 14 subjects without neurological signs and 8 Alzheimer's patients. Proteins were separated by one- and two-dimensional gel electrophoresis and analyzed by Coomassie blue and immuno-blot staining. We identified that the glial fibrillary acidic and tau proteins are more ubiquitinated in brain tissues of Alzheimer's patients. Furthermore, glial fibrillary proteins were also found in nitrosylated state and further characterized by 2D Western blots and identified. Since reactive astrocytes localized prominently around senile plaques one can speculate that elements of plaques such as beta-amyloid proteins may activate surrounding glial elements and proteins.

FRAX(®) Bone Mineral Density Task Force of the 2010 Joint International Society for Clinical Densitometry International Osteoporosis Foundation Position Development Conference.

FRAX(®) is a fracture risk assessment algorithm developed by the World Health Organization in cooperation with other medical organizations and societies. Using easily available clinical information and femoral neck bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA), when available, FRAX(®) is used to predict the 10-year probability of hip fracture and major osteoporotic fracture. These values may be included in country specific guidelines to aid clinicians in determining when fracture risk is sufficiently high that the patient is likely to benefit from pharmacological therapy to reduce that risk. Since the introduction of FRAX(®) into clinical practice, many practical clinical questions have arisen regarding its use. To address such questions, the International Society for Clinical Densitometry (ISCD) and International Osteoporosis Foundations (IOF) assigned task forces to review the best available medical evidence and make recommendations for optimal use of FRAX(®) in clinical practice. Questions were identified and divided into three general categories. A task force was assigned to investigating the medical evidence in each category and developing clinically useful recommendations. The BMD Task Force addressed issues that included the potential use of skeletal sites other than the femoral neck, the use of technologies other than DXA, and the deletion or addition of clinical data for FRAX(®) input. The evidence and recommendations were presented to a panel of experts at the ISCD-IOF FRAX(®) Position Development Conference, resulting in the development of ISCD-IOF Official Positions addressing FRAX(®)-related issues.

A comparison of the performance of modern screen-film and digital mammography systems.

This work compares the detector performance and image quality of the new Kodak Min-R EV mammography screen-film system with the Fuji CR Profect detector and with other current mammography screen-film systems from Agfa, Fuji and Kodak. Basic image quality parameters (MTF, NPS, NEQ and DQE) were evaluated for a 28 kV Mo/Mo (HVL = 0.646 mm Al) beam using different mAs exposure settings. Compared with other screen-film systems, the new Kodak Min-R EV detector has the highest contrast and a low intrinsic noise level, giving better NEQ and DQE results, especially at high optical density. Thus, the properties of the new mammography film approach those of a fine mammography detector, especially at low frequency range. Screen-film systems provide the best resolution. The presampling MTF of the digital detector has a value of 15% at the Nyquist frequency and, due to the spread size of the laser beam, the use of a smaller pixel size would not permit a significant improvement of the detector resolution. The dual collection reading technology increases significantly the low frequency DQE of the Fuji CR system that can at present compete with the most efficient mammography screen-film systems.

Changes in volume, surface estimate, three-dimensional shape and total number of neurons of the human primary visual cortex from midgestation until old age.

Macroscopic features such as volume, surface estimate, thickness and caudorostral length of the human primary visual cortex (Brodman's area 17) of 46 human brains between midgestation and 93 years were studied by means of camera lucida drawings from serial frontal sections. Individual values were best fitted by a logistic function from midgestation to adulthood and by a regression line between adulthood and old age. Allometric functions were calculated to study developmental relationships between all the features. The three-dimensional shape of area 17 was also reconstructed from the serial sections in 15 cases and correlated with the sequence of morphological events. The sulcal pattern of area 17 begins to develop around 21 weeks of gestation but remains rather simple until birth, while it becomes more convoluted, particularly in the caudal part, during the postnatal period. Until birth, a large increase in cortical thickness (about 83% of its mean adult value) and caudorostral length (69%) produces a moderate increase in cortical volume (31%) and surface estimate (40%) of area 17. After birth, the cortical volume and surface undergo their maximum growth rate, in spite of a rather small increase in cortical thickness and caudorostral length. This is due to the development of the pattern of gyrification within and around the calcarine fissure. All macroscopic features have reached the mean adult value by the end of the first postnatal year. With aging, the only features to undergo significant regression are the cortical surface estimate and the caudorostral length. The total number of neurons in area 17 shows great interindividual variability at all ages. No decrease in the postnatal period or in aging could be demonstrated.

Integrating sexuality into gynaecological consultations: gynaecologists' perspectives

There are currently few studies exploring doctors' personal perspectives on integrating sexuality into medical consultations. This study focuses on the views of gynaecologists on introducing, or not introducing, sexuality into their work. A total of 30 semistructured interviews were conducted with gynaecologists in the French-speaking part of Switzerland. The thematic content analysis and computer-assisted lexical analysis (Alceste) on the interview transcripts highlighted four categories: perceptions and description of sexuality, patient's sexological history, training in sexology and perceived difficulties. It is observed that, above all, the 'medical dimension' characterises gynaecologists' perceptions. Of greater interest is our observation of disparities in gynaecologists' discussion of their practice, which is often the product of lay knowledge based on common sense and/or personal experience. Finally, the decision to integrate questions relating to sexuality seems to depend on non-medical factors such as the personal experience, interest or gender of the doctor.

A Monte Carlo-based procedure for independent monitor unit calculation in IMRT treatment plans.

Intensity-modulated radiotherapy (IMRT) treatment plan verification by comparison with measured data requires having access to the linear accelerator and is time consuming. In this paper, we propose a method for monitor unit (MU) calculation and plan comparison for step and shoot IMRT based on the Monte Carlo code EGSnrc/BEAMnrc. The beamlets of an IMRT treatment plan are individually simulated using Monte Carlo and converted into absorbed dose to water per MU. The dose of the whole treatment can be expressed through a linear matrix equation of the MU and dose per MU of every beamlet. Due to the positivity of the absorbed dose and MU values, this equation is solved for the MU values using a non-negative least-squares fit optimization algorithm (NNLS). The Monte Carlo plan is formed by multiplying the Monte Carlo absorbed dose to water per MU with the Monte Carlo/NNLS MU. Several treatment plan localizations calculated with a commercial treatment planning system (TPS) are compared with the proposed method for validation. The Monte Carlo/NNLS MUs are close to the ones calculated by the TPS and lead to a treatment dose distribution which is clinically equivalent to the one calculated by the TPS. This procedure can be used as an IMRT QA and further development could allow this technique to be used for other radiotherapy techniques like tomotherapy or volumetric modulated arc therapy.

Direct in vitro comparison of six three-dimensional positive contrast methods for susceptibility marker imaging.

PURPOSE: To compare different techniques for positive contrast imaging of susceptibility markers with MRI for three-dimensional visualization. As several different techniques have been reported, the choice of the suitable method depends on its properties with regard to the amount of positive contrast and the desired background suppression, as well as other imaging constraints needed for a specific application. MATERIALS AND METHODS: Six different positive contrast techniques are investigated for their ability to image at 3 Tesla a single susceptibility marker in vitro. The white marker method (WM), susceptibility gradient mapping (SGM), inversion recovery with on-resonant water suppression (IRON), frequency selective excitation (FSX), fast low flip-angle positive contrast SSFP (FLAPS), and iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) were implemented and investigated. RESULTS: The different methods were compared with respect to the volume of positive contrast, the product of volume and signal intensity, imaging time, and the level of background suppression. Quantitative results are provided, and strengths and weaknesses of the different approaches are discussed. CONCLUSION: The appropriate choice of positive contrast imaging technique depends on the desired level of background suppression, acquisition speed, and robustness against artifacts, for which in vitro comparative data are now available.

Spectrally selective B1-insensitive T2 magnetization preparation sequence.

A T(2) magnetization-preparation (T(2) Prep) sequence is proposed that is insensitive to B(1) field variations and simultaneously provides fat suppression without any further increase in specific absorption rate (SAR). Increased B(1) inhomogeneity at higher magnetic field strength (B(0) > or = 3T) necessitates a preparation sequence that is less sensitive to B(1) variations. For the proposed technique, T(2) weighting in the image is achieved using a segmented B(1)-insensitive rotation (BIR-4) adiabatic pulse by inserting two equally long delays, one after the initial reverse adiabatic half passage (AHP), and the other before the final AHP segment of a BIR-4 pulse. This sequence yields T(2) weighting with both B(1) and B(0) insensitivity. To simultaneously suppress fat signal (at the cost of B(0) insensitivity), the second delay is prolonged so that fat accumulates additional phase due to its chemical shift. Numerical simulations as well as phantom and in vivo image acquisitions were performed to show the efficacy of the proposed technique.

Objective assessment of image quality in conventional and digital mammography taking into account dynamic range.

The goal of this work is to develop a method to objectively compare the performance of a digital and a screen-film mammography system in terms of image quality. The method takes into account the dynamic range of the image detector, the detection of high and low contrast structures, the visualisation of the images and the observer response. A test object, designed to represent a compressed breast, was constructed from various tissue equivalent materials ranging from purely adipose to purely glandular composition. Different areas within the test object permitted the evaluation of low and high contrast detection, spatial resolution and image noise. All the images (digital and conventional) were captured using a CCD camera to include the visualisation process in the image quality assessment. A mathematical model observer (non-prewhitening matched filter), that calculates the detectability of high and low contrast structures using spatial resolution, noise and contrast, was used to compare the two technologies. Our results show that for a given patient dose, the detection of high and low contrast structures is significantly better for the digital system than for the conventional screen-film system studied. The method of using a test object with a large tissue composition range combined with a camera to compare conventional and digital imaging modalities can be applied to other radiological imaging techniques. In particular it could be used to optimise the process of radiographic reading of soft copy images.

Estimating the confidence level of white matter connections obtained with MRI tractography.

BACKGROUND: Since the emergence of diffusion tensor imaging, a lot of work has been done to better understand the properties of diffusion MRI tractography. However, the validation of the reconstructed fiber connections remains problematic in many respects. For example, it is difficult to assess whether a connection is the result of the diffusion coherence contrast itself or the simple result of other uncontrolled parameters like for example: noise, brain geometry and algorithmic characteristics. METHODOLOGY/PRINCIPAL FINDINGS: In this work, we propose a method to estimate the respective contributions of diffusion coherence versus other effects to a tractography result by comparing data sets with and without diffusion coherence contrast. We use this methodology to assign a confidence level to every gray matter to gray matter connection and add this new information directly in the connectivity matrix. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that whereas we can have a strong confidence in mid- and long-range connections obtained by a tractography experiment, it is difficult to distinguish between short connections traced due to diffusion coherence contrast from those produced by chance due to the other uncontrolled factors of the tractography methodology.

Validation of two echocardiographic indexes to improve the diagnosis of complex coarctations.

OBJECTIVES: Coarctation of the aorta is one of the most common congenital heart defects. Its diagnosis may be difficult in the presence of a patent ductus arteriosus, of other complex defects or of a poor echocardiographic window. We sought to demonstrate that the carotid-subclavian artery index (CSA index) and the isthmus-descending aorta ratio (I/D ratio), two recently described echocardiographic indexes, are effective in detection of isolated and complex aortic coarctations in children younger and older than 3 months of age. The CSA index is the ratio of the distal aortic arch diameter to the distance between the left carotid artery and the left subclavian artery. It is highly suggestive of a coarctation when it is <1.5. The I/D ratio defined as the diameter of the isthmus to the diameter of the descending aorta, suggests an aortic coarctation when it is less than 0.64. METHODS: This is a retrospective cohort study in a tertiary care children's hospital. Review of all echocardiograms in children aged 0-18 years with a diagnosis of coarctation seen at the author's institution between 1996 and 2006. An age- and sex-matched control group without coarctation was constituted. Offline echocardiographic measurements of the aortic arch were performed in order to calculate the CSA index and I/D ratio. RESULTS: Sixty-eight patients were included in the coarctation group, 24 in the control group. Patients with coarctation had a significantly lower CSA index (0.84+/-0.39 vs 2.65+/-0.82, p<0.0001) and I/D ratio (0.58+/-0.18 vs 0.98+/-0.19, p<0.0001) than patients in the control group. Associated cardiac defects and age of the child did not significantly alter the CSA index or the I/D ratio. CONCLUSIONS: A CSA index less than 1.5 is highly suggestive of coarctation independent of age and of the presence of other cardiac defects. I/D ratio alone is less specific than CSA alone at any age and for any associated cardiac lesion. The association of both indexes improves sensitivity and permits diagnosis of coarctation in all patients based solely on a bedside echocardiographic measurement.

Kvalitatiivisen aineiston tietokoneavusteisen analyysin lähtökohtia

Abstract: Towards computer-assisted qualitative data analysis

Official Positions for FRAX® clinical regarding rheumatoid arthritis from Joint Official Positions Development Conference of the International Society for Clinical Densitometry and International Osteoporosis Foundation on FRAX®.

Rheumatoid arthritis is the only secondary cause of osteoporosis that is considered independent of bone density in the FRAX(®) algorithm. Although input for rheumatoid arthritis in FRAX(®) is a dichotomous variable, intuitively, one would expect that more severe or active disease would be associated with a greater risk for fracture. We reviewed the literature to determine if specific disease parameters or medication use could be used to better characterize fracture risk in individuals with rheumatoid arthritis. Although many studies document a correlation between various parameters of disease activity or severity and decreased bone density, fewer have associated these variables with fracture risk. We reviewed these studies in detail and concluded that disability measures such as HAQ (Health Assessment Questionnaire) and functional class do correlate with clinical fractures but not morphometric vertebral fractures. One large study found a strong correlation with duration of disease and fracture risk but additional studies are needed to confirm this. There was little evidence to correlate other measures of disease such as DAS (disease activity score), VAS (visual analogue scale), acute phase reactants, use of non-glucocorticoid medications and increased fracture risk. We concluded that FRAX(®) calculations may underestimate fracture probability in patients with impaired functional status from rheumatoid arthritis but that this could not be quantified at this time. At this time, other disease measures cannot be used for fracture prediction. However only a few, mostly small studies addressed other disease parameters and further research is needed. Additional questions for future research are suggested.

An active contour-based atlas registration model applied to automatic subthalamic nucleus targeting on MRI: method and validation.

This paper presents a new non parametric atlas registration framework, derived from the optical flow model and the active contour theory, applied to automatic subthalamic nucleus (STN) targeting in deep brain stimulation (DBS) surgery. In a previous work, we demonstrated that the STN position can be predicted based on the position of surrounding visible structures, namely the lateral and third ventricles. A STN targeting process can thus be obtained by registering these structures of interest between a brain atlas and the patient image. Here we aim to improve the results of the state of the art targeting methods and at the same time to reduce the computational time. Our simultaneous segmentation and registration model shows mean STN localization errors statistically similar to the most performing registration algorithms tested so far and to the targeting expert's variability. Moreover, the computational time of our registration method is much lower, which is a worthwhile improvement from a clinical point of view.

Nonlinear analysis of human physical activity patterns in health and disease.

The reliable and objective assessment of chronic disease state has been and still is a very significant challenge in clinical medicine. An essential feature of human behavior related to the health status, the functional capacity, and the quality of life is the physical activity during daily life. A common way to assess physical activity is to measure the quantity of body movement. Since human activity is controlled by various factors both extrinsic and intrinsic to the body, quantitative parameters only provide a partial assessment and do not allow for a clear distinction between normal and abnormal activity. In this paper, we propose a methodology for the analysis of human activity pattern based on the definition of different physical activity time series with the appropriate analysis methods. The temporal pattern of postures, movements, and transitions between postures was quantified using fractal analysis and symbolic dynamics statistics. The derived nonlinear metrics were able to discriminate patterns of daily activity generated from healthy and chronic pain states.