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Sample records for linear clinical progression

  1. Clinical management of progressive myopia

    PubMed Central

    Aller, T A

    2014-01-01

    Myopia has been increasing in prevalence throughout the world, reaching over 90% in some East Asian populations. There is increasing evidence that whereas genetics clearly have an important role, the type of visual environment to which one is exposed to likely influences the onset, progression, and cessation of myopia. Consequently, attempts to either modify the environment or to reduce the exposure of the eye to various environmental stimuli to eye growth through the use of various optical devices are well under way at research centers around the globe. The most promising of current treatments include low-percentage atropine, bifocal soft contact lenses, orthokeratology, and multifocal spectacles. These methods are discussed briefly and are then categorized in terms of their expected degree of myopia progression control. A clinical strategy is presented for selecting the most effective treatment for the appropriate type of patient at the optimal stage of refractive development to achieve the maximum control of myopia progression. PMID:24357844

  2. Progress report on the SLAC Linear Collider

    SciTech Connect

    Rees, J.

    1986-06-01

    The SLAC Linear Collider project (SLC) is reported as being near completion. The performance specifications are tabulated both for the initial form and for eventual goals. Various parts of the SLC are described and the status of their construction is reported, including the front end electron gun and booster, the linac, damping ring, positron source, SLC arcs, and conventional facilities. 5 refs., 12 figs. (LEW)

  3. Non-linearity in clinical practice.

    PubMed

    Petros, Peter

    2003-05-01

    The whole spectrum of medicine consists of complex non-linear systems that are balanced and interact with each other. How non-linearity confers stability on a system and explains variation and uncertainty in clinical medicine is discussed. A major theme is that a small alteration in initial conditions may have a major effect on the end result. In the context of non-linearity, it is argued that 'evidence-based medicine' (EBM) as it exists today can only ever be relevant to a small fraction of the domain of medicine, that the 'art of medicine' consists of an intuitive 'tuning in' to these complex systems and as such is not so much an art as an expression of non-linear science. The main cause of iatrogenic disease is interpreted as a failure to understand the complexity of the systems being treated. Case study examples are given and analysed in non-linear terms. It is concluded that good medicine concerns individualized treatment of an individual patient whose body functions are governed by non-linear processes. EBM as it exists today paints with a broad and limited brush, but it does promise a fresh new direction. In this context, we need to expand the spectrum of scientific medicine to include non-linearity, and to look upon the 'art of medicine' as a historical (but unstated) legacy in this domain.

  4. [From clinical judgment to linear regression model.

    PubMed

    Palacios-Cruz, Lino; Pérez, Marcela; Rivas-Ruiz, Rodolfo; Talavera, Juan O

    2013-01-01

    When we think about mathematical models, such as linear regression model, we think that these terms are only used by those engaged in research, a notion that is far from the truth. Legendre described the first mathematical model in 1805, and Galton introduced the formal term in 1886. Linear regression is one of the most commonly used regression models in clinical practice. It is useful to predict or show the relationship between two or more variables as long as the dependent variable is quantitative and has normal distribution. Stated in another way, the regression is used to predict a measure based on the knowledge of at least one other variable. Linear regression has as it's first objective to determine the slope or inclination of the regression line: Y = a + bx, where "a" is the intercept or regression constant and it is equivalent to "Y" value when "X" equals 0 and "b" (also called slope) indicates the increase or decrease that occurs when the variable "x" increases or decreases in one unit. In the regression line, "b" is called regression coefficient. The coefficient of determination (R(2)) indicates the importance of independent variables in the outcome.

  5. Radio frequency noise from clinical linear accelerators.

    PubMed

    Burke, B; Lamey, M; Rathee, S; Murray, B; Fallone, B G

    2009-04-21

    There is a great deal of interest in image-guided radiotherapy (IGRT), and to advance the state of IGRT, an integrated linear accelerator-magnetic resonance (linac-MR) system has been proposed. Knowledge of the radiofrequency (RF) emissions near a linac is important for the design of appropriate RF shielding to facilitate the successful integration of these two devices. The frequency spectra of both electric and magnetic fields of RF emission are measured using commercially available measurement probes near the treatment couch in three clinical linac vaults with distinct physical layouts. The magnitude spectrum of the RF power emitted from these three linacs is then estimated. The electric field spectrum was also measured at several distances from the linac modulator in order to assess the effects of variations in spatial location in the treatment vault. A large fraction of RF power is emitted at frequencies below 5 MHz. However, the measured RF power at the Larmor frequency (8.5 MHz) of the proposed 0.2 T MR in the linac-MR (0.4-14.6 microW m(-2)) is still large enough to cause artifacts in MR images. Magnetron-based linacs generally emit much larger RF power than klystron-based linacs. In the frequency range of 1-50 MHz, only slight variation in the measured electric field is observed as a function of measurement position. This study suggests that the RF emissions are strong enough to cause image artifacts in MRI systems.

  6. International Linear Collider-A Technical Progress Report

    SciTech Connect

    Elsen, Eckhard; Harrison, Mike; Hesla, Leah; Ross, Marc; Royole-Degieux, Perrine; Takahashi, Rika; Walker, Nicholas; Warmbein, Barbara; Yamamoto, Akira; Yokoya, Kaoru; Zhang, Min; /Beijing, Inst. High Energy Phys.

    2011-11-04

    The International Linear Collider: A Technical Progress Report marks the halfway point towards the Global Design Effort fulfilling its mandate to follow up the ILC Reference Design Report with a more optimised Technical Design Report (TDR) by the end of 2012. The TDR will be based on much of the work reported here and will contain all the elements needed to propose the ILC to collaborating governments, including a technical design and implementation plan that are realistic and have been better optimised for performance, cost and risk. We are on track to develop detailed plans for the ILC, such that once results from the Large Hadron Collider (LHC) at CERN establish the main science goals and parameters of the next machine, we will be in good position to make a strong proposal for this new major global project in particle physics. The two overriding issues for the ILC R&D programme are to demonstrate that the technical requirements for the accelerator are achievable with practical technologies, and that the ambitious physics goals can be addressed by realistic ILC detectors. This GDE interim report documents the impressive progress on the accelerator technologies that can make the ILC a reality. It highlights results of the technological demonstrations that are giving the community increased confidence that we will be ready to proceed with an ILC project following the TDR. The companion detector and physics report document likewise demonstrates how detector designs can meet the ambitious and detailed physics goals set out by the ILC Steering Committee. LHC results will likely affect the requirements for the machine design and the detectors, and we are monitoring that very closely, intending to adapt our design as those results become available.

  7. Clinical Approach to Progressive Supranuclear Palsy

    PubMed Central

    Ling, Helen

    2016-01-01

    Sixty years ago, Steele, Richardson and Olszewski designated progressive supranuclear palsy (PSP) as a new clinicopathological entity in their seminal paper. Since then, in addition to the classic Richardson’s syndrome (RS), different clinical phenotypic presentations have been linked with this four-repeat tauopathy. The clinical heterogeneity is associated with variability of regional distribution and severity of abnormal tau accumulation and neuronal loss. In PSP subtypes, the presence of certain clinical pointers may be useful for antemortem prediction of the underlying PSP-tau pathology. Midbrain atrophy on conventional MRI correlates with the clinical phenotype of RS but is not predictive of PSP pathology. Cerebrospinal fluid biomarkers and tau ligand positron emission tomography are promising biomarkers of PSP. A multidisciplinary approach to meet the patients’ complex needs is the current core treatment strategy for this devastating disorder. PMID:26828211

  8. [Ear keloid and clinical research progress].

    PubMed

    Du, Guangyuan; Zhu, Jiang

    2014-04-01

    Keloid refers to the damaged skin due to excessive fibroblast proliferation. Ear is one predilection site. The pathogenesis of ear keloid is not very clear, and the treatment is also varied. Surgery, postoperative radiotherapy and laser treatment, steroid hormones, pressure therapy are the basic treatment methods. Integrated application of a variety of treatments, classification research and new materials using revealed the prospect for the treatment of the disease. This thesis reviews literature about ear keloid in recent 10 years, and introduces this disease and clinical research progress.

  9. Optimal composite scores for longitudinal clinical trials under the linear mixed effects model.

    PubMed

    Ard, M Colin; Raghavan, Nandini; Edland, Steven D

    2015-01-01

    Clinical trials of chronic, progressive conditions use rate of change on continuous measures as the primary outcome measure, with slowing of progression on the measure as evidence of clinical efficacy. For clinical trials with a single prespecified primary endpoint, it is important to choose an endpoint with the best signal-to-noise properties to optimize statistical power to detect a treatment effect. Composite endpoints composed of a linear weighted average of candidate outcome measures have also been proposed. Composites constructed as simple sums or averages of component tests, as well as composites constructed using weights derived from more sophisticated approaches, can be suboptimal, in some cases performing worse than individual outcome measures. We extend recent research on the construction of efficient linearly weighted composites by establishing the often overlooked connection between trial design and composite performance under linear mixed effects model assumptions and derive a formula for calculating composites that are optimal for longitudinal clinical trials of known, arbitrary design. Using data from a completed trial, we provide example calculations showing that the optimally weighted linear combination of scales can improve the efficiency of trials by almost 20% compared with the most efficient of the individual component scales. Additional simulations and analytical results demonstrate the potential losses in efficiency that can result from alternative published approaches to composite construction and explore the impact of weight estimation on composite performance.

  10. Progress towards clinically useful aldosterone synthase inhibitors.

    PubMed

    Cerny, Matthew A

    2013-01-01

    Owing to the high degree of similarity between aldosterone synthase (CYP11B2) and cortisol synthase (CYP11B1), the design of selective inhibitors of one or the other of these two enzymes was, at one time, thought to be impossible. Through development of novel enzyme screening assays and significant medicinal chemistry efforts, highly potent inhibitors of CYP11B2 have been identified with selectivities approaching 1000-fold between the two enzymes. Many of these molecules also possess selectivity against other steroidogenic cytochromes P450 (e.g. CYP17A1 and CYP19A1) as well as hepatic drug metabolizing P450s. Though not as well developed or explored, inhibitors of CYP11B1, with selectivities approaching 50-fold, have also been identified. The therapeutic benefits of affecting the renin-angiotensin-aldosterone system have been well established with the therapeutically useful angiotensin-converting enzymes inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists. Data regarding the additional benefits of an aldosterone synthase inhibitor (ASi) are beginning to emerge from animal models and human clinical trials. Despite great promise and much progress, additional challenges still exist in the path towards development of a therapeutically useful ASi.

  11. From linear to nonlinear control means: a practical progression.

    PubMed

    Gao, Zhiqiang

    2002-04-01

    With the rapid advance of digital control hardware, it is time to take the simple but effective proportional-integral-derivative (PID) control technology to the next level of performance and robustness. For this purpose, a nonlinear PID and active disturbance rejection framework are introduced in this paper. It complements the existing theory in that (1) it actively and systematically explores the use of nonlinear control mechanisms for better performance, even for linear plants; (2) it represents a control strategy that is rather independent of mathematical models of the plants, thus achieving inherent robustness and reducing design complexity. Stability analysis, as well as software/hardware test results, are presented. It is evident that the proposed framework lends itself well in seeking innovative solutions to practical problems while maintaining the simplicity and the intuitiveness of the existing technology.

  12. Progress in UWB generation with linear silicon switches

    NASA Astrophysics Data System (ADS)

    Cardwell, Kendall W.; Giorgi, David M.; McIntyre, Iain A.; Solone, Paul J.; Stuurman, K.; Zucker, Oved S. F.

    1993-06-01

    The use of linear photoconductive switches rather than nonlinear switches for the generation of Ultra-Wide-Band (UWB) pulses provides advantages such as jitter-free operation, low losses, and a reduction of the electrical and mechanical stresses in the switch. These advantages lead to the operation of many switches in series and/or parallel, higher average powers and longer lifetimes. Energy Compression Research Corporation (ECR) has demonstrated an advanced UWB source based on light activated silicon switches (LASS). The UWB source consists of a single LASS device mounted on a low impedance (< 0.5 (Omega) ) microstrip transmission line and a high fidelity impedance transformer connected to a 50 (Omega) coaxial connection. The voltage was measured at low impedance and 50 (Omega) to verify the efficiency and fidelity of the impedance transformer. After a transformation of 110:1 in impedance, the measurement at the end of the transformer verified that pulse rise-time was less than 100 ps and the overall efficiency was 50%. The system was tested up to 10 kV into 50 (Omega) before connector breakdown limited further increase. Larger powers can be radiated if the transformer is directly connected to the antenna.

  13. Both Financial and Cognitive Decline Predict Clinical Progression in MCI

    PubMed Central

    Gerstenecker, Adam; Triebel, Kristen L.; Martin, Roy; Snyder, Scott; Marson, Daniel C.

    2015-01-01

    We investigated the roles of financial/functional and cognitive abilities in predicting clinical progression in patients with mild cognitive impairment (MCI). In a longitudinal sample of 51 patients with consensus-conference diagnosed MCI likely due to Alzheimer’s disease (AD). Two-year change scores were calculated for a performance measure of functional ability, cognitive variables, and three outcome measures used to track progression in neurologic disorders. We examined patterns of financial and cognitive decline across the two-year study period, and used this data and the three outcome variables to construct discrete predictor models of clinical progression in MCI. We found that both financial skills and cognitive abilities declined over the two-year study period, were significantly associated with clinical progression, and contributed unique variance all three predictor models. The resulting models accounted for 40–75% of variance in clinical progression across outcome variables. Taken together, our results indicate that changes in both cognitive abilities and higher-order functional skills appear integral to understanding clinical progression in MCI likely due to AD. Specifically, declines in financial skills contribute unique variance to measures commonly used to track progression in neurological disorders associated with aging and thus represent an important functional marker of clinical progression in prodromal AD. PMID:26900988

  14. Clinical implementation of electron energy changes of varian linear accelerators.

    PubMed

    Zhang, Sean; Liengsawangwong, Praimakorn; Lindsay, Patricia; Prado, Karl; Sun, Tzouh-Liang; Steadham, Roy; Wang, Xiaochun; Salehpour, Mohammad; Gillin, Michael

    2009-10-27

    Modern dual photon energy linear accelerators often come with a few megavoltage electron beams. The megavoltage electron beam has limited range and relative sharp distal falloff in its depth dose curve compared to that of megavoltage photon beam. Its radiation dose is often delivered appositionally to cover the target volume to its distal 90% depth dose (d90), while avoiding the normal--sometimes critical--structure immediately distal to the target. Varian linear accelerators currently offer selected electron beams of 4, 6, 9, 12, 16 and 20 MeV electron beam energies. However, intermediate electron energy is often needed for optimal dose distribution. In this study we investigated electron beam characteristics and implemented two intermediate 7 and 11 MeV electron beams on Varian linear accelerators. Comprehensive tests and measurements indicated the new electron beams met all dosimetry parameter criteria and operational safety standards. Between the two new electron beams and the existing electron beams we were able to provide a choice of electron beams of 4, 6, 7, 9, 11, 12, 16 and 20 MeV electron energies, which had d90 depth between 1.5 cm and 6.0 cm (from 1.5 cm to 4.0 cm in 0.5 cm increments) to meet our clinical needs.

  15. Clinical Use of OCT in Assessing Glaucoma Progression

    PubMed Central

    Kotowski, Jacek; Wollstein, Gadi; Folio, Lindsey S.; Ishikawa, Hiroshi; Schuman, Joel S.

    2012-01-01

    Detection of disease progression is an important and challenging component of glaucoma management. Optical coherence tomography (OCT) has proved to be valuable in the detection of glaucomatous damage. With its high resolution and proven measurement reproducibility, OCT has the potential to become an important tool for glaucoma progression detection. This manuscript presents the capabilities of the OCT technology pertinent for detection of progressive glaucomatous damage and provides a review of the current knowledge on the device’s clinical performance. PMID:21790113

  16. Manual linear movements to assess spasticity in a clinical setting.

    PubMed

    Marinelli, Lucio; Trompetto, Carlo; Mori, Laura; Vigo, Gabriele; Traverso, Elisabetta; Colombano, Federica; Abbruzzese, Giovanni

    2013-01-01

    In a clinical setting, where motor-driven systems are not readily available, the major difficulty in the assessment of the stretch reflex lies in the control of passive limb displacement velocity. A potential approach to this problem arises from the use of manual sinusoidal movements (made by continuous alternating flexions and extensions) paced by an external stimulus. Unfortunately, there are conditions in which sinusoidal movements induce interfering phenomena such as the shortening reaction or postactivation depression. In the present paper, a novel manual method to control the velocity of passive linear movements is described and the results obtained from both healthy subjects and spastic patients are reported. This method is based on the synchronisation of movements with tones played by a metronome at different speeds. In a first set of experiments performed in healthy subjects, we demonstrated consistent control of velocity during passive limb movements using this method. Four joints usually examined during muscle tone assessment were tested: wrist, elbow, knee and ankle joints. Following this, we conducted a longitudinal assessment of the stretch reflex amplitude in wrist flexor muscles in patients with spasticity treated with botulinum toxin type A. The evaluators were not only able to vary the movement velocity based on the metronome speed, but also could reproduce the respective speeds two weeks later, despite the changing degree of hypertonia. This method is easy to perform in a clinical setting and hardware requirements are minimal, making it an attractive and robust procedure for the widespread clinical assessment of reflex hypertonia.

  17. Clinical Investigation Program Annual Progress Report

    DTIC Science & Technology

    1989-09-30

    pre-op obstructive side, and is this subjectively noted by the patient to the point of causing secondary obstructive symptoms , of any degree on the...Lipolytic Enzymes in Sedentary, Healthy Men ................. 109 87/110A C The Role of Excess Prostaglandin Production in Causing the Abnormal...Duration of Symptoms Important? ... 154 89/105 0 Role of Blood Pressure Control in Progression of Diabetic Nephropathy and Other Microangiopathies .155 89

  18. Clinical Trials: Key to Medical Progress

    MedlinePlus

    ... all the time in nearly every area of medical research. To Find Out More To find out more ... widely available, or help others by contributing to medical research. The latest, most complete information about clinical trials ...

  19. Progress testing 2.0: clinical skills meets necessary science

    PubMed Central

    Gold, Jonathan; DeMuth, Robin; Mavis, Brian; Wagner, Dianne

    2015-01-01

    Introduction Progress testing has been widely used in medical schools to test scientific knowledge but has not been reported for assessing clinical skills. Development We designed a novel progress examination that included assessments of both clinical performance and underlying basic and social science knowledge. This Progress Clinical Skills Examination (PCSE) was given to 21 early medical students at the beginning and end of a 6-week pilot test of a new medical school curriculum. Implementation This examination was feasible for early students, easy to map to curricular objectives, and easy to grade using a combination of assessment strategies. Future directions Use of a PCSE is feasible for early medical students. As medical schools integrate clinical experience with underlying knowledge, this type of examination holds promise. Further data are needed to validate this examination as an accurate measure of clinical performance and knowledge. PMID:25948045

  20. Progress testing 2.0: clinical skills meets necessary science.

    PubMed

    Gold, Jonathan; DeMuth, Robin; Mavis, Brian; Wagner, Dianne

    2015-01-01

    Introduction Progress testing has been widely used in medical schools to test scientific knowledge but has not been reported for assessing clinical skills. Development We designed a novel progress examination that included assessments of both clinical performance and underlying basic and social science knowledge. This Progress Clinical Skills Examination (PCSE) was given to 21 early medical students at the beginning and end of a 6-week pilot test of a new medical school curriculum. Implementation This examination was feasible for early students, easy to map to curricular objectives, and easy to grade using a combination of assessment strategies. Future directions Use of a PCSE is feasible for early medical students. As medical schools integrate clinical experience with underlying knowledge, this type of examination holds promise. Further data are needed to validate this examination as an accurate measure of clinical performance and knowledge.

  1. Progress in Geriatrics: A Clinical Care Update.

    ERIC Educational Resources Information Center

    Blanchette, Patricia Lanoie; And Others

    1997-01-01

    This issue includes 18 theme articles that examine clinical care, conditions, and practice as they relate to older adults. It contains articles on the following: men's and women's health, depression, dementia, hypertension, incontinence, bone pain, infections, preventive medicine, geriatric medicine, health care delivery, managed care, long-term…

  2. Clinical Investigation Program. Annual Progress Report

    DTIC Science & Technology

    1990-10-01

    Adult Pigs (0) 54H89 Claybaugh, J. R. 27 Responses of Water and Electrolyte Regulating Hormones During a Saturation Dive to 450M (C) 56A89 Dice, M. S...28 Mechanism of Cold Induced Diuresis (0) 39H88 Freund, B. J. 29 Hormonal and Renal Responses to Exercise: Effects of Exercise Intensity (C) (SP) 4A88...Disturbances of the Renin-Angiotensin-Aldosterone, Antidiuretic Hormone , and Atrial Natriuretic Hormone Axes (0) 43H89 Kortepeter, M. G. 49 Clinical Utility

  3. Radiopharmaceuticals: Progress and clinical perspectives. Volume I

    SciTech Connect

    Fritzberg, A.R.

    1986-01-01

    This volume examines the radiopharmaceuticals from both the clinical and pharmaceutical research viewpoints. Classes of radiopharmaceuticals are covered by organ type, including the heart, brain, liver, kidney, adrenal, blood, and bone. Also included are discussions of radiolabeled antibodies for cancer; cyclotron-produced radiopharmaceuticals; receptor agents; radiopharmaceutical design; and animal and human evaluation studies. VOLUME I: Contents include: Cationic Radiotracers as Myocardial Radiopharmaceuticals, Brain Radiopharmaceuticals, Antibody imaging and Therapy in Human Cancer, Advances in Renal Radiopharmaceuticals, Advances in the Development of Hepatobiliary Radiopharmaceuticals, Radiopharmaceutical Design, The Adrenal Medulla and its Diseases, and Index.

  4. Laboratory Persistence and Clinical Progression of Small Monoclonal Abnormalities

    PubMed Central

    Murray, David L.; Seningen, Justin L.; Dispenzieri, Angela; Snyder, Melissa R.; Kyle, Robert A.; Rajkumar, S. Vincent; Katzmann, Jerry A.

    2014-01-01

    Monoclonal gammopathy of undetermined significance (MGUS) that presents with no quantifiable M spike on immunofixation electrophoresis (IFE) can be termed IFE MGUS. We retrospectively identified patients with IFE MGUS who were monitored with at least 1 subsequent assessment that included an IFE, and evaluated the persistence of the monoclonal protein and the progression of disease. Although the monoclonal proteins persisted in the majority of patients, 16% did not experience this persistence, and had no documented immunomodulatory therapy. After a median follow-up of 3.9 years, the disease clinically progressed in 14 patients (3.2%). Eight of these 14 patients with clinical progression had an immunoglobulin (Ig) A IFE M protein and 6 had an IgG M protein. This study demonstrates that in some patients with IFE MGUS, the M proteins are transient and that IgA IFE MGUS is more likely to persist and progress to myeloma. PMID:23010717

  5. Macular Preprocessing of Linear Acceleratory Stimuli: Implications for the Clinic

    NASA Technical Reports Server (NTRS)

    Ross, M. D.; Hargens, Alan R. (Technical Monitor)

    1996-01-01

    Three-dimensional reconstructions of innervation patterns in rat maculae were carried out using serial section images sent to a Silicon Graphics workstation from a transmission electron microscope. Contours were extracted from mosaicked sections, then registered and visualized using Biocomputation Center software. Purposes were to determine innervation patterns of type II cells and areas encompassed by vestibular afferent receptive fields. Terminals on type II cells typically are elongated and compartmentalized into parts varying in vesicular content; reciprocal and serial synapses are common. The terminals originate as processes of nearby calyces or from nerve fibers passing to calyces outside the immediate vicinity. Thus, receptive fields of the afferents overlap in unique ways. Multiple processes are frequent; from 4 to 6 afferents supply 12-16 terminals on a type II cell. Processes commonly communicate with two type II cells. The morphology indicates that extensive preprocessing of linear acceleratory stimuli occurs peripherally, as is true also of visual and olfactory systems. Clinically, this means that loss of individual nerve fibers may not be noticed behaviorally, due to redundancy (receptive field overlap). However, peripheral processing implies the presence of neuroactive agents whose loss can acutely or chronically alter normal peripheral function and cause balance disorders. (Platform presentation preferred - Theme 11)

  6. [Clinical characteristics, progression and risk factors of geographic atrophy].

    PubMed

    Brinkmann, C K; Adrion, C; Mansmann, U; Schmitz-Valckenberg, S; Holz, F G

    2010-11-01

    Geographic atrophy (GA) as the late stage manifestation of age-related macular degeneration (AMD) is a progressive disease process afflicting the retinal pigment epithelium, choriocapillaris and the outer neurosensory retina. GA represents a complex, multifactorial disease governed by the interdependence of genetic, endogenous and exogenous factors. Diagnosis and monitoring of GA progression is largely based on various retinal imaging modalities. After the breakthrough in the treatment of wet AMD GA represents a large clinical challenge. Recent studies have contributed to a better understanding of the pathophysiological pathways, natural history and predictive markers for progression.

  7. Department of Clinical Investigation Annual Progress Report: Fiscal Year 1989

    DTIC Science & Technology

    1989-01-01

    Bacterially Synthetized b Human Granulocyte Colony Stimulating Factor (hg-CSF) Against Pseudomonas aeruginosa Infection DEPARTMENT OF MEDICINE Allergy ...C-01) A Clinical Trial to Evaluate Postoperative 30 Immunotherapy and Postoperative Systemic Chemotherapy in the Management of Resectable Colon...Publications/Presentations: None to date. -6- Annual Progress Report DEPARTMENT OF MEDICINE Allergy and Immunology Service Date: 1 October 1989 Protocol

  8. Ultrasound clinical progress monitoring: Who, where and how?

    PubMed

    Harrison, Gill

    2015-11-01

    Prior to assessment of final ultrasound clinical competency it is important to monitor clinical progress, provide high quality feedback and encourage skills development. The role of the supervisor, mentor and assessor are fundamental to the on-going progress monitoring of ultrasound trainees. This article forms the second part of a larger project which was to elicit ultrasound practitioners' opinions on how progress should be monitored, where and by whom. An on-line questionnaire was used to gain opinions from ultrasound practitioners. Totally, 116 responses were received from professionals with an interest in ultrasound assessment. Results suggested that experienced, qualified ultrasound practitioners should undertake the role of supervisor and assessor, having been prepared for that role by the training centre. Formative monitoring should take place both within the clinical department and possibly the training centre, using a range of methods. Following completion of the training, practitioners should have a preceptorship period to consolidate their knowledge and skills for 3 to 6 months or until further competencies have been demonstrated. Formative progress monitoring should be a recognised part of ultrasound training. Essentially, staff undertaking supervision and assessor roles should be supported and trained to ensure a high quality, consistent learning experience for ultrasound trainees. Additionally, they should provide appropriate feedback to the trainee and education centre.

  9. Unification of the "burst" and "linear" theories of periodontal disease progression: a multilevel manifestation of the same phenomenon.

    PubMed

    Gilthorpe, M S; Zamzuri, A T; Griffiths, G S; Maddick, I H; Eaton, K A; Johnson, N W

    2003-03-01

    Previously, burst and linear theories for periodontal disease progression were proposed based on different but limited statistical methods of analysis. Multilevel modeling provides a new approach, yielding a more comprehensive model. Random coefficient models were used to analyze longitudinal periodontal data consisting of repeated measures (level 1), sites (level 2), teeth (level 3), and subjects (level 4). Large negative and highly significant correlations between random linear and quadratic time coefficients indicated that subjects and teeth with greater-than-average linear change experienced decelerated variation. Conversely, subjects and teeth with less-than-average linear change experienced accelerated variation. Change therefore exhibited a dynamic regression to the mean at the tooth and subject levels. Since no equilibrium was attained throughout the study, changes were cyclical. When considered as a multilevel system, the "linear" and "burst" theories of periodontal disease progression are a manifestation of the same phenomenon: Some sites improve while others progress, in a cyclical manner.

  10. Multi-task linear programming discriminant analysis for the identification of progressive MCI individuals.

    PubMed

    Yu, Guan; Liu, Yufeng; Thung, Kim-Han; Shen, Dinggang

    2014-01-01

    Accurately identifying mild cognitive impairment (MCI) individuals who will progress to Alzheimer's disease (AD) is very important for making early interventions. Many classification methods focus on integrating multiple imaging modalities such as magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET). However, the main challenge for MCI classification using multiple imaging modalities is the existence of a lot of missing data in many subjects. For example, in the Alzheimer's Disease Neuroimaging Initiative (ADNI) study, almost half of the subjects do not have PET images. In this paper, we propose a new and flexible binary classification method, namely Multi-task Linear Programming Discriminant (MLPD) analysis, for the incomplete multi-source feature learning. Specifically, we decompose the classification problem into different classification tasks, i.e., one for each combination of available data sources. To solve all different classification tasks jointly, our proposed MLPD method links them together by constraining them to achieve the similar estimated mean difference between the two classes (under classification) for those shared features. Compared with the state-of-the-art incomplete Multi-Source Feature (iMSF) learning method, instead of constraining different classification tasks to choose a common feature subset for those shared features, MLPD can flexibly and adaptively choose different feature subsets for different classification tasks. Furthermore, our proposed MLPD method can be efficiently implemented by linear programming. To validate our MLPD method, we perform experiments on the ADNI baseline dataset with the incomplete MRI and PET images from 167 progressive MCI (pMCI) subjects and 226 stable MCI (sMCI) subjects. We further compared our method with the iMSF method (using incomplete MRI and PET images) and also the single-task classification method (using only MRI or only subjects with both MRI and PET images

  11. Palaeoenvironmental reconstructions from linear dunefields: recent progress, current challenges and future directions

    NASA Astrophysics Data System (ADS)

    Telfer, M. W.; Hesse, P. P.

    2013-10-01

    This paper reviews recent progress in the use of linear dunes as ‘geoproxies' of late Quaternary environmental change, summarises the challenges facing their use, and explores some potential solutions to these challenges. Large areas of the swathes of linear dunes which occupy the continental interior of southern Africa, Australia, and parts of central Asia and southern America currently have limited or negligible aeolian activity. They have been recognised as offering potential information about past environments for more than a century, but only with the widespread application of luminescence dating during the 1990s did they realistically start to offer the prospect of being an extensive, dateable proxy of late Quaternary palaeoenvironments and, possibly, palaeoclimates. Dating aeolian dune sands with luminescence methods is generally (although not always) relatively straightforward. Over the past twenty years, a large number (>1000) of luminescence ages have been added to the global dataset, yet there has also been significant criticism of some of the rationale underpinning much of the interpretation of the records derived. At the landscape scale, developments of arguably equal importance have come from improved geomorphological understanding based on the wider availability of remotely-sensed data and the paradigm of dunefield evolution as a self-organising complex system. Current challenges are identified in three key regions: incomplete understanding of how the process geomorphology of linear dunes affect the accumulation and preservation of sediment, a lack of clarity regarding the temporal and spatial scale of the response in a dynamic environmental setting and uncertainty surrounding the drivers of changing rates of net accumulation. Solutions to these challenges lie within diverse research methodologies. Certainly, further field study is required, with improvement required in understanding system responses to changing environmental stimuli at scales from

  12. Pathophysiology of major depressive disorder: mechanisms involved in etiology are not associated with clinical progression.

    PubMed

    Verduijn, J; Milaneschi, Y; Schoevers, R A; van Hemert, A M; Beekman, A T F; Penninx, B W J H

    2015-09-29

    Meta-analyses support the involvement of different pathophysiological mechanisms (inflammation, hypothalamic-pituitary (HPA)-axis, neurotrophic growth and vitamin D) in major depressive disorder (MDD). However, it remains unknown whether dysregulations in these mechanisms are more pronounced when MDD progresses toward multiple episodes and/or chronicity. We hypothesized that four central pathophysiological mechanisms of MDD are not only involved in etiology, but also associated with clinical disease progression. Therefore, we expected to find increasingly more dysregulation across consecutive stages of MDD progression. The sample from the Netherlands Study of Depression and Anxiety (18-65 years) consisted of 230 controls and 2333 participants assigned to a clinical staging model categorizing MDD in eight stages (0, 1A, 1B, 2, 3A, 3B, 3C and 4), from familial risk at MDD (stage 0) to chronic MDD (stage 4). Analyses of covariance examined whether pathophysiological mechanism markers (interleukin (IL)-6, C-reactive protein (CRP), cortisol, brain-derived neurotrophic factor and vitamin D) showed a linear trend across controls, those at risk for MDD (stages 0, 1A and 1B), and those with full-threshold MDD (stages 2, 3A, 3B, 3C and 4). Subsequently, pathophysiological differences across separate stages within those at risk and with full-threshold MDD were examined. A linear increase of inflammatory markers (CRP P=0.026; IL-6 P=0.090), cortisol (P=0.025) and decrease of vitamin D (P<0.001) was found across the entire sample (for example, from controls to those at risk and those with full-threshold MDD). Significant trends of dysregulations across stages were present in analyses focusing on at-risk individuals (IL-6 P=0.050; cortisol P=0.008; vitamin D P<0.001); however, no linear trends were found in dysregulations for any of the mechanisms across more progressive stages of full-threshold MDD. Our results support that the examined pathophysiological mechanisms are

  13. Clinical progression in Parkinson disease and the neurobiology of axons.

    PubMed

    Cheng, Hsiao-Chun; Ulane, Christina M; Burke, Robert E

    2010-06-01

    Despite tremendous growth in recent years in our knowledge of the molecular basis of Parkinson disease (PD) and the molecular pathways of cell injury and death, we remain without therapies that forestall disease progression. Although there are many possible explanations for this lack of success, one is that experimental therapeutics to date have not adequately focused on an important component of the disease process, that of axon degeneration. It remains unknown what neuronal compartment, either the soma or the axon, is involved at disease onset, although some have proposed that it is the axons and their terminals that take the initial brunt of injury. Nevertheless, this concept has not been formally incorporated into many of the current theories of disease pathogenesis, and it has not achieved a wide consensus. More importantly, in view of growing evidence that the molecular mechanisms of axon degeneration are separate and distinct from the canonical pathways of programmed cell death that mediate soma destruction, the possibility of early involvement of axons in PD has not been adequately emphasized as a rationale to explore the neurobiology of axons for novel therapeutic targets. We propose that ongoing degeneration of axons, not cell bodies, is the primary determinant of clinically apparent progression of disease, and that future experimental therapeutics intended to forestall disease progression will benefit from a new focus on the distinct mechanisms of axon degeneration.

  14. Non-linear dynamics models characterizing long-term virological data from AIDS clinical trials.

    PubMed

    Verotta, Davide; Schaedeli, Franziska

    2002-04-01

    Human immunodeficiency virus (HIV) dynamics represent a complicated variant of the text-book case of non-linear dynamics: predator-prey interaction. The interaction can be described as naturally reproducing T-cells (prey) hunted and killed by virus (predator). Virus reproduce and increase in number as a consequence of successful predation; this is countered by the production of T-cells and the reaction of the immune system. Multi-drug anti-HIV therapy attempts to alter the natural dynamics of the predator-prey interaction by decreasing the reproductive capability of the virus and hence predation. These dynamics are further complicated by varying compliance to treatment and insurgence of resistance to treatment. When following the temporal progression of viral load in plasma during therapy one observes a short-term (1-12 weeks) decrease in viral load. In the long-term (more than 12 weeks from the beginning of therapy) the reduction in viral load is either sustained, or it is followed by a rebound, oscillations and a new (generally lower than at the beginning of therapy) viral load level. Biomathematicians have investigated these dynamics by means of simulations. However the estimation of the parameters associated with the dynamics from real data has been mostly limited to the case of simplified, in particular linearized, models. Linearized model can only describe the short-term changes of viral load during therapy and can only predict (apparent) suppression. In this paper we put forward relatively simple models to characterize long-term virus dynamics which can incorporate different factors associated with resurgence: (Fl) the intrinsic non-linear HIV-1 dynamics, (F2) drug exposure and in particular compliance to treatment, and (F3) insurgence of resistant HIV-1 strains. The main goal is to obtain models which are mathematically identifiable given only measurements of viral load, while retaining the most crucial features of HIV dynamics. For the purpose of

  15. Clinical implications of epithelial cell plasticity in cancer progression.

    PubMed

    Aparicio, Luis A; Blanco, Moisés; Castosa, Raquel; Concha, Ángel; Valladares, Manuel; Calvo, Lourdes; Figueroa, Angélica

    2015-09-28

    In the last few years, the role of epithelial cell plasticity in cancer biology research has gained increasing attention. This concept refers to the ability of the epithelial cells to dynamically switch between different phenotypic cellular states. This programme is particularly relevant during the epithelial-to-mesenchymal transition (EMT) in cancer progression. During colonization, epithelial cells first activate the EMT programme to disseminate from a primary tumour to reach a distant tissue site. During this process, cells are transported into the circulation and are able to escape the immune system of the host. Then, a reverse process called mesenchymal-to-epithelial transition (MET) occurs on cells that settle in the distant organs. Although epithelial cell plasticity has an important impact on tumour biology, the clinical relevance of this concept remains to be recapitulated. In this review, we will update the current state of epithelial cell plasticity in cancer progression and its clinical implications for the design of therapeutic strategies, the acquisition of multidrug resistance, and future perspectives for the management of cancer patients.

  16. Differentiation of progressive supranuclear palsy: clinical, imaging and laboratory tools.

    PubMed

    Liscic, R M; Srulijes, K; Gröger, A; Maetzler, W; Berg, D

    2013-05-01

    Progressive supranuclear palsy (PSP) is the most common atypical parkinsonian syndrome comprising two main clinical subtypes: Richardson's syndrome (RS), characterized by prominent postural instability, supranuclear vertical gaze palsy and frontal dysfunction; and PSP-parkinsonism (PSP-P) which is characterized by an asymmetric onset, tremor and moderate initial therapeutic response to levodopa. The early clinical features of PSP-P are often difficult to discern from idiopathic Parkinson's disease (PD), and other atypical parkinsonian disorders, including multiple system atrophy (MSA) and corticobasal syndrome (CBS). In addition, rare PSP subtypes may be overlooked or misdiagnosed if there are atypical features present. The differentiation between atypical parkinsonian disorders and PD is important because the prognoses are different, and there are different responses to therapy. Structural and functional imaging, although currently of limited diagnostic value for individual use in early disease, may contribute valuable information in the differential diagnosis of PSP. A growing body of evidence shows the importance of CSF biomarkers in distinguishing between atypical parkinsonian disorders particularly early in their course when disease-modifying therapies are becoming available. However, specific diagnostic CSF biomarkers have yet to be identified. In the absence of reliable disease-specific markers, we provide an update of the recent literature on the assessment of clinical symptoms, pathology, neuroimaging and biofluid markers that might help to distinguish between these overlapping conditions early in the course of the disease.

  17. Progress in Rett Syndrome: from discovery to clinical trials.

    PubMed

    Percy, Alan K

    2016-09-01

    Fifty years ago, Andreas Rett described a disorder in 22 females featuring prominent regression of fine motor and communication skills, cognitive impairment, stereotypic movements, periodic breathing, and gait abnormalities. This disorder became known as Rett syndrome (RTT) following the report of Hagberg et al. in 1983. Although RTT was scarcely recognized at that time in the United States, here the efforts of Rett and Hagberg led to rapid progress in recognition and diagnosis, a clearer understanding of its clinical and pathological underpinnings, and, ultimately, identification of mutations in the methyl-CpG-binding protein 2 (MECP2) gene as the primary cause of this unique and challenging neurodevelopmental disorder. Thereafter, a natural history study and critical translational research in animal models paved the way for potential disease-modifying agents to be assessed in human clinical trials. To be successful, the energies of the international community at all levels, including researchers in clinical and basic science, funding agencies, pharmaceutical companies, patient advocates, and, above all, parents and their children are essential. Otherwise, hopes for effective treatment, if not, a cure, will remain unfulfilled.

  18. Outlier detection method in linear regression based on sum of arithmetic progression.

    PubMed

    Adikaram, K K L B; Hussein, M A; Effenberger, M; Becker, T

    2014-01-01

    We introduce a new nonparametric outlier detection method for linear series, which requires no missing or removed data imputation. For an arithmetic progression (a series without outliers) with n elements, the ratio (R) of the sum of the minimum and the maximum elements and the sum of all elements is always 2/n : (0,1]. R ≠ 2/n always implies the existence of outliers. Usually, R < 2/n implies that the minimum is an outlier, and R > 2/n implies that the maximum is an outlier. Based upon this, we derived a new method for identifying significant and nonsignificant outliers, separately. Two different techniques were used to manage missing data and removed outliers: (1) recalculate the terms after (or before) the removed or missing element while maintaining the initial angle in relation to a certain point or (2) transform data into a constant value, which is not affected by missing or removed elements. With a reference element, which was not an outlier, the method detected all outliers from data sets with 6 to 1000 elements containing 50% outliers which deviated by a factor of ±1.0e - 2 to ±1.0e + 2 from the correct value.

  19. A progressive transmission image coder using linear phase uniform filterbanks as block transforms.

    PubMed

    Tran, T D; Nguyen, T Q

    1999-01-01

    This paper presents a novel image coding scheme using M-channel linear phase perfect reconstruction filterbanks (LPPRFBs) in the embedded zerotree wavelet (EZW) framework introduced by Shapiro (1993). The innovation here is to replace the EZWs dyadic wavelet transform by M-channel uniform-band maximally decimated LPPRFBs, which offer finer frequency spectrum partitioning and higher energy compaction. The transform stage can now be implemented as a block transform which supports parallel processing and facilitates region-of-interest coding/decoding. For hardware implementation, the transform boasts efficient lattice structures, which employ a minimal number of delay elements and are robust under the quantization of lattice coefficients. The resulting compression algorithm also retains all the attractive properties of the EZW coder and its variations such as progressive image transmission, embedded quantization, exact bit rate control, and idempotency. Despite its simplicity, our new coder outperforms some of the best image coders published previously in the literature, for almost all test images (especially natural, hard-to-code ones) at almost all bit rates.

  20. Primary progressive aphasia: linguistic patterns and clinical variants.

    PubMed

    Silveri, Maria Caterina; Pravatà, Emanuele; Brita, Anna Clelia; Improta, Erika; Ciccarelli, Nicoletta; Rossi, Paola; Colosimo, Cesare

    2014-08-01

    We investigated whether primary progressive aphasias (PPA) reflect non-random degradation of linguistic dimensions that might be supported by different neural subsystems and to what extent this degradation contributes to the emergence of clinical entities: semantic (S), logopenic (L) and nonfluent (NF) aphasia; apraxia of speech was also considered if associated with language disorders (AOS/aph). Forty-two aphasic patients are reported. Two main definable patterns of linguistic deficits tended to emerge that corresponded with identifiable patterns of brain atrophy, and probably diseases: the S variant, which principally expresses the impact of a "deep" cognitive (semantic) disorder on language, and AOS/aph in which "peripheral" executive components play a significant role. By contrast, NF aphasia emerged as a heterogeneous variant due to disorganization of various dimensions within the linguistic domain, that assumes different patterns depending on the differential distribution of atrophy in the perisylvian regions.

  1. Classifying the Progression of Ductal Carcinoma from Single-Cell Sampled Data via Integer Linear Programming: A Case Study.

    PubMed

    Catanzaro, Daniele; Shackney, Stanley E; Schaffer, Alejandro A; Schwartz, Russell

    2016-01-01

    Ductal Carcinoma In Situ (DCIS) is a precursor lesion of Invasive Ductal Carcinoma (IDC) of the breast. Investigating its temporal progression could provide fundamental new insights for the development of better diagnostic tools to predict which cases of DCIS will progress to IDC. We investigate the problem of reconstructing a plausible progression from single-cell sampled data of an individual with synchronous DCIS and IDC. Specifically, by using a number of assumptions derived from the observation of cellular atypia occurring in IDC, we design a possible predictive model using integer linear programming (ILP). Computational experiments carried out on a preexisting data set of 13 patients with simultaneous DCIS and IDC show that the corresponding predicted progression models are classifiable into categories having specific evolutionary characteristics. The approach provides new insights into mechanisms of clonal progression in breast cancers and helps illustrate the power of the ILP approach for similar problems in reconstructing tumor evolution scenarios under complex sets of constraints.

  2. Clinical correlations of microstructural changes in progressive supranuclear palsy.

    PubMed

    Tessitore, Alessandro; Giordano, Alfonso; Caiazzo, Giuseppina; Corbo, Daniele; De Micco, Rosa; Russo, Antonio; Liguori, Sara; Cirillo, Mario; Esposito, Fabrizio; Tedeschi, Gioacchino

    2014-10-01

    In patients with progressive supranuclear palsy (PSP), previous reports have shown a severe white matter (WM) damage involving supra and infratentorial regions including cerebellum. In the present study, we investigated potential correlations between WM integrity loss and clinical-cognitive features of patients with PSP. By using magnetic resonance imaging and diffusion tensor imaging with tract based spatial statistic analysis, we analyzed WM volume in 18 patients with PSP and 18 healthy controls (HCs). All patients and HCs underwent a detailed clinical and neuropsychological evaluation. Relative to HCs, patients with PSP showed WM changes encompassing supra and infratentorial areas such as corpus callosum, fornix, midbrain, inferior fronto-occipital fasciculus, anterior thalamic radiation, superior cerebellar peduncle, superior longitudinal fasciculus, uncinate fasciculus, cingulate gyrus, and cortico-spinal tract bilaterally. Among different correlations between motor-cognitive features and WM structural abnormalities, we detected a significant association between fronto-cerebellar WM loss and executive cognitive impairment in patients with PSP. Our findings, therefore, corroborate the hypothesis that cognitive impairment in PSP may result from both "intrinsic" and "extrinsic" frontal lobe dysfunction, likely related to cerebellar disconnection.

  3. Measuring progress in clinical governance: assessing the reliability and validity of the Clinical Governance Climate Questionnaire.

    PubMed

    Freeman, T

    2003-11-01

    Despite a lack of conceptual clarity, the importance of cultural change to clinical governance is widely accepted. While generic measures of organizational performance, culture and climate are available, their relationship to clinical governance is unclear. Consequently, there is currently no valid and reliable measure of clinical governance climate. This study aimed to address the deficiency by reducing a pool of clinical governance climate indicators developed via previous qualitative research, describing a latent factor structure and assessing the internal consistency and external validity of the factor model. The resultant instrument, the Clinical Governance Climate Questionnaire (CGCQ), attained high internal consistency and external (discriminant and construct) validity in a study population of healthcare Trust staff. It consists of 60 items distributed across six sub-scales of clinical governance: planned and integrated quality improvement; proactive risk management; absence of unjust blame and punishment; working with colleagues; training and development; and organizational learning. The measure enables those charged with leading the clinical governance agenda in UK healthcare organizations to assess the progress of organizational development initiatives, highlighting areas requiring particular attention. They might also be of interest to those concerned about the negative unintended consequences of performance management.

  4. Clinical characteristics and progression of liver abscess caused by toxocara

    PubMed Central

    Ha, Kyung Ho; Song, Jung Eun; Kim, Byung Seok; Lee, Chang Hyeong

    2016-01-01

    AIM: To evaluate the clinical characteristics and progression of liver abscess caused by toxocara. METHODS: We retrospectively reviewed the medical records of patients with serum IgG antibody to Toxocara canis and liver abscess diagnosed using abdominal computed tomography between February 2010 and February 2015. Among 84 patients exhibiting serum IgG antibody to Toxocara canis, 34 patients were diagnosed with liver asbscess and treated with albendazole. A follow-up period of 1 year was conducted. RESULTS: Mean patient age was 53 (34-79) years, with 26 (76.5%) patients being male. Twenty-one (61.7%) patients were moderate or heavy drinkers, 23 (67.6%) patients had a history of eating raw meat or liver and 6 (17.6%) patients owned pet dogs or cats. Main patient symptoms consisted of right upper quadrant pain, fever, and fatigue; 18 (52.9%) patients, however, presented with no symptoms. Lung involvement was detected in 444 (11.7%) patients. The eosinophil count increased in 29 (85.3%) patients at initial diagnosis, and decreased in most patients after albendazole treatment. The initial serum IgE level increased in 25 (73.5%) patients, but exhibited various response levels after albendazole treatment. Liver abscess formation improved in all patients. CONCLUSION: The liver abscess was improved with albendazole treatment. PMID:27366302

  5. [Inflammatory linear verrucous epidermal nevus. Clinical and histopathological aspects of 7 cases].

    PubMed

    Kuri, R; Ruíz Maldonado, R; Tamayo, L

    1978-01-01

    The inflammatory linear verrucous nevus is a recently described variety of epidermal nevus clinically and histologically characterized by an inflammatory component. The lesion stars at birth or at early age, pruritus is constant. Histologically the picture is psoriasiform. The therapeutic response is poor. Seven cases are presented. Associated extracutaneous alterations were presented in four of them.

  6. Body mass index, weight change, and clinical progression in mild cognitive impairment and Alzheimer disease.

    PubMed

    Besser, Lilah M; Gill, Dawn P; Monsell, Sarah E; Brenowitz, Willa; Meranus, Dana H; Kukull, Walter; Gustafson, Deborah R

    2014-01-01

    The speed and severity of clinical progression after Alzheimer disease (AD) diagnosis varies and depends on multiple factors, most not well elucidated. We assessed whether body mass index (BMI) and 1-year weight change (WC) are associated with clinical progression in amnestic mild cognitive impairment (aMCI) and early-stage AD. Longitudinal data comprising 2268 aMCI and 1506 AD participants in the National Alzheimer's Coordinating Center's Uniform Data Set were used to examine nuances of clinical progression by BMI and WC, as well as potential variations in associations by age, sex, BMI (WC model), or apolipoprotein E genotype. In aMCI, high BMI (vs. moderate BMI) was associated with slower progression; weight loss (vs. no WC) was associated with faster progression. In AD, no significant differences were observed in clinical progression by BMI or WC. The association between BMI and clinical progression varied significantly by apolipoprotein E genotype in AD, and the association between WC and clinical progression varied significantly by sex and BMI in aMCI. Baseline BMI and 1-year WC in late life may serve as early prognostic indicators in aMCI and early-stage AD. If replicated, these results may help in counseling patients on anticipated clinical progression and suggest windows of opportunity for intervention.

  7. Clinical trials in progressive multiple sclerosis: lessons learned and future perspectives

    PubMed Central

    Ontaneda, Daniel; Fox, Robert J.; Chataway, Jeremy

    2015-01-01

    Progressive multiple sclerosis is characterized by the gradual accrual of disability independent of relapses and can occur with disease onset (primary progressive) or preceded by a relapsing disease course (secondary progressive). An effective disease modifying treatment for progressive multiple sclerosis has not been identified, and the results of clinical trials to date have been generally disappointing. Ongoing advances in our understanding of pathogenesis, identification of novel targets for neuro-protection, and improved outcome measures have the potential to lead to effective treatments for progressive multiple sclerosis. In this review lessons learned from previous clinical trials and perspectives from current trials in progressive multiple sclerosis are summarized. Promising clinical, imaging, and biological markers will also be reviewed, along with novel clinical trial designs. PMID:25772899

  8. [Clinical types of FTLD: progressive nonfluent aphasia; comparative discussions on the associated clinical presentations].

    PubMed

    Fukui, Toshiya

    2009-11-01

    Progressive nonfluent aphasia (PNFA) is one of the 3 clinical presentations of frontotemporal lobar degeneration (FTLD), the other 2 being frontotemporal dementia and semantic dementia (SD). PNFA and SD, both representing relentlessly progressive language impairment in the realm of FTLD, may share a large part with primary progressive aphasia (PPA). A salient distinction between PPA and PNFA or SD is that PPA includes another clinical type, namely, logopenic/phonemic aphasia (LPA), which is not represented in FTLD. This is primarily because LPA is usually caused by Alzheimer's disease (AD) and the brunt of the lesion is localized at the left temporo-parietal region of the brain. Further, PNFA/SD should be limited to the clinical consequencies of FTLD while PPA is more generous with regard to its causal pathology. By definition, PNFA is an expressive language impairment which is characterized by effortful speech, phonemic errors, grammatical impairment, and word-finding difficulties. Reading and writing may be comparatively impaired. Comprehension of single word meaning is normal, while comprehension of sentencies may sometimes be impaired. PNFA should be differentiated from SD, LPA, and pure progressive apraxia of speech (AOS or alternatively referred to as aphemia or anarthria). SD may be distinguished from PNFA by virtue of its fluency, characteristic loss of word meaning and absence of agrammatism. LPA is similar to PNFA, yet differs in that there is preservation of grammatical skills and speech motor function that is devoid of AOS and/or dysarthria. AOS is an impairment at the level of speech motor programming without language impairment. Thus, there may be a double dissociation between AOS and PNFA i. e., PNFA may or may not accompany AOS and vice versa. PNFA is associated with a localized lesion in the left frontotemporal area of the brain. Immunohistochemical investigations have revealed that ubiquitin/TAR DNA binding protein-43 (TDA-43) positive and tau

  9. Alzheimer's disease progression model based on integrated biomarkers and clinical measures

    PubMed Central

    Qiu, Yue; Li, Liang; Zhou, Tian-yan; Lu, Wei

    2014-01-01

    Aim: Biomarkers and image markers of Alzheimer's disease (AD), such as cerebrospinal fluid Aβ42 and p-tau, are effective predictors of cognitive decline or dementia. The aim of this study was to integrate these markers with a disease progression model and to identify their abnormal ranges. Methods: The data of 395 participants, including 86 normal subjects, 108 early mild cognitive impairment (EMCI) subjects, 120 late mild cognitive impairment (LMCI) subjects, and 81 AD subjects were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. For the participants, baseline and long-term data on cerebrospinal fluid Aβ42 and p-tau, hippocampal volume, and ADAS-cog were available. Various linear and nonlinear models were tested to determine the associations among the ratio of Aβ42 to p-tau (the Ratio), hippocampal volume and ADAS-cog. Results: The most likely models for the Ratio, hippocampal volume, and ADAS-cog (logistic, Emax, and linear models, respectively) were used to construct the final model. Baseline disease state had an impact on all the 3 endpoints (the Ratio, hippocampal volume, and ADAS-cog), while APOEε4 genotype and age only influence the Ratio and hippocampal volume. Conclusion: The Ratio can be used to identify the disease stage for an individual, and clinical measures integrated with the Ratio improve the accuracy of mild cognitive impairment (MCI) to AD conversion forecasting. PMID:25088003

  10. Development of an evidence-based clinical practice guideline on linear growth measurement of children.

    PubMed

    Foote, Jan M; Brady, Linda H; Burke, Amber L; Cook, Jennifer S; Dutcher, Mary E; Gradoville, Kathleen M; Groos, Jennifer A; Kinkade, Kimberly M; Meeks, Reylon A; Mohr, Pamela J; Schultheis, Debra S; Walker, Brenda S; Phillips, Kirk T

    2011-08-01

    Growth is an important indicator of child health; however, measurements are frequently inaccurate and unreliable. This article reviews the literature on linear growth measurement error and describes methods used to develop and evaluate an evidence-based clinical practice guideline on the measurement of recumbent length and stature of infants, children, and adolescents. Systematic methods were used to identify evidence to answer clinical questions about growth measurement. A multidisciplinary team critically appraised and synthesized the evidence to develop clinical practice recommendations using an evidence-based practice rating scheme. The guideline was prospectively evaluated through internal and external reviews and a pilot study to ensure its validity and reliability. Adoption of the clinical practice guideline can improve the accuracy and reliability of growth measurement data.

  11. [The first linear electron accelerator Therac 15-Saturne in clinical service. 2. Measurement of electron radiation].

    PubMed

    Strauch, B

    1985-09-01

    Therac 15-Saturne is a linear accelerator for photon and electron radiation with a double scattering screen system. It has proved its worth during more than three years of clinical use. The dosimetric data of both kinds of radiation correspond to the international requirements for modern therapy units. The trimmer system for electron radiation is equipped with a continuous field size adjustment device for the whole range of field sizes. Thus a fast and precise adjustment is possible without any changing of tubes.

  12. PROGRESS WITH THE JLC/NLC X-BAND LINEAR COLLIDER DESIGN

    SciTech Connect

    Raubenheimer, Tor O

    2000-11-06

    An electron/positron linear collider with a center-of-mass energy between 0.5 and 1 TeV would be an important complement to the physics program of the LHC in the next decade. The Next Linear Collider (NLC) is being designed by a US collaboration (FNAL, LBNL, LLNL, and SLAC) which is working closely with the Japanese collaboration that is designing the Japanese Linear Collider (JLC). This paper will discuss the technical difficulties encountered as well as the changes that have been made to the NLC design over the last year. These changes include improvements to the X-band rf system as well as modifications to the beam delivery system. The net effect has been to reduce the length of the collider from about 32 km to 25 km and to reduce the number of klystrons and modulators by a factor of two. Together these lead to significant cost savings.

  13. Prognostic Factors Toward Clinically Relevant Radiographic Progression in Patients With Rheumatoid Arthritis in Clinical Practice

    PubMed Central

    Koga, Tomohiro; Okada, Akitomo; Fukuda, Takaaki; Hidaka, Toshihiko; Ishii, Tomonori; Ueki, Yukitaka; Kodera, Takao; Nakashima, Munetoshi; Takahashi, Yuichi; Honda, Seiyo; Horai, Yoshiro; Watanabe, Ryu; Okuno, Hiroshi; Aramaki, Toshiyuki; Izumiyama, Tomomasa; Takai, Osamu; Miyashita, Taiichiro; Sato, Shuntaro; Kawashiri, Shin-ya; Iwamoto, Naoki; Ichinose, Kunihiro; Tamai, Mami; Origuchi, Tomoki; Nakamura, Hideki; Aoyagi, Kiyoshi; Eguchi, Katsumi; Kawakami, Atsushi

    2016-01-01

    Abstract To determine prognostic factors of clinically relevant radiographic progression (CRRP) in patients with rheumatoid arthritis (RA) in clinical practice. We performed a multicenter prospective study in Japan of biological disease-modifying antirheumatic drug (bDMARD)-naive RA patients with moderate to high disease activity treated with conventional synthetic DMARDs (csDMARDs) at study entry. We longitudinally observed 408 patients for 1 year and assessed disease activity every 3 months. CRRP was defined as yearly progression of modified total Sharp score (mTSS) > 3.0 U. We also divided the cohort into 2 groups based on disease duration (<3 vs ≥3 years) and performed a subgroup analysis. CRRP was found in 10.3% of the patients. A multiple logistic regression analysis revealed that the independent variables to predict the development of CRRP were: CRP at baseline (0.30 mg/dL increase, 95% confidence interval [CI] 1.01–1.11), time-integrated Disease Activity Score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) during the 1 year postbaseline (12.4-unit increase, 95%CI 1.17–2.59), RA typical erosion at baseline (95%CI 1.56–21.1), and the introduction of bDMARDs (95%CI 0.06–0.38). The subgroup analysis revealed that time-integrated DAS28-ESR is not a predictor whereas the introduction of bDMARDs is a significant protective factor for CRRP in RA patients with disease duration <3 years. We identified factors that could be used to predict the development of CRRP in RA patients treated with DMARDs. These variables appear to be different based on the RA patients’ disease durations. PMID:27124044

  14. 1!Serum urate as a predictor of clinical and radiographic progression in Parkinson’s disease

    PubMed Central

    Schwarzschild, Michael A.; Schwid, Steven R.; Marek, Kenneth; Watts, Arthur; Lang, Anthony E.; Oakes, David; Shoulson, Ira; Ascherio, Alberto

    2008-01-01

    Context Prospective epidemiological studies consistently indicate that Parkinson’s disease (PD) risk declines with increasing serum urate. Objective To determine whether serum urate, a purine metabolite and potent antioxidant, predicts prognosis in PD. Design, Setting, and Participants Prospective study among 804 subjects with early PD enrolled in the PRECEPT study, a clinical trial of the neuroprotectant potential of CEP-1347, conducted between April 2002 and August 2005 (average follow-up time 21.4 months). Main Outcome Measures The primary study endpoint was progression to clinical disability sufficient to warrant dopaminergic therapy. Cox proportional hazards models were used to estimate the hazard ratio (HR) of reaching endpoint according to quintiles of baseline serum urate, adjusting for gender, age and other potential covariates. Change in striatal uptake of [123I]β-CIT, a marker for the presynaptic dopamine transporter, was assessed with linear regression for a subset of 399 subjects. Results The adjusted HR of reaching endpoint declined with increasing baseline concentrations of urate; subjects in the top quintile reached the endpoint at only half the rate of subjects in the bottom quintile (HR=0.51; 95% CI: 0.37 to 0.72; p=0.0002). This association was markedly stronger in men (HR=0.39; 95% CI: 0.26 to 0.60; p<0.0001) than in women (HR=0.77; 95% CI: 0.39 to 1.50; p=0.4). The percent loss in striatal [123I]β-CIT uptake also improved with increasing serum urate concentrations (overall p for trend=0.002; men, p=0.0008; women, p= 0.4). Conclusion These findings identify serum urate as the first molecular factor directly linked to the progression of typical PD and suggest that targeting urate or its determinants could be an effective disease modifying therapy in PD. PMID:18413464

  15. A novel method for the measurement of linear body segment parameters during clinical gait analysis.

    PubMed

    Geil, Mark D

    2013-09-01

    Clinical gait analysis is a valuable tool for the understanding of motion disorders and treatment outcomes. Most standard models used in gait analysis rely on predefined sets of body segment parameters that must be measured on each individual. Traditionally, these parameters are measured using calipers and tape measures. The process can be time consuming and is prone to several sources of error. This investigation explored a novel method for rapid recording of linear body segment parameters using magnetic-field based digital calipers commonly used for a different purpose in prosthetics and orthotics. The digital method was found to be comparable to traditional in all linear measures and data capture was significantly faster with the digital method, with mean time savings for 10 measurements of 2.5 min. Digital calipers only record linear distances, and were less accurate when diameters were used to approximate limb circumferences. Experience in measuring BSPs is important, as an experienced measurer was significantly faster than a graduate student and showed less difference between methods. Comparing measurement of adults vs. children showed greater differences with adults, and some method-dependence. If the hardware is available, digital caliper measurement of linear BSPs is accurate and rapid.

  16. The Clinical Use of Hypnotic Regression and Progression in Psychotherapy.

    ERIC Educational Resources Information Center

    Goldberg, Bruce

    1990-01-01

    Discusses concept of time in therapy, presenting theoretical and clinical foundations to illustrate the validity of guiding patients into past lives and future lifetimes through hypnosis to resolve self-defeating sequences. (Author/TE)

  17. Progress through Collaboration - Office of Cancer Clinical Proteomics Research

    Cancer.gov

    The National Cancer Institute (NCI), through the Office of Cancer Clinical Proteomics Research (OCCPR), has signed two Memorandums of Understanding (MOUs) in the areas of sharing proteomics reagents and protocols and also in regulatory science.

  18. Progressive Magnetic Resonance Image Reconstruction Based on Iterative Solution of a Sparse Linear System

    PubMed Central

    Fahmy, Ahmed S.; Gabr, Refaat E.; Heberlein, Keith; Hu, Xiaoping P.

    2006-01-01

    Image reconstruction from nonuniformly sampled spatial frequency domain data is an important problem that arises in computed imaging. Current reconstruction techniques suffer from limitations in their model and implementation. In this paper, we present a new reconstruction method that is based on solving a system of linear equations using an efficient iterative approach. Image pixel intensities are related to the measured frequency domain data through a set of linear equations. Although the system matrix is too dense and large to solve by direct inversion in practice, a simple orthogonal transformation to the rows of this matrix is applied to convert the matrix into a sparse one up to a certain chosen level of energy preservation. The transformed system is subsequently solved using the conjugate gradient method. This method is applied to reconstruct images of a numerical phantom as well as magnetic resonance images from experimental spiral imaging data. The results support the theory and demonstrate that the computational load of this method is similar to that of standard gridding, illustrating its practical utility. PMID:23165034

  19. Accuracy of Linear Measurements Using Cone Beam Computed Tomography in Comparison with Clinical Measurements

    PubMed Central

    Rokn, Amir Reza; Hashemi, Kazem; Akbari, Solmaz; Kharazifard, Mohammad Javad; Barikani, Hamidreza; Panjnoosh, Mehrdad

    2016-01-01

    Objectives: This study sought to evaluate the accuracy and errors of linear measurements of mesiodistal dimensions of Kennedy Class III edentulous space using cone beam computed tomography (CBCT) in comparison with clinical measurements. Materials and Methods: Nineteen Kennedy Class III dental arches were evaluated. An impression was made of each dental arch and poured with dental stone. The distance was measured on dental cast using a digital Vernier caliper with an accuracy of 0.1mm and on CBCT scans. Finally, the linear mesiodistal measurements were compared and the accuracy of CBCT technique was evaluated by calculating absolute value of errors, intra-class correlation coefficient and simple linear regression model. Results: In comparison with the cast method, estimation of size on CBCT scans had an error of −8.46% (underestimation) to 5.21% (overestimation). In 26.5% of the cases, an accepted error of ±1% was found. The absolute value of errors was found to be in the range of 0.21–8.46mm with an average value of 2.86 ±2.30mm. Conclusions: Although the measurements revealed statistically significant differences, this does not indicate a lower accuracy for the CBCT technique. In fact, CBCT can provide some information as a paraclinical tool and the clinician can combine these data with clinical data and achieve greater accuracy. Undoubtedly, calibration of data collected by clinical and paraclinical techniques and the clinician’s expertise in use of CBCT software programs can increase the accuracy of implant placement. PMID:28127327

  20. Tendon tissue engineering: progress, challenges, and translation to the clinic.

    PubMed

    Shearn, J T; Kinneberg, K R; Dyment, N A; Galloway, M T; Kenter, K; Wylie, C; Butler, D L

    2011-06-01

    The tissue engineering field has made great strides in understanding how different aspects of tissue engineered constructs (TECs) and the culture process affect final tendon repair. However, there remain significant challenges in developing strategies that will lead to a clinically effective and commercially successful product. In an effort to increase repair quality, a better understanding of normal development, and how it differs from adult tendon healing, may provide strategies to improve tissue engineering. As tendon tissue engineering continues to improve, the field needs to employ more clinically relevant models of tendon injury such as degenerative tendons. We need to translate successes to larger animal models to begin exploring the clinical implications of our treatments. By advancing the models used to validate our TECs, we can help convince our toughest customer, the surgeon, that our products will be clinically efficacious. As we address these challenges in musculoskeletal tissue engineering, the field still needs to address the commercialization of products developed in the laboratory. TEC commercialization faces numerous challenges because each injury and patient is unique. This review aims to provide tissue engineers with a summary of important issues related to engineering tendon repairs and potential strategies for producing clinically successful products.

  1. Transfinite element methodology for nonlinear/linear transient thermal modelling/analysis - Progress and recent advances

    NASA Technical Reports Server (NTRS)

    Tamma, Kumar K.; Railkar, Sudhir B.

    1988-01-01

    The 'transfinite element method' (TFEM) proposed by Tamma and Railkar (1987 and 1988) for the analysis of linear and nonlinear heat-transfer problems is described and demonstrated. The TFEM combines classical Galerkin and transform approaches with state-of-the-art FEMs to obtain a flexible hybrid modeling scheme. The fundamental principles of the TFEM and the derivation of the governing equations are reviewed, and numerical results for sample problems are presented in extensive graphs and briefly characterized. Problems analyzed include a square plate with a hole, a rectangular plate with natural and essential boundary conditions and varying thermal conductivity, the Space Shuttle thermal protection system, a bimaterial plate subjected to step temperature variations, and solidification in a semiinfinite liquid slab.

  2. [Overview of Clinical Progress in Pulmonary Ground-glass Nodules].

    PubMed

    Li, Lei; Liu, Dan; Zhu, Yingying; Li, Weimin

    2016-02-01

    Ground-glass nodules (GGNs) was a special type of pulmonary nodules. With the progress of high resolution CT (HRCT), it achieved a higher positive rate and attracted much attention in recent years. For lacking characteristic symptoms, the early diagnosis of lung cancer was difficult even nowadays. However, it had been proved that GGNs was well associated with lung cancer in previous studies. Therefore, optimized managements of GGNs could help diagnosis and treatments of lung cancer at early stage. In this review, we summarized the definition, classification, imaging characteristics, growing history, molecular pathological features and suggested managements of GGNs.

  3. Defining natural history: assessment of the ability of college students to aid in characterizing clinical progression of Niemann-Pick disease, type C.

    PubMed

    Shin, Jenny; Epperson, Katrina; Yanjanin, Nicole M; Albus, Jennifer; Borgenheimer, Laura; Bott, Natalie; Brennan, Erin; Castellanos, Daniel; Cheng, Melissa; Clark, Michael; Devany, Margaret; Ensslin, Courtney; Farivari, Nina; Fernando, Shanik; Gabriel, Lauren; Gallardo, Rani; Castleman, Moriah; Gutierrez, Olimpia; Herschel, Allison; Hodge, Sarah; Horst, Anne; Howard, Mary; James, Evan; Jones, Lindsey; Kearns, Mary; Kelly, Mary; Kim, Christine; Kiser, Kinzie; Klazura, Gregory; Knoedler, Chris; Kolbus, Emily; Lange, Lauren; Lee, Joan; Li, Eileena; Lu, Wei; Luttrell, Andrew; Ly, Emily; McKeough, Katherine; McSorley, Brianna; Miller, Catherine; Mitchell, Sean; Moon, Abbey; Moser, Kevin; O'Brien, Shane; Olivieri, Paula; Patzwahl, Aaron; Pereira, Marie; Pymento, Craig; Ramelb, Erin; Ramos, Bryce; Raya, Teresa; Riney, Stephen; Roberts, Geoff; Robertshaw, Mark; Rudolf, Frannie; Rund, Samuel; Sansone, Stephanie; Schwartz, Lindsay; Shay, Ryan; Siu, Edwin; Spear, Timothy; Tan, Catherine; Truong, Marisa; Uddin, Mairaj; Vantrieste, Jennifer; Veloz, Omar; White, Elizabeth; Porter, Forbes D; Haldar, Kasturi

    2011-01-01

    Niemann-Pick Disease, type C (NPC) is a fatal, neurodegenerative, lysosomal storage disorder. It is a rare disease with broad phenotypic spectrum and variable age of onset. These issues make it difficult to develop a universally accepted clinical outcome measure to assess urgently needed therapies. To this end, clinical investigators have defined emerging, disease severity scales. The average time from initial symptom to diagnosis is approximately 4 years. Further, some patients may not travel to specialized clinical centers even after diagnosis. We were therefore interested in investigating whether appropriately trained, community-based assessment of patient records could assist in defining disease progression using clinical severity scores. In this study we evolved a secure, step wise process to show that pre-existing medical records may be correctly assessed by non-clinical practitioners trained to quantify disease progression. Sixty-four undergraduate students at the University of Notre Dame were expertly trained in clinical disease assessment and recognition of major and minor symptoms of NPC. Seven clinical records, randomly selected from a total of thirty seven used to establish a leading clinical severity scale, were correctly assessed to show expected characteristics of linear disease progression. Student assessment of two new records donated by NPC families to our study also revealed linear progression of disease, but both showed accelerated disease progression, relative to the current severity scale, especially at the later stages. Together, these data suggest that college students may be trained in assessment of patient records, and thus provide insight into the natural history of a disease.

  4. Liver transplantation for progressive familial intrahepatic cholestasis: clinical and histopathological findings, outcome and impact on growth.

    PubMed

    Aydogdu, Sema; Cakir, Murat; Arikan, C; Tumgor, Gokhan; Yuksekkaya, Hasan Ali; Yilmaz, Funda; Kilic, Murat

    2007-09-01

    In this study, we analyze the demographic features, clinical and histopathological findings in patients who underwent liver transplantation for progressive familial intrahepatic cholestasis. We also analyze outcome and impact of liver transplantation on growth and bone mineral content. Most of the patients were presented with jaundice mainly beginning within the first six months. At the time of initial admission; eight patients had short stature (height SD score<2), and four patients had weight SD score<2. Liver transplantation were performed at the age of 43.2+/-27 months (range 9 to 96 months), 6.5+/-3.5 months later after the first admission. Infection, surgical complications and osmotic diarrhea associated with severe metabolic acidosis were noted in 41.4%, 16.6% and 33.3%, respectively. One patient developed posttransplant lymphoproliferative disorder. Overall; 1 year graft and patient survival was 69.2% and 75%, respectively. At the end of the 1st year only 2 patients had height SD score<2. Linear regression of height gain against increase in total body BMD measured at the time of transplantation and 1 year after liver transplantation gave a coefficient r=0.588 (p=0.074). No correlation was found between the height gain and age and PELD score at time of transplantation, and no difference was noted between the sexes and donor type. Liver transplantation is effective treatment modality with good outcome and little morbidity, and increases the growth acceleration in patients with PFIC associated with cirrhosis.

  5. A LINEAR ACTUATED TORSIONAL DEVICE TO REPLICATE CLINICALLY RELEVANT SPIRAL FRACTURES IN LONG BONES

    PubMed Central

    Edwards, W. Brent; Troy, Karen L.

    2012-01-01

    To better understand the mechanisms underlying spiral fracture we would like to carry out biomechanical tests of long bones loaded in torsion to failure. A device was fabricated to perform torsional tests of long bones using a single-axis linear actuator. The principal operation of the device was to transform the vertical displacement of a material testing machine’s linear actuator into rotational movement using a spur gear and rack system. Accuracy and precision of the device were quantified using cast-acrylic rods with known torque-rotation behavior. Cadaveric experimentation was used to replicate a clinically relevant spiral fracture in eleven human proximal tibiae; strain gage data were recorded for a single specimen. The device had an experimental error less than 0.2 Nm and was repeatable to within 0.3%. Strain gage data were in line with those expected from pure torsion and the cadaveric tibiae illustrated spiral fractures at ultimate torque and rotation values of 130.6 ± 53.2 Nm and 8.3 ± 1.5°, respectively. Ultimate torque was highly correlated with DXA assessed bone mineral density (r = 0.87; p<0.001). The device presented is applicable to any torsional testing of long bone when only a single-axis linear actuator is available. PMID:23025174

  6. A linear-actuated torsional device to replicate clinically relevant spiral fractures in long bones.

    PubMed

    Edwards, W Brent; Troy, Karen L

    2012-09-01

    To better understand the mechanisms underlying spiral fracture we would like to carry out biomechanical tests of long bones loaded in torsion to failure. A device was fabricated to perform torsional tests of long bones using a single-axis linear actuator. The principal operation of the device was to transform the vertical displacement of a material testing machine's linear actuator into rotational movement using a spur gear and rack system. Accuracy and precision of the device were quantified using cast-acrylic rods with known torque-rotation behavior. Cadaveric experimentation was used to replicate a clinically relevant spiral fracture in eleven human proximal tibiae; strain-gage data were recorded for a single specimen. The device had an experimental error of less than 0.2 Nm and was repeatable to within 0.3%. Strain gage data were in line with those expected from pure torsion and the cadaveric tibiae illustrated spiral fractures at ultimate torque and rotation values of 130.6 +/- 53.2 Nm and 8.3 +/- 1.5 degrees, respectively. Ultimate torque was highly correlated with DXA assessed bone mineral density (r = 0.87; p < 0.00 1). The device presented is applicable to any torsional testing of long bone when only a single-axis linear actuator is available.

  7. Linear Atom Guides: Guiding Rydberg Atoms and Progress Toward an Atom Laser

    NASA Astrophysics Data System (ADS)

    Traxler, Mallory A.

    In this thesis, I explore a variety of experiments within linear, two-wire, magnetic atom guides. Experiments include guiding of Rydberg atoms; transferring between states while keeping the atoms contained within the guide; and designing, constructing, and testing a new experimental apparatus. The ultimate goal of the atom guiding experiments is to develop a continuous atom laser. The guiding of 87Rb 59D5/2 Rydberg atoms is demonstrated. The evolution of the atoms is driven by the combined effects of dipole forces acting on the center-of-mass degree of freedom as well as internal-state transitions. Time delayed microwave and state-selective field ionization, along with ion detection, are used to investigate the evolution of the internal-state distribution as well as the Rydberg atom motion while traversing the guide. The observed decay time of the guided-atom signal is about five times that of the initial state. A population transfer between Rydberg states contributes to this lengthened lifetime, and also broadens the observed field ionization spectrum. The population transfer is attributed to thermal transitions and, to a lesser extent, initial state-mixing due to Rydberg-Rydberg collisions. Characteristic signatures in ion time-of-flight signals and spatially resolved images of ion distributions, which result from the coupled internal-state and center-of-mass dynamics, are discussed. Some groups have used a scheme to make BECs where atoms are optically pumped from one reservoir trap to a final state trap, irreversibly transferring those atoms from one trap to the other. In this context, transfer from one guided ground state to another is studied. In our setup, before the atoms enter the guide, they are pumped into the | F = 1, mF = --1> state. Using two repumpers, one tuned to the F = 1 → F' = 0 transition (R10) and the other tuned to the F = 1 → F' = 2 transition (R12), the atoms are pumped between these guided states. Magnetic reflections within the guide

  8. From selection hits to clinical leads: progress in aptamer discovery

    PubMed Central

    Maier, Keith E; Levy, Matthew

    2016-01-01

    Aptamers were discovered more than 25 years ago, yet only one has been approved by the US Food and Drug Administration to date. With some noteworthy advances in their chemical design and the enzymes we use to make them, aptamers and aptamer-based therapeutics have seen a resurgence in interest. New aptamer drugs are being approved for clinical evaluation, and it is certain that we will see increasingly more aptamers and aptamer-like drugs in the future. In this review, we will discuss the production of aptamers with an emphasis on the advances and modifications that enabled early aptamers to succeed in clinical trials as well as those that are likely to be important for future generations of these drugs. PMID:27088106

  9. Department of Clinical Investigation Annual Research Progress Report.

    DTIC Science & Technology

    1995-09-30

    Cell Lysate with Subsequent Recovery of DNA Other nominees were: Adolescent Risk Behavior and the Influence of Parents and Education by MAJ Brent V... Adolescent Risk Behavior and the Influence of Parents and Education Start Date: 09/02/94 Est. Completion Date: Department: Clinical Investigation...activities, and parental involvement in providing students with information and guidance, have any effect on adolescent risk taking behavior. Technical

  10. Plasma HIV-1 Tropism and the Risk of Short-Term Clinical Progression to AIDS or Death

    PubMed Central

    Cozzi-Lepri, Alessandro; Phillips, Andrew; Noguera-Julian, Marc; Bickel, Markus; Sedlacek, Dalibor; Zilmer, Kai; Clotet, Bonaventura; Lundgren, Jens D.; Paredes, Roger

    2017-01-01

    Objective To investigate if plasma HIV-1 tropism testing could identify subjects at higher risk for clinical progression and death in routine clinical management. Design Nested case-control study within the EuroSIDA cohort. Methods Cases were subjects with AIDS or who died from any cause, with a plasma sample with HIV-1 RNA >1000 copies/mL available for tropism testing 3 to 12 months prior to the event. At least 1 control matched for age, HIV-1 RNA and HCV status at the time of sampling were selected per each case. Conditional logistic regression was used to investigate exposures associated with clinical progression to AIDS or death. A linear mixed model with random intercept was used to compare CD4+T-cell slopes by HIV tropism over the 12 months following the date of sampling. Results The study included 266 subjects, 100 cases and 166 controls; one quarter had X4 HIV; 26% were ART-naïve. Baseline factors independently associated with clinical progression or death were female gender (OR = 2.13 vs. male, 95CI = 1.04, 4.36), p = 0.038), CD4+T-cell count (OR = 0.90 (95CI = 0.80, 1.00) per 100 cells/mm3 higher, p = 0.058), being on ART (OR = 2.72 vs. being off-ART (95CI = 1.15, 6.41), p = 0.022) and calendar year of sample [OR = 0.84 (95CI = 0.77, 0.91) per more recent year, p<0.001). Baseline tropism was not associated with the risk of clinical progression or death. CD4+T-cell slopes did not differ within or between tropism groups. Conclusions The predictive role of plasma tropism determined using 454 sequencing in the context of people receiving cART with detectable VL is not helpful to identify subjects at higher risk for clinical progression to AIDS or death. PMID:28129343

  11. [Progress of low-energy shockwave therapy in clinical application].

    PubMed

    Xin, Zhong-cheng; Liu, Jing; Wang, Lin; Li, Hui-xi

    2013-08-18

    A shock wave is a transient pressure disturbance that propagates rapidly in three-dimensional space. It is associated with a sudden rise from ambient pressure to its maximum pressure. Shock wave therapy in urology is primarily used to disintegrate urolithiasis. Recently, low-energy shock wave therapy (LESWT), which is a novel convenient and cost-effective therapeutic modality, is extended to treat other pathological conditions including coronary heart disease, musculoskeletal disorders and erectile dysfunction. However, the exact therapeutic mechanisms and clinical safety and efficacy of LESWT remain to be investigated. Based on the results of previous studies, it is suggested that LESWT could regulate angiogenesis-related growth factors expression including endothelial nitric oxide synthase (eNOS), vessel endothelial growth factor (VEGF) and proliferating cell nuclear antigen (PCNA), which might induce the ingrowth of neovascularization that improves blood supply and increases cell proliferation and eventual tissue regeneration for restore pathological changes. The further studies on cellular and molecular biological changes by LESWT for clarification its mechanism and clinical safety and efficacy studies are recommended.

  12. Progress and prospects: hurdles to cardiovascular gene therapy clinical trials.

    PubMed

    Hedman, M; Hartikainen, J; Ylä-Herttuala, S

    2011-08-01

    Several gene therapy approaches have been designed for the treatment of cardiovascular diseases. A positive finding is that the safety of cardiovascular gene therapy has been excellent even in long-term follow-up. However, several hurdles to this field are still present. A major disappointing feature of the trials is that while preclinical and uncontrolled phase-I gene therapy trials have been positive, none of the randomized controlled phase-II/III cardiovascular gene therapy trials have shown clinically relevant positive effects. Low gene transfer efficiency seems to be associated with several trials. A sophisticated efficient delivery method for cardiovascular applications is still lacking and only low concentrations of the gene product are produced in the target tissues. Only a few gene therapy vectors can be produced in large scale. In addition, inflammatory reactions against vectors and inability to regulate gene expression are still present. Furthermore, a strong placebo effect is affecting the results in gene therapy trials, and long-term trials have become more difficult to conduct because of the multiplicity of therapies applied simultaneously on the patients. This review summarizes advances and obstacles of current cardiovascular clinical gene therapy trials.

  13. Editorial: Process to progress? Investigative trials, mechanism and clinical science.

    PubMed

    Green, Jonathan

    2015-01-01

    In 2002 Helena Kraemer and colleagues published an important article on the analysis of clinical trials in mental health, which advocated a planned focus on mechanisms to investigate the processes behind treatment effects. Kraemer et al. considered not only new approaches to mediation analysis, but also a theoretical approach to factors, both pre-treatment and during treatment, that might moderate this mediation. Trials should not just be about whether a treatment 'worked', but how it worked; with the results informing modification of the intervention for the next trial by discarding aspects that were not effective and reinforcing aspects that were - an iterative procedure towards greater effectiveness. Can we enjoy similar ambitions for complex interventions within mental health? It is not so long ago when the received wisdom within the clinical and much of the research community was that it was simply impossible in practice to mount randomised controlled trials relevant to the kind of psychosocial interventions we use in child and adolescent mental health (CAMHS). How different the situation is now, with burgeoning interest in a systematic evidence base for psychological treatment and the possibilities for unexpected advances (as well as unexpected harms). Nevertheless it is probably still fair to say that the systematic use of process and mechanism study within trials in our field is the exception rather than the rule. What are the possibilities and implications for our field?

  14. Advancing Clostridia to Clinical Trial: Past Lessons and Recent Progress

    PubMed Central

    Mowday, Alexandra M.; Guise, Christopher P.; Ackerley, David F.; Minton, Nigel P.; Lambin, Philippe; Dubois, Ludwig J.; Theys, Jan; Smaill, Jeff B.; Patterson, Adam V.

    2016-01-01

    Most solid cancers contain regions of necrotic tissue. The extent of necrosis is associated with poor survival, most likely because it reflects aggressive tumour outgrowth and inflammation. Intravenously injected spores of anaerobic bacteria from the genus Clostridium infiltrate and selectively germinate in these necrotic regions, providing cancer-specific colonisation. The specificity of this system was first demonstrated over 60 years ago and evidence of colonisation has been confirmed in multiple tumour models. The use of “armed” clostridia, such as in Clostridium Directed Enzyme Prodrug Therapy (CDEPT), may help to overcome some of the described deficiencies of using wild-type clostridia for treatment of cancer, such as tumour regrowth from a well-vascularised outer rim of viable cells. Successful preclinical evaluation of a transferable gene that metabolises both clinical stage positron emission tomography (PET) imaging agents (for whole body vector visualisation) as well as chemotherapy prodrugs (for conditional enhancement of efficacy) would be a valuable early step towards the prospect of “armed” clostridia entering clinical evaluation. The ability to target the immunosuppressive hypoxic tumour microenvironment using CDEPT may offer potential for synergy with recently developed immunotherapy strategies. Ultimately, clostridia may be most efficacious when combined with conventional therapies, such as radiotherapy, that sterilise viable aerobic tumour cells. PMID:27367731

  15. Expanding the spectrum of phenotypes associated with germline PIGA mutations: a child with developmental delay, accelerated linear growth, facial dysmorphisms, elevated alkaline phosphatase, and progressive CNS abnormalities.

    PubMed

    van der Crabben, Saskia N; Harakalova, Magdalena; Brilstra, Eva H; van Berkestijn, Frédérique M C; Hofstede, Floris C; van Vught, Adrianus J; Cuppen, Edwin; Kloosterman, Wigard; Ploos van Amstel, Hans Kristian; van Haaften, Gijs; van Haelst, Mieke M

    2014-01-01

    Phosphatidyl inositol glycan (PIG) enzyme subclasses are involved in distinct steps of glycosyl phosphatidyl inositol anchor protein biosynthesis. Glycolsyl phosphatidyl inositol-anchored proteins have heterogeneous functions; they can function as enzymes, adhesion molecules, complement regulators and co-receptors in signal transduction pathways. Germline mutations in genes encoding different members of the PIG family result in diverse conditions with (severe) developmental delay, (neonatal) seizures, hypotonia, CNS abnormalities, growth abnormalities, and congenital abnormalities as hallmark features. The variability of clinical features resembles the typical diversity of other glycosylation pathway deficiencies such as the congenital disorders of glycosylation. Here, we report the first germline missense mutation in the PIGA gene associated with accelerated linear growth, obesity, central hypotonia, severe refractory epilepsy, cardiac anomalies, mild facial dysmorphic features, mildly elevated alkaline phosphatase levels, and CNS anomalies consisting of progressive cerebral atrophy, insufficient myelinization, and cortical MRI signal abnormalities. X-exome sequencing in the proband identified a c.278C>T (p.Pro93Leu) mutation in the PIGA gene. The mother and maternal grandmother were unaffected carriers and the mother showed 100% skewing of the X-chromosome harboring the mutation. These results together with the clinical similarity of the patient reported here and the previously reported patients with a germline nonsense mutation in PIGA support the determination that this mutation caused the phenotype in this family.

  16. Recent progress and clinical importance on pharmacogenetics in cancer therapy

    PubMed Central

    Soh, Thomas I Peng; Yong, Wei Peng; Innocenti, Federico

    2013-01-01

    Recent advances have provided unprecedented opportunities to identify prognostic and predictive markers of efficacy of cancer therapy. Genetic markers can be used to exclude patients who will not benefit from therapy, exclude patients at high risk of severe toxicity, and adjust dosing. Genomic approaches for marker discovery now include genome-wide association studies and tumor DNA sequencing. The challenge is now to select markers for which there is enough evidence to transition them to the clinic. The hurdles include the inherent low frequency of many of these markers, the lengthy validation process through trials, as well as legislative and economic hurdles. Attempts to answer questions about certain markers more quickly have led to an increased popularity of trials with enrichment design, especially in the light of the dramatic phase I results seen in recent months. Personalized medicine in oncology is a step closer to reality. PMID:21950596

  17. Assessment of Waveform Similarity in Clinical Gait Data: The Linear Fit Method

    PubMed Central

    Iosa, M.; Cereatti, A.; Merlo, A.; Campanini, I.; Paolucci, S.; Cappozzo, A.

    2014-01-01

    The assessment of waveform similarity is a crucial issue in gait analysis for the comparison of kinematic or kinetic patterns with reference data. A typical scenario is in fact the comparison of a patient's gait pattern with a relevant physiological pattern. This study aims to propose and validate a simple method for the assessment of waveform similarity in terms of shape, amplitude, and offset. The method relies on the interpretation of these three parameters, obtained through a linear fit applied to the two data sets under comparison plotted one against the other after time normalization. The validity of this linear fit method was tested in terms of appropriateness (comparing real gait data of 34 patients with cerebrovascular accident with those of 15 healthy subjects), reliability, sensitivity, and specificity (applying a cluster analysis on the real data). Results showed for this method good appropriateness, 94.1% of sensitivity, 93.3% of specificity, and good reliability. The LFM resulted in a simple method suitable for analysing the waveform similarity in clinical gait analysis. PMID:25126548

  18. Interventional multispectral photoacoustic imaging with a clinical linear array ultrasound probe for guiding nerve blocks

    NASA Astrophysics Data System (ADS)

    Xia, Wenfeng; West, Simeon J.; Nikitichev, Daniil I.; Ourselin, Sebastien; Beard, Paul C.; Desjardins, Adrien E.

    2016-03-01

    Accurate identification of tissue structures such as nerves and blood vessels is critically important for interventional procedures such as nerve blocks. Ultrasound imaging is widely used as a guidance modality to visualize anatomical structures in real-time. However, identification of nerves and small blood vessels can be very challenging, and accidental intra-neural or intra-vascular injections can result in significant complications. Multi-spectral photoacoustic imaging can provide high sensitivity and specificity for discriminating hemoglobin- and lipid-rich tissues. However, conventional surface-illumination-based photoacoustic systems suffer from limited sensitivity at large depths. In this study, for the first time, an interventional multispectral photoacoustic imaging (IMPA) system was used to image nerves in a swine model in vivo. Pulsed excitation light with wavelengths in the ranges of 750 - 900 nm and 1150 - 1300 nm was delivered inside the body through an optical fiber positioned within the cannula of an injection needle. Ultrasound waves were received at the tissue surface using a clinical linear array imaging probe. Co-registered B-mode ultrasound images were acquired using the same imaging probe. Nerve identification was performed using a combination of B-mode ultrasound imaging and electrical stimulation. Using a linear model, spectral-unmixing of the photoacoustic data was performed to provide image contrast for oxygenated and de-oxygenated hemoglobin, water and lipids. Good correspondence between a known nerve location and a lipid-rich region in the photoacoustic images was observed. The results indicate that IMPA is a promising modality for guiding nerve blocks and other interventional procedures. Challenges involved with clinical translation are discussed.

  19. Progress in Cleveland Clinic-Nimbus total artificial heart development.

    PubMed

    Harasaki, H; Fukamachi, K; Massiello, A; Chen, J F; Himley, S C; Fukumura, F; Muramoto, K; Niu, S; Wika, K; Davies, C R

    1994-01-01

    A totally implantable, Cleveland Clinic-Nimbus total artificial heart (TAH) uses electrohydraulic energy conversion and an automatic left master-alternate mode control scheme, with a filling sensitivity of 1.0 l/min/mmHg and a maximum output of 9.5 l/min. The TAHs were tested in 12 calves for 1-120 days with normal major organ and blood cell function. Post-operative suppression of platelet aggregation recovered by the second post-operative week. The gelatin-coated pump surface generally was clean without any anticoagulants and free from infection. Embolism, which occurred in two cases, was caused by complications attributable to fungal infection in a Dacron graft and by thrombus formed around a jugular vein catheter. A system with a hybridized microcircuit controller in the interventricular space has been tested successfully in the three most recent cases, with a peak device surface temperature elevation of 6.5 degrees C. Heat effects were confined to the tissues immediately adjacent to the hottest spots. The carbon fiber-reinforced epoxy housing and 60 ml butyl rubber compliance chamber showed good tissue compatibility with a thin, fibrous tissue capsule. The transcutaneous energy transmission system and the internal battery functioned well as designed in the most recent animal implant.

  20. A Probabilistic Reasoning Method for Predicting the Progression of Clinical Findings from Electronic Medical Records

    PubMed Central

    Goodwin, Travis; Harabagiu, Sanda M.

    2015-01-01

    In this paper, we present a probabilistic reasoning method capable of generating predictions of the progression of clinical findings (CFs) reported in the narrative portion of electronic medical records. This method benefits from a probabilistic knowledge representation made possible by a graphical model. The knowledge encoded in the graphical model considers not only the CFs extracted from the clinical narratives, but also their chronological ordering (CO) made possible by a temporal inference technique described in this paper. Our experiments indicate that the predictions about the progression of CFs achieve high performance given the COs induced from patient records. PMID:26306238

  1. From inhibition of radiographic progression to maintaining structural integrity: a methodological framework for radiographic progression in rheumatoid arthritis and psoriatic arthritis clinical trials.

    PubMed

    Landewé, Robert; Strand, Vibeke; van der Heijde, Désirée

    2013-07-01

    Usually, a clinical trial in rheumatoid arthritis and psoriatic arthritis aiming to demonstrate that a new antirheumatic drug treatment can inhibit progression of structural damage has a 'superiority design': The new treatment is compared to placebo or to another active treatment. Currently, many new drug treatments have shown to be able to completely suppress progression (progression rates close to zero). For largely unknown reasons, during the last 10 years, radiographic progression rates in clinical trials have gradually decreased, so that progression rates in the comparator groups are often too low to demonstrate meaningful inhibition, and thus superiority of the new treatment. We here propose an alternative framework to demonstrate that new treatments have the ability to 'preserve structural integrity' rather than to 'inhibit radiographic progression'. Anno 2013, preserving structural integrity is conceptually more realistic than inhibiting radiographic progression.

  2. Commensurate Priors for Incorporating Historical Information in Clinical Trials Using General and Generalized Linear Models.

    PubMed

    Hobbs, Brian P; Sargent, Daniel J; Carlin, Bradley P

    2012-08-28

    Assessing between-study variability in the context of conventional random-effects meta-analysis is notoriously difficult when incorporating data from only a small number of historical studies. In order to borrow strength, historical and current data are often assumed to be fully homogeneous, but this can have drastic consequences for power and Type I error if the historical information is biased. In this paper, we propose empirical and fully Bayesian modifications of the commensurate prior model (Hobbs et al., 2011) extending Pocock (1976), and evaluate their frequentist and Bayesian properties for incorporating patient-level historical data using general and generalized linear mixed regression models. Our proposed commensurate prior models lead to preposterior admissible estimators that facilitate alternative bias-variance trade-offs than those offered by pre-existing methodologies for incorporating historical data from a small number of historical studies. We also provide a sample analysis of a colon cancer trial comparing time-to-disease progression using a Weibull regression model.

  3. Microphthalmia with linear skin defects (MLS) syndrome: Clinical, cytogenetic, and molecular characterization

    SciTech Connect

    Lindsay, E.A.; Grillo, A.; Ferrero, G.B.; Baldini, A.; Ballabio, A.; Zoghbi, H.Y.; Roth, E.J.; Magenis, E.; Grompe, M.; Hulten, M.

    1994-01-15

    The microphthalmia with linear skin defects (MLS) syndrome (MIM309801) is a severe developmental disorder observed in XX individuals with distal Xp segmental monosomy. The phenotype of this syndrome overlaps with that of both Aicardi (MIM 305050) and Goltz (MIM 305600) syndromes, two X-linked dominant, male-lethal disorders. Here the authors report the clinical, cytogenetic, and molecular characterization of 3 patients with this syndrome. Two of these patients are females with a terminal Xpter-p22.2 deletion. One of these 2 patients had an aborted fetus with anencephaly and the same chromosome abnormality. The third patient is an XX male with Xp/Yp exchange spanning the SRY gene which results in distal Xp monosomy. The extensive clinical variability observed in these patients and the results of the molecular analysis suggest that X-inactivation plays an important role in determining the phenotype of the MLS syndrome. The authors propose that the MLS, Aicardi, and Goltz syndromes are due to the involvement of the same gene(s), and that different patterns of X-inactivation are responsible for the phenotypic differences observed in these 3 disorders. However, they cannot rule out that each component of the MLS phenotype is caused by deletion of a different gene (a contiguous gene syndrome). 24 refs., 4 figs., 1 tab.

  4. Histologically Benign, Clinically Aggressive: Progressive Non-Optic Pathway Pilocytic Astrocytomas in Adults with NF1

    PubMed Central

    Strowd, Roy E.; Rodriguez, Fausto J.; McLendon, Roger E.; Vredenburgh, James J.; Chance, Aaron B.; Jallo, George; Olivi, Alessandro; Ahn, Edward S.; Blakeley, Jaishri O.

    2016-01-01

    Although optic pathway gliomas are the most common brain tumors associated with neurofibromatosis type 1 (NF1), extra-optic gliomas occur and may behave more aggressively with outcomes that differ by age. A retrospective case-control study was designed to describe the clinical course of adult NF1 patients with progressive extra-optic pilocytic astrocytomas (PAs) and compare to a pediatric cohort. Data for patients treated at the Johns Hopkins Comprehensive Neurofibromatosis Center from 2003 to 2013 were reviewed to identify cases (adults, age >18) and controls (pediatric, age <18) with clinically or radiographically progressive extra-optic PAs. Demographic, clinical, histologic, and radiographic data were collected. Three adult NF1 cases and four pediatric NF1 controls were identified. Mean age was 32.3 ± 9.5 years, 66% male (cases); 12.8±4.2 years, 100% male (controls). Symptomatic progression occurred in two-of-three adults (67%) while the majority of pediatric patients presented with isolated radiographic progression (n=3, 75%). Onset tended to be more rapid in adults (4±1 vs. 14±8.3 months, P=0.10). Subtotal resection was the treatment for all pediatric patients. Radiotherapy (n=2), chemotherapy (n=2), and targeted, biologic agents (n=2) were administered in adults. Although all pediatric patients are living, outcomes were universally poor in adults with progression to death in all (median survival 17.1 months, range 6.6–30.3). In conclusion, despite grade I histology, all three adult NF1 patients with progressive extra-optic PAs suffered an aggressive clinical course which was not seen in pediatric patients. Clinicians should be aware of this clinico-histologic discrepancy when counseling and managing adult NF1 patients with progressive extra-optic PAs. PMID:26992069

  5. Histologically benign, clinically aggressive: Progressive non-optic pathway pilocytic astrocytomas in adults with NF1.

    PubMed

    Strowd, Roy E; Rodriguez, Fausto J; McLendon, Roger E; Vredenburgh, James J; Chance, Aaron B; Jallo, George; Olivi, Alessandro; Ahn, Edward S; Blakeley, Jaishri O

    2016-06-01

    Although optic pathway gliomas are the most common brain tumors associated with neurofibromatosis type 1 (NF1), extra-optic gliomas occur and may behave more aggressively with outcomes that differ by age. A retrospective case-control study was designed to describe the clinical course of adult NF1 patients with progressive extra-optic pilocytic astrocytomas (PAs) and compare to a pediatric cohort. Data for patients treated at the Johns Hopkins Comprehensive Neurofibromatosis Center from 2003 to 2013 were reviewed to identify cases (adults, age >18) and controls (pediatric, age <18) with clinically or radiographically progressive extra-optic PAs. Demographic, clinical, histologic, and radiographic data were collected. Three adult NF1 cases and four pediatric NF1 controls were identified. Mean age was 32.3 ± 9.5 years, 66% male (cases); 12.8 ± 4.2 years, 100% male (controls). Symptomatic progression occurred in two-of-three adults (67%) while the majority of pediatric patients presented with isolated radiographic progression (n = 3, 75%). Onset tended to be more rapid in adults (4 ± 1 vs. 14 ± 8.3 months, P = 0.10). Subtotal resection was the treatment for all pediatric patients. Radiotherapy (n = 2), chemotherapy (n = 2), and targeted, biologic agents (n = 2) were administered in adults. Although all pediatric patients are living, outcomes were universally poor in adults with progression to death in all (median survival 17.1 months, range 6.6-30.3). In conclusion, despite grade I histology, all three adult NF1 patients with progressive extra-optic PAs suffered an aggressive clinical course which was not seen in pediatric patients. Clinicians should be aware of this clinico-histologic discrepancy when counseling and managing adult NF1 patients with progressive extra-optic PAs. © 2016 Wiley Periodicals, Inc.

  6. Clinical commissioning and use of the Novalis Tx linear accelerator for SRS and SBRT.

    PubMed

    Kim, Jinkoo; Wen, Ning; Jin, Jian-Yue; Walls, Nicole; Kim, Sangroh; Li, Haisen; Ren, Lei; Huang, Yimei; Doemer, Anthony; Faber, Kathleen; Kunkel, Tina; Balawi, Ahssan; Garbarino, Kimberly; Levin, Kenneth; Patel, Samir; Ajlouni, Munther; Miller, Brett; Nurushev, Teamor; Huntzinger, Calvin; Schulz, Raymond; Chetty, Indrin J; Movsas, Benjamin; Ryu, Samuel

    2012-05-10

    The purpose of this study was to perform comprehensive measurements and testing of a Novalis Tx linear accelerator, and to develop technical guidelines for com-missioning from the time of acceptance testing to the first clinical treatment. The Novalis Tx (NTX) linear accelerator is equipped with, among other features, a high-definition MLC (HD120 MLC) with 2.5 mm central leaves, a 6D robotic couch, an optical guidance positioning system, as well as X-ray-based image guidance tools to provide high accuracy radiation delivery for stereotactic radiosurgery and stereotactic body radiation therapy procedures. We have performed extensive tests for each of the components, and analyzed the clinical data collected in our clinic. We present technical guidelines in this report focusing on methods for: (1) efficient and accurate beam data collection for commissioning treatment planning systems, including small field output measurements conducted using a wide range of detectors; (2) commissioning tests for the HD120 MLC; (3) data collection for the baseline characteristics of the on-board imager (OBI) and ExacTrac X-ray (ETX) image guidance systems in conjunction with the 6D robotic couch; and (4) end-to-end testing of the entire clinical process. Established from our clinical experience thus far, recommendations are provided for accurate and efficient use of the OBI and ETX localization systems for intra- and extracranial treatment sites. Four results are presented. (1) Basic beam data measurements: Our measurements confirmed the necessity of using small detectors for small fields. Total scatter factors varied significantly (30% to approximately 62%) for small field measurements among detectors. Unshielded stereotactic field diode (SFD) overestimated dose by ~ 2% for large field sizes. Ion chambers with active diameters of 6 mm suffered from significant volume averaging. The sharpest profile penumbra was observed for the SFD because of its small active diameter (0.6 mm). (2

  7. Linear Energy Transfer-Guided Optimization in Intensity Modulated Proton Therapy: Feasibility Study and Clinical Potential

    SciTech Connect

    Giantsoudi, Drosoula; Grassberger, Clemens; Craft, David; Niemierko, Andrzej; Trofimov, Alexei; Paganetti, Harald

    2013-09-01

    Purpose: To investigate the feasibility and potential clinical benefit of linear energy transfer (LET) guided plan optimization in intensity modulated proton therapy (IMPT). Methods and Materials: A multicriteria optimization (MCO) module was used to generate a series of Pareto-optimal IMPT base plans (BPs), corresponding to defined objectives, for 5 patients with head-and-neck cancer and 2 with pancreatic cancer. A Monte Carlo platform was used to calculate dose and LET distributions for each BP. A custom-designed MCO navigation module allowed the user to interpolate between BPs to produce deliverable Pareto-optimal solutions. Differences among the BPs were evaluated for each patient, based on dose–volume and LET–volume histograms and 3-dimensional distributions. An LET-based relative biological effectiveness (RBE) model was used to evaluate the potential clinical benefit when navigating the space of Pareto-optimal BPs. Results: The mean LET values for the target varied up to 30% among the BPs for the head-and-neck patients and up to 14% for the pancreatic cancer patients. Variations were more prominent in organs at risk (OARs), where mean LET values differed by a factor of up to 2 among the BPs for the same patient. An inverse relation between dose and LET distributions for the OARs was typically observed. Accounting for LET-dependent variable RBE values, a potential improvement on RBE-weighted dose of up to 40%, averaged over several structures under study, was noticed during MCO navigation. Conclusions: We present a novel strategy for optimizing proton therapy to maximize dose-averaged LET in tumor targets while simultaneously minimizing dose-averaged LET in normal tissue structures. MCO BPs show substantial LET variations, leading to potentially significant differences in RBE-weighted doses. Pareto-surface navigation, using both dose and LET distributions for guidance, provides the means for evaluating a large variety of deliverable plans and aids in

  8. Early postoperative tumor progression predicts clinical outcome in glioblastoma-implication for clinical trials.

    PubMed

    Merkel, Andreas; Soeldner, Dorothea; Wendl, Christina; Urkan, Dilek; Kuramatsu, Joji B; Seliger, Corinna; Proescholdt, Martin; Eyupoglu, Ilker Y; Hau, Peter; Uhl, Martin

    2017-01-18

    Molecular markers define the diagnosis of glioblastoma in the new WHO classification of 2016, challenging neuro-oncology centers to provide timely treatment initiation. The aim of this study was to determine whether a time delay to treatment initiation was accompanied by signs of early tumor progression in an MRI before the start of radiotherapy, and, if so, whether this influences the survival of glioblastoma patients. Images from 61 patients with early post-surgery MRI and a second MRI just before the start of radiotherapy were examined retrospectively for signs of early tumor progression. Survival information was analyzed using the Kaplan-Meier method, and a Cox multivariate analysis was performed to identify independent variables for survival prediction. 59 percent of patients showed signs of early tumor progression after a mean time of 24.1 days from the early post-surgery MRI to the start of radiotherapy. Compared to the group without signs of early tumor progression, which had a mean time of 23.3 days (p = 0.685, Student's t test), progression free survival was reduced from 320 to 185 days (HR 2.3; CI 95% 1.3-4.0; p = 0.0042, log-rank test) and overall survival from 778 to 329 days (HR 2.9; CI 95% 1.6-5.1; p = 0.0005). A multivariate Cox regression analysis revealed that the Karnofsky performance score, O-6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation, and signs of early tumor progression are prognostic markers of overall survival. Early tumor progression at the start of radiotherapy is associated with a worse prognosis for glioblastoma patients. A standardized baseline MRI might allow for better patient stratification.

  9. Robust Classification and Segmentation of Planar and Linear Features for Construction Site Progress Monitoring and Structural Dimension Compliance Control

    NASA Astrophysics Data System (ADS)

    Maalek, R.; Lichti, D. D.; Ruwanpura, J.

    2015-08-01

    The application of terrestrial laser scanners (TLSs) on construction sites for automating construction progress monitoring and controlling structural dimension compliance is growing markedly. However, current research in construction management relies on the planned building information model (BIM) to assign the accumulated point clouds to their corresponding structural elements, which may not be reliable in cases where the dimensions of the as-built structure differ from those of the planned model and/or the planned model is not available with sufficient detail. In addition outliers exist in construction site datasets due to data artefacts caused by moving objects, occlusions and dust. In order to overcome the aforementioned limitations, a novel method for robust classification and segmentation of planar and linear features is proposed to reduce the effects of outliers present in the LiDAR data collected from construction sites. First, coplanar and collinear points are classified through a robust principal components analysis procedure. The classified points are then grouped using a robust clustering method. A method is also proposed to robustly extract the points belonging to the flat-slab floors and/or ceilings without performing the aforementioned stages in order to preserve computational efficiency. The applicability of the proposed method is investigated in two scenarios, namely, a laboratory with 30 million points and an actual construction site with over 150 million points. The results obtained by the two experiments validate the suitability of the proposed method for robust segmentation of planar and linear features in contaminated datasets, such as those collected from construction sites.

  10. Clinical, Cognitive and Anatomical Evolution from Nonfluent Progressive Aphasia to Corticobasal Syndrome: A Case Report

    PubMed Central

    Gorno-Tempini, Maria Luisa; Murray, Ryan C.; Rankin, Katherine P.; Weiner, Michael W.; Miller, Bruce L.

    2008-01-01

    Recent clinical and pathological studies have suggested that frontotemporal lobar degeneration (FTLD) and corticobasal syndrome (CBS) show clinical and pathological overlap. We present four years of longitudinal clinical, cognitive and anatomical data in the case of a 56-year-old woman, AS, whose clinical picture evolved from FTLD to CBS. For the first three years, AS showed a progressive speech and language disorder compatible with a diagnosis of the nonfluent aphasia variant of FTLD. At year four, 10 years after her first symptom, AS developed the classical clinical signs of CBS, including alien limb phenomenon and dystonia. Voxel-based morphometry (VBM) applied to AS’s four annual scans showed progression of atrophy from the inferior posterior frontal gyrus, to the left insula and finally to the medial frontal lobe. This case demonstrates the clinical overlap between FTLD and CBS and shows that the two can appear in the same patient at different stages of the disease in relation to the progression of anatomical damage. PMID:15788282

  11. Perfusion and diffusion MRI of glioblastoma progression in a four-year prospective temozolomide clinical trial

    SciTech Connect

    Leimgruber, Antoine; Ostermann, Sandrine; Yeon, Eun Jo; Buff, Evelyn; Maeder, Philippe P.; Stupp, Roger; Meuli, Reto A. . E-mail: Reto.Meuli@chuv.ch

    2006-03-01

    Purpose: This study was performed to determine the impact of perfusion and diffusion magnetic resonance imaging (MRI) sequences on patients during treatment of newly diagnosed glioblastoma. Special emphasis has been given to these imaging technologies as tools to potentially anticipate disease progression, as progression-free survival is frequently used as a surrogate endpoint. Methods and Materials: Forty-one patients from a phase II temolozomide clinical trial were included. During follow-up, images were integrated 21 to 28 days after radiochemotherapy and every 2 months thereafter. Assessment of scans included measurement of size of lesion on T1 contrast-enhanced, T2, diffusion, and perfusion images, as well as mass effect. Classical criteria on tumor size variation and clinical parameters were used to set disease progression date. Results: A total of 311 MRI examinations were reviewed. At disease progression (32 patients), a multivariate Cox regression determined 2 significant survival parameters: T1 largest diameter (p < 0.02) and T2 size variation (p < 0.05), whereas perfusion and diffusion were not significant. Conclusion: Perfusion and diffusion techniques cannot be used to anticipate tumor progression. Decision making at disease progression is critical, and classical T1 and T2 imaging remain the gold standard. Specifically, a T1 contrast enhancement over 3 cm in largest diameter together with an increased T2 hypersignal is a marker of inferior prognosis.

  12. Magnetic-mediated hyperthermia for cancer treatment: Research progress and clinical trials

    NASA Astrophysics Data System (ADS)

    Zhao, Ling-Yun; Liu, Jia-Yi; Ouyang, Wei-Wei; Li, Dan-Ye; Li, Li; Li, Li-Ya; Tang, Jin-Tian

    2013-10-01

    Research progress and frontiers of magnetic-mediated hyperthermia (MMH) are presented, along with clinical trials in Germany, the US, Japan, and China. Special attention is focused on MMH mediated by magnetic nanoparticles, and multifunctional magnetic devices for cancer multimodality treatment are also introduced.

  13. Low normal CSF Aβ42 levels predict clinical progression in non-demented subjects.

    PubMed

    Tijms, Betty M; Bertens, Daniela; Slot, Rosalinde E; Gouw, Alida A; Teunissen, Charlotte E; Scheltens, Philip; van der Flier, Wiesje M; Visser, Pieter Jelle

    2017-03-20

    We studied whether continuous lower normal cerebrospinal fluid (CSF) amyloid β 1-42 (≥640 pg/ml) levels related with rate of clinical progression in a sample of 393 non-demented memory clinic patients. Lower normal levels were associated with faster clinical progression and this depended on baseline cognitive status (subjective cognitive decline: HR = 0.59, p <.05; mild cognitive impairment: HR=0.12, p <.001), indicating that normal CSF amyloid levels do not exclude incident Alzheimer's disease. These findings suggest that research on preclinical markers for Alzheimer's disease should take the continuum of CSF amyloid β 1-42 levels within the normal range into account. This article is protected by copyright. All rights reserved.

  14. Missing data and measurement variability in assessing progression-free survival endpoint in randomized clinical trials.

    PubMed

    Sridhara, Rajeshwari; Mandrekar, Sumithra J; Dodd, Lori E

    2013-05-15

    Progression-free survival (PFS) is frequently used as the primary efficacy endpoint in the evaluation of cancer treatment that is considered for marketing approval. Missing or incomplete data problems become more acute with a PFS endpoint (compared with overall survival). In a given clinical trial, it is common to observe incomplete data due to premature treatment discontinuation, missed or flawed assessments, change of treatment, lack of follow-up, and unevaluable data. When incomplete data issues are substantial, interpretation of the data becomes tenuous. Plans to prevent, minimize, or properly analyze incomplete data are critical for generalizability of results from the clinical trial. Variability in progressive disease measurement between radiologists further contributes to data problems with a PFS endpoint. The repercussions of this on phase III clinical trials are complex and depend on several factors, including the magnitude of the variability and whether there is a systematic reader evaluation bias favoring one treatment arm particularly in open-label trials.

  15. Linear quadratic modeling of increased late normal-tissue effects in special clinical situations

    SciTech Connect

    Jones, Bleddyn . E-mail: b.jones.1@bham.ac.uk; Dale, Roger G.; Gaya, Andrew M.

    2006-03-01

    Purpose: To extend linear quadratic theory to allow changes in normal-tissue radiation tolerance after exposure to cytotoxic chemotherapy, after surgery, and in elderly patients. Methods: Examples of these situations are analyzed by use of the biologic effective dose (BED) concept. Changes in tolerance can be allowed for by: estimation of either the contribution of the additional factor as an equivalent BED or the equivalent dose in 2-Gy fractions or by the degree of radiosensitization by a mean dose-modifying factor (x). Results: The estimated x value is 1.063 (95% confidence limits for the mean, 1.056 to 1.070) for subcutaneous fibrosis after cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy and radiotherapy in breast cancer. The point estimate of x is 1.18 for the additional risk of gastrointestinal late-radiation effects after abdominal surgery in lymphoma patients (or 10.62 Gy at 2 Gy per fraction). For shoulder fibrosis in patients older than 60 years after breast and nodal irradiation, x is estimated to be 1.033 (95% confidence limits for the mean, 1.028 to 1.0385). The equivalent BED values were CMF chemotherapy (6.48 Gy{sub 3}), surgery (17.73 Gy{sub 3}), and age (3.61 Gy{sub 3}). Conclusions: The LQ model can, in principle, be extended to quantify reduced normal-tissue tolerance in special clinical situations.

  16. Purse-String Versus Linear Conventional Skin Wound Closure of an Ileostomy: A Randomized Clinical Trial

    PubMed Central

    Alvandipour, Mina; Gharedaghi, Babak; Khodabakhsh, Hamed

    2016-01-01

    Purpose Infection is one of the most frequent complications that can occur after ileostomy closure. The incidence of wound infection depends on the skin closure technique, but there is no agreement on the perfect closure method for an ileostomy wound. The aim of this study was to evaluate the incidence of infection, the patient's approval, and the patient's pain between purse-string closure (PSC) and the usual linear closure (LC) of a stoma wound. Methods This randomized clinical trial enrolled 66 patients who underwent a stoma closure from February 2015 to May 2015 in Sari Emam Khomeini Hospital. Patients were divided into 2 groups according to the stoma closing method: the PSC group (n = 34) and the LC group (n = 32). The incidences of infection for the 2 groups were compared, and the patients' satisfaction and pain with the stoma were determined by using a questionnaire. Results Infection occurred in 1 of 34 PSC patients (2.9%) and in 7 of 32 LC patients (21.8%), and this difference was statistically significant (P = 0.021). Patients in the PSC group were more satisfied with the resulting wound scar and its cosmetic appearance at one month and three months after surgery (P = 0.043). Conclusion After stoma closure, PSC was associated with a significantly lower incidence of wound infection and greater patient satisfaction compared to LC. However, the healing period for patients who underwent PSC was longer than it was for those who underwent LC. PMID:27626025

  17. Multi-scale Modeling of the Cardiovascular System: Disease Development, Progression, and Clinical Intervention.

    PubMed

    Zhang, Yanhang; Barocas, Victor H; Berceli, Scott A; Clancy, Colleen E; Eckmann, David M; Garbey, Marc; Kassab, Ghassan S; Lochner, Donna R; McCulloch, Andrew D; Tran-Son-Tay, Roger; Trayanova, Natalia A

    2016-09-01

    Cardiovascular diseases (CVDs) are the leading cause of death in the western world. With the current development of clinical diagnostics to more accurately measure the extent and specifics of CVDs, a laudable goal is a better understanding of the structure-function relation in the cardiovascular system. Much of this fundamental understanding comes from the development and study of models that integrate biology, medicine, imaging, and biomechanics. Information from these models provides guidance for developing diagnostics, and implementation of these diagnostics to the clinical setting, in turn, provides data for refining the models. In this review, we introduce multi-scale and multi-physical models for understanding disease development, progression, and designing clinical interventions. We begin with multi-scale models of cardiac electrophysiology and mechanics for diagnosis, clinical decision support, personalized and precision medicine in cardiology with examples in arrhythmia and heart failure. We then introduce computational models of vasculature mechanics and associated mechanical forces for understanding vascular disease progression, designing clinical interventions, and elucidating mechanisms that underlie diverse vascular conditions. We conclude with a discussion of barriers that must be overcome to provide enhanced insights, predictions, and decisions in pre-clinical and clinical applications.

  18. MRI/MRS as a surrogate marker for clinical progression in GM1 gangliosidosis.

    PubMed

    Regier, Debra S; Kwon, Hyuk Joon; Johnston, Jean; Golas, Gretchen; Yang, Sandra; Wiggs, Edythe; Latour, Yvonne; Thomas, Sarah; Portner, Cindy; Adams, David; Vezina, Gilbert; Baker, Eva H; Tifft, Cynthia J

    2016-03-01

    Background GM1 gangliosidosis is a lysosomal storage disorder caused by mutations in GLB1, encoding β-galactosidase. The range of severity is from type I infantile disease, lethal in early childhood, to type III adult onset, resulting in gradually progressive neurological symptoms in adulthood. The intermediate group of patients has been recently classified as having type II late infantile subtype with onset of symptoms at one to three years of age or type II juvenile subtype with symptom onset at 2-10 years. To characterize disease severity and progression, six Late infantile and nine juvenile patients were evaluated using magnetic resonance imaging (MRI), and MR spectroscopy (MRS). Since difficulties with ambulation (gross motor function) and speech (expressive language) are often the first reported symptoms in type II GM1, patients were also scored in these domains. Deterioration of expressive language and ambulation was more rapid in the late infantile patients. Fourteen MRI scans in six Late infantile patients identified progressive atrophy in the cerebrum and cerebellum. Twenty-six MRI scans in nine juvenile patients revealed greater variability in extent and progression of atrophy. Quantitative MRS demonstrated a deficit of N-acetylaspartate in both the late infantile and juvenile patients with greater in the late infantile patients. This correlates with clinical measures of ambulation and expressive language. The two subtypes of type II GM1 gangliosidosis have different clinical trajectories. MRI scoring, quantitative MRS and brain volume correlate with clinical disease progression and may serve as important minimally-invasive outcome measures for clinical trials.

  19. Linear viral load increase of a single HPV-type in women with multiple HPV infections predicts progression to cervical cancer.

    PubMed

    Depuydt, Christophe E; Thys, Sofie; Beert, Johan; Jonckheere, Jef; Salembier, Geert; Bogers, Johannes J

    2016-11-01

    Persistent high-risk human papillomavirus (HPV) infection is strongly associated with development of high-grade cervical intraepithelial neoplasia or cancer (CIN3+). In single type infections, serial type-specific viral-load measurements predict the natural history of the infection. In infections with multiple HPV-types, the individual type-specific viral-load profile could distinguish progressing HPV-infections from regressing infections. A case-cohort natural history study was established using samples from untreated women with multiple HPV-infections who developed CIN3+ (n = 57) or cleared infections (n = 88). Enriched cell pellet from liquid based cytology samples were subjected to a clinically validated real-time qPCR-assay (18 HPV-types). Using serial type-specific viral-load measurements (≥3) we calculated HPV-specific slopes and coefficient of determination (R(2) ) by linear regression. For each woman slopes and R(2) were used to calculate which HPV-induced processes were ongoing (progression, regression, serial transient, transient). In transient infections with multiple HPV-types, each single HPV-type generated similar increasing (0.27copies/cell/day) and decreasing (-0.27copies/cell/day) viral-load slopes. In CIN3+, at least one of the HPV-types had a clonal progressive course (R(2)  ≥ 0.85; 0.0025copies/cell/day). In selected CIN3+ cases (n = 6), immunostaining detecting type-specific HPV 16, 31, 33, 58 and 67 RNA showed an even staining in clonal populations (CIN3+), whereas in transient virion-producing infections the RNA-staining was less in the basal layer compared to the upper layer where cells were ready to desquamate and release newly-formed virions. RNA-hybridization patterns matched the calculated ongoing processes measured by R(2) and slope in serial type-specific viral-load measurements preceding the biopsy. In women with multiple HPV-types, serial type-specific viral-load measurements predict the natural history of the

  20. Cerebrospinal fluid cortisol and clinical disease progression in MCI and dementia of Alzheimer's type.

    PubMed

    Popp, Julius; Wolfsgruber, Steffen; Heuser, Isabella; Peters, Oliver; Hüll, Michael; Schröder, Johannes; Möller, Hans-Jürgen; Lewczuk, Piotr; Schneider, Anja; Jahn, Holger; Luckhaus, Christian; Perneczky, Robert; Frölich, Lutz; Wagner, Michael; Maier, Wolfgang; Wiltfang, Jens; Kornhuber, Johannes; Jessen, Frank

    2015-02-01

    Increased peripheral and central nervous system cortisol levels have been reported in Alzheimer's disease (AD) and may reflect dysfunction of cerebral components of the hypothalamic-pituitary-adrenal (HPA) axis. However, brain exposure to high cortisol concentrations may also accelerate disease progression and cognitive decline. The objectives of this study were to investigate whether HPA-axis dysregulation occurs at early clinical stages of AD and whether plasma and CSF cortisol levels are associated with clinical disease progression. Morning plasma and CSF cortisol concentrations were obtained from the subjects with AD dementia, mild cognitive impairment of AD type (MCI-AD), MCI of other type (MCI-O), and controls with normal cognition included in a multicenter study from the German Dementia Competence Network. A clinical and neuropsychological follow-up was performed in a subgroup of participants with MCI-AD, MCI-O, and AD dementia. CSF cortisol concentrations were increased in the subjects with AD dementia or MCI-AD compared with subjects with MCI-O or normal cognition. After controlling for possible confounders including CSF measures of amyloid beta1-42 and total tau, higher baseline CSF cortisol levels were associated with faster clinical worsening and cognitive decline in MCI-AD. The findings suggest that HPA-axis dysregulation occurs at the MCI stage of AD and may accelerate disease progression and cognitive decline.

  1. Clinical Cancer Advances 2017: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology.

    PubMed

    Burstein, Harold J; Krilov, Lada; Aragon-Ching, Jeanny B; Baxter, Nancy N; Chiorean, E Gabriela; Chow, Warren Allen; De Groot, John Frederick; Devine, Steven Michael; DuBois, Steven G; El-Deiry, Wafik S; Epstein, Andrew S; Heymach, John; Jones, Joshua Adam; Mayer, Deborah K; Miksad, Rebecca A; Pennell, Nathan A; Sabel, Michael S; Schilsky, Richard L; Schuchter, Lynn Mara; Tung, Nadine; Winkfield, Karen Marie; Wirth, Lori J; Dizon, Don S

    2017-02-01

    A MESSAGE FROM ASCO'S PRESIDENT I am pleased to present Clinical Cancer Advances 2017, which highlights the most promising advances in patient-oriented cancer research over the past year. The report gives us an opportunity to reflect on what an exciting time it is for cancer research and how swiftly our understanding of cancer has improved. One year ago, the White House announced the national Cancer Moonshot program to accelerate progress against cancer. This shared vision of progress has reinvigorated the research community, identified new areas of scientific collaboration, and raised our ambitions regarding what may be possible beyond the progress we have already made. When I entered the field 35 years ago, I could not have imagined where we would be today. We can now detect cancer earlier, target treatments more effectively, and manage adverse effects more effectively to enable patients to live better, more fulfilling lives. Today, two of three people with cancer live at least 5 years after diagnosis, up from roughly one of two in the 1970s. This progress has resulted from decades of incremental advances that have collectively expanded our understanding of the molecular underpinnings of cancer. There is no better current example of this than ASCO's 2017 Advance of the Year: Immunotherapy 2.0. Over the last year, there has been a wave of new successes with immunotherapy. Research has proven this approach can be effective against a wide range of hard-to-treat advanced cancers previously considered intractable. Researchers are now working to identify biologic markers that can help increase the effectiveness of treatment and determine who is most likely to benefit from immunotherapy. This knowledge will enable oncologists to make evidence-based decisions so as many patients as possible might benefit from this new type of treatment. Each successive advance builds on the previous hard work of generations of basic, translational, and clinical cancer researchers

  2. Progress in Metabolomics Standardisation and its Significance in Future Clinical Laboratory Medicine

    PubMed Central

    Koal, Therese

    2016-01-01

    Today, the technology of ‘targeted’ based metabolomics is pivotal in the clinical analysis workflow as it provides information of metabolic phenotyping (metabotypes) by enhancing our understanding of metabolism of complex diseases, biomarker discovery for disease development, progression, treatment, and drug function and assessment. This review is focused on surveying and providing a gap analysis on metabolic phenotyping with a focus on targeted based metabolomics from an instrumental, technical point-of-view discussing the state-of-the-art instrumentation, pre- to post- analytical aspects as well as an overall future necessity for biomarker discovery and future (pre-) clinical routine application. PMID:28149265

  3. The role of technological progress vs. accidental discoveries and clinical experience in the evolution of dialysis

    PubMed Central

    Wańkowicz, Zofia

    2013-01-01

    The 50th anniversary of dialysotherapy celebrated by nephrologists around the world in 2012 provided an opportunity for discussion on the role of clinical experience in relation to technological progress in the evolution of dialysis, especially of recently observed inadequate decrease in mortality/morbidity rates of patients on chronic dialysis. My report, based on almost 50 years of career in nephrology, refers the evolution of dialysis, from catharsis to modern dialysotherapy with special attention devoted to nowadays gravely underestimated role of clinical experience and personalized professional care for patients. PMID:24226207

  4. The role of technological progress vs. accidental discoveries and clinical experience.

    PubMed

    Wańkowicz, Zofia

    2013-11-13

    The 50th anniversary of dialysotherapy celebrated by nephrologists around the world in 2012 provided an opportunity for discussion on the role of clinical experience in relation to technological progress in the evolution of dialysis, especially of recently observed inadequate decrease in mortality/morbidity rates of patients on chronic dialysis. My report, based on almost 50 years of career in nephrology, refers the evolution of dialysis, from catharsis to modern dialysotherapy with special attention devoted to nowadays gravely underestimated role of clinical experience and personalized professional care for patients.

  5. AFOMP Policy No 5: career progression for clinical medical physicists in AFOMP countries.

    PubMed

    Round, W H; Stefanoyiannis, A P; Ng, K H; Rodriguez, L V; Thayalan, K; Han, Y; Tang, F; Fukuda, S; Srivastava, R; Krisanachinda, A; Shiau, A C; Deng, X

    2015-06-01

    This policy statement, which is the fifth of a series of documents being prepared by the Asia-Oceania Federation of Organizations for Medical Physics Professional Development Committee, gives guidance on how clinical medical physicists' careers should progress from their initial training to career end. It is not intended to be prescriptive as in some AFOMP countries career structures are already essentially defined by employment awards and because such matters will vary considerably from country to country depending on local culture, employment practices and legislation. It is intended to be advisory and set out options for member countries and employers of clinical medical physicists to develop suitable career structures.

  6. Defining phenotypes and disease progression in sarcomeric cardiomyopathies: contemporary role of clinical investigations.

    PubMed

    Olivotto, Iacopo; d'Amati, Giulia; Basso, Cristina; Van Rossum, Albert; Patten, Monica; Emdin, Michele; Pinto, Yigal; Tomberli, Benedetta; Camici, Paolo G; Michels, Michelle

    2015-04-01

    Mutations in cardiac sarcomere protein genes are associated with a variety of clinical phenotypes, including hypertrophic (HCM), dilated (DCM), and restrictive (RCM) cardiomyopathy as well as left ventricular non-compaction, with the overlap of morpho-functional manifestations in individual patients and families. Over time, initial phenotypes may undergo profound changes which determine clinical course and disease progression. Although genetic defects causing HCM and DCM have opposite effects at the myofilament level, a number of downstream maladaptive mechanisms, ranging from microvascular dysfunction and ischaemia to myocardial fibrosis and from diastolic dysfunction to abnormal sympathetic activation and arrhythmogenesis, seem to recur in sarcomeric cardiomyopathies, independent of the presenting phenotype. The extent and rate at which each of these features occur and evolve may be radically different in each form of cardiomyopathy, determining a clinical heterogeneity that is not only cross-sectional, but also longitudinal, i.e. time-related. Timely and sensitive detection of these long-term modifications in the clinical setting is a key to preventing advanced disease and identifying novel therapeutic targets. The present review evaluates the contribution of contemporary technology to pre-clinical diagnosis, characterization of phenotypes, and assessment of disease progression in sarcomere cardiomyopathies, including echocardiography, positron emission tomography, magnetic resonance, pathology, and circulating biomarkers.

  7. Cutaneous angiosarcoma clinically presenting as progressive solid facial edema in a 43-year-old male.

    PubMed

    Choi, Won-Tak; Stetsenko, Galina Y; Zhang, Jiong; Olerud, John E; Argenyi, Zsolt B; George, Evan

    2013-11-15

    Cutaneous angiosarcoma of the head and neck is a rare, highly malignant neoplasm; prognosis is heavily influenced by tumor size, resectability, and stage at initial diagnosis. Most patients present with one to several erythematous to violaceous patches, plaques, or nodules. However, the clinical presentation is highly variable and leads to delayed diagnosis. We report cutaneous angiosarcoma in a 43-year-old man who presented with an 11-month history of progressive solid (non-pitting) edema involving his entire face, scalp, eyelids, and neck without characteristic clinical features of cutaneous angiosarcoma. A skin biopsy had shown non-specific findings consistent with solid facial edema or rosacea. Various etiologies were considered but there was no significant improvement after directed medical therapy. Repeat skin biopsies revealed angiosarcoma involving the dermis and sub-cutis. Computed tomography (CT) of the chest showed multiple lung nodules bilaterally and a lytic lesion in the T6 vertebra consistent with metastases. He was treated with single agent chemotherapy (paclitaxel), and had a partial response that restored his ability to open both eyes spontaneously; However, his edema has recently progressed 7 months after diagnosis. This is a rare example of cutaneous angiosarcoma presenting as progressive solid facial edema, which underscores the diverse range of clinical manifestations associated with this neoplasm.

  8. Poor R wave progression in the precordial leads: clinical implications for the diagnosis of myocardial infarction.

    PubMed

    DePace, N L; Colby, J; Hakki, A H; Manno, B; Horowitz, L N; Iskandrian, A S

    1983-12-01

    A definite diagnosis of anterior myocardial infarction is often difficult to make in patients when a pattern of poor R wave progression in the precordial leads is present on the electrocardiogram. The purpose of this study was to determine whether a mathematical model could be devised to identify patients with anterior infarction among 102 consecutive patients with poor R wave progression. Each patient underwent exercise testing with thallium scanning. The diagnosis of anterior infarction was established in 20 (20%) of the 102 patients by the presence of fixed thallium-201 perfusion defects in the anterior wall or septum, or both. With the use of a multivariate stepwise discriminant analysis of clinical and electrocardiographic variables, five variables (sex, ST-T changes, S wave amplitude in leads V2 and V3 and the sum of the R wave amplitude in leads V3 and V4) that were statistically significant by univariate analysis were selected by the model to identify patients with anterior infarction (sensitivity 85%, specificity 71%). The discriminant model was subsequently applied prospectively to an additional 21 patients with poor R wave progression and provided a sensitivity of 85% and a specificity of 88%. Thus, anterior infarction (fixed thallium-201 defects in the anteroseptal segments) was present in 20% of patients with poor R wave progression in the precordial leads; and a mathematical model can be used to identify a subset of patients with anterior infarction in a group of patients with poor R wave progression.

  9. Assessment of Poisson, logit, and linear models for genetic analysis of clinical mastitis in Norwegian Red cows.

    PubMed

    Vazquez, A I; Gianola, D; Bates, D; Weigel, K A; Heringstad, B

    2009-02-01

    Clinical mastitis is typically coded as presence/absence during some period of exposure, and records are analyzed with linear or binary data models. Because presence includes cows with multiple episodes, there is loss of information when a count is treated as a binary response. The Poisson model is designed for counting random variables, and although it is used extensively in epidemiology of mastitis, it has rarely been used for studying the genetics of mastitis. Many models have been proposed for genetic analysis of mastitis, but they have not been formally compared. The main goal of this study was to compare linear (Gaussian), Bernoulli (with logit link), and Poisson models for the purpose of genetic evaluation of sires for mastitis in dairy cattle. The response variables were clinical mastitis (CM; 0, 1) and number of CM cases (NCM; 0, 1, 2, ..). Data consisted of records on 36,178 first-lactation daughters of 245 Norwegian Red sires distributed over 5,286 herds. Predictive ability of models was assessed via a 3-fold cross-validation using mean squared error of prediction (MSEP) as the end-point. Between-sire variance estimates for NCM were 0.065 in Poisson and 0.007 in the linear model. For CM the between-sire variance was 0.093 in logit and 0.003 in the linear model. The ratio between herd and sire variances for the models with NCM response was 4.6 and 3.5 for Poisson and linear, respectively, and for model for CM was 3.7 in both logit and linear models. The MSEP for all cows was similar. However, within healthy animals, MSEP was 0.085 (Poisson), 0.090 (linear for NCM), 0.053 (logit), and 0.056 (linear for CM). For mastitic animals the MSEP values were 1.206 (Poisson), 1.185 (linear for NCM response), 1.333 (logit), and 1.319 (linear for CM response). The models for count variables had a better performance when predicting diseased animals and also had a similar performance between them. Logit and linear models for CM had better predictive ability for healthy

  10. Clinical cancer advances 2011: Annual Report on Progress Against Cancer from the American Society of Clinical Oncology.

    PubMed

    Vogelzang, Nicholas J; Benowitz, Steven I; Adams, Sylvia; Aghajanian, Carol; Chang, Susan Marina; Dreyer, Zoann Eckert; Janne, Pasi A; Ko, Andrew H; Masters, Greg A; Odenike, Olatoyosi; Patel, Jyoti D; Roth, Bruce J; Samlowski, Wolfram E; Seidman, Andrew D; Tap, William D; Temel, Jennifer S; Von Roenn, Jamie H; Kris, Mark G

    2012-01-01

    A message from ASCO'S President. It has been forty years since President Richard Nixon signed the National Cancer Act of 1971, which many view as the nation's declaration of the "War on Cancer." The bill has led to major investments in cancer research and significant increases in cancer survival. Today, two-thirds of patients survive at least five years after being diagnosed with cancer compared with just half of all diagnosed patients surviving five years after diagnosis in 1975. The research advances detailed in this year's Clinical Cancer Advances demonstrate that improvements in cancer screening, treatment, and prevention save and improve lives. But although much progress has been made, cancer remains one of the world's most serious health problems. In the United States, the disease is expected to become the nation's leading cause of death in the years ahead as our population ages. I believe we can accelerate the pace of progress, provided that everyone involved in cancer care works together to achieve this goal. It is this viewpoint that has shaped the theme for my presidential term: Collaborating to Conquer Cancer. In practice, this means that physicians and researchers must learn from every patient's experience, ensure greater collaboration between members of a patient's medical team, and involve more patients in the search for cures through clinical trials. Cancer advocates, insurers, and government agencies also have important roles to play. Today, we have an incredible opportunity to improve the quality of cancer care by drawing lessons from the real-world experiences of patients. The American Society of Clinical Oncology (ASCO) is taking the lead in this area, in part through innovative use of health information technology. In addition to our existing quality initiatives, ASCO is working with partners to develop a comprehensive rapid-learning system for cancer care. When complete, this system will provide physicians with personalized, real

  11. Progress and prospects of gene therapy clinical trials for the muscular dystrophies.

    PubMed

    Bengtsson, Niclas E; Seto, Jane T; Hall, John K; Chamberlain, Jeffrey S; Odom, Guy L

    2016-04-15

    Clinical trials represent a critical avenue for new treatment development, where early phases (I, I/II) are designed to test safety and effectiveness of new therapeutics or diagnostic indicators. A number of recent advances have spurred renewed optimism toward initiating clinical trials and developing refined therapies for the muscular dystrophies (MD's) and other myogenic disorders. MD's encompass a heterogeneous group of degenerative disorders often characterized by progressive muscle weakness and fragility. Many of these diseases result from mutations in genes encoding proteins of the dystrophin-glycoprotein complex (DGC). The most common and severe form among children is Duchenne muscular dystrophy, caused by mutations in the dystrophin gene, with an average life expectancy around 25 years of age. Another group of MD's referred to as the limb-girdle muscular dystrophies (LGMDs) can affect boys or girls, with different types caused by mutations in different genes. Mutation of the α-sarcoglycan gene, also a DGC component, causes LGMD2D and represents the most common form of LGMD. Early preclinical and clinical trial findings support the feasibility of gene therapy via recombinant adeno-associated viral vectors as a viable treatment approach for many MDs. In this mini-review, we present an overview of recent progress in clinical gene therapy trials of the MD's and touch upon promising preclinical advances.

  12. In utero stem cell transplantation and gene therapy: Recent progress and the potential for clinical application.

    PubMed

    McClain, Lauren E; Flake, Alan W

    2016-02-01

    Advances in prenatal diagnosis have led to the prenatal management and treatment of a variety of congenital diseases. Although surgical treatment has been successfully applied to specific anatomic defects that place the fetus at a risk of death or life-long disability, the indications for fetal surgical intervention have remained relatively limited. By contrast, prenatal stem cell and gene therapy await clinical application, but they have tremendous potential to treat a broad range of genetic disorders. If there are biological advantages unique to fetal development that favor fetal stem cell or gene therapy over postnatal treatment, prenatal therapy may become the preferred approach to the treatment of any disease that can be prenatally diagnosed and cured by stem cell or gene therapy. Here, we review the field including recent progress toward clinical application and imminent clinical trials for cellular and gene therapy.

  13. Aurora Kinase Inhibitors in Oncology Clinical Trials: Current State of the Progress.

    PubMed

    Falchook, Gerald S; Bastida, Christel C; Kurzrock, Razelle

    2015-12-01

    The Aurora kinase family of kinases (Aurora A, B, and C) are involved in multiple mitotic events, and aberrant expression of these kinases is associated with tumorigenesis. Aurora A and Aurora B are validated anticancer targets, and the development of Aurora kinase inhibitors has progressed from preclinical to clinical studies. A variety of Aurora A, B and pan-Aurora kinase inhibitors have entered the clinic. The main side effects include febrile neutropenia, stomatitis, gastrointestinal toxicity, hypertension, and fatigue. Responses including complete remissions have been described in diverse, advanced malignancies, most notably ovarian cancer and acute myelogenous leukemia. This review highlights the biologic rationale for Aurora kinase as a target, and clinical trials involving Aurora kinase inhibitors, with particular emphasis on published early phase studies, and the observed anti-tumor activity of these agents.

  14. Clinical and MRI models predicting amyloid deposition in progressive aphasia and apraxia of speech.

    PubMed

    Whitwell, Jennifer L; Weigand, Stephen D; Duffy, Joseph R; Strand, Edythe A; Machulda, Mary M; Senjem, Matthew L; Gunter, Jeffrey L; Lowe, Val J; Jack, Clifford R; Josephs, Keith A

    2016-01-01

    Beta-amyloid (Aβ) deposition can be observed in primary progressive aphasia (PPA) and progressive apraxia of speech (PAOS). While it is typically associated with logopenic PPA, there are exceptions that make predicting Aβ status challenging based on clinical diagnosis alone. We aimed to determine whether MRI regional volumes or clinical data could help predict Aβ deposition. One hundred and thirty-nine PPA (n = 97; 15 agrammatic, 53 logopenic, 13 semantic and 16 unclassified) and PAOS (n = 42) subjects were prospectively recruited into a cross-sectional study and underwent speech/language assessments, 3.0 T MRI and C11-Pittsburgh Compound B PET. The presence of Aβ was determined using a 1.5 SUVR cut-point. Atlas-based parcellation was used to calculate gray matter volumes of 42 regions-of-interest across the brain. Penalized binary logistic regression was utilized to determine what combination of MRI regions, and what combination of speech and language tests, best predicts Aβ (+) status. The optimal MRI model and optimal clinical model both performed comparably in their ability to accurately classify subjects according to Aβ status. MRI accurately classified 81% of subjects using 14 regions. Small left superior temporal and inferior parietal volumes and large left Broca's area volumes were particularly predictive of Aβ (+) status. Clinical scores accurately classified 83% of subjects using 12 tests. Phonological errors and repetition deficits, and absence of agrammatism and motor speech deficits were particularly predictive of Aβ (+) status. In comparison, clinical diagnosis was able to accurately classify 89% of subjects. However, the MRI model performed well in predicting Aβ deposition in unclassified PPA. Clinical diagnosis provides optimum prediction of Aβ status at the group level, although regional MRI measurements and speech and language testing also performed well and could have advantages in predicting Aβ status in unclassified PPA subjects.

  15. Primary Progressive Apraxia of Speech: Clinical Features and Acoustic and Neurologic Correlates

    PubMed Central

    Strand, Edythe A.; Clark, Heather; Machulda, Mary; Whitwell, Jennifer L.; Josephs, Keith A.

    2015-01-01

    Purpose This study summarizes 2 illustrative cases of a neurodegenerative speech disorder, primary progressive apraxia of speech (AOS), as a vehicle for providing an overview of the disorder and an approach to describing and quantifying its perceptual features and some of its temporal acoustic attributes. Method Two individuals with primary progressive AOS underwent speech-language and neurologic evaluations on 2 occasions, ranging from 2.0 to 7.5 years postonset. Performance on several tests, tasks, and rating scales, as well as several acoustic measures, were compared over time within and between cases. Acoustic measures were compared with performance of control speakers. Results Both patients initially presented with AOS as the only or predominant sign of disease and without aphasia or dysarthria. The presenting features and temporal progression were captured in an AOS Rating Scale, an Articulation Error Score, and temporal acoustic measures of utterance duration, syllable rates per second, rates of speechlike alternating motion and sequential motion, and a pairwise variability index measure. Conclusions AOS can be the predominant manifestation of neurodegenerative disease. Clinical ratings of its attributes and acoustic measures of some of its temporal characteristics can support its diagnosis and help quantify its salient characteristics and progression over time. PMID:25654422

  16. Clinical and ABCB11 profiles in Korean infants with progressive familial intrahepatic cholestasis

    PubMed Central

    Park, Ji Sook; Ko, Jae Sung; Seo, Jeong Kee; Moon, Jin Soo; Park, Sung Sup

    2016-01-01

    AIM: To investigate clinical profiles and mutations of ABCB11 in Koreans with progressive familial intrahepatic cholestasis 2 and review the differences between Koreans and others. METHODS: Of 47 patients with neonatal cholestasis, five infants had chronic intrahepatic cholestasis with normal γ-glutamyl transpeptidase. Direct sequencing analyses of ABCB11, including exons and introns, were performed from peripheral blood. RESULTS: Living donor-liver transplantation was performed in four patients because of rapidly progressive hepatic failure and hepatocellular carcinoma. Three missense mutations were found in two patients: compound heterozygous 677C>T (S226L)/3007G>A (G1003R) and heterozygous 2296G>A (G766R). The mutations were located near and in the transmembranous space. CONCLUSION: Alterations in the transmembrane of the bile salt export pump in the Korean infants were different from those previously reported in Chinese, Japanease, Taiwanese, and European patients. PMID:27239116

  17. Clinical and neuroimaging biomarkers of amyloid-negative logopenic primary progressive aphasia

    PubMed Central

    Whitwell, Jennifer L.; Duffy, Joseph R.; Strand, Edythe A.; Machulda, Mary M.; Senjem, Matthew L.; Schwarz, Christopher G.; Reid, Robert; Baker, Matthew C.; Perkerson, Ralph B.; Lowe, Val J.; Rademakers, Rosa; Jack, Clifford R.; Josephs, Keith A.

    2015-01-01

    Logopenic primary progressive aphasia (lvPPA) is a progressive language disorder characterized by anomia, difficulty repeating complex sentences, and phonological errors. The majority, although not all, lvPPA patients have underlying Alzheimer’s disease. We aimed to determine whether clinical or neuroimaging features differ according to the deposition of Aβ on Pittsburgh-compound B PET in lvPPA. Clinical features, patterns of atrophy on MRI, hypometabolism on FDG-PET, and white matter tract degeneration were compared between six PiB-negative and 20 PiB-positive lvPPA patients. PiB-negative patients showed more asymmetric left-sided patterns of atrophy, hypometabolism and white matter tract degeneration, with greater left anteromedial temporal and medial prefrontal involvement, than PiB-positive patients. PiB-positive patients showed greater involvement of right temporoparietal and frontal lobes. There was very little evidence for clinical differences between the groups. Strikingly asymmetric neuroimaging findings with relatively preserved right hemisphere may provide clues that AD pathology is absent in lvPPA. PMID:25658633

  18. Clinical features and disability milestones in multiple system atrophy and progressive supranuclear palsy.

    PubMed

    Lee, Sang-Wook; Koh, Seong-Beom

    2012-10-01

    Multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) are an adult-onset progressive neurodegenerative disorder that are known to display diverse clinical features and disease progression. We aim to characterize the clinical features and disease progression in patients with MSA and PSP by using a number of relevant disability milestones in Koreans. Forty-one patients with MSA and 14 patients with PSP had been enrolled. The mean age at onset of MSA-C, MSA-P and PSP was 56.7 ± 7.8, 62.5 ± 8.0, 68.9 ± 6.1 years respectively. The most commonly reported symptom at disease onset is disequilibrium/dizziness in MSA-C, tremor in MSA-P and frequent falling in PSP. The mean duration of reaching milestones after disease onset in MSA-C were as followings: 20.8 (urinary incontinence), 22.9 (frequent falling), 27.8 (wheelchair bound), 31.8 (dysarthria) and 35.8 months (diagnosis). The mean duration of reaching milestones after disease onset were 22.0 (urinary incontinence), 32.6 (frequent falling and diagnosis), 41.2 (dysarthria), 61.4 months (wheelchair bound) in MSA-P and 16.8 (dysarthria), 21.6 (diagnosis), 21.7 (frequent falling), 24.0 months (wheel chair bound) in PSP. In the case of MSA, dizziness may occur for the first time. Thus, when the patient complains of non-specific dizziness, a follow-up examination to distinguish it from MSA can be helpful. There was a trend for patients with MSA-C to reach more disability milestones than in MSA-P and PSP before diagnosis. It may explain why patients with MSA-C are required more detail history taking and neurologic examination at an earlier stage.

  19. Sativex(®) and clinical-neurophysiological measures of spasticity in progressive multiple sclerosis.

    PubMed

    Leocani, Letizia; Nuara, Arturo; Houdayer, Elise; Schiavetti, Irene; Del Carro, Ubaldo; Amadio, Stefano; Straffi, Laura; Rossi, Paolo; Martinelli, Vittorio; Vila, Carlos; Sormani, Maria Pia; Comi, Giancarlo

    2015-11-01

    Despite the proven efficacy of Sativex(®) (9-delta-tetrahydrocannabinol plus cannabidiol) oromucosal spray in reducing spasticity symptoms in multiple sclerosis (MS), little is known about the neurophysiological correlates of such effects. The aim of the study was to investigate the effects of Sativex on neurophysiological measures of spasticity (H/M ratio) and corticospinal excitability in patients with progressive MS. This was a randomized, double-blind, placebo-controlled, crossover study. Consecutive subjects with progressive MS and lower limb spasticity referred to our center were randomized to 4 weeks' treatment (including 2 weeks' titration) with Sativex or placebo, with crossover after a 2-week washout. Clinical and neurophysiological measures (H/M ratio and cortical excitability) of spasticity were assessed. The H/M ratio was the primary outcome, with sample size calculation of 40 patients. Of 44 recruited patients, 34 were analyzed due to 6 drop-outs and 4 exclusions, which lowered the power of the study to show differences between treatments. Neurophysiological measures did not differ significantly according to treatment and did not correlate significantly with clinical response. Response on the modified Ashworth scale (at least 20 % improvement) was significantly more frequent after Sativex than placebo (50 vs 23.5 %; p = 0.041; McNemar). Side effects did not differ significantly according to treatment. Our findings confirm the clinical benefit of Sativex on MS spasticity. The lack of corresponding changes in corticospinal excitability and on the monosynaptic component, of the stretch reflex, although in a limited sample size, points to the involvement of other spinal and supraspinal mechanisms in the physiopathology of spasticity in progressive MS.

  20. Completed suicide in a case of clinically diagnosed progressive supranuclear palsy.

    PubMed

    Wiener, Jennifer; Moran, Maria T; Haut, Marc W

    2015-08-01

    We present the clinical history and the cognitive and behavioral presentations of a male patient with suspected progressive supranuclear palsy (PSP) who fatally shot himself in the head. We believe his act of suicide was the consequence of impulsivity, rather than primary depression or mood disturbance. In cases of suspected PSP and other atypical parkinsonisms, health professionals must be aware of neurobehavioral risk factors for suicide attempts and completions to promote patient safety; however, the literature on this topic is sparse. Our case highlights the potentially lethal consequences of impulsivity and other neuropsychiatric symptoms in PSP and related syndromes.

  1. TGF-β Signaling in Gastrointestinal Cancers: Progress in Basic and Clinical Research

    PubMed Central

    Yokobori, Takehiko; Nishiyama, Masahiko

    2017-01-01

    Transforming growth factor (TGF)-β superfamily proteins have many important biological functions, including regulation of tissue differentiation, cell proliferation, and migration in both normal and cancer cells. Many studies have reported that TGF-β signaling is associated with disease progression and therapeutic resistance in several cancers. Similarly, TGF-β-induced protein (TGFBI)—a downstream component of the TGF-β signaling pathway—has been shown to promote and/or inhibit cancer. Here, we review the state of basic and clinical research on the roles of TGF-β and TGFBI in gastrointestinal cancers. PMID:28106769

  2. Impact of Aspiration Pneumonia on the Clinical Course of Progressive Supranuclear Palsy: A Retrospective Cohort Study

    PubMed Central

    Tomita, Satoshi; Oeda, Tomoko; Umemura, Atsushi; Kohsaka, Masayuki; Park, Kwiyoung; Yamamoto, Kenji; Sugiyama, Hiroshi; Mori, Chiaki; Inoue, Kimiko; Fujimura, Harutoshi; Sawada, Hideyuki

    2015-01-01

    Introduction Although aspiration pneumonia is the most common complication of progressive supranuclear palsy (PSP), the clinical impact of aspiration pneumonia on disease course and survival has not been fully estimated. Thus, we retrospectively analyzed the prognostic factors and clinical consequences of pneumonia in PSP. Methods The clinical course of patients with aspiration pneumonia was surveyed. The association between baseline clinical features (2 years from disease onset) and latency to the initial development of pneumonia was investigated using survival time and Cox regression analyses. Results Ninety patients with a clinical diagnosis of PSP were observed for 5.1±3.8 years (mean±SD), and 22 had aspiration pneumonia. Subsequently, 20 patients (91%) had to discontinue oral feeding entirely and 13 (59%) died, whereas, of 68 patients without pneumonia, only three patients (4%) died. Time to initial development of pneumonia was strongly correlated with survival time (Spearman R = 0.92, P<0.001), with a mean latency of 2.3 years to death. Among baseline clinical features, early fall episodes and cognitive decline were significant predictors of pneumonia (P = 0.001 and P<0.001, respectively, log rank test). Cox regression analysis demonstrated that early fall episodes (adjusted hazard ratio: 3.9, 95% confidence interval: 1.2–12.5, P = 0.03) and cognitive decline (adjusted hazard ratio: 5.2, 95% confidence interval: 1.4–19.3, P = 0.02) independently predicted pneumonia. By contrast, dysphagia was not associated with pneumonia (P = 0.2, log rank test). Conclusion Initial development of pneumonia indicates an unfavorable clinical course and predicts survival time (mean survival time 2.3 years). Patients with early falls and cognitive decline were at high risk of early development of pneumonia. PMID:26270456

  3. Twenty-Year Clinical Progression of Dysferlinopathy in Patients from Dagestan.

    PubMed

    Umakhanova, Zoya R; Bardakov, Sergei N; Mavlikeev, Mikhail O; Chernova, Olga N; Magomedova, Raisat M; Akhmedova, Patimat G; Yakovlev, Ivan A; Dalgatov, Gimat D; Fedotov, Valerii P; Isaev, Artur A; Deev, Roman V

    2017-01-01

    To date, over 30 genes with mutations causing limb-girdle muscle dystrophy have been described. Dysferlinopathies are a form of limb-girdle muscle dystrophy type 2B with an incidence ranging from 1:1,300 to 1:200,000 in different populations. In 1996, Dr. S. N. Illarioshkin described a family from the Botlikhsky district of Dagestan, where limb-girdle muscle dystrophy type 2B and Miyoshi myopathy were diagnosed in 12 members from three generations of a large Avar family. In 2000, a previously undescribed mutation in the DYSF gene (c.TG573/574AT; p. Val67Asp) was detected in the affected members of this family. Twenty years later, in this work, we re-examine five known and seven newly affected family members previously diagnosed with dysferlinopathy. We observed disease progression in family members who were previously diagnosed and noted obvious clinical polymorphism of the disease. A typical clinical case is provided.

  4. Cyclooxygenase and Alzheimer's disease: implications for preventive initiatives to slow the progression of clinical dementia.

    PubMed

    Pasinetti, G M.

    2001-08-01

    Industry and academia are devoting a tremendous amount of resources to the testing of anti-inflammatory drugs for the treatment of Alzheimer's disease (AD). This trend is the result of the growing consensus supporting the inflammatory hypothesis of AD. If anti-inflammatory strategies succeed in slowing the rate of disease progression, the impact on patients and families could be enormous. However, given the large number of candidates in the pool of anti-inflammatory drugs and given their widely divergent activities, it is essential to use methods which optimizes drug selection and study design. Pilot studies of anti-inflammatory regimens are useful in determining tolerability. However, these studies have limited value in estimating effective size since disease-modification, rather than symptomatic improvement, is the ultimate goal. Better understanding of the influence of inflammatory activity and the specific mechanisms which play an early role in the progression of the disease, will improve the likelihood of successfully identifying an effective anti-inflammatory treatment strategy. This review outlines directions in research that address possible contributions of cyclooxygenase (COX)-2, COX-1 and other inflammatory mediators to AD neurodegeneration. Finally, this article addresses potential interventions designed to control segments of classical inflammatory cascades in the brain in which cyclooxygenase is highly implicated. These considerations are critical to understand the role of cyclooxygenase in the clinical progression of AD.

  5. Optimising translational oncology in clinical practice: strategies to accelerate progress in drug development.

    PubMed

    Stahel, R; Bogaerts, J; Ciardiello, F; de Ruysscher, D; Dubsky, P; Ducreux, M; Finn, S; Laurent-Puig, P; Peters, S; Piccart, M; Smit, E; Sotiriou, C; Tejpar, S; Van Cutsem, E; Tabernero, J

    2015-02-01

    Despite intense efforts, the socioeconomic burden of cancer remains unacceptably high and treatment advances for many common cancers have been limited, suggesting a need for a new approach to drug development. One issue central to this lack of progress is the heterogeneity and genetic complexity of many tumours. This results in considerable variability in therapeutic response and requires knowledge of the molecular profile of the tumour to guide appropriate treatment selection for individual patients. While recent advances in the molecular characterisation of different cancer types have the potential to transform cancer treatment through precision medicine, such an approach presents a major economic challenge for drug development, since novel targeted agents may only be suitable for a small cohort of patients. Identifying the patients who would benefit from individual therapies and recruiting sufficient numbers of patients with particular cancer subtypes into clinical trials is challenging, and will require collaborative efforts from research groups and industry in order to accelerate progress. A number of molecular screening platforms have already been initiated across Europe, and it is hoped that these networks, along with future collaborations, will benefit not only patients but also society through cost reductions as a result of more efficient use of resources. This review discusses how current developments in translational oncology may be applied in clinical practice in the future, assesses current programmes for the molecular characterisation of cancer and describes possible collaborative approaches designed to maximise the benefits of translational science for patients with cancer.

  6. Monitoring progression in Friedreich ataxia (FRDA): the use of clinical scales.

    PubMed

    Bürk, Katrin; Schulz, Stefanie R; Schulz, Jörg B

    2013-08-01

    Friedreich ataxia (FRDA) is a progressive neurodegenerative disorder associated with ataxia, dysarthria, pyramidal tract signs, sensory loss, cardiomyopathy and diabetes. There is no cure for FRDA so far. Studies of the natural history of the disease and future therapeutic trials require development of appropriate outcome markers. Since any therapeutic benefit is expected to modulate deterioration over time rather than to reverse disability, potential outcome measures must be sensitive instruments carefully analysed for their significance. Clinical scales may represent an appropriate measuring tool. Over the last few years the construction, evaluation and validation of sensitive clinical scales for the assessment of disease severity and progression in ataxia have had considerable impact on our understanding of the disease. Currently, there are three different scales that are most frequently applied: The International Cooperative Ataxia Rating Scale (ICARS), the Friedreich Ataxia Rating Scale (FARS) and the Scale for the Assessment and Rating of Ataxia (SARA). All scales have been validated and compared with regard to their testing properties.

  7. Pediatric Targeted Therapy: Clinical Feasibility of Personalized Diagnostics in Children with Relapsed and Progressive Tumors.

    PubMed

    Selt, Florian; Deiß, Alica; Korshunov, Andrey; Capper, David; Witt, Hendrik; van Tilburg, Cornelis M; Jones, David T W; Witt, Ruth; Sahm, Felix; Reuss, David; Kölsche, Christian; Ecker, Jonas; Oehme, Ina; Hielscher, Thomas; von Deimling, Andreas; Kulozik, Andreas E; Pfister, Stefan M; Witt, Olaf; Milde, Till

    2016-07-01

    The "pediatric targeted therapy" (PTT) program aims to identify the presence and activity of druggable targets and evaluate the clinical benefit of a personalized treatment approach in relapsed or progressive tumors on an individual basis. 10 markers (HDAC2, HR23B, p-AKT, p-ERK, p-S6, p-EGFR, PDGFR-alpha/beta, p53 and BRAFV600E) were analyzed by immunohistochemistry. Pediatric patients with tumors independent of the histological diagnosis, with relapse or progression after treatment according to standard protocols were included. N = 61/145 (42%) cases were eligible for analysis between 2009 and 2013, the most common entities being brain tumors. Immunohistochemical stainings were evaluated by the H-Score (0-300). In 93% of the cases potentially actionable targets were identified. The expressed or activated pathways were histone deacetylase (HDACs; 83.0% of cases positive), EGFR (87.2%), PDGFR (75.9%), p53 (50.0%), MAPK/ERK (43.3%) and PI3K/mTOR (36.1%). Follow-up revealed partial or full implementation of PTT results in treatment decision-making in 41% of the cases. Prolonged disease stabilization responses in single cases were noticed, however, response rates did not differ from cases treated with other modalities. Further studies evaluating the feasibility and clinical benefit of personalized diagnostic approaches using paraffin material are warranted.

  8. Factors that influence career progression among postdoctoral clinical academics: a scoping review of the literature

    PubMed Central

    Ranieri, Veronica; Barratt, Helen; Fulop, Naomi; Rees, Geraint

    2016-01-01

    Background The future of academic medicine is uncertain. Concerns regarding the future availability of qualified and willing trainee clinical academics have been raised worldwide. Of significant concern is our failure to retain postdoctoral trainee clinical academics, who are likely to be our next generation of leaders in scientific discovery. Objectives To review the literature about factors that may influence postdoctoral career progression in early career clinical academics. Design This study employed a scoping review method. Three reviewers separately assessed whether the articles found fit the inclusion criteria. Data sources PubMed, Scopus, Web of Science and Google Scholar (1991–2015). Article selection The review encompassed a broad search of English language studies published anytime up to November 2015. All articles were eligible for inclusion, including research papers employing either quantitative or qualitative methods, as well as editorials and other summary articles. Data extraction Data extracted from included publications were charted according to author(s), sample population, study design, key findings, country of origin and year of publication. Results Our review identified 6 key influences: intrinsic motivation, work–life balance, inclusiveness, work environment, mentorship and availability of funding. It also detected significant gaps within the literature about these influences. Conclusions Three key steps are proposed to help support postdoctoral trainee clinical academics. These focus on ensuring that researchers feel encouraged in their workplace, involved in collaborative dialogue with key stakeholders and able to access reliable information regarding their chosen career pathway. Finally, we highlight recommendations for future research. PMID:27798036

  9. Progress with palbociclib in breast cancer: latest evidence and clinical considerations

    PubMed Central

    Rocca, Andrea; Schirone, Alessio; Maltoni, Roberta; Bravaccini, Sara; Cecconetto, Lorenzo; Farolfi, Alberto; Bronte, Giuseppe; Andreis, Daniele

    2016-01-01

    Deregulation of the cell cycle is a hallmark of cancer, and research on cell cycle control has allowed identification of potential targets for anticancer treatment. Palbociclib is a selective inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6), which are involved, with their coregulatory partners cyclin D, in the G1-S transition. Inhibition of this step halts cell cycle progression in cells in which the involved pathway, including the retinoblastoma protein (Rb) and the E2F family of transcription factors, is functioning, although having been deregulated. Among breast cancers, those with functioning cyclin D-CDK4/6-Rb-E2F are mainly hormone-receptor (HR) positive, with some HER2-positive and rare triple-negative cases. Deregulation results from genetic or otherwise occurring hyperactivation of molecules subtending cell cycle progression, or inactivation of cell cycle inhibitors. Based on results of randomized clinical trials, palbociclib was granted accelerated approval by the US Food and Drug Administration (FDA) for use in combination with letrozole as initial endocrine-based therapy for metastatic disease in postmenopausal women with HR-positive, HER2-negative breast cancer, and was approved for use in combination with fulvestrant in women with HR-positive, HER2-negative advanced breast cancer with disease progression following endocrine therapy. This review provides an update of the available knowledge on the cell cycle and its regulation, on the alterations in cyclin D-CDK4/6-Rb-E2F axis in breast cancer and their roles in endocrine resistance, on the preclinical activity of CDK4/6 inhibitors in breast cancer, both as monotherapy and as partners of combinatorial synergic treatments, and on the clinical development of palbociclib in breast cancer. PMID:28203301

  10. Progress with palbociclib in breast cancer: latest evidence and clinical considerations.

    PubMed

    Rocca, Andrea; Schirone, Alessio; Maltoni, Roberta; Bravaccini, Sara; Cecconetto, Lorenzo; Farolfi, Alberto; Bronte, Giuseppe; Andreis, Daniele

    2017-02-01

    Deregulation of the cell cycle is a hallmark of cancer, and research on cell cycle control has allowed identification of potential targets for anticancer treatment. Palbociclib is a selective inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6), which are involved, with their coregulatory partners cyclin D, in the G1-S transition. Inhibition of this step halts cell cycle progression in cells in which the involved pathway, including the retinoblastoma protein (Rb) and the E2F family of transcription factors, is functioning, although having been deregulated. Among breast cancers, those with functioning cyclin D-CDK4/6-Rb-E2F are mainly hormone-receptor (HR) positive, with some HER2-positive and rare triple-negative cases. Deregulation results from genetic or otherwise occurring hyperactivation of molecules subtending cell cycle progression, or inactivation of cell cycle inhibitors. Based on results of randomized clinical trials, palbociclib was granted accelerated approval by the US Food and Drug Administration (FDA) for use in combination with letrozole as initial endocrine-based therapy for metastatic disease in postmenopausal women with HR-positive, HER2-negative breast cancer, and was approved for use in combination with fulvestrant in women with HR-positive, HER2-negative advanced breast cancer with disease progression following endocrine therapy. This review provides an update of the available knowledge on the cell cycle and its regulation, on the alterations in cyclin D-CDK4/6-Rb-E2F axis in breast cancer and their roles in endocrine resistance, on the preclinical activity of CDK4/6 inhibitors in breast cancer, both as monotherapy and as partners of combinatorial synergic treatments, and on the clinical development of palbociclib in breast cancer.

  11. Word-finding difficulty: a clinical analysis of the progressive aphasias

    PubMed Central

    Rohrer, Jonathan D.; Knight, William D.; Warren, Jane E.; Fox, Nick C.; Rossor, Martin N.; Warren, Jason D.

    2008-01-01

    The patient with word-finding difficulty presents a common and challenging clinical problem. The complaint of ‘word-finding difficulty’ covers a wide range of clinical phenomena and may signify any of a number of distinct pathophysiological processes. Although it occurs in a variety of clinical contexts, word-finding difficulty generally presents a diagnostic conundrum when it occurs as a leading or apparently isolated symptom, most often as the harbinger of degenerative disease: the progressive aphasias. Recent advances in the neurobiology of the focal, language-based dementias have transformed our understanding of these processes and the ways in which they breakdown in different diseases, but translation of this knowledge to the bedside is far from straightforward. Speech and language disturbances in the dementias present unique diagnostic and conceptual problems that are not fully captured by classical models derived from the study of vascular and other acute focal brain lesions. This has led to a reformulation of our understanding of how language is organized in the brain. In this review we seek to provide the clinical neurologist with a practical and theoretical bridge between the patient presenting with word-finding difficulty in the clinic and the evidence of the brain sciences. We delineate key illustrative speech and language syndromes in the degenerative dementias, compare these syndromes with the syndromes of acute brain damage, and indicate how the clinical syndromes relate to emerging neurolinguistic, neuroanatomical and neurobiological insights. We propose a conceptual framework for the analysis of word-finding difficulty, in order both better to define the patient's complaint and its differential diagnosis for the clinician and to identify unresolved issues as a stimulus to future work. PMID:17947337

  12. Word-finding difficulty: a clinical analysis of the progressive aphasias.

    PubMed

    Rohrer, Jonathan D; Knight, William D; Warren, Jane E; Fox, Nick C; Rossor, Martin N; Warren, Jason D

    2008-01-01

    The patient with word-finding difficulty presents a common and challenging clinical problem. The complaint of 'word-finding difficulty' covers a wide range of clinical phenomena and may signify any of a number of distinct pathophysiological processes. Although it occurs in a variety of clinical contexts, word-finding difficulty generally presents a diagnostic conundrum when it occurs as a leading or apparently isolated symptom, most often as the harbinger of degenerative disease: the progressive aphasias. Recent advances in the neurobiology of the focal, language-based dementias have transformed our understanding of these processes and the ways in which they breakdown in different diseases, but translation of this knowledge to the bedside is far from straightforward. Speech and language disturbances in the dementias present unique diagnostic and conceptual problems that are not fully captured by classical models derived from the study of vascular and other acute focal brain lesions. This has led to a reformulation of our understanding of how language is organized in the brain. In this review we seek to provide the clinical neurologist with a practical and theoretical bridge between the patient presenting with word-finding difficulty in the clinic and the evidence of the brain sciences. We delineate key illustrative speech and language syndromes in the degenerative dementias, compare these syndromes with the syndromes of acute brain damage, and indicate how the clinical syndromes relate to emerging neurolinguistic, neuroanatomical and neurobiological insights. We propose a conceptual framework for the analysis of word-finding difficulty, in order both better to define the patient's complaint and its differential diagnosis for the clinician and to identify unresolved issues as a stimulus to future work.

  13. Meniscus Induced Cartilaginous Damage and Non-linear Gross Anatomical Progression of Early-stage Osteoarthritis in a Canine Model

    PubMed Central

    Kahn, David; Mittelstaedt, Daniel; Matyas, John; Qu, Xiangui; Lee, Ji Hyun; Badar, Farid; Les, Clifford; Zhuang, Zhiguo; Xia, Yang

    2016-01-01

    Background: The predictable outcome of the anterior cruciate ligament transection (ACLT) canine model, and the similarity to naturally occurring osteoarthritis (OA) in humans, provide a translatable method for studying OA. Still, evidence of direct meniscus-induced cartilaginous damage has not been identified, and gross-anatomical blinded scoring of early-stage OA has not been performed. Objective: A gross anatomical observation and statistical analysis of OA progression to determine meniscus induced cartilaginous damage, to measure the macroscopic progression of OA, and to address matters involving arthroscopic and surgical procedures of the knee. Method: Unblinded assessment and blinded scoring of meniscal, tibial, femoral, and patellar damage were performed for control and at four time points following unilateral ACLT: 3-week (N=4), 8-week (N=4), 12-week (N=5), and 25-week (N=4). Mixed-model statistics illustrates damage (score) progression; Wilcoxon rank-sum tests compared time-point scores; and Wilcoxon signed-rank tests compared ACLT and contralateral scores, and meniscus and tibia scores. Result: Damage was manifest first on the posterior aspect of the medial meniscus and subsequently on the tibia and femur, implying meniscal damage can precede, coincide with, and aggravate cartilage damage. Damage extent varied chronologically and was dependent upon the joint component. Meniscal damage was evident at 3 weeks and progressed through 25-weeks. Meniscal loose bodies corresponded to tibial cartilage damage location and extent through 12 weeks, followed by cartilage repair activity after complete meniscal degeneration. Conclusion: This study provides additional information for understanding OA progression, identifying OA biomarkers, and arthroscopic and meniscectomy procedures. PMID:28144379

  14. T Cell Vaccination Benefits Relapsing Progressive Multiple Sclerosis Patients: A Randomized, Double-Blind Clinical Trial

    PubMed Central

    Karussis, Dimitrios; Shor, Hagai; Yachnin, Julia; Lanxner, Naama; Amiel, Merav; Baruch, Keren; Keren-Zur, Yael; Haviv, Ofra; Filippi, Massimo; Petrou, Panayiota; Hajag, Shalom; Vourka-Karussis, Urania; Vaknin-Dembinsky, Adi; Khoury, Salim; Abramsky, Oded; Atlan, Henri; Cohen, Irun R.; Abulafia-Lapid, Rivka

    2012-01-01

    Background T-cell vaccination (TCV) for multiple sclerosis (MS) refers to treatment with autologous anti-myelin T-cells, attenuated by irradiation. Previously published clinical trials have been all open-labeled. Aim To evaluate the safety and efficacy of TCV in progressive MS, in a double-blind, controlled clinical trial. Methodology Twenty-six patients with relapsing-progressive MS were enrolled in the study (mean age: 39±9.8 years; mean EDSS: 4.4±1.7). T-cell lines reactive to 9 different peptides of the myelin antigens, MBP, MOG and PLP were raised from the patients' peripheral blood. The patients were randomized into two groups: 19 were treated with TCV (four subcutaneous injections of 10–30×106 T-cells, attenuated by irradiation, on days 1, 30, 90 and 180) and 7 patients were treated with sham injections. Twenty-four patients (17 in the TCV group and 7 in the placebo) were eligible for per-protocol analysis. Results At one year following the inclusion, an increase in the EDSS (+0.50) and an increase in 10-meter walking time (+0.18 sec), were observed in the placebo group; in the TCV group there was a decrease in the EDSS (−0.44; p<0.01) and in the 10-meter walking time (0.84 sec; p<0.005). Sixteen of the 17 patients (94.1%) in the TCV group remained relapse-free during the year of the study, as compared to 42.9% in the placebo group (p = 0.01 and p = 0.03 with adjustment). The proportion of patients with any relapse during the year of the study in the TCV-group, was reduced by 89.6%., as compared to the placebo-treated group. MRI parameters did not change significantly. Conclusions This is the first controlled, double-blind trial with TCV in progressive MS. The results demonstrate the feasibility and safety of the procedure, and provide significant indications of clinical efficacy. Further studies with larger groups of subjects are warranted. Trial Registration ClinicalTrials.gov NCT01448252 PMID:23272061

  15. [The first linear electron accelerator, the Therac 15 Saturne, in clinical service. I. Technical data and measurements in photon radiation].

    PubMed

    Strauch, B

    1983-09-01

    A report is given about the linear electron accelerator operating at the Alfried Krupp Krankenhaus in Essen. This is the first accelerator of the type Therac Saturne supplied for 15 MeV. Besides a description of the most important technical data and the service instructions, dosimetric data for 12 MV photon radiation are presented. The authors communicate the clinical experiences gained hitherto with the accelerator and the patient-orientated verification and recording system which has still to be improved, especially as far as the recording part is concerned. The accelerator meets the requirements of radiologic oncology.

  16. Clinical progression and outcome of dysphagia following thermal burn injury: a prospective cohort study.

    PubMed

    Rumbach, Anna F; Ward, Elizabeth C; Cornwell, Petrea L; Bassett, Lynell V; Muller, Michael J

    2012-01-01

    The objectives of this study were 1) to establish clinical profiles of dysphagic and nondysphagic individuals following thermal burn injury and 2) to provide a clinical profile of the progression and outcome of dysphagia resolution by hospital discharge for a dysphagic cohort. A total of 438 consecutively admitted patients with thermal burns were included. All patients underwent a clinical swallowing examination. Medical parameters regarding burn presentation and its treatment and speech-language pathology specific variables from admission to discharge were collected for each participant. Dysphagia was identified in 49 patients via clinical assessment, and their course of recovery was followed up until the point of dysphagia resolution or discharge. No significant difference was observed between the dysphagic and nondysphagic groups in age, gender, and injury etiology. However, the dysphagic cohort was significantly different from the nondysphagic group in all variables pertaining to injury presentation and medical management. Individuals with dysphagia took significantly longer to start, and maintain, oral intake and required nonoral supplementation for three and a half times longer than those who were nondysphagic. Length of speech-language pathology intervention averaged 1 month for the dysphagics and increased with dysphagia severity. Return to normal fluid consistencies occurred in >75% of dysphagic individuals by week 7 after injury, although resumption of normal diet textures was more protracted, with 75% resuming normal oral intake by week 9. Dysphagia had resolved in 50% of the cohort by week 6, and by hospital discharge, 85% of the dysphagic individuals had resumed normal oral intake of thin fluids and a general diet. This is the first large prospective cohort study to establish clinical profiles of dysphagic and nondysphagic cohorts and document the nature of dysphagia and patterns of recovery within the thermal burn population. These current data will

  17. Anti-dementia medications: current prescriptions in clinical practice and new agents in progress

    PubMed Central

    Stella, Florindo; Radanovic, Márcia; Canineu, Paulo Renato; de Paula, Vanessa J. R.

    2015-01-01

    Almost three decades after the publication of the first clinical studies with tacrine, the pharmacological treatment of Alzheimer’s disease (AD) remains a challenge. Randomized clinical trials have yielded evidence of significant – although modest and transient – benefit from cholinergic replacement therapy for people diagnosed with AD, and disease modification with antidementia compounds is still an urgent, unmet need. The natural history of AD is very long, and its pharmacological treatment must acknowledge different needs according to the stage of the disease process. Cognitive and functional deterioration evolves gradually since the onset of clinical symptoms, which may be preceded by several years or perhaps decades of silent, presymptomatic neurodegeneration. Therefore, the pharmacological treatment of AD must ideally comprise both a symptomatic effect to preserve or improve cognition and a disease-modifying effect to tackle the progression of the pathological process. Primary prevention is the ultimate goal, should these strategies be delivered to patients with preclinical AD. In this article, we briefly address the pharmaceutical compounds that are currently used for the symptomatic treatment of AD and discuss the ongoing strategies designed to modify its natural course. PMID:26301069

  18. Predictive factors of rapidly progressive-interstitial lung disease in patients with clinically amyopathic dermatomyositis.

    PubMed

    Xu, Y; Yang, C S; Li, Y J; Liu, X D; Wang, J N; Zhao, Q; Xiao, W G; Yang, P T

    2016-01-01

    Clinically amyopathic dermatomyositis (CADM) is a unique subset of dermatomyositis, showing a high incidence of lung involvements. The aim of this study is to identify risk factors, other than melanoma differentiation-associated protein (MDA)-5, for developing rapidly progressive-interstitial lung disease (RP-ILD) in patients with CADM. Forty CADM patients, in whom 11 patients developed RP-ILD, were enrolled. Clinical features and laboratory findings were compared between the patients with and without RP-ILD. We found that skin ulceration, CRP, serum ferritin, anti-MDA5 Ab, and lymphocytopenia were significantly associated with ILD. Multivariate logistic regression analysis indicated that anti-MDA5 Ab(+), elevated CRP, and decreased counts of lymphocyte were independent risk factors for RP-ILD, which can provide a precise predict for RP-ILD in CADM patients. When anti-MDA5 Ab(+) was removed from the multivariate regression model, using skin ulcerations, elevated serum ferritin and decreased counts of lymphocyte can also precisely predict RP-ILD. Except for MDA-5, more commonly available clinical characteristics, such as skin ulcerations, serum ferritin, and count of lymphocyte may also help to predict prognosis in CADM.

  19. RETURN TO PLAY PROGRESSION FOR RUGBY FOLLOWING INJURY TO THE LOWER EXTREMITY: A CLINICAL COMMENTARY AND REVIEW OF THE LITERATURE

    PubMed Central

    Davis, Chelseana C.

    2016-01-01

    Background & Purpose Rugby requires unique demands from its players. Those involved in rehabilitation and care of these athletes must possess an understanding of both the game and various positions. There have been numerous reports focusing on the physiological demands and biomechanical analyses of various components of gameplay, but no specific progression has been developed to assist clinicians assessing the readiness to return of a player after injury. The purpose of this clinical commentary is to outline testing components, general gameplay guidelines, movement progressions, and sport and position-specific progressions related to rugby gameplay following a lower extremity injury. Description of Topic This commentary provides a recommended progression for clinical use for use in a return to rugby program. It includes metabolic considerations, advanced strengthening exercises, agility exercises, and incorporation of drills specific to the sport of rugby that may be performed with the clinician or with assistance from team members. This progression also includes testing parameters for each phase and guidance for clinicians regarding the ability to gauge readiness to return to sport. Discussion It is essential that an athlete returning to the sport of rugby undertake a guided, graduated return to sport progression to ensure safety and to decrease the risk of re-injury. This proposed return to sport progression outlines key parameters for both the sport as a whole and for various specific positions. Level of Evidence Level 5 – Clinical Commentary, Review of Literature PMID:27104062

  20. Clinically meaningful parameters of progression and long-term outcome of Parkinson disease: An international consensus statement.

    PubMed

    Puschmann, Andreas; Brighina, Laura; Markopoulou, Katerina; Aasly, Jan; Chung, Sun Ju; Frigerio, Roberta; Hadjigeorgiou, Georgios; Kõks, Sulev; Krüger, Rejko; Siuda, Joanna; Wider, Christian; Zesiewicz, Theresa A; Maraganore, Demetrius M

    2015-07-01

    Parkinson disease (PD) is associated with a clinical course of variable duration, severity, and a combination of motor and non-motor features. Recent PD research has focused primarily on etiology rather than clinical progression and long-term outcomes. For the PD patient, caregivers, and clinicians, information on expected clinical progression and long-term outcomes is of great importance. Today, it remains largely unknown what factors influence long-term clinical progression and outcomes in PD; recent data indicate that the factors that increase the risk to develop PD differ, at least partly, from those that accelerate clinical progression and lead to worse outcomes. Prospective studies will be required to identify factors that influence progression and outcome. We suggest that data for such studies is collected during routine office visits in order to guarantee high external validity of such research. We report here the results of a consensus meeting of international movement disorder experts from the Genetic Epidemiology of Parkinson's Disease (GEO-PD) consortium, who convened to define which long-term outcomes are of interest to patients, caregivers and clinicians, and what is presently known about environmental or genetic factors influencing clinical progression or long-term outcomes in PD. We propose a panel of rating scales that collects a significant amount of phenotypic information, can be performed in the routine office visit and allows international standardization. Research into the progression and long-term outcomes of PD aims at providing individual prognostic information early, adapting treatment choices, and taking specific measures to provide care optimized to the individual patient's needs.

  1. Methodological Quality and Reporting of Generalized Linear Mixed Models in Clinical Medicine (2000–2012): A Systematic Review

    PubMed Central

    Casals, Martí; Girabent-Farrés, Montserrat; Carrasco, Josep L.

    2014-01-01

    Background Modeling count and binary data collected in hierarchical designs have increased the use of Generalized Linear Mixed Models (GLMMs) in medicine. This article presents a systematic review of the application and quality of results and information reported from GLMMs in the field of clinical medicine. Methods A search using the Web of Science database was performed for published original articles in medical journals from 2000 to 2012. The search strategy included the topic “generalized linear mixed models”,“hierarchical generalized linear models”, “multilevel generalized linear model” and as a research domain we refined by science technology. Papers reporting methodological considerations without application, and those that were not involved in clinical medicine or written in English were excluded. Results A total of 443 articles were detected, with an increase over time in the number of articles. In total, 108 articles fit the inclusion criteria. Of these, 54.6% were declared to be longitudinal studies, whereas 58.3% and 26.9% were defined as repeated measurements and multilevel design, respectively. Twenty-two articles belonged to environmental and occupational public health, 10 articles to clinical neurology, 8 to oncology, and 7 to infectious diseases and pediatrics. The distribution of the response variable was reported in 88% of the articles, predominantly Binomial (n = 64) or Poisson (n = 22). Most of the useful information about GLMMs was not reported in most cases. Variance estimates of random effects were described in only 8 articles (9.2%). The model validation, the method of covariate selection and the method of goodness of fit were only reported in 8.0%, 36.8% and 14.9% of the articles, respectively. Conclusions During recent years, the use of GLMMs in medical literature has increased to take into account the correlation of data when modeling qualitative data or counts. According to the current recommendations, the quality of

  2. Experimental Therapies and Ongoing Clinical Trials to Slow Down Progression of ADPKD

    PubMed Central

    Irazabal, Maria V.; Torres, Vicente E.

    2014-01-01

    The improvement of imaging techniques over the years has contributed to the understanding of the natural history of autosomal dominant polycystic kidney disease, and facilitated the observation of its structural progression. Advances in molecular biology and genetics have made possible a greater understanding of the genetics, molecular, and cellular pathophysiologic mechanisms responsible for its development and have laid the foundation for the development of potential new therapies. Therapies targeting genetic mechanisms in ADPKD have inherent limitations. As a result, most experimental therapies at the present time are aimed at delaying the growth of the cysts and associated interstitial inflammation and fibrosis by targeting tubular epithelial cell proliferation and fluid secretion by the cystic epithelium. Several interventions affecting many of the signaling pathways disrupted in ADPKD have been effective in animal models and some are currently being tested in clinical trials. PMID:23971644

  3. Experimental therapies and ongoing clinical trials to slow down progression of ADPKD.

    PubMed

    Irazabal, Maria V; Torres, Vicente E

    2013-02-01

    The improvement of imaging techniques over the years has contributed to the understanding of the natural history of autosomal dominant polycystic kidney disease, and facilitated the observation of its structural progression. Advances in molecular biology and genetics have made possible a greater understanding of the genetics, molecular, and cellular pathophysiologic mechanisms responsible for its development and have laid the foundation for the development of potential new therapies. Therapies targeting genetic mechanisms in ADPKD have inherent limitations. As a result, most experimental therapies at the present time are aimed at delaying the growth of the cysts and associated interstitial inflammation and fibrosis by targeting tubular epithelial cell proliferation and fluid secretion by the cystic epithelium. Several interventions affecting many of the signaling pathways disrupted in ADPKD have been effective in animal models and some are currently being tested in clinical trials.

  4. Progressive muscle proteome changes in a clinically relevant pig model of Duchenne muscular dystrophy

    PubMed Central

    Fröhlich, Thomas; Kemter, Elisabeth; Flenkenthaler, Florian; Klymiuk, Nikolai; Otte, Kathrin A.; Blutke, Andreas; Krause, Sabine; Walter, Maggie C.; Wanke, Rüdiger; Wolf, Eckhard; Arnold, Georg J.

    2016-01-01

    Duchenne muscular dystrophy (DMD) is caused by genetic deficiency of dystrophin and characterized by massive structural and functional changes of skeletal muscle tissue, leading to terminal muscle failure. We recently generated a novel genetically engineered pig model reflecting pathological hallmarks of human DMD better than the widely used mdx mouse. To get insight into the hierarchy of molecular derangements during DMD progression, we performed a proteome analysis of biceps femoris muscle samples from 2-day-old and 3-month-old DMD and wild-type (WT) pigs. The extent of proteome changes in DMD vs. WT muscle increased markedly with age, reflecting progression of the pathological changes. In 3-month-old DMD muscle, proteins related to muscle repair such as vimentin, nestin, desmin and tenascin C were found to be increased, whereas a large number of respiratory chain proteins were decreased in abundance in DMD muscle, indicating serious disturbances in aerobic energy production and a reduction of functional muscle tissue. The combination of proteome data for fiber type specific myosin heavy chain proteins and immunohistochemistry showed preferential degeneration of fast-twitch fiber types in DMD muscle. The stage-specific proteome changes detected in this large animal model of clinically severe muscular dystrophy provide novel molecular readouts for future treatment trials. PMID:27634466

  5. Power Calculations and Placebo Effect for Future Clinical Trials in Progressive Supranuclear Palsy

    PubMed Central

    Stamelou, Maria; Schöpe, Jakob; Wagenpfeil, Stefan; Ser, Teodoro Del; Bang, Jee; Lobach, Iryna Y.; Luong, Phi; Respondek, Gesine; Oertel, Wolfgang H.; Boxer, Adam L.; Höglinger, Günter U.

    2016-01-01

    Background Two recent randomized, placebo-controlled trials of putative disease-modifying agents (davunetide, tideglusib) in progressive supranuclear palsy (PSP) failed to show efficacy, but generated data relevant for future trials. Methods We provide sample size calculations based on data collected in 187 PSP patients assigned to placebo in these trials. A placebo effect was calculated. Results The total PSP-Rating Scale required the least number of patients per group (N = 51) to detect a 50% change in the 1-year progression and 39 when including patients with ≤ 5 years disease duration. The Schwab and England Activities of Daily Living required 70 patients per group and was highly correlated with the PSP-Rating Scale. A placebo effect was not detected in these scales. Conclusions We propose the 1-year PSP-Rating Scale score change as the single primary readout in clinical neuroprotective or disease-modifying trials. The Schwab and England Activities of Daily Living could be used as a secondary outcome. PMID:26948290

  6. Task-specific writing tremor: clinical phenotypes, progression, treatment outcomes, and proposed nomenclature.

    PubMed

    Ondo, William G; Satija, Pankaj

    2012-02-01

    Task-specific tremor diagnoses remain controversial. We evaluated 56 subjects seen with writing tremor. The diagnosis was made if there was a clear history of exclusive tremor while writing for at least 3 years before noticing tremor in any other scenario and the continued presence of writing tremor as the most prominent aspect of their tremor disorder on examination. The age of tremor onset was 47.2 ± 18.0 years (73.2% male). Ethnic backgrounds were Caucasian (68.4%), African (23.2%), Hispanic (5.2%), and Asian/Indian (3.3%), and 44% reported any tremor in a first degree relative. Writing tremor often progressed to other task-specific tremors or rest tremor but not to immediate postural tremor, as usually seen in essential tremor. The other tremor provoking scenarios were eating/drinking (14), brushing teeth/shaving/make-up (5), typing (2), suture removal (1), and drafting (1) and occurred a mean of 7.5 years after the onset of writing tremor. Fourteen developed a "rest" (true rest or crescendo) tremor but only 2 of these met clinical criteria for Parkinson's disease. Pharmacologic treatments of writing tremor, including with ethanol, were generally poor, whereas deep brain stimulation of the ventral intermediate (VIM) thalamus was successful. Compared with patients with "classic" essential tremor in our clinic, writing tremor patients were more likely African, more likely male, had an older age of onset, a lower likelihood of familial tremor, and were more refractory to tremor medications and ethanol. This supports segregation between task-specific tremor and essential tremor but does not support the specific diagnosis of "writing tremor" because many patients progress to tremor with other tasks.

  7. End-points and clinical trial design in pulmonary arterial hypertension: have we made progress?

    PubMed

    Peacock, A J; Naeije, R; Galiè, N; Rubin, L

    2009-07-01

    There is enormous interest in the treatment of pulmonary arterial hypertension (PAH), so it is appropriate to consider the design of trials of new therapies and the end-points to be measured when trying to decide whether or not a therapy is effective. In May 2003, the first meeting devoted solely to the discussion of end-points and trial design in PAH was held in Gleneagles, UK. At that time, most of the randomised controlled trials in PAH had used 6-min walking distance and/or resting haemodynamics as their primary end-points. The present article considers the progress that has been made since 2003. It deals with aspects of clinical trial design (such as noninferiority, superiority and withdrawal trials), considers end-points used in previous and current studies (such as 6-min walking distance, time to clinical worsening, haemodynamics, imaging and plasma brain natriuretic peptide), and considers what end-points might be used in the future. The second end-points meeting was held in Turnberry, UK, in June 2007. It had a similar format to the first meeting. Much of what is presented here is a summary of the workshops from that meeting. An attempt has been made to both summarise the current state of end-points and trial design and suggest new ways in which they could be improved. The present article forms one of a series being published in the European Respiratory Journal on pulmonary hypertension.

  8. Pathological and Clinical Spectrum of Progressive Supranuclear Palsy: With Special Reference to Astrocytic Tau Pathology.

    PubMed

    Yokoyama, Yuichi; Toyoshima, Yasuko; Shiga, Atsushi; Tada, Mari; Kitamura, Hideaki; Hasegawa, Kazuko; Onodera, Osamu; Ikeuchi, Takeshi; Someya, Toshiyuki; Nishizawa, Masatoyo; Kakita, Akiyoshi; Takahashi, Hitoshi

    2016-03-01

    Progressive supranuclear palsy (PSP) is a four-repeat tauopathy with tau-positive, argyrophilic tuft-shaped astrocytes (TAs). We performed a pathological and clinical investigation in 40 consecutive autopsied Japanese patients with pathological diagnoses of PSP or PSP-like disease. Unequivocal TAs were present in 22 cases, all of which were confirmed to be PSP. Such TAs were hardly detected in the other 18 cases, which instead exhibited tau-positive, argyrophilic astrocytes, appearing as comparatively small clusters with central nuclei of irregularly shaped, coarse structures (equivocal TAs). Cluster analysis of the distribution pattern of tau-related pathology for these 18 cases identified two subgroups, pallido-nigro-luysian atrophy (PNLA) Type 1 (n = 9) and Type 2 (n = 9), the former being distinguished from the latter by the presence of tau-related lesions in the motor cortex, pontine nucleus and cerebellar dentate nucleus in addition to the severely affected PNL system. The duration from symptom onset until becoming wheelchair-bound was significantly longer in PNLA Type 1. Immunoblotting of samples from the three disease conditions revealed band patterns of low-molecular-mass tau fragments at ∼35 kDa. These findings shed further light on the wide pathological and clinical spectrum of four-repeat tauopathy, representing PSP in the broad sense rather than classical PSP.

  9. 466 Bee venom Immunotherapy with Standardized Extract, Two Case Comunication and Clinical Progress

    PubMed Central

    Cardona, Aristoteles Alvarez; Nieto, Leticia Hernandez; Melendez, Alvaro Pedroza

    2012-01-01

    Background Bee venom immunotherapy is a safe and effective treatment, indicated in patients with previous history of severe systemic reactions to bee venom, demonstrating succesful desensitization in more than 90% of cases with standardized extract. Currently in Mexico there is no standardized extract commercially available for treatment, despite of having high activity of beekeeping and occupational exposure with at least 17,478 registered stings per year and an annually honey production of nearly 70 tons. Methods We present the clinical progress of 2 patients with history of severe systemic reactions to bee venom and occupational exposure, both with demonstrated sensitization by specific IgE and who underwent specific immunotherapy with standardized extract (Alk-US) reaching a maintenance weekly dose of 100 mcg (PLA2) for the last 4 years. Results Both patients sufered of accidental stings after reached the maintenance dose presenting mild local reactions to stings. Both patients had very different clinical course presenting a wide variety of adverse reactions during desensitization protocol; from mild local to generalized reactions all generally well tolerated allowed to reach the maintenance dose with succesful desensitization proved by accidental exposure without severe systemic reactions. Conclusions Bee venom specific immunotherapy with standardized extract is a well tolerated and efective treatment preventing the development of life threathening reactions in sensitized patients. It is important to promote the use and availability of standardized extract in developing countries with poor safety measures and high occupational exposure.

  10. The hypocretin/orexin system in sleep disorders: preclinical insights and clinical progress.

    PubMed

    Chow, Matthew; Cao, Michelle

    2016-01-01

    Much of the understanding of the hypocretin/orexin (HCRT/OX) system in sleep-wake regulation came from narcolepsy-cataplexy research. The neuropeptides hypocretin-1 and -2/orexin-A and -B (HCRT-1 and -2/OX-A and -B, respectively), as we know, are intimately involved in the regulation wakefulness. The HCRT/OX system regulates sleep-wake control through complex interactions between monoaminergic/cholinergic (wake-promoting) and gamma-aminobutyric acid-ergic (sleep-promoting) neuronal systems. Deficiency of HCRT/OX results in loss of sleep-wake control or stability with consequent unstable transitions between wakefulness to nonrapid eye movement and rapid eye movement sleep. This manifests clinically as abnormal daytime sleepiness with sleep attacks and cataplexy. Research on the development of HCRT/OX agonists and antagonists for the treatment of sleep disorders has dramatically increased with the US Food and Drug Administration approval of the first-in-class dual HCRT/OX receptor antagonist for the treatment of insomnia. This review focuses on the origin, mechanisms of HCRT/OX receptors, clinical progress, and applications for the treatment of sleep disorders.

  11. The hypocretin/orexin system in sleep disorders: preclinical insights and clinical progress

    PubMed Central

    Chow, Matthew; Cao, Michelle

    2016-01-01

    Much of the understanding of the hypocretin/orexin (HCRT/OX) system in sleep–wake regulation came from narcolepsy–cataplexy research. The neuropeptides hypocretin-1 and -2/orexin-A and -B (HCRT-1 and -2/OX-A and -B, respectively), as we know, are intimately involved in the regulation wakefulness. The HCRT/OX system regulates sleep–wake control through complex interactions between monoaminergic/cholinergic (wake-promoting) and gamma-aminobutyric acid-ergic (sleep-promoting) neuronal systems. Deficiency of HCRT/OX results in loss of sleep–wake control or stability with consequent unstable transitions between wakefulness to nonrapid eye movement and rapid eye movement sleep. This manifests clinically as abnormal daytime sleepiness with sleep attacks and cataplexy. Research on the development of HCRT/OX agonists and antagonists for the treatment of sleep disorders has dramatically increased with the US Food and Drug Administration approval of the first-in-class dual HCRT/OX receptor antagonist for the treatment of insomnia. This review focuses on the origin, mechanisms of HCRT/OX receptors, clinical progress, and applications for the treatment of sleep disorders. PMID:27051324

  12. Progress of near-infrared spectroscopy and topography for brain and muscle clinical applications.

    PubMed

    Wolf, Martin; Ferrari, Marco; Quaresima, Valentina

    2007-01-01

    This review celebrates the 30th anniversary of the first in vivo near-infrared (NIR) spectroscopy (NIRS) publication, which was authored by Professor Frans Jobsis. At first, NIRS was utilized to experimentally and clinically investigate cerebral oxygenation. Later it was applied to study muscle oxidative metabolism. Since 1993, the discovery that the functional activation of the human cerebral cortex can be explored by NIRS has added a new dimension to the research. To obtain simultaneous multiple and localized information, a further major step forward was achieved by introducing NIR imaging (NIRI) and tomography. This review reports on the progress of the NIRS and NIRI instrumentation for brain and muscle clinical applications 30 years after the discovery of in vivo NIRS. The review summarizes the measurable parameters in relation to the different techniques, the main characteristics of the prototypes under development, and the present commercially available NIRS and NIRI instrumentation. Moreover, it discusses strengths and limitations and gives an outlook into the "bright" future.

  13. Twenty-Year Clinical Progression of Dysferlinopathy in Patients from Dagestan

    PubMed Central

    Umakhanova, Zoya R.; Bardakov, Sergei N.; Mavlikeev, Mikhail O.; Chernova, Olga N.; Magomedova, Raisat M.; Akhmedova, Patimat G.; Yakovlev, Ivan A.; Dalgatov, Gimat D.; Fedotov, Valerii P.; Isaev, Artur A.; Deev, Roman V.

    2017-01-01

    To date, over 30 genes with mutations causing limb-girdle muscle dystrophy have been described. Dysferlinopathies are a form of limb-girdle muscle dystrophy type 2B with an incidence ranging from 1:1,300 to 1:200,000 in different populations. In 1996, Dr. S. N. Illarioshkin described a family from the Botlikhsky district of Dagestan, where limb-girdle muscle dystrophy type 2B and Miyoshi myopathy were diagnosed in 12 members from three generations of a large Avar family. In 2000, a previously undescribed mutation in the DYSF gene (c.TG573/574AT; p. Val67Asp) was detected in the affected members of this family. Twenty years later, in this work, we re-examine five known and seven newly affected family members previously diagnosed with dysferlinopathy. We observed disease progression in family members who were previously diagnosed and noted obvious clinical polymorphism of the disease. A typical clinical case is provided. PMID:28337173

  14. Progress in understanding disruptions triggered by massive gas injection via 3D non-linear MHD modelling with JOREK

    NASA Astrophysics Data System (ADS)

    Nardon, E.; Fil, A.; Hoelzl, M.; Huijsmans, G.; contributors, JET

    2017-01-01

    3D non-linear MHD simulations of a D 2 massive gas injection (MGI) triggered disruption in JET with the JOREK code provide results which are qualitatively consistent with experimental observations and shed light on the physics at play. In particular, it is observed that the gas destabilizes a large m/n  =  2/1 tearing mode, with the island O-point coinciding with the gas deposition region, by enhancing the plasma resistivity via cooling. When the 2/1 island gets so large that its inner side reaches the q  =  3/2 surface, a 3/2 tearing mode grows. Simulations suggest that this is due to a steepening of the current profile right inside q  =  3/2. Magnetic field stochastization over a large fraction of the minor radius as well as the growth of higher n modes ensue rapidly, leading to the thermal quench (TQ). The role of the 1/1 internal kink mode is discussed. An I p spike at the TQ is obtained in the simulations but with a smaller amplitude than in the experiment. Possible reasons are discussed.

  15. Clinical outcome, valve dysfunction, and progressive aortic dilation in a pediatric population with isolated bicuspid aortic valve.

    PubMed

    Spaziani, Gaia; Ballo, Piercarlo; Favilli, Silvia; Fibbi, Veronica; Buonincontri, Lorenzo; Pollini, Iva; Zuppiroli, Alfredo; Chiappa, Enrico

    2014-06-01

    The aim of this study was to explore the medium-term clinical outcome and the risk of progression of aortic valve disease and aortic dilation in pediatric patients with isolated bicuspid aortic valve (BAV). 179 pediatric patients with isolated BAV were prospectively followed from January 1995 to December 2010. Patients with severe valve dysfunction at baseline were excluded. Clinical outcome included cardiac death, infective endocarditis, aortic complications, cardiac surgery and percutaneous valvuloplasty. Echocardiographic endpoints were: progression of aortic stenosis (AS) or regurgitation (AR) and progressive aortic enlargement at different levels of the aortic root, evaluated as z-score. The median age at diagnosis was 7.8 [2.7-12.0] years. After a median followup of 5.4 [2.3-9.2] years, all patients were alive. The clinical endpoint occurred in 4 (2.2 %) patients (0.41 events per 100 patient-years). A progression of AS and AR was observed in 9 (5.0 %) and 29 (16.2 %) patients, respectively. The z-scores at the end of follow-up were not significantly different from baseline at the annulus, Valsalva sinuses and sinotubular junction, whereas a slight increase was observed at the level of the ascending aorta (1.9 vs 1.5, p = 0.046). Significant progressive aortic dilation occurred in a minority of patients (10.6, 5.6, 9.5, and 19.0 % respectively). The clinical outcome in pediatric patients with isolated BAV is favourable and the progression of aortic valve dysfunction and aortic dilation is relatively slow. These findings may be taken into account to better guide risk assessment and clinical follow-up in these patients.

  16. Direct reconstruction of the source intensity distribution of a clinical linear accelerator using a maximum likelihood expectation maximization algorithm.

    PubMed

    Papaconstadopoulos, P; Levesque, I R; Maglieri, R; Seuntjens, J

    2016-02-07

    Direct determination of the source intensity distribution of clinical linear accelerators is still a challenging problem for small field beam modeling. Current techniques most often involve special equipment and are difficult to implement in the clinic. In this work we present a maximum-likelihood expectation-maximization (MLEM) approach to the source reconstruction problem utilizing small fields and a simple experimental set-up. The MLEM algorithm iteratively ray-traces photons from the source plane to the exit plane and extracts corrections based on photon fluence profile measurements. The photon fluence profiles were determined by dose profile film measurements in air using a high density thin foil as build-up material and an appropriate point spread function (PSF). The effect of other beam parameters and scatter sources was minimized by using the smallest field size ([Formula: see text] cm(2)). The source occlusion effect was reproduced by estimating the position of the collimating jaws during this process. The method was first benchmarked against simulations for a range of typical accelerator source sizes. The sources were reconstructed with an accuracy better than 0.12 mm in the full width at half maximum (FWHM) to the respective electron sources incident on the target. The estimated jaw positions agreed within 0.2 mm with the expected values. The reconstruction technique was also tested against measurements on a Varian Novalis Tx linear accelerator and compared to a previously commissioned Monte Carlo model. The reconstructed FWHM of the source agreed within 0.03 mm and 0.11 mm to the commissioned electron source in the crossplane and inplane orientations respectively. The impact of the jaw positioning, experimental and PSF uncertainties on the reconstructed source distribution was evaluated with the former presenting the dominant effect.

  17. Progressive ataxia and palatal tremor (PAPT): clinical and MRI assessment with review of palatal tremors.

    PubMed

    Samuel, Michael; Torun, Nurhan; Tuite, Paul J; Sharpe, James A; Lang, Anthony E

    2004-06-01

    Palatal tremor has been subdivided into essential (EPT) and symptomatic palatal tremor (SPT). A subgroup of the SPT form has a syndrome of progressive ataxia and palatal tremor (PAPT). Published details of cases of PAPT are sparse and the disorder appears heterogeneous. We present clinical and MRI features of six patients with sporadic PAPT who attended The University Health Network between 1991 and 2002. Eye movements were recorded using a magnetic search coil technique. We review previously reported cases of PAPT from the English language literature and relate this disorder to EPT and SPT. PAPT may be divided into sporadic and familial forms. We identified 22 other prior reported cases of sporadic PAPT. Sporadic PAPT is a subtype of SPT in which progressive cerebellar degeneration is the most symptomatic feature. A combination of vertical nystagmus and palatal tremor was found in one of our cases. Internuclear ophthalmoplegia, a new finding, was present in two of our patients and indicated additional brainstem dysfunction. Inferior olivary high signal abnormalities were present on MRI in all of our cases. The cause of sporadic PAPT remains uncertain. In some previous reports of sporadic PAPT, the combination of brainstem or pontine atrophy, parkinsonism, autonomic dysfunction or corticospinal tract abnormalities suggests a diagnosis of multiple system atrophy, although pathological verification is lacking. Familial PAPT is associated with marked brainstem and cervical cord atrophy with corticospinal tract findings, but the typical olivary MRI abnormalities have not been reported. A substitution in the glial fibrillary acidic protein (GFAP) gene has been described in a family with PAPT, raising the possibility of Alexander's disease. One other familial syndrome of PAPT, termed 'dark dentate disease', has also been reported. PAPT is a subgroup of SPT in which ataxia progresses and is not usually the result of a monophasic illness. Eye movement abnormalities suggest

  18. Effect of Creatine Monohydrate on Clinical Progression in Patients With Parkinson Disease

    PubMed Central

    2015-01-01

    IMPORTANCE There are no treatments available to slow or prevent the progression of Parkinson disease, despite its global prevalence and significant health care burden. The National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson Disease program was established to promote discovery of potential therapies. OBJECTIVE To determine whether creatine monohydrate was more effective than placebo in slowing long-term clinical decline in participants with Parkinson disease. DESIGN, SETTING, AND PATIENTS The Long-term Study 1, a multicenter, double-blind, parallel-group, placebo-controlled, 1:1 randomized efficacy trial. Participants were recruited from 45 investigative sites in the United States and Canada and included 1741 men and women with early (within 5 years of diagnosis) and treated (receiving dopaminergic therapy) Parkinson disease. Participants were enrolled from March 2007 to May 2010 and followed up until September 2013. INTERVENTIONS Participants were randomized to placebo or creatine (10 g/d) monohydrate for a minimum of 5 years (maximum follow-up, 8 years). MAIN OUTCOMES AND MEASURES The primary outcome measure was a difference in clinical decline from baseline to 5-year follow-up, compared between the 2 treatment groups using a global statistical test. Clinical status was defined by 5 outcome measures: Modified Rankin Scale, Symbol Digit Modalities Test, PDQ-39 Summary Index, Schwab and England Activities of Daily Living scale, and ambulatory capacity. All outcomes were coded such that higher scores indicated worse outcomes and were analyzed by a global statistical test. Higher summed ranks (range, 5–4775) indicate worse outcomes. RESULTS The trial was terminated early for futility based on results of a planned interim analysis of participants enrolled at least 5 years prior to the date of the analysis (n = 955). The median follow-up time was 4 years. Of the 955 participants, the mean of the summed ranks for placebo was 2360 (95

  19. Presence of specific MHC Class II expressed alleles associates with clinical disease in ovine progressive pneumonia virus (OPPV) infected sheep

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A genetic tool hypothesized to predict which OPPV infected sheep will progress to debilitating clinical disease is MHC Class II Ovis aries (Ovar)-DRB1. Previously, fifteen Ovar-DRB1 beta 1 expressed alleles were identified in a ewe-lamb flock of 32 originating from an Idaho flock using RT-PCR, clon...

  20. Down syndrome: genes, model systems, and progress towards pharmacotherapies and clinical trials for cognitive deficits.

    PubMed

    Busciglio, J; Capone, G; O'Bryan, J; O'Byran, J P; Gardiner, K J

    2013-01-01

    Down syndrome (DS) is caused by an extra copy of all or part of the long arm of human chromosome 21 (HSA21). While the complete phenotype is both complex, involving most organs and organ systems, and variable in severity among individuals, intellectual disability (ID) is seen in all people with DS and may have the most significant impact on quality of life. Because the worldwide incidence of DS remains at approximately 1 in 1,000 live births, DS is the most common genetic cause of ID. In recent years, there have been important advances in our understanding of the functions of genes encoded by HSA21 and in the number and utility of in vitro and in vivo systems for modeling DS. Of particular importance, several pharmacological treatments have been shown to rescue learning and memory deficits in one mouse model of DS, the Ts65Dn. Because adult mice were used in the majority of these experiments, there is considerable interest in extending the studies to human clinical trials, and a number of trials have been completed, are in progress or are being planned. A recent conference brought together researchers with a diverse array of expertise and interests to discuss (1) the functions of HSA21 genes with relevance to ID in DS, (2) the utility of model systems including Caenorhabditis elegans, zebrafish and mouse, as well as human neural stem cells and induced pluripotent stems cells, for studies relevant to ID in DS, (3) outcome measures used in pharmacological treatment of mouse models of DS and (4) outcome measures suitable for clinical trials for cognition in adults and children with DS.

  1. Real-time photoacoustic and ultrasound imaging: a simple solution for clinical ultrasound systems with linear arrays.

    PubMed

    Montilla, Leonardo G; Olafsson, Ragnar; Bauer, Daniel R; Witte, Russell S

    2013-01-07

    Recent clinical studies have demonstrated that photoacoustic imaging (PAI) provides important diagnostic information during a routine breast exam for cancer. PAI enhances contrast between blood vessels and background tissue, which can help characterize suspicious lesions. However, most PAI systems are either not compatible with commercial ultrasound systems or inefficiently deliver light to the region of interest, effectively reducing the sensitivity of the technique. To address and potentially overcome these limitations, we developed an accessory for a standard linear ultrasound array that optimizes light delivery for PAI. The photoacoustic enabling device (PED) exploits an optically transparent acoustic reflector to help direct laser illumination to the region of interest. This study compares the PED with standard fiber bundle illumination in scattering and non-scattering media. In scattering media with the same incident fluence, the PED enhanced the photoacoustic signal by 18 dB at a depth of 5 mm and 6 dB at a depth of 20 mm. To demonstrate in vivo feasibility, we also used the device to image a mouse with a pancreatic tumor. The PED identified blood vessels at the periphery of the tumor, suggesting that PAI provides complementary contrast to standard pulse echo ultrasound. The PED is a simple and inexpensive solution that facilitates the translation of PAI technology to the clinic for routine screening of breast cancer.

  2. A double-blind clinical trial of mitoxantrone versus methylprednisolone in relapsing, secondary progressive multiple sclerosis.

    PubMed

    van de Wyngaert, F A; Beguin, C; D'Hooghe, M B; Dooms, G; Lissoir, F; Carton, H; Sindic, C J

    2001-12-01

    A double-blind clinical trial of mitoxantrone versus methylprednisolone was performed in 49 patients with relapsing, secondary multiple sclerosis. Patients were randomized to receive 13 infusions of mitoxantrone 12 mg/m2 (n = 28), or 13 infusions of 1 g of methylprednisolone (n = 21), over 32 months. Twenty-four patients completed the trial. There were no statistical differences between the two groups of patients at study entry. A significant improvement in the Expanded Disability Scale Score (EDSS) was observed in the mitoxantrone group after one year of treatment (p < 0.0022). The total number of relapses, the mean number of relapses/patient/year, and the total number of gadolinium-enhanced lesions on bi-annual MRI scans were significantly decreased in the mitoxantrone group throughout the study period. Nausea, vomiting, and alopecia were more frequent in the mitoxantrone-treated patients. Mitoxantrone has a role in the treatment of MS patients with frequent exacerbations and rapid disease progression.

  3. Progress in Early Childhood Caries and Opportunities in Research, Policy, and Clinical Management.

    PubMed

    Garcia, Raul; Borrelli, Belinda; Dhar, Vineet; Douglass, Joanna; Gomez, Francisco Ramos; Hieftje, Kimberly; Horowitz, Alice; Li, Yihong; Ng, Man Wai; Twetman, Svante; Tinanoff, Norman

    2015-01-01

    The 2014 Early Childhood Caries Conference encompassed evidence-based reviews on the state of the science regarding early childhood carries (ECC) epidemiology, etiology, prevention, and disease management. The purpose of this paper was to discuss the work presented at the conference and identify opportunities in research, policy, and clinical management that may improve early childhood caries outcomes and lower costs of care. While great progress has been made since the 1997 ECC Conference, there remains a paucity of high-quality evidence from randomized controlled trials on what are the most effective means to prevent and manage ECC. Analyses of studies indicate that some approaches, such as chlorhexidine, iodine, and remineralizing agents, have not shown consistent findings in preventing ECC. However, evidence exists to yield recommendations in some areas. There are useful risk assessment indicators to identify preschool children at risk for caries. Fluoridated toothpaste and fluoride varnish currently are the most effective chemotherapeutic strategies to prevent ECC. Motivational interviewing, a form of patient-centered counseling, is effective for motivating oral health behaviors and shows promise for reducing caries. Additionally, evidence is emerging that shows the value of chronic disease management approaches and integrating ECC oral health care within medical care settings. Recommendations for future directions in ECC research and policy were also key outcomes of the conference.

  4. Progression of MRI markers in cerebral small vessel disease: Sample size considerations for clinical trials

    PubMed Central

    Zeestraten, Eva; Lambert, Christian; Chis Ster, Irina; Williams, Owen A; Lawrence, Andrew J; Patel, Bhavini; MacKinnon, Andrew D; Barrick, Thomas R; Markus, Hugh S

    2016-01-01

    Detecting treatment efficacy using cognitive change in trials of cerebral small vessel disease (SVD) has been challenging, making the use of surrogate markers such as magnetic resonance imaging (MRI) attractive. We determined the sensitivity of MRI to change in SVD and used this information to calculate sample size estimates for a clinical trial. Data from the prospective SCANS (St George’s Cognition and Neuroimaging in Stroke) study of patients with symptomatic lacunar stroke and confluent leukoaraiosis was used (n = 121). Ninety-nine subjects returned at one or more time points. Multimodal MRI and neuropsychologic testing was performed annually over 3 years. We evaluated the change in brain volume, T2 white matter hyperintensity (WMH) volume, lacunes, and white matter damage on diffusion tensor imaging (DTI). Over 3 years, change was detectable in all MRI markers but not in cognitive measures. WMH volume and DTI parameters were most sensitive to change and therefore had the smallest sample size estimates. MRI markers, particularly WMH volume and DTI parameters, are more sensitive to SVD progression over short time periods than cognition. These markers could significantly reduce the size of trials to screen treatments for efficacy in SVD, although further validation from longitudinal and intervention studies is required. PMID:26036939

  5. Corticobasal degeneration: an autopsy case clinically diagnosed as progressive supranuclear palsy.

    PubMed

    Shiozawa, M; Fukutani, Y; Sasaki, K; Isaki, K; Hamano, T; Hirayama, M; Imamura, K; Mukai, M; Arai, N; Cairns, N J

    2000-01-01

    We report an autopsy case diagnosed clinically as progressive supranuclear palsy (PSP), but neuropathologically confirmed as corticobasal degeneration (CBD). A 56-year-old Japanese woman slowly developed parkinsonism, dementia, character change, followed by vertical gaze palsy and dystonia. Brain MRI demonstrated diffuse cerebral atrophy with severe shrinkage of the brain stem tegmentum. The SPECT images using 123I-IMP disclosed symmetrical hypoperfusion in the frontal lobes. She died of respiratory failure at the age of 71. Gross inspection of the brain showed diffuse, symmetrical atrophy of the cerebrum and marked atrophy of the Luysian body, globus pallidus, substantia nigra and nuclei of the brain stem tegmentum. Microscopically, neuronal loss and fibrillary gliosis were observed in the Luysian body, globus pallidus, substantia nigra and nuclei of the brain stem tegmentum. The cerebellar dentate nucleus showed mild neuronal loss with some grumose degeneration. Neurofibrillary tangles were found only in the Luysian body, substantia nigra and raphe nuclei, whilst tau-positive inclusions were observed more extensively. Astrocytic plaques and swollen achromatic neurones were found in the postcentral gyrus. There were no tuft-shaped astrocytes in the brain. The clinicopathological similarities and differences between PSP and CBD are discussed.

  6. Pirfenidone in patients with rapidly progressive interstitial lung disease associated with clinically amyopathic dermatomyositis

    NASA Astrophysics Data System (ADS)

    Li, Ting; Guo, Li; Chen, Zhiwei; Gu, Liyang; Sun, Fangfang; Tan, Xiaoming; Chen, Sheng; Wang, Xiaodong; Ye, Shuang

    2016-09-01

    To evaluate the efficacy of pirfenidone in patients with rapidly progressive interstitial lung disease (RPILD) related to clinically amyopathic dermatomyositis (CADM), we conducted an open-label, prospective study with matched retrospective controls. Thirty patients diagnosed with CADM-RPILD with a disease duration <6 months at Renji Hospital South Campus from June 2014 to November 2015 were prospectively enrolled and treated with pirfenidone at a target dose of 1800 mg/d in addition to conventional treatment, such as a glucocorticoid and/or other immunosuppressants. Matched patients without pirfenidone treatment (n = 27) were retrospectively selected as controls between October 2012 and September 2015. We found that the pirfenidone add-on group displayed a trend of lower mortality compared with the control group (36.7% vs 51.9%, p = 0.2226). Furthermore, the subgroup analysis indicated that the pirfenidone add-on had no impact on the survival of acute ILD patients (disease duration <3 months) (50% vs 50%, p = 0.3862) while for subacute ILD patients (disease duration 3–6 months), the pirfenidone add-on (n = 10) had a significantly higher survival rate compared with the control subgroup (n = 9) (90% vs 44.4%, p = 0.0450). Our data indicated that the pirfenidone add-on may improve the prognosis of patients with subacute ILD related to CADM.

  7. Differential role of intravenous anesthetics in colorectal cancer progression: implications for clinical application

    PubMed Central

    Wang, Xiaofei; Yao, Xueqing; Chen, Yeming; Tao, Tao; Sun, Xuegang; Xu, Lijun; Tang, Jing; Zhao, Liang

    2016-01-01

    Anesthetics are unavoidable to colorectal cancer (CRC) patients who underwent surgical treatment. Thus, the molecular mechanisms underlying the role of the intravenous anesthetics in CRC metastasis are still unclear. In this study, the effects of intravenous anesthetics, such as propofol, etomidate and dexmedetomidine, on cell migration were determined. The migration of CRC cells was inhibited by propofol in vitro, but not in vivo. Etomidate, however, promoted the migration of CRC cells both in vitro and in vivo. Epithelial-mesenchymal transition (EMT) mediated the promotive effect of propofol and etomidate on the migration of CRC cells through PI3K/AKT signaling pathway. Dexmedetomidine alone or in combination with propofol or etomidate had minor effect on the migration of CRC cells. These findings indicate that propofol inhibites CRC cell migration in vitro. Etomidate playes a role for prompting CRC metastasis progression by activating (PI3K)/AKT signaling and inducing EMT. It provides an important hint for the clinical application of these anesthetics. PMID:27780923

  8. Progress of artificial pancreas devices toward clinical use: the first outpatient studies

    PubMed Central

    Russell, Steven J.

    2015-01-01

    Purpose of review This article describes recent progress in the automated control of glycemia in type 1 diabetes with artificial pancreas devices that combine continuous glucose monitoring with automated decision-making and insulin delivery. Recent findings After a gestation period of closely supervised feasibility studies in research centers, the last 2 years have seen publication of studies testing these devices in outpatient environments, and many more such studies are ongoing. The most basic form of automation, suspension of insulin delivery for actual or predicted hypoglycemia, has been shown to be effective and well tolerated, and a first-generation device has actually reached the market. Artificial pancreas devices that actively dose insulin fall into two categories, those that dose insulin alone and those that also use glucagon to prevent and treat hypoglycemia (bihormonal artificial pancreas). Initial outpatient clinical trials have shown that both strategies can improve glycemic management in comparison with patient-controlled insulin pump therapy, but only the bihormonal strategy has been tested without restrictions on exercise. Summary Artificial pancreas technology has the potential to reduce acute and chronic complications of diabetes and mitigate the burden of diabetes self-management. Successful outpatient studies bring these technologies one step closer to availability for patients. PMID:25692927

  9. PREDICTING FOOT PROGRESSION ANGLE DURING GAIT USING TWO CLINICAL MEASURES IN HEALTHY ADULTS, A PRELIMINARY STUDY

    PubMed Central

    Winters, Kyle; Kampwerth, Teri; McAfee, Blake; Payne, Lisa; Roeckenhaus, Tara; Ross, Sandy A.

    2016-01-01

    ABSTRACT Background The foot progression angle (FPA) is related to the transverse plane rotation of the lower extremities and associated with many lower extremity conditions. Purpose The purpose of this study was to examine how two commonly used clinical measures, tibio-fibular torsion (TF) and hip rotation, can be used to predict FPA during gait in healthy adults. Study Design Cross-sectional study design Methods Passive hip internal and external rotation ranges of motion and TF torsion were measured with a 12-inch goniometer while the FPA (degree of toe-in/out) was measured with the GAITRite during midstance in sixty participants. The data was analyzed using a multiple regression model. Results Hip ER was not significant and was therefore excluded from the final model. The final model included passive hip IR and TF torsion (F = 19.64; p < .001; multiple R2 = .41; adjusted R2 = .39). Simple binary correlations showed that hip IR had a moderate negative correlation (r = -.40) with FPA (the greater the hip IR, the greater the in-toeing) while TF torsion had a positive correlation (r = .39) with FPA (the greater the external TF torsion. the greater the out-toeing). Conclusions Greater amount of passive hip IR predicts in-toeing while greater TF torsion predicts out-toeing of the foot during midstance phase of gait. Level of Evidence Level 2 PMID:27274426

  10. Predicting Progression from Mild Cognitive Impairment to Alzheimer's Dementia Using Clinical, MRI, and Plasma Biomarkers via Probabilistic Pattern Classification

    PubMed Central

    Korolev, Igor O.; Symonds, Laura L.; Bozoki, Andrea C.

    2016-01-01

    Background Individuals with mild cognitive impairment (MCI) have a substantially increased risk of developing dementia due to Alzheimer's disease (AD). In this study, we developed a multivariate prognostic model for predicting MCI-to-dementia progression at the individual patient level. Methods Using baseline data from 259 MCI patients and a probabilistic, kernel-based pattern classification approach, we trained a classifier to distinguish between patients who progressed to AD-type dementia (n = 139) and those who did not (n = 120) during a three-year follow-up period. More than 750 variables across four data sources were considered as potential predictors of progression. These data sources included risk factors, cognitive and functional assessments, structural magnetic resonance imaging (MRI) data, and plasma proteomic data. Predictive utility was assessed using a rigorous cross-validation framework. Results Cognitive and functional markers were most predictive of progression, while plasma proteomic markers had limited predictive utility. The best performing model incorporated a combination of cognitive/functional markers and morphometric MRI measures and predicted progression with 80% accuracy (83% sensitivity, 76% specificity, AUC = 0.87). Predictors of progression included scores on the Alzheimer's Disease Assessment Scale, Rey Auditory Verbal Learning Test, and Functional Activities Questionnaire, as well as volume/cortical thickness of three brain regions (left hippocampus, middle temporal gyrus, and inferior parietal cortex). Calibration analysis revealed that the model is capable of generating probabilistic predictions that reliably reflect the actual risk of progression. Finally, we found that the predictive accuracy of the model varied with patient demographic, genetic, and clinical characteristics and could be further improved by taking into account the confidence of the predictions. Conclusions We developed an accurate prognostic model for predicting

  11. Clinical value of nutritional status in neurodegenerative diseases: What is its impact and how it affects disease progression and management?

    PubMed

    Tsagalioti, Eftyhia; Trifonos, Christina; Morari, Aggeliki; Vadikolias, Konstantinos; Giaginis, Constantinos

    2016-11-30

    Neurodegenerative diseases constitute a major problem of public health that is associated with an increased risk of mortality and poor quality of life. Malnutrition is considered as a major problem that worsens the prognosis of patients suffering from neurodegenerative diseases. In this aspect, the present review is aimed to critically collect and summarize all the available existing clinical data regarding the clinical impact of nutritional assessment in neurodegenerative diseases, highlighting on the crucial role of nutritional status in disease progression and management. According to the currently available clinical data, the nutritional status of patients seems to play a very important role in the development and progression of neurodegenerative diseases. A correct nutritional evaluation of neurodegenerative disease patients and a right nutrition intervention is essential in monitoring their disease.

  12. Enhanced expression of centromere protein F predicts clinical progression and prognosis in patients with prostate cancer.

    PubMed

    Zhuo, Yang-Jia; Xi, Ming; Wan, Yue-Ping; Hua, Wei; Liu, Yuan-Ling; Wan, Song; Zhou, Yu-Lin; Luo, Hong-Wei; Wu, Shu-Lin; Zhong, Wei-De; Wu, Chin-Lee

    2015-04-01

    Centromere protein F (CENPF) is a protein associated with the centromere-kinetochore complex and chromosomal segregation during mitosis. Previous studies have demonstrated that the upregulation of CENPF may be used as a proliferation marker of malignant cell growth in tumors. The overexpression of CENPF has also been reported to be associated with a poor prognosis in human cancers. However, the clinical significance of CENPF in prostate cancer (PCa) has not yet been fully elucidated. Thus, the aim of the present study was to determine the association of CENPF with tumor progression and prognosis in patients with PCa. The expression of CENPF at the protein level in human PCa and non-cancerous prostate tissues was detected by immunohistochemical analysis, which was further validated using a microarray-based dataset (NCBI GEO accession no: GSE21032) at the mRNA level. Subsequently, the association of CENPF expression with the clinicopathological characteristics of the patients with PCa was statistically analyzed. Immunohistochemistry and dataset analysis revealed that CENPF expression was significantly increased in the PCa tissues compared with the non-cancerous prostate tissues [immunoreactivity score (IRS): PCa, 177.98 ± 94.096 vs. benign, 121.30 ± 89.596, P < 0.001; mRNA expression in the dataset: PCa, 5.67 ± 0.47 vs. benign, 5.40 ± 0.11; P < 0.001]. Additionally, as revealed by the dataset, the upregulation of CENPF mRNA expression in the PCa tissues significantly correlated with a higher Gleason score (GS, P = 0.005), an advanced pathological stage (P = 0.008), the presence of metastasis (P < 0.001), a shorter overall survival (P=0.003) and prostate-specific antigen (PSA) failure (P < 0.001). Furthermore, both univariate and multivariate analyses revealed that the upregulation of CENPF was an independent predictor of poor biochemical recurrence (BCR)-free survival (P < 0.001 and P = 0.012, respectively). Our data suggest that the increased expression of CENPF

  13. Evaluation of Study and Patient Characteristics of Clinical Studies in Primary Progressive Multiple Sclerosis: A Systematic Review

    PubMed Central

    Ziemssen, T.; Rauer, S.; Stadelmann, C.; Henze, T.; Koehler, J.; Penner, I.-K.; Lang, M.; Poehlau, D.; Baier-Ebert, M.; Schieb, H.; Meuth, S.

    2015-01-01

    Background So far, clinical studies in primary progressive MS (PPMS) have failed to meet their primary efficacy endpoints. To some extent this might be attributable to the choice of assessments or to the selection of the study population. Objective The aim of this study was to identify outcome influencing factors by analyzing the design and methods of previous randomized studies in PPMS patients without restriction to intervention or comparator. Methods A systematic literature search was conducted in MEDLINE, EMBASE, BIOSIS and the COCHRANE Central Register of Controlled Trials (inception to February 2015). Keywords included PPMS, primary progressive multiple sclerosis and chronic progressive multiple sclerosis. Randomized, controlled trials of at least one year’s duration were selected if they included only patients with PPMS or if they reported sufficient PPMS subgroup data. No restrictions with respect to intervention or comparator were applied. Study quality was assessed by a biometrics expert. Relevant baseline characteristics and outcomes were extracted and compared. Results Of 52 PPMS studies identified, four were selected. Inclusion criteria were notably different among studies with respect to both the definition of PPMS and the requirements for the presence of disability progression at enrolment. Differences between the study populations included the baseline lesion load, pretreatment status and disease duration. The rate of disease progression may also be an important factor, as all but one of the studies included a large proportion of patients with a low progression rate. In addition, the endpoints specified could not detect progression adequately. Conclusion Optimal PPMS study methods involve appropriate patient selection, especially regarding the PPMS phenotype and progression rate. Functional composite endpoints might be more sensitive than single endpoints in capturing progression. PMID:26393519

  14. Previously Unidentified Single Nucleotide Polymorphisms in HIV/AIDS Cases Associate with Clinical Parameters and Disease Progression

    PubMed Central

    Bakhteeva, Liliia B.; Khasanova, Gulshat R.; Tillett, Richard L.; Schlauch, Karen A.

    2016-01-01

    The genetic background of an individual plays an important role in the progression of HIV infection to AIDS. Identifying previously unknown or uncharacterized single nucleotide polymorphisms (SNPs) that associate with disease progression may reveal important therapeutic targets and provide a greater understanding of disease pathogenesis. In the present study, we employed ultra-high multiplex PCR on an Ion Torrent next-generation sequencing platform to sequence 23 innate immune genes from 94 individuals with HIV/AIDS. This data was used to identify potential associations of SNPs with clinical parameters and disease progression. SNPs that associated with an increased viral load were identified in the genes for the interleukin 15 receptor (IL15RA), toll-like receptor 7 (TLR7), tripartite motif-containing protein 5 (TRIM5), and two killer-cell immunoglobulin-like receptors (KIR2DL1 and KIR2DL3). Additionally, SNPs that associated with progression from HIV infection to AIDS were identified in two 2′-5′-oligoadenylate synthetase genes (OAS2 and OAS3). In contrast, other SNPs identified in OAS2 and OAS3 genes, as well as in the TRIM5 and KIR2DS4 genes, were associated with a slower progression of disease. Taken together, our data demonstrates the utility of ultra-high multiplex PCR in identifying polymorphisms of potential clinical significance and further,identifies SNPs that may play a role in HIV pathogenesis. PMID:28050553

  15. Drug-associated progressive multifocal leukoencephalopathy: a clinical, radiological, and cerebrospinal fluid analysis of 326 cases.

    PubMed

    Maas, Roderick P P W M; Muller-Hansma, Annemarie H G; Esselink, Rianne A J; Murk, Jean-Luc; Warnke, Clemens; Killestein, Joep; Wattjes, Mike P

    2016-10-01

    The implementation of a variety of immunosuppressive therapies has made drug-associated progressive multifocal leukoencephalopathy (PML) an increasingly prevalent clinical entity. The purpose of this study was to investigate its diagnostic characteristics and to determine whether differences herein exist between the multiple sclerosis (MS), neoplasm, post-transplantation, and autoimmune disease subgroups. Reports of possible, probable, and definite PML according to the current diagnostic criteria were obtained by a systematic search of PubMed and the Dutch pharmacovigilance database. Demographic, epidemiologic, clinical, radiological, cerebrospinal fluid (CSF), and histopathological features were extracted from each report and differences were compared between the disease categories. In the 326 identified reports, PML onset occurred on average 29.5 months after drug introduction, varying from 14.2 to 37.8 months in the neoplasm and MS subgroups, respectively. The most common overall symptoms were motor weakness (48.6 %), cognitive deficits (43.2 %), dysarthria (26.3 %), and ataxia (24.1 %). The former two also constituted the most prevalent manifestations in each subgroup. Lesions were more often localized supratentorially (87.7 %) than infratentorially (27.4 %), especially in the frontal (64.1 %) and parietal lobes (46.6 %), and revealed enhancement in 27.6 % of cases, particularly in the MS (42.9 %) subgroup. Positive JC virus results in the first CSF sample were obtained in 63.5 %, while conversion after one or more negative outcomes occurred in 13.7 % of cases. 52.2 % of patients died, ranging from 12.0 to 83.3 % in the MS and neoplasm subgroups, respectively. In conclusion, despite the heterogeneous nature of the underlying diseases, motor weakness and cognitive changes were the two most common manifestations of drug-associated PML in all subgroups. The frontal and parietal lobes invariably constituted the predilection sites of drug

  16. Anatomic, clinical, and neuropsychological correlates of spelling errors in primary progressive aphasia.

    PubMed

    Shim, Hyungsub; Hurley, Robert S; Rogalski, Emily; Mesulam, M-Marsel

    2012-07-01

    This study evaluates spelling errors in the three subtypes of primary progressive aphasia (PPA): agrammatic (PPA-G), logopenic (PPA-L), and semantic (PPA-S). Forty-one PPA patients and 36 age-matched healthy controls were administered a test of spelling. The total number of errors and types of errors in spelling to dictation of regular words, exception words and nonwords, were recorded. Error types were classified based on phonetic plausibility. In the first analysis, scores were evaluated by clinical diagnosis. Errors in spelling exception words and phonetically plausible errors were seen in PPA-S. Conversely, PPA-G was associated with errors in nonword spelling and phonetically implausible errors. In the next analysis, spelling scores were correlated to other neuropsychological language test scores. Significant correlations were found between exception word spelling and measures of naming and single word comprehension. Nonword spelling correlated with tests of grammar and repetition. Global language measures did not correlate significantly with spelling scores, however. Cortical thickness analysis based on MRI showed that atrophy in several language regions of interest were correlated with spelling errors. Atrophy in the left supramarginal gyrus and inferior frontal gyrus (IFG) pars orbitalis correlated with errors in nonword spelling, while thinning in the left temporal pole and fusiform gyrus correlated with errors in exception word spelling. Additionally, phonetically implausible errors in regular word spelling correlated with thinning in the left IFG pars triangularis and pars opercularis. Together, these findings suggest two independent systems for spelling to dictation, one phonetic (phoneme to grapheme conversion), and one lexical (whole word retrieval).

  17. A Case of Sarcoidosis with Interstitial Lung Disease Mimicking Clinically Amyopathic Dermatomyositis and Rapidly Progressive Interstitial Lung Disease

    PubMed Central

    Nogi, Shinichi; Sasaki, Noriko; Chinen, Naofumi; Honda, Kiri; Saito, Eiko; Wakabayashi, Takayuki; Yamada, Chiho; Suzuki, Yasuo

    2014-01-01

    Here, we report a patient with sarcoidosis who developed edematous erythema and interstitial lung disease. At the initial visit, clinically amyopathic dermatomyositis (CADM) with rapidly progressive interstitial lung disease (RP-ILD) was suspected because he had progressive dyspnea but no muscle weakness. The presence of anti-CADM-140/MDA5 autoantibodies was immediately assessed to facilitate a precise diagnosis, with negative results. Thereafter, skin and transbronchial lung biopsies revealed noncaseating granuloma with Langhans giant cells in both specimens, leading to a diagnosis of sarcoidosis. In this case, clinical features of skin and lung were unable to distinguish DM (including CADM) from sarcoidosis, but the lack of anti-CADM-140/MDA5 antibody was useful for differentiating CADM with RP-ILD mimicking sarcoidosis from bona fide sarcoidosis. PMID:25431723

  18. A study of familial MELAS: evaluation of A3243G mutation, clinical phenotype, and magnetic resonance spectroscopy-monitored progression.

    PubMed

    Chen, Chunnuan; Xiong, Nian; Wang, Yuhui; Xiong, Jing; Huang, Jinsha; Zhang, Zhentao; Wang, Tao

    2012-01-01

    The clinical manifestations of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS syndrome) are nonspecific and can easily be misdiagnosed. Magnetic resonance spectroscopy (MRS)-based detection of lactate in the brain has been found to be of diagnostic help in MELAS syndrome, however, the issue of whether MRS features vary by stage remains unresolved. We assessed the causative mutation and radiological features of a family of MELAS. Four of the family members harbored the A3243G mutation, probably of maternal inheritance. However, the clinical phenotypic expression was different in these patients. MRS showed a lactate peak, decreased N-acetylaspartate, choline, and creatine, which became more pronounced with progression of the disease, demonstrating that brain-MRS-based detection of lactate may be a suitable way to monitor the progression and treatment of MELAS.

  19. FTLD-TDP and progressive supranuclear palsy in comorbidity-a report of two cases with different clinical presentations.

    PubMed

    Storey, Kateřina; Johanidesová, Silvie; Matěj, Radoslav; Keller, Jiří; Rohan, Zdeněk; Rusina, Robert

    2016-12-03

    Frontotemporal lobar degeneration with transactive response DNA-binding protein 43 (FTLD-TDP) and progressive supranuclear palsy (PSP) are distinct neurodegenerations with different clinical presentations. We report two cases with FTLD-TDP and PSP in comorbidity: a patient with amnestic dementia developing frontal lobe dementia, Parkinsonism and supranuclear gaze palsy and a patient with cerebellar ataxia and nystagmus developing akinesia, rigidity, and subcortical dementia. Neuropathological examination revealed neuronal and glial tau pathology together with ubiquitin, and phospho-TDP-43-immunoreactivities in the hippocampus, striatum, mesencephalon, and frontal and temporal cortices. Clinical and neuropathological correlations in atypical neurodegenerations are crucial to describe new entities of overlapping syndromes.

  20. [A clinical case of progressive supranuclear palsy with long-term frontal presentation preceding the onset of gaze palsy].

    PubMed

    Yoshiike, Takuya; Ueda, Satoshi; Takahashi, Masahiko; Suda, Kiyoko; Furuta, Ko; Koyama, Keiko

    2014-01-01

    Progressive supranuclear palsy (PSP) is a neurodegenerative disorder with diverse clinical phenotypes characterized by supranuclear gaze palsy, parkinsonism with postural instability, and frontal dementia. The early and accurate diagnosis of PSP remains difficult because of the variable combination of symptoms and frequent lack of gaze abnormalities early in the disease course. Moreover, a subset of PSP shows behavioral changes as the initial presentation, which considerably overlaps with the clinical picture of frontotemporal dementia (FTD). Thus, this subgroup possibly needs psychiatric assessments. Here, we describe a clinical case of PSP difficult to differentiate from FTD because the frontal presentation persisted without gaze palsy until the late stage of the clinical course. A 58-year-old man was admitted to our hospital for the reconsideration of a diagnosis of FTD. Disinhibited and gambling behaviors inconsistent with his previous personality first appeared at around the age of 45, with gradual progression, followed by memory deficits, executive dysfunction, and a slowing of mental processes. Recurrent sexual disinhibition led him to undergo psychiatric consultation at the age of 57. Downward gaze palsy and postural instability with recurrent falls emerged 8 months after the first psychiatric examination, and he was clinically diagnosed with PSP 13 years after the initial frontal presentation. PSP should be considered in the differential diagnosis of patients presenting with frontal lobe symptoms, even in psychiatric practice.

  1. Clinical Advances in Fibrosis Progression of Chronic Hepatitis B and C

    PubMed Central

    Wu, Ye-Jiao; Xu, Ming-Yi; Lu, Lun-Gen

    2014-01-01

    Chronic liver diseases, such as chronic hepatitis B (CHB) and chronic hepatitis C (CHC), are characterized by the presence of liver fibrosis, which may ultimately lead to cirrhosis. The progression of fibrosis is associated with various factors. Here, we review recent advances in the study of factors related to the progression rate of CHB- and CHC-induced fibrosis. Identification of these factors and establishment of a scoring system for cirrhosis risk are particularly important for predicting cirrhosis development, planning individualized treatment, and preventing fibrosis progression. PMID:26357628

  2. Analysis of midwifery students' written reflections to evaluate progression in learning during clinical practice at birthing units.

    PubMed

    Persson, Eva K; Kvist, Linda J; Ekelin, Maria

    2015-03-01

    Written daily reflections during clinical practice on birthing units have been used during several years in midwifery education at Lund University, Sweden. However, the usefulness of these reflections for evaluation of progression in learning and professional development of students has to date not been evaluated. In order to analyse written reflections, two taxonomies developed by Bloom and Pettersen have been applied to the texts. Progression in the professional development of midwifery students can be seen through levels of complexity in cognitive and psycho-motor learning areas and also in the description of learning situations. Progression can be seen from a basic description of facts in simple situations at the beginning of the students' practice to a complex description of complicated situations towards the end of the practice. Written daily reflections appear to be a suitable method to help students to reflect in a structured way, thereby helping their professional development. Reflections can help clinical supervisors to understand the needs of the individual student and to support their knowledge accruement. Daily written reflections on clinical practice can be of use in other health education programs.

  3. [A clinical trial of neutron capture therapy for brain tumors]. Technical progress report 1988

    SciTech Connect

    Zamenhof, R.G.

    1988-12-31

    This report describes progress made in refining of neutron-induced alpha tract autoradiography, in designing epithermal neutron bean at MITR-II and in planning treatment dosimetry using Monte Carlo techniques.

  4. Mitigating preventable chronic disease: Progress report of the Cleveland Clinic's Lifestyle 180 program

    PubMed Central

    2011-01-01

    Background Poor lifestyle choices are key in development and progression of preventable chronic diseases. The purpose of the study was to design and test a program to mitigate the physical and fiscal consequences of chronic diseases. Methods Here we report the outcomes for 429 participants with one or more chronic conditions, including obesity, hypertension, hyperlipidemia and diabetes mellitus, many of whom had failed traditional disease management programs, who enrolled into a comprehensive lifestyle intervention. The Lifestyle 180 program integrates nutrition, physical activity and stress management interventions and was conducted at the Wellness Institute of the Cleveland Clinic, United States. An intensive 6 week immersion course, with 8 hours of group instruction per week, was followed by 3 follow-up, 4 hour-long sessions over the course of 6 months. Results Changes in biometric (weight, height, waist circumference, resting heart rate and blood pressure) and laboratory variables (fasting lipid panel, blood glucose, insulin, hemoglobin A1c, ultra sensitive C-reactive protein) at 6 months were compared with baseline (pre-post analysis). At week 30, biometric and laboratory data were available for 244 (57%) and 299 (70%) participants, respectively. These had a mean ± SD reduction in weight (6.8 ± 6.9 kg, P < 0.001), waist circumference (6.1 ± 7.3 cm, P < 0.001), glucose (4.5 ± 29.6 mg/dL or 0.25 ± 1.64 mmol/L, P = 0.009), triglycerides (26.4 ± 58.5 mg/dL or 0.30 ± 0.66 mmol/L, P < 0.001), low-density lipoprotein cholesterol (LDL) (7.9 ± 25.1 mg/dL or 0.2 ± 0.65 mmol/L, P < 0.001), hemoglobin A1c (HgbA1c) (0.20 ± 0.64%, P = 0.001), insulin (3.8 ± 11 microU/ml or 26.6 ± 76.4 ρmol, P < 0.001) and ultra sensitive C-reactive protein (US - CRP) (0.9 ± 4.8 mg/dL or 7.3 ± 40.2 nmol/L, P = 0.012), an increase in mean high-density lipoprotein cholesterol (HDL) (3.7 ± 8.4 mg/dL or 0.1 ± 0.22, P < 0.001), and decreased use of medications. Conclusion

  5. New 40Ar/39Ar Ages for Savai'i Island Reinstate Samoa as a Hotspot Trail with a Linear Age Progression

    NASA Astrophysics Data System (ADS)

    Koppers, A. A.; Russell, J. A.; Staudigel, H.; Hart, S. R.

    2006-12-01

    The volcanic islands and seamounts of the Samoan Archipelago have long been considered problematic in terms of the hotspot hypothesis. Existing K/Ar and 40Ar/39Ar measurements on subaerial samples from the Samoan islands have consistently given ages that are too young by several Myrs, conflicting with the expected linear age progression model. Previous data from the volcanic series and cones on Savai'i Island gave a range of ages between 0.2 and 2.1 Ma. This is in contrast to an age of 5.2 Ma that a Pacific plate motion of 7.1 cm/yr would predict for the onset of the shield building stage on Savai'i (Workman et al. 2004). The oldest shield ages for the islands of Upolu (2.7 My) and Tutuila (1.6 My) young eastward, toward the volcanically active Vailulu'u seamount that marks the current location of the Samoan hotspot (Hart et al. 2000; Staudigel et al. 2006). However, these ages are younger than predicted by the plate-speed model with 4.4 My and 2.7 My, respectively. The omnipresence of only young post-erosional volcanism on Savai'i has lead to extensive discussions on the origin of Samoan volcanism, and is often used as an argument against a possible hotspot and mantle plume origin. We present new 40Ar/39Ar data on volcanic samples from the deep flanks and rifts of Savai'i and a group of Samoan seamounts that were dredged during the ALIA Expedition. Twelve ages from eight different dredge locations confirm the predicted 7.1 cm/yr age progression for the Samoan hotspot. Three different volcanic samples from dredge ALIA-115, on the deepest portion of the SW flank of Savai'i Island, give indistinguishable ages (2σ confidence level) ranging from 4.99 to 5.21 Ma. In addition, a sample from dredge ALIA-128, on the NE flank of Savai'i, gives an age of 4.74 Ma. These results clearly demonstrate that the onset of the shield-building stage on Savai'i occurred much earlier than the oldest volcanics (2.1 Ma) sampled subaerially on the island. Sr-Nd-Pb isotopes and trace

  6. Estimation of absorbed dose in clinical radiotherapy linear accelerator beams: Effect of ion chamber calibration and long-term stability.

    PubMed

    Ravichandran, Ramamoorthy; Binukumar, Johnson Pichy; Davis, Cheriyathmanjiyil Antony

    2013-10-01

    The measured dose in water at reference point in phantom is a primary parameter for planning the treatment monitor units (MU); both in conventional and intensity modulated/image guided treatments. Traceability of dose accuracy therefore still depends mainly on the calibration factor of the ion chamber/dosimeter provided by the accredited Secondary Standard Dosimetry Laboratories (SSDLs), under International Atomic Energy Agency (IAEA) network of laboratories. The data related to Nd,water calibrations, thermoluminescent dosimetry (TLD) postal dose validation, inter-comparison of different dosimeter/electrometers, and validity of Nd,water calibrations obtained from different calibration laboratories were analyzed to find out the extent of accuracy achievable. Nd,w factors in Gray/Coulomb calibrated at IBA, GmBH, Germany showed a mean variation of about 0.2% increase per year in three Farmer chambers, in three subsequent calibrations. Another ion chamber calibrated in different accredited laboratory (PTW, Germany) showed consistent Nd,w for 9 years period. The Strontium-90 beta check source response indicated long-term stability of the ion chambers within 1% for three chambers. Results of IAEA postal TL "dose intercomparison" for three photon beams, 6 MV (two) and 15 MV (one), agreed well within our reported doses, with mean deviation of 0.03% (SD 0.87%) (n = 9). All the chamber/electrometer calibrated by a single SSDL realized absorbed doses in water within 0.13% standard deviations. However, about 1-2% differences in absorbed dose estimates observed when dosimeters calibrated from different calibration laboratories are compared in solid phantoms. Our data therefore imply that the dosimetry level maintained for clinical use of linear accelerator photon beams are within recommended levels of accuracy, and uncertainties are within reported values.

  7. Long-term outcome in BRAFV600E melanoma patients treated with vemurafenib: Patterns of disease progression and clinical management of limited progression

    PubMed Central

    Puzanov, Igor; Amaravadi, Ravi K.; McArthur, Grant A.; Flaherty, Keith T.; Chapman, Paul B.; Sosman, Jeffrey A.; Ribas, Antoni; Shackleton, Mark; Hwu, Patrick; Chmielowski, Bartosz; Nolop, Keith B.; Lin, Paul S.; Kim, Kevin B.

    2016-01-01

    Introduction Vemurafenib induces tumour regression in most patients with BRAFV600E-mutant melanoma; eventually, most experience progressive disease (PD). Long-term follow-up of patients with BRAFV600E melanoma treated in the phase 1 vemurafenib trial is reported. Methods Patients received vemurafenib 240–1120 mg (dose escalation cohort) or 960 mg (extension cohort) orally twice daily. Clinical response was evaluated every 8 weeks by RECIST. Patients with PD amenable to local therapy (surgery or radiotherapy) were allowed to continue vemurafenib after progression. Overall survival (OS) from time of treatment initiation and from PD was estimated. Sites of PD were recorded. Results Forty-eight patients (escalation cohort, n = 16; extension cohort, n = 32) received therapeutic doses of vemurafenib (≥240 mg twice daily). Forty-three patients had PD by the time of this analysis, and 5 remained progression free (follow-up time, 1.2–56.1 months). Median OS was 14 months (range, 1.2–56.1); 3- and 4-year melanoma-specific survival rate in the extension cohort was 26% and 19%, respectively. Median OS was 26.0 months (range, 7.7–56.1) among 20 patients who continued vemurafenib after local therapy. Median treatment duration beyond initial PD was 3.8 months (range, 1.1–26.6). In the extension cohort, 6 and 5 patients were alive after 3 and 4 years, respectively, on vemurafenib monotherapy. Conclusions Some patients with melanoma achieved long-term survival with vemurafenib monotherapy. Continuation of vemurafenib after PD might be beneficial in some patients because remaining disease might continue to respond to BRAF inhibition. PMID:25980594

  8. Piperacillin-tazobactam-induced linear IgA bullous dermatosis presenting clinically as Stevens-Johnson syndrome/toxic epidermal necrolysis overlap.

    PubMed

    Adler, N R; McLean, C A; Aung, A K; Goh, M S Y

    2017-04-01

    Linear IgA bullous dermatosis (LABD) is a subepidermal autoimmune bullous disease characterized by linear IgA deposition at the basement membrane zone, which is visualized by direct immunofluorescence. Patients with LABD typically present with widespread vesicles and bullae; however, this is not necessarily the case, as the clinical presentation of this disease is heterogeneous. LABD clinically presenting as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) is an infrequent, yet well-described phenomenon. Most cases of LABD are idiopathic, but some cases are drug-induced. Multiple drugs have been implicated in the development of LABD. We report a case of piperacillin-tazobactam-induced LABD presenting clinically as SJS/TEN overlap. This is the first reported case of a strong causal association between piperacillin-tazobactam and the development of LABD.

  9. The Nociceptin Opioid Receptor (NOP) as a Therapeutic Target: Progress in Translation from Preclinical Research to Clinical Utility

    PubMed Central

    Zaveri, Nurulain T.

    2016-01-01

    In the two decades since the discovery of the nociceptin opioid receptor (NOP) and its ligand, nociceptin/orphaninFQ (N/OFQ), steady progress has been achieved in understanding the pharmacology of this fourth opioid receptor/peptide system, aided by genetic and pharmacologic approaches. This research spawned an explosion of small-molecule NOP receptor ligands from discovery programs in major pharmaceutical companies. NOP agonists have been investigated for their efficacy in preclinical models of anxiety, cough, substance abuse, pain (spinal and peripheral) and urinary incontinence, whereas NOP antagonists have been investigated for treatment of pain, depression and motor symptoms in Parkinson’s disease. Translation of preclinical findings into the clinic is guided by PET and receptor occupancy studies, particularly for NOP antagonists. Recent progress in preclinical NOP research suggests that NOP agonists may have clinical utility for pain treatment and substance abuse pharmacotherapy. This review discusses the progress towards validating the NOP-N/OFQ system as a therapeutic target. PMID:26878436

  10. Clinical, molecular and immune analysis of dabrafenib and trametinib in metastatic melanoma patients that progressed on BRAF inhibitor monotherapy: a phase II clinical trial

    PubMed Central

    Chen, Guo; McQuade, Jennifer L.; Panka, David J.; Hudgens, Courtney W.; Amin-Mansour, Ali; Mu, Xinmeng Jasmine; Bahl, Samira; Jane-Valbuena, Judit; Wani, Khalida M.; Reuben, Alexandre; Creasy, Caitlyn A.; Jiang, Hong; Cooper, Zachary A.; Roszik, Jason; Bassett, Roland L.; Joon, Aron Y.; Simpson, Lauren M.; Mouton, Rosalind D.; Glitza, Isabella C.; Patel, Sapna P.; Hwu, Wen-Jen; Amaria, Rodabe N.; Diab, Adi; Hwu, Patrick; Lazar, Alexander J.; Wargo, Jennifer A.; Garraway, Levi A.; Tetzlaff, Michael T.; Sullivan, Ryan J.; Kim, Kevin B.; Davies, Michael A.

    2016-01-01

    Importance Combined treatment with dabrafenib and trametinib (CombiDT) achieves clinical responses in only ~15% of BRAF inhibitor (BRAFi)-refractory metastatic melanoma patients, in contrast to the high activity observed in BRAFi-naïve patients. Identifying correlates of response and mechanisms of resistance in this population will facilitate clinical management and rational therapeutic development. Objective To determine correlates of benefit from CombiDT therapy in BRAFi-refractory metastatic melanoma patients. Design Single-center, single-arm prospective phase II study of CombiDT in patients with BRAFV600 metastatic melanoma resistant to BRAFi monotherapy conducted between September 2012 and October 2014. Setting University of Texas MD Anderson Cancer Center. Participants 28 patients were screened and 23 enrolled. Key eligibility criteria included: BRAFV600 metastatic melanoma, prior BRAFi monotherapy, measurable disease (RECIST 1.1), and accessible tumor for biopsy. Intervention Patients were treated with dabrafenib (150 mg twice daily) and trametinib (2 mg daily) continuously until disease progression or intolerance. All participants underwent a mandatory baseline biopsy, and optional biopsies were performed on-treatment and at progression. Whole-exome sequencing, RT-PCR for BRAF splicing, RNAseq and IHC were performed on tumor samples, and blood was analyzed for levels of circulating BRAFV600. Main outcome measures Primary endpoint was overall response rate (ORR). Progression-free survival (PFS) and overall survival (OS) were secondary clinical endpoints. Results Among evaluable patients, the confirmed ORR was 10%, disease control rate (DCR) was 45%, and median PFS was 13 weeks. Clinical benefit was associated with duration of prior BRAFi >6 months (DCR 73% vs. 11% for ≤6 months, p=0.02) and decrease in circulating BRAFV600 at day 8 of cycle 1 (DCR 75% vs. 18% for no decrease, p=0.015), but not by pre-treatment MAPK pathway mutations or activation. On

  11. REDUCTION IN HEPATIC INFLAMMATION IS ASSOCIATED WITH LESS FIBROSIS PROGRESSION AND FEWER CLINICAL OUTCOMES IN ADVANCED HEPATITIS C

    PubMed Central

    Morishima, Chihiro; Shiffman, Mitchell L.; Dienstag, Jules L.; Lindsay, Karen L; Szabo, Gyongyi; Everson, Gregory T.; Lok, Anna S.; Di Bisceglie, Adrian M.; Ghany, Marc G.; Naishadham, Deepa; Morgan, Timothy R.; Wright, Elizabeth C.

    2013-01-01

    Objective During the Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial, 3.5 years of maintenance peginterferon-alfa-2a therapy did not affect liver fibrosis progression or clinical outcomes among 1,050 prior interferon nonresponders with advanced fibrosis or cirrhosis. We investigated whether reduced hepatic inflammation was associated with clinical benefit in 834 patients with a baseline and follow-up biopsy 1.5 years after randomization to peginterferon or observation. Methods Relationships between change in hepatic inflammation (Ishak HAI) and serum ALT, fibrosis progression and clinical outcomes after randomization, and HCV RNA decline before and after randomization were evaluated. Histologic change was defined as a ≥2-point difference in HAI or Ishak fibrosis score between biopsies. Results Among 657 patients who received full-dose peginterferon/ribavirin “lead-in” therapy before randomization, year-1.5 HAI improvement was associated with lead-in HCV RNA suppression in both randomized treated (P <0.0001) and control (P = 0.0001) groups, even in the presence of recurrent viremia. This relationship persisted at year 3.5 in both treated (P = 0.001) and control (P = 0.01) groups. Among 834 patients followed for a median of 6 years, fewer clinical outcomes occurred in patients with improved HAI at year 1.5 compared to those without such improvement in both treated (P = 0.03) and control (P = 0.05) groups. Among patients with Ishak 3–4 fibrosis at baseline, those with improved HAI at year 1.5 had less fibrosis progression at year 1.5 in both treated (P = 0.0003) and control (P = 0.02) groups. Conclusion Reduced hepatic inflammation (measured 1.5 and 3.5 years after randomization) was associated with profound virological suppression during lead-in treatment with full-dose peginterferon/ribavirin and with decreased fibrosis progression and clinical outcomes, independent of randomized treatment. PMID:22688849

  12. Anatomic, Clinical, and Neuropsychological Correlates of Spelling Errors in Primary Progressive Aphasia

    ERIC Educational Resources Information Center

    Shim, HyungSub; Hurley, Robert S.; Rogalski, Emily; Mesulam, M.-Marsel

    2012-01-01

    This study evaluates spelling errors in the three subtypes of primary progressive aphasia (PPA): agrammatic (PPA-G), logopenic (PPA-L), and semantic (PPA-S). Forty-one PPA patients and 36 age-matched healthy controls were administered a test of spelling. The total number of errors and types of errors in spelling to dictation of regular words,…

  13. Senescent fibroblasts in melanoma initiation and progression: an integrated theoretical, experimental, and clinical approach.

    PubMed

    Kim, Eunjung; Rebecca, Vito; Fedorenko, Inna V; Messina, Jane L; Mathew, Rahel; Maria-Engler, Silvya S; Basanta, David; Smalley, Keiran S M; Anderson, Alexander R A

    2013-12-01

    We present an integrated study to understand the key role of senescent fibroblasts in driving melanoma progression. Based on the hybrid cellular automata paradigm, we developed an in silico model of normal skin. The model focuses on key cellular and microenvironmental variables that regulate interactions among keratinocytes, melanocytes, and fibroblasts, key components of the skin. The model recapitulates normal skin structure and is robust enough to withstand physical as well as biochemical perturbations. Furthermore, the model predicted the important role of the skin microenvironment in melanoma initiation and progression. Our in vitro experiments showed that dermal fibroblasts, which are an important source of growth factors in the skin, adopt a secretory phenotype that facilitates cancer cell growth and invasion when they become senescent. Our coculture experiments showed that the senescent fibroblasts promoted the growth of nontumorigenic melanoma cells and enhanced the invasion of advanced melanoma cells. Motivated by these experimental results, we incorporated senescent fibroblasts into our model and showed that senescent fibroblasts transform the skin microenvironment and subsequently change the skin architecture by enhancing the growth and invasion of normal melanocytes. The interaction between senescent fibroblasts and the early-stage melanoma cells leads to melanoma initiation and progression. Of microenvironmental factors that senescent fibroblasts produce, proteases are shown to be one of the key contributing factors that promoted melanoma development from our simulations. Although not a direct validation, we also observed increased proteolytic activity in stromal fields adjacent to melanoma lesions in human histology. This leads us to the conclusion that senescent fibroblasts may create a prooncogenic skin microenvironment that cooperates with mutant melanocytes to drive melanoma initiation and progression and should therefore be considered as a

  14. Clinical and genetic factors associated with progression of geographic atrophy lesions in age-related macular degeneration.

    PubMed

    Grassmann, Felix; Fleckenstein, Monika; Chew, Emily Y; Strunz, Tobias; Schmitz-Valckenberg, Steffen; Göbel, Arno P; Klein, Michael L; Ratnapriya, Rinki; Swaroop, Anand; Holz, Frank G; Weber, Bernhard H F

    2015-01-01

    Worldwide, age-related macular degeneration (AMD) is a serious threat to vision loss in individuals over 50 years of age with a pooled prevalence of approximately 9%. For 2020, the number of people afflicted with this condition is estimated to reach 200 million. While AMD lesions presenting as geographic atrophy (GA) show high inter-individual variability, only little is known about prognostic factors. Here, we aimed to elucidate the contribution of clinical, demographic and genetic factors on GA progression. Analyzing the currently largest dataset on GA lesion growth (N = 388), our findings suggest a significant and independent contribution of three factors on GA lesion growth including at least two genetic factors (ARMS2_rs10490924 [P < 0.00088] and C3_rs2230199 [P < 0.00015]) as well as one clinical component (presence of GA in the fellow eye [P < 0.00023]). These correlations jointly explain up to 7.2% of the observed inter-individual variance in GA lesion progression and should be considered in strategy planning of interventional clinical trials aimed at evaluating novel treatment options in advanced GA due to AMD.

  15. Diet-induced mouse model of fatty liver disease and nonalcoholic steatohepatitis reflecting clinical disease progression and methods of assessment.

    PubMed

    Clapper, Jason R; Hendricks, Michelle D; Gu, Guibao; Wittmer, Carrie; Dolman, Carrie S; Herich, John; Athanacio, Jennifer; Villescaz, Christiane; Ghosh, Soumitra S; Heilig, Joseph S; Lowe, Carolyn; Roth, Jonathan D

    2013-10-01

    Shortcomings of previously reported preclinical models of nonalcoholic steatohepatitis (NASH) include inadequate methods used to induce disease and assess liver pathology. We have developed a dietary model of NASH displaying features observed clinically and methods for objectively assessing disease progression. Mice fed a diet containing 40% fat (of which ∼18% was trans fat), 22% fructose, and 2% cholesterol developed three stages of nonalcoholic fatty liver disease (steatosis, steatohepatitis with fibrosis, and cirrhosis) as assessed by histological and biochemical methods. Using digital pathology to reconstruct the left lateral and right medial lobes of the liver, we made comparisons between and within lobes to determine the uniformity of collagen deposition, which in turn informed experimental sampling methods for histological, biochemical, and gene expression analyses. Gene expression analyses conducted with animals stratified by disease severity led to the identification of several genes for which expression highly correlated with the histological assessment of fibrosis. Importantly, we have established a biopsy method allowing assessment of disease progression. Mice subjected to liver biopsy recovered well from the procedure compared with sham-operated controls with no apparent effect on liver function. Tissue obtained by biopsy was sufficient for gene and protein expression analyses, providing the opportunity to establish an objective method of assessing liver pathology before subjecting animals to treatment. The improved assessment techniques and the observation that mice fed the high-fat diet exhibit many clinically relevant characteristics of NASH establish a preclinical model for identifying pharmacological interventions with greater likelihood of translating to the clinic.

  16. Validation of Novel Biomarkers for Prostate Cancer Progression by the Combination of Bioinformatics, Clinical and Functional Studies

    PubMed Central

    Väänänen, Riina-Minna; Mattsson, Jesse; Li, Yifeng; Tallgrén, Terhi; Tong Ochoa, Natalia; Bjartell, Anders; Åkerfelt, Malin; Taimen, Pekka; Boström, Peter J.

    2016-01-01

    The identification and validation of biomarkers for clinical applications remains an important issue for improving diagnostics and therapy in many diseases, including prostate cancer. Gene expression profiles are routinely applied to identify diagnostic and predictive biomarkers or novel targets for cancer. However, only few predictive markers identified in silico have also been validated for clinical, functional or mechanistic relevance in disease progression. In this study, we have used a broad, bioinformatics-based approach to identify such biomarkers across a spectrum of progression stages, including normal and tumor-adjacent, premalignant, primary and late stage lesions. Bioinformatics data mining combined with clinical validation of biomarkers by sensitive, quantitative reverse-transcription PCR (qRT-PCR), followed by functional evaluation of candidate genes in disease-relevant processes, such as cancer cell proliferation, motility and invasion. From 300 initial candidates, eight genes were selected for validation by several layers of data mining and filtering. For clinical validation, differential mRNA expression of selected genes was measured by qRT-PCR in 197 clinical prostate tissue samples including normal prostate, compared against histologically benign and cancerous tissues. Based on the qRT-PCR results, significantly different mRNA expression was confirmed in normal prostate versus malignant PCa samples (for all eight genes), but also in cancer-adjacent tissues, even in the absence of detectable cancer cells, thus pointing to the possibility of pronounced field effects in prostate lesions. For the validation of the functional properties of these genes, and to demonstrate their putative relevance for disease-relevant processes, siRNA knock-down studies were performed in both 2D and 3D organotypic cell culture models. Silencing of three genes (DLX1, PLA2G7 and RHOU) in the prostate cancer cell lines PC3 and VCaP by siRNA resulted in marked growth arrest

  17. Validation of Novel Biomarkers for Prostate Cancer Progression by the Combination of Bioinformatics, Clinical and Functional Studies.

    PubMed

    Alinezhad, Saeid; Väänänen, Riina-Minna; Mattsson, Jesse; Li, Yifeng; Tallgrén, Terhi; Tong Ochoa, Natalia; Bjartell, Anders; Åkerfelt, Malin; Taimen, Pekka; Boström, Peter J; Pettersson, Kim; Nees, Matthias

    2016-01-01

    The identification and validation of biomarkers for clinical applications remains an important issue for improving diagnostics and therapy in many diseases, including prostate cancer. Gene expression profiles are routinely applied to identify diagnostic and predictive biomarkers or novel targets for cancer. However, only few predictive markers identified in silico have also been validated for clinical, functional or mechanistic relevance in disease progression. In this study, we have used a broad, bioinformatics-based approach to identify such biomarkers across a spectrum of progression stages, including normal and tumor-adjacent, premalignant, primary and late stage lesions. Bioinformatics data mining combined with clinical validation of biomarkers by sensitive, quantitative reverse-transcription PCR (qRT-PCR), followed by functional evaluation of candidate genes in disease-relevant processes, such as cancer cell proliferation, motility and invasion. From 300 initial candidates, eight genes were selected for validation by several layers of data mining and filtering. For clinical validation, differential mRNA expression of selected genes was measured by qRT-PCR in 197 clinical prostate tissue samples including normal prostate, compared against histologically benign and cancerous tissues. Based on the qRT-PCR results, significantly different mRNA expression was confirmed in normal prostate versus malignant PCa samples (for all eight genes), but also in cancer-adjacent tissues, even in the absence of detectable cancer cells, thus pointing to the possibility of pronounced field effects in prostate lesions. For the validation of the functional properties of these genes, and to demonstrate their putative relevance for disease-relevant processes, siRNA knock-down studies were performed in both 2D and 3D organotypic cell culture models. Silencing of three genes (DLX1, PLA2G7 and RHOU) in the prostate cancer cell lines PC3 and VCaP by siRNA resulted in marked growth arrest

  18. Precision Medicine in NCI’s National Clinical Trials Network: Progress and Lessons Learned

    Cancer.gov

    NCI’s Jeff Abrams, M.D., Acting Director for Clinical Research in the Division of Cancer Treatment and Diagnosis (DCTD) and Associate Director of the Cancer Therapy Evaluation Program (CTEP) and Nita Seibel, M.D., Head of the Pediatric Solid Tumor Therapeutics in the Clinical Investigations Branch of CTEP, DCTD will host a Google Hangout on Air. The discussion will be moderated by Andrea Denicoff, R.N., N.P, Head, NCTN Clinical Trials Operations in the Investigational Drug Branch of CTEP, DCTD.

  19. Clinical outcomes of two main variants of progressive supranuclear palsy and multiple system atrophy: a prospective natural history study.

    PubMed

    Jecmenica-Lukic, Milica; Petrovic, Igor N; Pekmezovic, Tatjana; Kostic, Vladimir S

    2014-08-01

    Progressive supranuclear palsy (PSP) and parkinsonian subtype of multiple system atrophy (MSA-P) are, after Parkinson's disease (PD), the most common forms of neurodegenerative parkinsonism. Clinical heterogeneity of PSP includes two main variants, Richardson syndrome (PSP-RS) and PSP-parkinsonism (PSP-P). Clinical differentiation between them may be impossible at least during the first 2 years of the disease. Little is known about the differences in natural course of PSP-RS and PSP-P and, therefore, in this study we prospectively followed the clinical outcomes of consecutive, pathologically unconfirmed patients with the clinical diagnoses of PSP-RS (51 patients), PSP-P (21 patients) and MSA-P (49 patients). Estimated mean survival time was 11.2 years for PSP-P, 6.8 years for PSP-RS, and 7.9 years for MSA-P, where a 5-year survival probabilities were 90, 66 and 78 %, respectively. More disabling course of PSP-RS compared to PSP-P was also highlighted through the higher number of milestones reached in the first 3 years of the disease, as well as in the trend to reach all clinical milestones earlier. We found that PSP-P variant had a more favorable course with longer survival, not only when compared to PSP-RS, but also when compared to another form of atypical parkinsonism, MSA-P.

  20. Annual Progress Report (Fiscal Year 1978) of the Clinical Investigation Service

    DTIC Science & Technology

    1978-01-01

    ology Service 2508 An Experimental Analysis of Aural Rehabilitation Using Programmed Instructions (FY-70 T). 2510 A Multidimensional Assessment of...Fluid Analysis in Rheumatic Disease (FY-73 T). 356 3117 Evaluation and Study of Patients with Primary and 363 Secondard Immunodeficiency...equipment has become extremely tight. The Chief, CIS, and his staff are constantly reviewing protocol progress, cost analysis is regularly conducted to

  1. Results of the primary outcome measure and clinical events from the Asymptomatic Carotid Artery Progression Study.

    PubMed

    Probstfield, J L; Margitic, S E; Byington, R P; Espeland, M A; Furberg, C D

    1995-09-28

    The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have proven to be more effective in reducing levels of low density lipoprotein (LDL) cholesterol and to be better tolerated than other lipid-lowering compounds. Most of the trials evaluating the effects of these new agents on progression of atherosclerosis have not included individuals asymptomatic for cardiovascular disease and who have LDL cholesterol levels at or below the limits established by the National Cholesterol Education Program for initiating treatment. The Asymptomatic Carotid Artery Progression Study (ACAPS) tested the effect of the HMG-CoA reductase inhibitor, lovastatin, on early-stage carotid atherosclerosis (as detected by B-mode ultrasonography) in 919 asymptomatic men and women, 40-79 years of age, who had LDL cholesterol levels between the 60th and 90th percentiles. Participants randomized into this double-blind, placebo-controlled, factorially designed study received lovastatin (20-40 mg/day) or lovastatin-placebo and warfarin (1 mg/day), or warfarin-placebo over a 3-year period. The progression of the mean maximum intimal-medial thickness (IMT) over 12 walls of both carotid arteries represented the primary outcome. Lovastatin treatment was associated with a reduction in progression of mean maximum IMT (p < 0.001). Levels of LDL cholesterol were reduced by 28% (43.5 mg/dl [11.25 mmol/liter]) in the lovastatin group within 6 months (p < 0.0001) and remained stable throughout the follow-up period, whereas these levels remained essentially unchanged in the lovastatin-placebo group. The difference in incidence of major cardiovascular events for patients in the lovastatin-placebo group was significant: 5 versus 14, respectively (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

  2. Have genomic discoveries in inflammatory bowel disease translated into clinical progress?

    PubMed

    Weizman, Adam V; Silverberg, Mark S

    2012-04-01

    Inflammatory bowel disease (IBD) is a heterogeneous disease that can be challenging to diagnose and manage. As a result, significant efforts have been made in attempting to identify clinical, genomic, and serologic markers of disease that can aid in patient assessment and treatment. Recent genomic discoveries have the potential to change clinical practice by identifying those susceptible to IBD, predict natural history and guide choice of therapy. Panels of genetic and genomic markers are more likely to emerge as clinical tools, as opposed to individual allelic variants. Serology and biomarkers are already being used and guiding management but await integration with genomic panels before achieving their maximal potential. This article reviews the current state of IBD genetics and evolving molecular approaches that may have potential clinical impact.

  3. Metabolic genes in cancer: their roles in tumor progression and clinical implications

    PubMed Central

    Furuta, Eiji; Okuda, Hiroshi; Kobayashi, Aya; Watabe, Kounosuke

    2010-01-01

    Re-programming of metabolic pathways is a hallmark of physiological changes in cancer cells. The expression of certain genes that directly control the rate of key metabolic pathways including glycolysis, lipogenesis and nucleotide synthesis are drastically altered at different stages of tumor progression. These alterations are generally considered as an adaptation of tumor cells; however, they also contribute to the progression of tumor cells to become more aggressive phenotypes. This review summarizes the recent information about the mechanistic link of these genes to oncogenesis and their potential utility as diagnostic markers as well as for therapeutic targets. We particularly focus on three groups of genes; GLUT1, G6PD, TKTL1 and PGI/AMF in glycolytic pathway, ACLY, ACC1 and FAS in lipogenesis and RRM1, RRM2 and TYMS for nucleotide synthesis. All these genes are highly up-regulated in a variety of tumor cells in cancer patients, and they play active roles in tumor progression rather than expressing merely as a consequence of phenotypic change of the cancer cells. Molecular dissection of their orchestrated networks and understanding the exact mechanism of their expression will provide a window of opportunity to target these genes for specific cancer therapy. We also reviewed existing database of gene microarray to validate the utility of these genes for cancer diagnosis. PMID:20122995

  4. MicroRNA expression profiles predict progression and clinical outcome in lung adenocarcinoma

    PubMed Central

    Lin, Kang; Xu, Tao; He, Bang-Shun; Pan, Yu-Qin; Sun, Hui-Ling; Peng, Hong-Xin; Hu, Xiu-Xiu; Wang, Shu-Kui

    2016-01-01

    Lung cancer is one of the leading causes of cancer death worldwide. Accumulating evidence has indicated that microRNAs (miRNAs) can be proposed as promising diagnostic and prognostic markers for various cancers. The current study analyzed the miRNA expression profiles of 418 lung adenocarcinoma (LUAD) cases obtained from The Cancer Genome Atlas dataset, with the aim to investigate the relationship of miRNAs with progression and prognosis of LUAD. A total of 185 miRNAs were found to be differentially expressed between LUAD tumor tissues and adjacent normal tissues. Among them, 13, 10, 0, and 10 miRNAs were discovered to be associated with pathologic T, N, M, and Stage, respectively. Interestingly, mir-200 family (mir-200a, mir-200b, and mir-429) was shown to play a critical role in the progression of LUAD. In the multivariate Cox regression analysis, mir-1468 (P=0.009), mir-212 (P=0.026), mir-3653 (P=0.012), and mir-31 (P=0.002) were significantly correlated with recurrence-free survival. With regard to overall survival, mir-551b (P=0.011), mir-3653 (P=0.016), and mir-31 (P=0.001) were proven as independent prognostic markers. In summary, this study identified the cancer-specific miRNAs that may predict the progression and prognosis of LUAD. PMID:27695346

  5. Patterns of disease progression in type 2 and 3 SMA: Implications for clinical trials

    PubMed Central

    Mercuri, Eugenio; Finkel, Richard; Montes, Jacqueline; Mazzone, Elena S.; Sormani, Maria Pia; Main, Marion; Ramsey, Danielle; Mayhew, Anna; Glanzman, Allan M.; Dunaway, Sally; Salazar, Rachel; Pasternak, Amy; Quigley, Janet; Pane, Marika; Pera, Maria Carmela; Scoto, Mariacristina; Messina, Sonia; Sframeli, Maria; Vita, Gian Luca; D'Amico, Adele; van den Hauwe, Marleen; Sivo, Serena; Goemans, Nathalie; Kaufmann, Petra; Darras, Basil T.; Bertini, Enrico; Muntoni, Francesco; De Vivo, Darryl C.

    2016-01-01

    The aim of the study was to establish 12-month changes in the Hammersmith Functional motor scale in a large cohort of SMA patients, to identify patterns of disease progression and the effect of different variables. 268 patients were included in this multicentric study. Their age ranged between 2.5 and 55.5 years at baseline, 68 were ambulant and 200 non-ambulant. The baseline scores ranged between 0 and 66 (mean 23.91, SD 20.09). The 12-month change was between −14 and +9 (mean −0.56, SD 2.72). Of the 268 patients, 206 (76.86%) had changes between −2 and +2 points. Ambulant and non-ambulant subjects had a different relationship between baseline values and age (p for age X ambulation interaction = 0.007). There was no association with age in ambulant subjects, while there was a significant heterogeneity at different age for non-ambulant patients (p < 0.001). The 12-month change (adjusted for baseline) was not associated with age in ambulant patients (p = 0.34), but it was significantly different among various age groups in non-ambulant patients. Our results suggest that there are different profiles of progression in ambulant and non-ambulant patients, and that age may play an important role in the progression of non-ambulant patients. PMID:26776503

  6. Minimal Clinically Important Worsening on the Progressive Supranuclear Palsy Rating Scale

    PubMed Central

    Hewer, Sarah; Varley, Sue; Boxer, Adam L.; Paul, Eldho; Williams, David R

    2016-01-01

    Structured Abstract Introduction Despite the widespread use of the PSP rating scale it is not known what change in this scale is meaningful for patients. Methods We analyzed data from a large clinical trial in PSP-Richardson’s syndrome (AL-108-231) to calculate minimal clinically important worsening. This was defined as the difference in mean change of PSP rating scale in subjects rated ‘a little worse’ and those rated ‘unchanged’ on the Clinicians’ Global Impression of Change Scale. A multivariate analysis using logistic regression assessed the relationship between clinical worsening, PSP rating scale, depression and activities of daily living. Results The minimal clinically important worsening on the PSP rating scale was 5.7 points, corresponding to the mean decline over six months in the trial. Changes in activities of daily living and PSP rating scale were significantly associated with clinical worsening. Conclusion Clinically meaningful change is measurable on the PSP rating scale over six months. PMID:27324431

  7. Enhancing Adolescent and Young Adult Oncology Research Within the National Clinical Trials Network: Rationale, Progress, and Emerging Strategies.

    PubMed

    Weiss, Aaron R; Nichols, Craig R; Freyer, David R

    2015-10-01

    Adolescent and Young Adult Oncology (AYAO, including patients 15-39 years of age) is an emerging discipline in the field of cancer treatment and research. Poorer survival outcomes for this population and characteristic age-related challenges in care have called attention to the need for increased AYAO research. This chapter outlines pressing questions and reviews recent progress in AYAO research within the current organizational structure of the federal clinical trials enterprise, emphasizing how the United States National Cancer Institute's National Clinical Trials Network (NCTN) has created novel opportunities for collaborative AYAO research among the pediatric and adult NCTN groups. Potential strategies for expanding AYAO research, both within the NCTN and with other partners in the federal and advocacy domains are identified.

  8. Severity score system for progressive myelopathy: development and validation of a new clinical scale

    PubMed Central

    Castilhos, R.M.; Blank, D.; Netto, C.B.O.; Souza, C.F.M.; Fernandes, L.N.T.; Schwartz, I.V.D.; Giugliani, R.; Jardim, L.B.

    2012-01-01

    Progressive myelopathies can be secondary to inborn errors of metabolism (IEM) such as mucopolysaccharidosis, mucolipidosis, and adrenomyeloneuropathy. The available scale, Japanese Orthopaedic Association (JOA) score, was validated only for degenerative vertebral diseases. Our objective is to propose and validate a new scale addressing progressive myelopathies and to present validating data for JOA in these diseases. A new scale, Severity Score System for Progressive Myelopathy (SSPROM), was constructed covering motor disability, sphincter dysfunction, spasticity, and sensory losses. Inter-and intra-rater reliabilities were measured. External validation was tested by applying JOA, the Expanded Disability Status Scale (EDSS), the Barthel index, and the Osame Motor Disability Score. Thirty-eight patients, 17 with adrenomyeloneuropathy, 3 with mucopolysaccharidosis I, 3 with mucopolysaccharidosis IV, 2 with mucopolysaccharidosis VI, 2 with mucolipidosis, and 11 with human T-cell lymphotropic virus type-1 (HTLV-1)-associated myelopathy participated in the study. The mean ± SD SSPROM and JOA scores were 74.6 ± 11.4 and 12.4 ± 2.3, respectively. Construct validity for SSPROM (JOA: r = 0.84, P < 0.0001; EDSS: r = −0.83, P < 0.0001; Barthel: r = 0.56, P < 0.002; Osame: r = −0.94, P < 0.0001) and reliability (intra-rater: r = 0.83, P < 0.0001; inter-rater: r = 0.94, P < 0.0001) were demonstrated. The metric properties of JOA were similar to those found in SSPROM. Several clinimetric requirements were met for both SSPROM and JOA scales. Since SSPROM has a wider range, it should be useful for follow-up studies on IEM myelopathies. PMID:22570090

  9. [Progress and challenges of clinical trials registration in Latin America and the Caribbean's].

    PubMed

    Reveiz, Ludovic; Saenz, Carla; Murasaki, Renato T; Cuervo, Luis G; Ramalho, Luciano

    2011-12-01

    Clinical trial registries are one of the main sources of information concerning health research interventions that have been or are being carried out throughout the world. The World Health Organization (WHO) established a minimum data set to be recorded (20 items), which was agreed upon internationally with the stakeholders, and established a network of primary and associated records. In addition to the register ClinicalTrial.Gov (of the United States of America), there are currently two primary registries in the Americas (from Brazil and Cuba) that meet WHO requirements and provide data to WHO's International Clinical Trials Registry Platform (ICTRP). Furthermore, there are important advances in the region related to the regulations, development and implementation of national registries and to the support of the ethics committees and editors to this initiative.

  10. Clinical reasoning: a 51-year-old man with cervical pain and progressively deteriorating gait.

    PubMed

    Rallis, Dimitrios; Tsirigotis, Panagiotis; Arvaniti, Chryssa; Sgouros, Spiros; Foukas, Periclis G; Oikonomopoulos, Nikolaos; Andronas, Nikolaos; Panayiotides, Ioannis G; Kouloulias, Vasilios; Papageorgiou, Sotirios; Voumvourakis, Konstantinos; Stamboulis, Eleftherios

    2013-05-28

    A 51-year-old Caucasian man presented with cervical pain, right hand weakness, and progressively deteriorating gait. Onset of symptoms occurred 1 month before admission with cervical pain that worsened during neck flexion. A few days later he noticed reduced dexterity and numbness of his right hand. During the following 3 weeks, his gait became increasingly unstable. Additionally, he reported erectile dysfunction and urinary hesitancy. No previous trauma was recalled. His medical and family history was unremarkable except for hypertension that was treated with angiotensin-converting enzyme inhibitors.

  11. Dendritic cells in cancer immunotherapy clinical trials: are we making progress?

    PubMed

    Butterfield, Lisa H

    2013-12-13

    Dendritic cells (DC) have been tested in cancer immunotherapy clinical trials for two decades. Over this time, the methods of DC culture (or manufacture) have evolved, the approaches for antigen loading have broadened, the maturation signals have varied and different sites of administration have been tested. The post-vaccination immunologic questions asked have also varied between trials and over time. In this review, I will consider multiple aspects of DC-based vaccines tested in cancer patients, including the cell culture, antigen loading, maturation, and delivery, as well as what we have learned from testing immune responses in vaccinated patients who have benefited clinically, and those who have not measurably benefited.

  12. Blood and Marrow Transplant Clinical Trials Network: progress since the State of the Science Symposium 2007.

    PubMed

    Ferrara, James L M

    2014-02-01

    Outcomes of hematopoietic cell transplantation continue to improve. New techniques have reduced transplant toxicities, and there are new sources of hematopoietic stem cells from related and unrelated donors. In June 2007, the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) convened a State of the Science Symposium (SOSS) in Ann Arbor and identified 11 high priority clinical trials for the network to pursue. This article reviews both the status of those trials and the record of achievement of the BMT CTN as it convenes another SOSS in Grapevine, Texas in February 2014.

  13. Localization to Xq22 and clinical update of a family with X-linked recessive mental retardation with progression sensorineural deafness, progressive tapeto-retinal degeneration and dystonia

    SciTech Connect

    Tranebjaerg, L.; Schwartz, C.; Huggins, K.; Barker, D.; Stevenson, R.; Arena, J.F.; Gedde-Dahl, T.; Mikkelsen, M.; Mellgren, S.; Anderson, K. ||||

    1994-07-15

    In a reinvestigation of a six-generation Norwegian family, originally reported with non-syndromic X-linked recessive deafness by Mohr and Mageroy, we have demonstrated several syndromic manifestations. The 10 clinically characterized affected males range in age from 14-61 years, and show progressive mental deterioration and visual disability. Ophthalmological and electrophysiological studies showed myopia, decreased visual acuity, combined cone-rod dystrophy as well as central areolar dystrophy by means of ERG. Brain CT-scans showed cortical and central atrophy without predilection to specific areas. Linkage analysis, using X-chromosomal RFLPs and CA-repeats, yielded a maximum LOD score of 4.37 with linkage to DXS17. DXS17 is localized to Xq22. One recombinant with COL4A5 (deficient in Alport syndrome) was observed. Results from the studies of this family will be important in reclassification of non-syndromic X-linked deafness since the family now represents syndromic deafness and XLMR with a specific phenotype.

  14. Exome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations that affect key pathways involved in cancer progression

    PubMed Central

    Lasorsa, Vito Alessandro; Formicola, Daniela; Pignataro, Piero; Cimmino, Flora; Calabrese, Francesco Maria; Mora, Jaume; Esposito, Maria Rosaria; Pantile, Marcella; Zanon, Carlo; De Mariano, Marilena; Longo, Luca; Hogarty, Michael D.; de Torres, Carmen; Tonini, Gian Paolo; Iolascon, Achille; Capasso, Mario

    2016-01-01

    The spectrum of somatic mutation of the most aggressive forms of neuroblastoma is not completely determined. We sought to identify potential cancer drivers in clinically aggressive neuroblastoma. Whole exome sequencing was conducted on 17 germline and tumor DNA samples from high-risk patients with adverse events within 36 months from diagnosis (HR-Event3) to identify somatic mutations and deep targeted sequencing of 134 genes selected from the initial screening in additional 48 germline and tumor pairs (62.5% HR-Event3 and high-risk patients), 17 HR-Event3 tumors and 17 human-derived neuroblastoma cell lines. We revealed 22 significantly mutated genes, many of which implicated in cancer progression. Fifteen genes (68.2%) were highly expressed in neuroblastoma supporting their involvement in the disease. CHD9, a cancer driver gene, was the most significantly altered (4.0% of cases) after ALK. Other genes (PTK2, NAV3, NAV1, FZD1 and ATRX), expressed in neuroblastoma and involved in cell invasion and migration were mutated at frequency ranged from 4% to 2%. Focal adhesion and regulation of actin cytoskeleton pathways, were frequently disrupted (14.1% of cases) thus suggesting potential novel therapeutic strategies to prevent disease progression. Notably BARD1, CHEK2 and AXIN2 were enriched in rare, potentially pathogenic, germline variants. In summary, whole exome and deep targeted sequencing identified novel cancer genes of clinically aggressive neuroblastoma. Our analyses show pathway-level implications of infrequently mutated genes in leading neuroblastoma progression. PMID:27009842

  15. Assessment of the progress of the back-pain patient 1981 Volvo Award in Clinical Science.

    PubMed

    Million, R; Hall, W; Nilsen, K H; Baker, R D; Jayson, M I

    1982-01-01

    Fifteen subjective variables reflecting the severity of back pain, the circumstances exacerbating symptoms, and the impact of the problem on life style were scored on Visual Analogue Scales. It was possible to combine the results from these assessments to provide a global subjective index. Repeated measurements by the same observer showed a high degree of reproducibility, but when performed by separate observers discrepancies arose in certain questions. By improving certain questions and standardizing their presentation to the patient, a considerable improvement in the correlation of results between observers was obtained. Objective assessments of spinal motion and straight leg raising and a global objective index showed a high degree of intraobserver reproducibility. This technique was applied to a study of relief of back pain by lumbar corsets when it was found that there was significantly greater relief of back pain by a corset with a lumbar support than one without a spinal support. We conclude that the emphasis in assessing the progress of the back-pain patient must be on the subjective parameters, and the technique developed offers a useful method for reliably assessing patients and following their progress.

  16. 50 years of pediatric immunology: progress and future, a clinical perspective.

    PubMed

    Singh, Surjit; Gupta, Anju; Rawat, Amit

    2013-01-08

    Rapidly evolving advances in the field of immunology over the last few decades have impacted the practice of clinical medicine in many ways. In fact, understanding the immunological basis of disease has been pivotal in deciphering the pathogenesis of several disease processes, infective or otherwise. As of today, there is hardly any specialty of medicine which is not influenced by immunology. Pediatric rheumatological disorders, vasculitides, Human Immunodeficiency Virus (HIV) infection, Primary Immunodeficiency Diseases (PIDs) and autoimmune disorders fall under the domain of clinical immunology. This specialty is poised to emerge as a major clinical specialty in our country. The gulf between bench and bedside is narrowing down as our understanding of the complex immunological mechanisms gets better. However, a lot still needs to be done in this field as the morbidity and mortality of some of these conditions is unacceptably high in the Indian setup. A number of medical schools and institutes in the country now have the resources and the wherewithal to develop into specialized centres of clinical immunology. We need to concentrate on training more physicians and pediatricians in this field. The future is bright and the prospects exciting.

  17. Annual Research Review: Progress in Using Brain Morphometry as a Clinical Tool for Diagnosing Psychiatric Disorders

    ERIC Educational Resources Information Center

    Haubold, Alexander; Peterson, Bradley S.; Bansal, Ravi

    2012-01-01

    Brain morphometry in recent decades has increased our understanding of the neural bases of psychiatric disorders by localizing anatomical disturbances to specific nuclei and subnuclei of the brain. At least some of these disturbances precede the overt expression of clinical symptoms and possibly are endophenotypes that could be used to diagnose an…

  18. [A clinical trial of neutron capture therapy for brain tumors]. Technical progress report, 1990

    SciTech Connect

    Zamenhof, R.G.

    1990-12-31

    This document briefly describes recent advances in the author`s laboratory. Topics described include neutron beam design, high- resolution autoradiography, boronated phenylalanine (BPA) distribution and survival studies in glioma bearing mice, computer- aided treatment planning, prompt gamma boron 10 analysis facility at MITI-II, non-rodent BPA toxicity studies, and preparations for clinical studies.

  19. Department of Clinical Investigation, Annual Research Progress Report, Fiscal Year 2006 (Madigan Army Medical Center)

    DTIC Science & Technology

    2006-09-30

    Findings in Bariatric Surgery Specimens DEPARTMENT OF PEDIATRICS Cason RL #203014 T L Clinical Use of Reticulocyte Hemoglobin to Detect Iron...Status: Ongoing Title: Incidental Anatomic and Histologic Findings in Bariatric Surgery Specimens Principal Investigator: MAJ Anne L. Champeaux, MC...Collection, review and analysis of bariatric surgery specimen reports generated by the MAMC Anatomic Pathology service from 1994 through 2004 to

  20. SLAC Linear Collider

    SciTech Connect

    Richter, B.

    1985-12-01

    A report is given on the goals and progress of the SLAC Linear Collider. The status of the machine and the detectors are discussed and an overview is given of the physics which can be done at this new facility. Some ideas on how (and why) large linear colliders of the future should be built are given.

  1. Personalised and Precision Medicine in Cancer Clinical Trials: Panacea for Progress or Pandora's Box?

    PubMed

    Lawler, Mark; Sullivan, Richard

    2015-01-01

    Cancer clinical trials have been one of the key foundations for significant advances in oncology. However, there is a clear recognition within the academic, care delivery and pharmaceutical/biotech communities that our current model of clinical trial discovery and development is no longer fit for purpose. Delivering transformative cancer care should increasingly be our mantra, rather than maintaining the status quo of, at best, the often miniscule incremental benefits that are observed with many current clinical trials. As we enter the era of precision medicine for personalised cancer care (precision and personalised medicine), it is important that we capture and utilise our greater understanding of the biology of disease to drive innovative approaches in clinical trial design and implementation that can lead to a step change in cancer care delivery. A number of advances have been practice changing (e.g. imatinib mesylate in chronic myeloid leukaemia, Herceptin in erb-B2-positive breast cancer), and increasingly we are seeing the promise of a number of newer approaches, particularly in diseases like lung cancer and melanoma. Targeting immune checkpoints has recently yielded some highly promising results. New algorithms that maximise the effectiveness of clinical trials, through for example a multi-stage, multi-arm type design are increasingly gaining traction. However, our enthusiasm for the undoubted advances that have been achieved are being tempered by a realisation that these new approaches may have significant cost implications. This article will address these competing issues, mainly from a European perspective, highlight the problems and challenges to healthcare systems and suggest potential solutions that will ensure that the cost/value rubicon is addressed in a way that allows stakeholders to work together to deliver optimal cost-effective cancer care, the benefits of which can be transferred directly to our patients.

  2. Department of Clinical Investigation Annual Research Progress Report, Fiscal Year 1987

    DTIC Science & Technology

    1987-10-01

    O’Rourke T, George CB: Clinical Usefulness of an Algorithm for the Early Diagnosis of Spinal Metastatic Disease. J Clin Oncol Submitted for...Comparison of Magnetic Resonance Imaging to Com- 4 puter Tomography in the Early Diagnosis of Metastases to the Axial Skeleton. Cancer -10- a...Truncus Arteriosus: A Review of Diagnosis and Current Management. Amer J Dis Children Hartman KR, Triche TT, Kinsella TJ, Miser JA: Histopathology: A

  3. Two young sisters with spinocerebellar ataxia type 2 showing different clinical progression of disease.

    PubMed

    Yiş, Uluç; Dirik, Eray; Kurul, Semra Hiz; Eken, Asli Gündoğdu; Başak, A Nazli

    2009-06-01

    Spinocerebellar ataxia type 2 is a neurodegenerative disease caused by a CAG repeat expansion in the ataxin-2 gene. Gain-of-toxic effects caused by expanded polyglutamine tracts are important for the disease pathogenesis and there is an inverse relationship between the number of CAG repeats and the age of onset and clinical severity. Previously, we reported an extended Turkish family with spinocerebellar ataxia type 2 with several affected members in three generations. Two sisters in this generation showed an earlier age of onset (5 and 7 years, respectively) than their father (30 years). In this paper, we present a further interesting finding regarding the disease onset and manifestation in the two sisters. Interestingly, the age of onset was delayed and the clinical severity of the disease was milder in the child who had more CAG repeats (84 vs. 70). This finding suggests that there are other factors contributing to the age of onset and clinical severity in spinocerebellar ataxia type 2 other than the increased CAG repeat.

  4. Progress in proteomics for clinical microbiology: MALDI-TOF MS for microbial species identification and more.

    PubMed

    van Belkum, Alex; Chatellier, Sonia; Girard, Victoria; Pincus, David; Deol, Parampal; Dunne, Wm Michael

    2015-01-01

    Although classical proteomic approaches are still used regularly in routine clinical diagnostic procedures, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) MS has recently moved into diagnostic microbiology laboratories. MALDI-TOF MS is currently replacing phenotypic microbial identification. Many laboratories now use MALDI-TOF MS for its high efficiency, both from a diagnostic and a cost-per-analysis point of view. The US FDA has now cleared two of the commercially available systems for in vitro diagnostics. This will further spark development of MS applications in antimicrobial susceptibility testing and epidemiology. This review summarizes the state of affairs of MALDI-TOF MS in clinical microbiology; however, this is an active field of research subject to rapid evolution. We emphasize assessment of the clinical relevance and studies focusing on data obtained through comparative analyses of different MALDI-TOF MS instrumentation and multicenter validation studies. The future of MALDI-TOF MS, including antimicrobial susceptibility testing and epidemiological typing, is also highlighted.

  5. Stem cells: progress in research and edging towards the clinical setting.

    PubMed

    Stanworth, S J; Newland, A C

    2001-01-01

    Mouse embryonic stem cells have been shown to differentiate into a variety of tissues in vitro and in transplantation experiments can produce many different cell types. Multipotent stem cells in adult humans have also shown a high degree of plasticity: haemopoietic stem cells, for example, have been shown to contribute to several other tissues, such as liver. From these simple observations there has been considerable extrapolation into the use of such putative totipotent stem cells in the clinical setting, with the development of 'designer' tissue engineering, whose aim is to create large tissues or even whole organs for clinical use. In practical terms, however, there are many limitations and difficulties and clinical use has been restricted to a very few settings, eg the use of fetal cells in Parkinson's disease. Nonetheless, there is enormous potential in this area, and also in the application of embryonic or adult stem cells as carriers for gene therapy; but the limitations of such treatment, in particular the stability of manipulated cells, and the problems of ageing and Ooncogenicity, not to mention a host of ethical and regulatory issues, all need to be considered.

  6. A longitudinal linear model of patient characteristics to predict failure to attend an inner-city chronic pain clinic

    PubMed Central

    Shaparin, N; White, RS; Andreae, MH; Hall, CB; Kaufman, AG

    2014-01-01

    Patients often fail to attend appointments in chronic pain clinics for unknown reasons. We hypothesized that certain patient characteristics predict failure to attend scheduled appointments pointing to systematic barriers to access chronic pain services for certain underserved populations. We collected retrospective data from a longitudinal observational cohort of patients at an academic pain clinic in Newark, New Jersey. To examine the effect of demographic factors on appointment status, we fit a marginal logistic regression using generalized estimating equations with exchangeable correlation. 1394 patients with 3488 total encounters between January 1, 2006 and December 31, 2009 were included. Spanish spoken as a primary language (alternatively Hispanic or other race) and living between five and ten miles from the clinic were associated with reduced odds of arriving for an appointment; making an appointment for a particular complaint such as cancer pain or back pain, an interventional pain procedure scheduled in connection with the appointment, unemployed status, and continuity of care (as measured by office visit number) were associated with increased odds of arriving. Spanish spoken as primary language and distance to the pain clinic predicted failure to attend a scheduled appointment in our cohort. If these constitute systematic barriers to access, they may be amendable to targeted interventions. Perspective We identified certain patient characteristics, specifically Spanish spoken as primary language and geographic distance from the clinic, that predict failure to attend an inner-city chronic pain clinic. These identified barriers to access chronic pain services may be modifiable by simple cost effective interventions. PMID:24747766

  7. What features improve the accuracy of the clinical diagnosis of progressive supranuclear palsy-parkinsonism (PSP-P)?

    PubMed

    Williams, David R; Lees, Andrew J

    2010-02-15

    Progressive supranuclear palsy-parkinsonism (PSP-P) is a primary tauopathy characterised by neurofibrillary degeneration, which is frequently mistaken for Parkinson's disease (PD), multiple system atrophy (MSA), and vascular parkinsonism (VP) at presentation. The aim of this study was to identify particular clinical features (green flags) that may be helpful in differentiating PSP-P from these other disorders. We identified 37 patients with PSP-P from 726 patients archived at the Queen Square Brain Bank. Using a retrospective case notes review the clinical features were compared between the PSP-P group and Lewy body associated parkinsonism (PD, n = 444 and dementia with Lewy bodies (DLB), n = 46), MSA (n = 90), and VP (n = 19), using the chi(2)-test for proportions for a two-by-two contingency table. The sensitivity, specificity, and positive predictive values (PPV) and negative predictive values (NPV) were calculated for individual clinical features. A specificity of >0.85 or a PPV of >0.85 were considered reliable discriminators. No clinical features were predictive of PSP-P, but late drug induced dyskinesias (specificity 0.92, PPV 0.99), late autonomic dysfunction (specificity 0.94, PPV 0.99) and any visual hallucinations (specificity 0.94, PPV 0.99) were better in distinguishing PD and PSP-P than predicted using operational diagnostic criteria for PD. PSP-P shares many clinical features with PD and DLB, MSA and VP, but visual hallucinations, drug induced dyskinesias and autonomic dysfunction are very uncommon and may be helpful exclusion criteria.

  8. The Long-term Clinical Outcome after Corneal Collagen Cross-linking in Korean Patients with Progressive Keratoconus

    PubMed Central

    Kim, Tae Gi; Kim, Ki Young; Han, Jung Bin

    2016-01-01

    Purpose To evaluate the long-term clinical effectiveness and safety of corneal collagen cross-linking (CXL) in progressive keratoconus compared with untreated contralateral eyes. Methods In this retrospective study, nine eyes of nine patients with progressive keratoconus who received CXL (treatment group) and nine untreated contralateral eyes with keratoconus (control group) were included. All patients were followed for at least 5 years and assessed with best-corrected visual acuity, maximum keratometry, mean keratometry, corneal astigmatism, and corneal thickness. Clinical data were collected preoperatively and at 1, 3, 6, 12, 24, 36, 48, and 60 months, postoperatively. Results Mean best-corrected visual acuity improved significantly from 0.58 ± 0.37 logarithm of minimum angle of resolution preoperatively to 0.39 ± 0.29 logarithm of minimum angle of resolution at 5 years after corneal CXL (p = 0.012). There was significant flattening of the maximum keratometry and mean keratometry from preoperative values of 63.39 ± 10.89 and 50.87 ± 6.27 diopter (D) to postoperative values of 60.89 ± 11.29 and 49.54 ± 7.23 D, respectively (p = 0.038, 0.021). Corneal astigmatism decreased significantly from 7.20 ± 1.83 D preoperatively to 5.41 ± 1.79 D postoperatively (p = 0.021). The thinnest corneal thickness decreased from 434.00 ± 54.13 to 365.78 ± 71.58 µm during 1 month after treatment, then increased to 402.67 ± 52.55 µm at 5 years, which showed a statistically significant decrease compared to the baseline (p = 0.020). In the untreated contralateral eyes, mean keratometry increased significantly at 2 years compared with the baseline (p = 0.043). Conclusions CXL seems to be an effective and safe treatment for halting the progression of keratoconus over a long-term follow-up period of up to 5 years in progressive keratoconus. PMID:27729752

  9. Progressive outer retinal necrosis syndrome: a comprehensive review of its clinical presentation, relationship to immune system status, and management.

    PubMed

    Austin

    2000-12-01

    Progressive outer retinal necrosis (PORN) syndrome is a form of the Varicella zoster virus (VZV) chorioretinitis found almost exclusively in people with the acquired immunodeficiency syndrome (AIDS). This destructive infection has an extremely rapid course that may lead to no light perception in affected eyes within days or weeks. Attempts at its treatment have had limited success. Rhegmatogenous retinal detachments often occur after the development of atrophic retinal holes, and silicone oil temponade has been found to be the most successful reattachment procedure. Unfortunately, cataract formation is common after such surgery. PORN needs to be differentiated from acute retinal necrosis (ARN) syndrome, a necrotizing retinitis that can also be caused by VZV. PORN and ARN are found at opposite ends of the spectrum of necrotizing herpetic retinopathies (NHR), where its clinical presentation depends upon immune system status. After a brief case presentation, the distinguishing clinical characteristics of PORN, its differentiation from ARN, attempts at its treatment, the role of the immune system status on its clinical appearance and treatment, and management of complications such as retinal detachment and subsequent cataracts are discussed.

  10. THE COOPERATIVE INTERNATIONAL NEUROMUSCULAR RESEARCH GROUP DUCHENNE NATURAL HISTORY STUDY: GLUCOCORTICOID TREATMENT PRESERVES CLINICALLY MEANINGFUL FUNCTIONAL MILESTONES AND REDUCES RATE OF DISEASE PROGRESSION AS MEASURED BY MANUAL MUSCLE TESTING AND OTHER COMMONLY USED CLINICAL TRIAL OUTCOME MEASURES

    PubMed Central

    HENRICSON, ERIK K.; ABRESCH, R. TED; CNAAN, AVITAL; HU, FENGMING; DUONG, TINA; ARRIETA, ADRIENNE; HAN, JAY; ESCOLAR, DIANA M.; FLORENCE, JULAINE M.; CLEMENS, PAULA R.; HOFFMAN, ERIC P.; McDONALD, CRAIG M.

    2014-01-01

    Introduction Glucocorticoid (GC) therapy in Duchenne muscular dystrophy (DMD) has altered disease progression, necessitating contemporary natural history studies. Methods The Cooperative Neuromuscular Research Group (CINRG) DMD Natural History Study (DMD-NHS) enrolled 340 DMD males, ages 2–28 years. A comprehensive battery of measures was obtained. Results A novel composite functional “milestone” scale scale showed clinically meaningful mobility and upper limb abilities were significantly preserved in GC-treated adolescents/young adults. Manual muscle test (MMT)-based calculations of global strength showed that those patients <10 years of age treated with steroids declined by 0.4±0.39 MMT unit/year, compared with −0.4±0.39 MMT unit/year in historical steroid-naive subjects. Pulmonary function tests (PFTs) were relatively preserved in steroid-treated adolescents. The linearity and magnitude of decline in measures were affected by maturational changes and functional status. Conclusions In DMD, long-term use of GCs showed reduced strength loss and preserved functional capabilities and PFTs compared with previous natural history studies performed prior to the widespread use of GC therapy. PMID:23649481

  11. Standards for Scalable Clinical Decision Support: Need, Current and Emerging Standards, Gaps, and Proposal for Progress

    PubMed Central

    Kawamoto, Kensaku; Del Fiol, Guilherme; Lobach, David F.; Jenders, Robert A

    2010-01-01

    Despite their potential to significantly improve health care, advanced clinical decision support (CDS) capabilities are not widely available in the clinical setting. An important reason for this limited availability of CDS capabilities is the application-specific and institution-specific nature of most current CDS implementations. Thus, a critical need for enabling CDS capabilities on a much larger scale is the development and adoption of standards that enable current and emerging CDS resources to be more effectively leveraged across multiple applications and care settings. Standards required for such effective scaling of CDS include (i) standard terminologies and information models to represent and communicate about health care data; (ii) standard approaches to representing clinical knowledge in both human-readable and machine-executable formats; and (iii) standard approaches for leveraging these knowledge resources to provide CDS capabilities across various applications and care settings. A number of standards do exist or are under development to meet these needs. However, many gaps and challenges remain, including the excessive complexity of many standards; the limited availability of easily accessible knowledge resources implemented using standard approaches; and the lack of tooling and other practical resources to enable the efficient adoption of existing standards. Thus, the future development and widespread adoption of current CDS standards will depend critically on the availability of tooling, knowledge bases, and other resources that make the adoption of CDS standards not only the right approach to take, but the cost-effective path to follow given the alternative of using a traditional, ad hoc approach to implementing CDS. PMID:21603283

  12. Standards for scalable clinical decision support: need, current and emerging standards, gaps, and proposal for progress.

    PubMed

    Kawamoto, Kensaku; Del Fiol, Guilherme; Lobach, David F; Jenders, Robert A

    2010-01-01

    Despite their potential to significantly improve health care, advanced clinical decision support (CDS) capabilities are not widely available in the clinical setting. An important reason for this limited availability of CDS capabilities is the application-specific and institution-specific nature of most current CDS implementations. Thus, a critical need for enabling CDS capabilities on a much larger scale is the development and adoption of standards that enable current and emerging CDS resources to be more effectively leveraged across multiple applications and care settings. Standards required for such effective scaling of CDS include (i) standard terminologies and information models to represent and communicate about health care data; (ii) standard approaches to representing clinical knowledge in both human-readable and machine-executable formats; and (iii) standard approaches for leveraging these knowledge resources to provide CDS capabilities across various applications and care settings. A number of standards do exist or are under development to meet these needs. However, many gaps and challenges remain, including the excessive complexity of many standards; the limited availability of easily accessible knowledge resources implemented using standard approaches; and the lack of tooling and other practical resources to enable the efficient adoption of existing standards. Thus, the future development and widespread adoption of current CDS standards will depend critically on the availability of tooling, knowledge bases, and other resources that make the adoption of CDS standards not only the right approach to take, but the cost-effective path to follow given the alternative of using a traditional, ad hoc approach to implementing CDS.

  13. Designing privacy-friendly digital whiteboards for mediation of clinical progress

    PubMed Central

    2014-01-01

    Background In hospitals, digital versions of dry-erase whiteboards are increasingly becoming more common. One of the purposes with such whiteboards is to support coordination of care by augmenting visibility and availability of clinical information. However, clinical information usually concerns patients and is regarded as sensitive personal health information, meaning that it should be access controlled. The purpose of this study is to explore how digital whiteboards can be designed for supporting coordination of care, by providing clinicians with useful information in a usable way, and at the same time protect patient privacy. Methods A demo application was designed, demonstrated and evaluated iteratively. In total, 15 professional ward nurses role-played a scenario in which the application played a central part. Afterwards, the participants were interviewed. All interviews were recorded, transcribed verbatim, and analysed qualitatively. Results The participants valued having updated clinical information presented on a digital whiteboard, even if the information was de-identified and abstracted. According to the participants, such information could possibly improve inter-departmental communication, reduce the number of electronic health record-logins, and make nurses more rapidly aware of new information. The participants expected that they would be able to re-identify much of the de-identified information in real situations based on their insight into their patients’ recent and expected care activities. Moreover, they also valued being able to easily access more detailed information and verify patient identities. While abstraction and de-identification was regarded to sufficiently protect the patients’ privacy, the nurses also pointed out the importance of having control over what can be seen by other patients and passers-by if detailed medical information was accessed on a digital whiteboard. Conclusions Presenting updated information from patient care

  14. Department of Clinical Investigation Annual Research Progress Report, Fiscal Year 1993. Volume 1

    DTIC Science & Technology

    1993-10-01

    Steroid In Reducing Post- Tonsillectomy Morbidity. 309 o0) C-89-91 Compassionate Use Protocol for Centoxin (HA-lA). (C) 310 C-90-91 Phase I Protocol...treated with Nd:YAG Laser to Patients Not Treated with Laser : Survival and Clinical data. Chest 1993; 10:44S. Atkins, J; Johnson, JE; Blanton, HM. The...Medical Center. 308 Detail Summary Sheet Date: 15 Dec 93 Protocol Number: C-76-91 Status: Ongoing Title: Efficacy of Steroid in Reducing Post- Tonsillectomy

  15. A Disintegrin and Metalloproteinase-12 (ADAM12): Function, Roles in Disease Progression, and Clinical Implications

    PubMed Central

    Nyren-Erickson, Erin K.; Jones, Justin M.; Srivastava, D. K.

    2013-01-01

    Background A disintegrin and metalloproteinase-12 (ADAM12) is a member of the greater ADAM family of enzymes: these are multifunctional, generally membrane-bound, zinc proteases for which there are forty genes known (21 of these appearing in humans). ADAM12 has been implicated in the pathogenesis of various cancers, liver fibrogenesis, hypertension, and asthma, and its elevation or decrease in human serum has been linked to these and other physiological/pathological conditions. Scope In this review, we begin with a brief overview of the ADAM family of enzymes and protein structure. We then discuss the role of ADAM12 in the progression and/or diagnosis of various disease conditions, and we will conclude with an exploration of currently known natural and synthetic inhibitors. Major Conclusions ADAM12 has potential to emerge as a successful drug target, although targeting the metalloproteinase domain with any specificity will be difficult to achieve due to structural similarity between the members of the ADAM and MMP family of enzymes. Overall, more research is required to establish ADAM12 being as a highly desirable biomarker and drug target of different diseases, and their selective inhibitors as potential therapeutic agents. General Significance Given the appearance of elevated levels of ADAM12 in various diseases, particularly breast cancer, our understanding of this enzyme both as a biomarker and a potential drug target could help make significant inroads into both early diagnosis and treatment of disease. PMID:23680494

  16. [Hormone receptors and HER-2 changes during breast cancer progression: clinical implications].

    PubMed

    Jacot, William; Pouderoux, Stéphane; Bibeau, Frédéric; Leaha, Cristina; Chateau, Marie-Christine; Chapelle, Angélique; Romieu, Gilles

    2011-10-01

    Breast cancer remains a major public health problem. Even if there is an increase in this cancer curability, metastatic breast cancer remains a lethal disease in the vast majority of cases. Therapeutic advances in the chemotherapeutic and targeted therapies fields induced an increase in survival, however the proportion of long survivors remains low. Phenotypic instability, an early process initiated during tumour progression, and continued on the metastatic stage of the disease, can be one of the putative hypotheses explaining these results. An increasing amount of scientific data are pledging for a reanalysis of the phenotypic profile regarding hormone receptors and HER-2 status of metastatic lesions in order to identify drugable targets and allow individualisation of the treatment of these metastatic breast cancer patients. Phenotypic changes between the primary tumour and the paired metastatic lymph nodes are a challenging pitfall, raising the question of which site has to be assessed in the adjuvant treatment decision process. This article presents a comprehensive analysis of the frequency of theses phenotypic changes altogether with new modalities to evaluate this phenotypic status.

  17. Transition of adult T-cell leukemia/lymphoma clones during clinical progression.

    PubMed

    Aoki, Sakura; Firouzi, Sanaz; López, Yosvany; Yamochi, Tadanori; Nakano, Kazumi; Uchimaru, Kaoru; Utusnomiya, Atae; Iwanaga, Masako; Watanabe, Toshiki

    2016-09-01

    Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell neoplasm caused by the transformation of HTLV-1-infected T cells. ATLL, especially its aggressive form, is known for its poor prognosis, even with intensive chemotherapy. ATLL cells are considered to be monoclonal; however, multiclonal proliferation or emergence of a new clone over time has been reported based on Southern blot analysis, although direct molecular evidence remains elusive. Furthermore, it is thought that clonal change may be a cause of early drug resistance in ATLL. To directly analyze potential clonal changes in ATLL during its clinical course, we used inverse PCR to detect integration sites in combination with a newly developed method using next-generation sequencing, and compared ATLL cell clonality at different time points. The results of inverse PCR indicated that the major clone was altered in three of 19 patients. Together with results from five patients, using this new method, we found direct evidence of clonal change occurring during the clinical course or in response to chemotherapy in ATLL. These results also highlight the importance of clonality analysis for understanding the mechanisms of ATLL development and drug resistance.

  18. Progress in the Discovery of Treatments for C. difficile Infection: A Clinical and Medicinal Chemistry Review

    PubMed Central

    Tsutsumi, Lissa S.; Owusu, Yaw B.; Hurdle, Julian G.; Sun, Dianqing

    2014-01-01

    Clostridium difficile is an anaerobic, Gram-positive pathogen that causes C. difficile infection, which results in significant morbidity and mortality. The incidence of C. difficile infection in developed countries has become increasingly high due to the emergence of newer epidemic strains, a growing elderly population, extensive use of broad spectrum antibiotics, and limited therapies for this diarrheal disease. Because treatment options currently available for C. difficile infection have some drawbacks, including cost, promotion of resistance, and selectivity problems, new agents are urgently needed to address these challenges. This review article focuses on two parts: the first part summarizes current clinical treatment strategies and agents under clinical development for C. difficile infection; the second part reviews newly reported anti-difficile agents that have been evaluated or reevaluated in the last five years and are in the early stages of drug discovery and development. Antibiotics are divided into natural product inspired and synthetic small molecule compounds that may have the potential to be more efficacious than currently approved treatments. This includes potency, selectivity, reduced cytotoxicity, and novel modes of action to prevent resistance. PMID:24236721

  19. Photodynamic therapy: Progress toward a scientific and clinical network in Latin America.

    PubMed

    Buzzá, Hilde H; da Silva, Ana Paula; Vollet Filho, José Dirceu; Ramirez, Dora Patricia; Trujillo, José Roberto; Inada, Natalia M; Moriyama, Lilian T; Kurachi, Cristina; Bagnato, Vanderlei S

    2016-03-01

    Cancer is one of the major challenges for Latin America health services, since the skin cancer is the most frequent lesion. This manuscript addresses an initiative for the treatment of basal cell carcinomas (BCC) by photodynamic therapy (PDT) based on a government-funded national program in Brazil. The program provides clinical training and facilitates access to drugs/equipment and significantly reduces PDT costs. It also lays foundations for the establishment of a Latin American research network to improve prevention, early detection and treatment of diseases. Centers have been established by direct contact (conferences, visits to healthcare facilities and official departments). A local training was divided into complementary theoretical and practical parts. This is an ongoing project that has involved 10 countries: Brazil, Bolivia Chile, Ecuador, El Salvador, Colombia, Cuba, Mexico, Peru and Venezuela, The initial results are encouraging and have provided assessment of Latin America patients relating, for example, the most common skin phototypes with incidence of BCC in such countries. The network is expected to produce relevant scientific information for PDT introduction in many countries. The experience acquired by local teams shall enable them to innovate PDT protocols and increase the number of skilled contributors/researchers to broaden knowledge on the ever-crescent PDT field in Latin America. The establishment of a collaboration network and introduction of other projects and experience exchange shall become an easier process with time. This PDT clinical research network is a start for the strengthening of Science in South Hemisphere countries.

  20. Recent Progress in Lab-on-a-Chip Technology and Its Potential Application to Clinical Diagnoses

    PubMed Central

    2013-01-01

    We present the construction of the lab-on-a-chip (LOC) system, a state-of-the-art technology that uses polymer materials (i.e., poly[dimethylsiloxane]) for the miniaturization of conventional laboratory apparatuses, and show the potential use of these microfluidic devices in clinical applications. In particular, we introduce the independent unit components of the LOC system and demonstrate how each component can be functionally integrated into one monolithic system for the realization of a LOC system. In specific, we demonstrate microscale polymerase chain reaction with the use of a single heater, a microscale sample injection device with a disposable plastic syringe and a strategy for device assembly under environmentally mild conditions assisted by surface modification techniques. In this way, we endeavor to construct a totally integrated, disposable microfluidic system operated by a single mode, the pressure, which can be applied on-site with enhanced device portability and disposability and with simple and rapid operation for medical and clinical diagnoses, potentially extending its application to urodynamic studies in molecular level. PMID:23610705

  1. Progress and problems for randomized clinical trials: from streptomycin to the era of megatrials.

    PubMed

    Hilbrich, Lutz; Sleight, Peter

    2006-09-01

    Randomized clinical trials (RCTs) are the definitive contributors to evidence-based medicine. RCTs assessing serious outcomes in cardiovascular disease have grown, with 'megatrials' becoming more common with the realization that wrong conclusions resulted from random error in inadequately sized trials. Simple design and a heterogeneous patient population were early features, but multinational trials have increased in scientific, logistical, bureaucratic, regulatory, and legal complexity. These studies now exceed the financial means of academia or medical charities. Governments have left the bill with the pharmaceutical industry, encouraging a symbiosis with academics, who contribute medical and scientific expertise, and access to patients. Industry provides pharmacological, pharmaceutical, technical and regulatory know-how, good clinical practice expertise, and legal assistance during the trial. Study supervision is then in the hands of an independent steering committee and associated subcommittees, until appropriate dissemination of results. Prospectively defined interaction with the sponsor facilitates unbiased design and conduct, but arrangements need careful implementation to avoid conflicts of interest. The patient is protected by a strong data safety monitoring board that is wholly independent. Megatrials are under threat from over-regulation, increasing costs, and difficulties in execution. These issues merit urgent public and political education and debate.

  2. Measurement of passive skeletal muscle mechanical properties in vivo: recent progress, clinical applications, and remaining challenges.

    PubMed

    Bilston, Lynne E; Tan, Kristy

    2015-02-01

    The ability to measure and quantify the properties of skeletal muscle in vivo as a method for understanding its complex physiological and pathophysiological behavior is important in numerous clinical settings, including rehabilitation. However, this remains a challenge to date due to the lack of a "gold standard" technique. Instead, there are a myriad of measuring techniques each with its own set of pros and cons. This review discusses the current state-of-the-art in elastography imaging techniques, i.e., ultrasound and magnetic resonance elastography, as applied to skeletal muscle, and briefly reviews other methods of measuring muscle mechanical behavior in vivo. While in vivo muscle viscoelastic properties can be measured, these techniques are largely limited to static or quasistatic measurements. Emerging elastography techniques are able to quantify muscle anisotropy and large deformation effects on stiffness, but, validation and optimization of these newer techniques is required. The development of reliable values for the mechanical properties of muscle across the population using these techniques are required to enable them to become more useful in rehabilitation and other clinical settings.

  3. TMPRSS2-ERG Fusion Gene Expression in Prostate Tumor Cells and Its Clinical and Biological Significance in Prostate Cancer Progression

    PubMed Central

    St. John, Jason; Powell, Katelyn; Conley-LaComb, M. Katie; Chinni, Sreenivasa R.

    2012-01-01

    TMPRSS2-Ets gene fusions were identified in prostate cancers where the promoter of transmembrane protease, serine 2 (TMPRSS2) fused with coding sequence of the erythroblastosis virus E26 (Ets) gene family members. TMPRSS2 is an androgen responsive transmembrane serine protease. Ets family members are oncogenic transcription factors that contain a highly conserved Ets DNA binding domain and an N-terminal regulatory domain. Fusion of these gene results in androgen dependent transcription of Ets factor in prostate tumor cells. The ERG is the most common fusion partner with TMPRSS2 promoter in prostate cancer patients. The high prevalence of these gene fusions, in particular TMPRSS2-ERG, makes them attractive as potential diagnostic and prognostic indicators, as well as making them a potential target for tailored therapies. This review focuses on the clinical and biological significance of TMPRSS2-ERG fusions and their role in PC development and progression. PMID:23264855

  4. Assessing the HIV Care Continuum in Latin America: progress in clinical retention, cART use and viral suppression

    PubMed Central

    Rebeiro, Peter F; Cesar, Carina; Shepherd, Bryan E; De Boni, Raquel B; Cortés, Claudia P; Rodriguez, Fernanda; Belaunzarán-Zamudio, Pablo; Pape, Jean W; Padgett, Denis; Hoces, Daniel; McGowan, Catherine C; Cahn, Pedro

    2016-01-01

    Introduction We assessed trends in HIV Care Continuum outcomes associated with delayed disease progression and reduced transmission within a large Latin American cohort over a decade: clinical retention, combination antiretroviral therapy (cART) use and viral suppression (VS). Methods Adults from Caribbean, Central and South America network for HIV epidemiology clinical cohorts in seven countries contributed data between 2003 and 2012. Retention was defined as two or more HIV care visits annually, >90 days apart. cART was defined as prescription of three or more antiretroviral agents annually. VS was defined as HIV-1 RNA <200 copies/mL at last measurement annually. cART and VS denominators were subjects with at least one visit annually. Multivariable modified Poisson regression was used to assess temporal trends and examine associations between age, sex, HIV transmission mode, cohort, calendar year and time in care. Results Among 18,799 individuals in retention analyses, 14,380 in cART analyses and 13,330 in VS analyses, differences existed between those meeting indicator definitions versus those not by most characteristics. Retention, cART and VS significantly improved from 2003 to 2012 (63 to 77%, 74 to 91% and 53 to 82%, respectively; p<0.05, each). Female sex (risk ratio (RR)=0.97 vs. males) and injection drug use as HIV transmission mode (RR=0.83 vs. male sexual contact with males (MSM)) were significantly associated with lower retention, but unrelated with cART or VS. MSM (RR=0.96) significantly decreased the probability of cART compared with heterosexual transmission. Conclusions HIV Care Continuum outcomes improved over time in Latin America, though disparities for vulnerable groups remain. Efforts must be made to increase retention, cART and VS, while engaging in additional research to sustain progress in these settings. PMID:27065108

  5. Macular Ganglion Cell -Inner Plexiform Layer Thickness Is Associated with Clinical Progression in Mild Cognitive Impairment and Alzheimers Disease

    PubMed Central

    Choi, Seong Hye; Park, Sang Jun

    2016-01-01

    Purpose We investigated the association of the macular ganglion cell-inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (RNFL) thicknesses with disease progression in mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Methods We recruited 42 patients with AD, 26 with MCI, and 66 normal elderly controls. The thicknesses of the RNFL and GCIPL were measured via spectral-domain optic coherent tomography in all participants at baseline. The patients with MCI or AD underwent clinical and neuropsychological tests at baseline and once every year thereafter for 2 years. Results The Clinical Dementia Rating scale-Sum of Boxes (CDR-SB) score exhibited significant negative relationships with the average GCIPL thickness (β = -0.15, p < 0.05) and the GCIPL thickness in the superotemporal, superonasal, and inferonasal sectors. The composite memory score exhibited significant positive associations with the average GCIPL thickness and the GCIPL thickness in the superotemporal, inferonasal, and inferotemporal sectors. The temporal RNFL thickness, the average and minimum GCIPL thicknesses, and the GCIPL thickness in the inferonasal, inferior, and inferotemporal sectors at baseline were significantly reduced in MCI patients who were converted to AD compared to stable MCI patients. The change of CDR-SB from baseline to 2 years exhibited significant negative associations with the average (β = -0.150, p = 0.006) and minimum GCIPL thicknesses as well as GCIPL thickness in the superotemporal, superior, superonasal, and inferonasal sectors at baseline. Conclusions Our data suggest that macular GCIPL thickness represents a promising biomarker for monitoring the progression of MCI and AD. PMID:27598262

  6. High-throughput sequencing and clinical microbiology: progress, opportunities and challenges.

    PubMed

    Pallen, Mark J; Loman, Nicholas J; Penn, Charles W

    2010-10-01

    High-throughput sequencing is sweeping through clinical microbiology, transforming our discipline in its wake. It is already providing an enhanced view of pathogen biology through rapid and inexpensive whole-genome sequencing and more sophisticated applications such as RNA-seq. It also promises to deliver high-resolution genomic epidemiology as the ultimate typing method for bacteria. However, the most revolutionary effect of this 'disruptive technology' is likely to be creation of a novel sequence-based, culture-independent diagnostic microbiology that incorporates microbial community profiling, metagenomics and single-cell genomics. We should prepare for the coming 'technological singularity' in sequencing, when this technology becomes so fast and so cheap that it threatens to out-compete existing diagnostic and typing methods in microbiology.

  7. Clinical characteristics and long-term progression of young patients with acute coronary syndrome in Brazil

    PubMed Central

    Soeiro, Alexandre de Matos; Fernandes, Felipe Lourenço; Soeiro, Maria Carolina Feres de Almeida; Serrano, Carlos Vicente; de Oliveira, Múcio Tavares

    2015-01-01

    Objective In Brazil, there are few descriptions in the literature on the angiographic pattern and clinical characteristics of young patients with acute coronary syndrome, despite the evident number of cases in the population. The objective of this study was to evaluate which clinical characteristics are most closely related to the acute coronary syndrome in young patients, and what long-term outcomes are in this population. Methods This is a prospective observational study with 268 patients aged under 55 years with acute coronary syndrome, carried out between May 2010 and May 2013. Data were obtained on demographics, laboratory test and angiography results, and the coronary treatment adopted. Statistical analysis was presented as percentages and absolute values. Results Approximately 57% were men and the median age was 50 years (30 to 55). The main risk factors were arterial hypertension (68%), smoking (67%), and dyslipidemia (43%). Typical pain was present in 90% of patients. In young individuals, 25.7% showed ST segment elevation. Approximately 56.5% of patients presented with a single-vessel angiographic pattern. About 7.1% were submitted to coronary bypass surgery, and 42.1% to percutaneous coronary angioplasty. Intrahospital mortality was 1.5%, and the combined event rate (cerebrovascular accident/stroke, cardiogenic shock, reinfarction, and arrhythmias) was 13.8%. After a mean follow-up of 10 months, mortality was 9.8%, while 25.4% of the patients had new ischemic events, and 37.3% required readmission to hospital. Conclusion In the short-term, young patients presented with mortality rates below what was expected when compared to the rates noted in other studies. However, there was a significant increase in the number of events in the 10-month follow-up. PMID:26466059

  8. Primary Progressive Aphasia

    MedlinePlus

    Primary progressive aphasia Overview By Mayo Clinic Staff Primary progressive aphasia (uh-FAY-zhuh) is a rare nervous system (neurological) syndrome ... your ability to communicate. People with primary progressive aphasia can have trouble expressing their thoughts and understanding ...

  9. Clinical improvement and radiological progression in a girl with early onset scoliosis (EOS) treated conservatively – a case report

    PubMed Central

    Weiss, Hans-Rudolf

    2006-01-01

    . However, the weight the patient gained cannot explain the cosmetical improvement in this case. Conservative treatment with a certain standard of quality seems a viable alternative for patients with Cobb angles of > 60° when surgical treatment is refused. Specialists in scoliosis management should be aware of the fact that curve progression can occur even if the clinical measurements show an improvement. PMID:16872503

  10. A warning to the Brazilian Speech-Language Pathology and Audiology community about the importance of scientific and clinical activities in primary progressive aphasia.

    PubMed

    Beber, Bárbara Costa; Brandão, Lenisa; Chaves, Márcia Lorena Fagundes

    2015-01-01

    This article aims to warn the Brazilian Speech-Language Pathology and Audiology scientific community about the importance and necessity of scientific and clinical activities regarding Primary Progressive Aphasia. This warning is based on a systematic literature review of the scientific production on Primary Progressive Aphasia, from which nine Brazilian articles were selected. It was observed that there is an obvious lack of studies on the subject, as all the retrieved articles were published in medical journals and much of it consisted of small samples; only two articles described the effectiveness of speech-language therapy in patients with Primary Progressive Aphasia. A perspective for the future in the area and characteristics of Speech-Language Therapy for Primary Progressive Aphasia are discussed. As a conclusion, it is evident the need for greater action by Speech-Language Pathology and Audiology on Primary Progressive Aphasia.

  11. A generalized partially linear mean-covariance regression model for longitudinal proportional data, with applications to the analysis of quality of life data from cancer clinical trials.

    PubMed

    Zheng, Xueying; Qin, Guoyou; Tu, Dongsheng

    2017-02-19

    Motivated by the analysis of quality of life data from a clinical trial on early breast cancer, we propose in this paper a generalized partially linear mean-covariance regression model for longitudinal proportional data, which are bounded in a closed interval. Cholesky decomposition of the covariance matrix for within-subject responses and generalized estimation equations are used to estimate unknown parameters and the nonlinear function in the model. Simulation studies are performed to evaluate the performance of the proposed estimation procedures. Our new model is also applied to analyze the data from the cancer clinical trial that motivated this research. In comparison with available models in the literature, the proposed model does not require specific parametric assumptions on the density function of the longitudinal responses and the probability function of the boundary values and can capture dynamic changes of time or other interested variables on both mean and covariance of the correlated proportional responses. Copyright © 2017 John Wiley & Sons, Ltd.

  12. Measurement of the restricted linear energy transfer of stray radiation close to the treatment volume of 12 and 18 MeV clinical photon beams.

    PubMed

    Makrigiorgos, G; Antonadou, D; Proukakis, C; Throuvalas, N

    1989-01-01

    The restricted dose mean linear energy transfer (LET) (L500,D) of the stray radiation field a few centimeters outside the treatment volume has been measured for 12 and 18 MV photons produced by a clinical Therac-20 (AECL) accelerator. The measurements were performed as a function of field size and distance from the edge of the treatment volume, using the method of the high-pressure ionization chamber. Contrary to what was found in a previous investigation for a clinical Co-60 unit and despite the presence of photoneutrons (in the case of 18 MV photons), the L500,D outside the beam does not increase significantly relative to the L500,D of the primary beam.

  13. Measurement of the restricted linear energy transfer of stray radiation close to the treatment volume of 12 and 18 MeV clinical photon beams

    SciTech Connect

    Makrigiorgos, G.; Antonadou, D.; Proukakis, C.; Throuvalas, N.

    1989-03-01

    The restricted dose mean linear energy transfer (LET) (L-bar/sub 500,//sub D/ ) of the stray radiation field a few centimeters outside the treatment volume has been measured for 12 and 18 MV photons produced by a clinical Therac-20 (AECL) accelerator. The measurements were performed as a function of field size and distance from the edge of the treatment volume, using the method of the high-pressure ionization chamber. Contrary to what was found in a previous investigation for a clinical Co-60 unit and despite the presence of photoneutrons (in the case of 18 MV photons), the L-bar/sub 500,//sub D/ outside the beam does not increase significantly relative to the L-bar/sub 500,//sub D/ of the primary beam.

  14. Progress in the treatment of locally advanced clinically resectable rectal cancer.

    PubMed

    Minsky, Bruce D

    2011-12-01

    There have been significant developments in the adjuvant treatment of locally advanced clinically resectable (T3 and/or N+) rectal cancer. Postoperative systemic chemotherapy plus concurrent pelvic irradiation (chemoradiation) significantly improves local control and survival compared with surgery alone. The German Rectal Cancer Trial confirmed that when chemoradiation is delivered preoperatively there is a significant decrease in acute and late toxicity and a corresponding increase in local control and sphincter preservation. Despite these advances, controversies remain. Among these controversies are the role of short-course radiation, whether postoperative adjuvant chemotherapy is necessary for all patients, and if the type of surgery after chemoradiation can be modified based on tumor response. Are there more accurate imaging techniques and/or molecular markers to help identify patients with positive pelvic nodes with the goal of reducing the chance of overtreatment with preoperative therapy. Will more effective systemic agents both improve outcome and modify the need for pelvic irradiation? This review examines the advances in chemoradiation as well as addresses these and other opportunities for improvement.

  15. Have Smartphones Contributed in the Clinical Progress of Oral and Maxillofacial Surgery?

    PubMed Central

    Dhuvad, Mukesh M.; Kshirsagar, Rajesh A.

    2015-01-01

    Background Dental surgeons who encounter complex situations, such as those in unscheduled care, often have limited resources to provide a structured and specialty care. Therefore, there is always a need for cost-effective, easy to handle, easy to carry “Smartphones”. Objective The purpose of this paper was to undertake a review of literature on “Smartphone in Oral and Maxillofacial Surgery” online data-base and discuss the case series with emphasis on the role of attending dental surgeon and the maxillofacial surgeon. Materials and Methods The available literature relevant to oral and maxillofacial surgery in online data-base of the United States National Library of Medicine: PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) was searched. The inclusion criterion was to review the published clinical papers, abstracts and evidence based reviews on ‘Uses of Smartphone in Oral and Maxillofacial Surgery’. Results Six articles were found with the search term “Smartphone in Oral and Maxillofacial Surgery” in the literature searched. Five articles met the inclusion criteria for the study. The relevant data was extracted, tabulated, and reviewed to draw evidence-based conclusions for uses of smartphone in oral and maxillofacial surgery. Conclusion Utilization of smartphones in oral and maxillofacial surgery facilitate in differential diagnosis, treatment, follow up, prevention of the disease further and thereby improve the quality of patient care without requiring the presence of the maxillofacial surgeon in remote areas. PMID:26501006

  16. Effects of acupressure on progress of labor and cesarean section rate: randomized clinical trial.

    PubMed

    Mafetoni, Reginaldo Roque; Shimo, Antonieta Keiko Kakuda

    2015-01-01

    OBJECTIVE To analyze the effects of acupressure at the SP6 point on labor duration and cesarean section rates in parturients served in a public maternity hospital. METHODS This controlled, randomized, double-blind, pragmatic clinical trial involved 156 participants with gestational age ≥ 37 weeks, cervical dilation ≥ 4 cm, and ≥ 2 contractions in 10 min. The women were randomly divided into an acupressure, placebo, or control group at a university hospital in an inland city in the state of Sao Paulo, Brazil, in 2013. Acupressure was applied to the SP6 point during contractions for 20 min. RESULTS The average labor duration was significantly different between the SP6 acupressure group [221.5 min (SD = 162.4)] versus placebo [397.9 min (SD = 265.6)] and versus control [381.9 min (SD = 358.3)] (p = 0.0047); however, the groups were similar regarding the cesarean section rates (p = 0.2526) and Apgar scores in the first minute (p = 0.9542) and the fifth minute (p = 0.7218) of life of the neonate. CONCLUSIONS The SP6 acupressure point proved to be a complementary measure to induce labor and may shorten the labor duration without causing adverse effects to the mother or the newborn. However, it did not affect the cesarean section rate.

  17. Effects of acupressure on progress of labor and cesarean section rate: randomized clinical trial

    PubMed Central

    Mafetoni, Reginaldo Roque; Shimo, Antonieta Keiko Kakuda

    2015-01-01

    OBJECTIVE To analyze the effects of acupressure at the SP6 point on labor duration and cesarean section rates in parturients served in a public maternity hospital. METHODS This controlled, randomized, double-blind, pragmatic clinical trial involved 156 participants with gestational age ≥ 37 weeks, cervical dilation ≥ 4 cm, and ≥ 2 contractions in 10 min. The women were randomly divided into an acupressure, placebo, or control group at a university hospital in an inland city in the state of Sao Paulo, Brazil, in 2013. Acupressure was applied to the SP6 point during contractions for 20 min. RESULTS The average labor duration was significantly different between the SP6 acupressure group [221.5 min (SD = 162.4)] versus placebo [397.9 min (SD = 265.6)] and versus control [381.9 min (SD = 358.3)] (p = 0.0047); however, the groups were similar regarding the cesarean section rates (p = 0.2526) and Apgar scores in the first minute (p = 0.9542) and the fifth minute (p = 0.7218) of life of the neonate. CONCLUSIONS The SP6 acupressure point proved to be a complementary measure to induce labor and may shorten the labor duration without causing adverse effects to the mother or the newborn. However, it did not affect the cesarean section rate. PMID:25741644

  18. Emdogain does not prevent progressive root resorption after replantation of avulsed teeth: a clinical study.

    PubMed

    Schjøtt, M; Andreasen, J O

    2005-02-01

    Emdogain has been shown in clinical and experimental studies to promote regeneration of all periodontal tissues: cementum with anchoring fibres, a functional, periodontal ligament and alveolar bone in connection with treatment of marginal periodontitis. The intention of this study was to analyse whether this regenerative capacity upon the periodontal ligament also worked in a trauma situation where a significant number of PDL cells have been eliminated because of unphysiologic storage or actual damage during avulsion or replantation. Furthermore if ankylosis sites already established because of earlier replantation after avulsion could be surgical removed and application of Emdogain could revert the ankylosis stage to a normal PDL situation. The first treatment situation was tested in seven patients with a total of 16 avulsed teeth with varying time of extra oral storage. The teeth were extra-orally endodontically treated and the root and socket covered with Emdogain before replantation. All teeth demonstrated subsequent ankylosis, primarily diagnosed by a percussion test. The second treatment situation where an ankylosis was already established constituted of seven patients with a total of 11 teeth because of previous replantation after avulsion. These teeth were all extracted, the ankylosis sites removed and the root and socket treated with Emdogain. After 6 months all teeth showed recurrence of ankylosis. It is concluded that Emdogain was not able to prevent or cure ankylosis.

  19. Reasoning with Linear Orders: Differential Parietal Cortex Activation in Sub-Clinical Depression. An fMRI Investigation in Sub-Clinical Depression and Controls

    PubMed Central

    Hinton, Elanor C.; Wise, Richard G.; Singh, Krish D.; von Hecker, Ulrich

    2015-01-01

    The capacity to learn new information and manipulate it for efficient retrieval has long been studied through reasoning paradigms, which also has applicability to the study of social behavior. Humans can learn about the linear order within groups using reasoning, and the success of such reasoning may vary according to affective state, such as depression. We investigated the neural basis of these latter findings using functional neuroimaging. Using BDI-II criteria, 14 non-depressed (ND) and 12 mildly depressed volunteers took part in a linear-order reasoning task during functional magnetic resonance imaging. The hippocampus, parietal, and prefrontal cortices were activated during the task, in accordance with previous studies. In the learning phase and in the test phase, greater activation of the parietal cortex was found in the depressed group, which may be a compensatory mechanism in order to reach the same behavioral performance as the ND group, or evidence for a different reasoning strategy in the depressed group. PMID:25646078

  20. Expression of FGFR3 and FGFR4 and clinical risk factors associated with progression-free survival in synovial sarcoma.

    PubMed

    Charbonneau, Bridget; Vogel, Rachel Isaksson; Manivel, J Carlos; Rizzardi, Anthony; Schmechel, Stephen C; Ognjanovic, Simona; Subramanian, Subbaya; Largaespada, David; Weigel, Brenda

    2013-09-01

    Although rare, synovial sarcoma (SS) is one of the most common soft tissue sarcomas affecting young adults. To investigate potential tumor markers related to synovial sarcoma prognosis, we carried out a single-institution retrospective analysis of 103 patients diagnosed with SS between 1980 and 2009. Clinical outcome data were obtained from medical records, and archived tissue samples were used to evaluate the relationship between progression-free survival (PFS) and several prognostic factors, including tumor expression of FGFR3 and FGFR4. No associations were found between PFS and gender, body mass index, tumor site, SS18-SSX translocation, or FGFR4 expression. As seen in previous studies, age at diagnosis (<35, 63% versus ≥35 years, 31% 10-year PFS; P = .033), histologic subtype (biphasic, 75% versus monophasic 34% 10-year PFS; P = .034), and tumor size (≤5 cm, 70% versus >5 cm, 22% 10-year PFS; P < .0001) were associated with PFS in SS patients. In addition, in a subset of patients with available archived tumor samples taken prior to chemotherapy or radiation (n = 34), higher FGFR3 expression was associated with improved PFS (P = .030). To the best of our knowledge, this is the largest study of SS to date to suggest a potential clinical role for FGFR3. While small numbers make this investigation somewhat exploratory, the findings merit future investigation on a larger scale.

  1. Plant-Derived Anti-Inflammatory Compounds: Hopes and Disappointments regarding the Translation of Preclinical Knowledge into Clinical Progress

    PubMed Central

    Fürst, Robert; Zündorf, Ilse

    2014-01-01

    Many diseases have been described to be associated with inflammatory processes. The currently available anti-inflammatory drug therapy is often not successful or causes intolerable side effects. Thus, new anti-inflammatory substances are still urgently needed. Plants were the first source of remedies in the history of mankind. Since their chemical characterization in the 19th century, herbal bioactive compounds have fueled drug development. Also, nowadays, new plant-derived agents continuously enrich our drug arsenal (e.g., vincristine, galantamine, and artemisinin). The number of new, pharmacologically active herbal ingredients, in particular that of anti-inflammatory compounds, rises continuously. The major obstacle in this field is the translation of preclinical knowledge into evidence-based clinical progress. Human trials of good quality are often missing or, when available, are frequently not suitable to really prove a therapeutical value. This minireview will summarize the current situation of 6 very prominent plant-derived anti-inflammatory compounds: curcumin, colchicine, resveratrol, capsaicin, epigallocatechin-3-gallate (EGCG), and quercetin. We will highlight their clinical potential and/or pinpoint an overestimation. Moreover, we will sum up the planned trials in order to provide insights into the inflammatory disorders that are hypothesized to be beneficially influenced by the compound. PMID:24987194

  2. Merkel Cell Carcinoma: Recent Progress and Current Priorities on Etiology, Pathogenesis, and Clinical Management

    PubMed Central

    2009-01-01

    Purpose To expedite improved understanding, diagnosis, treatment, and prevention of Merkel cell carcinoma (MCC), a rare malignancy of cutaneous neuroendocrine cells that has a 28% 2-year mortality rate. Methods This article summarizes a workshop that discussed the state-of-the-art research and priorities for research on MCC and on a new human polyomavirus (ie, MCPyV) recently discovered in 80% of MCC tumors. Results Normal Merkel cells are widely distributed in the epidermis near the end of nerve axons and may function as mechanoreceptors or chemoreceptors. Malignant MCC cells typically stain for cytokeratin 20 as well as for other epithelial and neuroendocrine markers. MCC subtypes, which are based on histology, on cell line growth properties, and on gene expression profiles, have been reported but have not been linked to prognosis. Clinical management has been empiric. MCPyV is clonally integrated at various sites in the human genome of MCC tumors, with truncating mutations in the viral, large T antigen gene that interrupt viral replication. MCPyV seroprevalence may be high, as with previously known human polyomaviruses. MCC risk is increased 11-fold with AIDS and with other cell-mediated immune deficiencies, B-cell neoplasms, and ultraviolet radiation exposure. Conclusion Development and validation of a range quantitative polymerase chain reaction and serologic assays for detection of MCPyV, as well as an infectious clone of the virus, would clarify the fundamental biology, natural history, and epidemiology of the virus, of MCC, and of other diseases. Contingent on standardized histologic diagnosis and staging of MCC, consortia are needed to clarify the risks and benefits of sentinel lymph node biopsy, adjuvant radiation therapy, and salvage therapies; consortia are needed also for epidemiologic studies of MCC etiology. PMID:19597021

  3. Linear and Nonlinear Growth Models for Value-Added Assessment: An Application to Spanish Primary and Secondary Schools' Progress in Reading Comprehension

    ERIC Educational Resources Information Center

    Lopez-Martin, Esther; Kuosmanen, Timo; Gaviria, Jose Luis

    2014-01-01

    Value-added models are considered one of the best alternatives not only for accountability purposes but also to improve the school system itself. The estimates provided by these models measure the contribution of schools to students' academic progress, once the effect of other factors outside school control are eliminated. The functional form for…

  4. Progression-Free Survival as a Surrogate for Overall Survival in Clinical Trials of Targeted Therapy in Advanced Solid Tumors.

    PubMed

    Michiels, Stefan; Saad, Everardo D; Buyse, Marc

    2017-03-23

    Over the past 15 years, targeted therapy has revolutionized the systemic treatment of cancer. In parallel, there has been a growing debate on the choice of end points in clinical trials in oncology. This debate basically hinges on the choice between overall survival (OS) and progression-free survival (PFS). PFS is advantageous because it is measured earlier than OS, requires a smaller sample size than OS to achieve the desired power, and is not influenced by cross-over. On the other hand, PFS is prone to measurement error and bias, and may not capture the entire treatment effect on the outcomes of most interest to patients with an incurable disease: a prolonged survival and improved quality of life. Therefore, how can we choose between two imperfect end points? The answer to this question would certainly be made easier if PFS could be demonstrated to be a valid surrogate for OS. The validation of a surrogate end point is best made using individual-patient data (IPD) from randomized trials, which allows for standardized assessments of the patient-level and the trial-level correlations between surrogate and final end points. Proper IPD meta-analytical evaluations for targeted agents have still been rare, and to our knowledge only three studies on this topic are currently available in the metastatic setting: one in breast cancer, one in colorectal cancer and one in lung cancer. Although these three studies suffer from limitations inherent to the availability of IPD and the design of the original clinical trials, they have not been able to validate PFS as surrogate for OS, because only modest correlations were found between these two end points, both at the patient and at the trial level. Even if properly conducted surrogate-endpoint evaluations have thus far been unsuccessful, these evaluations are a step in the right direction and can be expected to be applied on a much larger scale in the era of data sharing of clinical trials.

  5. A clinical review on extreme hypofractionated stereotactic body radiation therapy for localized prostate cancer using nonrobotic linear accelerators.

    PubMed

    Macias, Victor A; Perez-Romasanta, Luis A

    2014-06-01

    Seven phase I-II studies fell within the inclusion criteria. Details on the radiotherapy technique, patient selection, fractionation scheme, exclusion criteria, treatment toxicity, quality-of-life, and tumor control were collected. The studies provide encouraging results of acute and late toxicity, with rare grade 3 events, that seem comparable to robotic SBRT. The biochemical disease-free survival rates look promising, but most patients belong to the low-risk group. The trials are limited by a short follow-up, small number of patients, and different approaches in prescribing dose and defining the acceptable dose heterogeneities. Currently, nonrobotic SBRT regimens should be used in the context of clinical trials.

  6. Interpretation and Visualization of Non-Linear Data Fusion in Kernel Space: Study on Metabolomic Characterization of Progression of Multiple Sclerosis

    PubMed Central

    Smolinska, Agnieszka; Blanchet, Lionel; Coulier, Leon; Ampt, Kirsten A. M.; Luider, Theo; Hintzen, Rogier Q.; Wijmenga, Sybren S.; Buydens, Lutgarde M. C.

    2012-01-01

    Background In the last decade data fusion has become widespread in the field of metabolomics. Linear data fusion is performed most commonly. However, many data display non-linear parameter dependences. The linear methods are bound to fail in such situations. We used proton Nuclear Magnetic Resonance and Gas Chromatography-Mass Spectrometry, two well established techniques, to generate metabolic profiles of Cerebrospinal fluid of Multiple Sclerosis (MScl) individuals. These datasets represent non-linearly separable groups. Thus, to extract relevant information and to combine them a special framework for data fusion is required. Methodology The main aim is to demonstrate a novel approach for data fusion for classification; the approach is applied to metabolomics datasets coming from patients suffering from MScl at a different stage of the disease. The approach involves data fusion in kernel space and consists of four main steps. The first one is to extract the significant information per data source using Support Vector Machine Recursive Feature Elimination. This method allows one to select a set of relevant variables. In the next step the optimized kernel matrices are merged by linear combination. In step 3 the merged datasets are analyzed with a classification technique, namely Kernel Partial Least Square Discriminant Analysis. In the final step, the variables in kernel space are visualized and their significance established. Conclusions We find that fusion in kernel space allows for efficient and reliable discrimination of classes (MScl and early stage). This data fusion approach achieves better class prediction accuracy than analysis of individual datasets and the commonly used mid-level fusion. The prediction accuracy on an independent test set (8 samples) reaches 100%. Additionally, the classification model obtained on fused kernels is simpler in terms of complexity, i.e. just one latent variable was sufficient. Finally, visualization of variables importance in

  7. Linear association between social anxiety symptoms and neural activations to angry faces: from subclinical to clinical levels.

    PubMed

    Carré, Arnaud; Gierski, Fabien; Lemogne, Cédric; Tran, Eric; Raucher-Chéné, Delphine; Béra-Potelle, Céline; Portefaix, Christophe; Kaladjian, Arthur; Pierot, Laurent; Besche-Richard, Chrystel; Limosin, Frédéric

    2014-06-01

    Social anxiety disorder (SAD), which is characterized by the fear of being rejected and negatively evaluated, involves altered brain activation during the processing of negative emotions in a social context. Although associated temperament traits, such as shyness or behavioral inhibition, have been studied, there is still insufficient knowledge to support the dimensional approach, which assumes a continuum from subclinical to clinical levels of social anxiety symptoms. This study used functional magnetic resonance imaging (fMRI) to examine the neural bases of individual differences in social anxiety. Our sample included participants with both healthy/subclinical as well as clinical levels of social anxiety. Forty-six participants with a wide range of social anxiety levels performed a gender decision task with emotional facial expressions during fMRI scanning. Activation in the left anterior insula and right lateral prefrontal cortex in response to angry faces was positively correlated with the level of social anxiety in a regression analysis. The results substantiate, with a dimensional approach, those obtained in previous studies that involved SAD patients or healthy and subclinical participants. It may help to refine further therapeutic strategies based on markers of social anxiety.

  8. Linear Energy Transfer Painting With Proton Therapy: A Means of Reducing Radiation Doses With Equivalent Clinical Effectiveness

    SciTech Connect

    Fager, Marcus; Toma-Dasu, Iuliana; Kirk, Maura; Dolney, Derek; Diffenderfer, Eric S.; Vapiwala, Neha; Carabe, Alejandro

    2015-04-01

    Purpose: The purpose of this study was to propose a proton treatment planning method that trades physical dose (D) for dose-averaged linear energy transfer (LET{sub d}) while keeping the radiobiologically weighted dose (D{sub RBE}) to the target the same. Methods and Materials: The target is painted with LET{sub d} by using 2, 4, and 7 fields aimed at the proximal segment of the target (split target planning [STP]). As the LET{sub d} within the target increases with increasing number of fields, D decreases to maintain the D{sub RBE} the same as the conventional treatment planning method by using beams treating the full target (full target planning [FTP]). Results: The LET{sub d} increased 61% for 2-field STP (2STP) compared to FTP, 72% for 4STP, and 82% for 7STP inside the target. This increase in LET{sub d} led to a decrease of D with 5.3 ± 0.6 Gy for 2STP, 4.4 ± 0.7 Gy for 4STP, and 5.3 ± 1.1 Gy for 7STP, keeping the DRBE at 90% of the volume (DRBE, 90) constant to FTP. Conclusions: LET{sub d} painting offers a method to reduce prescribed dose at no cost to the biological effectiveness of the treatment.

  9. Progressive Reduction in Cortical Thickness as Psychosis Develops: A Multisite Longitudinal Neuroimaging Study of Youth at Elevated Clinical Risk

    PubMed Central

    Cannon, Tyrone D.; Chung, Yoonho; He, George; Sun, Daqiang; Jacobson, Aron; van Erp, Theo G. M.; McEwen, Sarah; Addington, Jean; Bearden, Carrie E.; Cadenhead, Kristin; Cornblatt, Barbara; Mathalon, Daniel H.; McGlashan, Thomas; Perkins, Diana; Jeffries, Clark; Seidman, Larry J.; Tsuang, Ming; Walker, Elaine; Woods, Scott W.; Heinssen, Robert

    2014-01-01

    Background Individuals at clinical high-risk (CHR) who progress to fully psychotic symptoms have been observed to show a steeper rate of cortical gray matter reduction compared with those without symptomatic progression and with healthy controls. Whether such changes reflect processes associated with the pathophysiology of schizophrenia or exposure to antipsychotic drugs is unknown. Methods In this multisite study, 274 CHR cases, including 35 who converted to psychosis, and 135 healthy comparison subjects were scanned with MRI at baseline, 12-month follow-up, and/or the point of conversion for those who developed fully psychotic symptoms. Results In a traveling subjects sub-study, we observed excellent reliability for measures of cortical thickness and subcortical volumes. Controlling for multiple comparisons throughout the brain, CHR converters showed a steeper rate of gray matter loss in right superior frontal, middle frontal, and medial orbitofrontal cortical regions, as well as a greater rate of expansion of the third ventricle, compared with CHR non-converters and healthy controls. Differential tissue loss was present among cases who had not received antipsychotic medications during the inter-scan interval and was predicted by baseline levels of an aggregate measure of pro-inflammatory cytokines in plasma. Conclusions These findings demonstrate that the brain changes are not explained by exposure to antipsychotic drugs, but likely play a role in psychosis pathophysiology. Given that the cortical changes were more pronounced among cases with briefer durations of prodromal symptoms, contributing factors may predominantly play a role in acute-onset forms of psychosis. PMID:25034946

  10. An evaluation of the various aspects of the progress in clinical applications of laser driven ionizing radiation

    NASA Astrophysics Data System (ADS)

    Hideghéty, K.; Szabó, E. R.; Polanek, R.; Szabó, Z.; Ughy, B.; Brunner, S.; Tőkés, T.

    2017-03-01

    There has been a vast development of laser-driven particle acceleration (LDPA) using high power lasers. This has initiated by the radiation oncology community to use the dose distribution and biological advantages of proton/heavy ion therapy in cancer treatment with a much greater accessibility than currently possible with cyclotron/synchrotron acceleration. Up to now, preclinical experiments have only been performed at a few LDPA facilities; technical solutions for clinical LDPA have been theoretically developed but there is still a long way to go for the clinical introduction of LDPA. Therefore, to explore the further potential bio-medical advantages of LDPA has pronounced importance. The main characteristics of LDPA are the ultra-high beam intensity, the flexibility in beam size reduction and the potential particle and energy selection whilst conventional accelerators generate single particle, quasi mono-energetic beams. There is a growing number of studies on the potential advantages and applications of Energy Modulated X-ray Radiotherapy, Modulated Electron Radiotherapy and Very High Energy Electron (VHEE) delivery system. Furthermore, the ultra-high space and/or time resolution of super-intense beams are under intensive investigation at synchrotrons (microbeam radiation and very high dose rate (> 40 Gy/s) electron accelerator flash irradiation) with growing evidence of significant improvement of the therapeutic index. Boron Neutron Capture Therapy (BNCT) is an advanced cell targeted binary treatment modality. Because of the high linear energy transfer (LET) of the two particles (7Li and 4He) released by 10BNC reaction, all of the energy is deposited inside the tumour cells, killing them with high probability, while the neighbouring cells are not damaged. The limited availability of appropriate neutron sources, prevent the more extensive exploration of clinical benefit of BNCT. Another boron-based novel binary approach is the 11B-Proton Fusion, which result in

  11. The Clinical Presentation of Mitochondrial Diseases in Children with Progressive Intellectual and Neurological Deterioration: A National, Prospective, Population-Based Study

    ERIC Educational Resources Information Center

    Verity, Christopher M.; Winstone, Anne Marie; Stellitano, Lesley; Krishnakumar, Deepa; Will, Robert; McFarland, Robert

    2010-01-01

    Aim: Our aim was to study the clinical presentation, mode of diagnosis, and epidemiology of mitochondrial disorders in children from the UK who have progressive intellectual and neurological deterioration (PIND). Method: Since April 1997, we have identified patients aged 16 years or younger with suspected PIND through the monthly notification card…

  12. PTEN deletion and heme oxygenase-1 overexpression cooperate in prostate cancer progression and are associated with adverse clinical outcome.

    PubMed

    Li, Yunru; Su, Jie; DingZhang, Xiao; Zhang, Jianguo; Yoshimoto, Maisa; Liu, Shuhong; Bijian, Krikor; Gupta, Ajay; Squire, Jeremy A; Alaoui Jamali, Moulay A; Bismar, Tarek A

    2011-05-01

    Overexpression of the pro-survival protein heme oxygenase-1 (HO-1) and loss of the pro-apoptotic tumour suppressor PTEN are common events in prostate cancer (PCA). We assessed the occurrence of both HO-1 expression and PTEN deletion in two cohorts of men with localized and castration-resistant prostate cancer (CRPC). The phenotypic cooperation of these markers was examined in preclinical and clinical models. Overall, there was a statistically significant difference in HO-1 epithelial expression between benign, high-grade prostatic intraepithelial neoplasia (HGPIN), localized PCA, and CRPC (p < 0.0001). The highest epithelial HO-1 expression was noted in CRPC (2.00 ± 0.89), followed by benign prostate tissue (1.49 ± 1.03) (p = 0.0003), localized PCA (1.20 ± 0.95), and HGPIN (1.07 ± 0.87) (p < 0.0001). However, the difference between HGPIN and PCA was not statistically significant (p = 0.21). PTEN deletions were observed in 35/55 (63.6%) versus 68/183 (37.1%) cases of CRPC and localized PCA, respectively. Although neither HO-1 overexpression nor PTEN deletions alone in localized PCA showed a statistically significant association with PSA relapse, the combined status of both markers correlated with disease progression (log-rank test, p = 0.01). In a preclinical model, inhibition of HO-1 by shRNA in PTEN-deficient PC3M cell line and their matched cells where PTEN is restored strongly reduced cell growth and invasion in vitro and inhibited tumour growth and lung metastasis formation in mice compared to cells where only HO-1 is inhibited or PTEN is restored. In summary, we provide clinical and experimental evidence for cooperation between epithelial HO-1 expression and PTEN deletions in relation to the PCA patient's outcome. These findings could potentially lead to the discovery of novel therapeutic modalities for advanced PCA.

  13. Linear Accelerators

    NASA Astrophysics Data System (ADS)

    Sidorin, Anatoly

    2010-01-01

    In linear accelerators the particles are accelerated by either electrostatic fields or oscillating Radio Frequency (RF) fields. Accordingly the linear accelerators are divided in three large groups: electrostatic, induction and RF accelerators. Overview of the different types of accelerators is given. Stability of longitudinal and transverse motion in the RF linear accelerators is briefly discussed. The methods of beam focusing in linacs are described.

  14. Modeling clinical progression and healthcare utilization of HIV-positive patients in British Columbia prior to death

    PubMed Central

    Cui, Zishan; Grafstein, Eric; Yip, Benita; Hogg, Robert; Montaner, Julio S.G.; Lima, Viviane Dias

    2014-01-01

    Objectives The extent in which clinical progression of HIV-positive patients leads to an increase in healthcare utilization, especially prior to their death, is unknown. Thus, we modeled trends in CD4 cell count and emergency department utilization and the likelihood of an emergency department visit leading to a transfer to acute care level facility prior to a patient’s death from non-accidental causes. Methods Eligible patients initiated HAART in British Columbia between August 1996 and June 2006 (N=457). Patients were followed until their death, which occurred on or before June 30, 2007 (period in which the emergency department visit data were available). Trends were modeled using generalized mixed effects. Results Patients experienced a significantly steep decline in CD4 cell count and a corresponding increase in the number of emergency department visits and transfers to acute level facilities in the five years prior to death. For every 6-month interval prior to death, the CD4 cell count decreased 13.22 cells/mm3, the risk of experiencing an emergency department visit increased by 9%, and among those ever admitted, the odds ratio of being transferred to an acute care level facility increased by 3%. Conclusions We showed that patients experienced a steep decline in CD4 cell count, which was associated with an increase in healthcare utilization prior to their death. These findings highlight the substantial residual avoidable burden that unsuccessfully managed HIV disease poses, even in the HAART era. Further strategies to enhance sustained and successful engagement in care are urgently needed to mitigate high healthcare utilization. PMID:24641495

  15. Study of flow and loss processes at the ends of a linear theta pinch. Progress report, June 1, 1979-September 30, 1980

    SciTech Connect

    York, T.M.; Klevans, E.H.

    1980-05-01

    Experimental and analytical studies of particle and energy loss at the ends of a linear theta pinch have been carried out. A study of transients occurring in the formation of reversed trapped fields within the coil, and of transients in the end region of a 25 cm long device was completed. A 1-D code has proven to be highly accurate in describing loss events and defining transport mechanisms in different experiments and is described here. A study of loss along field lines in a 50 cm long device has generated new information on loss velocity, axial and radial temperature gradients, and has established an initial effort in understanding thermal loss to the walls. Rotation and parallel trapped fields have been added to the existing 0-D code. A new technique crowbar switch and magnetic field prediction code have been developed. Direct measurment of electron velocity with Thomson scattering was accomplished experimentally. A Nd-glass laser system, frequency doubled, is being developed for low density diagnostics. Theoretical results that accurately predict confinement in FRX devices are described.

  16. Pre-cART Elevation of CRP and CD4+ T-cell Immune Activation Associated with HIV Clinical Progression in a Multinational Case-Cohort Study

    PubMed Central

    Balagopal, Ashwin; Asmuth, David M.; Yang, Wei-Teng; Campbell, Thomas B.; Gupte, Nikhil; Smeaton, Laura; Kanyama, Cecilia; Grinsztejn, Beatriz; Santos, Breno; Supparatpinyo, Khuanchai; Badal-Faesen, Sharlaa; Lama, Javier R.; Lalloo, Umesh G.; Zulu, Fatima; Pawar, Jyoti S; Riviere, Cynthia; Kumarasamy, Nagalingeswaran; Hakim, James; Li, Xiao-Dong; Pollard, Richard B.; Semba, Richard D.; Thomas, David L.; Bollinger, Robert C.; Gupta, Amita

    2015-01-01

    Background Despite the success of combination antiretroviral therapy (cART), a subset of HIV-infected patients who initiate cART develop early clinical progression to AIDS; therefore some cART initiators are not fully benefitted by cART. Immune activation pre-cART may predict clinical progression in cART initiators. Methods A case-cohort study (n=470) within the multinational Prospective Evaluation of Antiretrovirals in Resource-Limited Settings (PEARLS) clinical trial (1571 HIV treatment-naïve adults who initiated cART; CD4+ T cell count <300 cells/mm3; nine countries) was conducted. A subcohort of 30 participants/country was randomly selected; additional cases were added from the main cohort. Cases (n=236 [random subcohort–36; main cohort–200]) had clinical progression (incident WHO Stage 3/4 event or death) within 96 weeks following cART initiation. Immune activation biomarkers were quantified pre-cART. Associations between biomarkers and clinical progression were examined using weighted multivariable Cox-proportional hazards models. Results Median age was 35 years, 45% were women, 49% black, 31% Asian, and 9% white. Median CD4+ T-cell count was 167 cells/mm3. In multivariate analysis, highest quartile CRP concentration (adjusted hazards ratio [aHR] 2.53, 95%CI 1.02-6.28) and CD4+ T-cell activation (aHR 5.18, 95CI 1.09-24.47) were associated with primary outcomes, compared to lowest quartiles. sCD14 had a trend towards association with clinical failure (aHR 2.24, 95%CI 0.96–5.21). Conclusions Measuring CRP and CD4+ T-cell activation may identify patients with CD4+ T cell counts < 300 cells/mm3 at risk for early clinical progression when initiating cART. Additional vigilance and symptom-based screening may be required in this subset of patients even after beginning cART. PMID:26017661

  17. Monte Carlo evaluation of the AAA treatment planning algorithm in a heterogeneous multilayer phantom and IMRT clinical treatments for an Elekta SL25 linear accelerator

    SciTech Connect

    Sterpin, E.; Tomsej, M.; Smedt, B. de; Reynaert, N.; Vynckier, S.

    2007-05-15

    The Anisotropic Analytical Algorithm (AAA) is a new pencil beam convolution/superposition algorithm proposed by Varian for photon dose calculations. The configuration of AAA depends on linear accelerator design and specifications. The purpose of this study was to investigate the accuracy of AAA for an Elekta SL25 linear accelerator for small fields and intensity modulated radiation therapy (IMRT) treatments in inhomogeneous media. The accuracy of AAA was evaluated in two studies. First, AAA was compared both with Monte Carlo (MC) and the measurements in an inhomogeneous phantom simulating lung equivalent tissues and bone ribs. The algorithm was tested under lateral electronic disequilibrium conditions, using small fields (2x2 cm{sup 2}). Good agreement was generally achieved for depth dose and profiles, with deviations generally below 3% in lung inhomogeneities and below 5% at interfaces. However, the effects of attenuation and scattering close to the bone ribs were not fully taken into account by AAA, and small inhomogeneities may lead to planning errors. Second, AAA and MC were compared for IMRT plans in clinical conditions, i.e., dose calculations in a computed tomography scan of a patient. One ethmoid tumor, one orophaxynx and two lung tumors are presented in this paper. Small differences were found between the dose volume histograms. For instance, a 1.7% difference for the mean planning target volume dose was obtained for the ethmoid case. Since better agreement was achieved for the same plans but in homogeneous conditions, these differences must be attributed to the handling of inhomogeneities by AAA. Therefore, inherent assumptions of the algorithm, principally the assumption of independent depth and lateral directions in the scaling of the kernels, were slightly influencing AAA's validity in inhomogeneities. However, AAA showed a good accuracy overall and a great ability to handle small fields in inhomogeneous media compared to other pencil beam convolution

  18. Monte carlo evaluation of the AAA treatment planning algorithm in a heterogeneous multilayer phantom and IMRT clinical treatments for an Elekta SL25 linear accelerator.

    PubMed

    Sterpin, E; Tomsej, M; De Smedt, B; Reynaert, N; Vynckier, S

    2007-05-01

    The Anisotropic Analytical Algorithm (AAA) is a new pencil beam convolution/superposition algorithm proposed by Varian for photon dose calculations. The configuration of AAA depends on linear accelerator design and specifications. The purpose of this study was to investigate the accuracy of AAA for an Elekta SL25 linear accelerator for small fields and intensity modulated radiation therapy (IMRT) treatments in inhomogeneous media. The accuracy of AAA was evaluated in two studies. First, AAA was compared both with Monte Carlo (MC) and the measurements in an inhomogeneous phantom simulating lung equivalent tissues and bone ribs. The algorithm was tested under lateral electronic disequilibrium conditions, using small fields (2 x 2 cm(2)). Good agreement was generally achieved for depth dose and profiles, with deviations generally below 3% in lung inhomogeneities and below 5% at interfaces. However, the effects of attenuation and scattering close to the bone ribs were not fully taken into account by AAA, and small inhomogeneities may lead to planning errors. Second, AAA and MC were compared for IMRT plans in clinical conditions, i.e., dose calculations in a computed tomography scan of a patient. One ethmoid tumor, one orophaxynx and two lung tumors are presented in this paper. Small differences were found between the dose volume histograms. For instance, a 1.7% difference for the mean planning target volume dose was obtained for the ethmoid case. Since better agreement was achieved for the same plans but in homogeneous conditions, these differences must be attributed to the handling of inhomogeneities by AAA. Therefore, inherent assumptions of the algorithm, principally the assumption of independent depth and lateral directions in the scaling of the kernels, were slightly influencing AAA's validity in inhomogeneities. However, AAA showed a good accuracy overall and a great ability to handle small fields in inhomogeneous media compared to other pencil beam convolution

  19. Progress in the Preclinical Discovery and Clinical Development of Class I and Dual Class I/IV Phosphoinositide 3-Kinase (PI3K) Inhibitors

    PubMed Central

    Shuttleworth, S.J; Silva, F.A; Cecil, A.R.L; Tomassi, C.D; Hill, T.J; Raynaud, F.I; Clarke, P.A; Workman, P

    2011-01-01

    The phosphoinositide 3-kinases (PI3Ks) constitute an important family of lipid kinase enzymes that control a range of cellular processes through their regulation of a network of signal transduction pathways, and have emerged as important therapeutic targets in the context of cancer, inflammation and cardiovascular diseases. Since the mid-late 1990s, considerable progress has been made in the discovery and development of small molecule ATP-competitive PI3K inhibitors, a number of which have entered early phase human trials over recent years from which key clinical results are now being disclosed. This review summarizes progress made to date, primarily on the discovery and characterization of class I and dual class I/IV subtype inhibitors, together with advances that have been made in translational and clinical research, notably in cancer. PMID:21649578

  20. Modeling trajectories of regional volume loss in progressive supranuclear palsy.

    PubMed

    Josephs, Keith A; Xia, Rong; Mandrekar, Jay; Gunter, Jeffrey L; Senjem, Matthew L; Jack, Clifford R; Whitwell, Jennifer L

    2013-07-01

    Progressive supranuclear palsy is a neurodegenerative disease with progressive brain atrophy over time. It is unknown which specific brain regions decline over time, whether regional volume loss occurs in a linear fashion, and whether regional atrophy correlates with clinical decline over time in progressive supranuclear palsy. Twenty-eight subjects meeting probable progressive supranuclear palsy criteria were prospectively recruited and completed 96 MRI scans over 2 years. Mixed-effect models were utilized to determine which regions had significant atrophy over time and whether decline was linear or nonlinear. We assessed 13 regions across the brain, as well as whole-brain and ventricular volume. Regional trajectories were also correlated with change in clinical measures of executive function and gait and ocular motor impairment. A linear decline was observed in all frontal and temporal regions, the superior parietal lobe, the thalamus, the caudate nuclei, and the midbrain, as well as in the whole brain. Ventricular expansion was also linear. Nonlinear decline was observed for the caudal middle frontal lobe and globus pallidus. Rates of change in the superior frontal lobe, thalamus, and midbrain were beyond those expected in normal aging. Decline in frontal lobe volume and the midbrain area correlated best to decline in clinical measures. In progressive supranuclear palsy, atrophy is occurring in multiple brain regions, particularly in those that have previously been implicated in the disease. Decline is mainly linear but can be nonlinear for some regions. The frontal lobe and midbrain seem to be playing the most significant roles in the progressive worsening of clinical signs in progressive supranuclear palsy.

  1. Collagen cross-linking effect on progressive keratoconus in patients younger than 18 years of age: A clinical trial

    PubMed Central

    Peyman, Alireza; Kamali, Ali; Khushabi, Maral; Nasrollahi, Kobra; Kargar, Neda; Taghaodi, Maryam; Razmjoo, Hasan; Fazel, Farhad; Salesi, Asiyeh

    2015-01-01

    Background: Keratoconus is a bilateral non-inflammatory corneal disease. Collagen cross-linking (CXL) is a new treatment option for the disease that uses ultraviolet A light irradiation and riboflavin administration. The aim of this study is to evaluate the effect of CXL on corneal topographic and refractive values in patients with keratoconus younger than 18 years of age. Materials and Methods: For the clinical trial study, 37 patients (64 eyes) younger than 18 years of age with progressive keratoconus were included. Age, sex, family history of keratoconus, and history of allergic disorders and eye rubbing were recorded. Refractive, topographic, and topometric indices were evaluated before and 12 months after the CXL with 3mW for 30 minutes. Results: Mean age (±SD) of the patients was 15.83 ± 1.53 years; 26 (70.3%) of the 37 patients were male. Fourteen (37.8%) had positive family history of keratoconus, 11 (29.7%) had history of allergic disorders, and 15 (40.5%) had positive history of eye rubbing. Of the refractive values, cylinder value decreased significantly from −4.50 ± 0.29 to −4.11 ± 0.28 (P = 0.001). Also, the logarithm of minimal angle of resolution (logMAR) uncorrected visual acuity (UCVA) and best corrected visual acuity (BCVA) improved significantly 12 months after CXL (P = 0.012 and 0.001, respectively). Maximum keratometry before and after the operation was 53.82 ± 0.72 and 53.33 ± 0.72, respectively (P = 0.018). Differences for simulated K values, the thinnest cornea pachymetry, keratoconus index (KI), index of highest asymmetry (IHA), and index of highest decentration (IHD) before and 12 months after the CXL were statistically significant (P = 0.015, 0.034, <0.001, 0.017, 0.019, and 0.004, respectively). Conclusion: CXL improves the refractory, topographic, and topometric indices in patients with keratoconus younger than 18 years of age. PMID:26693470

  2. The effect of Neuroform stent-assisted coil embolization of wide-necked intracranial aneurysms and clinical factors on progressive aneurysm occlusion on angiographic follow-up.

    PubMed

    Gu, Da-Qun; Zhang, Xin; Luo, Bin; Long, Xiao-Ao; Duan, Chuan-Zhi

    2013-02-01

    Stent-assisted coil embolization is an endovascular treatment for wide-necked intracranial aneurysms, but the durability of this treatment is not well known. The aim of this study is to investigate the effect of the Neuroform stent (Boston Scientific/Target, Fremont, CA, USA) in progressive occlusion of wide-necked intracranial aneurysms, and to assess any correlation between clinical factors and angiographic follow-up results. The records of 52 patients treated with a Neuroform stent were retrieved for analysis of population characteristics, initial and follow-up angiographic results, and clinical outcomes. Initial angiographic results showed complete occlusion in 21 (40.4%), neck remnants in 22 (42.3%), and residual aneurysms in nine (17.3%). Angiographic follow-up was available in 45 of 52 (86.5%) patients: complete occlusion was achieved in 32 (71.1%), neck remnants were present in eight (17.8%) and residual aneurysms in five (11.1%). Of 31 patients with immediate incomplete obliteration, progressive complete occlusion was achieved in 16 of 28 (57.1%) patients. Clinical follow-up showed good outcomes according to the modified Rankin Scale score. A univariate analysis showed that there was no effect of the tested clinical variables of patient age (p=0.823), gender (p=0.419), aneurysm location (p=0.394), size (p=0.625) and rupture status (p=0.721) on aneurysm occlusion at follow-up. We conclude that the Neuroform stent-assisted neck remodelling technique improves progressive occlusion of wide-necked intracranial aneurysms with good clinical outcomes.

  3. Effects of Prednisolone on Disease Progression in Antiretroviral-Untreated HIV Infection: A 2-Year Randomized, Double-Blind Placebo-Controlled Clinical Trial

    PubMed Central

    Kasang, Christa; Kalluvya, Samuel; Majinge, Charles; Kongola, Gilbert; Mlewa, Mathias; Massawe, Irene; Kabyemera, Rogatus; Magambo, Kinanga; Ulmer, Albrecht; Klinker, Hartwig; Gschmack, Eva; Horn, Anne; Koutsilieri, Eleni; Preiser, Wolfgang; Hofmann, Daniela; Hain, Johannes; Müller, Andreas; Dölken, Lars; Weissbrich, Benedikt; Rethwilm, Axel; Stich, August; Scheller, Carsten

    2016-01-01

    Background HIV-disease progression correlates with immune activation. Here we investigated whether corticosteroid treatment can attenuate HIV disease progression in antiretroviral-untreated patients. Methods Double-blind, placebo-controlled randomized clinical trial including 326 HIV-patients in a resource-limited setting in Tanzania (clinicaltrials.gov NCT01299948). Inclusion criteria were a CD4 count above 300 cells/μl, the absence of AIDS-defining symptoms and an ART-naïve therapy status. Study participants received 5 mg prednisolone per day or placebo for 2 years. Primary endpoint was time to progression to an AIDS-defining condition or to a CD4-count below 200 cells/μl. Results No significant change in progression towards the primary endpoint was observed in the intent-to-treat (ITT) analysis (19 cases with prednisolone versus 28 cases with placebo, p = 0.1407). In a per-protocol (PP)-analysis, 13 versus 24 study participants progressed to the primary study endpoint (p = 0.0741). Secondary endpoints: Prednisolone-treatment decreased immune activation (sCD14, suPAR, CD38/HLA-DR/CD8+) and increased CD4-counts (+77.42 ± 5.70 cells/μl compared to -37.42 ± 10.77 cells/μl under placebo, p < 0.0001). Treatment with prednisolone was associated with a 3.2-fold increase in HIV viral load (p < 0.0001). In a post-hoc analysis stratifying for sex, females treated with prednisolone progressed significantly slower to the primary study endpoint than females treated with placebo (ITT-analysis: 11 versus 21 cases, p = 0.0567; PP-analysis: 5 versus 18 cases, p = 0.0051): No changes in disease progression were observed in men. Conclusions This study could not detect any significant effects of prednisolone on disease progression in antiretroviral-untreated HIV infection within the intent-to-treat population. However, significant effects were observed on CD4 counts, immune activation and HIV viral load. This study contributes to a better understanding of the role of immune

  4. Prospective study on the incidence and progression of clinical signs in naïve dogs naturally infected by Leishmania infantum.

    PubMed

    Foglia Manzillo, Valentina; Di Muccio, Trentina; Cappiello, Sivia; Scalone, Aldo; Paparcone, Rosa; Fiorentino, Eleonora; Gizzarelli, Manuela; Gramiccia, Marina; Gradoni, Luigi; Oliva, Gaetano

    2013-01-01

    The incidence of clinical and clinicopathological signs associated with the progression of infection was evaluated prospectively in 329 naïve young dogs exposed to Leishmania infantum transmission and examined periodically during 22 months (M). The dogs were part of Leishmania vaccine investigations performed under natural conditions. Vaccinated groups were considered in the evaluation when the vaccine resulted non-protective and the appearance and progression of signs did not differ statistically from controls at each time point, otherwise only control groups were included. 115 beagles were part of 3 studies (A to C) performed in the same kennel; 214 owned dogs (29 breeds, 2.3% beagles) were included in a study (D) performed in 45 endemic sites. At M22 the prevalence of any Leishmania infection stage classified as subpatent, active asymptomatic, or symptomatic was 59.8% in studies A-C and 29.2% in study D. Despite different breed composition and infection incidence, the relative proportion of active infections and the progression and type of clinical and clinicopathological signs have been similar in both study sets. All asymptomatic active infections recorded have invariably progressed to full-blown disease, resulting in 56 sick dogs at M22. In these dogs, lymph nodes enlargement and weight loss--recorded from M12--were the most common signs. Cutaneous signs were seen late (M18) and less frequently. Ocular signs appeared even later, being sporadically recorded at M22. Most clinicopathological alterations became evident from M12, although a few cases of thrombocytopenia or mild non-regenerative anemia were already observed at M6. Albumin/globulin inversions were recorded from M12 and urea/creatinine increase appeared mostly from M18. Altogether our findings indicate that any susceptible young dogs naturally infected by L. infantum present a common pattern of progression of signs during 2 years post infection, providing clues for medical and epidemiological

  5. Linear regression analysis of survival data with missing censoring indicators

    PubMed Central

    Wang, Qihua

    2010-01-01

    Linear regression analysis has been studied extensively in a random censorship setting, but typically all of the censoring indicators are assumed to be observed. In this paper, we develop synthetic data methods for estimating regression parameters in a linear model when some censoring indicators are missing. We define estimators based on regression calibration, imputation, and inverse probability weighting techniques, and we prove all three estimators are asymptotically normal. The finite-sample performance of each estimator is evaluated via simulation. We illustrate our methods by assessing the effects of sex and age on the time to non-ambulatory progression for patients in a brain cancer clinical trial. PMID:20559722

  6. LINEAR ACCELERATOR

    DOEpatents

    Christofilos, N.C.; Polk, I.J.

    1959-02-17

    Improvements in linear particle accelerators are described. A drift tube system for a linear ion accelerator reduces gap capacity between adjacent drift tube ends. This is accomplished by reducing the ratio of the diameter of the drift tube to the diameter of the resonant cavity. Concentration of magnetic field intensity at the longitudinal midpoint of the external sunface of each drift tube is reduced by increasing the external drift tube diameter at the longitudinal center region.

  7. Expression and clinical significance of estrogen-regulated long non-coding RNAs in estrogen receptor α-positive ovarian cancer progression.

    PubMed

    Qiu, Jun-Jun; Ye, Le-Chi; Ding, Jing-Xin; Feng, Wei-Wei; Jin, Hong-Yan; Zhang, Ying; Li, Qing; Hua, Ke-Qin

    2014-04-01

    Estrogen (E2) has long been implicated in epithelial ovarian cancer (EOC) progression. The effects of E2 on cancer progression can be mediated by numerous target genes, including coding RNAs and, more recently, non-coding RNAs (ncRNAs). Among the ncRNAs, long ncRNAs (lncRNAs) have emerged as new regulators in cancer progression; therefore, our aim was to determine whether the expression of any lncRNAs is regulated by E2 and, if so, whether a subset of these lncRNAs have some clinical significance in EOC progression. A microarray was performed to identify E2-regulated lncRNAs in E2 receptor (ER) α-positive EOC cells. Bioinformatics analyses of lncRNAs were conducted, focusing on gene ontology and pathway analyses. Quantitative real-time polymerase chain reactions were performed to confirm the expression of certain lncRNAs in ERα-positive EOC tissues. The correlation between certain lncRNA expression and clinicopathological factors as well as prognosis in ERα-positive EOC patients was then analyzed. We showed that 115 lncRNAs exhibited significant changes in E2-treated SKOV3 cells compared with untreated controls. Most of these lncRNAs were predicated to have potential to contribute to cancer progression. Notably, three candidates (TC0100223, TC0101686 and TC0101441) were aberrantly expressed in ERα-positive compared to ERα-negative EOC tissues, showing correlations with some malignant cancer phenotypes such as advanced FIGO stage and/or high histological grade. Furthermore, multivariate analysis indicated that TC0101441 was an independent prognostic factor for overall survival. Taken together, these results indicate for the first time that E2 can modulate lncRNA expression in ERα-positive EOC cells and that certain lncRNAs are correlated with advanced cancer progression and suggestive of a prognostic indicator in ERα-positive EOC patients. Knowledge of these E2-regulated lncRNAs could aid in the future understanding of the estrogenic effect on EOC progression

  8. SU-E-T-782: Using Light Output From Doped Plastic Scintillators to Resolve the Linear Energy Transfer Spectrum of Clinical Electron Beams

    SciTech Connect

    Nusrat, H; Pang, G; Ahmad, S; Keller, B; Sarfehnia, A

    2015-06-15

    Purpose: This research seeks to develop a portable, clinically-suitable linear energy transfer (LET) detector. In radiotherapy, absorbed dose is commonly used to measure the amount of delivered radiation, though, it is not a good indicator of actual biological damage. LET is the energy absorbed per unit length by a medium along charged particle’s pathway; studies have shown that LET correlates well with relative biological effectiveness (RBE). Methods: According to Birks’ law, light output of plastic scintillators is stopping-power dependent. This dependency can be varied through doping by various high-Z elements. By measuring light output signals of differently doped plastic scintillators (represented by column vector S, where each row corresponds to different scintillator material), the fluence of charged particles of a given LET (represented by column vector Φ, where each row corresponds to different LET bins) can be unfolded by S=R*Φ where R is system response matrix (each row represents a different scintillator, each column corresponds to different electron LET). Monte Carlo (MC) GEANT4.10.1 was used to evaluate ideal detector response of BC408 scintillating material doped with various concentrations of several high Z dopants. Measurements were performed to validate MC. Results: Signal for 1%-lead doped BC408 and the non-doped scintillator was measured experimentally by guiding light emitted by the scintillator (via in-house made taper, fiber system) to a PMT and then an electrometer. Simulations of 1%Pb-doped scintillator to non-doped scintillator revealed 9.3% reduction in light output for 6 MeV electrons which compared well (within uncertainty) with measurements showing 10% reduction (6MeV electrons). Conclusion: Measurements were used to validate MC simulation of light output from doped scintillators. The doping of scintillators is a viable technique to induce LET dependence. Our goal is to use this effect to resolve the LET spectrum of an incident

  9. A Randomized Clinical Trial of Acceptance and Commitment Therapy versus Progressive Relaxation Training for Obsessive-Compulsive Disorder

    ERIC Educational Resources Information Center

    Twohig, Michael P.; Hayes, Steven C.; Plumb, Jennifer C.; Pruitt, Larry D.; Collins, Angela B.; Hazlett-Stevens, Holly; Woidneck, Michelle R.

    2010-01-01

    Objective: Effective treatments for obsessive-compulsive disorder (OCD) exist, but additional treatment options are needed. The effectiveness of 8 sessions of acceptance and commitment therapy (ACT) for adult OCD was compared with progressive relaxation training (PRT). Method: Seventy-nine adults (61% female) diagnosed with OCD (mean age = 37…

  10. [Anarthria, progressive apraxia and extrapyramidal syndrome: an uncommon clinical form of corticobasal degeneration? A case studied by HMPAO Tc99m single-photon emission tomography].

    PubMed

    Fayet, G; Vercelletto, M; Bertout, C; De Kersaint-Gilly, A; Fève, J R

    1995-04-01

    A 48-year-old man presented with impaired joint movement and buccofacial apraxia. The disease progressed for six years associating an akineto-hypertonic syndrome, marked anarthria, saliva incontinence, bi-opercular syndrome, bucco-facial apraxia, severe global gestual apraxia and a frontal syndrom. Oculo-motricity and gait were normal. Magnetic resonance imaging of the brain demonstrated fronto-parietal atrophy and HMPAO Tc99 tomography revealed hypoperfusion of the cortex clearly predominating in the left parietal region. These particular findings with predominantly intense joint involvement is similar to the clinical picture in corticobasal degeneration--subcortical signs (progressively uncontrollable hypertonia) together with cortical signs (severe gestual apraxia). The neuroradiological imaging and functional results also suggest a degenerative process.

  11. The International Linear Collider Progress Report 2015

    SciTech Connect

    Yamamoto, Akira

    2015-07-15

    The ILC technical design is now being adapted to the preferred candidate site. Changes in layout are being managed by a rigorous change-control procedure. Series production of cavities for the European XFEL has shown that cavities can be mass-produced in industry with a performance well above XFEL requirements and close to that needed for the ILC. A number of technical developments are under way with a view to further reducing the ILC cost. This work must continue through the preparatory stage for ILC construction once resources become available. A summary of the design updates and of the further preparatory work needed is summarized in tabular form in the Appendix.

  12. Initial Study of Radiological and Clinical Efficacy Radioembolization Using 188Re-Human Serum Albumin (HSA) Microspheres in Patients with Progressive, Unresectable Primary or Secondary Liver Cancers

    PubMed Central

    Nowicki, Mirosław L.; Ćwikła, Jarosław B.; Sankowski, Artur J.; Shcherbinin, Sergey; Grimes, Josh; Celler, Anna; Buscombe, John R.; Bator, Andrzej; Pech, Maciej; Mikołajczak, Renata; Pawlak, Dariusz

    2014-01-01

    Background The aim of this initial study was to evaluate the clinical and radiological effectiveness of radioembolization (RE) using 188Re-Human Serum Albumin (HSA) microspheres in patients with advanced, progressive, unresectable primary or secondary liver cancers, not suitable to any other form of therapy. Material/Methods Overall, we included 13 patients with 20 therapy sessions. Clinical and radiological responses were assessed at 6 weeks after therapy, and then every 3 months. The objective radiological response was classified according to Response Evaluation Criteria in Solid Tumors (RECIST) v.1.0 by sequential MRI. Adverse events were evaluated using NCI CTCAE v.4.03. Results There were 4 patients with hepatocellular carcinoma (HCC), 6 with metastatic colorectal cancer (mCRC), 2 with neuroendocrine carcinoma (NEC), and 1 patient with ovarian carcinoma. Mean administered activity of 188Re HSA was 7.24 GBq (range 3.8–12.4) A high microspheres labeling efficacy of over 97±2.1% and low urinary excretion of 188Re (6.5±2.3%) during first 48-h follow-up. Median overall survival (OS) for all patients was 7.1 months (CI 6.2–13.3) and progression-free survival (PFS) was 5.1 months (CI 2.4–9.9). In those patients who had a clinical partial response (PR), stable disease (SD), and disease progression (DP) as assessed 6 weeks after therapy, the median OS was 9/5/4 months, respectively, and PFS was 5/2/0 months, respectively. The treatment adverse events (toxicity) were at an acceptable level. Initially and after 6 weeks, the CTC AE was grade 2, while after 3 months it increased to grade 3 in 4 subjects. This effect was mostly related to rapid cancer progression in this patient subgroup. Conclusions The results of this preliminary study indicate that RE using 188Re HSA is feasible and a viable option for palliative therapy in patients with extensive progressive liver cancer. It was well tolerated by most patients, with a low level of toxicity during the 3 months of

  13. Pattern of gp120 sequence divergence linked to a lack of clinical progression in human immunodeficiency virus type 1 infection.

    PubMed Central

    Wang, W K; Essex, M; McLane, M F; Mayer, K H; Hsieh, C C; Brumblay, H G; Seage, G; Lee, T H

    1996-01-01

    Differential rates of AIDS development and/or T4 lymphocyte depletion in HIV-1-infected individuals remain unexplained. The hypothesis that qualitative differences in selection pressure in vivo may account for different rates of disease progression was addressed in nine eligible study participants from a cohort of 315 homosexual men who have been followed since 1985. Disproportionately fewer changes in variable regions and more in C3 of gp12O were found to be significantly associated with slower disease progression. Our finding provides the first example to demonstrate that differential selection pressure related to the emergence of HIV-1 variants is associated with long term nonprogression. Candidate vaccines that elicit strong selection pressure on C3 of gp120 are likely to provide better protection than those targeting variable regions. PMID:8692880

  14. Annual Research Progress Report Fiscal Year 1990. Volume 2. Department of Clinical Investigation (Brooke Army Medical Center)

    DTIC Science & Technology

    1990-10-01

    including tissue from the mesosalpinx acquired during a tubal ligation and a human embryo. Fifteen day old rat embryos will be used asthe primary...Medulloblastoma: 607 Cisplatin/VP-16 Pre- vs Post -Irradiation. (0) POG 9046 Molecular Genetic Study of Wilms’ Tumor and Nephrogenic Rests. 608 (0) POG 9047...Groups A and B will begin treatment 30 minutes post chlorine exposure. Progress: Bench research has been completed. Final paper for publication in

  15. A protocol for evaluating progressive levels of simulation fidelity in the development of technical skills, integrated performance and woman centred clinical assessment skills in undergraduate midwifery students

    PubMed Central

    2013-01-01

    Background Simulation as a pedagogical approach has been used in health professional education to address the need to safely develop effective clinical skills prior to undertaking clinical practice. However, evidence for the use of simulation in midwifery is largely anecdotal, and research evaluating the effectiveness of different levels of simulation fidelity are lacking. Woman centred care is a core premise of the midwifery profession and describes the behaviours of an individual midwife who demonstrates safe and effective care of the individual woman. Woman centred care occurs when the midwife modifies the care to ensure the needs of each individual woman are respected and addressed. However, a review of the literature demonstrates an absence of a valid and reliable tool to measure the development of woman centred care behaviours. This study aims to determine which level of fidelity in simulated learning experiences provides the most effective learning outcomes in the development of woman centred clinical assessment behaviors and skills in student midwives. Methods/Design Three-arm, randomised, intervention trial. In this research we plan to: a) trial three levels of simulation fidelity - low, medium and progressive, on student midwives performing the procedure of vaginal examination; b) measure clinical assessment skills using the Global Rating Scale (GRS) and Integrated Procedural Performance Instrument (IPPI); and c) pilot the newly developed Woman Centred Care Scale (WCCS) to measure clinical behaviors related to Woman-Centredness. Discussion This project aims to enhance knowledge in relation to the appropriate levels of fidelity in simulation that yield the best educational outcomes for the development of woman centred clinical assessment in student midwives. The outcomes of this project may contribute to improved woman centred clinical assessment for student midwives, and more broadly influence decision making regarding education resource allocation for

  16. Multiple sclerosis: integration of modeling with biology, clinical and imaging measures to provide better monitoring of disease progression and prediction of outcome.

    PubMed

    Goodwin, Shikha Jain

    2016-12-01

    Multiple Sclerosis (MS) is a major cause of neurological disability in adults and has an annual cost of approximately $28 billion in the United States. MS is a very complex disorder as demyelination can happen in a variety of locations throughout the brain; therefore, this disease is never the same in two patients making it very hard to predict disease progression. A modeling approach which combines clinical, biological and imaging measures to help treat and fight this disorder is needed. In this paper, I will outline MS as a very heterogeneous disorder, review some potential solutions from the literature, demonstrate the need for a biomarker and will discuss how computational modeling combined with biological, clinical and imaging data can help link disparate observations and decipher complex mechanisms whose solutions are not amenable to simple reductionism.

  17. Multiple sclerosis: integration of modeling with biology, clinical and imaging measures to provide better monitoring of disease progression and prediction of outcome

    PubMed Central

    Goodwin, Shikha Jain

    2016-01-01

    Multiple Sclerosis (MS) is a major cause of neurological disability in adults and has an annual cost of approximately $28 billion in the United States. MS is a very complex disorder as demyelination can happen in a variety of locations throughout the brain; therefore, this disease is never the same in two patients making it very hard to predict disease progression. A modeling approach which combines clinical, biological and imaging measures to help treat and fight this disorder is needed. In this paper, I will outline MS as a very heterogeneous disorder, review some potential solutions from the literature, demonstrate the need for a biomarker and will discuss how computational modeling combined with biological, clinical and imaging data can help link disparate observations and decipher complex mechanisms whose solutions are not amenable to simple reductionism. PMID:28197176

  18. Progress in anterior chamber angle imaging for glaucoma risk prediction - A review on clinical equipment, practice and research.

    PubMed

    V K, Shinoj; Hong, Xun Jie Jeesmond; V M, Murukeshan; M, Baskaran; Tin, Aung

    2016-12-01

    The visualization capabilities of various ocular imaging instruments can generally be categorized into photographic (e.g. gonioscopy, Pentacam, RetCam) and optical tomographic (e.g. optical coherence tomography (OCT), photoacoustic (PA) imaging, ultrasound biomicriscopy (UBM)) methods. These imaging instruments allow vision researchers and clinicians to visualize the iridocorneal angle, and are essential in the diagnosis and management of glaucoma. Each of these imaging modalities has particular benefits and associated drawbacks in obtaining repeatable and reliable measurement in the evaluation of the angle. This review article in this context summarized recent progresses in anterior chamber imaging techniques in glaucoma diagnosis and follow-up procedures.

  19. [THE FACTORS OF THE PROGRESSION OF METABOLIC DISORDERS IN THE PANCREAS IN PATIENTS WITH ASSOCIATED CLINICAL VARIANTS OF THE CHRONIC PANCREATITIS AND TYPE 2 DIABETES MELLITUS].

    PubMed

    Zhuravlyova, L V; Shekhovtsova, Y O

    2015-01-01

    The purpose of the present study was to determine the causal factors of the progression of metabolic disorders in pancreatic tissue and their relationships in patients with assotiated clinical variants of chronic pancreatitis (CP) and type 2 diabetes mellitus (T2DM). The study involved of 76 patients with CP and T2DM. The causes of progression of metabolic disorders in the pancreas in patients with associated clinical variants of CP and T2DM has been analyzed. The most significant of them were insulin resistance and abdominal obesity, which promotes early formation of the metabolic syndrome and the activation of fibrogenesis and steatosis in the pancreas and is caused by dyslipidemia, impaired glucose metabolism and the development of systemic inflammation and imbalance of adipocytokines. The relationships between adipocytokines, body weight and individual components of the metabolic syndrome in patients with CP and T2DM suggests the involvement of these hormones of adipose tissue in the formation of the metabolic syndrome and its components.

  20. Optical imaging in vivo with a focus on paediatric disease: technical progress, current preclinical and clinical applications and future perspectives

    PubMed Central

    Napp, Joanna; Mathejczyk, Julia E.

    2011-01-01

    To obtain information on the occurrence and location of molecular events as well as to track target-specific probes such as antibodies or peptides, drugs or even cells non-invasively over time, optical imaging (OI) technologies are increasingly applied. Although OI strongly contributes to the advances made in preclinical research, it is so far, with the exception of optical coherence tomography (OCT), only very sparingly applied in clinical settings. Nevertheless, as OI technologies evolve and improve continuously and represent relatively inexpensive and harmful methods, their implementation as clinical tools for the assessment of children disease is increasing. This review focuses on the current preclinical and clinical applications as well as on the future potential of OI in the clinical routine. Herein, we summarize the development of different fluorescence and bioluminescence imaging techniques for microscopic and macroscopic visualization of microstructures and biological processes. In addition, we discuss advantages and limitations of optical probes with distinct mechanisms of target-detection as well as of different bioluminescent reporter systems. Particular attention has been given to the use of near-infrared (NIR) fluorescent probes enabling observation of molecular events in deeper tissue. PMID:21221568

  1. Cytokine profile during latent and slowly progressive primary tuberculosis: a possible role for interleukin-15 in mediating clinical disease.

    PubMed

    Abebe, F; Mustafa, T; Nerland, A H; Bjune, G A

    2006-01-01

    Recently, mouse models for latent (LTB) and slowly progressive primary tuberculosis (SPTB) have been established. However, cytokine profiles during the two models are not well established. Using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) we studied the expression levels of interleukin (IL)-2, IL-4, IL-10, IL-12, IL-15, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha during the course of LTB and SPTB in the lungs and spleens of B6D2F1Bom mice infected with the H37Rv strain of Mycobacterium tuberculosis (Mtb). The results show that, except for IL-4, cytokine expression levels were significantly higher during SPTB than LTB in both the lungs and spleens. During LTB, all the cytokines (except IL-2 in the lungs) had higher expression levels during the initial period of infection both in the lungs and spleens. During SPTB, the expression levels of IL-15 increased significantly from phases 1 to 3 in the lungs. The expression levels of IL-10, IL-12 and IFN-gamma increased significantly from 2 to 3 in the lungs. IL-10 and IL-15 increased significantly from phases 2 to 3, whereas that of TNF-alpha decreased significantly and progressively from phases 1 to 3 in the spleens. Over-expression of proinflammatory cytokines during active disease has been well documented, but factor(s) underlying such over-expression is not known. In the present study, there was a progressive and significant increase in the expression levels of IL-15, together with Th1 cytokines (IL-12 and IFN-gamma) during SPTB but a significant decrease during LTB. IL-15 is known to up-regulate the production of proinflammatory cytokines, IL-1beta, IL-8, IL-12, IL-17, IFN-gamma and TNF-alpha and has an inhibitory effect on activation-induced cell death. IL-15 is known to be involved in many proinflammatory disease states such as rheumatoid arthritis, sarcoidosis, inflammatory bowel diseases, autoimmune diabetes, etc. Our results, together with the above observations

  2. Mesomelic dysplasia with acral synostoses Verloes-David-Pfeiffer type: follow-up study documents progressive clinical course.

    PubMed

    Isidor, Bertrand; Hamel, Antoine; Plasschaert, Frank; Claus, Lieve; Mercier, Jacques-Marie; Mortier, Geert R; Leroy, Jules G; Verloes, Alain; David, Albert

    2009-10-01

    Verloes-David-Pfeiffer mesomelia-synostoses syndrome is an autosomal-dominant form of mesomelic dysplasia comprising typical acral synostoses combined with ptosis, hypertelorism, palatal abnormality, CHD, and ureteral anomalies. Since the original reports in 1995, two other patients have been described with this syndrome, one of them the patient reported in 1998 by Day-Salvatore. In this article, we report on the follow-up of some of the original cases and review the literature. We confirm that the Verloes-David-Pfeiffer syndrome (VDPS) is a progressive skeletal disorder that despite repeated corrective surgical intervention leads to severe limb deformities. No mutations were detected in the FLNB gene. To date, the cause and the pathogenesis of VDPS remain unknown. The latter is characterized in this study as a syndromic type of skeletal dysplasia because besides congenital malformations and multiple acromelic synostoses arising prenatally, VDPS manifests in postnatal life as a severe osteochondrodysplasia.

  3. [The clinical and forensic psychiatric assessment of attack-like progressive schizophrenia with the Kandinsky-Clérambault syndrome].

    PubMed

    Vasil'ev, V D

    1992-01-01

    Overall 200 patients suffering from attack-like progressive schizophrenia associated with Kandinsky-Clérambault syndrome were examined. All the patients underwent compulsory treatment at the psychiatric hospitals. Two varieties of schizophrenia associated with Kandinsky-Clérambault syndrome were distinguished: psychotic (127 persons) and psychopath-like (73 persons). The psychotic variety is characterized by the growth of personality disintegration because of changes to a greater degree in the thinking sphere, whereas the psychopath-like variety is marked by alterations in the affective volitional sphere. The psychopathological mechanisms of socially dangerous action of the patients at the preproductive and productive stages of endogenous process are described depending on the varieties distinguished.

  4. International Union of Basic and Clinical Pharmacology. LXXVI. Current Progress in the Mammalian TRP Ion Channel Family

    PubMed Central

    Wu, Long-Jun; Sweet, Tara-Beth

    2010-01-01

    Transient receptor potential (TRP) channels are a large family of ion channel proteins, surpassed in number in mammals only by voltage-gated potassium channels. TRP channels are activated and regulated through strikingly diverse mechanisms, making them suitable candidates for cellular sensors. They respond to environmental stimuli such as temperature, pH, osmolarity, pheromones, taste, and plant compounds, and intracellular stimuli such as Ca2+ and phosphatidylinositol signal transduction pathways. However, it is still largely unknown how TRP channels are activated in vivo. Despite the uncertainties, emerging evidence using TRP channel knockout mice indicates that these channels have broad function in physiology. Here we review the recent progress on the physiology, pharmacology and pathophysiological function of mammalian TRP channels. PMID:20716668

  5. LINEAR ACCELERATOR

    DOEpatents

    Colgate, S.A.

    1958-05-27

    An improvement is presented in linear accelerators for charged particles with respect to the stable focusing of the particle beam. The improvement consists of providing a radial electric field transverse to the accelerating electric fields and angularly introducing the beam of particles in the field. The results of the foregoing is to achieve a beam which spirals about the axis of the acceleration path. The combination of the electric fields and angular motion of the particles cooperate to provide a stable and focused particle beam.

  6. Linear Clouds

    NASA Technical Reports Server (NTRS)

    2006-01-01

    [figure removed for brevity, see original site] Context image for PIA03667 Linear Clouds

    These clouds are located near the edge of the south polar region. The cloud tops are the puffy white features in the bottom half of the image.

    Image information: VIS instrument. Latitude -80.1N, Longitude 52.1E. 17 meter/pixel resolution.

    Note: this THEMIS visual image has not been radiometrically nor geometrically calibrated for this preliminary release. An empirical correction has been performed to remove instrumental effects. A linear shift has been applied in the cross-track and down-track direction to approximate spacecraft and planetary motion. Fully calibrated and geometrically projected images will be released through the Planetary Data System in accordance with Project policies at a later time.

    NASA's Jet Propulsion Laboratory manages the 2001 Mars Odyssey mission for NASA's Office of Space Science, Washington, D.C. The Thermal Emission Imaging System (THEMIS) was developed by Arizona State University, Tempe, in collaboration with Raytheon Santa Barbara Remote Sensing. The THEMIS investigation is led by Dr. Philip Christensen at Arizona State University. Lockheed Martin Astronautics, Denver, is the prime contractor for the Odyssey project, and developed and built the orbiter. Mission operations are conducted jointly from Lockheed Martin and from JPL, a division of the California Institute of Technology in Pasadena.

  7. Molecular mechanisms and clinical applications of miR-22 in regulating malignant progression in human cancer (Review)

    PubMed Central

    Wang, Jingyu; Li, Yuan; Ding, Meiman; Zhang, Honghe; Xu, Xiaoming; Tang, Jinlong

    2017-01-01

    miRNAs (microRNAs) have been validated to play fateful roles in the occurrence and development of cancers by post-transcriptionally targeting 3′-untranslated regions of the downstream gene mRNAs to repress mRNA expression. Mounting investigations forcefully document that not only does miR-22 biologically impinge on the processes of senescence, energy supply, angiogenesis, EMT (epithelial-mesenchymal transition), proliferation, migration, invasion, metastasis and apoptosis, but also it genetically or epigenetically exerts dual (inhibitory/promoting cancer) effects in various cancers via CNAs (copy number alterations), SNPs (single nucleotide polymorphisms), methylation, acetylation and even more momentously hydroxymethylation. Additionally, miR-22 expression may fluctuate with cancer progression in the body fluids of cancer patients and miR-22 could amplify its inhibitory or promoting effects through partaking in positive or negative feedback loops and interplaying with many other related miRNAs in the cascade of events, making it possible for miR-22 to be a promising and complementary or even independent cancer biomarker in some cancers and engendering profound influences on the early diagnosis, therapeutics, supervising curative effects and prognosis. PMID:28000852

  8. A subpopulation that may correspond to granulocytic myeloid-derived suppressor cells reflects the clinical stage and progression of cutaneous melanoma

    PubMed Central

    Miller, Karolina; Kandolf-Sekulovic, Lidija; Mijuskovic, Zeljko; Zolotarevski, Lidija; Jovic, Milena; Gacevic, Milomir; Djukic, Mirjana; Arsenijevic, Nebojsa; Vojvodic, Danilo

    2016-01-01

    Seventy-eight melanoma patients and 10 healthy individuals were examined. Follow-up examinations of all melanoma patients were performed regularly every three months. Myeloid-derived suppressor cells (MDSC) were defined as lineage negative (CD3−, CD19−, CD56−), HLA-DR−/low, CD11b+ and CD33+. Classification of granulocytic (GrMDSC) and monocytic (MoMDSC) subsets was based on the CD15 and CD14 expression, respectively. Unlike the MoMDSC, that were present in 60% of healthy controls and 15% of melanoma patients, the GrMDSC were present in all examined participants, and the melanoma patients were found to have statistically higher frequencies compared with healthy controls. Accordingly, we kept focused on GrMDSC frequencies in relation to the melanoma stages and course of the disease. The GrMDSC values are highest in stage IV melanoma patients, with statistical significance compared with stages IA, IB, IIA and IIB. Patients with progression had statistically higher GrMDSC counts comparing with those with stable disease (P = 0.0079). Patients who had progression-free interval (PFI) < 12 months showed significantly higher GrMDSC values compared with those with PFI > 12 months (P = 0.0333). GrMDSC showed significant negative correlation with PFI intervals (P = 0.0095). The GrMDSC subset was predominant in all our patients. We confirmed that GrMDSC do accumulate early in the peripheral blood of melanoma patients and their frequencies correlate narrowly with the clinical stage and the spread of the disease. The increase in GrMDSC frequencies correlates well with a progressive disease and could be considered a potential predictive biomarker of high-risk melanoma cases that are more likely to have a shorter PFI. PMID:26391013

  9. Progress in the clinical imaging research of bone diseases on ankle and foot sesamoid bones and accessory ossicles.

    PubMed

    Li, Xiaozhong; Shi, Lenian; Liu, Taiyun; Wang, Lin

    2012-08-01

    Sesamoid bones and accessory ossicles are research focuses of foot and ankle surgery. Pains of the foot and ankle are related to sesamoid bones and accessory ossicles. The specific anatomical and functional relationship of sesamoid bones and accessory ossicles can cause such bone diseases as the dislocation of sesamoid bones and accessory bones, infection, inflammation and necrosis of sesamoid bones, cartilage softening, tenosynovitis of sesamoid bones and the sesamoid bone syndrome. However, these bone diseases are often misdiagnosed or mistreated. In patients with trauma history, relevant diseases of sesamoid bones and accessory ossicles as above mentioned are highly probable to be misdiagnosed as avulsion fractures. In such cases, radiographic findings may provide a basis for clinical diagnosis.

  10. Promising approaches to circumvent the blood-brain barrier: progress, pitfalls and clinical prospects in brain cancer

    PubMed Central

    Papademetriou, Iason T; Porter, Tyrone

    2015-01-01

    Brain drug delivery is a major challenge for therapy of central nervous system (CNS) diseases. Biochemical modifications of drugs or drug nanocarriers, methods of local delivery, and blood–brain barrier (BBB) disruption with focused ultrasound and microbubbles are promising approaches which enhance transport or bypass the BBB. These approaches are discussed in the context of brain cancer as an example in CNS drug development. Targeting to receptors enabling transport across the BBB offers noninvasive delivery of small molecule and biological cancer therapeutics. Local delivery methods enable high dose delivery while avoiding systemic exposure. BBB disruption with focused ultrasound and microbubbles offers local and noninvasive treatment. Clinical trials show the prospects of these technologies and point to challenges for the future. PMID:26488496

  11. Progress in the capture, manipulation, and delivery of medical media and its impact on education, clinical care, and research.

    PubMed

    Bernardo, Theresa M; Malinowski, Robert P

    2005-01-01

    In this article, advances in the application of medical media to education, clinical care, and research are explored and illustrated with examples, and their future potential is discussed. Impact is framed in terms of the Sloan Consortium's five pillars of quality education: access; student and faculty satisfaction; learning effectiveness; and cost effectiveness. (Hiltz SR, Zhang Y, Turoff M. Studies of effectiveness of learning networks. In Bourne J, Moore J, ed. Elements of Quality Online Education. Needham, MA: Sloan-Consortium, 2002:15-45). The alternatives for converting analog media (text, photos, graphics, sound, video, animations, radiographs) to digital media and direct digital capture are covered, as are options for storing, manipulating, retrieving, and sharing digital collections. Diagnostic imaging is given particular attention, clarifying the difference between computerized radiography and digital radiography and explaining the accepted standard (DICOM) and the advantages of Web PACS. Some novel research applications of medical media are presented.

  12. Works in progress #7. Clinical experience with the Accu-Path threaded acetabular cup. A preliminary report.

    PubMed

    Harwin, S F; Stern, R E; Kulick, R G

    1991-10-01

    Clinical experience with the Accu-Path threaded titanium hemispheric cup is presented. A series of 62 cases was followed for an average of 28.1 months (range, 6 to 48). Primary surgery was performed in 50 cases and revision surgery in 12. The surgical technique is described in detail. Preoperative Harris scores improved from 28 to 93 in primary cases and from 24 to 84 in revision cases. Complications included 3.2% dislocation, 3.2% loss of cup position, and 1.6% recurrent subluxation. The overall reoperation rate was 8% (8% in primary surgery and 8.3% in revision surgery). Roentgenographic analysis is discussed. The importance of preservation of the subchondral plate and a rim fit in the use of this implant is stressed. It is not indicated in those with loss of the plate due either to prior surgery (as in revision) or in aggressive over-reaming in primary cases. Although the overall results were encouraging, caution was recommended--especially in revision surgery or in the patient with severe osteopenia.

  13. Experiments on linear high beta helical axis stellarators to study simulated toroidal effects and Alfven-wave heating: (Annual) progress report No. 1, February 16, 1987-November 15, 1987

    SciTech Connect

    Ribe, F.L.

    1987-01-01

    This paper discusses experiments on linear high beta helical axis stellarators. Experiments considered are: formation of linear high beta heliac plasma configurations; Alfven wave heating in a straight tube and in a linear high beat stellarator; shifted hardcore heliac studies; a system for measuring the timing of high-current switches in a pulsed high voltage fusion experiment; HBQM general refurbishment; and proposed experiment on excitation of the m = 1 tilt mode in field-reversed configurations. (LSP)

  14. Clinical significance of Anoctamin-1 gene at 11q13 in the development and progression of head and neck squamous cell carcinomas

    PubMed Central

    Rodrigo, Juan P.; Menéndez, Sofía Tirados; Hermida-Prado, Francisco; Álvarez-Teijeiro, Saúl; Villaronga, M. Ángeles; Alonso-Durán, Laura; Vallina, Aitana; Martínez-Camblor, Pablo; Astudillo, Aurora; Suárez, Carlos; María García-Pedrero, Juana

    2015-01-01

    This study investigates the clinical significance of Anoctamin-1 gene mapping at 11q13 amplicon in both the development and progression of head and neck squamous cell carcinomas (HNSCC). ANO1 protein expression was evaluated by immunohistochemistry in a cohort of 372 surgically treated HNSCC patients and also in 35 laryngeal precancerous lesions. ANO1 gene amplification was determined by real-time PCR in all the laryngeal premalignancies and 60 of the HNSCCs, and molecular data correlated with clinical outcome. ANO1 gene amplification was frequently detected in both premalignant lesions (63%) and HNSCC tumours (58%), whereas concomitant ANO1 expression occurred at a much lower frequency (20 and 22%). Interestingly, laryngeal dysplasias harbouring ANO1 gene amplification showed a higher risk of malignant transformation (HR = 3.62; 95% CI 0.79–16.57; P = 0.097; Cox regression). ANO1 expression and gene amplification showed no significant associations with clinicopathological parameters in HNSCC. However, remarkably ANO1 expression differentially influenced patient survival depending on the tumour site. Collectively, this study provides original evidence demonstrating the distinctive impact of ANO1 expression on HNSCC prognosis depending on the tumour site. PMID:26498851

  15. Clinical significance of Anoctamin-1 gene at 11q13 in the development and progression of head and neck squamous cell carcinomas.

    PubMed

    Rodrigo, Juan P; Menéndez, Sofía Tirados; Hermida-Prado, Francisco; Álvarez-Teijeiro, Saúl; Villaronga, M Ángeles; Alonso-Durán, Laura; Vallina, Aitana; Martínez-Camblor, Pablo; Astudillo, Aurora; Suárez, Carlos; María García-Pedrero, Juana

    2015-10-26

    This study investigates the clinical significance of Anoctamin-1 gene mapping at 11q13 amplicon in both the development and progression of head and neck squamous cell carcinomas (HNSCC). ANO1 protein expression was evaluated by immunohistochemistry in a cohort of 372 surgically treated HNSCC patients and also in 35 laryngeal precancerous lesions. ANO1 gene amplification was determined by real-time PCR in all the laryngeal premalignancies and 60 of the HNSCCs, and molecular data correlated with clinical outcome. ANO1 gene amplification was frequently detected in both premalignant lesions (63%) and HNSCC tumours (58%), whereas concomitant ANO1 expression occurred at a much lower frequency (20 and 22%). Interestingly, laryngeal dysplasias harbouring ANO1 gene amplification showed a higher risk of malignant transformation (HR = 3.62; 95% CI 0.79-16.57; P = 0.097; Cox regression). ANO1 expression and gene amplification showed no significant associations with clinicopathological parameters in HNSCC. However, remarkably ANO1 expression differentially influenced patient survival depending on the tumour site. Collectively, this study provides original evidence demonstrating the distinctive impact of ANO1 expression on HNSCC prognosis depending on the tumour site.

  16. Progressive dysembryoplastic neuroepithelial tumour.

    PubMed

    Alexander, Hamish; Tannenburg, Anthony; Walker, David G; Coyne, Terry

    2015-01-01

    Dysembryoplastic neuroepithelial tumour (DNET) is a benign tumour characterised by cortical location and presentation with drug resistant partial seizures in children. Recently the potential for malignant transformation has been reported, however progression without malignant transformation remains rare. We report a case of clinical and radiologic progression of a DNET in a girl 10 years after initial biopsy.

  17. Preserved Collateral Blood Flow in the Endovascular M2CAO Model Allows for Clinically Relevant Profiling of Injury Progression in Acute Ischemic Stroke

    PubMed Central

    Little, Philip; Kvist, Ola; Grankvist, Rikard; Jonsson, Stefan; Damberg, Peter; Söderman, Michael; Arnberg, Fabian; Holmin, Staffan

    2017-01-01

    Interventional treatment regimens have increased the demand for accurate understanding of the progression of injury in acute ischemic stroke. However, conventional animal models severely inhibit collateral blood flow and mimic the malignant infarction profile not suitable for treatment. The aim of this study was to provide a clinically relevant profile of the emergence and course of ischemic injury in cases suitable for acute intervention, and was achieved by employing a M2 occlusion model (M2CAO) that more accurately simulates middle cerebral artery (MCA) occlusion in humans. Twenty-five Sprague-Dawley rats were subjected to Short (90 min), Intermediate (180 min) or Extended (600 min) transient M2CAO and examined longitudinally with interleaved diffusion-, T2- and arterial spin labeling perfusion-weighted magnetic resonance imaging before and after reperfusion. We identified a rapid emergence of cytotoxic edema within tissue regions undergoing infarction, progressing in several distinct phases in the form of subsequent moderation and then reversal at 230 min (p < 0.0001). We identified also the early emergence of vasogenic edema, which increased consistently before and after reperfusion (p < 0.0001). The perfusion of the penumbra correlated more strongly to the perfusion of adjacent tissue regions than did the perfusion of regions undergoing infarction (p = 0.0088). This was interpreted as an effect of preserved collateral blood flow during M2CAO. Accordingly, we observed only limited recruitment of penumbra regions to the infarction core. However, a gradual increase in infarction size was still occurring as late as 10 hours after M2CAO. Our results indicate that patients suffering MCA branch occlusion stand to benefit from interventional therapy for an extended time period after the emergence of ischemic injury. PMID:28068417

  18. Progressive multiple sclerosis

    PubMed Central

    Ontaneda, Daniel; Fox, Robert J.

    2015-01-01

    Purpose to Review To highlight the pathological features and clinical aspects of progressive multiple sclerosis (PMS). To highlight results of clinical trial experience to date and review ongoing clinical trials and perspective new treatment options. Explain the challenges of clinical trial design in PMS. Recent Findings MS has been identified as a chronic immune mediated disease, and the progressive phase of the disease appears to have significant neurodegenerative mechanisms. The classification of the course of PMS has been re-organized into categories of active vs. inactive inflammatory disease and the presence vs. absence of gradual disease progression. This differentiation allows clearer conceptualization of PMS and possibly even more efficient recruitment of PMS subjects into clinical trials. Clinical trial experience to date in PMS has been negative with anti-inflammatory medications used in relapsing MS. Simvastatin was recently tested in a phase II trial and showed a 43% reduction on annualized atrophy progression in secondary progressive MS. Ongoing PMS trials are currently being conducted with the phosphodiesterase inhibitor ibudilast, S1P modulator siponimod, and anti-B-cell therapy ocrelizumab. Several efforts for development of outcome measures in PMS are ongoing. Summary PMS represents a significant challenge, as the pathogenesis of the disease is not well understood, no validated outcome metrics have been established, and clinical trial experience to date has been disappointing. Advances in the understanding of the disease and lessons learned in previous clinical trials are paving the way for successful development of disease modifying agents for this disease. PMID:25887766

  19. Parameters of disease progression in long-term experimental feline retrovirus (feline immunodeficiency virus and feline leukemia virus) infections: hematology, clinical chemistry, and lymphocyte subsets.

    PubMed

    Hofmann-Lehmann, R; Holznagel, E; Ossent, P; Lutz, H

    1997-01-01

    After several years of latency, feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV) cause fatal disease in the cat. The aim of this study was to determine laboratory parameters characteristic of disease progression which would allow a better description of the asymptomatic phase and a better understanding of the pathogenesis of the two infections. Therefore, experimentally infected cats (FIV and/or FeLV positive) and control animals were observed over a period of 6.5 years under identical conditions. Blood samples were analyzed for the following: complete hematology, clinical chemistry, serum protein electrophoresis, and determination of CD4+ and CD8+ lymphocyte subsets. The following hematological and clinical chemistry parameters were markedly changed in the FIV-infected animals from month 9 onwards: glucose, serum protein, gamma globulins, sodium, urea, phosphorus, lipase, cholesterol, and triglyceride. In FeLV infection, the markedly changed parameters were mean corpuscular volume, mean corpuscular hemoglobin, aspartate aminotransferase, and urea. In contrast to reports of field studies, neither FIV-positive nor FeLV-positive animals developed persistent leukopenia, lymphopenia, or neutropenia. A significant decrease was found in the CD4+/CD8+ ratio in FIV-positive and FIV-FeLV-positive animals mainly due to loss of CD4+ lymphocytes. In FeLV-positive cats, both CD4+ and, to a lesser degree, CD8+ lymphocytes were decreased in long-term infection. The changes in FIV infection may reflect subclinical kidney dysfunction, changes in energy and lipid metabolism, and transient activation of the humoral immune response as described for human immunodeficiency virus (HIV) infections. The changes in FeLV infection may also reflect subclinical kidney dysfunction and, in addition, changes in erythrocyte and immune function of the animals. No severe clinical signs were observed in the FIV-positive cats, while FeLV had a severe influence on the life

  20. Parameters of disease progression in long-term experimental feline retrovirus (feline immunodeficiency virus and feline leukemia virus) infections: hematology, clinical chemistry, and lymphocyte subsets.

    PubMed Central

    Hofmann-Lehmann, R; Holznagel, E; Ossent, P; Lutz, H

    1997-01-01

    After several years of latency, feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV) cause fatal disease in the cat. The aim of this study was to determine laboratory parameters characteristic of disease progression which would allow a better description of the asymptomatic phase and a better understanding of the pathogenesis of the two infections. Therefore, experimentally infected cats (FIV and/or FeLV positive) and control animals were observed over a period of 6.5 years under identical conditions. Blood samples were analyzed for the following: complete hematology, clinical chemistry, serum protein electrophoresis, and determination of CD4+ and CD8+ lymphocyte subsets. The following hematological and clinical chemistry parameters were markedly changed in the FIV-infected animals from month 9 onwards: glucose, serum protein, gamma globulins, sodium, urea, phosphorus, lipase, cholesterol, and triglyceride. In FeLV infection, the markedly changed parameters were mean corpuscular volume, mean corpuscular hemoglobin, aspartate aminotransferase, and urea. In contrast to reports of field studies, neither FIV-positive nor FeLV-positive animals developed persistent leukopenia, lymphopenia, or neutropenia. A significant decrease was found in the CD4+/CD8+ ratio in FIV-positive and FIV-FeLV-positive animals mainly due to loss of CD4+ lymphocytes. In FeLV-positive cats, both CD4+ and, to a lesser degree, CD8+ lymphocytes were decreased in long-term infection. The changes in FIV infection may reflect subclinical kidney dysfunction, changes in energy and lipid metabolism, and transient activation of the humoral immune response as described for human immunodeficiency virus (HIV) infections. The changes in FeLV infection may also reflect subclinical kidney dysfunction and, in addition, changes in erythrocyte and immune function of the animals. No severe clinical signs were observed in the FIV-positive cats, while FeLV had a severe influence on the life

  1. Linear immunoglobulin A bullous dermatosis.

    PubMed

    Fortuna, Giulio; Marinkovich, M Peter

    2012-01-01

    Linear immunoglobulin A (IgA) bullous dermatosis, also known as linear IgA disease, is an autoimmune mucocutaneous disorder characterized by subepithelial bullae, with IgA autoantibodies directed against several different antigens in the basement membrane zone. Its immunopathologic characteristic resides in the presence of a continuous linear IgA deposit along the basement membrane zone, which is clearly visible on direct immunofluorescence. This disorder shows different clinical features and distribution when adult-onset of linear IgA disease is compared with childhood-onset. Diagnosis is achieved via clinical, histopathologic, and immunopathologic examinations. Two common therapies are dapsone and sulfapyridine, which reduce the inflammatory response and achieve disease remission in a variable period of time.

  2. The MRI-Linear Accelerator Consortium: Evidence-Based Clinical Introduction of an Innovation in Radiation Oncology Connecting Researchers, Methodology, Data Collection, Quality Assurance, and Technical Development.

    PubMed

    Kerkmeijer, Linda G W; Fuller, Clifton D; Verkooijen, Helena M; Verheij, Marcel; Choudhury, Ananya; Harrington, Kevin J; Schultz, Chris; Sahgal, Arjun; Frank, Steven J; Goldwein, Joel; Brown, Kevin J; Minsky, Bruce D; van Vulpen, Marco

    2016-01-01

    An international research consortium has been formed to facilitate evidence-based introduction of MR-guided radiotherapy (MR-linac) and to address how the MR-linac could be used to achieve an optimized radiation treatment approach to improve patients' survival, local, and regional tumor control and quality of life. The present paper describes the organizational structure of the clinical part of the MR-linac consortium. Furthermore, it elucidates why collaboration on this large project is necessary, and how a central data registry program will be implemented.

  3. The MRI-Linear Accelerator Consortium: Evidence-Based Clinical Introduction of an Innovation in Radiation Oncology Connecting Researchers, Methodology, Data Collection, Quality Assurance, and Technical Development

    PubMed Central

    Kerkmeijer, Linda G. W.; Fuller, Clifton D.; Verkooijen, Helena M.; Verheij, Marcel; Choudhury, Ananya; Harrington, Kevin J.; Schultz, Chris; Sahgal, Arjun; Frank, Steven J.; Goldwein, Joel; Brown, Kevin J.; Minsky, Bruce D.; van Vulpen, Marco

    2016-01-01

    An international research consortium has been formed to facilitate evidence-based introduction of MR-guided radiotherapy (MR-linac) and to address how the MR-linac could be used to achieve an optimized radiation treatment approach to improve patients’ survival, local, and regional tumor control and quality of life. The present paper describes the organizational structure of the clinical part of the MR-linac consortium. Furthermore, it elucidates why collaboration on this large project is necessary, and how a central data registry program will be implemented. PMID:27790408

  4. New non-linear color look-up table for visualization of brain fractional anisotropy based on normative measurements - principals and first clinical use.

    PubMed

    Keller, Jiří; Rulseh, Aaron M; Komárek, Arnošt; Latnerová, Iva; Rusina, Robert; Brožová, Hana; Vymazal, Josef

    2013-01-01

    Fractional anisotropy (FA) is the most commonly used quantitative measure of diffusion in the brain. Changes in FA have been reported in many neurological disorders, but the implementation of diffusion tensor imaging (DTI) in daily clinical practice remains challenging. We propose a novel color look-up table (LUT) based on normative data as a tool for screening FA changes. FA was calculated for 76 healthy volunteers using 12 motion-probing gradient directions (MPG), a subset of 59 subjects was additionally scanned using 30 MPG. Population means and 95% prediction intervals for FA in the corpus callosum, frontal gray matter, thalamus and basal ganglia were used to create the LUT. Unique colors were assigned to inflection points with continuous ramps between them. Clinical use was demonstrated on 17 multiple system atrophy (MSA) patients compared to 13 patients with Parkinson disease (PD) and 17 healthy subjects. Four blinded radiologists classified subjects as MSA/non-MSA. Using only the LUT, high sensitivity (80%) and specificity (84%) were achieved in differentiating MSA subjects from PD subjects and controls. The LUTs generated from 12 and 30 MPG were comparable and accentuate FA abnormalities.

  5. New Non-Linear Color Look-Up Table for Visualization of Brain Fractional Anisotropy Based on Normative Measurements – Principals and First Clinical Use

    PubMed Central

    Keller, Jiří; Rulseh, Aaron M.; Komárek, Arnošt; Latnerová, Iva; Rusina, Robert; Brožová, Hana; Vymazal, Josef

    2013-01-01

    Fractional anisotropy (FA) is the most commonly used quantitative measure of diffusion in the brain. Changes in FA have been reported in many neurological disorders, but the implementation of diffusion tensor imaging (DTI) in daily clinical practice remains challenging. We propose a novel color look-up table (LUT) based on normative data as a tool for screening FA changes. FA was calculated for 76 healthy volunteers using 12 motion-probing gradient directions (MPG), a subset of 59 subjects was additionally scanned using 30 MPG. Population means and 95% prediction intervals for FA in the corpus callosum, frontal gray matter, thalamus and basal ganglia were used to create the LUT. Unique colors were assigned to inflection points with continuous ramps between them. Clinical use was demonstrated on 17 multiple system atrophy (MSA) patients compared to 13 patients with Parkinson disease (PD) and 17 healthy subjects. Four blinded radiologists classified subjects as MSA/non-MSA. Using only the LUT, high sensitivity (80%) and specificity (84%) were achieved in differentiating MSA subjects from PD subjects and controls. The LUTs generated from 12 and 30 MPG were comparable and accentuate FA abnormalities. PMID:23990954

  6. Consequences of removing the flattening filter from linear accelerators in generating high dose rate photon beams for clinical applications: A Monte Carlo study verified by measurement

    NASA Astrophysics Data System (ADS)

    Ishmael Parsai, E.; Pearson, David; Kvale, Thomas

    2007-08-01

    An Elekta SL-25 medical linear accelerator (Elekta Oncology Systems, Crawley, UK) has been modelled using Monte Carlo simulations with the photon flattening filter removed. It is hypothesized that intensity modulated radiation therapy (IMRT) treatments may be carried out after the removal of this component despite it's criticality to standard treatments. Measurements using a scanning water phantom were also performed after the flattening filter had been removed. Both simulated and measured beam profiles showed that dose on the central axis increased, with the Monte Carlo simulations showing an increase by a factor of 2.35 for 6 MV and 4.18 for 10 MV beams. A further consequence of removing the flattening filter was the softening of the photon energy spectrum leading to a steeper reduction in dose at depths greater than the depth of maximum dose. A comparison of the points at the field edge showed that dose was reduced at these points by as much as 5.8% for larger fields. In conclusion, the greater photon fluence is expected to result in shorter treatment times, while the reduction in dose outside of the treatment field is strongly suggestive of more accurate dose delivery to the target.

  7. Expression and clinical significance of the Kv3.4 potassium channel subunit in the development and progression of head and neck squamous cell carcinomas.

    PubMed

    Menéndez, Sofía Tirados; Rodrigo, Juan P; Allonca, Eva; García-Carracedo, Darío; Alvarez-Alija, Gustavo; Casado-Zapico, Sara; Fresno, Manuel F; Rodríguez, Carmen; Suárez, Carlos; García-Pedrero, Juana M

    2010-08-01

    The concept of ion channels as membrane therapeutic targets and diagnostic/prognostic biomarkers has attracted growing attention. We therefore investigated the expression pattern and clinical significance of the Kv3.4 potassium channel subunit during the development and progression of head and neck squamous cell carcinomas (HNSCCs). KCNC4 mRNA levels were determined by real-time RT-PCR in both HNSCC tissue specimens and derived cell lines. Kv3.4 protein expression was evaluated by immunohistochemistry in paraffin-embedded tissue specimens from 84 patients with laryngeal/pharyngeal squamous cell carcinomas and 67 patients with laryngeal dysplasias. Molecular alterations were correlated with clinicopathological parameters and patient outcome. Increased KCNC4 mRNA levels were found in 15 (54%) of 28 tumours, compared to the corresponding normal epithelia and varied mRNA levels were detected in 12 HNSCC-derived cell lines analysed. Increased Kv3.4 protein expression was observed in 34 (40%) of 84 carcinomas and also at early stages of HNSCC tumourigenesis. Thus, 35 (52%) of 67 laryngeal lesions displayed Kv3.4-positive staining in the dysplastic areas, whereas both stromal cells and normal adjacent epithelia exhibited negligible expression. No significant correlations were found between Kv3.4-positive expression in HNSCC and clinical data; however, Kv3.4 expression tended to diminish in advanced-stage tumours. Interestingly, patients carrying Kv3.4-positive dysplasias experienced a significantly higher laryngeal cancer incidence than did those with negative lesions (p = 0.0209). In addition, functional studies using HNSCC cells revealed that inhibition of Kv3.4 expression by siRNA leads to the inhibition of cell proliferation via selective cell cycle arrest at the G2/M phase without affecting apoptosis. Collectively, these data demonstrate for the first time that Kv3.4 expression is frequently increased during HNSCC tumourigenesis and correlated significantly with a

  8. FTLD-TDP with motor neuron disease, visuospatial impairment and a progressive supranuclear palsy-like syndrome: broadening the clinical phenotype of TDP-43 proteinopathies. A report of three cases

    PubMed Central

    2011-01-01

    Background Frontotemporal lobar degeneration with ubiquitin and TDP-43 positive neuronal inclusions represents a novel entity (FTLD-TDP) that may be associated with motor neuron disease (FTLD-MND); involvement of extrapyramidal and other systems has also been reported. Case presentation We present three cases with similar clinical symptoms, including Parkinsonism, supranuclear gaze palsy, visuospatial impairment and a behavioral variant of frontotemporal dementia, associated with either clinically possible or definite MND. Neuropathological examination revealed hallmarks of FTLD-TDP with major involvement of subcortical and, in particular, mesencephalic structures. These cases differed in onset and progression of clinical manifestations as well as distribution of histopathological changes in the brain and spinal cord. Two cases were sporadic, whereas the third case had a pathological variation in the progranulin gene 102 delC. Conclusions Association of a "progressive supranuclear palsy-like" syndrome with marked visuospatial impairment, motor neuron disease and early behavioral disturbances may represent a clinically distinct phenotype of FTLD-TDP. Our observations further support the concept that TDP-43 proteinopathies represent a spectrum of disorders, where preferential localization of pathogenetic inclusions and neuronal cell loss defines clinical phenotypes ranging from frontotemporal dementia with or without motor neuron disease, to corticobasal syndrome and to a progressive supranuclear palsy-like syndrome. PMID:21569259

  9. Phase I clinical trial of sipuleucel-T combined with escalating doses of ipilimumab in progressive metastatic castrate-resistant prostate cancer

    PubMed Central

    Scholz, Mark; Yep, Sabrina; Chancey, Micah; Kelly, Colleen; Chau, Ken; Turner, Jeffrey; Lam, Richard; Drake, Charles G

    2017-01-01

    Background Sipuleucel-T (SIP-T), which functions by stimulating cancer-specific dendritic cells, prolongs survival in men with prostate cancer. Ipilimumab (IPI) achieved a borderline survival advantage in a large randomized trial. SIP-T and IPI are potentially synergistic. Patients and Methods Nine men with progressive metastatic castrate-resistant prostate cancer (mCRPC) were treated prospectively with SIP-T followed immediately by IPI with one of the following doses of IPI: 1 mg/kg at 1 week after SIP-T; 1 mg/kg at 1 and 4 weeks after SIP-T; or 1 mg/kg at 1, 4, and 7 weeks after SIP-T. Three patients were evaluated at each level. Cancer-specific immunoglobulins directed at granulocyte-macrophage-colony-stimulating factor/prostatic acid phosphatase (PAP) fusion protein (PA2024) and PAP were measured prior to SIP-T, after SIP-T, 1 week after IPI, every other month for 5 months, then every 3 months for an additional 12 months. Results Adverse events of SIP-T were consistent with previous reports. IPI only caused a transient grade 1 rash in one patient. Median age, Gleason score, and number of previous hormonal interventions were 77 years, 8, and 3, respectively. Eight men had bone metastases and one had lymph node metastasis. Statistically significant increases in serum immunoglobulin G (IgG) and IgG-IgM specific for PA2024 and PAP occurred after SIP-T. An additional statistically significant increase in the aforementioned immunoglobulins – above the levels achieved by SIP-T – occurred after IPI. Median clinical follow-up was 36 months (range: 26–40). Three patients died from progressive disease after 9, 18, and 20 months. Out of the remaining six patients, five of them needed further treatment that included abiraterone acetate, enzalutamide, radium-223 dichloride, and spot radiation. One patient had an undetectable PSA, who did not receive any other treatment except spot radiation. Median PSA at last follow-up for the surviving patients was 3.8 (range: 0.6

  10. A critical study of different Monte Carlo scoring methods of dose average linear-energy-transfer maps calculated in voxelized geometries irradiated with clinical proton beams.

    PubMed

    Cortés-Giraldo, M A; Carabe, A

    2015-04-07

    We compare unrestricted dose average linear energy transfer (LET) maps calculated with three different Monte Carlo scoring methods in voxelized geometries irradiated with proton therapy beams with three different Monte Carlo scoring methods. Simulations were done with the Geant4 (Geometry ANd Tracking) toolkit. The first method corresponds to a step-by-step computation of LET which has been reported previously in the literature. We found that this scoring strategy is influenced by spurious high LET components, which relative contribution in the dose average LET calculations significantly increases as the voxel size becomes smaller. Dose average LET values calculated for primary protons in water with voxel size of 0.2 mm were a factor ~1.8 higher than those obtained with a size of 2.0 mm at the plateau region for a 160 MeV beam. Such high LET components are a consequence of proton steps in which the condensed-history algorithm determines an energy transfer to an electron of the material close to the maximum value, while the step length remains limited due to voxel boundary crossing. Two alternative methods were derived to overcome this problem. The second scores LET along the entire path described by each proton within the voxel. The third followed the same approach of the first method, but the LET was evaluated at each step from stopping power tables according to the proton kinetic energy value. We carried out microdosimetry calculations with the aim of deriving reference dose average LET values from microdosimetric quantities. Significant differences between the methods were reported either with pristine or spread-out Bragg peaks (SOBPs). The first method reported values systematically higher than the other two at depths proximal to SOBP by about 15% for a 5.9 cm wide SOBP and about 30% for a 11.0 cm one. At distal SOBP, the second method gave values about 15% lower than the others. Overall, we found that the third method gave the most consistent

  11. Statistical analysis of Amenamevir (ASP2151) between pharmacokinetics and clinical efficacies with non-linear effect model for the treatment of genital herpes.

    PubMed

    Takada, Akitsugu; Katashima, Masataka; Kaibara, Atsunori; Sawamoto, Taiji; Zhang, Wenhui; Keirns, James

    2014-09-01

    Amenamevir is the international non-proprietary name for ASP2151 synthesized by Astellas Pharma, Inc. It is a structurally novel class of helicase-primase inhibitor and demonstrated more potency in vitro anti-viral activity with low cytotoxicity against varicella-zoster virus (VZV), herpes simplex virus type 1 (HSV-1), and herpes simplex virus type 2 (HSV-2) than acyclovir (ACV). Phase II randomized trial assessed the safety and efficacy of ASP2151 for episodic therapy of recurrent genital herpes was conducted. Participants self-initiated with ASP2151 (100, 200, or 400 mg daily for 3 days), ASP2151 (1,200 mg as a single dose), placebo for 3 days, or Valacyclovir (500 mg twice daily for 3 days). We present a first population pharmacokinetic (PPK) modeling analysis of Amenamevir for genital herpes patients. The final model retained the effect of Weight and Albumin on CL. Statistical analysis between pharmacokinetics and clinical efficacies was done by using the time above 200 ng/mL (T200 ). T200 derived from the final PPK model to consider the correlation with Time to lesion healing and viral shedding. This finding suggested that it could be necessary to maintain the Amenamevir concentration above the threshold level to prevent the virus replication.

  12. Molecular Characterization and Clinical Implications of Spindle Cells in Nasopharyngeal Carcinoma: A Novel Molecule-Morphology Model of Tumor Progression Proposed

    PubMed Central

    Luo, Weiren; Yao, Kaitai

    2013-01-01

    Up to now, the precise molecular and morphological changes underlying the invasive and metastatic properties of nasopharyngeal carcinoma (NPC) remain largely unresolved. We speculate that neoplastic spindle cells, which are prominently found in the invasive tumor front and the surrounding stroma, might be responsible for the aggressive patterns. Expression profiling of various biomarkers relevant to cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) was performed by tissue microarray-based immunohistochemistry in NPC samples. The expression of EBER and LMP1 was detected by in situ hybridization and immunohistochemistry, respectively. We found that overexpression of CSCs-related markers (ALDH1, Nanog and ABCG2) and up-regulation of EMT markers (Fibronectin, MMP-2, Periostin, SPARC, Snail and Slug), together with E- to N-cadherin switching, occurred preferentially in tumors containing a large proportion of spindle-shaped malignant cells. Furthermore, CSCs-like properties were highly present in spindle cells compared with non-spindle cells of tumors, and correlated strongly with EMT features. In addition, EBV-related factors EBER and LMP1 were highly expressed and correlated strongly with CSCs and EMT characteristics in neoplastic spindle cells. Importantly, high proportion of spindle cells (≥20%) correlated significantly with various aggressive aspects including lymph node metastasis (P = 0.031) and local recurrence (P = 0.014). Patients with high proportion of spindle cells had poor survival (P = 0.004), though it was not an independent value. In conclusion, we demonstrate that spindle cells could be valuable morphological indicators of tumor progression and unfavorable prognosis of NPC. An integrated molecule-morphology model of NPC firstly constructed may shed significant light on the metastatic cascade and clinical relevance of patients. PMID:24349446

  13. Evaluating the Role of Corticosteroid Pulse Therapy in Patients With Secondary Progressive Multiple Sclerosis Receiving Mitoxantrone: A Double Blind Randomized Controlled Clinical Trial

    PubMed Central

    Rahimdel, Abolghasem; Zeinali, Ahmad; Mellat, Ali

    2015-01-01

    Background: Multiple sclerosis (MS) is a central nervous system disorder with periods of recurrence and recovery. Mitoxantrone has been approved for secondary progressive MS (SPMS) treatment but data lacks the role of corticosteroid pulse therapy in SPMS. Objectives: To evaluate the role of corticosteroid pulse therapy in patients with SPMS receiving mitoxantrone. Patients and Methods: A double blind randomized controlled clinical trial was performed on 71 patients with SPMS referred to Shahid Sadoughi Hospital (Yazd, Iran) for receiving mitoxantrone in two groups. The first group (35 patients) received 20 mg mitoxantrone plus 500 mg methylprednisolone monthly for six months. The second group (36 patients) received the same dosage of mitoxantrone plus 100 CC of 5% dextrose water monthly for six months. Expanded disability status scale (EDSS), MRI plaques in both groups before and after the treatment completion and six months after the end of trial were compared together. Results: 28 men and 43 women enrolled in the study. MRI plaques number reduced in groups significantly (2.29 vs. 2.17) without significant difference between the groups (P = 0.782). Six months after trial completion, plaques number increased in groups without significantly difference (0.72 vs. 0.77, P = 0.611). The mean value of EDSS showed significant reduction at the end of treatment in groups (0.79 and 0.53) without significant difference between the groups (P = 0.953). Six months after trial completion, EDSS increased in groups without significant difference (0.35 vs. 0.43, P = 0.624). Conclusions: Corticosteroid pulse therapy in SPMS was effective in inflammatory process, but could not postpone or decline the neurodegenerative process and besides the imposing side effects could not result in significant improvement in EDSS and MRI plaques number in long term. PMID:26566454

  14. Evaluation of the expression of stem cell markers in human breast cancer reveals a correlation with clinical progression and metastatic disease in ductal carcinoma.

    PubMed

    Martin, Tracey Amanda; Jiang, Wen Guo

    2014-01-01

    The tumor stem cell theory could explain how patients with metastatic disease show clinical relapse several months after starting treatment due to the survival of a small group of cells with unique characteristics. We examined the distribution and expression of a panel of stem cell markers in human breast cancer primary tumors. Human breast tissues were processed for immunohistochemistry, and RNA was extracted for analysis by quantitative-PCR. Immunohistochemical assay revealed that CD44 was strongly expressed in background endothelia and epithelia. CD133 expression was lost in tumor-associated endothelial cells. Conversely, CD49b was strongly stained in the tumors, associated vessels and ducts but was weakly stained in the background epithelia. q-PCR analysis revealed that CD44 and PSCA were reduced in patients with poor outcome (metastatic disease and death from breast cancer), with a marked reduction in ductal carcinoma, particularly with metastasis to bone although these did not reach significant difference. CD133 was significantly reduced in patients with metastatic disease and was also significantly reduced in patients with ductal carcinoma/bone metastasis. Conversely, CD49F was increased in patients with a poor outcome and those with ductal cancer and bone metastases. This is the first study to determine the distribution and expression pattern of these stem cell markers in human breast cancer. There was a significant association between loss of expression and metastatic disease in patients with breast cancer. Such differential expression may play a part in breast cancer disease progression, and suggests that the current stem cell theory may not hold true for all cancer types.

  15. The accuracy of linear measurements of maxillary and mandibular edentulous sites in cone-beam computed tomography images with different fields of view and voxel sizes under simulated clinical conditions

    PubMed Central

    Ramesh, Aruna; Pagni, Sarah

    2016-01-01

    Purpose The objective of this study was to investigate the effect of varying resolutions of cone-beam computed tomography images on the accuracy of linear measurements of edentulous areas in human cadaver heads. Intact cadaver heads were used to simulate a clinical situation. Materials and Methods Fiduciary markers were placed in the edentulous areas of 4 intact embalmed cadaver heads. The heads were scanned with two different CBCT units using a large field of view (13 cm×16 cm) and small field of view (5 cm×8 cm) at varying voxel sizes (0.3 mm, 0.2 mm, and 0.16 mm). The ground truth was established with digital caliper measurements. The imaging measurements were then compared with caliper measurements to determine accuracy. Results The Wilcoxon signed rank test revealed no statistically significant difference between the medians of the physical measurements obtained with calipers and the medians of the CBCT measurements. A comparison of accuracy among the different imaging protocols revealed no significant differences as determined by the Friedman test. The intraclass correlation coefficient was 0.961, indicating excellent reproducibility. Inter-observer variability was determined graphically with a Bland-Altman plot and by calculating the intraclass correlation coefficient. The Bland-Altman plot indicated very good reproducibility for smaller measurements but larger discrepancies with larger measurements. Conclusion The CBCT-based linear measurements in the edentulous sites using different voxel sizes and FOVs are accurate compared with the direct caliper measurements of these sites. Higher resolution CBCT images with smaller voxel size did not result in greater accuracy of the linear measurements. PMID:27358816

  16. Liver fibrosis progression and clinical outcomes are intertwined: role of CD4+ T-cell count and NRTI exposure from a large cohort of HIV/HCV-coinfected patients with detectable HCV-RNA

    PubMed Central

    Focà, Emanuele; Fabbiani, Massimiliano; Prosperi, Mattia; Quiros Roldan, Eugenia; Castelli, Francesco; Maggiolo, Franco; Di Filippo, Elisa; Di Giambenedetto, Simona; Gagliardini, Roberta; Saracino, Annalisa; Di Pietro, Massimo; Gori, Andrea; Sighinolfi, Laura; Pan, Angelo; Postorino, Maria Concetta; Torti, Carlo

    2016-01-01

    Abstract Introduction: Patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) suffer from faster progression of liver fibrosis (LF) and have greater risk of worse clinical outcomes. We evaluated predictors and incidence of these events in a large multicentre cohort. Methods: We selected all HIV-infected patients starting a first-line combination antiretroviral therapy (cART), with detectable HCV-RNA, without exposure to interferon/ribavirin, with ≥2 fibrosis-4 index (FIB-4) classifications before cART. Kaplan–Meier analysis was used to estimate incidence of clinical events (AIDS, non-AIDS related, deaths) and LF progression (via transitions: from FIB-4 class 1 to 2 or 3, from class 2 to class 3, and worsening by 0.5 point). Multivariate Cox regression was used to assess predictors, baseline, or time updated. Results: One thousand four hundred thirty-three patients were selected. Overall, 745 clinical events occurred, with an incidence of 7.6% over 9811 person-year of follow-up (PYFU) and a median survival time of 9.36 years. Incidence of LF progression from FIB-4 class 1 to 2 or 3 was 12.4%, and from FIB-4 class 2 to 3 was 7% with a median survival time of 5.67 and 10.35 years, respectively. At multivariate analyses, intravenous drug use and time-updated gamma-glutamyl transferase (γGT) were negative predictors for any outcomes, either clinical or FIB-4 progression. Higher CD4+ T-cell protected from clinical events, and lower HIV-RNA and higher CD4+ T-cell appeared to protect from FIB-4 transitions. Moreover, independently from the viro-immunological status, current FIB-4 class 3 predicted clinical events. Occurrence of AIDS and cardiovascular/kidney events were significant predictors of 0.5 point worsening and transitions of FIB-4, respectively. Prolonged exposure to nucleos(t)ide reverse transcriptase inhibitors (NRTI) was a negative predictor for any outcomes. Conclusion: Both clinical and LF progression in HIV

  17. [Recent progress and challenges in investigator-driven clinical development of novel drugs and medical devices at the University of Tokyo Hospital].

    PubMed

    Arakawa, Yoshihiro

    2013-01-01

    At the University of Tokyo Hospital, investigator-driven clinical development of novel drugs and medical devices is mainly supported by the Translational Research Center and Clinical Research Support Center. The former supports non-clinical research and the preparation of test materials and the latter supports clinical trials. The Clinical Research Support Center was established in 2010 by the reorganization of the former Clinical Research Center, which was established in 2001. The center adopted International Conference on Harmonisation-Good Clinical Practice (ICH-GCP) as a standard guideline for clinical trials and prepared standard operation procedures and templates for protocols and informed consent documents in 2001 and, thereafter, provided consultation services to researchers for protocol development. In 2010, the service was extended to project management, data management and monitoring to support the credibility of clinical trials. In 2011, The University of Tokyo Hospital was selected by the government as a base for the early and exploratory clinical development of drugs in the fields of psychological and neurological diseases. For this purpose, a phase 1 unit for early phase clinical pharmacology trials is now being built. The center provides training courses for clinical research coordinators and hold seminars for clinical researchers; however, the biggest challenge remains the education and training of medical students who will lead clinical trials in the future.

  18. [Linear lichen planopilaris of the face].

    PubMed

    Cañadas, Nadia G; Luna, Paula C; Etcheverry, Mauro D; Nocito, Mabel J; Castellanos Posse, Maria L; Marchesi, Carolina; Garuti, Romina A; Carmona Cuello, Lucía E; Carabajal, Graciela; Mazzini, Miguel A

    2010-07-15

    Linear lichen planopilaris of the face is a rare variant of lichen plano- pilaris. Asymptomatic follicular papules in a linear configuration are the characteristic clinical features. The incidence is still unknown, but there are a few cases reported exclusively in male adults. We present the case of a fourteen-year-old girl with linear lichen planopilaris of the face. Improvement was obtained with the use of tacrolimus 0.03 percent ointment.

  19. Placing clinical variables on a common linear scale of empirically based risk as a step towards construction of a general patient acuity score from the electronic health record: a modelling study

    PubMed Central

    Rothman, Steven I; Rothman, Michael J; Solinger, Alan B

    2013-01-01

    Objective To explore the hypothesis that placing clinical variables of differing metrics on a common linear scale of all-cause postdischarge mortality provides risk functions that are directly correlated with in-hospital mortality risk. Design Modelling study. Setting An 805-bed community hospital in the southeastern USA. Participants 42302 inpatients admitted for any reason, excluding obstetrics, paediatric and psychiatric patients. Outcome measures All-cause in-hospital and postdischarge mortalities, and associated correlations. Results Pearson correlation coefficients comparing in-hospital risks with postdischarge risks for creatinine, heart rate and a set of 12 nursing assessments are 0.920, 0.922 and 0.892, respectively. Correlation between postdischarge risk heart rate and the Modified Early Warning System (MEWS) component for heart rate is 0.855. The minimal excess risk values for creatinine and heart rate roughly correspond to the normal reference ranges. We also provide the risks for values outside that range, independent of expert opinion or a regression model. By summing risk functions, a first-approximation patient risk score is created, which correctly ranks 6 discharge categories by average mortality with p<0.001 for differences in category means, and Tukey's Honestly Significant Difference Test confirmed that the means were all different at the 95% confidence level. Conclusions Quantitative or categorical clinical variables can be transformed into risk functions that correlate well with in-hospital risk. This methodology provides an empirical way to assess inpatient risk from data available in the Electronic Health Record. With just the variables in this paper, we achieve a risk score that correlates with discharge disposition. This is the first step towards creation of a universal measure of patient condition that reflects a generally applicable set of health-related risks. More importantly, we believe that our approach opens the door to a way of

  20. Genomic Analyses of Breast Cancer Progression Reveal Distinct Routes of Metastasis Emergence

    PubMed Central

    Krøigård, Anne Bruun; Larsen, Martin Jakob; Brasch-Andersen, Charlotte; Lænkholm, Anne-Vibeke; Knoop, Ann S.; Jensen, Jeanette Dupont; Bak, Martin; Mollenhauer, Jan; Thomassen, Mads; Kruse, Torben A.

    2017-01-01

    A main controversy in cancer research is whether metastatic abilities are present in the most advanced clone of the primary tumor or result from independently acquired aberrations in early disseminated cancer cells as suggested by the linear and the parallel progression models, respectively. The genetic concordance between different steps of malignant progression is mostly unexplored as very few studies have included cancer samples separated by both space and time. We applied whole exome sequencing and targeted deep sequencing to 26 successive samples from six patients with metastatic estrogen receptor (ER)-positive breast cancer. Our data provide support for both linear and parallel progression towards metastasis. We report for the first time evidence of metastasis-to-metastasis seeding in breast cancer. Our results point to three distinct routes of metastasis emergence. This may have profound clinical implications and provides substantial novel molecular insights into the timing and mutational evolution of breast cancer metastasis. PMID:28276460

  1. Progressive hemifacial atrophy

    PubMed Central

    Sande, Abhijeet; Risbud, Mukund; Kshar, Avinash; Paranjpe, Arati Oka

    2013-01-01

    Progressive hemifacial atrophy, also known as Parry-Romberg Syndrome, is an uncommon degenerative and poorly understood condition. It is characterized by a slow and progressive but self-limited atrophy affecting one side of the face. The incidence and the cause of this alteration are unknown. A cerebral disturbance of fat metabolism has been proposed as a primary cause. Possible factors that are involved in the pathogenesis include trauma, viral infections, heredity, endocrine disturbances and auto-immunity. The most common complications that appear in association to this disorder are: trigeminal neuralgia, facial paresthesia, severe headache and epilepsy. Characteristically, the atrophy progresses slowly for several years and, it becomes stable. The objective of this work is, through the presentation of a clinical case, to accomplish a literature review concerning general characteristics, etiology, physiopathology and treatment of progressive hemifacial atrophy. PMID:23878573

  2. Linear integrated circuits

    NASA Astrophysics Data System (ADS)

    Young, T.

    This book is intended to be used as a textbook in a one-semester course at a variety of levels. Because of self-study features incorporated, it may also be used by practicing electronic engineers as a formal and thorough introduction to the subject. The distinction between linear and digital integrated circuits is discussed, taking into account digital and linear signal characteristics, linear and digital integrated circuit characteristics, the definitions for linear and digital circuits, applications of digital and linear integrated circuits, aspects of fabrication, packaging, and classification and numbering. Operational amplifiers are considered along with linear integrated circuit (LIC) power requirements and power supplies, voltage and current regulators, linear amplifiers, linear integrated circuit oscillators, wave-shaping circuits, active filters, DA and AD converters, demodulators, comparators, instrument amplifiers, current difference amplifiers, analog circuits and devices, and aspects of troubleshooting.

  3. A linear programming manual

    NASA Technical Reports Server (NTRS)

    Tuey, R. C.

    1972-01-01

    Computer solutions of linear programming problems are outlined. Information covers vector spaces, convex sets, and matrix algebra elements for solving simultaneous linear equations. Dual problems, reduced cost analysis, ranges, and error analysis are illustrated.

  4. Linear Accelerator (LINAC)

    MedlinePlus

    ... equipment? How is safety ensured? What is this equipment used for? A linear accelerator (LINAC) is the ... Therapy (SBRT) . top of page How does the equipment work? The linear accelerator uses microwave technology (similar ...

  5. IR Linearity Monitor

    NASA Astrophysics Data System (ADS)

    Hilbert, Bryan

    2012-10-01

    These observations will be used to monitor the signal non-linearity of the IR channel, as well as to update the IR channel non-linearity calibration reference file. The non-linearity behavior of each pixel in the detector will be investigated through the use of full frame and subarray flat fields, while the photometric behavior of point sources will be studied using observations of 47 Tuc. This is a continuation of the Cycle 19 non-linearity monitor, program 12696.

  6. IR linearity monitor

    NASA Astrophysics Data System (ADS)

    Hilbert, Bryan

    2013-10-01

    These observations will be used to monitor the signal non-linearity of the IR channel, as well as to update the IR channel non-linearity calibration reference file. The non-linearity behavior of each pixel in the detector will be investigated through the use of full frame and subarray flat fields, while the photometric behavior of point sources will be studied using observations of 47 Tuc. This is a continuation of the Cycle 20 non-linearity monitor, program 13079.

  7. Effect of Sitagliptin and Metformin on Prediabetes Progression to Type 2 Diabetes - A Randomized, Double-Blind, Double-Arm, Multicenter Clinical Trial: Protocol for the Sitagliptin and Metformin in PreDiabetes (SiMePreD) Study

    PubMed Central

    2016-01-01

    Background The high prevalence and incidence of type 2 diabetes mellitus (DM), and its associated morbidity and mortality, has prompted growing international interest and effort in the primary prevention of this disease. Primary prevention is possible since type 2 DM is preceded by prediabetes, offering a window opportunity to treat patients, and prevent the emergence of advanced disease. Sitagliptin is an oral dipeptidyl peptidase-IV inhibitor that preserves existing beta cell function and increases beta cell mass. These two effects have been demonstrated both in vitro and in animal studies, and current clinical data show that sitagliptin is safe. Metformin, a biguanide, reduces insulin resistance and inhibits hepatic gluconeogenesis, and has an excellent safety profile. The combination of metformin and sitagliptin, targeting both characteristics of prediabetes (insulin resistance and progressive beta cell degeneration), may potentially slow or halt the progression from prediabetes to type 2 DM. This paper describes the rationale and design of the Sitagliptin and Metformin in PreDiabetes (SiMePreD) study. Objective The aim of this study is to determine the effect of sitagliptin and metformin on progression from prediabetes to type 2 DM. The objectives of the study are to determine the effects of metformin and placebo on glycemic endpoints, the effects of sitagliptin and metformin on glycemic endpoints, the effects of metformin and placebo on incidence of cardiovascular disease and death, and the effects of sitagliptin and metformin on incidence of cardiovascular disease and death. Methods This is a randomized, double-blind, multicenter clinical study that will determine if the combination of metformin and sitagliptin is effective in preventing the progression from prediabetes to type 2 DM. The study will contain two arms (metformin/sitagliptin and metformin/placebo). Primary endpoints include the number of subjects progressing from prediabetes to type 2 DM, the

  8. Linear-Algebra Programs

    NASA Technical Reports Server (NTRS)

    Lawson, C. L.; Krogh, F. T.; Gold, S. S.; Kincaid, D. R.; Sullivan, J.; Williams, E.; Hanson, R. J.; Haskell, K.; Dongarra, J.; Moler, C. B.

    1982-01-01

    The Basic Linear Algebra Subprograms (BLAS) library is a collection of 38 FORTRAN-callable routines for performing basic operations of numerical linear algebra. BLAS library is portable and efficient source of basic operations for designers of programs involving linear algebriac computations. BLAS library is supplied in portable FORTRAN and Assembler code versions for IBM 370, UNIVAC 1100 and CDC 6000 series computers.

  9. A boosted optimal linear learner for retinal vessel segmentation

    NASA Astrophysics Data System (ADS)

    Poletti, E.; Grisan, E.

    2014-03-01

    Ocular fundus images provide important information about retinal degeneration, which may be related to acute pathologies or to early signs of systemic diseases. An automatic and quantitative assessment of vessel morphological features, such as diameters and tortuosity, can improve clinical diagnosis and evaluation of retinopathy. At variance with available methods, we propose a data-driven approach, in which the system learns a set of optimal discriminative convolution kernels (linear learner). The set is progressively built based on an ADA-boost sample weighting scheme, providing seamless integration between linear learner estimation and classification. In order to capture the vessel appearance changes at different scales, the kernels are estimated on a pyramidal decomposition of the training samples. The set is employed as a rotating bank of matched filters, whose response is used by the boosted linear classifier to provide a classification of each image pixel into the two classes of interest (vessel/background). We tested the approach fundus images available from the DRIVE dataset. We show that the segmentation performance yields an accuracy of 0.94.

  10. Non-progressive juvenile spinal muscular atrophy of the distal upper limb (Hirayama's disease): a clinical variant of the benign monomelic amyotrophy.

    PubMed

    Nascimento, O J; Freitas, M R

    2000-09-01

    Hirayama's disease (HD) is frequently found in Asia, and is rarely referred among westerners. It affects young people with higher incidence in males. It is a focal distal amyotrophy with unilateral or asymmetric bilateral involvement of C7, C8 and T1 innervated muscles. HD appears sporadically and has a benign evolution with clinical stabilization in around one year. We report four young male patients with clinical and electrophysiological alterations described in HD, which were followed-up during 5 years. Electromyographic findings were indicative of lower motor neuron involvement. We analyzed cervical MRI aiming at understanding if a questionable spinal cord compression could be implicated in the pathogenesis, but no abnormality was verified. In view of its clinical, and EMG characteristics, HD is no more than a benign monomelic amyotrophy (BMA) clinical variant, and not a specific disease. This eponym could be considered only for the distal upper limb variant (Hirayama's variant) of the BMA.

  11. Towards a Future Linear Collider and The Linear Collider Studies at CERN

    ScienceCinema

    None

    2016-07-12

    During the week 18-22 October, more than 400 physicists will meet at CERN and in the CICG (International Conference Centre Geneva) to review the global progress towards a future linear collider. The 2010 International Workshop on Linear Colliders will study the physics, detectors and accelerator complex of a linear collider covering both the CLIC and ILC options. Among the topics presented and discussed will be the progress towards the CLIC Conceptual Design Report in 2011, the ILC Technical Design Report in 2012, physics and detector studies linked to these reports, and an increasing numbers of common working group activities. The seminar will give an overview of these topics and also CERN’s linear collider studies, focusing on current activities and initial plans for the period 2011-16. n.b: The Council Chamber is also reserved for this colloquium with a live transmission from the Main Auditorium.

  12. The mutation p.Ser298Pro in the sulphamidase gene (SGSH) is associated with a slowly progressive clinical phenotype in mucopolysaccharidosis type IIIA (Sanfilippo A syndrome).

    PubMed

    Meyer, Ann; Kossow, Kai; Gal, Andreas; Steglich, Cordula; Mühlhausen, Chris; Ullrich, Kurt; Braulke, Thomas; Muschol, Nicole

    2008-05-01

    Mucopolysaccharidosis type IIIA (MPS IIIA, Sanfilippo A syndrome) is caused by mutations in the N-sulfoglucosamine sulfohydrolase (SGSH) gene and the resulting defective lysosomal degradation of the glycosaminoglycan heparan sulfate. The onset and progression of the disease are highly variable. Seventy-five mutations distributed over the SGSH gene have been described. We here report on the analysis of the natural course of the disease in 54 MPS IIIA patients through the use of a detailed questionnaire and four-point scoring system and an examination of the underlying mutations. By assessing the degree of developmental regression over time a group of seven patients with a slowly progressive course of the disease were identified. In these seven patients and in 3 other mildly affected patients the missense mutation c.892T>C (p.Ser298Pro) was found on one allele. These patients showed a lower frequency and later onset of the typical symptoms of the disease. The onset of regression in speech abilities and cognitive functions were delayed by 0.7 and 0.8 years, respectively, and the onset of regression of motor functions occurred 6.1 years later than in all other MPS IIIA patients. Severe regression in speech, cognitive and motor functions were delayed by 5, 5.9, and 11.2 years, respectively. These data suggest that in MPS IIIA patients carrying the mutation p.Ser298Pro a slowly progressive phenotype can be predicted and this may have an important impact on parental counselling and therapeutic interventions.

  13. Disease Severity and Progression in Progressive Supranuclear Palsy and Multiple System Atrophy: Validation of the NNIPPS – PARKINSON PLUS SCALE

    PubMed Central

    Payan, Christine A. M.; Viallet, François; Landwehrmeyer, Bernhard G.; Bonnet, Anne-Marie; Borg, Michel; Durif, Franck; Lacomblez, Lucette; Bloch, Frédéric; Verny, Marc; Fermanian, Jacques; Agid, Yves; Ludolph, Albert C.

    2011-01-01

    Background The Natural History and Neuroprotection in Parkinson Plus Syndromes (NNIPPS) study was a large phase III randomized placebo-controlled trial of riluzole in Progressive Supranuclear Palsy (PSP, n = 362) and Multiple System Atrophy (MSA, n = 398). To assess disease severity and progression, we constructed and validated a new clinical rating scale as an ancillary study. Methods and Findings Patients were assessed at entry and 6-montly for up to 3 years. Evaluation of the scale's psychometric properties included reliability (n = 116), validity (n = 760), and responsiveness (n = 642). Among the 85 items of the initial scale, factor analysis revealed 83 items contributing to 15 clinically relevant dimensions, including Activity of daily Living/Mobility, Axial bradykinesia, Limb bradykinesia, Rigidity, Oculomotor, Cerebellar, Bulbar/Pseudo-bulbar, Mental, Orthostatic, Urinary, Limb dystonia, Axial dystonia, Pyramidal, Myoclonus and Tremor. All but the Pyramidal dimension demonstrated good internal consistency (Cronbach α≥0.70). Inter-rater reliability was high for the total score (Intra-class coefficient = 0.94) and 9 dimensions (Intra-class coefficient = 0.80–0.93), and moderate (Intra-class coefficient = 0.54–0.77) for 6. Correlations of the total score with other clinical measures of severity were good (rho≥0.70). The total score was significantly and linearly related to survival (p<0.0001). Responsiveness expressed as the Standardized Response Mean was high for the total score slope of change (SRM = 1.10), though higher in PSP (SRM = 1.25) than in MSA (SRM = 1.0), indicating a more rapid progression of PSP. The slope of change was constant with increasing disease severity demonstrating good linearity of the scale throughout disease stages. Although MSA and PSP differed quantitatively on the total score at entry and on rate of progression, the relative contribution of clinical dimensions to overall

  14. Progressive Return to Activity Following Acute Concussion/Mild Traumatic Brain Injury: Guidance for the Primary Care Manager in Deployed and Non-deployed Settings (Clinical Support Tool)

    DTIC Science & Technology

    2014-01-01

    rehabilitation provider for daily m onitored progressive return to activity process J • Rem ain in Stage 1 - Rest B • Provide sym ptom m anagem ent...m ild) on NSI) NoYes No Yes Yes No • Rem ain at Stage 1 - Rest B • Provide sym ptom m anagem ent • Provide follow -up guidance E • Refer to... Sleep issues D. Exertional Testing • Exert to 65-85% of target heart rate (THR=220-age) using push-ups, sit-ups, running in place, step aerobics

  15. Siblings with the adult-onset slowly progressive type of pantothenate kinase-associated neurodegeneration and a novel mutation, Ile346Ser, in PANK2: clinical features and (99m)Tc-ECD brain perfusion SPECT findings.

    PubMed

    Doi, Hiroshi; Koyano, Shigeru; Miyatake, Satoko; Matsumoto, Naomichi; Kameda, Tomoaki; Tomita, Atsuko; Miyaji, Yosuke; Suzuki, Yume; Sawaishi, Yukio; Kuroiwa, Yoshiyuki

    2010-03-15

    Pantothenate kinase-associated neurodegeneration (PKAN), formerly known as Hallervorden-Spatz syndrome (HSS), is an autosomal recessive neurodegenerative disorder characterized by iron accumulation in the brain. Mutations in the pantothenate kinase 2 (PANK2) gene are known to be responsible for PKAN. Several studies have revealed correlations between clinical phenotypes and particular PANK2 mutations. The adult-onset slowly progressive type of PKAN with PANK2 mutations is very rare. In this report, we describe siblings with the adult-onset slowly progressive type of PKAN with a novel mutation, Ile346Ser, in PANK2. The siblings had the same mutation in PANK2 and had common clinical signs such as misalignment of teeth, a high arched palate, hollow feet, a slight cognitive decline, and an apparent executive dysfunction, although they showed different patterns of movement disorders. Thus, even if PKAN patients have identical mutations, it is likely that they will present with different types of movement disorders. Brain perfusion single photon emission computed tomography in both patients showed decreased regional cerebral blood flow in the bilateral frontoparietal lobes, the globus pallidus, the striatum, and around the ventriculus quartus. Cardiac uptake of [(123)I] meta-iodobenzylguanidine was normal in both patients. Analysis of genotype-phenotype correlations and the elucidation of mutational effects on pantothenate kinase 2 function, expression, and structure are important for understanding the mechanisms of PKAN.

  16. Linear collider: a preview

    SciTech Connect

    Wiedemann, H.

    1981-11-01

    Since no linear colliders have been built yet it is difficult to know at what energy the linear cost scaling of linear colliders drops below the quadratic scaling of storage rings. There is, however, no doubt that a linear collider facility for a center of mass energy above say 500 GeV is significantly cheaper than an equivalent storage ring. In order to make the linear collider principle feasible at very high energies a number of problems have to be solved. There are two kinds of problems: one which is related to the feasibility of the principle and the other kind of problems is associated with minimizing the cost of constructing and operating such a facility. This lecture series describes the problems and possible solutions. Since the real test of a principle requires the construction of a prototype I will in the last chapter describe the SLC project at the Stanford Linear Accelerator Center.

  17. Encouraging Early Clinical Outcomes With Helical Tomotherapy-Based Image-Guided Intensity-Modulated Radiation Therapy for Residual, Recurrent, and/or Progressive Benign/Low-Grade Intracranial Tumors: A Comprehensive Evaluation

    SciTech Connect

    Gupta, Tejpal

    2012-02-01

    Purpose: To report early clinical outcomes of helical tomotherapy (HT)-based image-guided intensity-modulated radiation therapy (IMRT) in brain tumors of varying shape, size, and location. Materials and Methods: Patients with residual, recurrent, and/or progressive low-grade intracranial and skull-base tumors were treated on a prospective protocol of HT-based IMRT and followed clinicoradiologically. Standardized metrics were used for plan evaluation and outcome analysis. Results: Twenty-seven patients with 30 lesions were treated to a median radiotherapy dose of 54 Gy in 30 fractions. All HT plans resulted in excellent target volume coverage with steep dose-gradients. The mean (standard deviation) dose homogeneity index and conformity index was 0.07 (0.05) and 0.71 (0.08) respectively. At first response assessment, 20 of 30 lesions were stable, whereas 9 showed partial regression. One patient with a recurrent clival chordoma though neurologically stable showed imaging-defined progression, whereas another patient with stable disease on serial imaging had sustained neurologic worsening. With a median follow-up of 19 months (interquartile range, 11-26 months), the 2-year clinicoradiological progression-free survival and overall survival was 93.3% and 100% respectively. Conclusions: Careful selection of radiotherapy technique is warranted for benign/low-grade brain tumors to achieve durable local control with minimum long-term morbidity. Large or complex-shaped tumors benefit most from IMRT. Our early clinical experience of HT-based IMRT for brain tumors has been encouraging.

  18. Linear mass actuator

    NASA Technical Reports Server (NTRS)

    Holloway, Sidney E., III (Inventor); Crossley, Edward A., Jr. (Inventor); Jones, Irby W. (Inventor); Miller, James B. (Inventor); Davis, C. Calvin (Inventor); Behun, Vaughn D. (Inventor); Goodrich, Lewis R., Sr. (Inventor)

    1992-01-01

    A linear mass actuator includes an upper housing and a lower housing connectable to each other and having a central passageway passing axially through a mass that is linearly movable in the central passageway. Rollers mounted in the upper and lower housings in frictional engagement with the mass translate the mass linearly in the central passageway and drive motors operatively coupled to the roller means, for rotating the rollers and driving the mass axially in the central passageway.

  19. Longitudinal Use of a Line Probe Assay for Human Immunodeficiency Virus Type 1 Protease Predicts Phenotypic Resistance and Clinical Progression in Patients Failing Highly Active Antiretroviral Therapy

    PubMed Central

    Servais, Jean; Lambert, Christine; Plesséria, Jean-Marc; Fontaine, Elodie; Robert, Isabelle; Arendt, Vic; Staub, Thérèse; Hemmer, Robert; Schneider, François; Schmit, Jean-Claude

    2002-01-01

    An observational study assessed the longitudinal use of a new line probe assay for the detection of protease mutations. Probe assays for detection of reverse transcriptase (Inno-LiPA HIV-1 RT; Innogenetics) and protease (prototype kit Inno-LiPA HIV Protease; Innogenetics) mutations gave results for 177 of 199 sequential samples collected over 2 years from 26 patients failing two nucleoside reverse transcriptase inhibitors and one protease inhibitor (first line: indinavir, n = 6; ritonavir, n = 10; and saquinavir, n = 10). Results were compared to recombinant virus protease inhibitor susceptibility data (n = 87) and to clinical and virological data. Combinations of protease mutations (M46I, G48V, I54V, V82A or -F, I84V, and L90M) predicted phenotypic resistance to the protease inhibitor and to nelfinavir. The sum of protease mutations was associated with virological and clinical outcomes from 6 and 3 months on, respectively. Moreover, a poorer clinical outcome was linked to the sum of reverse transcriptase mutations. In conclusion, despite the limited number of patients studied and the restricted number of codons investigated, probe assay-based genotyping correlates with phenotypic drug resistance and predicts new Centers for Disease Control and Prevention stage B and C clinical events and virological outcome. Line probe assays provide additional prognostic information and should be prospectively investigated for their potential for treatment monitoring. PMID:12019110

  20. THE FIRST GRADE CLINIC--A MEDIUM FOR EARLY IDENTIFICATION OF PHYSICAL, SOCIAL, EMOTIONAL, AND MENTAL DEVELOPMENT FACTOR THAT MAY TEND TO BLOCK OR IMPEDE SCHOOL PROGRESS.

    ERIC Educational Resources Information Center

    MCGAHAN, F.E.

    DURING A 5-YEAR PERIOD, A FIRST GRADE CLINIC IDENTIFIED, AT THE START OF EACH SCHOOL YEAR, CHILDREN WITH DEVIATIONS IN BEHAVIOR, SOCIAL AND EMOTIONAL ADJUSTMENT, AND MENTAL MATURATION THAT MIGHT BLOCK OR RETARD SUCCESS IN SCHOOL. THESE CHILDREN WERE REFERRED FOR FURTHER DIAGNOSTIC EVALUATIONS. THE PROGRAM WAS FIRST TRIED IN ONE CLASSROOM. A 3-YEAR…

  1. Do Raven's Colored Progressive Matrices Function in the Same Way in Typical and Clinical Populations? Insights from the Intellectual Disability Field

    ERIC Educational Resources Information Center

    Facon, Bruno; Magis, David; Nuchadee, Marie-Laure; De Boeck, Paul

    2011-01-01

    Standardized tests are used widely in comparative studies of clinical populations, either as dependent or control variables. Yet, one cannot always be sure that the test items measure the same constructs in the groups under study. In the present work, 460 participants with intellectual disability of undifferentiated etiology and 488 typical…

  2. Fault tolerant linear actuator

    DOEpatents

    Tesar, Delbert

    2004-09-14

    In varying embodiments, the fault tolerant linear actuator of the present invention is a new and improved linear actuator with fault tolerance and positional control that may incorporate velocity summing, force summing, or a combination of the two. In one embodiment, the invention offers a velocity summing arrangement with a differential gear between two prime movers driving a cage, which then drives a linear spindle screw transmission. Other embodiments feature two prime movers driving separate linear spindle screw transmissions, one internal and one external, in a totally concentric and compact integrated module.

  3. Linear phase compressive filter

    DOEpatents

    McEwan, Thomas E.

    1995-01-01

    A phase linear filter for soliton suppression is in the form of a laddered series of stages of non-commensurate low pass filters with each low pass filter having a series coupled inductance (L) and a reverse biased, voltage dependent varactor diode, to ground which acts as a variable capacitance (C). L and C values are set to levels which correspond to a linear or conventional phase linear filter. Inductance is mapped directly from that of an equivalent nonlinear transmission line and capacitance is mapped from the linear case using a large signal equivalent of a nonlinear transmission line.

  4. Linear phase compressive filter

    DOEpatents

    McEwan, T.E.

    1995-06-06

    A phase linear filter for soliton suppression is in the form of a laddered series of stages of non-commensurate low pass filters with each low pass filter having a series coupled inductance (L) and a reverse biased, voltage dependent varactor diode, to ground which acts as a variable capacitance (C). L and C values are set to levels which correspond to a linear or conventional phase linear filter. Inductance is mapped directly from that of an equivalent nonlinear transmission line and capacitance is mapped from the linear case using a large signal equivalent of a nonlinear transmission line. 2 figs.

  5. Recombineering linear BACs.

    PubMed

    Chen, Qingwen; Narayanan, Kumaran

    2015-01-01

    Recombineering is a powerful genetic engineering technique based on homologous recombination that can be used to accurately modify DNA independent of its sequence or size. One novel application of recombineering is the assembly of linear BACs in E. coli that can replicate autonomously as linear plasmids. A circular BAC is inserted with a short telomeric sequence from phage N15, which is subsequently cut and rejoined by the phage protelomerase enzyme to generate a linear BAC with terminal hairpin telomeres. Telomere-capped linear BACs are protected against exonuclease attack both in vitro and in vivo in E. coli cells and can replicate stably. Here we describe step-by-step protocols to linearize any BAC clone by recombineering, including inserting and screening for presence of the N15 telomeric sequence, linearizing BACs in vivo in E. coli, extracting linear BACs, and verifying the presence of hairpin telomere structures. Linear BACs may be useful for functional expression of genomic loci in cells, maintenance of linear viral genomes in their natural conformation, and for constructing innovative artificial chromosome structures for applications in mammalian and plant cells.

  6. Clinical progression in Charcot-Marie-Tooth disease type 1A duplication: clinico-electrophysiological and MRI longitudinal study of a family.

    PubMed

    Berciano, José; Gallardo, Elena; García, Antonio; Ramón, César; Infante, Jon; Combarros, Onofre

    2010-10-01

    Long-term follow-up studies in Charcot-Marie-Tooth disease type 1 duplication (CMT1A) are scanty. Here we describe a longitudinal study in a CMT1A pedigree. Our CMT1A pedigree comprised 11 examined patients, ages between 13 and 83 (median, 36) years, serially evaluated for up to 26 years. In all 11 patients we carried out electrophysiological evaluation, and in three of them magnetic resonance imaging (MRI) of lower-limb musculature. The 54-year-old proband patient, yearly examined as of age 28, developed at age 48 gradual and progressive distal lower-leg weakness ascending to thigh musculature. His serial electrophysiological studies showed diffuse slowing of motor conduction velocity, absence or severe attenuation of distal compound muscle action potentials, and spontaneous muscle activity in the tibialis anterior and rectus femoris. Two MRI studies of lower limbs, at ages 51 and 54, showed extensive fatty atrophy of lower-leg musculature, and progressive and distally accentuated fatty atrophy of anterior and posterior femoral muscles. An outstanding finding in the first MRI was the presence of marked edema of anterior femoral musculature, which to a great degree was replaced by fatty atrophy in the second study. Muscle edema was also noted in lower-leg and posterior femoral musculature. There was minimal fatty atrophy of the gluteus maximus, the remaining pelvic muscles being preserved. The other ten patients showed mild or moderate phenotype, which remained quiescent over the period of observation. Electrophysiological studies disclosed diffuse and uniform slowing of nerve conduction velocities; in no case was spontaneous muscle activity recorded. MRI showed the CMT1A characteristic pattern of distally accentuated fatty atrophy involving foot and lower-leg musculature with preservation of thigh musculature. We conclude that a small proportion of patients with CMT1A develop a late progression of disease manifested with accentuated distal leg weakness ascending

  7. Clinical, immunological, and immunogenetic aspects of autoantibody production against Ro/SSA, La/SSB and their linear epitopes in primary Sjögren's syndrome (pSS): a European multicentre study

    PubMed Central

    Tzioufas, A; Wassmuth, R; Dafni, U; Guialis, A; Haga, H; Isenberg, D; Jonsson, R; Kalden, J; Kiener, H; Sakarellos, C; Smolen, J; Sutcliffe, N; Vitali, C; Yiannaki, E; Moutsopoulos, H

    2002-01-01

    Objectives: To investigate the clinical and immunogenetic aspects of antibody formation against Ro/SSA and La/SSB as well as their linear B cell epitopes in patients with primary Sjögren's syndrome (pSS) from different European countries. Patients and methods: Ninety patients with pSS from six European centres were studied. Serum samples from all patients were tested in a control laboratory for anti-Ro/SSA and anti-La/SSB autoantibodies by RNA precipitation assay and autoantibodies to the previously reported B cell linear epitopes of Ro 60 kDa (p169–190aa and p211–232aa) and La/SSB (p147–154aa, p291–302aa, p301–318aa, and p349–364aa). DNA from 88 patients was used for the determination of HLA-DRB1, -DQA1, and -DQB1 genotypes. Analysis of the results was performed in the 88 patients who were genotyped and tested also for antipeptide antibodies. Results: Antibodies to B cell epitopes of Ro 60 kDa were detected at a low frequency (range 10–37%). In contrast, B cell epitopes of La/SSB were detected frequently (range 58–86%) among the anti-La/SSB positive sera. Autoantibodies to the La/SSB epitope, p349–364aa, were significantly positively associated with longer disease duration (p<0.05), recurrent or permanent parotid gland enlargement (p<0.005), and a higher proportion of non-exocrine manifestations (p<0.005), compared with patients without autoantibodies. The presence of anti-Ro/SSA and anti-La/SSB autoantibodies was significantly associated with the presence of HLA-DRB1*03 and DQB1*02 (p=0.038 and p=0.034, respectively). This association was even more prominent and extended to HLA-DQA1*0501 when patients were stratified according the presence of autoantibodies to discrete La/SSB B cell epitopes in comparison with autoantibody negative patients (p<0.01). They were found also to be highly associated with the alleles HLA-DQB1*02 and HLA-DQA1*0501 as well as the presence of a shared amino acid motif in the region 59–69aa of DQB1 first domain (p<0

  8. Periodontal disease progression in type II non-insulin-dependent diabetes mellitus patients (NIDDM). Part I--Probing pocket depth and clinical attachment.

    PubMed

    Novaes, A B; Gutierrez, F G; Novaes, A B

    1996-01-01

    Periodontal disease progression of 30 type II diabetic patients (NIDDM) and 30 patients in whom diabetes was not detected was evaluated. Age ranged from 30 to 77 years. To determine the periodontal condition, probing pocket depth and periodontal attachment loss were measured; to determine the metabolic control of the patients, glycosylated hemoglobin and fasting glucose were measured. At the end of the study, the diabetic group was divided into three subgroups, according to the metabolic state of the patients: controlled patients, moderately controlled patients, and poorly controlled patients. Comparing the diabetic and the control groups as a whole, there was no statistically significant difference in probing pocket depth, but significance (P < 0.01) was observed for attachment loss. When diabetic patients were divided into subgroups, significant differences were observed between the poorly controlled and the control groups (P < 0.01) for both the probing pocket depth and periodontal attachment. The glycosylated hemoglobin test was more reliable than the fasting glucose analysis.

  9. Linear Equations: Equivalence = Success

    ERIC Educational Resources Information Center

    Baratta, Wendy

    2011-01-01

    The ability to solve linear equations sets students up for success in many areas of mathematics and other disciplines requiring formula manipulations. There are many reasons why solving linear equations is a challenging skill for students to master. One major barrier for students is the inability to interpret the equals sign as anything other than…

  10. Linear drug eruption.

    PubMed

    Alfonso, R; Belinchon, I

    2001-01-01

    Linear eruptions are sometimes associated with systemic diseases and they may also be induced by various drugs. Paradoxically, such acquired inflammatory skin diseases tend to follow the system of Blaschko's lines. We describe a case of unilateral linear drug eruption caused by ibuprofen, which later became bilateral and generalized.

  11. Linearization of Robot Manipulators

    NASA Technical Reports Server (NTRS)

    Kreutz, Kenneth

    1987-01-01

    Four nonlinear control schemes equivalent. Report discusses theory of nonlinear feedback control of robot manipulator, emphasis on control schemes making manipulator input and output behave like decoupled linear system. Approach, called "exact external linearization," contributes efforts to control end-effector trajectories, positions, and orientations.

  12. Post Kalman progress

    NASA Technical Reports Server (NTRS)

    Sonnabend, David

    1995-01-01

    In a paper here last year, an idea was put forward that much greater performance could be obtained from an observer, relative to a Kalman filter if more general performance indices were adopted, and the full power spectra of all the noises were employed. The considerable progress since then is reported here. Included are an extension of the theory to regulators, direct calculation of the theory's fundamental quantities - the noise effect integrals - for several theoretical spectra, and direct derivations of the Riccati equations of LQG (Linear-Quadratic-Gaussian) and Kalman theory yielding new insights.

  13. [Progress in optical imaging].

    PubMed

    Bremer, C; Ntziachristos, V; Mahmood, U; Tung, C H; Weissleder, R

    2001-02-01

    Different optical imaging technologies have significantly progressed over the last years. Besides advances in imaging techniques and image reconstruction, new "smart" optical contrast agents have been developed which can be used to detect molecular targets (such as endogenous enzymes) in vivo. The combination of novel imaging technologies coupled with smart agents bears great diagnostic potential both clinically and experimentally. This overview outlines the basic principles of optical imaging and summarizes the current state of the art.

  14. Linear models: permutation methods

    USGS Publications Warehouse

    Cade, B.S.; Everitt, B.S.; Howell, D.C.

    2005-01-01

    Permutation tests (see Permutation Based Inference) for the linear model have applications in behavioral studies when traditional parametric assumptions about the error term in a linear model are not tenable. Improved validity of Type I error rates can be achieved with properly constructed permutation tests. Perhaps more importantly, increased statistical power, improved robustness to effects of outliers, and detection of alternative distributional differences can be achieved by coupling permutation inference with alternative linear model estimators. For example, it is well-known that estimates of the mean in linear model are extremely sensitive to even a single outlying value of the dependent variable compared to estimates of the median [7, 19]. Traditionally, linear modeling focused on estimating changes in the center of distributions (means or medians). However, quantile regression allows distributional changes to be estimated in all or any selected part of a distribution or responses, providing a more complete statistical picture that has relevance to many biological questions [6]...

  15. Linear force device

    NASA Technical Reports Server (NTRS)

    Clancy, John P.

    1988-01-01

    The object of the invention is to provide a mechanical force actuator which is lightweight and manipulatable and utilizes linear motion for push or pull forces while maintaining a constant overall length. The mechanical force producing mechanism comprises a linear actuator mechanism and a linear motion shaft mounted parallel to one another. The linear motion shaft is connected to a stationary or fixed housing and to a movable housing where the movable housing is mechanically actuated through actuator mechanism by either manual means or motor means. The housings are adapted to releasably receive a variety of jaw or pulling elements adapted for clamping or prying action. The stationary housing is adapted to be pivotally mounted to permit an angular position of the housing to allow the tool to adapt to skewed interfaces. The actuator mechanisms is operated by a gear train to obtain linear motion of the actuator mechanism.

  16. Linear Immunoglobulin A dermatosis mimicking Toxic Epidermal Necrolysis: a case report of etanercept treatment.

    PubMed

    Prieto-Barrios, M; Velasco-Tamariz, V; Tous-Romero, F; Burillo-Martinez, S; Zarco-Olivo, C; Rodriguez-Peralto, J L; Ortiz-Romero, P L

    2017-02-21

    A 65-year-old pluripathological woman attended our hospital with a cutaneous eruption of sudden appearance after vancomycin treatment. She presented targetoid lesions affecting approximately 25-30% of her body surface, large erosions, with mucosal lesions and positive Nikolsky sign. Under the initial clinical suspicion of Toxic Epidermal Necrolysis (TEN), and considering recent literature of its successful use in these cases, she was treated with a single dose of anti-Tumor Necrosis Factor (anti-TNF) agent etanercept. Subsequently, the exanthema progression stopped and resolution of the lesions happened in a few days. Later on, histopathology revealed a subepidermal blister with dense neutrophilic infiltrate and linear deposits of IgA on the dermoepidermal junction allowing us to stablish the diagnosis of drug-induced linear immunoglobulin A (IgA) dermatosis mimicking TEN. Linear IgA dermatosis can have severe clinical manifestations, even mimicking TEN, with high mortality, especially the drug-induced cases. We have not found any other report of linear IgA dermatosis treated with etanercept in the English literature. Anti-TNF medications could represent useful therapeutic alternatives in this dermatosis. This article is protected by copyright. All rights reserved.

  17. Embodied, Symbolic and Formal Thinking in Linear Algebra

    ERIC Educational Resources Information Center

    Stewart, Sepideh; Thomas, Michael O. J.

    2007-01-01

    Students often find their first university linear algebra experience very challenging. While coping with procedural aspects of the subject, solving linear systems and manipulating matrices, they may struggle with crucial conceptual ideas underpinning them, making it very difficult to progress in more advanced courses. This research has sought to…

  18. Progressive cerebral atrophy in neuromyelitis optica.

    PubMed

    Warabi, Yoko; Takahashi, Toshiyuki; Isozaki, Eiji

    2015-12-01

    We report two cases of neuromyelitis optica patients with progressive cerebral atrophy. The patients exhibited characteristic clinical features, including elderly onset, secondary progressive tetraparesis and cognitive impairment, abnormally elevated CSF protein and myelin basic protein levels, and extremely highly elevated serum anti-AQP-4 antibody titer. Because neuromyelitis optica pathology cannot switch from an inflammatory phase to the degenerative phase until the terminal phase, neuromyelitis optica rarely appears as a secondary progressive clinical course caused by axonal degeneration. However, severe intrathecal inflammation and massive destruction of neuroglia could cause a secondary progressive clinical course associated with cerebral atrophy in neuromyelitis optica patients.

  19. Progressive supranuclear palsy: progression and survival.

    PubMed

    Arena, Julieta E; Weigand, Stephen D; Whitwell, Jennifer L; Hassan, Anhar; Eggers, Scott D; Höglinger, Günter U; Litvan, Irene; Josephs, Keith A

    2016-02-01

    Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disorder characterized by postural instability and falls, vertical supranuclear gaze palsy, parkinsonism with poor levodopa response, pseudobulbar palsy, and frontal release signs. The natural history of the disease has been previously described. However, the time frame of appearance of clinical milestones and how these symptoms may relate to survival in PSP are unknown. The primary objective was to determine the prevalence of symptoms at different stages of PSP and to estimate the time of appearance of clinical symptoms characteristic of the disease. Second, we determined the association between clinical symptoms and survival. We prospectively studied 35 PSP patients during assessments scheduled every 6 months for up to 2 years. We estimated symptoms prevalence and the association between symptoms and survival. The median age of onset was 65.9 years (IQR 60.6-70.0), and the median time from onset to first assessment was 3.0 years (IQR 2.4-3.9). The most commonly reported symptoms at baseline were: motor (100%) followed by cognitive/behavioral (89%), systemic and bulbar (80%), and sleep disturbances (60%). Slowness of movement, falls, neck stiffness and difficulty looking up/down had high prevalence from baseline, while balance and gait impairment were less common at baseline but increased in prevalence over time. The presence of sleep disturbances, and possibly hallucinations, was associated with increased death risk. Improved recognition of the clinical spectrum and milestones of PSP advances knowledge of the disease, helps earlier diagnosis, and allows prognostic predictions.

  20. Pre-clinical evaluation of voltage-gated calcium channel blockers derived from the spider P. nigriventer in glioma progression.

    PubMed

    Nicoletti, Natália Fontana; Erig, Thaís Cristina; Zanin, Rafael Fernandes; Roxo, Marcelo Ricardo; Ferreira, Nelson Pires; Gomez, Marcus Vinicius; Morrone, Fernanda Bueno; Campos, Maria Martha

    2017-04-01

    This study investigated the effects of P/Q- and N-type voltage-gated calcium channel (VGCC) blockers derived from P. nigriventer in glioma progression, by means of in vitro and in vivo experiments. Glioma cells M059J, U-138MG and U-251MG were used to evaluate the antiproliferative effects of P/Q- and N-type VGCC inhibitors PhTx3-3 and Phα1β from P. nigriventer (0.3-100 pM), in comparison to MVIIC and MVIIA from C. magus (0.3-100 pM), respectively. The toxins were also analyzed in a glioma model induced by implantation of GL261 mouse cells. PhTx3-3, Phα1β and MVIIA displayed significant inhibitory effects on the proliferation and viability of all tested glioma cell lines, and evoked cell death mainly with apoptosis characteristics, as indicated by Annexin V/propidium iodide (PI) positivity. The antiproliferative effects of toxins were confirmed by flow cytometry using Ki67 staining. None of the tested toxins altered the proliferation rates of the N9 non-tumor glial cell line. Noteworthy, the administration of the preferential N-type VGCC inhibitors, Phα1β (50 pmol/site; i.c.v.), its recombinant form CTK 01512-2 (50 pmol/site; i.c.v. and i.t.), or MVIIA (10 pmol/site; i.c.v.) caused significant reductions of tumor areas in vivo. N-type VGCC inhibition by Phα1β, CTK 01512-2, and MVIIA led to a marked increase of GFAP-activated astrocytes, and Iba-1-positive microglia, in the peritumoral region, which might explain, at least in part, the inhibitory effects of the toxins in tumor development. This study provides novel evidence on the potential effects of P. nigriventer-derived P/Q-, and mainly, N-type VGCC inhibitors, in glioma progression.

  1. Linear ubiquitination in immunity.

    PubMed

    Shimizu, Yutaka; Taraborrelli, Lucia; Walczak, Henning

    2015-07-01

    Linear ubiquitination is a post-translational protein modification recently discovered to be crucial for innate and adaptive immune signaling. The function of linear ubiquitin chains is regulated at multiple levels: generation, recognition, and removal. These chains are generated by the linear ubiquitin chain assembly complex (LUBAC), the only known ubiquitin E3 capable of forming the linear ubiquitin linkage de novo. LUBAC is not only relevant for activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs) in various signaling pathways, but importantly, it also regulates cell death downstream of immune receptors capable of inducing this response. Recognition of the linear ubiquitin linkage is specifically mediated by certain ubiquitin receptors, which is crucial for translation into the intended signaling outputs. LUBAC deficiency results in attenuated gene activation and increased cell death, causing pathologic conditions in both, mice, and humans. Removal of ubiquitin chains is mediated by deubiquitinases (DUBs). Two of them, OTULIN and CYLD, are constitutively associated with LUBAC. Here, we review the current knowledge on linear ubiquitination in immune signaling pathways and the biochemical mechanisms as to how linear polyubiquitin exerts its functions distinctly from those of other ubiquitin linkage types.

  2. Student Learning of Basis, Span and Linear Independence in Linear Algebra

    ERIC Educational Resources Information Center

    Stewart, Sepideh; Thomas, Michael O. J.

    2010-01-01

    One of the earlier, more challenging concepts in linear algebra at university is that of basis. Students are often taught procedurally how to find a basis for a subspace using matrix manipulation, but may struggle with understanding the construct of basis, making further progress harder. We believe one reason for this is because students have…

  3. Auricular Acupuncture Versus Progressive Muscle Relaxation in Patients with Anxiety Disorders or Major Depressive Disorder: A Prospective Parallel Group Clinical Trial.

    PubMed

    de Lorent, Lukas; Agorastos, Agorastos; Yassouridis, Alexander; Kellner, Michael; Muhtz, Christoph

    2016-08-01

    Although acupuncture treatment is increasingly in demand among psychiatric patients, to date no studies have investigated the effectiveness of auricular acupuncture (AA) in treating anxiety disorders or major depressive disorder. Thus, this study aimed to compare the effectiveness of AA versus progressive muscle relaxation (PMR), a standardized and accepted relaxation method. We examined 162 patients with a primary diagnosis of anxiety disorder or major depressive disorder, and each patient chose between treatment with AA, executed according to the National Acupuncture Detoxification Association protocol, and treatment with PMR. Each group had treatments twice a week for 4 weeks. Before and after treatment, each participant rated four items on a visual analog scale: anxiety, tension, anger/aggression, and mood. Statistical analyses were performed with the original visual analog scale scores and the Change-Intensity Index, an appropriate indicator of the difference between two values of a variable. Our results show that treatment with AA significantly decreased tension, anxiety, and anger/aggression throughout the 4 weeks, but did not elevate mood. Between AA and PMR, no statistically significant differences were found at any time. Thus, we suggest that both AA and PMR may be useful, equally-effective additional interventions in the treatment of the above-mentioned disorders.

  4. Optimal Linear Control.

    DTIC Science & Technology

    1979-12-01

    OPTIMAL LINEAR CONTROL C.A. HARVEY M.G. SAFO NOV G. STEIN J.C. DOYLE HONEYWELL SYSTEMS & RESEARCH CENTER j 2600 RIDGWAY PARKWAY j [ MINNEAPOLIS...RECIPIENT’S CAT ALC-’ W.IMIJUff’? * J~’ CR2 15-238-4F TP P EI)ŕll * (~ Optimal Linear Control ~iOGRPR UBA m a M.G Lnar o Con_ _ _ _ _ _ R PORT__ _ _ I RE...Characterizations of optimal linear controls have been derived, from which guides for selecting the structure of the control system and the weights in

  5. Linear magnetic bearing

    NASA Technical Reports Server (NTRS)

    Studer, P. A. (Inventor)

    1983-01-01

    A linear magnetic bearing system having electromagnetic vernier flux paths in shunt relation with permanent magnets, so that the vernier flux does not traverse the permanent magnet, is described. Novelty is believed to reside in providing a linear magnetic bearing having electromagnetic flux paths that bypass high reluctance permanent magnets. Particular novelty is believed to reside in providing a linear magnetic bearing with a pair of axially spaced elements having electromagnets for establishing vernier x and y axis control. The magnetic bearing system has possible use in connection with a long life reciprocating cryogenic refrigerator that may be used on the space shuttle.

  6. Rationale and Design of a Phase I Clinical Trial to Evaluate HSV G207 Alone or with a Single Radiation Dose in Children with Progressive or Recurrent Malignant Supratentorial Brain Tumors.

    PubMed

    Waters, Alicia M; Johnston, James M; Reddy, Alyssa T; Fiveash, John; Madan-Swain, Avi; Kachurak, Kara; Bag, Asim K; Gillespie, G Yancey; Markert, James M; Friedman, Gregory K

    2017-02-24

    Primary central nervous system tumors are the most common solid neoplasm of childhood and the leading cause of cancer related death in pediatric patients. Survival rates for children with malignant supratentorial brain tumors are poor despite aggressive treatment with combinations of surgery, radiation, and chemotherapy; and survivors often suffer from damaging lifelong sequelae from current therapies. Novel innovative treatments are greatly needed. One promising new approach is the use of a genetically engineered, conditionally replicating herpes simplex virus (HSV) that has shown tumor specific tropism and potential efficacy in the treatment of malignant brain tumors. G207 is a genetically engineered HSV-1 lacking genes essential for replication in normal brain cells. Safety has been established in preclinical investigations involving intracranial inoculation in the highly HSV-sensitive owl monkey (Aotus nancymai), and in three adult phase I trials in recurrent/progressive high-grade gliomas. No dose-limiting toxicities were seen in the adult studies and a maximum tolerated dose was not reached. Approximately half of the 35 treated adults had radiographic or neuropathologic evidence of response at a minimum of one time point. Preclinical studies in pediatric brain tumor models indicate that a variety of pediatric tumor types are highly sensitive to killing by G207. This clinical protocol outlines a first in human children study of intratumoral inoculation of an oncolytic virus via catheters placed directly into recurrent or progressive supratentorial malignant tumors.

  7. Rationale and Design of a Phase 1 Clinical Trial to Evaluate HSV G207 Alone or with a Single Radiation Dose in Children with Progressive or Recurrent Malignant Supratentorial Brain Tumors.

    PubMed

    Waters, Alicia M; Johnston, James M; Reddy, Alyssa T; Fiveash, John; Madan-Swain, Avi; Kachurak, Kara; Bag, Asim K; Gillespie, G Yancey; Markert, James M; Friedman, Gregory K

    2017-03-01

    Primary central nervous system tumors are the most common solid neoplasm of childhood and the leading cause of cancer-related death in pediatric patients. Survival rates for children with malignant supratentorial brain tumors are poor despite aggressive treatment with combinations of surgery, radiation, and chemotherapy, and survivors often suffer from damaging lifelong sequelae from current therapies. Novel innovative treatments are greatly needed. One promising new approach is the use of a genetically engineered, conditionally replicating herpes simplex virus (HSV) that has shown tumor-specific tropism and potential efficacy in the treatment of malignant brain tumors. G207 is a genetically engineered HSV-1 lacking genes essential for replication in normal brain cells. Safety has been established in preclinical investigations involving intracranial inoculation in the highly HSV-sensitive owl monkey (Aotus nancymai), and in three adult phase 1 trials in recurrent/progressive high-grade gliomas. No dose-limiting toxicities were seen in the adult studies and a maximum tolerated dose was not reached. Approximately half of the 35 treated adults had radiographic or neuropathologic evidence of response at a minimum of one time point. Preclinical studies in pediatric brain tumor models indicate that a variety of pediatric tumor types are highly sensitive to killing by G207. This clinical protocol outlines a first in human children study of intratumoral inoculation of an oncolytic virus via catheters placed directly into recurrent or progressive supratentorial malignant tumors.

  8. CSF levels of Aβ1-38/Aβ1-40/Aβ1-42 and (11)C PiB-PET studies in three clinical variants of primary progressive aphasia and Alzheimer's disease.

    PubMed

    Ikeda, Masaki; Tashiro, Yuichi; Takai, Eriko; Kurose, Sachiko; Fugami, Naoko; Tsuda, Kazuhisa; Arisaka, Yukiko; Kodaira, Sayaka; Fujita, Yukio; Makioka, Kouki; Mizuno, Yuji; Shimada, Hirotaka; Harigaya, Yasuo; Takatama, Masamitsu; Amari, Masakuni; Yamazaki, Tsuneo; Yamaguchi, Haruyasu; Higuchi, Tetsuya; Okamoto, Koichi; Tsushima, Yoshito; Ikeda, Yoshio

    2014-12-01

    Primary progressive aphasia (PPA) is a cognitive syndrome characterized by progressive and isolated language impairments due to neurodegenerative diseases. Recently, an international group of experts published a Consensus Classification of the three PPA clinical variants (naPPA, svPPA and lvPPA). We analyzed 24 patients with PPA by cognitive functions, neuroimaging (MRI, (99 m)Tc ECD-SPECT, (11)C PiB-PET and FDG-PET) and cerebrospinal fluid (CSF) analysis (ptau-181, Aβ1-42, Aβ1-40 and Aβ1-38), to elucidate relationships between neuroimaging studies and biochemical findings in the three PPA clinical variants. Cognitive and speech functions were measured by mini-mental state examination and standard language test of aphasia. The patients with lvPPA showed significant decreases in CSF Aβ1-42 and ratios of Aβ1-42/Aβ1-40 and Aβ1-42/Aβ1-38, and significant increases in CSF ptau-181 and ratios of ptau-181/Aβ1-42 and ptau-181/Aβ1-38; these findings were similar to those of patients with Alzheimer's disease (AD). We observed a higher frequency of the ApoE ε4 allele in the lvPPA patients relative to the two other PPA variants. In (11)C PiB-PET of lvPPA patients, PiB positive findings were detected in cortices of frontal, temporal and parietal lobes and the posterior cingulate, where massive Aβ may accumulate due to AD. Our results of AD-CSF markers including Aβ1-38 and (11)C PiB-PET in the lvPPA patients demonstrate a common pathological mechanism with the occurrence of AD.

  9. Inertial Linear Actuators

    NASA Technical Reports Server (NTRS)

    Laughlin, Darren

    1995-01-01

    Inertial linear actuators developed to suppress residual accelerations of nominally stationary or steadily moving platforms. Function like long-stroke version of voice coil in conventional loudspeaker, with superimposed linear variable-differential transformer. Basic concept also applicable to suppression of vibrations of terrestrial platforms. For example, laboratory table equipped with such actuators plus suitable vibration sensors and control circuits made to vibrate much less in presence of seismic, vehicular, and other environmental vibrational disturbances.

  10. Linear system theory

    NASA Technical Reports Server (NTRS)

    Callier, Frank M.; Desoer, Charles A.

    1991-01-01

    The aim of this book is to provide a systematic and rigorous access to the main topics of linear state-space system theory in both the continuous-time case and the discrete-time case; and the I/O description of linear systems. The main thrusts of the work are the analysis of system descriptions and derivations of their properties, LQ-optimal control, state feedback and state estimation, and MIMO unity-feedback systems.

  11. Linear Resonance Cooler.

    DTIC Science & Technology

    1985-04-01

    for a Stirling cycle cryocooler . 26 * .*o .. * COMPRESSOR MOTOR FORCE VERSUS ROTOR AXIAL POSITION COMPRESSOR P-V DIAGRAM *COMPRESSOR MOTOR COMPRESSOR...potential. However, the limited test program has demonstrated the application of linear motor drive technology to a Stirling cycle cryocooler design. L...Ace-ss Ion& For flTIC TAB - TABLE OF CONTENTS TITLE IPAGE - 2. DETAILED DESIGN OF LINEAR RESONANCE CRYOCOOLER ......... 3 2.2 Expander

  12. Non-Linear Control Allocation Using Piecewise Linear Functions

    DTIC Science & Technology

    2003-08-01

    A novel method is presented for the solution of the non- linear control allocation problem. Historically, control allocation has been performed by... linear control allocation problem to be cast as a piecewise linear program. The piecewise linear program is ultimately cast as a mixed-integer linear...piecewise linear control allocation method is shown to be markedly improved when compared to the performance of a more traditional control allocation approach that assumes linearity.

  13. Randomized clinical trial: Nucleos(t)ide analogues improved survival of CHB-related HCC patients via reducing severity and progression of malignancy

    PubMed Central

    Chen, Liwen; Cao, Zhujun; Bao, Rebecca; Zhou, Huijuan; Tang, Weiliang; Lu, Jie; Lin, Lanyi; Xie, Qing; Bao, Shisan; Wang, Hui

    2016-01-01

    Background The influence of nucleos(t)ide analogues (NAs) to treat Chronic hepatitis B (CHB) related hepatocellular carcinoma (HCC) remains to be explored. Aim To investigate if NAs reduce the severity and progression of CHB-related HCC. Results Among 532 patients, there were 118 or 414 CHB-related HCC with or without NAs therapy, respectively. BCLC scores, serum level of ALT/AST and HBV DNA were compared. During follow-up, the survival period of CHB-related HCC patients with sustained NAs is significantly longer than that with NAs post-HCC and NAs naïve (p < 0.05). Factors significantly associated with the poor overall survival of CHB-related HCC include BCLC scores (hazard ratio, 1.84 [95% confidence interval, 1.57−2.15], p < 0.001), NAs post-HCC or NAs naïve (1.33 [1.07−1.65], p < 0.01), serum AST ≥ 40 IU/L (1.48 [1.03−2.12], p < 0.05) and HBV DNA ≥ 104 copies/ml (1.36 [1.01−1.83], p < 0.001). Methods Outcomes of 532 CHB-related HCC patients with/without NAs were investigated. Overall survival of CHB-related HCC patients, NAs naïve (n = 156), NAs received post-HCC (n = 258) and NAs sustained (n = 118) were determined. Conclusions NAs reduced severity of CHB-related HCC patients. Sustained NAs is an important factor associated with the extended survival of CHB-related HCC patients. PMID:27329718

  14. Progressive supranuclear palsy.

    PubMed

    Golbe, Lawrence I

    2014-04-01

    Progressive supranuclear palsy is a disorder of tau protein aggregation. Its clinical spectrum is now known to be wider than originally described, with a phenotype resembling Parkinson disease accounting for a third of cases. However, at least half of the patients with PSP exhibit the classic bradykinesia with disproportionate postural instability, erect posture with nuchal rigidity, frontal behavioral and cognitive changes, vertical gaze palsy, and other disabling brainstem deficits. Nonmendelian genetic risk factors exist, but PSP is almost entirely sporadic, with a prevalence of five to six persons per 100,000, mean onset age of 63, and median survival of 7 years. Clinical diagnostic criteria with excellent specificity and a clinical rating scale sensitive to progression are available. Diagnosis remains clinical, although magnetic resonance imaging and cerebrospinal fluid measures are showing promise as early-stage screening tools. Multiple candidate neuroprotective medications have proven ineffective to date. Treatment remains supportive, although coenzyme Q-10 has shown preliminary symptomatic efficacy and levodopa may provide transient, modest benefit.

  15. Prevalence and clinical relevance of occult hepatitis B in the fibrosis progression and antiviral response to INF therapy in HIV-HCV-coinfected patients.

    PubMed

    Laguno, Montserrat; Larrousse, Maria; Blanco, José Luis; Leon, Agathe; Milinkovic, Ana; Martínez-Rebozler, Maria; Loncá, Montserrat; Martinez, Esteban; Sanchez-Tapias, Jose Maria; de Lazzari, Elisa; Gatell, José Maria; Costa, Josep; Mallolas, Josep

    2008-04-01

    Occult hepatitis B virus (HBV) infection is diagnosed when HBc antibodies (HBcAb) and HBV DNA are detectable in serum while hepatitis B surface antigen (HBsAg) is not. This situation has been frequently described in patients with chronic hepatitis C virus (HCV) infection. The objective of this study was to evaluate the prevalence of occult hepatitis B in HIV-HCV-coinfected patients and its clinical relevance in liver histology and viral response after interferon therapy for HCV. A total of 238 HIV-HCV-infected patients,negative for HBsAg, were included. Serum samples were analyzed for the presence of HBV DNA and HBcAb.HBV DNA quantification was determined with the Cobas TaqMan HBV Test (detection limit 6 IU/ml). Data from liver biopsy and laboratory tests were also analyzed. HBcAb resulted in 142 (60%) patients, being the independent associated factors: male gender, previous history of intravenous drug use, age, CD4 count,and HAV antibody presence. Among 90 HBcAb patients that we could analyze, HBV DNA was positive in 15 (16.7% of occult hepatitis B infection in this group, and 6.3% in the whole HIV-HCV cohort studied). No baseline factors, liver histology, or HCV therapy response were related to the presence of HBV DNA. We found that occult hepatitis B is a frequent condition present in at least 6.3% of our HCV-HIV patients and in more than 16% of those with HBcAb. Despite the high prevalence, this phenomenon does not seem to affect the clinical evolution of chronic hepatitis C or modify the viral response to interferon-based HCV therapies

  16. Quantifying disease progression in amyotrophic lateral sclerosis.

    PubMed

    Simon, Neil G; Turner, Martin R; Vucic, Steve; Al-Chalabi, Ammar; Shefner, Jeremy; Lomen-Hoerth, Catherine; Kiernan, Matthew C

    2014-11-01

    Amyotrophic lateral sclerosis (ALS) exhibits characteristic variability of onset and rate of disease progression, with inherent clinical heterogeneity making disease quantitation difficult. Recent advances in understanding pathogenic mechanisms linked to the development of ALS impose an increasing need to develop strategies to predict and more objectively measure disease progression. This review explores phenotypic and genetic determinants of disease progression in ALS, and examines established and evolving biomarkers that may contribute to robust measurement in longitudinal clinical studies. With targeted neuroprotective strategies on the horizon, developing efficiencies in clinical trial design may facilitate timely entry of novel treatments into the clinic.

  17. The cost of linearization

    NASA Astrophysics Data System (ADS)

    Morel, Danielle; Levy, William B.

    2006-03-01

    Information processing in the brain is metabolically expensive and energy usage by the different components of the nervous system is not well understood. In a continuing effort to explore the costs and constraints of information processing at the single neuron level, dendritic processes are being studied. More specifically, the role of various ion channel conductances is explored in terms of integrating dendritic excitatory synaptic input. Biophysical simulations of dendritic behavior show that the complexity of voltage-dependent, non-linear dendritic conductances can produce simplicity in the form of linear synaptic integration. Over increasing levels of synaptic activity, it is shown that two types of voltage-dependent conductances produce linearization over a limited range. This range is determined by the parameters defining the ion channel and the 'passive' properties of the dendrite. A persistent sodium and a transient A-type potassium channel were considered at steady-state transmembrane potentials in the vicinity of and hyperpolarized to the threshold for action potential initiation. The persistent sodium is seen to amplify and linearize the synaptic input over a short range of low synaptic activity. In contrast, the A-type potassium channel has a broader linearization range but tends to operate at higher levels of synaptic bombardment. Given equivalent 'passive' dendritic properties, the persistent sodium is found to be less costly than the A-type potassium in linearizing synaptic input.

  18. Monomelic amyotrophy with late progression.

    PubMed

    Rowin, J; Meriggioli, M N; Cochran, E J

    2001-04-01

    Monomelic amyotrophy is a sporadic juvenile-onset disease that presents with gradual onset of weakness and atrophy in the hand muscles unilaterally. Generally, this disease is considered a 'benign' and non-progressive motor neuron disease, which stabilizes within five years of onset. We discuss a case that illustrates that monomelic amyotrophy may rarely exhibit late clinical progression to the lower extremities after a prolonged period of disease stability.

  19. Relation between clinical findings and progression of cerebral cortical pathology in MM1-type sporadic Creutzfeldt-Jakob disease: proposed staging of cerebral cortical pathology.

    PubMed

    Iwasaki, Yasushi; Tatsumi, Shinsui; Mimuro, Maya; Kitamoto, Tetsuyuki; Hashizume, Yoshio; Yoshida, Mari

    2014-06-15

    In our pathologic observation of the cerebral cortex including the neocortex, hippocampus, and limbic cortex in 43 Japanese patients with MM1-type sporadic Creutzfeldt-Jakob disease, the earliest pathologic finding was spongiform change and next was gliosis. Subsequently, neuropil rarefaction appeared, followed by neuron loss. On the basis of these observations, we propose the following cortical pathologic staging: Stage I, spongiform change; Stage II, hypertrophic astrocytosis; Stage III, neuropil rarefaction; Stage IV, neuron loss; Stage V, status spongiosus; and Stage VI, large cavity formation. We also suggest a more simple staging classification: Stages I and II, mild; Stages III and IV, moderate; and Stages V and VI, severe involvement. Based on statistical analysis of the cases, strong correlation coefficients were obtained between the neocortical and limbic pathologic stage and both total disease duration and brain weight. We estimated that the first observation times of cortical hyperintensity on diffusion-weighted images of magnetic resonance imaging, myoclonus, and periodic sharp wave complexes on the electroencephalogram approximately correspond to the early phase of Stage II of the neocortex. The time to reach the akinetic mutism state approximately corresponds to the middle phase of Stage II of the neocortex. Therefore, we think that approximate clinical manifestations at death, total disease duration, and brain weight can be estimated according to the pathologic stage of the neocortex or limbic cortex. Panencephalopathic-type pathology appeared approximately 12 months after disease onset, and this time approximately corresponds to the middle phase of Stage III of the neocortex.

  20. No Evidence for Association of β-Defensin Genomic Copy Number with HIV Susceptibility, HIV Load during Clinical Latency, or Progression to AIDS.

    PubMed

    Abujaber, Razan; Shea, Patrick R; McLaren, Paul J; Lakhi, Shabir; Gilmour, Jill; Allen, Susan; Fellay, Jacques; Hollox, Edward J

    2017-01-01

    Common single-nucleotide variation in the host accounts for 25% of the variability in the plasma levels of HIV during the clinical latency stage (viral load set point). However, the role of rare variants and copy number variants remains relatively unexplored. Previous work has suggested copy number variation of a cluster of β-defensin genes affects HIV load in treatment-naïve sub-Saharan Africans and rate of response to antiretroviral treatment. Here we analyse a total of 1827 individuals from two cohorts of HIV-infected individuals from Europe and sub-Saharan Africa to investigate the role of β-defensin copy number variation on HIV load at set point. We find no evidence for association of copy number with viral load. We also compare distribution of β-defensin copy number between European cases and controls and find no differences, arguing against a role of β-defensin copy number in HIV acquisition. Taken together, our data argue against an effect of copy number variation of the β-defensin region in the spontaneous control of HIV infection.

  1. Determination of the most appropriate method for extrapolating overall survival data from a placebo-controlled clinical trial of lenvatinib for progressive, radioiodine-refractory differentiated thyroid cancer

    PubMed Central

    Tremblay, Gabriel; Livings, Christopher; Crowe, Lydia; Kapetanakis, Venediktos; Briggs, Andrew

    2016-01-01

    Background Cost-effectiveness models for the treatment of long-term conditions often require information on survival beyond the period of available data. Objectives This paper aims to identify a robust and reliable method for the extrapolation of overall survival (OS) in patients with radioiodine-refractory differentiated thyroid cancer receiving lenvatinib or placebo. Methods Data from 392 patients (lenvatinib: 261, placebo: 131) from the SELECT trial are used over a 34-month period of follow-up. A previously published criterion-based approach is employed to ascertain credible estimates of OS beyond the trial data. Parametric models with and without a treatment covariate and piecewise models are used to extrapolate OS, and a holistic approach, where a series of statistical and visual tests are considered collectively, is taken in determining the most appropriate extrapolation model. Results A piecewise model, in which the Kaplan–Meier survivor function is used over the trial period and an extrapolated tail is based on the Exponential distribution, is identified as the optimal model. Conclusion In the absence of long-term survival estimates from clinical trials, survival estimates often need to be extrapolated from the available data. The use of a systematic method based on a priori determined selection criteria provides a transparent approach and reduces the risk of bias. The extrapolated OS estimates will be used to investigate the potential long-term benefits of lenvatinib in the treatment of radioiodine-refractory differentiated thyroid cancer patients and populate future cost-effectiveness analyses. PMID:27418847

  2. Targeting ECM Disrupts Cancer Progression.

    PubMed

    Venning, Freja A; Wullkopf, Lena; Erler, Janine T

    2015-01-01

    Metastatic complications are responsible for more than 90% of cancer-related deaths. The progression from an isolated tumor to disseminated metastatic disease is a multistep process, with each step involving intricate cross talk between the cancer cells and their non-cellular surroundings, the extracellular matrix (ECM). Many ECM proteins are significantly deregulated during the progression of cancer, causing both biochemical and biomechanical changes that together promote the metastatic cascade. In this review, the influence of several ECM proteins on these multiple steps of cancer spread is summarized. In addition, we highlight the promising (pre-)clinical data showing benefits of targeting these ECM macromolecules to prevent cancer progression.

  3. Targeting ECM Disrupts Cancer Progression

    PubMed Central

    Venning, Freja A.; Wullkopf, Lena; Erler, Janine T.

    2015-01-01

    Metastatic complications are responsible for more than 90% of cancer-related deaths. The progression from an isolated tumor to disseminated metastatic disease is a multistep process, with each step involving intricate cross talk between the cancer cells and their non-cellular surroundings, the extracellular matrix (ECM). Many ECM proteins are significantly deregulated during the progression of cancer, causing both biochemical and biomechanical changes that together promote the metastatic cascade. In this review, the influence of several ECM proteins on these multiple steps of cancer spread is summarized. In addition, we highlight the promising (pre-)clinical data showing benefits of targeting these ECM macromolecules to prevent cancer progression. PMID:26539408

  4. Superconducting linear actuator

    NASA Technical Reports Server (NTRS)

    Johnson, Bruce; Hockney, Richard

    1993-01-01

    Special actuators are needed to control the orientation of large structures in space-based precision pointing systems. Electromagnetic actuators that presently exist are too large in size and their bandwidth is too low. Hydraulic fluid actuation also presents problems for many space-based applications. Hydraulic oil can escape in space and contaminate the environment around the spacecraft. A research study was performed that selected an electrically-powered linear actuator that can be used to control the orientation of a large pointed structure. This research surveyed available products, analyzed the capabilities of conventional linear actuators, and designed a first-cut candidate superconducting linear actuator. The study first examined theoretical capabilities of electrical actuators and determined their problems with respect to the application and then determined if any presently available actuators or any modifications to available actuator designs would meet the required performance. The best actuator was then selected based on available design, modified design, or new design for this application. The last task was to proceed with a conceptual design. No commercially-available linear actuator or modification capable of meeting the specifications was found. A conventional moving-coil dc linear actuator would meet the specification, but the back-iron for this actuator would weigh approximately 12,000 lbs. A superconducting field coil, however, eliminates the need for back iron, resulting in an actuator weight of approximately 1000 lbs.

  5. A case of linear lichen planus pigmentosus.

    PubMed

    Seo, Jong Keun; Lee, Hyun Jae; Lee, Deborah; Choi, Joon Hee; Sung, Ho-Suck

    2010-08-01

    Lichen planus pigmentosus (LPP) is chronic pigmentary disorder that shows diffuse or reticulated hyperpigmented, dark brown macules on the sun-exposed areas such as the face, neck and other flexural folds. Clinically, it is different from classical lichen planus because LPP has a longer clinical course and it manifests with dark brown macules. In case of LPP, involvement of the scalp, nail or mucosal area is rare. The histopathological findings of the lesions show an atrophic epidermis, the presence of melanophages and a vacuolar alteration of the basal cell layer with a sparse lymphohistiocytic lichenoid infiltration. Although there have been a few reports of LPP, there have only 3 cases of linear LPP along the lines of Blaschko in the Korean dermatologic literature. Our patient had lesions on the neck and chin with a linear pattern. In this report, we describe a very rare case of LPP with a linear distribution related to Blaschko's lines on the neck and chin areas.

  6. Linear encoding device

    NASA Technical Reports Server (NTRS)

    Leviton, Douglas B. (Inventor)

    1993-01-01

    A Linear Motion Encoding device for measuring the linear motion of a moving object is disclosed in which a light source is mounted on the moving object and a position sensitive detector such as an array photodetector is mounted on a nearby stationary object. The light source emits a light beam directed towards the array photodetector such that a light spot is created on the array. An analog-to-digital converter, connected to the array photodetector is used for reading the position of the spot on the array photodetector. A microprocessor and memory is connected to the analog-to-digital converter to hold and manipulate data provided by the analog-to-digital converter on the position of the spot and to compute the linear displacement of the moving object based upon the data from the analog-to-digital converter.

  7. Secondary progression is not the only explanation.

    PubMed

    Palavra, Filipe; Tur, Carmen; Tintoré, Mar; Rovira, Àlex; Montalban, Xavier

    2014-01-01

    Multiple sclerosis is an inflammatory demyelinating disorder of the central nervous system. Its presentation is variable and its course and prognosis are unpredictable. Approximately 85% of individuals present a relapsing-remitting form of the disease, but some patients may evolve into a progressive course, accumulating irreversible neurological disability, defining its secondary progressive phase. Despite all the advances that had been reached in terms of diagnosis, many decisions are still taken based only on pure clinical skills. We present the case of a patient that, after being diagnosed with a clinically isolated syndrome many years ago, seemed to be entering in a secondary progressive course, developing a clinical picture dominated by a progressive gait disturbance. Nevertheless, multiple sclerosis heterogeneity asks for some clinical expertise, in order to exclude all other possible causes for patients' complaints. Here we present an important red flag in the differential diagnosis of secondary progressive multiple sclerosis.

  8. Reviewing progress: 7 year trends in characteristics of adults and children enrolled at HIV care and treatment clinics in the United Republic of Tanzania

    PubMed Central

    2013-01-01

    Background To evaluate the on-going scale-up of HIV programs, we assessed trends in patient characteristics at enrolment and ART initiation over 7 years of implementation. Methods Data were from Optimal Models, a prospective open cohort study of HIV-infected (HIV+) adults (≥15 years) and children (<15 years) enrolled from January 2005 to December 2011 at 44 HIV clinics in 3 regions of mainland Tanzania (Kagera, Kigoma, Pwani) and Zanzibar. Comparative statistics for trends in characteristics of patients enrolled in 2005–2007, 2008–2009 and 2010–2011 were examined. Results Overall 62,801 HIV + patients were enrolled: 58,102(92.5%) adults, (66.5% female); 4,699(7.5%) children. Among adults, pregnant women enrolment increased: 6.8%, 2005–2007; 12.1%, 2008–2009; 17.2%, 2010–2011; as did entry into care from prevention of mother-to-child HIV transmission (PMTCT) programs: 6.6%, 2005–2007; 9.5%, 2008–2009; 12.6%, 2010–2011 . WHO stage IV at enrolment declined: 27.1%, 2005–2007; 20.2%, 2008–2009; 11.1% 2010–2011. Of the 42.5% and 29.5% with CD4+ data at enrolment and ART initiation respectively, median CD4+ count increased: 210 cells/μL, 2005–2007; 262 cells/μL, 2008–2009; 266 cells/μL 2010–2011; but median CD4+ at ART initiation did not change (148 cells/μL overall). Stavudine initiation declined: 84.9%, 2005–2007; 43.1%, 2008–2009; 19.7%, 2010–2011. Among children, median age (years) at enrolment decreased from 6.1(IQR:2.7-10.0) in 2005–2007 to 4.8(IQR:1.9-8.6) in 2008–2009, and 4.1(IQR:1.5-8.1) in 2010–2011 and children <24 months increased from 18.5% to 26.1% and 31.5% respectively. Entry from PMTCT was 7.0%, 2005–2007; 10.7%, 2008–2009; 15.0%, 2010–2011. WHO stage IV at enrolment declined from 22.9%, 2005–2007, to 18.3%, 2008–2009 to 13.9%, 2010–2011. Proportion initiating stavudine was 39.8% 2005–2007; 39.5%, 2008–2009; 26.1%, 2010–2011. Median age at ART initiation also declined significantly

  9. Brain iron deposition fingerprints in Parkinson's disease and progressive supranuclear palsy.

    PubMed

    Boelmans, Kai; Holst, Brigitte; Hackius, Marc; Finsterbusch, Jürgen; Gerloff, Christian; Fiehler, Jens; Münchau, Alexander

    2012-03-01

    It can be difficult to clinically distinguish between classical Parkinson's disease (PD) and progressive supranuclear palsy. Previously, there have been no biomarkers that reliably allow this distinction to be made. We report that an abnormal brain iron accumulation is a marker for ongoing neurodegeneration in both conditions, but the conditions differ with respect to the anatomical distribution of these accumulations. We analyzed quantitative T2' maps as markers of regional brain iron content from PD and progressive supranuclear palsy patients and compared them to age-matched control subjects. T2-weighted and T2*-weighted images were acquired in 30 PD patients, 12 progressive supranuclear palsy patients, and 24 control subjects at 1.5 Tesla. Mean T2' values were determined in regions-of-interest in the basal ganglia, thalamus, and white matter within each hemisphere. The main findings were shortened T2' values in the caudate nucleus, globus pallidus, and putamen in progressive supranuclear palsy compared to PD patients and controls. A stepwise linear discriminant analysis allowed progressive supranuclear palsy patients to be distinguished from PD patients and the healthy controls. All progressive supranuclear palsy patients were correctly classified. No progressive supranuclear palsy patient was classified as a healthy control, no healthy controls were incorrectly classified as having progressive supranuclear palsy, and only 6.7% of the PD patients were incorrectly classified as progressive supranuclear palsy. Regional decreases of T2' relaxation times in parts of the basal ganglia reflecting increased brain iron load in these areas are characteristic for progressive supranuclear palsy but not PD patients.

  10. Linear motion valve

    NASA Technical Reports Server (NTRS)

    Chandler, J. A. (Inventor)

    1985-01-01

    The linear motion valve is described. The valve spool employs magnetically permeable rings, spaced apart axially, which engage a sealing assembly having magnetically permeable pole pieces in magnetic relationship with a magnet. The gap between the ring and the pole pieces is sealed with a ferrofluid. Depletion of the ferrofluid is minimized.

  11. On Solving Linear Recurrences

    ERIC Educational Resources Information Center

    Dobbs, David E.

    2013-01-01

    A direct method is given for solving first-order linear recurrences with constant coefficients. The limiting value of that solution is studied as "n to infinity." This classroom note could serve as enrichment material for the typical introductory course on discrete mathematics that follows a calculus course.

  12. Improved Electrohydraulic Linear Actuators

    NASA Technical Reports Server (NTRS)

    Hamtil, James

    2004-01-01

    A product line of improved electrohydraulic linear actuators has been developed. These actuators are designed especially for use in actuating valves in rocket-engine test facilities. They are also adaptable to many industrial uses, such as steam turbines, process control valves, dampers, motion control, etc. The advantageous features of the improved electrohydraulic linear actuators are best described with respect to shortcomings of prior electrohydraulic linear actuators that the improved ones are intended to supplant. The flow of hydraulic fluid to the two ports of the actuator cylinder is controlled by a servo valve that is controlled by a signal from a servo amplifier that, in turn, receives an analog position-command signal (a current having a value between 4 and 20 mA) from a supervisory control system of the facility. As the position command changes, the servo valve shifts, causing a greater flow of hydraulic fluid to one side of the cylinder and thereby causing the actuator piston to move to extend or retract a piston rod from the actuator body. A linear variable differential transformer (LVDT) directly linked to the piston provides a position-feedback signal, which is compared with the position-command signal in the servo amplifier. When the position-feedback and position-command signals match, the servo valve moves to its null position, in which it holds the actuator piston at a steady position.

  13. Learning from observation, feedback, and intervention in linear and non-linear task environments.

    PubMed

    Henriksson, Maria P; Enkvist, Tommy

    2016-12-12

    This multiple-cue judgment study investigates whether we can manipulate the judgment strategy and increase accuracy in linear and non-linear cue-criterion environments just by changing the training mode. Three experiments show that accuracy in simple linear additive task environments are improved with feedback training and intervention training, while accuracy in complex multiplicative tasks are improved with observational training. The observed interaction effect suggests that the training mode invites different strategies that are adjusted as a function of experience to the demands from the underlying cue-criterion structure. Thus, feedback and the intervention training modes invite cue abstraction, an effortful but successful strategy in combination with simple linear task structures, and observational training invites exemplar memory processes, a simple but successful strategy in combination with complex non-linear task structures. The study discusses adaptive cognition and the implication of the different training modes across a life span and for clinical populations.

  14. Thematic Progression in a Cardiologist's Text: Context, Frames and Progression.

    ERIC Educational Resources Information Center

    Salter, Robert T.

    Thematic progression (TP) is examined in the text of a communication between a cardiologist and a general practitioner concerning a patient, offering a clinical diagnosis of the patient's condition. Analysis of the discourse looks at the field, tenor, and mode of the communication as a context for TP. The methods of analysis are first described,…

  15. Progressive Multifocal Leukoencephalopathy

    MedlinePlus

    ... clumsiness; progressive weakness; and visual, speech, and sometimes personality changes. The progression of deficits leads to life- ... clumsiness; progressive weakness; and visual, speech, and sometimes personality changes. The progression of deficits leads to life- ...

  16. Linear Lumbar Localized Lysis of Elastic Fibers

    PubMed Central

    Tschen, Jaime A.

    2013-01-01

    Background: The absence or loss of elastic fibers in the skin is referred to as dermal elastolysis. Purpose: This paper describes a woman with a distinctive clinical presentation of mid-dermal elastolysis characterized morphologically by multiple horizontal raised bands on the lower back. Methods: A 20-year-old Filipino woman presented with multiple asymptomatic, flesh-colored, raised, firm, linear, cord-like bands on the lumbar area of her back. There were neither similar lesions elsewhere nor a family member with this condition. Results: Microscopic examination of the raised band showed nearly complete absence of elastic fibers in the mid dermis. In contrast, a biopsy of symmetrically located normal-appearing skin showed a uniform distribution of elastic fibers throughout the dermis. Linear lumbar localized elastolysis is a descriptive designation that accurately reflects a correlation of the clinical and pathological changes of this condition. Conclusion: The clinical differential of raised horizontal cord-like bands on the lower back (without a family history of an inherited elastic fiber disorder, a prior history of trauma, or a significant change in weight or exercise habit) includes linear focal elastosis and linear lumbar localized elastolysis. Microscopic evaluation of a Verhoeff-van Gieson stained lesion specimen (which may be accompanied by a biopsy of normal-appearing skin for comparison) will readily differentiate these conditions. The former is usually characterized by increased elastic fibers, whereas the latter, as in this patient, shows a paucity or absence of elastic fibers in the mid dermis. PMID:23882313

  17. Reciprocating linear motor

    NASA Technical Reports Server (NTRS)

    Goldowsky, Michael P. (Inventor)

    1987-01-01

    A reciprocating linear motor is formed with a pair of ring-shaped permanent magnets having opposite radial polarizations, held axially apart by a nonmagnetic yoke, which serves as an axially displaceable armature assembly. A pair of annularly wound coils having axial lengths which differ from the axial lengths of the permanent magnets are serially coupled together in mutual opposition and positioned with an outer cylindrical core in axial symmetry about the armature assembly. One embodiment includes a second pair of annularly wound coils serially coupled together in mutual opposition and an inner cylindrical core positioned in axial symmetry inside the armature radially opposite to the first pair of coils. Application of a potential difference across a serial connection of the two pairs of coils creates a current flow perpendicular to the magnetic field created by the armature magnets, thereby causing limited linear displacement of the magnets relative to the coils.

  18. Relativistic Linear Restoring Force

    ERIC Educational Resources Information Center

    Clark, D.; Franklin, J.; Mann, N.

    2012-01-01

    We consider two different forms for a relativistic version of a linear restoring force. The pair comes from taking Hooke's law to be the force appearing on the right-hand side of the relativistic expressions: d"p"/d"t" or d"p"/d["tau"]. Either formulation recovers Hooke's law in the non-relativistic limit. In addition to these two forces, we…

  19. Combustion powered linear actuator

    DOEpatents

    Fischer, Gary J.

    2007-09-04

    The present invention provides robotic vehicles having wheeled and hopping mobilities that are capable of traversing (e.g. by hopping over) obstacles that are large in size relative to the robot and, are capable of operation in unpredictable terrain over long range. The present invention further provides combustion powered linear actuators, which can include latching mechanisms to facilitate pressurized fueling of the actuators, as can be used to provide wheeled vehicles with a hopping mobility.

  20. Linear induction accelerator

    DOEpatents

    Buttram, M.T.; Ginn, J.W.

    1988-06-21

    A linear induction accelerator includes a plurality of adder cavities arranged in a series and provided in a structure which is evacuated so that a vacuum inductance is provided between each adder cavity and the structure. An energy storage system for the adder cavities includes a pulsed current source and a respective plurality of bipolar converting networks connected thereto. The bipolar high-voltage, high-repetition-rate square pulse train sets and resets the cavities. 4 figs.

  1. Wideband Linear Phase Modulator

    NASA Technical Reports Server (NTRS)

    Mysoor, Narayan R.; Mueller, Robert O.

    1994-01-01

    Phase modulator for transmission in X band provides large phase deviation that remains nearly linear with voltage over relatively wide range. Operates with low loss over wide frequency band and with stable characteristics over wide temperature range. Phase modulator contains two varactor-diode phase shifters coupled via circulators. Separate drive circuit applies modulating voltages to varactor diodes. Modulation voltages vary in accordance with input to drive circuit.

  2. Linear lichen planus in children - Case report*

    PubMed Central

    Horowitz, Marcia Raquel; Vidal, Marcela de Lima; Resende, Manuela Oliveira; Teixeira, Márcia Almeida Galvão; Cavalcanti, Silvana Maria de Morais; de Alencar, Eliane Ruth Barbosa

    2013-01-01

    Lichen planus is an uncommon disease in children, and only 2 to 3% of affected patients are under twenty years of age. This dermatosis may appear in several clinical forms, which vary according to the morphology and distribution of lesions. In less than 0.2% of all lichen planus cases, the lesions are distributed along the lines of Blaschko, and is a variant called linear lichen planus. This is a case report of a patient aged two years and eight months, who presented keratotic violaceous papules, affecting the abdomen, buttocks and right thigh, distributed along the lines of Blaschko. Histopathological examination confirmed a diagnosis of linear lichen planus. PMID:24346902

  3. Comparison of build-up dose between Elekta and Varian linear accelerators for high-energy photon beams using radiochromic film and clinical implications for IMRT head and neck treatments.

    PubMed

    Paelinck, L; De Wagter, C; Van Esch, A; Duthoy, W; Depuydt, T; De Neve, W

    2005-02-07

    Skin toxicity has been reported for IMRT of head and neck cancer. The purpose of this study was to investigate the dose in the build-up region delivered by a 6 MV treatment plan for which important skin toxicity was observed. We also investigated if the different designs of the treatment head of an Elekta and a Varian linear accelerator, especially the lower position of the Varian multi-leaf collimator, give rise to different build-up doses. For regular square open beams, the build-up dose along the central beam axis is higher for the Varian machine than for the Elekta machine, both for 6 MV and 18 MV. At the Elekta machine at 18 MV, the superficial dose of a diamond shaped 10 x 10 cm2 field is 3.6% lower than the superficial dose of a regular 10 x 10 cm2 field. This effect is not seen at 6 MV. At the Varian machine, the superficial dose of the diamond shaped field is respectively 3.5 and 14.2% higher than the superficial dose of the regular 10 x 10 cm2 field for 6 MV and 18 MV. Despite the differences measured in build-up dose for single beams between the Elekta and the Varian linear accelerator, there were no measurable differences in superficial dose when a typical IMRT dose plan of 6 MV for a head and neck tumour is executed at the two machines.

  4. The effect of non-linear human visual system components on linear model observers

    NASA Astrophysics Data System (ADS)

    Zhang, Yani; Pham, Binh T.; Eckstein, Miguel P.

    2004-05-01

    Linear model observers have been used successfully to predict human performance in clinically relevant visual tasks for a variety of backgrounds. On the other hand, there has been another family of models used to predict human visual detection of signals superimposed on one of two identical backgrounds (masks). These masking models usually include a number of non-linear components in the channels that reflect properties of the firing of cells in the primary visual cortex (V1). The relationship between these two traditions of models has not been extensively investigated in the context of detection in noise. In this paper, we evaluated the effect of including some of these non-linear components into a linear channelized Hotelling observer (CHO), and the associated practical implications for medical image quality evaluation. In particular, we evaluate whether the rank order evaluation of two compression algorithms (JPEG vs. JPEG 2000) is changed by inclusion of the non-linear components. The results show: a) First that the simpler linear CHO model observer outperforms CHO model with the nonlinear components investigated. b) The rank order of model observer performance for the compression algorithms did not vary when the non-linear components were included. For the present task, the results suggest that the addition of the physiologically based channel non-linearities to a channelized Hotelling might add complexity to the model observers without great impact on medical image quality evaluation.

  5. Progressive myoclonic epilepsies

    PubMed Central

    Michelucci, Roberto; Canafoglia, Laura; Striano, Pasquale; Gambardella, Antonio; Magaudda, Adriana; Tinuper, Paolo; La Neve, Angela; Ferlazzo, Edoardo; Gobbi, Giuseppe; Giallonardo, Anna Teresa; Capovilla, Giuseppe; Visani, Elisa; Panzica, Ferruccio; Avanzini, Giuliano; Tassinari, Carlo Alberto; Bianchi, Amedeo; Zara, Federico

    2014-01-01

    Objective: To define the clinical spectrum and etiology of progressive myoclonic epilepsies (PMEs) in Italy using a database developed by the Genetics Commission of the Italian League against Epilepsy. Methods: We collected clinical and laboratory data from patients referred to 25 Italian epilepsy centers regardless of whether a positive causative factor was identified. PMEs of undetermined origins were grouped using 2-step cluster analysis. Results: We collected clinical data from 204 patients, including 77 with a diagnosis of Unverricht-Lundborg disease and 37 with a diagnosis of Lafora body disease; 31 patients had PMEs due to rarer genetic causes, mainly neuronal ceroid lipofuscinoses. Two more patients had celiac disease. Despite extensive investigation, we found no definitive etiology for 57 patients. Cluster analysis indicated that these patients could be grouped into 2 clusters defined by age at disease onset, age at myoclonus onset, previous psychomotor delay, seizure characteristics, photosensitivity, associated signs other than those included in the cardinal definition of PME, and pathologic MRI findings. Conclusions: Information concerning the distribution of different genetic causes of PMEs may provide a framework for an updated diagnostic workup. Phenotypes of the patients with PME of undetermined cause varied widely. The presence of separate clusters suggests that novel forms of PME are yet to be clinically and genetically characterized. PMID:24384641

  6. Automated MRI-based classification of primary progressive aphasia variants

    PubMed Central

    Wilson, Stephen M.; Ogar, Jennifer M.; Laluz, Victor; Growdon, Matthew; Jang, Jung; Glenn, Shenly; Miller, Bruce L.; Weiner, Michael W.; Gorno-Tempini, Maria Luisa

    2009-01-01

    Degeneration of language regions in the dominant hemisphere can result in primary progressive aphasia (PPA), a clinical syndrome characterized by progressive deficits in speech and/or language function. Recent studies have identified three variants of PPA: progressive non-fluent aphasia (PNFA), semantic dementia (SD) and logopenic progressive aphasia (LPA). Each variant is associated with characteristic linguistic features, distinct patterns of brain atrophy, and different likelihoods of particular underlying pathogenic processes, which makes correct differential diagnosis highly clinically relevant. Evaluation of linguistic behavior can be challenging for non-specialists, and neuroimaging findings in single subjects are often difficult to evaluate by eye. We investigated the utility of automated structural MR image analysis to discriminate PPA variants (N=86) from each other and from normal controls (N=115). T1 images were preprocessed to obtain modulated grey matter (GM) images. Feature selection was performed with principal components analysis (PCA) on GM images as well as images of lateralized atrophy. PC coefficients were classified with linear support vector machines, and a cross-validation scheme was used to obtain accuracy rates for generalization to novel cases. The overall mean accuracy in discriminating between pairs of groups was 92.2%. For one pair of groups, PNFA and SD, we also investigated the utility of including several linguistic variables as features. Models with both imaging and linguistic features performed better than models with only imaging or only linguistic features. These results suggest that automated methods could assist in the differential diagnosis of PPA variants, enabling therapies to be targeted to likely underlying etiologies. PMID:19501654

  7. Alteration of mTOR signaling occurs early in the progression of Alzheimer disease (AD): analysis of brain from subjects with pre-clinical AD, amnestic mild cognitive impairment and late-stage AD.

    PubMed

    Tramutola, Antonella; Triplett, Judy C; Di Domenico, Fabio; Niedowicz, Dana M; Murphy, Michael P; Coccia, Raffaella; Perluigi, Marzia; Butterfield, D Allan

    2015-06-01

    The clinical symptoms of Alzheimer disease (AD) include a gradual memory loss and subsequent dementia, and neuropathological deposition of senile plaques and neurofibrillary tangles. At the molecular level, AD subjects present overt amyloid β (Aβ) production and tau hyperphosphorylation. Aβ species have been proposed to overactivate the phosphoinositide3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) axis, which plays a central role in proteostasis. The current study investigated the status of the PI3K/Akt/mTOR pathway in post-mortem tissue from the inferior parietal lobule (IPL) at three different stages of AD: late AD, amnestic mild cognitive impairment (MCI) and pre-clinical AD (PCAD). Our findings suggest that the alteration of mTOR signaling and autophagy occurs at early stages of AD. We found a significant increase in Aβ (1-42) levels, associated with reduction in autophagy (Beclin-1 and LC-3) observed in PCAD, MCI, and AD subjects. Related to the autophagy impairment, we found a hyperactivation of PI3K/Akt/mTOR pathway in IPL of MCI and AD subjects, but not in PCAD, along with a significant decrease in phosphatase and tensin homolog. An increase in two mTOR downstream targets, p70S6K and 4EBP1, occurred in AD and MCI subjects. Both AD and MCI subjects showed increased, insulin receptor substrate 1, a candidate biomarker of brain insulin resistance, and GSK-3β, a kinase targeting tau phosphorylation. Nevertheless, tau phosphorylation was increased in the clinical groups. The results hint at a link between Aβ and the PI3K/Akt/mTOR axis and provide further insights into the relationship between AD pathology and insulin resistance. In addition, we speculate that the alteration of mTOR signaling in the IPL of AD and MCI subjects, but not in PCAD, is due to the lack of substantial increase in oxidative stress. The figure represents the three different stages of Alzheimer Disease: Preclinical Alzheimer Disease (PCAD), Mild cognitive impairment (MCI

  8. Clinical Investigation Program Annual Progress Report.

    DTIC Science & Technology

    1985-09-30

    Meals. Diabetes 30:465, 1981. (5) Sanders, L.R., Hofeldt, F.D., Kirk, M., and Levin, J.: Refined Carbohydrate as a Contributing Factor in Reactive...M.C., and Levin, J.: Refined Carbohydrate as a Contributing Factor in Reactive Hypoglycemia. Southern Medical Journal 75:1072-1075, 1982...only problem encountered is cell suspension technique needs refinement . The major principal investigator (CPT Collazo) has departed FANC. However, would

  9. Clinical Investigation Program Annual Progress Report.

    DTIC Science & Technology

    1983-09-30

    the Treatment of Seasonal Allergic Rhinitis. J Allergy Clin Immunol 71:412, 1983. (C) Dantzler, B.S., Martin, B.G. and Nelson, H.S.: The Effect of... Immunotherapy . Ann Allergy 50:19, 1983. (C) Weber, R.W., Smith, J.A. and Nelson, H.S.: Aerosolized Terbutaline in Asthmatics: Development of Subsensitivity with...Ragweed Immunotherapy Prior to or Following the Pollen Season . Presented: 39th Annual Congress, American College of Allergists, New Orleans, LA, 29

  10. Clinical Investigation Program Annual Progress Report

    DTIC Science & Technology

    1988-10-20

    Immunology, Anaheim, CA, March 1988. Weber RW, Vaughan TR, and Dolen WK: A Ten Year Review of Adverse Reactions to Immunotherapy . Presented: Aspen Allergy ...Area Following Antihistamine or Antihistamine/Decongestant Therapy in Subjects with Seasonal Allergic Rhinitis. Presented: American Academy of Allergy ...Defined Medium and Study of Thin Growth and Immunological Characteristics (0) (P) ........ o. . o.. ..... . .... 44 83/122 The Role of Food Allergy in

  11. Clinical Investigation Program: Annual Progress Report

    DTIC Science & Technology

    1992-09-30

    Diagnosis and Tracing of Disorders Marked by Altered Patterns of Peripheral Blood Flow (PR) .................. 232 87/204 0 Mechanism Based Treatment of...resolution follow-up: Frostbite, Charcot Joints, Carpel Tunnel Syndrome, Fibrositis, Sympathetic Distrophy and Peripheral Neuropathy , Pre-amputation...awarded IND. May be continued on a separate sheet, and designated as "(14)e" Peripheral neuropathy , which developed in one subj ect, was reported to the

  12. Clinical Investigation Program. Annual Progress Report.

    DTIC Science & Technology

    1981-09-30

    Page 73/135 Active Antigens in House Dust (0) (P) (PR) .......... ... 030 74/101 Immuno-chemical Evaluation of Myeloproliferative and...Plasmaproliferative Diseases (C) (P) (PR) .......... .. 032 74/110 Reactive Hypoglycemia: An Analysis of Glucose-Insulin- Glucagon Interrelationships and Counter...78/118 A Precision Measurement of Anatomic Deadspace Using Multiple Inert Gas Analysis , Comparison with Fowler’s Technique and Application to Steady

  13. Clinical Investigation Program Annual Progress Report

    DTIC Science & Technology

    1989-10-01

    ICoughlin WF, Laberge JM, Dresner ML, Kennon WG, Huang YC: Percutaneous Drainage of Neonatal Hedrometrocolpos (Drainage of Hydrometrocolpos). Pediatr3...and its Beta Subunit in Three Events of Pregnancy. Armed Forces ACOG (AFACOG) Mtg, Washington D.C., 5-9 November 1989 Letterie GS, Laberge J, Miyazawa...advances from the TAMC General Surgery Residency. Shogun Medical Society, Honolulu, Hawaii, 23-25 May 1988 m Barcia PJ, Laberge J: Management of Oriental

  14. Clinical Investigation Program Annual Progress Report.

    DTIC Science & Technology

    1984-09-30

    Pulmonary Disease Service %* Hendrix, C.: Bronchoalveolar Lavage Analysis in Sarcoidosis . Presented: 36th Annual Carl Tempel Symposium, Denver, CO, January...1984. (C). Hendrix, C.: Bronchoalveolar Lavage in Analysis in Sarcoidosis . Presented: American College of Physicians Associates Meeting, Denver, CO... Sarcoidosis Alveolitis I (12) Accumulative MEDCASE:’ (13) Est Accum OMA Cost:* *Refer to Unit Summary Sheet of this report. (14) a. Date, Latest HUC

  15. Clinical Investigation Program Annual Progress Report

    DTIC Science & Technology

    1993-09-30

    the Prevention of Neoplastic Polyps -- A Multicenter Study ................. 211 93/138 0 A Screening Study for Myocardial Sarcoidosis Comparing...Enzenauer RJ, West SG: Posttraumatic stress disor- der presenting as fibromyalgia. Am J Med, 94:548, 1993. 3 . Enzenauer RJ, West SG: Sarcoidosis in...Status: Ongoing (4) Title: A Screening Study for Myocardial Sarcoidosis Comparing Transesophageal Echocardiography, Transthoracic Echocardiography

  16. Clinical Investigation Program. Annual Research Progress Report.

    DTIC Science & Technology

    1980-09-30

    needed to determine th,. usefullnes of thi s mn thod as an adjunct to the diagnosis ,ind consequent ly ins i tu- I iona I in p ’ogenic arthritis...are obtained from biopsy or mastectomy sp(cimens. Each sample is cut into many small pieces and distributed, for culture, in a battery of hormone

  17. Two Group Development Patterns of Virtual Learning Teams: Linear Progression and Adaptive Progression

    ERIC Educational Resources Information Center

    Yoon, Seung Won

    2006-01-01

    This study examined member behaviors, distribution of performed behaviors, and development-shaping forces in order to identify group development patterns of virtual learning teams. Participants of this study were 7 newly formed virtual learning teams working on a final group project in a 12-week online graduate-level course. Examining the group…

  18. Ultrasonic linear measurement system

    NASA Technical Reports Server (NTRS)

    Marshall, Scot H. (Inventor)

    1991-01-01

    An ultrasonic linear measurement system uses the travel time of surface waves along the perimeter of a three-dimensional curvilinear body to determine the perimeter of the curvilinear body. The system can also be used piece-wise to measure distances along plane surfaces. The system can be used to measure perimeters where use of laser light, optical means or steel tape would be extremely difficult, time consuming or impossible. It can also be used to determine discontinuities in surfaces of known perimeter or dimension.

  19. Lead screw linear actuator

    NASA Technical Reports Server (NTRS)

    Perkins, Gerald S. (Inventor)

    1980-01-01

    A linear actuator which can apply high forces is described, which includes a reciprocating rod having a threaded portion engaged by a nut that is directly coupled to the rotor of an electric motor. The nut is connected to the rotor in a manner that minimizes loading on the rotor, by the use of a coupling that transmits torque to the nut but permits it to shift axially and radially with respect to the rotor. The nut has a threaded hydrostatic bearing for engaging the threaded rod portion, with an oilcarrying groove in the nut being interrupted.

  20. Sparse linear programming subprogram

    SciTech Connect

    Hanson, R.J.; Hiebert, K.L.

    1981-12-01

    This report describes a subprogram, SPLP(), for solving linear programming problems. The package of subprogram units comprising SPLP() is written in Fortran 77. The subprogram SPLP() is intended for problems involving at most a few thousand constraints and variables. The subprograms are written to take advantage of sparsity in the constraint matrix. A very general problem statement is accepted by SPLP(). It allows upper, lower, or no bounds on the variables. Both the primal and dual solutions are returned as output parameters. The package has many optional features. Among them is the ability to save partial results and then use them to continue the computation at a later time.

  1. Clinical evaluation of regenerative potential of type I collagen membrane along with xenogenic bone graft in the treatment of periodontal intrabony defects assessed with surgical re-entry and radiographic linear and densitometric analysis

    PubMed Central

    Sowmya, N. K.; Tarun Kumar, A. B.; Mehta, D. S.

    2010-01-01

    Background and Objectives: The primary goal of periodontal therapy is to restore the tooth supporting tissues lost due to periodontal disease. The aim of the present study was to compare the efficacy of combination of type I collagen (GTR membrane) and xenogenic bone graft with open flap debridement (OFD) in treatment of periodontal intrabony defects. Materials and Methods: Twenty paired intrabony defects were surgically treated using split mouth design. The defects were randomly assigned to treatment with OFD + collagen membrane + bone graft (Test) or OFD alone (Control). The clinical efficacy of two treatment modalities was evaluated at 9 month postoperatively by clinical, radiographical, and intrasurgical (re-entry) parameters. The measurements included probing pocket depth (PD), clinical attachment level (CAL), gingival recession (GR), bone fill (BF), bone density (BD) and intra bony component (INTRA). Results: The mean reduction in PD at 0–9 month was 3.3±0.82 mm and CAL gain of 3.40±1.51 mm occurred in the collagen membrane + bone graft (Test) group; corresponding values for OFD (Control) were 2.20±0.63 mm and 1.90±0.57 mm. Similar pattern of improvement was observed when radiographical and intra-surgical (re-entry) post operative evaluation was made. All improvement in different parameters was statistically significant (P< 0.01). Interpretation and Conclusion: Treatment with a combination of collagen membrane and bone graft led to a significantly more favorable clinical outcome in intrabony defects as compared to OFD alone. PMID:20922075

  2. Clinical ethics revisited

    PubMed Central

    Singer, Peter A; Pellegrino, Edmund D; Siegler, Mark

    2001-01-01

    A decade ago, we reviewed the field of clinical ethics; assessed its progress in research, education, and ethics committees and consultation; and made predictions about the future of the field. In this article, we revisit clinical ethics to examine our earlier observations, highlight key developments, and discuss remaining challenges for clinical ethics, including the need to develop a global perspective on clinical ethics problems. PMID:11346456

  3. Linear IgA Bullous Dermatosis

    PubMed Central

    Chaudhari, Soham

    2015-01-01

    Linear immunoglobulin A bullous dermatosis is a rare autoimmune mucocutaneous disorder caused by immunoglobulin A autoantibodies produced against several different antigens in the basement membrane zone. Clinically, it is characterized by tense vesicles or bullae, which on histopathological exam demonstrate subepidermal blister with a predominantly neutrophilic infiltrate. A smooth, linear pattern of immunoglobulin A deposition in the basement membrane zone on direct immunofluorescence is considered the gold standard for establishing a diagnosis. Treatment consists of dapsone or sulfapyridine. The authors report a 60-year-old woman who presented with pruritic erythematous patches and plaques on her trunk, back, and legs without blisters, who was diagnosed with eczema for several months with no response to prior treatments. A biopsy was performed, which was consistent with linear immunoglobulin A bullous dermatosis and later confirmed by direct immunofluorescence studies. The authors present this case to increase awareness of this rare disease, which could manifest in a nonclassical, nonblistering fashion. PMID:26557220

  4. Induction linear accelerators

    NASA Astrophysics Data System (ADS)

    Birx, Daniel

    1992-03-01

    Among the family of particle accelerators, the Induction Linear Accelerator is the best suited for the acceleration of high current electron beams. Because the electromagnetic radiation used to accelerate the electron beam is not stored in the cavities but is supplied by transmission lines during the beam pulse it is possible to utilize very low Q (typically<10) structures and very large beam pipes. This combination increases the beam breakup limited maximum currents to of order kiloamperes. The micropulse lengths of these machines are measured in 10's of nanoseconds and duty factors as high as 10-4 have been achieved. Until recently the major problem with these machines has been associated with the pulse power drive. Beam currents of kiloamperes and accelerating potentials of megavolts require peak power drives of gigawatts since no energy is stored in the structure. The marriage of liner accelerator technology and nonlinear magnetic compressors has produced some unique capabilities. It now appears possible to produce electron beams with average currents measured in amperes, peak currents in kiloamperes and gradients exceeding 1 MeV/meter, with power efficiencies approaching 50%. The nonlinear magnetic compression technology has replaced the spark gap drivers used on earlier accelerators with state-of-the-art all-solid-state SCR commutated compression chains. The reliability of these machines is now approaching 1010 shot MTBF. In the following paper we will briefly review the historical development of induction linear accelerators and then discuss the design considerations.

  5. Linearly Forced Isotropic Turbulence

    NASA Technical Reports Server (NTRS)

    Lundgren, T. S.

    2003-01-01

    Stationary isotropic turbulence is often studied numerically by adding a forcing term to the Navier-Stokes equation. This is usually done for the purpose of achieving higher Reynolds number and longer statistics than is possible for isotropic decaying turbulence. It is generally accepted that forcing the Navier-Stokes equation at low wave number does not influence the small scale statistics of the flow provided that there is wide separation between the largest and smallest scales. It will be shown, however, that the spectral width of the forcing has a noticeable effect on inertial range statistics. A case will be made here for using a broader form of forcing in order to compare computed isotropic stationary turbulence with (decaying) grid turbulence. It is shown that using a forcing function which is directly proportional to the velocity has physical meaning and gives results which are closer to both homogeneous and non-homogeneous turbulence. Section 1 presents a four part series of motivations for linear forcing. Section 2 puts linear forcing to a numerical test with a pseudospectral computation.

  6. On unitary reconstruction of linear optical networks

    NASA Astrophysics Data System (ADS)

    Tillmann, Max; Schmidt, Christian; Walther, Philip

    2016-11-01

    Linear optical elements are pivotal instruments in the manipulation of classical and quantum states of light. Recent progress in integrated quantum photonic technology enabled the implementation of large numbers of such elements on chip, in particular passively stable interferometers. However, it is a challenge to characterize the optical transformation of such a device as the individual optical elements are not directly accessible. Thus only an effective overall transformation can be recovered. Here we present a reconstruction approach based on a global optimization of element parameters and compare it to two prominently used approaches. We numerically evaluate their performance for networks up to 14 modes and various levels of error on the primary data.

  7. Quantum theory of light propagation - Linear medium

    NASA Astrophysics Data System (ADS)

    Abram, I.

    1987-06-01

    A quantum-mechanical formalism has been developed which permits the treatment of light propagation within the conceptual framework of quantum optics. The formalism rests on the calculation of the momentum operator for the radiation field, and yields directly a description for the spatial progression of the electromagnetic waves. In this paper, a quantum-mechanical treatment for refraction and reflection is given by applying the formalism to propagation through a linear dielectric. The fidelity with which this formalism reproduces all results known from classical optics demonstrates its validity.

  8. Comet LINEAR Splits Further

    NASA Astrophysics Data System (ADS)

    2001-05-01

    Third Nucleus Observed with the VLT Summary New images from the VLT show that one of the two nuclei of Comet LINEAR (C/2001 A2), now about 100 million km from the Earth, has just split into at least two pieces . The three fragments are now moving through space in nearly parallel orbits while they slowly drift apart. This comet will pass through its perihelion (nearest point to the Sun) on May 25, 2001, at a distance of about 116 million kilometres. It has brightened considerably due to the splitting of its "dirty snowball" nucleus and can now be seen with the unaided eye by observers in the southern hemisphere as a faint object in the southern constellation of Lepus (The Hare). PR Photo 18a/01 : Three nuclei of Comet LINEAR . PR Photo 18b/01 : The break-up of Comet LINEAR (false-colour). Comet LINEAR splits and brightens ESO PR Photo 18a/01 ESO PR Photo 18a/01 [Preview - JPEG: 400 x 438 pix - 55k] [Normal - JPEG: 800 x 875 pix - 136k] ESO PR Photo 18b/01 ESO PR Photo 18b/01 [Preview - JPEG: 367 x 400 pix - 112k] [Normal - JPEG: 734 x 800 pix - 272k] Caption : ESO PR Photo 18a/01 shows the three nuclei of Comet LINEAR (C/2001 A2). It is a reproduction of a 1-min exposure in red light, obtained in the early evening of May 16, 2001, with the 8.2-m VLT YEPUN (UT4) telescope at Paranal. ESO PR Photo 18b/01 shows the same image, but in a false-colour rendering for more clarity. The cometary fragment "B" (right) has split into "B1" and "B2" (separation about 1 arcsec, or 500 km) while fragment "A" (upper left) is considerably fainter. Technical information about these photos is available below. Comet LINEAR was discovered on January 3, 2001, and designated by the International Astronomical Union (IAU) as C/2001 A2 (see IAU Circular 7564 [1]). Six weeks ago, it was suddenly observed to brighten (IAUC 7605 [1]). Amateurs all over the world saw the comparatively faint comet reaching naked-eye magnitude and soon thereafter, observations with professional telescopes indicated

  9. On the linear programming bound for linear Lee codes.

    PubMed

    Astola, Helena; Tabus, Ioan

    2016-01-01

    Based on an invariance-type property of the Lee-compositions of a linear Lee code, additional equality constraints can be introduced to the linear programming problem of linear Lee codes. In this paper, we formulate this property in terms of an action of the multiplicative group of the field [Formula: see text] on the set of Lee-compositions. We show some useful properties of certain sums of Lee-numbers, which are the eigenvalues of the Lee association scheme, appearing in the linear programming problem of linear Lee codes. Using the additional equality constraints, we formulate the linear programming problem of linear Lee codes in a very compact form, leading to a fast execution, which allows to efficiently compute the bounds for large parameter values of the linear codes.

  10. EDITORIAL: Catalysing progress Catalysing progress

    NASA Astrophysics Data System (ADS)

    Demming, Anna

    2010-01-01

    Examples of the merits of blue-sky research in the history of science are legion. The invention of the laser, celebrating its 50th anniversary this year, is an excellent example. When it was invented it was considered to be 'a solution waiting for a problem', and yet the level to which it has now infiltrated our day-to-day technological landscape speaks volumes. At the same time it is also true to say that the direction of research is also at times rightly influenced by the needs and concerns of the general public. Over recent years, growing concerns about the environment have had a noticeable effect on research in nanotechnology, motivating work on a range of topics from green nanomaterial synthesis [1] to high-efficiency solar cells [2] and hydrogen storage [3]. The impact of the world's energy consumption on the welfare of the planet is now an enduring and well founded concern. In the face of an instinctive reluctance to curtail habits of comfort and convenience and the appendages of culture and consumerism, research into renewable and more efficient energy sources seem an encouraging approach to alleviating an impending energy crisis. Fuel cells present one alternative to traditional combustion cells that have huge benefits in terms of the efficiency of energy conversion and the limited harmful emissions. In last week's issue of Nanotechnology, Chuan-Jian Zhong and colleagues at the State University of New York at Binghamton in the USA presented an overview of research on nanostructured catalysts in fuel cells [4]. The topical review includes insights into the interactions between nanoparticles and between nanoparticles and their substrate as well as control over the composition and nanostructure of catalysts. The review also serves to highlight how the flourishing of nanotechnology research has heralded great progress in the exploitation of catalysts with nanostructures ingeniously controlled to maximize surface area and optimize energetics for synthesis

  11. Differences in Treatment Effect Size Between Overall Survival and Progression-Free Survival in Immunotherapy Trials: A Meta-Epidemiologic Study of Trials With Results Posted at ClinicalTrials.gov.

    PubMed

    Tan, Aidan; Porcher, Raphael; Crequit, Perrine; Ravaud, Philippe; Dechartres, Agnes

    2017-04-04

    Purpose We aimed to compare treatment effect sizes between overall survival (OS) and progression-free survival (PFS) in trials of US Food and Drug Administration-approved oncology immunotherapy drugs with results posted at ClinicalTrials.gov . Methods We searched ClinicalTrials.gov for phase II to IV cancer trials of Food and Drug Administration-approved immunotherapy drugs and selected those reporting results for both OS and PFS. For each trial, we extracted the hazard ratios (HRs) with 95% CIs for both outcomes and evaluated the differences by a ratio of HRs (rHRs): the HR for PFS to that for OS. We performed a random effects meta-analysis across trials to obtain a summary rHR. We also evaluated surrogacy of PFS for OS by the coefficient of determination and the surrogacy threshold effect, the minimal value of HR for PFS to predict a non-null effect on OS. Results We identified 51 trials assessing 14 drugs across 15 conditions. Treatment effect sizes were 17% greater, on average, with PFS than with OS (rHR, 0.83; 95% CI, 0.79 to 0.88; I(2) = 34.4%; P = .01; τ(2) = 0.0129). Nearly one half of the trials (n = 23, 45%) showed statistically significant benefits for PFS but not for OS. Differences were great for trials of obinutuzumab (rHR, 0.21; 95% CI, 0.08 to 0.54), bevacizumab (rHR, 0.75; 95% CI, 0.67 to 0.84), and rituximab (rHR, 0.79; 95% CI, 0.64 to 0.98). The coefficient of determination was 38% and the surrogacy threshold effect was 0.50. Conclusion Treatment effect sizes in trials of immunotherapy drugs were greater for PFS than for OS, with important differences for some drugs, which is consistent with surrogacy metrics. Caution must be taken when interpreting PFS in the absence of OS data.

  12. Non-linear oscillations

    NASA Astrophysics Data System (ADS)

    Hagedorn, P.

    The mathematical pendulum is used to provide a survey of free and forced oscillations in damped and undamped systems. This simple model is employed to present illustrations for and comparisons between the various approximation schemes. A summary of the Liapunov stability theory is provided. The first and the second method of Liapunov are explained for autonomous as well as for nonautonomous systems. Here, a basic familiarity with the theory of linear oscillations is assumed. La Salle's theorem about the stability of invariant domains is explained in terms of illustrative examples. Self-excited oscillations are examined, taking into account such oscillations in mechanical and electrical systems, analytical approximation methods for the computation of self-excited oscillations, analytical criteria for the existence of limit cycles, forced oscillations in self-excited systems, and self-excited oscillations in systems with several degrees of freedom. Attention is given to Hamiltonian systems and an introduction to the theory of optimal control is provided.

  13. Positrons for linear colliders

    SciTech Connect

    Ecklund, S.

    1987-11-01

    The requirements of a positron source for a linear collider are briefly reviewed, followed by methods of positron production and production of photons by electromagnetic cascade showers. Cross sections for the electromagnetic cascade shower processes of positron-electron pair production and Compton scattering are compared. A program used for Monte Carlo analysis of electromagnetic cascades is briefly discussed, and positron distributions obtained from several runs of the program are discussed. Photons from synchrotron radiation and from channeling are also mentioned briefly, as well as positron collection, transverse focusing techniques, and longitudinal capture. Computer ray tracing is then briefly discussed, followed by space-charge effects and thermal heating and stress due to showers. (LEW)

  14. Linear Elastic Waves

    NASA Astrophysics Data System (ADS)

    Revenough, Justin

    Elastic waves propagating in simple media manifest a surprisingly rich collection of phenomena. Although some can't withstand the complexities of Earth's structure, the majority only grow more interesting and more important as remote sensing probes for seismologists studying the planet's interior. To fully mine the information carried to the surface by seismic waves, seismologists must produce accurate models of the waves. Great strides have been made in this regard. Problems that were entirely intractable a decade ago are now routinely solved on inexpensive workstations. The mathematical representations of waves coded into algorithms have grown vastly more sophisticated and are troubled by many fewer approximations, enforced symmetries, and limitations. They are far from straightforward, and seismologists using them need a firm grasp on wave propagation in simple media. Linear Elastic Waves, by applied mathematician John G. Harris, responds to this need.

  15. HEAVY ION LINEAR ACCELERATOR

    DOEpatents

    Van Atta, C.M.; Beringer, R.; Smith, L.

    1959-01-01

    A linear accelerator of heavy ions is described. The basic contributions of the invention consist of a method and apparatus for obtaining high energy particles of an element with an increased charge-to-mass ratio. The method comprises the steps of ionizing the atoms of an element, accelerating the resultant ions to an energy substantially equal to one Mev per nucleon, stripping orbital electrons from the accelerated ions by passing the ions through a curtain of elemental vapor disposed transversely of the path of the ions to provide a second charge-to-mass ratio, and finally accelerating the resultant stripped ions to a final energy of at least ten Mev per nucleon.

  16. Linear Proof Mass Actuator

    NASA Technical Reports Server (NTRS)

    Holloway, Sidney E., III

    1994-01-01

    This paper describes the mechanical design, analysis, fabrication, testing, and lessons learned by developing a uniquely designed spaceflight-like actuator. The linear proof mass actuator (LPMA) was designed to attach to both a large space structure and a ground test model without modification. Previous designs lacked the power to perform in a terrestrial environment while other designs failed to produce the desired accelerations or frequency range for spaceflight applications. Thus, the design for a unique actuator was conceived and developed at NASA Langley Research Center. The basic design consists of four large mechanical parts (mass, upper housing, lower housing, and center support) and numerous smaller supporting components including an accelerometer, encoder, and four drive motors. Fabrication personnel were included early in the design phase of the LPMA as part of an integrated manufacturing process to alleviate potential difficulties in machining an already challenging design. Operating testing of the LPMA demonstrated that the actuator is capable of various types of load functions.

  17. Linear Proof Mass Actuator

    NASA Technical Reports Server (NTRS)

    Holloway, S. E., III

    1995-01-01

    This paper describes the mechanical design, analysis, fabrication, testing, and lessons learned by developing a uniquely designed spaceflight-like actuator. The Linear Proof Mass Actuator (LPMA) was designed to attach to both a large space structure and a ground test model without modification. Previous designs lacked the power to perform in a terrestrial environment while other designs failed to produce the desired accelerations or frequency range for spaceflight applications. Thus, the design for a unique actuator was conceived and developed at NASA Langley Research Center. The basic design consists of four large mechanical parts (Mass, Upper Housing, Lower Housing, and Center Support) and numerous smaller supporting components including an accelerometer, encoder, and four drive motors. Fabrication personnel were included early in the design phase of the LPMA as part of an integrated manufacturing process to alleviate potential difficulties in machining an already challenging design. Operational testing of the LPMA demonstrated that the actuator is capable of various types of load functions.

  18. Non Linear Conjugate Gradient

    SciTech Connect

    Newman, Gregory A.; Commer, Michael

    2006-11-17

    Software that simulates and inverts electromagnetic field data for subsurface electrical properties (electrical conductivity) of geological media. The software treats data produced by a time harmonic source field excitation arising from the following antenna geometery: loops and grounded bipoles, as well as point electric and magnetic dioples. The inversion process is carried out using a non-linear conjugate gradient optimization scheme, which minimizes the misfit between field data and model data using a least squares criteria. The software is an upgrade from the code NLCGCS_MP ver 1.0. The upgrade includes the following components: Incorporation of new 1 D field sourcing routines to more accurately simulate the 3D electromagnetic field for arbitrary geologic& media, treatment for generalized finite length transmitting antenna geometry (antennas with vertical and horizontal component directions). In addition, the software has been upgraded to treat transverse anisotropy in electrical conductivity.

  19. Basic Linear Acoustics

    NASA Astrophysics Data System (ADS)

    Pierce, Alan

    This chapter deals with the physical and mathematical aspects of sound when the disturbances are, in some sense, small. Acoustics is usually concerned with small-amplitude phenomena, and consequently a linear description is usually applicable. Disturbances are governed by the properties of the medium in which they occur, and the governing equations are the equations of continuum mechanics, which apply equally to gases, liquids, and solids. These include the mass, momentum, and energy equations, as well as thermodynamic principles. The viscosity and thermal conduction enter into the versions of these equations that apply to fluids. Fluids of typical great interest are air and sea water, and consequently this chapter includes a summary of their relevant acoustic properties. The foundation is also laid for the consideration of acoustic waves in elastic solids, suspensions, bubbly liquids, and porous media.

  20. Basic Linear Acoustics

    NASA Astrophysics Data System (ADS)

    Pierce, Alan D.

    This chapter deals with the physical and mathematical aspects of sound when the disturbances are, in some sense, small. Acoustics is usually concerned with small-amplitude phenomena, and consequently a linear description is usually acoustics applicable. Disturbances are governed by the properties of the medium in which they occur, and the governing equations are the equations of continuum mechanics, which apply equally to gases, liquids, and solids. These include the mass, momentum, and energy equations, as well as thermodynamic principles. The viscosity and thermal conduction enter into the versions of these equations that apply to fluids. Fluids of typical great interest are air and sea water, and consequently this chapter includes a summary of their relevant acoustic properties. The foundation is also laid for the consideration of acoustic waves in elastic solids, suspensions, bubbly liquids, and porous media.

  1. Computer Program For Linear Algebra

    NASA Technical Reports Server (NTRS)

    Krogh, F. T.; Hanson, R. J.

    1987-01-01

    Collection of routines provided for basic vector operations. Basic Linear Algebra Subprogram (BLAS) library is collection from FORTRAN-callable routines for employing standard techniques to perform basic operations of numerical linear algebra.

  2. Learning oncogenetic networks by reducing to mixed integer linear programming.

    PubMed

    Shahrabi Farahani, Hossein; Lagergren, Jens

    2013-01-01

    Cancer can be a result of accumulation of different types of genetic mutations such as copy number aberrations. The data from tumors are cross-sectional and do not contain the temporal order of the genetic events. Finding the order in which the genetic events have occurred and progression pathways are of vital importance in understanding the disease. In order to model cancer progression, we propose Progression Networks, a special case of Bayesian networks, that are tailored to model disease progression. Progression networks have similarities with Conjunctive Bayesian Networks (CBNs) [1],a variation of Bayesian networks also proposed for modeling disease progression. We also describe a learning algorithm for learning Bayesian networks in general and progression networks in particular. We reduce the hard problem of learning the Bayesian and progression networks to Mixed Integer Linear Programming (MILP). MILP is a Non-deterministic Polynomial-time complete (NP-complete) problem for which very good heuristics exists. We tested our algorithm on synthetic and real cytogenetic data from renal cell carcinoma. We also compared our learned progression networks with the networks proposed in earlier publications. The software is available on the website https://bitbucket.org/farahani/diprog.

  3. Interior-Point Methods for Linear Programming: A Review

    ERIC Educational Resources Information Center

    Singh, J. N.; Singh, D.

    2002-01-01

    The paper reviews some recent advances in interior-point methods for linear programming and indicates directions in which future progress can be made. Most of the interior-point methods belong to any of three categories: affine-scaling methods, potential reduction methods and central path methods. These methods are discussed together with…

  4. Linear scleroderma associated with ptosis and motility disorders.

    PubMed Central

    Suttorp-Schulten, M S; Koornneef, L

    1990-01-01

    A case is reported in which an 11-year-old girl developed progressive ptosis and a subsequent motility disorder of the right eye. The diagnosis linear scleroderma en coup de sabre was established. Atrophy of the upper levator palpebral and superior rectus muscle could be shown on CT scan. Images PMID:2223709

  5. 40 CFR 51.1009 - Reasonable further progress (RFP) requirements.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... milestone year, emissions will be at a level consistent with generally linear progress in reducing emissions... plan are derived. (6) For purposes of establishing motor vehicle emissions budgets for...

  6. 40 CFR 51.1009 - Reasonable further progress (RFP) requirements.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... milestone year, emissions will be at a level consistent with generally linear progress in reducing emissions... plan are derived. (6) For purposes of establishing motor vehicle emissions budgets for...

  7. 40 CFR 51.1009 - Reasonable further progress (RFP) requirements.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... milestone year, emissions will be at a level consistent with generally linear progress in reducing emissions... plan are derived. (6) For purposes of establishing motor vehicle emissions budgets for...

  8. 40 CFR 51.1009 - Reasonable further progress (RFP) requirements.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... milestone year, emissions will be at a level consistent with generally linear progress in reducing emissions... plan are derived. (6) For purposes of establishing motor vehicle emissions budgets for...

  9. [Linear IgA bullous dermatosis: the importance of a correct differential diagnosis].

    PubMed

    Colombo, M; Volpini, S; Orini, S; Fazi, M C; Vettore, E; Tedoldi, S; Cappellaro, E

    2008-06-01

    Linear IgA bullous dermatosis is an acquired subepidermal blistering disease which belongs to bullous autoimmune diseases, along with dermatitis herpetiformis and bullous pemphigoid. Inflammatory blisters are the main clinical characteristics and the areas of common involvement are: perioral region, abdomen, perineum, buttocks and the interior side of thighs. Essential for the diagnosis is to find by direct immunofluorescence the presence of a linear band of IgA antibodies at the level of the basement membrane. We present the case of a 5 year-old Moroccan girl which arrived at our First Aid Department for bullous dermatitis, localized mainly on the abdomen, legs and thighs. During a short stay in Morocco, a month before, the little girl was stung by an insect and developed bullous dermatitis by a residual lesion. The child was in a good state of health but blood exams showed an increase of total IgE antibodies. The girl was admitted and during her hospitalisation we made a skin biopsy which led to a diagnosis of linear IgA dermatosis. She began a steroid therapy and there was a progressive regression of the lesions. At present, she does not take medicines anymore, she feels well and is submitted to ambulatory medical follow-up.

  10. Multispecialty Clinic Practice

    PubMed Central

    Margolin, David A.; Beck, David E.

    2011-01-01

    A multispecialty clinic practice is a common practice arrangement for colorectal surgeons. This type of practice has a variety of features, both positive and negative. The authors explore location, practice patterns, lifestyles, compensation, and academic opportunities associated with a multispecialty clinic practice. This information can assist younger surgeons in choosing a practice opportunity and guide experienced surgeons through their career progression. PMID:22654568

  11. Progressive familial intrahepatic cholestasis.

    PubMed

    Srivastava, Anshu

    2014-03-01

    Progressive familial intrahepatic cholestasis (PFIC) is a group of rare disorders which are caused by defect in bile secretion and present with intrahepatic cholestasis, usually in infancy and childhood. These are autosomal recessive in inheritance. The estimated incidence is about 1 per 50,000 to 1 per 100,000 births, although exact prevalence is not known. These diseases affect both the genders equally and have been reported from all geographical areas. Based on clinical presentation, laboratory findings, liver histology and genetic defect, these are broadly divided into three types-PFIC type 1, PFIC type 2 and PFIC type 3. The defect is in ATP8B1 gene encoding the FIC1 protein, ABCB 11 gene encoding BSEP protein and ABCB4 gene encoding MDR3 protein in PFIC1, 2 and 3 respectively. The basic defect is impaired bile salt secretion in PFIC1/2 whereas in PFIC3, it is reduced biliary phospholipid secretion. The main clinical presentation is in the form of cholestatic jaundice and pruritus. Serum gamma glutamyl transpeptidase (GGT) is normal in patients with PFIC1/2 while it is raised in patients with PFIC3. Treatment includes nutritional support (adequate calories, supplementation of fat soluble vitamins and medium chain triglycerides) and use of medications to relieve pruritus as initial therapy followed by biliary diversion procedures in selected patients. Ultimately liver transplantation is needed in most patients as they develop progressive liver fibrosis, cirrhosis and end stage liver disease. Due to the high risk of developing liver tumors in PFIC2 patients, monitoring is recommended from infancy. Mutation targeted pharmacotherapy, gene therapy and hepatocyte transplantation are being explored as future therapeutic options.

  12. LINEAR - DERIVATION AND DEFINITION OF A LINEAR AIRCRAFT MODEL

    NASA Technical Reports Server (NTRS)

    Duke, E. L.

    1994-01-01

    The Derivation and Definition of a Linear Model program, LINEAR, provides the user with a powerful and flexible tool for the linearization of aircraft aerodynamic models. LINEAR was developed to provide a standard, documented, and verified tool to derive linear models for aircraft stability analysis and control law design. Linear system models define the aircraft system in the neighborhood of an analysis point and are determined by the linearization of the nonlinear equations defining vehicle dynamics and sensors. LINEAR numerically determines a linear system model using nonlinear equations of motion and a user supplied linear or nonlinear aerodynamic model. The nonlinear equations of motion used are six-degree-of-freedom equations with stationary atmosphere and flat, nonrotating earth assumptions. LINEAR is capable of extracting both linearized engine effects, such as net thrust, torque, and gyroscopic effects and including these effects in the linear system model. The point at which this linear model is defined is determined either by completely specifying the state and control variables, or by specifying an analysis point on a trajectory and directing the program to determine the control variables and the remaining state variables. The system model determined by LINEAR consists of matrices for both the state and observation equations. The program has been designed to provide easy selection of state, control, and observation variables to be used in a particular model. Thus, the order of the system model is completely under user control. Further, the program provides the flexibility of allowing alternate formulations of both the state and observation equations. Data describing the aircraft and the test case is input to the program through a terminal or formatted data files. All data can be modified interactively from case to case. The aerodynamic model can be defined in two ways: a set of nondimensional stability and control derivatives for the flight point of

  13. Winding for linear pump

    DOEpatents

    Kliman, G.B.; Brynsvold, G.V.; Jahns, T.M.

    1989-08-22

    A winding and method of winding for a submersible linear pump for pumping liquid sodium are disclosed. The pump includes a stator having a central cylindrical duct preferably vertically aligned. The central vertical duct is surrounded by a system of coils in slots. These slots are interleaved with magnetic flux conducting elements, these magnetic flux conducting elements forming a continuous magnetic field conduction path along the stator. The central duct has placed therein a cylindrical magnetic conducting core, this core having a cylindrical diameter less than the diameter of the cylindrical duct. The core once placed to the duct defines a cylindrical interstitial pumping volume of the pump. This cylindrical interstitial pumping volume preferably defines an inlet at the bottom of the pump, and an outlet at the top of the pump. Pump operation occurs by static windings in the outer stator sequentially conveying toroidal fields from the pump inlet at the bottom of the pump to the pump outlet at the top of the pump. The winding apparatus and method of winding disclosed uses multiple slots per pole per phase with parallel winding legs on each phase equal to or less than the number of slots per pole per phase. The slot sequence per pole per phase is chosen to equalize the variations in flux density of the pump sodium as it passes into the pump at the pump inlet with little or no flux and acquires magnetic flux in passage through the pump to the pump outlet. 4 figs.

  14. Winding for linear pump

    DOEpatents

    Kliman, Gerald B.; Brynsvold, Glen V.; Jahns, Thomas M.

    1989-01-01

    A winding and method of winding for a submersible linear pump for pumping liquid sodium is disclosed. The pump includes a stator having a central cylindrical duct preferably vertically aligned. The central vertical duct is surrounded by a system of coils in slots. These slots are interleaved with magnetic flux conducting elements, these magnetic flux conducting elements forming a continuous magnetic field conduction path along the stator. The central duct has placed therein a cylindrical magnetic conducting core, this core having a cylindrical diameter less than the diameter of the cylindrical duct. The core once placed to the duct defines a cylindrical interstitial pumping volume of the pump. This cylindrical interstitial pumping volume preferably defines an inlet at the bottom of the pump, and an outlet at the top of the pump. Pump operation occurs by static windings in the outer stator sequentially conveying toroidal fields from the pump inlet at the bottom of the pump to the pump outlet at the top of the pump. The winding apparatus and method of winding disclosed uses multiple slots per pole per phase with parallel winding legs on each phase equal to or less than the number of slots per pole per phase. The slot sequence per pole per phase is chosen to equalize the variations in flux density of the pump sodium as it passes into the pump at the pump inlet with little or no flux and acquires magnetic flux in passage through the pump to the pump outlet.

  15. Linear Rogowski coil

    NASA Astrophysics Data System (ADS)

    Nassisi, V.; Delle Side, D.

    2017-02-01

    Nowadays, the employment and development of fast current pulses require sophisticated systems to perform measurements. Rogowski coils are used to diagnose cylindrical shaped beams; therefore, they are designed and built with a toroidal structure. Recently, to perform experiments of radiofrequency biophysical stresses, flat transmission lines have been developed. Therefore, in this work we developed a linear Rogowski coil to detect current pulses inside flat conductors. The system is first approached by means of transmission line theory. We found that, if the pulse width to be diagnosed is comparable with the propagation time of the signal in the detector, it is necessary to impose a uniform current as input pulse, or to use short coils. We further analysed the effect of the resistance of the coil and the influence of its magnetic properties. As a result, the device we developed is able to record pulses lasting for some hundreds of nanoseconds, depending on the inductance, load impedance, and resistance of the coil. Furthermore, its response is characterized by a sub-nanosecond rise time (˜100 ps). The attenuation coefficient depends mainly on the turn number of the coil, while the fidelity of the response depends both on the magnetic core characteristics and on the current distribution along the plane conductors.

  16. Linear induction pump

    DOEpatents

    Meisner, John W.; Moore, Robert M.; Bienvenue, Louis L.

    1985-03-19

    Electromagnetic linear induction pump for liquid metal which includes a unitary pump duct. The duct comprises two substantially flat parallel spaced-apart wall members, one being located above the other and two parallel opposing side members interconnecting the wall members. Located within the duct are a plurality of web members interconnecting the wall members and extending parallel to the side members whereby the wall members, side members and web members define a plurality of fluid passageways, each of the fluid passageways having substantially the same cross-sectional flow area. Attached to an outer surface of each side member is an electrically conductive end bar for the passage of an induced current therethrough. A multi-phase, electrical stator is located adjacent each of the wall members. The duct, stators, and end bars are enclosed in a housing which is provided with an inlet and outlet in fluid communication with opposite ends of the fluid passageways in the pump duct. In accordance with a preferred embodiment, the inlet and outlet includes a transition means which provides for a transition from a round cross-sectional flow path to a substantially rectangular cross-sectional flow path defined by the pump duct.

  17. Generalized Linear Covariance Analysis

    NASA Technical Reports Server (NTRS)

    Carpenter, James R.; Markley, F. Landis

    2014-01-01

    This talk presents a comprehensive approach to filter modeling for generalized covariance analysis of both batch least-squares and sequential estimators. We review and extend in two directions the results of prior work that allowed for partitioning of the state space into solve-for'' and consider'' parameters, accounted for differences between the formal values and the true values of the measurement noise, process noise, and textita priori solve-for and consider covariances, and explicitly partitioned the errors into subspaces containing only the influence of the measurement noise, process noise, and solve-for and consider covariances. In this work, we explicitly add sensitivity analysis to this prior work, and relax an implicit assumption that the batch estimator's epoch time occurs prior to the definitive span. We also apply the method to an integrated orbit and attitude problem, in which gyro and accelerometer errors, though not estimated, influence the orbit determination performance. We illustrate our results using two graphical presentations, which we call the variance sandpile'' and the sensitivity mosaic,'' and we compare the linear covariance results to confidence intervals associated with ensemble statistics from a Monte Carlo analysis.

  18. Linear cochlear mechanics.

    PubMed

    Zweig, George

    2015-08-01

    An active, three-dimensional, short-wavelength model of cochlear mechanics is derived from an older, one-dimensional, long-wavelength model containing time-delay forces. Remarkably, the long-wavelength model with nonlocal temporal interactions behaves like a short-wavelength model with instantaneous interactions. The cochlear oscillators are driven both by the pressure and its time derivative, the latter presumably a proxy for forces contributed by outer hair cells. The admittance in the short-wavelength region is used to find an integral representation of the transfer function valid for all wavelengths. There are only two free parameters: the pole position in the complex frequency plane of the admittance, and the slope of the transfer-function phase at low frequencies. The new model predicts a dip in amplitude and a corresponding rapid drop in phase, past the peak of the traveling wave. Linear models may be compared by their wavelengths, and if they have the same dimension, by the singularity structure of their admittances.

  19. Berkeley Proton Linear Accelerator

    DOE R&D Accomplishments Database

    Alvarez, L. W.; Bradner, H.; Franck, J.; Gordon, H.; Gow, J. D.; Marshall, L. C.; Oppenheimer, F. F.; Panofsky, W. K. H.; Richman, C.; Woodyard, J. R.

    1953-10-13

    A linear accelerator, which increases the energy of protons from a 4 Mev Van de Graaff injector, to a final energy of 31.5 Mev, has been constructed. The accelerator consists of a cavity 40 feet long and 39 inches in diameter, excited at resonance in a longitudinal electric mode with a radio-frequency power of about 2.2 x 10{sup 6} watts peak at 202.5 mc. Acceleration is made possible by the introduction of 46 axial "drift tubes" into the cavity, which is designed such that the particles traverse the distance between the centers of successive tubes in one cycle of the r.f. power. The protons are longitudinally stable as in the synchrotron, and are stabilized transversely by the action of converging fields produced by focusing grids. The electrical cavity is constructed like an inverted airplane fuselage and is supported in a vacuum tank. Power is supplied by 9 high powered oscillators fed from a pulse generator of the artificial transmission line type.

  20. Linear Rogowski coil.

    PubMed

    Nassisi, V; Delle Side, D

    2017-02-01

    Nowadays, the employment and development of fast current pulses require sophisticated systems to perform measurements. Rogowski coils are used to diagnose cylindrical shaped beams; therefore, they are designed and built with a toroidal structure. Recently, to perform experiments of radiofrequency biophysical stresses, flat transmission lines have been developed. Therefore, in this work we developed a linear Rogowski coil to detect current pulses inside flat conductors. The system is first approached by means of transmission line theory. We found that, if the pulse width to be diagnosed is comparable with the propagation time of the signal in the detector, it is necessary to impose a uniform current as input pulse, or to use short coils. We further analysed the effect of the resistance of the coil and the influence of its magnetic properties. As a result, the device we developed is able to record pulses lasting for some hundreds of nanoseconds, depending on the inductance, load impedance, and resistance of the coil. Furthermore, its response is characterized by a sub-nanosecond rise time (∼100 ps). The attenuation coefficient depends mainly on the turn number of the coil, while the fidelity of the response depends both on the magnetic core characteristics and on the current distribution along the plane conductors.

  1. Mother and daughter with a terminal Xp deletion: implication of chromosomal mosaicism and X-inactivation in the high clinical variability of the microphthalmia with linear skin defects (MLS) syndrome.

    PubMed

    Wimplinger, Isabella; Rauch, Anita; Orth, Ulrike; Schwarzer, Ulrich; Trautmann, Udo; Kutsche, Kerstin

    2007-01-01

    The microphthalmia with linear skin defects (MLS or MIDAS) syndrome is a rare X-linked dominant inherited disorder with male lethality, associated with segmental aneuploidy of the Xp22.2 region in most of the cases. However, we recently described heterozygous sequence alterations in a single gene, HCCS, in females with MLS. Beside the classical MLS phenotype, occasional features such as sclerocornea, agenesis of the corpus callosum, and congenital heart defects can occur. Although the majority of cases are sporadic, mother-to-daughter transmission has been observed and a high intra- and interfamilial phenotypic variability exists. We describe an asymptomatic mother and her daughter presenting with the typical features of MLS syndrome. By cytogenetic analysis both females were found to have a terminal Xp deletion with the breakpoint in Xp22.2, mapping near to or within the MSL3L1 gene which is located centromeric to HCCS. FISH analysis revealed that the mother is a mosaic with 45,X(11)/46,X,del(X)(p22.2)(89), while in all cells of the MLS-affected daughter a hybridization pattern consistent with a 46,X,del(X)(p22.2) karyotype was detected. By haplotype analysis we identified the paternal X chromosome of the mother to carry the terminal Xp deletion. X-inactivation studies showed a completely skewed pattern in mother and daughter with the deleted X chromosome to be preferentially inactivated in their peripheral blood cells. We suggest that both chromosomal mosaicism as well as functional X chromosome mosaicism could contribute to the lack of any typical MLS feature in individuals with a heterozygous MLS-associated mutation. The 45,X cell population, that most likely is also present in other tissues of the mother, might have protected her from developing MLS. Nonetheless, a non-random X-inactivation pattern in favor of activity of the wild-type X chromosome in the early blastocyte could also account for the apparent lack of any disease sign in this female.

  2. Linear and non-linear interdependence of EEG and HRV frequency bands in human sleep.

    PubMed

    Chaparro-Vargas, Ramiro; Dissanayaka, P Chamila; Patti, Chanakya Reddy; Schilling, Claudia; Schredl, Michael; Cvetkovic, Dean

    2014-01-01

    The characterisation of functional interdependencies of the autonomic nervous system (ANS) stands an evergrowing interest to unveil electroencephalographic (EEG) and Heart Rate Variability (HRV) interactions. This paper presents a biosignal processing approach as a supportive computational resource in the estimation of sleep dynamics. The application of linear, non-linear methods and statistical tests upon 10 overnight polysomnographic (PSG) recordings, allowed the computation of wavelet coherence and phase locking values, in order to identify discerning features amongst the clinical healthy subjects. Our findings showed that neuronal oscillations θ, α and σ interact with cardiac power bands at mid-to-high rank of coherence and phase locking, particularly during NREM sleep stages.

  3. Evidence-based medical perspectives: the evolving role of PSA for early detection, monitoring of treatment response, and as a surrogate end point of efficacy for interventions in men with different clinical risk states for the prevention and progression of prostate cancer.

    PubMed

    Lieberman, Ronald

    2004-01-01

    Following FDA approval and introduction into the clinic in the mid-1980s, PSA testing has become arguably the most versatile serum tumor marker in urologic oncology with clinical use for early detection (screening) of prostate cancer (PC), risk stratification for clinical staging, prognosis, intermediate biomarker for monitoring tumor recurrence, and more recently as an intermediate biomarker for assessing therapeutic response to antiandrogens, radiation therapy, and chemotherapy. PSA now routinely guides health care providers for the clinical management of PC over a wide range of clinical risk states for men at risk of PC, after local definitive therapy and after systemic therapy to prevent progression to metastatic bone disease, and to palliate men with hormone refractory prostate cancer (HRPC). To further assess the evidence that supports these clinical applications, this commentary reviews and critically evaluates the emerging body of new data focusing on several recently published seminal articles by D'Amico et al and Thompson et al, the new National Comprehensive Cancer Network 2004 recommendations for starting PSA testing at the age of 40 years old, the latest results from 2 phase 3 randomized, controlled trials of taxane-based regimens showing improved survival for men with HRPC, and the recent US FDA Public Workshop on Clinical Trial Endpoints in Prostate Cancer that helped to distill and synthesize the current state of the art and the progress toward validation of PSA metrics (eg, PSA velocity) as a surrogate end point (SE) for treatment efficacy with taxane-based regimens. Furthermore, several randomized, controlled chemoprevention trials in progress evaluating agents such as selenium and vitamin E in high-risk cohorts are well poised to confirm the validity of PSA as an SE for clinical efficacy for the prevention and progression of PC. Although there continues to be a need to validate better biomarkers before diagnosis of PC (more sensitive and specific

  4. Myopia: attempts to arrest progression

    PubMed Central

    Saw, S M; Gazzard, G; Au Eong, K-G; Tan, D T H

    2002-01-01

    Previous studies have evaluated the efficacy of several interventions to decrease the progression of myopia. These include devices that alter the perception of the visual environment and pharmacological treatments. There is no conclusive evidence thus far that alteration of the pattern of spectacle wear, bifocals, ocular hypotensives, or contact lenses retards the progression of myopia. Several randomised clinical trials have demonstrated that the rate of progression of myopia is lower in children given atropine eye drops than those given placebo. However, atropine is associated with short term side effects such as photophobia and possible long term adverse events including light induced retinal damage and cataract formation. Other more selective antimuscarinic agents such as pirenzipine are presently being evaluated. Further well conducted randomised clinical trials with large sample sizes and adequate follow up designed to evaluate treatments to retard the progression of myopia should be conducted, since the identification of an effective intervention may have a greater public health impact on the burden and morbidity from myopia than the few treatments currently available. PMID:12386095

  5. PATHWAYS OF MEDICAL PROGRESS.

    PubMed

    Wiggers, C J

    1940-01-12

    During the three decades that have passed, medical science has ascended to a high plateau of achievement. The climb has involved several pathways; among them: (1) the physiological approach toward disease as experiments which nature performs on organisms, (2) the more intelligent interpretation of the functional reactions of the body in disease in accordance with latest discoveries in physiology, (3) the supplementation of observable phenomena through use of laboratory instruments, (4) the assumption of active investigation both on patients and experimental animals by clinicians themselves, (5) the shuttling of problems between clinical and experimental laboratories and (6) correlated research in clinical and physiological departments. As we look down from the heights we have reached, we have reason to be pleased with our progress; but when we look ahead we become aware that there are still high mountain ranges to be climbed. We realize that their ascent can not be accomplished by employing merely the methods, equipment and strategy that have proved successful so far; we must improve the application of principles that are old and well established, and evolve others that are new. Above all, we from laboratories and clinics must join hands to help each other climb; and through correlated team-work overcome the great obstacles that jealous nature places in our way. I have ventured to suggest a few directions which such mutual help may take. They include (1) means by which new fundamental discoveries can be utilized more quickly by clinicians and practitioners of medicine; (2) plans by which younger clinical investigators can be given approximately the same opportunity for training in research technique as their colleagues entering experimental sciences; (3) pleas that the shuttling of problems between hospitals and laboratories of fundamental science may continue in order that the ultimate significance of clinical results may be better understood and that the

  6. Tracking motor impairments in the progression of Huntington's disease.

    PubMed

    Long, Jeffery D; Paulsen, Jane S; Marder, Karen; Zhang, Ying; Kim, Ji-In; Mills, James A

    2014-03-01

    The Unified Huntington's Disease Rating Scale is used to characterize motor impairments and establish motor diagnosis. Little is known about the timing of diagnostic confidence level categories and the trajectory of motor impairments during the prodromal phase. Goals of this study were to estimate the timing of categories, model the prodromal trajectory of motor impairments, estimate the rate of motor impairment change by category, and provide required sample size estimates for a test of efficacy in clinical trials. In total, 1010 gene-expanded participants from the Neurobiological Predictors of Huntington's Disease (PREDICT-HD) trial were analyzed. Accelerated failure time models were used to predict the timing of categories. Linear mixed effects regression was used to model the longitudinal motor trajectories. Age and length of gene expansion were incorporated into all models. The timing of categories varied significantly by gene expansion, with faster progression associated with greater expansion. For the median expansion, the third diagnostic confidence level category was estimated to have a first occurrence 1.5 years before diagnosis, and the second and first categories were estimated to occur 6.75 years and 19.75 years before diagnosis, respectively. Motor impairments displayed a nonlinear prodromal course. The motor impairment rate of change increased as the diagnostic confidence level increased, with added acceleration for higher progression scores. Motor items can detect changes in motor impairments before diagnosis. Given a sufficiently high progression score, there is evidence that the diagnostic confidence level can be used for prodromal staging. Implications for Huntington's disease research and the planning of clinical trials of efficacy are discussed.

  7. PROGRESS IN ACUTE MYELOID LEUKEMIA

    PubMed Central

    Kadia, Tapan M.; Ravandi, Farhad; O’Brien, Susan; Cortes, Jorge; Kantarjian, Hagop M.

    2014-01-01

    Significant progress has been made in the treatment of acute myeloid leukemia (AML). Steady gains in clinical research and a renaissance of genomics in leukemia have led to improved outcomes. The recognition of tremendous heterogeneity in AML has allowed individualized treatments of specific disease entities within the context of patient age, cytogenetics, and mutational analysis. The following is a comprehensive review of the current state of AML therapy and a roadmap of our approach to these distinct disease entities. PMID:25441110

  8. Progress in breast cancer: overview.

    PubMed

    Arteaga, Carlos L

    2013-12-01

    This edition of CCR Focus titled Research in Breast Cancer: Frontiers in Genomics, Biology, and Clinical Investigation reviews six topics that cover areas of translational research of high impact in breast cancer. These topics represent areas of breast cancer research where significant progress has occurred but also where very important challenges remain. The papers in this CCR Focus section are contributed by experts in the respective areas of investigation. Herein, key aspects of these contributions and the research directions they propose are reviewed.

  9. Linear Algebraic Method for Non-Linear Map Analysis

    SciTech Connect

    Yu,L.; Nash, B.

    2009-05-04

    We present a newly developed method to analyze some non-linear dynamics problems such as the Henon map using a matrix analysis method from linear algebra. Choosing the Henon map as an example, we analyze the spectral structure, the tune-amplitude dependence, the variation of tune and amplitude during the particle motion, etc., using the method of Jordan decomposition which is widely used in conventional linear algebra.

  10. Damage Identification with Linear Discriminant Operators

    SciTech Connect

    Farrar, C.R.; Nix, D.A.; Duffey, T.A.; Cornwell, P.J.; Pardoen, G.C.

    1999-02-08

    This paper explores the application of statistical pattern recognition and machine learning techniques to vibration-based damage detection. First, the damage detection process is described in terms of a problem in statistical pattern recognition. Next, a specific example of a statistical-pattern-recognition-based damage detection process using a linear discriminant operator, ''Fisher's Discriminant'', is applied to the problem of identifying structural damage in a physical system. Accelerometer time histories are recorded from sensors attached to the system as that system is excited using a measured input. Linear Prediction Coding (LPC) coefficients are utilized to convert the accelerometer time-series data into multi-dimensional samples representing the resonances of the system during a brief segment of the time series. Fisher's discriminant is then used to find the linear projection of the LPC data distributions that best separates data from undamaged and damaged systems. The method i s applied to data from concrete bridge columns as the columns are progressively damaged. For this case, the method captures a clear distinction between undamaged and damaged vibration profiles. Further, the method assigns a probability of damage that can be used to rank systems in order of priority for inspection.

  11. Stars and linear dunes on Mars

    NASA Technical Reports Server (NTRS)

    Edgett, Kenneth S.; Blumberg, Dan G.

    1994-01-01

    A field containing 11 star and incipient star dunes occurs on Mars at 8.8 deg S, 270.9 deg W. Examples of linear dunes are found in a crater at 59.4 deg S, 343 deg W. While rare, dune varieties that form in bi- and multidirectional wind regimes are not absent from the surface of Mars. The occurence of both of these dune fields offers new insight into the nature of martian wind conditions and sand supply. The linear dunes appears to have formed through modification of a formerly transverse aeolian deposit, suggesting a relatively recent change in local wind direction. The 11 dunes in the star dune locality show a progressive change from barchan to star form as each successive dune has traveled up into a valley, into a more complex wind regime. The star dunes corroborate the model of N. Lancaster (1989), for the formation of star dunes by projection of transverse dunes into a complex, topographically influenced wind regime. The star dunes have dark streaks emanating from them, providing evidence that the dunes were active at or near the time the relevant image was obtained by the Viking 1 orbiter in 1978. The star and linear dunes described here are located in different regions on the martian surface. Unlike most star and linear dunes on Earth, both martian examples are isolated occurrences; neither is part of a major sand sea. Previously published Mars general circulation model results suggest that the region in which the linear dune field occurs should be a bimodal wind regime, while the region in which the star dunes occur should be unimodal. The star dunes are probably the result of localized complication of the wind regime owing to topographic confinement of the dunes. Local topographic influence on wind regime is also evident in the linear dune field, as there are transverse dunes in close proximity to the linear dunes, and their occurrence is best explained by funneling of wind through a topographic gap in the upwind crater wall.

  12. A Case of Linear Lichen Planus Pigmentosus

    PubMed Central

    Seo, Jong Keun; Lee, Hyun Jae; Choi, Joon Hee; Sung, Ho-Suck

    2010-01-01

    Lichen planus pigmentosus (LPP) is chronic pigmentary disorder that shows diffuse or reticulated hyperpigmented, dark brown macules on the sun-exposed areas such as the face, neck and other flexural folds. Clinically, it is different from classical lichen planus because LPP has a longer clinical course and it manifests with dark brown macules. In case of LPP, involvement of the scalp, nail or mucosal area is rare. The histopathological findings of the lesions show an atrophic epidermis, the presence of melanophages and a vacuolar alteration of the basal cell layer with a sparse lymphohistiocytic lichenoid infiltration. Although there have been a few reports of LPP, there have only 3 cases of linear LPP along the lines of Blaschko in the Korean dermatologic literature. Our patient had lesions on the neck and chin with a linear pattern. In this report, we describe a very rare case of LPP with a linear distribution related to Blaschko's lines on the neck and chin areas. PMID:20711271

  13. Turbulence Spreading into Linearly Stable Zone and Transport Scaling

    SciTech Connect

    T.S. Hahm; P.H. Diamond; Z. Lin; K. Itoh; S.-I. Itoh

    2003-10-20

    We study the simplest problem of turbulence spreading corresponding to the spatio-temporal propagation of a patch of turbulence from a region where it is locally excited to a region of weaker excitation, or even local damping. A single model equation for the local turbulence intensity I(x, t) includes the effects of local linear growth and damping, spatially local nonlinear coupling to dissipation and spatial scattering of turbulence energy induced by nonlinear coupling. In the absence of dissipation, the front propagation into the linearly stable zone occurs with the property of rapid progression at small t, followed by slower subdiffusive progression at late times. The turbulence radial spreading into the linearly stable zone reduces the turbulent intensity in the linearly unstable zone, and introduces an additional dependence on the rho* is always equal to rho i/a to the turbulent intensity and the transport scaling. These are in broad, semi-quantitative agreements with a number of global gyrokinetic simulation results with zonal flows and without zonal flows. The front propagation stops when the radial flux of fluctuation energy from the linearly unstable region is balanced by local dissipation in the linearly stable region.

  14. Defining secondary progressive multiple sclerosis.

    PubMed

    Lorscheider, Johannes; Buzzard, Katherine; Jokubaitis, Vilija; Spelman, Tim; Havrdova, Eva; Horakova, Dana; Trojano, Maria; Izquierdo, Guillermo; Girard, Marc; Duquette, Pierre; Prat, Alexandre; Lugaresi, Alessandra; Grand'Maison, François; Grammond, Pierre; Hupperts, Raymond; Alroughani, Raed; Sola, Patrizia; Boz, Cavit; Pucci, Eugenio; Lechner-Scott, Jeanette; Bergamaschi, Roberto; Oreja-Guevara, Celia; Iuliano, Gerardo; Van Pesch, Vincent; Granella, Franco; Ramo-Tello, Cristina; Spitaleri, Daniele; Petersen, Thor; Slee, Mark; Verheul, Freek; Ampapa, Radek; Amato, Maria Pia; McCombe, Pamela; Vucic, Steve; Sánchez Menoyo, José Luis; Cristiano, Edgardo; Barnett, Michael H; Hodgkinson, Suzanne; Olascoaga, Javier; Saladino, Maria Laura; Gray, Orla; Shaw, Cameron; Moore, Fraser; Butzkueven, Helmut; Kalincik, Tomas

    2016-09-01

    sclerosis based on the Expanded Disability Status Scale and information about preceding relapses provides a tool for a reproducible, accurate and timely diagnosis that requires a very short confirmation period. If applied broadly, the definition has the potential to strengthen the design and improve comparability of clinical trials and observational studies in secondary progressive multiple sclerosis.

  15. Male Sex Is Independently Associated with Faster Disability Accumulation in Relapse-Onset MS but Not in Primary Progressive MS

    PubMed Central

    Ribbons, Karen Ann; McElduff, Patrick; Boz, Cavit; Trojano, Maria; Izquierdo, Guillermo; Duquette, Pierre; Girard, Marc; Grand’Maison, Francois; Hupperts, Raymond; Grammond, Pierre; Oreja-Guevara, Celia; Petersen, Thor; Bergamaschi, Roberto; Giuliani, Giorgio; Barnett, Michael; van Pesch, Vincent; Amato, Maria-Pia; Iuliano, Gerardo; Fiol, Marcela; Slee, Mark; Verheul, Freek; Cristiano, Edgardo; Fernandez-Bolanos, Ricardo; Saladino, Maria-Laura; Rio, Maria Edite; Cabrera-Gomez, Jose; Butzkueven, Helmut; van Munster, Erik; Den Braber-Moerland, Leontien; La Spitaleri, Daniele; Lugaresi, Alessandra; Shaygannejad, Vahid; Gray, Orla; Deri, Norma; Alroughani, Raed; Lechner-Scott, Jeannette

    2015-01-01

    Background Multiple Sclerosis is more common in women than men and females have more relapses than men. In a large international cohort we have evaluated the effect of gender on disability accumulation and disease progression to determine if male MS patients have a worse clinical outcome than females. Methods Using the MSBase Registry, data from 15,826 MS patients from 25 countries was analysed. Changes in the severity of MS (EDSS) were compared between sexes using a repeated measures analysis in generalised linear mixed models. Kaplan-Meier analysis was used to test for sex difference in the time to reach EDSS milestones 3 and 6 and the secondary progressive MS. Results In relapse onset MS patients (n = 14,453), males progressed significantly faster in their EDSS than females (0.133 vs 0.112 per year, P<0.001,). Females had a reduced risk of secondary progressive MS (HR (95% CI) = 0.77 (0.67 to 0.90) P = 0.001). In primary progressive MS (n = 1,373), there was a significant increase in EDSS over time in males and females (P<0.001) but there was no significant sex effect on the annualized rate of EDSS change. Conclusion Among registrants of MSBase, male relapse-onset patients accumulate disability faster than female patients. In contrast, the rate of disability accumulation between male and female patients with primary progressive MS is similar. PMID:26046348

  16. Linear Proof-Mass Actuator

    NASA Technical Reports Server (NTRS)

    Holloway, Sidney E., III; Crossley, Edward A.; Miller, James B.; Jones, Irby W.; Davis, C. Calvin; Behun, Vaughn D.; Goodrich, Lewis R., Sr.

    1995-01-01

    Linear proof-mass actuator (LPMA) is friction-driv