Grey and White Matter Magnetisation Transfer Ratio Measurements in the Lumbosacral Enlargement: A Pilot In Vivo Study at 3T

Magnetisation transfer (MT) imaging of the central nervous system has provided further insight into the pathophysiology of neurological disease. However, the use of this method to study the lower spinal cord has been technically challenging, despite the important role of this region, not only for motor control of the lower limbs, but also for the neural control of lower urinary tract, sexual and bowel functions. In this study, the feasibility of obtaining reliable grey matter (GM) and white matter (WM) magnetisation transfer ratio (MTR) measurements within the lumbosacral enlargement (LSE) was investigated in ten healthy volunteers using a clinical 3T MRI system. The mean cross-sectional area of the LSE (LSE-CSA) and the mean GM area (LSE-GM-CSA) were first obtained by means of image segmentation and tissue-specific (i.e. WM and GM) MTR measurements within the LSE were subsequently obtained. The reproducibility of the segmentation method and MTR measurements was assessed from repeated measurements and their % coefficient of variation (%COV). Mean (± SD) LSE-CSA across 10 healthy subjects was 59.3 (± 8.4) mm2 and LSE-GM-CSA was 17.0 (± 3.1) mm2. The mean intra- and inter-rater % COV for measuring the LSE-CSA were 0.8% and 2.3%, respectively and for the LSE-GM-CSA were 3.8% and 5.4%, respectively. Mean (± SD) WM-MTR was 43.2 (± 4.4) and GM-MTR was 40.9 (± 4.3). The mean scan-rescan % COV for measuring WM-MTR was 4.6% and for GM-MTR was 3.8%. Using a paired t-test, a statistically significant difference was identified between WM-MTR and GM-MTR in the LSE (p<0.0001). This pilot study has shown that it is possible to obtain reliable tissue-specific MTR measurements within the LSE using a clinical MR system at 3T. The MTR acquisition and analysis protocol presented in this study can be used in future investigations of intrinsic spinal cord diseases that affect the LSE

Fast and reproducible in vivo T1 mapping of the human cervical spinal cord

PURPOSE: To develop a fast and robust method for measuring T1 in the whole cervical spinal cord in vivo, and to assess its reproducibility. METHODS: A spatially nonselective adiabatic inversion pulse is combined with zonally oblique-magnified multislice echo-planar imaging to produce a reduced field-of-view inversion-recovery echo-planar imaging protocol. Multi- inversion time data are obtained by cycling slice order throughout sequence repetitions. Measurement of T1 is performed using 12 inversion times for a total protocol duration of 7 min. Reproducibility of regional T1 estimates is assessed in a scan-rescan experiment on five heathy subjects. RESULTS: Regional mean (standard deviation) T1 was: 1108.5 (±77.2) ms for left lateral column, 1110.1 (±83.2) ms for right lateral column, 1150.4 (±102.6) ms for dorsal column, and 1136.4 (±90.8) ms for gray matter. Regional T1 estimates showed good correlation between sessions (Pearson correlation coefficient = 0.89 (P value < 0.01); mean difference = 2 ms, 95% confidence interval ± 20 ms); and high reproducibility (intersession coefficient of variation approximately 1% in all the regions considered, intraclass correlation coefficient = 0.88 (P value < 0.01, confidence interval 0.71-0.95)). CONCLUSIONS: T1 estimates in the cervical spinal cord are reproducible using inversion-recovery zonally oblique-magnified multislice echo-planar imaging. The short acquisition time and large coverage of this method paves the way for accurate T1 mapping for various spinal cord pathologies. Magn Reson Med, 2017. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited

Feasibility of in vivo multi-parametric quantitative magnetic resonance imaging of the healthy sciatic nerve with a unified signal readout protocol

Magnetic resonance neurography (MRN) has been used successfully over the years to investigate the peripheral nervous system (PNS) because it allows early detection and precise localisation of neural tissue damage. However, studies demonstrating the feasibility of combining MRN with multi-parametric quantitative magnetic resonance imaging (qMRI) methods, which provide more specific information related to nerve tissue composition and microstructural organisation, can be invaluable. The translation of emerging qMRI methods previously validated in the central nervous system to the PNS offers real potential to characterise in patients in vivo the underlying pathophysiological mechanisms involved in a plethora of conditions of the PNS. The aim of this study was to assess the feasibility of combining MRN with qMRI to measure diffusion, magnetisation transfer and relaxation properties of the healthy sciatic nerve in vivo using a unified signal readout protocol. The reproducibility of the multi-parametric qMRI protocol as well as normative qMRI measures in the healthy sciatic nerve are reported. The findings presented herein pave the way to the practical implementation of joint MRN-qMRI in future studies of pathological conditions affecting the PNS

Assessing Lumbar Plexus and Sciatic Nerve Damage in Relapsing-Remitting Multiple Sclerosis Using Magnetisation Transfer Ratio

Background: Multiple sclerosis (MS) has traditionally been regarded as a disease confined to the central nervous system (CNS). However, neuropathological, electrophysiological, and imaging studies have demonstrated that the peripheral nervous system (PNS) is also involved, with demyelination and, to a lesser extent, axonal degeneration representing the main pathophysiological mechanisms. Aim: The purpose of this study was to assess PNS damage at the lumbar plexus and sciatic nerve anatomical locations in people with relapsing-remitting MS (RRMS) and healthy controls (HCs) in vivo using magnetisation transfer ratio (MTR), which is a known imaging biomarker sensitive to alterations in myelin content in neural tissue, and not previously explored in the context of PNS damage in MS. Method: Eleven HCs (7 female, mean age 33.6 years, range 24-50) and 15 people with RRMS (12 female, mean age 38.5 years, range 30-56) were recruited for this study and underwent magnetic resonance imaging (MRI) investigations together with clinical assessments using the expanded disability status scale (EDSS). Magnetic resonance neurography (MRN) was first used for visualisation and identification of the lumbar plexus and the sciatic nerve and MTR imaging was subsequently performed using identical scan geometry to MRN, enabling straightforward co-registration of all data to obtain global and regional mean MTR measurements. Linear regression models were used to identify differences in MTR values between HCs and people with RRMS and to identify an association between MTR measures and EDSS. Results: MTR values in the sciatic nerve of people with RRMS were found to be significantly lower compared to HCs, but no significant MTR changes were identified in the lumbar plexus of people with RRMS. The median EDSS in people with RRMS was 2.0 (range, 0-3). No relationship between the MTR measures in the PNS and EDSS were identified at any of the anatomical locations studied in this cohort of people with RRMS. Conclusion: The results from this study demonstrate the presence of PNS damage in people with RRMS and support the notion that these changes, suggestive of demyelination, maybe occurring independently at different anatomical locations within the PNS. Further investigations to confirm these findings and to clarify the pathophysiological basis of these alterations are warranted

Designing an automated clinical decision support system to match clinical practice guidelines for opioid therapy for chronic pain

Abstract Background Opioid prescribing for chronic pain is common and controversial, but recommended clinical practices are followed inconsistently in many clinical settings. Strategies for increasing adherence to clinical practice guideline recommendations are needed to increase effectiveness and reduce negative consequences of opioid prescribing in chronic pain patients. Methods Here we describe the process and outcomes of a project to operationalize the 2003 VA/DOD Clinical Practice Guideline for Opioid Therapy for Chronic Non-Cancer Pain into a computerized decision support system (DSS) to encourage good opioid prescribing practices during primary care visits. We based the DSS on the existing ATHENA-DSS. We used an iterative process of design, testing, and revision of the DSS by a diverse team including guideline authors, medical informatics experts, clinical content experts, and end-users to convert the written clinical practice guideline into a computable algorithm to generate patient-specific recommendations for care based upon existing information in the electronic medical record (EMR), and a set of clinical tools. Results The iterative revision process identified numerous and varied problems with the initially designed system despite diverse expert participation in the design process. The process of operationalizing the guideline identified areas in which the guideline was vague, left decisions to clinical judgment, or required clarification of detail to insure safe clinical implementation. The revisions led to workable solutions to problems, defined the limits of the DSS and its utility in clinical practice, improved integration into clinical workflow, and improved the clarity and accuracy of system recommendations and tools. Conclusions Use of this iterative process led to development of a multifunctional DSS that met the approval of the clinical practice guideline authors, content experts, and clinicians involved in testing. The process and experiences described provide a model for development of other DSSs that translate written guidelines into actionable, real-time clinical recommendations.http://deepblue.lib.umich.edu/bitstream/2027.42/78267/1/1748-5908-5-26.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78267/2/1748-5908-5-26.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/78267/3/1748-5908-5-26-S3.TIFFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78267/4/1748-5908-5-26-S2.TIFFhttp://deepblue.lib.umich.edu/bitstream/2027.42/78267/5/1748-5908-5-26-S1.TIFFPeer Reviewe

The use of the SAEM algorithm in MONOLIX software for estimation of population pharmacokinetic-pharmacodynamic-viral dynamics parameters of maraviroc in asymptomatic HIV subjects

Using simulated viral load data for a given maraviroc monotherapy study design, the feasibility of different algorithms to perform parameter estimation for a pharmacokinetic-pharmacodynamic-viral dynamics (PKPD-VD) model was assessed. The assessed algorithms are the first-order conditional estimation method with interaction (FOCEI) implemented in NONMEM VI and the SAEM algorithm implemented in MONOLIX version 2.4. Simulated data were also used to test if an effect compartment and/or a lag time could be distinguished to describe an observed delay in onset of viral inhibition using SAEM. The preferred model was then used to describe the observed maraviroc monotherapy plasma concentration and viral load data using SAEM. In this last step, three modelling approaches were compared; (i) sequential PKPD-VD with fixed individual Empirical Bayesian Estimates (EBE) for PK, (ii) sequential PKPD-VD with fixed population PK parameters and including concentrations, and (iii) simultaneous PKPD-VD. Using FOCEI, many convergence problems (56%) were experienced with fitting the sequential PKPD-VD model to the simulated data. For the sequential modelling approach, SAEM (with default settings) took less time to generate population and individual estimates including diagnostics than with FOCEI without diagnostics. For the given maraviroc monotherapy sampling design, it was difficult to separate the viral dynamics system delay from a pharmacokinetic distributional delay or delay due to receptor binding and subsequent cellular signalling. The preferred model included a viral load lag time without inter-individual variability. Parameter estimates from the SAEM analysis of observed data were comparable among the three modelling approaches. For the sequential methods, computation time is approximately 25% less when fixing individual EBE of PK parameters with omission of the concentration data compared with fixed population PK parameters and retention of concentration data in the PD-VD estimation step. Computation times were similar for the sequential method with fixed population PK parameters and the simultaneous PKPD-VD modelling approach. The current analysis demonstrated that the SAEM algorithm in MONOLIX is useful for fitting complex mechanistic models requiring multiple differential equations. The SAEM algorithm allowed simultaneous estimation of PKPD and viral dynamics parameters, as well as investigation of different model sub-components during the model building process. This was not possible with the FOCEI method (NONMEM version VI or below). SAEM provides a more feasible alternative to FOCEI when facing lengthy computation times and convergence problems with complex models

Testicular tuberculosis presenting with metastatic intracranial tuberculomas only: a case report

<p>Abstract</p> <p>Introduction</p> <p>Intracranial tuberculomas are a rare complication of tuberculosis occurring through hematogenous spread from an extracranial source, most often of pulmonary origin. Testicular tuberculosis with only intracranial spread is an even rarer finding and to the best of our knowledge, has not been reported in the literature. Clinical suspicion or recognition and prompt diagnosis are important because early treatment can prevent patient deterioration and lead to clinical improvement.</p> <p>Case presentation</p> <p>We present the case of a 51-year-old African man with testicular tuberculosis and multiple intracranial tuberculomas who was initially managed for testicular cancer with intracranial metastasis. He had undergone left radical orchidectomy, but subsequently developed hemiparesis and lost consciousness. Following histopathological confirmation of the postoperative sample as chronic granulomatous infection due to tuberculosis, he sustained significant clinical improvement with antituberculous therapy, recovered fully and was discharged at two weeks post-treatment.</p> <p>Conclusion</p> <p>The clinical presentation of intracranial tuberculomas from an extracranial source is protean, and delayed diagnosis could have devastating consequences. The need to have a high index of suspicion is important, since neuroimaging features may not be pathognomonic.</p

Имитация распределенной обработки информации в вычислительных системах и локальных вычислительных сетях

Предложено использовать для анализа вариантов организации распределенной обработки информации в вычислительных системах и локальных вычислительных сетях вероятностный граф реализации вычислительного процесса с явными связями типа вероятностных сетевых графиков.Запропоновано використовувати для аналізу варіантів організації розподіленої обробки інформації в обчислювальних системах і в локальних обчислювальних мережах імовірнісний граф реалізації обчислювального процесу з явними зв’язками типу імовірнісних сіткових графіків.It іs оffered to use for analyzing variants of organization of distributed information processing in computing systems and local computing networks a probabilistic graph for realizing a computing process with evident relationships of the type probabilistic network diagrams

Cellular Radiosensitivity: How much better do we understand it?

Purpose: Ionizing radiation exposure gives rise to a variety of lesions in DNA that result in genetic instability and potentially tumorigenesis or cell death. Radiation extends its effects on DNA by direct interaction or by radiolysis of H2O that generates free radicals or aqueous electrons capable of interacting with and causing indirect damage to DNA. While the various lesions arising in DNA after radiation exposure can contribute to the mutagenising effects of this agent, the potentially most damaging lesion is the DNA double strand break (DSB) that contributes to genome instability and/or cell death. Thus in many cases failure to recognise and/or repair this lesion determines the radiosensitivity status of the cell. DNA repair mechanisms including homologous recombination (HR) and non-homologous end-joining (NHEJ) have evolved to protect cells against DNA DSB. Mutations in proteins that constitute these repair pathways are characterised by radiosensitivity and genome instability. Defects in a number of these proteins also give rise to genetic disorders that feature not only genetic instability but also immunodeficiency, cancer predisposition, neurodegeneration and other pathologies. Conclusions: In the past fifty years our understanding of the cellular response to radiation damage has advanced enormously with insight being gained from a wide range of approaches extending from more basic early studies to the sophisticated approaches used today. In this review we discuss our current understanding of the impact of radiation on the cell and the organism gained from the array of past and present studies and attempt to provide an explanation for what it is that determines the response to radiation