Science.gov

Sample records for linear clinical progression

  1. Progressive Image Coding by Hierarchical Linear Approximation.

    ERIC Educational Resources Information Center

    Wu, Xiaolin; Fang, Yonggang

    1994-01-01

    Proposes a scheme of hierarchical piecewise linear approximation as an adaptive image pyramid. A progressive image coder comes naturally from the proposed image pyramid. The new pyramid is semantically more powerful than regular tessellation but syntactically simpler than free segmentation. This compromise between adaptability and complexity…

  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. 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

  4. 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.

  5. [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.

  6. 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.

  7. 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.

  8. 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

  9. Hybrid antibiotics - clinical progress and novel designs.

    PubMed

    Parkes, Alastair L; Yule, Ian A

    2016-07-01

    There is a growing need for new antibacterial agents, but success in development of antibiotics in recent years has been limited. This has led researchers to investigate novel approaches to finding compounds that are effective against multi-drug resistant bacteria, and that delay onset of resistance. One such strategy has been to link antibiotics to produce hybrids designed to overcome resistance mechanisms. The concept of dual-acting hybrid antibiotics was introduced and reviewed in this journal in 2010. In the present review the authors sought to discover how clinical candidates described had progressed, and to examine how the field has developed. In three sections the authors cover the clinical progress of hybrid antibiotics, novel agents produced from hybridisation of two or more small-molecule antibiotics, and novel agents produced from hybridisation of antibiotics with small-molecules that have complementary activity. Many key questions regarding dual-acting hybrid antibiotics remain to be answered, and the proposed benefits of this approach are yet to be demonstrated. While Cadazolid in particular continues to progress in the clinic, suggesting that there is promise in hybridisation through covalent linkage, it may be that properties other than antibacterial activity are key when choosing a partner molecule.

  10. Linear IgA disease: clinical presentation, diagnosis, and pathogenesis.

    PubMed

    Venning, Vanessa A

    2012-05-01

    Linear IgA disease is one of the rarer subepidermal blistering diseases. Linear IgA disease is a chronic, acquired, autoimmune blistering disease that is characterized by subepidermal blistering and linear deposition of IgA basement membrane antibodies. The disease affects both children and adults and, although there are some differences in their clinical presentations, there is considerable overlap with shared immunopathology and immunogenetics. Copyright © 2012 Elsevier Inc. All rights reserved.

  11. [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.

  12. RECENT PROGRESS TOWARD A MUON RECIRCULATING LINEAR ACCELERATOR

    SciTech Connect

    Slawomir Bogacz, Vasiliy Morozov, Yves Roblin, Kevin Beard

    2012-07-01

    Both Neutrino Factories (NF) and Muon Colliders (MC) require very rapid acceleration due to the short lifetime of muons. After a capture and bunching section, a linac raises the energy to about 900 MeV, and is followed by one or more Recirculating Linear Accelerators (RLA), possibly followed by a Rapid Cycling Synchnotron (RCS) or Fixed-Field Alternating Gradient (FFAG) ring. A RLA reuses the expensive RF linac section for a number of passes at the price of having to deal with different energies within the same linac. Various techniques including pulsed focusing quadruopoles, beta frequency beating, and multipass arcs have been investigated via simulations to improve the performance and reduce the cost of such RLAs.

  13. 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.

  14. 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.

  15. 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. Copyright © 2015 John Wiley & Sons, Ltd.

  16. Overlap between linear scleroderma, progressive facial hemiatrophy and immune-inflammatory encephalitis in a paediatric cohort.

    PubMed

    De Somer, Lien; Morren, Marie-Anne; Muller, P C E Hissink; Despontin, Karine; Jansen, Katrien; Lagae, Lieven; Wouters, Carine

    2015-09-01

    Linear scleroderma en coup the sabre (LSCS), progressive facial hemiatrophy (PFH) and autoimmune encephalitis are distinct clinical entities, although patients with overlapping features have been reported. We performed a multicenter retrospective review of a series of children with LSCS and/or PFH to explore the relation between these entities. The files of 16 children were reviewed, 11 presented with LSCS, 5 with PFH, with time overlapping cutaneous features were seen. Extracutaneous signs were found in both groups. ANA were present in more than 50 % of patients. Almost half of our patients presented with CNS manifestations comprising unilateral headache, migraine and epilepsy with or without abnormalities on MRI. Brain biopsy in one patient was consistent with Rasmussen encephalitis. In two other children, associated autoimmune manifestations were present. Our patient cohort brings more arguments to consider LSCS and PFH as a single disease entity with LSCS and superficial skin involvement at one end of the spectrum and PFH with involvement of subcutaneous deep tissue at the other end. In both entities, encephalitis can be observed. Our findings of circulating ANA, intradermal lymphocytes and IgG, intrathecal IgG production and clinical improvement with immunosuppressive therapy endorse the concept of a possible common immune-inflammatory pathogenesis. • LSCS, PFH and immune-inflammatory encephalitis are distinct clinical entities, but patients with overlapping features have been reported. • We present a unique paediatric cohort with LSCS, PFH and/or encephalitis. • We endorse the concept of a common immune-inflammatory disease process.

  17. Progress in Clinical Encapsulated Islet Xenotransplantation.

    PubMed

    Cooper, David K C; Matsumoto, Shinichi; Abalovich, Adrian; Itoh, Takeshi; Mourad, Nizar I; Gianello, Pierre R; Wolf, Eckhard; Cozzi, Emanuele

    2016-11-01

    At the 2015 combined congress of the Cell Transplant Society, International Pancreas and Islet Transplant Association, and International Xenotransplantation Association, a symposium was held to discuss recent progress in pig islet xenotransplantation. The presentations focused on 5 major topics - (1) the results of 2 recent clinical trials of encapsulated pig islet transplantation, (2) the inflammatory response to encapsulated pig islets, (3) methods to improve the secretion of insulin by pig islets, (4) genetic modifications to the islet-source pigs aimed to protect the islets from the primate immune and/or inflammatory responses, and (5) regulatory aspects of clinical pig islet xenotransplantation. Trials of microencapsulated porcine islet transplantation to treat unstable type 1 diabetic patients have been associated with encouraging preliminary results. Further advances to improve efficacy may include (1) transplantation into a site other than the peritoneal cavity, which might result in better access to blood, oxygen, and nutrients; (2) the development of a more biocompatible capsule and/or the minimization of a foreign body reaction; (3) pig genetic modification to induce a greater secretion of insulin by the islets, and/or to reduce the immune response to islets released from damaged capsules; and (4) reduction of the inflammatory response to the capsules/islets by improvements in the structure of the capsules and/or in genetic engineering of the pigs and/or in some form of drug therapy. Ethical and regulatory frameworks for islet xenotransplantation are already available in several countries, and there is now a wider international perception of the importance of developing an internationally harmonized ethical and regulatory framework.

  18. 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.

  19. Progressive Skill Development and Progressive Clinical Experience Responsibility

    ERIC Educational Resources Information Center

    Knight, Kenneth L.

    2008-01-01

    This editorial describes the swinging pendulum of the role of clinical supervision in relation to the clinical skill development of students in athletic training programs. In the past, students working as interns were essentially assistant athletic trainers with little direct supervision, which resulted in decisions being made with less than…

  20. Transitional progressive multiple sclerosis: a clinical and imaging study

    PubMed Central

    Gayou, A.; Brochet, B.; Dousset, V.

    1997-01-01

    OBJECTIVE—To study the prevalence and the natural course of transitional progressive multiple sclerosis (TPMS). This clinical form is defined by a progressive course beginning many years after an isolated bout.
METHODS—214 consecutive outpatients with definite or probable multiple sclerosis were studied. The prevalence of TPMS was established. Patients with TPMS were compared with patients with other progressive forms of multiple sclerosis according to the clinical course. A prospective one year follow up study was performed in a subgroup of patients to compare progression of the disease using clinical indices and MRI.
RESULTS—In this clinical population of 214 outpatients with multiple sclerosis, 55 had secondary progressive multiple sclerosis (SPMS), 38 primary progressive multiple sclerosis (PPMS), and 12 TPMS. Retrospective analysis of the clinical data of these patients shows that TPMS is very similar to SPMS at the beginning of the disease (age at onset, time before progression, clinical symptoms at onset, progression index). In addition a cohort of patients was prospectively followed up clinically and by MRI for one year.
CONCLUSIONS—The results did not show any significant differences between the three forms during this follow up. However, all data showed a concordant trend suggesting that at this progressive stage, TPMS is closer to PPMS in terms of progression of disability and new MRI lesions.

 PMID:9328264

  1. Transitional progressive multiple sclerosis: a clinical and imaging study.

    PubMed

    Gayou, A; Brochet, B; Dousset, V

    1997-09-01

    To study the prevalence and the natural course of transitional progressive multiple sclerosis (TPMS). This clinical form is defined by a progressive course beginning many years after an isolated bout. 214 consecutive outpatients with definite or probable multiple sclerosis were studied. The prevalence of TPMS was established. Patients with TPMS were compared with patients with other progressive forms of multiple sclerosis according to the clinical course. A prospective one year follow up study was performed in a subgroup of patients to compare progression of the disease using clinical indices and MRI. In this clinical population of 214 outpatients with multiple sclerosis, 55 had secondary progressive multiple sclerosis (SPMS), 38 primary progressive multiple sclerosis (PPMS), and 12 TPMS. Retrospective analysis of the clinical data of these patients shows that TPMS is very similar to SPMS at the beginning of the disease (age at onset, time before progression, clinical symptoms at onset, progression index). In addition a cohort of patients was prospectively followed up clinically and by MRI for one year. The results did not show any significant differences between the three forms during this follow up. However, all data showed a concordant trend suggesting that at this progressive stage, TPMS is closer to PPMS in terms of progression of disability and new MRI lesions.

  2. Progressive Surgical Autonomy in a Plastic Surgery Resident Clinic

    PubMed Central

    Scott, Jillian K.; Gao, Lani; Lee, Tara M.; Waldrop, Jimmy L.; Sargent, Larry A.; Kennedy, J. Woody; Rehm, Jason P.; Brzezienski, Mark A.

    2017-01-01

    Background: Resident clinics are thought to catalyze educational milestone achievement through opportunities for progressively autonomous surgical care, but studies are lacking for general plastic surgery resident clinics (PSRCs). We demonstrate the achievement of increased surgical autonomy and continuity of care in a PSRC. Methods: A retrospective review of all patients seen in a PSRC from October 1, 2010, to October 1, 2015, was conducted. Our PSRC is supervised by faculty plastic surgery attendings, though primarily run by chief residents in an accredited independent plastic surgery training program. Surgical autonomy was scored on a 5-point scale based on dictated operative reports. Graduated chief residents were additionally surveyed by anonymous online survey. Results: Thousand one hundred forty-four patients were seen in 3,390 clinic visits. Six hundred fifty-three operations were performed by 23 total residents, including 10 graduating chiefs. Senior resident autonomy averaged 3.5/5 (SD = 1.5), 3.6/5 (SD = 1.5), to 3.8/5 (SD = 1.3) in postgraduate years 6, 7, and 8, respectively. A linear mixed model analysis demonstrated that training level had a significant impact on operative autonomy when comparing postgraduate years 6 and 8 (P = 0.026). Graduated residents’ survey responses (N = 10; 100% response rate) regarded PSRC as valuable for surgical experience (4.1/5), operative autonomy (4.4/5), medical knowledge development (4.7/5), and the practice of Accreditation Council of Graduate Medical Education core competencies (4.3/5). Preoperative or postoperative continuity of care was maintained in 93.5% of cases. Conclusion: The achievement of progressive surgical autonomy may be demonstrated within a PSRC model. PMID:28607848

  3. 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

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

    PubMed

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

    2016-01-01

    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 disease (AD), two-year change scores were calculated for a performance measure of functional ability, cognitive variables, and 3 outcome measures used to track progression in neurological disorders. We examined patterns of financial and cognitive decline across the 2-year study period, and used these data and the 3 outcome variables to construct discrete predictor models of clinical progression in MCI. We found that both financial skills and cognitive abilities declined over the 2-year study period, were significantly associated with clinical progression, and contributed unique variance to all 3 predictor models. The resulting models accounted for 40% to 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.

  5. 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.

  6. Clinical Trials: Key to Medical Progress

    MedlinePlus

    ... to control high blood pressure. There are clinical trials going on all the time in nearly every area of medical research. To Find Out More To find out more about clinical trials and how to participate, go to: www.clinicaltrials. ...

  7. 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

  8. Radiopharmaceuticals: Progress and clinical perspectives. Volume II

    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. The contents of VOLUME II include: Radiolabeled Leukocytes and Platelets, Thrombus-Localizing Radiopharmaceutical, Radiolabeled Red Blood Cells as Diagnostic Radiopharmaceuticals, Radiopharmaceuticals for Imaging Reticuloendothelial Systems, Clinical Potential of Receptor Based Radiopharmaceuticals, Clinical Potential of Positron-Emitting Radiopharmaceuticals, Bone Radiopharmaceuticals, and Index.

  9. 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

  10. 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.

  11. 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…

  12. 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…

  13. 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.

  14. 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

  15. Clinical Investigation Program Annual Progress Report

    DTIC Science & Technology

    1989-10-01

    Surgery,fesidents Using Rat Nerves and Vessels (0) 1_ - -- 9H88 Boice, G. W. A Comparison of Conplete Maxillary 50 Dentur Retention Before and After... History of HTLV- 11 55Infection and Disease in a United States itary Population (0) 58H88 Farrell, S. E. BIG ANP in Salt and Water Retention 56 States (T...Breast Cancer Patients (T) NSABP Berenberg, J. A Clinical Trial to Evaluate Natural 179B17(86) History and Treatment of Patients with

  16. Clinical Investigation Program Annual Progress Report.

    DTIC Science & Technology

    1984-09-30

    Gastric Inhibitory Polypeptide (GIP) in Various Disorders of Carbohydrate Metabolism. (O) .......... 122 84/106 Respiratory Patterns in Hypogonadal...about due to the decreased use of dogs and cats for teaching and training. The Service also obtained a renovated blood gas analyzer from Respiratory ...directly related laboratory workr into the clinical problems of significant concern in the health care of members of the military community. To provide

  17. 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

  18. 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.

  19. Clinically isolated aortitis: pitfalls, progress, and possibilities.

    PubMed

    Cinar, Ilkay; Wang, He; Stone, James R

    Non-infectious aortitis may be caused by several distinct systemic rheumatologic diseases. In some patients, aortitis is identified either pathologically or radiologically in the absence of clinical evidence of a systemic vasculitis. By consensus nomenclature, such cases are referred to as clinically isolated aortitis (CIA). Some systemic disorders may initially present as CIA including giant cell arteritis (GCA), IgG4-related disease, infectious aortitis, and granulomatosis with polyangiitis. CIA most commonly occurs in women of European descent over the age of 50 and, thus, mirrors the gender, age, and geographic distribution of GCA. CIA most often demonstrates a granulomatous/giant cell pattern of inflammation (GPI), and CIA-GPI is pathologically indistinguishable from aortitis due to GCA. In many cases, CIA may be a manifestation of extracranial GCA. CIA is being identified both pathologically in resected aortic tissue and radiologically by computed tomography scanning, magnetic resonance imaging, and fluorodeoxyglucose positron emission tomography. However, there appears to be significant differences between pathologically defined CIA and radiologically defined CIA. Multiple studies have shown that patients with CIA are at increased risk for subsequent aortic events (new aneurysms or dissections) and thus it is recommended to monitor these patients with periodic aortic imaging. While the data is currently limited, there is increasing evidence that at least some patients with CIA may benefit from immunosuppressive therapy. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. [Is progressive anarthria a clinical form of Pick complex?].

    PubMed

    Dobato, J L; Barón-Rubio, M; Valle de Juan, M C; Barriga, F J; Sánchez-Sánchez, C; Sánchez del Río, M; Pardo-Moreno, J; Pareja, J A; Vela, L

    Progressive anarthria is defined as a clinical entity with a degenerative origin consisting in progressive difficulty in articulating while grammatical, semantic and graphic aspects of language are preserved. It is included within the group of processes affecting restricted areas of the brain although its exact nosological location is not clear. We report two cases that progressed clinically towards frontotemporal dementia and corticobasal degeneration, respectively. Case 1: a male who, at the age of 72, began with speech difficulties while comprehension and reading/writing skills were preserved. Three years later he developed apathy, bulimia, sexual indiscretions and aggressiveness, with preservation of visual memory, visual-constructional capacity and elementary writing skills. Case 2: a male who, at the age of 70, began with speech disorders, which were associated two years later to generalised slowness with Hoehn and Yahr stage II akinetic-rigid symptoms; another two years later, he developed a dystonic attitude and melokinetic apraxia in the left upper limb. The two cases, which were initially compatible with progressive anarthria, progressed clinically towards frontotemporal dementia and corticobasal degeneration, which are entities that are included in 'Pick complex'. This is a concept that we believe to be useful from a clinical point of view, given the variability that exists in the histology of the entities that have been proposed as members of this syndrome group, together with the progression of the cases described in the literature and the ones we have reported in this work.

  1. 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

  2. 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)

  3. 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)

  4. [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.

  5. Monte Carlo simulation of a clinical linear accelerator.

    PubMed

    Lin, S Y; Chu, T C; Lin, J P

    2001-12-01

    The effects of the physical parameters of an electron beam from a Siemens PRIMUS clinical linear accelerator (linac) on the dose distribution in water were investigated by Monte Carlo simulation. The EGS4 user code, OMEGA/BEAM, was used in this study. Various incident electron beams, for example, with different energies, spot sizes and distances from the point source, were simulated using the detailed linac head structure in the 6 MV photon mode. Approximately 10 million particles were collected in the scored plane, which was set under the reticle to form the so-called phase space file. The phase space file served as a source for simulating the dose distribution in water using DOSXYZ. Dose profiles at Dmax (1.5 cm) and PDD curves were calculated following simulating about 1 billion histories for dose profiles and 500 million histories for percent depth dose (PDD) curves in a 30 x 30 x 30 cm3 water phantom. The simulation results were compared with the data measured by a CEA film and an ion chamber. The results show that the dose profiles are influenced by the energy and the spot size, while PDD curves are primarily influenced by the energy of the incident beam. The effect of the distance from the point source on the dose profile is not significant and is recommended to be set at infinity. We also recommend adjusting the beam energy by using PDD curves and, then, adjusting the spot size by using the dose profile to maintain the consistency of the Monte Carlo results and measured data.

  6. Multidimensional latent trait linear mixed model: an application in clinical studies with multivariate longitudinal outcomes.

    PubMed

    Wang, Jue; Luo, Sheng

    2017-09-10

    Multilevel item response theory (MLIRT) models have been widely used to analyze the multivariate longitudinal data of mixed types (e.g., categorical and continuous) in clinical studies. The MLIRT models often have unidimensional assumption, that is, the multiple outcomes are clinical manifestations of a univariate latent variable. However, the unidimensional assumption may be unrealistic because some diseases may be heterogeneous and characterized by multiple impaired domains with variable clinical symptoms and disease progressions. We relax this assumption and propose a multidimensional latent trait linear mixed model (MLTLMM) to allow multiple latent variables and within-item multidimensionality (one outcome can be a manifestation of more than one latent variable). We conduct extensive simulation studies to assess the unidimensional MLIRT model and the proposed MLTLMM model. The simulation studies suggest that the MLTLMM model outperforms unidimensional model when the multivariate longitudinal outcomes are manifested by multiple latent variables. The proposed model is applied to two motivating studies of amyotrophic lateral sclerosis: a clinical trial of ceftriaxone and the Pooled Resource Open-Access ALS Clinical Trials database. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  7. 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.

  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. Estimating Typical Multiple Sclerosis Disability Progression Speed from Clinical Observations

    PubMed Central

    Brown, Murray G.; Asbridge, Mark; Hicks, Vern; Kirby, Sarah; Murray, Thomas J.; Andreou, Pantelis; Lin, Dong

    2014-01-01

    Introduction Multiple sclerosis (MS) is a chronic disease of the central nervous system. Estimates of MS natural history (NH) disability progression speed from clinical observations vary worldwide. This may reflect, in part, variance in censoring-bias) (missing observations) and assumptions about when irreversible disability progression events occurred. We test whether estimates of progression speed which assume midpoint survival time at irreversible disability endpoints are significantly faster than estimates which assume maximum survival time, and are more stable across study groups and time periods. Methods Our Nova Scotia NH study population includes 2,240 definite relapsing-onset multiple sclerosis (R-MS) natural history patients with 18,078 Expanded Disability Status Scale (EDSS) clinical observations in study period 1979–2010. Progression speed is measured by rate-of-change in range EDSS 0–6 and by survival time at irreversible endpoints EDSS 1–9. Midpoint censoring-bias-reduction methods are applied to clinical observations. Findings Typical EDSS increase per year in range EDSS 0–6, assuming midpoint survival time, is estimated to be 0.168 for all R-MS, 0.204 for eventually-DMD-treated patients and 0.155 for never-DMD-treated patients. Estimates assuming midpoint rather than maximum survival time are significantly faster: 16% faster for all R-MS natural history patients, 6% faster for eventually-DMD-treated patients, and 21% faster for never-DMD-treated patients. The variability of estimates across study groups and time periods decreased when midpoint survival time was assumed. Conclusions Estimates of typical disease progression speed from 1979–2010 Nova Scotia clinical observations are sensitive to censoring-bias and to analysts’ survival time assumptions. Censoring-bias-adjusted estimates of typical natural history disability progression speed in relapsing-onset multiple sclerosis patients are significantly faster, and less variable within

  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. Evidence for clinical progression of unipolar and bipolar disorders.

    PubMed

    Kessing, L V; Andersen, P K

    2017-01-01

    It is a widely held belief that affective disorders are progressive of nature; however, some recent reviews have questioned this belief. The objective of the present systematic literature review was to present evidence for associations between number of affective episodes and (i) the risk of recurrence of episodes, (ii) probability of recovery from episodes, (iii) severity of episodes, (iv) the threshold for developing episodes, and (v) progression of cognitive deficits in unipolar and bipolar disorders. A systematic review comprising an extensive literature search conducted in Medline, Embase, and PsychInfo up to September 2016 and including cross-references from identified papers and reviews. Most of the five areas are superficially investigated and hampered by methodological challenges. Nevertheless, studies with the longest follow-up periods, using survival analysis methods, taking account of the individual heterogeneity all support a clinical progressive course of illness. Overall, increasing number of affective episodes seems to be associated with (i) increasing risk of recurrence, (ii) increasing duration of episodes, (iii) increasing symptomatic severity of episodes, (iv) decreasing threshold for developing episodes, and (v) increasing risk of developing dementia. Although the course of illness is heterogeneous, there is evidence for clinical progression of unipolar and bipolar disorders. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. A clinically relevant wound assessment method to monitor healing progression.

    PubMed

    Barber, Sharon

    2008-03-01

    One of the most important principles of wound management is periodic assessment and documentation of wound healing. Documentation of healing progress over time allows providers to assess the effectiveness of care to maximize healing. Several methods to determine wound healing progress currently exist and include dimensional, visual, and physiological assessments. However, because existing tools often require correlation of subjective assessments, are time-consuming, and may not consider that wound healing occurs from the "bottom up," a more objective and quicker approach to monitor healing progression was pursued. The purpose of this case study is to describe a once pen-and-paper tool that has now been computerized (the Barber Measuring Tool) that builds a graphical representation of a patient's individual wound healing progress to facilitate clinical decisions regarding the patient's plan of care. The tool, which is currently used for all wound patients in the author's facility, calculates wound volume using a simple formula and tracks this measurement as a percent of baseline over time in the patient's chart. Although formal research to establish validity and reliability of this tool has yet to be conducted, the tool has been used with more than 400 patients and has provided an accurate representation of healing progress. Studies to support proliferating use of this tool are warranted.

  14. Verifying and evaluating progressive addition lenses in clinical practice.

    PubMed

    Bell, G R

    2001-04-01

    Despite the fact that more than 50% of multifocal lenses dispensed in the United States are progressive addition lenses, adequate methods for clinical verification of these lenses have been lacking. Using automated lens meter techniques, the author describes a simplified method for verification of these complex lenses. Thirty pairs of progressive lenses were measured in a modified method using a Humphrey 330 Lens Analyzer. Fifteen pairs were "premium-quality" progressive lenses: fifteen pairs were "non-premium-quality" progressives. Five criteria were assessed on each lens: Distance Zone Width (DZW). Intermediate Zone Width (IZW), Near Zone Width (NZW), Drop Distance (DD), and Maximum Astigmatic Distortion (MAD). "Premium-quality" progressive lenses failed to demonstrate clear-cut superiority over "non-premium-quality" progressive lenses in the five specified criteria. Individual measurements indicate considerable product inconsistency affected every brand tested. Premium- and non-premium-quality progressive lenses demonstrated similar performance characteristics in this study. Zone size variation in these lenses was found to be considerable, a characteristic that seemed to cut across brand lines. The AO Compact lens seemed to demonstrate a shorter drop distance than other lenses, which does enhance its suitability for use with small frames. A comparison of the Essilor Natural PAL to the Younger Image lens showed little difference in the categories measured, although peripheral distortions seemed closer to the reading zone in the image. A comparison of the MAD of lenses in this study to lenses tested in 1986 indicates a considerable improvement has been made in that important characteristic.

  15. Partner, Learn, Progress: a conceptual model for continuous clinical education.

    PubMed

    Henderson, Amanda; Winch, Sarah; Heel, Alison

    2006-02-01

    In practice disciplines, such as nursing, learning can be maximised through experience located in the clinical setting. However, placement in the clinical setting does not automatically mean that the learner's professional practice will improve. Experiences in 'real-life' settings need to be effectively facilitated to obtain the desired outcomes. This paper through the discussion of 'Partner, Learn, Progress' details a conceptual model for promoting learning in the clinical context. 'Partner' refers to the positive association between the learner and the experienced clinician that engenders trust. It occurs on a personal level in the context of a broader social and political environment. 'Learn' refers to the process whereby the experienced clinician is able to assist the learner make sense of theoretical knowledge or knowledge that has previously been 'distal' to their practice to be integrated into their immediate practice. The clinician requires to be cognisant of the learner's existing knowledge level so that the activities and accompanying discussion assist in making connections between theory and practice. Learning incorporates mutual collaboration whereby the learner is able to practise the application of knowledge in a safe context and make their own connections. The further exploration of meanings through experiences, feelings, attitudes leads the learner to 'progress': the development of knowledge. Such a conceptual model provides a framework for educators and supervisors of clinical learning to educate and learn from the next generation of nurses that will lead the nursing profession into the future.

  16. Which ante mortem clinical features predict progressive supranuclear palsy pathology?

    PubMed

    Respondek, Gesine; Kurz, Carolin; Arzberger, Thomas; Compta, Yaroslau; Englund, Elisabet; Ferguson, Leslie W; Gelpi, Ellen; Giese, Armin; Irwin, David J; Meissner, Wassilios G; Nilsson, Christer; Pantelyat, Alexander; Rajput, Alex; van Swieten, John C; Troakes, Claire; Josephs, Keith A; Lang, Anthony E; Mollenhauer, Brit; Müller, Ulrich; Whitwell, Jennifer L; Antonini, Angelo; Bhatia, Kailash P; Bordelon, Yvette; Corvol, Jean-Christophe; Colosimo, Carlo; Dodel, Richard; Grossman, Murray; Kassubek, Jan; Krismer, Florian; Levin, Johannes; Lorenzl, Stefan; Morris, Huw; Nestor, Peter; Oertel, Wolfgang H; Rabinovici, Gil D; Rowe, James B; van Eimeren, Thilo; Wenning, Gregor K; Boxer, Adam; Golbe, Lawrence I; Litvan, Irene; Stamelou, Maria; Höglinger, Günter U

    2017-07-01

    Progressive supranuclear palsy (PSP) is a neuropathologically defined disease presenting with a broad spectrum of clinical phenotypes. To identify clinical features and investigations that predict or exclude PSP pathology during life, aiming at an optimization of the clinical diagnostic criteria for PSP. We performed a systematic review of the literature published since 1996 to identify clinical features and investigations that may predict or exclude PSP pathology. We then extracted standardized data from clinical charts of patients with pathologically diagnosed PSP and relevant disease controls and calculated the sensitivity, specificity, and positive predictive value of key clinical features for PSP in this cohort. Of 4166 articles identified by the database inquiry, 269 met predefined standards. The literature review identified clinical features predictive of PSP, including features of the following 4 functional domains: ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction. No biomarker or genetic feature was found reliably validated to predict definite PSP. High-quality original natural history data were available from 206 patients with pathologically diagnosed PSP and from 231 pathologically diagnosed disease controls (54 corticobasal degeneration, 51 multiple system atrophy with predominant parkinsonism, 53 Parkinson's disease, 73 behavioral variant frontotemporal dementia). We identified clinical features that predicted PSP pathology, including phenotypes other than Richardson's syndrome, with varying sensitivity and specificity. Our results highlight the clinical variability of PSP and the high prevalence of phenotypes other than Richardson's syndrome. The features of variant phenotypes with high specificity and sensitivity should serve to optimize clinical diagnosis of PSP. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

  17. Proteomic analysis of mitochondria: biological and clinical progresses in cancer.

    PubMed

    Wang, Yang; Zhang, Jing; Li, Bin; He, Qing-Yu

    2017-10-01

    Mitochondria play important roles in regulating multiple biological processes and signalling pathways in eukaryotic cells, and mitochondrial dysfunction may result in a wide range of serious diseases, including cancer. With improvements in the identification of mitochondrial proteins, mitochondrial proteomics has made great achievements. In particular, this approach has been widely used to compare tumour cells at different stages of malignancy. Therefore, there is an urgent need to identify and characterize the function of mitochondrial proteins in cancer progression and to determine the involved mechanisms. Areas covered: We provide an overview of recent progress related to mitochondrial proteomics in cancer and the application of comparative mitochondrial proteomics in various biological processes, including apoptosis, necroptosis, autophagy and metastasis, as well as clinical progress in cancer. Proteomics-related reports were found using PubMed and Google Scholar databases. Expert commentary: Understanding both post-translational modification and post-translational processing is important in the comprehensive characterization of protein function. The application of comparative mitochondrial proteomics to investigate clinical samples and cancer cells will contribute to our understanding of the molecular interplay of mitochondrial proteins in the development of cancer. This approach will mine more biomarkers for diagnosis and prognosis and improve therapeutic outcomes among cancer patients.

  18. Glenohumeral arthritis after Latarjet procedure: Progression and it's clinical significance.

    PubMed

    Kee, Young Moon; Kim, Hwan Jin; Kim, Jung Youn; Rhee, Yong Girl

    2017-09-01

    The risk factors of glenohumeral arthritis after the Latarjet procedure remain relatively unexplored. The purposes of this study are to evaluate the clinical significance of glenohumeral arthritis after the Latarjet procedure, and to investigate risk factors associated with arthritis progression. We evaluated 110 patients (110 shoulders) who underwent the Latarjet procedure for recurrent anterior shoulder instability. Patients had a mean age of 23.8 years (range, 14-52 years) at the time of the operation, and the mean duration of follow-up was 31 months (range, 24-111 months). At the last follow-up, the mean Visual Analog Scale (VAS), Rowe and University of California at Los Angeles (UCLA) scores significantly improved from 3.1, 36.5 and 23.6 points preoperatively to 1.6, 87.6 and 32.6 points (all P < 0.05, respectively). The postoperative rate of recurrence was 5.4%. Among the 14 shoulders with preoperative arthritis, 8 (57.1%) showed progression of arthritis at the last follow up. New occurrence or progression of arthritis after the Latarjet procedure was in 20 shoulders (18.2%). At the final, overall prevalence of arthritis was 23.6% (26 shoulders). The non-arthritis group showed significantly better functional outcomes (VAS score: 0.9, Rowe Score: 89.3, UCLA score: 33.5) than the arthritis group (2.1, 84.9, 29.2; all P < 0.05, respectively). Preoperative generalized laxity and lateral overhang were associated with glenohumeral arthritis progression after surgery. (all P < 0.05, retrospectively). The Latarjet procedure yielded satisfactory functional outcomes with low recurrent rate at mid-term follow-up. Development or progression of arthritis was observed in 18.2% of patients, postoperatively. Glenohumeral arthritis after the Latarjet procedure had an adverse effect on clinical outcome. Generalized laxity and lateral overhang should be considered as risk factors of progression to glenohumeral arthritis after the Latarjet procedure. Copyright © 2017 The

  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. 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.

  1. The progressive systemic sclerosis/systemic lupus overlap: an unusual clinical progression.

    PubMed Central

    Asherson, R A; Angus, H; Mathews, J A; Meyers, O; Hughes, G R

    1991-01-01

    Three patients with the unusual combinations of discoid lupus, systemic lupus erythematosus (SLE), and progressive systemic sclerosis (PSS) are reported. The first patient developed PSS eight years after a diagnosis of discoid lupus had been made and this was complicated by myositis six years later. The second patient developed PSS more than 20 years after being diagnosed as having SLE. The third patient developed SLE with predominant features of urticarial vasculitis six years after PSS. Mild myositis also ensued. There were no antibodies to U1RNP demonstrable in any of these patients. The clinical progression of SLE to PSS or vice versa in the absence of features of mixed connective tissue disease is distinctly uncommon. Images PMID:2042989

  2. Alzheimer's Disease Neuroimaging Initiative 2 Clinical Core: Progress and plans.

    PubMed

    Aisen, Paul S; Petersen, Ronald C; Donohue, Michael; Weiner, Michael W

    2015-07-01

    This article reviews the current status of the Clinical Core of the Alzheimer's Disease Neuroimaging Initiative (ADNI), and summarizes planning for the next stage of the project. Clinical Core activities and plans were synthesized based on discussions among the Core leaders and external advisors. The longitudinal data in ADNI-2 provide natural history data on a clinical trials population and continue to inform refinement and standardization of assessments, models of trajectories, and clinical trial methods that have been extended into sporadic preclinical Alzheimer's disease (AD). Plans for the next phase of the ADNI project include maintaining longitudinal follow-up of the normal and mild cognitive impairment cohorts, augmenting specific clinical cohorts, and incorporating novel computerized cognitive assessments and patient-reported outcomes. A major hypothesis is that AD represents a gradually progressive disease that can be identified precisely in its long presymptomatic phase, during which intervention with potentially disease-modifying agents may be most useful. Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  3. 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.

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

    PubMed Central

    Catanzaro, Daniele; Schäffer, 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. PMID:26353381

  5. 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.

  6. 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

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

    PubMed Central

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

    2015-01-01

    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

  8. 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.

  9. 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

  10. Clinical scales in progressive MS: predicting long-term disability.

    PubMed

    Bosma, Libertje V A E; Kragt, Jolijn J; Knol, Dirk L; Polman, Chris H; Uitdehaag, Bernard M J

    2012-03-01

    To determine which short-term changes on clinical scales including the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg test (9HPT) and Guy's Neurological Disability Scale (GNDS) are most predictive of long-term outcome of disability as rated by the EDSS in progressive multiple sclerosis (MS). From a longitudinal database, all progressive patients, both primary (PP) and secondary (SP), were selected on the basis of at least two complete examinations being available within a time interval of 1-2 years (short-term change). All patients who fulfilled the selection criteria were invited for a third visit after an interval of at least 3 years (long-term outcome). We used ordinal logistic regression to see which early changes were most predictive of the long-term EDSS. 181 patients fulfilled the selection criteria. Early change on EDSS and T25FW were the best predictors of long-term EDSS; both were significant predictors in a 'single predictor' model. Early EDSS change was a slightly stronger single predictor (R(2) 0.38, Wald χ(2) 42.65, p < 0.001) compared with early T25FW change (R(2) 0.27, Wald χ(2) 12.35, p < 0.001). Adding early T25FW change to early EDSS change in a 'combined predictor' model improved prediction (p = 0.036). Both early change on EDSS and T25FW predict long-term EDSS with comparable strength. Early change on T25FW adds significant independent information and improves the prediction model with early EDSS change only. Therefore we support the use of early T25FW examinations in future clinical trials in progressive MS.

  11. 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.

  12. 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.

  13. [Progressive myoclonic epilepsy: clinical characteristics of 18 patients].

    PubMed

    Vistorte, A; Sardiñas, N; Esteban, E M; Vargas-Díaz, J; Novoa-López, L; Rojas-Massippe, E; Pestana, E M

    The term progressive myoclonic epilepsy (PME) includes a groups of heterogeneous conditions, with genetic causes, characterized by having different types of seizures, basically myoclonic, and other neurological findings due to a progressive lesion of the central nervous system. To demonstrate the aetiology and clinico-encephalographic changes seen in patients with PME. A retrospective, descriptive study was done of patients attended for PME in the Instituto de Neurología y Neurocirugía de Cuba between 1990 and 1995. Eighteen patients were included. All were interviewed and had a physical examination, EEG and the specific complementary tests for each aetiology. There was a predominance of neural ceroid lipofuschinosis in 10 patients (55.5%), and in 9 of these the illness started before the age of 9 years. The second most frequent condition was myoclonic epilepsy with red-torn fibres (16.6%) and Unverricht-Lundborg disease (16.6%). The latter began in late childhood or adolescence. The most marked clinical characteristics were epilepsy, which was difficult to control and intellectual deterioration in 100%, followed by cerebellar signs in 88.8%. Myoclonias were the commonest type of seizures (94.4%) and many children presented with prior tonic-clonic seizures (88.8%). Response to treatment was poor but the best results were obtained using valproate either alone or associated with benzodiazepines.

  14. [Clinical neurophysiology for estimation of progression and prognosis in ALS].

    PubMed

    Pouget, J

    2004-01-01

    The role of clinical neurophysiology in the evaluation of disease progression in ALS has to be precised. To be included in the methodology of therapeutic trials, neurophysiological methods have to be quantitative, sensitive and reproducible. Their goal is to assess peripheral and central motor neuron loss but also compensatory processes such as reinnervation. The peripheral motor neuron loss can be evaluated by compound muscle action potential amplitude and mainly by motor unit number estimate (MUNE). Peripheral reinnervation can be evaluated by fiber density and macro-MUP amplitude. Functional aspects of reinnervation can be assessed by jitter measurement or the occurrence of decrement when using repetitive stimulation. Central motor neuron loss can be evaluated by transcranial magnetic stimulation and the triple collision technique (TST). Among the various electrophysiological approaches, MUNE and TST seem to be the most appropriate to evaluate peripheral and central motor neuron loss over time in ALS.

  15. 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.

  16. Progressive Surgical Autonomy Observed in a Hand Surgery Resident Clinic Model.

    PubMed

    Day, Kristopher M; Zoog, Evon S; Kluemper, Chase T; Scott, Jillian K; Steffen, Caleb M; Kennedy, James Woodfin; Jemison, David Marshall; Rehm, Jason P; Brzezienski, Mark A

    2017-09-26

    Resident clinics (RCs) are intended to catalyze the achievement of educational milestones through progressively autonomous patient care. However, few studies quantify their effect on competency-based surgical education, and no previous publications focus on hand surgery RCs (HRCs). We demonstrate the achievement of progressive surgical autonomy in an HRC model. A retrospective review of all patients seen in a weekly half-day HRC from October 2010 to October 2015 was conducted. Investigators compiled data on patient demographics, provider encounters, operational statistics, operative details, and dictated surgical autonomy on an ascending 5 point scoring system. A tertiary hand surgery referral center. A total of 2295 HRC patients were evaluated during the study period in 5173 clinic visits. There was an average of 22.6 patients per clinic, including 9.0 new patients with 6.5 emergency room referrals. Totally, 825 operations were performed by 39 residents. Trainee autonomy averaged 2.1/5 (standard deviation [SD] = 1.2), 3.4/5 (SD = 1.3), 2.1/5 (SD = 1.3), 3.4/5 (SD = 1.2), 3.2/5 (SD = 1.5), 3.5/5 (SD = 1.5), 4.0/5 (SD = 1.2), 4.1/5 (SD = 1.2), in postgraduate years 1 to 8, respectively. Linear mixed model analysis demonstrated training level significantly effected operative autonomy (p = 0.0001). Continuity of care was maintained in 79.3% of cases, and patients were followed an average of 3.9 clinic encounters over 12.4 weeks. Our HRC appears to enable surgical trainees to practice supervised autonomous surgical care and provide a forum in which to observe progressive operative competency achievement during hand surgery training. Future studies comparing HRC models to non-RC models will be required to further define quality-of-care delivery within RCs. Copyright © 2017. Published by Elsevier Inc.

  17. 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.

  18. Detection and measurement of clinically meaningful visual field progression in clinical trials for glaucoma.

    PubMed

    De Moraes, C Gustavo; Liebmann, Jeffrey M; Levin, Leonard A

    2017-01-01

    Glaucomatous visual field progression has both personal and societal costs and therefore has a serious impact on quality of life. At the present time, intraocular pressure (IOP) is considered to be the most important modifiable risk factor for glaucoma onset and progression. Reduction of IOP has been repeatedly demonstrated to be an effective intervention across the spectrum of glaucoma, regardless of subtype or disease stage. In the setting of approval of IOP-lowering therapies, it is expected that effects on IOP will translate into benefits in long-term patient-reported outcomes. Nonetheless, the effect of these medications on IOP and their associated risks can be consistently and objectively measured. This helps to explain why regulatory approval of new therapies in glaucoma has historically used IOP as the outcome variable. Although all approved treatments for glaucoma involve IOP reduction, patients frequently continue to progress despite treatment. It would therefore be beneficial to develop treatments that preserve visual function through mechanisms other than lowering IOP. The United States Food and Drug Administration (FDA) has stated that they will accept a clinically meaningful definition of visual field progression using Glaucoma Change Probability criteria. Nonetheless, these criteria do not take into account the time (and hence, the speed) needed to reach significant change. In this paper we provide an analysis based on the existing literature to support the hypothesis that decreasing the rate of visual field progression by 30% in a trial lasting 12-18 months is clinically meaningful. We demonstrate that a 30% decrease in rate of visual field progression can be reliably projected to have a significant effect on health-related quality of life, as defined by validated instruments designed to measure that endpoint. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Clonal expansion and linear genome evolution through breast cancer progression from pre-invasive stages to asynchronous metastasis.

    PubMed

    Krøigård, Anne Bruun; Larsen, Martin Jakob; Lænkholm, Anne-Vibeke; Knoop, Ann S; Jensen, Jeanette D; Bak, Martin; Mollenhauer, Jan; Kruse, Torben A; Thomassen, Mads

    2015-03-20

    Evolution of the breast cancer genome from pre-invasive stages to asynchronous metastasis is complex and mostly unexplored, but highly demanded as it may provide novel markers for and mechanistic insights in cancer progression. The increasing use of personalized therapy of breast cancer necessitates knowledge of the degree of genomic concordance between different steps of malignant progression as primary tumors often are used as surrogates of systemic disease. Based on exome sequencing we performed copy number profiling and point mutation detection on successive steps of breast cancer progression from one breast cancer patient, including two different regions of Ductal Carcinoma In Situ (DCIS), primary tumor and an asynchronous metastasis. We identify a remarkable landscape of somatic mutations, retained throughout breast cancer progression and with new mutational events emerging at each step. Our data, contrary to the proposed model of early dissemination of metastatic cells and parallel progression of primary tumors and metastases, provide evidence of linear progression of breast cancer with relatively late dissemination from the primary tumor. The genomic discordance between the different stages of tumor evolution in this patient emphasizes the importance of molecular profiling of metastatic tissue directing molecularly targeted therapy at recurrence.

  20. [New technology for linear colliders]. Annual progress report and renewal proposal

    SciTech Connect

    McIntyre, P.M.

    1992-08-12

    This report discusses the following topics on research of microwave amplifiers for linear colliders: Context in current microwave technology development; gated field emission for microwave cathodes; cathode fabrication and tests; microwave cathode design using field emitters; and microwave localization.

  1. 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.

  2. 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

  3. 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.

  4. [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.

  5. 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.

  6. 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

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

    PubMed

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

    2017-01-01

    To investigate if plasma HIV-1 tropism testing could identify subjects at higher risk for clinical progression and death in routine clinical management. Nested case-control study within the EuroSIDA cohort. 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. 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. 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.

  8. Effect of linear polarized light irradiation near the stellate ganglion in skin blood flow of fingers in patients with progressive systemic sclerosis.

    PubMed

    Lee, Chih-Hung; Chen, Gwo-Shing; Yu, Hsin-Su

    2006-02-01

    The purpose of this study is to evaluate the effect of linear polarized light irradiation near the stellate ganglion area on cutaneous blood flow in fingers of patients with progressive systemic sclerosis. Sympathetic overactivity is known to be present in patients with progressive systemic sclerosis. Recently introduced linear polarized light irradiation is designed to simulate noninvasive stellate ganglion block to decrease sympathetic output. Five patients with progressive systemic sclerosis and three normal healthy controls were studied. Linear polarized light (Super Lizer) was irradiated near the stellate ganglion on the right side of the neck at 358 J/cm(2) for 10 min. Then, laser Doppler flowmetry, laser Doppler imager, and capillary microscopy were used to measure the cutaneous blood flow of the right fourth finger for 30 min. No significant alternations of the skin blood flow between normal controls and patients with progressive systemic sclerosis after linear polarized light irradiation were detected. The effect of linear polarized light on the microcirculation of patients with progressive systemic sclerosis was minimal and transient. The effect of linear polarized light in treating patients with progressive systemic sclerosis may not result from the improvement of skin blood flow. Therefore, the use of linear polarized light in those patients to increase cutaneous blood flow should not be overemphasized.

  9. [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

  10. 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

  11. 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

  12. [Progress in methodological characteristics of clinical practice guideline for osteoarthritis].

    PubMed

    Xing, D; Wang, B; Lin, J H

    2017-06-01

    At present, several clinical practice guidelines for the treatment of osteoarthritis have been developed by institutes or societies. The ultimate purpose of developing clinical practice guidelines is to formulate the process in the treatment of osteoarthritis effectively. However, the methodologies used in developing clinical practice guidelines may place an influence on the transformation and application of that in treating osteoarthritis. The present study summarized the methodological features of individual clinical practice guideline and presented the tools for quality evaluation of clinical practice guideline. The limitations of current osteoarthritis guidelines of China are also indicated. The review article might help relevant institutions improve the quality in developing guide and clinical transformation.

  13. 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.

  14. 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.

  15. Deformation Bands as Linear Elastic Fractures: Progress in Theory and Observation

    NASA Astrophysics Data System (ADS)

    Sternlof, K.; Pollard, D.

    2001-12-01

    Deformation bands (DBs) are thin, tabular, bounded features of highly localized shear and/or compaction that commonly occur as systematic and pervasive arrays in porous sandstone. They also constitute an active area of theoretical and experimental research into the compressive failure of granular materials. Based on our ongoing study of DBs in the field, we propose that they originate at stress concentrations and propagate as brittle fractures in a linear elastic medium. Furthermore, we suggest that individual DB morphology is largely dominated by the closing (anti-mode I) component of the displacement discontinuity accommodated. The notion of DBs as "anti-cracks" akin to pressure solution surfaces is not new. But close examination of real DB arrays within the unifying context of linear elastic fracture mechanics is needed to add depth and bring quantitative rigor to our understanding of the phenomenon. Thus, we are building a body of detailed data based on field observation and thin-section analysis to substantiate and expand our central hypothesis, while also laying the foundation for an effort to replicate realistic DB arrays using numerical modeling techniques. Our field effort focuses on the Jurassic Aztec Sandstone as exposed in and around the Valley of Fire State Park, Nevada. This area offers expansive and varied DB exposures within a thick and relatively consistent sequence of dune-dominated aeolian sandstone. We will present interim results, interpretations and conclusions specific to the elastic nature of DBs, in particular comparing our data to the three distinct fracture-tip models: the dislocation, and the crack with and without cohesive end zones. Each of these models predicts substantially different near-tip stress fields for the same material under the same remote loading conditions, leading to different expectations for basic DB shape, structure, and propagation and mechanical interaction behavior. These expectations will be compared to and judged

  16. [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.

  17. 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.

  18. Estimating WAIS-IV indexes: proration versus linear scaling in a clinical sample.

    PubMed

    Umfleet, Laura Glass; Ryan, Joseph J; Gontkovsky, Sam T; Morris, Jeri

    2012-04-01

    We compared the accuracy of proration and linear scaling for estimating Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV), Verbal Comprehension Index (VCI), and Perceptual Reasoning Index (PRI) composites from all possible two subtest combinations. The purpose was to provide practice relevant psychometric results in a clinical sample. The present investigation was an archival study that used mostly within-group comparisons. We analyzed WAIS-IV data of a clinical sample comprising 104 patients with brain damage and 37 with no known neurological impairment. In both clinical samples, actual VCI and PRI scores were highly correlated with estimated index scores based on proration and linear scaling (all rs ≥.95). In the brain-impaired sample, significant mean score differences between the actual and estimated composites were found in two comparisons, but these differences were less than three points; no other significant differences emerged. Overall, findings demonstrate that proration and linear scaling methods are feasible procedures when estimating actual Indexes. There was no advantage of one computational method over the other. © 2012 Wiley Periodicals, Inc.

  19. 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

  20. 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

  1. 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

  2. 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.

  3. 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.

  4. 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)

  5. [Progress of orthodontics in the clinical and basic research].

    PubMed

    Zhao, Zhi-He

    2008-06-01

    In recent years, clinical diagnostic and treatment techniques of orthodontics have been developed rapidly. The orthopedic mechanism of malocclusion has been the hot spot of basic research of orthodontics.

  6. 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)

  7. [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.

  8. 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.

  9. Tendon Tissue Engineering: Progress, Challenges, and Translation to the Clinic

    PubMed Central

    Shearn, Jason T.; Kinneberg, Kirsten R.C.; Dyment, Nathaniel A.; Galloway, Marc T.; Kenter, Keith; Wylie, Christopher; Butler, David L.

    2013-01-01

    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. PMID:21625053

  10. 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

  11. Effect of creatine monohydrate on clinical progression in patients with Parkinson disease: a randomized clinical trial.

    PubMed

    Kieburtz, Karl; Tilley, Barbara C; Elm, Jordan J; Babcock, Debra; Hauser, Robert; Ross, G Webster; Augustine, Alicia H; Augustine, Erika U; Aminoff, Michael J; Bodis-Wollner, Ivan G; Boyd, James; Cambi, Franca; Chou, Kelvin; Christine, Chadwick W; Cines, Michelle; Dahodwala, Nabila; Derwent, Lorelei; Dewey, Richard B; Hawthorne, Katherine; Houghton, David J; Kamp, Cornelia; Leehey, Maureen; Lew, Mark F; Liang, Grace S Lin; Luo, Sheng T; Mari, Zoltan; Morgan, John C; Parashos, Sotirios; Pérez, Adriana; Petrovitch, Helen; Rajan, Suja; Reichwein, Sue; Roth, Jessie Tatsuno; Schneider, Jay S; Shannon, Kathleen M; Simon, David K; Simuni, Tanya; Singer, Carlos; Sudarsky, Lewis; Tanner, Caroline M; Umeh, Chizoba C; Williams, Karen; Wills, Anne-Marie

    2015-02-10

    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. To determine whether creatine monohydrate was more effective than placebo in slowing long-term clinical decline in participants with Parkinson disease. 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. Participants were randomized to placebo or creatine (10 g/d) monohydrate for a minimum of 5 years (maximum follow-up, 8 years). 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. 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% CI, 2249-2470) and for creatine was 2414 (95% CI, 2304-2524). The global statistical test

  12. [Good clinical practice:impediment of source of progress?].

    PubMed

    Dormont, J

    2000-04-15

    On the bases of the Declaration of Helsinki (1964), the law called Huriet-Sérusclat (1988) and several subsequent decrees have clearly defined the appropriate organization and management of clinical trials in France. The law on the Commission de l'informatique et des libertés (1978) and several European regulations have also to be taken into account. This extensive legal and regulatory system has been the source of a major improvement in the scientific quality of clinical trials and in the security of participating persons. Indirectly, it has also improved daily clinical care, as physicians have learned how to inform their patients and have been trained to use protocols and standard operative procedures. However, the legal and regulatory pressure has increased the cost and complexity of trials to such an extent that no clinician with his own resources is now able to be the sponsor of a trial involving more than a few patients. In addition to trials organized by pharmaceutical companies for drug development, health authorities in France and Europe should consider to support major clinical trials on therapeutic strategies with public health implications. A few examples can be acknowledged thus far, but a real policy remains to be defined.

  13. 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.

  14. REVIEW: Back to the future: the history and development of the clinical linear accelerator

    NASA Astrophysics Data System (ADS)

    Thwaites, David I.; Tuohy, John B.

    2006-07-01

    The linear accelerator (linac) is the accepted workhorse in radiotherapy in 2006. The first medical linac treated its first patient, in London, in 1953, so the use of these machines in clinical practice has been almost co-existent with the lifetime of Physics in Medicine and Biology. This review is a personal selection of things the authors feel are interesting in the history, particularly the early history, and development of clinical linacs. A brief look into the future is also given. One significant theme throughout is the continuity of ideas, building on previous experience. We hope the review might re-connect younger radiotherapy physicists in particular with some of the history and emphasize the continual need, in any human activity, to remain aware of the past, in order to make best use of past experience when taking decisions in the present.

  15. 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

  16. 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.

  17. Accuracy of linear measurement in the Galileos cone beam computed tomography under simulated clinical conditions

    PubMed Central

    Ganguly, R; Ruprecht, A; Vincent, S; Hellstein, J; Timmons, S; Qian, F

    2011-01-01

    Objectives The aim of this study was to determine the geometric accuracy of cone beam CT (CBCT)-based linear measurements of bone height obtained with the Galileos CBCT (Sirona Dental Systems Inc., Bensheim, Hessen, Germany) in the presence of soft tissues. Methods Six embalmed cadaver heads were imaged with the Galileos CBCT unit subsequent to placement of radiopaque fiduciary markers over the buccal and lingual cortical plates. Electronic linear measurements of bone height were obtained using the Sirona software. Physical measurements were obtained with digital calipers at the same location. This distance was compared on all six specimens bilaterally to determine accuracy of the image measurements. Results The findings showed no statistically significant difference between the imaging and physical measurements (P > 0.05) as determined by a paired sample t-test. The intraclass correlation was used to measure the intrarater reliability of repeated measures and there was no statistically significant difference between measurements performed at the same location (P > 0.05). Conclusions The Galileos CBCT image-based linear measurement between anatomical structures within the mandible in the presence of soft tissues is sufficiently accurate for clinical use. PMID:21697155

  18. 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. © 2013 Wiley Periodicals, Inc.

  19. 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

  20. Clinical aspects of melatonin intervention in Alzheimer's disease progression.

    PubMed

    Cardinali, Daniel P; Furio, Analía M; Brusco, Luis I

    2010-09-01

    Melatonin secretion decreases in Alzheimer´s disease (AD) and this decrease has been postulated as responsible for the circadian disorganization, decrease in sleep efficiency and impaired cognitive function seen in those patients. Half of severely ill AD patients develop chronobiological day-night rhythm disturbances like an agitated behavior during the evening hours (so-called "sundowning"). Melatonin replacement has been shown effective to treat sundowning and other sleep wake disorders in AD patients. The antioxidant, mitochondrial and antiamyloidogenic effects of melatonin indicate its potentiality to interfere with the onset of the disease. This is of particularly importance in mild cognitive impairment (MCI), an etiologically heterogeneous syndrome that precedes dementia. The aim of this manuscript was to assess published evidence of the efficacy of melatonin to treat AD and MCI patients. PubMed was searched using Entrez for articles including clinical trials and published up to 15 January 2010. Search terms were "Alzheimer" and "melatonin". Full publications were obtained and references were checked for additional material where appropriate. Only clinical studies with empirical treatment data were reviewed. The analysis of published evidence made it possible to postulate melatonin as a useful ad-on therapeutic tool in MCI. In the case of AD, larger randomized controlled trials are necessary to yield evidence of effectiveness (i.e. clinical and subjective relevance) before melatonin´s use can be advocated.

  1. Biomarkers in Scleroderma: Progressing from Association to Clinical Utility.

    PubMed

    Ligon, Colin; Hummers, Laura K

    2016-03-01

    Scleroderma is a heterogenous disease characterized by autoimmunity, a characteristic vasculopathy, and often widely varying extents of deep organ fibrosis. Recent advances in the understanding of scleroderma's evolution have improved the ability to identify subgroups of patients with similar prognosis in order to improve risk stratification, enrich clinical trials for patients likely to benefit from specific therapies, and identify promising therapeutic targets for intervention. High-throughput technologies have recently identified fibrotic and inflammatory effectors in scleroderma that exhibit strong prognostic ability and may be tied to disease evolution. Increasingly, the use of collections of assayed circulating proteins and patterns of gene expression in tissue has replaced single-marker investigations in understanding the evolution of scleroderma and in objectively characterizing disease extent. Lastly, identification of shared patterns of disease evolution has allowed classification of patients into latent disease subtypes, which may allow rapid clinical prognostication and targeted management in both clinical and research settings. The concept of biomarkers in scleroderma is expanding to include nontraditional measures of aggregate protein signatures and disease evolution. This review examines the recent advances in biomarkers with a focus on those approaches poised to guide prospective management or themselves serve as quantitative surrogate disease outcomes.

  2. 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.

  3. Fluent Versus Nonfluent Primary Progressive Aphasia: A Comparison of Clinical and Functional Neuroimaging Features

    ERIC Educational Resources Information Center

    Clark, D.G.; Charuvastra, A.; Miller, B.L.; Shapira, J.S.; Mendez, M.F.

    2005-01-01

    To better characterize fluent and nonfluent variants of primary progressive aphasia (PPA). Although investigators have recognized both fluent and nonfluent patients with PPA (Mesulam, 2001), the clinical and neuroimaging features of these variants have not been fully defined. We present clinical and neuropsychological data on 47 PPA patients…

  4. Progressing the utilisation of pharmacogenetics and pharmacogenomics into clinical care.

    PubMed

    Trent, Ronald J; Cheong, Pak Leng; Chua, Eng Wee; Kennedy, Martin A

    2013-06-01

    Understanding human genetic variation and how it impacts on gene function is a major focus in genomic-based research. Translation of this knowledge into clinical care is exemplified by pharmacogenetics/pharmacogenomics. The identification of particular gene variants that might influence drug uptake, metabolism, distribution or excretion promises a more effective personalised medicine approach in choosing the right drug or its dose for any particular individual. Adverse drug responses can then be avoided or mitigated. An understanding of germline or acquired (somatic) DNA mutations can also be used to identify drugs that are more likely to be therapeutically beneficial. This represents an area of growing interest in the treatment of cancer.

  5. 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.

  6. [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.

  7. 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?

  8. 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.

  9. 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

  10. Non-HDL Cholesterol and Triglycerides: Implications for Coronary Atheroma Progression and Clinical Events.

    PubMed

    Puri, Rishi; Nissen, Steven E; Shao, Mingyuan; Elshazly, Mohamed B; Kataoka, Yu; Kapadia, Samir R; Tuzcu, E Murat; Nicholls, Stephen J

    2016-11-01

    Non-high-density lipoprotein cholesterol (non-HDLC) levels reflect the full burden of cholesterol transported in atherogenic lipoproteins. Genetic studies suggest a causal association between elevated triglycerides (TGs)-rich lipoproteins and atherosclerosis. We evaluated associations between achieved non-HDLC and TG levels on changes in coronary atheroma volume. Data were analyzed from 9 clinical trials involving 4957 patients with coronary disease undergoing serial intravascular ultrasonography to assess changes in percent atheroma volume (ΔPAV) and were evaluated against on-treatment non-HDLC and TG levels. The effects of lower (<100 mg/dL) versus higher (≥100 mg/dL) achieved non-HDLC levels and lower (<200 mg/dL) versus higher (≥200 mg/dL) achieved TG levels were evaluated in populations with variable on-treatment low-density lipoprotein cholesterol (LDLC) linearly associated with ΔPAV. Overt PAV progression (ΔPAV>0) was associated with achieved TG levels >200 mg/dL, respectively. Lower on-treatment non-HDLC and TG levels associated with significant PAV regression compared with higher non-HDLC and TG levels across all levels of LDLC and C-reactive protein and irrespective of diabetic status (P<0.001 across all comparisons). ΔPAV were more strongly influenced by changes in non-HDLC (β=0.62; P<0.001) compared with changes in LDLC (β=0.51; P<0.001). Kaplan-Meier sensitivity analyses demonstrated significantly greater major adverse cardiovascular event rates in those with higher versus lower non-HDLC and TG levels, with an earlier separation of the non-HDLC compared with the LDLC curve. Achieved non-HDLC levels seem more closely associated with coronary atheroma progression than LDLC. Plaque progression associates with achieved TGs, but only above levels of 200 mg/dL. These observations support a more prominent role for non

  11. Serum urate as a predictor of clinical and radiographic progression in Parkinson disease.

    PubMed

    Schwarzschild, Michael A; Schwid, Steven R; Marek, Kenneth; Watts, Arthur; Lang, Anthony E; Oakes, David; Shoulson, Ira; Ascherio, Alberto; Hyson, Christopher; Gorbold, Emily; Rudolph, Alice; Kieburtz, Karl; Fahn, Stanley; Gauger, Lisa; Goetz, Christopher; Seibyl, John; Forrest, Misser; Ondrasik, John

    2008-06-01

    To determine whether concentration of serum urate, a purine metabolite and potent antioxidant that has been linked to a reduced risk of Parkinson disease (PD), predicts prognosis in PD. Prospective study. The Parkinson Research Examination of CEP-1347 Trial (PRECEPT) study, which investigated the effects of a potential neuroprotectant on rates of PD progression, was conducted between April 2002 and August 2005 (average follow-up time 21.4 months). Eight hundred four subjects with early PD enrolled in the PRECEPT study. The primary study end point was progression to clinical disability sufficient to warrant dopaminergic therapy. Cox proportional hazards models were used to estimate the hazard ratio (HR) of reaching end point according to quintiles of baseline serum urate concentration, adjusting for sex, age, and other potential covariates. Change in striatal uptake of iodine I 123-labeled 2-beta-carbomethoxy-3-beta-(4-iodophenyl)tropane ([(123)I]beta-CIT), a marker for the presynaptic dopamine transporter, was assessed with linear regression for a subset of 399 subjects. The adjusted HR of reaching end point declined with increasing baseline concentrations of urate; subjects in the top quintile reached the end point at only half the rate of subjects in the bottom quintile (HR, 0.51; 95% confidence interval [CI], 0.37-0.72; P for trend < .001). This association was markedly stronger in men (HR, 0.39; 95% CI, 0.26-0.60; P for trend < .001) than in women (HR, 0.77; 95% CI, 0.39-1.50; P for trend = .33). The percentage of loss in striatal [(123)I]beta-CIT uptake also improved with increasing serum urate concentrations (overall P for trend = .002; men, P = .001; women, P = .43). 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. Trial Registration clinicaltrials.gov Identifier: NCT00040404.

  12. 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

  13. 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

  14. Belatacept in clinical and experimental transplantation - progress and promise.

    PubMed

    Rangel, Erika B

    2010-04-01

    Belatacept is a fusion protein composed of the Fc fragment of a human IgG(1) immunoglobulin linked to the extracellular domain of cytotoxic T-lymphocyte-associated antigen 4 (CTLA4). CTLA4 is a molecule crucial for T-cell costimulation, selectively blocking the process of T-cell activation. Belatacept binds surface costimulatory ligands (CD80 and CD86) of antigen-presenting cells. Studies on nonhuman primates, as well as phase II and III clinical trials are here reviewed. Belatacept is a promising therapy in organ transplantation and in the future can be used to induce tolerance. Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.

  15. Overview summary of clinical heavier-ion progress in Japan

    NASA Astrophysics Data System (ADS)

    Matsufuji, N.

    2017-06-01

    Swift ion beams such as carbon has unique characteristics suitable for treating deep-seated tumours. In Japan, carbon-ion radiotherapy was started in 1994 at Heavy Ion Medical Accelerator in Chiba (HIMAC) at National Institute of Radiological Sciences and more than 10,000 patients have been treated by Aug. 2016. Clinical outcomes show superior efficacy of carbon ions even against radioresistant tumour while keeping the quality of life at high level, and also the usefulness of hypofractionated irradiation down to the completion of the course of lung-cancer treatment in 1 day. During the decades, the improvement of hardware and software technology such as 3D scanning technique, superconducting rotating gantry or biology model have been carried out aiming at further optimized ion-beam radiotherapy as well as reducing the cost of the facility. The developed technology has been transferred to the following facilities. As of 2016, 5 carbon ion radiotherapy facilities are in operation in Japan.

  16. Normative data and clinically significant effect sizes for single-item numerical linear analogue self-assessment (LASA) scales.

    PubMed

    Singh, Jasvinder A; Satele, Daniel; Pattabasavaiah, Suneetha; Buckner, Jan C; Sloan, Jeff A

    2014-12-18

    Single-item assessments have been the most often-used measures in National Cancer Institute (NCI) cancer control clinical trials, but normative data are not available. Our objective was to examine the normative data and clinically significant effect sizes for single-item numerical linear analogue self-assessment (LASA) scale for overall quality of life (QOL). We analyzed baseline data from 36 clinical trials and 6 observational studies with various populations, including healthy volunteers, cancer trial patients (patients with advanced incurable cancer or patients receiving treatment with curative intent) and hospice patients as well as their caregivers. The overall QOL LASA was rated 0 (as bad as it can be) to 10 (as good as it can be). We calculated the summary statistics and the proportion of patients reporting a clinically meaningful deficit (CMD) of a score equal to 5 or less on the 0-10 scale. In total, for the collective sample of 9,295 individuals, the average overall QOL reported was 7.39 (SD = 2.11) with a markedly skewed distribution with roughly 17% reporting a score of 5 or below indicating a clinically significant deficit in overall QOL. Hospice patients report a much worse average score of 5.7 upon entry to hospice; hospice caregivers average 7.4. Cancer patients vary within these two extremes with most patients averaging in the 7's on the 0-10 scale (range, 0 to 10 p-value < 0.0001). Men and women's QOL distributions were virtually identical (with average of 7.6 vs. 7.5, p-value = 0.046). Overall QOL was weakly related to performance status with a Spearman correlation coefficient of -0.29 (p-value < 0.0001). Overall QOL was related to tumor response (p-value = 0.0094), i.e. patients with a full or partial response reported a CMD in 11.4% of cases compared to 14.4% among those with stable disease and 18.5% among those with disease progression. Data missingness was high for performance status and tumor response associations. This

  17. Dopamine Transporter Neuroimaging as an Enrichment Biomarker in Early Parkinson's Disease Clinical Trials: A Disease Progression Modeling Analysis.

    PubMed

    Conrado, Daniela J; Nicholas, Timothy; Tsai, Kuenhi; Macha, Sreeraj; Sinha, Vikram; Stone, Julie; Corrigan, Brian; Bani, Massimo; Muglia, Pierandrea; Watson, Ian A; Kern, Volker D; Sheveleva, Elena; Marek, Kenneth; Stephenson, Diane T; Romero, Klaus

    2017-07-27

    Given the recognition that disease-modifying therapies should focus on earlier Parkinson's disease stages, trial enrollment based purely on clinical criteria poses significant challenges. The goal herein was to determine the utility of dopamine transporter neuroimaging as an enrichment biomarker in early motor Parkinson's disease clinical trials. Patient-level longitudinal data of 672 subjects with early-stage Parkinson's disease in the Parkinson's Progression Markers Initiative (PPMI) observational study and the Parkinson Research Examination of CEP-1347 Trial (PRECEPT) clinical trial were utilized in a linear mixed-effects model analysis. The rate of worsening in the motor scores between subjects with or without a scan without evidence of dopamine transporter deficit was different both statistically and clinically. The average difference in the change from baseline of motor scores at 24 months between biomarker statuses was -3.16 (90% confidence interval [CI] = -0.96 to -5.42) points. Dopamine transporter imaging could identify subjects with a steeper worsening of the motor scores, allowing trial enrichment and 24% reduction of sample size. Published 2017. This article is a U.S. Government work and is in the public domain in the USA. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  18. 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.

  19. [Prospective study of 221 community acquired pneumonias followed up in an outpatient clinic. Etiology and clinical-radiological progression].

    PubMed

    Javier Alvarez Gutiérrez, F; del Castillo Otero, D; García Fernández, A; Romero Romero, B; José del Rey Pérez, J; Soto Campos, G; Castillo Gómez, J

    2001-02-10

    All the community acquired pneumonia followed up in an outpatient clinic were prospectively studied in order to determine: etiology, clinical-radiological characteristics and its progression with diagnostic and therapeutic protocols. We arranged clinical evaluation protocols, etiological diagnosis by means of serology (in the first visit and three weeks later); and when necessary, by means of fiberbronchoscopy (protected microbiological brush), as well as clinical and radiological progression (up to three visits) after empirical treatment. Initially, 240 patients were included, of which 221 were fully followed up. Etiological diagnosis was obtained in 86 patients (39%). The bacteria most frequently isolated was Coxiella burnetii (12.2%), followed up Mycoplasma pneumoniae and Legionella pneumophila. Two cases of Strepcococus pneumoniae were diagnosed. The most frequent radiological onset was alveolar infiltrate (86%). The initial empiric treatment were macrolids (71%) or second generation cephalosporines (22%). Most patients presented a favourable clinical and radiological progression. Only 2 patients needed admission to the hospital (< 1%). In community acquired pneumonias studied in our outpatient clinic we found a high number of "atypical" agents. Treatment with macrolids or second generation cephalosporines are appropriate for these patients.

  20. Predictors and clinical significance of progression or regression of asymptomatic carotid stenosis.

    PubMed

    Kakkos, Stavros K; Nicolaides, Andrew N; Charalambous, Ioanna; Thomas, Dafydd; Giannopoulos, Argyrios; Naylor, A Ross; Geroulakos, George; Abbott, Anne L

    2014-04-01

    To determine baseline clinical and ultrasonographic plaque factors predictive of progression or regression of asymptomatic carotid stenosis and the predictive value of changes in stenosis severity on risk of first ipsilateral cerebral or retinal ischemic events (including stroke). A total of 1121 patients with asymptomatic carotid stenosis of 50% to 99% in relation to the bulb diameter (European Carotid Surgery Trial [ECST] method) underwent six monthly clinical assessments and carotid duplexes for up to 8 years (mean follow-up, 4 years). Progression or regression was considered present if there was a change of at least one grade higher or lower, respectively, persisting for at least two consecutive examinations. Regression occurred in 43 (3.8%), no change in 856 (76.4%), and progression in 222 (19.8%) patients. Younger age, high grades of stenosis, absence of discrete white areas in the plaque, and taking lipid lowering therapy were independent baseline predictors of increased incidence of regression. High serum creatinine, male gender, not taking lipid lowering therapy, low grades of stenosis, and increased plaque area were independent baseline predictors of progression. One hundred and thirty first ipsilateral cerebral or retinal ischemic events, including 59 strokes, occurred. Forty (67.8%) of the strokes occurred in patients whose stenosis was unchanged, 19 (32.2%) in those with progression, and zero in those with regression. For the entire cohort, the 8-year cumulative ipsilateral cerebral ischemic stroke rate was zero in patients with regression, 9% if the stenosis was unchanged, and 16% if there was progression (average annual stroke rates of 0%, 1.1%, and 2.0%, respectively; log-rank, P = .05; relative risk in patients with progression, 1.92; 95% confidence interval, 1.14-3.25). For patients with baseline stenosis 70% to 99% in relation to the distal internal carotid (North American Symptomatic Carotid Endarterectomy Trial [NASCET] method), in the absence

  1. 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

  2. Pseudotumour cerebri in children: Aetiology, clinical features, and progression.

    PubMed

    Mosquera Gorostidi, A; Iridoy Zulet, M; Azcona Ganuza, G; Gembero Esarte, E; Yoldi Petri, M E; Aguilera Albesa, S

    2017-01-09

    The definition, associated aetiologies, diagnosis, and treatment of idiopathic intracranial hypertension, or pseudotumour cerebri (PTC), are constantly being revised in the paediatric population. Our study included children younger than 15 years old with PTC and attended at a reference hospital in the past 12 years. We analysed the clinical and epidemiological features of our sample and the diagnostic and treatment approaches. PTC was defined as presence of intracranial hypertension (CSF opening pressure>25cmH2O) and absence of space-occupying lesions in brain MR images. A total of 12 children with PTC were included; mean age was 10 years and 90% were girls. Weight was normal in all patients. Eighty-two percent of the patients had symptoms: headache (66%), diplopia (8%), and visual loss (8%). All of them displayed papilloedema (17% unilaterally). Lumbar puncture (LP) provided the diagnosis in all cases and 91% showed no relevant MRI findings. A potential cause of PTC was identified in 5 cases: pharmacological treatment in 2 and infection (Mycoplasma pneumoniae [M. pneumoniae]) in 3. Ninety-one per cent of the patients received treatment: 75% underwent several LPs and 42% received acetazolamide and/or prednisone. Outcomes were favourable in all cases. The incidence of PTC was estimated at approximately 1 case per 100 000 children/years, in line with data reported by previous studies. Overweight was not found to be a risk factor for PTC in this population. M. pneumoniae infection may trigger PTC and cause recurrences at later stages. The absence of symptoms seems to be independent from the degree of intracranial hypertension. Acetazolamide treatment is effective in most cases, and it represents a viable alternative to repeated LP. Copyright © 2016 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  3. 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.

  4. Renal Morphology, Clinical Findings, and Progression Rate in Mesoamerican Nephropathy.

    PubMed

    Wijkström, Julia; González-Quiroz, Marvin; Hernandez, Mario; Trujillo, Zulma; Hultenby, Kjell; Ring, Anneli; Söderberg, Magnus; Aragón, Aurora; Elinder, Carl-Gustaf; Wernerson, Annika

    2017-05-01

    Mesoamerican nephropathy (MeN) is a chronic kidney disease affecting rural inhabitants in Central America. We have previously described the renal morphology in 8 patients from El Salvador. To confirm the renal pathology, we have studied kidney biopsies from patients with MeN in Nicaragua. Follow-up urine and blood samples from both biopsy studies were collected to investigate the natural history. Case series. In the kidney biopsy study, 19 male sugarcane workers in Nicaragua with suspected MeN were investigated with questionnaires, kidney biopsies, and blood and urine analysis. Inclusion criteria were age 20 to 65 years and plasma creatinine level of 1.13 to 2.49mg/dL or estimated glomerular filtration rate (eGFR) of 30 to 80mL/min/1.73m(2). Exclusion criteria were proteinuria with protein excretion > 3g/24 h, uncontrolled hypertension, diabetes mellitus, or other known kidney disease. In the follow up-study, blood and urine from the kidney biopsy study in Nicaragua (n=18) and our previous biopsy study of MeN cases in El Salvador (n=7) were collected 1 to 1.5 and 2 to 2.5 years after biopsy, respectively. Renal morphology, clinical, and biochemical characteristics, change in eGFR per year. eGFR was calculated using the CKD-EPI creatinine (eGFRcr), cystatin C (eGFRcys), and creatinine-cystatin C (eGFRcr-cys) equations. In the kidney biopsy study, participants had a mean eGFRcr of 57 (range, 33-96) mL/min/1.73m(2). 47% had low plasma sodium and 21% had low plasma potassium levels. 16 kidney biopsies were representative and showed glomerulosclerosis (mean, 38%), glomerular hypertrophy, and signs of chronic glomerular ischemia. Mild to moderate tubulointerstitial damage and mostly mild vascular changes were seen. In the follow up-study, median duration of follow-up was 13 (range, 13-27) months. Mean change in eGFRcr was -4.4±8.4 (range, -27.7 to 10.2) mL/min/1.73m(2) per year. Most patients had stopped working with sugarcane cultivation. 3 biopsy specimens had 4 or

  5. 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.

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

    PubMed Central

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

    2014-01-01

    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. PMID:24795786

  7. 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.

  8. 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

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

    PubMed

    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.

  10. 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.

  11. Microphthalmia with linear skin defects (MLS) syndrome: clinical, cytogenetic, and molecular characterization of 11 cases.

    PubMed

    Morleo, Manuela; Pramparo, Tiziano; Perone, Lucia; Gregato, Giuliana; Le Caignec, Cedric; Mueller, Robert F; Ogata, Tsutomu; Raas-Rothschild, Annick; de Blois, Marie Christine; Wilson, Louise C; Zaidman, Gerald; Zuffardi, Orsetta; Ballabio, Andrea; Franco, Brunella

    2005-08-30

    The microphthalmia with linear skin defects (MLS) syndrome (MIM 309801) is a severe and rare developmental disorder, which is inherited as an X-linked dominant trait with male lethality. In the vast majority of patients, this syndrome is associated with terminal deletion of the Xp22.3 region. Thirty-five cases have been described to date in the literature since the first description of the syndrome in the early 1990s. We now report on the clinical, cytogenetic, and molecular characterization of 11 patients, 7 of whom have not been described previously. Seven of these patients have chromosomal abnormalities of the short arm of the X-chromosome, which were characterized and defined by fluorescence in situ hybridization (FISH) analysis. Intriguingly, one of the patients displays an interstitial Xp22.3 deletion, which to the best of our knowledge is the first reported for this condition. Finally we report on the identification and molecular characterization of four cases with clinical features of MLS but apparently normal karyotypes, verified by FISH analysis using genomic clones spanning the MLS minimal critical region, and with genome-wide analysis using a 1 Mb resolution BAC microarray. These patients made it possible to undertake mutation screening of candidate genes and may prove critical for the identification of the gene responsible for this challenging and intriguing genetic disease. (c) 2005 Wiley-Liss, Inc.

  12. 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.

  13. Deep Gray Matter Involvement on Brain MRI Scans Is Associated with Clinical Progression in Multiple Sclerosis

    PubMed Central

    Neema, Mohit; Arora, Ashish; Healy, Brian C.; Guss, Zachary D.; Brass, Steven D.; Duan, Yang; Buckle, Guy J.; Glanz, Bonnie I.; Stazzone, Lynn; Khoury, Samia J.; Weiner, Howard L.; Guttmann, Charles R.G.; Bakshi, Rohit

    2009-01-01

    BACKGROUND Conventional brain MRI lesion measures have unreliable associations with clinical progression in multiple sclerosis (MS). Gray matter imaging may improve clinical-MRI correlations. METHODS We tested if gray matter MRI measures and conventional measures of lesions/atrophy predicted clinical progression in a 4-year longitudinal study of 97 patients with MS. Baseline and follow-up brain MRI were analyzed for basal ganglia and thalamic normalized T2 signal intensity, whole brain T2-hyperintense lesion volume, and whole brain atrophy. Logistic regression tested the ability of baseline or on-study change in MRI to predict disability progression, as reported by area under the receiver operator characteristics curve (AUC). RESULTS Lower caudate T2-intensity at baseline (P = .04; AUC = .69) and on-study decreasing T2-intensity in the putamen (P = .03; AUC = .70) and thalamus (P = .01; AUC = .71) were the MRI variables associated with clinical progression when regression modeling was adjusted for length of follow-up interval, baseline EDSS, disease duration, age, and sex. CONCLUSIONS Gray matter T2-hypointensity, suggestive of excessive iron deposition is associated with worsening disability in patients with MS. Gray matter MRI assessment may be able to capture neurodegenerative aspects of the disease, with more clinical relevance than derived from conventional MRI measures. PMID:19192042

  14. Computed tomographic findings in progressive supranuclear palsy: correlation with clinical grade.

    PubMed

    Schonfeld, S M; Golbe, L I; Sage, J I; Safer, J N; Duvoisin, R C

    1987-01-01

    We report clinical and computed tomography (CT) findings in 17 patients with progressive supranuclear palsy (PSP). Patients were divided into four clinical groups according to the severity of the disease and functional disability. In Grade 1, patients demonstrated minor disability and decreased anteroposterior (AP) diameter of the midbrain tegmentum was present. As the disease progressed clinically to Grade 2, more severe atrophy of the pons and midbrain and dilatation of the quadrigeminal plate cistern were noted. The most severe stages of clinical disability (Grades 3 and 4) were characterized radiologically by dilatation of the aqueduct, progressive dilatation of the third and fourth ventricles and atrophy of the temporal lobes. Cortical atrophy was variable and not a prominent radiological feature. Midbrain and pontine AP diameters were significantly smaller in PSP patients than normal patients. Serial studies showed progressive involution of the pons and midbrain and enlargement of the third ventricle. While the most obvious CT changes in PSP occur late in the disease, CT may in fact suggest the correct diagnosis long before the classic clinical picture is evident.

  15. 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.

  16. 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

  17. 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

  18. Linear energy transfer-guided optimization in intensity modulated proton therapy: feasibility study and clinical potential.

    PubMed

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

    2013-09-01

    To investigate the feasibility and potential clinical benefit of linear energy transfer (LET) guided plan optimization in intensity modulated proton therapy (IMPT). 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. 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. 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 identifying the clinically optimal solution. Copyright © 2013

  19. 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

  20. 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.

  1. 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

  2. An evaluation of molecular and clinical remission in rheumatoid arthritis by assessing radiographic progression

    PubMed Central

    van der Helm-van Mil, Annette H. M.; Knevel, Rachel; Cavet, Guy; Huizinga, Tom W. J.; Haney, Douglas J.

    2013-01-01

    Objectives. To determine whether molecular remission defined by a multi-biomarker disease activity (MBDA) score predicts a reduced risk of joint damage progression, and whether the MBDA score can augment existing classifications of remission. Methods. The study examined 271 visits for 163 RA patients in the Leiden Early Arthritis Cohort. The MBDA score and other variables from each visit were evaluated for prediction of progression [change in Sharp–van der Heijde Score (ΔSHS) >3] over the ensuing 12 months. Positive likelihood ratios (PLRs) for non-progression were calculated for remission based upon DAS based on 28-joint counts and CRP (DAS28-CRP <2.32), EULAR/ACR Boolean criteria and MBDA score (≤25). Results. Ninety-three per cent of patients in MBDA-defined remission did not experience progression, compared with 70% of patients not in MBDA remission (P = 0.001). There were no significant differences in the fraction of non-progressers between patients in remission and those not in remission using either DAS28-CRP or EULAR/ACR criteria. The PLR for non-progression over 12 months for MBDA remission was 4.73 (95% CI 1.67, 15.0). Among patients in DAS28-CRP remission, those with a high MBDA score were 2.3 times as likely (95% CI 1.1, 3.7) to have joint damage progression during the next year. Conclusion. MBDA-defined remission was an indicator of limited radiographic progression over the following 12 months. For patients in DAS28-CRP remission, high MBDA scores were a significant indicator of elevated risk of progression. MBDA results may provide a useful adjunct to clinical assessment to identify progression-free remission and assess subclinical disease. PMID:23287359

  3. 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

  4. CE: Original Research: Creating an Evidence-Based Progression for Clinical Advancement Programs.

    PubMed

    Burke, Kathleen G; Johnson, Tonya; Sites, Christine; Barnsteiner, Jane

    2017-05-01

    : Background: The Institute of Medicine (IOM) and the Quality and Safety Education for Nurses (QSEN) project have identified six nursing competencies and supported their integration into undergraduate and graduate nursing curricula nationwide. But integration of those competencies into clinical practice has been limited, and evidence for the progression of competency proficiency within clinical advancement programs is scant. Using an evidence-based approach and building on the competencies identified by the IOM and QSEN, a team of experts at an academic health system developed eight competency domains and 186 related knowledge, skills, and attitudes (KSAs) for professional nursing practice. The aim of our study was to validate the eight identified competencies and 186 related KSAs and determine their developmental progression within a clinical advancement program. Using the Delphi technique, nursing leadership validated the newly identified competency domains and KSAs as essential to practice. Clinical experts from 13 Magnet-designated hospitals with clinical advancement programs then participated in Delphi rounds aimed at reaching consensus on the developmental progression of the 186 KSAs through four levels of clinical advancement. Two Delphi rounds resulted in consensus by the expert participants. All eight competency domains were determined to be essential at all four levels of clinical practice. At the novice level of practice, the experts identified a greater number of KSAs in the domains of safety and patient- and family-centered care. At more advanced practice levels, the experts identified a greater number of KSAs in the domains of professionalism, teamwork, technology and informatics, and continuous quality improvement. Incorporating the eight competency domains and the 186 KSAs into a framework for clinical advancement programs will likely result in more clearly defined role expectations; enhance accountability; and elevate and promote nursing practice

  5. 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.

  6. 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

  7. 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.

  8. Clinical Cancer Advances 2013: Annual Report on Progress Against Cancer from the American Society of Clinical Oncology.

    PubMed

    Patel, Jyoti D; Krilov, Lada; Adams, Sylvia; Aghajanian, Carol; Basch, Ethan; Brose, Marcia S; Carroll, William L; de Lima, Marcos; Gilbert, Mark R; Kris, Mark G; Marshall, John L; Masters, Gregory A; O'Day, Steven J; Polite, Blasé; Schwartz, Gary K; Sharma, Sunil; Thompson, Ian; Vogelzang, Nicholas J; Roth, Bruce J

    2014-01-10

    Since its founding in 1964, the American Society of Clinical Oncology (ASCO) has been committed to improving cancer outcomes through research and the delivery of quality care. Research is the bedrock of discovering better treatments--providing hope to the millions of individuals who face a cancer diagnosis each year. The studies featured in "Clinical Cancer Advances 2013: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology" represent the invaluable contributions of thousands of patients who participate in clinical trials and the scientists who conduct basic and clinical research. The insights described in this report, such as how cancers hide from the immune system and why cancers may become resistant to targeted drugs, enable us to envision a future in which cancer will be even more controllable and preventable. The scientific process is thoughtful, deliberate, and sometimes slow, but each advance, while helping patients, now also points toward new research questions and unexplored opportunities. Both dramatic and subtle breakthroughs occur so that progress against cancer typically builds over many years. Success requires vision, persistence, and a long-term commitment to supporting cancer research and training. Our nation's longstanding investment in federally funded cancer research has contributed significantly to a growing array of effective new treatments and a much deeper understanding of the drivers of cancer. But despite this progress, our position as a world leader in advancing medical knowledge and our ability to attract the most promising and talented investigators are now threatened by an acute problem: Federal funding for cancer research has steadily eroded over the past decade, and only 15% of the ever-shrinking budget is actually spent on clinical trials. This dismal reality threatens the pace of progress against cancer and undermines our ability to address the continuing needs of our patients. Despite this

  9. Outcome Measures in Relapsing-Remitting Multiple Sclerosis: Capturing Disability and Disease Progression in Clinical Trials

    PubMed Central

    Lavery, Amy M.; Verhey, Leonard H.; Waldman, Amy T.

    2014-01-01

    Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease that manifests as acute relapses and progressive disability. As a primary endpoint for clinical trials in MS, disability is difficult to both characterize and measure. Furthermore, the recovery from relapses and the rate of disability vary considerably among patients. Given these challenges, investigators have developed and studied the performance of various outcome measures and surrogate endpoints in MS clinical trials. This review defines the outcome measures and surrogate endpoints used to date in MS clinical trials and presents challenges in the design of both adult and pediatric trials. PMID:24883205

  10. 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.

  11. 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.

  12. 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.

  13. Malignant pigmented villonodular synovitis in the knee - report of a case with rapid clinical progression.

    PubMed

    Imakiire, Naoaki; Fujino, Takashi; Morii, Takeshi; Honya, Keita; Mochizuki, Kazuo; Satomi, Kazuhiko; Fujioka, Yasunori

    2011-01-07

    Malignant pigmented villonodular synovitis (PVNS) (or malignant giant cell tumor of tendon sheath (GCTTS) is an extremely rare condition defined as a malignant lesion occurring with concomitant or previously documented PVNS at the same site. To date, only less than 20 cases have been reported in English literatures. We report a case of malignant PVNS in the knee in a 56-year-old woman with unpredictable rapid progression. This case raised a caution that when atypical components in specimens of recurrent benign PVNS are detected, even if low-grade or tiny, both pathologists and surgeons should consider the risk of malignant PVNS, which could display aggressive clinical progression.

  14. 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.

  15. Ultrasonographic predictors for clinical and radiological progression in knee osteoarthritis after 2 years of follow-up.

    PubMed

    Bevers, Karen; Vriezekolk, Johanna E; Bijlsma, Johannes W J; van den Ende, Cornelia H M; den Broeder, Alfons A

    2015-11-01

    The aim of this study was to investigate the association between a set of US features and radiographic and clinical progression of knee OA after 2 years of follow-up. A total of 125 patients fulfilling ACR clinical criteria for knee OA underwent US examination of the most symptomatic knee. The US protocol included assessment of synovial hypertrophy, joint effusion, infrapatellar bursitis, Baker's cyst, medial meniscus protrusion and cartilage thickness. Clinical progression was defined using the inverse Osteoarthritis Research Society International responder criteria or progression to total knee replacement. Radiological progression was defined as a ≥2 point increase in Altman score or progression to total knee replacement. Regression analyses were performed with baseline ultrasonographic features as independent variables and progression (two separate models for clinical progression and radiographic progression) as the dependent variable. A total of 31 (25%) patients fulfilled the criteria of clinical progression and 60 (48%) patients fulfilled the criteria of radiological progression. The presence of Baker's cyst showed a statistically significant association with clinical [odds ratio (OR) 3.07 (95% CI 1.21, 7.78)] as well as radiological [OR 2.84 (95% CI 1.17, 6.90)] progression. Synovial hypertrophy showed a weaker but consistent association with clinical as well as radiological progression [OR 2.11 (95% CI 0.80, 5.57)]. We demonstrated a longitudinal association between Baker's cyst (and to a lesser extent synovial hypertrophy) at baseline and radiological and clinical progression after 2 years. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  16. 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.

  17. HIV-1 Genetic Variability in Cuba and Implications for Transmission and Clinical Progression.

    PubMed

    Blanco, Madeline; Machado, Liuber Y; Díaz, Héctor; Ruiz, Nancy; Romay, Dania; Silva, Eladio

    2015-10-01

    INTRODUCTION Serological and molecular HIV-1 studies in Cuba have shown very low prevalence of seropositivity, but an increasing genetic diversity attributable to introduction of many HIV-1 variants from different areas, exchange of such variants among HIV-positive people with several coinciding routes of infection and other epidemiologic risk factors in the seropositive population. The high HIV-1 genetic variability observed in Cuba has possible implications for transmission and clinical progression. OBJECTIVE Study genetic variability for the HIV-1 env, gag and pol structural genes in Cuba; determine the prevalence of B and non-B subtypes according to epidemiologic and behavioral variables and determine whether a relationship exists between genetic variability and transmissibility, and between genetic variability and clinical disease progression in people living with HIV/AIDS. METHODS Using two molecular assays (heteroduplex mobility assay and nucleic acid sequencing), structural genes were characterized in 590 people with HIV-1 (480 men and 110 women), accounting for 3.4% of seropositive individuals in Cuba as of December 31, 2013. Nonrandom sampling, proportional to HIV prevalence by province, was conducted. Relationships between molecular results and viral factors, host characteristics, and patients' clinical, epidemiologic and behavioral variables were studied for molecular epidemiology, transmission, and progression analyses. RESULTS Molecular analysis of the three HIV-1 structural genes classified 297 samples as subtype B (50.3%), 269 as non-B subtypes (45.6%) and 24 were not typeable. Subtype B prevailed overall and in men, mainly in those who have sex with men. Non-B subtypes were prevalent in women and heterosexual men, showing multiple circulating variants and recombinant forms. Sexual transmission was the predominant form of infection for all. B and non-B subtypes were encountered throughout Cuba. No association was found between subtypes and

  18. Rapid clinical progression to diagnosis among African-American men with systemic lupus erythematosus.

    PubMed

    Arbuckle, M R; James, J A; Dennis, G J; Rubertone, M V; McClain, M T; Kim, X R; Harley, J B

    2003-01-01

    The initial clinical course of systemic lupus erythematosus (SLE) is variable, ranging from relatively minor manifestations progressing over years to rapid onset of fulminate disease. We sought to identify factors associated with the rapid manifestation of SLE. Chart review of military medical records was used to identify 130 patients who met the American College of Rheumatology classification criteria for SLE. Demographics, clinical criteria date of occurrence, and the date of SLE classification (at least four clinical criteria) met were documented. Prospectively stored serum samples prior to the diagnosis were evaluated for SLE autoantibodies. Median time from the first recorded criteria to diagnosis was significantly shorter in African-American (AA) males compared with AA females and European American (EA) females and males combined. AA males were more likely to have nephritis as their first clinical symptom. Also, less time transpired between the first clinical criterion and SLE diagnosis in AA males with nephritis than in other groups presenting with nephritis. Even when cases presenting with nephritis were excluded, a diagnosis of SLE was made more rapidly in AA males. African-American men progress from initial clinical manifestations to SLE diagnosis more rapidly than other ethnic or gender groups.

  19. NET Blood Transcript Analysis Defines the Crossing of the Clinical Rubicon: When Stable Disease Becomes Progressive.

    PubMed

    Pavel, Marianne; Jann, Henning; Prasad, Vikas; Drozdov, Ignat; Modlin, Irvin M; Kidd, Mark

    2017-01-01

    A key issue in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is early identification and prediction of disease progression. Clinical evaluation and imaging are limited due to the lack of sensitivity and disease indolence. We assessed the NETest as a predictive and prognostic marker of progression in a long-term follow-up study. GEP-NETs (n = 34) followed for a median 4 years (2.2-5.4) were evaluated. WHO tumor grade/stage grade 1: n = 17, grade 2: n = 14, grade 3: n = 1 (for 2, no grade was available); 31 (91%) were stage IV. Baseline and longitudinal imaging and blood biomarkers were available in all, and progression was defined per standard clinical protocols (RECIST 1.0). The NETest was measured by quantitative PCR of blood and multianalyte algorithmic analysis (disease activity scaled 0-100% with low <40% and high activity risk cutoffs >80%); chromogranin A (CgA) was measured by radioimmunoassay (normal <150 µg/l); progression-free survival (PFS) was analyzed by Cox proportional-hazard regression and Kaplan-Meier analysis. At baseline, 100% were NETest positive, and CgA was elevated in 50%. The only baseline variable (Cox modeling) associated with PFS was NETest (hazard ratio = 1.022, 95% confidence interval = 1.005-1.04; p < 0.012). Using Kaplan-Meier analyses, the baseline NETest (>80%) was significantly associated (p = 0.01) with disease progression (median PFS 0.68 vs. 2.78 years with <40% levels). The NETest was more informative (96%) than CgA changes (25%) in consistently predicting disease alterations (40%, p < 2 × 10-5, χ2 = 18). The NETest had an earlier time point change than imaging (1.02 ± 0.15 years). Baseline NETest levels >40% in stable disease were 100% prognostic of disease progression versus CgA (χ2 = 5, p < 0.03). Baseline NETest values <40% accurately (100%) predicted stability over 5 years (p = 0.05, χ2 = 3.8 vs. CgA). The NETest correlated with a well-differentiated GEP-NET clinical status. The NETest has

  20. Subjective cognitive concerns and neuropsychiatric predictors of progression to the early clinical stages of Alzheimer disease.

    PubMed

    Donovan, Nancy J; Amariglio, Rebecca E; Zoller, Amy S; Rudel, Rebecca K; Gomez-Isla, Teresa; Blacker, Deborah; Hyman, Bradley T; Locascio, Joseph J; Johnson, Keith A; Sperling, Reisa A; Marshall, Gad A; Rentz, Dorene M

    2014-12-01

    To examine neuropsychiatric and neuropsychological predictors of progression from normal to early clinical stages of Alzheimer disease (AD). From a total sample of 559 older adults from the Massachusetts Alzheimer's Disease Research Center longitudinal cohort, 454 were included in the primary analysis: 283 with clinically normal cognition (CN), 115 with mild cognitive impairment (MCI), and 56 with subjective cognitive concerns (SCC) but no objective impairment, a proposed transitional group between CN and MCI. Two latent cognitive factors (memory-semantic, attention-executive) and two neuropsychiatric factors (affective, psychotic) were derived from the Alzheimer's Disease Centers' Uniform Data Set neuropsychological battery and Neuropsychiatric Inventory brief questionnaire. Factors were analyzed as predictors of time to progression to a worse diagnosis using a Cox proportional hazards regression model with backward elimination. Covariates included baseline diagnosis, gender, age, education, prior depression, antidepressant medication, symptom duration, and interaction terms. Higher/better memory-semantic factor score predicted lower hazard of progression (hazard ratio [HR] = 0.4 for 1 standard deviation [SD] increase, p <0.0001), and higher/worse affective factor score predicted higher hazard (HR = 1.3 for one SD increase, p = 0.01). No other predictors were significant in adjusted analyses. Using diagnosis as a sole predictor of transition to MCI, the SCC diagnosis carried a fourfold risk of progression compared with CN (HR = 4.1, p <0.0001). These results identify affective and memory-semantic factors as significant predictors of more rapid progression from normal to early stages of cognitive decline and highlight the subgroup of cognitively normal elderly with SCC as those with elevated risk of progression to MCI. Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

  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. 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.

  3. Progression of subcortical atrophy and iron deposition in multiple system atrophy: a comparison between clinical subtypes.

    PubMed

    Lee, Jae-Hyeok; Kim, Tae-Hyung; Mun, Chi-Woong; Kim, Tae-Hyoung; Han, Yong-Hee

    2015-08-01

    Magnetic resonance imaging (MRI) can be useful not only for the diagnosis of multiple system atrophy (MSA) itself, but also to distinguish between different clinical subtypes. This study aimed to investigate whether there are differences in the progression of subcortical atrophy and iron deposition between two variants of MSA. Two serial MRIs at baseline and follow-up were analyzed in eight patients with the parkinsonian variant MSA (MSA-P), nine patients with cerebellar variant MSA (MSA-C), and fifteen patients with Parkinson's disease (PD). The R2* values and volumes were calculated for the selected subcortical structures (caudate nucleus, putamen, globus pallidus, and thalamus) using an automated region-based analysis. In both volume and R2*, a higher rate of progression was identified in MSA-P patients. Volumetric analysis showed significantly more rapid progression of putamen and caudate nucleus in MSA-P than in MSA-C. With regard to R2* changes, a significant increase at follow-up and a higher rate of progression were identified in the putamen of MSA-P group compared to MSA-C and PD groups. This longitudinal study revealed different progression rates of MRI markers between MSA-P and MSA-C. Iron-related degeneration in the putamen may be more specific for MSA-P.

  4. 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

  5. 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

  6. Cancer imaging by optical coherence tomography: preclinical progress and clinical potential.

    PubMed

    Vakoc, Benjamin J; Fukumura, Dai; Jain, Rakesh K; Bouma, Brett E

    2012-04-05

    The past decade has seen dramatic technological advances in the field of optical coherence tomography (OCT) imaging. These advances have driven commercialization and clinical adoption in ophthalmology, cardiology and gastrointestinal cancer screening. Recently, an array of OCT-based imaging tools that have been developed for preclinical intravital cancer imaging applications has yielded exciting new capabilities to probe and to monitor cancer progression and response in vivo. Here, we review these results, forecast the future of OCT for preclinical cancer imaging and discuss its exciting potential to translate to the clinic as a tool for monitoring cancer therapy.

  7. 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.

  8. 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

  9. 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. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

  10. Crowdsourced analysis of clinical trial data to predict amyotrophic lateral sclerosis progression.

    PubMed

    Küffner, Robert; Zach, Neta; Norel, Raquel; Hawe, Johann; Schoenfeld, David; Wang, Liuxia; Li, Guang; Fang, Lilly; Mackey, Lester; Hardiman, Orla; Cudkowicz, Merit; Sherman, Alexander; Ertaylan, Gokhan; Grosse-Wentrup, Moritz; Hothorn, Torsten; van Ligtenberg, Jules; Macke, Jakob H; Meyer, Timm; Schölkopf, Bernhard; Tran, Linh; Vaughan, Rubio; Stolovitzky, Gustavo; Leitner, Melanie L

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with substantial heterogeneity in its clinical presentation. This makes diagnosis and effective treatment difficult, so better tools for estimating disease progression are needed. Here, we report results from the DREAM-Phil Bowen ALS Prediction Prize4Life challenge. In this crowdsourcing competition, competitors developed algorithms for the prediction of disease progression of 1,822 ALS patients from standardized, anonymized phase 2/3 clinical trials. The two best algorithms outperformed a method designed by the challenge organizers as well as predictions by ALS clinicians. We estimate that using both winning algorithms in future trial designs could reduce the required number of patients by at least 20%. The DREAM-Phil Bowen ALS Prediction Prize4Life challenge also identified several potential nonstandard predictors of disease progression including uric acid, creatinine and surprisingly, blood pressure, shedding light on ALS pathobiology. This analysis reveals the potential of a crowdsourcing competition that uses clinical trial data for accelerating ALS research and development.

  11. 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.

  12. Modeling progression risk for smoldering multiple myeloma: results from a prospective clinical study.

    PubMed

    Cherry, Benjamin M; Korde, Neha; Kwok, Mary; Manasanch, Elisabet E; Bhutani, Manisha; Mulquin, Marcia; Zuchlinski, Diamond; Yancey, Mary Ann; Maric, Irina; Calvo, Katherine R; Braylan, Raul; Stetler-Stevenson, Maryalice; Yuan, Constance; Tembhare, Prashant; Zingone, Adriana; Costello, Rene; Roschewski, Mark J; Landgren, Ola

    2013-10-01

    The risk of progression to multiple myeloma (MM) from the precursor condition smoldering MM (SMM) varies considerably among individual patients. Reliable markers for progression to MM are vital to advance the understanding of myeloma precursor disease and for the development of intervention trials designed to delay/prevent MM. The Mayo Clinic and Spanish PETHEMA have proposed models to stratify patient risk based on clinical parameters. The aim of our study was to define the degree of concordance between these two models by comparing the distribution of patients with SMM classified as low, medium and high risk for progression. A total of 77 patients with SMM were enrolled in our prospective natural history study. Per study protocol, each patient was assigned risk scores based on both the Mayo and the Spanish models. The Mayo Clinic model identified 38, 35 and four patients as low, medium and high risk, respectively. The Spanish PETHEMA model classified 17, 22 and 38 patients as low, medium and high risk, respectively. There was significant discordance in overall patient risk classification (28.6% concordance) and in classifying patients as low versus high (p < 0.0001), low versus non-low (p = 0.0007) and high versus non-high (p < 0.0001) risk. There is a need for prospectively validated models to characterize individual patient risk of transformation to MM.

  13. Progression of liver stiffness predicts clinical events in HIV/HCV-coinfected patients with compensated cirrhosis.

    PubMed

    Merchante, Nicolás; Téllez, Francisco; Rivero-Juárez, Antonio; Ríos-Villegas, Maria José; Merino, Dolores; Márquez-Solero, Manuel; Omar, Mohamed; Recio, Eva; Pérez-Pérez, Montserrat; Camacho, Ángela; Macías-Dorado, Sara; Macías, Juan; Lorenzo-Moncada, Sandra; Rivero, Antonio; Pineda, Juan A

    2015-12-07

    Our objective was to assess the predictive value of the changes of liver stiffness (LS) for clinical outcome in HIV/HCV-coinfected patients with compensated liver cirrhosis and a LS value < 40 kPa. Prospective cohort of 275 HIV/HCV-coinfected patients with cirrhosis, no previous liver decompensation (LD) and LS < 40 kPa. The time from diagnosis to LD and/or hepatocellular carcinoma (HCC) and the predictors of this outcome were evaluated. Significant progression of LS was defined as an increase ≥ 30 % over the baseline value at any time during the follow-up. After a median (Q1-Q3) follow-up of 32 (20-48) months, 19 (6.9 %, 95 % CI: 3.8 %-9.9 %) patients developed a first LD and/or HCC. At the end of the follow-up, 247 (90 %) patients had undergone a further LS examination. Of them, 77 (31 %) patients had a significant progression of LS. The mean (SD) survival time free of LD and/or HCC was 67 (3) and 77 (1) months in patients with or without significant progression of LS (p = 0.01). Significant progression of LS was an independent predictor of LD and/or HCC (Adjusted Hazard Ratio 4.63; 95 % confidence interval: 1.34-16.02; p = 0.015). Significant progression of LS is associated with a higher risk of clinical events in HIV/HCV-coinfected patients with compensated cirrhosis and LS < 40 kPa.

  14. Is modified clinical activity score an accurate indicator of diplopia progression in Graves' orbitopathy patients?

    PubMed

    Kim, Ji Won; Woo, Young Jun; Yoon, Jin Sook

    2016-12-30

    The aim of this study is to describe characteristics of Graves' orbitopathy (GO) patients with progressive diplopia and to consider whether modified clinical activity score (CAS) is a useful indicator for prediction of diplopia progression. Medical records and images of GO patients with progressive diplopia were retrospectively reviewed. Clinical parameters (e.g., modified CAS, modified NOSPECS score, exophthalmometry results, score of diplopia, and prevalence of optic neuropathy) were evaluated. Thyroid stimulating hormone receptor autoantibody (TRAb) values were determined. Maximum recti muscle diameters and extraocular muscle (EOM) indices were evaluated. Sixty-three of the 435 GO patients had progressive diplopia; 44.4% (28/63) of these patients had a low CAS (<3). The subgroup analysis (by modified CAS, group 1: CAS<3, group 2: CAS≥3) revealed that the mean modified NOSPECS score and exophthalmos value were significantly higher in group 2 (7.2, 19.1 mm) compared with group 1 patients (5.5, 17.7 mm) (p<0.001, p=0.037, respectively). Score of diplopia, prevalence of optic neuropathy and the positive rate and level of TRAb were not significantly different between groups. There were no differences in maximum recti muscle diameters or EOM indices between the two groups. Diplopia may progress even in patients with a low modified CAS. CAS may not reflect the inflammatory activity of myopathy, especially in mild to moderate GO with low NOSPECS and exophthalmos values. Careful patient follow-up using subjective and objective measures for diplopia should be performed.

  15. 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.

  16. Pure akinesia with gait freezing: a third clinical phenotype of progressive supranuclear palsy.

    PubMed

    Williams, David R; Holton, Janice L; Strand, Kate; Revesz, Tamas; Lees, Andrew J

    2007-11-15

    The clinical syndrome of pure akinesia has most often been associated with progressive supranuclear palsy (PSP) and is characterized by difficulty initiating gait and "freezing" during walking, writing and speaking. Similar syndromes have been described under the rubrics of primary progressive freezing gait and primary gait ignition failure. We investigated the specificity of the clinical syndrome of pure akinesia with gait freezing (PAGF) for PSP-tau pathology. Among 749 patients archived at the QSBB, only 7 fulfilled proposed diagnostic criteria of: gradual onset of freezing of gait or speech; absent limb rigidity and tremor; no sustained response to levodopa; and no dementia or ophthalmoplegia in the first 5 years of disease. In these cases detailed pathological examination was performed. PSP was the pathological diagnosis in six patients, and Parkinson's disease (PD) in the seventh. As defined, this syndrome had a positive predictive value of 86% for PSP-tau pathology. In the cases with PSP there were no additional features of coexistent vascular or PD and the median PSP-tau score was 3, reflecting relative mild tau load. The clinical syndrome of PAGF appears to have a high specificity for PSP-tau pathology. This relatively uncommon presentation of PSP-tau pathology has less severe tau accumulation than in the more common, "classic" PSP clinical phenotype: Richardson's disease. (c) 2007 Movement Disorder Society.

  17. 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

  18. 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

  19. Primary and transitional progressive MS: a clinical and MRI cross-sectional study.

    PubMed

    Stevenson, V L; Miller, D H; Rovaris, M; Barkhof, F; Brochet, B; Dousset, V; Dousset, V; Filippi, M; Montalban, X; Polman, C H; Rovira, A; de Sa, J; Thompson, A J

    1999-03-10

    Ten percent of patients with MS have a progressive course from onset with no history of relapses or remissions. A smaller subgroup follow a similar progressive course but have a single relapse at some point (transitional progressive [TP] MS). To date these patients have been excluded from receiving licensed treatments for MS and from most therapeutic trials. To document the clinical and MRI characteristics of a large cohort of progressive patients, including 158 with primary progressive (PP) MS and 33 with TPMS. Data from a small reference group of 20 patients with secondary progressive (SP) MS are also presented for reference. Patients were recruited from six European centers. All underwent a clinical assessment including scoring on the Expanded Disability Status Scale (EDSS) and MRI of the brain and spinal cord. The men-to-women ratio was 81:77 (51% men) in the PP group, 14:19 (42% men) in the TP group, and 5:15 (25% men) in the SP group. The mean age at disease onset was significantly higher in the PP group than it was in the other two groups (PP 40.2 years, TP 34.9 years, SP 28.7 years). On MRI the PP group had lower mean brain T2 and T1 hypointensity lesion loads than the SP group (T2 12.02 versus 27.74 cm3, p = 0.001; T1 4.34 versus 7.04 cm3, p = 0.015). The SP and TP cohorts had significantly more T2-weighted lesions in the spinal cord than the PP patients, and the SP cohort had the greatest degree of atrophy. There was a correlation in the PP and TP patients between EDSS score and brain and spinal cord atrophy (r = 0.3, 0.2, p < or = 0.006) but not with brain lesion load. The PP and TP patients who presented with spinal cord pathology had significantly lower brain T2 and T1 lesion loads than those with non-spinal cord presentations (p = 0.002). The monitoring of disease progression in PPMS is difficult, although measures of atrophy correlate with the EDSS and appear most promising. This study increases our understanding of this unique patient group, which

  20. 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.

  1. 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.

  2. 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

  3. 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.

  4. Non-linear finite element analysis of the failure progression of fiber-reinforced ceramics produced by tape casting technique.

    PubMed

    Tanimoto, Yasuhiro; Hayakawa, Tohru; Nemoto, Kimiya; Nishiwaki, Tsuyoshi

    2006-06-01

    The purpose of this study was to investigate the failure progression process of fiber-reinforced ceramic by finite element (FE) analysis. The three-dimensional FE model for three-point bending simulation was 40 mm long, 4 mm wide, 3 mm thick, and with a span length of 30 mm. Nodal force with load increment of 20 N was applied at the center of the upper surface of the beam. To evaluate matrix fracture and fiber fracture, von Mises criterion and Tsai-Hill criterion were used respectively. Consequently, the stress-deflection curve obtained from FE simulation agreed with that obtained from the experimental testing. Differences in flexural strength and modulus between the analytical and experimental results were 1.3 and -2.9% respectively--demonstrating a close agreement between both results. In conclusion, the FE model applied in the present study was shown to be valid for predicting the failure progression of fiber-reinforced ceramics.

  5. Ant colony method to control variance reduction techniques in the Monte Carlo simulation of clinical electron linear accelerators

    NASA Astrophysics Data System (ADS)

    García-Pareja, S.; Vilches, M.; Lallena, A. M.

    2007-09-01

    The ant colony method is used to control the application of variance reduction techniques to the simulation of clinical electron linear accelerators of use in cancer therapy. In particular, splitting and Russian roulette, two standard variance reduction methods, are considered. The approach can be applied to any accelerator in a straightforward way and permits, in addition, to investigate the "hot" regions of the accelerator, an information which is basic to develop a source model for this therapy tool.

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

    PubMed

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

    2016-05-28

    To investigate clinical profiles and mutations of ABCB11 in Koreans with progressive familial intrahepatic cholestasis 2 and review the differences between Koreans and others. 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. 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. 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.

  7. Body weight is a robust predictor of clinical progression in Huntington disease.

    PubMed

    van der Burg, Jorien M M; Gardiner, Sarah L; Ludolph, Albert C; Landwehrmeyer, G Bernhard; Roos, Raymund A C; Aziz, N Ahmad

    2017-09-01

    Unintended weight loss is a hallmark of Huntington disease (HD), but it is unknown to what extent weight loss impacts the rate of disease progression. Therefore, using longitudinal data from the Enroll-HD study, we assessed the association between baseline body mass index (BMI) and the rate of clinical progression in 5,821 HD mutation carriers. We found that high baseline BMI was associated with a significantly slower rate of functional, motor, and cognitive deterioration (all p < 0.001), independent of mutant HTT CAG repeat size. Our findings provide strong rationale for exploration of systemic metabolism as a therapeutic target in HD. Ann Neurol 2017;82:479-483. © 2017 American Neurological Association.

  8. 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

  9. Magnetic Resonance Disease Severity Scale predicts clinical progression in multiple sclerosis

    PubMed Central

    Bakshi, Rohit; Neema, Mohit; Healy, Brian C; Liptak, Zsuzsanna; Betensky, Rebecca A; Buckle, Guy J; Gauthier, Susan A; Stankiewicz, James; Meier, Dominik; Egorova, Svetlana; Arora, Ashish; Guss, Zachary D; Glanz, Bonnie; Khoury, Samia J; Guttmann, Charles RG; Weiner, Howard L

    2009-01-01

    Objective Combine MRI measures of disease severity into a multiple sclerosis (MS) composite score. Design Retrospectively analysis of prospectively collected data Setting Community-based and referral subspecialty clinic in an academic hospital Patients 103 patients with MS [age (mean ± SD) 42.7 ± 9.1 years, disease duration 14.1 ± 9.2 years, EDSS score 3.3 ± 2.2, 60% (n=62) relapsing-remitting (RR), 32% (n=33) secondary progressive (SP), and 8% (n=8) primary progressive]. Main outcome measures Brain MRI measures included baseline T2 hyperintense (T2LV) and T1 hypointense (T1LV) lesion volume, and brain parenchymal fraction (BPF), a marker of global atrophy. The ratio of T1LV to T2LV assessed lesion severity. A Magnetic Resonance Disease Severity Scale (MRDSS) score, on a continuous scale from 0 to 10, was derived for each patient using T2LV, BPF, and T1/T2 ratio. Results MRDSS score averaged 5.1 ± 2.6. Baseline MRI and EDSS correlations were moderate for BPF, T1/T2, and MRDSS and weak for T2LV. MRDSS showed a larger effect size than any of the individual MRI components in distinguishing RR from SP patients. Models containing either T2LV or MRDSS were significantly associated with EDSS disability progression during the 3.2 ± 0.3 year observation period, when adjusting for baseline EDSS score. Conclusions Combining brain MRI lesion and atrophy measures can predict clinical progression in patients with MS and provides the basis to develop an MRI-based continuous scale as a marker of MS disease severity. PMID:19001162

  10. 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.

  11. 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

  12. Assessing Decline: Visualising Progression in Huntington's Disease using a Clinical Dashboard with Enroll-HD Data.

    PubMed

    Walker, Thomas; Ghosh, Boyd; Kipps, Christopher

    2017-01-01

    In Huntington's disease (HD), it remains unclear how symptom severity and rate of symptomatic change relates to age and CAG repeat number (CAGn). It is often difficult for clinicians to assess whether an affected individual's symptoms are progressing at a similar rate to their affected peers, limiting their ability to intervene at the most appropriate time. To develop a clinical dashboard that compares an individual's total motor score (TMS), total functional capacity (TFC) and symbol digit modality test (SDMT) scores against a global cohort, controlling for age and CAGn. The dashboard could then be used by clinicians to identify individuals progressing at a disproportionate rate to his or her peers. Annualised longitudinal clinical assessment scores from the Enroll-HD dataset were used to generate decline trajectories of the global cohort, allowing cross-sectional (TMS n = 734; TFC n = 734; SDMT n = 694) and longitudinal (TMS n = 270; TFC n = 270; SDMT n = 247) comparison with individual clinical symptom rating scores, to assess decline relative to affected peers. An electronic dashboard with a dynamic output display was created that rapidly compares clinical symptom rating scores of a specific individual against affected peers from a global cohort of comparable CAGn. This study shows the potential for use of multi-centre trial data in allowing comparison of the individual to a larger group to facilitate improved decision-making for individual patients. Visualisation of these metrics via a clinical dashboard demonstrates how it may aid identification of those with disproportionate decline, offering potential for intervention at specific critical points in the disease course.

  13. 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.

  14. 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

  15. 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.

  16. 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.

  17. 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.

  18. 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

  19. [Clinical features, mutation of the GNAS1 and pathogenesis of progressive osseous heteroplasia].

    PubMed

    Wu, Feng-qi; Wang, Li; Zou, Ji-zhen; Huang, Xiao-lan; Yuan, Xin-yu

    2012-01-01

    To investigate the clinical features, mutation of the GNAS1 and pathogenesis of progressive osseous heteroplasia (POH). The typical clinical, pathological and radiographic features of a boy with POH were collected and summarized following family survey. The GNAS1 gene sequence of all family members were amplified by polymerase chain reaction (PCR) and the products were sequenced directly to identify the mutations. A literature review and long-term follow up were also conducted. The patient was an 11-year-old boy who had the onset in infancy, which indicates a chronic progressive cause of disease. The clinical features include the unsmooth local skin of the right shank where spread many rigid rice-like or irregular slabby uplifts, slabby bone-like sclerosis on the left lower mandible, left masticatory muscles, in lateral subcutaneous site of left hip joint and deep tissue, accompanied by gradually progressive difficulty in opening mouth. Histopathology showed that there were loosened hyperplasia of fibroblast and interstitial edema with punctiformed ossification. Radiographs showed flocculence hyperdense image in the subcutaneous tissues and muscles around left lower mandible, and the left masticatory muscles were obviously involved. The 3-dimensional computed tomography showed dislocations of the left temporomandibular joint. Sheeted hyperdense image with inequable density could be noted in lateral muscles of the left hip. And lamellar hyperdense image parallel to the long axis of the bone could be seen in the subcutaneous dorsum of the left foot and achilles tendon. Macro-thumb and of brachydactylia of the hands and feet were not present. The level of calcium, phosphorus and alkaline phosphatase in the blood were normal. Brother of same father but different mothers was free of the disease and no patient of the same disease was found in maternal line and paternal lines. A mutated allele in exon 7 and a polymorphism in exon 5 were found in GNAS1 gene in both of the

  20. Estimating cancer survival and clinical outcome based on genetic tumor progression scores.

    PubMed

    Rahnenführer, Jörg; Beerenwinkel, Niko; Schulz, Wolfgang A; Hartmann, Christian; von Deimling, Andreas; Wullich, Bernd; Lengauer, Thomas

    2005-05-15

    In cancer research, prediction of time to death or relapse is important for a meaningful tumor classification and selecting appropriate therapies. Survival prognosis is typically based on clinical and histological parameters. There is increasing interest in identifying genetic markers that better capture the status of a tumor in order to improve on existing predictions. The accumulation of genetic alterations during tumor progression can be used for the assessment of the genetic status of the tumor. For modeling dependences between the genetic events, evolutionary tree models have been applied. Mixture models of oncogenetic trees provide a probabilistic framework for the estimation of typical pathogenetic routes. From these models we derive a genetic progression score (GPS) that estimates the genetic status of a tumor. GPS is calculated for glioblastoma patients from loss of heterozygosity measurements and for prostate cancer patients from comparative genomic hybridization measurements. Cox proportional hazard models are then fitted to observed survival times of glioblastoma patients and to times until PSA relapse following radical prostatectomy of prostate cancer patients. It turns out that the genetically defined GPS is predictive even after adjustment for classical clinical markers and thus can be considered a medically relevant prognostic factor. Mtreemix, a software package for estimating tree mixture models, is freely available for non-commercial users at http://mtreemix.bioinf.mpi-sb.mpg.de. The raw cancer datasets and R code for the analysis with Cox models are available upon request from the corresponding author.

  1. Klotho plays a critical role in clear cell renal cell carcinoma progression and clinical outcome.

    PubMed

    Kim, Ji-Hee; Hwang, Kyu-Hee; Lkhagvadorj, Sayamaa; Jung, Jae Hung; Chung, Hyun Chul; Park, Kyu-Sang; Kong, In Deok; Eom, Minseob; Cha, Seung-Kuy

    2016-05-01

    Klotho functions as a tumor suppressor predominantly expressed in renal tubular cells, the origin of clear cell renal cell carcinoma (ccRCC). Altered expression and/or activity of growth factor receptor have been implicated in ccRCC development. Although Klotho suppresses a tumor progression through growth factor receptor signaling including insulin-like growth factor-1 receptor (IGF-1R), the role of Klotho acting on IGF-1R in ccRCC and its clinical relevance remains obscure. Here, we show that Klotho is favorable prognostic factor for ccRCC and exerts tumor suppressive role for ccRCC through inhibiting IGF-1R signaling. Our data shows the following key findings. First, in tumor tissues, the level of Klotho and IGF-1R expression are low or high, respectively, compared to that of adjacent non-neoplastic parenchyma. Second, the Klotho expression is clearly low in higher grade of ccRCC and is closely associated with clinical outcomes in tumor progression. Third, Klotho suppresses IGF-1-stimulated cell proliferation and migration by inhibiting PI3K/Akt pathway. These results provide compelling evidence supporting that Klotho acting on IGF-1R signaling functions as tumor suppressor in ccRCC and suggest that Klotho is a potential carcinostatis substance for ccRCC.

  2. 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.

  3. 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.

  4. 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.

  5. 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

  6. Analysis of change in the presence of informative censoring: application to a longitudinal clinical trial of progressive renal disease.

    PubMed

    Schluchter, M D; Greene, T; Beck, G J

    2001-04-15

    The rate of change in a continuous variable, measured serially over time, is often used as an outcome in longitudinal studies or clinical trials. When patients terminate the study before the scheduled end of the study, there is a potential for bias in estimation of rate of change using standard methods which ignore the missing data mechanism. These methods include the use of unweighted generalized estimating equations methods and likelihood-based methods assuming an ignorable missing data mechanism. We present a model for analysis of informatively censored data, based on an extension of the two-stage linear random effects model, where each subject's random intercept and slope are allowed to be associated with an underlying time to event. The joint distribution of the continuous responses and the time-to-event variable are then estimated via maximum likelihood using the EM algorithm, and using the bootstrap to calculate standard errors. We illustrate this methodology and compare it to simpler approaches and usual maximum likelihood using data from a multi-centre study of the effects of diet and blood pressure control on progression of renal disease, the Modification of Diet in Renal Disease (MDRD) Study. Sensitivity analyses and simulations are used to evaluate the performance of this methodology in the context of the MDRD data, under various scenarios where the drop-out mechanism is ignorable as well as non-ignorable.

  7. Levels of uninvolved immunoglobulins predict clinical status and progression-free survival for multiple myeloma patients.

    PubMed

    Harutyunyan, Nika M; Vardanyan, Suzie; Ghermezi, Michael; Gottlieb, Jillian; Berenson, Ariana; Andreu-Vieyra, Claudia; Berenson, James R

    2016-07-01

    Multiple myeloma (MM) is characterized by the enhanced production of the same monoclonal immunoglobulin (M-Ig or M protein). Techniques such as serum protein electrophoresis and nephelometry are routinely used to quantify levels of this protein in the serum of MM patients. However, these methods are not without their shortcomings and problems accurately quantifying M proteins remain. Precise quantification of the types and levels of M-Ig present is critical to monitoring patient response to therapy. In this study, we investigated the ability of the HevyLite (HLC) immunoassay to correlate with clinical status based on levels of involved and uninvolved antibodies. In our cohort of MM patients, we observed that significantly higher ratios and greater differences of involved HLC levels compared to uninvolved HLC levels correlated with a worse clinical status. Similarly, higher absolute levels of involved HLC antibodies and lower levels of uninvolved HLC antibodies also correlated with a worse clinical status and a shorter progression-free survival. These findings suggest that the HLC assay is a useful and a promising tool for determining the clinical status and survival time for patients with multiple myeloma. © 2016 John Wiley & Sons Ltd.

  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. Clinical and magnetic resonance imaging predictors of disease progression in multiple sclerosis: a nine-year follow-up study.

    PubMed

    Lavorgna, L; Bonavita, S; Ippolito, D; Lanzillo, R; Salemi, G; Patti, F; Valentino, P; Coniglio, G; Buccafusca, M; Paolicelli, D; d'Ambrosio, A; Bresciamorra, V; Savettieri, G; Zappia, M; Alfano, B; Gallo, A; Simone, Il; Tedeschi, G

    2014-02-01

    The objective of this paper is to identify clinical or magnetic resonance imaging (MRI) predictors of long-term clinical progression in a large cohort of multiple sclerosis (MS) patients. A total of 241 relapsing-remitting (RR) MS patients were included in a nine-year follow-up (FU) study. The reference MRIs were acquired at baseline (BL) as part of a multicenter, cross-sectional, clinical-MRI study. Volumetric MRI metrics were measured by a fully automated, operator-independent, multi-parametric segmentation method. Clinical progression was evaluated as defined by: conversion from RR to secondary progressive (SP) disease course; progression of Expanded Disability Status Scale (EDSS); achievement and time to reach EDSS 4. We concluded that conversion from RR to SP (OR 0.79; CI 0.7-0.9), progression of EDSS (OR 0.85; CI 0.77-0.93), achievement of EDSS 4 (OR 0.8; CI 0.7-0.9), and time to reach EDSS 4 (HR 0.88; CI 0.82-0.94) were all predicted by BL gray matter (GM) volume and, except for progression of EDSS, by BL EDSS (respectively: (OR 2.88; CI 1.9-4.36), (OR 2.7; CI 1.7-4.2), (HR 3.86; CI 1.94-7.70)). BL GM volume and EDSS are the best long-term predictors of disease progression in RRMS patients with a relatively long and mild disease.

  10. 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

  11. 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.

  12. Progression of Mild Cognitive Impairment to Dementia in Clinic- vs Community-Based Cohorts

    PubMed Central

    Farias, Sarah Tomaszewski; Mungas, Dan; Reed, Bruce R.; Harvey, Danielle; DeCarli, Charles

    2010-01-01

    Background Mild cognitive impairment is increasingly recognized as an important public health problem associated with increased risk of developing dementia. Annual conversion rates, however, vary across different studies with clinic samples showing higher rates of conversion than community-based samples. Objectives To establish whether the rates of conversion from mild cognitive impairment to dementia differed according to recruitment source and, if so, to investigate factors that might explain this discrepancy. Design Rates and predictors of conversion were examined in a prospective longitudinal study at a single center. Setting Among the participants, 46% were recruited from a clinical setting and 54% were recruited directly through community outreach. Participants One hundred eleven individuals with mild cognitive impairment were followed up longitudinally for an average of 2.4 years (range, 0.5–4.0 years). Main Outcome Measures Conversion from mild cognitive impairment to dementia. Results During the follow-up period, 28 individuals progressed to dementia with a mean (SD) time to conversion of 2.19 (0.72) years. The clinic sample had an annual conversion rate of 13%, whereas the community sample had an annual conversion rate of 3%. In a Cox proportional hazards model, clinic recruitment source alone was associated with an increased hazard of incident dementia (hazard ratio=3.50; 95% confidence interval, 1.31–9.18; P=.01). When other variables were added to the model, only baseline functional impairment as measured by the Clinical Dementia Rating Scale (and no demographic, cognitive, or neuroimaging variables or mild cognitive impairment subtype) accounted for the differences in conversion rates across the 2 cohorts. Conclusions These findings add to the growing literature to suggest that the degree of functional impairment at baseline is an important predictor of conversion to dementia and may help explain differences in findings between epidemiological and

  13. 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

  14. Pulmonary vein reconnection and arrhythmia progression after antral linear catheter ablation of paroxysmal and persistent atrial fibrillation.

    PubMed

    Wasmer, Kristina; Dechering, Dirk G; Köbe, Julia; Mönnig, Gerold; Pott, Christian; Frommeyer, Gerrit; Lange, Philipp S; Kochhäuser, Simon; Eckardt, Lars

    2016-09-01

    Assumption of different substrates is the basis for different ablation strategies in patients with paroxysmal and persistent atrial fibrillation (AF). We aimed to investigate pulmonary vein reconnection and influence on progression of initial paroxysmal (pAF) versus persistent atrial fibrillation (perAF). Between January 2010 and November 2012, 149 patients (117 men, mean age 59 ± 11 years, range 27-80 years) underwent at least one redo antral pulmonary vein isolation (PVI) using NavX-guided irrigated-tip radiofrequency catheter ablation. We analyzed whether and where reconnection of pulmonary veins was detected, and whether there were differences between patients with pAF and perAF. Of the 149 patients who underwent a redo antral PVI, 80 patients had pAF and 69 had perAF. One, two and three redo PVIs were performed in 149, 26 and 6 patients, respectively. Reconnection of at least one PV was detected in all patients at the second PVI, in 19 of 26 patients (73 %) at the third PVI and 5 of 6 patients (83 %) at the fourth PVI. 20 (29 %) patients with perAF prior to the first PVI had pAF at the second PVI, whereas 15 (19 %) patients with initial pAF had persistent AF at the time of the first redo procedure. From the second to the third PVI, four patients had developed perAF after previous pAF and two with per AF now had pAF. PV reconnection was observed independent of underlying AF type. At the second redo procedure, of those with reconnected veins 12 had pAF and 13 perAF. At the third redo procedure, four patients had pAF and four perAF. Most patients with recurrent AF after PVI showed at least one reconnected vein during redo procedures. Reconnection was identified irrespective of the underlying AF type. Progression from pAF to perAF and vice versa was observed irrespective of the initial AF type.

  15. Clinical predictors of disease progression in multiple sclerosis patients with relapsing onset in a nation-wide cohort.

    PubMed

    Alroughani, R A; Akhtar, S; Ahmed, S F; Al-Hashel, J Y

    2015-01-01

    Predicting disease progression over time is challenging despite the available literature data. To assess whether baseline clinical variables of MS patients would predict the conversion to progressive phase of the disease. Utilizing the national MS registry, patients who had relapsing onsets and had confirmed EDSS score at baseline and follow-up visits were included. Primary progressive MS and CIS patients were excluded. Clinical variables (gender, age at onset, disease duration, number of relapses, EDSS score) were collected. The end point was conversion to secondary progressive MS. Chi Square and multivariable logistic regression were used to determine the influence of clinical variables on disease progression. Data of 803 MS patients with relapsing onset were analyzed. Eighty five (10.6%) patients reached the end point. The risk of disease progression was significantly higher in men (p=0.015), in patients who developed MS≥40 years of age (p=0.041) and who had ≥3 relapses during their disease course (p<0.001). Spinal cord presentation at onset was predictive of progression (aOR=2.01; p=0.06) while optic neuritis at onset was associated with lower risk of progression (aOR=0.30; p=0.03). EDSS score at first visit did not influence disease progression when tested at 2 different cutoffs (EDSS<4 vs. ≥4 and EDSS<6 vs. ≥6) using multivariable logistic regression analysis (p=0.960 and p=0.866), respectively. Men and patients who presented at age 40 yeas or beyond had increased risk of MS progression. Spinal cord symptoms at onset and 3 or more relapses were predictive of progression.

  16. 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.

  17. [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.

  18. SU-F-P-51: Similarity Analysis of the Linear Accelerator Machines Based On Clinical Simulation

    SciTech Connect

    Li, K

    2016-06-15

    Purpose: To evaluate the clinical rationale for Truebeam and Trilogy Linac machines from Varian Medical System as exchangeable treatment modalities in the same radiation oncology department. Methods: Intensity Modulated Radiotherapy (IMRT) plans for different diseases were selected for this study. These disease sites included brain, head and neck, breast, lung, and prostate. The parameters selected for this study were the energy amount, Monitor Unit (MU); dose coverage of target reflected by prescription isodose volume(PIV); dose spillage described by the volume of 50% isodoseline of the prescription; and dose homogeneities represented by the maximum dose (MaxD) and the minimum dose (MinD) of target volume (TV) and critical structure (CS). Each percentage difference between the values of these parameters formed an element of a matrix, which was called Similarity Comparison Matrix(SCM). The elements of the SCM were then simplified by dimensional conversion algorithm, which was used to determine clinical similarity between two machines through a single value. Results: For the selected clinical cases in this study, the average percentage differences between Trilogy and Truebeam in MU was 0.28% with standard deviation(SD) 0.66%, PIV was 0.23% with SD 0.20%, Volume at 50% prescription dose was 0.31% with SD at 0.78%, MaxD at TV is 0.26% with SD 0.35%, MinD at TV is −0.04% with SD 0.51%, MaxD in CS is −0.53% with SD 0.92%, and MinD in CS 3.31%, with SD at 2.89%. The sum, product, geometric and harmonic mean for the matrix elements were 19.0%, 0.00%, 0.19%, and 0.00%. Conclusion: A method to compare two machines in clinical level was developed and some reference values were calculated for decision-making in clinical practice, and this strategy could be expanded to different clinical applications.

  19. Infectious keratitis progressing to endophthalmitis: a 15-year study of microbiology, associated factors, and clinical outcomes.

    PubMed

    Henry, Christopher R; Flynn, Harry W; Miller, Darlene; Forster, Richard K; Alfonso, Eduardo C

    2012-12-01

    To describe the incidence, microbiology, associated factors, and clinical outcomes of patients with infectious keratitis progressing to endophthalmitis. Nonrandomized, retrospective, consecutive case series. All patients treated for culture-proven keratitis and endophthalmitis between January 1, 1995 and December 31, 2009, at the Bascom Palmer Eye Institute. Ocular microbiology and medical records were reviewed on all patients with positive corneal and intraocular cultures over the period of the study. Univariate analysis was performed to obtain P values described in the study. Microbial isolates, treatment strategies, and visual acuity (VA) outcomes. A total of 9934 corneal cultures were performed for suspected infectious keratitis. Only 49 eyes (0.5%) progressed to culture-proven endophthalmitis. Fungi (n = 26) were the most common responsible organism followed by gram-positive bacteria (n = 13) and gram-negative bacteria (n = 10). Topical steroid use (37/49 [76%]) was the most common associated factor identified in the current study, followed by previous surgery (30/49 [61%]), corneal perforation (17/49 [35%]), dry eye (15/49 [31%]), relative immune compromise (10/49 [20%]), organic matter trauma (9/49 [18%]), and contact lens wear (3/49 [6%]). There were 27 patients in whom a primary infectious keratitis developed into endophthalmitis, and 22 patients in whom an infectious keratitis adjacent to a previous surgical wound progressed into endophthalmitis. Patients in the primary keratitis group were more likely to be male (22/27 [81%] vs 8/22 [36%]; P = 0.001), have history of organic matter trauma (8/27 [30%] vs 1/22 [5%]); P = 0.030), and have fungal etiology (21/27 [78%] vs 5/22 [23%]; P<0.001). Patients in the surgical wound-associated group were more likely to use topical steroids (20/22 [91%] vs 17/27 [63%]; P = 0.024). A VA of ≥ 20/50 was achieved in 7 of 49 patients (14%), but was <5/200 in 34 of 49 (69%) at last follow-up. Enucleation or evisceration

  20. 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

  1. Recent publications from the Alzheimer's Disease Neuroimaging Initiative: Reviewing progress toward improved AD clinical trials.

    PubMed

    Weiner, Michael W; Veitch, Dallas P; Aisen, Paul S; Beckett, Laurel A; Cairns, Nigel J; Green, Robert C; Harvey, Danielle; Jack, Clifford R; Jagust, William; Morris, John C; Petersen, Ronald C; Saykin, Andrew J; Shaw, Leslie M; Toga, Arthur W; Trojanowski, John Q

    2017-04-01

    The Alzheimer's Disease Neuroimaging Initiative (ADNI) has continued development and standardization of methodologies for biomarkers and has provided an increased depth and breadth of data available to qualified researchers. This review summarizes the over 400 publications using ADNI data during 2014 and 2015. We used standard searches to find publications using ADNI data. (1) Structural and functional changes, including subtle changes to hippocampal shape and texture, atrophy in areas outside of hippocampus, and disruption to functional networks, are detectable in presymptomatic subjects before hippocampal atrophy; (2) In subjects with abnormal β-amyloid deposition (Aβ+), biomarkers become abnormal in the order predicted by the amyloid cascade hypothesis; (3) Cognitive decline is more closely linked to tau than Aβ deposition; (4) Cerebrovascular risk factors may interact with Aβ to increase white-matter (WM) abnormalities which may accelerate Alzheimer's disease (AD) progression in conjunction with tau abnormalities; (5) Different patterns of atrophy are associated with impairment of memory and executive function and may underlie psychiatric symptoms; (6) Structural, functional, and metabolic network connectivities are disrupted as AD progresses. Models of prion-like spreading of Aβ pathology along WM tracts predict known patterns of cortical Aβ deposition and declines in glucose metabolism; (7) New AD risk and protective gene loci have been identified using biologically informed approaches; (8) Cognitively normal and mild cognitive impairment (MCI) subjects are heterogeneous and include groups typified not only by "classic" AD pathology but also by normal biomarkers, accelerated decline, and suspected non-Alzheimer's pathology; (9) Selection of subjects at risk of imminent decline on the basis of one or more pathologies improves the power of clinical trials; (10) Sensitivity of cognitive outcome measures to early changes in cognition has been improved and

  2. 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.

  3. Application and student evaluation of a Clinical Progression Portfolio: a pilot.

    PubMed

    Cooke, Marie; Mitchell, Marion; Moyle, Wendy; Henderson, Amanda; Murfield, Jenny

    2010-07-01

    Clinical practicums are often limited by a lack of meaningful communication between nursing students and registered nurses (RNs). This pilot study evaluated the utility of the Clinical Progression Portfolio (CPP) to enable students to learn how to initiate engagement with their RNs and to develop their capacity as students to learn. The study employed a descriptive survey design, with a convenience sample of second-year Bachelor of Nursing (BN) students in Brisbane, Australia. Questionnaires were completed by 129 students from 20 clinical practicum groups. Students who used the CPP were more favourable in their usefulness ratings (-rpb=0.531, p<0.001) and, furthermore, those that used the CPP most frequently were also more favourable (r=0.555, p<0.001). Students thought the CPP helped clarify learning and target appropriate practicum opportunities. When used, the CPP was an important part of practicum, used frequently and considered useful. The CPP format met the needs of students as it was pocket-sized. Overall, students reported that the CPP was a useful learning and communication tool as it provided them direction in how they might maximise opportunities to address their learning needs. Copyright 2009 Elsevier Ltd. All rights reserved.

  4. 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

  5. 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

  6. Clinical predictors of conduction disease progression in type I myotonic muscular dystrophy.

    PubMed

    Nazarian, Saman; Wagner, Kathryn R; Caffo, Brian S; Tomaselli, Gordon F

    2011-02-01

    Patients with type I myotonic muscular dystrophy (DM1) are at risk for sudden death due to atrioventricular conduction block. We sought to characterize the trends and predictors of time-dependent electrocardiographic (ECG) variations in patients with DM1. Seventy patients with DM1 underwent standard electrocardiography at first evaluation and routine and symptom prompted follow-up. Individual variations in ECG conduction intervals were assessed using spaghetti plots. Clinical predictors of conduction disease progression were assessed using multivariate random effects regression models of panel data clustered by patient and adjusted for heart rate. Substantial individual variability was noted in time-dependent changes in PR, QRS, and QTc intervals of patients with DM1. Changes in the QTc interval were closely associated with prolongation of the QRS interval. Age, the presence of paroxysmal atrial flutter or fibrillation, and the number of cytosine-thymine-guanine (CTG) repeats were independent positive predictors of time-dependent PR and QRS prolongation during long-term follow-up. Female sex was negatively associated with PR prolongation but positively associated with QTc prolongation. Lower left ventricular ejection fraction was associated with greater QRS interval progression during long-term follow-up but was not predictive of PR interval progression. Patients with DM1 can develop rapid changes in cardiac conduction intervals. Paroxysmal atrial flutter or fibrillation, older age, and larger CTG expansions predict greater time-dependent PR and QRS interval prolongation and warrant particular attention in the arrhythmic evaluation of this high risk patient subset. ©2010, The Authors. Journal compilation ©2010 Wiley Periodicals, Inc.

  7. Bcl-2, Bax and p53 expression in B-CLL in relation to in vitro survival and clinical progression.

    PubMed

    Aguilar-Santelises, M; Rottenberg, M E; Lewin, N; Mellstedt, H; Jondal, M

    1996-04-22

    Our previous data have shown that isolated leukemic cells from progressive chronic lymphocytic leukemia (B-CLL) patients respond to growth stimulation in vitro and express high levels of p53, immunoreactive with the configuration-specific antibody PAb 240. We have now analyzed the in vitro survival of B-CLL cells in relation to Bcl-2, Bax alpha and p53 expression and compared this with the clinical progression of the disease. Leukemic cells from patients with progressive disease demonstrated higher in vitro survival, compared with non-progressive B-CLL and normal B cells. All cells were sensitive to treatment with a combination of glucocorticoid and cAMP. Bcl-2 protein levels were not related to clinical progression, as measured by flow cytometry. Competitive PCR showed that Bcl-2 mRNA was over-expressed in most of the B-CLL samples and that p53 mRNA expression was similar between B-CLL groups and normal values and thus not related to clinical progression. However, since Bax alpha expression was lower in progressive than in non-progressive patients, the Bcl-2/Bax alpha ratio at the mRNA level was significantly higher in the progressive group. Our data suggest that the Bcl-2/Bax alpha ratio is important for the regulation of B-CLL cell survival, that p53 over-expression in progressive B-CLL is the result of post-transcriptional modifications and that a directed PKA activation may potentiate the cytolytic effect of glucocorticoids in vivo.

  8. 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

  9. 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

  10. 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

  11. 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.

  12. 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

  13. 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.

  14. 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. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  15. Altered blood pressure progression in the community and its relation to clinical events.

    PubMed

    Ingelsson, Erik; Gona, Philimon; Larson, Martin G; Lloyd-Jones, Donald M; Kannel, William B; Vasan, Ramachandran S; Levy, Daniel

    2008-07-14

    Long-term blood pressure (BP) progression and its importance as a predictor of clinical outcome have not been well characterized across different periods. We evaluated period trends for 3 BP variables (long-term slope and mean BP during a baseline period of 16 years, and last baseline value) in an earlier period (1953-1971; n = 1644, mean participant age, 61 years) and in a later period (1971-1990; n = 1040, mean participant age, 58 years) in participants in the Framingham Heart Study who initially did not have hypertension. In addition, we explored the relation of BP to cardiovascular disease incidence and all-cause mortality in the 2 periods, each with up to 16 years of follow-up. Long-term slope, mean, and last baseline BP measurements were significantly lower in the later period (P < .001). Rates of hypertension control (BP <140/90 mm Hg) were higher in the later vs the earlier period (32% vs 23%; P < .001). Multivariate hazard ratios for the relation of BP to outcomes were generally lower in the later period; this was statistically significant for the relation of last baseline BP to all-cause mortality (hazard ratio for 1-SD increase in systolic BP, 1.02 vs 1.25, P = .03; hazard ratio for diastolic BP, 1.00 vs 1.23, P = .04). We found evidence that BP levels in the community have changed over time, coinciding with improved rates of hypertension control and attenuation of BP-mortality relations. These findings are consistent with the hypothesis that hypertension treatment in the community has altered the natural history of BP progression and its relation to clinical outcome.

  16. 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.

  17. Clinical features, management and outcomes of progressive outer retinal necrosis (PORN) in southern Thailand.

    PubMed

    Sittivarakul, Wantanee; Aui-aree, Nipat

    2009-03-01

    To study the demographics, clinical features, treatment, and visual outcomes of progressive outer retinal necrosis (PORN) in a group of Thai patients. All cases of AIDS with a clinical diagnosis of PORN in a major tertiary referral hospital in southern Thailand between January 2003 and June 2007 were retrospectively reviewed. Demographic data, clinical features, treatment regimens, and visual outcomes were analyzed. Seven patients (11 eyes) were studied. The mean age was 44.7 years. The median CD4 count was 12 cells/mm3. A known history of cutaneous zoster was documented in 57% of cases. The median follow-up period was 17 weeks. Fifty-seven percent of the patients had bilateral disease. A majority of eyes (45.4%) had initial visual acuity of less than 20/50 to equal to or better than 20/200. About two-thirds of the eyes had anterior chamber cells. Vitritis and retinal lesions scattered throughout both posterior pole and peripheral retina were found in 72.7%. Either intravenous acyclovir in combination with intravitreal ganciclovir injections or intravenous aclyclovir alone was used for initial treatment. Retinal detachment occurred in 54.5%. Final visual acuity worsened (loss of 3 lines on the ETDRS chart or more) in 60%. Visual acuity was no light perception in 45.5% at the final recorded follow-up. Demographics, clinical features and treatment outcomes of PORN in this group of Thai patients were comparable with studies from other countries. Visual prognosis is still poor with current treatment regimens.

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

    PubMed

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

    2016-10-21

    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. To review the literature about factors that may influence postdoctoral career progression in early career clinical academics. This study employed a scoping review method. Three reviewers separately assessed whether the articles found fit the inclusion criteria. PubMed, Scopus, Web of Science and Google Scholar (1991-2015). 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 extracted from included publications were charted according to author(s), sample population, study design, key findings, country of origin and year of publication. 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. 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  19. Experimental Platform for Ultra-high Dose Rate FLASH Irradiation of Small Animals Using a Clinical Linear Accelerator.

    PubMed

    Schüler, Emil; Trovati, Stefania; King, Gregory; Lartey, Frederick; Rafat, Marjan; Villegas, Manuel; Praxel, A Joe; Loo, Billy W; Maxim, Peter G

    2017-01-01

    A key factor limiting the effectiveness of radiation therapy is normal tissue toxicity, and recent preclinical data have shown that ultra-high dose rate irradiation (>50 Gy/s, "FLASH") potentially mitigates this effect. However, research in this field has been strongly limited by the availability of FLASH irradiators suitable for small animal experiments. We present a simple methodologic approach for FLASH electron small animal irradiation with a clinically available linear accelerator (LINAC). We investigated the FLASH irradiation potential of a Varian Clinac 21EX in both clinical mode and after tuning of the LINAC. We performed detailed FLUKA Monte Carlo and experimental dosimetric characterization at multiple experimental locations within the LINAC head. Average dose rates of ≤74 Gy/s were achieved in clinical mode, and the dose rate after tuning exceeded 900 Gy/s. We obtained 220 Gy/s at 1-cm depth for a >4-cm field size with 90% homogeneity throughout a 2-cm-thick volume. We present an approach for using a clinical LINAC for FLASH irradiation. We obtained dose rates exceeding 200 Gy/s after simple tuning of the LINAC, with excellent dosimetric properties for small animal experiments. This will allow for increased availability of FLASH irradiation to the general research community. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Imaging changes following stereotactic radiosurgery for metastatic intracranial tumors: differentiating pseudoprogression from tumor progression and its effect on clinical practice

    PubMed Central

    Kleinberg, Lawrence; Rigamonti, Daniele

    2014-01-01

    Stereotactic radiosurgery has become standard adjuvant treatment for patients with metastatic intracranial lesions. There has been a growing appreciation for benign imaging changes following radiation that are difficult to distinguish from true tumor progression. These imaging changes, termed pseudoprogression, carry significant implications for patient management. In this review, we discuss the current understanding of pseudoprogression in metastatic brain lesions, research to differentiate pseudoprogression from true progression, and clinical implications of pseudoprogression on treatment decisions. PMID:24233257

  1. 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.

  2. 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

  3. 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.

  4. 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.

  5. 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

  6. 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.

  7. 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.

  8. Expression of oncogenic BARD1 isoforms affects colon cancer progression and correlates with clinical outcome.

    PubMed

    Zhang, Y-Q; Pilyugin, M; Kuester, D; Leoni, V P; Li, L; Casula, G; Zorcolo, L; Schneider-Stock, R; Atzori, L; Irminger-Finger, I

    2012-08-07

    Colon cancer predisposition is associated with mutations in BRCA1. BRCA1 protein stability depends on binding to BARD1. In different cancers, expression of differentially spliced BARD1 isoforms is correlated with poor prognosis and decreased patient survival. We therefore suspected a role of BARD1 isoforms in colon cancer. We performed immunohistochemistry in 168 colorectal cancers, using four antibodies directed against differentially expressed regions of BARD1. We determined structure and relative expression of BARD1 mRNA isoforms in 40 tumour and paired normal peri-tumour tissues. BARD1 expression was correlated with clinical outcome. BARD1 isoforms were expressed in 98% of cases and not correlated with BRCA1. BARD1 mRNA isoforms were upregulated in all tumours as compared with paired normal peri-tumour tissues. Non-correlated expression and localisation of different epitopes suggested insignificant expression of full-length (FL) BARD1. Expression of N- and C-terminal epitopes correlated with increased survival, but expression of epitopes mapping to the middle of BARD1 correlated with decreased survival. Middle epitopes are present in oncogenic BARD1 isoforms, which have pro-proliferative functions. Correlated upregulation of only N- and C-terminal epitopes reflects the expression of isoforms BARD1δ and BARD1φ. Our results suggest that BARD1 isoforms, but not FL BARD1, are expressed in colon cancer and affect its progression and clinical outcome.

  9. Artificial gametes: a systematic review of biological progress towards clinical application.

    PubMed

    Hendriks, Saskia; Dancet, Eline A F; van Pelt, Ans M M; Hamer, Geert; Repping, Sjoerd

    2015-01-01

    Recent progress in the formation of artificial gametes, i.e. gametes generated by manipulation of their progenitors or of somatic cells, has led to scientific and societal discussion about their use in medically assisted reproduction (MAR). Artificial gametes could potentially help infertile men and women but also post-menopausal women and gay couples conceive genetically related children. This systematic review aimed to provide insight in the progress of biological research towards clinical application of artificial gametes. The electronic database 'Medline/Pubmed' was systematically searched with medical subject heading (MesH) terms, and reference lists of eligible studies were hand searched. Studies in English between January 1970 and December 2013 were selected based on meeting a priori defined starting- and end-points of gamete development, including gamete formation, fertilization and the birth of offspring. For each biologically plausible method to form artificial gametes, data were extracted on the potential to generate artificial gametes that might be used to achieve fertilization and to result in the birth of offspring in animals and humans. The systematic search yielded 2424 articles, and 70 studies were included after screening. In animals, artificial sperm and artificial oocytes generated from germline stem cells (GSCs), embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have resulted in the birth of viable offspring. Also in animals, artificial sperm and artificial oocytes have been generated from somatic cells directly, i.e. without documentation of intermediate stages of stem- or germ cell development or (epi)genetic status. Finally, although the subsequent embryos showed hampered development, haploidization by transplantation of a somatic cell nucleus into an enucleated donor oocyte has led to fertilized artificial oocytes. In humans, artificial sperm has been generated from ESCs and iPSCs. Artificial human oocytes have been

  10. Juvenile-onset clinically amyopathic dermatomyositis: an overview of recent progress in diagnosis and management.

    PubMed

    Walling, Hobart W; Gerami, Pedram; Sontheimer, Richard D

    2010-01-01

    Juvenile-onset amyopathic dermatomyositis is an uncommon variant of juvenile-onset dermatomyositis (JDM), characterized by the hallmark cutaneous features of dermatomyositis for at least 6 months without clinical or laboratory evidence of muscle disease. Cutaneous calcinosis, vasculopathy, and interstitial lung disease frequently complicate the course of classic JDM (typical JDM with myositis) but are infrequent in amyopathic JDM. Recent literature suggests that approximately 75% of amyopathic JDM patients will remain free from muscle disease after years of follow-up, while approximately 25% of patients will evolve to having classic JDM. No clinical, laboratory, or ancillary parameters have been found to be predictive for this transition to muscle disease. Treatment of the cutaneous disease of amyopathic JDM centers on photoprotection and topical therapies directed against inflammation. Oral antimalarials are effective for cutaneous disease not adequately controlled with topical care. Systemic corticosteroids, while central to the treatment of classic JDM, are controversial in the treatment of amyopathic JDM. Randomized controlled trials are not available to guide the management of this disease. Proponents for early aggressive systemic corticosteroid therapy for amyopathic JDM advocate that this intervention may decrease the likelihood of progression to classic JDM, and/or prevent disease-specific complications of JDM such as calcinosis. Opponents of early intervention with systemic corticosteroids favor expectant management directed toward controlling skin disease, citing the predictable adverse effects of systemic corticosteroids in the face of uncertain benefit. Other therapeutic options for severe and recalcitrant cutaneous disease, including methotrexate, intravenous immunoglobulin, and rituximab, are reviewed, as are treatment options for calcinosis cutis. In weighing the available evidence, the authors conclude that early aggressive treatment of amyopathic

  11. Transepithelial corneal collagen crosslinking for progressive keratoconus: 24-month clinical results.

    PubMed

    Caporossi, Aldo; Mazzotta, Cosimo; Paradiso, Anna Lucia; Baiocchi, Stefano; Marigliani, Davide; Caporossi, Tomaso

    2013-08-01

    To assess the clinical results of transepithelial collagen crosslinking (CXL) in patients 26 years and younger with progressive keratoconus suitable for epithelium-off (epi-off) CXL. Department of Ophthalmology, Siena University Hospital, Siena, Italy. Prospective case series. The study included 26 eyes (26 patients) treated by transepithelial (epithelium-on) CXL. The mean age was 22 years (range 11 to 26 years) (10 younger than 18 years; 16 between 19 years and 26 years). Preoperative and postoperative examinations included uncorrected (UDVA) and corrected (CDVA) distance visual acuities, simulated maximum keratometry (K), coma and spherical aberration, and corneal optical coherence tomography optical pachymetry. The solution for transepithelial CXL (Ricrolin TE) comprised riboflavin 0.1%, dextran 15.0%, trometamol (Tris), and ethylenediaminetetraacetic acid. Ultraviolet-A treatment was performed with the Caporossi Baiocchi Mazzotta X Linker Vega at 3 mW/cm(2). After relative improvement in the first 3 to 6 months, the UDVA and CDVA gradually returned to baseline preoperative values. After 12 months of stability, the simulated maximum K value worsened at 24 months. Coma aberration showed no statistically significant change. Spherical aberration increased at 24 months. Pachymetry showed a progressive, statistically significant decrease at 24 months. Fifty percent of pediatric patients were retreated with epi-off CXL due to significant deterioration of all parameters after 12 months of follow-up. Functional results after transepithelial CXL showed keratoconus instability, in particular in pediatric patients 18 years old and younger; there was also functional regression in patients between 19 years and 26 years old after 24 months of follow-up. mentioned. Copyright © 2013 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.

  12. Cross-section Trichometry: A Clinical Tool for Assessing the Progression and Treatment Response of Alopecia.

    PubMed

    Wikramanayake, Tongyu Cao; Mauro, Lucia M; Tabas, Irene A; Chen, Anne L; Llanes, Isabel C; Jimenez, Joaquin J

    2012-10-01

    To properly assess the progression and treatment response of alopecia, one must measure the changes in hair mass, which is influenced by both the density and diameter of hair. Unfortunately, a convenient device for hair mass evaluation had not been available to dermatologists until the recent introduction of the cross-section trichometer, which directly measures the cross-sectional area of an isolated bundle of hair. We sought to evaluate the accuracy and sensitivity of the HairCheck(®) device, a commercial product derived from the original cross-section trichometer. Bundles of surgical silk and human hair were used to evaluate the ability of the HairCheck(®) device to detect and measure small changes in the number and diameter of strands, and bundle weight. Strong correlations were observed between the bundle's cross-sectional area, displayed as the numeric Hair Mass Index (HMI), the number of strands, the silk/hair diameter, and the bundle dry weight. HMI strongly correlated with the number and diameter of silk/hair, and the weight of the bundle, suggesting that it can serve as a valid indicator of hair mass. We have given the name cross-section trichometry (CST) to the methodology of obtaining the HMI using the HairCheck(®) system. CST is a simple modality for the quantification of hair mass, and may be used as a convenient and useful tool to clinically assess changes in hair mass caused by thinning, shedding, breakage, or growth in males and females with progressive alopecia or those receiving alopecia treatment.

  13. Cross-section Trichometry: A Clinical Tool for Assessing the Progression and Treatment Response of Alopecia

    PubMed Central

    Wikramanayake, Tongyu Cao; Mauro, Lucia M; Tabas, Irene A; Chen, Anne L; Llanes, Isabel C; Jimenez, Joaquin J

    2012-01-01

    Background: To properly assess the progression and treatment response of alopecia, one must measure the changes in hair mass, which is influenced by both the density and diameter of hair. Unfortunately, a convenient device for hair mass evaluation had not been available to dermatologists until the recent introduction of the cross-section trichometer, which directly measures the cross-sectional area of an isolated bundle of hair. Objective: We sought to evaluate the accuracy and sensitivity of the HairCheck® device, a commercial product derived from the original cross-section trichometer. Materials and Methods: Bundles of surgical silk and human hair were used to evaluate the ability of the HairCheck® device to detect and measure small changes in the number and diameter of strands, and bundle weight. Results: Strong correlations were observed between the bundle's cross-sectional area, displayed as the numeric Hair Mass Index (HMI), the number of strands, the silk/hair diameter, and the bundle dry weight. Conclusion: HMI strongly correlated with the number and diameter of silk/hair, and the weight of the bundle, suggesting that it can serve as a valid indicator of hair mass. We have given the name cross-section trichometry (CST) to the methodology of obtaining the HMI using the HairCheck® system. CST is a simple modality for the quantification of hair mass, and may be used as a convenient and useful tool to clinically assess changes in hair mass caused by thinning, shedding, breakage, or growth in males and females with progressive alopecia or those receiving alopecia treatment. PMID:23766610

  14. Clinical and Experimental Progression of a New Model of Human Prostate Cancer and Therapeutic Approach

    PubMed Central

    de Pinieux, Gonzague; Legrier, Marie-Emmanuelle; Poirson-Bichat, Florence; Courty, Yves; Bras-Gonçalves, Rui; Dutrillaux, Anne-Marie; Némati, Fariba; Oudard, Stéphane; Lidereau, Rosette; Broqua, Pierre; Junien, Jean-Louis; Dutrillaux, Bernard; Poupon, Marie-France

    2001-01-01

    We report the clinical evolution of a prostate cancer, metastasizing to lungs and bones, recurring locally, and escaping from anti-androgen therapy. Key event of biological progression of the patient’s tumor was the coincidence of allelic imbalance accumulation and of bone metastases occurrence. The recurrent tumor was established as the transplantable xenograft PAC120 in nude mice, where it grew locally. PAC120 displayed the same immunophenotype of the original tumor (positive for keratin, vimentin, prostatic acid phosphatase, and Leu-7) and expressed human HOXB9, HOXA4, HER-2/neu, and prostate-specific antigen genes, as detected by reverse transcriptase-polymerase chain reaction. It formed lung micrometastases detected by mRNA expression of human genes. Cytogenetic analysis demonstrated numerous alterations reflecting the tumor evolution. PAC120 was still hormone-dependent; its growth was strongly inhibited by the new gonadotropin-releasing hormone antagonist FE 200486 but weakly by gonadotropin-releasing hormone superagonist D-Trp6-luteinizing-hormone releasing hormone (decapeptyl). Tumor growth inhibition induced by anti-hormone therapy was linked to the hormone deprivation degree, more important and more stable with FE 200486 than with D-Trp6-luteinizing-hormone releasing hormone. Surgical castration of mice led to tumor regressions but did not prevent late recurrences. Transition to hormone-independent tumors was frequently associated with a mucoid differentiation or with a neuroendocrine-like pattern. Independent variations of mRNA expression of HER-2/neu and prostate-specific antigen were observed in hormone-independent tumors whereas HOXB9 gene expression was constant. In conclusion, PAC120 xenograft, a new model of hormone-dependent prostate cancer retained the progression potential of the original tumor, opening the opportunity to study the hormone dependence escape mechanism. PMID:11485933

  15. Weight change, obesity and risk of prostate cancer progression among men with clinically localized prostate cancer.

    PubMed

    Dickerman, Barbra A; Ahearn, Thomas U; Giovannucci, Edward; Stampfer, Meir J; Nguyen, Paul L; Mucci, Lorelei A; Wilson, Kathryn M

    2017-09-01

    Obesity is associated with an increased risk of fatal prostate cancer. We aimed to elucidate the importance and relevant timing of obesity and weight change for prostate cancer progression. We identified 5,158 men diagnosed with localized prostate cancer (clinical stage T1/T2) from 1986 to 2012 in the Health Professionals Follow-up Study. Men were followed for biochemical recurrence and lethal prostate cancer (development of distant metastasis or prostate cancer-specific mortality) until 2012. Cox regression estimated hazard ratios (HRs) for body mass index (BMI) at age 21, BMI at diagnosis, "long-term" weight change from age 21 to diagnosis and "short-term" weight change over spans of 4 and 8 years preceding diagnosis. Because weight, weight change and mortality are strongly associated with smoking, we repeated analyses among never smokers only (N = 2,559). Among all patients, neither weight change nor BMI (at age 21 or at diagnosis) was associated with lethal prostate cancer. Among never smokers, long-term weight gain was associated with an increased risk of lethal disease (HR for gaining >30 pounds vs. stable weight [±10 pounds] 1.59, 95% CI, 1.01-2.50, p-trend = 0.06). Associations between weight change, BMI and lethal prostate cancer were stronger for men with BMI ≥ 25 at age 21 compared to those with BMI < 25. Weight change and obesity were not associated with an increased risk of biochemical recurrence. Our findings among never smoker men diagnosed with localized prostate cancer suggest a positive association between long-term weight gain and risk of lethal prostate cancer. Metabolic changes associated with weight gain may promote prostate cancer progression. © 2017 UICC.

  16. The clinical and laboratory characteristics of acute spontaneous urticaria and its progression to chronic spontaneous urticaria.

    PubMed

    Magen, Eli; Zueva, Ekaterina; Mishal, Joseph; Schlesinger, Menachem

    2016-09-01

    The natural history of the progression from acute spontaneous urticaria (ASU) to chronic spontaneous urticaria (CSU), CSU remains poorly understood. To identify clinical and laboratory patient attributes that may be predictive of ASU progression to CSU. We prospectively studied consecutive adult patients (age ≥ 18 years) with a diagnosis of urticaria of <6 weeks' duration. Healthy age- and sex-matched subjects served as controls. At study entry, autologous serum skin test (ASST), complete blood cell count, erythrocyte sedimentation rate, thyroid function tests, antinuclear antibodies, antithyroglobulin and antiperoxidase antibodies, and immunoglobulin E level were assessed in all the subjects. ASST and urticaria activity score assessment were performed in all the patients at baseline and then at weeks 7, 12, 24, and 48. Of 114 patients with acute urticaria and without identifiable causes, 73 patients (64%) were included in the ASU group, 41 patients in the CSU group (36%), and 44 healthy subjects in the control group. At baseline, 26 patients in the CSU group (63.4%) had a positive ASST result, whereas only 17 patients with a positive ASST result (23.3%) were revealed in the ASU group (p < 0.001). Patients with baseline ASST positive results were characterized by more profound basopenia (mean [standard deviation], 0.05 ± 0.08 cell/mm(3)) and more anti-thyroid peroxidase antibodies (18 [41.8%]) than those with the negative baseline ASST result (mean [standard deviation], 0.13 ± 0.09 cell/mm(3), p < 0.001 more profound basopenia; and 13 (18.1%), p = 0.009 more thyroid peroxidase antibodies). We observed the disappearance of ASST positive result in some patients with CSU with baseline positive ASST results, whereas, in some subjects with CSU, baseline negative ASST results came to be positive results throughout the study period. A baseline positive ASST result of patients with ASU was a significant determinant (odds ratio 5.91 [95% confidence interval, 2

  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. Initial clinical experience with image-guided linear accelerator-based spinal radiosurgery for treatment of benign nerve sheath tumors.

    PubMed

    Selch, Michael T; Lin, Kevin; Agazaryan, Nzhde; Tenn, Steve; Gorgulho, Alessandra; DeMarco, John J; DeSalles, Antonio A F

    2009-12-01

    Stereotactic radiosurgery has proven a safe and effective treatment of cranial nerve sheath tumors. A similar approach should be successful for histologically identical spinal nerve sheath tumors. The preliminary results of linear accelerator-based spinal radiosurgery were retrospectively reviewed for a group of 25 nerve sheath tumors. Tumor location was cervical 11, lumbar 10, and thoracic 4. Thirteen tumors caused sensory disturbance, 12 pain, and 9 weakness. Tumor size varied from 0.9 to 4.1 cm (median, 2.1 cm). Radiosurgery was performed with a 60-MV linear accelerator equipped with a micro-multileaf collimator. Median peripheral dose and prescription isodose were 12 Gy and 90%, respectively. Image guidance involved optical tracking of infrared reflectors, fusion of amorphous silicon radiographs with dynamically reconstructed digital radiographs, and automatic patient positioning. Follow-up varied from 12 to 58 months (median, 18). There have been no local failures. Tumor size remained stable in 18 cases, and 7 (28%) demonstrated more than 2 mm reduction in tumor size. Of 34 neurologic symptoms, 4 improved. There has been no clinical or imaging evidence for spinal cord injury. One patient had transient increase in pain and one transient increase in numbness. Results of this limited experience indicate linear accelerator-based spinal radiosurgery is feasible for treatment of benign nerve sheath tumors. Further follow-up is necessary, but our results imply spinal radiosurgery may represent a therapeutic alternative to surgery for nerve sheath tumors. Symptom resolution may require a prescribed dose of more than 12 Gy. Copyright 2009 Elsevier Inc. All rights reserved.

  19. Clinical spectrum of females with HCCS mutation: from no clinical signs to a neonatal lethal form of the microphthalmia with linear skin defects (MLS) syndrome.

    PubMed

    van Rahden, Vanessa A; Rau, Isabella; Fuchs, Sigrid; Kosyna, Friederike K; de Almeida, Hiram Larangeira; Fryssira, Helen; Isidor, Bertrand; Jauch, Anna; Joubert, Madeleine; Lachmeijer, Augusta M A; Zweier, Christiane; Moog, Ute; Kutsche, Kerstin

    2014-04-15

    Segmental Xp22.2 monosomy or a heterozygous HCCS mutation is associated with the microphthalmia with linear skin defects (MLS) or MIDAS (microphthalmia, dermal aplasia, and sclerocornea) syndrome, an X-linked disorder with male lethality. HCCS encodes the holocytochrome c-type synthase involved in mitochondrial oxidative phosphorylation (OXPHOS) and programmed cell death. We characterized the X-chromosomal abnormality encompassing HCCS or an intragenic mutation in this gene in six new female patients with an MLS phenotype by cytogenetic analysis, fluorescence in situ hybridization, sequencing, and quantitative real-time PCR. The X chromosome inactivation (XCI) pattern was determined and clinical data of the patients were reviewed. Two terminal Xp deletions of ≥ 11.2 Mb, two submicroscopic copy number losses, one of ~850 kb and one of ≥ 3 Mb, all covering HCCS, 1 nonsense, and one mosaic 2-bp deletion in HCCS are reported. All females had a completely (>98:2) or slightly skewed (82:18) XCI pattern. The most consistent clinical features were microphthalmia/anophthalmia and sclerocornea/corneal opacity in all patients and congenital linear skin defects in 4/6. Additional manifestations included various ocular anomalies, cardiac defects, brain imaging abnormalities, microcephaly, postnatal growth retardation, and facial dysmorphism. However, no obvious clinical sign was observed in three female carriers who were relatives of one patient. Our findings showed a wide phenotypic spectrum ranging from asymptomatic females with an HCCS mutation to patients with a neonatal lethal MLS form. Somatic mosaicism and the different ability of embryonic cells to cope with an OXPHOS defect and/or enhanced cell death upon HCCS deficiency likely underlie the great variability in phenotypes.

  20. Clinical spectrum of females with HCCS mutation: from no clinical signs to a neonatal lethal form of the microphthalmia with linear skin defects (MLS) syndrome

    PubMed Central

    2014-01-01

    Background Segmental Xp22.2 monosomy or a heterozygous HCCS mutation is associated with the microphthalmia with linear skin defects (MLS) or MIDAS (microphthalmia, dermal aplasia, and sclerocornea) syndrome, an X-linked disorder with male lethality. HCCS encodes the holocytochrome c-type synthase involved in mitochondrial oxidative phosphorylation (OXPHOS) and programmed cell death. Methods We characterized the X-chromosomal abnormality encompassing HCCS or an intragenic mutation in this gene in six new female patients with an MLS phenotype by cytogenetic analysis, fluorescence in situ hybridization, sequencing, and quantitative real-time PCR. The X chromosome inactivation (XCI) pattern was determined and clinical data of the patients were reviewed. Results Two terminal Xp deletions of ≥11.2 Mb, two submicroscopic copy number losses, one of ~850 kb and one of ≥3 Mb, all covering HCCS, 1 nonsense, and one mosaic 2-bp deletion in HCCS are reported. All females had a completely (>98:2) or slightly skewed (82:18) XCI pattern. The most consistent clinical features were microphthalmia/anophthalmia and sclerocornea/corneal opacity in all patients and congenital linear skin defects in 4/6. Additional manifestations included various ocular anomalies, cardiac defects, brain imaging abnormalities, microcephaly, postnatal growth retardation, and facial dysmorphism. However, no obvious clinical sign was observed in three female carriers who were relatives of one patient. Conclusion Our findings showed a wide phenotypic spectrum ranging from asymptomatic females with an HCCS mutation to patients with a neonatal lethal MLS form. Somatic mosaicism and the different ability of embryonic cells to cope with an OXPHOS defect and/or enhanced cell death upon HCCS deficiency likely underlie the great variability in phenotypes. PMID:24735900

  1. 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.

  2. 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.

  3. 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

  4. What is the Clinically Relevant Relative Biologic Effectiveness? A Warning for Fractionated Treatments With High Linear Energy Transfer Radiation

    SciTech Connect

    Dasu, Alexandru Toma-Dasu, Iuliana

    2008-03-01

    Purpose: To study the clinically relevant relative biologic effectiveness (RBE) of fractionated treatments with high linear energy transfer (LET) radiation and to identify the important factors that might influence the transfer of tolerance and curative levels from low LET radiation. These are important questions in the light of the growing interest for the therapeutic use of radiation with higher LET than electrons or photons. Methods and Materials: The RBE of various fractionated schedules was analyzed with theoretical models for radiation effect, and the resulting predictions were compared with the published clinical and experimental data regarding fractionated irradiation with high LET radiation. Results: The clinically relevant RBE increased for greater doses per fraction, in contrast to the predictions from single-dose experiments. Furthermore, the RBE for late-reacting tissues appeared to modify more quickly than that for early-reacting tissues. These aspects have quite important clinical implications, because the increased biologic effectiveness reported for this type of radiation would otherwise support the use of hypofractionation. Thus, the differential between acute and late-reacting tissues could put the late-reacting normal tissues at more risk from high LET irradiation; however, at the same time, it could increase the therapeutic window for slow-growing tumors. Conclusions: The modification of the RBE with the dose per fraction must be carefully taken into consideration when devising fractionated treatments with high LET radiation. Neglecting to do so might result in an avalanche of complications that could obscure the potential advantages of the therapeutic use of this type of radiation.

  5. Clinical marker for Alzheimer disease pathology in logopenic primary progressive aphasia.

    PubMed

    Giannini, Lucia A A; Irwin, David J; McMillan, Corey T; Ash, Sharon; Rascovsky, Katya; Wolk, David A; Van Deerlin, Vivianna M; Lee, Edward B; Trojanowski, John Q; Grossman, Murray

    2017-06-13

    To determine whether logopenic features of phonologic loop dysfunction reflect Alzheimer disease (AD) neuropathology in primary progressive aphasia (PPA). We performed a retrospective case-control study of 34 patients with PPA with available autopsy tissue. We compared baseline and longitudinal clinical features in patients with primary AD neuropathology to those with primary non-AD pathologies. We analyzed regional neuroanatomic disease burden in pathology-defined groups using postmortem neuropathologic data. A total of 19/34 patients had primary AD pathology and 15/34 had non-AD pathology (13 frontotemporal lobar degeneration, 2 Lewy body disease). A total of 16/19 (84%) patients with AD had a logopenic spectrum phenotype; 5 met published criteria for the logopenic variant (lvPPA), 8 had additional grammatical or semantic deficits (lvPPA+), and 3 had relatively preserved sentence repetition (lvPPA-). Sentence repetition was impaired in 68% of patients with PPA with AD pathology; forward digit span (DF) was impaired in 90%, substantially higher than in non-AD PPA (33%, p < 0.01). Lexical retrieval difficulty was common in all patients with PPA and did not discriminate between groups. Compared to non-AD, PPA with AD pathology had elevated microscopic neurodegenerative pathology in the superior/midtemporal gyrus, angular gyrus, and midfrontal cortex (p < 0.01). Low DF scores correlated with high microscopic pathologic burden in superior/midtemporal and angular gyri (p ≤ 0.03). Phonologic loop dysfunction is a central feature of AD-associated PPA and specifically correlates with temporoparietal neurodegeneration. Quantitative measures of phonologic loop function, combined with modified clinical lvPPA criteria, may help discriminate AD-associated PPA. © 2017 American Academy of Neurology.

  6. 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.

  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. 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.

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

    PubMed

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

    2016-09-12

    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.

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

    PubMed Central

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

    2016-01-01

    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. PMID:27615411

  11. [Hope for Huntington's disease patients: first clinical gene silencing study in progress].

    PubMed

    Rollnik, Jens D

    2017-08-01

    Huntington's disease (HD) is an autosomal-dominant inherited neurodegenerative disorder, characterized by motor, psychiatric and cognitive symptoms for which as yet no causal treatment is available. It has a prevalence of 1 : 10 000 in Germany. Its cause is a mutation in the Huntington gene (CAG-repeat). The mutation induces a polyglutamine expansion in the huntingtin protein (HTT). Mutant HTT (mHTT) has cytotoxic properties, aggregates in the cell and leads to complex pathophysiological disturbances ending in cell death. This review explains the principles of gene silencing which suppresses transcription and translation of huntingtin. One way to achieve gene silencing is the use of antisense oligonucleotides (ASO) that bind to pre-mRNA. Since August 2015, a first clinical trial with ASO (study drug: IONIS-HTTRx) in early manifest HD patients is in progress (NCT02519036). Results from this study could lead to a first causal treatment option in HD. Georg Thieme Verlag KG Stuttgart · New York.

  12. 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.

  13. 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.

  14. 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.

  15. 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

  16. Role of Chronic Inflammation in Myopia Progression: Clinical Evidence and Experimental Validation.

    PubMed

    Lin, Hui-Ju; Wei, Chang-Ching; Chang, Ching-Yao; Chen, Ter-Hsin; Hsu, Yu-An; Hsieh, Yi-Ching; Chen, Hsuan-Ju; Wan, Lei

    2016-08-01

    Prevention and treatment of myopia is an important public problem worldwide. We found a higher incidence of myopia among patients with inflammatory diseases such as type 1 diabetes mellitus (7.9%), uveitis (3.7%), or systemic lupus erythematosus (3.5%) compared to those without inflammatory diseases (p<0.001) using data from children (<18years old) in the National Health Insurance Research database. We then examined the inhibition of myopia by atropine in Syrian hamsters with monocular form deprivation (MFD), an experimental myopia model. We found atropine downregulated inflammation in MFD eyes. The expression levels of c-Fos, nuclear factor κB (NFκB), interleukin (IL)-6, and tumor necrosis factor (TNF)-α were upregulated in myopic eyes and downregulated upon treatment with atropine. The relationship between the inflammatory response and myopia was investigated by treating MFD hamsters with the immunosuppressive agent cyclosporine A (CSA) or the inflammatory stimulators lipopolysaccharide (LPS) or peptidoglycan (PGN). Myopia progression was slowed by CSA application but was enhanced by LPS and PGN administration. The levels of c-Fos, NF-κB, IL-6, and TNF-α were upregulated in LPS- and PGN-treated eyes and downregulated by CSA treatment. These findings provide clinical and experimental evidence that inflammation plays a crucial role in the development of myopia. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  17. 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

  18. 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

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

    USDA-ARS?s Scientific Manuscript database

    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. Measurement and Treatment of Radiographic Progression in Ankylosing Spondylitis: Lessons Learned from Observational Studies and Clinical Trials

    PubMed Central

    Louie, Grant H.; Ward, Michael M.

    2014-01-01

    PURPOSE OF REVIEW One of the major goals of treatment of ankylosing spondylitis (AS) is to prevent or slow the development of spinal new bone formation. Recent observational studies are compared to results from clinical trials for the effects of tumor necrosis factor-alpha inhibitors (TNFi) and nonsteroidal anti-inflammatory drugs (NSAIDs) on radiographic measures of spinal damage. RECENT FINDINGS Data from clinical trials indicate that treatment up to 2 years with TNFi was not associated with a difference in rates of progression of spinal damage, compared to historical controls. These studies were based on open-label extensions, and analyzed as cohort studies. Recent observational studies have suggested that TNFi may reduce radiographic progression. The different conclusions may be related to the longer treatment and observation period of these observational studies, which may have permitted detection of changes in this slowly evolving process. There is emerging evidence from a clinical trial and retrospective studies that continuous NSAID use may slow radiographic progression. SUMMARY Lack of evidence that TNFi slow radiographic progression in AS in data from clinical trials may be due to the design of these studies, and possibly not a true null treatment effect. PMID:24389865

  1. Randomized Controlled Trial in Clinical Settings to Evaluate Effectiveness of Coping Skills Education Used with Progressive Tinnitus Management

    ERIC Educational Resources Information Center

    Henry, James A.; Thielman, Emily J.; Zaugg, Tara L.; Kaelin, Christine; Schmidt, Caroline J.; Griest, Susan; McMillan, Garnett P.; Myers, Paula; Rivera, Izel; Baldwin, Robert; Carlson, Kathleen

    2017-01-01

    Purpose: This randomized controlled trial evaluated, within clinical settings, the effectiveness of coping skills education that is provided with progressive tinnitus management (PTM). Method: At 2 Veterans Affairs medical centers, N = 300 veterans were randomized to either PTM intervention or 6-month wait-list control. The PTM intervention…

  2. Do Clinical and Translational Science Graduate Students Understand Linear Regression? Development and Early Validation of the REGRESS Quiz

    PubMed Central

    2013-01-01

    Abstract Introduction Although regression is widely used for reading and publishing in the medical literature, no instruments were previously available to assess students’ understanding. The goal of this study was to design and assess such an instrument for graduate students in Clinical and Translational Science and Public Health. Methods A 27‐item REsearch on Global Regression Expectations in StatisticS (REGRESS) quiz was developed through an iterative process. Consenting students taking a course on linear regression in a Clinical and Translational Science program completed the quiz pre‐ and postcourse. Student results were compared to practicing statisticians with a master's or doctoral degree in statistics or a closely related field. Results Fifty‐two students responded precourse, 59 postcourse , and 22 practicing statisticians completed the quiz. The mean (SD) score was 9.3 (4.3) for students precourse and 19.0 (3.5) postcourse (P < 0.001). Postcourse students had similar results to practicing statisticians (mean (SD) of 20.1(3.5); P = 0.21). Students also showed significant improvement pre/postcourse in each of six domain areas (P < 0.001). The REGRESS quiz was internally reliable (Cronbach's alpha 0.89). Conclusion The initial validation is quite promising with statistically significant and meaningful differences across time and study populations. Further work is needed to validate the quiz across multiple institutions. PMID:24330688

  3. Extracting drug mechanism and pharmacodynamic information from clinical electroencephalographic data using generalised semi-linear canonical correlation analysis.

    PubMed

    Brain, P; Strimenopoulou, F; Diukova, A; Berry, E; Jolly, A; Hall, J E; Wise, R G; Ivarsson, M; Wilson, F J

    2014-12-01

    Conventional analysis of clinical resting electroencephalography (EEG) recordings typically involves assessment of spectral power in pre-defined frequency bands at specific electrodes. EEG is a potentially useful technique in drug development for measuring the pharmacodynamic (PD) effects of a centrally acting compound and hence to assess the likelihood of success of a novel drug based on pharmacokinetic-pharmacodynamic (PK-PD) principles. However, the need to define the electrodes and spectral bands to be analysed a priori is limiting where the nature of the drug-induced EEG effects is initially not known. We describe the extension to human EEG data of a generalised semi-linear canonical correlation analysis (GSLCCA), developed for small animal data. GSLCCA uses data from the whole spectrum, the entire recording duration and multiple electrodes. It provides interpretable information on the mechanism of drug action and a PD measure suitable for use in PK-PD modelling. Data from a study with low (analgesic) doses of the μ-opioid agonist, remifentanil, in 12 healthy subjects were analysed using conventional spectral edge analysis and GSLCCA. At this low dose, the conventional analysis was unsuccessful but plausible results consistent with previous observations were obtained using GSLCCA, confirming that GSLCCA can be successfully applied to clinical EEG data.

  4. 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.

  5. Do clinical and translational science graduate students understand linear regression? Development and early validation of the REGRESS quiz.

    PubMed

    Enders, Felicity

    2013-12-01

    Although regression is widely used for reading and publishing in the medical literature, no instruments were previously available to assess students' understanding. The goal of this study was to design and assess such an instrument for graduate students in Clinical and Translational Science and Public Health. A 27-item REsearch on Global Regression Expectations in StatisticS (REGRESS) quiz was developed through an iterative process. Consenting students taking a course on linear regression in a Clinical and Translational Science program completed the quiz pre- and postcourse. Student results were compared to practicing statisticians with a master's or doctoral degree in statistics or a closely related field. Fifty-two students responded precourse, 59 postcourse , and 22 practicing statisticians completed the quiz. The mean (SD) score was 9.3 (4.3) for students precourse and 19.0 (3.5) postcourse (P < 0.001). Postcourse students had similar results to practicing statisticians (mean (SD) of 20.1(3.5); P = 0.21). Students also showed significant improvement pre/postcourse in each of six domain areas (P < 0.001). The REGRESS quiz was internally reliable (Cronbach's alpha 0.89). The initial validation is quite promising with statistically significant and meaningful differences across time and study populations. Further work is needed to validate the quiz across multiple institutions. © 2013 Wiley Periodicals, Inc.

  6. 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

  7. Development of clinical recommendations for progressive return to activity after military mild traumatic brain injury: guidance for rehabilitation providers.

    PubMed

    McCulloch, Karen L; Goldman, Sarah; Lowe, Lynn; Radomski, Mary Vining; Reynolds, John; Shapiro, Rita; West, Therese A

    2015-01-01

    Previously published mild traumatic brain injury (mTBI) management guidelines provide very general recommendations to return individuals with mTBI to activity. This lack of specific guidance creates variation in military rehabilitation. The Office of the Army Surgeon General in collaboration with the Defense and Veterans Brain Injury Center, a component center of the Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury, convened an expert working group to review the existing literature and propose clinical recommendations that standardize rehabilitation activity progression following mTBI. A Progressive Activity Working Group consisted of 11 Department of Defense representatives across all service branches, 7 Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury representatives, and 8 academic/research/civilian experts with experience assessing and treating individuals with mTBI for return to activity. An expert working group meeting included the Progressive Activity Working Group and 15 additional subject matter experts. In February 2012, the Progressive Activity Working Group was established to determine the need and purpose of the rehabilitation recommendations. Following literature review, a table was created on the basis of the progression from the Zurich consensus statement on concussion in sport. Issues were identified for discussion with a meeting of the larger expert group during a July 2012 conference. Following development of rehabilitation guidance, the Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury coordinated a similar process for military primary care providers. End products for rehabilitation and primary care providers include specific recommendations for return to activity after concussion. A 6-stage progression specifies activities in physical, cognitive, and balance/vestibular domains and allows for resumption of activity for those with low-level or

  8. Monitoring progression of clinical reasoning skills during health sciences education using the case method - a qualitative observational study.

    PubMed

    Orban, Kristina; Ekelin, Maria; Edgren, Gudrun; Sandgren, Olof; Hovbrandt, Pia; Persson, Eva K

    2017-09-11

    Outcome- or competency-based education is well established in medical and health sciences education. Curricula are based on courses where students develop their competences and assessment is also usually course-based. Clinical reasoning is an important competence, and the aim of this study was to monitor and describe students' progression in professional clinical reasoning skills during health sciences education using observations of group discussions following the case method. In this qualitative study students from three different health education programmes were observed while discussing clinical cases in a modified Harvard case method session. A rubric with four dimensions - problem-solving process, disciplinary knowledge, character of discussion and communication - was used as an observational tool to identify clinical reasoning. A deductive content analysis was performed. The results revealed the students' transition over time from reasoning based strictly on theoretical knowledge to reasoning ability characterized by clinical considerations and experiences. Students who were approaching the end of their education immediately identified the most important problem and then focused on this in their discussion. Practice knowledge increased over time, which was seen as progression in the use of professional language, concepts, terms and the use of prior clinical experience. The character of the discussion evolved from theoretical considerations early in the education to clinical reasoning in later years. Communication within the groups was supportive and conducted with a professional tone. Our observations revealed progression in several aspects of students' clinical reasoning skills on a group level in their discussions of clinical cases. We suggest that the case method can be a useful tool in assessing quality in health sciences education.

  9. Vitamin D and clinical disease progression in HIV infection: results from the EuroSIDA study.

    PubMed

    Viard, Jean-Paul; Souberbielle, Jean-Claude; Kirk, Ole; Reekie, Joanne; Knysz, Brygida; Losso, Marcelo; Gatell, Jose; Pedersen, Court; Bogner, Johannes R; Lundgren, Jens D; Mocroft, Amanda

    2011-06-19

    We examined the association between vitamin D [25(OH)D] level and disease progression in HIV infection. Within the EuroSIDA study, 2000 persons were randomly selected for 25(OH)D measurement in stored plasma samples closest to study entry. 25(OH)D results were stratified into tertiles. Factors associated with 25(OH)D levels and associations of 25(OH) levels with subsequent risk of all-cause mortality, AIDS and non-AIDS events were analyzed. Of 1985 persons with 25(OH)D levels available, 23.7% had 25(OH)D below 10, 65.3% between 10 and 30, and 11% above 30 ng/ml. At the time of 25(OH)D measurement, older persons, persons of black ethnic origin, living outside Southern Europe/Argentina, sampled during winter, and infected with HIV through nonhomosexual exposure were at higher odds of having low 25(OH)D levels, whereas persons receiving protease inhibitors were at lower odds. Compared to those in the lowest 25(OH)D tertile (<12 ng/ml), those in the middle (12-20) and higher (>20) tertiles had a significantly lower risk of clinical progression during subsequent follow-up. Adjusted incidence rate ratios for all-cause mortality were 0.68 (95% CI 0.47-0.99, P = 0.045) and 0.56 (95% CI 0.37-0.83, P = 0.0039), and for AIDS events were 0.58 (95% CI 0.39-0.87, P = 0.0086) and 0.61 (95% CI 0.40-0.93, P = 0.020), for the middle and higher tertiles, respectively. There was a similar, nonsignificant reduced incidence of non-AIDS events in the middle and higher tertiles. 25(OH)D deficiency was frequent in HIV-infected persons (83% on combined antiretroviral therapy), and was independently associated with a higher risk of mortality and AIDS events. Causality relationships should be examined, because of potential public health consequences.

  10. 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

  11. 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

  12. 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

  13. Normalization and backscatter spectral analysis of human carotid arterial data acquired using a clinical linear array ultrasound imaging system.

    PubMed

    Sareen, Meghna; Waters, Kendall; Nair, Anuja; Vince, D Geoffrey

    2008-01-01

    The risk of plaque rupture in carotid atherosclerotic disease is associated more closely with the composition of plaque rather than the severity of stenosis. The constituents of plaque can be determined from ultrasonic spectral parameters obtained from normalized backscatter tissue data. Calibration of the data is done using echoes off a specular reflector which removes the system response of an ultrasound transducer, Terason (Teratech Corporation), from the backscatter data. A reference spectrum study is used to compare specular reflectors based on time domain (echo) and frequency domain (power spectrum, centroid and parabola test) analysis. Nylon and a tissue-mimicking phantom (velocity = 1560 m/s, slope of attenuation = 0.7 dB/cm MHz) have an intermediate acoustic impedance with respect to water and appear good choices as specular reflectors for clinical ultrasound imaging scanners compared to Plexiglas and other higher reflecting materials. A tissue-mimicking phantom is used to correct for attenuation in plaque, diffraction and saturation of electronics of the ultrasound scanner. Autoregressive power spectrum estimation methods are used to extract spectral parameters (spectral slope, y-intercept, midband fit, maximum and minimum power with corresponding frequencies, and integrated backscatter) from calibrated tissue data and linear and quadratic discriminant rules developed for classification of carotid arterial plaque. Regions of interest (n = 64; 64 samples x 8 scan lines with 30 MHz sampling frequency) consisting of 48 fibrous-fibrofatty (Class 1), 11 thrombus-necrotic core (Class 2), and 5 dense calcium (Class 3) areas selected for analysis show that fibrosis can be differentiated from necrosis and calcification. The quadratic discriminant rule identified necrosis with a lower misclassification rate (9.1%) than the linear discriminant rule (18.2%).

  14. 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.

  15. 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

  16. Design and End Points of Clinical Trials for Patients With Progressive Prostate Cancer and Castrate Levels of Testosterone: Recommendations of the Prostate Cancer Clinical Trials Working Group

    PubMed Central

    Scher, Howard I.; Halabi, Susan; Tannock, Ian; Morris, Michael; Sternberg, Cora N.; Carducci, Michael A.; Eisenberger, Mario A.; Higano, Celestia; Bubley, Glenn J.; Dreicer, Robert; Petrylak, Daniel; Kantoff, Philip; Basch, Ethan; Kelly, William Kevin; Figg, William D.; Small, Eric J.; Beer, Tomasz M.; Wilding, George; Martin, Alison; Hussain, Maha

    2014-01-01

    Purpose To update eligibility and outcome measures in trials that evaluate systemic treatment for patients with progressive prostate cancer and castrate levels of testosterone. Methods A committee of investigators experienced in conducting trials for prostate cancer defined new consensus criteria by reviewing previous criteria, Response Evaluation Criteria in Solid Tumors (RECIST), and emerging trial data. Results The Prostate Cancer Clinical Trials Working Group (PCWG2) recommends a two-objective paradigm: (1) controlling, relieving, or eliminating disease manifestations that are present when treatment is initiated and (2) preventing or delaying disease manifestations expected to occur. Prostate cancers progressing despite castrate levels of testosterone are considered castration resistant and not hormone refractory. Eligibility is defined using standard disease assessments to authenticate disease progression, prior treatment, distinct clinical subtypes, and predictive models. Outcomes are reported independently for prostate-specific antigen (PSA), imaging, and clinical measures, avoiding grouped categorizations such as complete or partial response. In most trials, early changes in PSA and/or pain are not acted on without other evidence of disease progression, and treatment should be continued for at least 12 weeks to ensure adequate drug exposure. Bone scans are reported as “new lesions” or “no new lesions,” changes in soft-tissue disease assessed by RECIST, and pain using validated scales. Defining eligibility for prevent/delay end points requires attention to estimated event frequency and/or random assignment to a control group. Conclusion PCWG2 recommends increasing emphasis on time-to-event end points (ie, failure to progress) as decision aids in proceeding from phase II to phase III trials. Recommendations will evolve as data are generated on the utility of intermediate end points to predict clinical benefit. PMID:18309951

  17. Linear accelerator-based stereotactic radiosurgery of intracranial meningiomas: results of the first 5 years of clinical practice.

    PubMed

    Abdelaziz, Osama S; Kandil, Alaa; El-Assaal, Shaaban; Abdelaziz, Amro; Rostom, Yosry; Rashed, Yaser

    2011-01-01

    Meningiomas are mostly benign but some are atypical or malignant. Surgical resection is curative when complete removal of benign meningiomas is contemplated. Incompletely excised and recurrent tumors are frequently treated with fractionated radiation therapy or stereotactic radiosurgery. The purpose of this study is to evaluate the short-term radiological and functional outcomes of a single center using linear accelerator (Linac) stereotactic radiosurgery for the treatment of intracranial meningiomas. Twenty-nine patients (12 males and 17 females) with 30 meningiomas, in different brain locations (skull base and non-skull base meningiomas), were treated with Linac-based stereotactic radiosurgery. The mean tumor volume was 6.3 cm³, and the mean tumor marginal and maximum doses were 10.9 and 15 Gy, respectively. The median prescribed isodose line was 80%. The patients were followed-up for a minimum of 3 years. Regarding radiological outcome, nine (30%) meningiomas demonstrated evident volume reduction, 19 (63.3%) meningiomas remained unchanged, and two (6.7%) meningiomas increased in size after radiosurgery. The local tumor control rates for skull base meningiomas and non-skull base meningiomas after radiosurgery were 90.9% and 100%, respectively. Regarding functional outcomes, 64% of patients presenting with cranial neuropathies showed improvement of their cranial nerve functions and 29% of patients remained unchanged. One patient had temporary trigeminal neuropathy. Although radiosurgery for meningiomas is generally effective and quite safe in achieving high control rates with minimum morbidity over short- and intermediate-term periods of follow-up, tumor progression might occur in a delayed manner after initial apparent control for few years. We recommend continued follow-up for longer periods to better assess the long-term outcomes.

  18. 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). Copyright © 2012 Elsevier Ltd. All rights reserved.

  19. Detection and Clinical Significance of Circulating Tumor Cells in Colorectal Cancer—20 Years of Progress

    PubMed Central

    Hardingham, Jennifer E; Grover, Phulwinder; Winter, Marnie; Hewett, Peter J; Price, Timothy J; Thierry, Benjamin

    2015-01-01

    Circulating tumor cells (CTC) may be defined as tumor- or metastasis-derived cells that are present in the bloodstream. The CTC pool in colorectal cancer (CRC) patients may include not only epithelial tumor cells, but also tumor cells undergoing epithelial–mesenchymal transition (EMT) and tumor stem cells. A significant number of patients diagnosed with early stage CRC subsequently relapse with recurrent or metastatic disease despite undergoing “curative” resection of their primary tumor. This suggests that an occult metastatic disease process was already underway, with viable tumor cells being shed from the primary tumor site, at least some of which have proliferative and metastatic potential and the ability to survive in the bloodstream. Such tumor cells are considered to be responsible for disease relapse in these patients. Their detection in peripheral blood at the time of diagnosis or after resection of the primary tumor may identify those early-stage patients who are at risk of developing recurrent or metastatic disease and who would benefit from adjuvant therapy. CTC may also be a useful adjunct to radiological assessment of tumor response to therapy. Over the last 20 years many approaches have been developed for the isolation and characterization of CTC. However, none of these methods can be considered the gold standard for detection of the entire pool of CTC. Recently our group has developed novel unbiased inertial microfluidics to enrich for CTC, followed by identification of CTC by imaging flow cytometry. Here, we provide a review of progress on CTC detection and clinical significance over the last 20 years. PMID:26605644

  20. Cytokine response signatures in disease progression and development of severe clinical outcomes for leptospirosis.

    PubMed

    Reis, Eliana A G; Hagan, José E; Ribeiro, Guilherme S; Teixeira-Carvalho, Andrea; Martins-Filho, Olindo A; Montgomery, Ruth R; Shaw, Albert C; Ko, Albert I; Reis, Mitermayer G

    2013-01-01

    The role of the immune response in influencing leptospirosis clinical outcomes is not yet well understood. We hypothesized that acute-phase serum cytokine responses may play a role in disease progression, risk for death, and severe pulmonary hemorrhage syndrome (SPHS). We performed a case-control study design to compare cytokine profiles in patients with mild and severe forms of leptospirosis. Among patients hospitalized with severe disease, we compared those with fatal and nonfatal outcomes. During active outpatient and hospital-based surveillance we prospectively enrolled 172 patients, 23 with mild disease (outpatient) and 149 with severe leptospirosis (hospitalized). Circulating concentrations of pro- and anti-inflammatory cytokines at the time of patient presentation were measured using a multiplex bead array assay. Concentrations of IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-17A, and TNF-α were significantly higher (P<0.05) in severe disease compared to mild disease. Among severe patients, levels of IL-6 (P<0.001), IL-8 (P = 0.0049) and IL-10 (P<0.001), were higher in fatal compared to non-fatal cases. High levels of IL-6 and IL-10 were independently associated (P<0.05) with case fatality after adjustment for age and days of symptoms. IL-6 levels were higher (P = 0.0519) among fatal cases who developed SPHS than among who did not. This study shows that severe cases of leptospirosis are differentiated from mild disease by a "cytokine storm" process, and that IL-6 and IL-10 may play an immunopathogenic role in the development of life-threatening outcomes in human leptospirosis.

  1. Anatomic, clinical, and neuropsychological correlates of spelling errors in Primary Progressive Aphasia

    PubMed Central

    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, 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). PMID:22579708

  2. Deficits in temporal processing correlate with clinical progression in Huntington's disease.

    PubMed

    Agostino, P V; Gatto, E M; Cesarini, M; Etcheverry, J L; Sanguinetti, A; Golombek, D A

    2017-10-01

    Precise temporal performance is crucial for several complex tasks. Time estimation in the second-to-minutes range-known as interval timing-involves the interaction of the basal ganglia and the prefrontal cortex via dopaminergic-glutamatergic pathways. Patients with Huntington's disease (HD) present deficits in cognitive and motor functions that require fine control of temporal processing. The objective of the present work was to assess temporal cognition through a peak-interval time (PI) production task in patients with HD and its potential correlation with the Unified Huntington's Disease Rating Scale (UHDRS). Patients with molecular diagnosis of HD and controls matched by age, sex and educational level (n=18/group) were tested for interval timing in short- (3 seconds), medium- (6 seconds) and long (12 seconds)-duration stimuli. Significant differences were observed in the PI task, with worse performance in HD compared to controls. Patients underestimated real time (left-shifted Peak location) for 6- and 12-second intervals (P<.05) and presented decreased temporal precision for all the intervals evaluated (P<.01). Importantly, a significant correlation was found between time performance and the UHDRS (P<.01). Patients' responses also deviated from the scalar property. Our results contribute to support that timing functions are impaired in HD in correlation with clinical deterioration. Recordings of cognitive performance related to timing could be a potential useful tool to measure the neurodegenerative progression of movement disorder-related pathologies. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. 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

  4. The Enhanced liver fibrosis score is associated with clinical outcomes and disease progression in patients with chronic liver disease.

    PubMed

    Irvine, Katharine M; Wockner, Leesa F; Shanker, Mihir; Fagan, Kevin J; Horsfall, Leigh U; Fletcher, Linda M; Ungerer, Jacobus P J; Pretorius, Carel J; Miller, Gregory C; Clouston, Andrew D; Lampe, Guy; Powell, Elizabeth E

    2016-03-01

    Current tools for risk stratification of chronic liver disease subjects are limited. We aimed to determine whether the serum-based ELF (Enhanced Liver Fibrosis) test predicted liver-related clinical outcomes, or progression to advanced liver disease, and to compare the performance of ELF to liver biopsy and non-invasive algorithms. Three hundred patients with ELF scores assayed at the time of liver biopsy were followed up (median 6.1 years) for liver-related clinical outcomes (n = 16) and clear evidence of progression to advanced fibrosis (n = 18), by review of medical records and clinical data. Fourteen of 73 (19.2%) patients with ELF score indicative of advanced fibrosis (≥9.8, the manufacturer's cut-off) had a liver-related clinical outcome, compared to only two of 227 (<1%) patients with ELF score <9.8. In contrast, the simple scores APRI and FIB-4 would only have predicted subsequent decompensation in six and four patients respectively. A unit increase in ELF score was associated with a 2.53-fold increased risk of a liver-related event (adjusted for age and stage of fibrosis). In patients without advanced fibrosis on biopsy at recruitment, 55% (10/18) with an ELF score ≥9.8 showed clear evidence of progression to advanced fibrosis (after an average 6 years), whereas only 3.5% of those with an ELF score <9.8 (8/207) progressed (average 14 years). In these subjects, a unit increase in ELF score was associated with a 4.34-fold increased risk of progression. The ELF score is a valuable tool for risk stratification of patients with chronic liver disease. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Clinical inertia causing new or progression of diabetic retinopathy in type 2 diabetes: A retrospective cohort study.

    PubMed

    Osataphan, Soravis; Chalermchai, Thep; Ngaosuwan, Kanchana

    2017-03-01

    Clinical inertia is a failure to intensify treatment according to evidence-based guidelines, and can have both short- and long-term adverse effects for type 2 diabetes (T2D). The aim of the present study was to demonstrate the effects of clinical inertia on glycemic control and diabetes-related complications. A retrospective cohort study was conducted at a university-based hospital in Thailand. Medical records were evaluated retrospectively from January 2010 to December 2014. Patients were classified into two groups: clinical inertia and non-inertia. Clinical inertia was defined as failure to initiate insulin within 3 months in patients with HbA1c ≥9 % who were already taking two oral antidiabetic agents. From 1206 records, 98 patients with mean HbA1c of 10.3 % were identified and enrolled in the study. The median follow-up time of these patients was 29.5 months and 68.4 % were classified into the clinical inertia group. The mean (± SD) HbA1c decrement in the clinical inertia and non-inertia groups was 0.82 ± 1.50 % and 3.02 ± 1.80 %, respectively, at 6 months (P < 0.001) and 1.46 ± 1.85 % and 3.04 ± 1.76 %, respectively, at the end of study (P < 0.001). Clinical inertia was associated with a significantly shorter median time to progression of diabetic retinopathy (DR); log rank test, P = 0.02 and a higher incidence of DR progression (10 vs 2.2 cases per 1000 person-months; P = 0.003). The adjusted incidence rate ratio for DR progression in the clinical inertia group was 4.92 (95 % confidence interval 1.11-21.77; P = 0.036). Being treated by general practitioners was the strongest risk factor associated with clinical inertia. Clinical inertia can cause persistently poor glycemic control and speed up the progression of DR in T2D. © 2016 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

  6. Intermediate clinical endpoints: a bridge between progression-free survival and overall survival in ovarian cancer trials.

    PubMed

    Matulonis, Ursula A; Oza, Amit M; Ho, Tony W; Ledermann, Jonathan A

    2015-06-01

    Ovarian cancer patients are usually diagnosed at an advanced stage, experience recurrence after platinum-based chemotherapy, and eventually develop resistance to chemotherapy. Overall survival (OS), which has improved in recent years as more active treatments have been incorporated into patient care, is regarded as the most clinically relevant endpoint in ovarian cancer trials. However, although there remains a significant need for new treatments that prolong OS further without compromising quality of life, it has become increasingly difficult to detect an OS benefit for investigational treatments because of the use of multiple lines of chemotherapy to treat ovarian cancer. Progression-free survival (PFS), which measures the time to disease progression or death, is unaffected by postprogression therapies but does not evaluate the long-term impact of investigational treatments on tumor biology and responses to future therapies. Recent clinical trials of targeted agents in relapsed ovarian cancer have shown improvements in PFS but not OS, and this is possibly reflective of the long postprogression survival (PPS) period associated with this disease. Intermediate endpoints such as the time to second disease progression or death and the time to second subsequent therapy or death may provide supportive evidence for clinically meaningful PFS improvements and may be used to determine whether these improvements persist beyond the first disease progression and throughout subsequent lines of therapy. For clinical trials that have settings with a long PPS duration and/or involve multiple rounds of postprogression therapy, a primary endpoint of PFS supported by intermediate clinical endpoints and OS may provide a more comprehensive approach for evaluating efficacy. © 2014 American Cancer Society.

  7. 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

  8. [Community acquired pneumonia in patients older than 60 years. Incidence of atypical agents and clinical-radiological progression].

    PubMed

    Alvarez Gutiérrez, F J; García Fernández, A; Elías Hernández, T; Romero Contreras, J; Romero Romero, B; Castillo Gómez, J

    2001-10-20

    Seventy five patients older than 60 years with a community acquired pneumonia followed up in an outpatient clinic, were prospectively studied in order to determine the incidence of atypical agents, clinical-radiological characteristics, progression and the differences with pneumonia in younger patients. Clinical-radiological evaluation protocols were activated in the first visit and in two subsequent controls. Etiological diagnosis was made by means of serology (in the first visit and three weeks later). Initially, 85 patients older than 60 years were included of which 75 non hospitalized were fully followed up. Also, in the comparative study, 216 outpatient clinic patients 60 years old or younger were followed up during the same period. In the first group the frequency of atypical agents was 33.3%. The most frequently isolated bacteria was Coxiella burnetii (13.3%)followed by virus and Legionella pneumophila. No case of Mycoplasma pneumoniae was diagnosed. The most frequent radiological onset was alveolar infiltrate (85%). The comparative study between the two populations (older or younger than 60 years), found few clinical differences (dyspnea more frequent in older,feverish chill in younger) and auscultation (crackles more frequent in older). We did not find differences remaining clinical-radiological or laboratory data. Most patients presented a favourable clinical and radiological progression. Only 2 patients needed hospital admission (2.7%). In outpatient clinic patients older than 60 years with community acquired pneumonia a high number of atypical agents have been found. The clinical-radiological evolution was satisfactory for most of them. Age was not a decisive element in determining hospital admissions.

  9. [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.

  10. Decrease in myocardial 123I-MIBG radioactivity in REM sleep behavior disorder: two patients with different clinical progression.

    PubMed

    Oguri, Takuya; Tachibana, Naoko; Mitake, Shigehisa; Kawanishi, Taketo; Fukuyama, Hidenao

    2008-07-01

    Although decrease in myocardial iodine-123 metaiodobenzylguanidine ((123)I-MIBG) radioactivity has been reported in patients with rapid eye movement (REM) sleep behavior disorder (RBD), its pathophysiology has not been thoroughly disclosed. We report two RBD patients with differing clinical progression, in whom myocardial (123)I-MIBG scintigraphy was performed. One 69-year-old patient had more than a 20-year history of idiopathic RBD and showed a decrease in myocardial (123)I-MIBG radioactivity. The other 69-year-old patient started to manifest nocturnal behaviors at age 62, then mild parkinsonism at age 68, and showed a similar decrease in myocardial (123)I-MIBG radioactivity both before and after the onset of parkinsonism. These cases suggest that RBD could develop in diverse patterns of clinical progression even if signs of underlying Lewy body pathology are uniformly indicated.

  11. 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

  12. 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.

  13. New clinical trial to study long-term progression of brain and spine cancers | Center for Cancer Research

    Cancer.gov

    Dr. Mark Gilbert, Chief, Neuro-Oncology Branch, describes an ambitious new clinical trial that, for the first time, will study the long-term progression of brain and spine cancers. The 10,000 patient trial is the largest of its kind and will follow patients throughout the course of their disease. In addition to identifying optimal treatments for common brain and spine cancers, the study focuses on treatment discovery for rare, overlooked cancers.

  14. [Clinical courses and risk factors for progression of smoldering multiple myeloma: a nationwide cohort study in Japan].

    PubMed

    Takamatsu, Yasushi; Muta, Tsuyoshi

    2015-08-01

    We carried out a cohort study of smoldering multiple myeloma (SMM) in Japan. The clinical data of 207 patients with SMM, median age 69 years (range: 27-90), were collected from 63 institutions. The subtype of myeloma was IgG type in 168, IgA type in 30, and Bence Jones type in 9 patients. At a median follow-up of 39 months, 53% of the patients had progressed to symptomatic MM (within 5 years of the initial diagnosis). As previously described, a serum free light chain ratio>8 or <0.125, along with the number of bone marrow plasma cells being 10% or more and the serum M-protein level being at least 3 g/dl, was a significant predictor of rapid progression. We found that the rate of increase in serum M-protein levels correlated negatively with the risk of progression. The probability of progression within 5 years was 100% in patients whose rate of serum M-protein level increase was 2 mg/dl/day or higher. This indicates that the serum M-protein level increase rate might be a useful predictor of disease progression in SMM.

  15. 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.

  16. [Research progress in mechanisms and clinical application for blonanserin and lurasidone in improving cognitive function of schizophrenia].

    PubMed

    Zheng, Qi; Liu, Bangshan; Xu, Shuyin; Liao, Mei; Zhang, Yan; Li, Lingjiang

    2017-04-28

    Cognition deficit is one of the most common symptoms of schizophrenia, including abstract thinking and memory, and attention deficits. Previous studies have suggested that the improvement of cognition is very important for the recovery of disease and social function for the patients. Recent studies indicated that two new atypical antipsychotics, blonanserin and lurasidone, are expected to improve the cognitive impairment in patients with schizophrenia. This review introduces pathogenesis of cognitive impairment in schizophrenia, mechanisms of blonanserin and lurasidone in the improvement of cognitive impairment and progress in their clinical application for schizophrenia. We hope that this review could guide clinical use of antipsychotics and provide new directions for future studies.

  17. 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

  18. [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.

  19. Autologous mesenchymal stem cell therapy for progressive supranuclear palsy: translation into a phase I controlled, randomized clinical study.

    PubMed

    Giordano, Rosaria; Canesi, Margherita; Isalberti, Maurizio; Isaias, Ioannis Ugo; Montemurro, Tiziana; Viganò, Mariele; Montelatici, Elisa; Boldrin, Valentina; Benti, Riccardo; Cortelezzi, Agostino; Fracchiolla, Nicola; Lazzari, Lorenza; Pezzoli, Gianni

    2014-01-17

    Progressive Supranuclear Palsy (PSP) is a sporadic and progressive neurodegenerative disease which belongs to the family of tauopathies and involves both cortical and subcortical structures. No effective therapy is to date available. Autologous bone marrow (BM) mesenchymal stem cells (MSC) from patients affected by different type of parkinsonisms have shown their ability to improve the dopaminergic function in preclinical and clinical models. It is also possible to isolate and expand MSC from the BM of PSP patients with the same proliferation rate and immuphenotypic profile as MSC from healthy donors. BM MSC can be efficiently delivered to the affected brain regions of PSP patients where they can exert their beneficial effects through different mechanisms including the secretion of neurotrophic factors.Here we propose a randomized, placebo-controlled, double-blind phase I clinical trial in patients affected by PSP with MSC delivered via intra-arterial injection. To our knowledge, this is the first clinical trial to be applied in a no-option parkinsonism that aims to test the safety and to exploit the properties of autologous mesenchymal stem cells in reducing disease progression. The study has been designed to test the safety of this "first-in-man" approach and to preliminarily explore its efficacy by excluding the placebo effect. NCT01824121.

  20. 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.

  1. 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

  2. Extrapolation chamber mounted on perspex for calibration of high energy photon and electron beams from a clinical linear accelerator.

    PubMed

    Ravichandran, R; Binukumar, J P; Sivakumar, S S; Krishnamurthy, K; Davis, C A

    2009-01-01

    The objective of the present study is to establish radiation standards for absorbed doses, for clinical high energy linear accelerator beams. In the nonavailability of a cobalt-60 beam for arriving at Nd, water values for thimble chambers, we investigated the efficacy of perspex mounted extrapolation chamber (EC) used earlier for low energy x-rays and beta dosimetry. Extrapolation chamber with facility for achieving variable electrode separations 10.5mm to 0.5mm using micrometer screw was used for calibrations. Photon beams 6 MV and 15 MV and electron beams 6 MeV and 15 MeV from Varian Clinac linacs were calibrated. Absorbed Dose estimates to Perspex were converted into dose to solid water for comparison with FC 65 ionisation chamber measurements in water. Measurements made during the period December 2006 to June 2008 are considered for evaluation. Uncorrected ionization readings of EC for all the radiation beams over the entire period were within 2% showing the consistency of measurements. Absorbed doses estimated by EC were in good agreement with in-water calibrations within 2% for photons and electron beams. The present results suggest that extrapolation chambers can be considered as an independent measuring system for absorbed dose in addition to Farmer type ion chambers. In the absence of standard beam quality (Co-60 radiations as reference Quality for Nd,water) the possibility of keeping EC as Primary Standards for absorbed dose calibrations in high energy radiation beams from linacs should be explored. As there are neither Standard Laboratories nor SSDL available in our country, we look forward to keep EC as Local Standard for hospital chamber calibrations. We are also participating in the IAEA mailed TLD intercomparison programme for quality audit of existing status of radiation dosimetry in high energy linac beams. The performance of EC has to be confirmed with cobalt-60 beams by a separate study, as linacs are susceptible for minor variations in dose

  3. Extrapolation chamber mounted on perspex for calibration of high energy photon and electron beams from a clinical linear accelerator

    PubMed Central

    Ravichandran, R.; Binukumar, J. P.; Sivakumar, S. S.; Krishnamurthy, K.; Davis, C. A.

    2009-01-01

    The objective of the present study is to establish radiation standards for absorbed doses, for clinical high energy linear accelerator beams. In the nonavailability of a cobalt-60 beam for arriving at Nd, water values for thimble chambers, we investigated the efficacy of perspex mounted extrapolation chamber (EC) used earlier for low energy x-rays and beta dosimetry. Extrapolation chamber with facility for achieving variable electrode separations 10.5mm to 0.5mm using micrometer screw was used for calibrations. Photon beams 6 MV and 15 MV and electron beams 6 MeV and 15 MeV from Varian Clinac linacs were calibrated. Absorbed Dose estimates to Perspex were converted into dose to solid water for comparison with FC 65 ionisation chamber measurements in water. Measurements made during the period December 2006 to June 2008 are considered for evaluation. Uncorrected ionization readings of EC for all the radiation beams over the entire period were within 2% showing the consistency of measurements. Absorbed doses estimated by EC were in good agreement with in-water calibrations within 2% for photons and electron beams. The present results suggest that extrapolation chambers can be considered as an independent measuring system for absorbed dose in addition to Farmer type ion chambers. In the absence of standard beam quality (Co-60 radiations as reference Quality for Nd,water) the possibility of keeping EC as Primary Standards for absorbed dose calibrations in high energy radiation beams from linacs should be explored. As there are neither Standard Laboratories nor SSDL available in our country, we look forward to keep EC as Local Standard for hospital chamber calibrations. We are also participating in the IAEA mailed TLD intercomparison programme for quality audit of existing status of radiation dosimetry in high energy linac beams. The performance of EC has to be confirmed with cobalt-60 beams by a separate study, as linacs are susceptible for minor variations in dose

  4. Microphthalmia and linear skin defects (MLS) and focal dermal hypoplasia of Goltz (FDHG); Clinical cytogenetic, and molecular studies

    SciTech Connect

    Schnur, R.E.; Wick, P.A.; Louis, A.

    1994-09-01

    MLS and FDHG syndromes have overlapping phenotypes, including linear skin defects or erosions that heal in cribiform patterns of atrophy and pigmentary change and asymmetric ocular defects. It has been postulated that MLS and FDHG phenotypes reflect changes in the same gene(s) as well as variable X-inactivation patterns. In order to explore this, we studied one new MLS and 2 FDHG patients at clinical, cytogenetic, and molecular levels. Phenotype comparison: We observed a greater variety and wider distribution of cutaneous lesions in FDHG. Only the MLS patient had microphthalmia and sclerocornea with other ocular changes. Skeletal lesions were seen in only one FDHG patient who also had additional problems. Cytogenetics: The MLS patient demonstrated a 46,XX,del(X)(p22) karyotype. We excluded a cryptic Y-translocation by FISH using a Y-chromosome paint. Both FDHG patients had 46,XX karyotypes. Molecular studies: For deletion analysis, somatic cell hybrids containing separated X homologues were made from EBV-transformed LBL lines of all 3 patients. Of 20 hybrids obtained from the MLS patient, only one contained the deleted X, but we recognize that a culture artifact may have occurred in LBL cells prior to fusion. There was also a suggestion of partial skewing of X-homologue representation in FDHG hybrids. The breakpoint for the MLS deletion, which arose on the paternally-derived homologue (by RFLPs), was between DXS16 and AMG; DXS70 and DXS85 were also deleted. This is consistent with reported breakpoints in other MLS patients. Neither FDHG patient was deleted at any of these loci. Our study provides a basis for additional testing in FDHG patients via somatic cell hybrids with new markers and candidate genes from the MLS critical region to confirm or negate the proposed mapping of FDHG to Xp22.3.

  5. 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.

  6. Achieving progress through clinical governance? A national study of health care managers' perceptions in the NHS in England.

    PubMed

    Freeman, T; Walshe, K

    2004-10-01

    A national cross sectional study was undertaken to explore the perceptions concerning the importance of, and progress in, aspects of clinical governance among board level and directorate managers in English acute, ambulance, and mental health/learning disabilities (MH/LD) trusts. A stratified sample of acute, ambulance, and mental health/learning disabilities trusts in England (n = 100), from each of which up to 10 board level and 10 directorate level managers were randomly sampled. Fieldwork was undertaken between April and July 2002 using the Organisational Progress in Clinical Governance (OPCG) schedule to explore managers' perceptions of the importance of, and organisational achievement in, 54 clinical governance competency items in five aggregated domains: improving quality; managing risks; improving staff performance; corporate accountability; and leadership and collaboration. The difference between ratings of importance and achievement was termed a shortfall. Of 1916 individuals surveyed, 1177 (61.4%) responded. The competency items considered most important and recording highest perceived achievement related to corporate accountability structures and clinical risks. The highest shortfalls between perceived importance and perceived achievement were reported in joint working across local health communities, feedback of performance data, and user involvement. When aggregated into domains, greatest achievement was perceived in the assurance related areas of corporate accountability and risk management, with considerably less perceived achievement and consequently higher shortfalls in quality improvement and leadership and collaboration. Directorate level managers' perceptions of achievement were found to be significantly lower than those of their board level colleagues on all domains other than improving performance. No differences were found in perceptions of achievement between different types of trusts, or between trusts at different stages in the Commission

  7. Achieving progress through clinical governance? A national study of health care managers' perceptions in the NHS in England

    PubMed Central

    Freeman, T; Walshe, K

    2004-01-01

    Background: A national cross sectional study was undertaken to explore the perceptions concerning the importance of, and progress in, aspects of clinical governance among board level and directorate managers in English acute, ambulance, and mental health/learning disabilities (MH/LD) trusts. Participants: A stratified sample of acute, ambulance, and mental health/learning disabilities trusts in England (n = 100), from each of which up to 10 board level and 10 directorate level managers were randomly sampled. Methods: Fieldwork was undertaken between April and July 2002 using the Organisational Progress in Clinical Governance (OPCG) schedule to explore managers' perceptions of the importance of, and organisational achievement in, 54 clinical governance competency items in five aggregated domains: improving quality; managing risks; improving staff performance; corporate accountability; and leadership and collaboration. The difference between ratings of importance and achievement was termed a shortfall. Results: Of 1916 individuals surveyed, 1177 (61.4%) responded. The competency items considered most important and recording highest perceived achievement related to corporate accountability structures and clinical risks. The highest shortfalls between perceived importance and perceived achievement were reported in joint working across local health communities, feedback of performance data, and user involvement. When aggregated into domains, greatest achievement was perceived in the assurance related areas of corporate accountability and risk management, with considerably less perceived achievement and consequently higher shortfalls in quality improvement and leadership and collaboration. Directorate level managers' perceptions of achievement were found to be significantly lower than those of their board level colleagues on all domains other than improving performance. No differences were found in perceptions of achievement between different types of trusts, or between

  8. Clinical progression of moderate-to-severe Alzheimer's disease and caregiver burden: a 12-month multicenter prospective observational study.

    PubMed

    Agüera-Ortiz, Luis; Frank-García, Ana; Gil, Pedro; Moreno, Alfonso

    2010-12-01

    Prospective studies on the clinical progression of Alzheimer's disease (AD) and its relationship to caregiver burden are needed to improve illness management and use of resources. This national, multicenter, observational study evaluated 1235 moderate to severe AD patients under routine care in Spain. Baseline cross-sectional sociodemographic and clinical data, and changes from baseline to month 12 of various neuropsychological tests and clinical ratings, including Blessed Dementia Scale, Mini-mental State Examination (MMSE), Hughes Clinical Dementia Rating sum-of-boxes (CDR-SB), Clinical Global Impression of Change (CGIC) and Zarit Caregiver Burden scales, were recorded and comprehensively analyzed. Baseline data were in accordance with characteristics consistently reported to influence AD risk regarding anthropometrics, sociocultural features and comorbidities. Significant progressive functional impairments (i.e. in routine activities and essential daily tasks) and cognitive (i.e. MMSE and CDR-SB) impairments were found at month 12. However, patients' behavior and caregivers' burden improved slightly, but significantly, corroborating the major influence of behavioral symptoms on caregivers' distress. Caregivers showed significantly lower burden with patients with higher levels of education and, to a lesser extent, when patients received AD-specific medication. Physicians accurately detected AD clinical evolution as their CGIC ratings significantly correlated with all tests. These findings reinforce previous AD knowledge and add data on the clinical course of advanced stages of AD. Caregiver burden depended more on patients' behavioral alterations than on their functional or cognitive declines; and it was diminished by their patients having higher levels of education and being treated with AD-specific medications. Research into unexplored factors that might reduce caregiver burden, ultimately benefiting both patients and caregivers, is encouraged.

  9. 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. © 2017 British Association of Dermatologists.

  10. 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,…

  11. 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,…

  12. 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

  13. [A clinical and epidemiological description of a series of patients diagnosed as suffering from progressive supranuclear palsy].

    PubMed

    Alvarez-González, E; Maragoto-Rizo, C; Arteche-Prior, M; Pérez-Parra, S; Carballo, M; Alvarez-González, L

    Progressive supranuclear palsy is a disease that normally presents only sporadically in adults and courses in a progressive, chronic manner. It is characterised by the presence of supranuclear ophthalmoplegia, postural instability, a Parkinsonian syndrome, pseudobulbar affect, cervical dystonia and cognitive impairment. We conducted a descriptive study of clinical and epidemiological features in a series of 18 patients who satisfied the mandatory NINDS-SPSP clinical eligibility criteria for the likely diagnosis of progressive supranuclear palsy, using the scale developed by Golbe et al. The mean age of onset of the disease was 58.6 +/- 8.2 years, 55.5% of the patients were males, the average history of the disease at the time of diagnosis was 4.39 +/- 2.3 years, and there was a diagnostic subregister in the first 4 years of the disease. Gait disorders, falls and slowness were the most frequently observed presenting forms of the disease. During their first four years with the disease, 75% of the patients were totally independent when it came to carrying out activities of daily living, whereas after the fourth year there was a predominance of the need for aid and absolute dependence. Dysphagia was more frequent in the later stages of the disease. Ocular motility disorders and impaired cognitive functioning were obvious in the initial stages of the disease, and there was a strong correlation between the length of time the disease had been coursing and the severity of the ocular and cognitive disorders.

  14. 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

  15. 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

  16. Annual Progress Report FY 93 (Walter Reed Army Medical Center, Department of Clinical Investigation). Clinical Investigation Program. Volume 2

    DTIC Science & Technology

    1993-01-01

    interest in patients with the antiphospholipid syndrome continues to arow, and appropriate lab testing has not yet been well defined. There have been no...patients with the Antiphospholipid syndrome and determining how well the coagulation assays and solid phase assays for the detection of... Antiphospholipid Antibody Syndrome (tPAS): Role of Antiphospholipid Antibodies (APLA) and B2-glycoprotein (gp)-I in the Clinical Manifestations of APAS KEYWORDS

  17. 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)

  18. Progress in the clinical development and utilization of vision prostheses: an update.

    PubMed

    Brandli, Alice; Luu, Chi D; Guymer, Robyn H; Ayton, Lauren N

    2016-01-01

    Vision prostheses, or "bionic eyes", are implantable medical bionic devices with the potential to restore rudimentary sight to people with profound vision loss or blindness. In the past two decades, this field has rapidly progressed, and there are now two commercially available retinal prostheses in the US and Europe, and a number of next-generation devices in development. This review provides an update on the development of these devices and a discussion on the future directions for the field.

  19. Department of Clinical Investigation Annual Research Progress Report, Fiscal Year 1993. Volume 2

    DTIC Science & Technology

    1993-10-01

    CTG). (0) SWOG 9217 Chemoprevention of Prostate Cancer with Finasteride , 553 (Proscar) Phase III Intergroup. (0) xliii Project page Number SWOG 9218...data. 552 Detail Summary Sheet Date: 15 Dec 93 Protocol Number: SWOG 9217 Status: Ongoing Title: "Chemoprevention of Prostate Cancer with Finasteride ...treated with finasteride and a group treated with placebo for seven years. Technical Approach: As outlined in the protocol schema Progress: This is a

  20. 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

  1. 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.

  2. 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.

  3. 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

  4. 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

  5. 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

  6. 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.

  7. Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria.

    PubMed

    Höglinger, Günter U; Respondek, Gesine; Stamelou, Maria; Kurz, Carolin; Josephs, Keith A; Lang, Anthony E; Mollenhauer, Brit; Müller, Ulrich; Nilsson, Christer; Whitwell, Jennifer L; Arzberger, Thomas; Englund, Elisabet; Gelpi, Ellen; Giese, Armin; Irwin, David J; Meissner, Wassilios G; Pantelyat, Alexander; Rajput, Alex; van Swieten, John C; Troakes, Claire; Antonini, Angelo; Bhatia, Kailash P; Bordelon, Yvette; Compta, Yaroslau; Corvol, Jean-Christophe; Colosimo, Carlo; Dickson, Dennis W; Dodel, Richard; Ferguson, Leslie; Grossman, Murray; Kassubek, Jan; Krismer, Florian; Levin, Johannes; Lorenzl, Stefan; Morris, Huw R; Nestor, Peter; Oertel, Wolfgang H; Poewe, Werner; Rabinovici, Gil; Rowe, James B; Schellenberg, Gerard D; Seppi, Klaus; van Eimeren, Thilo; Wenning, Gregor K; Boxer, Adam L; Golbe, Lawrence I; Litvan, Irene

    2017-06-01

    PSP is a neuropathologically defined disease entity. Clinical diagnostic criteria, published in 1996 by the National Institute of Neurological Disorders and Stroke/Society for PSP, have excellent specificity, but their sensitivity is limited for variant PSP syndromes with presentations other than Richardson's syndrome. We aimed to provide an evidence- and consensus-based revision of the clinical diagnostic criteria for PSP. We searched the PubMed, Cochrane, Medline, and PSYCInfo databases for articles published in English since 1996, using postmortem diagnosis or highly specific clinical criteria as the diagnostic standard. Second, we generated retrospective standardized clinical data from patients with autopsy-confirmed PSP and control diseases. On this basis, diagnostic criteria were drafted, optimized in two modified Delphi evaluations, submitted to structured discussions with consensus procedures during a 2-day meeting, and refined in three further Delphi rounds. Defined clinical, imaging, laboratory, and genetic findings serve as mandatory basic features, mandatory exclusion criteria, or context-dependent exclusion criteria. We identified four functional domains (ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction) as clinical predictors of PSP. Within each of these domains, we propose three clinical features that contribute different levels of diagnostic certainty. Specific combinations of these features define the diagnostic criteria, stratified by three degrees of diagnostic certainty (probable PSP, possible PSP, and suggestive of PSP). Clinical clues and imaging findings represent supportive features. Here, we present new criteria aimed to optimize early, sensitive, and specific clinical diagnosis of PSP on the basis of currently available evidence. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

  8. 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.

  9. 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.

  10. Clinical symptoms of right ventricular failure in experimental chronic pressure load are associated with progressive diastolic dysfunction.

    PubMed

    Borgdorff, Marinus A J; Koop, Anne Marie C; Bloks, Vincent W; Dickinson, Michael G; Steendijk, Paul; Sillje, Herman H W; van Wiechen, Maarten P H; Berger, Rolf M F; Bartelds, Beatrijs

    2015-02-01

    Right ventricular failure (RVF) due to pressure load is a major cause of death in congenital heart diseases and pulmonary hypertension. The mechanisms of RVF are unknown. We used an experimental approach based upon clinical signs of RVF to delineate functional and biological processes associated with RVF. Wistar rats were subjected to a pulmonary artery banding (PAB n=12) or sham surgery (CON, n=7). After 52±5days, 5/12 PAB rats developed clinical symptoms of RVF (inactivity, ruffled fur, dyspnea, ascites) necessitating termination (PAB+CF). We compared these to PAB rats with RVF without clinical symptoms (PAB-). PAB resulted in reduced cardiac output, RV stroke volume, TAPSE, and increased end diastolic pressure (all p<0.05 vs. CON) in all rats, but PAB+CF rats were significantly more affected than PAB-, despite similar pressure load (p=ns). Pressure-volume analysis showed enhanced contractility (end systolic elastance) in PAB- and PAB+CF, but diastolic function (end diastolic elastance, end diastolic pressure) deteriorated especially in PAB+CF. In PAB+CF capillary density was lower than in PAB-. Gene-array analysis revealed downregulation of both fatty acid oxidation and carbohydrate metabolism in PAB+CF. Chronic PAB led to different degrees of RVF, with half of the rats developing severe clinical symptoms of RVF, associated with progressive deterioration of diastolic function, hypoxia-prone myocardium, increased response to oxidative stress and suppressed myocardial metabolism. This model represents clinical RVF and allows for unraveling of mechanisms involved in the progression from RV adaptation to RV failure and the effect of intervention on these mechanisms. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. 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

  12. 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

  13. Progressive Dosing of Observed Real-Life Clinical Exposure for Nurse Practitioner Training.

    PubMed

    Reyes, Imelda; Close, Sharron; Rodriguez, Jeannie; Evans, Dian

    2017-09-01

    In most advanced practice programs, preceptors are relied on for providing student clinical experiences. Preceptor feedback often indicates that many students show competency deficits in well child care, case presentation, and clinical skills. An innovative preclinical experience was developed using nonscripted pediatric patient and family volunteers from the local community. During the three 4-hour experiences, students obtained a health history, performed a full physical examination, and presented their findings using a standardized case presentation format. Student anxiety and levels of confidence were assessed before and after each experience. Student anxiety decreased, and self-confidence and clinical skill competencies improved. Students who participated in the experiences with faculty demonstrated improved entry-level competencies, compared with previous cohorts who had not received the intervention. Preclinical experiences using pediatric patients improved advanced practice nursing student confidence and competencies and reduced anxiety, improving overall entry-level clinical performance. [J Nurs Educ. 2017;56(9):552-555.]. Copyright 2017, SLACK Incorporated.

  14. 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.

  15. The Integration of Clinical Care and Laboratory Research. A Model for Medical Progress.

    DTIC Science & Technology

    1995-05-01

    identified the causes of vari- catch the interest of the membership. To help in that ous diseases (infection and search, I have reviewed the...clinical problems and causes of co- ment of war wounds, was moved to San Antonio, Tex, morbidity. Even though the occurrence of invasive burn- and...conducting in other organs remains the most frequent cause of death both clinical and laboratory studies of burn injury. That in burn patients, and the

  16. Clinical progression of severely immunosuppressed HIV-infected patients depends on virological and immunological improvement irrespective of baseline status.

    PubMed

    Ferrer, Elena; Curto, Jordi; Esteve, Anna; Miro, Jose M; Tural, Cristina; Murillas, Javier; Segura, Ferran; Barrufet, Pilar; Casabona, Jordi; Podzamczer, Daniel

    2015-12-01

    The aim of this study was to analyse factors associated with progression to AIDS/death in severely immunosuppressed HIV-infected patients receiving ART. This study included naive patients from the PISCIS Cohort with CD4 <200 cells/mm(3) at enrolment and who initiated ART consisting of two nucleoside analogues plus either a PI or an NNRTI between 1998 and 2011. The PISCIS Cohort is a multicentre, observational study of HIV-infected individuals aged >18 years followed at 14 participating hospitals in Catalonia and the Balearic Islands (Spain). Clinical and laboratory parameters were assessed every 3-4 months during follow-up. Cox regression models were used to assess the effect of CD4 and viral load on the risk of progression to AIDS/death, adjusting for baseline variables and confounders. 2295 patients were included and, after 5 years, 69.9% reached CD4 ≥200 cells/mm(3), 64.4% had an undetectable viral load and 482 (21%) progressed to AIDS/death. The lowest rate of disease progression was found in patients who reached both immunological and viral responses during follow-up, regardless of their baseline situation (1.9% in baseline CD4 >100 cells/mm(3) and viral load <5 log copies/mL; 2.3% in baseline CD4 ≤100 cells/mm(3) and/or viral load >5 log copies/mL). Achieving a CD4 count ≥200 cells/mm(3) was the main predictor of decreased progression to AIDS/death. In those not reaching this CD4 threshold, virological response reduced disease progression by half. Even in the worse baseline scenario of CD4 ≤100 cells/mm(3) and high baseline viral loads, positive virological and immunological responses were associated with dramatic decreases in progression. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  17. 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

  18. Links among theory, research, and practice: cornerstones of clinical scientific progress.

    PubMed

    Jensen, P S

    1999-12-01

    Discusses how explicit links among clinical theory, research, and practice are necessary if a clinical discipline is to survive in the managed care marketplace of today. Robust links among theory, research, and practice enable the elaboration of a systematic body of clinical knowledge that is practical in its deployment, effective in its methods, and compelling in its rationale. Moreover, theoretical advances are increasingly necessary, in that they allow scientists to categorize and prioritize the growing amount of empirically derived information, determine how pieces of multilevel data fit together, identify knowledge gaps, and set priorities for future studies. As shown by some of the articles in this special section, evolving theories of behavior have several characteristics in common; namely that they are developmental, transactional, contextual, adaptational, multilevel, and multidetermined. Concerns may be raised, however, as to whether current research methods are fully adequate to test these newer, more complex, multilevel theories or the clinical phenomena they seek to characterize. To address these difficulties, as well as to increase the pace of scientific advances that may result from propitious links among theory, research, and practice, I offer several recommendations to clinical psychology in general and to clinical child psychological research in particular.

  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. 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

  1. CYP24A1 Expression Inversely Correlates with Melanoma Progression: Clinic-Pathological Studies

    PubMed Central

    Brożyna, Anna A.; Jochymski, Cezary; Janjetovic, Zorica; Jóźwicki, Wojciech; Tuckey, Robert C.; Slominski, Andrzej T.

    2014-01-01

    The major role of 24-hydroxylase (CYP24A1) is to maintain 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) homeostasis. Recently, it has been discovered that CYP24A1 also catalyses the hydroxylation of 20(OH)D3, producing dihydroxy-derivatives that show very effective antitumorigenic activities. Previously we showed a negative correlation of vitamin D receptor (VDR) and CYP27B1 expression with progression, aggressiveness and overall or disease-free survivals of skin melanomas. Therefore, we analyzed CYP24A1 expression in relation to clinicopathomorphological features of nevi, skin melanomas and metastases. In melanocytic tumors, the level of CYP24A1 was higher than in the normal epidermis. The statistically highest mean CYP24A1 level was found in nevi and early stage melanomas. With melanoma progression, CYP24A1 levels decreased and in advanced stages were comparable to the normal epidermis and metastases. Furthermore, the CYP24A1 expression positively correlated with VDR and CYP27B1, and negatively correlated with mitotic activity. Lower CYP24A1 levels correlated with the presence of ulceration, necrosis, nodular type and amelanotic phenotypes. Moreover, a lack of detectable CYP24A1 expression was related to shorter overall and disease-free survival. In conclusion, the local vitamin D endocrine system affects melanoma behavior and an elevated level of CYP24A1 appears to have an important impact on the formation of melanocytic nevi and melanomagenesis, or progression, at early stages of tumor development. PMID:25334067

  2. 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.

  3. Progress in the clinical development and utilization of vision prostheses: an update

    PubMed Central

    Brandli, Alice; Luu, Chi D; Guymer, Robyn H; Ayton, Lauren N

    2016-01-01

    Vision prostheses, or “bionic eyes”, are implantable medical bionic devices with the potential to restore rudimentary sight to people with profound vision loss or blindness. In the past two decades, this field has rapidly progressed, and there are now two commercially available retinal prostheses in the US and Europe, and a number of next-generation devices in development. This review provides an update on the development of these devices and a discussion on the future directions for the field. PMID:28539798

  4. Disseminated superficial actinic porokeratosis co-existing with linear and verrucous porokeratosis in an elderly woman: Update on the genetics and clinical expression of porokeratosis.

    PubMed

    Murase, Jenny; Gilliam, Anita C

    2010-11-01

    Disseminated superficial actinic porokeratosis (DSAP) is the most common form of porokeratosis, occurring mainly in women on the extremities as atrophic patches rimmed by a ridge of keratin (the cornoid lamella that is diagnostic of porokeratosis histologically and is thought to be a clonal keratinocyte proliferation). DSAP can sometimes coexist with other forms of porokeratosis (Mibelli, linear porokeratosis, porokeratosis palmaris et plantaris disseminata, and punctate porokeratosis). Rare variants of linear porokeratosis are the hyperkeratotic and verrucous forms which usually occur on the buttocks or perianal area. We present clinical and histopathologic findings from biopsy specimens of a 73-year-old woman with DSAP on the distal extremities, linear/segmental porokeratosis on thighs, and verrucous porokeratosis on buttocks and mons pubis. The verrucous lesions had been present for 30+ years, the DSAP and linear lesions for 10+ years. Biopsy specimens from distal extremity showed classic features of DSAP with infrequent cornoid lamellae separated by atrophic epidermis. Biopsy specimens from the mons pubis and thigh showed epidermal hyperplasia with multiple, almost contiguous, broad cornoid lamellae. Coexisting variants of porokeratosis are rare and our conclusions are drawn from a few cases in the literature. The rare variants of porokeratosis are of interest because the clinical morphology correlates with the histopathology. Copyright © 2009 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

  5. 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.

  6. Relationship between intrapartum transperineal ultrasound measurement of angle of progression and head-perineum distance with correlation to conventional clinical parameters of labor progress and time to delivery.

    PubMed

    Chan, Ying Tze Viola; Ng, Vivian Kwun Sin; Yung, Wai Kuen; Lo, Tsz Kin; Leung, Wing Cheong; Lau, Wai Lam

    2015-08-01

    To assess whether angle of progression (AOP) and head-perineum distance (HPD) measured by intrapartum transperineal ultrasound (ITU) correlate with clinical fetal head station (station); and whether AOP versus HPD varies during uterine contraction and relaxation. In a subset of primiparous women, whether these ITU parameters correlate with time to normal spontaneous delivery (TD). We evaluated prospectively 100 primiparous and multiparous women at term in active labor. Transabdominal and transperineal ultrasound (sagittal and transverse plane) were used to measure fetal head position and ITU parameters, respectively. Digitally palpated station and cervical dilatation were also noted. The results were compared using regression and correlation coefficients. Station was moderately correlated with AOP (r = 0.579) and HPD (r = -0.497). AOP was highly correlated with HPD during uterine contraction (r = -0.703) and relaxation (r = -0.647). In the subgroup of primiparous women, natural log of TD has the highest correlation with HPD and AOP during uterine contraction (r = 0.742), making prediction of TD similar to that of using cervical dilatation. ITU parameters were moderately correlated with station. There was constant high correlation between AOP and HPD. Prediction of TD in primiparous women using ITU parameters was similar to that of using cervical dilatation.

  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. Weight as predictors of clinical progression and treatment failure: results from the TREAT Asia Pediatric HIV Observational Database.

    PubMed

    Kariminia, Azar; Durier, Nicolas; Jourdain, Gonzague; Saghayam, Suneeta; Do, Chau V; Nguyen, Lam Van; Hansudewechakul, Rawiwan; Lumbiganon, Pagakrong; Chokephaibulkit, Kulkanya; Truong, Khanh Huu; Sirisanthana, Virat; Ung, Vibol; Vonthanak, Saphonn; Ananworanich, Jintanat; Nik Yusoff, Nik Khairulddin; Kurniati, Nia; Azahar Razali, Kamarul; Fong, Moy Siew; Nallusamy, Revathy; Wati, Dewi Kumara

    2014-09-01

    To evaluate the value of time-updated weight and height in predicting clinical progression, and immunological and virological failure in children receiving combination antiretroviral therapy (cART). We used Cox regression to analyze data of a cohort of Asian children. A total of 2608 children were included; median age at cART was 5.7 years. Time-updated weight for age z score < -3 was associated with mortality (P < 0.001) independent of CD4% and < -2 was associated with immunological failure (P ≤ 0.03) independent of age at cART. Weight monitoring provides useful data to inform clinical management of children on cART in resource-limited settings.

  9. Powder-in-bottle formulation of SU011248. Enabling rapid progression into human clinical trials.

    PubMed

    Sistla, Anand; Sunga, Alan; Phung, Kenneth; Koparkar, Arun; Shenoy, Narmada

    2004-01-01

    SU011248 is an oral, multitargeted receptor tyrosine kinase inhibitor (anti PDGFR, VEGFR, Kit, and Flt3) for the treatment of solid tumors. The powder-in-bottle (PIB) approach was used to accelerate development and introduction into Phase I clinical trials. This approach consists of extemporaneously compounding the active pharmaceutical ingredient (API) into a solution or a suspension in the clinic prior to oral administration. The development consisted of physico-chemical assessment, constitution fluid selection, weighing and dosing validation, and stability evaluation of API, before and after constitution with the fluid. Of the oral liquids evaluated, apple juice was selected as the constitution fluid. Particle size of SU011248 had an impact on the weighing validation and the dissolution time. Particle size specifications of breadth d90 < 180 microm and length d90 < 750 microm were set to achieve pharmaceutical acceptability. Dosing validation studies showed complete recovery of SU011248 from the bottle over a dose range of 10 to 2200 mg. SU011248 is stable as the solid API. Following constitution with apple juice, the product is stable through the predicted duration of compounding and dosing at the clinical site. This approach provided a high degree of dosing flexibility during the initial phase of clinical trials. Additionally, the PIB approach reduced the time and API required for clinical development and supplies to < 2 months and < 100 gm, respectively.

  10. Prevalence of Prostate Cancer Clinical States and Mortality in the United States: Estimates Using a Dynamic Progression Model

    PubMed Central

    Scher, Howard I.; Solo, Kirk; Valant, Jason; Todd, Mary B.; Mehra, Maneesha

    2015-01-01

    Objective To identify patient populations most in need of treatment across the prostate cancer disease continuum, we developed a novel dynamic transition model based on risk of disease progression and mortality. Design and Outcome Measurements We modeled the flow of patient populations through eight prostate cancer clinical states (PCCS) that are characterized by the status of the primary tumor, presence of metastases, prior and current treatment, and testosterone levels. Simulations used published US incidence rates for each year from 1990. Progression and mortality rates were derived from published clinical trials, meta-analyses, and observational studies. Model outputs included the incidence, prevalence, and mortality for each PCCS. The impact of novel treatments was modeled in three distinct scenarios: metastatic castration-resistant prostate cancer (mCRPC), non-metastatic CRPC (nmCRPC), or both. Results and Limitations The model estimated the prevalence of prostate cancer as 2,219,280 in the US in 2009 and 3,072,480 in 2020, and incidence of mCRPC as 36,100 and 42,970, respectively. All-cause mortality in prostate cancer was estimated at 168,290 in 2009 and 219,360 in 2020, with 20.5% and 19.5% of these deaths, respectively, occurring in men with mCRPC. The majority (86%) of incidence flow into mCRPC states was from the nmCRPC clinical state. In the scenario with novel interventions for nmCRPC states, the progression to mCRPC is reduced, thus decreasing mCRPC incidence by 12% in 2020, with a sustained decline in mCRPC mortality. A limitation of the model is that it does not estimate prostate cancer—specific mortality. Conclusion The model informs clinical trial design for prostate cancer by quantifying outcomes in PCCS, and demonstrates the impact of an effective therapy applied in an earlier clinical state of nmCRPC on the incidence of mCRPC morbidity and subsequent mortality. PMID:26460686

  11. 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.

  12. Progressive Tinnitus Management Level 3 Skills Education: A 5-Year Clinical Retrospective.

    PubMed

    Edmonds, Catherine M; Ribbe, Cheri; Thielman, Emily J; Henry, James A

    2017-09-18

    The primary purpose of this study was to determine whether progressive tinnitus management Level 3 skills education workshops conducted at the Bay Pines and Boston Veterans Affairs hospitals result in consistent use of the presented tinnitus management strategies by patients 1-5 years after completing the workshops. In fiscal year (FY) 2015, the tinnitus workshop follow-up form was mailed to all veterans who completed the Level 3 workshops between FY 2010 and FY 2014. Data were compiled to determine which, if any, of the skills taught in the workshops were being used 1-5 years after completion of the workshops and the impact on quality-of-life indicators. All self-management skills were being utilized up to 5 years postcompletion; therapeutic sound was utilized the most. The majority of patients reported an improved ability to manage reactions to tinnitus and improved quality-of-life indicators. Over 90% of patients from both sites recommended the program to others with tinnitus. The self-management skills taught in the progressive tinnitus management Level 3 workshops are sustained over time even when limited resources prevent the full complement of workshops or the involvement of mental health services. The workshops can also be successfully implemented through remote delivery via videoconferencing (telehealth). https://doi.org/10.23641/asha.5370883.

  13. [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.

  14. Translating metastasis-related biomarkers to the clinic--progress and pitfalls.

    PubMed

    Bidard, François-Clément; Pierga, Jean-Yves; Soria, Jean-Charles; Thiery, Jean Paul

    2013-03-01

    In the context of metastatic disease, preclinical models have been used primarily to decipher different steps of the metastatic cascade. Numerous molecular processes operate in these model systems, but none of these has been successfully translated to the clinic. We discuss some of the successes and failures of preclinical models in metastasis research and suggest some of the clues for more clinically relevant research. These potential avenues of research include: the use of adequate statistical methods and well-annotated cohorts in biomarker discovery; an objective assessment of the level of evidence provided by each biomarker; the development of robust molecular or cellular surrogates of metastasis in patients; and original designs for clinical trials.

  15. Low levels of Stat5a protein in breast cancer are associated with tumor progression and unfavorable clinical outcomes

    PubMed Central

    2012-01-01

    Introduction Signal transducer and activator of transcripton-5a (Stat5a) and its close homologue, Stat5b, mediate key physiological effects of prolactin and growth hormone in mammary glands. In breast cancer, loss of nuclear localized and tyrosine phosphorylated Stat5a/b is associated with poor prognosis and increased risk of antiestrogen therapy failure. Here we quantify for the first time levels of Stat5a and Stat5b over breast cancer progression, and explore their potential association with clinical outcome. Methods Stat5a and Stat5b protein levels were quantified in situ in breast-cancer progression material. Stat5a and Stat5b transcript levels in breast cancer were correlated with clinical outcome in 936 patients. Stat5a protein was further quantified in four archival cohorts totaling 686 patients with clinical outcome data by using multivariate models. Results Protein levels of Stat5a but not Stat5b were reduced in primary breast cancer and lymph node metastases compared with normal epithelia. Low tumor levels of Stat5a but not Stat5b mRNA were associated with poor prognosis. Experimentally, only limited overlap between Stat5a- and Stat5b-modulated genes was found. In two cohorts of therapy-naïve, node-negative breast cancer patients, low nuclear Stat5a protein levels were an independent marker of poor prognosis. Multivariate analysis of two cohorts treated with antiestrogen monotherapy revealed that low nuclear Stat5a levels were associated with a more than fourfold risk of unfavorable outcome. Conclusions Loss of Stat5a represents a new independent marker of poor prognosis in node-negative breast cancer and may be a predictor of response to antiestrogen therapy if validated in randomized clinical trials. PMID:23036105

  16. Effect of Selumetinib versus Chemotherapy on Progression-Free Survival in Uveal Melanoma: A Randomized Clinical Trial

    PubMed Central

    Carvajal, Richard D.; Sosman, Jeffrey A.; Quevedo, Jorge Fernando; Milhem, Mohammed M.; Joshua, Anthony Michael; Kudchadkar, Ragini R.; Linette, Gerald P.; Gajewski, Thomas F.; Lutzky, Jose; Lawson, David H.; Lao, Christopher D.; Flynn, Patrick J.; Albertini, Mark R.; Sato, Takami; Lewis, Karl; Doyle, Austin; Ancell, Kristin; Panageas, Katherine S.; Bluth, Mark; Hedvat, Cyrus; Erinjeri, Joseph; Ambrosini, Grazia; Marr, Brian; Abramson, David; Dickson, Mark Andrew; Wolchok, Jedd D.; Chapman, Paul B.; Schwartz, Gary K.

    2014-01-01

    Importance Uveal melanoma is characterized by mutations in GNAQ and GNA11, resulting in MAPK pathway activation. Objective To assess the efficacy of selumetinib, a selective, non-ATP competitive inhibitor of MEK1 and MEK2, in uveal melanoma. Design Randomized open-label phase II clinical trial comparing selumetinib versus chemotherapy. Those receiving chemotherapy could receive selumetinib at the time of radiographic progression. Setting Fifteen academic oncology centers. Participants 120 patients with metastatic uveal melanoma. Interventions 101 patients were randomized on a 1:1 ratio to selumetinib 75 mg orally twice daily on a continual basis (n=50) or chemotherapy (temozolomide 150 mg/m2 orally daily for 5 of every 28 days or DTIC 1000 mg/m2 intravenously every 21 days; investigator choice; n=51) until disease progression, death, intolerable toxicity, or withdrawal of consent. Following primary outcome analysis, enrollment continued in a non-randomized fashion to the superior therapy. Main Outcomes Final analysis of progression-free survival, the primary endpoint, was assessed as of April 22, 2013. Additional endpoints, including overall survival, response rate, and safety/toxicity, were assessed as of December 31, 2013. Results Median progression-free survival for those randomized to chemotherapy and selumetinib was 7 (95% CI, 4.3 – 8.4; median treatment duration of 8 weeks (IQR, 4.3–16)) and 15.9 weeks (95% CI, 8.4 – 21.1; median treatment duration of 16.1 weeks (IQR, 8.1–25.3)), respectively (hazard ratio 0.46; 95% CI, 0.30 – 0.71; p < 0.001). Median overall survival was 9.1 (95% CI, 6.1 – 11.1) and 11.8 months (95% CI, 9.8 – 15.7) for those randomized to chemotherapy and selumetinib, respectively (hazard ratio 0.66; 95% CI, 0.41–1.06; p=0.09). No objective responses were observed with chemotherapy. 49% of patients treated with selumetinib achieved tumor regression, with 14% achieving an objective radiographic response to therapy. Treatment

  17. 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.

  18. 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.

  19. 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…

  20. 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.

  1. 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…

  2. [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.

  3. Recent progress in the design and clinical development of electronic-nose technologies

    Treesearch

    Dan Wilson

    2016-01-01

    Electronic-nose (e-nose) devices are instruments designed to detect and discriminate between precise complex gaseous mixtures of volatile organic compounds derived from specific organic sources, such as clinical test samples from patients, based on electronic aroma signature patterns (distinct digital sensor responses) resulting from the combined outputs of a...

  4. 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

  5. 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.

  6. Clinical factors, anticitrullinated peptide antibodies and MRI-detected subclinical inflammation in relation to progression from clinically suspect arthralgia to arthritis.

    PubMed

    van Steenbergen, Hanna W; Mangnus, Lukas; Reijnierse, Monique; Huizinga, Tom W J; van der Helm-van Mil, Annette H M

    2016-10-01

    Patients with clinically suspect arthralgia (CSA) have, according to their rheumatologists, an increased risk of rheumatoid arthritis (RA), but their actual outcome is unexplored. This longitudinal study investigated (1) progression from CSA to clinically detectable arthritis and (2) associations of clinical factors, serological factors (among which are anticitrullinated peptide antibodies (ACPAs)) and MRI-detected subclinical inflammation with arthritis development. 150 patients with CSA were followed for ≥6 months. At baseline, clinical and serological data were collected and unilateral 1.5 T-MRI of metacarpophalangeal (MCP), wrist and metatarsophalangeal (MTP) joints was made. MRI scoring was done according to the RA MRI scoring system. Subclinical MRI inflammation was defined based on MRI results of 193 symptom-free persons. During follow-up (median=75 weeks, IQR=41-106 weeks), 30 patients developed clinical arthritis; 87% did so <20 weeks after inclusion. In multivariable analyses, age, localisation of initial symptoms in small and large joints (compared with small joints only), C-reactive protein level, ACPA-positivity and subclinical MRI inflammation significantly associated with arthritis development; ACPA and MRI inflammation were most strongly associated (HR (95% CI) respectively, 6.43 (2.57 to 16.05) and 5.07 (1.77 to 14.50)). After 1-year follow-up, 31% of the patients with MRI inflammation and 71% of the ACPA-positive patients with MRI inflammation had progressed to arthritis. Forty-three per cent of the patients that developed arthritis within 1 year were ACPA-negative; 78% of them had subclinical MRI inflammation at baseline. When MRI inflammation was absent arthritis development was infrequent (6% in all patients with CSA and 3% in ACPA-negative patients with CSA). Subclinical MRI inflammation precedes clinical arthritis with a few months. Subclinical MRI inflammation is, independent of other factors such as ACPA, associated with

  7. Progressive retinal atrophy in the Polski Owczarek Nizinny dog: a clinical and genetic study.

    PubMed

    Svensson, Marika; Olsén, Lena; Winkler, Paige A; Petersen-Jones, Simon M; Bergström, Tomas; Garncarz, Yacek; Narfström, Kristina

    2016-05-01

    To describe ophthalmic, functional, structural, and genetical characteristics of progressive retinal atrophy (PRA) in the polski owczarek nizinny (PON) breed of dog. Client-owned PON dogs (n = 82) from Sweden. Routine examination for presumed inherited eye disease was performed in all dogs. Bilateral full-field electroretinography (ERG) was performed in 11 affected and 4 control dogs. Eyes from one affected dog were studied with light microscopy. DNA samples from 34 Swedish and 30 PON dogs collected by Michigan State University (MSU) were tested for the mutations causing the rcd4 and prcd forms of PRA. Sixteen of the eighty-two Swedish dogs were diagnosed with PRA. Slight vascular attenuation, first seen at 4.5 years of age, preceded changes in tapetal reflectivity. The initial ERG changes in affected dogs showed markedly diminished rod responses, while cone responses were barely affected. Eventually, cone responses were also reduced. Retinal morphology showed approximately a 50% reduction of photoreceptor nuclei in the outer nuclear layer. Fourteen of fifteen PRA-affected Swedish dogs and eighteen of twenty of the MSU PRA-affected dogs tested genetically were positive for the rcd4 mutation. All tested dogs were negative for the mutation causing prcd-PRA. PRA of PON dogs is a late-onset degenerative disease with slow progression. There is early loss of rod function, while the cone system deteriorates later. The rcd4 mutation in the C2ORF71 gene was associated with the majority of the PRA cases tested. The possibility of additional forms of PRA in the breed cannot be excluded. © 2015 American College of Veterinary Ophthalmologists.

  8. [Clinical features, risk factors and progresses on treatment of recurrent Vogt-Koyanagi-Harada disease].

    PubMed

    Jia, S S; Zhao, C; Liu, X S; Zhang, M F

    2017-04-11

    Vogt-Koyanagi-Harada disease(VKH) is a bilateral, granulomatous panuveitis associated with central nervous system, auditory, and integumentary manifestations. Clinically, VKH usually responds well to early aggressive glucocorticosteroid treatment and may be cured without any clinically significant sequelae. Some patients, however, may enter the chronic recurrent phase, which may result in marked loss of vision due to complications such as complicated cataract, secondary glaucoma and maculopathy. Recurrent VKH is mainly characterized by anterior uveitis associated with thickening of the choroid. Initial poor visual acuity, severe anterior chamber reaction, choroidal folds,rapid tapering of systemic corticosteroids or inadequate duration of treatment, and development of extraocular manifestations may be risk factors of disease recurrence. Prolonged glucocorticosteroid treatment has been suggested as effective strategy for recurrence of VKH. The positive effects of other immunosuppressive agents and biologic agents on treatment of chronic recurrent and refractory VKH have been gradually recognized by the uveitis community. (Chin J Ophthalmol, 2017, 53: 317-320).

  9. Department of Clinical Investigation Annual Research Progress Report: Fiscal Year 1990

    DTIC Science & Technology

    1990-09-30

    Survey of Army Meeting, US Retirees University of the Health Sciences 10/01/89 DEPARTMENT OF PEDIATRICS Atkinson AW Receptive Language Annual Meeting...81/12 Stages I and II Carcinoma of the Endometrium DOWNEY GO 0 GOG #40: A Clinical-Pathologic Study 270 #81/79 of Stages I and II Uterine Sarcomas...Recurrent Carcinoma of the Endometrium DOWNEY GO C GOG 83: A Clinico-Pathologic Study of 284 #85/90 Simultaneous Endometrial and Ovarian Carcinomas 39

  10. Department of Clinical Investigation Annual Research Progress Report, Fiscal Year 1989

    DTIC Science & Technology

    1989-09-30

    evalu- ated by history, physical examination and tympanogram. Physical examination will include ears , pneumatic otoscopy, nose , throat , palate, lymph...Carcinoma Syndromes Blakeslee DB Associated with Benign Head and Neck Tumors. H & N Jr for the Sci Special H & N 11(3): 247-51, 1989 Smith DB, Woody EA...treated in the usual manner. A peak flow study and a routine physical exam with special attention to nose , pharynx , and face for evidence of clinical

  11. Clinical Aspects of Melatonin Intervention in Alzheimer’s Disease Progression

    PubMed Central

    Cardinali, Daniel P; Furio, Analía M; Brusco, Luis I

    2010-01-01

    Melatonin secretion decreases in Alzheimer´s disease (AD) and this decrease has been postulated as responsible for the circadian disorganization, decrease in sleep efficiency and impaired cognitive function seen in those patients. Half of severely ill AD patients develop chronobiological day-night rhythm disturbances like an agitated behavior during the evening hours (so-called “sundowning”). Melatonin replacement has been shown effective to treat sundowning and other sleep wake disorders in AD patients. The antioxidant, mitochondrial and antiamyloidogenic effects of melatonin indicate its potentiality to interfere with the onset of the disease. This is of particularly importance in mild cognitive impairment (MCI), an etiologically heterogeneous syndrome that precedes dementia. The aim of this manuscript was to assess published evidence of the efficacy of melatonin to treat AD and MCI patients. PubMed was searched using Entrez for articles including clinical trials and published up to 15 January 2010. Search terms were “Alzheimer” and “melatonin”. Full publications were obtained and references were checked for additional material where appropriate. Only clinical studies with empirical treatment data were reviewed. The analysis of published evidence made it possible to postulate melatonin as a useful ad-on therapeutic tool in MCI. In the case of AD, larger randomized controlled trials are necessary to yield evidence of effectiveness (i.e. clinical and subjective relevance) before melatonin´s use can be advocated. PMID:21358972

  12. 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.

  13. 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.

  14. Defining the proteomic landscape of rheumatoid arthritis: progress and prospective clinical applications.

    PubMed

    Lourido, Lucía; Blanco, Francisco J; Ruiz-Romero, Cristina

    2017-05-01

    The heterogeneity of Rheumatoid Arthritis (RA) and the absence of clinical tests accurate enough to identify the early stages of this disease have hampered its management. Therefore, proteomics research is increasingly focused on the discovery of novel biological markers, which would not only be able make an early diagnosis, but also to gain insight into the different pathological mechanisms underlying the heterogeneity of RA and also to stratify patients, which is critical to enabling effective treatments. Areas covered: The proteomic approaches that have been utilised to provide knowledge about RA pathogenesis, and to identify biomarkers for RA diagnosis, prognosis, disease monitoring and prediction of response to therapy, are summarized. Expert commentary: Although each proteomic study is unique in its design, all of them have contributed to the understanding of RA pathogenesis and the discovery of promising biomarkers for patient stratification, which would improve clinical care of RA patients. Still, efforts need to be made to validate these findings and translate them into clinical practice.

  15. 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…

  16. 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…

  17. 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

  18. Interpretation and visualization of non-linear data fusion in kernel space: study on metabolomic characterization of progression of multiple sclerosis.

    PubMed

    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

    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. 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. 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 kernel space was achieved.

  19. 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

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

    PubMed

    Kim, Tae Gi; Kim, Ki Young; Han, Jung Bin; Jin, Kyung Hyun

    2016-10-01

    To evaluate the long-term clinical effectiveness and safety of corneal collagen cross-linking (CXL) in progressive keratoconus compared with untreated contralateral eyes. 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. 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). 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.

  1. The Economic and Clinical Impact of Sustained Use of a Progressive Mobility Program in a Neuro-ICU.

    PubMed

    Hester, Jeannette M; Guin, Peggy R; Danek, Gale D; Thomas, Jaime R; Titsworth, William L; Reed, Richard K; Vasilopoulos, Terrie; Fahy, Brenda G

    2017-06-01

    To investigate a progressive mobility program in a neurocritical care population with the hypothesis that the benefits and outcomes of the program (e.g., decreased length of stay) would have a significant positive economic impact. Retrospective analysis of economic and clinical outcome data before, immediately following, and 2 years after implementation of the Progressive Upright Mobility Protocol Plus program (UF Health Shands Hospital, Gainesville, FL) involving a series of planned movements in a sequential manner with an additional six levels of rehabilitation in the neuro-ICU at UF Health Shands Hospital. Thirty-bed neuro-ICU in an academic medical center. Adult neurologic and neurosurgical patients: 1,118 patients in the pre period, 731 patients in the post period, and 796 patients in the sustained period. Implementation of Progressive Upright Mobility Protocol Plus. ICU length of stay decreased from 6.5 to 5.8 days in the immediate post period and 5.9 days in the sustained period (F(2,2641) = 3.1; p = 0.045). Hospital length of stay was reduced from 11.3 ± 14.1 days to 8.6 ± 8.8 post days and 8.8 ± 9.3 days sustained (F(2,2641) = 13.0; p < 0.001). The impact of the study intervention on ICU length of stay (p = 0.031) and hospital length of stay (p < 0.001) remained after adjustment for age, sex, diagnoses, sedation, and ventilation. Hospital-acquired infections were reduced by 50%. Average total cost per patient after adjusting for inflation was significantly reduced by 16% (post period) and 11% (sustained period) when compared with preintervention (F(2,2641) = 3.1; p = 0.045). Overall, these differences translated to an approximately $12.0 million reduction in direct costs from February 2011 through the end of 2013. An ongoing progressive mobility program in the neurocritical care population has clinical and financial benefits associated with its implementation and should be considered.

  2. Risk Adjustment for Lumbar Dysfunction: Comparison of Linear Mixed Models With and Without Inclusion of Between-Clinic Variation as a Random Effect.

    PubMed

    Yen, Sheng-Che; Corkery, Marie B; Chui, Kevin K; Manjourides, Justin; Wang, Ying-Chih; Resnik, Linda J

    2015-12-01

    Valid comparison of patient outcomes of physical therapy care requires risk adjustment for patient characteristics using statistical models. Because patients are clustered within clinics, results of risk adjustment models are likely to be biased by random, unobserved between-clinic differences. Such bias could lead to inaccurate prediction and interpretation of outcomes. The purpose of this study was to determine if including between-clinic variation as a random effect would improve the performance of a risk adjustment model for patient outcomes following physical therapy for low back dysfunction. This was a secondary analysis of data from a longitudinal cohort of 147,623 patients with lumbar dysfunction receiving physical therapy in 1,470 clinics in 48 states of the United States. Three linear mixed models predicting patients' functional status (FS) at discharge, controlling for FS at intake, age, sex, number of comorbidities, surgical history, and health care payer, were developed. Models were: (1) a fixed-effect model, (2) a random-intercept model that allowed clinics to have different intercepts, and (3) a random-slope model that allowed different intercepts and slopes for each clinic. Goodness of fit, residual error, and coefficient estimates were compared across the models. The random-effect model fit the data better and explained an additional 11% to 12% of the between-patient differences compared with the fixed-effect model. Effects of payer, acuity, and number of comorbidities were confounded by random clinic effects. Models may not have included some variables associated with FS at discharge. The clinics studied may not be representative of all US physical therapy clinics. Risk adjustment models for functional outcome of patients with lumbar dysfunction that control for between-clinic variation performed better than a model that does not. © 2015 American Physical Therapy Association.

  3. [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.

  4. 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

  5. Assessment of audit methodologies for bias evaluation of tumor progression in oncology clinical trials.

    PubMed

    Zhang, Jenny J; Zhang, Lijun; Chen, Huanyu; Murgo, Anthony J; Dodd, Lori E; Pazdur, Richard; Sridhara, Rajeshwari

    2013-05-15

    As progression-free survival (PFS) has become increasingly used as the primary endpoint in oncology phase III trials, the U.S. Food and Drug Administration (FDA) has generally required a complete-case blinded independent central review (BICR) of PFS to assess and reduce potential bias in the investigator or local site evaluation. However, recent publications and FDA analyses have shown a high correlation between local site evaluation and BICR assessments of the PFS treatment effect, which questions whether complete-case BICR is necessary. One potential alternative is to use BICR as an audit tool to detect evaluation bias in the local site evaluation. In this article, the performance characteristics of two audit methods proposed in the literature are evaluated on 26 prospective, randomized phase III registration trials in nonhematologic malignancies. The results support that a BICR audit to assess potential bias in the local site evaluation is a feasible approach. However, implementation and logistical challenges need further consideration and discussion. ©2013 AACR

  6. Clinical outcomes of nitinol staples for preventing curve progression in idiopathic scoliosis.

    PubMed

    Lavelle, William F; Samdani, Amer F; Cahill, Patrick J; Betz, Randal R

    2011-01-01

    Although bracing for idiopathic scoliosis is moderately successful, its efficacy has been called into question and it carries associated psychosocial ramifications. In this study we report the background, rationale, indications, surgical techniques, and early results of vertebral body stapling (VBS) in patients with idiopathic scoliosis. We reviewed the literature on growth modulation of the growing spine and the concepts behind the use of VBS as a fusionless strategy. The indications are derived from retrospectively reviewed patients with idiopathic scoliosis treated with VBS followed for a minimum of 2 years. Indications for staple use included: (a) age <13 years in girls and 15 in boys, (b) Risser 0 or 1 and/or 1 year of growth remaining on wrist radiograph, (c) coronal curve <45 degrees with minimal rotation and flexible to <25 degrees on a side bending radiograph, and (d) sagittal thoracic curve <40 degrees. Thoracic curves measuring <35 degrees had a success rate of 77.7%. Curves which reached ≤ 20 degrees on first erect radiograph had a success rate of 85.7%. Thoracic curves greater than 35 degrees were not successful and require alternative treatments. Lumbar curves demonstrated a success rate of 86.7%. Some patients with idiopathic scoliosis with moderate curves (25 to 45 degrees) and high risk of progression can be safely treated with VBS as an alternative to bracing. Level III.

  7. 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

  8. Infectious Keratitis Progressing to Endophthalmitis: A 15-Year-Study of Microbiology, Associated Factors, and Clinical Outcomes

    PubMed Central

    Henry, Christopher R.; Flynn, Harry W.; Miller, Darlene; Forster, Richard K.; Alfonso, Eduardo C.

    2012-01-01

    Purpose To describe the incidence, microbiology, associated factors and clinical outcomes of patients with infectious keratitis progressing to endophthalmitis. Design Non-randomized, retrospective, consecutive case series. Participants All patients treated for culture-proven keratitis and endophthalmitis between January 1, 1995 and December 31, 2009 at the Bascom Palmer Eye Institute. Methods Ocular microbiology and medical records were reviewed on all patients with positive corneal and intraocular cultures over the period of the study. Univariate anaylsis was performed to obtain p values described in the study. Main Outcome Measures Microbial isolates, treatment strategies, visual acuity outcomes. Results A total of 9934 corneal cultures were performed for suspected infectious keratitis. Only 49 eyes (0.5%) progressed to culture-proven endophthalmitis. Fungi (n=26) were the most common responsible organism followed by gram positive bacteria (n=13) and gram negative bacteria (n=10). Topical steroid use (37/49[76%]) was the most common associated factor identified in the current study, followed by previous surgery (30/49[61%]), corneal perforation (17/49[35%]), dry eye (15/49[31%]), relative immune compromise (10/49[20%]), organic matter trauma (9/49[18%]) and contact lens wear (3/49[6%]). There were 27 patients in which a primary infectious keratitis developed into endophthalmitis, and 22 patients in which an infectious keratitis adjacent to a previous surgical wound progressed into endophthalmitis. Patients in the primary keratitis group were more likely to be male (22/27[81%] vs. 8/22[36%], p=0.001), have history of organic matter trauma (8/27[30%] vs. 1/22[5%]), p=0.030), and have fungal etiology (21/27[78%] vs. 5/22[23%], p<0.001). Patients in the surgical-wound-associated group were more likely to use topical steroids (20/22[91%] vs. 17/27[63%], p=0.024). Visual acuity of ≥20/50 was achieved in 7/49[14%] patients, but was <5/200 in 34/49[69%] patients at

  9. 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

  10. 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.

  11. 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

  12. Clinical and Immunological Markers of Dengue Progression in a Study Cohort from a Hyperendemic Area in Malaysia

    PubMed Central

    Rathakrishnan, Anusyah; Klekamp, Benjamin; Wang, Seok Mui; Komarasamy, Thamil Vaani; Natkunam, Santha Kumari; Sathar, Jameela; Azizan, Azliyati; Sanchez-Anguiano, Aurora; Manikam, Rishya; Sekaran, Shamala Devi

    2014-01-01

    Background With its elusive pathogenesis, dengue imposes serious healthcare, economic and social burden on endemic countries. This study describes the clinical and immunological parameters of a dengue cohort in a Malaysian city, the first according to the WHO 2009 dengue classification. Methodology and Findings This longitudinal descriptive study was conducted in two Malaysian hospitals where patients aged 14 and above with clinical symptoms suggestive of dengue were recruited with informed consent. Among the 504 participants, 9.3% were classified as non-dengue, 12.7% without warning signs, 77.0% with warning signs and 1.0% with severe dengue based on clinical diagnosis. Of these, 37% were misdiagnosed as non-dengue, highlighting the importance of both clinical diagnosis and laboratory findings. Thrombocytopenia, prolonged clotting time, liver enzymes, ALT and AST served as good markers for dengue progression but could not distinguish between patients with and without warning signs. HLA-A*24 and -B*57 were positively associated with Chinese and Indians patients with warning signs, respectively, whereas A*03 may be protective in the Malays. HLA-A*33 was also positively associated in patients with warning signs when compared to those without. Dengue NS1, NS2A, NS4A and NS4B were found to be important T cell epitopes; however with no apparent difference between with and without warning signs patients. Distinction between the 2 groups of patients was also not observed in any of the cytokines analyzed; nevertheless, 12 were significantly differentially expressed at the different phases of illness. Conclusion The new dengue classification system has allowed more specific detection of dengue patients, however, none of the clinical parameters allowed distinction of patients with and without warning signs. While the HLA-A*33 may be predictive marker for development of warning signs; larger studies will be needed to support this findings. PMID:24647042

  13. Clinical and immunological markers of dengue progression in a study cohort from a hyperendemic area in Malaysia.

    PubMed

    Rathakrishnan, Anusyah; Klekamp, Benjamin; Wang, Seok Mui; Komarasamy, Thamil Vaani; Natkunam, Santha Kumari; Sathar, Jameela; Azizan, Azliyati; Sanchez-Anguiano, Aurora; Manikam, Rishya; Sekaran, Shamala Devi

    2014-01-01

    With its elusive pathogenesis, dengue imposes serious healthcare, economic and social burden on endemic countries. This study describes the clinical and immunological parameters of a dengue cohort in a Malaysian city, the first according to the WHO 2009 dengue classification. This longitudinal descriptive study was conducted in two Malaysian hospitals where patients aged 14 and above with clinical symptoms suggestive of dengue were recruited with informed consent. Among the 504 participants, 9.3% were classified as non-dengue, 12.7% without warning signs, 77.0% with warning signs and 1.0% with severe dengue based on clinical diagnosis. Of these, 37% were misdiagnosed as non-dengue, highlighting the importance of both clinical diagnosis and laboratory findings. Thrombocytopenia, prolonged clotting time, liver enzymes, ALT and AST served as good markers for dengue progression but could not distinguish between patients with and without warning signs. HLA-A*24 and -B*57 were positively associated with Chinese and Indians patients with warning signs, respectively, whereas A*03 may be protective in the Malays. HLA-A*33 was also positively associated in patients with warning signs when compared to those without. Dengue NS1, NS2A, NS4A and NS4B were found to be important T cell epitopes; however with no apparent difference between with and without warning signs patients. Distinction between the 2 groups of patients was also not observed in any of the cytokines analyzed; nevertheless, 12 were significantly differentially expressed at the different phases of illness. The new dengue classification system has allowed more specific detection of dengue patients, however, none of the clinical parameters allowed distinction of patients with and without warning signs. While the HLA-A*33 may be predictive marker for development of warning signs; larger studies will be needed to support this findings.

  14. 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.

  15. 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.

  16. 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

  17. 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.

  18. Progress in Using Brain Morphometry as a Clinical Tool for Diagnosing Psychiatric Disorders

    PubMed Central

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

    2014-01-01

    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 individual accurately as having a specific psychiatric disorder. More accurate diagnoses could significantly reduce the emotional and financial burden of disease by aiding clinicians in implementing appropriate treatments earlier and in tailoring treatment to the individual needs. Several methods, especially those based on machine learning, have been proposed that use anatomical brain measures and gold-standard diagnoses of participants to learn decision rules that classify a person automatically as having one disorder rather than another. We review the general principles and procedures for machine learning, particularly as applied to diagnostic classification, and then review the procedures that have thus far attempted to diagnose psychiatric illnesses automatically using anatomical measures of the brain. We discuss the strengths and limitations of extant procedures and note that the sensitivity and specificity of these procedures in their most successful implementations have approximated 90%. Although these methods have not yet been applied within clinical settings, they provide strong evidence that individual patients can be diagnosed accurately using the spatial pattern of disturbances across the brain. PMID:22394424

  19. 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.

  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. 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.

  2. Early clinical and neuroradiological worsening after radiotherapy and concomitant temozolomide in patients with glioblastoma: tumour progression or radionecrosis?

    PubMed

    Peca, C; Pacelli, R; Elefante, A; Del Basso De Caro, M L; Vergara, P; Mariniello, G; Giamundo, A; Maiuri, F

    2009-05-01

    This study investigates the diagnosis and management of patients with resected brain glioblastomas who presented early clinical and neuroradiological worsening after the completion of the Stupp protocol. Its aim is to discuss the occurrence of early radionecrosis. Fifty patients with brain glioblastoma treated by surgical resection and Stupp protocol were reviewed; 15 among them (30%) had early clinical and neuroradiological worsening at the 6-month follow-up. The MR spectroscopy and surgical findings of these patients are reviewed. MR spectroscopy was in favour of tumour recurrence in 14 among 15 patients and showed radionecrosis in one. Among 10 patients who were reoperated on, 7 had histologically verified tumour recurrence or regrowth, whereas in 3 histopathology showed necrosis without evidence of tumour. The 7 patients with tumour progression had prevalence of focal neuroradiological signs (6/7) and a survival of 7.5-12 months (median survival 10 months). The 4 patients with early radionecrosis (including one patient who was not reoperated on) had clinical worsening with mental deterioration, confusion and ataxia, and MR spectroscopy positive for tumour recurrence in 3. Three were alive 24-30 months after the end of the radiotherapy, whereas one died at 40 months. Early radionecrosis after the Stupp protocol is not a rare event due to the radiosensitization effect of temozolomide. This phenomenon may predict a durable response to radiotherapy. MR spectroscopy may simulate tumour recurrence. A correct diagnosis is necessary to avoid useless reoperations and incorrect withdrawal of temozolomide.

  3. Randomized Controlled Trial in Clinical Settings to Evaluate Effectiveness of Coping Skills Education Used With Progressive Tinnitus Management.

    PubMed

    Henry, James A; Thielman, Emily J; Zaugg, Tara L; Kaelin, Christine; Schmidt, Caroline J; Griest, Susan; McMillan, Garnett P; Myers, Paula; Rivera, Izel; Baldwin, Robert; Carlson, Kathleen

    2017-05-24

    This randomized controlled trial evaluated, within clinical settings, the effectiveness of coping skills education that is provided with progressive tinnitus management (PTM). At 2 Veterans Affairs medical centers, N = 300 veterans were randomized to either PTM intervention or 6-month wait-list control. The PTM intervention involved 5 group workshops: 2 led by an audiologist (teaching how to use sound as therapy) and 3 by a psychologist (teaching coping skills derived from cognitive behavioral therapy). It was hypothesized that PTM would be more effective than wait-list control in reducing functional effects of tinnitus and that there would be no differences in effectiveness between sites. At both sites, a statistically significant improvement in mean Tinnitus Functional Index scores was seen at 6 months for the PTM group. Combined data across sites revealed a statistically significant improvement in Tinnitus Functional Index relative to wait-list control. The effect size for PTM using the Tinnitus Functional Index was 0.36 (small). Results suggest that PTM is effective at reducing tinnitus-related functional distress in clinical settings. Although effect sizes were small, they provide evidence of clinical effectiveness of PTM in the absence of stringent research-related inclusion criteria and with a relatively small number of sessions of cognitive behavioral therapy.

  4. 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 ...

  5. Statistics in review. Part 2: generalised linear models, time-to-event and time-series analysis, evidence synthesis and clinical trials.

    PubMed

    Moran, John L; Solomon, Patricia J

    2007-06-01

    In Part I, we reviewed graphical display and data summary, followed by a consideration of linear regression models. Generalised linear models, structured in terms of an exponential response distribution and link function, are now introduced, subsuming logistic and Poisson regression. Time-to-event ("survival") analysis is developed from basic principles of hazard rate, and survival, cumulative distribution and density functions. Semi-parametric (Cox) and parametric (accelerated failure time) regression models are contrasted. Time-series analysis is explicated in terms of trend, seasonal, and other cyclical and irregular components, and further illustrated by development of a classical Box-Jenkins ARMA (autoregressive moving average) model for monthly ICU-patient hospital mortality rates recorded over 11 years. Multilevel (random-effects) models and principles of meta-analysis are outlined, and the review concludes with a brief consideration of important statistical aspects of clinical trials: sample size determination, interim analysis and "early stopping".

  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. 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. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Bacterial translocation and clinical progression of HCV-related cirrhosis in HIV-infected patients.

    PubMed

    Merchante, N; Aldámiz-Echevarría, T; García-Álvarez, M; Rivero-Juárez, A; Macías, J; Miralles, P; Jiménez-Sousa, M A; Mancebo, M; Pérez-Latorre, L; Pineda-Tenor, D; Berenguer, J; Resino, S; Pineda, J A

    2017-08-07

    The aim of the study was to evaluate whether bacterial translocation (BT) predicts the clinical outcome in HIV/HCV-coinfected patients with compensated cirrhosis. A cohort of 282 HIV/HCV-coinfected patients with cirrhosis and no previous liver decompensation (LD) was recruited. Serum levels of the DNA sequences encoding the well-conserved 16S rRNA subunit (16S rDNA), the lipopolysaccharide (LPS) and soluble CD14 (sCD14) at diagnosis of cirrhosis were measured. Primary endpoint was the emergence of the first LD and/or death of any cause. Secondary endpoints were LD, liver-related death (LRD) and death of any cause. A