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Sample records for accelerated disease progression

  1. Plasma viral RNA load predicts disease progression in accelerated feline immunodeficiency virus infection.

    PubMed Central

    Diehl, L J; Mathiason-Dubard, C K; O'Neil, L L; Hoover, E A

    1996-01-01

    Viral RNA load has been shown to indicate disease stage and predict the rapidity of disease progression in human immunodeficiency virus type 1 (HIV-1)-infected individuals. We had previously demonstrated that feline immunodeficiency virus (FIV) RNA levels in plasma correlate with disease stage in infected cats. Here we expand upon those observations by demonstrating that plasma virus load is 1 to 2 logs higher in cats with rapidly progressive FIV disease than in long-term survivors. Differences in plasma FIV RNA levels are evident by 1 to 2 weeks after infection and are consistent throughout infection. We also evaluated humoral immune responses in FIV-infected cats for correlation with survival times. Total anti-FIV antibody titers did not differ between cats with rapidly progressive FIV disease and long-term survivors. These findings indicate that virus replication plays an important role in FIV disease progression, as it does in HIV-1 disease progression. The parallels in virus loads and disease progressions between HIV-1 and FIV support the idea that the accelerated disease model is well suited for the study of therapeutic agents directed at reducing lentiviral replication. PMID:8642679

  2. Hypertension accelerates the progression of Alzheimer-like pathology in a mouse model of the disease.

    PubMed

    Cifuentes, Diana; Poittevin, Marine; Dere, Ekrem; Broquères-You, Dong; Bonnin, Philippe; Benessiano, Joëlle; Pocard, Marc; Mariani, Jean; Kubis, Nathalie; Merkulova-Rainon, Tatyana; Lévy, Bernard I

    2015-01-01

    Cerebrovascular impairment is frequent in patients with Alzheimer disease and is believed to influence clinical manifestation and severity of the disease. Cardiovascular risk factors, especially hypertension, have been associated with higher risk of developing Alzheimer disease. To investigate the mechanisms underlying the hypertension, Alzheimer disease cross talk, we established a mouse model of dual pathology by infusing hypertensive doses of angiotensin II into transgenic APPPS1 mice overexpressing mutated human amyloid precursor and presenilin 1 proteins. At 4.5 months, at the early stage of disease progression, only hypertensive APPPS1 mice presented impairment of temporal order memory performance in the episodic-like memory task. This cognitive deficit was associated with an increased number of cortical amyloid deposits (223±5 versus 207±5 plaques/mm(2); P<0.05) and a 2-fold increase in soluble amyloid levels in the brain and in plasma. Hypertensive APPPS1 mice presented several cerebrovascular alterations, including a 25% reduction in cerebral microvessel density and a 30% to 40% increase in cerebral vascular amyloid deposits, as well as a decrease in vascular endothelial growth factor A expression in the brain, compared with normotensive APPPS1 mice. Moreover, the brain levels of nitric oxide synthase 1 and 3 and the nitrite/nitrate levels were reduced in hypertensive APPPS1 mice (by 49%, 34%, and 33%, respectively, compared with wild-type mice; P<0.05). Our results indicate that hypertension accelerates the development of Alzheimer disease-related structural and functional alterations, partially through cerebral vasculature impairment and reduced nitric oxide production.

  3. H63D HFE genotype accelerates disease progression in animal models of amyotrophic lateral sclerosis.

    PubMed

    Nandar, Wint; Neely, Elizabeth B; Simmons, Zachary; Connor, James R

    2014-12-01

    H63D HFE is associated with iron dyshomeostasis and oxidative stress; each of which plays an important role in amyotrophic lateral sclerosis (ALS) pathogenesis. To examine the role of H63D HFE in ALS, we generated a double transgenic mouse line (SOD1/H67D) carrying the H67D HFE (homologue of human H63D) and SOD1(G93A) mutations. We found double transgenic mice have shorter survival and accelerated disease progression. We examined parameters in the lumbar spinal cord of double transgenic mice at 90days (presymptomatic), 110days (symptomatic) and end-stage. Transferrin receptor and L-ferritin expression, both indicators of iron status, were altered in double transgenic and SOD1 mice starting at 90days, indicating loss of iron homeostasis in these mice. However, double transgenic mice had higher L-ferritin expression than SOD1 mice. Double transgenic mice exhibited increased Iba-1 immunoreactivity and caspase-3 levels, indicating increased microglial activation which would be consistent with the higher L-ferritin levels. Although both SOD1 and double transgenic mice had increased GFAP expression, the magnitude of the increase was higher in double transgenic mice at 110days, suggesting increased gliosis in these mice. Increased hemeoxygenase-1 and decreased nuclear factor E2-related factor 2 levels in double transgenic mice strongly suggest the accelerated disease process could be associated with increased oxidative stress. There was no evidence of TAR-DNA-binding protein 43 mislocalization to the cytoplasm in double transgenic mice; however, there was evidence suggesting neurofilament disruption, which has been reported in ALS. Our findings indicate H63D HFE modifies ALS pathophysiology via pathways involving oxidative stress, gliosis and disruption of cellular functions.

  4. Water, sanitation and hygiene for accelerating and sustaining progress on neglected tropical diseases: a new Global Strategy 2015-20.

    PubMed

    Boisson, Sophie; Engels, Dirk; Gordon, Bruce A; Medlicott, Kate O; Neira, Maria P; Montresor, Antonio; Solomon, Anthony W; Velleman, Yael

    2016-03-01

    Neglected tropical diseases (NTDs) affect over 1 billion people. Safe water, sanitation and hygiene (WASH) contribute to prevention and management of most NTDs. Linking WASH and NTD interventions has potential to impact on multiple NTDs and can help secure sustainable and equitable progress towards universal access to WASH. The need to address the determinants of NTDs has been acknowledged. In response, WHO has published a new Global Strategy: 'Water, Sanitation and Hygiene for accelerating and sustaining progress on Neglected Tropical Diseases'. The Strategy focuses on cross-cutting actions that benefit disease control and care efforts, and strengthen health systems. Implementation of the strategy and the accompanying action plan can help ensure that the health and development agenda leaves no one behind.

  5. Water, sanitation and hygiene for accelerating and sustaining progress on neglected tropical diseases: a new Global Strategy 2015-20.

    PubMed

    Boisson, Sophie; Engels, Dirk; Gordon, Bruce A; Medlicott, Kate O; Neira, Maria P; Montresor, Antonio; Solomon, Anthony W; Velleman, Yael

    2016-03-01

    Neglected tropical diseases (NTDs) affect over 1 billion people. Safe water, sanitation and hygiene (WASH) contribute to prevention and management of most NTDs. Linking WASH and NTD interventions has potential to impact on multiple NTDs and can help secure sustainable and equitable progress towards universal access to WASH. The need to address the determinants of NTDs has been acknowledged. In response, WHO has published a new Global Strategy: 'Water, Sanitation and Hygiene for accelerating and sustaining progress on Neglected Tropical Diseases'. The Strategy focuses on cross-cutting actions that benefit disease control and care efforts, and strengthen health systems. Implementation of the strategy and the accompanying action plan can help ensure that the health and development agenda leaves no one behind. PMID:26940305

  6. Calcium channel inhibition accelerates polycystic kidney disease progression in the Cy/+ rat.

    PubMed

    Nagao, S; Nishii, K; Yoshihara, D; Kurahashi, H; Nagaoka, K; Yamashita, T; Takahashi, H; Yamaguchi, T; Calvet, J P; Wallace, D P

    2008-02-01

    In polycystic kidney disease, abnormal epithelial cell proliferation is the main factor leading to cyst formation and kidney enlargement. Cyclic AMP (cAMP) is mitogenic in cystic but antimitogenic in normal human kidney cells, which is due to reduced steady-state intracellular calcium levels in cystic compared to the normal cells. Inhibition of intracellular calcium entry with channel blockers, such as verapamil, induced cAMP-dependent cell proliferation in normal renal cells. To determine if calcium channel blockers have a similar effect on cell proliferation in vivo, Cy/+ rats, a model of dominant polycystic kidney disease, were treated with verapamil. Kidney weight and cyst index were elevated in verapamil-treated Cy/+ rats. This was associated with increased cell proliferation and apoptosis, elevated expression, and phosphorylation of B-Raf with stimulation of the mitogen-activated protein kinase MEK/ERK (mitogen-activated protein kinase kinase/extracellular-regulated kinase) pathway. Verapamil had no effect on kidney morphology or B-Raf stimulation in wild-type rats. We conclude that treatment of Cy/+ rats with calcium channel blockers increases activity of the B-Raf/MEK/ERK pathway accelerating cyst growth in the presence of endogenous cAMP, thus exacerbating renal cystic disease.

  7. Identifying disease mutations in genomic medicine settings: current challenges and how to accelerate progress

    PubMed Central

    2012-01-01

    The pace of exome and genome sequencing is accelerating, with the identification of many new disease-causing mutations in research settings, and it is likely that whole exome or genome sequencing could have a major impact in the clinical arena in the relatively near future. However, the human genomics community is currently facing several challenges, including phenotyping, sample collection, sequencing strategies, bioinformatics analysis, biological validation of variant function, clinical interpretation and validity of variant data, and delivery of genomic information to various constituents. Here we review these challenges and summarize the bottlenecks for the clinical application of exome and genome sequencing, and we discuss ways for moving the field forward. In particular, we urge the need for clinical-grade sample collection, high-quality sequencing data acquisition, digitalized phenotyping, rigorous generation of variant calls, and comprehensive functional annotation of variants. Additionally, we suggest that a 'networking of science' model that encourages much more collaboration and online sharing of medical history, genomic data and biological knowledge, including among research participants and consumers/patients, will help establish causation and penetrance for disease causal variants and genes. As we enter this new era of genomic medicine, we envision that consumer-driven and consumer-oriented efforts will take center stage, thus allowing insights from the human genome project to translate directly back into individualized medicine. PMID:22830651

  8. Muon Collider Progress: Accelerators

    SciTech Connect

    Zisman, Michael S.

    2011-09-10

    A muon collider would be a powerful tool for exploring the energy-frontier with leptons, and would complement the studies now under way at the LHC. Such a device would offer several important benefits. Muons, like electrons, are point particles so the full center-of-mass energy is available for particle production. Moreover, on account of their higher mass, muons give rise to very little synchrotron radiation and produce very little beamstrahlung. The first feature permits the use of a circular collider that can make efficient use of the expensive rf system and whose footprint is compatible with an existing laboratory site. The second feature leads to a relatively narrow energy spread at the collision point. Designing an accelerator complex for a muon collider is a challenging task. Firstly, the muons are produced as a tertiary beam, so a high-power proton beam and a target that can withstand it are needed to provide the required luminosity of ~1 × 10{sup 34} cm{sup –2}s{sup –1}. Secondly, the beam is initially produced with a large 6D phase space, which necessitates a scheme for reducing the muon beam emittance (“cooling”). Finally, the muon has a short lifetime so all beam manipulations must be done very rapidly. The Muon Accelerator Program, led by Fermilab and including a number of U.S. national laboratories and universities, has undertaken design and R&D activities aimed toward the eventual construction of a muon collider. Design features of such a facility and the supporting R&D program are described.

  9. Epigenetic pathway targets for the treatment of disease: accelerating progress in the development of pharmacological tools: IUPHAR Review 11

    PubMed Central

    Tough, David F; Lewis, Huw D; Rioja, Inmaculada; Lindon, Matthew J; Prinjha, Rab K

    2014-01-01

    The properties of a cell are determined both genetically by the DNA sequence of its genes and epigenetically through processes that regulate the pattern, timing and magnitude of expression of its genes. While the genetic basis of disease has been a topic of intense study for decades, recent years have seen a dramatic increase in the understanding of epigenetic regulatory mechanisms and a growing appreciation that epigenetic misregulation makes a significant contribution to human disease. Several large protein families have been identified that act in different ways to control the expression of genes through epigenetic mechanisms. Many of these protein families are finally proving tractable for the development of small molecules that modulate their function and represent new target classes for drug discovery. Here, we provide an overview of some of the key epigenetic regulatory proteins and discuss progress towards the development of pharmacological tools for use in research and therapy. PMID:25060293

  10. Nonalcoholic Fatty Liver Disease Progression in Rats is Accelerated by Splenic Regulation of Liver PTEN/AKT

    PubMed Central

    Wang, Ziming; Li, Naishu; Wang, Biao; Lin, Jianhua

    2015-01-01

    Background/Aim: The spleen has been reported to participate in the development of nonalcoholic fatty liver disease (NAFLD), but the mechanism has not been fully characterized. This study aims to elucidate how the spleen affects the development of NAFLD in a rat model. Materials and Methods: Following either splenectomy or sham operation, male Sprague–Dawley (SD) rats were fed a high-fat diet to drive the development of NAFLD; animals fed a normal diet were used as controls. Two months after surgery, livers and blood samples were collected. Serum lipids were measured; liver histology, phosphatase and tensin homologue deleted on chromosome 10 (PTEN) gene expression, and the ratio of pAkt/Akt were determined. Results: Splenectomy increased serum lipids, except triglyceride (TG) and high-density lipoprotein (HDL), in animals fed either a high-fat or normal diet. Furthermore, splenectomy significantly accelerated hepatic steatosis. Western blot analysis and real-time polymerase chain reaction showed splenectomy induced significant downregulation of PTEN expression and a high ratio of pAkt/Akt in the livers. Conclusions: The spleen appears to play a role in the development of NAFLD, via a mechanism involving downregulation of hepatic PTEN expression. PMID:26228367

  11. The PGE2 EP2 receptor accelerates disease progression and inflammation in a model of amyotrophic lateral sclerosis

    PubMed Central

    Liang, Xibin; Wang, Qian; Shi, Ju; Lokteva, Ludmila; Breyer, Richard M.; Montine, Thomas J.; Andreasson, Katrin

    2009-01-01

    Objective Inflammation has emerged as an important factor in disease progression in human and transgenic models of amyotrophic lateral sclerosis (ALS). Recent studies demonstrate that the prostaglandin E2 EP2 receptor is a major regulator of inflammatory oxidative injury in innate immunity. We tested whether EP2 signaling participated in disease pathogenesis in the G93A superoxide dismutase (SOD) model of familial ALS. Methods We examined the phenotype of G93A SOD mice lacking the EP2 receptor and performed immunocytochemistry, quantitative reverse transcriptase polymerase chain reaction, and Western analyses to determine the mechanism of EP2 toxicity in this model. Results EP2 receptor is significantly induced in G93A SOD mice in astrocytes and microglia in parallel with increases in expression of proinflammatory enzymes and lipid peroxidation. In human ALS, EP2 receptor immunoreactivity was upregulated in astrocytes in ventral spinal cord. In aging G93A SOD mice, genetic deletion of the prostaglandin E2 EP2 receptor improved motor strength and extended survival. Deletion of the EP2 receptor in G93A SOD mice resulted in significant reductions in levels of proinflammatory effectors, including cyclooxygenase-1, cyclooxygenase-2, inducible nitric oxide synthase, and components of the NADPH oxidase complex. In alternate models of inflammation, including the lipopolysaccharide model of innate immunity and the APPSwe-PS1ΔE9 model of amyloidosis, deletion of EP2 also reduced expression of proinflammatory genes. Interpretation These data suggest that prostaglandin E2 signaling via the EP2 receptor functions in the mutant SOD model and more broadly in inflammatory neurodegeneration to regulate expression of a cassette of proinflammatory genes. Inhibition of EP2 signaling may represent a novel strategy to downregulate the inflammatory response in neurodegenerative disease. PMID:18825663

  12. Antioxidants accelerate lung cancer progression in mice.

    PubMed

    Sayin, Volkan I; Ibrahim, Mohamed X; Larsson, Erik; Nilsson, Jonas A; Lindahl, Per; Bergo, Martin O

    2014-01-29

    Antioxidants are widely used to protect cells from damage induced by reactive oxygen species (ROS). The concept that antioxidants can help fight cancer is deeply rooted in the general population, promoted by the food supplement industry, and supported by some scientific studies. However, clinical trials have reported inconsistent results. We show that supplementing the diet with the antioxidants N-acetylcysteine (NAC) and vitamin E markedly increases tumor progression and reduces survival in mouse models of B-RAF- and K-RAS-induced lung cancer. RNA sequencing revealed that NAC and vitamin E, which are structurally unrelated, produce highly coordinated changes in tumor transcriptome profiles, dominated by reduced expression of endogenous antioxidant genes. NAC and vitamin E increase tumor cell proliferation by reducing ROS, DNA damage, and p53 expression in mouse and human lung tumor cells. Inactivation of p53 increases tumor growth to a similar degree as antioxidants and abolishes the antioxidant effect. Thus, antioxidants accelerate tumor growth by disrupting the ROS-p53 axis. Because somatic mutations in p53 occur late in tumor progression, antioxidants may accelerate the growth of early tumors or precancerous lesions in high-risk populations such as smokers and patients with chronic obstructive pulmonary disease who receive NAC to relieve mucus production. PMID:24477002

  13. Antioxidants accelerate lung cancer progression in mice.

    PubMed

    Sayin, Volkan I; Ibrahim, Mohamed X; Larsson, Erik; Nilsson, Jonas A; Lindahl, Per; Bergo, Martin O

    2014-01-29

    Antioxidants are widely used to protect cells from damage induced by reactive oxygen species (ROS). The concept that antioxidants can help fight cancer is deeply rooted in the general population, promoted by the food supplement industry, and supported by some scientific studies. However, clinical trials have reported inconsistent results. We show that supplementing the diet with the antioxidants N-acetylcysteine (NAC) and vitamin E markedly increases tumor progression and reduces survival in mouse models of B-RAF- and K-RAS-induced lung cancer. RNA sequencing revealed that NAC and vitamin E, which are structurally unrelated, produce highly coordinated changes in tumor transcriptome profiles, dominated by reduced expression of endogenous antioxidant genes. NAC and vitamin E increase tumor cell proliferation by reducing ROS, DNA damage, and p53 expression in mouse and human lung tumor cells. Inactivation of p53 increases tumor growth to a similar degree as antioxidants and abolishes the antioxidant effect. Thus, antioxidants accelerate tumor growth by disrupting the ROS-p53 axis. Because somatic mutations in p53 occur late in tumor progression, antioxidants may accelerate the growth of early tumors or precancerous lesions in high-risk populations such as smokers and patients with chronic obstructive pulmonary disease who receive NAC to relieve mucus production.

  14. Progress of Laser-Driven Plasma Accelerators

    SciTech Connect

    Nakajima, Kazuhisa

    2007-07-11

    There is a great interest worldwide in plasma accelerators driven by ultra-intense lasers which make it possible to generate ultra-high gradient acceleration and high quality particle beams in a much more compact size compared with conventional accelerators. A frontier research on laser and plasma accelerators is focused on high energy electron acceleration and ultra-short X-ray and Tera Hertz radiations as their applications. These achievements will provide not only a wide range of sciences with benefits of a table-top accelerator but also a basic science with a tool of ultrahigh energy accelerators probing an unknown extremely microscopic world.Harnessing the recent advance of ultra-intense ultra-short pulse lasers, the worldwide research has made a tremendous breakthrough in demonstrating high-energy high-quality particle beams in a compact scale, so called ''dream beams on a table top'', which represents monoenergetic electron beams from laser wakefield accelerators and GeV acceleration by capillary plasma-channel laser wakefield accelerators. This lecture reviews recent progress of results on laser-driven plasma based accelerator experiments to quest for particle acceleration physics in intense laser-plasma interactions and to present new outlook for the GeV-range high-energy laser plasma accelerators.

  15. Progress in Alzheimer's disease.

    PubMed

    Galimberti, Daniela; Scarpini, Elio

    2012-02-01

    After more than one century from Alois Alzheimer and Gaetano Perusini's first report, progress has been made in understanding the pathogenic steps of Alzheimer's disease (AD), as well as in its early diagnosis. This review discusses recent findings leading to the formulation of novel criteria for diagnosis of the disease even in a preclinical phase, by using biological markers. In addition, treatment options will be discussed, with emphasis on new disease-modifying compounds and future trial design suitable to test these drugs in an early phase of the disease.

  16. Acceleration of purine degradation by periodontal diseases.

    PubMed

    Barnes, V M; Teles, R; Trivedi, H M; Devizio, W; Xu, T; Mitchell, M W; Milburn, M V; Guo, L

    2009-09-01

    Periodontal diseases, such as gingivitis and periodontitis, are characterized by bacterial plaque accumulation around the gingival crevice and the subsequent inflammation and destruction of host tissues. To test the hypothesis that cellular metabolism is altered as a result of host-bacteria interaction, we performed an unbiased metabolomic profiling of gingival crevicular fluid (GCF) collected from healthy, gingivitis, and periodontitis sites in humans, by liquid and gas chromatography mass spectrometry. The purine degradation pathway, a major biochemical source for reactive oxygen species (ROS) production, was significantly accelerated at the disease sites. This suggests that periodontal-disease-induced oxidative stress and inflammation are mediated through this pathway. The complex host-bacterial interaction was further highlighted by depletion of anti-oxidants, degradation of host cellular components, and accumulation of bacterial products in GCF. These findings provide new mechanistic insights and a panel of comprehensive biomarkers for periodontal disease progression. PMID:19767584

  17. Acceleration of purine degradation by periodontal diseases.

    PubMed

    Barnes, V M; Teles, R; Trivedi, H M; Devizio, W; Xu, T; Mitchell, M W; Milburn, M V; Guo, L

    2009-09-01

    Periodontal diseases, such as gingivitis and periodontitis, are characterized by bacterial plaque accumulation around the gingival crevice and the subsequent inflammation and destruction of host tissues. To test the hypothesis that cellular metabolism is altered as a result of host-bacteria interaction, we performed an unbiased metabolomic profiling of gingival crevicular fluid (GCF) collected from healthy, gingivitis, and periodontitis sites in humans, by liquid and gas chromatography mass spectrometry. The purine degradation pathway, a major biochemical source for reactive oxygen species (ROS) production, was significantly accelerated at the disease sites. This suggests that periodontal-disease-induced oxidative stress and inflammation are mediated through this pathway. The complex host-bacterial interaction was further highlighted by depletion of anti-oxidants, degradation of host cellular components, and accumulation of bacterial products in GCF. These findings provide new mechanistic insights and a panel of comprehensive biomarkers for periodontal disease progression.

  18. SuperB Progress Report for Accelerator

    SciTech Connect

    Biagini, M.E.; Boni, R.; Boscolo, M.; Buonomo, B.; Demma, T.; Drago, A.; Esposito, M.; Guiducci, S.; Mazzitelli, G.; Pellegrino, L.; Preger, M.A.; Raimondi, P.; Ricci, R.; Rotundo, U.; Sanelli, C.; Serio, M.; Stella, A.; Tomassini, S.; Zobov, M.; Bertsche, K.; Brachman, A.; /SLAC /Novosibirsk, IYF /INFN, Pisa /Pisa U. /Orsay, LAL /Annecy, LAPP /LPSC, Grenoble /IRFU, SPP, Saclay /DESY /Cockroft Inst. Accel. Sci. Tech. /U. Liverpool /CERN

    2012-02-14

    This report details the progress made in by the SuperB Project in the area of the Collider since the publication of the SuperB Conceptual Design Report in 2007 and the Proceedings of SuperB Workshop VI in Valencia in 2008. With this document we propose a new electron positron colliding beam accelerator to be built in Italy to study flavor physics in the B-meson system at an energy of 10 GeV in the center-of-mass. This facility is called a high luminosity B-factory with a project name 'SuperB'. This project builds on a long history of successful e+e- colliders built around the world, as illustrated in Figure 1.1. The key advances in the design of this accelerator come from recent successes at the DAFNE collider at INFN in Frascati, Italy, at PEP-II at SLAC in California, USA, and at KEKB at KEK in Tsukuba Japan, and from new concepts in beam manipulation at the interaction region (IP) called 'crab waist'. This new collider comprises of two colliding beam rings, one at 4.2 GeV and one at 6.7 GeV, a common interaction region, a new injection system at full beam energies, and one of the two beams longitudinally polarized at the IP. Most of the new accelerator techniques needed for this collider have been achieved at other recently completed accelerators including the new PETRA-3 light source at DESY in Hamburg (Germany) and the upgraded DAFNE collider at the INFN laboratory at Frascati (Italy), or during design studies of CLIC or the International Linear Collider (ILC). The project is to be designed and constructed by a worldwide collaboration of accelerator and engineering staff along with ties to industry. To save significant construction costs, many components from the PEP-II collider at SLAC will be recycled and used in this new accelerator. The interaction region will be designed in collaboration with the particle physics detector to guarantee successful mutual use. The accelerator collaboration will consist of several groups at present universities and national

  19. Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression

    PubMed Central

    Gao, Hui-Ming; Hong, Jau-Shyong

    2016-01-01

    Neurodegenerative diseases are a group of chronic, progressive disorders characterized by the gradual loss of neurons in discrete areas of the central nervous system (CNS). The mechanism(s) underlying their progressive nature remains unknown but a timely and well-controlled inflammatory reaction is essential for the integrity and proper function of the CNS. Substantial evidence has documented a common inflammatory mechanism in various neurodegenerative diseases. We hypothesize that in the diseased CNS, interactions between damaged neurons and dysregulated, overactivated microglia create a vicious self-propagating cycle causing uncontrolled, prolonged inflammation that drives the chronic progression of neurodegenerative diseases. We further propose that dynamic modulation of this inflammatory reaction by interrupting the vicious cycle might become a disease-modifying therapeutic strategy for neurodegenerative diseases. PMID:18599350

  20. Accelerator Technology Division progress report, FY 1992

    SciTech Connect

    Schriber, S.O.; Hardekopf, R.A.; Heighway, E.A.

    1993-07-01

    This report briefly discusses the following topics: The Ground Test Accelerator Program; Defense Free-Electron Lasers; AXY Programs; A Next Generation High-Power Neutron-Scattering Facility; JAERI OMEGA Project and Intense Neutron Sources for Materials Testing; Advanced Free-Electron Laser Initiative; Superconducting Supercollider; The High-Power Microwave (HPM) Program; Neutral Particle Beam (NPB) Power Systems Highlights; Industrial Partnering; Accelerator Physics and Special Projects; Magnetic Optics and Beam Diagnostics; Accelerator Design and Engineering; Radio-Frequency Technology; Accelerator Theory and Free-Electron Laser Technology; Accelerator Controls and Automation; Very High-Power Microwave Sources and Effects; and GTA Installation, Commissioning, and Operations.

  1. Hypoxia inducible factor (HIF)-2α accelerates disease progression in mouse models of leukemia and lymphoma but is not a poor prognosis factor in human AML.

    PubMed

    Forristal, C E; Brown, A L; Helwani, F M; Winkler, I G; Nowlan, B; Barbier, V; Powell, R J; Engler, G A; Diakiw, S M; Zannettino, A C W; Martin, S; Pattabiraman, D; D'Andrea, R J; Lewis, I D; Levesque, J P

    2015-10-01

    Hypoxia-inducible factor (HIF)-1α accumulation promotes hematopoietic stem cells' quiescence and is necessary to maintain their self-renewal. However, the role of HIF-2α in hematopoietic cells is less clear. We investigated the role of HIF-2α in leukemia and lymphoma cells. HIF-2α expression was high in subsets of human and mouse leukemia and lymphoma cells, whereas it was low in normal bone marrow leukocytes. To investigate the role of HIF-2α, we transduced human HIF-2α cDNA in mouse syngeneic models of myeloid preleukemia and a transgenic model of B lymphoma. Ectopic expression of HIF-2α accelerated leukemia cell proliferation in vitro. Mice transplanted with cells transduced with HIF-2α died significantly faster of leukemia or B lymphoma than control mice transplanted with empty vector-transduced cells. Conversely, HIF-2α knockdown in human myeloid leukemia HL60 cells decreased proliferation in vitro and significantly prolonged animal survival following transplantation. In human acute myeloid leukemia (AML), HIF-2α mRNA was significantly elevated in several subsets such as the t(15;17), inv(16), complex karyotype and favorable cytogenetic groups. However, patients with high HIF-2α expression had a trend to higher disease-free survival in univariate analysis. The different effects of HIF-2α overexpression in mouse models of leukemia and human AML illustrates the complexity of this mutliclonal disease.

  2. Theoretical problems in accelerator physics. Progress report

    SciTech Connect

    Kroll, N.M.

    1993-08-01

    This report discusses the following topics in accelerator physics: radio frequency pulse compression and power transport; computational methods for the computer analysis of microwave components; persistent wakefields associated with waveguide damping of higher order modes; and photonic band gap cavities.

  3. Progress Towards Doubling the Beam Power at Fermilab's Accelerator Complex

    SciTech Connect

    Kourbanis, ioanis

    2014-06-01

    After a 14 month shutdown accelerator modifications and upgrades are in place to allow us doubling of the Main Injector beam power. We will discuss the past MI high power operation and the current progress towards doubling the power.

  4. Progress Towards Doubling the Beam Power at Fermilab's Accelerator Complex

    SciTech Connect

    Kourbanis, Ioanis

    2014-07-01

    After a 16 month shutdown to reconfigure the Fermilab Accelerators for high power operations, the Fermilab Accelerator Complex is again providing beams for numerous Physics Experiments. By using the Recycler to slip stack protons while the Main Injector is ramping, the beam power at 120 GeV can reach 700 KW, a factor of 2 increase. The progress towards doubling the Fermilab's Accelerator complex beam power will be presented.

  5. Theoretical problems in accelerator physics. Progress report

    SciTech Connect

    Not Available

    1994-08-01

    This is the second progress report submitted under the author`s current grant and covers progress made since the submission of the first progress report in August 1993. During this period the author has continued to spend approximately one half of his time at SLAC and most of the projects reported here were carried out in collaboration with individuals and groups at SLAC. Except where otherwise noted, reference numbers in the text refer to the attached list of current contract publications. Copies of the publications, numbered in agreement with the publication list, are included with this report.

  6. Restriction Factors in HIV-1 Disease Progression.

    PubMed

    Merindol, Natacha; Berthoux, Lionel

    2015-01-01

    About 35 million people worldwide were living with HIV-1 at the end of 2013 and over 25 million have already died of AIDS. AIDS patients show high variability in the speed of disease progression in the absence of treatment. While certain immunological traits have been shown to correlate with accelerated or slowed progression in some subjects, including slow progressors, factors controlling HIV-1 replication and disease kinetics remain largely enigmatic. The importance of T lymphocytes and of protective HLA-alleles is undeniable, but not sufficient to explain every attenuated phenotype. A thorough understanding of HIV-1 infection control in these patient subsets may help the development of novel strategies for treatment and prevention. Restriction factors are type I interferon-induced specialized cellular proteins that block viruses at different steps of their life cycle. TRIM5α, Mx2/MxB, TRIM22/Staf50, SAMHD1, p21/CDKN1, tetherin/BST2/CD137, APOBEC3G and APOBEC3F have all been proposed to inhibit HIV-1, often with gene variant- or cellular context-specificity. Recent evidence highlights their possible implication in AIDS disease progression. In this review, we depict their restrictive activity against HIV-1 and recapitulate the latest data on their potential role in vivo, in both normal and slow progressors.

  7. Statins and progressive renal disease.

    PubMed

    Buemi, Michele; Senatore, Massimino; Corica, Francesco; Aloisi, Carmela; Romeo, Adolfo; Cavallaro, Emanuela; Floccari, Fulvio; Tramontana, Domenico; Frisina, Nicola

    2002-01-01

    Thanks to the administration of hypocholesterolemic drugs, important advances have been made in the treatment of patients with progressive renal disease. In vitro and in vivo findings demonstrate that statins, the inhibitors of HMG-CoA reductase, can provide protection against kidney diseases characterized by inflammation and/or enhanced proliferation of epithelial cells occurring in rapidly progressive glomerulonephritis, or by increased proliferation of mesangial cells occurring in IgA nephropathy. Many of the beneficial effects obtained occur independent of reduced cholesterol levels because statins can directly inhibit the proliferation of different cell types (e.g., mesangial, renal tubular, and vascular smooth muscle cells), and can also modulate the inflammatory response, thus inhibiting macrophage recruitment and activation, as well as fibrosis. The mechanisms underlying the action of statins are not yet well understood, although recent data in the literature indicate that they can directly affect the proliferation/apoptosis balance, the down-regulation of inflammatory chemokines, and the cytogenic messages mediated by the GTPases Ras superfamily. Therefore, as well as reducing serum lipids, statins and other lipid-lowering agents may directly influence intracellular signaling pathways involved in the prenylation of low molecular weight proteins that play a crucial role in cell signal transduction and cell activation. Statins appear to have important potential in the treatment of progressive renal disease, although further studies are required to confirm this in humans.

  8. Interleukin 6 Accelerates Mortality by Promoting the Progression of the Systemic Lupus Erythematosus-Like Disease of BXSB.Yaa Mice.

    PubMed

    Jain, Shweta; Park, Giljun; Sproule, Thomas J; Christianson, Gregory J; Leeth, Caroline M; Wang, Hongsheng; Roopenian, Derry C; Morse, Herbert C

    2016-01-01

    IL6 is a multifunctional cytokine that drives terminal B cell differentiation and secretion of immunoglobulins. IL6 also cooperates with IL21 to promote differentiation of CD4+ T follicular helper cells (TFH). Elevated serum levels of IL6 correlate with disease flares in patients with systemic lupus erythematosus (SLE). We previously reported that IL21 produced by TFH plays a critical role in the development of the SLE-like disease of BXSB.Yaa mice. To examine the possible contributions of IL6 to disease, we compared disease parameters in IL6-deficient and IL6-competent BXSB.Yaa mice. We report that survival of IL6-deficient BXSB.Yaa mice was significantly prolonged in association with significant reductions in a variety of autoimmune manifestations. Moreover, B cells stimulated by co-engagement of TLR7 and B cell receptor (BCR) produced high levels of IL6 that was further augmented by stimulation with Type I interferon (IFN1). Importantly, the frequencies of TFH and serum levels of IL21 were significantly reduced in IL6-deficient mice. These findings suggest that high-level production of IL6 by B cells induced by integrated signaling from the IFN1 receptor, TLR7 and BCR promotes the differentiation of IL21-secreting TFH in a signaling sequence that drives the lethal autoimmune disease of BXSB.Yaa mice. PMID:27050763

  9. Interleukin 6 Accelerates Mortality by Promoting the Progression of the Systemic Lupus Erythematosus-Like Disease of BXSB.Yaa Mice

    PubMed Central

    Jain, Shweta; Park, Giljun; Sproule, Thomas J.; Christianson, Gregory J.; Leeth, Caroline M.; Wang, Hongsheng; Roopenian, Derry C.; Morse, Herbert C.

    2016-01-01

    IL6 is a multifunctional cytokine that drives terminal B cell differentiation and secretion of immunoglobulins. IL6 also cooperates with IL21 to promote differentiation of CD4+ T follicular helper cells (TFH). Elevated serum levels of IL6 correlate with disease flares in patients with systemic lupus erythematosus (SLE). We previously reported that IL21 produced by TFH plays a critical role in the development of the SLE-like disease of BXSB.Yaa mice. To examine the possible contributions of IL6 to disease, we compared disease parameters in IL6-deficient and IL6-competent BXSB.Yaa mice. We report that survival of IL6-deficient BXSB.Yaa mice was significantly prolonged in association with significant reductions in a variety of autoimmune manifestations. Moreover, B cells stimulated by co-engagement of TLR7 and B cell receptor (BCR) produced high levels of IL6 that was further augmented by stimulation with Type I interferon (IFN1). Importantly, the frequencies of TFH and serum levels of IL21 were significantly reduced in IL6-deficient mice. These findings suggest that high-level production of IL6 by B cells induced by integrated signaling from the IFN1 receptor, TLR7 and BCR promotes the differentiation of IL21-secreting TFH in a signaling sequence that drives the lethal autoimmune disease of BXSB.Yaa mice. PMID:27050763

  10. Accelerator Technology Program. Progress report, January-June 1980

    SciTech Connect

    Knapp, E.A.; Jameson, R.A.

    1980-03-01

    The activities of Los Alamos Scientific Laboratory's (LASL) Accelerator Technology (AT) Division during the first six months of calendar 1980 are discussed. This report is organized around major projects of the Division, reflecting a wide variety of applications and sponsors. The first section summarizes progress on the Proton Storage Ring to be located between LAMPF and the LASL Pulsed Neutron Research facility, followed by a section on the gyrocon, a new type of high-power, high-efficiency radio-frequency (rf) amplifier. The third section discusses the racetrack microtron being developed jointly by AT Division and the National Bureau of Standards; the fourth section concerns the free-electron studies. The fifth section covers the radio-frequency quadrupole linear accelerator, a new concept for the acceleration of low-velocity particles; this section is followed by a section discussing heavy ion fusion accelerator development. The next section reports activities in the Fusion Materials Irradiation Test program, a collaborative effort with the Hanford Engineering Development Laboratory. The final section deals first with development of H/sup -/ ion sources and injectors, then with accelerator instrumentation and beam dynamics.

  11. Shading reduces coral-disease progression

    NASA Astrophysics Data System (ADS)

    Muller, E. M.; van Woesik, R.

    2009-09-01

    The growing incidence of tropical-marine diseases is attributed to increases in pathogen prevalence and virulence associated with global warming. Additionally, the compromised-host hypothesis suggests that rising ocean temperatures may increase disease activity by making the corals more susceptible to ubiquitous pathogens. We tested the effects of reducing irradiance stress on coral-disease progression rates by shading corals showing signs consistent with white-plague disease. Our results showed that white-plague disease on shaded corals progressed significantly more slowly than on controls. Although the mechanisms are unknown, this study suggests that light intensity influences the rate of coral-disease progression.

  12. Progress toward a prototype recirculating ion induction accelerator

    SciTech Connect

    Friedman, A.; Barnard, J.J.; Cable, M.D.

    1996-06-01

    The U.S. Inertial Fusion Energy (IFE) Program is developing the physics and technology of ion induction accelerators, with the goal of electric power production by means of heavy ion beam-driven inertial fusion (commonly called heavy ion fusion, or HIF). Such accelerators are the principal candidates for inertial fusion power production applications, because they are expected to enjoy high efficiency, inherently high pulse repetition frequency (power plants are expected to inject and burn several fusion targets per second), and high reliability. In addition (and in contrast with laser beams, which are focused with optical lenses) heavy-ion beams will be focused onto the target by magnetic fields, which cannot be damaged by target explosions. Laser beams are used in present-day and planned near-term facilities (such as LLNUs Nova and the National Ignition Facility, which is being designed) because they can focus beams onto very small, intensely illuminated spots for scaled experiments and because the laser technology is already available. An induction accelerator works by passing the beam through a series of accelerating modules, each of which applies an electromotive force to the beam as it goes by; effectively, the beam acts as the secondary winding of a series of efficient one-turn transformers. The authors present plans for and progress toward the development of a small (4.5-m-diam) prototype recirculator, which will accelerate singly charged potassium ions through 15 laps, increasing the ion energy from 80 to 320 keV and the beam current from 2 to 8 mA. Beam confinement and bending are effected with permanent-magnet quadrupoles and electric dipoles, respectively. The design is based on scaling laws and on extensive particle and fluid simulations of the behavior of the space charge-dominated beam.

  13. Pathophysiology and management of progressive renal disease.

    PubMed

    Brown, S A; Crowell, W A; Brown, C A; Barsanti, J A; Finco, D R

    1997-09-01

    Recently, the hypothesis that all renal diseases are inherently progressive and self-perpetuating has focused attention on adaptive changes in renal structure and function that occur whenever renal function is reduced. These glomerular adaptations to renal disease include increases in filtration rate, capillary pressure and size, and are referred to as glomerular hyperfiltration, glomerular hypertension and glomerular hypertrophy, respectively. Extrarenal changes, such as dietary phosphate excess, systemic hypertension, hyperlipidaemia, acidosis and hyperparathyroidism occur in animals with renal disease and may be contributors to progression of renal disease. Emphasis in the management of companion animals with renal disease has shifted to identifying, understanding and controlling those processes that play a role in the progression from early to end-stage renal failure. Advances made by veterinary nephrologists in the past 15 years permit resolution of old controversies, formulation of new hypotheses and discussion of unresolved issues about the nature of progressive renal disease in dogs and cats. PMID:9308397

  14. Accelerator technology program. Progress report, January-December 1979

    SciTech Connect

    Knapp, E.A.; Jameson, R.A.

    1980-11-01

    The activities of Los Alamos Scientific Laboratory's (LASL) Accelerator Technology (AT) Division during the calendar year 1979 are highlighted, with references to more detailed reports. This report is organized around the major projects of the Division, reflecting a wide variety of applications and sponsors. The first section covers the Fusion Materials Irradiation Test program, a collaborative effort with the Hanford Engineering Development Laboratory; the second section summarizes progress on the Proton Storage Ring to be built between LAMPF and the LASL Pulsed Neutron Research facility. A new project that achieved considerable momentum during the year is described next - the free-electron laser studies; the following section discusses the status of the Pion Generator for Medical Irradiation program. Next, two more new programs, the racetrack microtron being developed jointly by AT-Division and the National Bureau of Standards and the radio-frequency (rf) accelerator development for heavy ion fusion, are outlined. Development activities on a new type of high-power, high-efficiency rf amplifier called the gyrocon are then reported, and the final sections cover development of H/sup -/ ion sources and injectors, and linear accelerator instrumentation and beam dynamics.

  15. Amyotrophic lateral sclerosis disease progression model.

    PubMed

    Gomeni, Roberto; Fava, Maurizio

    2014-03-01

    Our objective was to develop: 1) a longitudinal model to describe amyotrophic lateral sclerosis (ALS) disease progression using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R); and 2) a probabilistic model to estimate the presence of clusters of trajectories in ALS progression over 12 months of treatment. Three hundred and thirty-eight patients treated with placebo from the PRO-ACT database were included in the analyses. A non-linear Weibull model best described the ALS disease progression, and a stepwise logistic regression approach was used to select the variables predicting a slow or fast disease progression. Results identified two clusters of trajectories: 1) slow disease progressors (46% of patients with a change from baseline of 13%); 2) fast disease progressors (54% of patients with a change from baseline of 49%). ROC curve analysis estimated the optimal cut-off for classifying patients as slow or fast disease progressors given ALSFRS-R measurements at 2-4 weeks. Results showed that the degree of ALS disease progression quantified by the ALSFRS-R symptomatic change on placebo is highly heterogeneous. In conclusion, this finding indicates the potential interest of disease progression models for implementing a population enrichment strategy to control the level of heterogeneity in the patients included in new trials.

  16. Modeling Disease Progression with Longitudinal Markers.

    PubMed

    Inoue, Lurdes Y T; Etzioni, Ruth; Morrell, Christopher; Müller, Peter

    2008-01-01

    In this paper we propose a Bayesian natural history model for disease progression based on the joint modeling of longitudinal biomarker levels, age at clinical detection of disease and disease status at diagnosis. We establish a link between the longitudinal responses and the natural history of the disease by using an underlying latent disease process which describes the onset of the disease and models the transition to an advanced stage of the disease as dependent on the biomarker levels. We apply our model to the data from the Baltimore Longitudinal Study of Aging on prostate specific antigen (PSA) to investigate the natural history of prostate cancer. PMID:24453387

  17. Complement activation in progressive renal disease

    PubMed Central

    Fearn, Amy; Sheerin, Neil Stephen

    2015-01-01

    Chronic kidney disease (CKD) is common and the cause of significant morbidity and mortality. The replacement of functioning nephrons by fibrosis is characteristic of progressive disease. The pathways that lead to fibrosis are not fully understood, although chronic non-resolving inflammation in the kidney is likely to drive the fibrotic response that occurs. In patients with progressive CKD there is histological evidence of inflammation in the interstitium and strategies that reduce inflammation reduce renal injury in pre-clinical models of CKD. The complement system is an integral part of the innate immune system but also augments adaptive immune responses. Complement activation is known to occur in many diverse renal diseases, including glomerulonephritis, thrombotic microangiopathies and transplant rejection. In this review we discuss current evidence that complement activation contributes to progression of CKD, how complement could cause renal inflammation and whether complement inhibition would slow progression of renal disease. PMID:25664245

  18. Parkinson's disease showing progressive conduction aphasia.

    PubMed

    Sakai, Kenji; Ono, Kenjiro; Harada, Hiromi; Shima, Keisuke; Notoya, Masako; Yamada, Masahito

    2012-04-01

    Patients with Parkinson's disease (PD) may develop progressive dementia late in their clinical course. Dementia in PD is mostly related to neuropathological findings of extensive Lewy bodies (LBs), with or without the coexistence of Alzheimer's disease (AD) pathology. Aphasia has been reported in patients with LB diseases with AD pathology; however, there have been no reports of typical PD patients developing progressive aphasia during their clinical course. We describe a female PD patient who later developed progressive conduction aphasia characterized by phonemic paraphasia and disturbance in repetition of short sentences without disturbance in writing or auditory comprehension. No episodes of fluctuations of attention, memory complaints, or planning errors were observed. She experienced episodes of visual hallucination. Her low scores on the Mini-Mental State Examination suggested impairment of orientation and attention, and her scores on Raven's Coloured Progressive Matrices test indicated impaired visuospatial functions. However, her cognitive deficits were not sufficiently severe to impair her daily life. Brain magnetic resonance images revealed atrophy of the left superior temporal gyrus and widening of the left sylvian fissure. [(18)F]-fluorodeoxyglucose positron emission tomography revealed glucose hypometabolism in the left cerebral hemisphere. These findings may be related to conduction aphasia. During the progression of PD lesions, the brainstem LB is assumed to take an upward course, extend to the limbic system, and then extend to the neocortex. Conduction aphasia observed in our patient may be associated with an unusual progression of the LB pathology from the brainstem to the left temporoparietal lobe. PMID:21879327

  19. Raised soluble P-selectin moderately accelerates atherosclerotic plaque progression.

    PubMed

    Woollard, Kevin J; Lumsden, Natalie G; Andrews, Karen L; Aprico, Andrea; Harris, Emma; Irvine, Jennifer C; Jefferis, Ann-maree; Fang, Lu; Kanellakis, Peter; Bobik, Alex; Chin-Dusting, Jaye P F

    2014-01-01

    Soluble P-selectin (sP-selectin), a biomarker of inflammatory related pathologies including cardiovascular and peripheral vascular diseases, also has pro-atherosclerotic effects including the ability to increase leukocyte recruitment and modulate thrombotic responses in vivo. The current study explores its role in progressing atherosclerotic plaque disease. Apoe-/- mice placed on a high fat diet (HFD) were given daily injections of recombinant dimeric murine P-selectin (22.5 µg/kg/day) for 8 or 16 weeks. Saline or sE-selectin injections were used as negative controls. In order to assess the role of sP-selectin on atherothrombosis an experimental plaque remodelling murine model, with sm22α-hDTR Apoe-/- mice on a HFD in conjunction with delivery of diphtheria toxin to induce targeted vascular smooth muscle apoptosis, was used. These mice were similarly given daily injections of sP-selectin for 8 or 16 weeks. While plaque mass and aortic lipid content did not change with sP-selectin treatment in Apoe-/- or SM22α-hDTR Apoe-/- mice on HFD, increased plasma MCP-1 and a higher plaque CD45 content in Apoe-/- HFD mice was observed. As well, a significant shift towards a more unstable plaque phenotype in the SM22α-hDTR Apoe-/- HFD mice, with increased macrophage accumulation and lower collagen content, leading to a lower plaque stability index, was observed. These results demonstrate that chronically raised sP-selectin favours progression of an unstable atherosclerotic plaque phenotype.

  20. Immune Inflammation and Disease Progression in Idiopathic Pulmonary Fibrosis.

    PubMed

    Balestro, Elisabetta; Calabrese, Fiorella; Turato, Graziella; Lunardi, Francesca; Bazzan, Erica; Marulli, Giuseppe; Biondini, Davide; Rossi, Emanuela; Sanduzzi, Alessandro; Rea, Federico; Rigobello, Chiara; Gregori, Dario; Baraldo, Simonetta; Spagnolo, Paolo; Cosio, Manuel G; Saetta, Marina

    2016-01-01

    The clinical course in idiopathic pulmonary fibrosis (IPF) is highly heterogeneous, with some patients having a slow progression and others an accelerated clinical and functional decline. This study aims to clinically characterize the type of progression in IPF and to investigate the pathological basis that might account for the observed differences in disease behavior. Clinical and functional data were analyzed in 73 IPF patients, followed long-time as candidates for lung transplantation. The forced vital capacity (FVC) change/year (< or ≥10% predicted) was used to define "slow" or "rapid" disease progression. Pathological abnormalities were quantified in the explanted lung of 41 out of 73 patients undergoing lung transplantation. At diagnosis, slow progressors (n = 48) showed longer duration of symptoms and lower FVC than rapid progressors (n = 25). Eleven slow and 3 rapid progressors developed an acute exacerbation (AE) during follow-up. Quantitative lung pathology showed a severe innate and adaptive inflammatory infiltrate in rapid progressors, markedly increased compared to slow progressors and similar to that observed in patients experiencing AE. The extent of inflammation was correlated with the yearly FVC decline (r = 0.52, p = 0.005). In conclusion an innate and adaptive inflammation appears to be a prominent feature in the lung of patients with IPF and could contribute to determining of the rate of disease progression. PMID:27159038

  1. Depressive Symptoms and Small Hippocampal Volume Accelerate the Progression to Dementia from Mild Cognitive Impairment.

    PubMed

    Chung, Jun Ku; Plitman, Eric; Nakajima, Shinichiro; Chakravarty, M Mallar; Caravaggio, Fernando; Takeuchi, Hiroyoshi; Gerretsen, Philip; Iwata, Yusuke; Patel, Raihaan; Mulsant, Benoit H; Graff-Guerrero, Ariel

    2015-01-01

    Previous studies have highlighted that decreased hippocampal volume, an early neural correlate of dementia, is commonly observed in patients with mild cognitive impairment (MCI). However, it is unclear whether neurodegenerative and resultant clinical trajectories are accelerated in MCI patients with concomitant depressive symptoms, leading to a faster conversion to dementia stages than those who are not depressed. No longitudinal study has investigated whether depressed amnestic MCI (DEP+aMCI) patients show an earlier onset of progression to dementia than non-depressed amnestic MCI (DEP-aMCI) patients and whether progressive hippocampal volume reductions are related in the conversion process. Using data from Alzheimer's Disease Neuroimaging Initiative, we examined 2-year follow-up data from 38 DEP+aMCI patients and 38 matched DEP-aMCI patients and compared their ages of conversion from aMCI to AD and trajectories of progressive hippocampal volume changes. DEP+ and DEP- patients were defined as having baseline Geriatric Depression Scale scores of 5 or above and 0, respectively. DEP+ converters showed earlier ages of conversion to dementia (p = 0.009) and greater left hippocampal volume loss than both DEP- converters and DEP+ non-converters over the 2-year period (p = 0.003, p = 0.001, respectively). These findings could not be explained by changes in total brain volume, differences in their clinical symptoms of dementia, daily functioning, or apolipoprotein E4 genotypes. No difference in conversion rate to dementia or progressive hippocampal volume change was found between DEP+ patients and DEP-patients, which suggested depressive symptoms themselves may not lead to progression of dementia from MCI. In conclusion, there is a synergistic effect of depressive symptoms and smaller left hippocampal volume in MCI patients that accelerates conversion to dementia.

  2. Recent progress in vaccines against fungal diseases.

    PubMed

    Cassone, Antonio; Casadevall, Arturo

    2012-08-01

    Diseases caused by fungi are increasingly impacting the health of the human population and now account for a large fraction of infectious disease complications in individuals with impaired immunity or breached tissue defenses. Antifungal therapy is often of limited effectiveness in these patients, resulting into treatment failures, chronic infections and unacceptable rates of mortality, morbidity and their associated costs. Consequently there is a real medical need for new treatments and preventive measures to combat fungal diseases and, toward this goal, safe and efficacious vaccines would constitute major progress. After decades of complacency and neglect of this critically important field of research, remarkable progress has been made in recent years. A number of highly immunogenic and protective vaccine formulations in preclinical setting have been developed, and at least two have undergone Phase 1 clinical trials as preventive and/or therapeutic tools against candidiasis.

  3. Challenges of modifying disease progression in prediagnostic Parkinson's disease.

    PubMed

    Salat, David; Noyce, Alastair J; Schrag, Anette; Tolosa, Eduardo

    2016-05-01

    Neurodegeneration in Parkinson's disease starts years before a clinical diagnosis can be reliably made. The prediagnostic phase of the disease offers a window of opportunity in which disease-modifying therapies-ie, those aimed at delaying or preventing the progression to overt disease and its many complications-could be most beneficial, but no such therapies are available at present. The unravelling of the mechanisms of neurodegeneration from the earliest stages, however, could lead to the development of new interventions whose therapeutic potential will need to be assessed in adequately designed clinical trials. Advances in the understanding of this prediagnostic phase of Parkinson's disease (for which the clinical diagnostic and prognostic markers used in more advanced disease stages are not applicable) will lead to the identification of biomarkers of neurodegeneration and its progression. These biomarkers will, in turn, help to identify the optimum population to be included and the most appropriate outcomes to be assessed in trials of disease-modifying drugs. Potential risks to minimally symptomatic participants, some of whom might not progress to manifest Parkinson's disease, and individuals who do not wish to know their mutation carrier status, could pose specific ethical dilemmas in the design of these trials. PMID:26993435

  4. JAK INHIBITION AND PROGRESSIVE KIDNEY DISEASE

    PubMed Central

    Brosius, Frank C.; He, John Cijiang

    2015-01-01

    Purpose of review To review the role of JAK-STAT signaling in the progression of chronic kidney diseases. Recent findings The JAK-STAT pathway transmits signals from extracellular ligands, including many cytokines and chemokines. While these responses are best characterized in lymphoid cells, they also occur in kidney cells such as podocytes, mesangial cells, and tubular cells. JAK-STAT expression and signaling abnormalities occur in humans and animal models of different chronic kidney diseases. Enhanced expression and augmented activity of JAK1, JAK2 and STAT3 promote diabetic nephropathy and their inhibition appears to reduce disease. Activation of JAK-STAT signaling in autosomal dominant polycystic kidney disease may play an important role in cyst growth. Activation of JAK-STAT signaling promotes HIV-associated nephropathy and may also participate in the tubular responses to chronic obstructive uropathy. Based on data from experimental models, inhibition of JAK-STAT signaling, via increased expression of the suppressors of cytokine signaling proteins or pharmacologic inhibition of JAK and STAT proteins, could play a therapeutic role in multiple chronic kidney diseases. Summary Activation of the JAK-STAT pathway appears to play a role in the progression of some chronic kidney diseases. More work is needed to determine the specific role the pathway plays in individual diseases. PMID:25415616

  5. How does diabetes accelerate Alzheimer disease pathology?

    PubMed

    Sims-Robinson, Catrina; Kim, Bhumsoo; Rosko, Andrew; Feldman, Eva L

    2010-10-01

    Diabetes and Alzheimer disease (AD)-two age-related diseases-are both increasing in prevalence, and numerous studies have demonstrated that patients with diabetes have an increased risk of developing AD compared with healthy individuals. The underlying biological mechanisms that link the development of diabetes with AD are not fully understood. Abnormal protein processing, abnormalities in insulin signaling, dysregulated glucose metabolism, oxidative stress, the formation of advanced glycation end products, and the activation of inflammatory pathways are features common to both diseases. Hypercholesterolemia is another factor that has received attention, owing to its potential association with diabetes and AD. This Review summarizes the mechanistic pathways that might link diabetes and AD. An understanding of this complex interaction is necessary for the development of novel drug therapies and lifestyle guidelines aimed at the treatment and/or prevention of these diseases.

  6. Taking Control of Castleman Disease: Leveraging Precision Medicine Technologies to Accelerate Rare Disease Research

    PubMed Central

    Newman, Samantha Kass; Jayanthan, Raj K.; Mitchell, Grant W.; Carreras Tartak, Jossie A.; Croglio, Michael P.; Suarez, Alexander; Liu, Amy Y.; Razzo, Beatrice M.; Oyeniran, Enny; Ruth, Jason R.; Fajgenbaum, David C.

    2015-01-01

    Castleman disease (CD) is a rare and heterogeneous disorder characterized by lymphadenopathy that may occur in a single lymph node (unicentric) or multiple lymph nodes (multicentric), the latter typically occurring secondary to excessive proinflammatory hypercytokinemia. While a cohort of multicentric Castleman disease (MCD) cases are caused by Human Herpes Virus-8 (HHV-8), the etiology of HHV-8 negative, idiopathic MCD (iMCD), remains unknown. Breakthroughs in “omics” technologies that have facilitated the development of precision medicine hold promise for elucidating disease pathogenesis and identifying novel therapies for iMCD. However, in order to leverage precision medicine approaches in rare diseases like CD, stakeholders need to overcome several challenges. To address these challenges, the Castleman Disease Collaborative Network (CDCN) was founded in 2012. In the past 3 years, the CDCN has worked to transform the understanding of the pathogenesis of CD, funded and initiated genomics and proteomics research, and united international experts in a collaborative effort to accelerate progress for CD patients. The CDCN’s collaborative structure leverages the tools of precision medicine and serves as a model for both scientific discovery and advancing patient care. PMID:26604862

  7. Genetic determinants of disease progression in Alzheimer's disease.

    PubMed

    Wang, Xingbin; Lopez, Oscar L; Sweet, Robert A; Becker, James T; DeKosky, Steven T; Barmada, Mahmud M; Demirci, F Yesim; Kamboh, M Ilyas

    2015-01-01

    There is a strong genetic basis for late-onset Alzheimer's disease (LOAD); thus far 22 genes/loci have been identified that affect the risk of LOAD. However, the relationships among the genetic variations at these loci and clinical progression of the disease have not been fully explored. In the present study, we examined the relationships of 22 known LOAD genes to the progression of AD in 680 AD patients recruited from the University of Pittsburgh Alzheimer's Disease Research Center. Patients were classified as "rapid progressors" if the Mini-Mental State Examination (MMSE) changed ≥3 points in 12 months and "slow progressors" if the MMSE changed ≤2 points. We also performed a genome-wide association study in this cohort in an effort to identify new loci for AD progression. Association analysis between single nucleotide polymorphisms (SNPs) and the progression status of the AD cases was performed using logistic regression model controlled for age, gender, dementia medication use, psychosis, and hypertension. While no significant association was observed with either APOE*4 (p = 0.94) or APOE*2 (p = 0.33) with AD progression, we found multiple nominally significant associations (p < 0.05) either within or adjacent to seven known LOAD genes (INPP5D, MEF2C, TREM2, EPHA1, PTK2B, FERMT2, and CASS4) that harbor both risk and protective SNPs. Genome-wide association analyses identified four suggestive loci (PAX3, CCRN4L, PIGQ, and ADAM19) at p < 1E-05. Our data suggest that short-term clinical disease progression in AD has a genetic basis. Better understanding of these genetic factors could help to improve clinical trial design and potentially affect the development of disease modifying therapies.

  8. Accelerator technology program. Progress report, January-June 1981

    SciTech Connect

    Knapp, E.A.; Jameson, R.A.

    1982-05-01

    This report covers the activities of Los Alamos National Laboratory's Accelerator Technology Division during the first 6 months of calendar 1981. We discuss the Division's major projects, which reflect a variety of applications and sponsors. The varied technologies concerned with the Proton Storage ring are concerned with the Proton Storage Ring are continuing and are discussed in detail. For the racetrack microtron (RTM) project, the major effort has been the design and construction of the demonstration RTM. Our development of the radio-frequency quadrupole (RFQ) linear accelerator continues to stimulate interest for many possible applications. Frequent contacts from other laboratories have revealed a wide acceptance of the RFQ principle in solving low-velocity acceleration problems. In recent work on heavy ion fusion we have developed ideas for funneling beams from RFQ linacs; the funneling process is explained. To test as many aspects as possible of a fully integrated low-energy portion of a Pion generator for Medical Irradiation (PIGMI) Accelerator, a prototype accelerator was designed to take advantage of several pieces of existing accelerator hardware. The important principles to be tested in this prototype accelerator are detailed. Our prototype gyrocon has been extensively tested and modified; we discuss results from our investigations. Our work with the Fusion Materials Irradiation Test Facility is reviewed in this report.

  9. Multiple Orderings of Events in Disease Progression.

    PubMed

    Young, Alexandra L; Oxtoby, Neil P; Huang, Jonathan; Marinescu, Razvan V; Daga, Pankaj; Cash, David M; Fox, Nick C; Ourselin, Sebastien; Schott, Jonathan M; Alexander, Daniel C

    2015-01-01

    The event-based model constructs a discrete picture of disease progression from cross-sectional data sets, with each event corresponding to a new biomarker becoming abnormal. However, it relies on the assumption that all subjects follow a single event sequence. This is a major simplification for sporadic disease data sets, which are highly heterogeneous, include distinct subgroups, and contain significant proportions of outliers. In this work we relax this assumption by considering two extensions to the event-based model: a generalised Mallows model, which allows subjects to deviate from the main event sequence, and a Dirichlet process mixture of generalised Mallows models, which models clusters of subjects that follow different event sequences, each of which has a corresponding variance. We develop a Gibbs sampling technique to infer the parameters of the two models from multi-modal biomarker data sets. We apply our technique to data from the Alzheimer's Disease Neuroimaging Initiative to determine the sequence in which brain regions become abnormal in sporadic Alzheimer's disease, as well as the heterogeneity of that sequence in the cohort. We find that the generalised Mallows model estimates a larger variation in the event sequence across subjects than the original event-based model. Fitting a Dirichlet process model detects three subgroups of the population with different event sequences. The Gibbs sampler additionally provides an estimate of the uncertainty in each of the model parameters, for example an individual's latent disease stage and cluster assignment. The distributions and mixtures of sequences that this new family of models introduces offer better characterisation of disease progression of heterogeneous populations, new insight into disease mechanisms, and have the potential for enhanced disease stratification and differential diagnosis. PMID:26223048

  10. [Tolerance of +Gz accelerations in chronic compensated cardiac muscle disease].

    PubMed

    Suvorov, P M; Bykova, Iu I

    1975-01-01

    The functional potentialities of the cardiovascular system were investigated during an exposure of people with compensated chronic diseases of the cardiac muscle to acceleration (+Gz). The test subjects were exposed to acceleration of 3 and 5 g for 30 sec with an interval of 5 min. The parameters of hemodynamics, ECG and visual perception were recorded. The systolic blood volume, cardiac output and specific peripheral resistance were derived from the Bremser-Ranke formula. Seventy one subjects with heart diseases and 23 healthy subjects were examined. The subjects with myocardiodystrophy and myocarditic cardiosclerosis (12+/-16) showed a reduced tolerance to accelerations. During an exposure the subjects with atherosclerotic cardiosclerosis showed a higher pressure in vessels of ear conch than the healthy subjects. The myocardiodystrophic subjects frequently (20%) exhibited an inversion of electrocardiographic T2. The subjects with heart diseases (27-33%) showed extrasystolic disturbances. The results may be used in medical expertise of pilots.

  11. [Tolerance of +Gz accelerations in chronic compensated cardiac muscle disease].

    PubMed

    Suvorov, P M; Bykova, Iu I

    1975-01-01

    The functional potentialities of the cardiovascular system were investigated during an exposure of people with compensated chronic diseases of the cardiac muscle to acceleration (+Gz). The test subjects were exposed to acceleration of 3 and 5 g for 30 sec with an interval of 5 min. The parameters of hemodynamics, ECG and visual perception were recorded. The systolic blood volume, cardiac output and specific peripheral resistance were derived from the Bremser-Ranke formula. Seventy one subjects with heart diseases and 23 healthy subjects were examined. The subjects with myocardiodystrophy and myocarditic cardiosclerosis (12+/-16) showed a reduced tolerance to accelerations. During an exposure the subjects with atherosclerotic cardiosclerosis showed a higher pressure in vessels of ear conch than the healthy subjects. The myocardiodystrophic subjects frequently (20%) exhibited an inversion of electrocardiographic T2. The subjects with heart diseases (27-33%) showed extrasystolic disturbances. The results may be used in medical expertise of pilots. PMID:1214489

  12. Depression and cancer: mechanisms and disease progression.

    PubMed

    Spiegel, David; Giese-Davis, Janine

    2003-08-01

    Depression and cancer commonly co-occur. The prevalence of depression among cancer patients increases with disease severity and symptoms such as pain and fatigue. The literature on depression as a predictor of cancer incidence is mixed, although chronic and severe depression may be associated with elevated cancer risk. There is divided but stronger evidence that depression predicts cancer progression and mortality, although disentangling the deleterious effects of disease progression on mood complicates this research, as does the fact that some symptoms of cancer and its treatment mimic depression. There is evidence that providing psychosocial support reduces depression, anxiety, and pain, and may increase survival time with cancer, although studies in this latter area are also divided. Psychophysiological mechanisms linking depression and cancer progression include dysregulation of the hypothalamic-pituitary-adrenal axis, especially diurnal variation in cortisol and melatonin. Depression also affects components of immune function that may affect cancer surveillance. Thus, there is evidence of a bidirectional relationship between cancer and depression, offering new opportunities for therapeutic intervention.

  13. Accelerator technology program. Progress report, July-December 1981

    SciTech Connect

    Knapp, E.A.; Jameson, R.A.

    1982-08-01

    We report on the major projects of the Los Alamos National Laboratory's Accelerator Technology Division during the last 6 months of calendar year 1981. We have continued work on the radio-frequency quadrupole linear accelerator; we are doing studies of octupole focusing. We have completed the design study on an unusual electron-linear radiographic machine that could obtain x rays of turbine engines operating under simulated flight-maneuver conditions on a centrifuge. In September we completed the 5-y PIon Generator for Medical Irradiation (PIGMI) program to develop the concept and technology for an accelerator-based facility to treat cancer in a hospital environment. The design and construction package for the site, building, and utilities for the Fusion Materials Irradiation Test (FMIT) facility has been completed, and we have begun to concentrate on tests of the rf power equipment and on the design, procurement, and installation of the 2-MeV proto-type accelerator. The Proton Storage Ring project has continued to mature. The main effort on the racetrack microtron (RTM) has been on the design and construction of various components for the demonstration RTM. On the gyrocon radio-frequency generator project, the gyrocon was rebuilt with a new electron gun and new water-cooled gun-focus coil; these new components have performed well. We have initiated a project to produce a klystron analysis code that will be useful in reducing the electrical-energy demand for accelerators. A free-electron laser amplifier experiment to test the performance of a tapered wiggler at high optical power has been successfully completed.

  14. Metabolome in progression to Alzheimer's disease

    PubMed Central

    Orešič, M; Hyötyläinen, T; Herukka, S-K; Sysi-Aho, M; Mattila, I; Seppänan-Laakso, T; Julkunen, V; Gopalacharyulu, P V; Hallikainen, M; Koikkalainen, J; Kivipelto, M; Helisalmi, S; Lötjönen, J; Soininen, H

    2011-01-01

    Mild cognitive impairment (MCI) is considered as a transition phase between normal aging and Alzheimer's disease (AD). MCI confers an increased risk of developing AD, although the state is heterogeneous with several possible outcomes, including even improvement back to normal cognition. We sought to determine the serum metabolomic profiles associated with progression to and diagnosis of AD in a prospective study. At the baseline assessment, the subjects enrolled in the study were classified into three diagnostic groups: healthy controls (n=46), MCI (n=143) and AD (n=47). Among the MCI subjects, 52 progressed to AD in the follow-up. Comprehensive metabolomics approach was applied to analyze baseline serum samples and to associate the metabolite profiles with the diagnosis at baseline and in the follow-up. At baseline, AD patients were characterized by diminished ether phospholipids, phosphatidylcholines, sphingomyelins and sterols. A molecular signature comprising three metabolites was identified, which was predictive of progression to AD in the follow-up. The major contributor to the predictive model was 2,4-dihydroxybutanoic acid, which was upregulated in AD progressors (P=0.0048), indicating potential involvement of hypoxia in the early AD pathogenesis. This was supported by the pathway analysis of metabolomics data, which identified upregulation of pentose phosphate pathway in patients who later progressed to AD. Together, our findings primarily implicate hypoxia, oxidative stress, as well as membrane lipid remodeling in progression to AD. Establishment of pathogenic relevance of predictive biomarkers such as ours may not only facilitate early diagnosis, but may also help identify new therapeutic avenues. PMID:22832349

  15. 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.

  16. Accelerator technology program. Progress report, July-December 1980

    SciTech Connect

    Knapp, E.A.; Jameson, R.A.

    1982-01-01

    The activities of Los Alamos National Laboratory's Accelerator Technology Division are discussed. This report covers the last six months of calendar 1980 and is organized around the Division's major projects. These projects reflect a wide variety of applications and sponsors. The major technological innovations promoted by the Pion Generator for Medical Irradiation (PIGMI) program have been developed; accelerator technologies relevant to the design of a medically practical PIGMI have been identified. A new group in AT Division deals with microwave and magnet studies; we describe the status of some of their projects. We discuss the prototype gyrocon, which has been completed, and the development of the radio-frequency quadrupole linear accelerator, which continues to stimulate interest for many possible applications. One section of this report briefly describes the results of a design study for an electron beam ion source that is ideally suited as an injector for a heavy ion linac; another section reports on a turbine engine test facility that will expose operating turbine engines to simulated maneuver forces. In other sections we discuss various activities: the Fusion Materials Irradiation Test program, the free-electron laser program, the racetrack microtron project, the Proton Storage ring, and H/sup -/ ion sources and injectors.

  17. Crevicular Fluid Biomarkers and Periodontal Disease Progression

    PubMed Central

    Oh, Min; Braun, Thomas M.; Ramseier, Christoph A.; Sugai, Jim V.; Giannobile, William V.

    2014-01-01

    Aim Assess the ability of a panel of gingival crevicular fluid (GCF) biomarkers as predictors of periodontal disease progression (PDP). Materials and Methods 100 individuals participated in a 12-month longitudinal investigation and categorized into 4 groups according to their periodontal status. GCF, clinical parameters, and saliva were collected bi-monthly. Sub-gingival plaque and serum were collected bi-annually. For 6 months, no periodontal treatment was provided. At 6-months, patients received periodontal therapy and continued participation from 6-12 months. GCF samples were analyzed by ELISA for MMP-8, MMP-9, OPG, CRP and IL-1β. Differences in median levels of GCF biomarkers were compared between stable and progressing participants using Wilcoxon Rank Sum test (p=0.05). Clustering algorithm was used to evaluate the ability of oral biomarkers to classify patients as either stable or progressing. Results Eighty-three individuals completed the 6-month monitoring phase. With the exception of GCF C-reactive protein, all biomarkers were significantly higher in the PDP group compared to stable patients. Clustering analysis showed highest sensitivity levels when biofilm pathogens and GCF biomarkers were combined with clinical measures, 74% (95% CI = 61,86). Conclusions Signature of GCF fluid-derived biomarkers combined with pathogens and clinical measures provides a sensitive measure for discrimination of PDP (ClinicalTrials.gov NCT00277745). PMID:24303954

  18. Measuring disease progression in corticobasal syndrome.

    PubMed

    Huang, Nancy; Hornberger, Michael; Hodges, John R; Burrell, James R

    2014-08-01

    Corticobasal syndrome (CBS) is a complex neurodegenerative disorder with marked clinical, neuropsychological, and pathological heterogeneity. Measurement of disease progression in CBS is complex and little understood. This study aimed to establish clinical and neuropsychological indicators of prognosis in CBS. Patients with CBS were retrospectively recruited from a frontotemporal dementia specific research clinic. All patients underwent detailed clinical and neuropsychological testing including the frontotemporal dementia rating scale (FRS). Using the differences in FRS logit scores over a period of 12 months, CBS patients were divided into rapid and slow progressor groups. Demographic, clinical and neuropsychological features were compared between the two groups. Sixteen participants who met defined criteria were included (9 males, 7 females; mean age 65.8 ± 22 years; median symptom duration 51.8 ± 22 years; mean duration of follow-up 11.4 ± 2.8 months). There were no significant differences between the rapid and slow progressors in age, gender, symptom duration, motor/cognitive presentation, and ACE-R scores at baseline. Clinically, slow progressors were significantly more likely to have a motor speech disorder, with a trend for more frequent dysgraphia, whereas rapid progressors were more likely to exhibit surface dyslexia. Rapid and slow progressor groups did not differ on neuropsychological performance. The presence of motor speech disorder, dysgraphia, and surface dyslexia may be useful in differentiating patients with rapid progression of CBS from those with a more indolent disease course. PMID:24893591

  19. Putaminal Diffusivity Correlates With Disease Progression in Parkinson's Disease

    PubMed Central

    Chan, Ling-Ling; Ng, Kia-Min; Yeoh, Chooi-Sum; Rumpel, H.; Li, Hui-Hua; Tan, Eng-King

    2016-01-01

    Abstract Diffusion tensor imaging (DTI) is an increasingly used noninvasive imaging tool. However its long-term clinical utility is unclear. Parkinson's disease (PD) is a common neurodegenerative disease. We prospectively examined a cohort of 46 Parkinson's disease (PD) patients who underwent diffusion tensor imaging (DTI) of the brain at baseline and 6 years later on a 1.5 Tesla scanner using a standardized protocol. DTI parameters of mean diffusivity (MD) and fractional anisotrophy (FA) were extracted using regions-of-interest (ROIs) analysis from various brain regions. Compared to the baseline scan, MD increased in all brain regions (P < 0.0001). FA increased in the substantia nigra and posterior putamen, but decreased in the frontal white matter (P < 0.0001). Linear regression analysis demonstrated that the MD in the anterior putamen increased 11.6 units (95% CI = [4.71, 18.43]) (P = 0.0003) for every unit increase of United PD Rating Scale (UPDRS). Our 6-year prospective longitudinal study demonstrated increased diffusivity in all brain regions and that in the anterior putamen correlated with disease progression. Serial diffusion data may be useful as an additional objective in vivo biomarker for motor progression in PD. PMID:26871779

  20. Final Progress Report - Heavy Ion Accelerator Theory and Simulation

    SciTech Connect

    Haber, Irving

    2009-10-31

    The use of a beam of heavy ions to heat a target for the study of warm dense matter physics, high energy density physics, and ultimately to ignite an inertial fusion pellet, requires the achievement of beam intensities somewhat greater than have traditionally been obtained using conventional accelerator technology. The research program described here has substantially contributed to understanding the basic nonlinear intense-beam physics that is central to the attainment of the requisite intensities. Since it is very difficult to reverse intensity dilution, avoiding excessive dilution over the entire beam lifetime is necessary for achieving the required beam intensities on target. The central emphasis in this research has therefore been on understanding the nonlinear mechanisms that are responsible for intensity dilution and which generally occur when intense space-charge-dominated beams are not in detailed equilibrium with the external forces used to confine them. This is an important area of study because such lack of detailed equilibrium can be an unavoidable consequence of the beam manipulations such as acceleration, bunching, and focusing necessary to attain sufficient intensity on target. The primary tool employed in this effort has been the use of simulation, particularly the WARP code, in concert with experiment, to identify the nonlinear dynamical characteristics that are important in practical high intensity accelerators. This research has gradually made a transition from the study of idealized systems and comparisons with theory, to study the fundamental scaling of intensity dilution in intense beams, and more recently to explicit identification of the mechanisms relevant to actual experiments. This work consists of two categories; work in direct support beam physics directly applicable to NDCX and a larger effort to further the general understanding of space-charge-dominated beam physics.

  1. Immune responses in rapidly progressive dementia: a comparative study of neuroinflammatory markers in Creutzfeldt-Jakob disease, Alzheimer's disease and multiple sclerosis.

    PubMed

    Stoeck, Katharina; Schmitz, Matthias; Ebert, Elisabeth; Schmidt, Christian; Zerr, Inga

    2014-10-15

    Immunological responses may contribute to disease progression and clinical heterogeneity in neurodegenerative dementia, for example, Alzheimer's disease (AD) and Creutzfeldt-Jakob disease (CJD). Recently, a rapidly progressive form of AD (rpAD) has been described. On neuropathological grounds classical AD and rpAD are not distinguishable at present. All those protein aggregopathies show a state of chronic inflammation with microglia activation and production of proinflammatory cytokines. In this context, it is hypothesized that the severity of the surrounding inflammation substantially contributes to disease progression and accelerated disease courses as seen in rpAD.

  2. How pregnancy can affect autoimmune diseases progression?

    PubMed

    Piccinni, Marie-Pierre; Lombardelli, Letizia; Logiodice, Federica; Kullolli, Ornela; Parronchi, Paola; Romagnani, Sergio

    2016-01-01

    Autoimmune disorders are characterized by tissue damage, caused by self-reactivity of different effectors mechanisms of the immune system, namely antibodies and T cells. Their occurrence may be associated with genetic and/or environmental predisposition and to some extent, have implications for fertility and obstetrics. The relationship between autoimmunity and reproduction is bidirectional. This review only addresses the impact of pregnancy on autoimmune diseases and not the influence of autoimmunity on pregnancy development. Th17/Th1-type cells are aggressive and pathogenic in many autoimmune disorders and inflammatory diseases. The immunology of pregnancy underlies the role of Th2-type cytokines to maintain the tolerance of the mother towards the fetal semi-allograft. Non-specific factors, including hormonal changes, favor a switch to Th2-type cytokine profile. In pregnancy Th2, Th17/Th2 and Treg cells accumulate in the decidua but may also be present in the mother's circulation and can regulate autoimmune responses influencing the progression of autoimmune diseases. PMID:27651750

  3. ["SOS SEIN 84" accelerated breast disease management: Patients satisfaction survey].

    PubMed

    Arnaud, Antoine; Dumuids, Magali; Mège, Alice; de Rauglaudre, Gaëtan; Regis Arnaud, Anne; Martin, Nicole; Dupuy Meurat, Françoise; Dolle, Sabine; Gallon, Elise; Serin, Daniel

    2016-05-01

    In case of a new breast symptom or an abnormal result of breast imaging, some women have a problem finding a quick answer to allay their anxiety. The Institut Sainte-Catherine in Avignon has set up a new form of accelerated disease management through the opening of a new dedicated consultation called SOS SEIN 84. We present the result of a prospective quality study of our first new patients.

  4. Progressive Nodular Histiocytosis Associated with Eale's Disease

    PubMed Central

    Williams, Abhilasha; Thomas, Abraham G; Kwatra, Kanwardeep Singh; Jain, Kunal

    2015-01-01

    Progressive nodular histiocytosis (PNH) is a rare normolipemic macrophage disorder and belongs to a subgroup of non-Langerhans cell histiocytosis (LCHs) which is characterized by a progressive course with no sign of spontaneous resolution but without systemic involvement. We report a 30-year-old gentleman who presented with skin lesions all over the body associated with gradual bilateral painless loss of vision. On examination, approximately 30 to 40, skin-colored, firm, non-tender papules and nodules were noted over the body especially on the face and trunk. A skin biopsy revealed a cellular tumor in the dermis composed of oval to spindle-shaped cells, positive for CD68 but negative for S-100, CD34, CD21, CD35 and HMB45, supporting a diagnosis of spindle cell histiocytic tumor. Ophthalmic examination revealed a generalized arteriolar attenuation in both eyes. He received Tab Imatinib 400 mg OD for 5 months followed by Tab Pazopanib 800 mg OD for 4 months and both the drugs were stopped due to lack of any response in the skin lesions. We report this case due to its rarity, characteristic clinical presentation, and its association with Eale's disease. Primary treatment remains surgical excision of bothersome lesions and optimal systemic treatment is still unknown. PMID:26288410

  5. Accelerating Regulatory Progress in Multi-Institutional Research

    PubMed Central

    Paolino, Andrea R.; Lauf, Sherry Lee; Pieper, Lisa E.; Rowe, Jared; Vargas, Ileana M.; Goff, Melissa A.; Daley, Matthew F.; Tuzzio, Leah; Steiner, John F.

    2014-01-01

    Purpose: Multi-institutional collaborations are necessary in order to create large and robust data sets that are needed to answer important comparative effectiveness research (CER) questions. Before scientific work can begin, a complex maze of administrative and regulatory requirements must be efficiently navigated to avoid project delays. Innovation: Staff from research, regulatory, and administrative teams involved in three HMO Research Network (HMORN) multi-institutional collaborations developed and employed novel approaches: to secure and maintain Institutional Review Board (IRB) approvals; to enable data sharing, and to expedite subawards for two data-only minimal risk studies. These novel approaches accelerated required processes and approvals while maintaining regulatory, human subjects, and institutional protections. Credibility: Outcomes from the processes described here are compared with processes outlined in the research and regulatory literature and with processes that have been used in previous multisite research collaborations. Conclusion and Discussion: Research, regulatory, and administrative staff are essential contributors to the success of multi-institutional collaborations. Their flexibility, creativity, and effective communication skills can lead to the development of efficient approaches to achieving the necessary oversight for these complex projects. Elements of these specific strategies can be adapted and used by other research networks. Other efforts in these areas should be evaluated and shared. The processes that help develop a “learning research system” play an important and complementary role in sustaining multi-institutional research collaborations. PMID:25848593

  6. STAT3 activation in monocytes accelerates liver cancer progression

    PubMed Central

    2011-01-01

    Background Signal transducer and activator of transcription 3 (STAT3) is an important transcription factor ubiquitously expressed in different cell types. STAT3 plays an essential role in cell survival, proliferation, and differentiation. Aberrantly hyper-activated STAT3 signaling in cancer cells and in the tumor microenvironment has been detected in a wide variety of human cancers and is considered an important factor for cancer initiation, development, and progression. However, the role of STAT3 activation in monocytes in the development of HCC has not been well understood. Methods Immunohistochemical analysis of phosphorylated STAT3 was performed on tissue microarray from HCC patients. Using a co-culture system in vivo, HCC cell growth was determined by the MTT assay. In vivo experiments were conducted with mice given diethylinitrosamine (DEN), which induces HCC was used to investigate the role of STAT3 expression in monocytes on tumor growth. Real-time PCR was used to determine the expression of cell proliferation and cell arrest associated genes in the tumor and nontumor tissue from liver. Results Phosphorylated STAT3 was found in human hepatocellular carcinoma tissue samples and was expressed in tumor cells and also in monocytes. Phosphorylated STAT3 expression in monocyte was significantly correlated to advanced clinical stage of HCC and a poor prognosis. Using a co-culture system in vivo, monocytes promoted HCC cell growth via the IL-6/STAT3 signaling pathway. The STAT3 inhibitor, NSC 74859, significantly suppressed tumor growth in vivo in mice with diethylinitrosamine (DEN)-induced HCC. In this animal model, blockade of STAT3 with NSC 74859 induced tumor cell apoptosis, while inhibiting both tumor cells and monocytes proliferation. Furthermore, NSC 74859 treatment suppressed cancer associated inflammation in DEN-induce HCC. Conclusion Our data suggest constitutively activated STAT3 monocytes promote liver tumorigenesis in clinical patients and animal

  7. Osteoarthritis accelerates and exacerbates Alzheimer's disease pathology in mice

    PubMed Central

    2011-01-01

    Background The purpose of this study was to investigate whether localized peripheral inflammation, such as osteoarthritis, contributes to neuroinflammation and neurodegenerative disease in vivo. Methods We employed the inducible Col1-IL1βXAT mouse model of osteoarthritis, in which induction of osteoarthritis in the knees and temporomandibular joints resulted in astrocyte and microglial activation in the brain, accompanied by upregulation of inflammation-related gene expression. The biological significance of the link between peripheral and brain inflammation was explored in the APP/PS1 mouse model of Alzheimer's disease (AD) whereby osteoarthritis resulted in neuroinflammation as well as exacerbation and acceleration of AD pathology. Results Induction of osteoarthritis exacerbated and accelerated the development of neuroinflammation, as assessed by glial cell activation and quantification of inflammation-related mRNAs, as well as Aβ pathology, assessed by the number and size of amyloid plaques, in the APP/PS1; Col1-IL1βXAT compound transgenic mouse. Conclusion This work supports a model by which peripheral inflammation triggers the development of neuroinflammation and subsequently the induction of AD pathology. Better understanding of the link between peripheral localized inflammation, whether in the form of osteoarthritis, atherosclerosis or other conditions, and brain inflammation, may prove critical to our understanding of the pathophysiology of disorders such as Alzheimer's, Parkinson's and other neurodegenerative diseases. PMID:21899735

  8. Experimental and theoretical investigation of high gradient acceleration. Progress report, June 1, 1991--February 1, 1992

    SciTech Connect

    Bekefi, G.; Chen, C.; Chen, S.; Danly, B.; Temkin, R.J.; Wurtele, J.S.

    1992-02-01

    This report contains a technical progress summary of the research conducted under the auspices of DOE Grant No. DE-FG0291ER-40648. ``Experimental and Theoretical Investigations of High Gradient Acceleration.`` This grant supports three research tasks: Task A consists of the design and fabrication of a 17GHz of photocathode gun, Task B supports the testing of high gradient acceleration using a 33GHz structure, and Task C comprises theoretical investigations, both in support of the experimental tasks and on critical physics issues for the development of high energy linear colliders. This report is organized as follows. The development of an rf gun design and research progress on the picosecond laser system is summarized in Sec. 2, the status of the studies of the LBL/Haimson high gradient structure, using a 50 MW free-electron laser is summarized in Sec. 3, and theoretical research progress is described in Sec. 4. Supporting material is contained in Appendices A-G.

  9. SIRT3 regulates progression and development of diseases of aging

    PubMed Central

    Bomze, Howard M.; Hirschey, Matthew D.

    2015-01-01

    The mitochondrial sirtuin SIRT3 is a protein deacylase that regulates almost every major aspect of mitochondrial biology, including nutrient oxidation, ATP generation, reactive oxygen species detoxification, mitochondrial dynamics, and the mitochondrial unfolded protein response. Interestingly, mice lacking SIRT3 (SIRT3KO), either spontaneously or when crossed with mouse models of disease, develop several diseases of aging at an accelerated pace, such as cancer, metabolic syndrome, cardiovascular disease, and neurodegenerative diseases, and thus might be a valuable model of accelerated aging. In this review we discuss SIRT3 functions in pathways involved in diseases of aging, how lack of SIRT3 might accelerate the aging process, and suggest that further studies on SIRT3 might help uncover important new pathways driving the aging process. PMID:26138757

  10. Stop chronic kidney disease progression: Time is approaching

    PubMed Central

    Sharaf El Din, Usama Abdel Azim; Salem, Mona Mansour; Abdulazim, Dina Ossama

    2016-01-01

    Progression of chronic kidney disease (CKD) is inevitable. However, the last decade has witnessed tremendous achievements in this field. Today we are optimistic; the dream of withholding this progression is about to be realistic. The recent discoveries in the field of CKD management involved most of the individual diseases leading the patients to end-stage renal disease. Most of these advances involved patients suffering diabetic kidney disease, chronic glomerulonephritis, polycystic kidney disease, renal amyloidosis and chronic tubulointerstitial disease. The chronic systemic inflammatory status and increased oxidative stress were also investigated. This inflammatory status influences the anti-senescence Klotho gene expression. The role of Klotho in CKD progression together with its therapeutic value are explored. The role of gut as a major source of inflammation, the pathogenesis of intestinal mucosal barrier damage, the role of intestinal alkaline phosphatase and the dietary and therapeutic implications add a novel therapeutic tool to delay CKD progression. PMID:27152262

  11. Stop chronic kidney disease progression: Time is approaching.

    PubMed

    Sharaf El Din, Usama Abdel Azim; Salem, Mona Mansour; Abdulazim, Dina Ossama

    2016-05-01

    Progression of chronic kidney disease (CKD) is inevitable. However, the last decade has witnessed tremendous achievements in this field. Today we are optimistic; the dream of withholding this progression is about to be realistic. The recent discoveries in the field of CKD management involved most of the individual diseases leading the patients to end-stage renal disease. Most of these advances involved patients suffering diabetic kidney disease, chronic glomerulonephritis, polycystic kidney disease, renal amyloidosis and chronic tubulointerstitial disease. The chronic systemic inflammatory status and increased oxidative stress were also investigated. This inflammatory status influences the anti-senescence Klotho gene expression. The role of Klotho in CKD progression together with its therapeutic value are explored. The role of gut as a major source of inflammation, the pathogenesis of intestinal mucosal barrier damage, the role of intestinal alkaline phosphatase and the dietary and therapeutic implications add a novel therapeutic tool to delay CKD progression. PMID:27152262

  12. Progress Report on Alzheimer Disease: Volume III.

    ERIC Educational Resources Information Center

    National Inst. on Aging (DHHS/PHS), Bethesda, MD.

    This report summarizes advances in the understanding of Alzheimer's disease, the major cause of mental disability among older Americans. The demography of the disease is discussed, noting that approximately 2.5 million American adults are afflicted with the disease and that the large increase in the number of Alzheimer's disease patients is due to…

  13. Deficiency of Ube3a in Huntington's disease mice brain increases aggregate load and accelerates disease pathology.

    PubMed

    Maheshwari, Megha; Shekhar, Shashi; Singh, Brijesh Kumar; Jamal, Imran; Vatsa, Naman; Kumar, Vipendra; Sharma, Ankit; Jana, Nihar Ranjan

    2014-12-01

    Huntington's disease (HD) is an inherited neurodegenerative disorder caused by abnormal expansion of CAG repeats in the gene encoding huntingtin. Mutant huntingtin undergoes proteolytic processing and its N-terminal fragment containing polyglutamine repeat accumulates as inclusion not only in nucleus but also in cytoplasm and neuronal processes. Here, we demonstrate that removal of ubiquitin ligase Ube3a selectively from HD mice brain resulted in accelerated disease phenotype and shorter lifespan in comparison with HD mice. The deficiency of Ube3a in HD mice brain also caused significant increase in global aggregates load, and these aggregates were less ubiquitinated when compared with age-matched HD mice. These Ube3a-maternal deficient HD mice also showed drastic reduction of DARPP-32, a dopamine-regulated phoshphoprotein in their striatum. These results emphasize the crucial role of Ube3a in the progression of HD and its immense potential as therapeutic target. PMID:25027318

  14. Mechanisms of disease progression in nonalcoholic fatty liver disease.

    PubMed

    Jou, Janice; Choi, Steve S; Diehl, Anna Mae

    2008-11-01

    Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of hepatic pathology, ranging from simple steatosis (also called nonalcoholic fatty liver or NAFL) in its most benign form, to cirrhosis in its most advanced form. Nonalcoholic steatohepatitis (NASH) is an intermediate level of hepatic pathology. Hepatocyte accumulation of triglyceride is a hallmark of NAFL and NASH, but this sometimes subsides once cirrhosis has developed. Triglyceride storage per se is not hepatotoxic. Rather, it is a marker of increased exposure of hepatocytes to potentially toxic fatty acids. NAFL progresses to NASH when adaptive mechanisms that protect hepatocytes from fatty acid-mediated lipotoxicity become overwhelmed and rates of hepatocyte death begin to outstrip mechanisms that normally regenerate dead hepatocytes. This triggers repair responses that involve activation of hepatic stellate cells to myofibroblasts. The myofibroblasts generate excessive matrix and produce factors that stimulate expansion of liver progenitor populations. The progenitor cells produce chemokines to attract various kinds of inflammatory cells to the liver. They also differentiate to replace the dead hepatocytes. The intensity of these repair responses generally parallel the degree of hepatocyte death, resulting in variable distortion of the hepatic architecture with fibrosis, infiltrating immune cells, and regenerating epithelial nodules. As in other types of chronic liver injury, cirrhosis ensues in patients with NAFLD when repair is extreme and sustained, but ultimately unsuccessful, at reconstituting healthy hepatic epithelia. PMID:18956293

  15. Interferon treatment of NZB mice: accelerated progression of autoimmune disease.

    PubMed Central

    Heremans, H; Billiau, A; Colombatti, A; Hilgers, J; de Somer, P

    1978-01-01

    The effect of long-term administration of interferon in New Zealand Black and New Zealand Black/New Zealand White F1 hybrid mice was studied. Treatment with moderate doses of interferon (10(4) units, five times weekly for 8 weeks) did not depress murine leukemia virus gp69/71 levels in serum and spleen, nor p30 levels in the spleen. Interferon given at 10(5.1) units (three times weekly for 37 weeks) caused an increased incidence of anti-erythrocyte antibodies in New Zealand Black mice. Finally, the hybrid mice given interferon at 10(6.0) units (three times weekly for 33 weeks) had increased renal immune complex deposits and increased incidences of proteinuria and anemia. Images PMID:213392

  16. Schwann cells expressing dismutase active mutant SOD1 unexpectedly slow disease progression in ALS mice

    PubMed Central

    Lobsiger, Christian S.; Boillee, Severine; McAlonis-Downes, Melissa; Khan, Amir M.; Feltri, M. Laura; Yamanaka, Koji; Cleveland, Don W.

    2009-01-01

    Neurodegeneration in an inherited form of ALS is non-cell-autonomous, with ALS-causing mutant SOD1 damage developed within multiple cell types. Selective inactivation within motor neurons of an ubiquitously expressed mutant SOD1 gene has demonstrated that mutant damage within motor neurons is a determinant of disease initiation, whereas mutant synthesis within neighboring astrocytes or microglia accelerates disease progression. We now report the surprising finding that diminished synthesis (by 70%) within Schwann cells of a fully dismutase active ALS-linked mutant (SOD1G37R) significantly accelerates disease progression, accompanied by reduction of insulin-like growth factor 1 (IGF-1) in nerves. Coupled with shorter disease duration in mouse models caused by dismutase inactive versus dismutase active SOD1 mutants, our findings implicate an oxidative cascade during disease progression that is triggered within axon ensheathing Schwann cells and that can be ameliorated by elevated dismutase activity. Thus, therapeutic down-regulation of dismutase active mutant SOD1 in familial forms of ALS should be targeted away from Schwann cells. PMID:19251638

  17. Research Finds Link Between Statin Use and Progressive Muscle Disease

    MedlinePlus

    ... Research Finds Link Between Statin Use and Progressive Muscle Disease Each year, millions of Americans take statins, ... people these benefits come at a cost: widespread muscle pain that persists as long as the drugs ...

  18. Posttraumatic Growth and HIV Disease Progression

    ERIC Educational Resources Information Center

    Milam, Joel

    2006-01-01

    The relationship between posttraumatic growth (PTG; perceiving positive changes since diagnosis) and disease status, determined by changes in viral load and CD4 count over time, was examined among 412 people living with HIV. In controlled multiple regression models, PTG was not associated with disease status over time for the entire sample.…

  19. Progress Report on Alzheimer's Disease: Volume II.

    ERIC Educational Resources Information Center

    National Inst. on Aging (DHHS/PHS), Bethesda, MD.

    This document provides an overview of the state of scientific study of Alzheimer's disease, a disease of catastrophic proportions whose symptoms include serious forgetfulness; changes in personality; confused, restless, and irritable behavior; and problems with judgment, concentration, writing, reading, speech, and naming of objects. It discusses…

  20. Progress and Challenges in Infectious Disease Cartography.

    PubMed

    Kraemer, Moritz U G; Hay, Simon I; Pigott, David M; Smith, David L; Wint, G R William; Golding, Nick

    2016-01-01

    Quantitatively mapping the spatial distributions of infectious diseases is key to both investigating their epidemiology and identifying populations at risk of infection. Important advances in data quality and methodologies have allowed for better investigation of disease risk and its association with environmental factors. However, incorporating dynamic human behavioural processes in disease mapping remains challenging. For example, connectivity among human populations, a key driver of pathogen dispersal, has increased sharply over the past century, along with the availability of data derived from mobile phones and other dynamic data sources. Future work must be targeted towards the rapid updating and dissemination of appropriately designed disease maps to guide the public health community in reducing the global burden of infectious disease.

  1. Progress and Challenges in Infectious Disease Cartography.

    PubMed

    Kraemer, Moritz U G; Hay, Simon I; Pigott, David M; Smith, David L; Wint, G R William; Golding, Nick

    2016-01-01

    Quantitatively mapping the spatial distributions of infectious diseases is key to both investigating their epidemiology and identifying populations at risk of infection. Important advances in data quality and methodologies have allowed for better investigation of disease risk and its association with environmental factors. However, incorporating dynamic human behavioural processes in disease mapping remains challenging. For example, connectivity among human populations, a key driver of pathogen dispersal, has increased sharply over the past century, along with the availability of data derived from mobile phones and other dynamic data sources. Future work must be targeted towards the rapid updating and dissemination of appropriately designed disease maps to guide the public health community in reducing the global burden of infectious disease. PMID:26604163

  2. Serum Resistin Level and Progression of Atherosclerosis during Glucocorticoid Therapy for Systemic Autoimmune Diseases

    PubMed Central

    Tanaka, Nahoko; Masuoka, Shotaro; Kusunoki, Natsuko; Nanki, Toshihiro; Kawai, Shinichi

    2016-01-01

    Adipokines are important regulators of several processes, including inflammation and atherosclerosis. In patients with systemic autoimmune diseases, atherosclerosis is accelerated with higher cardiovascular morbidity and mortality. We prospectively investigated the association of adipokines and glucocorticoid therapy with progression of premature atherosclerosis in 38 patients starting glucocorticoid therapy for systemic autoimmune diseases. To detect premature atherosclerosis, carotid ultrasonography was performed at initiation of glucocorticoid therapy and after a mean three-year follow-up period. The ankle-brachial pressure index and cardio-ankle vascular index (CAVI) were measured. Serum adipokine levels were determined with enzyme-linked immunosorbent assay kits. Twenty-three patients (60.5%) had carotid artery plaque at baseline. The carotid artery intima-media thickness (IMT) increased significantly during follow-up. Glucocorticoids reduced the serum resistin level, while increasing serum leptin and high molecular weight-adiponectin. There was slower progression of atherosclerosis (carotid IMT and CAVI) at follow-up in patients with greater reduction of serum resistin and with higher cumulative prednisolone dose. In conclusion, progression of premature atherosclerosis occurred at an early stage of systemic autoimmune diseases before initiation of glucocorticoid therapy. Since resistin, an inflammation and atherosclerosis related adipokine, is reduced by glucocorticoids, glucocortidoid therapy may not accelerate atherosclerosis in patients with systemic autoimmune diseases. PMID:27649254

  3. Serum Resistin Level and Progression of Atherosclerosis during Glucocorticoid Therapy for Systemic Autoimmune Diseases.

    PubMed

    Tanaka, Nahoko; Masuoka, Shotaro; Kusunoki, Natsuko; Nanki, Toshihiro; Kawai, Shinichi

    2016-09-16

    Adipokines are important regulators of several processes, including inflammation and atherosclerosis. In patients with systemic autoimmune diseases, atherosclerosis is accelerated with higher cardiovascular morbidity and mortality. We prospectively investigated the association of adipokines and glucocorticoid therapy with progression of premature atherosclerosis in 38 patients starting glucocorticoid therapy for systemic autoimmune diseases. To detect premature atherosclerosis, carotid ultrasonography was performed at initiation of glucocorticoid therapy and after a mean three-year follow-up period. The ankle-brachial pressure index and cardio-ankle vascular index (CAVI) were measured. Serum adipokine levels were determined with enzyme-linked immunosorbent assay kits. Twenty-three patients (60.5%) had carotid artery plaque at baseline. The carotid artery intima-media thickness (IMT) increased significantly during follow-up. Glucocorticoids reduced the serum resistin level, while increasing serum leptin and high molecular weight-adiponectin. There was slower progression of atherosclerosis (carotid IMT and CAVI) at follow-up in patients with greater reduction of serum resistin and with higher cumulative prednisolone dose. In conclusion, progression of premature atherosclerosis occurred at an early stage of systemic autoimmune diseases before initiation of glucocorticoid therapy. Since resistin, an inflammation and atherosclerosis related adipokine, is reduced by glucocorticoids, glucocortidoid therapy may not accelerate atherosclerosis in patients with systemic autoimmune diseases.

  4. Serum Resistin Level and Progression of Atherosclerosis during Glucocorticoid Therapy for Systemic Autoimmune Diseases.

    PubMed

    Tanaka, Nahoko; Masuoka, Shotaro; Kusunoki, Natsuko; Nanki, Toshihiro; Kawai, Shinichi

    2016-01-01

    Adipokines are important regulators of several processes, including inflammation and atherosclerosis. In patients with systemic autoimmune diseases, atherosclerosis is accelerated with higher cardiovascular morbidity and mortality. We prospectively investigated the association of adipokines and glucocorticoid therapy with progression of premature atherosclerosis in 38 patients starting glucocorticoid therapy for systemic autoimmune diseases. To detect premature atherosclerosis, carotid ultrasonography was performed at initiation of glucocorticoid therapy and after a mean three-year follow-up period. The ankle-brachial pressure index and cardio-ankle vascular index (CAVI) were measured. Serum adipokine levels were determined with enzyme-linked immunosorbent assay kits. Twenty-three patients (60.5%) had carotid artery plaque at baseline. The carotid artery intima-media thickness (IMT) increased significantly during follow-up. Glucocorticoids reduced the serum resistin level, while increasing serum leptin and high molecular weight-adiponectin. There was slower progression of atherosclerosis (carotid IMT and CAVI) at follow-up in patients with greater reduction of serum resistin and with higher cumulative prednisolone dose. In conclusion, progression of premature atherosclerosis occurred at an early stage of systemic autoimmune diseases before initiation of glucocorticoid therapy. Since resistin, an inflammation and atherosclerosis related adipokine, is reduced by glucocorticoids, glucocortidoid therapy may not accelerate atherosclerosis in patients with systemic autoimmune diseases. PMID:27649254

  5. Slowing progression along the renal disease continuum.

    PubMed

    Kopyt, Nelson P

    2005-04-01

    Patients in whom nephropathy develops as a result of hypertension or diabetes mellitus are more likely to die of cardiovascular disease (CVD) than of kidney disease. An early sign of impending nephropathy is microalbuminuria, defined as urinary excretion of albumin at a rate of 28.8 mg/24 h to 288 mg/24 h. Microalbuminuria is a marker of endothelial dysfunction, vascular injury, and renal disease and CVD, and it is associated with increased risk for myocardial infarction. Oxidative stress and endothelial dysfunction are unifying factors mediated by the renin-angiotensin system in renal disease and CVD. Clinical trials show reduced cardiovascular risk and a reversal of microalbuminuria with the use of agents that affect the renin-angiotensin system: angiotensin-receptor blockers in patients with type 2 diabetes mellitus and nephropathy, or angiotensin-converting enzyme inhibitors in patients with type 1 diabetes mellitus.

  6. Potential mechanisms of disease progression and management of advanced-phase chronic myeloid leukemia

    PubMed Central

    Jabbour, Elias J.; Hughes, Timothy P.; Cortés, Jorge E.; Kantarjian, Hagop M.; Hochhaus, Andreas

    2014-01-01

    Despite vast improvements in treatment of Philadelphia chromosome–positive chronic myeloid leukemia (CML) in chronic phase (CP), advanced stages of CML, accelerated phase or blast crisis, remain notoriously difficult to treat. Treatments that are highly effective against CML-CP produce disappointing results against advanced disease. Therefore, a primary goal of therapy should be to maintain patients in CP for as long as possible, by (1) striving for deep, early molecular response to treatment; (2) using tyrosine kinase inhibitors that lower risk of disease progression; and (3) more closely observing patients who demonstrate cytogenetic risk factors at diagnosis or during treatment. PMID:24050507

  7. Recent achievements in restorative neurology: Progressive neuromuscular diseases

    SciTech Connect

    Dimitrijevic, M.R.; Kakulas, B.A.; Vrbova, G.

    1986-01-01

    This book contains 27 chapters. Some of the chapter titles are: Computed Tomography of Muscles in Neuromuscular Disease; Mapping the Genes for Muscular Dystrophy; Trophic Factors and Motor Neuron Development; Size of Motor Units and Firing Rate in Muscular Dystrophy; Restorative Possibilities in Relation to the Pathology of Progressive Neuromuscular Disease; and An Approach to the Pathogenesis of some Congenital Myopathies.

  8. Accelerator research studies. Technical progress report, June 1, 1991--May 31, 1992

    SciTech Connect

    Not Available

    1992-02-01

    The Accelerator Research Studies program at the University of Maryland, sponsored by the Department of Energy under grant number DE-FG05-91ER40642, is currently in the first year of a three-year funding cycle. The program consists of the following three tasks: TASK A, Study of Transport and Longitudinal Compression of Intense, High-Brightness Beams, TASK B, Study of Collective Ion Acceleration by Intense Electron Beams and Pseudospark Produced High Brightness Electron Beams; TASK C, Study of a Gyroklystron High-power Microwave Source for Linear Colliders. In this report we document the progress that has been made during the past year for each of the three tasks.

  9. Experimental and theoretical investigation of high gradient acceleration. Progress report, February 1, 1992--January 31, 1993

    SciTech Connect

    Wurtele, J.S.; Bekefi, G.; Chen, C.; Chen, S.C.; Temkin, R.J.

    1993-01-01

    This report contains a technical progress summary of the research conducted under the auspices of DOE Grant No. DE-AC02-91-ER40648, ``Experimental and Theoretical Investigations of High Gradient Acceleration``. This grant supports three research tasks: Task A consists of the design, fabrication and testing of a 17GHz RF photocathode gun, which can produce 2ps electron pulses with up to 1nC of charge at 2MeV energy and at a 1OHz repetition rate. Task B supports the testing of high gradient acceleration at 33GHz structure, and Task C comprises theoretical investigations, both in support of the experimental tasks and on critical physics issues for the development of high energy linear colliders.

  10. Progress toward externally powered x-band dielectric-loaded accelerating structures.

    SciTech Connect

    Gai, W.; Power, J. G.; Liu, W.; Jing, C.; Gold, S. H.; Kinead, A. K.; Tantawi, S. G.; Dolgashev, V.; Kanareykin, A.; Konecny, R.; Wanming, L.

    2010-06-01

    We summarize recent progress in a program to develop externally powered dielectric-loaded accelerating (DLA) structures that can sustain high accelerating gradients. High-power RF tests of earlier structures showed strong multipactor loading. In addition, arcing at dielectric joints between the uniform DLA structure and matching sections at either end limited the achievable gradient. In this paper, we study the onset of multipactor in a DLA structure. We also study the effect of thin-film TiN coatings applied by atomic layer deposition and the effect of a reduction in the inner diameter of the structure. Test results of these structures show significant decreases in multipactor loading. We also test new structure designs that eliminate separate dielectric matching sections and, thus, the requirement for dielectric joints, including a DLA structure using a coaxial coupler and a clamped DLA structure. The clamped structure demonstrated a significantly improved gradient without breakdown.

  11. The Global Nutrition Report 2014: actions and accountability to accelerate the world's progress on nutrition.

    PubMed

    Haddad, Lawrence; Achadi, Endang; Bendech, Mohamed Ag; Ahuja, Arti; Bhatia, Komal; Bhutta, Zulfiqar; Blössner, Monika; Borghi, Elaine; Colecraft, Esi; de Onis, Mercedes; Eriksen, Kamilla; Fanzo, Jessica; Flores-Ayala, Rafael; Fracassi, Patrizia; Kimani-Murage, Elizabeth; Nago Koukoubou, Eunice; Krasevec, Julia; Newby, Holly; Nugent, Rachel; Oenema, Stineke; Martin-Prével, Yves; Randel, Judith; Requejo, Jennifer; Shyam, Tara; Udomkesmalee, Emorn; Reddy, K Srinath

    2015-04-01

    In 2013, the Nutrition for Growth Summit called for a Global Nutrition Report (GNR) to strengthen accountability in nutrition so that progress in reducing malnutrition could be accelerated. This article summarizes the results of the first GNR. By focusing on undernutrition and overweight, the GNR puts malnutrition in a new light. Nearly every country in the world is affected by malnutrition, and multiple malnutrition burdens are the "new normal." Unfortunately, the world is off track to meet the 2025 World Health Assembly (WHA) targets for nutrition. Many countries are, however, making good progress on WHA indicators, providing inspiration and guidance for others. Beyond the WHA goals, nutrition needs to be more strongly represented in the Sustainable Development Goal (SDG) framework. At present, it is only explicitly mentioned in 1 of 169 SDG targets despite the many contributions improved nutritional status will make to their attainment. To achieve improvements in nutrition status, it is vital to scale up nutrition programs. We identify bottlenecks in the scale-up of nutrition-specific and nutrition-sensitive approaches and highlight actions to accelerate coverage and reach. Holding stakeholders to account for delivery on nutrition actions requires a well-functioning accountability infrastructure, which is lacking in nutrition. New accountability mechanisms need piloting and evaluation, financial resource flows to nutrition need to be made explicit, nutrition spending targets should be established, and some key data gaps need to be filled. For example, many UN member states cannot report on their WHA progress and those that can often rely on data >5 y old. The world can accelerate malnutrition reduction substantially, but this will require stronger accountability mechanisms to hold all stakeholders to account.

  12. Erbb2 up-regulation of ADAM12 expression accelerates skin cancer progression.

    PubMed

    Rao, Velidi H; Vogel, Kristen; Yanagida, Jodi K; Marwaha, Nitin; Kandel, Amrit; Trempus, Carol; Repertinger, Susan K; Hansen, Laura A

    2015-10-01

    Solar ultraviolet (UV) radiation can cause severe damage to the skin and is the primary cause of most skin cancer. UV radiation causes DNA damage leading to mutations and also activates the Erbb2/HER2 receptor through indirect mechanisms involving reactive oxygen species. We hypothesized that Erbb2 activation accelerates the malignant progression of UV-induced skin cancer. Following the induction of benign squamous papillomas by UV exposure of v-ras(Ha) transgenic Tg.AC mice, mice were treated topically with the Erbb2 inhibitor AG825 and tumor progression monitored. AG825 treatment reduced tumor volume, increased tumor regression, and delayed the development of malignant squamous cell carcinoma (SCC). Progression to malignancy was associated with increased Erbb2 and ADAM12 (A Disintegin And Metalloproteinase 12) transcripts and protein, while inhibition of Erbb2 blocked the increase in ADAM12 message upon malignant progression. Similarly, human SCC and SCC cell lines had increased ADAM12 protein and transcripts when compared to normal controls. To determine whether Erbb2 up-regulation of ADAM12 contributed to malignant progression of skin cancer, Erbb2 expression was modulated in cultured SCC cells using forced over-expression or siRNA targeting, demonstrating up-regulation of ADAM12 by Erbb2. Furthermore, ADAM12 transfection or siRNA targeting revealed that ADAM12 increased both the migration and invasion of cutaneous SCC cells. Collectively, these results suggest Erbb2 up-regulation of ADAM12 as a novel mechanism contributing to the malignant progression of UV-induced skin cancer. Inhibition of Erbb2/HER2 reduced tumor burden, increased tumor regression, and delayed the progression of benign skin tumors to malignant SCC in UV-exposed mice. Inhibition of Erbb2 suppressed the increase in metalloproteinase ADAM12 expression in skin tumors, which in turn increased migration and tumor cell invasiveness.

  13. Markers predicting progression of human immunodeficiency virus-related disease.

    PubMed Central

    Tsoukas, C M; Bernard, N F

    1994-01-01

    Human immunodeficiency virus (HIV) interacts with the immune system throughout the course of infection. For most of the disease process, HIV activates the immune system, and the degree of activation can be assessed by measuring serum levels of molecules such as beta 2-microglobulin and neopterin, as well as other serum and cell surface phenotype markers. The levels of some of these markers correlate with clinical progression of HIV disease, and these markers may be useful as surrogate markers for development of clinical AIDS. Because the likelihood and timing of development of clinical AIDS following seroconversion, for any particular individual, are not readily predictable, the use of nonclinical disease markers has become critically important to patient management. Surrogate markers of HIV infection are, by definition, measurable traits that correlate with disease progression. An ideal marker should identify patients at highest risk of disease progression, provide information on how long an individual has been infected, help in staging HIV disease, predict development of opportunistic infections associated with AIDS, monitor the therapeutic efficacy of immunomodulating or antiviral treatments, and the easily quantifiable, reliable, clinically available, and affordable. This review examines the current state of knowledge and the role of surrogate markers in the natural history and treatment of HIV infection. The clinical usefulness of each marker is assessed with respect to the criteria outlined for the ideal surrogate marker for HIV disease progression. PMID:8118788

  14. UCLA accelerator research and development. Progress report, [November 1, 1991--July 31, 1992

    SciTech Connect

    Cline, D.B.

    1992-09-01

    This progress report covers work supported by the above DOE grant over the period November 1, 1991 to July 31, 1992. The work is a program of experimental and theoretical studies in advanced particle accelerator research and development for high energy physics applications. The program features research at particle beam facilities in the United States and includes research on novel high power sources, novel focussing systems (e.g. plasma lens), beam monitors, novel high brightness, high current gun systems, and novel flavor factories in particular the {phi} Factory.

  15. Allergic diseases: the price of civilisational progress

    PubMed Central

    Sowa, Paweł; Rutkowska-Talipska, Joanna; Sulkowski, Stanisław; Rutkowski, Ryszard

    2014-01-01

    Atopic disorders are a major global health problem. The prevalence of asthma, allergic rhinitis and atopic dermatitis has been increasing over the last four decades, both in the industrialized and developing countries. It seems to be related to changes in the social structure, increasing industrialization, pollution and dietary changes. Many hypotheses link the allergy epidemic to stringent hygiene, dominance of a westernized lifestyle and an accelerated pace of life. Dietary antioxidants, lipids, sodium, vitamin D seem also to be implicated. We endeavour to review the most relevant theories with a special emphasis on the hygiene, antioxidative, lipid and air pollution hypotheses. It is however important to note that none of them explains all the aspects of unprecedented rise in the prevalence of allergic disorders. A complex interplay between host's immune response, invading pathogens, diversity of environmental factors and genetic background seems to be of a particular importance. Current allergy epidemic is multifactorial and basic and epidemiologic studies are warranted to further our understanding of this phenomenon. PMID:25097472

  16. Drug Development for Alzheimer's Disease: Recent Progress

    PubMed Central

    Ji, Wonjin

    2010-01-01

    Alzheimer's disease, the most common cause of dementia, is characterized by two major pathological hallmarks: amyloid plaques and neurofibrillary tangles. Based on these two indicators, an amyloid cascade hypothesis was proposed, and accordingly, most current therapeutic approaches are now focused on the removal of β-amyloid peptides (Aβ from the brain. Additionally, strategies for blocking tau hyperphosphorylation and aggregation have been suggested, including the development of drugs that can block the formation of tangles. However, there are no true disease-modifying drugs in the current market, though many drugs based on theories other than Aβ and tau pathology are under development. The purpose of this review was to provide information on the current development of AD drugs and to discuss the issues related to drug development. PMID:22110351

  17. Guanabenz Treatment Accelerates Disease in a Mutant SOD1 Mouse Model of ALS.

    PubMed

    Vieira, Fernando G; Ping, Qinggong; Moreno, Andy J; Kidd, Joshua D; Thompson, Kenneth; Jiang, Bingbing; Lincecum, John M; Wang, Monica Z; De Zutter, Gerard S; Tassinari, Valerie R; Levine, Beth; Hatzipetros, Theo; Gill, Alan; Perrin, Steven

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by loss of motor neurons. The mechanisms leading to motor neuron degeneration in ALS are unclear. However, there is evidence for involvement of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in ALS, notably in mutant SOD1 mediated models of ALS. Stress induced phosphorylation of the eIF2 alpha subunit by eukaryotic translation initiation factor 2-alpha kinase 3 Perk activates the UPR. Guanabenz is a centrally acting alpha2 adrenergic receptor agonist shown to interact with a regulatory subunit of the protein phosphatase, Pp1/Gadd34, and selectively disrupt the dephosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eif2alpha). Here we demonstrate that guanabenz is protective in fibroblasts expressing G93A mutant SOD1 when they are exposed to tunicamycin mediated ER stress. However, in contrast to other reports, guanabenz treatment accelerated ALS-like disease progression in a strain of mutant SOD1 transgenic ALS mice. This study highlights challenges of pharmacological interventions of cellular stress responses in whole animal models of ALS.

  18. Guanabenz Treatment Accelerates Disease in a Mutant SOD1 Mouse Model of ALS

    PubMed Central

    Vieira, Fernando G.; Ping, Qinggong; Moreno, Andy J.; Kidd, Joshua D.; Thompson, Kenneth; Jiang, Bingbing; Lincecum, John M.; Wang, Monica Z.; De Zutter, Gerard S.; Tassinari, Valerie R.; Levine, Beth; Hatzipetros, Theo; Gill, Alan; Perrin, Steven

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by loss of motor neurons. The mechanisms leading to motor neuron degeneration in ALS are unclear. However, there is evidence for involvement of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in ALS, notably in mutant SOD1 mediated models of ALS. Stress induced phosphorylation of the eIF2 alpha subunit by eukaryotic translation initiation factor 2-alpha kinase 3 Perk activates the UPR. Guanabenz is a centrally acting alpha2 adrenergic receptor agonist shown to interact with a regulatory subunit of the protein phosphatase, Pp1/Gadd34, and selectively disrupt the dephosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eif2alpha). Here we demonstrate that guanabenz is protective in fibroblasts expressing G93A mutant SOD1 when they are exposed to tunicamycin mediated ER stress. However, in contrast to other reports, guanabenz treatment accelerated ALS-like disease progression in a strain of mutant SOD1 transgenic ALS mice. This study highlights challenges of pharmacological interventions of cellular stress responses in whole animal models of ALS. PMID:26288094

  19. Regulatory T cells delay disease progression in Alzheimer-like pathology.

    PubMed

    Dansokho, Cira; Ait Ahmed, Dylla; Aid, Saba; Toly-Ndour, Cécile; Chaigneau, Thomas; Calle, Vanessa; Cagnard, Nicolas; Holzenberger, Martin; Piaggio, Eliane; Aucouturier, Pierre; Dorothée, Guillaume

    2016-04-01

    Recent studies highlight the implication of innate and adaptive immunity in the pathophysiology of Alzheimer's disease, and foster immunotherapy as a promising strategy for its treatment. Vaccines targeting amyloid-β peptide provided encouraging results in mouse models, but severe side effects attributed to T cell responses in the first clinical trial AN1792 underlined the need for better understanding adaptive immunity in Alzheimer's disease. We previously showed that regulatory T cells critically control amyloid-β-specific CD4(+) T cell responses in both physiological and pathological settings. Here, we analysed the impact of regulatory T cells on spontaneous disease progression in a murine model of Alzheimer's disease. Early transient depletion of regulatory T cells accelerated the onset of cognitive deficits in APPPS1 mice, without altering amyloid-β deposition. Earlier cognitive impairment correlated with reduced recruitment of microglia towards amyloid deposits and altered disease-related gene expression profile. Conversely, amplification of regulatory T cells through peripheral low-dose IL-2 treatment increased numbers of plaque-associated microglia, and restored cognitive functions in APPPS1 mice. These data suggest that regulatory T cells play a beneficial role in the pathophysiology of Alzheimer's disease, by slowing disease progression and modulating microglial response to amyloid-β deposition. Our study highlights the therapeutic potential of repurposed IL-2 for innovative immunotherapy based on modulation of regulatory T cells in Alzheimer's disease.

  20. Regulatory T cells delay disease progression in Alzheimer-like pathology.

    PubMed

    Dansokho, Cira; Ait Ahmed, Dylla; Aid, Saba; Toly-Ndour, Cécile; Chaigneau, Thomas; Calle, Vanessa; Cagnard, Nicolas; Holzenberger, Martin; Piaggio, Eliane; Aucouturier, Pierre; Dorothée, Guillaume

    2016-04-01

    Recent studies highlight the implication of innate and adaptive immunity in the pathophysiology of Alzheimer's disease, and foster immunotherapy as a promising strategy for its treatment. Vaccines targeting amyloid-β peptide provided encouraging results in mouse models, but severe side effects attributed to T cell responses in the first clinical trial AN1792 underlined the need for better understanding adaptive immunity in Alzheimer's disease. We previously showed that regulatory T cells critically control amyloid-β-specific CD4(+) T cell responses in both physiological and pathological settings. Here, we analysed the impact of regulatory T cells on spontaneous disease progression in a murine model of Alzheimer's disease. Early transient depletion of regulatory T cells accelerated the onset of cognitive deficits in APPPS1 mice, without altering amyloid-β deposition. Earlier cognitive impairment correlated with reduced recruitment of microglia towards amyloid deposits and altered disease-related gene expression profile. Conversely, amplification of regulatory T cells through peripheral low-dose IL-2 treatment increased numbers of plaque-associated microglia, and restored cognitive functions in APPPS1 mice. These data suggest that regulatory T cells play a beneficial role in the pathophysiology of Alzheimer's disease, by slowing disease progression and modulating microglial response to amyloid-β deposition. Our study highlights the therapeutic potential of repurposed IL-2 for innovative immunotherapy based on modulation of regulatory T cells in Alzheimer's disease. PMID:26912648

  1. A review of disease progression models of Parkinson's disease and applications in clinical trials.

    PubMed

    Venuto, Charles S; Potter, Nicholas B; Ray Dorsey, E; Kieburtz, Karl

    2016-07-01

    Quantitative disease progression models for neurodegenerative disorders are gaining recognition as important tools for drug development and evaluation. In Parkinson's disease (PD), several models have described longitudinal changes in the Unified Parkinson's Disease Rating Scale (UPDRS), one of the most utilized outcome measures for PD trials assessing disease progression. We conducted a literature review to examine the methods and applications of quantitative disease progression modeling for PD using a combination of key words including "Parkinson disease," "progression," and "model." For this review, we focused on models of PD progression quantifying changes in the total UPDRS scores against time. Four different models reporting equations and parameters have been published using linear and nonlinear functions. The reasons for constructing disease progression models of PD thus far have been to quantify disease trajectories of PD patients in active and inactive treatment arms of clinical trials, to quantify and discern symptomatic and disease-modifying treatment effects, and to demonstrate how model-based methods may be used to design clinical trials. The historical lack of efficiency of PD clinical trials begs for model-based simulations in planning for studies that result in more informative conclusions, particularly around disease modification. © 2016 International Parkinson and Movement Disorder Society.

  2. Lipid-Altering Therapies and the Progression of Atherosclerotic Disease

    SciTech Connect

    Wierzbicki, Anthony S.

    2007-04-15

    Lipids play a key role in the progression of atherosclerosis, and lipid-lowering therapies have been studied for 30 years in coronary disease. Measurement of the progression of atherosclerosis through carotid intima-media thickness, coronary mean lumen diameter, and, mostly recently, intravascular ultrasound is generally accepted. This article reviews the role of lipid-lowering therapies in changing the rate of atherosclerosis progression in the coronary and carotid circulations. Statins are the primary therapy used to reduce atherosclerosis and cardiovascular events, including strokes and transient ischemic attacks, and have benefits in reducing events in patients undergoing carotid endarterectomy. In contrast, data for other agents, including fibrates and nicotinic acid, in reducing the progression of atherosclerosis are less extensive and not as well known. There is increasing interest in optimizing the whole lipid profile, as this might deliver extra benefits over and above statin therapy alone. Initial proof of this concept has recently come from studies that measured the progression of atherosclerosis and showed that adding nicotinic acid to statin therapy and, more directly, infusion of high-density lipoprotein-like particles reduced progression and indeed might induce regression of the disease. It is likely that the management of significant carotid stenosis will become ever more drug focused and will be customized to the lipid profile of each patient with intervention reserved only for late-stage symptomatic disease.

  3. Accelerating Progress in Eating Disorders Prevention: A Call for Policy Translation Research and Training.

    PubMed

    Austin, S Bryn

    2016-01-01

    The public health burden of eating disorders is well documented, and over the past several decades, researchers have made important advances in the prevention of eating disorders and related problems with body image. Despite these advances, however, several critical limitations to the approaches developed to date leave the field far from achieving the large-scale impact that is needed. This commentary provides a brief review of what achievements in prevention have been made and identifies the gaps that limit the potential for greater impact on population health. A plan is then offered with specific action steps to accelerate progress in high-impact prevention, most compellingly by promoting a shift in priorities to policy translation research and training for scholars through the adoption of a triggers-to-action framework. Finally, the commentary provides an example of the application of the triggers-to-action framework as practiced at the Strategic Training Initiative for the Prevention of Eating Disorders, a program based at the Harvard T. H. Chan School of Public Health and Boston Children's Hospital. Much has been achieved in the nearly 30 years of research carried out for the prevention of eating disorders and body image problems, but several critical limitations undermine the field's potential for meaningful impact. Through a shift in the field's priorities to policy translation research and training with an emphasis on macro-environmental influences, the pace of progress in prevention can be accelerated and the potential for large-scale impact substantially improved.

  4. Role of sodium intake in the progression of chronic kidney disease.

    PubMed

    Ritz, Eberhard; Koleganova, Nadezda; Piecha, Grzegorz

    2009-01-01

    The relation of salt to hypertension and kidney disease had been well known at the turn of the last century, but the importance of salt has been grossly neglected more recently. There is a close link between salt intake and hypertension, as well as partially blood pressure-independent target organ damage including renal disease. In the general population, high salt intake is associated with hypertension and cardiovascular events. Salt loading also increases albuminuria in individuals without primary renal disease and raises excretion of albumin and protein in patients with renal disease. It aggravates proteinuria and glomerulosclerosis and accelerates progression in most animal models of renal damage. The effect of salt restriction cannot be reproduced by treatment with diuretics. Inappropriate increase of intrarenal angiotensin II and increased reactive oxygen species are the major culprits responsible for salt-related renal damage.

  5. [Therapeutic strategies to prevent chronic kidney disease progression].

    PubMed

    Schmidt, B M W

    2012-07-01

    Chronic kidney disease (CKD) is highly prevalent. Independent from the underlying disease, measures capable of decreasing the progression of CKD have been identified. Lowering of blood pressure and proteinuria are most important. As the potential risk of aggressive blood pressure-lowering strategies has become obvious, the current very low blood pressure goals are doubted. Thus, patients have to be treated individually taking into consideration each patient's preexisting cardiovascular damage and the risk of CKD progression. Additional modifiable risk factors are blood glucose in diabetic patients, lipids, anemia, uric acid, vitamin D, protein intake, and smoking.

  6. Accelerating progress at contaminated sediment sites: moving from guidance to practice.

    PubMed

    Bridges, Todd S; Nadeau, Steven C; McCulloch, Megan C

    2012-04-01

    Contaminated sediments are a pervasive problem in the United States. Significant economic, ecological, and social issues are intertwined in addressing the nation's contaminated sediment problem. Managing contaminated sediments has become increasingly resource intensive, with some investigations costing tens of millions of dollars and the majority of remediation projects proceeding at a slow pace. At present, the approaches typically used to investigate, evaluate, and remediate contaminated sediment sites in the United States have largely fallen short of producing timely, risk-based, cost-effective, long-term solutions. With the purpose of identifying opportunities for accelerating progress at contaminated sediment sites, the US Army Corps of Engineers-Engineer Research and Development Center and the Sediment Management Work Group convened a workshop with experienced experts from government, industry, consulting, and academia. Workshop participants identified 5 actions that, if implemented, would accelerate the progress and increase the effectiveness of risk management at contaminated sediment sites. These actions included: 1) development of a detailed and explicit project vision and accompanying objectives, achievable short-term and long-term goals, and metrics of remedy success at the outset of a project, with refinement occurring as needed throughout the duration of the project; 2) strategic engagement of stakeholders in a more direct and meaningful process; 3) optimization of risk reduction, risk management processes, and remedy selection addressing 2 important elements: a) the deliberate use of early action remedies, where appropriate, to accelerate risk reduction; and b) the systematic and sequential development of a suite of actions applicable to the ultimate remedy, starting with monitored natural recovery and adding engineering actions as needed to satisfy the project's objectives; 4) an incentive process that encourages and rewards risk reduction; and 5

  7. Impact of glucocorticoids and chronic stress on progression of Parkinson's disease.

    PubMed

    Kibel, Aleksandar; Drenjancević-Perić, Ines

    2008-12-01

    Parkinson's disease, a chronic progressive neurodegenerative disorder, has a mainly unknown multifactorial etiology. It is characterized by progressive degeneration of dopaminergic neurons. Chronic stress, a condition mediated by elevated concentrations of glucocorticoids over an extended period of time, has been shown to be unfavourable for neurons and to cause damage and neuronal loss in certain brain areas. Glucocorticoids are most probably not toxic in a direct manner, but can make neuronal damage through several potential indirect mechanisms in combination with other destructive factors. We postulate that chronic stress will have a harmful effect on patients with Parkinson's disease, facilitating neuronal degeneration and accelerating progression of clinical manifestations. The damaging impact on neurons will not be because of direct cytotoxicity, but by putting them into an energetically unfavourable condition, in which they will be more sensitive to destructive factors caused by the primary process. Possible mechanisms include elevation of excitatory amino acid concentration, which are excitotoxic, disruption of calcium homeostasis, metabolic disturbance or impairment of neurogenesis. This could have significant implications for patients with Parkinson's disease and chronic stress, or patients with glucocorticoid treatment for various immunopathological diseases, as well as patients with abnormal secretion of glucocorticoids such as in Cushing's syndrome. If confirmed, this hypothesis would represent a valuable advancement in care of patients with Parkinson's disease.

  8. Is Progressive Chronic Kidney Disease a Slow Acute Kidney Injury?

    PubMed

    Cowgill, Larry D; Polzin, David J; Elliott, Jonathan; Nabity, Mary B; Segev, Gilad; Grauer, Gregory F; Brown, Scott; Langston, Cathy; van Dongen, Astrid M

    2016-11-01

    International Renal Interest Society chronic kidney disease Stage 1 and acute kidney injury Grade I categorizations of kidney disease are often confused or ignored because patients are nonazotemic and generally asymptomatic. Recent evidence suggests these seemingly disparate conditions may be mechanistically linked and interrelated. Active kidney injury biomarkers have the potential to establish a new understanding for traditional views of chronic kidney disease, including its early identification and possible mediators of its progression, which, if validated, would establish a new and sophisticated paradigm for the understanding and approach to the diagnostic evaluation, and treatment of urinary disease in dogs and cats.

  9. Is Progressive Chronic Kidney Disease a Slow Acute Kidney Injury?

    PubMed

    Cowgill, Larry D; Polzin, David J; Elliott, Jonathan; Nabity, Mary B; Segev, Gilad; Grauer, Gregory F; Brown, Scott; Langston, Cathy; van Dongen, Astrid M

    2016-11-01

    International Renal Interest Society chronic kidney disease Stage 1 and acute kidney injury Grade I categorizations of kidney disease are often confused or ignored because patients are nonazotemic and generally asymptomatic. Recent evidence suggests these seemingly disparate conditions may be mechanistically linked and interrelated. Active kidney injury biomarkers have the potential to establish a new understanding for traditional views of chronic kidney disease, including its early identification and possible mediators of its progression, which, if validated, would establish a new and sophisticated paradigm for the understanding and approach to the diagnostic evaluation, and treatment of urinary disease in dogs and cats. PMID:27593574

  10. Clinical Progression in Parkinson's Disease and the Neurobiology of Axons

    PubMed Central

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

    2010-01-01

    In spite of tremendous growth in recent years in our knowledge of the molecular basis of Parkinson's disease and the molecular pathways of cell injury and death, we remain without therapies that forestall disease progression. While 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 it is ongoing degeneration of axons, not cell bodies, that 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. PMID:20517933

  11. Accuracy Improvement for Predicting Parkinson’s Disease Progression

    PubMed Central

    Nilashi, Mehrbakhsh; Ibrahim, Othman; Ahani, Ali

    2016-01-01

    Parkinson’s disease (PD) is a member of a larger group of neuromotor diseases marked by the progressive death of dopamineproducing cells in the brain. Providing computational tools for Parkinson disease using a set of data that contains medical information is very desirable for alleviating the symptoms that can help the amount of people who want to discover the risk of disease at an early stage. This paper proposes a new hybrid intelligent system for the prediction of PD progression using noise removal, clustering and prediction methods. Principal Component Analysis (PCA) and Expectation Maximization (EM) are respectively employed to address the multi-collinearity problems in the experimental datasets and clustering the data. We then apply Adaptive Neuro-Fuzzy Inference System (ANFIS) and Support Vector Regression (SVR) for prediction of PD progression. Experimental results on public Parkinson’s datasets show that the proposed method remarkably improves the accuracy of prediction of PD progression. The hybrid intelligent system can assist medical practitioners in the healthcare practice for early detection of Parkinson disease. PMID:27686748

  12. Africa's health: could the private sector accelerate the progress towards health MDGs?

    PubMed Central

    2011-01-01

    Background Out of 1.484 billion disability-adjusted life years lost globally in 2008, 369.1 million (25%) were lost in the WHO African Region. Despite the heavy disease burden, the majority of countries in the Region are not on track to achieve Millennium Development Goals (MDG) 4 (reducing child mortality), 5 (improving maternal health), and 6 (combating HIV/AIDS, malaria and other diseases). This article provides an overview of the state of public health, summarizes 2010-2015 WHO priorities, and explores the role that private sector could play to accelerate efforts towards health MDGs in the African Region. Discussion Of the 752 total resolutions adopted by the WHO Regional Committee for Africa (RC) between years 1951 and 2010, 45 mention the role of the private sector. We argue that despite the rather limited role implied in RC resolutions, the private sector has a pivotal role in supporting the achievement of health MDGs, and articulating efforts with 2010-2015 priorities for WHO in the African Region: provision of normative and policy guidance as well as strengthening partnerships and harmonization; supporting the strengthening of health systems based on the Primary Health Care approach; putting the health of mothers and children first; accelerating actions on HIV/AIDS, malaria and tuberculosis; intensifying the prevention and control of communicable and noncommunicable diseases; and accelerating response to the determinants of health. Conclusion The very high maternal and children mortality, very high burden of communicable and non-communicable diseases, health systems challenges, and inter-sectoral issues related to key determinants of health are too heavy for the public sector to address alone. Therefore, there is clear need for the private sector, given its breadth, scope and size, to play a more significant role in supporting governments, communities and partners to develop and implement national health policies and strategic plans; strengthen health

  13. Weight Loss Predicts Progression of Mild Cognitive Impairment to Alzheimer’s Disease

    PubMed Central

    Cova, Ilaria; Rossi, Annalia; Cucumo, Valentina; Ghiretti, Roberta; Maggiore, Laura; Pomati, Simone; Galimberti, Daniela; Scarpini, Elio; Mariani, Claudio; Caracciolo, Barbara

    2016-01-01

    Background Weight loss is common in people with Alzheimer’s disease (AD) and it could be a marker of impending AD in Mild Cognitive Impairment (MCI) and improve prognostic accuracy, if accelerated progression to AD would be shown. Aims To assess weight loss as a predictor of dementia and AD in MCI. Methods One hundred twenty-five subjects with MCI (age 73.8 ± 7.1 years) were followed for an average of 4 years. Two weight measurements were carried out at a minimum time interval of one year. Dementia was defined according to DSM-IV criteria and AD according to NINCDS-ADRDA criteria. Weight loss was defined as a ≥4% decrease in baseline weight. Results Fifty-three (42.4%) MCI progressed to dementia, which was of the AD-type in half of the cases. Weight loss was associated with a 3.4-fold increased risk of dementia (95% CI = 1.5–6.9) and a 3.2-fold increased risk of AD (95% CI = 1.4–8.3). In terms of years lived without disease, weight loss was associated to a 2.3 and 2.5 years earlier onset of dementia and AD. Conclusions Accelerated progression towards dementia and AD is expected when weight loss is observed in MCI patients. Weight should be closely monitored in elderly with mild cognitive impairment. PMID:26990757

  14. Progress in public-private partnerships to fight neglected diseases.

    PubMed

    Gustavsen, Kenneth; Hanson, Christy

    2009-01-01

    In the global fight against neglected tropical diseases (NTDs), public health partnerships involving donations of medicines by pharmaceutical companies are enabling access to treatment for millions of people worldwide. These partnerships collaborate with other disease programs and a range of key stakeholders to develop and improve programs to control and eliminate NTDs. Although progress is being made against NTDs, continued success depends on a policy environment that supports appropriate levels of engagement and collaboration from all participants.

  15. COMT Val158Met Polymorphism Modulates Huntington's Disease Progression

    PubMed Central

    Rebeix, Isabelle; Dupoux, Emmanuel; Durr, Alexandra; Brice, Alexis; Charles, Perrine; Cleret de Langavant, Laurent; Youssov, Katia; Verny, Christophe; Damotte, Vincent; Azulay, Jean-Philippe; Goizet, Cyril; Simonin, Clémence; Tranchant, Christine; Maison, Patrick; Rialland, Amandine; Schmitz, David; Jacquemot, Charlotte; Fontaine, Bertrand; Bachoud-Lévi, Anne-Catherine

    2016-01-01

    Little is known about the genetic factors modulating the progression of Huntington’s disease (HD). Dopamine levels are affected in HD and modulate executive functions, the main cognitive disorder of HD. We investigated whether the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene, which influences dopamine (DA) degradation, affects clinical progression in HD. We carried out a prospective longitudinal multicenter study from 1994 to 2011, on 438 HD gene carriers at different stages of the disease (34 pre-manifest; 172 stage 1; 130 stage 2; 80 stage 3; 17 stage 4; and 5 stage 5), according to Total Functional Capacity (TFC) score. We used the Unified Huntington’s Disease Rating Scale to evaluate motor, cognitive, behavioral and functional decline. We genotyped participants for COMT polymorphism (107 Met-homozygous, 114 Val-homozygous and 217 heterozygous). 367 controls of similar ancestry were also genotyped. We compared clinical progression, on each domain, between groups of COMT polymorphisms, using latent-class mixed models accounting for disease duration and number of CAG (cytosine adenine guanine) repeats. We show that HD gene carriers with fewer CAG repeats and with the Val allele in COMT polymorphism displayed slower cognitive decline. The rate of cognitive decline was greater for Met/Met homozygotes, which displayed a better maintenance of cognitive capacity in earlier stages of the disease, but had a worse performance than Val allele carriers later on. COMT polymorphism did not significantly impact functional and behavioral performance. Since COMT polymorphism influences progression in HD, it could be used for stratification in future clinical trials. Moreover, DA treatments based on the specific COMT polymorphism and adapted according to disease duration could potentially slow HD progression. PMID:27657697

  16. Identification of B6SJL mSOD1(G93A) mouse subgroups with different disease progression rates.

    PubMed

    Haulcomb, Melissa M; Mesnard-Hoaglin, Nichole A; Batka, Richard J; Meadows, Rena M; Miller, Whitney M; Mcmillan, Kathryn P; Brown, Todd J; Sanders, Virginia M; Jones, Kathryn J

    2015-12-15

    Disease progression rates among patients with amyotrophic lateral sclerosis (ALS) vary greatly. Although the majority of affected individuals survive 3-5 years following diagnosis, some subgroups experience a more rapidly progressing form, surviving less than 1 year, and other subgroups experience slowly progressing forms, surviving nearly 50 years. Genetic heterogeneity and environmental factors pose significant barriers in investigating patient progression rates. Similar to the case for humans, variation in survival within the mSOD1 mouse has been well documented, but different progression rates have not been investigated. The present study identifies two subgroups of B6SJL mSOD1(G93A) mice with different disease progression rates, a fast progression group (FPG) and slow progression group, as evidenced by differences in the rate of motor function decline. In addition, increased disease-associated gene expression within the FPG facial motor nucleus confirmed the presence of a more severe phenotype. We hypothesize that a more severe disease phenotype could be the result of 1) an earlier onset of axonal disconnection with a consistent degeneration rate or 2) a more severe or accelerated degenerative process. We performed a facial nerve transection axotomy in both mSOD1 subgroups prior to disease onset as a method to standardize the axonal disconnection. Instead of leading to comparable gene expression in both subgroups, this standardization did not eliminate the severe phenotype in the FPG facial nucleus, suggesting that the FPG phenotype is the result of a more severe or accelerated degenerative process. We theorize that these mSOD1 subgroups are representative of the rapid and slow disease phenotypes often experienced in ALS.

  17. Magnetic Shielding Accelerates the Proliferation of Human Neuroblastoma Cell by Promoting G1-Phase Progression

    PubMed Central

    Liu, Ying; Bartlett, Perry F.; He, Rong-qiao

    2013-01-01

    Organisms have been exposed to the geomagnetic field (GMF) throughout evolutionary history. Exposure to the hypomagnetic field (HMF) by deep magnetic shielding has recently been suggested to have a negative effect on the structure and function of the central nervous system, particularly during early development. Although changes in cell growth and differentiation have been observed in the HMF, the effects of the HMF on cell cycle progression still remain unclear. Here we show that continuous HMF exposure significantly increases the proliferation of human neuroblastoma (SH-SY5Y) cells. The acceleration of proliferation results from a forward shift of the cell cycle in G1-phase. The G2/M-phase progression is not affected in the HMF. Our data is the first to demonstrate that the HMF can stimulate the proliferation of SH-SY5Y cells by promoting cell cycle progression in the G1-phase. This provides a novel way to study the mechanism of cells in response to changes of environmental magnetic field including the GMF. PMID:23355897

  18. Magnetic shielding accelerates the proliferation of human neuroblastoma cell by promoting G1-phase progression.

    PubMed

    Mo, Wei-chuan; Zhang, Zi-jian; Liu, Ying; Bartlett, Perry F; He, Rong-qiao

    2013-01-01

    Organisms have been exposed to the geomagnetic field (GMF) throughout evolutionary history. Exposure to the hypomagnetic field (HMF) by deep magnetic shielding has recently been suggested to have a negative effect on the structure and function of the central nervous system, particularly during early development. Although changes in cell growth and differentiation have been observed in the HMF, the effects of the HMF on cell cycle progression still remain unclear. Here we show that continuous HMF exposure significantly increases the proliferation of human neuroblastoma (SH-SY5Y) cells. The acceleration of proliferation results from a forward shift of the cell cycle in G1-phase. The G2/M-phase progression is not affected in the HMF. Our data is the first to demonstrate that the HMF can stimulate the proliferation of SH-SY5Y cells by promoting cell cycle progression in the G1-phase. This provides a novel way to study the mechanism of cells in response to changes of environmental magnetic field including the GMF. PMID:23355897

  19. Distinctly altered gut microbiota in the progression of liver disease.

    PubMed

    Xie, Guoxiang; Wang, Xiaoning; Liu, Ping; Wei, Runmin; Chen, Wenlian; Rajani, Cynthia; Hernandez, Brenda Y; Alegado, Rosanna; Dong, Bing; Li, Defa; Jia, Wei

    2016-04-12

    Recent studies underscore important roles of intestinal microbiota and the bacterial lipopolysaccharides (LPS) production in the pathogenesis of liver disease. However, how gut microbiota alters in response to the development of steatosis and subsequent progression to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) remains unclear. We aimed to study the gut microbial changes over liver disease progression using a streptozotocin-high fat diet (STZ-HFD) induced NASH-HCC C57BL/6J mouse model that is highly relevant to human liver disease. The fecal microbiota at various liver pathological stages was analyzed by 16S rDNA gene pyrosequencing. Both UniFrac analysis and partial least squares-discriminant analysis showed significant structural alterations in gut microbiota during the development of liver disease. Co-abundance network analysis highlighted relationships between genera. Spearman correlation analysis revealed that the bacterial species, Atopobium spp., Bacteroides spp., Bacteroides vulgatus, Bacteroides acidifaciens, Bacteroides uniformis, Clostridium cocleatum, Clostridium xylanolyticum and Desulfovibrio spp., markedly increased in model mice, were positively correlated with LPS levels and pathophysiological features. Taken together, the results showed that the gut microbiota was altered significantly in the progression of liver disease. The connection between the gut microbial ecology and the liver pathology may represent potential targets for the prevention and treatment of chronic liver disease and HCC. PMID:27036035

  20. Distinctly altered gut microbiota in the progression of liver disease

    PubMed Central

    Xie, Guoxiang; Wang, Xiaoning; Liu, Ping; Wei, Runmin; Chen, Wenlian; Rajani, Cynthia; Hernandez, Brenda Y.; Alegado, Rosanna; Dong, Bing; Li, Defa; Jia, Wei

    2016-01-01

    Recent studies underscore important roles of intestinal microbiota and the bacterial lipopolysaccharides (LPS) production in the pathogenesis of liver disease. However, how gut microbiota alters in response to the development of steatosis and subsequent progression to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) remains unclear. We aimed to study the gut microbial changes over liver disease progression using a streptozotocin-high fat diet (STZ-HFD) induced NASH-HCC C57BL/6J mouse model that is highly relevant to human liver disease. The fecal microbiota at various liver pathological stages was analyzed by 16S rDNA gene pyrosequencing. Both UniFrac analysis and partial least squares-discriminant analysis showed significant structural alterations in gut microbiota during the development of liver disease. Co-abundance network analysis highlighted relationships between genera. Spearman correlation analysis revealed that the bacterial species, Atopobium spp., Bacteroides spp., Bacteroides vulgatus, Bacteroides acidifaciens, Bacteroides uniformis, Clostridium cocleatum, Clostridium xylanolyticum and Desulfovibrio spp., markedly increased in model mice, were positively correlated with LPS levels and pathophysiological features. Taken together, the results showed that the gut microbiota was altered significantly in the progression of liver disease. The connection between the gut microbial ecology and the liver pathology may represent potential targets for the prevention and treatment of chronic liver disease and HCC. PMID:27036035

  1. Oxidized high-density lipoprotein accelerates atherosclerosis progression by inducing the imbalance between treg and teff in LDLR knockout mice.

    PubMed

    Ru, Ding; Zhiqing, He; Lin, Zhu; Feng, Wu; Feng, Zhang; Jiayou, Zhang; Yusheng, Ren; Min, Fan; Chun, Liang; Zonggui, Wu

    2015-05-01

    High density lipoprotein (HDL) dysfunction has been widely reported in clinic, and oxidation of HDL (ox-HDL) was shown to be one of the most common modifications in vivo and participate in the progression of atherosclerosis. But the behind mechanisms are still elusive. In this study, we firstly analyzed and found strong relationship between serum ox-HDL levels and risk factors of coronary artery diseases in clinic, then the effects of ox-HDL in initiation and progression of atherosclerosis in LDLR knockout mice were investigated by infusion of ox-HDL dissolved in chitosan hydrogel before the formation of lesions in vivo. Several new evidence were shown: (i) the serum levels of ox-HDL peaked early before the formation of lesions in LDLR mice fed with high fat diet similar to oxidative low density lipoprotein, (ii) the formation of atherosclerotic lesions could be accelerated by infusion of ox-HDL, (iii) the pro-atherosclerotic effects of ox-HDL were accompanied by imbalanced levels of effector and regulatory T cells and relative gene expressions, which implied that imbalance of teff and treg might contribute to the pro-atherosclerosis effects of ox-HDL.

  2. Oxidized high-density lipoprotein accelerates atherosclerosis progression by inducing the imbalance between treg and teff in LDLR knockout mice.

    PubMed

    Ru, Ding; Zhiqing, He; Lin, Zhu; Feng, Wu; Feng, Zhang; Jiayou, Zhang; Yusheng, Ren; Min, Fan; Chun, Liang; Zonggui, Wu

    2015-05-01

    High density lipoprotein (HDL) dysfunction has been widely reported in clinic, and oxidation of HDL (ox-HDL) was shown to be one of the most common modifications in vivo and participate in the progression of atherosclerosis. But the behind mechanisms are still elusive. In this study, we firstly analyzed and found strong relationship between serum ox-HDL levels and risk factors of coronary artery diseases in clinic, then the effects of ox-HDL in initiation and progression of atherosclerosis in LDLR knockout mice were investigated by infusion of ox-HDL dissolved in chitosan hydrogel before the formation of lesions in vivo. Several new evidence were shown: (i) the serum levels of ox-HDL peaked early before the formation of lesions in LDLR mice fed with high fat diet similar to oxidative low density lipoprotein, (ii) the formation of atherosclerotic lesions could be accelerated by infusion of ox-HDL, (iii) the pro-atherosclerotic effects of ox-HDL were accompanied by imbalanced levels of effector and regulatory T cells and relative gene expressions, which implied that imbalance of teff and treg might contribute to the pro-atherosclerosis effects of ox-HDL. PMID:25912129

  3. Computational Approaches for Translational Clinical Research in Disease Progression

    PubMed Central

    McGuire, Mary F.; Iyengar, M. Sriram; Mercer, David W.

    2011-01-01

    Today, there is an ever-increasing amount of biological and clinical data available that could be used to enhance a systems-based understanding of disease progression through innovative computational analysis. In this paper we review a selection of published research regarding computational methodologies, primarily from systems biology, that support translational research from the molecular level to the bedside, with a focus on applications in trauma and critical care. Trauma is the leading cause of mortality in Americans under 45 years of age, and its rapid progression offers both opportunities and challenges for computational analysis of trends in molecular patterns associated with outcomes and therapeutic interventions. This review presents methods and domain-specific examples that may inspire the development of new algorithms and computational methods that utilize both molecular and clinical data for diagnosis, prognosis and therapy in disease progression. PMID:21712727

  4. Nonparametric inference and uniqueness for periodically observed progressive disease models.

    PubMed

    Griffin, Beth Ann; Lagakos, Stephen W

    2010-04-01

    In many studies examining the progression of HIV and other chronic diseases, subjects are periodically monitored to assess their progression through disease states. This gives rise to a specific type of panel data which have been termed "chain-of-events data"; e.g. data that result from periodic observation of a progressive disease process whose states occur in a prescribed order and where state transitions are not observable. Using a discrete time semi-Markov model, we develop an algorithm for nonparametric estimation of the distribution functions of sojourn times in a J state progressive disease model. Issues of uniqueness for chain-of-events data are not well-understood. Thus, a main goal of this paper is to determine the uniqueness of the nonparametric estimators of the distribution functions of sojourn times within states. We develop sufficient conditions for uniqueness of the nonparametric maximum likelihood estimator, including situations where some but not all of its components are unique. We illustrate the methods with three examples. PMID:19629683

  5. Systemic and renal lipids in kidney disease development and progression.

    PubMed

    Wahl, Patricia; Ducasa, Gloria Michelle; Fornoni, Alessia

    2016-03-15

    Altered lipid metabolism characterizes proteinuria and chronic kidney diseases. While it is thought that dyslipidemia is a consequence of kidney disease, a large body of clinical and experimental studies support that altered lipid metabolism may contribute to the pathogenesis and progression of kidney disease. In fact, accumulation of renal lipids has been observed in several conditions of genetic and nongenetic origins, linking local fat to the pathogenesis of kidney disease. Statins, which target cholesterol synthesis, have not been proven beneficial to slow the progression of chronic kidney disease. Therefore, other therapeutic strategies to reduce cholesterol accumulation in peripheral organs, such as the kidney, warrant further investigation. Recent advances in the understanding of the biology of high-density lipoprotein (HDL) have revealed that functional HDL, rather than total HDL per se, may protect from both cardiovascular and kidney diseases, strongly supporting a role for altered cholesterol efflux in the pathogenesis of kidney disease. Although the underlying pathophysiological mechanisms responsible for lipid-induced renal damage have yet to be uncovered, several studies suggest novel mechanisms by which cholesterol, free fatty acids, and sphingolipids may affect glomerular and tubular cell function. This review will focus on the clinical and experimental evidence supporting a causative role of lipids in the pathogenesis of proteinuria and kidney disease, with a primary focus on podocytes.

  6. Postural Sway as a Marker of Progression in Parkinson's disease: a Pilot Longitudinal Study

    PubMed Central

    Carlson-Kuhta, Patricia; Zampieri, Cris; Nutt, John G.; Chiari, Lorenzo; Horak, Fay B.

    2013-01-01

    Objective measures of postural control that are sensitive to Parkinson's Disease (PD) progression would improve patient care and accelerate clinical trials. Although measures of postural sway during quiet stance in untreated PD have been shown to differ from age-matched control subjects, it is not known if sway measures change with disease progression in early PD. In this pilot study, we asked whether accelerometer-based metrics of sway could provide a practical tool for monitoring progression of postural dyscontrol in people with untreated or newly treated PD. We examined 13 subjects with PD and 12 healthy, age-matched control subjects. The PD subjects had been recently diagnosed and had not started any antiparkinsonian medications at the baseline session. All subjects were tested 3-to-6 months and 12 months after the baseline session. Subjects were asked to stand quietly for two minutes while wearing an inertial sensor on their posterior trunk that measured trunk linear acceleration. Our results suggested that objective sway measures deteriorated over one year despite minimal changes in UPDRS motor scores. Medio-lateral (ML) sway measures were more sensitive than antero-posterior sway measures in detecting progression. The ML JERK was larger in the PD group than the control group across all three testing sessions. The ML sway dispersion and ML sway velocity were also significantly higher in PD compared to control subjects by the 12-month evaluation. It is feasible to measure progression of PD prior to onset of treatment using accelerometer-based measures of quiet standing. PMID:22750016

  7. Recent progress of imaging agents for Parkinson's disease.

    PubMed

    Wu, Xiaoai; Cai, Huawei; Ge, Ran; Li, Lin; Jia, Zhiyun

    2014-12-01

    Parkinson's disease (PD) is a common progressive, neurodegenerative brain disease that is promoted by mitochondrial dysfunction, oxidative stress, protein aggregation and proteasome dysfunction in the brain. Compared with computer tomography (CT) or magnetic resonance imaging (MRI), non-invasive nuclear radiopharmaceuticals have great significance for the early diagnosis of PD due to their high sensitivity and specificity in atypical and preclinical cases. Based on the development of coordination chemistry and chelator design, radionuclides may be delivered to lesions by attaching to PD-related transporters and receptors, such as dopamine, serotonin, and others. In this review, we comprehensively detailed the current achievements in radionuclide imaging in Parkinson's disease. PMID:25977680

  8. Recent Progress of Imaging Agents for Parkinson's Disease

    PubMed Central

    Wu, Xiaoai; Cai, Huawei; Ge, Ran; Li, Lin; Jia, Zhiyun

    2014-01-01

    Parkinson's disease (PD) is a common progressive, neurodegenerative brain disease that is promoted by mitochondrial dysfunction, oxidative stress, protein aggregation and proteasome dysfunction in the brain. Compared with computer tomography (CT) or magnetic resonance imaging (MRI), non-invasive nuclear radiopharmaceuticals have great significance for the early diagnosis of PD due to their high sensitivity and specificity in atypical and preclinical cases. Based on the development of coordination chemistry and chelator design, radionuclides may be delivered to lesions by attaching to PD-related transporters and receptors, such as dopamine, serotonin, and others. In this review, we comprehensively detailed the current achievements in radionuclide imaging in Parkinson’s disease. PMID:25977680

  9. Progressive diaphyseal dysplasia (Engelmann disease): scintigraphic-radiographic-clinical correlations

    SciTech Connect

    Kumar, B.; Murphy, W.A.; Whyte, M.P.

    1981-07-01

    Four patients (2 males, 2 females; ages 15-47 yrs.) with variable clinical, radiographic, and scintigraphic manifestations of progressive diaphyseal dysplasia (PDD) or Engelmann disease were studied with 99mTc methylene diphosphonate bone imaging and radiographic skeletal surveys. Comparison of the results of the two imaging procedures showed that some affected bones were scintigraphically normal but radiographically abnormal and vice versa. These findings suggest that the lesions of PDD may mature, causing a significant decrease in disease activity, and that abnormally increased radiopharmaceutical accumulation during bone scintigraphy appears to be a sensitive indicator of disease activity.

  10. Serum Bilirubin and Disease Progression in Mild COPD

    PubMed Central

    Apperley, Scott; Park, Hye Yun; Holmes, Daniel T.; Wise, Robert A.; Connett, John E.

    2015-01-01

    BACKGROUND: COPD is a chronic inflammatory disorder associated with oxidative stress. Serum bilirubin has potent antioxidant actions, and higher concentrations have been shown to protect against oxidative stress. The relation between serum bilirubin and COPD progression is unknown. METHODS: Serum bilirubin was measured in 4,680 smokers aged 35 to 60 years old with mild to moderate airflow limitation. The relationship of serum bilirubin to postbronchodilator FEV1 and rate of FEV1 decline over 3 to 9 years was determined using regression modeling. Total and disease-specific mortality were also ascertained. RESULTS: Serum bilirubin was positively related to FEV1 (P < .001). Serum bilirubin was also negatively related to the annual decline in FEV1 when adjusted for baseline demographics, pack-years smoked, and baseline measures of lung function (P = .01). Additionally, serum bilirubin was negatively associated with risk of death from coronary heart disease (P = .03); however, the relationships between bilirubin and other mortality end points were not statistically significant (P > .05). CONCLUSIONS: Bilirubin is inversely related to COPD disease severity and progression. Higher serum bilirubin concentration was associated with a higher FEV1 and less annual decline in FEV1. Bilirubin was also associated with less coronary heart disease mortality. These data support the hypothesis that bilirubin has a protective effect on COPD disease progression, possibly through its antioxidant actions. Bilirubin may prove useful as an easily accessible and readily available blood-based COPD biomarker. PMID:25539285

  11. Predictors of autosomal dominant polycystic kidney disease progression.

    PubMed

    Schrier, Robert W; Brosnahan, Godela; Cadnapaphornchai, Melissa A; Chonchol, Michel; Friend, Keith; Gitomer, Berenice; Rossetti, Sandro

    2014-11-01

    Autosomal dominant polycystic kidney disease is a genetic disorder associated with substantial variability in its natural course within and between affected families. Understanding predictors for rapid progression of this disease has become increasingly important with the emergence of potential new treatments. This systematic review of the literature since 1988 evaluates factors that may predict and/or effect autosomal dominant polycystic kidney disease progression. Predicting factors associated with early adverse structural and/or functional outcomes are considered. These factors include PKD1 mutation (particularly truncating mutation), men, early onset of hypertension, early and frequent gross hematuria, and among women, three or more pregnancies. Increases in total kidney volume and decreases in GFR and renal blood flow greater than expected for a given age also signify rapid disease progression. Concerning laboratory markers include overt proteinuria, macroalbuminuria, and perhaps, elevated serum copeptin levels in affected adults. These factors and others may help to identify patients with autosomal dominant polycystic kidney disease who are most likely to benefit from early intervention with novel treatments.

  12. Progress on laser plasma accelerator development using transverselyand longitudinally shaped plasmas

    SciTech Connect

    Leemans, Wim P.; Esarey, E.; Geddes, C.G.R.; Toth, Cs.; Schroeder, C.B.; Nakamura, K.; Gonsalves, A.J.; Panasenko, D.; Cormier-Michel, E.; Plateau, G.R.; Lin, C.; Bruhwiler, D.L.; Cary, J.R.

    2009-03-31

    A summary of progress at Lawrence Berkeley National Laboratory is given on: (1) experiments on down-ramp injection; (2) experiments on acceleration in capillary discharge plasma channels; and (3) simulations of a staged laser wakefield accelerator (LWFA). Control of trapping in a LWFA using plasma density down-ramps produced electron bunches with absolute longitudinal and transverse momentum spreads more than ten times lower than in previous experiments (0.17 and 0.02 MeV Ic FWHM, respectively) and with central momenta of 0.76 +- 0.02 MeV Ic, stable over a week of operation. Experiments were also carried out using a 40 TW laser interacting with a hydrogen-filled capillary discharge waveguide. For a 15 mm long, 200 mu m diameter capillary, quasi-monoenergetic bunches up to 300 MeV were observed. By detuning discharge delay from optimum guiding performance, self-trapping was found to be stabilized. For a 33 mm long, 300 mu m capillary, a parameter regime with high energy bunches, up to 1 Ge V, was found. In this regime, peak electron energy was correlated with the amount of trapped charge. Simulations show that bunches produced on a down-ramn and iniected into a channel-guided LWFA can produce stable beams with 0.2 MeV Ic-class momentum spread at high energies.

  13. Progress in Wind-and-React Bi-2212 Accelerator Magnet Technology

    SciTech Connect

    Godeke, A.; Cheng, D.; Dietderich, D.R.; Hannaford, C.R.; Prestemon, S.O.; Sabbi, G.; Wang, X.; Hikichi, Y.; Nishioka, J.; Hasegawa, T.

    2009-08-16

    We report on our progress in the development of the technology for the application of Bi{sub 2}Sr{sub 2}CaCu{sub 2}O{sub 8+x}(Bi-2212) in Wind-and-React accelerator magnets. A series of superconducting subscale coils has been manufactured at LBNL and reacted at the wire manufacturer SWCC. Selected coils are impregnated and tested in self-field, even though the coils exhibited leakage during the partial melt heat treatment. Other coils have been disassembled after reaction and submitted to critical current (Ic) tests on individual cable sections. We report on the results of the current carrying capacity of the coils. Voltage-current (VI) transitions were reproducibly measured up to a quench currents around 1400 A, which is 25% of the expected performance. The results indicate that the coils are limited by the inner windings. We further compare possibilities to use Bi-2212 and Nb{sub 3}Sn tilted solenoid, and YBa{sub 2}Cu{sub 3}O{sub 7-{delta}} (YBCO) racetrack inserts to increase the magnetic field in HD2, a 36 mm bore Nb{sub 3}Sn dipole magnet which recently achieved a bore magnetic field of 13.8 T. The application of Bi-2212 and/or YBCO in accelerator type magnets, if successful, will open the road to higher magnetic fields, far surpassing the limitations of Nb{sub 3}Sn magnet technology.

  14. Rapidly progressive dementias and the treatment of human prion diseases

    PubMed Central

    Lyketsos, Constantine G

    2012-01-01

    Importance of the field Rapidly progressive dementia (RPD) has many possible etiologies and definitive treatment is reliant upon an accurate diagnosis from an appropriate diagnostic work-up. A large portion of the neurodegenerative causes of RPD are due to prion diseases (e.g., Creutzfeldt–Jakob disease). The study of prion diseases, for which there is no currently available treatment, has public health implications and is becoming increasingly more relevant to our understanding of other protein misfolding disorders including Alzheimer’s disease, frontotemporal degeneration, and Parkinson’s disease. Areas covered in this review This article begins with an overview of the etiologies and diagnostic work-up of RPD followed by a detailed review of the literature concerning the treatment of human prion diseases (1971 to present). What the reader will gain The reader will understand the differential diagnosis and work-up of RPD as it pertains to its treatment, as well as an in-depth understanding of treatments of human prion diseases. Take home message An accurate diagnosis of the cause of RPD is of paramount importance when determining appropriate treatment. Most studies of the treatment for human prion diseases are case reports or case series, and results from only one randomized, placebo-controlled study have been reported in the literature (flupirtine). Studies have been hindered by disease heterogeneity and lack of standardized outcome measures. Although no effective prion disease treatment has been revealed through these studies, they provide important considerations for future studies. PMID:21091283

  15. The beneficial role of intensive exercise on Parkinson disease progression.

    PubMed

    Frazzitta, Giuseppe; Balbi, Pietro; Maestri, Roberto; Bertotti, Gabriella; Boveri, Natalia; Pezzoli, Gianni

    2013-06-01

    In the last decade, a considerable number of articles has shown that exercise is effective in improving motor performance in Parkinson disease. In particular, recent studies have focused on the efficacy of intensive exercise in achieving optimal results in the rehabilitation of patients with Parkinson disease. The effects of intensive exercise in promoting cell proliferation and neuronal differentiation in animal models are reported in a large cohort of studies, and these neuroplastic effects are probably related to increased expression of a variety of neurotrophic factors. The authors outline the relation between intensive exercises and neuroplastic activity on animal models of Parkinson disease and discuss the clinical results of different intensive strategies on motor performance and disease progression in patients with Parkinson disease.

  16. Amyotrophic Lateral Sclerosis: A Focus on Disease Progression

    PubMed Central

    Calvo, Ana C.; Manzano, Raquel; Mendonça, Deise M. F.; Muñoz, María J.; Zaragoza, Pilar

    2014-01-01

    Since amyotrophic lateral sclerosis (ALS) was discovered and described in 1869 as a neurodegenerative disease in which motor neuron death is induced, a wide range of biomarkers have been selected to identify therapeutic targets. ALS shares altered molecular pathways with other neurodegenerative diseases, such as Alzheimer's, Huntington's, and Parkinson's diseases. However, the molecular targets that directly influence its aggressive nature remain unknown. What is the first link in the neurodegenerative chain of ALS that makes this disease so peculiar? In this review, we will discuss the progression of the disease from the viewpoint of the potential biomarkers described to date in human and animal model samples. Finally, we will consider potential therapeutic strategies for ALS treatment and future, innovative perspectives. PMID:25157374

  17. Accelerating progress at contaminated sediment sites: moving from guidance to practice.

    PubMed

    Bridges, Todd S; Nadeau, Steven C; McCulloch, Megan C

    2012-04-01

    Contaminated sediments are a pervasive problem in the United States. Significant economic, ecological, and social issues are intertwined in addressing the nation's contaminated sediment problem. Managing contaminated sediments has become increasingly resource intensive, with some investigations costing tens of millions of dollars and the majority of remediation projects proceeding at a slow pace. At present, the approaches typically used to investigate, evaluate, and remediate contaminated sediment sites in the United States have largely fallen short of producing timely, risk-based, cost-effective, long-term solutions. With the purpose of identifying opportunities for accelerating progress at contaminated sediment sites, the US Army Corps of Engineers-Engineer Research and Development Center and the Sediment Management Work Group convened a workshop with experienced experts from government, industry, consulting, and academia. Workshop participants identified 5 actions that, if implemented, would accelerate the progress and increase the effectiveness of risk management at contaminated sediment sites. These actions included: 1) development of a detailed and explicit project vision and accompanying objectives, achievable short-term and long-term goals, and metrics of remedy success at the outset of a project, with refinement occurring as needed throughout the duration of the project; 2) strategic engagement of stakeholders in a more direct and meaningful process; 3) optimization of risk reduction, risk management processes, and remedy selection addressing 2 important elements: a) the deliberate use of early action remedies, where appropriate, to accelerate risk reduction; and b) the systematic and sequential development of a suite of actions applicable to the ultimate remedy, starting with monitored natural recovery and adding engineering actions as needed to satisfy the project's objectives; 4) an incentive process that encourages and rewards risk reduction; and 5

  18. Aluminum involvement in the progression of Alzheimer's disease.

    PubMed

    Walton, J R

    2013-01-01

    The neuroanatomic specificity with which Alzheimer's disease (AD) progresses could provide clues to AD etiopathology. Magnetic resonance imaging studies of AD clinical progression have confirmed general conclusions from earlier studies of AD neuropathological progression wherein neurofibrillary tangle pathology was observed to spread along a well-defined sequence of corticocortical and corticosubcortical connections, preferentially affecting certain cell types, while sparing others. Identical and non-identical twin studies have consistently shown AD has mixed (environmental and genetic) etiopathogenesis. The decades-long prodromal phase over which AD develops suggests slow but progressive accumulation of a toxic or infective agent over time. Major environmental candidates are reviewed to assess which best fits the profile of an agent that slowly accrues in susceptible cell types of AD-vulnerable brain regions to toxic levels by old age, giving rise to AD neuropathology without rapid neuronal lysis. Chronic aluminum neurotoxicity best matches this profile. Many humans routinely ingest aluminum salts as additives contained in processed foods and alum-treated drinking water. The physical properties of aluminum and ferric iron ions are similar, allowing aluminum to use mechanisms evolved for iron to enter vulnerable neurons involved in AD progression, accumulate in those neurons, and cause neurofibrillary damage. The genetic component of AD etiopathogenesis apparently involves a susceptibility gene, yet to be identified, that increases aluminum absorption because AD and Down syndrome patients have higher than normal plasma, and brain, aluminum levels. This review describes evidence for aluminum involvement in AD neuropathology and the clinical progression of sporadic AD.

  19. 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.

  20. Nutrient enrichment enhances black band disease progression in corals

    NASA Astrophysics Data System (ADS)

    Voss, Joshua D.; Richardson, Laurie L.

    2006-11-01

    Infectious diseases are recognized as significant contributors to the dramatic loss of corals observed worldwide. However, the causes of increased coral disease prevalence and severity are not well understood. One potential factor is elevated nutrient concentration related to localized anthropogenic activities such as inadequate waste water treatment or terrestrial runoff. In this study the effect of nutrient enrichment on the progression of black band disease (BBD) was investigated using both in situ and laboratory experiments. Experimental increases in localized nutrient availability using commercial time release fertilizer in situ resulted in doubling of BBD progression and coral tissue loss in the common reef framework coral Siderastrea siderea. Laboratory experiments in which artificially infected S. siderea colonies were exposed to increased nitrate concentrations (up to 3 μM) demonstrated similar increases in BBD progression. These findings provide evidence that the impacts of this disease on coral populations are exacerbated by nutrient enrichment and that management to curtail excess nutrient loading may be important for reducing coral cover loss due to BBD.

  1. [Progress of Autoantibody Examinations for Connective Tissue Diseases].

    PubMed

    Akashi, Kengo; Saegusa, Jun; Morinobu, Akio

    2015-05-01

    Connective tissue diseases are chronic inflammatory diseases that can affect multiple organs and, thus, have a broad spectrum of clinical presentations. Various autoantibodies are detected in patients with connective tissue diseases, represented by anti-nuclear antibody for systemic lupus erythematosus (SLE), systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM), Sjögren's syndrome, and mixed connective tissue disease. Assessment of the autoantibody profile is fundamental for the clinical management of patients with connective tissue diseases, providing important data for the diagnosis, clinical characterization, and disease activity evaluation. Anti-ribosomal P antibody and anti-NMDA receptor antibody are associated with neuropsychiatric SLE. Anti-synthetase syndrome comprises the association of myositis (PM/DM), interstitial lung disease, fever, Raynaud's phenomenon, mechanic's hands, and anti-aminoacyl tRNA synthetase antibodies. Anti-MDA5 antibody is detected in patients with clinically amyopathic DM, often complicated by rapidly progressive interstitial lung disease. Between 50 and 75% of malignancy-associated DM patients are positive for anti-TIF1-γ antibody. Anti-RNA polymerase III antibody is associated with diffuse cutaneous SSc and renal crisis. This review focuses on the importance and usefulness of these autoantibodies for the diagnosis and management of patients with connective tissue diseases in clinical practice.

  2. Paediatric cholestatic liver disease: Diagnosis, assessment of disease progression and mechanisms of fibrogenesis

    PubMed Central

    Pereira, Tamara N; Walsh, Meagan J; Lewindon, Peter J; Ramm, Grant A

    2010-01-01

    Cholestatic liver disease causes significant morbidity and mortality in children. The diagnosis and management of these diseases can be complicated by an inability to detect early stages of fibrosis and a lack of adequate interventional therapy. There is no single gold standard test that accurately reflects the presence of liver disease, or that can be used to monitor fibrosis progression, particularly in conditions such as cystic fibrosis. This has lead to controversy over how suspected liver disease in children is detected and diagnosed. This review discusses the challenges in using commonly available methods to diagnose hepatic fibrosis and monitor disease progression in children with cholestatic liver disease. In addition, the review examines the mechanisms hypothesised to be involved in the development of hepatic fibrogenesis in paediatric cholestatic liver injury which may ultimately aid in identifying new modalities to assist in both disease detection and therapeutic intervention. PMID:21607144

  3. Potential of APDM mobility lab for the monitoring of the progression of Parkinson's disease.

    PubMed

    Mancini, Martina; Horak, Fay B

    2016-05-01

    APDM's Mobility Lab system provides portable, validated, reliable, objective measures of balance and gait that are sensitive to Parkinson's disease (PD). In this review, we describe the potential of objective measures collected with the Mobility Lab system for tracking longitudinal progression of PD. Balance and gait are among the most important motor impairments influencing quality of life for people with PD. Mobility Lab uses body-worn, Opal sensors on the legs, trunk and arms during prescribed tasks, such as the instrumented Get Up and Go test or quiet stance, to quickly quantify the quality of balance and gait in the clinical environment. The same Opal sensors can be sent home with patients to continuously monitor the quality of their daily activities. Objective measures have the potential to monitor progression of mobility impairments in PD throughout its course to improve patient care and accelerate clinical trials. PMID:26872510

  4. Potential of APDM mobility lab for the monitoring of the progression of Parkinson's disease.

    PubMed

    Mancini, Martina; Horak, Fay B

    2016-05-01

    APDM's Mobility Lab system provides portable, validated, reliable, objective measures of balance and gait that are sensitive to Parkinson's disease (PD). In this review, we describe the potential of objective measures collected with the Mobility Lab system for tracking longitudinal progression of PD. Balance and gait are among the most important motor impairments influencing quality of life for people with PD. Mobility Lab uses body-worn, Opal sensors on the legs, trunk and arms during prescribed tasks, such as the instrumented Get Up and Go test or quiet stance, to quickly quantify the quality of balance and gait in the clinical environment. The same Opal sensors can be sent home with patients to continuously monitor the quality of their daily activities. Objective measures have the potential to monitor progression of mobility impairments in PD throughout its course to improve patient care and accelerate clinical trials.

  5. A murine tumor progression model for pancreatic cancer recapitulating the genetic alterations of the human disease

    PubMed Central

    Wagner, Martin; Greten, Florian R.; Weber, Christoph K.; Koschnick, Stefan; Mattfeldt, Torsten; Deppert, Wolfgang; Kern, Horst; Adler, Guido; Schmid, Roland M.

    2001-01-01

    This study describes a tumor progression model for ductal pancreatic cancer in mice overexpressing TGF-α. Activation of Ras and Erk causes induction of cyclin D1-Cdk4 without increase of cyclin E or PCNA in ductal lesions. Thus, TGF-α is able to promote progression throughout G1, but not S phase. Crossbreeding with p53 null mice accelerates tumor development in TGF-α transgenic mice dramatically. In tumors developing in these mice, biallelic deletion of Ink4a/Arf or LOH of the Smad4 locus is found suggesting that loci in addition to p53 are involved in antitumor activities. We conclude that these genetic events are critical for pancreatic tumor formation in mice. This model recapitulates pathomorphological features and genetic alterations of the human disease. PMID:11159909

  6. The effects of electroshock on immune function and disease progression in juvenile spring chinook salmon

    USGS Publications Warehouse

    VanderKooi, S.P.; Maule, A.G.; Schreck, C.B.

    2001-01-01

    Although much is known about the effects of electroshock on fish physiology, consequences to the immune system and disease progression have not received attention. Our objectives were to determine the effects of electroshock on selected immune function in juvenile spring chinook salmon Oncorhynchus tshawytscha, the mechanism of any observed alteration, and the effects of electroshock on disease progression. We found that the ability of anterior kidney leukocytes to generate antibody-producing cells (APC) was suppressed 3 h after a pulsed-DC electroshock (300 V, 50 Hz, 8 ms pulse width) but recovered within 24 h. This response was similar in timing and magnitude to that of fish subjected to an acute handling stress. The mechanism of suppression is hypothesized to be via an elevation of plasma cortisol concentrations in response to stress. Other monitored immune functions, skin mucous lysozyme levels, and respiratory burst activity were not affected by exposure to electroshock. The progression of a Renibacterium salmoninarum (RS) infection may have been altered after exposure to an electroshock. The electroshock did not affect infection severity or the number of mortalities, but may have accelerated the time to death. The limited duration of APC suppression and lack of effects on lysozyme and respiratory burst, as well as infection severity and mortality levels in RS-infected fish, led us to conclude that electrofishing under the conditions we tested is a safe procedure in regards to immunity and disease.

  7. Glomerular pathology and the progression of chronic kidney disease.

    PubMed

    Lemley, Kevin V

    2016-06-01

    Structural studies of the glomerulus, largely undertaken in animal models, have informed our understanding of the progression of chronic kidney disease (CKD) for decades. A fundamental tenet of that understanding is that a loss of podocytes underlies progression in many or most cases of progressive CKD. Recent attempts have been made to reconcile earlier findings from glomerular physiology (the primacy of glomerular capillary hypertension in causation of secondary glomerular sclerosis) with structural findings and have suggested a more detailed model of the mechanisms underlying podocyte detachment as viable cells. A new appreciation of the main locus of mechanical challenges to the podocyte (in the filtration slit) may both explain the renoprotective action of some current therapies and help to suggest novel therapeutic strategies. PMID:27122538

  8. Progression of asymptomatic peripheral artery disease over 1 year.

    PubMed

    Mohler, Emile R; Bundens, Warner; Denenberg, Julie; Medenilla, Elizabeth; Hiatt, William R; Criqui, Michael H

    2012-02-01

    The pathophysiology and time course of an individual converting from asymptomatic peripheral artery disease (PAD) to symptomatic claudication is unclear. The objectives of this study were: (1) to characterize the extent of atherosclerotic disease in individuals with an abnormal ankle-brachial index (ABI), but without claudication; and over 1 year of follow-up to (2) evaluate the progression of PAD using ultrasound imaging, (3) determine changes in the ABI and leg pain symptoms, and (4) correlate PAD progression with changes in the ABI and leg symptoms. We hypothesized that PAD progression would be associated with the development of claudication and changes in the ABI, 6-minute walk distance (6-MWD), and walking quality of life. Individuals with a reduced ABI but without typical intermittent claudication noted on community screening were invited to undergo baseline and 1-year follow-up assessment, including duplex ultrasound. The initial and repeat evaluations included measurement of the ABI, lower extremity duplex arterial mapping, and assessment of leg pain and functional status. Of the 50 people studied, 44 (88%) had significant atherosclerotic lesions in the lower extremity arteries, affecting 80 legs. A total of 33 of 50 individuals (66%) returned for the 1-year follow-up visit. On ultrasound examination, two of 18 normal legs developed PAD, and in 48 legs with PAD at baseline, 17 legs (35%) developed new or progressive lesions. Thirteen legs developed new claudication. Overall, there was no significant worsening in the ABI, 6-MWD, or the Walking Impairment Questionnaire (WIQ). However, legs with new lesions or lesion progression were significantly more likely to develop claudication, and the 13 legs (seven subjects) developing claudication showed a significant decline in the 6-MWD. In conclusion, these data indicate that a significant number of people with asymptomatic PAD show progression over 1 year, that such individuals are more likely to develop

  9. State-space size considerations for disease-progression models.

    PubMed

    Regnier, Eva D; Shechter, Steven M

    2013-09-30

    Markov models of disease progression are widely used to model transitions in patients' health state over time. Usually, patients' health status may be classified according to a set of ordered health states. Modelers lump together similar health states into a finite and usually small, number of health states that form the basis of a Markov chain disease-progression model. This increases the number of observations used to estimate each parameter in the transition probability matrix. However, lumping together observably distinct health states also obscures distinctions among them and may reduce the predictive power of the model. Moreover, as we demonstrate, precision in estimating the model parameters does not necessarily improve as the number of states in the model declines. This paper explores the tradeoff between lumping error introduced by grouping distinct health states and sampling error that arises when there are insufficient patient data to precisely estimate the transition probability matrix. PMID:23609629

  10. Tissue stiffness dictates development, homeostasis, and disease progression.

    PubMed

    Handorf, Andrew M; Zhou, Yaxian; Halanski, Matthew A; Li, Wan-Ju

    2015-01-01

    Tissue development is orchestrated by the coordinated activities of both chemical and physical regulators. While much attention has been given to the role that chemical regulators play in driving development, researchers have recently begun to elucidate the important role that the mechanical properties of the extracellular environment play. For instance, the stiffness of the extracellular environment has a role in orienting cell division, maintaining tissue boundaries, directing cell migration, and driving differentiation. In addition, extracellular matrix stiffness is important for maintaining normal tissue homeostasis, and when matrix mechanics become imbalanced, disease progression may ensue. In this article, we will review the important role that matrix stiffness plays in dictating cell behavior during development, tissue homeostasis, and disease progression.

  11. State-space size considerations for disease-progression models.

    PubMed

    Regnier, Eva D; Shechter, Steven M

    2013-09-30

    Markov models of disease progression are widely used to model transitions in patients' health state over time. Usually, patients' health status may be classified according to a set of ordered health states. Modelers lump together similar health states into a finite and usually small, number of health states that form the basis of a Markov chain disease-progression model. This increases the number of observations used to estimate each parameter in the transition probability matrix. However, lumping together observably distinct health states also obscures distinctions among them and may reduce the predictive power of the model. Moreover, as we demonstrate, precision in estimating the model parameters does not necessarily improve as the number of states in the model declines. This paper explores the tradeoff between lumping error introduced by grouping distinct health states and sampling error that arises when there are insufficient patient data to precisely estimate the transition probability matrix.

  12. Tissue Stiffness Dictates Development, Homeostasis, and Disease Progression

    PubMed Central

    Handorf, Andrew M; Zhou, Yaxian; Halanski, Matthew A; Li, Wan-Ju

    2015-01-01

    Abstract Tissue development is orchestrated by the coordinated activities of both chemical and physical regulators. While much attention has been given to the role that chemical regulators play in driving development, researchers have recently begun to elucidate the important role that the mechanical properties of the extracellular environment play. For instance, the stiffness of the extracellular environment has a role in orienting cell division, maintaining tissue boundaries, directing cell migration, and driving differentiation. In addition, extracellular matrix stiffness is important for maintaining normal tissue homeostasis, and when matrix mechanics become imbalanced, disease progression may ensue. In this article, we will review the important role that matrix stiffness plays in dictating cell behavior during development, tissue homeostasis, and disease progression. PMID:25915734

  13. Advantage of rare HLA supertype in HIV disease progression.

    PubMed

    Trachtenberg, Elizabeth; Korber, Bette; Sollars, Cristina; Kepler, Thomas B; Hraber, Peter T; Hayes, Elizabeth; Funkhouser, Robert; Fugate, Michael; Theiler, James; Hsu, Yen S; Kunstman, Kevin; Wu, Samuel; Phair, John; Erlich, Henry; Wolinsky, Steven

    2003-07-01

    The highly polymorphic human leukocyte antigen (HLA) class I molecules help to determine the specificity and repertoire of the immune response. The great diversity of these antigen-binding molecules confers differential advantages in responding to pathogens, but presents a major obstacle to distinguishing HLA allele-specific effects. HLA class I supertypes provide a functional classification for the many different HLA alleles that overlap in their peptide-binding specificities. We analyzed the association of these discrete HLA supertypes with HIV disease progression rates in a population of HIV-infected men. We found that HLA supertypes alone and in combination conferred a strong differential advantage in responding to HIV infection, independent of the contribution of single HLA alleles that associate with progression of the disease. The correlation of the frequency of the HLA supertypes with viral load suggests that HIV adapts to the most frequent alleles in the population, providing a selective advantage for those individuals who express rare alleles.

  14. Naturalism about health and disease: adding nuance for progress.

    PubMed

    Kingma, Elselijn

    2014-12-01

    The literature on health and diseases is usually presented as an opposition between naturalism and normativism. This article argues that such a picture is too simplistic: there is not one opposition between naturalism and normativism, but many. I distinguish four different domains where naturalist and normativist claims can be contrasted: (1) ordinary usage, (2) conceptually clean versions of "health" and "disease," (3) the operationalization of dysfunction, and (4) the justification for that operationalization. In the process I present new arguments in response to Schwartz (2007) and Hausman (2012) and expose a link between the arguments made by Schwartz (2007) and Kingma (2010). Distinguishing naturalist claims at these four domains will allow us to make progress by (1) providing more nuanced, intermediate positions about a possible role for values in health and disease; and (2) assisting in the addressing of relativistic worries about the value-ladenness of health and disease.

  15. Progress and prospects: stem cells and neurological diseases.

    PubMed

    Gögel, S; Gubernator, M; Minger, S L

    2011-01-01

    The central nervous system has limited capacity of regenerating lost tissue in slowly progressive, degenerative neurological conditions such as Parkinson's disease (PD), Alzheimer's disease or Huntington's disease (HD), or in acute injuries resulting in rapid cell loss for example, in cerebrovascular damage (for example, stroke) or spinal cord injury. Although the adult brain contains small numbers of stem cells in restricted areas, they do not contribute significantly to functional recovery. Transplantation of stem cells or stem cell-derived progenitors has long been seen as a therapeutic solution to repair the damaged brain. With the advent of the induced pluripotent stem cells technique a new and potentially better source for transplantable cells may be available in future. This review aims to highlight current strategies to replace lost cellular populations in neurodegenerative diseases with the focus on HD and PD and traumatic brain injuries such as stroke, discussing many of the technical and biological issues associated with central nervous system cell transplantation. PMID:20882052

  16. Type-1 cannabinoid receptor activity during Alzheimer's disease progression.

    PubMed

    Manuel, Iván; González de San Román, Estíbaliz; Giralt, M Teresa; Ferrer, Isidro; Rodríguez-Puertas, Rafael

    2014-01-01

    The activity of CB1 cannabinoid receptors was studied in postmortem brain samples of Alzheimer's disease (AD) patients during clinical deterioration. CB1 activity was higher at earlier AD stages in limited hippocampal areas and internal layers of frontal cortex, but a decrease was observed at the advanced stages. The pattern of modification appears to indicate initial hyperactivity of the endocannabinoid system in brain areas that lack classical histopathological markers at earlier stages of AD, indicating an attempt to compensate for the initial synaptic impairment, which is then surpassed by disease progression. These results suggest that initial CB1 stimulation might have therapeutic relevance.

  17. Sulodexide and glycosaminoglycans in the progression of renal disease.

    PubMed

    Masola, Valentina; Zaza, Gianluigi; Gambaro, Giovanni

    2014-02-01

    Experimental data in cell cultures and animal models suggest that sulodexide and glycosaminoglycans are potentially effective drugs to treat chronic kidney diseases and prevent progression to renal failure. However, no conclusive evidence support the use of them in human renal disease. In acute and chronic glomerulonephritis, only few studies have been performed. Sulodexide has been more intensely investigated in diabetic nephropathy (DN) where the body of data supports its effectiveness as an antialbuminuric agent in early stages. Unfortunately, there is no study in DN patients on the effect of sulodexide on clinical end points.

  18. The cholinergic hypothesis of Alzheimer's disease: a review of progress

    PubMed Central

    Francis, P.; Palmer, A.; Snape, M.; Wilcock, G.

    1999-01-01

    Alzheimer's disease is one of the most common causes of mental deterioration in elderly people, accounting for around 50%-60% of the overall cases of dementia among persons over 65 years of age. The past two decades have witnessed a considerable research effort directed towards discovering the cause of Alzheimer's disease with the ultimate hope of developing safe and effective pharmacological treatments. This article examines the existing scientific applicability of the original cholinergic hypothesis of Alzheimer's disease by describing the biochemical and histopathological changes of neurotransmitter markers that occur in the brains of patients with Alzheimer's disease both at postmortem and neurosurgical cerebral biopsy and the behavioural consequences of cholinomimetic drugs and cholinergic lesions. Such studies have resulted in the discovery of an association between a decline in learning and memory, and a deficit in excitatory amino acid (EAA) neurotransmission, together with important roles for the cholinergic system in attentional processing and as a modulator of EAA neurotransmission. Accordingly, although there is presently no "cure" for Alzheimer's disease, a large number of potential therapeutic interventions have emerged that are designed to correct loss of presynaptic cholinergic function. A few of these compounds have confirmed efficacy in delaying the deterioration of symptoms of Alzheimer's disease, a valuable treatment target considering the progressive nature of the disease. Indeed, three compounds have received European approval for the treatment of the cognitive symptoms of Alzheimer's disease, first tacrine and more recently, donepezil and rivastigmine, all of which are cholinesterase inhibitors.

 PMID:10071091

  19. Biomarkers of progression of chronic obstructive pulmonary disease (COPD)

    PubMed Central

    Vaughan, Annalicia; Dent, Annette G.; O’Hare, Phoebe E.; Goh, Felicia; Bowman, Rayleen V.; Fong, Kwun M.; Yang, Ian A.

    2014-01-01

    Disease progression of chronic obstructive pulmonary disease (COPD) is variable, with some patients having a relatively stable course, while others suffer relentless progression leading to severe breathlessness, frequent acute exacerbations of COPD (AECOPD), respiratory failure and death. Radiological markers such as CT emphysema index, bronchiectasis and coronary artery calcification (CAC) have been linked with increased mortality in COPD patients. Molecular changes in lung tissue reflect alterations in lung pathology that occur with disease progression; however, lung tissue is not routinely accessible. Cell counts (including neutrophils) and mediators in induced sputum have been associated with lung function and risk of exacerbations. Examples of peripheral blood biological markers (biomarkers) include those associated with lung function (reduced CC-16), emphysema severity (increased adiponectin, reduced sRAGE), exacerbations and mortality [increased CRP, fibrinogen, leukocyte count, IL-6, IL-8, and tumor necrosis factor α (TNF-α)] including increased YKL-40 with mortality. Emerging approaches to discovering markers of gene-environment interaction include exhaled breath analysis [volatile organic compounds (VOCs), exhaled breath condensate], cellular and systemic responses to exposure to air pollution, alterations in the lung microbiome, and biomarkers of lung ageing such as telomere length shortening and reduced levels of sirtuins. Overcoming methodological challenges in sampling and quality control will enable more robust yet easily accessible biomarkers to be developed and qualified, in order to optimise personalised medicine in patients with COPD. PMID:25478195

  20. [Studies on the mode of progression of alcoholic liver disease].

    PubMed

    Yoshida, N; Hatori, T; Ueno, Y; Shibata, M; Sadamoto, T; Yamamuro, W; Sumino, Y; Nonaka, H; Sugimoto, M; Abei, T

    1991-12-01

    In order to elucidate the mode of progression of alcoholic liver disease, relationships among the drinking style, laboratory data, anti-HCV antibody and histological changes were investigated on 36 patients in whom the liver biopsy was repeatedly done. Following results were obtained (1) In the group of continuous drinking over 100g ethanol per day, histological progression was found in 11 of 13 patients (85%) regardless of positive anti-HCV. On the other hand, in the group of abstinence or temperance less than 60g daily alcohol intake, histological improvement was found in 6 of 11 patients (55%). (2) Histological improvement was predominantly seen by abstinence or temperance in the cases with lower levels of serum IgA and adenosine deaminase (ADA) on hospitalization and those with rapid decrease in serum gamma-GTP after hospitalization. In conclusion, the amount of ethanol was considered to be the most important factor to affect on a progression of alcoholic liver diseases. Assessment of laboratory data such as IgA and ADA on hospitalization and change in gamma-GTP after hospitalization were also thought to be useful in foreseeing the prognosis of alcoholic liver disease.

  1. Reevaluating Measures of Disease Progression in Facioscapulohumeral Muscular Dystrophy

    PubMed Central

    Statland, Jeffrey M.; McDermott, Michael P.; Heatwole, Chad; Martens, William B.; Pandya, Shree; van der Kooi, E.L.; Kissel, John T.; Wagner, Kathryn R.; Tawil, Rabi

    2013-01-01

    Recent advances in the understanding of the molecular pathophysiology of facioscapulohumeral muscular dystrophy (FSHD) have identified potential therapeutic targets. Consequently, an accurate understanding of disease progression in FSHD is crucial for the design of future clinical trials. Data from 228 subjects in 3 clinical trials and 1 natural history study were compared to examine disease progression in FSHD. All studies utilized the same techniques for manual muscle testing and maximum voluntary isometric contraction testing. Both techniques yield a total strength score that can be followed over time as an indicator of disease progression. Whereas natural history data showed a decrease in strength over 1 year, there was an apparent increase in strength at 6 months in 2 of the 3 clinical trials in both the placebo and treatment groups, that persisted for up to 1 year for maximum voluntary isometric contraction testing. Variability estimates from the clinical trial data were consistent with those seen in the natural history data. Patients in clinical trials in FSHD may have better outcomes than those in natural history studies, regardless of treatment assignment, emphasizing the importance of placebo groups and the need for caution when interpreting the strength results of controlled and uncontrolled trials. PMID:23406877

  2. Risk Factors for Progression of Chronic Kidney Disease

    PubMed Central

    Staples, Amy; Wong, Craig

    2010-01-01

    Purpose of Review Provides an overview of the identified risk factors for chronic kidney disease (CKD) progression emphasizing the pediatric population. Recent findings Over the past ten years, there have been significant changes to our understanding and study of pre-terminal kidney failure. Recent refinements in the measurement of glomerular filtration rate (GFR) and GFR estimating equations are important tools for identification and association of risk factors for CKD progression in children. In pediatric CKD, lower level of kidney function at presentation, higher levels of proteinuria, and hypertension are known markers for a more rapid decline in GFR. Anemia and other reported risk factors from the pre-genomic era have need for further study and validation. Genome-wide association studies have identified genetic loci which have provided novel genetic risk factors for CKD progression. Summary With cohort studies of children with CKD becoming mature, they have started to yield important refinements to the assessment of CKD progression. While many of the traditional risk factors for renal progression will certainly be assessed, such cohorts will be important for evaluating novel risk factors identified by genome-wide studies. PMID:20090523

  3. High Water Intake and Progression of Chronic Kidney Diseases

    PubMed Central

    Choi, Hoon Young; Park, Hyeong Cheon

    2015-01-01

    Impact of water intake on the courses of chronic kidney and urinary tract diseases, such as urolithiasis, urinary tract infections, chronic kidney diseases (CKD), autosomal dominant polycystic kidney diseases and bladder cancer, has recently been studied. It still remains controversial whether increased water intake slows the progression of CKD or not. However, high water intake suppresses plasma levels of arginine vasopressin (AVP), which is expected to be beneficial for the preservation of the kidney function. Previous studies suggest that water intake suppresses plasma levels of AVP, and high levels of AVP have been suggested to play deleterious roles in animal models of kidney disease. Moreover, recent epidemic of CKD of unknown origin, which was supposed to be related to the insufficient water intake and chronic volume depletion, has been reported in Central America, further suggesting that the suppression of AVP by sustained water intake might be beneficial in this CKD population. Indeed, the data from recent studies were consistent with the view that high water intake is associated with slower progression of CKD. However, contradictory findings also exist. The intriguing effects of increased urine volume in preserving the glomerular filtration rate in human patients with CKD require more large and well-designed randomized prospective clinical trials. PMID:26848303

  4. High Water Intake and Progression of Chronic Kidney Diseases.

    PubMed

    Choi, Hoon Young; Park, Hyeong Cheon; Ha, Sung Kyu

    2015-12-01

    Impact of water intake on the courses of chronic kidney and urinary tract diseases, such as urolithiasis, urinary tract infections, chronic kidney diseases (CKD), autosomal dominant polycystic kidney diseases and bladder cancer, has recently been studied. It still remains controversial whether increased water intake slows the progression of CKD or not. However, high water intake suppresses plasma levels of arginine vasopressin (AVP), which is expected to be beneficial for the preservation of the kidney function. Previous studies suggest that water intake suppresses plasma levels of AVP, and high levels of AVP have been suggested to play deleterious roles in animal models of kidney disease. Moreover, recent epidemic of CKD of unknown origin, which was supposed to be related to the insufficient water intake and chronic volume depletion, has been reported in Central America, further suggesting that the suppression of AVP by sustained water intake might be beneficial in this CKD population. Indeed, the data from recent studies were consistent with the view that high water intake is associated with slower progression of CKD. However, contradictory findings also exist. The intriguing effects of increased urine volume in preserving the glomerular filtration rate in human patients with CKD require more large and well-designed randomized prospective clinical trials. PMID:26848303

  5. [Characteristics of molecular genetics and research progress on mitochondrial diseases].

    PubMed

    Zhang, Meng; Si, Yanmei; Zhao, Juan

    2016-10-01

    Mitochondrial diseases is a group of metabolic disorders caused by abnormal structure and dysfunction of mitochondrial DNA (mtDNA). Abnormalities of mtDNA include point mutations, deletions, and rearrangements and depletion of mtDNA. These may affect the ability of mitochondria to generate energy in cells of various tissues and organs. As many factors are involved in the regulation of mtDNA mutations, most mitochondrial diseases may manifest great genetic heterogeneity and a wide spectrum of clinical manifestations. On the other hand, for the low prevalence of single disease, these disorders may be easily missed or with delayed diagnosis. This review focuses on the pathological mutations and benign variations of mtDNA, and research progress on such disorders. PMID:27577231

  6. Aluminum involvement in the progression of Alzheimer's disease.

    PubMed

    Walton, J R

    2013-01-01

    The neuroanatomic specificity with which Alzheimer's disease (AD) progresses could provide clues to AD etiopathology. Magnetic resonance imaging studies of AD clinical progression have confirmed general conclusions from earlier studies of AD neuropathological progression wherein neurofibrillary tangle pathology was observed to spread along a well-defined sequence of corticocortical and corticosubcortical connections, preferentially affecting certain cell types, while sparing others. Identical and non-identical twin studies have consistently shown AD has mixed (environmental and genetic) etiopathogenesis. The decades-long prodromal phase over which AD develops suggests slow but progressive accumulation of a toxic or infective agent over time. Major environmental candidates are reviewed to assess which best fits the profile of an agent that slowly accrues in susceptible cell types of AD-vulnerable brain regions to toxic levels by old age, giving rise to AD neuropathology without rapid neuronal lysis. Chronic aluminum neurotoxicity best matches this profile. Many humans routinely ingest aluminum salts as additives contained in processed foods and alum-treated drinking water. The physical properties of aluminum and ferric iron ions are similar, allowing aluminum to use mechanisms evolved for iron to enter vulnerable neurons involved in AD progression, accumulate in those neurons, and cause neurofibrillary damage. The genetic component of AD etiopathogenesis apparently involves a susceptibility gene, yet to be identified, that increases aluminum absorption because AD and Down syndrome patients have higher than normal plasma, and brain, aluminum levels. This review describes evidence for aluminum involvement in AD neuropathology and the clinical progression of sporadic AD. PMID:23380995

  7. Accelerated vascular disease in systemic lupus erythematosus: role of macrophage.

    PubMed

    Al Gadban, Mohammed M; Alwan, Mohamed M; Smith, Kent J; Hammad, Samar M

    2015-04-01

    Atherosclerosis is a chronic inflammatory condition that is considered a major cause of death worldwide. Striking phenomena of atherosclerosis associated with systemic lupus erythematosus (SLE) is its high incidence in young patients. Macrophages are heterogeneous cells that differentiate from hematopoietic progenitors and reside in different tissues to preserve tissue integrity. Macrophages scavenge modified lipids and play a major role in the development of atherosclerosis. When activated, macrophages secret inflammatory cytokines. This activation triggers apoptosis of cells in the vicinity of macrophages. As such, macrophages play a significant role in tissue remodeling including atherosclerotic plaque formation and rupture. In spite of studies carried on identifying the role of macrophages in atherosclerosis, this role has not been studied thoroughly in SLE-associated atherosclerosis. In this review, we address factors released by macrophages as well as extrinsic factors that may control macrophage behavior and their effect on accelerated development of atherosclerosis in SLE. PMID:25638414

  8. Activin A accelerates the progression of fetal oocytes throughout meiosis and early oogenesis in the mouse.

    PubMed

    Liang, Gui-Jin; Zhang, Xi-Feng; Wang, Jun-Jie; Sun, Yuan-Chao; Sun, Xiao-Feng; Cheng, Shun-Feng; Li, Lan; De Felici, Massimo; Shen, Wei

    2015-10-15

    Activins can exert several roles in ovary development. However, little is known about their involvement in early mammalian oogenesis. In this study, we reported that activin receptors (including ActRIA, ActRIB, ActRIIA, and ActRIIB) are expressed throughout the development of the mouse ovaries from 12.5 days postcoitum (dpc) to 21 days postparturition (dpp). Moreover, we found that in vitro, the addition of activin A (ActA) to the culture medium of 12.5 dpc ovarian tissues accelerated the progression of oocytes throughout meiotic prophase I stages. This result was reproduced in vivo following administration of ActA to pregnant mice. The in vitro effect of ActA was associated with increased expression of premeiotic and meiotic genes (including Dazl, Spo11, Stra8, Scp3, and Rec8) in the ovarian tissues. Mechanistically, ActA-dependent SMAD3 signaling modulated the expression of members of the retinoic acid (RA) system, including the RA degradation CYP26B1 enzyme and the RA receptors. Finally, ActA promoted the survival and growth of fetal and early postnatal oocytes and primordial follicle assembly both in vitro and in vivo. In conclusion, the present study identifies new roles of ActA in early oogenesis and suggested that ActA and RA might cooperate in promoting meiosis in female germ cells.

  9. Atg4b-Dependent Autophagic Flux Alleviates Huntington’s Disease Progression

    PubMed Central

    Proenca, Catia C.; Stoehr, Natacha; Bernhard, Mario; Seger, Shanon; Genoud, Christel; Roscic, Ana; Paganetti, Paolo; Liu, Shanming; Murphy, Leon O.; Kuhn, Rainer; Bouwmeester, Tewis; Galimberti, Ivan

    2013-01-01

    The accumulation of aggregated mutant huntingtin (mHtt) inclusion bodies is involved in Huntigton’s disease (HD) progression. Medium sized-spiny neurons (MSNs) in the corpus striatum are highly vulnerable to mHtt aggregate accumulation and degeneration, but the mechanisms and pathways involved remain elusive. Here we have developed a new model to study MSNs degeneration in the context of HD. We produced organotypic cortico-striatal slice cultures (CStS) from HD transgenic mice mimicking specific features of HD progression. We then show that induction of autophagy using catalytic inhibitors of mTOR prevents MSNs degeneration in HD CStS. Furthermore, disrupting autophagic flux by overexpressing Atg4b in neurons and slice cultures, accelerated mHtt aggregation and neuronal death, suggesting that Atg4b-dependent autophagic flux influences HD progression. Under these circumstances induction of autophagy using catalytic inhibitors of mTOR was inefficient and did not affect mHtt aggregate accumulation and toxicity, indicating that mTOR inhibition alleviates HD progression by inducing Atg4b-dependent autophagic flux. These results establish modulators of Atg4b-dependent autophagic flux as new potential targets in the treatment of HD. PMID:23861892

  10. A transcriptional network underlies susceptibility to kidney disease progression

    PubMed Central

    Laouari, Denise; Burtin, Martine; Phelep, Aurélie; Bienaime, Frank; Noel, Laure-Hélène; Lee, David C; Legendre, Christophe; Friedlander, Gérard; Pontoglio, Marco; Terzi, Fabiola

    2012-01-01

    The molecular networks that control the progression of chronic kidney diseases (CKD) are poorly defined. We have recently shown that the susceptibility to development of renal lesions after nephron reduction is controlled by a locus on mouse chromosome 6 and requires epidermal growth factor receptor (EGFR) activation. Here, we identified microphthalmia-associated transcription factor A (MITF-A), a bHLH-Zip transcription factor, as a modifier of CKD progression. Sequence analysis revealed a strain-specific mutation in the 5′ UTR that decreases MITF-A protein synthesis in lesion-prone friend virus B NIH (FVB/N) mice. More importantly, we dissected the molecular pathway by which MITF-A modulates CKD progression. MITF-A interacts with histone deacetylases to repress the transcription of TGF-α, a ligand of EGFR, and antagonizes transactivation by its related partner, transcription factor E3 (TFE3). Consistent with the key role of this network in CKD, Tgfa gene inactivation protected FVB/N mice from renal deterioration after nephron reduction. These data are relevant to human CKD, as we found that the TFE3/MITF-A ratio was increased in patients with damaged kidneys. Our study uncovers a novel transcriptional network and unveils novel potential prognostic and therapeutic targets for preventing human CKD progression. PMID:22711280

  11. Weight loss interventions and progression of diabetic kidney disease.

    PubMed

    Docherty, Neil G; Canney, Aoife L; le Roux, Carel W

    2015-08-01

    Progressive renal impairment (diabetic kidney disease (DKD)) occurs in upwards of 40 % of patients with obesity and type 2 diabetes mellitus (T2DM) and is a cause of significant morbidity and mortality. Means of attenuating the progression of DKD focus on amelioration of risk factors. Visceral obesity is implicated as a causative agent in impaired metabolic and cardiovascular control in T2DM, and various approaches primarily targeting weight have been examined for their impact on markers of renal injury and dysfunction in DKD. The current report summarises the evidence base for the impact of surgical, lifestyle and pharmacological approaches to weight loss on renal end points in DKD. The potential for a threshold of weight loss more readily achievable by surgical intervention to be a prerequisite for renal improvement is highlighted. Comparing efficacious non-surgical weight loss strategies with surgical strategies in appropriately powered and controlled prospective studies is a priority for the field.

  12. An Examination of the Impact of Accelerating Community College Students' Progression through Developmental Education

    ERIC Educational Resources Information Center

    Hodara, Michelle; Jaggars, Shanna Smith

    2014-01-01

    In an effort to improve developmental education students' outcomes, community colleges have been experimenting with acceleration strategies. Models of acceleration allow students to complete their developmental requirements in a shorter amount of time. However, there has been limited empirical research on the effects of accelerating students'…

  13. Quantifying Parkinson's disease progression by simulating gait patterns

    NASA Astrophysics Data System (ADS)

    Cárdenas, Luisa; Martínez, Fabio; Atehortúa, Angélica; Romero, Eduardo

    2015-12-01

    Modern rehabilitation protocols of most neurodegenerative diseases, in particular the Parkinson Disease, rely on a clinical analysis of gait patterns. Currently, such analysis is highly dependent on both the examiner expertise and the type of evaluation. Development of evaluation methods with objective measures is then crucial. Physical models arise as a powerful alternative to quantify movement patterns and to emulate the progression and performance of specific treatments. This work introduces a novel quantification of the Parkinson disease progression using a physical model that accurately represents the main gait biomarker, the body Center of Gravity (CoG). The model tracks the whole gait cycle by a coupled double inverted pendulum that emulates the leg swinging for the single support phase and by a damper-spring System (SDP) that recreates both legs in contact with the ground for the double phase. The patterns generated by the proposed model are compared with actual ones learned from 24 subjects in stages 2,3, and 4. The evaluation performed demonstrates a better performance of the proposed model when compared with a baseline model(SP) composed of a coupled double pendulum and a mass-spring system. The Frechet distance measured differences between model estimations and real trajectories, showing for stages 2, 3 and 4 distances of 0.137, 0.155, 0.38 for the baseline and 0.07, 0.09, 0.29 for the proposed method.

  14. FoxO3a and disease progression

    PubMed Central

    Nho, Richard Seonghun; Hergert, Polla

    2014-01-01

    The Forkhead box O (FoxO) family has recently been highlighted as an important transcriptional regulator of crucial proteins associated with the many diverse functions of cells. So far, FoxO1, FoxO3a, FoxO4 and FoxO6 proteins have been identified in humans. Although each FoxO family member has its own role, unlike the other FoxO families, FoxO3a has been extensively studied because of its rather unique and pivotal regulation of cell proliferation, apoptosis, metabolism, stress management and longevity. FoxO3a alteration is closely linked to the progression of several types of cancers, fibrosis and other types of diseases. In this review, we will examine the function of FoxO3a in disease progression and also explore FoxO3a’s regulatory mechanisms. We will also discuss FoxO3a as a potential target for the treatment of several types of disease. PMID:25225602

  15. Regulatory B cells correlate with HIV disease progression.

    PubMed

    Jiao, Yanmei; Wang, Xi; Zhang, Tong; Sun, Lijun; Wang, Rui; Li, Wei; Ji, Yunxia; Wu, Hao; Liu, Cuie

    2014-08-01

    A rare subset of IL-10-producing B cells, named Breg, was recently identified in mice and humans. Currently, there are no unified cell surface markers to identify Breg, and the relationship between the frequency of Breg and HIV disease progression in chronic HIV infection is unclear. In the present study, we determined whether the cell surface markers of Breg reported for other diseases are suitable for identifying Breg in HIV-infected patients. In addition, we examined the relationship between Breg and HIV disease progression. We found that Breg frequency correlated positively with viral load and negatively with CD4 count in chronic HIV infection. Following antiretroviral treatment, the CD4 count increased and the frequency of Breg decreased stepwise. There was no difference in IL-10 expression of CD1d(hi) or CD1d(lo) cells isolated from HIV-infected patients. Therefore, CD1d may not be a marker of Breg in HIV-infected patients.

  16. Inactivation of the transcription factor GLI1 accelerates pancreatic cancer progression.

    PubMed

    Mills, Lisa D; Zhang, Lizhi; Marler, Ronald; Svingen, Phyllis; Fernandez-Barrena, Maite G; Dave, Maneesh; Bamlet, William; McWilliams, Robert R; Petersen, Gloria M; Faubion, William; Fernandez-Zapico, Martin E

    2014-06-01

    The role of GLI1 in pancreatic tumor initiation promoting the progression of preneoplastic lesions into tumors is well established. However, its function at later stages of pancreatic carcinogenesis remains poorly understood. To address this issue, we crossed the gli1 knock-out (GKO) animal with cre-dependent pancreatic activation of oncogenic kras concomitant with loss of the tumor suppressor tp53 (KPC). Interestingly, in this model, GLI1 played a tumor-protective function, where survival of GKO/KPC mice was reduced compared with KPC littermates. Both cohorts developed pancreatic cancer without significant histopathological differences in survival studies. However, analysis of mice using ultrasound-based imaging at earlier time points showed increased tumor burden in GKO/KPC mice. These animals have larger tumors, decreased body weight, increased lactate dehydrogenase production, and severe leukopenia. In vivo and in vitro expression studies identified FAS and FAS ligand (FASL) as potential mediators of this phenomenon. The FAS/FASL axis, an apoptotic inducer, plays a role in the progression of pancreatic cancer, where its expression is usually lost or significantly reduced in advanced stages of the disease. Chromatin immunoprecipitation and reporter assays identified FAS and FASL as direct targets of GLI1, whereas GKO/KPC mice showed lower levels of this ligand compared with KPC animals. Finally, decreased levels of apoptosis were detected in tumor tissue in the absence of GLI1 by TUNEL staining. Together, these findings define a novel pathway regulated by GLI1 controlling pancreatic tumor progression and provide a new theoretical framework to help with the design and analysis of trials targeting GLI1-related pathways. PMID:24737325

  17. Immune Evasion Mechanisms of Entamoeba histolytica: Progression to Disease

    PubMed Central

    Begum, Sharmin; Quach, Jeanie; Chadee, Kris

    2015-01-01

    Entamoeba histolytica (Eh) is a protozoan parasite that infects 10% of the world's population and results in 100,000 deaths/year from amebic dysentery and/or liver abscess. In most cases, this extracellular parasite colonizes the colon by high affinity binding to MUC2 mucin without disease symptoms, whereas in some cases, Eh triggers an aggressive inflammatory response upon invasion of the colonic mucosa. The specific host-parasite factors critical for disease pathogenesis are still not well characterized. From the parasite, the signature events that lead to disease progression are cysteine protease cleavage of the C-terminus of MUC2 that dissolves the mucus layer followed by Eh binding and cytotoxicity of the mucosal epithelium. The host mounts an ineffective excessive host pro-inflammatory response following contact with host cells that causes tissue damage and participates in disease pathogenesis as Eh escapes host immune clearance by mechanisms that are not completely understood. Ameba can modulate or destroy effector immune cells by inducing neutrophil apoptosis and suppressing respiratory burst or nitric oxide (NO) production from macrophages. Eh adherence to the host cells also induce multiple cytotoxic effects that can promote cell death through phagocytosis, apoptosis or by trogocytosis (ingestion of living cells) that might play critical roles in immune evasion. This review focuses on the immune evasion mechanisms that Eh uses to survive and induce disease manifestation in the host. PMID:26696997

  18. Progress Toward Eliminating Hepatitis A Disease in the United States.

    PubMed

    Murphy, Trudy V; Denniston, Maxine M; Hill, Holly A; McDonald, Marian; Klevens, Monina R; Elam-Evans, Laurie D; Nelson, Noele P; Iskander, John; Ward, John D

    2016-02-12

    Hepatitis A virus (HAV) disease disproportionately affects adolescents and young adults, American Indian/Alaska Native and Hispanic racial/ethnic groups, and disadvantaged populations. During 1996-2006, the Advisory Committee on Immunization Practices (ACIP) made incremental changes in hepatitis A (HepA) vaccination recommendations to increase coverage for children and persons at high risk for HAV infection. This report examines the temporal association of ACIP-recommended HepA vaccination and disparities (on the absolute scale) in cases of HAV disease and on seroprevalence of HAV-related protection (measured as antibody to HAV [anti-HAV]). ACIP-recommended childhood HepA vaccination in the United States has eliminated most absolute disparities in HAV disease by age, race/ethnicity, and geographic area with relatively modest ≥1-dose and ≥2-dose vaccine coverage. However, the increasing proportion of cases of HAV disease among adults with identified and unidentified sources of exposure underscores the importance of considering new strategies for preventing HAV infection among U.S. adults. For continued progress to be made toward elimination of HAV disease in the United States, additional strategies are needed to prevent HAV infection among an emerging population of susceptible adults. Notably, HAV infection remains endemic in much of the world, contributing to U.S. cases through international travel and the global food economy. PMID:26916458

  19. Immune Evasion Mechanisms of Entamoeba histolytica: Progression to Disease.

    PubMed

    Begum, Sharmin; Quach, Jeanie; Chadee, Kris

    2015-01-01

    Entamoeba histolytica (Eh) is a protozoan parasite that infects 10% of the world's population and results in 100,000 deaths/year from amebic dysentery and/or liver abscess. In most cases, this extracellular parasite colonizes the colon by high affinity binding to MUC2 mucin without disease symptoms, whereas in some cases, Eh triggers an aggressive inflammatory response upon invasion of the colonic mucosa. The specific host-parasite factors critical for disease pathogenesis are still not well characterized. From the parasite, the signature events that lead to disease progression are cysteine protease cleavage of the C-terminus of MUC2 that dissolves the mucus layer followed by Eh binding and cytotoxicity of the mucosal epithelium. The host mounts an ineffective excessive host pro-inflammatory response following contact with host cells that causes tissue damage and participates in disease pathogenesis as Eh escapes host immune clearance by mechanisms that are not completely understood. Ameba can modulate or destroy effector immune cells by inducing neutrophil apoptosis and suppressing respiratory burst or nitric oxide (NO) production from macrophages. Eh adherence to the host cells also induce multiple cytotoxic effects that can promote cell death through phagocytosis, apoptosis or by trogocytosis (ingestion of living cells) that might play critical roles in immune evasion. This review focuses on the immune evasion mechanisms that Eh uses to survive and induce disease manifestation in the host. PMID:26696997

  20. Progress Toward Eliminating Hepatitis A Disease in the United States.

    PubMed

    Murphy, Trudy V; Denniston, Maxine M; Hill, Holly A; McDonald, Marian; Klevens, Monina R; Elam-Evans, Laurie D; Nelson, Noele P; Iskander, John; Ward, John D

    2016-02-12

    Hepatitis A virus (HAV) disease disproportionately affects adolescents and young adults, American Indian/Alaska Native and Hispanic racial/ethnic groups, and disadvantaged populations. During 1996-2006, the Advisory Committee on Immunization Practices (ACIP) made incremental changes in hepatitis A (HepA) vaccination recommendations to increase coverage for children and persons at high risk for HAV infection. This report examines the temporal association of ACIP-recommended HepA vaccination and disparities (on the absolute scale) in cases of HAV disease and on seroprevalence of HAV-related protection (measured as antibody to HAV [anti-HAV]). ACIP-recommended childhood HepA vaccination in the United States has eliminated most absolute disparities in HAV disease by age, race/ethnicity, and geographic area with relatively modest ≥1-dose and ≥2-dose vaccine coverage. However, the increasing proportion of cases of HAV disease among adults with identified and unidentified sources of exposure underscores the importance of considering new strategies for preventing HAV infection among U.S. adults. For continued progress to be made toward elimination of HAV disease in the United States, additional strategies are needed to prevent HAV infection among an emerging population of susceptible adults. Notably, HAV infection remains endemic in much of the world, contributing to U.S. cases through international travel and the global food economy.

  1. Foot-and-mouth disease vaccines: progress and problems.

    PubMed

    Cao, Yimei; Lu, Zengjun; Liu, Zaixin

    2016-06-01

    Foot-and-mouth disease (FMD) has been a major threat to livestock across the world. The predominant method of controlling this disease in endemic regions is through regular vaccination with inactivated vaccine. However, there are many limitations. For instance, cultivation of virulent FMD virus (FMDV) in the manufacturing units poses a risk of escape from production sites. Vaccines may sometimes contain traces of FMD viral non-structural proteins (NSPs), therefore, interfering with the NSP-based serological differentiation infected from vaccinated animals (DIVA). Moreover, vaccines are unable to eliminate virus from carrier animals. To address the shortcomings of inactivated vaccines, many efforts are currently devoted to develop novel vaccines including attenuated and/or marker inactivated vaccines, recombinant protein vaccines, synthetic peptide vaccines, and empty capsid vaccines. Here, we review the research progress of novel vaccines, problems that remain to be solved, and also raise some suggestions that would help in the development of FMD vaccines.

  2. Foot-and-mouth disease vaccines: progress and problems.

    PubMed

    Cao, Yimei; Lu, Zengjun; Liu, Zaixin

    2016-06-01

    Foot-and-mouth disease (FMD) has been a major threat to livestock across the world. The predominant method of controlling this disease in endemic regions is through regular vaccination with inactivated vaccine. However, there are many limitations. For instance, cultivation of virulent FMD virus (FMDV) in the manufacturing units poses a risk of escape from production sites. Vaccines may sometimes contain traces of FMD viral non-structural proteins (NSPs), therefore, interfering with the NSP-based serological differentiation infected from vaccinated animals (DIVA). Moreover, vaccines are unable to eliminate virus from carrier animals. To address the shortcomings of inactivated vaccines, many efforts are currently devoted to develop novel vaccines including attenuated and/or marker inactivated vaccines, recombinant protein vaccines, synthetic peptide vaccines, and empty capsid vaccines. Here, we review the research progress of novel vaccines, problems that remain to be solved, and also raise some suggestions that would help in the development of FMD vaccines. PMID:26760264

  3. Evaluation of disease progression in INCL by MR spectroscopy

    PubMed Central

    Baker, Eva H; Levin, Sondra W; Zhang, Zhongjian; Mukherjee, Anil B

    2015-01-01

    Objective Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating neurodegenerative storage disease caused by palmitoyl-protein thioesterase-1 deficiency, which impairs degradation of palmitoylated proteins (constituents of ceroid) by lysosomal hydrolases. Consequent lysosomal ceroid accumulation leads to neuronal injury. As part of a pilot study to evaluate treatment benefits of cysteamine bitartrate and N-acetylcysteine, we quantitatively measured brain metabolite levels using magnetic resonance spectroscopy (MRS). Methods A subset of two patients from a larger treatment and follow-up study underwent serial quantitative single-voxel MRS examinations of five anatomical sites. Three echo times were acquired in order to estimate metabolite T2. Measured metabolite levels included correction for partial volume of cerebrospinal fluid. Comparison of INCL patients was made to a reference group composed of asymptomatic and minimally symptomatic Niemann-Pick disease type C patients. Results In INCL patients, N-acetylaspartate (NAA) was abnormally low at all locations upon initial measurement, and further declined throughout the follow-up period. In the cerebrum (affected early in the disease course), choline and myo-inositol were initially elevated and fell during the follow-up period, whereas in the cerebellum and brainstem (affected later), choline and myo-inositol were initially normal and rose subsequently. Interpretation Choline and myo-inositol levels in our patients are consistent with patterns of neuroinflammation observed in two INCL mouse models. Low, persistently declining NAA was expected based on the progressive, irreversible nature of the disease. Progression of metabolite levels in INCL has not been previously quantified; therefore the results of this study serve as a reference for quantitative evaluation of future therapeutic interventions. PMID:26339674

  4. Risk Factors for Development and Progression of Chronic Kidney Disease

    PubMed Central

    Tsai, Wan-Chuan; Wu, Hon-Yen; Peng, Yu-Sen; Ko, Mei-Ju; Wu, Ming-Shiou; Hung, Kuan-Yu; Wu, Kwan-Dun; Chu, Tzong-Shinn; Chien, Kuo-Liong

    2016-01-01

    Abstract The risk factors influencing the natural course of chronic kidney disease (CKD) are complex and heterogeneous, and few systematic reviews to date have focused on this issue. The aim of the study is to identify the risk factors for disease development and progression in each stage of CKD. We conducted electronic literature searches of PubMed, MEDLINE, Scopus, and the Cochrane Library up to October 15, 2012, for observational studies evaluating the risk factors on the development or progression of CKD. Eligible studies should have collected repeated information that could evaluate changes in renal function. Extracted information from all the included studies was synthesized narratively. Quality assessments were performed using the Newcastle–Ottawa Scale. An exploratory random-effects meta-analysis was performed where feasible to pool effect sizes across studies for a specific risk factor in a specific outcome. We identified 38 cohort studies and 2 case-control studies from 40 articles, with a total of 318,898 participants from 14 countries. The follow-up duration ranged from 1.5 to 16 years. The majority of the included studies were of high quality. The baseline CKD stages of the included studies ranged from normal to later stages, and only 19 studies could be classified into a specific range of CKD stages during follow-up. Three risk factors from studies of the same baseline and follow-up CKD stages were eligible for the exploratory meta-analysis, including male sex, substantial proteinuria, and diabetes. The hazard ratios for the progression from CKD stages 3–5 to end-stage renal disease (ESRD) were 1.37 (95% confidence interval 1.17–1.62), 1.64 (1.01–2.66), and 1.16 (0.98–1.38) for male sex, substantial proteinuria, and diabetes, respectively. In conclusion, our analyses comprehensively summarize the initiating and perpetuating factors for CKD. Male sex and substantial proteinuria are significant perpetuating factors for the progression from

  5. Early Statin Use and the Progression of Alzheimer Disease

    PubMed Central

    Lin, Feng-Cheng; Chuang, Yun-Shiuan; Hsieh, Hui-Min; Lee, Tzu-Chi; Chiu, Kuei-Fen; Liu, Ching-Kuan; Wu, Ming-Tsang

    2015-01-01

    Abstract The protective effect of statin on Alzheimer disease (AD) is still controversial, probably due to the debate about when to start the use of statin and the lack of any large-scale randomized evidence that actually supports the hypothesis. The purpose of this study was to examine the protective effect of early statin use on mild-to-moderate AD in the total Taiwanese population. This was a total population-based case-control study, using the total population of Taiwanese citizens seen in general medical practice; therefore, the findings can be applied to the general population. The study patients were those with newly diagnosed dementia (ICD-9 290.x) and prescribed any acetylcholinesterase inhibitors (AChEI) from the Taiwan National Health Insurance dataset in 1997 to 2008. The newly diagnosed eligible mild-to-moderate AD patients were traced from the dates of their index dates, which was defined as the first day to receive any AChEI treatment, back to 1 year (exposure period) to categorize them into AD with early statin use and without early statin use. Early statin use was defined as patients using statin before AChEI treatment. Alzheimer disease patients with early statin use were those receiving any statin treatment during the exposure period. Then, we used propensity-score-matched strategy to match these 2 groups as 1:1. The matched study patients were followed-up from their index dates. The primary outcome was the discontinuation of AChEI treatment, indicating AD progression. There were 719 mild-to-moderate AD-paired patients with early statin use and without early statin use for analyses. Alzheimer disease progression was statistically lower in AD patients with early statin use than those without (P = 0.00054). After adjusting for other covariates, mild-to-moderate AD patients with early stain use exhibited a 0.85-risk (95% CI = 0.76–0.95, P = 0.0066) to have AD progression than those without. Early statin use was significantly associated

  6. Interleukin-1 haplotype and periodontal disease progression following therapy.

    PubMed

    Ehmke, B; Kress, W; Karch, H; Grimm, T; Klaiber, B; Flemmig, T F

    1999-12-01

    The purpose of this study was to assess the prognostic value of the IL-1 haplotype on the progression of periodontal disease following therapy. 48 adult patients with untreated periodontitis harboring Actinobacillus actinomycetemcomitans and/or Porphyromonas gingivalis were randomly assigned to receive full-mouth scaling alone (control) or in combination with systemic metronidazole plus amoxicillin and supragingival irrigation with chlorhexidine digluconate (test). All patients received supportive periodontal therapy at 3 to 6 months intervals. In 33 patients, lymphocyte DNA was analyzed for polymorphism in the IL-1A gene at position -889 and IL-1B gene at position +3953. Overall, 16 of 33 patients (7 of 17 test and 9 of 16 control) carried the IL-1 haplotype. 2 years following initial periodontal therapy, no differences in the survival rates of sites or teeth not exhibiting probing attachment loss of 2 mm or more compared to baseline, were found between patients who tested positive (85% sites, 53% teeth) and patients who tested negative (89% sites, 56% teeth) for the IL-1 haplotype. The results indicated that the IL-1 haplotype may be of limited value for the prognosis of periodontal disease progression following non-surgical periodontal therapy.

  7. Evaluating Alzheimer's Disease Progression by Modeling Crosstalk Network Disruption

    PubMed Central

    Liu, Haochen; Wei, Chunxiang; He, Hua; Liu, Xiaoquan

    2016-01-01

    Aβ, tau, and P-tau have been widely accepted as reliable markers for Alzheimer's disease (AD). The crosstalk between these markers forms a complex network. AD may induce the integral variation and disruption of the network. The aim of this study was to develop a novel mathematic model based on a simplified crosstalk network to evaluate the disease progression of AD. The integral variation of the network is measured by three integral disruption parameters. The robustness of network is evaluated by network disruption probability. Presented results show that network disruption probability has a good linear relationship with Mini Mental State Examination (MMSE). The proposed model combined with Support vector machine (SVM) achieves a relative high 10-fold cross-validated performance in classification of AD vs. normal and mild cognitive impairment (MCI) vs. normal (95% accuracy, 95% sensitivity, 95% specificity for AD vs. normal; 90% accuracy, 94% sensitivity, 83% specificity for MCI vs. normal). This research evaluates the progression of AD and facilitates AD early diagnosis. PMID:26834548

  8. Intracranial Hemodynamic Changes During Adult Moyamoya Disease Progression

    PubMed Central

    Kwag, Hyun-Jeong; Jeong, Dong-Wook; Lee, Suk Hoon; Kim, Dae Hyun

    2008-01-01

    Background and purpose This study evaluated the changes in blood flow velocity in the anterior and posterior intracranial circulations according to the progression of moyamoya disease in adult patients. Methods We evaluated Suzuki's angiographic stage and mean blood flow velocity (MBFV) changes in intracranial vessels from both sides in 19 adult moyamoya patients. We then analyzed the linearity of MBFV changes from early to late moyamoya stages in each intracranial vessel using piecewise linear regression models. Results The MBFV in the middle cerebral artery, terminal internal carotid artery, and anterior cerebral artery increased non linearly until stage III, and then decreased progressively up to stage VI. The ophthalmic artery also showed nonlinear velocity changes, with an increase in MBFV up to stage IV, followed by a decrease in MBFV up to stage VI. The MBFV of the basilar artery increased linearly from a normal velocity at an early moyamoya stage to a stenotic velocity at a late stage. There was no statistically significant regression model for the relationship between the MBFV in the posterior cerebral artery and moyamoya stage. Conclusions The nonlinear and/or linear MBFV changes associated with variable intracranial vessels might be useful in initial and follow-up evaluations of different stages of moyamoya disease. PMID:19513306

  9. Natural Progression of Canine Glycogen Storage Disease Type IIIa

    PubMed Central

    Brooks, Elizabeth D; Yi, Haiqing; Austin, Stephanie L; Thurberg, Beth L; Young, Sarah P; Fyfe, John C; Kishnani, Priya S; Sun, Baodong

    2016-01-01

    Glycogen storage disease type IIIa (GSD IIIa) is caused by a deficiency of glycogen debranching enzyme activity. Hepatomegaly, muscle degeneration, and hypoglycemia occur in human patients at an early age. Long-term complications include liver cirrhosis, hepatic adenomas, and generalized myopathy. A naturally occurring canine model of GSD IIIa that mimics the human disease has been described, with progressive liver disease and skeletal muscle damage likely due to excess glycogen deposition. In the current study, long-term follow-up of previously described GSD IIIa dogs until 32 mo of age (n = 4) and of family-owned GSD IIIa dogs until 11 to 12 y of age (n = 2) revealed that elevated concentrations of liver and muscle enzyme (AST, ALT, ALP, and creatine phosphokinase) decreased over time, consistent with hepatic cirrhosis and muscle fibrosis. Glycogen deposition in many skeletal muscles; the tongue, diaphragm, and heart; and the phrenic and sciatic nerves occurred also. Furthermore, the urinary biomarker Glc4, which has been described in many types of GSD, was first elevated and then decreased later in life. This urinary biomarker demonstrated a similar trend as AST and ALT in GSD IIIa dogs, indicating that Glc4 might be a less invasive biomarker of hepatocellular disease. Finally, the current study further demonstrates that the canine GSD IIIa model adheres to the clinical course in human patients with this disorder and is an appropriate model for developing novel therapies. PMID:26884409

  10. 2-Hydroxyestradiol slows progression of experimental polycystic kidney disease

    PubMed Central

    Oyama, Terry T.; Lindsley, Jessie N.; Schutzer, William E.; Beard, Douglas R.; Gattone, Vincent H.; Komers, Radko

    2012-01-01

    Male gender is a risk factor for progression of polycystic kidney disease (PKD). 17β-Estradiol (E2) protects experimentally, but clinical use is limited by adverse effects. Novel E2 metabolites provide many benefits of E2 without stimulating the estrogen receptor, and thus may be safer. We hypothesized that E2 metabolites are protective in a model of PKD. Studies were performed in male control Han:SPRD rats, and in cystic males treated with orchiectomy, 2-methoxyestradiol, 2-hydroxyestradiol (2-OHE), or vehicle, from age 3 to 12 wk. Cystic rats exhibited renal functional impairment (∼50% decrease in glomerular filtration and renal plasma flow rates, P < 0.05) and substantial cyst development (20.5 ± 2.0% of cortex area). 2-OHE was the most effective in limiting cysts (6.0 ± 0.7% of cortex area, P < 0.05 vs. vehicle-treated cystic rats) and preserving function, in association with suppression of proliferation, apoptosis, and angiogenesis markers. Downregulation of p21 expression and increased expression of Akt, the mammalian target of rapamycin (mTOR), and some of its downstream effectors were significantly reversed by 2-OHE. Thus, 2-OHE limits disease progression in a cystic rodent model. Mechanisms include reduced renal cell proliferation, apoptosis, and angiogenesis. These effects may be mediated, at least in part, by preservation of p21 and suppression of Akt and mTOR. Estradiol metabolites may represent a novel, safe intervention to slow progression of PKD. PMID:22160773

  11. Pristane-Accelerated Autoimmune Disease in (SWR X NZB) F1 Mice Leads to Prominent Tubulointerstitial Inflammation and Human Lupus Nephritis-Like Fibrosis

    PubMed Central

    Gardet, Agnes; Chou, Wei C.; Reynolds, Taylor L.; Velez, Diana B.; Fu, Kai; Czerkowicz, Julia M.; Bajko, Jeffrey; Ranger, Ann M.; Allaire, Normand; Kerns, Hannah M.; Ryan, Sarah; Legault, Holly M.; Dunstan, Robert W.; Lafyatis, Robert; Lukashev, Matvey; Viney, Joanne L.; Browning, Jeffrey L.; Rabah, Dania

    2016-01-01

    Mouse models lupus nephritis (LN) have provided important insights into disease pathogenesis, although none have been able to recapitulate all features of the human disease. Using comprehensive longitudinal analyses, we characterized a novel accelerated mouse model of lupus using pristane treatment in SNF1 (SWR X NZB F1) lupus prone mice (pristane-SNF1 mice). Pristane treatment in SNF1 mice accelerated the onset and progression of proteinuria, autoantibody production, immune complex deposition and development of renal lesions. At week 14, the pristane-SNF1 model recapitulated kidney disease parameters and molecular signatures seen in spontaneous disease in 36 week-old SNF1 mice and in a traditional IFNα-accelerated NZB X NZW F1 (BWF1) model. Blood transcriptome analysis revealed interferon, plasma cell, neutrophil, T-cell and protein synthesis signatures in the pristane-SNF1 model, all known to be present in the human disease. The pristane-SNF1 model appears to be particularly useful for preclinical research, robustly exhibiting many characteristics reminiscent of human disease. These include i) a stronger upregulation of the cytosolic nucleic acid sensing pathway, which is thought to be key component of the pathogenesis of the human disease, and ii) more prominent kidney interstitial inflammation and fibrosis, which have been both associated with poor prognosis in human LN. To our knowledge, this is the only accelerated model of LN that exhibits a robust tubulointerstitial inflammatory and fibrosis response. Taken together our data show that the pristane-SNF1 model is a novel accelerated model of LN with key features similar to human disease. PMID:27760209

  12. The effect of post-traumatic stress disorder on HIV disease progression following hurricane Katrina.

    PubMed

    Reilly, Kathleen H; Clark, Rebecca A; Schmidt, Norine; Benight, Charles C; Kissinger, Patricia

    2009-10-01

    Post-traumatic stress disorder (PTSD) is a common psychological outcome of any disaster. The purpose of this study was to examine the effects of PTSD on disease progression among HIV-infected persons in metropolitan New Orleans post-hurricane Katrina. One-year post-storm, a convenience sample of 145 HIV-infected patients who returned to care at the HIV Outpatient Program clinic in New Orleans were interviewed. Clinical factors pre and one and two years post-disaster were abstracted from medical records and compared by PTSD status. Of the 145 participants, 37.2% had PTSD. Those with PTSD were more likely than those without PTSD to have detectable plasma viral loads at both follow-up time points post-disaster and more likely to have CD4 cell counts <200/mm(3) two years post-disaster. They were also more likely to have had medication interruptions immediately post-disaster. Our findings corroborate the findings of others that PTSD accelerates HIV disease progression. Disaster planners should consider the special counseling and medication safeguards needs of HIV-infected persons.

  13. Exogenous hydrogen sulfide exerts proliferation, anti-apoptosis, migration effects and accelerates cell cycle progression in multiple myeloma cells via activating the Akt pathway.

    PubMed

    Zheng, Dong; Chen, Ziang; Chen, Jingfu; Zhuang, Xiaomin; Feng, Jianqiang; Li, Juan

    2016-10-01

    Hydrogen sulfide (H2S), regarded as the third gaseous transmitter, mediates and induces various biological effects. The present study investigated the effects of H2S on multiple myeloma cell progression via amplifying the activation of Akt pathway in multiple myeloma cells. The level of H2S produced in multiple myeloma (MM) patients and healthy subjects was measured using enzyme-linked immunosorbent assay (ELISA). MM cells were treated with 500 µmol/l NaHS (a donor of H2S) for 24 h. The expression levels of phosphorylated-Akt (p-Akt), Bcl-2 and caspase-3 were measured by western blot assay. Cell viability was detected by Cell Counting Kit 8 (CCK-8). The cell cycle was analyzed by flow cytometry. Our results show that the concentration of H2S was higher in MM patients and that it increased in parallel with disease progression. Treating MM cells with 500 µmol/l NaHS for 24 h markedly increased the expression level of Bcl-2 and the activation of p-Akt, however, the expression level of caspase-3 was decreased, cell viability was increased, and cell cycle progression was accelerated in MM cells. NaHS also induced migration in MM cells in transwell migration assay. Furthermore, co-treatment of MM cells with 500 µmol/l NaHS and 50 µmol/l LY294002 for 24 h significantly overset these effects. In conclusion, our findings demonstrate that the Akt pathway contributes to NaHS-induced cell proliferation, migration and acceleration of cell cycle progression in MM cells. PMID:27513630

  14. Structural Imaging and Parkinson’s Disease: Moving Toward Quantitative Markers of Disease Progression

    PubMed Central

    Sterling, N.W.; Lewis, M.M.; Du, G.; Huang, X.

    2016-01-01

    Parkinson’s disease (PD) is a progressive age-related neurodegenerative disorder. Although the pathological hallmark of PD is dopaminergic cell death in the substantia nigra pars compacta, widespread neurodegenerative changes occur throughout the brain as disease progresses. Postmortem studies, for example, have demonstrated the presence of Lewy pathology, apoptosis, and loss of neurotransmitters and interneurons in both cortical and subcortical regions of PD patients. Many in vivo structural imaging studies have attempted to gauge PD-related pathology, particularly in gray matter, with the hope of identifying an imaging biomarker. Reports of brain atrophy in PD, however, have been inconsistent, most likely due to differences in the studied populations (i.e. different disease stages and/or clinical subtypes), experimental designs (i.e. cross-sectional vs. longitudinal), and image analysis methodologies (i.e. automatic vs. manual segmentation). This review attempts to summarize the current state of gray matter structural imaging research in PD in relationship to disease progression, reconciling some of the differences in reported results, and to identify challenges and future avenues. PMID:27258697

  15. Biomarkers for disease progression and AAV therapeutic efficacy in feline Sandhoff disease

    PubMed Central

    Bradbury, Allison M; Gray-Edwards, Heather L; Shirley, Jamie L; McCurdy, Victoria J; Colaco, Alexandria N; Randle, Ashley N; Christopherson, Pete W; Bird, Allison C; Johnson, Aime K; Wilson, Diane U; Hudson, Judith A; De Pompa, Nicholas L; Sorjonen, Donald C; Brunson, Brandon L; Jeyakumar, Mylvaganam; Platt, Frances M; Baker, Henry J; Cox, Nancy R; Sena-Esteves, Miguel; Martin, Douglas R

    2014-01-01

    The GM2 gangliosidoses, Tay-Sachs disease (TSD) and Sandhoff disease (SD), are progressive neurodegenerative disorders that are caused by a mutation in the enzyme β-N-acetylhexosaminidase (Hex). Due to the recent emergence of novel experimental treatments, biomarker development has become particularly relevant in GM2 gangliosidosis as an objective means to measure therapeutic efficacy. Here we describe blood, cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), and electrodiagnostic methods for evaluating disease progression in the feline SD model and application of these approaches to assess AAV-mediated gene therapy. SD cats were treated by intracranial injections of the thalami combined with either the deep cerebellar nuclei or a single lateral ventricle using AAVrh8 vectors encoding feline Hex. Significantly altered in untreated SD cats, blood and CSF based biomarkers were normalized after AAV gene therapy. Also reduced after treatment were expansion of the lysosomal compartment in peripheral blood mononuclear cells and elevated activity of secondary lysosomal enzymes. MRI changes characteristic of the gangliosidoses were documented in SD cats and normalized after AAV gene therapy. The minimally invasive biomarkers reported herein should be useful to assess disease progression of untreated GM2 patients and those in future clinical trials. PMID:25284324

  16. Biomarkers for disease progression and AAV therapeutic efficacy in feline Sandhoff disease.

    PubMed

    Bradbury, Allison M; Gray-Edwards, Heather L; Shirley, Jamie L; McCurdy, Victoria J; Colaco, Alexandria N; Randle, Ashley N; Christopherson, Pete W; Bird, Allison C; Johnson, Aime K; Wilson, Diane U; Hudson, Judith A; De Pompa, Nicholas L; Sorjonen, Donald C; Brunson, Brandon L; Jeyakumar, Mylvaganam; Platt, Frances M; Baker, Henry J; Cox, Nancy R; Sena-Esteves, Miguel; Martin, Douglas R

    2015-01-01

    The GM2 gangliosidoses, Tay-Sachs disease (TSD) and Sandhoff disease (SD), are progressive neurodegenerative disorders that are caused by a mutation in the enzyme β-N-acetylhexosaminidase (Hex). Due to the recent emergence of novel experimental treatments, biomarker development has become particularly relevant in GM2 gangliosidosis as an objective means to measure therapeutic efficacy. Here we describe blood, cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), and electrodiagnostic methods for evaluating disease progression in the feline SD model and application of these approaches to assess AAV-mediated gene therapy. SD cats were treated by intracranial injections of the thalami combined with either the deep cerebellar nuclei or a single lateral ventricle using AAVrh8 vectors encoding feline Hex. Significantly altered in untreated SD cats, blood and CSF based biomarkers were largely normalized after AAV gene therapy. Also reduced after treatment were expansion of the lysosomal compartment in peripheral blood mononuclear cells and elevated activity of secondary lysosomal enzymes. MRI changes characteristic of the gangliosidoses were documented in SD cats and normalized after AAV gene therapy. The minimally invasive biomarkers reported herein should be useful to assess disease progression of untreated SD patients and those in future clinical trials. PMID:25284324

  17. Serum immune markers and disease progression in an incident Parkinson's disease cohort (ICICLE‐PD)

    PubMed Central

    Wijeyekoon, Ruwani; Yarnall, Alison J.; Lawson, Rachael A.; Breen, David P.; Evans, Jonathan R.; Cummins, Gemma A.; Duncan, Gordon W.; Khoo, Tien K.; Burn, David J.; Barker, Roger A.

    2016-01-01

    ABSTRACT Background The immune system is a promising therapeutic target for disease modification in Parkinson's disease (PD), but appropriate immune‐related biomarkers must be identified to allow patient stratification for trials and tracking of therapeutic effects. The objective of this study was to investigate whether immune markers in peripheral blood are candidate prognostic biomarkers through determining their relationship with disease progression in PD. Methods Serum samples were collected in incident PD cases and age‐matched controls. Subjects were clinically evaluated at baseline and 18 and 36 months. Ten cytokines and C‐reactive protein were measured, with data reduction using principal‐component analysis, and relationships between component scores and motor (MDS Unified Parkinson's Disease Rating Scale — part 3) and cognitive (Mini Mental State Examination [MMSE]) measures of disease severity/progression were investigated. Results TNF‐α, IL1‐β, IL‐2, and IL‐10 were higher in PD (n = 230) than in controls (n = 93), P ≤ 0.001). Principal‐component analysis of log‐transformed data resulted in a 3‐component solution explaining 51% of the variance. Higher “proinflammatory” and lower “anti‐inflammatory” component scores were associated with more rapid motor progression over 36 months (P < 0.05), and higher “proinflammatory” component scores were associated with lower MMSE at all times (P < 0.05). Multiple linear regression analysis with adjustment for covariates confirmed “anti‐inflammatory” component score was the strongest predictor of slower motor progression (β = −0.22, P = 0.002), whereas proinflammatory cytokines were associated with lower baseline MMSE (β = −0.175, P = 0.007). Conclusions Serum immune marker profile is predictive of disease progression in PD and hence a potential prognostic biomarker. However, interventional trials are needed to clarify whether peripheral immune changes

  18. A Bayesian nonlinear mixed-effects disease progression model

    PubMed Central

    Kim, Seongho; Jang, Hyejeong; Wu, Dongfeng; Abrams, Judith

    2016-01-01

    A nonlinear mixed-effects approach is developed for disease progression models that incorporate variation in age in a Bayesian framework. We further generalize the probability model for sensitivity to depend on age at diagnosis, time spent in the preclinical state and sojourn time. The developed models are then applied to the Johns Hopkins Lung Project data and the Health Insurance Plan for Greater New York data using Bayesian Markov chain Monte Carlo and are compared with the estimation method that does not consider random-effects from age. Using the developed models, we obtain not only age-specific individual-level distributions, but also population-level distributions of sensitivity, sojourn time and transition probability. PMID:26798562

  19. Smart garments in chronic disease management: progress and challenges

    NASA Astrophysics Data System (ADS)

    Khosla, Ajit

    2012-10-01

    This paper presents the progress made developments in the area of Smart Garments for chronic disease management over last 10 years. A large number of health monitoring smart garments and wearable sensors have been manufactured to monitor patient's physiological parameters such as electrocardiogram, blood pressure, body temperature, heart rate, oxygen saturation, while patient is not in hospital. In last few years with the advancement in smartphones and cloud computing it is now possible to send the measure physiological data to any desired location. However there are many challenges in the development of smart garment systems. The two major challenges are development of new lightweight power sources and there is a need for global standardization and a road map for development of smart garments. In this paper we will discuss current state-of-theart smart garments and wearable sensor systems. Also discussed will be the new emerging trends in smart garment research and development.

  20. Remnant nephron physiology and the progression of chronic kidney disease.

    PubMed

    Schnaper, H William

    2014-02-01

    In chronic kidney disease, ongoing failure of individual nephrons leads to the progressive loss of renal function. This process results in part from a cellular and molecular response to injury that represents an attempt to maintain homeostasis but instead initiates a program that damages the nephron. As nephrons are lost, compensation by the remaining nephrons exacerbates glomerular pathophysiology. The delivery of excessive amounts of biologically active molecules to the distal nephron and tubulointerstitium generates inflammation and cellular dedifferentiation. Energy requirements of hyperfunctioning nephrons exceed the metabolic substrate available to the renal tubule, and inadequacy of the local vascular supply promotes hypoxia/ischemia and consequent acidosis and reactive oxygen species generation. In this way, mechanisms activated to maintain biological balance ultimately lead to demise of the nephron.

  1. Decreased RECQL5 correlated with disease progression of osteosarcoma.

    PubMed

    Wu, Junlong; Zhi, Liqiang; Dai, Xin; Cai, Qingchun; Ma, Wei

    2015-11-27

    Human RecQ helicase family, consisting of RECQL, RECQL4, RECQL5, BLM and WRN, has critical roles in genetic stability and tumorigenesis. Although RECQL5 has been reported to correlate with the susceptibility to malignances including osteosarcoma, the specific effect on tumor genesis and progression is not yet clarified. Here we focused on the relationship between RECQL5 expression and osteosarcoma disease progression, and further investigated the function of RECQL5 on MG-63 cell proliferation and apoptosis. By immunohistochemical analysis, qRT-PCR and western blot, we found that RECQL5 expression was downregulated in osteosarcoma tissues and cells. Patients with advanced tumor stage and low grade expressed lower RECQL5. To construct a stable RECQL5 overexpression osteosarcoma cell line (MG-63-RECQL5), RECQL5 gene was inserted into the human AAVS1 safe harbor by CRISPR/Cas9 system. The overexpression of RECQL5 was verified by qRT-PCR and western blot. Cell proliferation, cell cycle and apoptosis assay revealed that RECQL5 overexpression inhibited proliferation, induced G1-phase arrest and promoted apoptosis in MG-63 cells. Collectively, our results suggested RECQL5 as a tumor suppressor in osteosarcoma and may be a potential therapeutic target for osteosarcoma treatment.

  2. Primary hyperaldosteronism, a mediator of progressive renal disease in cats.

    PubMed

    Javadi, S; Djajadiningrat-Laanen, S C; Kooistra, H S; van Dongen, A M; Voorhout, G; van Sluijs, F J; van den Ingh, T S G A M; Boer, W H; Rijnberk, A

    2005-01-01

    In recent years, there has been renewed interest in primary hyperaldosteronism, particularly because of its possible role in the progression of kidney disease. While most studies have concerned humans and experimental animal models, we here report on the occurrence of a spontaneous form of (non-tumorous) primary hyperaldosteronism in cats. At presentation, the main physical features of 11 elderly cats were hypokalemic paroxysmal flaccid paresis and loss of vision due to retinal detachment with hemorrhages. Primary hyperaldosteronism was diagnosed on the basis of plasma concentrations of aldosterone (PAC) and plasma renin activity (PRA), and the calculation of the PAC:PRA ratio. In all animals, PACs were at the upper end or higher than the reference range. The PRAs were at the lower end of the reference range, and the PAC:PRA ratios exceeded the reference range. Diagnostic imaging by ultrasonography and computed tomography revealed no or only very minor changes in the adrenals compatible with nodular hyperplasia. Adrenal gland histopathology revealed extensive micronodular hyperplasia extending from zona glomerulosa into the zona fasciculata and reticularis. In three cats, plasma urea and creatinine concentrations were normal when hyperaldosteronism was diagnosed but thereafter increased to above the upper limit of the respective reference range. In the other eight cats, urea and creatinine concentrations were raised at first examination and gradually further increased. Even in end-stage renal insufficiency, there was a tendency to hypophosphatemia rather than to hyperphosphatemia. The histopathological changes in the kidneys mimicked those of humans with hyperaldosteronism: hyaline arteriolar sclerosis, glomerular sclerosis, tubular atrophy and interstitial fibrosis. The non-tumorous form of primary hyperaldosteronism in cats has many similarities with "idiopathic" primary hyperaldosteronism in humans. The condition is associated with progressive renal disease

  3. Effects of lowering LDL cholesterol on progression of kidney disease.

    PubMed

    Haynes, Richard; Lewis, David; Emberson, Jonathan; Reith, Christina; Agodoa, Lawrence; Cass, Alan; Craig, Jonathan C; de Zeeuw, Dick; Feldt-Rasmussen, Bo; Fellström, Bengt; Levin, Adeera; Wheeler, David C; Walker, Rob; Herrington, William G; Baigent, Colin; Landray, Martin J

    2014-08-01

    Lowering LDL cholesterol reduces the risk of developing atherosclerotic events in CKD, but the effects of such treatment on progression of kidney disease remain uncertain. Here, 6245 participants with CKD (not on dialysis) were randomly assigned to simvastatin (20 mg) plus ezetimibe (10 mg) daily or matching placebo. The main prespecified renal outcome was ESRD (defined as the initiation of maintenance dialysis or kidney transplantation). During 4.8 years of follow-up, allocation to simvastatin plus ezetimibe resulted in an average LDL cholesterol difference (SEM) of 0.96 (0.02) mmol/L compared with placebo. There was a nonsignificant 3% reduction in the incidence of ESRD (1057 [33.9%] cases with simvastatin plus ezetimibe versus 1084 [34.6%] cases with placebo; rate ratio, 0.97; 95% confidence interval [95% CI], 0.89 to 1.05; P=0.41). Similarly, allocation to simvastatin plus ezetimibe had no significant effect on the prespecified tertiary outcomes of ESRD or death (1477 [47.4%] events with treatment versus 1513 [48.3%] events with placebo; rate ratio, 0.97; 95% CI, 0.90 to 1.04; P=0.34) or ESRD or doubling of baseline creatinine (1189 [38.2%] events with treatment versus 1257 [40.2%] events with placebo; rate ratio, 0.93; 95% CI, 0.86 to 1.01; P=0.09). Exploratory analyses also showed no significant effect on the rate of change in eGFR. Lowering LDL cholesterol by 1 mmol/L did not slow kidney disease progression within 5 years in a wide range of patients with CKD.

  4. Plasma viscosity increase with progression of peripheral arterial atherosclerotic disease.

    PubMed

    Poredos, P; Zizek, B

    1996-03-01

    -macroglobulin (r=0.78, P < 0.01). These results indicate that in patients with peripheral arterial disease plasma viscosity increases with the progression of the atherosclerotic process and is correlated with the clinical stages of the disease.

  5. Progress in radiocarbon dating with the Chalk River MP tandem accelerator

    SciTech Connect

    Andrews, H.R.; Ball, G.C.; Brown, R.M.; Davies, W.G.; Imahori, Y.; Milton, J.C.D.

    1980-01-01

    The evolution of a tandem accelerator /sup 14/C dating system at Chalk River is recounted. Background problems and sources of instability are discussed and solutions are described. Details of sample chemistry and source preparation are presented.

  6. Haematuria as a risk factor for chronic kidney disease progression in glomerular diseases: A review.

    PubMed

    Moreno, Juan Antonio; Yuste, Claudia; Gutiérrez, Eduardo; Sevillano, Ángel M; Rubio-Navarro, Alfonso; Amaro-Villalobos, Juan Manuel; Praga, Manuel; Egido, Jesús

    2016-04-01

    Haematuria has long been considered to be a benign condition associated with glomerular diseases. However, new evidences suggest that haematuria has a pathogenic role in promoting kidney disease progression. An increased risk for end-stage renal disease has been reported in adolescents and young adults with persistent microscopic haematuria. A persistent impairment of renal function has been also reported following macroscopic haematuria-associated acute kidney injury in immunoglobulin A nephropathy. Haematuria-induced renal damage has been related to oxidant, cytotoxic and inflammatory effects induced by haemoglobin or haem released from red blood cells. The pathophysiological origin of haematuria may be due to a more fragile and easily ruptured glomerular filtration barrier, as reported in several glomerular diseases. In this review we describe a number of the key issues associated with the epidemiology and pathogenesis of haematuria-associated diseases, provide an update of recent knowledge on the role of haematuria on renal function outcome and discuss specific therapeutic approaches in this setting. KEY SUMMARY POINTS: 1. Glomerular haematuria is a common observation in a number of renal diseases that may lead to persistent renal injury. 2. Haematuria in children differs from that in adults in specific aspects, particularly in the frequency of glomerular diseases and renal disease outcome. 3. Regular follow-up of renal function in children with isolated microhaematuria may be recommended. PMID:25980470

  7. The Dynamics of Disease Progression in Cystic Fibrosis

    PubMed Central

    Adler, Frederick R.; Liou, Theodore G.

    2016-01-01

    In cystic fibrosis, statistical models have been more successful in predicting mortality than the time course of clinical status. We develop a system of partial differential equations that simultaneously track mortality and patient status, with all model parameters estimated from the extensive and carefully maintained database from the Cystic Fibrosis Foundation. Cystic fibrosis is an autosomal recessive disease that leads to loss of lung function, most commonly assessed using the Forced Expiratory Volume in 1 second (FEV1%). This loss results from inflammation secondary to chronic bacterial infections, particularly Pseudomonas aeruginosa, methicillin-sensitive Staphylococcus aureus (MSSA) and members of the virulent Burkholderia complex. The model tracks FEV1% and carriage of these three bacteria over the course of a patient’s life. Analysis of patient state changes from year to year reveals four feedback loops: a damaging positive feedback loop between P. aeruginosa carriage and lower FEV1%, negative feedback loops between P. aeruginosa and MSSA and between P. aeruginosa and Burkholderia, and a protective positive feedback loop between MSSA carriage and higher FEV1%. The partial differential equations built from this data analysis accurately capture the life-long progression of the disease, quantify the key role of high annual FEV1% variability in reducing survivorship, the relative unimportance of short-term bacterial interactions for long-term survival, and the potential benefits of eradicating the most harmful bacteria. PMID:27248696

  8. The Dynamics of Disease Progression in Cystic Fibrosis.

    PubMed

    Adler, Frederick R; Liou, Theodore G

    2016-01-01

    In cystic fibrosis, statistical models have been more successful in predicting mortality than the time course of clinical status. We develop a system of partial differential equations that simultaneously track mortality and patient status, with all model parameters estimated from the extensive and carefully maintained database from the Cystic Fibrosis Foundation. Cystic fibrosis is an autosomal recessive disease that leads to loss of lung function, most commonly assessed using the Forced Expiratory Volume in 1 second (FEV1%). This loss results from inflammation secondary to chronic bacterial infections, particularly Pseudomonas aeruginosa, methicillin-sensitive Staphylococcus aureus (MSSA) and members of the virulent Burkholderia complex. The model tracks FEV1% and carriage of these three bacteria over the course of a patient's life. Analysis of patient state changes from year to year reveals four feedback loops: a damaging positive feedback loop between P. aeruginosa carriage and lower FEV1%, negative feedback loops between P. aeruginosa and MSSA and between P. aeruginosa and Burkholderia, and a protective positive feedback loop between MSSA carriage and higher FEV1%. The partial differential equations built from this data analysis accurately capture the life-long progression of the disease, quantify the key role of high annual FEV1% variability in reducing survivorship, the relative unimportance of short-term bacterial interactions for long-term survival, and the potential benefits of eradicating the most harmful bacteria. PMID:27248696

  9. Pluripotent stem cells for Parkinson's disease: progress and challenges.

    PubMed

    Zeng, Xianmin; Couture, Larry A

    2013-04-15

    Parkinson's disease (PD) is a common debilitating neurodegenerative disease. The motor symptoms of PD are caused mainly by a progressive loss of dopaminergic neurons from the substania nigra, resulting in a loss of dopamine production. Current therapies are palliative and, in the long term, ineffective. In addition, some can result in significant clinical side effects. The relatively localized pathology of PD makes it an ideal candidate for cell replacement therapy. Initial efforts focused on fetal cell transplantation, and significant clinical benefit lasting more than 10 years has been reported in some cases. However, the approach is controversial and results have been inconsistent. Inherent limitations of this approach for widespread use are the limited availability and variability of transplant material. In contrast, the self-renewal and differentiation potential of human pluripotent stem cells (hPSCs) make them a promising alternative cell source for cell replacement therapy for PD. Efforts in the past decade have demonstrated that hPSCs can be induced to differentiate in culture to functional dopaminergic neurons. Studies in delivering these cells into PD animal models have demonstrated survival, engraftment, and behavioral deficit improvements. Several groups are developing these cells with clinical trials in mind. Here, we review the state of the technology and consider the suitability of current manufacturing processes, cell purity, and tumorgenicity for clinical testing.

  10. Chronic NOS inhibition accelerates NAFLD progression in an obese rat model

    PubMed Central

    Sheldon, Ryan D.; Padilla, Jaume; Jenkins, Nathan T.; Laughlin, M. Harold

    2015-01-01

    The progression in nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis is a serious health concern, but the underlying mechanisms remain unclear. We hypothesized that chronic inhibition of nitric oxide (NO) synthase (NOS) via Nω-nitro-l-arginine methyl ester (l-NAME) would intensify liver injury in a rat model of obesity, insulin resistance, and NAFLD. Obese Otsuka Long-Evans Tokushima fatty (OLETF) and lean Long-Evans Tokushima Otsuka (LETO) rats received control or l-NAME (65–70 mg·kg−1·day−1)-containing drinking water for 4 wk. l-NAME treatment significantly (P < 0.05) reduced serum NO metabolites and food intake in both groups. Remarkably, despite no increase in body weight, l-NAME treatment increased hepatic triacylglycerol content (+40%, P < 0.05) vs. control OLETF rats. This increase was associated with impaired (P < 0.05) hepatic mitochondrial state 3 respiration. Interestingly, the opposite effect was found in LETO rats, where l-NAME increased (P < 0.05) hepatic mitochondrial state 3 respiration. In addition, l-NAME induced a shift toward proinflammatory M1 macrophage polarity, as indicated by elevated hepatic CD11c (P < 0.05) and IL-1β (P = 0.07) mRNA in OLETF rats and reduced expression of the anti-inflammatory M2 markers CD163 and CD206 (P < 0.05) in LETO rats. Markers of total macrophage content (CD68 and F4/80) mRNA were unaffected by l-NAME in either group. In conclusion, systemic NOS inhibition in the obese OLETF rats reduced hepatic mitochondrial respiration, increased hepatic triacylglycerol accumulation, and increased hepatic inflammation. These findings suggest an important role for proper NO metabolism in the hepatic adaptation to obesity. PMID:25573175

  11. Chronic NOS inhibition accelerates NAFLD progression in an obese rat model.

    PubMed

    Sheldon, Ryan D; Padilla, Jaume; Jenkins, Nathan T; Laughlin, M Harold; Rector, R Scott

    2015-03-15

    The progression in nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis is a serious health concern, but the underlying mechanisms remain unclear. We hypothesized that chronic inhibition of nitric oxide (NO) synthase (NOS) via N(ω)-nitro-L-arginine methyl ester (L-NAME) would intensify liver injury in a rat model of obesity, insulin resistance, and NAFLD. Obese Otsuka Long-Evans Tokushima fatty (OLETF) and lean Long-Evans Tokushima Otsuka (LETO) rats received control or L-NAME (65-70 mg·kg(-1)·day(-1))-containing drinking water for 4 wk. L-NAME treatment significantly (P < 0.05) reduced serum NO metabolites and food intake in both groups. Remarkably, despite no increase in body weight, L-NAME treatment increased hepatic triacylglycerol content (+40%, P < 0.05) vs. control OLETF rats. This increase was associated with impaired (P < 0.05) hepatic mitochondrial state 3 respiration. Interestingly, the opposite effect was found in LETO rats, where L-NAME increased (P < 0.05) hepatic mitochondrial state 3 respiration. In addition, L-NAME induced a shift toward proinflammatory M1 macrophage polarity, as indicated by elevated hepatic CD11c (P < 0.05) and IL-1β (P = 0.07) mRNA in OLETF rats and reduced expression of the anti-inflammatory M2 markers CD163 and CD206 (P < 0.05) in LETO rats. Markers of total macrophage content (CD68 and F4/80) mRNA were unaffected by L-NAME in either group. In conclusion, systemic NOS inhibition in the obese OLETF rats reduced hepatic mitochondrial respiration, increased hepatic triacylglycerol accumulation, and increased hepatic inflammation. These findings suggest an important role for proper NO metabolism in the hepatic adaptation to obesity. PMID:25573175

  12. Diagnosis of dementia and treatment of Alzheimer's disease. Pharmacologic management of disease progression and cognitive impairment.

    PubMed Central

    van Reekum, R.; Simard, M.; Farcnik, K.

    1999-01-01

    OBJECTIVE: To highlight the importance of family physicians in the management of Alzheimer's disease (AD) and related dementias. To provide an update on the diagnostic workup of people with suspected dementia and on the pharmacologic management of cognitive impairment and disease progression in AD. QUALITY OF EVIDENCE: MEDLINE and Psychological Abstracts were searched using the terms "cognitive enhancers" or a specific drug name and "dementia (exp)." Evidence is generally limited but promising. Methodologic flaws in existing research likely to affect clinicians are briefly reviewed. MAIN MESSAGE: Increasing evidence suggests that early intervention can delay the progression of AD and improve the symptoms and function of those affected. Available treatments have modest but important effects on the outcome of patients with AD; some patients respond dramatically. Most currently available treatments are relatively safe in carefully selected cases. CONCLUSIONS: The diagnostic workup of most cases of dementia can at least be initiated in family physicians' offices. Beginning the workup is important because, for treating AD, the earlier you start, the better. Donepezil, vitamin E, and, in the near future, propentofylline are the main pharmacologic choices for improving cognition and slowing disease progression. PMID:10216793

  13. Low-dose exposure to inorganic mercury accelerates disease and mortality in acquired murine lupus.

    PubMed

    Via, Charles S; Nguyen, Phuong; Niculescu, Florin; Papadimitriou, John; Hoover, Dennis; Silbergeld, Ellen K

    2003-08-01

    Inorganic mercury (iHg) is known to induce autoimmune disease in susceptible rodent strains. Additionally, in inbred strains of mice prone to autoimmune disease, iHg can accelerate and exacerbate disease manifestations. Despite these well-known links between iHg and autoimmunity in animal models, no association between iHg alone and autoimmune disease in humans has been documented. However, it is possible that low-level iHg exposure can interact with disease triggers to enhance disease expression or susceptibility. To address whether exposure to iHg can alter the course of subsequent acquired autoimmune disease, we used a murine model of acquired autoimmunity, lupus-like chronic graft-versus-host disease (GVHD), in which autoimmunity is induced using normal, nonautoimmune prone donor and F1 recipient mice resistant to Hg-induced autoimmunity. Our results indicate that a 2-week exposure to low-dose iHg (20 or 200 micro g/kg every other day) to donor and host mice ending 1 week before GVHD induction can significantly worsen parameters of disease severity, resulting in premature mortality. iHg pretreatment clearly worsened chronic lupus-like disease, rather than GVHD worsening iHg immunotoxicity. These results are consistent with the hypothesis that low-level, nontoxic iHg preexposure may interact with other risk factors, genetic or acquired, to promote subsequent autoimmune disease development.

  14. Genetic variants in DNA repair pathways are not associated with disease progression among multiple myeloma patients.

    PubMed

    Thyagarajan, Bharat; Arora, Mukta; Guan, Weihua; Barcelo, Helene; Jackson, Scott; Kumar, Shaji; Gertz, Morie

    2013-11-01

    DNA damage induced by high dose melphalan and autologous transplantation is repaired by the nucleotide excision repair (NER) and base excision repair (BER) pathways. We evaluated the association between single nucleotide polymorphisms (SNPs) (n=311) in the NER and BER pathways and disease progression in 695 multiple myeloma patients who underwent autologous transplantation. None of the SNPs were associated with disease progression. Pathway based analyses showed that the NER pathway had a borderline association with disease progression (p=0.09). These findings suggest that common variation in the NER and BER pathways do not substantially influence disease progression in multiple myeloma patients.

  15. Homoarginine and Progression of Chronic Kidney Disease: Results from the Mild to Moderate Kidney Disease Study

    PubMed Central

    Drechsler, Christiane; Kollerits, Barbara; Meinitzer, Andreas; März, Winfried; Ritz, Eberhard; König, Paul; Neyer, Ulrich; Pilz, Stefan; Wanner, Christoph; Kronenberg, Florian

    2013-01-01

    Background Homoarginine is an amino acid derivative mainly synthesized in the kidney. It is suggested to increase nitric oxide availability, enhance endothelial function and to protect against cardiovascular diseases. We aimed to investigate the relation between homoarginine, kidney function and progression of chronic kidney disease (CKD). Methods We measured plasma homoarginine concentrations in baseline samples of the Mild to Moderate Kidney Disease (MMKD) Study, a prospective cohort study of 227 patients with CKD in Europe. Homoarginine concentrations were available in 182 of the baseline samples and in 139 of the prospectively-followed patients. We correlated homoarginine concentrations to parameters of kidney function. The association between homoarginine and progression of CKD was assessed during a follow-up of up to seven years (median 4.45 years, interquartile range 2.54–5.19) using Cox regression analysis. Progression of CKD was defined as doubling of baseline serum creatinine and/or end-stage renal disease. Results Study participants were at baseline on average 47±13 years old and 65% were male. Mean±standard deviation of homoarginine concentrations were 2.5±1.1 µmol/L and concentrations were incrementally lower at lower levels of GFR with mean concentrations of 2.90±1.02 µmol/L (GFR>90 ml/min), 2.64±1.06 µmol/L (GFR 60–90 ml/min), 2.52±1.24 µmol/L (GFR 30–60 ml/min) and 2.05±0.78 µmol/L (GFR<30 ml/min), respectively (p = 0.002). The age- and sex-adjusted risk to reach the renal endpoint was significantly higher by 62% with each decrease by one standard deviation (1.1 µmol/L) of homoarginine (HR 1.62, 95% CI 1.16–2.27, p = 0.005). This association was independent of proteinuria (HR 1.56, 95% CI 1.11–2.20, p = 0.01), and was slightly attenuated when adjusting for GFR (HR 1.40 (95% CI 0.98–1.98, p = 0.06). Conclusions Homoarginine concentrations are directly correlated with kidney function and are significantly

  16. Attenuation of Upper Body Accelerations during Gait: Piloting an Innovative Assessment Tool for Parkinson's Disease.

    PubMed

    Buckley, Christopher; Galna, Brook; Rochester, Lynn; Mazzà, Claudia

    2015-01-01

    The objective of the current investigation was to explore whether upper body accelerations obtained during gait provide sensitive measures of postural control in people with Parkinson's disease (PD). Thirteen people with PD (70 ± 11 years) and nineteen age-matched controls (70 ± 7 years) walked continuously for two minutes while wearing three inertial sensors located on their lower back (L5), shoulder level (C7), and head. Magnitude (root mean square (RMS)), attenuation (attenuation coefficient), and smoothness (Harmonic ratios, HR) of the accelerations were calculated. People with PD demonstrated greater RMS, particularly in the mediolateral direction, but similar harmonic ratio of head accelerations compared to controls. In addition, they did not attenuate accelerations through the trunk and neck as well as control participants. Our findings indicate that measuring upper body movement provides unique information regarding postural control in PD and that poor attenuation of acceleration from the pelvis to the head contributes to impaired head control. This information is simple to measure and appears to be sensitive to PD and, consequently, is proposed to benefit researchers and clinicians. PMID:26539532

  17. Huntington's disease accelerates epigenetic aging of human brain and disrupts DNA methylation levels

    PubMed Central

    Horvath, Steve; Langfelder, Peter; Kwak, Seung; Aaronson, Jeff; Rosinski, Jim; Vogt, Thomas F.; Eszes, Marika; Faull, Richard L.M.; Curtis, Maurice A.; Waldvogel, Henry J.; Choi, Oi-Wa; Tung, Spencer; Vinters, Harry V.; Coppola, Giovanni; Yang, X. William

    2016-01-01

    Age of Huntington's disease (HD) motoric onset is strongly related to the number of CAG trinucleotide repeats in the huntingtin gene, suggesting that biological tissue age plays an important role in disease etiology. Recently, a DNA methylation based biomarker of tissue age has been advanced as an epigenetic aging clock. We sought to inquire if HD is associated with an accelerated epigenetic age. DNA methylation data was generated for 475 brain samples from various brain regions of 26 HD cases and 39 controls. Overall, brain regions from HD cases exhibit a significant epigenetic age acceleration effect (p=0.0012). A multivariate model analysis suggests that HD status increases biological age by 3.2 years. Accelerated epigenetic age can be observed in specific brain regions (frontal lobe, parietal lobe, and cingulate gyrus). After excluding controls, we observe a negative correlation (r=−0.41, p=5.5×10−8) between HD gene CAG repeat length and the epigenetic age of HD brain samples. Using correlation network analysis, we identify 11 co-methylation modules with a significant association with HD status across 3 broad cortical regions. In conclusion, HD is associated with an accelerated epigenetic age of specific brain regions and more broadly with substantial changes in brain methylation levels. PMID:27479945

  18. Huntington's disease accelerates epigenetic aging of human brain and disrupts DNA methylation levels.

    PubMed

    Horvath, Steve; Langfelder, Peter; Kwak, Seung; Aaronson, Jeff; Rosinski, Jim; Vogt, Thomas F; Eszes, Marika; Faull, Richard L M; Curtis, Maurice A; Waldvogel, Henry J; Choi, Oi-Wa; Tung, Spencer; Vinters, Harry V; Coppola, Giovanni; Yang, X William

    2016-07-01

    Age of Huntington's disease (HD) motoric onset is strongly related to the number of CAG trinucleotide repeats in the huntingtin gene, suggesting that biological tissue age plays an important role in disease etiology. Recently, a DNA methylation based biomarker of tissue age has been advanced as an epigenetic aging clock. We sought to inquire if HD is associated with an accelerated epigenetic age. DNA methylation data was generated for 475 brain samples from various brain regions of 26 HD cases and 39 controls. Overall, brain regions from HD cases exhibit a significant epigenetic age acceleration effect (p=0.0012). A multivariate model analysis suggests that HD status increases biological age by 3.2 years. Accelerated epigenetic age can be observed in specific brain regions (frontal lobe, parietal lobe, and cingulate gyrus). After excluding controls, we observe a negative correlation (r=-0.41, p=5.5×10-8) between HD gene CAG repeat length and the epigenetic age of HD brain samples. Using correlation network analysis, we identify 11 co-methylation modules with a significant association with HD status across 3 broad cortical regions. In conclusion, HD is associated with an accelerated epigenetic age of specific brain regions and more broadly with substantial changes in brain methylation levels. PMID:27479945

  19. Analysis of disease progress as a basis for evaluating disease management practices.

    PubMed

    Jeger, M J

    2004-01-01

    The relationship between epidemiology and disease management is long-standing but sometimes tenuous. It may seem self-evident that improved understanding of epidemic processes will lead to more effective control practices but this remains a testable proposition rather than demonstrated reality. A wide range of models differing in mathematical sophistication and computational complexity has been proposed as a means of achieving a greater understanding of epidemiology and carrying this through to improved management. The potential exists to align these modeling approaches to evaluation of control practices and prediction of the consequent epidemic outcomes, but these have yet to make a major impact on practical disease management. For the immediate future simpler pragmatic approaches for analysis of disease progress, using nonlinear growth functions and/or integrated measures such as area under disease progress curves, will play a key role in informing tactical and strategic decisions on control treatments. These approaches have proved useful in describing control effectiveness and, in some cases, optimizing or changing control practices.

  20. Putaminal Diffusivity Correlates With Disease Progression in Parkinson's Disease: Prospective 6-Year Study.

    PubMed

    Chan, Ling-Ling; Ng, Kia-Min; Yeoh, Chooi-Sum; Rumpel, H; Li, Hui-Hua; Tan, Eng-King

    2016-02-01

    Diffusion tensor imaging (DTI) is an increasingly used noninvasive imaging tool. However its long-term clinical utility is unclear. Parkinson's disease (PD) is a common neurodegenerative disease.We prospectively examined a cohort of 46 Parkinson's disease (PD) patients who underwent diffusion tensor imaging (DTI) of the brain at baseline and 6 years later on a 1.5 Tesla scanner using a standardized protocol. DTI parameters of mean diffusivity (MD) and fractional anisotrophy (FA) were extracted using regions-of-interest (ROIs) analysis from various brain regions.Compared to the baseline scan, MD increased in all brain regions (P < 0.0001). FA increased in the substantia nigra and posterior putamen, but decreased in the frontal white matter (P < 0.0001). Linear regression analysis demonstrated that the MD in the anterior putamen increased 11.6 units (95% CI = [4.71, 18.43]) (P = 0.0003) for every unit increase of United PD Rating Scale (UPDRS).Our 6-year prospective longitudinal study demonstrated increased diffusivity in all brain regions and that in the anterior putamen correlated with disease progression. Serial diffusion data may be useful as an additional objective in vivo biomarker for motor progression in PD.

  1. In silico regulatory analysis for exploring human disease progression

    PubMed Central

    Holloway, Dustin T; Kon, Mark; DeLisi, Charles

    2008-01-01

    Background An important goal in bioinformatics is to unravel the network of transcription factors (TFs) and their targets. This is important in the human genome, where many TFs are involved in disease progression. Here, classification methods are applied to identify new targets for 152 transcriptional regulators using publicly-available targets as training examples. Three types of sequence information are used: composition, conservation, and overrepresentation. Results Starting with 8817 TF-target interactions we predict an additional 9333 targets for 152 TFs. Randomized classifiers make few predictions (~2/18660) indicating that our predictions for many TFs are significantly enriched for true targets. An enrichment score is calculated and used to filter new predictions. Two case-studies for the TFs OCT4 and WT1 illustrate the usefulness of our predictions: • Many predicted OCT4 targets fall into the Wnt-pathway. This is consistent with known biology as OCT4 is developmentally related and Wnt pathway plays a role in early development. • Beginning with 15 known targets, 354 predictions are made for WT1. WT1 has a role in formation of Wilms' tumor. Chromosomal regions previously implicated in Wilms' tumor by cytological evidence are statistically enriched in predicted WT1 targets. These findings may shed light on Wilms' tumor progression, suggesting that the tumor progresses either by loss of WT1 or by loss of regions harbouring its targets. • Targets of WT1 are statistically enriched for cancer related functions including metastasis and apoptosis. Among new targets are BAX and PDE4B, which may help mediate the established anti-apoptotic effects of WT1. • Of the thirteen TFs found which co-regulate genes with WT1 (p ≤ 0.02), 8 have been previously implicated in cancer. The regulatory-network for WT1 targets in genomic regions relevant to Wilms' tumor is provided. Conclusion We have assembled a set of features for the targets of human TFs and used them to

  2. Metabolic Syndrome and Periodontal Disease Progression in Men.

    PubMed

    Kaye, E K; Chen, N; Cabral, H J; Vokonas, P; Garcia, R I

    2016-07-01

    Metabolic syndrome, a cluster of 3 or more risk factors for cardiovascular disease, is associated with periodontal disease, but few studies have been prospective in design. This study's aim was to determine whether metabolic syndrome predicts tooth loss and worsening of periodontal disease in a cohort of 760 men in the Department of Veterans Affairs Dental Longitudinal Study and Normative Aging Study who were followed up to 33 y from 1981 to 2013. Systolic and diastolic blood pressures were measured with a standard mercury sphygmomanometer. Waist circumference was measured in units of 0.1 cm following a normal expiration. Fasting blood samples were measured in duplicate for glucose, triglyceride, and high-density lipoprotein. Calibrated periodontists served as dental examiners. Periodontal outcome events on each tooth were defined as progression to predefined threshold levels of probing pocket depth (≥5 mm), clinical attachment loss (≥5 mm), mobility (≥0.5 mm), and alveolar bone loss (≥40% of the distance from the cementoenamel junction to the root apex, on radiographs). Hazards ratios (95% confidence intervals) of tooth loss or a periodontitis event were estimated from tooth-level extended Cox proportional hazards regression models that accounted for clustering of teeth within individuals and used time-dependent status of metabolic syndrome. Covariates included age, education, smoking status, plaque level, and initial level of the appropriate periodontal disease measure. Metabolic syndrome as defined by the International Diabetes Federation increased the hazards of tooth loss (1.39; 1.08 to 1.79), pocket depth ≥5 mm (1.37; 1.14 to 1.65), clinical attachment loss ≥5 mm (1.19; 1.00 to 1.41), alveolar bone loss ≥40% (1.25; 1.00 to 1.56), and tooth mobility ≥0.5 mm (1.43; 1.07 to 1.89). The number of positive metabolic syndrome conditions was also associated with each of these outcomes. These findings suggest that the metabolic disturbances that

  3. Will the future lie in multitude? A critical appraisal of biomarker panel studies on prediction of diabetic kidney disease progression.

    PubMed

    Schutte, Elise; Gansevoort, Ron T; Benner, Jacqueline; Lutgers, Helen L; Lambers Heerspink, Hiddo J

    2015-08-01

    Diabetic kidney disease is diagnosed and staged by albuminuria and estimated glomerular filtration rate. Although albuminuria has strong predictive power for renal function decline, there is still variability in the rate of renal disease progression across individuals that are not fully captured by the level of albuminuria. Therefore, research focuses on discovering and validating additional biomarkers that improve risk stratification for future renal function decline and end-stage renal disease in patients with diabetes, on top of established biomarkers. Most studies address the value of single biomarkers to predict progressive renal disease and aim to understand the mechanisms that underlie accelerated renal function decline. Since diabetic kidney disease is a disease encompassing several pathophysiological processes, a combination of biomarkers may be more likely to improve risk prediction than a single biomarker. In this review, we provide an overview of studies on the use of multiple biomarkers and biomarker panels, appraise their study design, discuss methodological pitfalls and make recommendations for future biomarker panel studies.

  4. Rhesus monkey model of liver disease reflecting clinical disease progression and hepatic gene expression analysis.

    PubMed

    Wang, Hong; Tan, Tao; Wang, Junfeng; Niu, Yuyu; Yan, Yaping; Guo, Xiangyu; Kang, Yu; Duan, Yanchao; Chang, Shaohui; Liao, Jianpeng; Si, Chenyang; Ji, Weizhi; Si, Wei

    2015-10-07

    Alcoholic liver disease (ALD) is a significant public health issue with heavy medical and economic burdens. The aetiology of ALD is not yet completely understood. The development of drugs and therapies for ALD is hampered by a lack of suitable animal models that replicate both the histological and metabolic features of human ALD. Here, we characterize a rhesus monkey model of alcohol-induced liver steatosis and hepatic fibrosis that is compatible with the clinical progression of the biochemistry and pathology in humans with ALD. Microarray analysis of hepatic gene expression was conducted to identify potential molecular signatures of ALD progression. The up-regulation of expression of hepatic genes related to liver steatosis (CPT1A, FASN, LEPR, RXRA, IGFBP1, PPARGC1A and SLC2A4) was detected in our rhesus model, as was the down-regulation of such genes (CYP7A1, HMGCR, GCK and PNPLA3) and the up-regulation of expression of hepatic genes related to liver cancer (E2F1, OPCML, FZD7, IGFBP1 and LEF1). Our results demonstrate that this ALD model reflects the clinical disease progression and hepatic gene expression observed in humans. These findings will be useful for increasing the understanding of ALD pathogenesis and will benefit the development of new therapeutic procedures and pharmacological reagents for treating ALD.

  5. Rhesus monkey model of liver disease reflecting clinical disease progression and hepatic gene expression analysis

    PubMed Central

    Wang, Hong; Tan, Tao; Wang, Junfeng; Niu, Yuyu; Yan, Yaping; Guo, Xiangyu; Kang, Yu; Duan, Yanchao; Chang, Shaohui; Liao, Jianpeng; Si, Chenyang; Ji, Weizhi; Si, Wei

    2015-01-01

    Alcoholic liver disease (ALD) is a significant public health issue with heavy medical and economic burdens. The aetiology of ALD is not yet completely understood. The development of drugs and therapies for ALD is hampered by a lack of suitable animal models that replicate both the histological and metabolic features of human ALD. Here, we characterize a rhesus monkey model of alcohol-induced liver steatosis and hepatic fibrosis that is compatible with the clinical progression of the biochemistry and pathology in humans with ALD. Microarray analysis of hepatic gene expression was conducted to identify potential molecular signatures of ALD progression. The up-regulation of expression of hepatic genes related to liver steatosis (CPT1A, FASN, LEPR, RXRA, IGFBP1, PPARGC1A and SLC2A4) was detected in our rhesus model, as was the down-regulation of such genes (CYP7A1, HMGCR, GCK and PNPLA3) and the up-regulation of expression of hepatic genes related to liver cancer (E2F1, OPCML, FZD7, IGFBP1 and LEF1). Our results demonstrate that this ALD model reflects the clinical disease progression and hepatic gene expression observed in humans. These findings will be useful for increasing the understanding of ALD pathogenesis and will benefit the development of new therapeutic procedures and pharmacological reagents for treating ALD. PMID:26442469

  6. High Energy Accelerator and Colliding Beam User Group: Progress report, March 1, 1988--February 28, 1989

    SciTech Connect

    Not Available

    1988-09-01

    This report discusses work carried out by the High Energy Accelerator and Colliding Beam User Group at the University of Maryland. Particular topics discussed are: OPAL experiment at LEP; deep inelastic muon interactions; B physics with the CLEO detector at CESR; further results from JADE; and search for ''small'' violation of the Pauli principle. (LSP)

  7. Cardiac acceleration at the onset of exercise: a potential parameter for monitoring progress during physical training in sports and rehabilitation.

    PubMed

    Hettinga, Florentina J; Monden, Paul G; van Meeteren, Nico L U; Daanen, Hein A M

    2014-05-01

    There is a need for easy-to-use methods to assess training progress in sports and rehabilitation research. The present review investigated whether cardiac acceleration at the onset of physical exercise (HRonset) can be used as a monitoring variable. The digital databases of Scopus and PubMed were searched to retrieve studies investigating HRonset. In total 652 studies were retrieved. These articles were then classified as having emphasis on HRonset in a sports or rehabilitation setting, which resulted in 8 of 112 studies with a sports application and 6 of 68 studies with a rehabilitation application that met inclusion criteria. Two co-existing mechanisms underlie HRonset: feedforward (central command) and feedback (mechanoreflex, metaboreflex, baroreflex) control. A number of studies investigated HRonset during the first few seconds of exercise (HRonsetshort), in which central command and the mechanoreflex determine vagal withdrawal, the major mechanism by which heart rate (HR) increases. In subsequent sports and rehabilitation studies, interest focused on HRonset during dynamic exercise over a longer period of time (HRonsetlong). Central command, mechanoreflexes, baroreflexes, and possibly metaboreflexes contribute to HRonset during the first seconds and minutes of exercise, which in turn leads to further vagal withdrawal and an increase in sympathetic activity. HRonset has been described as the increase in HR compared with resting state (delta HR) or by exponential modeling, with measurement intervals ranging from 0-4 s up to 2 min. Delta HR was used to evaluate HRonsetshort over the first 4 s of exercise, as well as for analyzing HRonsetlong. In exponential modeling, the HR response to dynamic exercise is biphasic, consisting of fast (parasympathetic, 0-10 s) and slow (sympathetic, 1-4 min) components. Although available studies differed largely in measurement protocols, cross-sectional and longitudinal training studies showed that studies analyzing HRonset

  8. Identification of unstable network modules reveals disease modules associated with the progression of Alzheimer's disease.

    PubMed

    Kikuchi, Masataka; Ogishima, Soichi; Miyamoto, Tadashi; Miyashita, Akinori; Kuwano, Ryozo; Nakaya, Jun; Tanaka, Hiroshi

    2013-01-01

    Alzheimer's disease (AD), the most common cause of dementia, is associated with aging, and it leads to neuron death. Deposits of amyloid β and aberrantly phosphorylated tau protein are known as pathological hallmarks of AD, but the underlying mechanisms have not yet been revealed. A high-throughput gene expression analysis previously showed that differentially expressed genes accompanying the progression of AD were more down-regulated than up-regulated in the later stages of AD. This suggested that the molecular networks and their constituent modules collapsed along with AD progression. In this study, by using gene expression profiles and protein interaction networks (PINs), we identified the PINs expressed in three brain regions: the entorhinal cortex (EC), hippocampus (HIP) and superior frontal gyrus (SFG). Dividing the expressed PINs into modules, we examined the stability of the modules with AD progression and with normal aging. We found that in the AD modules, the constituent proteins, interactions and cellular functions were not maintained between consecutive stages through all brain regions. Interestingly, the modules were collapsed with AD progression, specifically in the EC region. By identifying the modules that were affected by AD pathology, we found the transcriptional regulation-associated modules that interact with the proteasome-associated module via UCHL5 hub protein, which is a deubiquitinating enzyme. Considering PINs as a system made of network modules, we found that the modules relevant to the transcriptional regulation are disrupted in the EC region, which affects the ubiquitin-proteasome system.

  9. Progress on Complications of Direct Bypass for Moyamoya Disease.

    PubMed

    Yu, Jinlu; Shi, Lei; Guo, Yunbao; Xu, Baofeng; Xu, Kan

    2016-01-01

    Moyamoya disease (MMD) involves progressive occlusion of the intracranial internal carotid artery resulting in formation of moyamoya-like vessels at the base of the brain. It can be characterized by hemorrhage or ischemia. Direct vascular bypass is the main and most effective treatment of MMD. However, patients with MMD differ from those with normal cerebral vessels. MMD patients have unstable intracranial artery hemodynamics and a poor blood flow reserve; therefore, during the direct bypass of superficial temporal artery (STA)-middle cerebral artery (MCA) anastomosis, perioperative risk factors and anesthesia can affect the hemodynamics of these patients. When brain tissue cannot tolerate a high blood flow rate, it becomes prone to hyperperfusion syndrome, which leads to neurological function defects and can even cause intracranial hemorrhage in severe cases. The brain tissue is prone to infarction when hemodynamic equilibrium is affected. In addition, bypass vessels become susceptible to occlusion or atrophy when blood resistance increases. Even compression of the temporalis affects bypass vessels. Because the STA is used in MMD surgery, the scalp becomes ischemic and is likely to develop necrosis and infection. These complications of MMD surgery are difficult to manage and are not well understood. To date, no systematic studies of the complications that occur after direct bypass in MMD have been performed, and reported complications are hidden among various case studies; therefore, this paper presents a review and summary of the literature in PubMed on the complications of direct bypass in MMD.

  10. Progress on Complications of Direct Bypass for Moyamoya Disease.

    PubMed

    Yu, Jinlu; Shi, Lei; Guo, Yunbao; Xu, Baofeng; Xu, Kan

    2016-01-01

    Moyamoya disease (MMD) involves progressive occlusion of the intracranial internal carotid artery resulting in formation of moyamoya-like vessels at the base of the brain. It can be characterized by hemorrhage or ischemia. Direct vascular bypass is the main and most effective treatment of MMD. However, patients with MMD differ from those with normal cerebral vessels. MMD patients have unstable intracranial artery hemodynamics and a poor blood flow reserve; therefore, during the direct bypass of superficial temporal artery (STA)-middle cerebral artery (MCA) anastomosis, perioperative risk factors and anesthesia can affect the hemodynamics of these patients. When brain tissue cannot tolerate a high blood flow rate, it becomes prone to hyperperfusion syndrome, which leads to neurological function defects and can even cause intracranial hemorrhage in severe cases. The brain tissue is prone to infarction when hemodynamic equilibrium is affected. In addition, bypass vessels become susceptible to occlusion or atrophy when blood resistance increases. Even compression of the temporalis affects bypass vessels. Because the STA is used in MMD surgery, the scalp becomes ischemic and is likely to develop necrosis and infection. These complications of MMD surgery are difficult to manage and are not well understood. To date, no systematic studies of the complications that occur after direct bypass in MMD have been performed, and reported complications are hidden among various case studies; therefore, this paper presents a review and summary of the literature in PubMed on the complications of direct bypass in MMD. PMID:27499690

  11. Progress on Complications of Direct Bypass for Moyamoya Disease

    PubMed Central

    Yu, Jinlu; Shi, Lei; Guo, Yunbao; Xu, Baofeng; Xu, Kan

    2016-01-01

    Moyamoya disease (MMD) involves progressive occlusion of the intracranial internal carotid artery resulting in formation of moyamoya-like vessels at the base of the brain. It can be characterized by hemorrhage or ischemia. Direct vascular bypass is the main and most effective treatment of MMD. However, patients with MMD differ from those with normal cerebral vessels. MMD patients have unstable intracranial artery hemodynamics and a poor blood flow reserve; therefore, during the direct bypass of superficial temporal artery (STA)-middle cerebral artery (MCA) anastomosis, perioperative risk factors and anesthesia can affect the hemodynamics of these patients. When brain tissue cannot tolerate a high blood flow rate, it becomes prone to hyperperfusion syndrome, which leads to neurological function defects and can even cause intracranial hemorrhage in severe cases. The brain tissue is prone to infarction when hemodynamic equilibrium is affected. In addition, bypass vessels become susceptible to occlusion or atrophy when blood resistance increases. Even compression of the temporalis affects bypass vessels. Because the STA is used in MMD surgery, the scalp becomes ischemic and is likely to develop necrosis and infection. These complications of MMD surgery are difficult to manage and are not well understood. To date, no systematic studies of the complications that occur after direct bypass in MMD have been performed, and reported complications are hidden among various case studies; therefore, this paper presents a review and summary of the literature in PubMed on the complications of direct bypass in MMD. PMID:27499690

  12. The Nrf2 pathway in the progression of renal disease.

    PubMed

    Zoja, Carlamaria; Benigni, Ariela; Remuzzi, Giuseppe

    2014-02-01

    The Nrf2/Keap1 system regulates the transcription of antioxidant and cytoprotective genes through direct Nrf2 binding to responsive elements in the promoter region of target genes or via Keap1-induced NF-kB inhibition. The association between oxidative stress and inflammation with progression of chronic kidney diseases (CKDs) directed attention towards bardoxolone methyl and its analogues, potent Nrf2/Keap1 inducers, as a potential modality of renoprotective intervention. In a phase II clinical trial (BEAM), bardoxolone methyl was shown to increase the estimated glomerular filtration rate (eGFR) in patients with CKD associated with type 2 diabetes. The study generated great interest but raised concerns as well, on the adverse event profile of the drug. Experiments in rats with type 2 diabetic nephropathy treated with bardoxolone methyl analogues reproduced some drawbacks of bardoxolone methyl therapy in humans. Despite these warnings, a long-term phase III trial (BEACON) was started that was prematurely terminated because of an excess serious adverse events and mortality. Lessons from the above studies suggest that before jumping into use in clinical practice, adequately designed experiments in animal models are needed to provide insights into pathogenetic mechanisms as well as unexpected side effects.

  13. Tubular atrophy in the pathogenesis of chronic kidney disease progression.

    PubMed

    Schelling, Jeffrey R

    2016-05-01

    The longstanding focus in chronic kidney disease (CKD) research has been on the glomerulus, which is sensible because this is where glomerular filtration occurs, and a large proportion of progressive CKD is associated with significant glomerular pathology. However, it has been known for decades that tubular atrophy is also a hallmark of CKD and that it is superior to glomerular pathology as a predictor of glomerular filtration rate decline in CKD. Nevertheless, there are vastly fewer studies that investigate the causes of tubular atrophy, and fewer still that identify potential therapeutic targets. The purpose of this review is to discuss plausible mechanisms of tubular atrophy, including tubular epithelial cell apoptosis, cell senescence, peritubular capillary rarefaction and downstream tubule ischemia, oxidative stress, atubular glomeruli, epithelial-to-mesenchymal transition, interstitial inflammation, lipotoxicity and Na(+)/H(+) exchanger-1 inactivation. Once a a better understanding of tubular atrophy (and interstitial fibrosis) pathophysiology has been obtained, it might then be possible to consider tandem glomerular and tubular therapeutic strategies, in a manner similar to cancer chemotherapy regimens, which employ multiple drugs to simultaneously target different mechanistic pathways.

  14. Accelerated Disease Onset with Stabilized Familial Amyotrophic Lateral Sclerosis (ALS)-linked Mutant TDP-43 Proteins*

    PubMed Central

    Watanabe, Shoji; Kaneko, Kumi; Yamanaka, Koji

    2013-01-01

    Abnormal protein accumulation is a pathological hallmark of neurodegenerative diseases, including accumulation of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis (ALS). Dominant mutations in the TDP-43 gene are causative for familial ALS; however, the relationship between mutant protein biochemical phenotypes and disease course and their significance to disease pathomechanism are not known. Here, we found that longer half-lives of mutant proteins correlated with accelerated disease onset. Based on our findings, we established a cell model in which chronic stabilization of wild-type TDP-43 protein provoked cytotoxicity and recapitulated pathogenic protein cleavage and insolubility to the detergent Sarkosyl, TDP-43 properties that have been observed in sporadic ALS lesions. Furthermore, these cells showed proteasomal impairment and dysregulation of their own mRNA levels. These results suggest that chronically increased stability of mutant or wild-type TDP-43 proteins results in a gain of toxicity through abnormal proteostasis. PMID:23235148

  15. Pembrolizumab Cutaneous Adverse Events and Their Association With Disease Progression

    PubMed Central

    Daud, Adil; Algazi, Alain; Gubens, Matthew; Luna, Sara Alcántara; Lin, Kevin; Quaglino, Pietro; Rappersberger, Klemens; Ortiz-Urda, Susana

    2016-01-01

    IMPORTANCE Immunomodulatory anticancer drugs, such as the anti–programmed death-1 drug pembrolizumab, have shown promising results in trials, and more patients will receive such treatments. Little is known about cutaneous adverse events (AEs) caused by these drugs and their possible correlation with treatment response. OBJECTIVE To describe the frequency and spectrum of cutaneous AEs linked with pembrolizumab and their possible correlation with treatment response. DESIGN, SETTING, AND PARTICIPANTS A single-institution, retrospective medical record review was conducted of patients with cancer who were treated with pembrolizumab from March 1, 2011, to May 28, 2014. The review comprised 83 consecutive patients who were enrolled in 2 clinical trials, received at least 1 dose of pembrolizumab, and had at least 1 follow-up visit. Patients were grouped according to the following therapeutic regimen for pembrolizumab: 43 received 10 mg/kg every 3 weeks, 24 received 10 mg/kg every 2 weeks, and 16 received 2 mg/kg every 3 weeks. Sixty-six patients were treated for melanoma, 15 patients for lung cancer, 1 patient for prostate cancer, and 1 patient for Merkel cell carcinoma. Median follow-up was 15 weeks (range, 2-105 weeks). The analysis was conducted from March 1 to September 30, 2014. MAIN OUTCOMES AND MEASURES Occurrence, severity, and type of cutaneous AEs, as well as disease progression and response to pembrolizumab treatment. RESULTS Thirty-five patients (42%) developed cutaneous AEs attributed to pembrolizumab. The most common cutaneous AEs were macular papular eruption (24 [29%]), pruritus (10 [12%]), and hypopigmentation (7 [8%]). All 7 patients who developed hypopigmentation were treated for melanoma. Survival analyses showed that patients who developed cutaneous AEs had significantly longer progression-free intervals in all 3 groups (pembrolizumab, 10 mg/kg, every 3 weeks, P = .001; pembrolizumab, 10 mg/kg, every 2 weeks, P = .003; pembrolizumab, 2 mg/kg, every 3

  16. Vascular endothelial growth factor as an angiogenesis biomarker for the progression of autosomal dominant polycystic kidney disease.

    PubMed

    Martins, D P; Souza, M A; Baitello, M E Lopes; Nogueira, V; Oliveira, C I Ferreira; Pinhel, M A de Souza; Caldas, H C; Filho, M A; Souza, D R Silva

    2016-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary nephropathy characterized by abnormal growth of epithelial cells. Genetic factors, including the vascular endothelial growth factor (VEGF) gene, play an important role in its progression. The main aim of this study was to evaluate the influence of VEGF-C936T polymorphism in the development and progression of ADPKD. In total, 302 individuals were studied and divided into two groups: G1 (73 patients with ADPKD) and G2 (229 individuals without the disease). Among the patients, 46 (63%) progressed to end-stage renal disease (ESRD), and required hemodialysis and/or renal transplant. These patients were re-grouped into G1-A for progression analysis. A peripheral blood sample was obtained from all subjects; the DNA was extracted and the VEGF-C936T polymorphism analyzed using polymerase chain reaction/restriction fragment length polymorphism. The significance level was set at P < 0.05. The homozygous wild-type genotype (C/C) was predominant in G1 (78%) and G2 (79%; P = 0.9249). We observed a significant reduction in the mean age of patients with the risk allele (C/T + T/T = 44.3 ± 13.4 years) compared to the C/C genotype (52.2 ± 9.6 years; P = 0.047) in G1-A. In conclusion, the VEGF-C936T polymorphism does not discriminate patients from controls. However, the presence of the T allele appears to accelerate the progression of ADPKD, anticipating ESRD, thereby suggesting its importance in the prognosis of the disease. However, the importance role played by VEGF gene variants in different populations and larger sample sizes must be verified. PMID:26909926

  17. 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.

  18. The Radiological Research Accelerator Facility. Progress report, December 1, 1991--November 30, 1992

    SciTech Connect

    Hall, E.J.

    1992-05-01

    The Radiological Research Accelerator Facility (RARAF) is based on a 4-MV Van de Graaff accelerator, which is used to generate a variety of well-characterized radiation beams for research in radiobiology, radiological physics, and radiation chemistry. It is part of the Center for Radiological Research (CRR) -- formerly the Radiological Research Laboratory (RRL) -- of Columbia University, and its operation is supported as a National Facility by the US Department of Energy (DOE). As such, RARAF is available to all potential users on an equal basis, and scientists outside the CRR are encouraged to submit proposals for experiments at RARAF. The operation of the Van de Graaff is supported by the DOE, but the research projects themselves must be supported separately. Experiments performed from May 1991--April 1992 are described.

  19. The Radiological Research Accelerator Facility. Progress report, December 1, 1992--November 30, 1993

    SciTech Connect

    Hall, E.J.; Marino, S.A.

    1993-05-01

    The Radiological Research Accelerator Facility (RARAF) is based on a 4-MV Van de Graaff accelerator, which is used to generate a variety of well-characterized radiation beams for research in radiobiology, radiological physics, and radiation chemistry. It is part of the Center for Radiological Research (CRR) - formerly the Radiological Research Laboratory of Columbia University, and its operation is supported as a National Facility by the US Department of Energy (DOE). As such, RARAF is available to all potential users on an equal basis and scientists outside the CRR are encouraged to submit proposals for experiments at RARAF. The operation of the Van de Graaff is supported by the DOE, but the research projects themselves must be supported separately. This report provides a listing and brief description of experiments performed at RARAF during the May 1, 1992 through April 30, 1993.

  20. Progress In Plasma Accelerator Development for Dynamic Formation of Plasma Liners

    NASA Technical Reports Server (NTRS)

    Thio, Y. C. Francis; Eskridge, Richard; Martin, Adam; Smith, James; Lee, Michael; Cassibry, Jason T.; Griffin, Steven; Rodgers, Stephen L. (Technical Monitor)

    2002-01-01

    An experimental plasma accelerator for magnetic target fusion (MTF) applications under development at the NASA Marshall Space Flight Center is described. The accelerator is a coaxial pulsed plasma thruster (Figure 1). It has been tested experimentally and plasma jet velocities of approx.50 km/sec have been obtained. The plasma jet has been photographed with 10-ns exposure times to reveal a stable and repeatable plasma structure (Figure 2). Data for velocity profile information has been obtained using light pipes and magnetic probes embedded in the gun walls to record the plasma and current transit respectively at various barrel locations. Preliminary spatially resolved spectral data and magnetic field probe data are also presented. A high speed triggering system has been developed and tested as a means of reducing the gun "jitter". This jitter is being characterized and future work for second generation "ultra-low jitter" gun development is being identified.

  1. The Radiological Research Accelerator Facility. Progress report, December 1, 1993--November 30, 1994

    SciTech Connect

    Hall, E.J.; Marino, S.A.

    1994-04-01

    This document begins with a general description of the facility to include historical and up-to-date aspects of design and operation. A user`s guide and a review of research using the facility follows. Next the accelerator utilization and operation and the development of the facilities is given. Personnel currently working at the facility are listed. Lastly, recent publications and literature cited are presented.

  2. Cocaine enhances HIV-1-induced CD4(+) T-cell apoptosis: implications in disease progression in cocaine-abusing HIV-1 patients.

    PubMed

    Pandhare, Jui; Addai, Amma B; Mantri, Chinmay K; Hager, Cynthia; Smith, Rita M; Barnett, Louis; Villalta, Fernando; Kalams, Spyros A; Dash, Chandravanu

    2014-04-01

    Substance abuse is a major barrier in eradication of the HIV epidemic because it serves as a powerful cofactor for viral transmission, disease progression, and AIDS-related mortality. Cocaine, one of the commonly abused drugs among HIV-1 patients, has been suggested to accelerate HIV disease progression. However, the underlying mechanism remains largely unknown. Therefore, we tested whether cocaine augments HIV-1-associated CD4(+) T-cell decline, a predictor of HIV disease progression. We examined apoptosis of resting CD4(+) T cells from HIV-1-negative and HIV-1-positive donors in our study, because decline of uninfected cells plays a major role in HIV-1 disease progression. Treatment of resting CD4(+) T cells with cocaine (up to 100 μmol/L concentrations) did not induce apoptosis, but 200 to 1000 μmol/L cocaine induced apoptosis in a dose-dependent manner. Notably, treatment of CD4(+) T cells isolated from healthy donors with both HIV-1 virions and cocaine significantly increased apoptosis compared with the apoptosis induced by cocaine or virions alone. Most important, our biochemical data suggest that cocaine induces CD4(+) T-cell apoptosis by increasing intracellular reactive oxygen species levels and inducing mitochondrial depolarization. Collectively, our results provide evidence of a synergy between cocaine and HIV-1 on CD4(+) T-cell apoptosis that may, in part, explain the accelerated disease observed in HIV-1-infected drug abusers.

  3. Progressive age-related changes in sleep and EEG profiles in the PLB1Triple mouse model of Alzheimer's disease.

    PubMed

    Jyoti, Amar; Plano, Andrea; Riedel, Gernot; Platt, Bettina

    2015-10-01

    Sleep disturbances are common in Alzheimer's disease (AD) and now assumed to contribute to disease onset and progression. Here, we investigated whether activity, sleep/wake pattern, and electroencephalogram (EEG) profiles are altered in the knock-in PLB1Triple mouse model from 5 to 21 months of age. PLB1Triple mice displayed a progressive increase in wakefulness and non-rapid eye movement sleep fragmentation from 9 months onward, whereas PLB1WT wild type controls showed such deterioration only at 21 months. Impaired habituation to spatial novelty was also detected in PLB1Triple mice. Hippocampal power spectra of transgenic mice revealed progressive, vigilance stage-, brain region-, and age-specific changes. Age had an impact on EEG spectra in both cohorts but led to accelerated genotype-dependent differences, ultimately affecting all bands at 21 months. Overall, although PLB1Triple animals display only subtle amyloid and tau pathologies, robust sleep-wake and EEG abnormalities emerged. We hypothesize that such endophenotypes are sensitive, noninvasive, and reliable biomarker to identify onset and progression of AD.

  4. Proteomics for prediction of disease progression and response to therapy in diabetic kidney disease.

    PubMed

    Pena, Michelle J; Mischak, Harald; Heerspink, Hiddo J L

    2016-09-01

    The past decade has resulted in multiple new findings of potential proteomic biomarkers of diabetic kidney disease (DKD). Many of these biomarkers reflect an important role in the (patho)physiology and biological processes of DKD. Situations in which proteomics could be applied in clinical practice include the identification of individuals at risk of progressive kidney disease and those who would respond well to treatment, in order to tailor therapy for those at highest risk. However, while many proteomic biomarkers have been discovered, and even found to be predictive, most lack rigorous external validation in sufficiently powered studies with renal endpoints. Moreover, studies assessing short-term changes in the proteome for therapy-monitoring purposes are lacking. Collaborations between academia and industry and enhanced interactions with regulatory agencies are needed to design new, sufficiently powered studies to implement proteomics in clinical practice. PMID:27344310

  5. Ezrin Is Associated with Disease Progression in Ovarian Carcinoma

    PubMed Central

    Horwitz, Vered; Davidson, Ben; Stern, Dganit; Tropé, Claes G.; Tavor Re’em, Tali; Reich, Reuven

    2016-01-01

    Objective Ezrin and p130Cas are structural proteins with an important role in signaling pathways and have been shown to promote cancer dissemination. We previously reported on overexpression of both ezrin and p130Cas in breast carcinoma effusions compared to primary carcinomas. Since ovarian and breast carcinomas share the ability to disseminate by forming malignant effusions, we sought to study the role of these molecules in ovarian carcinoma (OC). Methods OC cell lines were cultured in two different 3-dimensional conditions, on alginate scaffolds and as spheroids, which served as models for solid tumor and malignant effusions, respectively. shRNA was used to reduce protein expression in the cells. The malignant potential was evaluated by chemo-invasion assay, branching capacity on Matrigel and rate of proliferation. Subsequently, clinical specimens of high-grade serous carcinoma effusions, ovarian tumors and solid metastases were analyzed for ezrin and p130Cas expression. Results Higher ezrin expression was found in cells composing the spheroids compared to their counterparts cultured on alginate scaffold and in clinical samples of malignant effusions compared to solid tumors. In addition, reduced Ezrin expression impaired the invasion ability and the branching capacity of OC cells to a greater extent than reduced p130Cas expression. However, ezrin and p130Cas expression in effusions was unrelated to clinical outcome. Conclusions The 3-dimensional cell cultures were found to mimic the different tumor sites and be applicable as a model. The in vitro results concur with the clinical specimen analysis, suggesting that in OC, the role of ezrin in disease progression is more pronounced than that of p130Cas. PMID:27622508

  6. Myeloperoxidase deficiency ameliorates progression of chronic kidney disease in mice.

    PubMed

    Lehners, Alexander; Lange, Sascha; Niemann, Gianina; Rosendahl, Alva; Meyer-Schwesinger, Catherine; Oh, Jun; Stahl, Rolf; Ehmke, Heimo; Benndorf, Ralf; Klinke, Anna; Baldus, Stephan; Wenzel, Ulrich Otto

    2014-08-15

    Myeloperoxidase (MPO) is an enzyme expressed in neutrophils and monocytes/macrophages. Beside its well-defined role in innate immune defence, it may also be responsible for tissue damage. To identify the role of MPO in the progression of chronic kidney disease (CKD), we investigated CKD in a model of renal ablation in MPO knockout and wild-type mice. CKD was induced by 5/6 nephrectomy. Mice were followed for 10 wk to evaluate the impact of MPO deficiency on renal morbidity. Renal ablation induced CKD in wild-type mice with increased plasma levels of MPO compared with controls. No difference was found between MPO-deficient and wild-type mice regarding albuminuria 1 wk after renal ablation, indicating similar acute responses to renal ablation. Over the next 10 wk, however, MPO-deficient mice developed significantly less albuminuria and glomerular injury than wild-type mice. This was accompanied by a significantly lower renal mRNA expression of the fibrosis marker genes plasminogen activator inhibitor-I, collagen type III, and collagen type IV as well as matrix metalloproteinase-2 and matrix metalloproteinase-9. MPO-deficient mice also developed less renal inflammation after renal ablation, as indicated by a lower infiltration of CD3-positive T cells and F4/80-positive monocytes/macrophages compared with wild-type mice. In vitro chemotaxis of monocyte/macrophages isolated from MPO-deficient mice was impaired compared with wild-type mice. No significant differences were observed for mortality and blood pressure after renal ablation. In conclusion, these results demonstrate that MPO deficiency ameliorates renal injury in the renal ablation model of CKD in mice.

  7. Mechanisms of Copper Ion Mediated Huntington's Disease Progression

    PubMed Central

    Fox, Jonathan H.; Kama, Jibrin A.; Lieberman, Gregory; Chopra, Raman; Dorsey, Kate; Chopra, Vanita; Volitakis, Irene; Cherny, Robert A.; Bush, Ashley I.; Hersch, Steven

    2007-01-01

    Huntington's disease (HD) is caused by a dominant polyglutamine expansion within the N-terminus of huntingtin protein and results in oxidative stress, energetic insufficiency and striatal degeneration. Copper and iron are increased in the striata of HD patients, but the role of these metals in HD pathogenesis is unknown. We found, using inductively-coupled-plasma mass spectroscopy, that elevations of copper and iron found in human HD brain are reiterated in the brains of affected HD transgenic mice. Increased brain copper correlated with decreased levels of the copper export protein, amyloid precursor protein. We hypothesized that increased amounts of copper bound to low affinity sites could contribute to pro-oxidant activities and neurodegeneration. We focused on two proteins: huntingtin, because of its centrality to HD, and lactate dehydrogenase (LDH), because of its documented sensitivity to copper, necessity for normoxic brain energy metabolism and evidence for altered lactate metabolism in HD brain. The first 171 amino acids of wild-type huntingtin, and its glutamine expanded mutant form, interacted with copper, but not iron. N171 reduced Cu2+ in vitro in a 1∶1 copper∶protein stoichiometry indicating that this fragment is very redox active. Further, copper promoted and metal chelation inhibited aggregation of cell-free huntingtin. We found decreased LDH activity, but not protein, and increased lactate levels in HD transgenic mouse brain. The LDH inhibitor oxamate resulted in neurodegeneration when delivered intra-striatially to healthy mice, indicating that LDH inhibition is relevant to neurodegeneration in HD. Our findings support a role of pro-oxidant copper-protein interactions in HD progression and offer a novel target for pharmacotherapeutics. PMID:17396163

  8. [Top ten progressions of clinical research in fundus diseases in China].

    PubMed

    2014-11-01

    Ten research items in the past five years representing the progression of clinical research in fundus diseases in China were voted by specialists from the Ocular Fundus Disease Group of Ophthalmology Society of Chinese Medical Association. Choroidal neovascular disease, pediatric retinal disease, polypoidal choroidal vasculopathy, intraocular malignant tumor, and intraocular infection caused by specific pathogens are covered. Novel treatment, like anti-VEGF medication, PDT, minimally invasive vitrectomy, and intraocular injection, establishment of the Clinical Research Center of New Drug Development, and the epidemiologic study of fundus diseases are also included. These landmark research progressions represent the power and influence of Chinese fundus disease scholars in the world.

  9. Heart failure progression is accelerated following myocardial infarction in type II diabetic rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Clinical studies have shown a greater incidence of myocardial infarction in diabetic patients and following an infarction, diabetes is associated with an increased risk for the development of left ventricular dysfunction and heart failure. The goal of this study was to determine if the progression o...

  10. Learning Biomarker Models for Progression Estimation of Alzheimer’s Disease

    PubMed Central

    Ledig, Christian; Guerrero, Ricardo; Molina-Abril, Helena; Frangi, Alejandro; Rueckert, Daniel

    2016-01-01

    Being able to estimate a patient’s progress in the course of Alzheimer’s disease and predicting future progression based on a number of observed biomarker values is of great interest for patients, clinicians and researchers alike. In this work, an approach for disease progress estimation is presented. Based on a set of subjects that convert to a more severe disease stage during the study, models that describe typical trajectories of biomarker values in the course of disease are learned using quantile regression. A novel probabilistic method is then derived to estimate the current disease progress as well as the rate of progression of an individual by fitting acquired biomarkers to the models. A particular strength of the method is its ability to naturally handle missing data. This means, it is applicable even if individual biomarker measurements are missing for a subject without requiring a retraining of the model. The functionality of the presented method is demonstrated using synthetic and—employing cognitive scores and image-based biomarkers—real data from the ADNI study. Further, three possible applications for progress estimation are demonstrated to underline the versatility of the approach: classification, construction of a spatio-temporal disease progression atlas and prediction of future disease progression. PMID:27096739

  11. A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation.

    PubMed

    Patel, Avinash; Lee, Hyun O; Jawerth, Louise; Maharana, Shovamayee; Jahnel, Marcus; Hein, Marco Y; Stoynov, Stoyno; Mahamid, Julia; Saha, Shambaditya; Franzmann, Titus M; Pozniakovski, Andrej; Poser, Ina; Maghelli, Nicola; Royer, Loic A; Weigert, Martin; Myers, Eugene W; Grill, Stephan; Drechsel, David; Hyman, Anthony A; Alberti, Simon

    2015-08-27

    Many proteins contain disordered regions of low-sequence complexity, which cause aging-associated diseases because they are prone to aggregate. Here, we study FUS, a prion-like protein containing intrinsically disordered domains associated with the neurodegenerative disease ALS. We show that, in cells, FUS forms liquid compartments at sites of DNA damage and in the cytoplasm upon stress. We confirm this by reconstituting liquid FUS compartments in vitro. Using an in vitro "aging" experiment, we demonstrate that liquid droplets of FUS protein convert with time from a liquid to an aggregated state, and this conversion is accelerated by patient-derived mutations. We conclude that the physiological role of FUS requires forming dynamic liquid-like compartments. We propose that liquid-like compartments carry the trade-off between functionality and risk of aggregation and that aberrant phase transitions within liquid-like compartments lie at the heart of ALS and, presumably, other age-related diseases. PMID:26317470

  12. Total Kidney Volume in Autosomal Dominant Polycystic Kidney Disease: A Biomarker of Disease Progression and Therapeutic Efficacy.

    PubMed

    Alam, Ahsan; Dahl, Neera K; Lipschutz, Joshua H; Rossetti, Sandro; Smith, Patricia; Sapir, Daniel; Weinstein, Jordan; McFarlane, Philip; Bichet, Daniel G

    2015-10-01

    Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially life-threatening monogenic disorder in humans, characterized by progressive development and expansion of fluid-filled cysts in the kidneys and other organs. Ongoing cyst growth leads to progressive kidney enlargement, whereas kidney function remains stable for decades as a result of hyperfiltration and compensation by unaffected nephrons. Kidney function irreversibly declines only in the late stages of the disease, when most of the parenchyma is lost to cystic and fibrotic tissue and the remaining compensatory capacity is overwhelmed. Hence, conventional kidney function measures, such as glomerular filtration rate, do not adequately assess disease progression in ADPKD, especially in its early stages. Given the recent development of potential targeted therapies in ADPKD, it has become critically important to identify relevant biomarkers that can be used to determine the degree of disease progression and evaluate the effects of therapeutic interventions on the course of the disease. We review the current evidence to provide an informed perspective on whether total kidney volume (TKV) is a suitable biomarker for disease progression and whether TKV can be used as an efficacy end point in clinical trials. We conclude that because cystogenesis is the central factor leading to kidney enlargement, TKV appears to be an appropriate biomarker and is gaining wider acceptance. Several studies have identified TKV as a relevant imaging biomarker for monitoring and predicting disease progression and support its use as a prognostic end point in clinical trials.

  13. Phosphorylated human tau associates with mouse prion protein amyloid in scrapie-infected mice but does not increase progression of clinical disease.

    PubMed

    Race, Brent; Phillips, Katie; Kraus, Allison; Chesebro, Bruce

    2016-07-01

    Tauopathies are a family of neurodegenerative diseases in which fibrils of human hyperphosphorylated tau (P-tau) are believed to cause neuropathology. In Alzheimer disease, P-tau associates with A-beta amyloid and contributes to disease pathogenesis. In familial human prion diseases and variant CJD, P-tau often co-associates with prion protein amyloid, and might also accelerate disease progression. To test this latter possibility, here we compared progression of amyloid prion disease in vivo after scrapie infection of mice with and without expression of human tau. The mice used expressed both anchorless prion protein (PrP) and membrane-anchored PrP, that generate disease associated amyloid and non-amyloid PrP (PrPSc) after scrapie infection. Human P-tau induced by scrapie infection was only rarely associated with non-amyloid PrPSc, but abundant human P-tau was detected at extracellular, perivascular and axonal deposits associated with amyloid PrPSc. This pathology was quite similar to that seen in familial prion diseases. However, association of human and mouse P-tau with amyloid PrPSc did not diminish survival time following prion infection in these mice. By analogy, human P-tau may not affect prion disease progression in humans. Alternatively, these results might be due to other factors, including rapidity of disease, blocking effects by mouse tau, or low toxicity of human P-tau in this model.

  14. Phosphorylated human tau associates with mouse prion protein amyloid in scrapie-infected mice but does not increase progression of clinical disease.

    PubMed

    Race, Brent; Phillips, Katie; Kraus, Allison; Chesebro, Bruce

    2016-07-01

    Tauopathies are a family of neurodegenerative diseases in which fibrils of human hyperphosphorylated tau (P-tau) are believed to cause neuropathology. In Alzheimer disease, P-tau associates with A-beta amyloid and contributes to disease pathogenesis. In familial human prion diseases and variant CJD, P-tau often co-associates with prion protein amyloid, and might also accelerate disease progression. To test this latter possibility, here we compared progression of amyloid prion disease in vivo after scrapie infection of mice with and without expression of human tau. The mice used expressed both anchorless prion protein (PrP) and membrane-anchored PrP, that generate disease associated amyloid and non-amyloid PrP (PrPSc) after scrapie infection. Human P-tau induced by scrapie infection was only rarely associated with non-amyloid PrPSc, but abundant human P-tau was detected at extracellular, perivascular and axonal deposits associated with amyloid PrPSc. This pathology was quite similar to that seen in familial prion diseases. However, association of human and mouse P-tau with amyloid PrPSc did not diminish survival time following prion infection in these mice. By analogy, human P-tau may not affect prion disease progression in humans. Alternatively, these results might be due to other factors, including rapidity of disease, blocking effects by mouse tau, or low toxicity of human P-tau in this model. PMID:27463540

  15. Accelerated tumor progression in mice lacking the ATP receptor P2X7.

    PubMed

    Adinolfi, Elena; Capece, Marina; Franceschini, Alessia; Falzoni, Simonetta; Giuliani, Anna L; Rotondo, Alessandra; Sarti, Alba C; Bonora, Massimo; Syberg, Susanne; Corigliano, Domenica; Pinton, Paolo; Jorgensen, Niklas R; Abelli, Luigi; Emionite, Laura; Raffaghello, Lizzia; Pistoia, Vito; Di Virgilio, Francesco

    2015-02-15

    The ATP receptor P2X7 (P2X7R or P2RX7) has a key role in inflammation and immunity, but its possible roles in cancer are not firmly established. In the present study, we investigated the effect of host genetic deletion of P2X7R in the mouse on the growth of B16 melanoma or CT26 colon carcinoma cells. Tumor size and metastatic dissemination were assessed by in vivo calliper and luciferase luminescence emission measurements along with postmortem examination. In P2X7R-deficient mice, tumor growth and metastatic spreading were accelerated strongly, compared with wild-type (wt) mice. Intratumoral IL-1β and VEGF release were drastically reduced, and inflammatory cell infiltration was abrogated nearly completely. Similarly, tumor growth was also greatly accelerated in wt chimeric mice implanted with P2X7R-deficient bone marrow cells, defining hematopoietic cells as a sufficient site of P2X7R action. Finally, dendritic cells from P2X7R-deficient mice were unresponsive to stimulation with tumor cells, and chemotaxis of P2X7R-less cells was impaired. Overall, our results showed that host P2X7R expression was critical to support an antitumor immune response, and to restrict tumor growth and metastatic diffusion. PMID:25542861

  16. Nonlinear ghost waves accelerate the progression of high-grade brain tumors

    NASA Astrophysics Data System (ADS)

    Pardo, Rosa; Martínez-González, Alicia; Pérez-García, Víctor M.

    2016-10-01

    We study a reduced continuous model describing the evolution of high grade gliomas in response to hypoxic events through the interplay of different cellular phenotypes. We show that hypoxic events, even when sporadic and/or limited in space, may have a crucial role on the acceleration of high grade gliomas growth. Our modeling approach is based on two cellular phenotypes. One of them is more migratory and a second one is more proliferative. Transitions between both phenotypes are driven by the local oxygen values, assumed in this simple model to be uniform. Surprisingly, even very localized in time hypoxia events leading to transient migratory populations have the potential to accelerate the tumor's invasion speed up to speeds close to those of the migratory phenotype. The high invasion speed persists for times much longer than the lifetime of the hypoxic event. Moreover, the phenomenon is observed both when the migratory cells form a persistent wave of cells located on the invasion front and when they form a evanescent "ghost" wave disappearing after a short time by decay to the more proliferative phenotype. Our findings are obtained through numerical simulations of the model equations both in 1D and higher dimensional scenarios. We also provide a deeper mathematical analysis of some aspects of the problem such as the conditions for the existence of persistent waves of cells with a more migratory phenotype.

  17. High energy accelerator and colliding beam user group: Progress report, March 1, 1987-February 29, 1988

    SciTech Connect

    Not Available

    1987-09-01

    Progress is reported on the OPAL experiment at LEP, including construction and assembly of the hadron calorimeter and development of OPAL software. Progress on the JADE experiment, which examines e/sup +/e/sup -/ interactions at PETRA, and of the PLUTO collaboration are also discussed. Experiments at Fermilab are reported, including deep inelastic muon scattering at TeV II, the D0 experiment at TeV I, and hadron jet physics. Neutrino-electron elastic scattering and a search for point-sources of ultra-high energy cosmic rays are reported. Other activities discussed include polarization in electron storage rings, participation in studies for the SSC and LEP 200, neutron-antineutron oscillations, and the work of the electronics support group. High energy physics computer experience is also discussed. 158 refs. (LEW)

  18. Regulator of G protein signaling 2 (RGS2) deficiency accelerates the progression of kidney fibrosis.

    PubMed

    Jang, Hee-Seong; Kim, Jee In; Noh, Mira; Rhee, Man Hee; Park, Kwon Moo

    2014-09-01

    The regulator of G protein signaling 2 (RGS2) is a potent negative regulator of Gq protein signals including the angiotensin II (AngII)/AngII receptor signal, which plays a critical role in the progression of fibrosis. However, the role of RGS2 on the progression of kidney fibrosis has not been assessed. Here, we investigated the role of RGS2 in kidney fibrosis induced by unilateral ureteral obstruction (UUO) in mice. UUO resulted in increased expression of RGS2 mRNA and protein in the kidney along with increases of AngII and its type 1 receptor (AT1R) signaling and fibrosis. Furthermore, UUO increased the levels of F4/80, Ly6G, myeloperoxidase, and CXCR4 in the kidneys. RGS2 deficiency significantly enhanced these changes in the kidney. RGS2 deletion in the bone marrow-derived cells by transplanting the bone marrow of RGS2 knock-out mice into wild type mice enhanced UUO-induced kidney fibrosis. Overexpression of RGS2 in HEK293 cells, a human embryonic kidney cell line, and RAW264.7 cells, a monocyte/macrophage line, inhibited the AngII-induced activation of ERK and increase of CXCR4 expression. These findings provide the first evidence that RGS2 negatively regulates the progression of kidney fibrosis following UUO, likely by suppressing fibrogenic and inflammatory responses through the inhibition of AngII/AT1R signaling.

  19. Regulator of G protein signaling 2 (RGS2) deficiency accelerates the progression of kidney fibrosis.

    PubMed

    Jang, Hee-Seong; Kim, Jee In; Noh, Mira; Rhee, Man Hee; Park, Kwon Moo

    2014-09-01

    The regulator of G protein signaling 2 (RGS2) is a potent negative regulator of Gq protein signals including the angiotensin II (AngII)/AngII receptor signal, which plays a critical role in the progression of fibrosis. However, the role of RGS2 on the progression of kidney fibrosis has not been assessed. Here, we investigated the role of RGS2 in kidney fibrosis induced by unilateral ureteral obstruction (UUO) in mice. UUO resulted in increased expression of RGS2 mRNA and protein in the kidney along with increases of AngII and its type 1 receptor (AT1R) signaling and fibrosis. Furthermore, UUO increased the levels of F4/80, Ly6G, myeloperoxidase, and CXCR4 in the kidneys. RGS2 deficiency significantly enhanced these changes in the kidney. RGS2 deletion in the bone marrow-derived cells by transplanting the bone marrow of RGS2 knock-out mice into wild type mice enhanced UUO-induced kidney fibrosis. Overexpression of RGS2 in HEK293 cells, a human embryonic kidney cell line, and RAW264.7 cells, a monocyte/macrophage line, inhibited the AngII-induced activation of ERK and increase of CXCR4 expression. These findings provide the first evidence that RGS2 negatively regulates the progression of kidney fibrosis following UUO, likely by suppressing fibrogenic and inflammatory responses through the inhibition of AngII/AT1R signaling. PMID:24973550

  20. Results of treatment intensification for progressive locoregional disease in head-and-neck cancer patients undergoing postoperative radiotherapy

    SciTech Connect

    Corry, June . E-mail: June.Corry@petermac.org; Rischin, Danny; Mukesh, Bickol N.; Porceddu, Sandro; Peters, Lester J.

    2005-04-01

    Purpose: Patients who develop progressive locoregional disease during radical surgery and postoperative radiotherapy for squamous cell carcinoma of the head and neck represent a management dilemma. We present our experience using treatment intensification for such patients. Methods and materials: A prospective record of eligible patients was kept between May 1998 and December 2001. The study included 15 patients, 11 men and 4 women (median age, 60 years); 67% had Stage III-IV disease. The sites of progression were primary in 3, nodes/scar in 10, and both primary and nodes in 2. Relative to the initial plan, treatment intensification was achieved by an increased radiation dose in 7 (using accelerated fractionation in 5), an increased radiation dose and the addition of concomitant chemotherapy in 7, and the addition of concomitant chemotherapy alone in 1 patient. Results: The median follow-up was 40 months. Eight patients had a complete response to intensified treatment. At the closeout date, 6 patients were alive with no evidence of disease. Eight patients had died with locoregional disease; two also had distant metastases. One patient was lost to follow-up after achieving a complete response. The median failure-free survival for all patients was 6 months, but for those with a complete response, it was 37 months. The median overall survival time was 28 months. The 2-year and 3-year overall survival rate was 50% and 42%, respectively. Acute mucosal and skin toxicity was increased relative to standard postoperative radiotherapy but was not dissimilar to that expected after radical definitive chemoradiotherapy. Conclusion: Intensification of treatment in patients who develop progressive locoregional disease is warranted, because it can lead to long-term disease control in a subset of patients with significant but acceptable toxicity.

  1. Seizures during the management of high-grade gliomas: clinical relevance to disease progression.

    PubMed

    Kim, Young-Hoon; Park, Chul-Kee; Kim, Tae Min; Choi, Seung Hong; Kim, Yu Jung; Choi, Byung Se; Han, Jung Ho; Lee, Se-Hoon; Kim, Chae-Yong; Kim, In Ah; Heo, Dae Seog; Kim, Il Han; Kim, Dong Gyu; Jung, Hee-Won

    2013-05-01

    This study was performed to evaluate the incidence of seizures with its implications on disease progression and the diagnostic value of post-ictal magnetic resonance images (MRI) during the management of high-grade gliomas (HGGs). A total of 406 consecutive patients with newly diagnosed HGGs were retrospectively reviewed. The incidence of seizures during the management was investigated. In patients who experienced a seizure, the causality between seizures and disease progression was assessed by pre-ictal, post-ictal (<1 month), and follow-up (<3 months) MRI. After a median follow-up of 17.4 months (range 0.1-88.3), seizures developed in 127 patients (31 %). Of the 127 patients, radiological progression at the post-ictal MRI was found in 83 patients (65 %) and the follow-up MRI confirmed progression in 79 patients (62 %). Four other patients (3 %) were shown to be progression-free. Among those without radiological progression at the post-ictal MRI, the follow-up MRI confirmed progression-free in 31 patients (24 %); however, 13 patients (10 %) revealed eventual progression. In the patients with a seizure, absence of preoperative seizures (p = 0.003), <95 % tumor resection (p = 0.001), and pre-ictal Karnofsky Performance Scale score ≤ 70 (p = 0.025) were significantly associated with disease progression. During the management of HGG, 31 % of patients experienced seizures; of these patients, 72 % harbored progressive disease. The post-ictal MRI is useful for detecting disease progression; however, there are pitfalls. Clinical settings should be considered together for diagnosing disease progression in patients with seizures.

  2. Harnessing collaborative technology to accelerate achievement of chronic disease management objectives for Canada.

    PubMed

    Thompson, Leslee J; Healey, Lindsay; Falk, Will

    2007-01-01

    Morgan and colleagues put forth a call to action for the transformation of the Canadian healthcare system through the adoption of a national chronic disease prevention and management (CDPM) strategy. They offer examples of best practices and national solutions including investment in clinical information technologies to help support improved care and outcomes. Although we acknowledge that the authors propose CDPM solutions that are headed in the right direction, more rapid deployment of solutions that harness the potential of advanced collaborative technologies is required. We provide examples of how technologies that exist today can help to accelerate the achievement of some key CDPM objectives.

  3. Cerebrovascular pathology during the progression of experimental Alzheimer's disease.

    PubMed

    Giannoni, Patrizia; Arango-Lievano, Margarita; Neves, Ines Das; Rousset, Marie-Claude; Baranger, Kévin; Rivera, Santiago; Jeanneteau, Freddy; Claeysen, Sylvie; Marchi, Nicola

    2016-04-01

    Clinical and experimental evidence point to a possible role of cerebrovascular dysfunction in Alzheimer's disease (AD). The 5xFAD mouse model of AD expresses human amyloid precursor protein and presenilin genes with mutations found in AD patients. It remains unknown whether amyloid deposition driven by these mutations is associated with cerebrovascular changes. 5xFAD and wild type mice (2 to 12months old; M2 to M12) were used. Thinned skull in vivo 2-photon microscopy was used to determine Aβ accumulation on leptomeningeal or superficial cortical vessels over time. Parenchymal microvascular damage was assessed using FITC-microangiography. Collagen-IV and CD31 were used to stain basal lamina and endothelial cells. Methoxy-XO4, Thioflavin-S or 6E10 were used to visualize Aβ accumulation in living mice or in fixed brain tissues. Positioning of reactive IBA1 microglia and GFAP astrocytes at the vasculature was rendered using confocal microscopy. Platelet-derived growth factor receptor beta (PDGFRβ) staining was used to visualize perivascular pericytes. In vivo 2-photon microscopy revealed Methoxy-XO4(+) amyloid perivascular deposits on leptomeningeal and penetrating cortical vessels in 5xFAD mice, typical of cerebral amyloid angiopathy (CAA). Amyloid deposits were visible in vivo at M3 and aggravated over time. Progressive microvascular damage was concomitant to parenchymal Aβ plaque accumulation in 5xFAD mice. Microvascular inflammation in 5xFAD mice presented with sporadic FITC-albumin leakages at M4 becoming more prevalent at M9 and M12. 3D colocalization showed inflammatory IBA1(+) microglia proximal to microvascular FITC-albumin leaks. The number of perivascular PDGFRβ(+) pericytes was significantly decreased at M4 in the fronto-parietal cortices, with a trend decrease observed in the other structures. At M9-M12, PDGFRβ(+) pericytes displayed hypertrophic perivascular ramifications contiguous to reactive microglia. Cerebral amyloid angiopathy and

  4. A Lipidomic Readout of Disease Progression in A Diet-Induced Mouse Model of Nonalcoholic Fatty Liver Disease

    PubMed Central

    Sanyal, Arun J.; Pacana, Tommy

    2015-01-01

    Multiple changes in lipid metabolism occur in nonalcoholic fatty liver disease. However, it is not known which of these contribute to disease progression. The objective of this study was to define changes in hepatic lipid composition over time in a diet-induced model of nonalcoholic fatty liver disease to identify changes associated with disease progression. A lipidomic approach was used to quantify individual lipid species with lipid classes of interest including diacylglycerols (DAG), cholesterol, phospholipids, plasmalogens, sphingolipids, and eicosanoids. C57b/S129J mice fed a high-fat, high-cholesterol diet developed fatty liver, inflammation, and ballooning by 16 weeks and extensive fibrosis by week 52. There was a marked increase in monounsaturated fatty acid containing DAGs and cholesterol esters by week 16 which decreased by week 52. The changes in DAG were associated with a 500- to 600-fold increase in phosphatidic acid (< 0.001) and its downstream product phosphatidylglycerol (P <0.01) whereas phosphatidylethanolamine, phosphatidylcholine, and phsophatidylserine all decreased. Disease progression was associated with a significant further decrease in phosphatidylcholine and phosphatidylethanolamine while several lysolecithin species increased. Disease progression was associated with a significant increase in the plasmalogen PC-P 16:0/16:1. Saturated fatty acid (16:0 and 18:0) containing ceramides, sphingosine, sphingosine-1-phosphate, dihydrosphingosine, and dihydrophingosine-1-phosphate increased by week 16 after high-fat high-cholesterol diet. Globotrioseacylceramide (GB3) also increased significantly by week 16 and increased further with disease progression. 12-hydroxyeicosatetranoic acid decreased at week 16 but increased with disease progression. In conclusion, multiple lipids were associated with disease progression and provide clues regarding lipid drivers of nonalcoholic steatohepatitis. PMID:26330688

  5. A Lipidomic Readout of Disease Progression in A Diet-Induced Mouse Model of Nonalcoholic Fatty Liver Disease.

    PubMed

    Sanyal, Arun J; Pacana, Tommy

    2015-01-01

    Multiple changes in lipid metabolism occur in nonalcoholic fatty liver disease. However, it is not known which of these contribute to disease progression. The objective of this study was to define changes in hepatic lipid composition over time in a diet-induced model of nonalcoholic fatty liver disease to identify changes associated with disease progression. A lipidomic approach was used to quantify individual lipid species with lipid classes of interest including diacylglycerols (DAG), cholesterol, phospholipids, plasmalogens, sphingolipids, and eicosanoids. C57b/S129J mice fed a high-fat, high-cholesterol diet developed fatty liver, inflammation, and ballooning by 16 weeks and extensive fibrosis by week 52. There was a marked increase in monounsaturated fatty acid containing DAGs and cholesterol esters by week 16 which decreased by week 52. The changes in DAG were associated with a 500- to 600-fold increase in phosphatidic acid (< 0.001) and its downstream product phosphatidylglycerol (P <0.01) whereas phosphatidylethanolamine, phosphatidylcholine, and phsophatidylserine all decreased. Disease progression was associated with a significant further decrease in phosphatidylcholine and phosphatidylethanolamine while several lysolecithin species increased. Disease progression was associated with a significant increase in the plasmalogen PC-P 16:0/16:1. Saturated fatty acid (16:0 and 18:0) containing ceramides, sphingosine, sphingosine-1-phosphate, dihydrosphingosine, and dihydrophingosine-1-phosphate increased by week 16 after high-fat high-cholesterol diet. Globotrioseacylceramide (GB3) also increased significantly by week 16 and increased further with disease progression. 12-hydroxyeicosatetranoic acid decreased at week 16 but increased with disease progression. In conclusion, multiple lipids were associated with disease progression and provide clues regarding lipid drivers of nonalcoholic steatohepatitis.

  6. Overview of progress on the improvement projects for the LANSCE accelerator and target facilities

    SciTech Connect

    Macek, R.J.; Browne, J.; Brun, T.; Donahue, J.B.; Fitzgerald, D.H.; Hoffman, E.; Pynn, R.; Schriber, S.; Weinacht, D.

    1997-06-01

    Three projects have been initiated since 1994 to improve the performance of the accelerator and target facilities for the Los Alamos Neutron Science Center (LANSCE). The LANSCE Reliability Improvement Project (LRIP) was separated into two phases. Phase 1, completed in 1995, targeted near-term improvements to beam reliability and availability that could be completed in one-year`s time. Phase 2, now underway and scheduled for completion in May 1998, consists of two projects: (a) implementation of direct H-injection for the Proton Storage Ring (PSR) and (b) an upgrade of the target/moderator system for the short pulse spallation neutron (SPSS) source. The latter will reduce the target change-out time from about 10 months to about three weeks. The third project, the SPSS Enhancement Project, is aimed at increasing the PSR output beam current to 200 {micro}A at 30 Hz and providing up to seven new neutron scattering instruments.

  7. Discrimination of EMG and acceleration measurements between patients with Parkinson's disease and healthy persons.

    PubMed

    Rissanen, Saara M; Kankaanpaa, Markku; Tarvainen, Mika P; Meigal, Alexander; Nuutinen, Juho; Jakala, Pekka; Airaksinen, Olavi; Karjalainen, Pasi A

    2010-01-01

    In this paper, we examine the potential of electromyographic (EMG) and acceleration measurements in discriminating patients with Parkinson's disease (PD) from healthy persons. Two types of muscle contractions are examined: static contractions of biceps brachii muscles and elbow extension movements. Twelve features are extracted from static and ten features from extension measurements. These features describe signal morphology and nonlinear characteristics, power spreading in EMG wavelet scalograms and spectral coherence. Principal component approach is applied separately for static and extension trial to reduce the number of features before discrimination. The discrimination between subjects is done in a two-dimensional space by applying cluster analysis to the best discriminating principal components. The discrimination power of the used method was estimated with EMG and acceleration data measured from 56 patients with PD and 59 healthy controls. In the cluster analysis, three clusters were formed: one cluster with most (85%) of the healthy persons and two clusters with 80% of patients. Patients were divided into two clusters based on their type of motor disability (problems during movement and/or static contraction). Discrimination results show that EMG and acceleration measurements are potential for discriminating patients with PD from healthy persons. Furthermore, they have potential in the objective clinical assessment of PD. PMID:21096652

  8. Exploration of Anaemia as a Progression Factor in African Americans with Cardiovascular Disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Despite the higher incidence of end stage renal disease (ESRD) among African Americans, whites in the United States population have a higher prevalence of chronic kidney disease. This may be due, in part, to a faster rate of progression to ESRD among African Americans with kidney disease. Anemia i...

  9. Economic analysis of opportunities to accelerate Alzheimer’s disease research and development

    PubMed Central

    Scott, Troy J; O'Connor, Alan C; Link, Albert N; Beaulieu, Travis J

    2014-01-01

    The development of disease-modifying treatments for Alzheimer's disease (AD) faces a number of barriers. Among these are the lack of surrogate biomarkers, the exceptional size and duration of clinical trials, difficulties in identifying appropriate populations for clinical trials, and the limitations of monotherapies in addressing such a complex multifactorial disease. This study sets out to first estimate the consequent impact on the expected cost of developing disease-modifying treatments for AD and then to estimate the potential benefits of bringing together industry, academic, and government stakeholders to co-invest in, for example, developing better biomarkers and cognitive assessment tools, building out advanced registries and clinical trial-readiness cohorts, and establishing clinical trial platforms to investigate combinations of candidate drugs and biomarkers from the portfolios of multiple companies. Estimates based on interviews with experts on AD research and development suggest that the cost of one new drug is now $5.7 billion (95% confidence interval (CI) $3.7–9.5 billion) and could be reduced to $2.0 billion (95% CI $1.5–2.9 billion). The associated acceleration in the arrival of disease-modifying treatments could reduce the number of case years of dementia by 7.0 million (95% CI 4.4–9.4 million) in the United States from 2025 through 2040. PMID:24673372

  10. Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis.

    PubMed

    El Oussini, Hajer; Bayer, Hanna; Scekic-Zahirovic, Jelena; Vercruysse, Pauline; Sinniger, Jérôme; Dirrig-Grosch, Sylvie; Dieterlé, Stéphane; Echaniz-Laguna, Andoni; Larmet, Yves; Müller, Kathrin; Weishaupt, Jochen H; Thal, Dietmar R; van Rheenen, Wouter; van Eijk, Kristel; Lawson, Roland; Monassier, Laurent; Maroteaux, Luc; Roumier, Anne; Wong, Philip C; van den Berg, Leonard H; Ludolph, Albert C; Veldink, Jan H; Witting, Anke; Dupuis, Luc

    2016-03-01

    Microglia are the resident mononuclear phagocytes of the central nervous system and have been implicated in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). During neurodegeneration, microglial activation is accompanied by infiltration of circulating monocytes, leading to production of multiple inflammatory mediators in the spinal cord. Degenerative alterations in mononuclear phagocytes are commonly observed during neurodegenerative diseases, yet little is known concerning the mechanisms leading to their degeneration, or the consequences on disease progression. Here we observed that the serotonin 2B receptor (5-HT2B), a serotonin receptor expressed in microglia, is upregulated in the spinal cord of three different transgenic mouse models of ALS. In mutant SOD1 mice, this upregulation was restricted to cells positive for CD11b, a marker of mononuclear phagocytes. Ablation of 5-HT2B receptor in transgenic ALS mice expressing mutant SOD1 resulted in increased degeneration of mononuclear phagocytes, as evidenced by fragmentation of Iba1-positive cellular processes. This was accompanied by decreased expression of key neuroinflammatory genes but also loss of expression of homeostatic microglial genes. Importantly, the dramatic effect of 5-HT2B receptor ablation on mononuclear phagocytes was associated with acceleration of disease progression. To determine the translational relevance of these results, we studied polymorphisms in the human HTR2B gene, which encodes the 5-HT2B receptor, in a large cohort of ALS patients. In this cohort, the C allele of SNP rs10199752 in HTR2B was associated with longer survival. Moreover, patients carrying one copy of the C allele of SNP rs10199752 showed increased 5-HT2B mRNA in spinal cord and displayed less pronounced degeneration of Iba1 positive cells than patients carrying two copies of the more common A allele. Thus, the 5-HT2B receptor limits degeneration of spinal cord mononuclear

  11. Inhibition of Aerobic Glycolysis Attenuates Disease Progression in Polycystic Kidney Disease

    PubMed Central

    Riwanto, Meliana; Kapoor, Sarika; Rodriguez, Daniel; Edenhofer, Ilka; Segerer, Stephan; Wüthrich, Rudolf P.

    2016-01-01

    Dysregulated signaling cascades alter energy metabolism and promote cell proliferation and cyst expansion in polycystic kidney disease (PKD). Here we tested whether metabolic reprogramming towards aerobic glycolysis (“Warburg effect”) plays a pathogenic role in male heterozygous Han:SPRD rats (Cy/+), a chronic progressive model of PKD. Using microarray analysis and qPCR, we found an upregulation of genes involved in glycolysis (Hk1, Hk2, Ldha) and a downregulation of genes involved in gluconeogenesis (G6pc, Lbp1) in cystic kidneys of Cy/+ rats compared with wild-type (+/+) rats. We then tested the effect of inhibiting glycolysis with 2-deoxyglucose (2DG) on renal functional loss and cyst progression in 5-week-old male Cy/+ rats. Treatment with 2DG (500 mg/kg/day) for 5 weeks resulted in significantly lower kidney weights (-27%) and 2-kidney/total-body-weight ratios (-20%) and decreased renal cyst index (-48%) compared with vehicle treatment. Cy/+ rats treated with 2DG also showed higher clearances of creatinine (1.98±0.67 vs 1.41±0.37 ml/min), BUN (0.69±0.26 vs 0.40±0.10 ml/min) and uric acid (0.38±0.20 vs 0.21±0.10 ml/min), and reduced albuminuria. Immunoblotting analysis of kidney tissues harvested from 2DG-treated Cy/+ rats showed increased phosphorylation of AMPK-α, a negative regulator of mTOR, and restoration of ERK signaling. Assessment of Ki-67 staining indicated that 2DG limits cyst progression through inhibition of epithelial cell proliferation. Taken together, our results show that targeting the glycolytic pathway may represent a promising therapeutic strategy to control cyst growth in PKD. PMID:26752072

  12. Periodontal disease's contribution to Alzheimer's disease progression in Down syndrome.

    PubMed

    Kamer, Angela R; Fortea, Juan O; Videla, Sebastià; Mayoral, Angela; Janal, Malvin; Carmona-Iragui, Maria; Benejam, Bessy; Craig, Ronald G; Saxena, Deepak; Corby, Patricia; Glodzik, Lidia; Annam, Kumar Raghava Chowdary; Robbins, Miriam; de Leon, Mony J

    2016-01-01

    People with Down syndrome (DS) are at an increased risk for Alzheimer's disease (AD). After 60 years of age, >50% of DS subjects acquire dementia. Nevertheless, the age of onset is highly variable possibly because of both genetic and environmental factors. Genetics cannot be modified, but environmental risk factors present a potentially relevant intervention for DS persons at risk for AD. Among them, inflammation, important in AD of DS type, is potential target. Consistent with this hypothesis, chronic peripheral inflammation and infections may contribute to AD pathogenesis in DS. People with DS have an aggressive form of periodontitis characterized by rapid progression, significant bacterial and inflammatory burden, and an onset as early as 6 years of age. This review offers a hypothetical mechanistic link between periodontitis and AD in the DS population. Because periodontitis is a treatable condition, it may be a readily modifiable risk factor for AD.

  13. Periodontal disease's contribution to Alzheimer's disease progression in Down syndrome.

    PubMed

    Kamer, Angela R; Fortea, Juan O; Videla, Sebastià; Mayoral, Angela; Janal, Malvin; Carmona-Iragui, Maria; Benejam, Bessy; Craig, Ronald G; Saxena, Deepak; Corby, Patricia; Glodzik, Lidia; Annam, Kumar Raghava Chowdary; Robbins, Miriam; de Leon, Mony J

    2016-01-01

    People with Down syndrome (DS) are at an increased risk for Alzheimer's disease (AD). After 60 years of age, >50% of DS subjects acquire dementia. Nevertheless, the age of onset is highly variable possibly because of both genetic and environmental factors. Genetics cannot be modified, but environmental risk factors present a potentially relevant intervention for DS persons at risk for AD. Among them, inflammation, important in AD of DS type, is potential target. Consistent with this hypothesis, chronic peripheral inflammation and infections may contribute to AD pathogenesis in DS. People with DS have an aggressive form of periodontitis characterized by rapid progression, significant bacterial and inflammatory burden, and an onset as early as 6 years of age. This review offers a hypothetical mechanistic link between periodontitis and AD in the DS population. Because periodontitis is a treatable condition, it may be a readily modifiable risk factor for AD. PMID:27239536

  14. 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.

  15. Weight preserving image registration for monitoring disease progression in lung CT.

    PubMed

    Gorbunova, Vladlena; Lol, Pechin; Ashraf, Haseem; Dirksen, Asger; Nielsen, Mads; de Bruijne, Marleen

    2008-01-01

    We present a new image registration based method for monitoring regional disease progression in longitudinal image studies of lung disease. A free-form image registration technique is used to match a baseline 3D CT lung scan onto a following scan. Areas with lower intensity in the following scan compared with intensities in the deformed baseline image indicate local loss of lung tissue that is associated with progression of emphysema. To account for differences in lung intensity owing to differences in the inspiration level in the two scans rather than disease progression, we propose to adjust the density of lung tissue with respect to local expansion or compression such that the total weight of the lungs is preserved during deformation. Our method provides a good estimation of regional destruction of lung tissue for subjects with a significant difference in inspiration level between CT scans and may result in a more sensitive measure of disease progression than standard quantitative CT measures.

  16. Long-distance dispersal and accelerating waves of disease: empirical relationships.

    PubMed

    Mundt, Christopher C; Sackett, Kathryn E; Wallace, LaRae D; Cowger, Christina; Dudley, Joseph P

    2009-04-01

    Classic approaches to modeling biological invasions predict a "traveling wave" of constant velocity determined by the invading organism's reproductive capacity, generation time, and dispersal ability. Traveling wave models may not apply, however, for organisms that exhibit long-distance dispersal. Here we use simple empirical relationships for accelerating waves, based on inverse power law dispersal, and apply them to diseases caused by pathogens that are wind dispersed or vectored by birds: the within-season spread of a plant disease at spatial scales of <100 m in experimental plots, historical plant disease epidemics at the continental scale, the unexpectedly rapid spread of West Nile virus across North America, and the transcontinental spread of avian influenza strain H5N1 in Eurasia and Africa. In all cases, the position of the epidemic front advanced exponentially with time, and epidemic velocity increased linearly with distance; regression slopes varied over a relatively narrow range among data sets. Estimates of the inverse power law exponent for dispersal that would be required to attain the rates of disease spread observed in the field also varied relatively little (1.74-2.36), despite more than a fivefold range of spatial scale among the data sets.

  17. Long-distance dispersal and accelerating waves of disease: empirical relationships.

    PubMed

    Mundt, Christopher C; Sackett, Kathryn E; Wallace, LaRae D; Cowger, Christina; Dudley, Joseph P

    2009-04-01

    Classic approaches to modeling biological invasions predict a "traveling wave" of constant velocity determined by the invading organism's reproductive capacity, generation time, and dispersal ability. Traveling wave models may not apply, however, for organisms that exhibit long-distance dispersal. Here we use simple empirical relationships for accelerating waves, based on inverse power law dispersal, and apply them to diseases caused by pathogens that are wind dispersed or vectored by birds: the within-season spread of a plant disease at spatial scales of <100 m in experimental plots, historical plant disease epidemics at the continental scale, the unexpectedly rapid spread of West Nile virus across North America, and the transcontinental spread of avian influenza strain H5N1 in Eurasia and Africa. In all cases, the position of the epidemic front advanced exponentially with time, and epidemic velocity increased linearly with distance; regression slopes varied over a relatively narrow range among data sets. Estimates of the inverse power law exponent for dispersal that would be required to attain the rates of disease spread observed in the field also varied relatively little (1.74-2.36), despite more than a fivefold range of spatial scale among the data sets. PMID:19249979

  18. Accelerating progress in Artificial General Intelligence: Choosing a benchmark for natural world interaction

    NASA Astrophysics Data System (ADS)

    Rohrer, Brandon

    2010-12-01

    Measuring progress in the field of Artificial General Intelligence (AGI) can be difficult without commonly accepted methods of evaluation. An AGI benchmark would allow evaluation and comparison of the many computational intelligence algorithms that have been developed. In this paper I propose that a benchmark for natural world interaction would possess seven key characteristics: fitness, breadth, specificity, low cost, simplicity, range, and task focus. I also outline two benchmark examples that meet most of these criteria. In the first, the direction task, a human coach directs a machine to perform a novel task in an unfamiliar environment. The direction task is extremely broad, but may be idealistic. In the second, the AGI battery, AGI candidates are evaluated based on their performance on a collection of more specific tasks. The AGI battery is designed to be appropriate to the capabilities of currently existing systems. Both the direction task and the AGI battery would require further definition before implementing. The paper concludes with a description of a task that might be included in the AGI battery: the search and retrieve task.

  19. Lutheran/basal cell adhesion molecule accelerates progression of crescentic glomerulonephritis in mice

    PubMed Central

    Huang, Jin; Filipe, Anne; Rahuel, Cécile; Bonnin, Philippe; Mesnard, Laurent; Guérin, Coralie; Wang, Yu; Le Van Kim, Caroline; Colin, Yves; Tharaux, Pierre-Louis

    2014-01-01

    Migration of circulating leukocytes from the vasculature into the surrounding tissue is an important component of the inflammatory response. Among the cell surface molecules identified as contributing to leukocyte extravasation is VCAM-1, expressed on activated vascular endothelium, which participates in all stages of leukocyte–endothelial interaction by binding to leukocyte surface expressed integrin VLA-4. However, not all VLA-4-mediated events can be linked to VCAM-1. A novel interaction between VLA-4 and endothelial Lutheran (Lu) blood group antigens and basal cell adhesion molecule (BCAM) proteins has been recently shown, suggesting that Lu/BCAM may have a role in leukocyte recruitments in inflamed tissues. Here, we assessed the participation of Lu/BCAM in the immunopathogenesis of crescentic glomerulonephritis. High expression of Lu/BCAM in glomeruli of mice with rapidly progressive glomerulonephritis suggests a potential role for the local expression of Lu/BCAM in nephritogenic recruitment of leukocytes. Genetic deficiency of Lu/BCAM attenuated glomerular accumulation of T cells and macrophages, crescent formation, and proteinuria, correlating with reduced fibrin and platelet deposition in glomeruli. Furthermore, we found a pro-adhesive interaction between human monocyte α4β1 integrin and Lu/BCAM proteins. Thus, Lu/BCAM may have a critical role in facilitating the accumulation of monocytes and macrophages, thereby exacerbating renal injury. PMID:24429403

  20. Comparative study of antibodies that are associated with disease progression in HIV disease.

    PubMed

    Tóth, F D; Süsal, C; Ujhelyi, E; Bánhegyi, D; Kiss, J; Daniel, V; Nagy, I; Opelz, G; Füst, G

    1994-06-01

    Two types of antibodies which previously were found to be inversely associated with CD4+ cell counts and which may contribute to the progression of HIV disease were measured in parallel in 55 serum samples of 7 longitudinally tested HIV-infected patients (4 homosexual men, 3 haemophilic men) and in 15 serum samples from 15 patients with advanced AIDS. HIV-infection enhancing antibodies were determined in the presence of near-physiologic human complement concentration using a complement receptor type 2 (CR2) carrying HIV-target cell line. IgG and IgA class autoantibodies directed against human IgG-Fab fragments were measured in specific ELISA assays. In agreement with our previous studies obtained in HIV-seropositive haemophilic patients, significant negative correlations were found between CD4+ cell counts and IgG anti-Fab and IgA anti-Fab antibodies (Spearman correlation coefficient r = -0.587, P < 0.0001; and r = -0.269, P = 0.024, respectively). A significant positive correlation was observed between complement-dependent enhancing antibodies and IgA anti-Fab antibodies (r = 0.408, P = 0.003), whereas the correlation with IgG anti-Fab antibodies was only weak (r = 0.288, P = 0.034). Serum samples with high titres of complement-dependent enhancing antibodies had almost 3 times higher IgA anti-Fab autoantibody activity than sera with low titres (P = 0.0038). Our findings indicate that the two disease markers in HIV disease, enhancing antibodies and autoantibodies directed against the Fab moiety of IgG, are not identical. However, anti-Fab antibodies may contribute to complement-dependent HIV infection enhancement. PMID:7959901

  1. The senescence-accelerated mouse (SAM): a higher oxidative stress and age-dependent degenerative diseases model.

    PubMed

    Chiba, Yoichi; Shimada, Atsuyoshi; Kumagai, Naoko; Yoshikawa, Keisuke; Ishii, Sanae; Furukawa, Ayako; Takei, Shiro; Sakura, Masaaki; Kawamura, Noriko; Hosokawa, Masanori

    2009-04-01

    The SAM strain of mice is actually a group of related inbred strains consisting of a series of SAMP (accelerated senescence-prone) and SAMR (accelerated senescence-resistant) strains. Compared with the SAMR strains, the SAMP strains show a more accelerated senescence process, a shorter lifespan, and an earlier onset and more rapid progress of age-associated pathological phenotypes similar to human geriatric disorders. The higher oxidative stress status observed in SAMP mice is partly caused by mitochondrial dysfunction, and may be a cause of this senescence acceleration and age-dependent alterations in cell structure and function. Based on our recent observations, we discuss a possible mechanism for mitochondrial dysfunction resulting in the excessive production of reactive oxygen species, and a role for the hyperoxidative stress status in neurodegeneration in SAMP mice. These SAM strains can serve as a useful tool to understand the cellular mechanisms of age-dependent degeneration, and to develop clinical interventions. PMID:18688709

  2. Accelerating the development of a therapeutic vaccine for human Chagas disease: rationale and prospects

    PubMed Central

    Zhan, Bin; Heffernan, Michael J; Jones, Kathryn; Valenzuela, Jesus G; Kamhawi, Shaden; Ortega, Jaime; de Leon Rosales, Samuel Ponce; Lee, Bruce Y; Bacon, Kristina M; Fleischer, Bernhard; Slingsby, BT; Cravioto, Miguel Betancourt; Tapia-Conyer, Roberto

    2013-01-01

    Chagas disease is a leading cause of heart disease affecting approximately 10 million people in Latin America and elsewhere worldwide. The two major drugs available for the treatment of Chagas disease have limited efficacy in Trypanosoma cruzi-infected adults with indeterminate (patients who have seroconverted but do not yet show signs or symptoms) and determinate (patients who have both seroconverted and have clinical disease) status; they require prolonged treatment courses and are poorly tolerated and expensive. As an alternative to chemotherapy, an injectable therapeutic Chagas disease vaccine is under development to prevent or delay Chagasic cardiomyopathy in patients with indeterminate or determinate status. The bivalent vaccine will be comprised of two recombinant T. cruzi antigens, Tc24 and TSA-1, formulated on alum together with the Toll-like receptor 4 agonist, E6020. Proof-of-concept for the efficacy of these antigens was obtained in preclinical testing at the Autonomous University of Yucatan. Here the authors discuss the potential for a therapeutic Chagas vaccine as well as the progress made towards such a vaccine, and the authors articulate a roadmap for the development of the vaccine as planned by the nonprofit Sabin Vaccine Institute Product Development Partnership and Texas Children’s Hospital Center for Vaccine Development in collaboration with an international consortium of academic and industrial partners in Mexico, Germany, Japan, and the USA. PMID:23151163

  3. Antigonadotropins: a novel strategy to halt Alzheimer's disease progression.

    PubMed

    Gregory, Christopher W; Atwood, Craig S; Smith, Mark A; Bowen, Richard L

    2006-01-01

    A significant amount of research has been focused on the relationship between hormones and Alzheimer's disease. However, the majority of this work has been on estrogen and more recently testosterone. A serendipitous patient encounter led one of us (RLB) to question whether other hormones of the hypothalamic-pituitary-gonadal axis could be playing a role in the pathogenesis of Alzheimer's disease. The age-related decline in reproductive function results in a dramatic decrease in serum estrogen and testosterone concentrations and an equally dramatic compensatory increase in serum luteinizing hormone concentrations. Indeed, there is growing evidence that the gonadotropin, luteinizing hormone, which regulates serum estrogen and testosterone concentrations, could be an important causative factor in the development of Alzheimer's disease. This review provides information supporting the "gonadotropin hypothesis," puts forth a novel mechanism of how changes in serum luteinizing hormone concentrations could contribute to the pathogenesis of Alzheimer's disease, and discusses potential therapeutic anti-gonadotropin compounds.

  4. Progress in Early Diagnosis of Sickle Cell Disease

    ERIC Educational Resources Information Center

    Pearson, Howard A.

    1971-01-01

    Discusses the basis of sickle cell Anemia, including: a description of the diseased blood, genetic implications, recognition of symptoms in infancy, the need for implementation of wide screening procedures, and the future prospects of a cure. (AJ)

  5. Bayesian modeling of incidence and progression of disease from cross-sectional data.

    PubMed

    Dunson, B; Baird, Donna D

    2002-12-01

    In the absence of longitudinal data, the current presence and severity of disease can be measured for a sample of individuals to investigate factors related to disease incidence and progression. In this article, Bayesian discrete-time stochastic models are developed for inference from cross-sectional data consisting of the age at first diagnosis, the current presence of disease, and one or more surrogates of disease severity. Semiparametric models are used for the age-specific hazards of onset and diagnosis, and a normal underlying variable approach is proposed for modeling of changes with latency time in disease severity. The model accommodates multiple surrogates of disease severity having different measurement scales and heterogeneity among individuals in disease progression. A Markov chain Monte Carlo algorithm is described for posterior computation, and the methods are applied to data from a study of uterine leiomyoma. PMID:12495135

  6. Changing bone patterns with progression of chronic kidney disease.

    PubMed

    Drüeke, Tilman B; Massy, Ziad A

    2016-02-01

    It is commonly held that osteitis fibrosa and mixed uremic osteodystrophy are the predominant forms of renal osteodystrophy in patients with chronic kidney disease. Osteitis fibrosa is a high-turnover bone disease resulting mainly from secondary hyperparathyroidism, and mixed uremic osteodystrophy is in addition characterized by a mineralization defect most often attributed to vitamin D deficiency. However, there is ancient and more recent evidence that in early chronic kidney disease stages adynamic bone disease characterized by low bone turnover occurs first, at least in a significant proportion of patients. This could be due to the initial predominance of bone turnover-inhibitory conditions such as resistance to the action of parathyroid hormone (PTH), reduced calcitriol levels, sex hormone deficiency, diabetes, and, last but not least, uremic toxins leading to repression of osteocyte Wnt/β-catenin signaling and increased expression of Wnt antagonists such as sclerostin, Dickkopf-1, and sFRP4. The development of high-turnover bone disease would occur only later on, when serum PTH levels are able to overcome peripheral PTH resistance and the other inhibitory factors of bone formation. Whether FGF23 and Klotho play a direct role in the transition from low- to high-turnover bone disease or participate only indirectly via regulating PTH secretion remains to be seen. PMID:26806832

  7. Accelerated hand bone mineral density loss is associated with progressive joint damage in hands and feet in recent-onset rheumatoid arthritis

    PubMed Central

    2010-01-01

    Introduction To investigate whether accelerated hand bone mineral density (BMD) loss is associated with progressive joint damage in hands and feet in the first year of rheumatoid arthritis (RA) and whether it is an independent predictor of subsequent progressive total joint damage after 4 years. Methods In 256 recent-onset RA patients, baseline and 1-year hand BMD was measured in metacarpals 2-4 by digital X-ray radiogrammetry. Joint damage in hands and feet were scored in random order according to the Sharp-van der Heijde method at baseline and yearly up to 4 years. Results 68% of the patients had accelerated hand BMD loss (>-0.003 g/cm2) in the first year of RA. Hand BMD loss was associated with progressive joint damage after 1 year both in hands and feet with odds ratios (OR) (95% confidence intervals [CI]) of 5.3 (1.3-20.9) and 3.1 (1.0-9.7). In univariate analysis, hand BMD loss in the first year was a predictor of subsequent progressive total joint damage after 4 years with an OR (95% CI) of 3.1 (1.3-7.6). Multivariate analysis showed that only progressive joint damage in the first year and anti-citrullinated protein antibody positivity were independent predictors of long-term progressive joint damage. Conclusions In the first year of RA, accelerated hand BMD loss is associated with progressive joint damage in both hands and feet. Hand BMD loss in the first year of recent-onset RA predicts subsequent progressive total joint damage, however not independent of progressive joint damage in the first year. PMID:20482894

  8. Immunization with hepatitis B vaccine accelerates SLE-like disease in a murine model.

    PubMed

    Agmon-Levin, Nancy; Arango, María-Teresa; Kivity, Shaye; Katzav, Aviva; Gilburd, Boris; Blank, Miri; Tomer, Nir; Volkov, Alex; Barshack, Iris; Chapman, Joab; Shoenfeld, Yehuda

    2014-11-01

    Hepatitis-B vaccine (HBVv) can prevent HBV-infection and associated liver diseases. However, concerns regarding its safety, particularly among patients with autoimmune diseases (i.e. SLE) were raised. Moreover, the aluminum adjuvant in HBVv was related to immune mediated adverse events. Therefore, we examined the effects of immunization with HBVv or alum on SLE-like disease in a murine model. NZBWF1 mice were immunized with HBVv (Engerix), or aluminum hydroxide (alum) or phosphate buffered saline (PBS) at 8 and 12 weeks of age. Mice were followed for weight, autoantibodies titers, blood counts, proteinuria, kidney histology, neurocognitive functions (novel object recognition, staircase, Y-maze and the forced swimming tests) and brain histology. Immunization with HBVv induced acceleration of kidney disease manifested by high anti-dsDNA antibodies (p < 0.01), early onset of proteinuria (p < 0.05), histological damage and deposition of HBs antigen in the kidney. Mice immunized with HBVv and/or alum had decreased cells counts mainly of the red cell lineage (p < 0.001), memory deficits (p < 0.01), and increased activated microglia in different areas of the brain compare with mice immunized with PBS. Anxiety-like behavior was more pronounced among mice immunized with alum. In conclusion, herein we report that immunization with the HBVv aggravated kidney disease in an animal model of SLE. Immunization with either HBVv or alum affected blood counts, neurocognitive functions and brain gliosis. Our data support the concept that different component of vaccines may be linked with immune and autoimmune mediated adverse events.

  9. Sertraline Slows Disease Progression and Increases Neurogenesis in N171-82Q mouse model of Huntington’s Disease

    PubMed Central

    Duan, Wenzhen; Peng, Qi; Masuda, Naoki; Ford, Eric; Tryggestad, Erik; Ladenheim, Bruce; Zhao, Ming; Cadet, Jean Lud; Wong, John; Ross, Christopher A.

    2013-01-01

    Huntington’s disease (HD) is an inherited progressive neurodegenerative disorder resulting from CAG repeat expansion in the gene that encodes for the protein huntingtin. To identify neuroprotective compound (s) that can slow down disease progression and can be administered long term with few side effects in Huntington’s disease, we investigated the effect of sertraline, a selective serotonin reuptake inhibitor (SSRI) which has been shown to upregulate BDNF levels in rodent brains. We report here that in HD mice sertraline increased BDNF levels, preserved chaperone protein HSP70 and Bcl-2 levels in brains, attenuated the progression of brain atrophy and behavioral abnormalities and thereby increased survival. Sertraline also enhanced neurogenesis, which appeared to be responsible for mediating the beneficial effects of sertraline in HD mice. Additionally, the effective levels of sertraline are comparable to the safe levels achievable in humans. The findings suggest that sertraline is a potential candidate for treatment of HD patients. PMID:18403212

  10. The pattern of depressive symptoms varies with progression of Parkinson's disease.

    PubMed Central

    Huber, S J; Freidenberg, D L; Paulson, G W; Shuttleworth, E C; Christy, J A

    1990-01-01

    Whether or not depressive symptoms increase in severity with progression of Parkinson's disease (PD) remains uncertain. Unlike previous studies, we examined whether the severity of specific features of depression (mood, self reproach, vegetative, and somatic symptoms) differ with respect to the progression of PD. Results indicated that symptoms related to both mood and self-reproach were present in the early stages of PD but did not increase in severity with advancing disease. Somatic features of depression were evident early and increased with disease progression, and vegetative symptoms were seen only in the later stages of PD. The different patterns of these depressive features with progression of PD may account in part for the variations seen in previous studies. PMID:2341838

  11. Early Alzheimer’s Disease Blocks Responses To Accelerating Self-Movement

    PubMed Central

    Fernandez, Roberto; Duffy, Charles J.

    2012-01-01

    We assessed the cortical processing of self-movement stimuli in aging and Alzheimer’s disease (AD). Our goal was to identify distinguishing effects on neural mechanisms related to driving and navigation. Young (YNC) and older (ONC) normal controls, and early AD patients (EAD) viewed real-world videos and dot motion stimuli simulating self-movement scenes. We recorded visual motion event related potentials (VMERPs) to stimulus motion coherence and speed. Aging delays motion evoked N200s, whereas AD diminishes response amplitudes. EADs respond to increments in motion coherence, but they are uniquely unresponsive to increments in motion speed that simulate accelerating self-movement. AD related impairments of self-movement processing may have grave consequences for driving safety and navigational independence. PMID:22341609

  12. Accelerated renal disease is associated with the development of metabolic syndrome in a glucolipotoxic mouse model.

    PubMed

    Martínez-García, Cristina; Izquierdo, Adriana; Velagapudi, Vidya; Vivas, Yurena; Velasco, Ismael; Campbell, Mark; Burling, Keith; Cava, Fernando; Ros, Manuel; Oresic, Matej; Vidal-Puig, Antonio; Medina-Gomez, Gema

    2012-09-01

    Individuals with metabolic syndrome are at high risk of developing chronic kidney disease (CKD) through unclear pathogenic mechanisms. Obesity and diabetes are known to induce glucolipotoxic effects in metabolically relevant organs. However, the pathogenic role of glucolipotoxicity in the aetiology of diabetic nephropathy is debated. We generated a murine model, the POKO mouse, obtained by crossing the peroxisome proliferator-activated receptor gamma 2 (PPARγ2) knockout (KO) mouse into a genetically obese ob/ob background. We have previously shown that the POKO mice showed: hyperphagia, insulin resistance, hyperglycaemia and dyslipidaemia as early as 4 weeks of age, and developed a complete loss of normal β-cell function by 16 weeks of age. Metabolic phenotyping of the POKO model has led to investigation of the structural and functional changes in the kidney and changes in blood pressure in these mice. Here we demonstrate that the POKO mouse is a model of renal disease that is accelerated by high levels of glucose and lipid accumulation. Similar to ob/ob mice, at 4 weeks of age these animals exhibited an increased urinary albumin:creatinine ratio and significantly increased blood pressure, but in contrast showed a significant increase in the renal hypertrophy index and an associated increase in p27(Kip1) expression compared with their obese littermates. Moreover, at 4 weeks of age POKO mice showed insulin resistance, an alteration of lipid metabolism and glomeruli damage associated with increased transforming growth factor beta (TGFβ) and parathyroid hormone-related protein (PTHrP) expression. At this age, levels of proinflammatory molecules, such as monocyte chemoattractant protein-1 (MCP-1), and fibrotic factors were also increased at the glomerular level compared with levels in ob/ob mice. At 12 weeks of age, renal damage was fully established. These data suggest an accelerated lesion through glucolipotoxic effects in the renal pathogenesis in POKO mice. PMID

  13. Accelerated renal disease is associated with the development of metabolic syndrome in a glucolipotoxic mouse model

    PubMed Central

    Martínez-García, Cristina; Izquierdo, Adriana; Velagapudi, Vidya; Vivas, Yurena; Velasco, Ismael; Campbell, Mark; Burling, Keith; Cava, Fernando; Ros, Manuel; Orešič, Matej; Vidal-Puig, Antonio; Medina-Gomez, Gema

    2012-01-01

    SUMMARY Individuals with metabolic syndrome are at high risk of developing chronic kidney disease (CKD) through unclear pathogenic mechanisms. Obesity and diabetes are known to induce glucolipotoxic effects in metabolically relevant organs. However, the pathogenic role of glucolipotoxicity in the aetiology of diabetic nephropathy is debated. We generated a murine model, the POKO mouse, obtained by crossing the peroxisome proliferator-activated receptor gamma 2 (PPARγ2) knockout (KO) mouse into a genetically obese ob/ob background. We have previously shown that the POKO mice showed: hyperphagia, insulin resistance, hyperglycaemia and dyslipidaemia as early as 4 weeks of age, and developed a complete loss of normal β-cell function by 16 weeks of age. Metabolic phenotyping of the POKO model has led to investigation of the structural and functional changes in the kidney and changes in blood pressure in these mice. Here we demonstrate that the POKO mouse is a model of renal disease that is accelerated by high levels of glucose and lipid accumulation. Similar to ob/ob mice, at 4 weeks of age these animals exhibited an increased urinary albumin:creatinine ratio and significantly increased blood pressure, but in contrast showed a significant increase in the renal hypertrophy index and an associated increase in p27Kip1 expression compared with their obese littermates. Moreover, at 4 weeks of age POKO mice showed insulin resistance, an alteration of lipid metabolism and glomeruli damage associated with increased transforming growth factor beta (TGFβ) and parathyroid hormone-related protein (PTHrP) expression. At this age, levels of proinflammatory molecules, such as monocyte chemoattractant protein-1 (MCP-1), and fibrotic factors were also increased at the glomerular level compared with levels in ob/ob mice. At 12 weeks of age, renal damage was fully established. These data suggest an accelerated lesion through glucolipotoxic effects in the renal pathogenesis in POKO mice

  14. Disease progression in patients with single, large-scale mitochondrial DNA deletions.

    PubMed

    Grady, John P; Campbell, Georgia; Ratnaike, Thiloka; Blakely, Emma L; Falkous, Gavin; Nesbitt, Victoria; Schaefer, Andrew M; McNally, Richard J; Gorman, Grainne S; Taylor, Robert W; Turnbull, Doug M; McFarland, Robert

    2014-02-01

    Single, large-scale deletions of mitochondrial DNA are a common cause of mitochondrial disease and cause a broad phenotypic spectrum ranging from mild myopathy to devastating multi-system syndromes such as Kearns-Sayre syndrome. Studies to date have been inconsistent on the value of putative predictors of clinical phenotype and disease progression such as mutation load and the size or location of the deletion. Using a cohort of 87 patients with single, large-scale mitochondrial DNA deletions we demonstrate that a variety of outcome measures such as COX-deficient fibre density, age-at-onset of symptoms and progression of disease burden, as measured by the Newcastle Mitochondrial Disease Adult Scale, are significantly (P < 0.05) correlated with the size of the deletion, the deletion heteroplasmy level in skeletal muscle, and the location of the deletion within the genome. We validate these findings with re-analysis of 256 cases from published data and clarify the previously conflicting information of the value of these predictors, identifying that multiple regression analysis is necessary to understand the effect of these interrelated predictors. Furthermore, we have used mixed modelling techniques to model the progression of disease according to these predictors, allowing a better understanding of the progression over time of this strikingly variable disease. In this way we have developed a new paradigm in clinical mitochondrial disease assessment and management that sidesteps the perennial difficulty of ascribing a discrete clinical phenotype to a broad multi-dimensional and progressive spectrum of disease, establishing a framework to allow better understanding of disease progression.

  15. Enhanced SIV replication and accelerated progression to AIDS in macaques primed to mount a CD4 T cell response to the SIV envelope protein

    PubMed Central

    Staprans, Silvija I.; Barry, Ashley P.; Silvestri, Guido; Safrit, Jeffrey T.; Kozyr, Natalia; Sumpter, Beth; Nguyen, Hanh; McClure, Harold; Montefiori, David; Cohen, Jeffrey I.; Feinberg, Mark B.

    2004-01-01

    Given the dual role of CD4 T cells as both immune effectors and targets for HIV infection, the balance of CD4 versus CD8 T cell-mediated responses induced by candidate AIDS vaccines may be critical in determining postvaccination infection outcomes. An attenuated recombinant varicella-zoster virus vaccine expressing the simian immunodeficiency virus (SIV) envelope (Env) elicited nonneutralizing Env-binding antibodies and little if any cytotoxic T lymphocyte responses in rhesus macaques (Macaca mulatta). After challenge with SIV, Env vaccinees manifested increased levels of SIV replication, more rapid CD4 depletion, and accelerated progression to AIDS compared with controls. Enhanced SIV replication correlated with increased CD4 T cell proliferation soon after SIV challenge, apparently the result of an anamnestic response to SIV antigens. Thus activation of virus-specific CD4 T cells at the time of exposure to a CD4 T cell-tropic lentivirus, in the absence of an effective CD8 response, may enhance virus replication and disease. These data suggest suggest that candidate AIDS vaccines may not simply be either efficacious or neutral; they may also have the potential to be harmful. PMID:15326293

  16. Blinding Trachoma: Systematic Review of Rates and Risk Factors for Progressive Disease

    PubMed Central

    Ramadhani, Athumani M.; Derrick, Tamsyn; Holland, Martin J.; Burton, Matthew J.

    2016-01-01

    Background Sight loss from trachoma is the end result of a scarring disease process starting in early childhood and characterised by repeated episodes of conjunctival inflammation (active trachoma). Subsequently, the conjunctiva becomes scarred, causing the eyelashes to turn inwards and scratch the cornea (trichiasis), damaging the corneal surface and leading to corneal opacification and visual impairment. It is thought that this process is initiated and driven by repeated infection with Chlamydia trachomatis. We review published longitudinal studies to re-examine the disease process, its progression rates and risk factors. Methodology/Principal Findings We searched PubMed for studies presenting incidence and progression data for the different stages of trachoma natural history. We only included studies reporting longitudinal data and identified 11 publications meeting this criterion. The studies were very heterogeneous in design, disease stage, duration, size and location, precluding meta-analysis. Severe conjunctival inflammation was consistently associated with incident and progressive scarring in five studies in which this was examined. One study reported an association between C. trachomatis infection and incident scarring. No studies have yet demonstrated an association between C. trachomatis infection and progressive scarring. Several studies conducted in regions with low prevalence active disease and C. trachomatis infection found evidence of on-going scarring progression. Conclusions/Significance Overall, there are few longitudinal studies that provide estimates of progression rates and risk factors, reflecting the challenges of conducting such studies. Our understanding of this disease process and the long-term impact of control measures is partial. Intense conjunctival inflammation was consistently associated with scarring, however, direct evidence demonstrating an association between C. trachomatis and progression is limited. This suggests that on

  17. Generative FDG-PET and MRI model of aging and disease progression in Alzheimer's disease.

    PubMed

    Dukart, Juergen; Kherif, Ferath; Mueller, Karsten; Adaszewski, Stanislaw; Schroeter, Matthias L; Frackowiak, Richard S J; Draganski, Bogdan

    2013-04-01

    The failure of current strategies to provide an explanation for controversial findings on the pattern of pathophysiological changes in Alzheimer's Disease (AD) motivates the necessity to develop new integrative approaches based on multi-modal neuroimaging data that captures various aspects of disease pathology. Previous studies using [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) and structural magnetic resonance imaging (sMRI) report controversial results about time-line, spatial extent and magnitude of glucose hypometabolism and atrophy in AD that depend on clinical and demographic characteristics of the studied populations. Here, we provide and validate at a group level a generative anatomical model of glucose hypo-metabolism and atrophy progression in AD based on FDG-PET and sMRI data of 80 patients and 79 healthy controls to describe expected age and symptom severity related changes in AD relative to a baseline provided by healthy aging. We demonstrate a high level of anatomical accuracy for both modalities yielding strongly age- and symptom-severity- dependant glucose hypometabolism in temporal, parietal and precuneal regions and a more extensive network of atrophy in hippocampal, temporal, parietal, occipital and posterior caudate regions. The model suggests greater and more consistent changes in FDG-PET compared to sMRI at earlier and the inversion of this pattern at more advanced AD stages. Our model describes, integrates and predicts characteristic patterns of AD related pathology, uncontaminated by normal age effects, derived from multi-modal data. It further provides an integrative explanation for findings suggesting a dissociation between early- and late-onset AD. The generative model offers a basis for further development of individualized biomarkers allowing accurate early diagnosis and treatment evaluation.

  18. The Lymphatic System in Disease Processes and Cancer Progression.

    PubMed

    Padera, Timothy P; Meijer, Eelco F J; Munn, Lance L

    2016-07-11

    Advances in our understanding of the structure and function of the lymphatic system have made it possible to identify its role in a variety of disease processes. Because it is involved not only in fluid homeostasis but also in immune cell trafficking, the lymphatic system can mediate and ultimately alter immune responses. Our rapidly increasing knowledge of the molecular control of the lymphatic system will inevitably lead to new and effective therapies for patients with lymphatic dysfunction. In this review, we discuss the molecular and physiological control of lymphatic vessel function and explore how the lymphatic system contributes to many disease processes, including cancer and lymphedema.

  19. RandomForest4Life: a Random Forest for predicting ALS disease progression.

    PubMed

    Hothorn, Torsten; Jung, Hans H

    2014-09-01

    We describe a method for predicting disease progression in amyotrophic lateral sclerosis (ALS) patients. The method was developed as a submission to the DREAM Phil Bowen ALS Prediction Prize4Life Challenge of summer 2012. Based on repeated patient examinations over a three- month period, we used a random forest algorithm to predict future disease progression. The procedure was set up and internally evaluated using data from 1197 ALS patients. External validation by an expert jury was based on undisclosed information of an additional 625 patients; all patient data were obtained from the PRO-ACT database. In terms of prediction accuracy, the approach described here ranked third best. Our interpretation of the prediction model confirmed previous reports suggesting that past disease progression is a strong predictor of future disease progression measured on the ALS functional rating scale (ALSFRS). We also found that larger variability in initial ALSFRS scores is linked to faster future disease progression. The results reported here furthermore suggested that approaches taking the multidimensionality of the ALSFRS into account promise some potential for improved ALS disease prediction.

  20. Human Herpesviruses as Copathogens of HIV Infection, Their Role in HIV Transmission, and Disease Progression

    PubMed Central

    Munawwar, Arshi; Singh, Sarman

    2016-01-01

    Of eight human herpesviruses (HHVs), often, only herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) find mention in medical literature as both of these viruses are commonly associated with genital lesions and oral ulcers, commonly known as cold sores. However, role of human herpesviruses as copathogens and in aggravation and in the transmission of other human diseases, especially the Acquired immunodeficiency syndrome (HIV/AIDS) has only very recently been recognized. Therefore, screening and treating subclinical HHV infections may offer slowing of HIV infection, disease progression, and its transmission. Beside HSV-1 and HSV-2, HHV-3 a causative agent of herpes zoster remained one of the first manifestations of HIV disease before the era of highly active antiretroviral therapy (HAART). HHV-5 also known as human Cytomegalovirus infection remains a significant risk factor for HIV-associated mortality and morbidity even in HAART era. It is proposed that Cytomegalovirus viremia could be a better predictor of HIV disease progression than CD4+ T-lymphocyte count. The role of HHV-4 or Epstein–Burr virus and HHV-6, HHV-7, and HHV-8 is still being investigated in HIV disease progression. This review provides insight into the current understanding about these 8 HHVs, their co-pathogenesis, and role in HIV/AIDS disease progression. The review also covers recent literature in favor and against administering anti-HHV treatment along with HAART for slower AIDS progression and interrupted sexual transmission. PMID:27013807

  1. TM4SF5 accelerates G1/S phase progression via cytosolic p27Kip1 expression and RhoA activity.

    PubMed

    Kim, Hyeonjung; Kang, Minkyung; Lee, Sin-Ae; Kwak, Tae Kyoung; Jung, Oisun; Lee, Hyo Jeong; Kim, Sung-Hoon; Lee, Jung Weon

    2010-08-01

    Transmembrane 4 L six family member 5 (TM4SF5) causes epithelial-mesenchymal transition (EMT) for aberrant cell proliferation. However, the effects of TM4SF5 expression on cell cycle are unknown so far. In this study, using hepatocytes that either ectopically or endogenously express TM4SF5 and human hepatocarcinoma tissues, the role of TM4SF5 in G1/S phase progression was examined. We found that TM4SF5 expression accelerated G1/S phase progression with facilitated cyclin D1 and E expression and Rb phosphorylation. Furthermore, TM4SF5 enhanced trafficking of CDK4 and cyclin D1 into the nucleus and induced complex formation between them. However, TM4SF5-facilitated G1/S phase progression was blocked by silencing of p27Kip1 using siRNA or by infection of active RhoA. Pharmacological inhibition of ROCK accelerated the G1/S phase progression of control TM4SF5-unexpressing cells. Altogether, these observations suggest that TM4SF5 accelerates G1/S phase progression with facilitated CDK4/cyclin D1 entry into the nucleus, which might be supported by TM4SF5-mediated actin reorganization through cytosolic p27Kip1 expression and Rho GTPase activity.

  2. Synthesis of survival and disease progression outcomes for health technology assessment of cancer therapies.

    PubMed

    Welton, N J; Willis, S R; Ades, A E

    2010-07-01

    Studies of clinical efficacy commonly report more than one clinical endpoint. For example, randomized controlled trials of treatments for cancer will normally report time to disease progression as well as overall survival. It is likely that disease progression will be associated with higher mortality rates. Disease progression rates will also have consequences for the societal economic burden of the disease. Economic evaluation of the cost-effectiveness of different treatment regimes therefore requires the joint estimation of both disease progression and mortality. We describe a model to combine evidence from studies reporting time to event summaries for disease progression and/or mortality, motivated by a systematic review of 1st-line treatment for advanced breast cancer to provide inputs for an economic evaluation as part of the National Institute for Health and Clinical Excellence (NICE) clinical guideline on treatment of advanced breast cancer in England and Wales. The review identified a network of treatment comparisons, which provides the basis for indirect comparison. A variety of outcomes were reported: overall survival, time to progression (overall and responders only), and the proportion of responder, stable, progressive disease, and non-assessable patients. There were only five trials, and not all trials reported all outcomes. The scarcity of the available evidence required us to make strong assumptions in order to identify model parameters. However, this evidence structure often occurs in health technology assessment (HTA) of treatments for cancer. We discuss the validity of the assumptions made, and the potential to assess their validity in other applications of HTA of cancer therapies. Copyright © 2011 John Wiley & Sons, Ltd. PMID:26061469

  3. Optical Assessment of Vascular Disease Progression and Treatment

    NASA Astrophysics Data System (ADS)

    Samuels, Joshua A.

    Vascular disease manifests itself in many different forms, including chronic ulcers which do not heal, impaired blood flow to the limbs, or damage to the natural reperfusion process. The current forms of assessing vascular disease are often subjective and provide incomplete knowledge about the tissue of interest. This work focused on developing non-invasive techniques to quantitatively evaluate three specific elements of vascular disease: diabetic ulcers, venous ulcers, and peripheral arterial disease. Diffuse Near Infrared Spectroscopy (DNIRS) was used to predict healing (82% positive predictive value) in diabetic ulcers after 4 weeks of assessment (sensitivity of 0.9 and specificity of 0.86; p<0.002), proving to be an alternative and superior method to wound size reduction alone (the current gold standard). A novel therapeutic ultrasound treatment for venous ulcers, using a low-frequency (20kHz), low intensity (<100mW/cm2 ISPTP), fully-wearable applicator, was assessed using DNIRS and Diffuse Correlation Spectroscopy (DCS), wherein it was established that capillary flow changes over time in healing venous ulcers compared to wounds which do not heal (p<0.01). It was also determined that the ultrasound therapy was successful at improving wound outcomes, specifically the rate of wound closure per week (p<0.05 for wound size, p<0.01 for optical data). Finally, DNIRS and DCS were used in conjunction to assess the reactive hyperemic response in patients with suspected Peripheral Arterial Disease (PAD). It was found that the time between the release of cuff occlusion in the diseased limb and the first peak of reperfusion (flow mediated dilatation) correlated to PAD severity, with longer times (>30 seconds) belonging to patients with PAD (p<0.05). Additionally, it was discovered that the magnitude of the reperfusion did not relate to PAD, but rather to tobacco use. Patients who smoked had reduced hyperemic responses (p<0.02), whether or not they had PAD. Overall, this

  4. Tobacco Smoking Is Not Associated With Accelerated Liver Disease in Human Immunodeficiency Virus-Hepatitis C Coinfection: A Longitudinal Cohort Analysis

    PubMed Central

    Costiniuk, Cecilia T.; Brunet, Laurence; Rollet-Kurhajec, Kathleen C.; Cooper, Curtis L.; Walmsley, Sharon L.; Gill, M. John; Martel-Laferriere, Valérie; Klein, Marina B.

    2016-01-01

    Background. Tobacco smoking has been shown to be an independent risk factor for liver fibrosis in hepatitis C virus (HCV) infection in some cross-sectional studies. No longitudinal study has confirmed this relationship, and the effect of tobacco exposure on liver fibrosis in human immunodeficiency virus (HIV)-HCV coinfected individuals is unknown. Methods. The study population consisted of participants from the Canadian Co-infection Cohort study (CTN 222), a multicenter longitudinal study of HIV-HCV coinfected individuals from 2003 to 2014. Data were analyzed for all participants who did not have significant fibrosis or end-stage liver disease (ESLD) at baseline. The association between time-updated tobacco exposure (ever vs nonsmokers and pack-years) and progression to significant liver fibrosis (defined as an aspartate-to-platelet ratio index [APRI] ≥1.5) or ESLD was assessed by pooled logistic regression. Results. Of 1072 participants included in the study, 978 (91%) had ever smoked, 817 (76%) were current smokers, and 161 (15%) were previous smokers. Tobacco exposure was not associated with accelerated progression to significant liver fibrosis nor with ESLD when comparing ever vs never smokers (odds ratio [OR] = 1.06, 95% confidence interval [CI], 0.43–1.69 and OR = 1.20, 95% CI, 0.21–2.18, respectively) or increases in pack-years smoked (OR = 1.05, 95% CI, 0.97–1.14 and OR = 0.94, 95% CI, 0.83–1.05, respectively). Both time-updated alcohol use in the previous 6 months and presence of detectable HCV ribonucleic acid were associated with APRI score ≥1.5. Conclusions. Tobacco exposure does not appear to be associated with accelerated progression of liver disease in this prospective study of HIV-HCV coinfected individuals. PMID:27047987

  5. A case of Gaucher's disease progressing to liver cirrhosis.

    PubMed

    Debnath, C R; Debnath, M R; Nabi, N; Khan, N A; Chakraborty, S

    2013-04-01

    We are going to present a 17 year old female with Gaucher's disease. The patient presented with fever, cough, respiratory distress & abdominal heaviness. There was mild pallor, redness of palm of hands & raised temperature. Liver was hugely enlarged along with splenomegaly. X-ray chest showed non specific bronchiectatic change in both lungs. Ultrasonography of abdomen revealed marked hepatosplenomegaly with no ascites. Bone marrow examination showed cellular marrow with plenty of megakaryocytes. Most of the cells were smear cells & there was histiocytes proliferation & infiltration of bone marrow by small atypical cells. Histologically, lipid was found in hepatocytes in moderate amount. The portal areas showed high lipid contents in macrophages. Different clinical findings & incidental diagnosis of lipid storage disease submerged us in diagnostic dilemma. We give conservative treatment with antibiotic cefuroxime, syrup lactulose & vitamins and this patient was improved. PMID:23715368

  6. Fifty communities putting prevention to work: accelerating chronic disease prevention through policy, systems and environmental change.

    PubMed

    Bunnell, Rebecca; O'Neil, Dara; Soler, Robin; Payne, Rebecca; Giles, Wayne H; Collins, Janet; Bauer, Ursula

    2012-10-01

    The burden of preventable chronic diseases is straining our nation's health and economy. Diseases caused by obesity and tobacco use account for the largest portions of this preventable burden. CDC funded 50 communities in 2010 to implement policy, systems, and environmental (PSE) interventions in a 2-year initiative. Funded communities developed PSE plans to reduce obesity, tobacco use, and second-hand smoke exposure for their combined 55 million residents. Community outcome objectives and milestones were categorized by PSE interventions as they related to media, access, promotion, pricing, and social support. Communities estimated population reach based on their jurisdiction's census data and target populations. The average proportion of each community's population that was reached was calculated for each intervention category. Outcome objectives that were achieved within 12 months of program initiation were identified from routine program records. The average proportion of a community's jurisdictional population reached by a specific intervention varied across interventions. Mean population reach for obesity-prevention interventions was estimated at 35%, with 14 (26%) interventions covering over 50% of the jurisdictional populations. For tobacco prevention, mean population reach was estimated at 67%, with 16 (84%) interventions covering more than 50% of the jurisdictional populations. Within 12 months, communities advanced over one-third of their obesity and tobacco-use prevention strategies. Tobacco interventions appeared to have higher potential population reach than obesity interventions within this initiative. Findings on the progress and potential reach of this major initiative may help inform future chronic disease prevention efforts.

  7. Serum lysyl oxidase-like 2 levels and idiopathic pulmonary fibrosis disease progression.

    PubMed

    Chien, Jason W; Richards, Thomas J; Gibson, Kevin F; Zhang, Yingze; Lindell, Kathleen O; Shao, Lixin; Lyman, Susan K; Adamkewicz, Joanne I; Smith, Victoria; Kaminski, Naftali; O'Riordan, Thomas

    2014-05-01

    We evaluated whether lysyl oxidase-like 2 (LOXL2), which promotes cross-linking of collagen in pathological stroma, was detectable in serum from idiopathic pulmonary fibrosis (IPF) patients, and assessed its relationship with IPF disease progression. Patients from the ARTEMIS-IPF (n=69) and the Genomic and Proteomic Analysis of Disease Progression in IPF (GAP) (n=104) studies were analysed. Baseline serum LOXL2 (sLOXL2) levels were compared with baseline clinical and physiological surrogates of disease severity, and the association with IPF disease progression was assessed using a classification and regression tree (CART) method. sLOXL2 correlated weakly with forced vital capacity and carbon monoxide diffusion capacity (r -0.24-0.05) in both cohorts. CART-determined thresholds were similar: ARTEMIS-IPF 800 pg·mL(-1) and GAP 700 pg·mL(-1). In ARTEMIS-IPF, higher sLOXL2 (>800 pg·mL(-1)) was associated with increased risk for disease progression (hazard ratio (HR) 5.41, 95% CI 1.65-17.73). Among GAP subjects with baseline spirometric data (n=70), higher sLOXL2 levels (>700 pg·mL(-1)) were associated with more disease progression events (HR 1.78, 95% CI 1.01-3.11). Among all GAP subjects, higher sLOXL2 levels were associated with increased risk for mortality (HR 2.28, 95% CI 1.18-4.38). These results suggest that higher sLOXL2 levels are associated with increased risk for IPF disease progression. However, due to multiple limitations, these results require validation.

  8. Effects of melatonin on cardiovascular diseases: progress in the past year

    PubMed Central

    Sun, Hang; Gusdon, Aaron M.; Qu, Shen

    2016-01-01

    Purpose of review Melatonin is a neuroendocrine hormone synthesized primarily by the pineal gland. Numerous studies have suggested that melatonin plays an important role in various cardiovascular diseases. In this article, recent progress regarding melatonin's effects on cardiovascular diseases is reviewed. Recent findings In the past year, studies have focused on the mechanism of protection of melatonin on cardiovascular diseases, including myocardial ischemia-reperfusion injury, myocardial hypoxia-reoxygenation injury, pulmonary hypertension, hypertension, atherosclerosis, valvular heart diseases, and other cardiovascular diseases. Summary Studies have demonstrated that melatonin has significant effects on ischemia-reperfusion injury, myocardial chronic intermittent hypoxia injury, pulmonary hypertension, hypertension, valvular heart diseases, vascular diseases, and lipid metabolism. As an inexpensive and well tolerated drug, melatonin may be a new therapeutic option for cardiovascular disease. PMID:27075419

  9. Accelerated Blood Clearance Phenomenon Reduces the Passive Targeting of PEGylated Nanoparticles in Peripheral Arterial Disease.

    PubMed

    Im, Hyung-Jun; England, Christopher G; Feng, Liangzhu; Graves, Stephen A; Hernandez, Reinier; Nickles, Robert J; Liu, Zhuang; Lee, Dong Soo; Cho, Steve Y; Cai, Weibo

    2016-07-20

    Peripheral arterial disease (PAD) is a leading global health concern. Due to limited imaging and therapeutic options, PAD and other ischemia-related diseases may benefit from the use of long circulating nanoparticles as imaging probes and/or drug delivery vehicles. Polyethylene glycol (PEG)-conjugated nanoparticles have shown shortened circulation half-lives in vivo when injected multiple times into a single subject. This phenomenon has become known as the accelerated blood clearance (ABC) effect. The phenomenon is of concern for clinical translation of nanomaterials as it limits the passive accumulation of nanoparticles in many diseases, yet it has not been evaluated using inorganic or organic-inorganic hybrid nanoparticles. Herein, we found that the ABC phenomenon was induced by reinjection of PEGylated long circulating organic-inorganic hybrid nanoparticles, which significantly reduced the passive targeting of (64)Cu-labeled PEGylated reduced graphene oxide-iron oxide nanoparticles ((64)Cu-RGO-IONP-PEG) in a murine model of PAD. Positron emission tomography (PET) imaging was performed at 3, 10, and 17 days postsurgical induction of hindlimb ischemia. At day 3 postsurgery, the nanoparticles displayed a long circulation half-life with enhanced accumulation in the ischemic hindlimb. At days 10 and 17 postsurgery, reinjected mice displayed a short circulation half-life and lower accumulation of the nanoparticles in the ischemic hindlimb, in comparison to the naïve group. Also, reinjected mice showed significantly higher liver uptake than the naïve group, indicating that the nanoparticles experienced higher sequestration by the liver in the reinjected group. Furthermore, photoacoustic (PA) imaging and Prussian blue staining confirmed the enhanced accumulation of the nanoparticles in the liver tissue of reinjected mice. These findings validate the ABC phenomenon using long circulating organic-inorganic hybrid nanoparticles upon multiple administrations to the same

  10. Accelerated Blood Clearance Phenomenon Reduces the Passive Targeting of PEGylated Nanoparticles in Peripheral Arterial Disease.

    PubMed

    Im, Hyung-Jun; England, Christopher G; Feng, Liangzhu; Graves, Stephen A; Hernandez, Reinier; Nickles, Robert J; Liu, Zhuang; Lee, Dong Soo; Cho, Steve Y; Cai, Weibo

    2016-07-20

    Peripheral arterial disease (PAD) is a leading global health concern. Due to limited imaging and therapeutic options, PAD and other ischemia-related diseases may benefit from the use of long circulating nanoparticles as imaging probes and/or drug delivery vehicles. Polyethylene glycol (PEG)-conjugated nanoparticles have shown shortened circulation half-lives in vivo when injected multiple times into a single subject. This phenomenon has become known as the accelerated blood clearance (ABC) effect. The phenomenon is of concern for clinical translation of nanomaterials as it limits the passive accumulation of nanoparticles in many diseases, yet it has not been evaluated using inorganic or organic-inorganic hybrid nanoparticles. Herein, we found that the ABC phenomenon was induced by reinjection of PEGylated long circulating organic-inorganic hybrid nanoparticles, which significantly reduced the passive targeting of (64)Cu-labeled PEGylated reduced graphene oxide-iron oxide nanoparticles ((64)Cu-RGO-IONP-PEG) in a murine model of PAD. Positron emission tomography (PET) imaging was performed at 3, 10, and 17 days postsurgical induction of hindlimb ischemia. At day 3 postsurgery, the nanoparticles displayed a long circulation half-life with enhanced accumulation in the ischemic hindlimb. At days 10 and 17 postsurgery, reinjected mice displayed a short circulation half-life and lower accumulation of the nanoparticles in the ischemic hindlimb, in comparison to the naïve group. Also, reinjected mice showed significantly higher liver uptake than the naïve group, indicating that the nanoparticles experienced higher sequestration by the liver in the reinjected group. Furthermore, photoacoustic (PA) imaging and Prussian blue staining confirmed the enhanced accumulation of the nanoparticles in the liver tissue of reinjected mice. These findings validate the ABC phenomenon using long circulating organic-inorganic hybrid nanoparticles upon multiple administrations to the same

  11. Electrostimulation to reduce synaptic scaling driven progression of Alzheimer's disease.

    PubMed

    Rowan, Mark S; Neymotin, Samuel A; Lytton, William W

    2014-01-01

    Cell death and synapse dysfunction are two likely causes of cognitive decline in AD. As cells die and synapses lose their drive, remaining cells suffer an initial decrease in activity. Neuronal homeostatic synaptic scaling then provides a feedback mechanism to restore activity. This homeostatic mechanism is believed to sense levels of activity-dependent cytosolic calcium within the cell and to adjust neuronal firing activity by increasing the density of AMPA synapses at remaining synapses to achieve balance. The scaling mechanism increases the firing rates of remaining cells in the network to compensate for decreases in network activity. However, this effect can itself become a pathology, as it produces increased imbalance between excitatory and inhibitory circuits, leading to greater susceptibility to further cell loss via calcium-mediated excitotoxicity. Here, we present a mechanistic explanation of how directed brain stimulation might be expected to slow AD progression based on computational simulations in a 470-neuron biomimetic model of a neocortical column. The simulations demonstrate that the addition of low-intensity electrostimulation (neuroprosthesis) to a network undergoing AD-like cell death can raise global activity and break this homeostatic-excitotoxic cascade. The increase in activity within the remaining cells in the column results in lower scaling-driven AMPAR upregulation, reduced imbalances in excitatory and inhibitory circuits, and lower susceptibility to ongoing damage.

  12. Bidirectional Translational Research: Progress in Understanding Addictive Diseases

    PubMed Central

    Kreek, MJ; Schlussman, SD; Reed, B; Zhang, Y; Nielsen, DA; Levran, O; Zhou, Y; Butelman, ER

    2009-01-01

    The focus of this review is primarily on recent developments in bidirectional translational research on the addictions, within the Laboratory of the Biology of Addictive Diseases at The Rockefeller University. This review is subdivided into major interacting aspects, including: a) Investigation of neurobiological and molecular adaptations (e.g., in genes for the opioid receptors or endogenous neuropeptides) in response to cocaine or opiates, administered under laboratory conditions modeling chronic patterns of human self-exposure (e.g., chronic escalating “binge”). b) The impact of such drug exposure on the hypothalamic-pituitary-adrenal (HPA) axis and interacting neuropeptidergic systems (e.g., opioid, orexin and vasopressin). c) Molecular genetic association studies using candidate gene and whole genome approaches, to define particular systems involved in vulnerability to develop specific addictions, and response to pharmacotherapy. d) Neuroendocrine challenge studies in normal volunteers and current addictive disease patients along with former addicts in treatment, to investigate differential pharmacodynamics and responsiveness of molecular targets, in particular those also investigated in the experimental and molecular genetic approaches described above. PMID:18725235

  13. Development assistance for neglected tropical diseases: progress since 2009.

    PubMed

    Liese, Bernhard H; Houghton, Natalia; Teplitskaya, Lyubov

    2014-09-01

    Neglected tropical diseases (NTDs) is an umbrella term for a diverse group of debilitating infections that represent the most common afflictions for 2.7 billion people living on less than US$2 per day. Major efforts have recently re-focused attention on NTDs, including structured advocacy by the Bill and Melinda Gates Foundation, technical and political support by WHO and large-scale drug donation programs by pharmaceutical companies. An analysis of the Official Development Assistance (ODA) for NTDs in 2009 showed that Development Assistance Committee members and multilateral donors had largely ignored funding NTD control projects. This study reviews the changes since 2009 and finds an increased engagement by pharmaceutical manufacturers through drug donation programs substantially increased by the 'London Declaration' in 2012, a focused effort of 77 public and private partners on control or elimination of the 10 most common NTDs, but no increase in ODA for NTDs between 2008 and 2012. The allocation of ODA still does not reflect the respective importance of these diseases.

  14. Prion protein polymorphisms affect chronic wasting disease progression.

    PubMed

    Johnson, Chad J; Herbst, Allen; Duque-Velasquez, Camilo; Vanderloo, Joshua P; Bochsler, Phil; Chappell, Rick; McKenzie, Debbie

    2011-01-01

    Analysis of the PRNP gene in cervids naturally infected with chronic wasting disease (CWD) suggested that PRNP polymorphisms affect the susceptibility of deer to infection. To test this effect, we orally inoculated 12 white-tailed deer with CWD agent. Three different PRNP alleles, wild-type (wt; glutamine at amino acid 95 and glycine at 96), Q95H (glutamine to histidine at amino acid position 95) and G96S (glycine to serine at position 96) were represented in the study cohort with 5 wt/wt, 3 wt/G96S, and 1 each wt/Q95H and Q95H/G96S. Two animals were lost to follow-up due to intercurrent disease. The inoculum was prepared from Wisconsin hunter-harvested homozygous wt/wt animals. All infected deer presented with clinical signs of CWD; the orally infected wt/wt had an average survival period of 693 days post inoculation (dpi) and G96S/wt deer had an average survival period of 956 dpi. The Q95H/wt and Q95H/G96S deer succumbed to CWD at 1,508 and 1,596 dpi respectively. These data show that polymorphisms in the PRNP gene affect CWD incubation period. Deer heterozygous for the PRNP alleles had extended incubation periods with the Q95H allele having the greatest effect.

  15. [Treatment with vitamin D and slowing of progression to severe stage of Alzheimer's disease].

    PubMed

    Chaves, Marcelo; Toral, Ana; Bisonni, Ana; Rojas, Juan I; Fernández, Cecilia; García Basalo, María José; Basallo, María J; Matusevich, Daniel; Cristiano, Edgardo; Golimstok, Angel

    2014-01-01

    The aim of the study was to analyze the impact of treatment with vitamin D in the progression of Alzheimer's disease. We performed a retrospective study including patients with mild stage of Alzheimer's disease with more than four years of follow-up. The presence of cardiovascular risk factors, osteoporosis, treatment with memantine, acetylcholinesterase inhibitors drugs and vitamin D were analyzed as independent variables. Time of progression to moderate and severe Alzheimer's disease was analyzed as dependent variable. The analysis was done using multivariate linear regression model, Kaplan Meier analysis, Chi-square and T test. Two hundred and two patients met the inclusion criteria. 11% of the patients (n = 23) remained in the mild stage of the disease, 54% (n = 110) developed the moderate form in a mean time of 3 ± 1.4 years while 35% (n = 69) developed the severe form in a mean time of 4.6 ± 1.4 years. Time of progression to severe stage of Alzheimer's disease was slower in patients under treatment with vitamin D compared with those without treatment (5.4 ± 0.4 years vs. 4.4 ± 0.16 years respectively, p=0.003). Treatment with vitamin D may be an independent protecting factor in the progression of Alzheimer's disease.

  16. Baseline predictors of renal disease progression in the African American Study of Hypertension and Kidney Disease.

    PubMed

    Norris, Keith C; Greene, Tom; Kopple, Joel; Lea, Janice; Lewis, Julia; Lipkowitz, Mike; Miller, Pete; Richardson, Annie; Rostand, Stephen; Wang, Xuelei; Appel, Lawrence J

    2006-10-01

    Patients with chronic kidney disease have an increased risk for progression to ESRD. The purpose of this study was to examine factors that predict increased risk for adverse renal outcomes. Cox regression was performed to assess the potential of 38 baseline risk factors to predict the clinical renal composite outcome of 50% or 25-ml/min per 1.73 m(2) GFR decline or ESRD among 1094 black patients with hypertensive nephrosclerosis (GFR 20 to 65 ml/min per 1.73 m(2)). Patients were trial participants who had been randomly assigned to one of two BP goals and to one of three antihypertensive regimens and followed for a range of 3 to 6.4 yr. In unadjusted and adjusted analyses, baseline proteinuria was consistently associated with an increased risk for adverse renal outcomes, even at low levels of proteinuria. The relationship of proteinuria with adverse renal outcomes also was evident in analyses that were stratified by level of GFR, which itself was associated with adverse renal outcomes but only at levels <40 ml/min. Other factors that were significantly associated with increased renal events after adjustment for baseline GFR, age, and gender, both with and without adjustment for baseline proteinuria, included serum creatinine, urea nitrogen, and phosphorus. In black patients with hypertensive nephrosclerosis, increased proteinuria, reduced GFR, and elevated levels of serum creatinine, urea nitrogen and phosphorus were directly associated with adverse clinical renal events. These findings identify a subset of this high-risk population that might benefit from even more aggressive treatment.

  17. The Riddle of Nonalcoholic Fatty Liver Disease: Progression From Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis

    PubMed Central

    Sharma, Mithun; Mitnala, Shasikala; Vishnubhotla, Ravi K.; Mukherjee, Rathin; Reddy, Duvvur N.; Rao, Padaki N.

    2015-01-01

    Nonalcoholic fatty liver (NAFL) is an emerging global epidemic which progresses to nonalcoholic steatohepatitis (NASH) and cirrhosis in a subset of subjects. Various reviews have focused on the etiology, epidemiology, pathogenesis and treatment of NAFLD. This review highlights specifically the triggers implicated in disease progression from NAFL to NASH. The integrating role of genes, dietary factors, innate immunity, cytokines and gut microbiome have been discussed. PMID:26155043

  18. The Riddle of Nonalcoholic Fatty Liver Disease: Progression From Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis.

    PubMed

    Sharma, Mithun; Mitnala, Shasikala; Vishnubhotla, Ravi K; Mukherjee, Rathin; Reddy, Duvvur N; Rao, Padaki N

    2015-06-01

    Nonalcoholic fatty liver (NAFL) is an emerging global epidemic which progresses to nonalcoholic steatohepatitis (NASH) and cirrhosis in a subset of subjects. Various reviews have focused on the etiology, epidemiology, pathogenesis and treatment of NAFLD. This review highlights specifically the triggers implicated in disease progression from NAFL to NASH. The integrating role of genes, dietary factors, innate immunity, cytokines and gut microbiome have been discussed.

  19. The Riddle of Nonalcoholic Fatty Liver Disease: Progression From Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis.

    PubMed

    Sharma, Mithun; Mitnala, Shasikala; Vishnubhotla, Ravi K; Mukherjee, Rathin; Reddy, Duvvur N; Rao, Padaki N

    2015-06-01

    Nonalcoholic fatty liver (NAFL) is an emerging global epidemic which progresses to nonalcoholic steatohepatitis (NASH) and cirrhosis in a subset of subjects. Various reviews have focused on the etiology, epidemiology, pathogenesis and treatment of NAFLD. This review highlights specifically the triggers implicated in disease progression from NAFL to NASH. The integrating role of genes, dietary factors, innate immunity, cytokines and gut microbiome have been discussed. PMID:26155043

  20. DiME: A Scalable Disease Module Identification Algorithm with Application to Glioma Progression

    PubMed Central

    Liu, Yunpeng; Tennant, Daniel A.; Zhu, Zexuan; Heath, John K.; Yao, Xin; He, Shan

    2014-01-01

    Disease module is a group of molecular components that interact intensively in the disease specific biological network. Since the connectivity and activity of disease modules may shed light on the molecular mechanisms of pathogenesis and disease progression, their identification becomes one of the most important challenges in network medicine, an emerging paradigm to study complex human disease. This paper proposes a novel algorithm, DiME (Disease Module Extraction), to identify putative disease modules from biological networks. We have developed novel heuristics to optimise Community Extraction, a module criterion originally proposed for social network analysis, to extract topological core modules from biological networks as putative disease modules. In addition, we have incorporated a statistical significance measure, B-score, to evaluate the quality of extracted modules. As an application to complex diseases, we have employed DiME to investigate the molecular mechanisms that underpin the progression of glioma, the most common type of brain tumour. We have built low (grade II) - and high (GBM) - grade glioma co-expression networks from three independent datasets and then applied DiME to extract potential disease modules from both networks for comparison. Examination of the interconnectivity of the identified modules have revealed changes in topology and module activity (expression) between low- and high- grade tumours, which are characteristic of the major shifts in the constitution and physiology of tumour cells during glioma progression. Our results suggest that transcription factors E2F4, AR and ETS1 are potential key regulators in tumour progression. Our DiME compiled software, R/C++ source code, sample data and a tutorial are available at http://www.cs.bham.ac.uk/~szh/DiME. PMID:24523864

  1. Mining Patterns of Disease Progression: A Topic-Model-Based Approach.

    PubMed

    Zhang, Lingxiao; Zhao, Junfeng; Wang, Yasha; Xie, Bing

    2016-01-01

    Knowledge of how diseases progress and transform is crucial for clinical decision making. Frequent pattern mining techniques, such as sequential pattern mining (SPM) algorithms, can automatically extract such knowledge from large collections of electronic medical records (EMR). However, EMR data are usually unorganized and highly noisy. Finding meaningful disease patterns often calls for manual manipulation such as cohort and feature selection on EMR data by medical professionals. In this paper, we propose a topic-model-based SPM approach to find disease progression patterns from diagnostic records. We improve the traditional SPM algorithms by filtering and grouping the diagnosis sequences according to different clinical topics. These topics represent certain clinical conditions with closely related diagnoses, and are detected without prior medical knowledge. The experiment on real-world EMR data shows that our approach is able to find meaningful progression patterns with less noises, and can help quickly identify interesting patterns related to a certain clinical condition with less human effort. PMID:27577403

  2. Wall Shear Stress Characteristics for the Progression of the Disease, Atherosclerosis

    NASA Astrophysics Data System (ADS)

    Goswami, P.; Mandal, D. K.; Manna, N. K.; Chakrabarti, S.

    2014-12-01

    Wall shear stress (WSS) characteristics of a stenosed artery which are the important physiological parameters for the progression of the arterial diseases atherosclerosis, are studied and compared for different Reynolds numbers and different Womersley numbers. Numerical simulations of physiological pulsatile flow through a model stenotic artery are performed by finite volume method. From this study, it is revealed that the chance of formation of atherosclerosis increases with increase in Reynolds number and decreases with increase in Womersley number. The phenomenon of mass transportation across arterial wall is more in case of increase in Womersley number rather than Reynolds number. The chance of formation of atheromatous plaque will be high with higher Reynolds number and Womersley number. In the low WSS region, high magnitude of Womersley number indicates high chance of progression of the disease atherosclerosis. High magnitude of Womersley number with low Reynolds number is more dangerous for the progression of the disease in the low WSS region.

  3. HIV-specific CD8+ T-cell proliferation is prospectively associated with delayed disease progression.

    PubMed

    McKinnon, Lyle R; Kaul, Rupert; Kimani, Joshua; Nagelkerke, Nico J; Wachihi, Charles; Fowke, Keith R; Ball, Terry Blake; Plummer, Francis A

    2012-03-01

    Human immunodeficiency virus (HIV)-specific CD8(+) T-cell proliferation is consistently correlated with enhanced host HIV immune control, but whether proliferative responses are a cause or consequence of immune protection is unclear. We measured Env-specific CD8(+) T-cell proliferation and interferon (IFN)-γ secretion in HIV-infected participants with CD4 counts >200, who then completed 121 person-years of prospective follow-up to monitor HIV disease progression. In all, 13 of 31 participants (42%) reached end point during longitudinal follow-up. Strong Env-specific CD8(+) T-cell proliferation (>10% of CD8(+) T cells) was observed in 14/31 participants at baseline, and this was associated with a longer time to HIV disease progression end point, stratified baseline CD4 count (P=0.016). No associations were observed for IFN-γ ELISPOT responses and progression (P>0.2). Strong proliferation remained significant in multivariate Cox regression analyses (P=0.044) as an independent predictor of delayed HIV disease progression, along with baseline CD4 count (P=0.04). Duration of HIV infection was associated with more rapid progression in univariate, but not multivariate, analysis (P=0.112). Age and baseline viral load were not predictive of progression. HIV-specific CD8(+) T-cell proliferation was a correlate of protective immunity in this prospective study; such responses may be important for HIV vaccine protection.

  4. Osteoarthritis disease progression model using six year follow-up data from the osteoarthritis initiative.

    PubMed

    Passey, Chaitali; Kimko, Holly; Nandy, Partha; Kagan, Leonid

    2015-03-01

    The objective was to develop a quantitative model of disease progression of knee osteoarthritis over 6 years using the total WOMAC score from patients enrolled into the Osteoarthritis Initiative (OAI) study. The analysis was performed using data from the Osteoarthritis Initiative database. The time course of the total WOMAC score of patients enrolled into the progression cohort was characterized using non-linear mixed effect modeling in NONMEM. The effect of covariates on the status of the disease and the progression rate was investigated. The final model provided a good description of the experimental data using a linear progression model with a common baseline (19 units of the total WOMAC score). The WOMAC score decreased by 1.77 units/year in 89% of the population or increased by 1.74 units/year in 11% of the population. Multiple covariates were found to affect the baseline and the rate of progression, including BMI, sex, race, the use of pain medications, and the limitation in activity due to symptoms. A mathematical model to describe the disease progression of osteoarthritis in the studied population was developed. The model identified two sub-populations with increasing or decreasing total WOMAC score over time, and the effect of important covariates was quantified.

  5. Minimally invasive treatment of Peyronie's disease: evidence-based progress.

    PubMed

    Jordan, Gerald H; Carson, Culley C; Lipshultz, Larry I

    2014-07-01

    Peyronie's disease (PD) is often physically and psychologically devastating for patients, and the goal of treatment is to improve symptoms and sexual function without adding treatment-related morbidity. The potential for treatment-related morbidity after more invasive interventions, e.g. surgery, creates a need for effective minimally invasive treatments. We critically examined the available literature using levels of evidence to determine the reported support for each treatment. Most available minimally invasive treatments lack critical support for effectiveness due to the absence of randomised, placebo-controlled trials (RCTs) or non-significant results after RCTs. Iontophoresis, oral therapies (vitamin E, potassium para-aminobenzoate, tamoxifen, carnitine, and colchicine), extracorporeal shockwave therapy, and intralesional injection with verapamil or nicardipine have shown mixed or negative results. Treatments that have decreased penile curvature deformity in Level 1 or Level 2 evidence-based, placebo-controlled studies include intralesional injection with interferon α-2b or collagenase clostridium histolyticum.

  6. PHD2: from hypoxia regulation to disease progression

    PubMed Central

    Meneses, Ana M; Wielockx, Ben

    2016-01-01

    Oxygen represents one of the major molecules required for the development and maintenance of life. An adequate response to hypoxia is therefore required for the functioning of the majority of living organisms and relies on the activation of the hypoxia-inducible factor (HIF) pathway. HIF prolyl hydroxylase domain-2 (PHD2) has long been recognized as the major regulator of this response, controlling a myriad of outcomes that range from cell death to proliferation. However, this enzyme has been associated with more pathways, making the role of this protein remarkably complex under distinct pathologies. While a protective role seems to exist in physiological conditions such as erythropoiesis; the picture is more complex during pathologies such as cancer. Since the regulation of this enzyme and its closest family members is currently considered as a possible therapy for various diseases, understanding the different particular roles of this protein is essential. PMID:27800508

  7. Hepatic inflammation and progressive liver fibrosis in chronic liver disease

    PubMed Central

    Czaja, Albert J

    2014-01-01

    Chronic liver inflammation drives hepatic fibrosis, and current immunosuppressive, anti-inflammatory, and anti-viral therapies can weaken this driver. Hepatic fibrosis is reversed, stabilized, or prevented in 57%-79% of patients by conventional treatment regimens, mainly by their anti-inflammatory actions. Responses, however, are commonly incomplete and inconsistently achieved. The fibrotic mechanisms associated with liver inflammation have been clarified, and anti-fibrotic agents promise to improve outcomes as adjunctive therapies. Hepatitis C virus and immune-mediated responses can activate hepatic stellate cells by increasing oxidative stress within hepatocytes. Angiotensin can be synthesized by activated hepatic stellate cells and promote the production of reactive oxygen species. Anti-oxidants (N-acetylcysteine, S-adenosyl-L-methionine, and vitamin E) and angiotensin inhibitors (losartin) have had anti-fibrotic actions in preliminary human studies, and they may emerge as supplemental therapies. Anti-fibrotic agents presage a new era of supplemental treatment for chronic liver disease. PMID:24627588

  8. Apoptosis as a Mechanism for Liver Disease Progression

    PubMed Central

    Guicciardi, Maria Eugenia; Gores, Gregory J.

    2011-01-01

    Hepatocyte injury is ubiquitous in clinical practice, and the mode of cell death associated with this injury is often apoptosis, especially by death receptors. Information from experimental systems demonstrates that hepatocyte apoptosis is sufficient to cause liver hepatic fibrogenesis. The mechanisms linking hepatocyte apoptosis to hepatic fibrosis remain incompletely understood, but likely relate to engulfment of apoptotic bodies by professional phagocytic cells and stellate cells, and release of mediators by cells undergoing apoptosis. Inhibition of apoptosis with caspase inhibitors has demonstrated beneficial effects in murine models of hepatic fibrosis. Recent studies implicating Toll-like receptor 9 (TLR9) in liver injury and fibrosis are also of particular interest. Engulfment of apoptotic bodies is one mechanism by which the TLR9 ligand (CpG DNA motifs) could be delivered to this intracellular receptor. These concepts suggest therapy focused on interrupting the cellular mechanisms linking apoptosis to fibrosis would be useful in human liver diseases. PMID:20960379

  9. Progress on conformal microwave array applicators for heating chestwall disease

    NASA Astrophysics Data System (ADS)

    Stauffer, P. R.; Maccarini, P. F.; Juang, T.; Jacobsen, S. K.; Gaeta, C. J.; Schlorff, J. L.; Milligan, A. J.

    2007-02-01

    Previous studies have reported the computer modeling, CAD design, and theoretical performance of single and multiple antenna arrays of Dual Concentric Conductor (DCC) square slot radiators driven at 915 and 433 MHz. Subsequently, practical CAD designs of microstrip antenna arrays constructed on thin and flexible printed circuit board (PCB) material were reported which evolved into large Conformal Microwave Array (CMA) sheets that could wrap around the surface of the human torso for delivering microwave energy to large areas of superficial tissue. Although uniform and adjustable radiation patterns have been demonstrated from multiple element applicators radiating into simple homogeneous phantom loads, the contoured and heterogeneous tissue loads typical of chestwall recurrent breast cancer have required additional design efforts to achieve good coupling and efficient heating from the increasingly larger conformal array applicators used to treat large area contoured patient anatomy. Thus recent work has extended the theoretical optimization of DCC antennas to improve radiation efficiency of each individual aperture and reduce mismatch reflections, radiation losses, noise, and cross coupling of the feedline distribution network of large array configurations. Design improvements have also been incorporated into the supporting bolus structure to maintain effective coupling of DCC antennas into contoured anatomy and to monitor and control surface temperatures under the entire array. New approaches for non-invasive monitoring of surface and sub-surface tissue temperatures under each independent heat source are described that make use of microwave radiometry and flexible sheet grid arrays of thermal sensors. Efforts to optimize the clinical patient interface and move from planar rectangular shapes to contoured vest applicators that accommodate entire disease in a larger number of patients are summarized. By applying heat more uniformly to large areas of contoured anatomy

  10. TWEAK and the progression of renal disease: clinical translation.

    PubMed

    Sanz, Ana B; Izquierdo, M Concepcion; Sanchez-Niño, Maria Dolores; Ucero, Alvaro C; Egido, Jesus; Ruiz-Ortega, Marta; Ramos, Adrián Mario; Putterman, Chaim; Ortiz, Alberto

    2014-02-01

    Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) activates the fibroblast growth factor-inducible-14 (Fn14) receptor. TWEAK has actions on intrinsic kidney cells and on inflammatory cells of potential pathophysiological relevance. The effects of TWEAK in tubular cells have been explored in most detail. In cultured murine tubular cells TWEAK induces the expression of inflammatory cytokines, downregulates the expression of Klotho, is mitogenic, and in the presence of sensitizing agents promotes apoptosis. Similar actions were observed on glomerular mesangial cells. In vivo TWEAK actions on healthy kidneys mimic cell culture observations. Increased expression of TWEAK and Fn14 was reported in human and experimental acute and chronic kidney injury. The role of TWEAK/Fn14 in kidney injury has been demonstrated in non-inflammatory compensatory renal growth, acute kidney injury and chronic kidney disease of immune and non-immune origin, including hyperlipidaemic nephropathy, lupus nephritis (LN) and anti-GBM nephritis. The nephroprotective effect of TWEAK or Fn14 targeting in immune-mediated kidney injury is the result of protection from TWEAK-induced injury of renal intrinsic cells, not from interference with the immune response. A phase I dose-ranging clinical trial demonstrated the safety of anti-TWEAK antibodies in humans. A phase II randomized placebo-controlled clinical trial exploring the efficacy, safety and tolerability of neutralizing anti-TWEAK antibodies as a tissue protection strategy in LN is ongoing. The eventual success of this trial may expand the range of kidney diseases in which TWEAK targeting should be explored.

  11. B-Cell Depletion Salvage Therapy in Rapidly Progressive Dermatomyositis Related Interstitial Lung Disease.

    PubMed

    Eissa, Khaled; Palomino, Jaime

    2016-01-01

    Interstitial lung disease (ILD) is a major cause of morbidity and mortality in patients with idiopathic inflammatory myopathies (IIM). Glucocorticoids are the initial standard treatment. However, many patients fail to respond and continue to progress despite treatment with high dose glucocorticoids. The efficacy of rituximab has been suggested in case reports and case series of refractory antisynthetase (AS) syndrome, but data on patients without auto-antibodies or with rapidly progressive ILD are scarce. We report a case of rapidly progressive dermatomyositis (DM) associated ILD treated successfully with B-cell depletion therapy. PMID:27389378

  12. Quantitative EEG parameters correlate with the progression of human prion diseases

    PubMed Central

    Wehner, Tim; Lowe, Jessica; Porter, Marie-Claire; Kenny, Joanna; Thompson, Andrew; Rudge, Peter; Collinge, John; Mead, Simon

    2016-01-01

    Background Prion diseases are universally fatal and often rapidly progressive neurodegenerative diseases. EEG has long been used in the diagnosis of sporadic Creutzfeldt-Jakob disease; however, the characteristic waveforms do not occur in all types of prion diseases. Here, we re-evaluate the utility of EEG by focusing on the development of biomarkers. We test whether abnormal quantitative EEG parameters can be used to measure disease progression in prion diseases or predict disease onset in healthy individuals at risk of disease. Methods In the National Prion Monitoring Cohort study, we did quantitative encephalography on 301 occasions in 29 healthy controls and 67 patients with prion disease. The patients had either inherited prion disease or sporadic Creutzfeldt-Jakob disease. We computed the main background frequency, the α and θ power and the α/θ power ratio, then averaged these within 5 electrode groups. These measurements were then compared among participant groups and correlated with functional and cognitive scores cross-sectionally and longitudinally. Results We found lower main background frequency, α power and α/θ power ratio and higher θ power in patients compared to control participants. The main background frequency, the power in the α band and the α/θ power ratio also differed in a consistent way among the patient groups. Moreover, the main background frequency and the α/θ power ratio correlated significantly with functional and cognitive scores. Longitudinally, change in these parameters also showed significant correlation with the change in clinical and cognitive scores. Conclusions Our findings support the use of quantitative EEG to follow the progression of prion disease, with potential to help evaluate the treatment effects in future clinical-trials. PMID:27413165

  13. Enzyme replacement therapy attenuates disease progression in a canine model of late-infantile neuronal ceroid lipofuscinosis (CLN2 disease)

    PubMed Central

    Katz, Martin L; Coates, Joan R; Sibigtroth, Christine M; Taylor, Jacob D; Carpentier, Melissa; Young, Whitney M; Wininger, Fred A; Kennedy, Derek; Vuillemenot, Brian R; O'Neill, Charles A

    2014-01-01

    Using a canine model of classical late-infantile neuronal ceroid lipofuscinosis (CLN2 disease), a study was conducted to evaluate the potential pharmacological activity of recombinant human tripeptidyl peptidase-1 (rhTPP1) enzyme replacement therapy administered directly to the cerebrospinal fluid (CSF). CLN2 disease is a hereditary neurodegenerative disorder resulting from mutations in CLN2, which encodes the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Infants with mutations in both CLN2 alleles develop normally but in the late-infantile/early-childhood period undergo progressive neurological decline accompanied by pronounced brain atrophy. The disorder, a form of Batten disease, is uniformly fatal, with clinical signs starting between 2 and 4 years of age and death usually occurring by the early teenage years. Dachshunds homozygous for a null mutation in the canine ortholog of CLN2 (TPP1) exhibit a similar disorder that progresses to end stage at 10.5–11 months of age. Administration of rhTPP1 via infusion into the CSF every other week, starting at approximately 2.5 months of age, resulted in dose-dependent significant delays in disease progression, as measured by delayed onset of neurologic deficits, improved performance on a cognitive function test, reduced brain atrophy, and increased life span. Based on these findings, a clinical study evaluating the potential therapeutic value of rhTPP1 administration into the CSF of children with CLN2 disease has been initiated. PMID:24938720

  14. Enzyme replacement therapy attenuates disease progression in a canine model of late-infantile neuronal ceroid lipofuscinosis (CLN2 disease).

    PubMed

    Katz, Martin L; Coates, Joan R; Sibigtroth, Christine M; Taylor, Jacob D; Carpentier, Melissa; Young, Whitney M; Wininger, Fred A; Kennedy, Derek; Vuillemenot, Brian R; O'Neill, Charles A

    2014-11-01

    Using a canine model of classical late-infantile neuronal ceroid lipofuscinosis (CLN2 disease), a study was conducted to evaluate the potential pharmacological activity of recombinant human tripeptidyl peptidase-1 (rhTPP1) enzyme replacement therapy administered directly to the cerebrospinal fluid (CSF). CLN2 disease is a hereditary neurodegenerative disorder resulting from mutations in CLN2, which encodes the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Infants with mutations in both CLN2 alleles develop normally but in the late-infantile/early-childhood period undergo progressive neurological decline accompanied by pronounced brain atrophy. The disorder, a form of Batten disease, is uniformly fatal, with clinical signs starting between 2 and 4 years of age and death usually occurring by the early teenage years. Dachshunds homozygous for a null mutation in the canine ortholog of CLN2 (TPP1) exhibit a similar disorder that progresses to end stage at 10.5-11 months of age. Administration of rhTPP1 via infusion into the CSF every other week, starting at approximately 2.5 months of age, resulted in dose-dependent significant delays in disease progression, as measured by delayed onset of neurologic deficits, improved performance on a cognitive function test, reduced brain atrophy, and increased life span. Based on these findings, a clinical study evaluating the potential therapeutic value of rhTPP1 administration into the CSF of children with CLN2 disease has been initiated.

  15. Renal Gene and Protein Expression Signatures for Prediction of Kidney Disease Progression

    PubMed Central

    Ju, Wenjun; Eichinger, Felix; Bitzer, Markus; Oh, Jun; McWeeney, Shannon; Berthier, Celine C.; Shedden, Kerby; Cohen, Clemens D.; Henger, Anna; Krick, Stefanie; Kopp, Jeffrey B.; Stoeckert, Christian J.; Dikman, Steven; Schröppel, Bernd; Thomas, David B.; Schlondorff, Detlef; Kretzler, Matthias; Böttinger, Erwin P.

    2009-01-01

    Although chronic kidney disease (CKD) is common, only a fraction of CKD patients progress to end-stage renal disease. Molecular predictors to stratify CKD populations according to their risk of progression remain undiscovered. Here we applied transcriptional profiling of kidneys from transforming growth factor-β1 transgenic (Tg) mice, characterized by heterogeneity of kidney disease progression, to identify 43 genes that discriminate kidneys by severity of glomerular apoptosis before the onset of tubulointerstitial fibrosis in 2-week-old animals. Among the genes examined, 19 showed significant correlation between mRNA expression in uninephrectomized left kidneys at 2 weeks of age and renal disease severity in right kidneys of Tg mice at 4 weeks of age. Gene expression profiles of human orthologs of the 43 genes in kidney biopsies were highly significantly related (R2 = 0.53; P < 0.001) to the estimated glomerular filtration rates in patients with CKD stages I to V, and discriminated groups of CKD stages I/II and III/IV/V with positive and negative predictive values of 0.8 and 0.83, respectively. Protein expression patterns for selected genes were successfully validated by immunohistochemistry in kidneys of Tg mice and kidney biopsies of patients with IgA nephropathy and CKD stages I to V, respectively. In conclusion, we developed novel mRNA and protein expression signatures that predict progressive renal fibrosis in mice and may be useful molecular predictors of CKD progression in humans. PMID:19465643

  16. Multivariate clustering of progression profiles reveals different depression patterns in prodromal Huntington disease

    PubMed Central

    Kim, Ji-in; Long, Jeffrey D.; Mills, James A.; McCusker, Elizabeth; Paulsen, Jane S.

    2015-01-01

    Objective Although Huntington disease (HD) is caused by an autosomal dominant mutation, its phenotypic presentation differs widely. Variability in clinical phenotypes of HD may reflect the existence of disease subtypes. This hypothesis was tested in prodromal participants from the longitudinal Neurobiological Predictors of Huntington's Disease (PREDICT-HD) study. Method We performed clustering using longitudinal data assessing motor, cognitive, and depression symptoms. Using data from 521 participants with 2716 data points, we fit growth mixture models (GMM) that identify groups based on multivariate trajectories. Results In various GMM, different phases of disease progression were partitioned by progression trajectories of motor and cognitive signs, and by overall level of depression symptoms. More progressed motor signs were accompanied by more progressed cognitive signs, but not always by higher levels of depressive symptoms. In several models, there were at least two groups with similar trajectories for motor and cognitive signs that showed different levels for depression symptoms - one with a very low level of depression and the other with a higher level of depression. Conclusions Findings indicate that at least intermediate HD progression might be associated with different levels of depression. Depression is one of the few symptoms that is treatable in HD and has implications for clinical care. Identification of potential depression subtypes may also help to select appropriate patients for clinical trials. PMID:26011117

  17. Coronary leukocyte activation in relation to progression of coronary artery disease.

    PubMed

    de Vries, Marijke A; Alipour, Arash; Birnie, Erwin; Westzaan, Andrew; van Santen, Selvetta; van der Zwan, Ellen; Liem, Anho H; van der Meulen, Noëlle; Cabezas, Manuel Castro

    2016-03-01

    Leukocyte activation has been linked to atherogenesis, but there is little in vivo evidence for its role in the progression of atherosclerosis. We evaluated the predictive value for progression of coronary artery disease (CAD) of leukocyte activation markers in the coronary circulation. Monocyte and neutrophil CD11b, neutrophil CD66b expression and intracellular neutrophil myeloperoxidase (MPO) in the coronary arteries were determined by flow cytometry in patients undergoing coronary angiography. The primary outcome included fatal and nonfatal myocardial infarction or arterial vascular intervention due to unstable angina pectoris. In total 99 subjects who were included, 70 had CAD at inclusion (26 patients had single-vessel disease, 18 patients had twovessel disease and 26 patients had three-vessel disease). The median follow-up duration was 2242 days (interquartile range: 2142-2358). During follow-up, 13 patients (13%) developed progression of CAD. Monocyte CD11b, neutrophil CD11b and CD66b expression and intracellular MPO measured in blood obtained from the coronary arteries were not associated with the progression of CAD. These data indicate that coronary monocyte CD11b, neutrophil CD11b and CD66b expression and intracellular MPO do not predict the risk of progression of CAD. PMID:26831871

  18. Nutrition-sensitive interventions and programmes: how can they help to accelerate progress in improving maternal and child nutrition?

    PubMed

    Ruel, Marie T; Alderman, Harold

    2013-08-10

    Acceleration of progress in nutrition will require effective, large-scale nutrition-sensitive programmes that address key underlying determinants of nutrition and enhance the coverage and effectiveness of nutrition-specific interventions. We reviewed evidence of nutritional effects of programmes in four sectors--agriculture, social safety nets, early child development, and schooling. The need for investments to boost agricultural production, keep prices low, and increase incomes is undisputable; targeted agricultural programmes can complement these investments by supporting livelihoods, enhancing access to diverse diets in poor populations, and fostering women's empowerment. However, evidence of the nutritional effect of agricultural programmes is inconclusive--except for vitamin A from biofortification of orange sweet potatoes--largely because of poor quality evaluations. Social safety nets currently provide cash or food transfers to a billion poor people and victims of shocks (eg, natural disasters). Individual studies show some effects on younger children exposed for longer durations, but weaknesses in nutrition goals and actions, and poor service quality probably explain the scarcity of overall nutritional benefits. Combined early child development and nutrition interventions show promising additive or synergistic effects on child development--and in some cases nutrition--and could lead to substantial gains in cost, efficiency, and effectiveness, but these programmes have yet to be tested at scale. Parental schooling is strongly associated with child nutrition, and the effectiveness of emerging school nutrition education programmes needs to be tested. Many of the programmes reviewed were not originally designed to improve nutrition yet have great potential to do so. Ways to enhance programme nutrition-sensitivity include: improve targeting; use conditions to stimulate participation; strengthen nutrition goals and actions; and optimise women's nutrition, time

  19. Nutrition-sensitive interventions and programmes: how can they help to accelerate progress in improving maternal and child nutrition?

    PubMed

    Ruel, Marie T; Alderman, Harold

    2013-08-10

    Acceleration of progress in nutrition will require effective, large-scale nutrition-sensitive programmes that address key underlying determinants of nutrition and enhance the coverage and effectiveness of nutrition-specific interventions. We reviewed evidence of nutritional effects of programmes in four sectors--agriculture, social safety nets, early child development, and schooling. The need for investments to boost agricultural production, keep prices low, and increase incomes is undisputable; targeted agricultural programmes can complement these investments by supporting livelihoods, enhancing access to diverse diets in poor populations, and fostering women's empowerment. However, evidence of the nutritional effect of agricultural programmes is inconclusive--except for vitamin A from biofortification of orange sweet potatoes--largely because of poor quality evaluations. Social safety nets currently provide cash or food transfers to a billion poor people and victims of shocks (eg, natural disasters). Individual studies show some effects on younger children exposed for longer durations, but weaknesses in nutrition goals and actions, and poor service quality probably explain the scarcity of overall nutritional benefits. Combined early child development and nutrition interventions show promising additive or synergistic effects on child development--and in some cases nutrition--and could lead to substantial gains in cost, efficiency, and effectiveness, but these programmes have yet to be tested at scale. Parental schooling is strongly associated with child nutrition, and the effectiveness of emerging school nutrition education programmes needs to be tested. Many of the programmes reviewed were not originally designed to improve nutrition yet have great potential to do so. Ways to enhance programme nutrition-sensitivity include: improve targeting; use conditions to stimulate participation; strengthen nutrition goals and actions; and optimise women's nutrition, time

  20. Salt intake, endothelial cell signaling, and progression of kidney disease.

    PubMed

    Sanders, Paul W

    2004-02-01

    It has been known for decades that increased dietary intake of salt (NaCl) shortens the life span of rats in a dose-dependent fashion. This review focuses specifically on the recently described biological effect and consequences of increased salt ingestion on the endothelium through a mechanism that is independent of blood pressure. Changes in salt intake are recognized by endothelial cells in the vascular tree and glomeruli through a physical process that promotes a series of signaling events involved in transcriptional regulation of genes that include transforming growth factor-beta1 (TGF-beta1) and the endothelial isoform of nitric oxide synthase (NOS3). A balance is struck between TGF-beta1 and NOS3 as salt intake varies and creates a negative feedback loop, because TGF-beta1 increased expression of NOS3 and NO inhibited production of TGF-beta1 in healthy rats. Changes in this feedback system have been observed in salt-sensitive hypertension and appear to impact end-organ damage, particularly the kidney. The data support an important benefit to reduction of salt intake in the setting of chronic kidney disease.

  1. Ebolavirus Vaccines: Progress in the Fight Against Ebola Virus Disease.

    PubMed

    Wu, Xiao-Xin; Yao, Hang-Ping; Wu, Nan-Ping; Gao, Hai-Nv; Wu, Hai-Bo; Jin, Chang-Zhong; Lu, Xiang-Yun; Xie, Tian-Shen; Li, Lan-Juan

    2015-01-01

    Ebolaviruses are highly infectious pathogens that cause lethal Ebola virus disease (EVD) in humans and non-human primates (NHPs). Due to their high pathogenicity and transmissibility, as well as the potential to be misused as a bioterrorism agent, ebolaviruses would threaten the health of global populations if not controlled. In this review, we describe the origin and structure of ebolaviruses and the development of vaccines from the beginning of the 1980s, including conventional ebolavirus vaccines, DNA vaccines, Ebola virus-like particles (VLPs), vaccinia virus-based vaccines, Venezuelan equine encephalitis virus (VEEV)-like replicon particles, Kunjin virus-based vaccine, recombinant Zaire Ebolavirusx2206;VP30, recombinant cytomegalovirus (CMV)-based vaccines, recombinant rabies virus (RABV)-based vaccines, recombinant paramyxovirus-based vaccines, adenovirus-based vaccines and vesicular stomatitis virus (VSV)-based vaccines. No licensed vaccine or specific treatment is currently available to counteract ebolavirus infection, although DNA plasmids and several viral vector approaches have been evaluated as promising vaccine platforms. These vaccine candidates have been confirmed to be successful in protecting NHPs against lethal infection. Moreover, these vaccine candidates were successfully advanced to clinical trials. The present review provides an update of the current research on Ebola vaccines, with the aim of providing an overview on current prospects in the fight against EVD.

  2. Ebolavirus Vaccines: Progress in the Fight Against Ebola Virus Disease.

    PubMed

    Wu, Xiao-Xin; Yao, Hang-Ping; Wu, Nan-Ping; Gao, Hai-Nv; Wu, Hai-Bo; Jin, Chang-Zhong; Lu, Xiang-Yun; Xie, Tian-Shen; Li, Lan-Juan

    2015-01-01

    Ebolaviruses are highly infectious pathogens that cause lethal Ebola virus disease (EVD) in humans and non-human primates (NHPs). Due to their high pathogenicity and transmissibility, as well as the potential to be misused as a bioterrorism agent, ebolaviruses would threaten the health of global populations if not controlled. In this review, we describe the origin and structure of ebolaviruses and the development of vaccines from the beginning of the 1980s, including conventional ebolavirus vaccines, DNA vaccines, Ebola virus-like particles (VLPs), vaccinia virus-based vaccines, Venezuelan equine encephalitis virus (VEEV)-like replicon particles, Kunjin virus-based vaccine, recombinant Zaire Ebolavirusx2206;VP30, recombinant cytomegalovirus (CMV)-based vaccines, recombinant rabies virus (RABV)-based vaccines, recombinant paramyxovirus-based vaccines, adenovirus-based vaccines and vesicular stomatitis virus (VSV)-based vaccines. No licensed vaccine or specific treatment is currently available to counteract ebolavirus infection, although DNA plasmids and several viral vector approaches have been evaluated as promising vaccine platforms. These vaccine candidates have been confirmed to be successful in protecting NHPs against lethal infection. Moreover, these vaccine candidates were successfully advanced to clinical trials. The present review provides an update of the current research on Ebola vaccines, with the aim of providing an overview on current prospects in the fight against EVD. PMID:26535889

  3. [Research Progress in Black Queen Cell Virus Causing Disease].

    PubMed

    Yang, Qian; Zhang, Jian; Song, Zhanyun; Zheng, Yan; Wang, Xianghui; Sui, Jiachen; Wang, Zhenguo; Mou, Jun

    2015-05-01

    In nature, honeybees are the most important pollinators. They play a vital role in both protecting the diversity of natural ecosystems, and maintaining the yield-improving effects of agroecosystems. But in recent years, epidemic disease in bees has caused huge losses. Black Queen Cell Virus (BQCV) is a bee pathogen that was first reported in 1955. It mainly infects bee larvae and pupae, making their bodies turn dark and black, and causing a massive decrease in the bee population. More specifically, the virus makes the exterior of the cell walls in the larvae and pupae turn black. BQCV is a seasonal epidemic, spread by means horizontal and vertical transmission, and is often unapparent. BQCV not only infects a variety of bee species, but also spiders, centipedes and other arthropods. It can also be coinfected with other honeybee viruses. In recent years, research has shown that the Nosema intestinal parasite plays an important role in BQCV transmission and bees carrying Nosema that become infected with BQCV have increased mortality. Here we summarize current research on the incidence, prevalence, geographical distribution and transmission of BQCV. PMID:26470541

  4. Postradiation imaging changes in the CNS: how can we differentiate between treatment effect and disease progression?

    PubMed Central

    Walker, Amanda J; Ruzevick, Jake; Malayeri, Ashkan A; Rigamonti, Daniele; Lim, Michael; Redmond, Kristin J; Kleinberg, Lawrence

    2015-01-01

    A familiar challenge for neuroradiologists and neuro-oncologists is differentiating between radiation treatment effect and disease progression in the CNS. Both entities are characterized by an increase in contrast enhancement on MRI and present with similar clinical signs and symptoms that may occur either in close temporal proximity to the treatment or later in the disease course. When radiation-related imaging changes or clinical deterioration are mistaken for disease progression, patients may be subject to unnecessary surgery and/or a change from otherwise effective therapy. Similarly, when disease progression is mistaken for treatment effect, a potentially ineffective therapy may be continued in the face of progressive disease. Here we describe the three types of radiation injury to the brain based on the time to development of signs and symptoms – acute, subacute and late – and then review specific imaging changes after intensity-modulated radiation therapy, stereotactic radiosurgery and brachytherapy. We provide an overview of these phenomena in the treatment of a wide range of malignant and benign CNS illnesses. Finally, we review the published data regarding imaging techniques under investigation to address this well-known problem. PMID:24947265

  5. Branched chain amino acid metabolism profiles in progressive human nonalcoholic fatty liver disease.

    PubMed

    Lake, April D; Novak, Petr; Shipkova, Petia; Aranibar, Nelly; Robertson, Donald G; Reily, Michael D; Lehman-McKeeman, Lois D; Vaillancourt, Richard R; Cherrington, Nathan J

    2015-03-01

    Nonalcoholic fatty liver disease (NAFLD) is a globally widespread disease of increasing clinical significance. The pathological progression of the disease from simple steatosis to nonalcoholic steatohepatitis (NASH) has been well defined, however, the contribution of altered branched chain amino acid metabolomic profiles to the progression of NAFLD is not known. The three BCAAs: leucine, isoleucine and valine are known to mediate activation of several important hepatic metabolic signaling pathways ranging from insulin signaling to glucose regulation. The purpose of this study is to profile changes in hepatic BCAA metabolite levels with transcriptomic changes in the progression of human NAFLD to discover novel mechanisms of disease progression. Metabolomic and transcriptomic data sets representing the spectrum of human NAFLD (normal, steatosis, NASH fatty, and NASH not fatty livers) were utilized for this study. During the transition from steatosis to NASH, increases in the levels of leucine (127% of normal), isoleucine (139%), and valine (147%) were observed. Carnitine metabolites also exhibited significantly elevated profiles in NASH fatty and NASH not fatty samples and included propionyl, hexanoyl, lauryl, acetyl and butyryl carnitine. Amino acid and BCAA metabolism gene sets were significantly enriched among downregulated genes during NASH. These cumulative alterations in BCAA metabolite and amino acid metabolism gene profiles represent adaptive physiological responses to disease-induced hepatic stress in NASH patients.

  6. Chronic Cerebral Hypoperfusion Accelerates Alzheimer's Disease Pathology with Cerebrovascular Remodeling in a Novel Mouse Model.

    PubMed

    Zhai, Yun; Yamashita, Toru; Nakano, Yumiko; Sun, Zhuoran; Shang, Jingwei; Feng, Tian; Morihara, Ryuta; Fukui, Yusuke; Ohta, Yasuyuki; Hishikawa, Nozomi; Abe, Koji

    2016-06-13

    Recently, aging societies have been showing an increasingly strong relationship between Alzheimer's disease (AD) and chronic cerebral hypoperfusion (HP). In the present study, we created a new mouse model for AD with HP, and investigated its clinical and pathological characteristics. Alzheimer's disease transgenic mice (APP23) were subjected to bilateral common carotid arteries stenosis with ameroid constrictors for slowly progressive cerebral HP. In contrast to simple APP23 mice, cerebral HP exacerbated motor and cognitive dysfunctions with white matter lesions and meningo-parenchymal amyloid-β (Aβ) burdens. Strong cerebrovascular inflammation and severe amyloid angiopathy with cerebrovascular remodeling were also observed in APP23 + HP mouse brains. An acetylcholinesterase inhibitor galantamine improved such clinical dysfunctions, retrieved above neuropathological characteristics, and enhanced nicotinic acetylcholine receptor (nAChR)-binding activity. The present study demonstrates that chronic cerebral HP enhanced cognitive/motor dysfunctions with parenchymal/cerebrovascular Aβ accumulation and cerebrovascular remodeling. These neuropathological abnormalities were greatly ameliorated by galantamine treatment associated with nAChR-mediated neuroprotection by allosterically potentiating ligand action. PMID:27314529

  7. The utility of cerebral blood flow imaging in patients with the unique syndrome of progressive dementia with motor neuron disease

    SciTech Connect

    Ohnishi, T.; Hoshi, H.; Jinnouchi, S.; Nagamachi, S.; Watanabe, K.; Mituyama, Y. )

    1990-05-01

    Two patients presenting with progressive dementia coupled with motor neuron disease underwent brain SPECT using N-isopropyl-p iodine-123-iodoamphetamine (({sup 123}I)IMP). The characteristic clinical features of progressive dementia and motor neuron disease were noted. IMP SPECT also revealed reduced uptake in the bilateral frontal and temporal regions, with no reduction of uptake in the parietal, parietal-occipital regions. We conclude that IMP SPECT has potential for the evaluation of progressive dementia with motor neuron disease.

  8. Osteoarthritis in the XXIst Century: Risk Factors and Behaviours that Influence Disease Onset and Progression

    PubMed Central

    Musumeci, Giuseppe; Aiello, Flavia Concetta; Szychlinska, Marta Anna; Di Rosa, Michelino; Castrogiovanni, Paola; Mobasheri, Ali

    2015-01-01

    Osteoarthritis (OA) is a growing public health problem across the globe, affecting more than half of the over 65 population. In the past, OA was considered a wear and tear disease, leading to the loss of articular cartilage and joint disability. Nowadays, thanks to advancements in molecular biology, OA is believed to be a very complex multifactorial disease. OA is a degenerative disease characterized by “low-grade inflammation” in cartilage and synovium, resulting in the loss of joint structure and progressive deterioration of cartilage. Although the disease can be dependent on genetic and epigenetic factors, sex, ethnicity, and age (cellular senescence, apoptosis and lubricin), it is also associated with obesity and overweight, dietary factors, sedentary lifestyle and sport injuries. The aim of this review is to highlight how certain behaviors, habits and lifestyles may be involved in the onset and progression of OA and to summarize the principal risk factors involved in the development of this complicated joint disorder. PMID:25785564

  9. Progress and problems in the biology, diagnostics, and therapeutics of prion diseases.

    PubMed

    Aguzzi, Adriano; Heikenwalder, Mathias; Miele, Gino

    2004-07-01

    The term "prion" was introduced by Stanley Prusiner in 1982 to describe the atypical infectious agent that causes transmissible spongiform encephalopathies, a group of infectious neurodegenerative diseases that include scrapie in sheep, Creutzfeldt-Jakob disease in humans, chronic wasting disease in cervids, and bovine spongiform encephalopathy in cattle. Over the past twenty years, the word "prion" has been taken to signify various subtly different concepts. In this article, we refer to the prion as the transmissible principle underlying prion diseases, without necessarily implying any specific biochemical or structural identity. When Prusiner started his seminal work, the study of transmissible spongiform encephalopathies was undertaken by only a handful of scientists. Since that time, the "mad cow" crisis has put prion diseases on the agenda of both politicians and the media. Significant progress has been made in prion disease research, and many aspects of prion pathogenesis are now understood. And yet the diagnostic procedures available for prion diseases are not nearly as sensitive as they ought to be, and no therapeutic intervention has been shown to reliably affect the course of the diseases. This article reviews recent progress in the areas of pathogenesis of, diagnostics of, and therapy for prion diseases and highlights some conspicuous problems that remain to be addressed in each of these fields. PMID:15254579

  10. Integration of water, sanitation and hygiene for the control of neglected tropical diseases: a review of progress and the way forward.

    PubMed

    Waite, Robyn C; Velleman, Yael; Woods, Geordie; Chitty, Alexandra; Freeman, Matthew C

    2016-03-01

    A WHO roadmap to control, eliminate and eradicate neglected tropical diseases (NTDs) proposes a public health approach integrating diverse prevention and treatment interventions. Water, sanitation and hygiene (WASH) has long been a recognized, yet under-prioritized intervention of global disease control efforts. Through collaboration with the WASH sector, efforts have been made to integrate WASH in NTD control. This article reviews progress made in recent years, explores mechanisms supporting advances, and identifies priorities and next steps for accelerating WASH integration. This paper reveals advances in collaboration between WASH and NTD sectors, resulting in progress made across areas of programming; research; advocacy and policy; training and capacity building; and mapping, data collection and monitoring. Face to face meetings between WASH and NTD sector experts with a clear purpose of informing wider sector discussions, and the development of actionable joint workplans, have been particularly critical in supporting progress. Priority next steps include building capacity for WASH programming among NTD control teams, coordination at the country level, and strengthening the epidemiological evidence and operational learning for joint WASH and NTD interventions. In order to accelerate WASH integration in NTD control through strong collaborations with the WASH sector, the NTD sector could make use of strong data management skills and advocacy opportunities.

  11. Integration of water, sanitation and hygiene for the control of neglected tropical diseases: a review of progress and the way forward.

    PubMed

    Waite, Robyn C; Velleman, Yael; Woods, Geordie; Chitty, Alexandra; Freeman, Matthew C

    2016-03-01

    A WHO roadmap to control, eliminate and eradicate neglected tropical diseases (NTDs) proposes a public health approach integrating diverse prevention and treatment interventions. Water, sanitation and hygiene (WASH) has long been a recognized, yet under-prioritized intervention of global disease control efforts. Through collaboration with the WASH sector, efforts have been made to integrate WASH in NTD control. This article reviews progress made in recent years, explores mechanisms supporting advances, and identifies priorities and next steps for accelerating WASH integration. This paper reveals advances in collaboration between WASH and NTD sectors, resulting in progress made across areas of programming; research; advocacy and policy; training and capacity building; and mapping, data collection and monitoring. Face to face meetings between WASH and NTD sector experts with a clear purpose of informing wider sector discussions, and the development of actionable joint workplans, have been particularly critical in supporting progress. Priority next steps include building capacity for WASH programming among NTD control teams, coordination at the country level, and strengthening the epidemiological evidence and operational learning for joint WASH and NTD interventions. In order to accelerate WASH integration in NTD control through strong collaborations with the WASH sector, the NTD sector could make use of strong data management skills and advocacy opportunities. PMID:26940306

  12. Neurofilament Light Chain in Blood and CSF as Marker of Disease Progression in Mouse Models and in Neurodegenerative Diseases.

    PubMed

    Bacioglu, Mehtap; Maia, Luis F; Preische, Oliver; Schelle, Juliane; Apel, Anja; Kaeser, Stephan A; Schweighauser, Manuel; Eninger, Timo; Lambert, Marius; Pilotto, Andrea; Shimshek, Derya R; Neumann, Ulf; Kahle, Philipp J; Staufenbiel, Matthias; Neumann, Manuela; Maetzler, Walter; Kuhle, Jens; Jucker, Mathias

    2016-07-01

    A majority of current disease-modifying therapeutic approaches for age-related neurodegenerative diseases target their characteristic proteopathic lesions (α-synuclein, Tau, Aβ). To monitor such treatments, fluid biomarkers reflecting the underlying disease process are crucial. We found robust increases of neurofilament light chain (NfL) in CSF and blood in murine models of α-synucleinopathies, tauopathy, and β-amyloidosis. Blood and CSF NfL levels were strongly correlated, and NfL increases coincided with the onset and progression of the corresponding proteopathic lesions in brain. Experimental induction of α-synuclein lesions increased CSF and blood NfL levels, while blocking Aβ lesions attenuated the NfL increase. Consistently, we also found NfL increases in CSF and blood of human α-synucleinopathies, tauopathies, and Alzheimer's disease. Our results suggest that CSF and particularly blood NfL can serve as a reliable and easily accessible biomarker to monitor disease progression and treatment response in mouse models and potentially in human proteopathic neurodegenerative diseases. PMID:27292537

  13. Neurofilament Light Chain in Blood and CSF as Marker of Disease Progression in Mouse Models and in Neurodegenerative Diseases.

    PubMed

    Bacioglu, Mehtap; Maia, Luis F; Preische, Oliver; Schelle, Juliane; Apel, Anja; Kaeser, Stephan A; Schweighauser, Manuel; Eninger, Timo; Lambert, Marius; Pilotto, Andrea; Shimshek, Derya R; Neumann, Ulf; Kahle, Philipp J; Staufenbiel, Matthias; Neumann, Manuela; Maetzler, Walter; Kuhle, Jens; Jucker, Mathias

    2016-07-01

    A majority of current disease-modifying therapeutic approaches for age-related neurodegenerative diseases target their characteristic proteopathic lesions (α-synuclein, Tau, Aβ). To monitor such treatments, fluid biomarkers reflecting the underlying disease process are crucial. We found robust increases of neurofilament light chain (NfL) in CSF and blood in murine models of α-synucleinopathies, tauopathy, and β-amyloidosis. Blood and CSF NfL levels were strongly correlated, and NfL increases coincided with the onset and progression of the corresponding proteopathic lesions in brain. Experimental induction of α-synuclein lesions increased CSF and blood NfL levels, while blocking Aβ lesions attenuated the NfL increase. Consistently, we also found NfL increases in CSF and blood of human α-synucleinopathies, tauopathies, and Alzheimer's disease. Our results suggest that CSF and particularly blood NfL can serve as a reliable and easily accessible biomarker to monitor disease progression and treatment response in mouse models and potentially in human proteopathic neurodegenerative diseases.

  14. Non cell autonomous upregulation of CDKN2 transcription linked to progression of chronic hepatitis C disease.

    PubMed

    Robinson, Mark W; McGuinness, Dagmara; Swann, Rachael; Barclay, Stephen; Mills, Peter R; Patel, Arvind H; McLauchlan, John; Shiels, Paul G

    2013-12-01

    Chronic hepatitis C virus infection (C-HC) is associated with higher mortality arising from hepatic and extrahepatic disease. This may be due to accelerated biological aging; however, studies in C-HC have thus far been based solely on telomere length as a biomarker of aging (BoA). In this study, we have evaluated CDKN2 locus transcripts as alternative BoAs in C-HC. Our results suggest that C-HC induces non-cell-autonomous senescence and accelerates biological aging. The CDKN2 locus may provide a link between C-HC and increased susceptibility to age-associated diseases and provides novel biomarkers for assessing its impact on aging processes in man.

  15. Genetic identification of two major modifier loci of polycystic kidney disease progression in pcy mice.

    PubMed Central

    Woo, D D; Nguyen, D K; Khatibi, N; Olsen, P

    1997-01-01

    Unlike the uniform disease progression in inbred animals, polycystic kidney disease (PKD) progression within human families can be highly variable. This may be due to environmental or genetic factors or both. To determine if PKD severity can be influenced by modifier genes, we carried out an intercross between DBA/2-pcy/pcy and Mus m. castaneous involving 3,105 6-wk-old F2 mice. Large differences in PKD severity were observed in this cross. In addition, 23/ 800 phenotypically normal mice were pcy/pcy genotypically. These results demonstrated that PKD progression in pcy/ pcy mice is a quantitative trait that is strongly modulated by modifier genes. Whole genome quantitative trait loci mapping of 114 selected pcy/pcy mice (68 with the mild PKD and 46 with severe PKD) identified two loci, MOP1 and MOP2 that strongly modulate PKD progression. MOP1 (max LOD score = 10.3 at D4Mit111) and MOP2 (max LOD score = 13.8 at D16Mit1) accounted for 36.7 and 46.8% of the phenotypic variance, respectively. Two-factor ANOVA of the phenotypes and genotypes of all 673 pcy/pcy mice from our cross indicated that MOP1 and MOP2 alleles regulate PKD progression in a complex additive manner. Characterization of these novel modifying loci may provide additional insights into the pathogenesis of polycystic kidney diseases. PMID:9329956

  16. Accelerated development of cerebral small vessel disease in young stroke patients

    PubMed Central

    Arntz, Renate M.; van den Broek, Steffen M.A.; van Uden, Inge W.M.; Ghafoorian, Mohsen; Platel, Bram; Rutten-Jacobs, Loes C.A.; Maaijwee, Noortje A.M.; Schaapsmeerders, Pauline; Schoonderwaldt, Hennie C.; van Dijk, Ewoud J.

    2016-01-01

    Objective: To study the long-term prevalence of small vessel disease after young stroke and to compare this to healthy controls. Methods: This prospective cohort study comprises 337 patients with an ischemic stroke or TIA, aged 18–50 years, without a history of TIA or stroke. In addition, 90 age- and sex-matched controls were included. At follow-up, lacunes, microbleeds, and white matter hyperintensity (WMH) volume were assessed using MRI. To investigate the relation between risk factors and small vessel disease, logistic and linear regression were used. Results: After mean follow-up of 9.9 (SD 8.1) years, 337 patients were included (227 with an ischemic stroke and 110 with a TIA). Mean age of patients was 49.8 years (SD 10.3) and 45.4% were men; for controls, mean age was 49.4 years (SD 11.9) and 45.6% were men. Compared with controls, patients more often had at least 1 lacune (24.0% vs 4.5%, p < 0.0001). In addition, they had a higher WMH volume (median 1.5 mL [interquartile range (IQR) 0.5–3.7] vs 0.4 mL [IQR 0.0–1.0], p < 0.001). Compared with controls, patients had the same volume WMHs on average 10–20 years earlier. In the patient group, age at stroke (β = 0.03, 95% confidence interval [CI] 0.02–0.04) hypertension (β = 0.22, 95% CI 0.04–0.39), and smoking (β = 0.18, 95% CI 0.01–0.34) at baseline were associated with WMH volume. Conclusions: Patients with a young stroke have a higher burden of small vessel disease than controls adjusted for confounders. Cerebral aging seems accelerated by 10–20 years in these patients, which may suggest an increased vulnerability to vascular risk factors. PMID:27521431

  17. Category and Letter Fluency in Semantic Dementia, Primary Progressive Aphasia, and Alzheimer's Disease

    ERIC Educational Resources Information Center

    Marczinski, Cecile A.; Kertesz, Andrew

    2006-01-01

    This study examined the impact of various degenerative dementias on access to semantic knowledge and the status of semantic representations. Patients with semantic dementia, primary progressive aphasia, and Alzheimer's disease were compared with elderly controls on tasks of category and letter fluency, with number of words generated, mean lexical…

  18. The Functional Transitions Model: Maximizing Ability in the Context of Progressive Disability Associated with Alzheimer's Disease

    ERIC Educational Resources Information Center

    Slaughter, Susan; Bankes, Jane

    2007-01-01

    The Functional Transitions Model (FTM) integrates the theoretical notions of progressive functional decline associated with Alzheimer's disease (AD), excess disability, and transitions occurring intermittently along the trajectory of functional decline. Application of the Functional Transitions Model to clinical practice encompasses the paradox of…

  19. Brain Substrates of Learning and Retention in Mild Cognitive Impairment Diagnosis and Progression to Alzheimer's Disease

    ERIC Educational Resources Information Center

    Chang, Yu-Ling; Bondi, Mark W.; Fennema-Notestine, Christine; McEvoy, Linda K.; Hagler, Donald J., Jr.; Jacobson, Mark W.; Dale, Anders M.

    2010-01-01

    Understanding the underlying qualitative features of memory deficits in mild cognitive impairment (MCI) can provide critical information for early detection of Alzheimer's disease (AD). This study sought to investigate the utility of both learning and retention measures in (a) the diagnosis of MCI, (b) predicting progression to AD, and (c)…

  20. Predialysis chronic kidney disease in 2010: Novel targets for slowing CKD progression.

    PubMed

    Carrero, Juan Jesús; Stenvinkel, Peter

    2011-02-01

    Several 2010 trials have provided novel information on how best to manage patients with predialysis chronic kidney disease (CKD). Armed with these new findings, nephrologists can find new means of slowing CKD progression by targeting blood-pressure control, acidosis and serum uric acid levels.

  1. Heroin Use and HIV Disease Progression: Results from a Pilot Study of a Russian Cohort.

    PubMed

    Edelman, E Jennifer; Cheng, Debbie M; Krupitsky, Evgeny M; Bridden, Carly; Quinn, Emily; Walley, Alexander Y; Lioznov, Dmitry A; Blokhina, Elena; Zvartau, Edwin; Samet, Jeffrey H

    2015-06-01

    Opioids have immunosuppressive properties, yet their impact on HIV disease progression remains unclear. Using longitudinal data from HIV-infected antiretroviral therapy-naïve Russian individuals (n = 77), we conducted a pilot study to estimate the effect of heroin use on HIV disease progression. Heroin use was categorized based on past 30 days self-reported use at baseline, 6 and 12 months as none, intermittent or persistent. We estimated the effect of heroin use on HIV disease progression, measured as change in CD4 count from baseline to 12 months, using multivariable linear regression. Those with intermittent (n = 21) and no heroin use (n = 39) experienced mean decreases in CD4 count from baseline to 12 months (-103 and -10 cells/mm(3), respectively; adjusted mean difference (AMD) -93; 95 % CI -245, 58). Those with persistent use (n = 17) showed a mean increase of 53 cells/mm(3) (AMD 63; 95 % CI -95, 220). Future studies exploring the effects of heroin withdrawal on HIV disease progression are warranted.

  2. Rapid Disease Progression With Delay in Treatment of Non-Small-Cell Lung Cancer

    SciTech Connect

    Mohammed, Nasiruddin; Kestin, Larry Llyn; Grills, Inga Siiner; Battu, Madhu; Fitch, Dwight Lamar; Wong, Ching-yee Oliver; Margolis, Jeffrey Harold; Chmielewski, Gary William; Welsh, Robert James

    2011-02-01

    Purpose: To assess rate of disease progression from diagnosis to initiation of treatment for Stage I-IIIB non-small-cell lung cancer (NSCLC). Methods and Materials: Forty patients with NSCLC underwent at least two sets of computed tomography (CT) and 18-fluorodeoxyglucose positron emission tomography (PET) scans at various time intervals before treatment. Progression was defined as development of any new lymph node involvement, site of disease, or stage change. Results: Median time interval between first and second CT scans was 13.4 weeks, and between first and second PET scans was 9.0 weeks. Median initial primary maximum tumor dimension (MTD) was 3.5 cm (0.6-8.5 cm) with a median standardized uptake value (SUV) of 13.0 (1.7-38.5). The median MTD increased by a median of 1.0 cm (mean, 1.6 cm) between scans for a median relative MTD increase of 35% (mean, 59%). Nineteen patients (48%) progressed between scans. Rate of any progression was 13%, 31%, and 46% at 4, 8, and 16 weeks, respectively. Upstaging occurred in 3%, 13%, and 21% at these intervals. Distant metastasis became evident in 3%, 13%, and 13% after 4, 8, and 16 weeks, respectively. T and N stage were associated with progression, whereas histology, grade, sex, age, and maximum SUV were not. At 3 years, overall survival for Stage III patients with vs. without progression was 18% vs. 67%, p = 0.05. Conclusions: With NSCLC, treatment delay can lead to disease progression. Diagnosis, staging, and treatment initiation should be expedited. After 4-8 weeks of delay, complete restaging should be strongly considered.

  3. Vitamin D Related Host Genetic Variants Alter HIV Disease Progression in Children

    PubMed Central

    Moodley, Amaran; Qin, Min; Singh, Kumud K.; Spector, Stephen A.

    2013-01-01

    Background Vitamin D deficiency is common in HIV infection and has been associated with advanced disease. This study investigated whether vitamin D related genetic variants were associated with disease progression in HIV-infected children. Methods The Fok-I (C/T), Bsm-I (G/A), GC (A/C), DHCR7 (G/T) and CYP2R1 (G/A) genetic variants were detected by RT-PCR in HIV-infected children who participated in the PACTG P152 and P300 protocols which pre-dated the availability of effective combination antiretroviral therapy. The primary endpoints included time to progression to the first HIV-related disease end-point (≥2 OI's, weight-growth failure) or death, which constituted the progression-free-survival. Analyses were performed for age >2 years and ≤2 years separately adjusting for race and treatment effect. Results Of the 998 children evaluated, 139 experienced HIV disease progression. For children >2 years, rapid disease progression was associated with the DHCR7 G allele compared to the T allele (G/G vs. T/T: HR=5.0, p=0.035, G/T vs. T/T: HR=4.5, p=0.042, G/G+G/T vs. T/T: HR=4.8, p=0.036), and the Bsm-I A allele compared to the G allele (A/G vs. G/G: HR=2.2, p=0.014 and A/G+A/A vs. G/G: HR=2.0, p=0.026). In children ≤2 years, the Bsm-I A allele increased the risk of disease progression in Hispanics (A/A vs. G/A+G/G: HR=2.8, p=0.03; A/A vs. G/G: HR=2.8, p=0.046) and whites (A/A vs. G/G: HR=6.6, p=0.025; A/A vs. G/A+G/G: HR=3.6, p=0.038). Conclusions Vitamin D related host genetic variants that alter the availability and activity of vitamin D are associated with risk of HIV disease progression in children, and may vary by age and race. PMID:23736144

  4. Progression from Beryllium Exposure to Chronic Beryllium Disease: An Analytic Model

    PubMed Central

    Harber, Philip; Bansal, Siddharth; Balmes, John

    2009-01-01

    Background Understanding the progression from beryllium exposure (BeE) to chronic beryllium disease (CBD) is essential for optimizing screening and early intervention to prevent CBD. Methods We developed an analytic Markov model of progression to CBD that assigns annual probabilities for progression through three states: from BeE to beryllium sensitization and then to CBD. We used calculations of the number in each state over time to assess which of several alternative progression models are most consistent with the limited available empirical data on prevalence and incidence. We estimated cost-effectiveness of screening considering both incremental (cost/case) and cumulative program costs. Results No combination of parameters for a simple model in which risk of progression remains constant over time can meet the empirical constraints of relatively frequent early cases and continuing development of new cases with long latencies. Modeling shows that the risk of progression is initially high and then declines over time. Also, it is likely that there are at least two populations that differ significantly in risk. The cost-effectiveness of repetitive screening declines over time, although new cases will still be found with long latencies. However, screening will be particularly cost-effective when applied to persons with long latencies who have not been previously screened. Conclusions To optimize use of resources, the intensity of screening should decrease over time. Estimation of lifetime cumulative CBD risk should consider the declining risk of progression over time. PMID:19590692

  5. Quantitative evaluation of disease progression in a longitudinal mild cognitive impairment cohort.

    PubMed

    Runtti, Hilkka; Mattila, Jussi; van Gils, Mark; Koikkalainen, Juha; Soininen, Hilkka; Lötjönen, Jyrki

    2014-01-01

    Several neuropsychological tests and biomarkers of Alzheimer's disease (AD) have been validated and their evolution over time has been explored. In this study, multiple heterogeneous predictors of AD were combined using a supervised learning method called Disease State Index (DSI). The behavior of DSI values over time was examined to study disease progression quantitatively in a mild cognitive impairment (MCI) cohort. The DSI method was applied to longitudinal data from 140 MCI cases that progressed to AD and 149 MCI cases that did not progress to AD during the follow-up. The data included neuropsychological tests, brain volumes from magnetic resonance imaging, cerebrospinal fluid samples, and apolipoprotein E from the Alzheimer's Disease Neuroimaging Initiative database. Linear regression of the longitudinal DSI values (including the DSI value at the point of MCI to AD conversion) was performed for each subject having at least three DSI values available (147 non-converters, 126 converters). Converters had five times higher slopes and almost three times higher intercepts than non-converters. Two subgroups were found in the group of non-converters: one group with stable DSI values over time and another group with clearly increasing DSI values suggesting possible progression to AD in the future. The regression parameters differentiated between the converters and the non-converters with classification accuracy of 76.9% for the slopes and 74.6% for the intercepts. In conclusion, this study demonstrated that quantifying longitudinal patient data using the DSI method provides valid information for follow-up of disease progression and support for decision making.

  6. HLA and interleukin 1 gene polymorphisms in primary biliary cirrhosis: associations with disease progression and disease susceptibility

    PubMed Central

    Donaldson, P; Agarwal, K; Craggs, A; Craig, W; James, O; Jones, D

    2001-01-01

    BACKGROUND AND AIMS—Twin and family studies suggest that there is a genetic component to primary biliary cirrhosis (PBC) but the genetic associations which have been described are weak with marked variations between centres. PBC is heterogeneous and genetic associations with disease progression may be obscured when the PBC population is analysed only as a whole and not subdivided.
METHODS—We have investigated two candidate gene loci in 164 well characterised patients, 88 (54%) of whom had advanced disease.
RESULTS—There was an increased frequency of the HLA DRB1*0801-DQA1*0401-DQB1*0402 haplotype in patients who had progressed to late stage disease (23% v 2% of controls; p=0000044; odds ratio (OR) 15.5, 95% confidence interval (CI) 3.52-68.4) but not in those with early stage disease (4% v 2%). Patients had a higher frequency of the IL-1B*1,1 genotype and lower frequencies of the IL-1B*1,2 and *2,2 genotypes (p=0.00078; OR 2.37, 95% CI 1.38-4.06), and higher frequency of the IL-1RN*1,1 genotype and lower frequency of the IL-1RN*1,2 genotype (p=0.0011; OR 2.28, 95% CI 1.34-3.89). The difference in the IL-1B*1,1 genotype distribution was most marked in patients with early stage disease (77% v 43% of controls; p=0.000003; OR 4.8, 95% CI 2.31-10) but the IL-1RN genotype distribution was similar in patients with early and late stage disease.
CONCLUSIONS—These data indicate a complex relationship between immunoregulatory genes and PBC. While the IL-1 genes are markers of both disease susceptibility and progression, HLA genes appear to be principally associated with disease progression.


Keywords: human leucocyte antigens; primary biliary cirrhosis; interleukin 1 PMID:11171832

  7. The Three Gorges Dam: Does it accelerate or delay the progress towards eliminating transmission of schistosomiasis in China?

    PubMed

    Zhou, Yi-Biao; Liang, Song; Chen, Yue; Jiang, Qing-Wu

    2016-01-01

    The Three Gorges Dam, located in the largest endemic area of schistosomiasis in China, is one of the world's largest hydroelectric projects to date. Some large-scale hydro projects have resulted in schistosomiasis emergence or re-emergence. Therefore, the dam's potential impact on the transmission of Schistosoma japonicum has raised concerns from medical researchers worldwide. A systematic literature review, coupled with an analysis of data on the water level and snail density in the Yangtze River was conducted to assess the impact of the dam on schistosomiasis transmission after more than 10 years of operation. The dam has significantly altered the water levels in the Yangtze River according to different seasons. These changes directly impact the ecology of the schistosome snail host. Due to the dam, there has been a reduction in the density of Oncomelania snails and/or changes in the distribution of snails. The prevalence of infection with S. japonicum has decreased in the downstream areas of the dam, including in the Dongting and Poyang Lakes. The prevalence of infection with S. japonicum in humans has decreased from 6.80 % in 2002 (before the dam began operating) to 0.50 % in 2012, and the number of people infected with S. japonicum have decreased from 94 208 in 2002 to 59 200 in 2011 in the Poyang Lake region. The presence of the dam does not seem to affect snail breeding or the prevalence of schistosomiasis in the Three Gorges Reservoir. Overall, the Three Gorges Dam has significantly contributed to changes in hydrology after more than 10 years of the dam operating. The changes caused by the dam, together with integrated control of schistosomiasis, might be accelerating the progress towards eliminating the transmission of S. japonicum in the middle and lower reaches of the Yangtze River. Despite the positive effect the dam is having in controlling S. japonicum transmission, continued surveillance is required to monitor the future ecological impacts of the

  8. The Three Gorges Dam: Does it accelerate or delay the progress towards eliminating transmission of schistosomiasis in China?

    PubMed

    Zhou, Yi-Biao; Liang, Song; Chen, Yue; Jiang, Qing-Wu

    2016-07-05

    The Three Gorges Dam, located in the largest endemic area of schistosomiasis in China, is one of the world's largest hydroelectric projects to date. Some large-scale hydro projects have resulted in schistosomiasis emergence or re-emergence. Therefore, the dam's potential impact on the transmission of Schistosoma japonicum has raised concerns from medical researchers worldwide. A systematic literature review, coupled with an analysis of data on the water level and snail density in the Yangtze River was conducted to assess the impact of the dam on schistosomiasis transmission after more than 10 years of operation. The dam has significantly altered the water levels in the Yangtze River according to different seasons. These changes directly impact the ecology of the schistosome snail host. Due to the dam, there has been a reduction in the density of Oncomelania snails and/or changes in the distribution of snails. The prevalence of infection with S. japonicum has decreased in the downstream areas of the dam, including in the Dongting and Poyang Lakes. The prevalence of infection with S. japonicum in humans has decreased from 6.80 % in 2002 (before the dam began operating) to 0.50 % in 2012, and the number of people infected with S. japonicum have decreased from 94 208 in 2002 to 59 200 in 2011 in the Poyang Lake region. The presence of the dam does not seem to affect snail breeding or the prevalence of schistosomiasis in the Three Gorges Reservoir. Overall, the Three Gorges Dam has significantly contributed to changes in hydrology after more than 10 years of the dam operating. The changes caused by the dam, together with integrated control of schistosomiasis, might be accelerating the progress towards eliminating the transmission of S. japonicum in the middle and lower reaches of the Yangtze River. Despite the positive effect the dam is having in controlling S. japonicum transmission, continued surveillance is required to monitor the future ecological impacts of the

  9. Clinical features and predictors for disease natural progression in adults with Pompe disease: a nationwide prospective observational study

    PubMed Central

    2012-01-01

    Background Due partly to physicians’ unawareness, many adults with Pompe disease are diagnosed with great delay. Besides, it is not well known which factors influence the rate of disease progression, and thus disease outcome. We delineated the specific clinical features of Pompe disease in adults, and mapped out the distribution and severity of muscle weakness, and the sequence of involvement of the individual muscle groups. Furthermore, we defined the natural disease course and identified prognostic factors for disease progression. Methods We conducted a single-center, prospective, observational study. Muscle strength (manual muscle testing, and hand-held dynamometry), muscle function (quick motor function test), and pulmonary function (forced vital capacity in sitting and supine positions) were assessed every 3–6 months and analyzed using repeated-measures ANOVA. Results Between October 2004 and August 2009, 94 patients aged between 25 and 75 years were included in the study. Although skeletal muscle weakness was typically distributed in a limb-girdle pattern, many patients had unfamiliar features such as ptosis (23%), bulbar weakness (28%), and scapular winging (33%). During follow-up (average 1.6 years, range 0.5-4.2 years), skeletal muscle strength deteriorated significantly (mean declines of −1.3% point/year for manual muscle testing and of −2.6% points/year for hand-held dynamometry; both p<0.001). Longer disease duration (>15 years) and pulmonary involvement (forced vital capacity in sitting position <80%) at study entry predicted faster decline. On average, forced vital capacity in supine position deteriorated by 1.3% points per year (p=0.02). Decline in pulmonary function was consistent across subgroups. Ten percent of patients declined unexpectedly fast. Conclusions Recognizing patterns of common and less familiar characteristics in adults with Pompe disease facilitates timely diagnosis. Longer disease duration and reduced pulmonary function

  10. Assembly and interrogation of Alzheimer's disease genetic networks reveal novel regulators of progression.

    PubMed

    Aubry, Soline; Shin, William; Crary, John F; Lefort, Roger; Qureshi, Yasir H; Lefebvre, Celine; Califano, Andrea; Shelanski, Michael L

    2015-01-01

    Alzheimer's disease (AD) is a complex multifactorial disorder with poorly characterized pathogenesis. Our understanding of this disease would thus benefit from an approach that addresses this complexity by elucidating the regulatory networks that are dysregulated in the neural compartment of AD patients, across distinct brain regions. Here, we use a Systems Biology (SB) approach, which has been highly successful in the dissection of cancer related phenotypes, to reverse engineer the transcriptional regulation layer of human neuronal cells and interrogate it to infer candidate Master Regulators (MRs) responsible for disease progression. Analysis of gene expression profiles from laser-captured neurons from AD and controls subjects, using the Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe), yielded an interactome consisting of 488,353 transcription-factor/target interactions. Interrogation of this interactome, using the Master Regulator INference algorithm (MARINa), identified an unbiased set of candidate MRs causally responsible for regulating the transcriptional signature of AD progression. Experimental assays in autopsy-derived human brain tissue showed that three of the top candidate MRs (YY1, p300 and ZMYM3) are indeed biochemically and histopathologically dysregulated in AD brains compared to controls. Our results additionally implicate p53 and loss of acetylation homeostasis in the neurodegenerative process. This study suggests that an integrative, SB approach can be applied to AD and other neurodegenerative diseases, and provide significant novel insight on the disease progression.

  11. Serum Uric Acid Predicts Progression of Subclinical Coronary Atherosclerosis in Individuals Without Renal Disease

    PubMed Central

    Rodrigues, Ticiana C.; Maahs, David M.; Johnson, Richard J.; Jalal, Diana I.; Kinney, Gregory L.; Rivard, Christopher; Rewers, Marian; Snell-Bergeon, Janet K.

    2010-01-01

    OBJECTIVE To examine uric acid (UA) as a possible predictor of the progression of coronary artery calcification (CAC) using data from the prospective Coronary Artery Calcification in Type 1 Diabetes (CACTI) Study. RESEARCH DESIGN AND METHODS CAC was measured by electron beam tomography at the baseline and at a follow-up 6.0 ± 0.5 years later. The study population included 443 participants with type 1 diabetes and 526 control subjects who were free of diagnosed coronary artery disease at baseline. The presence of renal disease was defined by the presence of albuminuria and/or low glomerular filtration rate. RESULTS In subjects without renal disease, serum UA predicted CAC progression (odds ratio 1.30 [95% CI 1.07–1.58], P = 0.007) independent of conventional cardiovascular risk factors including diabetes and the presence of metabolic syndrome. CONCLUSIONS Serum UA levels predict the progression of coronary atherosclerosis and may be useful in identifying who is at risk for vascular disease in the absence of significant chronic kidney disease. PMID:20798338

  12. Utility of quantitative ultrasound for tracking the progression of polycystic kidney disease

    NASA Astrophysics Data System (ADS)

    Hall, Timothy J.; Khant, Htet A.; Insana, Michael F.; Wood, John G.; Zhu, Yanning; Preston, David; Cowley, Benjamin D.

    2000-04-01

    We are combining techniques of quantitative ultrasonic imaging to study polycystic kidney disease (PKD) as the disease progresses to renal failure. Our goal is to use ultrasound noninvasively to detect morphological changes early in the disease process when interventions are most likely to be successful and prior to a significant loss in renal function. We are examining the kidneys of normal rats and those with PKD at various ages with several techniques to obtain comprehensive knowledge of the disease progression. The Han:SPRD rat inherits PKD as an autosomal dominant trait (ADPKD) that closely mimics ADPKD in humans. Changes in renal function are assessed using tracer kinetics (DTPA) and IOH clearance). Ultrasonic techniques, based on measurements of acoustic backscatter coefficients and parameters derived from these measurements, are sensitive to microscopic changes in the tissue morphology. Elasticity imaging is used to study the changes in the tissue macrostructure. All acoustic measurements are made using a state-of-the-art clinical imaging system (Siemens Elegra). Our results show that ultrasonic techniques are very sensitive to early changes in renal microstructure and macrostructure. Ultrasound can be used to detect changes in the renal cortex long before there is a measurable loss of renal function. These techniques are also useful for monitoring the progression of the disease. Most importantly, these techniques are noninvasive and directly applicable to humans.

  13. Transgenic over-expression of mammalian heparanase delays prion disease onset and progression

    PubMed Central

    Kovalchuk Ben-Zaken, O; Nissan, I; Tzaban, S; Taraboulos, A; Zcharia, E; Matzger, S; Shafat, I; Vlodavsky, I; Tal, Y.

    2015-01-01

    Cellular heparan sulfate (HS) has a dual role in scrapie pathogenesis; it is required for PrPSc (scrapie prion protein) formation and facilitates infection of cells, mediating cellular uptake of prions. We examined the involvement of heparanase, a mammalian endoglycosidase degrading HS, in scrapie infection. In cultured cells, heparanase treatment or over-expression resulted in a profound decrease in PrPSc. Moreover, disease onset and progression were dramatically delayed in scrapie infected transgenic mice over-expressing heparanase. Together, our results provide direct in vivo evidence for the involvement of intact HS in the pathogenesis of prion disease and the protective role of heparanase both in terms of susceptibility to infection and disease progression. PMID:26168721

  14. Measurement of Beryllium in Biological Samples by Accelerator Mass Spectrometry: Applications for Studying Chronic Beryllium Disease

    SciTech Connect

    Chiarappa-Zucca, M L; Finkel, R C; Martinelli, R E; McAninch, J E; Nelson, D O; Turtletaub, K W

    2004-04-15

    A method using accelerator mass spectrometry (AMS) has been developed for quantifying attomoles of beryllium (Be) in biological samples. This method provides the sensitivity to trace Be in biological samples at very low doses with the purpose of identifying the molecular targets involved in chronic beryllium disease. Proof of the method was tested by administering 0.001, 0.05, 0.5 and 5.0 {micro}g {sup 9}Be and {sup 10}Be by intraperitoneal injection to male mice and removing spleen, liver, femurs, blood, lung, and kidneys after 24 h exposure. These samples were prepared for AMS analysis by tissue digestion in nitric acid, followed by further organic oxidation with hydrogen peroxide and ammonium persulfate and lastly, precipitation of Be with ammonium hydroxide, and conversion to beryllium oxide at 800 C. The {sup 10}Be/{sup 9}Be ratio of the extracted beryllium oxide was measured by AMS and Be in the original sample was calculated. Results indicate that Be levels were dose-dependent in all tissues and the highest levels were measured in the spleen and liver. The measured {sup 10}Be/{sup 9}Be ratios spanned 4 orders of magnitude, from 10{sup -10} to 10{sup -14}, with a detection limit of 3.0 x 10{sup -14}, which is equivalent to 0.8 attomoles of {sup 10}Be. These results show that routine quantification of nanogram levels of Be in tissues is possible and that AMS is a sensitive method that can be used in biological studies to understand the molecular dosimetry of Be and mechanisms of toxicity.

  15. An Unrecognized Rash Progressing to Lyme Carditis: Important Features and Recommendations Regarding Lyme Disease.

    PubMed

    Lee, Shawn; Singla, Montish

    2016-01-01

    We present a case report of 46-year-old man with no medical history, who complained of extreme fatigue, near-syncope, and palpitations. He initially presented in complete heart block. A transvenous pacemaker was placed in the emergency department, and he was started empirically on Ceftriaxone for Lyme disease. He was admitted and over the course of the next few days, his rhythm regressed to Mobitz type I first-degree atrioventricular block and then to normal sinus rhythm. This case report highlights some important features regarding Lyme carditis, a rare presentation of early disseminated Lyme disease (seen in a few weeks to months after the initial tick bite). In 25%-30% of patients, the characteristic targetoid rash may not be seen, a likely culprit of the disease not being detected early and progressing to disseminated disease. The most common cardiac complaint of Lyme disease is palpitations, occurring in 6.6% of patients, which may not accurately reflect progression into disseminated Lyme disease because it is a nonspecific finding. Conduction abnormality, occurring in 1.8% of patients, is a more specific finding of Borrelia invading cardiac tissue. Finally, this case report highlights a recommendation that patients with confirmed Lyme disease or those presenting with cardiac abnormalities or symptoms who have an atypical profile for a cardiac event should be screened with a 12-lead electrocardiogram, Lyme serology, and be considered for antibiotic therapy with the possibility of temporary pacing.

  16. Cyclooxygenase product inhibition with acetylsalicylic acid slows disease progression in the Han:SPRD-Cy rat model of polycystic kidney disease.

    PubMed

    Ibrahim, Naser H M; Gregoire, Melanie; Devassy, Jessay G; Wu, Yinhong; Yoshihara, Daisuke; Yamaguchi, Tamio; Nagao, Shizuko; Aukema, Harold M

    2015-01-01

    Renal cyclooxygenase (COX) derived eicosanoids are elevated and lipoxygenase (LOX) products are reduced in the Han:SPRD-Cy rat model of polycystic kidney disease (PKD). Selective COX2 inhibition reduces kidney disease progression, but COX1 levels also are elevated in this model. Since the effect of reducing the products of both COX isoforms and the role of LOX products is not known, weanling normal and diseased Han:SPRD-cy littermates were given either low dose acetylsalicylic acid (ASA), nordihydroguaiaretic (NDGA) or no treatment for eight weeks. Renal eicosanoids were altered in the diseased compared to normal cortex, with COX products being higher and LOX products being lower. ASA reduced COX products, cyst growth and kidney water content, while NDGA reduced LOX products without altering disease progression or kidney function. Hence, a human equivalent ASA dose equal to less than one regular strength aspirin per day slowed disease progression, while further reduction of LOX products did not worsen disease progression.

  17. [Impact of lipid metabolism parameters on the development and progression of coronary artery disease : An update].

    PubMed

    Sinning, D; Leistner, D M; Landmesser, U

    2016-06-01

    Disorders of lipid metabolism play a major role in the development and progression of coronary artery disease. Dyslipidemia therefore plays a central role in therapeutic approaches for prevention and treatment of cardiovascular events associated with coronary artery disease. Epidemiological studies have shown an association between various lipid metabolism parameters, the risk of developing coronary artery disease and progression of a pre-existing disease. In particular, increased levels of low-density lipoprotein cholesterol (LDL-C), reduced levels of HDL cholesterol (HDL-C), as well as high levels of triglycerides and increased lipoprotein(a) [Lp(a)] levels can be taken into account when assessing the risk stratification of patients for primary prevention of coronary artery disease. Lifestyle and dietary changes, intensified statin therapy and possibly the addition of ezetimibe remain the major interventions in both primary and secondary prevention of coronary artery disease, as they improve the prognosis particularly by lowering levels of LDL-C. Recently, genetic studies have contributed to extending our understanding of the relationship between lipid metabolism and coronary artery disease. A causal role for progression of coronary artery disease could be demonstrated for LDL-C, Lpa and triglyceride-rich lipoproteins (TRL), which could not be demonstrated for HDL-C in various studies. Furthermore, the effect of reduction of LDL-C by proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition and by the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib on cardiovascular events is currently being investigated in large clinical outcome study programs.

  18. RIPK3-Mediated Necroptosis and Apoptosis Contributes to Renal Tubular Cell Progressive Loss and Chronic Kidney Disease Progression in Rats

    PubMed Central

    Zhu, Yongjun; Cui, Hongwang; Xia, Yunfeng; Gan, Hua

    2016-01-01

    Tubulointerstitial fibrosis (TIF) is caused by the progressive loss of renal tubular cells and the consequent replacement of the extracellular matrix. The progressive depletion of renal tubular cells results from apoptosis and necroptosis; however, the relative significance of each of these cell death mechanisms at different stages during the progression of chronic kidney disease (CKD) remains unclear. We sought to explore the mechanisms of renal tubular cell death during the early and intermediate stages of chronic renal damage of subtotal nephrectomied (SNx) rats. The results of tissue histological assays indicated that the numbers of necrotic dying cells and apoptotic cells were significantly higher in kidney tissues derived from a rat model of CKD. In addition, there was a significant increase in necroptosis observed by transmission electron microscopy (TEM) and an increase in the proportion of TUNEL-positive cells in kidney tissues from SNx rats compared with control rats, and necrostatin-1 (Nec-1) could inhibit necroptosis and reduce the proportion of TUNEL-positive cells. More importantly, we observed a significant increase in the incidence of necroptosis compared with apoptosis by TEM in vivo and in vitro and a significant increase in the proportion of TUNEL-positive tubular epithelial cells that did not express caspase-3 compared with those expressing cleaved caspase-3 in vitro. Furthermore, treatment with Nec-1 and zVAD strongly reduced necroptosis- and apoptosis-mediated renal tubular cell death and decreased the levels of blood urea nitrogen and serum creatinine and tubular damage scores of SNx rats. These results suggest that necroptotic cell death plays a more significant role than apoptosis in mediating the loss of renal tubular cells in SNx rats and that effectively blocking both necroptosis and apoptosis improves renal function and tubular damage at early and intermediate stages of CKD. PMID:27281190

  19. RIPK3-Mediated Necroptosis and Apoptosis Contributes to Renal Tubular Cell Progressive Loss and Chronic Kidney Disease Progression in Rats.

    PubMed

    Zhu, Yongjun; Cui, Hongwang; Xia, Yunfeng; Gan, Hua

    2016-01-01

    Tubulointerstitial fibrosis (TIF) is caused by the progressive loss of renal tubular cells and the consequent replacement of the extracellular matrix. The progressive depletion of renal tubular cells results from apoptosis and necroptosis; however, the relative significance of each of these cell death mechanisms at different stages during the progression of chronic kidney disease (CKD) remains unclear. We sought to explore the mechanisms of renal tubular cell death during the early and intermediate stages of chronic renal damage of subtotal nephrectomied (SNx) rats. The results of tissue histological assays indicated that the numbers of necrotic dying cells and apoptotic cells were significantly higher in kidney tissues derived from a rat model of CKD. In addition, there was a significant increase in necroptosis observed by transmission electron microscopy (TEM) and an increase in the proportion of TUNEL-positive cells in kidney tissues from SNx rats compared with control rats, and necrostatin-1 (Nec-1) could inhibit necroptosis and reduce the proportion of TUNEL-positive cells. More importantly, we observed a significant increase in the incidence of necroptosis compared with apoptosis by TEM in vivo and in vitro and a significant increase in the proportion of TUNEL-positive tubular epithelial cells that did not express caspase-3 compared with those expressing cleaved caspase-3 in vitro. Furthermore, treatment with Nec-1 and zVAD strongly reduced necroptosis- and apoptosis-mediated renal tubular cell death and decreased the levels of blood urea nitrogen and serum creatinine and tubular damage scores of SNx rats. These results suggest that necroptotic cell death plays a more significant role than apoptosis in mediating the loss of renal tubular cells in SNx rats and that effectively blocking both necroptosis and apoptosis improves renal function and tubular damage at early and intermediate stages of CKD.

  20. Management of almond leaf scorch disease: long term data on yield, tree vitality, and disease progress

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Almond leaf scorch (ALS) disease has been a chronic problem for California almond growers. This disease is caused by the bacterial pathogen Xylella fastidiosa and is transmitted by xylem-feeding insects. Previous research suggested that retaining, rather than roguing, ALS-affected trees may be more ...

  1. The Relationship between Uric Acid Levels and Huntington’s Disease Progression

    PubMed Central

    Auinger, Peggy; Kieburtz, Karl; McDermott, Michael P.

    2009-01-01

    Uric acid (UA) may be associated with the progression of Parkinson’s disease and related neurodegenerative conditions; however, its association with Huntington’s disease (HD) progression has not been explored. A secondary analysis of 347 subjects from the CARE-HD clinical trial was performed to examine the relationship between baseline UA levels and the level of functional decline in HD. Outcomes included change in scores at 30 months for the Unified Huntington’s Disease Rating Scale components. There was less worsening of total functional capacity over time with increasing baseline UA levels (adjusted mean worsening in scores: 3.17, 2.99, 2.95, 2.28, 2.21, from lowest to highest UA quintile, p=0.03). These data suggest a possible association between higher UA levels and slower HD progression, particularly as measured by total functional capacity. If confirmed, UA could be an important predictor and potentially modifiable factor affecting the rate of HD progression. PMID:20063429

  2. Progress on stem cell research towards the treatment of Parkinson's disease.

    PubMed

    Gibson, Stuart A J; Gao, Guo-Dong; McDonagh, Katya; Shen, Sanbing

    2012-04-03

    Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive accumulation of Lewy body inclusions along with selective destruction of dopaminergic (DA) neurons in the nigrostriatal tract of the brain. Genetic studies have revealed much about the pathophysiology of PD, enabling the identification of both biomarkers for diagnosis and genetic targets for therapeutic treatment, which are evolved in tandem with the development of stem cell technologies. The discovery of induced pluripotent stem (iPS) cells facilitates the derivation of stem cells from adult somatic cells for personalized treatment and thus overcomes not only the limited availability of human embryonic stem cells but also ethical concerns surrounding their use. Non-viral, non-integration, or non-DNA-mediated reprogramming technologies are being developed. Protocols for generating midbrain DA neurons are undergoing constant refinement. The iPS cell-derived DA neurons provide cellular models for investigating disease progression in vitro and for screening molecules of novel therapeutic potential and have beneficial effects on improving the behavior of parkinsonian animals. Further progress in the development of safer non-viral/non-biased reprogramming strategies and the subsequent generation of homogenous midbrain DA neurons shall pave the way for clinical trials. A combined approach of drugs, cell replacement, and gene therapy to stop disease progression and to improve treatment may soon be within our reach.

  3. Progress with anti-tumor necrosis factor therapeutics for the treatment of inflammatory bowel disease.

    PubMed

    Fernandes, Carlos; Allocca, Mariangela; Danese, Silvio; Fiorino, Gionata

    2015-01-01

    Anti-tumor necrosis factor (TNF) therapy is a valid, effective and increasingly used option in inflammatory bowel disease management. Nevertheless, further knowledge and therapeutic indications regarding these drugs are still evolving. Anti-TNF therapy may be essential to achieve recently proposed end points, namely mucosal healing, prevention of bowel damage and prevention of patient's disability. Anti-TNF drugs are also suggested to be more effective in early disease, particularly in early Crohn's disease. Moreover, its efficacy for prevention of postoperative recurrence in Crohn's disease is still debated. Costs and adverse effects, the relevance of drug monitoring and the possibility of anti-TNF therapy withdrawal in selected patients are still debated issues. This review aimed to describe and discuss the most relevant data about the progress with anti-TNF therapy for the management of inflammatory bowel disease.

  4. Beneficial effects of the β-secretase inhibitor GRL-8234 in 5XFAD Alzheimer's transgenic mice lessen during disease progression.

    PubMed

    Devi, Latha; Tang, Jordan; Ohno, Masuo

    2015-01-01

    The β-secretase enzyme BACE1, which initiates the cleavage of amyloid precursor protein (APP) into the amyloid-β (Aβ) peptide, is a prime therapeutic target for Alzheimer's disease (AD). However, recent investigations using genetic animal models raise concern that therapeutic BACE1 inhibition may encounter the dramatic reduction of efficacy in ameliorating AD-like pathology and memory deficits during disease progression. Here, we compared the effects of the potent and selective small-molecule BACE1 inhibitor GRL-8234 in different pathological stages of AD mouse model. Specifically, we administered GRL-8234 (33.4 mg/kg, i.p.) once daily for 2 months to 5XFAD transgenic mice, which showed modest (4 months) and massive (10 months of age) Aβ plaque deposition at starting points. Chronic treatments with GRL-8234 reversed memory impairments, as tested by the spontaneous alternation Y-maze task, in the younger 5XFAD group concomitant with significant reductions in cerebral Aβ42 levels. In contrast, only marginal reductions of Aβ42 were observed in 12-month-old 5XFAD mice treated with GRL-8234 and their memory function remained impaired. We found that not only BACE1 but also full-length APP expression was significantly elevated with progressive Aβ accumulation in 5XFAD mice, while GRL-8234 failed to affect these detrimental mechanisms that further accelerate plaque growth in brains of older 5XFAD mice. Therefore, our results provide important insights into the mechanisms by which Aβ accumulation and related memory impairments become less responsive to rescue by BACE1 inhibition during the course of AD development.

  5. Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease

    SciTech Connect

    Lake, April D.; Novak, Petr; Shipkova, Petia; Aranibar, Nelly; Robertson, Donald; Reily, Michael D.; Lu, Zhenqiang; Lehman-McKeeman, Lois D.; Cherrington, Nathan J.

    2013-04-15

    Bile acids (BAs) have many physiological roles and exhibit both toxic and protective influences within the liver. Alterations in the BA profile may be the result of disease induced liver injury. Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of chronic liver disease characterized by the pathophysiological progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The hypothesis of this study is that the ‘classical’ (neutral) and ‘alternative’ (acidic) BA synthesis pathways are altered together with hepatic BA composition during progression of human NAFLD. This study employed the use of transcriptomic and metabolomic assays to study the hepatic toxicologic BA profile in progressive human NAFLD. Individual human liver samples diagnosed as normal, steatosis, and NASH were utilized in the assays. The transcriptomic analysis of 70 BA genes revealed an enrichment of downregulated BA metabolism and transcription factor/receptor genes in livers diagnosed as NASH. Increased mRNA expression of BAAT and CYP7B1 was observed in contrast to decreased CYP8B1 expression in NASH samples. The BA metabolomic profile of NASH livers exhibited an increase in taurine together with elevated levels of conjugated BA species, taurocholic acid (TCA) and taurodeoxycholic acid (TDCA). Conversely, cholic acid (CA) and glycodeoxycholic acid (GDCA) were decreased in NASH liver. These findings reveal a potential shift toward the alternative pathway of BA synthesis during NASH, mediated by increased mRNA and protein expression of CYP7B1. Overall, the transcriptomic changes of BA synthesis pathway enzymes together with altered hepatic BA composition signify an attempt by the liver to reduce hepatotoxicity during disease progression to NASH. - Highlights: ► Altered hepatic bile acid composition is observed in progressive NAFLD. ► Bile acid synthesis enzymes are transcriptionally altered in NASH livers. ► Increased levels of taurine and conjugated bile acids

  6. Vitamin-D pathway genes and HIV-1 disease progression in injection drug users.

    PubMed

    Laplana, Marina; Sánchez-de-la-Torre, Manuel; Puig, Teresa; Caruz, Antonio; Fibla, Joan

    2014-07-15

    Vitamin-D has pleiotropic effects on calcium and bone metabolism, cellular growth control, cell differentiation and modulation of both innate and acquired immune response. Previous studies revealed the association of vitamin-D receptor gene (VDR) polymorphism with infection diseases including HIV-1 infection. To assess for association between polymorphisms of vitamin-D pathway genes CYP27B1, vitamin-D binding protein (VDBP) and VDR with HIV-1 infection, disease progression to acquired immunodeficiency syndrome (AIDS) was analysed according to CDC93 criteria in a cohort of 185 HIV-1 seroprevalent patients belonging to the injection drug users. Genotype data was obtained from rs10877012, rs3782130 and rs4646536 markers at CYP27B1 locus; rs7041 and rs4588 at VDBP locus; and rs11568820, rs4516035, rs2228570, rs1544410 and rs17878969 at VDR locus. Distribution of genotypes between patients grouped by outcome was compared by contingency table analysis. Marker-marker interaction was assessed by a MDR analysis. Assuming an additive model for VDR markers, a Kaplan-Meier survival analysis was employed to evaluate association with disease progression. Among vitamin-D pathway genes, VDR locus reveals specific 5'UTR and 3'UTR diplotype combinations associated with both, slower and faster progression to AIDS. Marker-marker interaction analysis indicates a strong interaction between VDR markers and a redundant effect for CYP27B1 markers. According to our results, VDR locus association follows an additive model in which increased genetic risk score for the VDR is directly correlated with AIDS progression rates. Our data supports a role of vitamin-D pathway gene variability on HIV-1 disease progression.

  7. Fibulin-1 Predicts Disease Progression in Patients With Idiopathic Pulmonary Fibrosis

    PubMed Central

    Unger, Sofia; Corte, Tamera J.; Keller, Michael; Wolters, Paul J.; Richeldi, Luca; Cerri, Stefania; Prêle, Cecilia M.; Hansbro, Philip M.; Argraves, William Scott; Oliver, Rema A.; Oliver, Brian G.; Black, Judith L.; Burgess, Janette K.

    2014-01-01

    BACKGROUND: The underlying mechanisms of idiopathic pulmonary fibrosis (IPF) are unknown. This progressive disease has high mortality rates, and current models for prediction of mortality have limited value in identifying which patients will progress. We previously showed that the glycoprotein fibulin-1 is involved in enhanced proliferation and wound repair by mesenchymal cells and, thus, may contribute to lung fibrosis in IPF. METHODS: Serum, lung tissue, and lung function values were obtained from four independent locations (Sydney, NSW, and Perth, WA, Australia; San Francisco, CA; and Modena, Italy). Patients with IPF were followed for a minimum of 1 year and progression was defined as a significant decline in lung function or death. Primary parenchymal lung fibroblasts of 15 patients with and without IPF were cultured under nonstimulatory conditions. Fibulin-1 levels in serum, and secreted or deposited by fibroblasts, were measured by western blot and in lung tissue by immunohistochemistry. RESULTS: Serum fibulin-1 levels were increased in patients with IPF compared with subjects without lung disease (P = .006). Furthermore, tissue fibulin-1 levels were increased in patients with IPF (P = .02) and correlated negatively with lung function (r = −0.9, P < .05). Primary parenchymal fibroblasts from patients with IPF produced more fibulin-1 than those from subjects without IPF (P < .05). Finally, serum fibulin-1 levels at first blood draw predicted disease progression in IPF within 1 year (area under the curve , 0.71; 95% CI, 0.57-0.86; P = .012). CONCLUSIONS: Fibulin-1 is a novel potential biomarker for disease progression in IPF and raises the possibility that it could be used as a target for the development of new treatments. PMID:24832167

  8. A Comparative Study Evaluating the Impact of Physical Exercise on Disease Progression in a Mouse Model of Alzheimer's Disease.

    PubMed

    Maliszewska-Cyna, Ewelina; Xhima, Kristiana; Aubert, Isabelle

    2016-05-01

    Evidence suggests that physical exercise can serve as a preventive strategy against Alzheimer's disease (AD). In contrast, much less is known about the impact of exercise when it is introduced after cognitive deficits are established. Using the TgCRND8 mouse model of amyloidosis, we compared the effects of exercise as an intervention strategy aimed at altering disease progression. Voluntary running for 1 month or 2 months was introduced in 3-month-old TgCRND8 mice, which exhibit amyloid-beta (Aβ) plaque pathology and cognitive deficits at this age. Specifically, we examined Aβ plaque load, spatial memory, and neurogenesis in the dentate gyrus in the hippocampus. After 1 month of running, TgCRND8 mice spent more time in the novel arm of the Y-maze compared to the familiar arms, indicating improved memory. The levels of doublecortin (a marker of immature neurons) were increased in TgCRND8 mice running for 1 month, but with no significant difference in the number of new mature neurons or plaque burden. As the disease progressed, running prevented further deficits in the Y-maze performance and hippocampal neurogenesis and it reduced plaque load pathology in TgCRND8 mice running for 2 months, compared to non-running transgenics. Therefore, the impact of running on memory, neurogenesis, and amyloid pathology was of greater significance when sustained through later stages of the disease. PMID:27163797

  9. MAPPING THE PROGRESSION OF ATROPHY IN EARLY AND LATE ONSET ALZHEIMER’S DISEASE

    PubMed Central

    Migliaccio, R; Agosta, F; Possin, KL; Canu, E; Filippi, M; Rabinovici, GD; Rosen, HJ; Miller, BL; Gorno-Tempini, ML

    2015-01-01

    The term early age-of-onset Alzheimer’s disease (EOAD) identifies patients who meet criteria for AD, but show onset of symptoms before the age of 65. We map progression of gray matter (GM) atrophy in EOAD patients compared to late onset AD (LOAD). T1-weighted MRI scans were obtained at diagnosis and one-year follow-up from 15 EOAD, 10 LOAD, and 38 age-matched controls. Voxel-based and tensor-based morphometry were used, respectively, to assess the baseline and progression of atrophy. At baseline, EOAD patients already showed a widespread atrophy in temporal, parietal, occipital and frontal cortices. After one year, EOAD had atrophy progression in medial temporal and medial parietal cortices. At baseline, LOAD patients showed atrophy in the medial temporal regions only, and, after one year, an extensive pattern of atrophy progression in the same neocortical cortices of EOAD. Although atrophy mainly involved different lateral neocortical or medial temporal hubs at baseline, it eventually progressed along the same brain default-network regions in both groups. The cortical region showing a significant progression in both groups was the medial precuneus/posterior cingulate. PMID:25737041

  10. Disease progression subtype discovery from longitudinal EMR data with a majority of missing values and unknown initial time points.

    PubMed

    Huopaniemi, Ilkka; Nadkarni, Girish; Nadukuru, Rajiv; Lotay, Vaneet; Ellis, Steve; Gottesman, Omri; Bottinger, Erwin P

    2014-01-01

    Electronic medical records (EMR) contain a longitudinal collection of laboratory data that contains valuable phenotypic information on disease progression of a large collection of patients. These data can be potentially used in medical research or patient care; finding disease progression subtypes is a particularly important application. There are, however, two significant difficulties in utilizing this data for statistical analysis: (a) a large proportion of data is missing and (b) patients are in very different stages of disease progression and there are no well-defined start points of the time series. We present a Bayesian machine learning model that overcomes these difficulties. The method can use highly incomplete time-series measurement of varying lengths, it aligns together similar trajectories in different phases and is capable of finding consistent disease progression subtypes. We demonstrate the method on finding chronic kidney disease progression subtypes.

  11. Disease progression despite early loss of polyglutamine protein expression in SCA7 mouse model.

    PubMed

    Helmlinger, Dominique; Abou-Sleymane, Gretta; Yvert, Gaël; Rousseau, Stéphane; Weber, Chantal; Trottier, Yvon; Mandel, Jean-Louis; Devys, Didier

    2004-02-25

    Nine neurodegenerative diseases including Huntington's disease (HD) and spinocerebellar ataxia type 7 (SCA7) are caused by an expansion of a polyglutamine (polyQ) stretch in the respective proteins. Aggregation of expanded polyQ-containing proteins into the nucleus is a hallmark of these diseases. Recent evidence indicates that transcriptional dysregulation may contribute to the molecular pathogenesis of these diseases. Using SCA7 and HD mouse models in which we recently described a retinal phenotype, we investigated whether altered gene expression underlies photoreceptor dysfunction. In both models, rhodopsin promoter activity was early and dramatically repressed, suggesting that downregulation of photoreceptor-specific genes plays a major role in polyQ-induced retinal dysfunction. Because the rhodopsin promoter drives mutant ataxin-7 expression in our SCA7 mice, we also assessed whether downregulation of mutant SCA7 transgene would reverse retinopathy progression and aggregate formation. Although residual expression of mutant ataxin-7 was found negligible from 9 weeks of age, SCA7 transgenic mice showed a progressive decline of photoreceptor activity leading to a complete loss of electroretinographic responses from 1 year of age. At this age, aggregates were cleared in only half of the photoreceptors, indicating that their formation is not fully reversible in this model. We demonstrate here that abolishing full-length mutant ataxin-7 expression did not reverse retinopathy progression in SCA7 mice, raising the possibility that some polyQ-induced pathological events might be irreversible. PMID:14985428

  12. View of God as benevolent and forgiving or punishing and judgmental predicts HIV disease progression.

    PubMed

    Ironson, Gail; Stuetzle, Rick; Ironson, Dale; Balbin, Elizabeth; Kremer, Heidemarie; George, Annie; Schneiderman, Neil; Fletcher, Mary Ann

    2011-12-01

    This study assessed the predictive relationship between View of God beliefs and change in CD4-cell and Viral Load (VL) in HIV positive people over an extended period. A diverse sample of HIVseropositive participants (N = 101) undergoing comprehensive psychological assessment and blood draws over the course of 4 years completed the View of God Inventory with subscales measuring Positive View (benevolent/forgiving) and Negative View of God (harsh/judgmental/punishing). Adjusting for initial disease status, age, gender, ethnicity, education, and antiretroviral medication (at every 6-month visit), a Positive View of God predicted significantly slower disease-progression (better preservation of CD4-cells, better control of VL), whereas a Negative View of God predicted faster disease-progression over 4 years. Effect sizes were greater than those previously demonstrated for psychosocial variables known to predict HIV-disease-progression, such as depression and coping. Results remained significant even after adjusting for church attendance and psychosocial variables (health behaviors, mood, and coping). These results provide good initial evidence that spiritual beliefs may predict health outcomes.

  13. Kinetics of disease progression and host response in a rat model of bubonic plague.

    PubMed

    Sebbane, Florent; Gardner, Donald; Long, Daniel; Gowen, Brian B; Hinnebusch, B Joseph

    2005-05-01

    Plague, caused by the gram-negative bacterium Yersinia pestis, primarily affects rodents but is also an important zoonotic disease of humans. Bubonic plague in humans follows transmission by infected fleas and is characterized by an acute, necrotizing lymphadenitis in the regional lymph nodes that drain the intradermal flea bite site. Septicemia rapidly follows with spread to spleen, liver, and other organs. We developed a model of bubonic plague using the inbred Brown Norway strain of Rattus norvegicus to characterize the progression and kinetics of infection and the host immune response after intradermal inoculation of Y. pestis. The clinical signs and pathology in the rat closely resembled descriptions of human bubonic plague. The bacteriology; histopathology; host cellular response in infected lymph nodes, blood, and spleen; and serum cytokine levels were analyzed at various times after infection to determine the kinetics and route of disease progression and to evaluate hypothesized Y. pestis pathogenic mechanisms. Understanding disease progression in this rat infection model should facilitate further investigations into the molecular pathogenesis of bubonic plague and the immune response to Y. pestis at different stages of the disease.

  14. Does study partner type impact the rate of Alzheimer's disease progression?

    PubMed

    Grill, Joshua D; Zhou, Yan; Karlawish, Jason; Elashoff, David

    2014-01-01

    Most patients with Alzheimer's disease (AD) do not have a spouse. Despite this, the majority of AD research participants enroll with a spouse study partner. It remains unclear if differences between AD patients who do and do not have a spouse may bias study results. In this study, we examined whether AD patients with different study partner types (spouse versus adult child) demonstrate different rates of disease progression over two years on three outcome measures commonly used in AD research, including clinical trials. We used data from the National Alzheimer's Coordinating Center Uniform Data Set to examine disease progression in participants age 55-90 with probable AD dementia. We examined disease progression as measured by the Clinical Dementia Rating Scale-Sum of the Boxes score, the Mini Mental Status Examination, and the Functional Assessment Questionnaire. Analyses were performed on data for all available eligible participants from the NACC UDS and after performing a propensity-matching model to better account for inherent differences between the populations of interest. Propensity matching was successful only when models did not include age and gender. For both propensity-matched analyses and those of all available data, we did not observe any differences between the study partner populations for any outcome measure. These results suggest that if investigators can improve in recruiting AD patients with adult child caregivers to research, the implications to study results may be minimal.

  15. Sexual dimorphism in disease onset and progression of a rat model of ALS.

    PubMed

    Suzuki, Masatoshi; Tork, Craig; Shelley, Brandon; McHugh, Jacalyn; Wallace, Kyle; Klein, Sandra M; Lindstrom, Mary J; Svendsen, Clive N

    2007-02-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease causing the progressive loss of brain and spinal cord motor neurons. The exact etiology of ALS is still uncertain, but males have consistently been shown to be at a higher risk for the disease than females. Recently, transgenic rats overexpressing mutant forms of the human SOD1 (hSOD1) gene have been established as a valuable disease model of ALS. Here we show that sexual dimorphism in disease onset is also observed in hSOD1G93A transgenic rats. Disease onset was consistently earlier in male than in female hSOD1G93A rats. We also found that hSOD1G93A male rats lost weight more rapidly following disease onset compared to hSOD1G93A females. Furthermore, we tested locomotor function using the Basso-Beattie-Bresnahan (BBB) rating scale and a beam walking test. We found that motor dysfunction started earlier in males than in females but progressed similarly in the two sexes. These results have important implications for future experimentation and therapeutic development using the rat model of ALS. PMID:17364431

  16. Identification of serological biomarkers of infection, disease progression and treatment efficacy for leprosy.

    PubMed

    Spencer, John S; Duthie, Malcolm S; Geluk, Annemieke; Balagon, Marivic F; Kim, Hee Jin; Wheat, William H; Chatterjee, Delphi; Jackson, Mary; Li, Wei; Kurihara, Jade N; Maghanoy, Armi; Mallari, Irene; Saunderson, Paul; Brennan, Patrick J; Dockrell, Hazel M

    2012-12-01

    Although leprosy is curable with drug treatment, the identification of biomarkers of infection, disease progression and treatment efficacy would greatly help to reduce the overall prevalence of the disease. Reliable biomarkers would also reduce the incidence of grade-2 disability by ensuring that those who are most at risk are diagnosed and treated early or offered repeated treatments in the case of relapse. In this study, we examined the reactivity of sera from lepromatous and tuberculoid leprosy patients (LPs) against a panel of 12 recombinant Mycobacterium leprae proteins and found that six proteins were strongly recognised by multibacillary (MB) patients, while only three were consistently recognised by paucibacillary patients. To better understand the dynamics of patient antibody responses during and after drug therapy, we measured antibody titres to four recombinant proteins, phenolic glycolipid-I and lipoarabinomannan at baseline and up to two years after diagnosis to investigate the temporal changes in the antibody titres. Reactivity patterns to individual antigens and decreases in antibody titres were patient-specific. Antibody titres to proteins declined more rapidly vs. those to carbohydrate and glycolipid antigens. Compared to baseline values, increases in antibody titres were observed during reactional episodes in one individual. Additionally, antibody responses against a subset of antigens that provided a good prognostic indicator of disease progression were analysed in 51 household contacts of MB index cases for up to two years. Although the majority of these contacts showed no change or exhibited decreases in antibody titres, seven individuals developed higher titres towards one or more of these antigens and one individual with progressively higher titres was diagnosed with borderline lepromatous leprosy 19 months after enrolment. The results of this study indicate that antibody titres to specific M. leprae antigens can be used to monitor treatment

  17. High Resolution Discovery Proteomics Reveals Candidate Disease Progression Markers of Alzheimer’s Disease in Human Cerebrospinal Fluid

    PubMed Central

    Lee, Anita Y. H.; Song, Qinghua; Liaw, Andy; Wiener, Matt; Paweletz, Cloud P.; Seeburger, Jeffrey L.; Li, Jenny; Meng, Fanyu; Deyanova, Ekaterina G.; Mazur, Matthew T.; Settlage, Robert E.; Zhao, Xuemei; Southwick, Katie; Du, Yi; Holder, Dan; Sachs, Jeffrey R.; Laterza, Omar F.; Dallob, Aimee; Chappell, Derek L.; Snyder, Karen; Modur, Vijay; King, Elizabeth; Joachim, Catharine; Bondarenko, Andrey Y.; Shearman, Mark; Soper, Keith A.; Smith, A. David; Potter, William Z.; Koblan, Ken S.; Sachs, Alan B.

    2015-01-01

    Disease modifying treatments for Alzheimer’s disease (AD) constitute a major goal in medicine. Current trends suggest that biomarkers reflective of AD neuropathology and modifiable by treatment would provide supportive evidence for disease modification. Nevertheless, a lack of quantitative tools to assess disease modifying treatment effects remains a major hurdle. Cerebrospinal fluid (CSF) biochemical markers such as total tau, p-tau and Ab42 are well established markers of AD; however, global quantitative biochemical changes in CSF in AD disease progression remain largely uncharacterized. Here we applied a high resolution open discovery platform, dMS, to profile a cross-sectional cohort of lumbar CSF from post-mortem diagnosed AD patients versus those from non-AD/non-demented (control) patients. Multiple markers were identified to be statistically significant in the cohort tested. We selected two markers SME-1 (p<0.0001) and SME-2 (p = 0.0004) for evaluation in a second independent longitudinal cohort of human CSF from post-mortem diagnosed AD patients and age-matched and case-matched control patients. In cohort-2, SME-1, identified as neuronal secretory protein VGF, and SME-2, identified as neuronal pentraxin receptor-1 (NPTXR), in AD were 21% (p = 0.039) and 17% (p = 0.026) lower, at baseline, respectively, than in controls. Linear mixed model analysis in the longitudinal cohort estimate a decrease in the levels of VGF and NPTXR at the rate of 10.9% and 6.9% per year in the AD patients, whereas both markers increased in controls. Because these markers are detected by mass spectrometry without the need for antibody reagents, targeted MS based assays provide a clear translation path for evaluating selected AD disease-progression markers with high analytical precision in the clinic. PMID:26270474

  18. HIV-1 DNA predicts disease progression and post-treatment virological control.

    PubMed

    Williams, James P; Hurst, Jacob; Stöhr, Wolfgang; Robinson, Nicola; Brown, Helen; Fisher, Martin; Kinloch, Sabine; Cooper, David; Schechter, Mauro; Tambussi, Giuseppe; Fidler, Sarah; Carrington, Mary; Babiker, Abdel; Weber, Jonathan; Koelsch, Kersten K; Kelleher, Anthony D; Phillips, Rodney E; Frater, John

    2014-01-01

    In HIV-1 infection, a population of latently infected cells facilitates viral persistence despite antiretroviral therapy (ART). With the aim of identifying individuals in whom ART might induce a period of viraemic control on stopping therapy, we hypothesised that quantification of the pool of latently infected cells in primary HIV-1 infection (PHI) would predict clinical progression and viral replication following ART. We measured HIV-1 DNA in a highly characterised randomised population of individuals with PHI. We explored associations between HIV-1 DNA and immunological and virological markers of clinical progression, including viral rebound in those interrupting therapy. In multivariable analyses, HIV-1 DNA was more predictive of disease progression than plasma viral load and, at treatment interruption, predicted time to plasma virus rebound. HIV-1 DNA may help identify individuals who could safely interrupt ART in future HIV-1 eradication trials. PMID:25217531

  19. HIV-1 DNA predicts disease progression and post-treatment virological control.

    PubMed

    Williams, James P; Hurst, Jacob; Stöhr, Wolfgang; Robinson, Nicola; Brown, Helen; Fisher, Martin; Kinloch, Sabine; Cooper, David; Schechter, Mauro; Tambussi, Giuseppe; Fidler, Sarah; Carrington, Mary; Babiker, Abdel; Weber, Jonathan; Koelsch, Kersten K; Kelleher, Anthony D; Phillips, Rodney E; Frater, John

    2014-09-12

    In HIV-1 infection, a population of latently infected cells facilitates viral persistence despite antiretroviral therapy (ART). With the aim of identifying individuals in whom ART might induce a period of viraemic control on stopping therapy, we hypothesised that quantification of the pool of latently infected cells in primary HIV-1 infection (PHI) would predict clinical progression and viral replication following ART. We measured HIV-1 DNA in a highly characterised randomised population of individuals with PHI. We explored associations between HIV-1 DNA and immunological and virological markers of clinical progression, including viral rebound in those interrupting therapy. In multivariable analyses, HIV-1 DNA was more predictive of disease progression than plasma viral load and, at treatment interruption, predicted time to plasma virus rebound. HIV-1 DNA may help identify individuals who could safely interrupt ART in future HIV-1 eradication trials.

  20. NMR-based lipidomic analysis of blood lipoproteins differentiates the progression of coronary heart disease.

    PubMed

    Kostara, Christina E; Papathanasiou, Athanasios; Psychogios, Nikolaos; Cung, Manh Thong; Elisaf, Moses S; Goudevenos, John; Bairaktari, Eleni T

    2014-05-01

    Abnormal lipid composition and metabolism of plasma lipoproteins play a crucial role in the pathogenesis of coronary heart disease (CHD). A (1)H NMR-based lipidomic approach was used to investigate the correlation of coronary artery stenosis with the atherogenic (non-HDL) and atheroprotective (HDL) lipid profiles in 99 patients with CHD of various stages of disease and compared with 60 patients with normal coronary arteries (NCA), all documented in coronary angiography. The pattern recognition models created from lipid profiles predicted the presence of CHD with a sensitivity of 87% and a specificity of 88% in the HDL model and with 90% and 89% in the non-HDL model, respectively. Patients with mild, moderate, and severe coronary artery stenosis were progressively differentiated from those with NCA in the non-HDL model with a statistically significant separation of severe stage from both mild and moderate. In the HDL model, the progressive differentiation of the disease stages was statistically significant only between patients with mild and severe coronary artery stenosis. The lipid constituents of lipoproteins that mainly characterized the initial stages and then the progression of the disease were the high levels of saturated fatty acids in lipids in both HDL and non-HDL particles, the low levels of HDL-phosphatidylcholine, HDL-sphingomyelin, and omega-3 fatty acids and linoleic acid in lipids in non-HDL particles. The conventional lipid marker, total cholesterol, found in low levels in HDL and in high levels in non-HDL, also contributed to the onset of the disease but with a much lower coefficient of significance. (1)H NMR-based lipidomic analysis of atherogenic and atheroprotective lipoproteins could contribute to the early evaluation of the onset of coronary artery disease and possibly to the establishment of an appropriate therapeutic option.

  1. Disease progression by infecting HIV-1 subtype in a seroconverter cohort in sub-Saharan Africa

    PubMed Central

    Amornkul, Pauli N.; Karita, Etienne; Kamali, Anatoli; Rida, Wasima N.; Sanders, Eduard J.; Lakhi, Shabir; Price, Matt A.; Kilembe, William; Cormier, Emmanuel; Anzala, Omu; Latka, Mary H.; Bekker, Linda-Gail; Allen, Susan A.; Gilmour, Jill; Fast, Patricia E.

    2013-01-01

    Objective: To describe immunologic, virologic, and clinical HIV disease progression by HIV-1 subtype among Africans with well documented estimated dates of HIV infection (EDIs). Design: Prospective cohort. Methods: Adults and youth with documented HIV-1 infection in the past 12 months were recruited from seroincidence cohorts in East and Southern Africa and followed at 3–6 month intervals. Blood for lymphocyte subset and viral load determination was collected at each visit. Pol was sequenced from the first positive specimen to ascertain subtype. Preantiretroviral therapy disease progression was measured by three time-to-event endpoints: CD4+ cell count 350 cells/μl or less, viral load measurement at least 1 × 105 copies/ml, and clinical AIDS. Results: From 2006 to 2011, 615 participants were enrolled at nine research centers in Kenya, Rwanda, South Africa, Uganda, and Zambia; 579 (94.1%) had viral subtyping completed. Predominant subtypes were C (256, 44.2%), A (209, 36.1%), and D (84, 14.5%). After adjustment for age, sex, and human leukocyte antigen alleles in Cox regression analyses, subtype C-infected participants progressed faster than subtype A to all three endpoints [CD4+ hazard ratio 1.60, 95% (confidence interval) CI 1.16, 2.20; viral load hazard ratio 1.59, 95% CI 1.12, 2.25; and AIDS hazard ratio 1.60, 95% CI 1.11, 2.31). Subtype D-infected participants reached high viral load more rapidly (hazard ratio 1.61, 95% CI 1.01, 2.57) and progressed nearly twice as fast to AIDS compared to subtype A (hazard ratio 1.93, 95% CI 1.21, 3.09). Conclusion: Subtype-specific differences in HIV disease progression suggest that the local subtype distribution be considered when planning HIV programs and designing and defining clinical endpoints for HIV prevention trials. PMID:24113395

  2. Gut Microbiota in HIV Infection: Implication for Disease Progression and Management

    PubMed Central

    Nwosu, Felix Chinweije; Avershina, Ekaterina; Wilson, Robert; Rudi, Knut

    2014-01-01

    Survival rates among HIV patients have significantly improved since the introduction of antiretroviral therapy (ART) in HIV management. However, persistent disease progression and clinical complications in virally suppressed individuals point to additional contributing factors other than HIV replication; microbial translocation is one such factor. The role of underlying commensal microbes and microbial products that traverse the intestinal lumen into systemic circulation in the absence of overt bacteraemia is under current investigation. This review focuses on current knowledge of the complex microbial communities and microbial markers involved in the disruption of mucosal immune T-cells in the promotion of inflammatory processes in HIV infections. Unanswered questions and aims for future studies are addressed. We provide perspective for discussing potential future therapeutic strategies focused on modulating the gut microbiota to abate HIV disease progression. PMID:25024700

  3. Atypical presentation of Creutzfeldt-Jakob disease: a rare but important cause of rapidly progressive dementia.

    PubMed

    Taillefer, Marguerite S; Tangarorang, Glendo L; Kuchel, George A; Menkes, Daniel L

    2011-09-01

    We report an atypical presentation of sporadic Creutzfeldt-Jakob disease (CJD) in a 74-year-old woman that illustrates the difficulty in diagnosing this rare, but important, cause of rapidly progressive dementia. Despite well-established criteria, this diagnosis is often missed or substantially delayed (Table 1). In this case, a precipitous cognitive decline associated with a urinary tract infection initiallysuggested delirium. Although atypical CJD was considered as a cause when symptoms persisted, a definitive diagnosis was established postmortem when the cerebrospinal fluid (CSF) prion protein 14-3-3 tested positive. Creutzfeldt-Jakob disease must be considered in the differential diagnosis of rapidly progressive dementia as Connecticut accounts for approximately three of the more than 200 cases diagnosed nationally.

  4. Estimation of renal cell carcinoma treatment effects from disease progression modeling

    PubMed Central

    Maitland, Michael L.; Wu, Kehua; Sharma, Manish R.; Jin, Yuyan; Kang, Soonmo Peter; Stadler, Walter M.; Karrison, Theodore G.; Ratain, Mark J.; Bies, Robert R.

    2013-01-01

    To improve future drug development efficiency in renal cell carcinoma (RCC), a disease progression model was developed with longitudinal tumor size data from a phase III trial of sorafenib in RCC. The best fit model was externally evaluated on 145 placebo-treated patients in a phase III trial of pazopanib, and incorporated baseline tumor size, a linear disease progression component, and an exponential drug effect parameter. With the model-estimated effect of sorafenib on RCC growth we calculated the power of randomized phase II trials between sorafenib and hypothetical comparators over a range of effects. A hypothetical comparator with 80% greater drug effect than sorafenib would have 82% power (one-sided α = 0.1) with 50 patients per arm. Model-based quantitation of treatment effect with CT imaging offers a scaffold on which to develop new, more efficient, phase II trial endpoints and analytic strategies for RCC. PMID:23443753

  5. Ion channel genes and human neurological disease: Recent progress, prospects, and challenges

    PubMed Central

    Cooper, Edward C.; Jan, Lily Yeh

    1999-01-01

    What do epilepsy, migraine headache, deafness, episodic ataxia, periodic paralysis, malignant hyperthermia, and generalized myotonia have in common? These human neurological disorders can be caused by mutations in genes for ion channels. Many of the channel diseases are “paroxysmal disorders” whose principal symptoms occur intermittently in individuals who otherwise may be healthy and active. Some of the ion channels that cause human neurological disease are old acquaintances previously cloned and extensively studied by channel specialists. In other cases, however, disease-gene hunts have led the way to the identification of new channel genes. Progress in the study of ion channels has made it possible to analyze the effects of human neurological disease-causing channel mutations at the level of the single channel, the subcellular domain, the neuronal network, and the behaving organism. PMID:10220366

  6. Identification and Progression of Heart Disease Risk Factors in Diabetic Patients from Longitudinal Electronic Health Records

    PubMed Central

    Jonnagaddala, Jitendra; Liaw, Siaw-Teng; Ray, Pradeep; Kumar, Manish; Dai, Hong-Jie; Hsu, Chien-Yeh

    2015-01-01

    Heart disease is the leading cause of death worldwide. Therefore, assessing the risk of its occurrence is a crucial step in predicting serious cardiac events. Identifying heart disease risk factors and tracking their progression is a preliminary step in heart disease risk assessment. A large number of studies have reported the use of risk factor data collected prospectively. Electronic health record systems are a great resource of the required risk factor data. Unfortunately, most of the valuable information on risk factor data is buried in the form of unstructured clinical notes in electronic health records. In this study, we present an information extraction system to extract related information on heart disease risk factors from unstructured clinical notes using a hybrid approach. The hybrid approach employs both machine learning and rule-based clinical text mining techniques. The developed system achieved an overall microaveraged F-score of 0.8302. PMID:26380290

  7. [Infectious diseases--the progress is huge--a lot remains to be done].

    PubMed

    Dan, M

    2009-11-01

    Huge progress has been achieved in the last century in preventing and treating infections. The discovery of antibiotics and the ongoing development of appropriate vaccines have decreased the incidence of many infectious diseases. This led Sir McFarland Burnett to state in 1962 that 'By the end of the Second World War it was possible to say that almost all of the major practical problems of dealing with infectious disease had been solved.' More recently, however, new challenges have emerged: antibiotic resistance is spreading in hospitals as well as in communities, nosocomial infections are both a health problem and economic burden, and new infections have been emerging while others are reemerging. The articles included in this issue of Harefuah, which is dedicated to infectious diseases, exemplify the continuing challenges presented to the medical community by these diseases.

  8. TLR4 mutant mice are protected from renal fibrosis and chronic kidney disease progression

    PubMed Central

    Souza, Ana C P; Tsuji, Takayuki; Baranova, Irina N; Bocharov, Alexander V; Wilkins, Kenneth J; Street, Jonathan M; Alvarez-Prats, Alejandro; Hu, Xuzhen; Eggerman, Thomas; Yuen, Peter S T; Star, Robert A

    2015-01-01

    Chronic kidney disease (CKD) is associated with persistent low-grade inflammation and immunosuppression. In this study we tested the role of Toll-like receptor 4, the main receptor for endotoxin (LPS), in a mouse model of renal fibrosis and in a model of progressive CKD that better resembles the human disease. C3HeJ (TLR4 mutant) mice have a missense point mutation in the TLR4 gene, rendering the receptor nonfunctional. In a model of renal fibrosis after folic acid injection, TLR4 mutant mice developed less interstititial fibrosis in comparison to wild-type (WT) mice. Furthermore, 4 weeks after 5/6 nephrectomy with continuous low-dose angiotensin II infusion, C3HeOuJ (TLR4 WT) mice developed progressive CKD with albuminuria, increased serum levels of BUN and creatinine, glomerulosclerosis, and interstitial fibrosis, whereas TLR4 mutant mice were significantly protected from CKD progression. TLR4 WT mice also developed low-grade systemic inflammation, splenocyte apoptosis and increased expression of the immune inhibitory receptor PD-1 in the spleen, which were not observed in TLR4 mutant mice. In vitro, endotoxin (LPS) directly upregulated NLRP3 inflammasome expression in renal epithelial cells via TLR4. In summary, TLR4 contributes to renal fibrosis and CKD progression, at least in part, via inflammasome activation in renal epithelial cells, and may also participate in the dysregulated immune response that is associated with CKD. PMID:26416975

  9. Matrix metalloproteinase inhibitor, doxycycline and progression of calcific aortic valve disease in hyperlipidemic mice

    PubMed Central

    Jung, Jae-Joon; Razavian, Mahmoud; Kim, Hye-Yeong; Ye, Yunpeng; Golestani, Reza; Toczek, Jakub; Zhang, Jiasheng; Sadeghi, Mehran M.

    2016-01-01

    Calcific aortic valve disease (CAVD) is the most common cause of aortic stenosis. Currently, there is no non-invasive medical therapy for CAVD. Matrix metalloproteinases (MMPs) are upregulated in CAVD and play a role in its pathogenesis. Here, we evaluated the effect of doxycycline, a nonselective MMP inhibitor on CAVD progression in the mouse. Apolipoprotein (apo)E−/− mice (n = 20) were fed a Western diet (WD) to induce CAVD. After 3 months, half of the animals was treated with doxycycline, while the others continued WD alone. After 6 months, we evaluated the effect of doxycycline on CAVD progression by echocardiography, MMP-targeted micro single photon emission computed tomography (SPECT)/computed tomography (CT), and tissue analysis. Despite therapeutic blood levels, doxycycline had no significant effect on MMP activation, aortic valve leaflet separation or flow velocity. This lack of effect on in vivo images was confirmed on tissue analysis which showed a similar level of aortic valve gelatinase activity, and inflammation between the two groups of animals. In conclusion, doxycycline (100 mg/kg/day) had no effect on CAVD progression in apoE−/− mice with early disease. Studies with more potent and specific inhibitors are needed to establish any potential role of MMP inhibition in CAVD development and progression. PMID:27619752

  10. The Patterns, Risk Factors, and Prediction of Progression in Chronic Kidney Disease: A Narrative Review.

    PubMed

    Collister, David; Ferguson, Thomas; Komenda, Paul; Tangri, Navdeep

    2016-07-01

    Chronic kidney disease (CKD) is a global public health problem that is associated with excess morbidity, mortality, and health resource utilization. The progression of CKD is defined by a decrease in glomerular filtration rate and leads to a variety of metabolic abnormalities including acidosis, hypertension, anemia, and mineral bone disorder. Lower glomerular filtration rate also bears a strong relationship with an increased risk of cardiovascular events, end-stage renal disease, and death. Patterns of CKD progression include linear and nonlinear trajectories, but kidney function can remain stable for years in some individuals. Addressing modifiable risk factors for the progression of CKD is needed to attenuate its associated morbidity and mortality. Developing effective risk prediction models for CKD progression is critical to identify patients who are more likely to benefit from interventions and more intensive monitoring. Accurate risk-prediction algorithms permit systems to best align health care resources with risk to maximize their effects and efficiency while guiding overall decision making. PMID:27475658

  11. Matrix metalloproteinase inhibitor, doxycycline and progression of calcific aortic valve disease in hyperlipidemic mice.

    PubMed

    Jung, Jae-Joon; Razavian, Mahmoud; Kim, Hye-Yeong; Ye, Yunpeng; Golestani, Reza; Toczek, Jakub; Zhang, Jiasheng; Sadeghi, Mehran M

    2016-01-01

    Calcific aortic valve disease (CAVD) is the most common cause of aortic stenosis. Currently, there is no non-invasive medical therapy for CAVD. Matrix metalloproteinases (MMPs) are upregulated in CAVD and play a role in its pathogenesis. Here, we evaluated the effect of doxycycline, a nonselective MMP inhibitor on CAVD progression in the mouse. Apolipoprotein (apo)E(-/-) mice (n = 20) were fed a Western diet (WD) to induce CAVD. After 3 months, half of the animals was treated with doxycycline, while the others continued WD alone. After 6 months, we evaluated the effect of doxycycline on CAVD progression by echocardiography, MMP-targeted micro single photon emission computed tomography (SPECT)/computed tomography (CT), and tissue analysis. Despite therapeutic blood levels, doxycycline had no significant effect on MMP activation, aortic valve leaflet separation or flow velocity. This lack of effect on in vivo images was confirmed on tissue analysis which showed a similar level of aortic valve gelatinase activity, and inflammation between the two groups of animals. In conclusion, doxycycline (100 mg/kg/day) had no effect on CAVD progression in apoE(-/-) mice with early disease. Studies with more potent and specific inhibitors are needed to establish any potential role of MMP inhibition in CAVD development and progression. PMID:27619752

  12. Progress towards the elimination of transmission of Chagas disease in Latin America.

    PubMed

    Moncayo, A

    1997-01-01

    From a global perspective, Chagas disease represents the third largest tropical disease burden after malaria and schistosomiasis. The estimated average annual per-capita gross domestic product in Latin America is US$2,966. The economic loss for the continent due to early mortality and disability by this disease in economically most productive young adults currently amounts to US$8,156 million which is equivalent to 2.5% of the external debt of the whole continent in 1995. In 1991, the Ministers of Health of Argentina, Bolivia, Brazil, Chile, Paraguay and Uruguay, launched the Southern Cone Initiative for elimination of transmission of Chagas disease. The progress towards elimination of vectorial and transfusional transmission of Chagas disease in Uruguay, Chile, Argentina and Brazil has been documented by reports from the national control programmes of the above countries. Current data on disinfestation of houses, coverage of screening in blood banks and serology in children and young adults indicate that the interruption of the vectorial and transfusional transmission of Chagas disease will be achieved in these countries as follows: Uruguay and Chile in 1999, Brazil and Argentina in 2003. By eliminating the transmission of Chagas disease in the above countries, the incidence of the disease in the whole of Latin America will be reduced by more than 70%. PMID:9477549

  13. Real-time progressive hyperspectral remote sensing detection methods for crop pest and diseases

    NASA Astrophysics Data System (ADS)

    Wu, Taixia; Zhang, Lifu; Peng, Bo; Zhang, Hongming; Chen, Zhengfu; Gao, Min

    2016-05-01

    Crop pests and diseases is one of major agricultural disasters, which have caused heavy losses in agricultural production each year. Hyperspectral remote sensing technology is one of the most advanced and effective method for monitoring crop pests and diseases. However, Hyperspectral facing serial problems such as low degree of automation of data processing and poor timeliness of information extraction. It resulting we cannot respond quickly to crop pests and diseases in a critical period, and missed the best time for quantitative spraying control on a fixed point. In this study, we take the crop pests and diseases as research point and breakthrough, using a self-development line scanning VNIR field imaging spectrometer. Take the advantage of the progressive obtain image characteristics of the push-broom hyperspectral remote sensor, a synchronous real-time progressive hyperspectral algorithms and models will development. Namely, the object's information will get row by row just after the data obtained. It will greatly improve operating time and efficiency under the same detection accuracy. This may solve the poor timeliness problem when we using hyperspectral remote sensing for crop pests and diseases detection. Furthermore, this method will provide a common way for time-sensitive industrial applications, such as environment, disaster. It may providing methods and technical reserves for the development of real-time detection satellite technology.

  14. Progressive loss of BDNF in a mouse model of Huntington's disease and rescue by BDNF delivery.

    PubMed

    Zuccato, Chiara; Liber, Daniel; Ramos, Catarina; Tarditi, Alessia; Rigamonti, Dorotea; Tartari, Marzia; Valenza, Marta; Cattaneo, Elena

    2005-08-01

    Huntingtin is a protein of 348 kDa that is mutated in Huntington's disease (HD), a dominantly inherited neurodegenerative disorder. Previous data have led us to propose that aspects of the disease arise from both a loss of the neuroprotective function of the wild-type protein, and a toxic activity gained by the mutant protein. In particular, we have shown that wild-type huntingtin stimulates the production of brain-derived neurotrophic factor (BDNF), a pro-survival factor for the striatal neurons that die in the pathology. Wild-type huntingtin controls BDNF gene transcription in cerebral cortex, which is then delivered to its striatal targets. In the disease state, supply of cortical BDNF to the striatum is strongly reduced, possibly leading to striatal vulnerability. Here we show that a reduction in cortical BDNF messenger level correlates with the progression of the disease in a mouse model of HD. In particular, we show that the progressive loss of mRNAs transcribed from BDNF exon II, III and IV follows a different pattern that may reflect different upstream mechanisms impaired by mutation in huntingtin. On this basis, we also discuss the possibility that delivery of BDNF may represent an useful strategy for Huntington's disease treatment. PMID:15967378

  15. Pazopanib treatment slows progression and stabilizes disease in patients with taxane-resistant cutaneous angiosarcoma.

    PubMed

    Ogata, Dai; Yanagisawa, Hiroto; Suzuki, Kenji; Oashi, Kohei; Yamazaki, Naoya; Tsuchida, Tetsuya

    2016-10-01

    Although cutaneous angiosarcoma (cAS) has one of the worst prognoses among malignant skin tumors, few effective drug options for secondary treatment have been discovered to date because of the limited number of cases. Therefore, this study was aimed at determining pazopanib's potential as a new cAS treatment option. We retrospectively evaluated five patients with taxane-resistant unresectable cAS treated with pazopanib at a university hospital. Their characteristics and treatment outcomes were retrieved from their records. Progression-free survival (PFS), overall survival (OS), disease progression, and toxicity were evaluated; furthermore, the response to pazopanib was assessed in relation to the expression of vascular endothelial growth factor receptor 2 (VEGFR-2). The median PFS from the time of pazopanib initiation was 94 days. Two patients showed partial response, two showed stable disease, and one had progressive disease in the case of the best overall response. VEGFR-2 expression was positive in all cases, and patients with high expression had improved median OS compared to that in those with low expression. VEGFR-2 expression was correlated with a longer OS. The most common toxicities were hypertension and anorexia followed by myelosuppression. This is the largest case series reported wherein pazopanib was used for taxane-resistant cAS. Although the cytoreductive effect and survival benefits were not significant in this small sample, we consider pazopanib a valid treatment option for preserving patients' quality of life. Our results suggest pazopanib treatment slows the progression of disease and stabilizes it in patients with taxane-resistant cAS.

  16. Current Progress in Nanotechnology Applications for Diagnosis and Treatment of Kidney Diseases

    PubMed Central

    Lee, Sue Hyun; Lee, Jung Bok; Bae, Min Soo; Balikov, Daniel A.; Hwang, Amy; Boire, Timothy C.; Kwon, Il Keun; Sung, Hak-Joon

    2016-01-01

    Significant progress has been made in nanomedicine, primarily in the form of nanoparticles, for theranostic applications to various diseases. A variety of materials, both organic and inorganic, have been used to develop nanoparticles with promise to achieve improved efficacy in medical applications as well as reduced systemic side effects compared to current standard of care medical practices. In particular, this article highlights the recent development and application of nanoparticles for diagnosing and treating nephropathologies. PMID:26121684

  17. Pazopanib treatment slows progression and stabilizes disease in patients with taxane-resistant cutaneous angiosarcoma.

    PubMed

    Ogata, Dai; Yanagisawa, Hiroto; Suzuki, Kenji; Oashi, Kohei; Yamazaki, Naoya; Tsuchida, Tetsuya

    2016-10-01

    Although cutaneous angiosarcoma (cAS) has one of the worst prognoses among malignant skin tumors, few effective drug options for secondary treatment have been discovered to date because of the limited number of cases. Therefore, this study was aimed at determining pazopanib's potential as a new cAS treatment option. We retrospectively evaluated five patients with taxane-resistant unresectable cAS treated with pazopanib at a university hospital. Their characteristics and treatment outcomes were retrieved from their records. Progression-free survival (PFS), overall survival (OS), disease progression, and toxicity were evaluated; furthermore, the response to pazopanib was assessed in relation to the expression of vascular endothelial growth factor receptor 2 (VEGFR-2). The median PFS from the time of pazopanib initiation was 94 days. Two patients showed partial response, two showed stable disease, and one had progressive disease in the case of the best overall response. VEGFR-2 expression was positive in all cases, and patients with high expression had improved median OS compared to that in those with low expression. VEGFR-2 expression was correlated with a longer OS. The most common toxicities were hypertension and anorexia followed by myelosuppression. This is the largest case series reported wherein pazopanib was used for taxane-resistant cAS. Although the cytoreductive effect and survival benefits were not significant in this small sample, we consider pazopanib a valid treatment option for preserving patients' quality of life. Our results suggest pazopanib treatment slows the progression of disease and stabilizes it in patients with taxane-resistant cAS. PMID:27613162

  18. Rapidly progressive Alzheimer’s disease features distinct structures of amyloid-β

    PubMed Central

    Cohen, Mark L.; Kim, Chae; Haldiman, Tracy; ElHag, Mohamed; Mehndiratta, Prachi; Pichet, Termsarasab; Lissemore, Frances; Shea, Michelle; Cohen, Yvonne; Chen, Wei; Blevins, Janis; Appleby, Brian S.; Surewicz, Krystyna; Surewicz, Witold K.; Sajatovic, Martha; Tatsuoka, Curtis; Zhang, Shulin; Mayo, Ping; Butkiewicz, Mariusz; Haines, Jonathan L.; Lerner, Alan J.

    2015-01-01

    Genetic and environmental factors that increase the risk of late-onset Alzheimer disease are now well recognized but the cause of variable progression rates and phenotypes of sporadic Alzheimer’s disease is largely unknown. We aimed to investigate the relationship between diverse structural assemblies of amyloid-β and rates of clinical decline in Alzheimer’s disease. Using novel biophysical methods, we analysed levels, particle size, and conformational characteristics of amyloid-β in the posterior cingulate cortex, hippocampus and cerebellum of 48 cases of Alzheimer’s disease with distinctly different disease durations, and correlated the data with APOE gene polymorphism. In both hippocampus and posterior cingulate cortex we identified an extensive array of distinct amyloid-β42 particles that differ in size, display of N-terminal and C-terminal domains, and conformational stability. In contrast, amyloid-β40 present at low levels did not form a major particle with discernible size, and both N-terminal and C- terminal domains were largely exposed. Rapidly progressive Alzheimer’s disease that is associated with a low frequency of APOE e4 allele demonstrates considerably expanded conformational heterogeneity of amyloid-β42, with higher levels of distinctly structured amyloid-β42 particles composed of 30–100 monomers, and fewer particles composed of < 30 monomers. The link between rapid clinical decline and levels of amyloid-β42 with distinct structural characteristics suggests that different conformers may play an important role in the pathogenesis of distinct Alzheimer’s disease phenotypes. These findings indicate that Alzheimer’s disease exhibits a wide spectrum of amyloid-β42 structural states and imply the existence of prion-like conformational strains.

  19. Rapidly progressive Alzheimer’s disease features distinct structures of amyloid-β

    PubMed Central

    Cohen, Mark L.; Kim, Chae; Haldiman, Tracy; ElHag, Mohamed; Mehndiratta, Prachi; Pichet, Termsarasab; Lissemore, Frances; Shea, Michelle; Cohen, Yvonne; Chen, Wei; Blevins, Janis; Appleby, Brian S.; Surewicz, Krystyna; Surewicz, Witold K.; Sajatovic, Martha; Tatsuoka, Curtis; Zhang, Shulin; Mayo, Ping; Butkiewicz, Mariusz; Haines, Jonathan L.; Lerner, Alan J.

    2015-01-01

    Genetic and environmental factors that increase the risk of late-onset Alzheimer disease are now well recognized but the cause of variable progression rates and phenotypes of sporadic Alzheimer’s disease is largely unknown. We aimed to investigate the relationship between diverse structural assemblies of amyloid-β and rates of clinical decline in Alzheimer’s disease. Using novel biophysical methods, we analysed levels, particle size, and conformational characteristics of amyloid-β in the posterior cingulate cortex, hippocampus and cerebellum of 48 cases of Alzheimer’s disease with distinctly different disease durations, and correlated the data with APOE gene polymorphism. In both hippocampus and posterior cingulate cortex we identified an extensive array of distinct amyloid-β42 particles that differ in size, display of N-terminal and C-terminal domains, and conformational stability. In contrast, amyloid-β40 present at low levels did not form a major particle with discernible size, and both N-terminal and C- terminal domains were largely exposed. Rapidly progressive Alzheimer’s disease that is associated with a low frequency of APOE e4 allele demonstrates considerably expanded conformational heterogeneity of amyloid-β42, with higher levels of distinctly structured amyloid-β42 particles composed of 30–100 monomers, and fewer particles composed of < 30 monomers. The link between rapid clinical decline and levels of amyloid-β42 with distinct structural characteristics suggests that different conformers may play an important role in the pathogenesis of distinct Alzheimer’s disease phenotypes. These findings indicate that Alzheimer’s disease exhibits a wide spectrum of amyloid-β42 structural states and imply the existence of prion-like conformational strains. PMID:25688081

  20. Progression of carotid-artery disease in type 2 diabetic patients: a cohort prospective study.

    PubMed

    Bosevski, Marijan; Stojanovska, Lily

    2015-01-01

    In order to assess the progression of carotid-artery disease in type 2 diabetic cohort (n=207 patients), the dynamic change in carotid intima-media thickness (CIMT) and the occurrence of plaques were followed for a period of 31.35±10.59 months. The mean CIMT at the beginning of the study was 0.9178±0.1447 mm, with a maximal value of 1.1210±0.2366 mm. The maximal value of CIMT changed by 0.07 mm/year. Progression of CIMT was noted in 86.8% and its regression in 7.8% of patients. The occurrence of carotid plaques was detected in 41.8% of patients. Multiple regression analysis revealed the maximal value of CIMT to be associated with diastolic blood pressure, despite mean CIMT being predicted by body mass index. The presence of peripheral arterial disease and hypo-high-density lipoproteinemia were found to be predictors for the occurrence of carotid plaques. Our data have clinical implications in predicting risk factors for the progression of carotid-artery disease in type 2 diabetic patients for their appropriate management. PMID:26527880

  1. Tumour necrosis factor-α inhibition can stabilize disease in progressive vitiligo.

    PubMed

    Webb, K C; Tung, R; Winterfield, L S; Gottlieb, A B; Eby, J M; Henning, S W; Le Poole, I C

    2015-09-01

    Tumour necrosis factor (TNF)-α, a proinflammatory cytokine central to many autoimmune diseases, has been implicated in the depigmentation process in vitiligo. We review its role in vitiligo by exploring its pro- and anti-inflammatory properties and examine the effects of blocking its actions with TNF-α antagonist therapeutics in reports available in the literature. We found that TNF-α inhibition halts disease progression in patients with progressive vitiligo but that, paradoxically, treatment can be associated with de novo vitiligo development in some patients when used for other autoimmune conditions, particularly when using adalimumab and infliximab. These studies reinforce the importance of stating appropriate outcomes measures, as most pilot trials propose to measure repigmentation, whereas halting depigmentation is commonly overlooked as a measure of success. We conclude that TNF-α inhibition has proven useful for patients with progressive vitiligo, where TNF-α inhibition is able to quash cytotoxic T-cell-mediated melanocyte destruction. However, a lingering concern for initiating de novo disease will likely prevent more widespread application of TNF inhibitors to treat vitiligo.

  2. Chronic and progressive Parkinson's disease MPTP model in adult and aged mice.

    PubMed

    Muñoz-Manchado, Ana B; Villadiego, Javier; Romo-Madero, Sonia; Suárez-Luna, Nela; Bermejo-Navas, Alfonso; Rodríguez-Gómez, José A; Garrido-Gil, Pablo; Labandeira-García, José L; Echevarría, Miriam; López-Barneo, José; Toledo-Aral, Juan J

    2016-01-01

    Despite the different animal models of Parkinson's disease developed during the last years, they still present limitations modelling the slow and progressive process of neurodegeneration. Here, we undertook a histological, neurochemical and behavioural analysis of a new chronic parkinsonian mouse model generated by the subcutaneous administration of low doses of MPTP (20 mg/kg, 3 times per week) for 3 months, using both young adult and aged mice. The MPTP-induced nigrostriatal neurodegeneration was progressive and was accompanied by a decrease in striatal dopamine levels and motor impairment. We also demonstrated the characteristic neuroinflammatory changes (microglial activation and astrogliosis) associated with the neurodegenerative process. Aged animals showed both a faster time course of neurodegeneration and an altered neuroinflammatory response. The long-term systemic application of low MPTP doses did not induce any increase in mortality in either young adult or aged mice and better resembles the slow evolution of the neurodegenerative process. This treatment could be useful to model different stages of Parkinson's disease, providing a better understanding of the pathophysiology of the disease and facilitating the testing of both protective and restorative treatments. Here, we show a new chronic and progressive parkinsonian mouse model, in young and aged mice. This model produces a stable degeneration of the dopaminergic nigrostriatal pathway, continuous neuroinflammatory reaction and motor deficits. Aged animals showed a faster neurodegeneration and an altered neuroinflammatory response. This treatment could be useful to model different stages of PD and to test both protective and restorative therapeutic approaches.

  3. Role of APOBEC3F Gene Variation in HIV-1 Disease Progression and Pneumocystis Pneumonia.

    PubMed

    An, Ping; Penugonda, Sudhir; Thorball, Christian W; Bartha, Istvan; Goedert, James J; Donfield, Sharyne; Buchbinder, Susan; Binns-Roemer, Elizabeth; Kirk, Gregory D; Zhang, Wenyan; Fellay, Jacques; Yu, Xiao-Fang; Winkler, Cheryl A

    2016-03-01

    Human APOBEC3 cytidine deaminases are intrinsic resistance factors to HIV-1. However, HIV-1 encodes a viral infectivity factor (Vif) that degrades APOBEC3 proteins. In vitro APOBEC3F (A3F) anti-HIV-1 activity is weaker than A3G but is partially resistant to Vif degradation unlike A3G. It is unknown whether A3F protein affects HIV-1 disease in vivo. To assess the effect of A3F gene on host susceptibility to HIV- acquisition and disease progression, we performed a genetic association study in six well-characterized HIV-1 natural cohorts. A common six-Single Nucleotide Polymorphism (SNP) haplotype of A3F tagged by a codon-changing variant (p. I231V, with allele (V) frequency of 48% in European Americans) was associated with significantly lower set-point viral load and slower rate of progression to AIDS (Relative Hazards (RH) = 0.71, 95% CI: 0.56, 0.91) and delayed development of pneumocystis pneumonia (PCP) (RH = 0.53, 95% CI: 0.37-0.76). A validation study in the International Collaboration for the Genomics of HIV (ICGH) showed a consistent association with lower set-point viral load. An in vitro assay revealed that the A3F I231V variant may influence Vif mediated A3F degradation. Our results provide genetic epidemiological evidence that A3F modulates HIV-1/AIDS disease progression.

  4. The Genetics of Human Autoimmune Disease: A Perspective on Progress in the Field and Future Directions

    PubMed Central

    Seldin, Michael F.

    2015-01-01

    Progress in defining the genetics of autoimmune disease has been dramatically enhanced by large scale genetic studies. Genome-wide approaches examining hundreds or for some diseases thousands of cases and controls have been implemented using high throughput genotyping and appropriate algorithms to provide a wealth of data over the last decade. These studies have identified hundreds of non-HLA loci as well as further defining HLA region variations that predispose to different autoimmune diseases. These studies to identify genetic risk loci are also complemented by progress in gene expression studies including definition of expression quantitative trait loci (eQTL), various alterations in chromatin structure including histone marks, DNase I sensitivity, repressed chromatin regions as well as transcript factor binding sites. Integration of this information can partially explain why particular variations can alter proclivity to autoimmune phenotypes. Despite our incomplete knowledge base with only partial definition of hereditary factors and possible functional connections, this progress has and will continue to facilitate a better understanding of critical pathways and critical changes in immunoregulation. Advances in defining and understanding functional variants potentially can lead to both novel therapeutics and personalized medicine in which therapeutic approaches are chosen based on particular molecular phenotypes and genomic alterations. PMID:26343334

  5. Progression of carotid-artery disease in type 2 diabetic patients: a cohort prospective study

    PubMed Central

    Bosevski, Marijan; Stojanovska, Lily

    2015-01-01

    In order to assess the progression of carotid-artery disease in type 2 diabetic cohort (n=207 patients), the dynamic change in carotid intima-media thickness (CIMT) and the occurrence of plaques were followed for a period of 31.35±10.59 months. The mean CIMT at the beginning of the study was 0.9178±0.1447 mm, with a maximal value of 1.1210±0.2366 mm. The maximal value of CIMT changed by 0.07 mm/year. Progression of CIMT was noted in 86.8% and its regression in 7.8% of patients. The occurrence of carotid plaques was detected in 41.8% of patients. Multiple regression analysis revealed the maximal value of CIMT to be associated with diastolic blood pressure, despite mean CIMT being predicted by body mass index. The presence of peripheral arterial disease and hypo-high-density lipoproteinemia were found to be predictors for the occurrence of carotid plaques. Our data have clinical implications in predicting risk factors for the progression of carotid-artery disease in type 2 diabetic patients for their appropriate management. PMID:26527880

  6. A case of adult moyamoya disease showing progressive angiopathy on cerebral angiography.

    PubMed

    Shirane, R; Mikawa, S; Ebina, T

    1999-09-01

    In moyamoya disease, progression of carotid occlusive lesion in an adult patient is very rare. We report a case of adult moyamoya disease with acute angiographical stage progression and hemodynamic deterioration. A 56-year-old female complaining of left motor weakness visited our department. On MRI, infarct lesion was found in the right white matter. On cerebral angiography, occlusive lesions in the bilateral internal carotid arterial siphons and moyamoya vessels were found. The right side was stage V and the left side was stage III. On IMP-SPECT, decreased cerebral hemodynamic reserve of the right cerebral hemisphere was found. In this patient, right STA-MCA anastomosis was performed. After operation, she became possible to walk and discharged to home. Five months after operation, good collateral formation and improvement of hemodynamic reserve in the right hemisphere were found. However, on left carotid arteriography, the anterior and middle cerebral arteries were only slightly imaged, and the disease state progressed to stage IV. In addition, decreased blood flow and hemodynamic reserve were appeared in the left hemisphere.

  7. Role of APOBEC3F Gene Variation in HIV-1 Disease Progression and Pneumocystis Pneumonia.

    PubMed

    An, Ping; Penugonda, Sudhir; Thorball, Christian W; Bartha, Istvan; Goedert, James J; Donfield, Sharyne; Buchbinder, Susan; Binns-Roemer, Elizabeth; Kirk, Gregory D; Zhang, Wenyan; Fellay, Jacques; Yu, Xiao-Fang; Winkler, Cheryl A

    2016-03-01

    Human APOBEC3 cytidine deaminases are intrinsic resistance factors to HIV-1. However, HIV-1 encodes a viral infectivity factor (Vif) that degrades APOBEC3 proteins. In vitro APOBEC3F (A3F) anti-HIV-1 activity is weaker than A3G but is partially resistant to Vif degradation unlike A3G. It is unknown whether A3F protein affects HIV-1 disease in vivo. To assess the effect of A3F gene on host susceptibility to HIV- acquisition and disease progression, we performed a genetic association study in six well-characterized HIV-1 natural cohorts. A common six-Single Nucleotide Polymorphism (SNP) haplotype of A3F tagged by a codon-changing variant (p. I231V, with allele (V) frequency of 48% in European Americans) was associated with significantly lower set-point viral load and slower rate of progression to AIDS (Relative Hazards (RH) = 0.71, 95% CI: 0.56, 0.91) and delayed development of pneumocystis pneumonia (PCP) (RH = 0.53, 95% CI: 0.37-0.76). A validation study in the International Collaboration for the Genomics of HIV (ICGH) showed a consistent association with lower set-point viral load. An in vitro assay revealed that the A3F I231V variant may influence Vif mediated A3F degradation. Our results provide genetic epidemiological evidence that A3F modulates HIV-1/AIDS disease progression. PMID:26942578

  8. Role of APOBEC3F Gene Variation in HIV-1 Disease Progression and Pneumocystis Pneumonia

    PubMed Central

    An, Ping; Penugonda, Sudhir; Thorball, Christian W.; Bartha, Istvan; Goedert, James J.; Donfield, Sharyne; Buchbinder, Susan; Binns-Roemer, Elizabeth; Kirk, Gregory D.; Zhang, Wenyan; Fellay, Jacques; Yu, Xiao-Fang; Winkler, Cheryl A.

    2016-01-01

    Human APOBEC3 cytidine deaminases are intrinsic resistance factors to HIV-1. However, HIV-1 encodes a viral infectivity factor (Vif) that degrades APOBEC3 proteins. In vitro APOBEC3F (A3F) anti-HIV-1 activity is weaker than A3G but is partially resistant to Vif degradation unlike A3G. It is unknown whether A3F protein affects HIV-1 disease in vivo. To assess the effect of A3F gene on host susceptibility to HIV- acquisition and disease progression, we performed a genetic association study in six well-characterized HIV-1 natural cohorts. A common six-Single Nucleotide Polymorphism (SNP) haplotype of A3F tagged by a codon-changing variant (p. I231V, with allele (V) frequency of 48% in European Americans) was associated with significantly lower set-point viral load and slower rate of progression to AIDS (Relative Hazards (RH) = 0.71, 95% CI: 0.56, 0.91) and delayed development of pneumocystis pneumonia (PCP) (RH = 0.53, 95% CI: 0.37–0.76). A validation study in the International Collaboration for the Genomics of HIV (ICGH) showed a consistent association with lower set-point viral load. An in vitro assay revealed that the A3F I231V variant may influence Vif mediated A3F degradation. Our results provide genetic epidemiological evidence that A3F modulates HIV-1/AIDS disease progression. PMID:26942578

  9. Circulating tumor cells are correlated with disease progression and treatment response in an orthotopic hepatocellular carcinoma model.

    PubMed

    Yan, Jun; Fan, Zhichao; Wu, Xiufeng; Xu, Min; Jiang, Jiahao; Tan, Changjun; Wu, Weizhong; Wei, Xunbin; Zhou, Jian

    2015-11-01

    Hepatocellular carcinoma (HCC) is a highly malignant tumor characterized by rapid progression, poor prognosis, and frequent hematogenous metastasis. A minimally invasive diagnostic biomarker that can predict disease progression and treatment response would be of extraordinary benefit. Therefore, we have investigated whether the number of circulating tumor cells (CTCs) is correlated with disease progression and treatment response in HCC. Here we report that the number of CTCs, monitored by in vivo flow cytometry (IVFC), is strongly correlated with disease progression and treatment response in a highly metastatic orthotopic nude mouse model of green fluorescent protein (GFP)-labeled HCC. Sorafenib treatment reduces the number of CTCs significantly. The decreased number of CTCs is consistent with low lung metastasis. This study has demonstrated a considerable clinical value of CTCs as a biomarker in predicting disease progression and monitoring therapeutic efficacy in patients with HCC.

  10. Failed Tubule Recovery, AKI-CKD Transition, and Kidney Disease Progression

    PubMed Central

    Weinberg, Joel M.; Kriz, Wilhelm; Bidani, Anil K.

    2015-01-01

    The transition of AKI to CKD has major clinical significance. As reviewed here, recent studies show that a subpopulation of dedifferentiated, proliferating tubules recovering from AKI undergo pathologic growth arrest, fail to redifferentiate, and become atrophic. These abnormal tubules exhibit persistent, unregulated, and progressively increasing profibrotic signaling along multiple pathways. Paracrine products derived therefrom perturb normal interactions between peritubular capillary endothelium and pericyte-like fibroblasts, leading to myofibroblast transformation, proliferation, and fibrosis as well as capillary disintegration and rarefaction. Although signals from injured endothelium and inflammatory/immune cells also contribute, tubule injury alone is sufficient to produce the interstitial pathology required for fibrosis. Localized hypoxia produced by microvascular pathology may also prevent tubule recovery. However, fibrosis is not intrinsically progressive, and microvascular pathology develops strictly around damaged tubules; thus, additional deterioration of kidney structure after the transition of AKI to CKD requires new acute injury or other mechanisms of progression. Indeed, experiments using an acute-on-chronic injury model suggest that additional loss of parenchyma caused by failed repair of AKI in kidneys with prior renal mass reduction triggers hemodynamically mediated processes that damage glomeruli to cause progression. Continued investigation of these pathologic mechanisms should reveal options for preventing renal disease progression after AKI. PMID:25810494

  11. Variants in GBA, SNCA, and MAPT influence Parkinson disease risk, age at onset, and progression.

    PubMed

    Davis, Albert A; Andruska, Kristin M; Benitez, Bruno A; Racette, Brad A; Perlmutter, Joel S; Cruchaga, Carlos

    2016-01-01

    Multiple genetic variants have been linked to risk of Parkinson disease (PD), but known mutations do not explain a large proportion of the total PD cases. Similarly, multiple loci have been associated with PD risk by genome-wide association studies (GWAS). The influence that genetic factors confer on phenotypic diversity remains unclear. Few studies have been performed to determine whether the GWAS loci are also associated with age at onset (AAO) or motor progression. We used 2 PD case-control data sets (Washington University and the Parkinson's Progression Markers Initiative) to determine whether polymorphisms located at the GWAS top hits (GBA, ACMSD/TMEM163, STK39, MCCC1/LAMP3, GAK/TMEM175, SNCA, and MAPT) show association with AAO or motor progression. We found associations between single nucleotide polymorphisms at the GBA and MAPT loci and PD AAO and progression. These findings reinforce the complex genetic basis of PD and suggest that distinct genes and variants explain the genetic architecture of PD risk, onset, and progression.

  12. The severity of acute kidney injury predicts progression to chronic kidney disease

    PubMed Central

    Chawla, Lakhmir S; Amdur, Richard L; Amodeo, Susan; Kimmel, Paul L; Palant, Carlos E

    2011-01-01

    Acute kidney injury (AKI) is associated with progression to advanced chronic kidney disease (CKD). We tested whether patients who survive AKI and are at higher risk for CKD progression can be identified during their hospital admission, thus providing opportunities to intervene. This was assessed in patients in the Department of Veterans Affairs Healthcare System hospitalized with a primary diagnosis indicating AKI (ICD9 codes 584.xx). In the exploratory phase, three multivariate prediction models for progression to stage 4 CKD were developed. In the confirmatory phase, the models were validated in 11,589 patients admitted for myocardial infarction or pneumonia during the same time frame that had RIFLE codes R, I, or F and complete data for all predictor variables. Of the 5351 patients in the AKI group, 728 entered stage 4 CKD after hospitalization. Models 1, 2, and 3 were all significant with ‘c' statistics of 0.82, 0.81, and 0.77, respectively. In model validation, all three were highly significant when tested in the confirmatory patients, with moderate to large effect sizes and good predictive accuracy (‘c' 0.81–0.82). Patients with AKI who required dialysis and then recovered were at especially high risk for progression to CKD. Hence, the severity of AKI is a robust predictor of progression to CKD. PMID:21430640

  13. G-protein signaling modulator 1 deficiency accelerates cystic disease in an orthologous mouse model of autosomal dominant polycystic kidney disease.

    PubMed

    Kwon, Michelle; Pavlov, Tengis S; Nozu, Kandai; Rasmussen, Shauna A; Ilatovskaya, Daria V; Lerch-Gaggl, Alexandra; North, Lauren M; Kim, Hyunho; Qian, Feng; Sweeney, William E; Avner, Ellis D; Blumer, Joe B; Staruschenko, Alexander; Park, Frank

    2012-12-26

    Polycystic kidney diseases are the most common genetic diseases that affect the kidney. There remains a paucity of information regarding mechanisms by which G proteins are regulated in the context of polycystic kidney disease to promote abnormal epithelial cell expansion and cystogenesis. In this study, we describe a functional role for the accessory protein, G-protein signaling modulator 1 (GPSM1), also known as activator of G-protein signaling 3, to act as a modulator of cyst progression in an orthologous mouse model of autosomal dominant polycystic kidney disease (ADPKD). A complete loss of Gpsm1 in the Pkd1(V/V) mouse model of ADPKD, which displays a hypomorphic phenotype of polycystin-1, demonstrated increased cyst progression and reduced renal function compared with age-matched cystic Gpsm1(+/+) and Gpsm1(+/-) mice. Electrophysiological studies identified a role by which GPSM1 increased heteromeric polycystin-1/polycystin-2 ion channel activity via Gβγ subunits. In summary, the present study demonstrates an important role for GPSM1 in controlling the dynamics of cyst progression in an orthologous mouse model of ADPKD and presents a therapeutic target for drug development in the treatment of this costly disease.

  14. The APOE locus advances disease progression in late onset familial Alzheimer`s disease but is not causative

    SciTech Connect

    Crawford, F.; Bennett, C.; Osborne, A.

    1994-09-01

    An association has been observed in several independent data sets between late onset Alzheimer`s disease (AD) and the APOE locus on chromosomes 19. We have examined the genotype in family history positive (FHP) and family history negative (FHN) cases and find a distortion of the APOE allele frequencies in accord with previous studies. However, when we examined the allele distribution of the at-risk siblings of the FHP group we found an excess of the {epsilon}4 allele which also differs significantly from historic controls but not from the affected siblings. The age distribution of the affected and unaffected siblings was similar, suggesting that the allelic frequency distortion in the unaffected siblings was not due to their being below the mean age of onset. Lod score linkage analysis, with age dependent onset and nonstringent specification of the genetic parameters, did not suggest linkage to the APOE locus. Furthermore, an analysis of variance of the age of disease-free survival suggested that APOE genotype contributes a small fraction of the total variance, indicating that the APOE locus is a poor predictor of disease-free survival time within late onset families. We suggest that the APOE locus enhances the rate of progression of the disease in otherwise predisposed individuals and that variation at this locus is not able in and of itself to cause this disease.

  15. Potential Clinical Value of Multiparametric PET in the Prediction of Alzheimer’s Disease Progression

    PubMed Central

    Chen, Xueqi; Zhou, Yun; Wang, Rongfu; Cao, Haoyin; Reid, Savina; Gao, Rui; Han, Dong

    2016-01-01

    Objective To evaluate the potential clinical value of quantitative functional FDG PET and pathological amyloid-β PET with cerebrospinal fluid (CSF) biomarkers and clinical assessments in the prediction of Alzheimer’s disease (AD) progression. Methods We studied 82 subjects for up to 96 months (median = 84 months) in a longitudinal Alzheimer’s Disease Neuroimaging Initiative (ADNI) project. All preprocessed PET images were spatially normalized to standard Montreal Neurologic Institute space. Regions of interest (ROI) were defined on MRI template, and standard uptake values ratios (SUVRs) to the cerebellum for FDG and amyloid-β PET were calculated. Predictive values of single and multiparametric PET biomarkers with and without clinical assessments and CSF biomarkers for AD progression were evaluated using receiver operating characteristic (ROC) analysis and logistic regression model. Results The posterior precuneus and cingulate SUVRs were identified for both FDG and amyloid-β PET in predicating progression in normal controls (NCs) and subjects with mild cognitive impairment (MCI). FDG parietal and lateral temporal SUVRs were suggested for monitoring NCs and MCI group progression, respectively. 18F-AV45 global cortex attained (78.6%, 74.5%, 75.4%) (sensitivity, specificity, accuracy) in predicting NC progression, which is comparable to the 11C-PiB global cortex SUVR’s in predicting MCI to AD. A logistic regression model to combine FDG parietal and posterior precuneus SUVR and Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog) Total Mod was identified in predicating NC progression with (80.0%, 94.9%, 93.9%) (sensitivity, specificity, accuracy). The selected model including FDG posterior cingulate SUVR, ADAS-Cog Total Mod, and Mini-Mental State Exam (MMSE) scores for predicating MCI to AD attained (96.4%, 81.2%, 83.6%) (sensitivity, specificity, accuracy). 11C-PiB medial temporal SUVR with MMSE significantly increased 11C-PiB PET AUC to 0.915 (p<0

  16. Substance use and HIV disease progression in the HAART era: implications for the primary prevention of HIV.

    PubMed

    Carrico, Adam W

    2011-05-23

    Prior to the era of highly active anti-retroviral therapy (HAART), cohort studies provided equivocal evidence to support the hypothesis that substance use predicts more rapid HIV disease progression. The present review examined the effects of substance use on HIV disease progression in cohort studies with follow-up that continued into the HAART era. Of the 20 studies included in this review, 16 observed that substance use predicted at least one indicator of HIV disease progression. Ten of the 11 studies that followed participants exclusively in the HAART era observed an effect of substance use on HIV disease progression. Findings across studies indicate that stimulant use promotes more rapid HIV disease progression and the effects of substance use on HIV disease progression can persist after controlling for self-reported HAART non-adherence. Future investigations that examine the bio-behavioral pathways whereby substance use promotes HIV disease progression should include: measures of HIV genotypic and phenotypic resistance, multi-method assessment of adherence, and assessment of co-morbid infections that are more prevalent among substance users. Although further mechanistic research is needed, findings from existing cohort studies have clear clinical implications. Implementing screening, brief intervention and referral to substance abuse treatment in HIV medical care could optimize health outcomes and decrease HIV transmission rates by boosting the effectiveness of "Test and Treat" approaches to HIV prevention.

  17. Temporal Profile of the Renal Transcriptome of HIV-1 Transgenic Mice during Disease Progression

    PubMed Central

    Fan, Ying; Wei, Chengguo; Xiao, Wenzhen; Zhang, Weijia; Wang, Niansong; Chuang, Peter Y.; He, John Cijiang

    2014-01-01

    Profiling of temporal changes of gene expression in the same kidney over the course of renal disease progression is challenging because repeat renal biopsies are rarely indicated in clinical practice. Here, we profiled the temporal change in renal transcriptome of HIV-1 transgenic mice (Tg26), an animal model for human HIV-associated nephropathy (HIVAN), and their littermates at three different time points (4, 8, and 12 weeks of age) representing early, middle, and late stages of renal disease by serial kidney biopsy. We analyzed both static levels of gene expression at three stages of disease and dynamic changes in gene expression between different stages. Analysis of static and dynamic changes in gene expression revealed that up-regulated genes at the early and middle stages are mostly involved in immune response and inflammation, whereas down-regulated genes mostly related to fatty acid and retinoid metabolisms. We validated the expression of a selected panel of genes that are up-regulated at the early stage (CCL2, CCL5, CXCL11, Ubd, Anxa1, and Spon1) by real-time PCR. Among these up-regulated genes, Spon1, which is a previously identified candidate gene for hypertension, was found to be up-regulated in kidney of human with diabetic nephropathy. Immunostaining of human biopsy samples demonstrated that protein expression of Spon1 was also markedly increased in kidneys of patients with both early and late HIVAN and diabetic nephropathy. Our studies suggest that analysis of both static and dynamic changes of gene expression profiles in disease progression avails another layer of information that could be utilized to gain a more comprehensive understanding of disease progression and identify potential biomarkers and drug targets. PMID:24667548

  18. Increased renal versican expression is associated with progression of chronic kidney disease.

    PubMed

    Rudnicki, Michael; Perco, Paul; Neuwirt, Hannes; Noppert, Susie-Jane; Leierer, Johannes; Sunzenauer, Judith; Eder, Susanne; Zoja, Carlamaria; Eller, Kathrin; Rosenkranz, Alexander R; Müller, Gerhard A; Mayer, Bernd; Mayer, Gert

    2012-01-01

    Novel prognostic markers for progression of kidney disease are needed to distinguish patients who might benefit from a more aggressive nephroprotective therapy. Expression of the proteoglycan versican was evaluated in renal transcriptomics profiles and in an independent set of 74 renal biopsies. Versican levels were correlated to histologic damage scores and to renal outcome, and versican expression and regulation was evaluated in vitro. In transcriptomics profiles of renal tissue versican was positively correlated with (i) histological parameters in kidney biopsies, (ii) progressive decline of renal function in proteinuric kidney diseases, and (iii) impaired renal function and histology scores in diabetic nephropathy. In an independent cohort of 74 biopsies of glomerular diseases renal RNA levels of versican isoforms V0 and V1, but not V2 and V3 correlated significantly with creatinine after a mean follow up time of 53 months. Versican isoforms V0 and V1 together with serum creatinine at time of biopsy and the degree of glomerulosclerosis predicted 20% and 24% of the variability of creatinine at follow up, which was significantly more than serum creatinine and histological parameters alone (16%). However, when patients with acute kidney failure at time of biopsy (n = 5) were excluded, the additive predictive value of versican V1 was only marginally higher (35%) than creatinine and glomerulosclerosis alone (34%). Versican isoforms V0 and V1 were primarily expressed in vitro in proximal tubule cells and in fibroblasts. The results in humans were confirmed in three rodent models of kidney disease, in which renal versican expression was significantly upregulated as compared to corresponding controls. These data show for the first time an association of renal versican isoform V0 and V1 expression with progressive renal disease.

  19. Do frequent moderate exacerbations contribute to progression of chronic obstructive pulmonary disease in patients who are ex-smokers?

    PubMed Central

    Dreyse, Jorge; Díaz, Orlando; Repetto, Paula B; Morales, Arturo; Saldías, Fernando; Lisboa, Carmen

    2015-01-01

    Background In addition to smoking, acute exacerbations are considered to be a contributing factor to progression of chronic obstructive pulmonary disease (COPD). However, these findings come from studies including active smokers, while results in ex-smokers are scarce and contradictory. The purpose of this study was to evaluate if frequent acute moderate exacerbations are associated with an accelerated decline in forced expiratory volume in one second (FEV1) and impairment of functional and clinical outcomes in ex-smoking COPD patients. Methods A cohort of 100 ex-smoking patients recruited for a 2-year follow-up study was evaluated at inclusion and at 6-monthly scheduled visits while in a stable condition. Evaluation included anthropometry, spirometry, inspiratory capacity, peripheral capillary oxygen saturation, severity of dyspnea, a 6-minute walking test, BODE (Body mass index, airflow Obstruction, Dyspnea, Exercise performance) index, and quality of life (St George’s Respiratory Questionnaire and Chronic Respiratory Disease Questionnaire). Severity of exacerbation was graded as moderate or severe according to health care utilization. Patients were classified as infrequent exacerbators if they had no or one acute exacerbation/year and frequent exacerbators if they had two or more acute exacerbations/year. Random effects modeling, within hierarchical linear modeling, was used for analysis. Results During follow-up, 419 (96% moderate) acute exacerbations were registered. At baseline, frequent exacerbators had more severe disease than infrequent exacerbators according to their FEV1 and BODE index, and also showed greater impairment in inspiratory capacity, forced vital capacity, peripheral capillary oxygen saturation, 6-minute walking test, and quality of life. However, no significant difference in FEV1 decline over time was found between the two groups (54.7±13 mL/year versus 85.4±15.9 mL/year in frequent exacerbators and infrequent exacerbators, respectively

  20. Search for major genes with progeny test data to accelerate the development of genetically superior loblolly pine. Technical progress report

    SciTech Connect

    2000-02-15

    This report details the progress of the three tasks of this project. The tasks are: (1) develop genetic models and analytical methods; (2) molecular confirmation of major gene segregation; and (3) develop strategies for marker-assisted breeding.

  1. Urinary Biomarkers for Monitoring Disease Progression in the Han:SPRD-cy Rat Model of Autosomal-Dominant Polycystic Kidney Disease

    PubMed Central

    Wiedmeyer, Charles E; Royal, Angela B

    2010-01-01

    The Han:SRPD-cy rat is a well-recognized model of human autosomal-dominant polycystic kidney disease. The disease is characterized by the development of progressive renal cysts, leading to declining renal function. Disease progression typically is monitored by measurement of plasma urea concentration. Although plasma urea may be an adequate measure of overall renal function, urinary biomarkers capable of accurately monitoring disease progression may be equally useful. The goal of this study was to assess several urinary biomarkers as potential markers of disease progression in male and female Han:SPRD-cy rats. These biomarkers were compared with changes in plasma urea concentration and morphometric changes as the disease progressed. Urinary activity of N-acetyl-β-D-glucosaminidase and concentration of α-glutathione S-transferase were measured as markers of proximal tubular dysfunction, glutathione S-transferase Yb1 as a distal tubular marker, and collagen IV as a biomarker for glomerular lesions. Urinary albumin was used as biomarker of glomerular or proximal tubular lesions. Albuminuria increased in male rats as the disease progressed, correlating with increasing plasma urea and morphologic changes. Urine concentrations of α-glutathione S-transferase decreased significantly in the male heterozygotic compared with wildtype rats in the later stages of the disease. Urinary concentrations of glutathione S-transferase Yb1 and collagen IV and activity of N-acetyl-β-D-glucosaminidase did not change during disease progression. Measurement of urinary albumin and concentrations of α-glutathione S-transferase may be useful for monitoring disease progression in the male Han:SPRD-cy rat model in future experiments. PMID:21262131

  2. Chronic kidney disease and the involvement of estrogen hormones in its pathogenesis and progression.

    PubMed

    Gluhovschi, Gh; Gluhovschi, A; Anastasiu, D; Petrica, Ligia; Gluhovschi, Cristina; Velciov, Silvia

    2012-01-01

    The kidney is under the influence of sexual hormones. Estrogens have a favourable role in the progression of some chronic renal diseases. Estrogen hormones act upon the nephron component cells, regulating several processes going on at this level. One of the most important actions of the estrogens is represented by the protective effect on the kidneys, estrogens attenuating glomerulosclerosis and tubulo-interstitial fibrosis. Thus, estrogens have nephroprotective effects. Phosphorus-calcium metabolism disturbances during chronic kidney disease are influenced by numerous regulatory factors: parathormone, vitamin D fibroblast growth factor, 23. Estrogens play an important part in disturbances of the phosphorus-calcium metabolism, co-operating with these factors. They exert favourable effects on renal osteodystrophy, the main consequence of phosphorus-calcium disturbances. Hormonal dysfunction in chronic kidney disease is clinically accompanied by sexual dysfunction that influences the life quality of these patients. In advanced stages of chronic kidney disease, especially in dialysed patients, these sexual dysfunctions can be more evident. Hormonal replacement therapy and estrogen therapy- receptor modulating therapy have an important role in correcting hormonal dysfunctions manifest in chronic kidney disease. Caution is necessary in case of a would-be pregnancy in patients with chronic kidney disease, given its risks and the complexity of the problem. Renal transplantation corrects to a great extent hormonal dysfunctions in chronic kidney disease. PMID:23326957

  3. [Periodontitis determining the onset and progression of Huntington's disease: review of the literature].

    PubMed

    Rodríguez Coyago, María Lourdes; Sánchez Temiño, Victoria Emilia

    2015-10-27

    Huntington's disease is a neurodegenerative disorder caused by the expansion of a CAG triplet in the huntingtin gene. It presents with physical, cognitive and psychiatric impairment at different ages in the adult, and has a fatal prognosis. Other than the number of triplet repetitions, there seem to be other factors that explain the onset of this disease at an earlier age. It is well known that neuroinflammation has a key role in neurodegenerative disorders; Huntington's disease is not an exception to that rule. Neuroinflammation exacerbates neuronal damage produced by mutation, by initiating aberrant activation of microglia cell, as well as astrocyte and dendritic cell dysfunction; also compromising the blood-brain barrier and activating the complement cascade. The latter as a direct and indirect effect of the mutation and other stimuli such as chronic infections. In this study, periodontitis is presented as a model of chronic oral infection and a systemic inflammation source. We hypothesize the potential role of periodontitis in Huntington's disease, and the mechanisms by which it contributes to the early onset and progress of the disease. We considered experimental studies, systematic reviews, meta-analyses, published in both Spanish and English, obtained from the PubMed and SciELO databases. There are various mechanisms that generate brain inflammation in these patients; mechanisms of innate immunity being especially prominent. Chronic oral-dental infections, such as periodontal disease, may be an exacerbating factor that adds to the neuroinflammation of Huntington'’s disease.

  4. The fundamental role of mechanical properties in the progression of cancer disease and inflammation

    NASA Astrophysics Data System (ADS)

    Mierke, Claudia Tanja

    2014-07-01

    The role of mechanical properties in cancer disease and inflammation is still underinvestigated and even ignored in many oncological and immunological reviews. In particular, eight classical hallmarks of cancer have been proposed, but they still ignore the mechanics behind the processes that facilitate cancer progression. To define the malignant transformation of neoplasms and finally reveal the functional pathway that enables cancer cells to promote cancer progression, these classical hallmarks of cancer require the inclusion of specific mechanical properties of cancer cells and their microenvironment such as the extracellular matrix as well as embedded cells such as fibroblasts, macrophages or endothelial cells. Thus, this review will present current cancer research from a biophysical point of view and will therefore focus on novel physical aspects and biophysical methods to investigate the aggressiveness of cancer cells and the process of inflammation. As cancer or immune cells are embedded in a certain microenvironment such as the extracellular matrix, the mechanical properties of this microenvironment cannot be neglected, and alterations of the microenvironment may have an impact on the mechanical properties of the cancer or immune cells. Here, it is highlighted how biophysical approaches, both experimental and theoretical, have an impact on the classical hallmarks of cancer and inflammation. It is even pointed out how these biophysical approaches contribute to the understanding of the regulation of cancer disease and inflammatory responses after tissue injury through physical microenvironmental property sensing mechanisms. The recognized physical signals are transduced into biochemical signaling events that guide cellular responses, such as malignant tumor progression, after the transition of cancer cells from an epithelial to a mesenchymal phenotype or an inflammatory response due to tissue injury. Moreover, cell adaptation to mechanical alterations, in

  5. Blockade of Gap Junction Hemichannel Suppresses Disease Progression in Mouse Models of Amyotrophic Lateral Sclerosis and Alzheimer's Disease

    PubMed Central

    Takeuchi, Hideyuki; Mizoguchi, Hiroyuki; Doi, Yukiko; Jin, Shijie; Noda, Mariko; Liang, Jianfeng; Li, Hua; Zhou, Yan; Mori, Rarami; Yasuoka, Satoko; Li, Endong; Parajuli, Bijay; Kawanokuchi, Jun; Sonobe, Yoshifumi; Sato, Jun; Yamanaka, Koji; Sobue, Gen; Mizuno, Tetsuya; Suzumura, Akio

    2011-01-01

    Background Glutamate released by activated microglia induces excitotoxic neuronal death, which likely contributes to non-cell autonomous neuronal death in neurodegenerative diseases, including amyotrophic lateral sclerosis and Alzheimer's disease. Although both blockade of glutamate receptors and inhibition of microglial activation are the therapeutic candidates for these neurodegenerative diseases, glutamate receptor blockers also perturbed physiological and essential glutamate signals, and inhibitors of microglial activation suppressed both neurotoxic/neuroprotective roles of microglia and hardly affected disease progression. We previously demonstrated that activated microglia release a large amount of glutamate specifically through gap junction hemichannel. Hence, blockade of gap junction hemichannel may be potentially beneficial in treatment of neurodegenerative diseases. Methods and Findings In this study, we generated a novel blood-brain barrier permeable gap junction hemichannel blocker based on glycyrrhetinic acid. We found that pharmacologic blockade of gap junction hemichannel inhibited excessive glutamate release from activated microglia in vitro and in vivo without producing notable toxicity. Blocking gap junction hemichannel significantly suppressed neuronal loss of the spinal cord and extended survival in transgenic mice carrying human superoxide dismutase 1 with G93A or G37R mutation as an amyotrophic lateral sclerosis mouse model. Moreover, blockade of gap junction hemichannel also significantly improved memory impairments without altering amyloid β deposition in double transgenic mice expressing human amyloid precursor protein with K595N and M596L mutations and presenilin 1 with A264E mutation as an Alzheimer's disease mouse model. Conclusions Our results suggest that gap junction hemichannel blockers may represent a new therapeutic strategy to target neurotoxic microglia specifically and prevent microglia-mediated neuronal death in various

  6. APOL1 Risk Variants Predict Histopathology and Progression to ESRD in HIV-Related Kidney Disease

    PubMed Central

    Wasser, Walter G.; Estrella, Michelle M.; Atta, Mohamed G.; Kuperman, Michael; Shemer, Revital; Rajasekaran, Arun; Tzur, Shay; Racusen, Lorraine C.; Skorecki, Karl

    2012-01-01

    With earlier institution of antiretroviral therapy, kidney diseases other than HIV-associated nephropathy (HIVAN) predominate in HIV-infected persons. Outcomes for these diseases are typically worse among those infected with HIV, but the reasons for this are not clear. Here, we examined the role of APOL1 risk variants in predicting renal histopathology and progression to ESRD in 98 HIV-infected African Americans with non-HIVAN kidney disease on biopsy. We used survival analysis to determine time to ESRD associated with APOL1 genotype. Among the 29 patients with two APOL1 risk alleles, the majority (76%) had FSGS and 10% had hypertensive nephrosclerosis. In contrast, among the 54 patients with one APOL1 risk allele, 47% had immune-complex GN as the predominant lesion and only 23% had FSGS. Among the 25 patients with no APOL1 risk allele, 40% had immune-complex GN and 12% had FSGS. In 310 person-years of observation, 29 patients progressed to ESRD. In adjusted analyses, individuals with two APOL1 risk alleles had a nearly three-fold higher risk for ESRD compared with those with one or zero risk alleles (P=0.03). In summary, these data demonstrate an association between APOL1 variants and renal outcomes in non-HIVAN kidney disease, suggesting a possible use for APOL1 genotyping to help guide the care of HIV-infected patients. PMID:22135313

  7. APOL1 risk variants predict histopathology and progression to ESRD in HIV-related kidney disease.

    PubMed

    Fine, Derek M; Wasser, Walter G; Estrella, Michelle M; Atta, Mohamed G; Kuperman, Michael; Shemer, Revital; Rajasekaran, Arun; Tzur, Shay; Racusen, Lorraine C; Skorecki, Karl

    2012-02-01

    With earlier institution of antiretroviral therapy, kidney diseases other than HIV-associated nephropathy (HIVAN) predominate in HIV-infected persons. Outcomes for these diseases are typically worse among those infected with HIV, but the reasons for this are not clear. Here, we examined the role of APOL1 risk variants in predicting renal histopathology and progression to ESRD in 98 HIV-infected African Americans with non-HIVAN kidney disease on biopsy. We used survival analysis to determine time to ESRD associated with APOL1 genotype. Among the 29 patients with two APOL1 risk alleles, the majority (76%) had FSGS and 10% had hypertensive nephrosclerosis. In contrast, among the 54 patients with one APOL1 risk allele, 47% had immune-complex GN as the predominant lesion and only 23% had FSGS. Among the 25 patients with no APOL1 risk allele, 40% had immune-complex GN and 12% had FSGS. In 310 person-years of observation, 29 patients progressed to ESRD. In adjusted analyses, individuals with two APOL1 risk alleles had a nearly three-fold higher risk for ESRD compared with those with one or zero risk alleles (P=0.03). In summary, these data demonstrate an association between APOL1 variants and renal outcomes in non-HIVAN kidney disease, suggesting a possible use for APOL1 genotyping to help guide the care of HIV-infected patients.

  8. Predicting Renal Failure Progression in Chronic Kidney Disease Using Integrated Intelligent Fuzzy Expert System

    PubMed Central

    Norouzi, Jamshid; Mirbagheri, Seyed Ahmad; Mazdeh, Mitra Mahdavi; Hosseini, Seyed Ahmad

    2016-01-01

    Background. Chronic kidney disease (CKD) is a covert disease. Accurate prediction of CKD progression over time is necessary for reducing its costs and mortality rates. The present study proposes an adaptive neurofuzzy inference system (ANFIS) for predicting the renal failure timeframe of CKD based on real clinical data. Methods. This study used 10-year clinical records of newly diagnosed CKD patients. The threshold value of 15 cc/kg/min/1.73 m2 of glomerular filtration rate (GFR) was used as the marker of renal failure. A Takagi-Sugeno type ANFIS model was used to predict GFR values. Variables of age, sex, weight, underlying diseases, diastolic blood pressure, creatinine, calcium, phosphorus, uric acid, and GFR were initially selected for the predicting model. Results. Weight, diastolic blood pressure, diabetes mellitus as underlying disease, and current GFR(t) showed significant correlation with GFRs and were selected as the inputs of model. The comparisons of the predicted values with the real data showed that the ANFIS model could accurately estimate GFR variations in all sequential periods (Normalized Mean Absolute Error lower than 5%). Conclusions. Despite the high uncertainties of human body and dynamic nature of CKD progression, our model can accurately predict the GFR variations at long future periods. PMID:27022406

  9. Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism

    PubMed Central

    Vujkovic-Cvijin, Ivan; Dunham, Richard M.; Iwai, Shoko; Maher, M. Cyrus; Albright, Rebecca G.; Broadhurst, Mara J.; Hernandez, Ryan D.; Lederman, Michael M.; Huang, Yong; Somsouk, Ma; Deeks, Steven G.; Hunt, Peter W.; Lynch, Susan V.; McCune, Joseph M.

    2014-01-01

    Progressive HIV infection is characterized by dysregulation of the intestinal immune barrier, translocation of immunostimulatory microbial products, and chronic systemic inflammation that is thought to drive progression of disease to AIDS. Elements of this pathologic process persist despite viral suppression during highly active antiretroviral therapy (HAART) and drivers of these phenomena remain poorly understood. Disrupted intestinal immunity can precipitate dysbiosis that induces chronic inflammation in the mucosa and periphery of mice. However, putative microbial drivers of HIV-associated immunopathology versus recovery have not been identified in humans. Using high-resolution bacterial community profiling, we identified a dysbiotic mucosal-adherent community enriched in Proteobacteria and depleted of Bacteroidia members that was associated with markers of mucosal immune disruption, T cell activation, and chronic inflammation in HIV-infected subjects. Furthermore, this dysbiosis was evident among HIV-infected subjects undergoing HAART, and the extent of dysbiosis correlated with activity of the kynurenine pathway of tryptophan metabolism and plasma concentrations of the inflammatory cytokine interleukin-6 (IL-6), two established markers of disease progression. Gut-resident bacteria with capacity to metabolize tryptophan through the kynurenine pathway were found to be enriched in HIV-infected subjects, strongly correlated with kynurenine levels in HIV-infected subjects, and capable of kynurenine production in vitro. These observations demonstrate a link between mucosal-adherent colonic bacteria and immunopathogenesis during progressive HIV infection, which is apparent even in the setting of viral suppression during HAART. This link suggests that gut-resident microbial populations may influence intestinal homeostasis during HIV disease. PMID:23843452

  10. Altered Metabolic Homeostasis in Amyotrophic Lateral Sclerosis: Mechanisms of Energy Imbalance and Contribution to Disease Progression.

    PubMed

    Ioannides, Zara A; Ngo, Shyuan T; Henderson, Robert D; McCombe, Pamela A; Steyn, Frederik J

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor neurones, which leads to paralysis and death in an average of 3 years following diagnosis. The cause of ALS is unknown, but there is substantial evidence that metabolic factors, including nutritional state and body weight, affect disease progression and survival. This review provides an overview of the characteristics of metabolic dysregulation in ALS focusing on mechanisms that lead to disrupted energy supply (at a whole-body and cellular level) and altered energy expenditure. We discuss how a decrease in energy supply occurs in parallel with an increase in energy demand and leads to a state of chronic energy deficit which has a negative impact on disease outcome in ALS. We conclude by presenting potential and tested strategies to compensate for, or correct this energy imbalance, and speculate on promising areas for further research. PMID:27400276

  11. Peripheral Biomarkers of Parkinson’s Disease Progression and Pioglitazone Effects

    PubMed Central

    Simon, David K.; Simuni, Tanya; Elm, Jordan; Clark-Matott, Joanne; Graebner, Allison K.; Baker, Liana; Dunlop, Susan R.; Emborg, Marina; Kamp, Cornelia; Morgan, John C.; Ross, G. Webster; Sharma, Saloni; Ravina, Bernard

    2016-01-01

    Pioglitazone, an oral hypoglycemic agent, recently failed to show promise as a disease-modifying agent in a 44-week phase 2 placebo-controlled study in 210 Parkinson’s disease (PD) subjects. We analyzed peripheral biomarkers, including leukocyte PGC-1α and target gene expression, plasma interleukin 6 (IL-6) as a marker of inflammation, and urine 8-hydroxydeoxyguanosine (8OHdG) as a marker of oxidative DNA damage. Baseline or changes from baseline in biomarker levels were not associated with the rate of progression of PD. Pioglitazone did not significantly alter biomarker levels. Other agents that more effectively target these mechanisms remain of potential interest as disease modifying therapies in PD. PMID:26444095

  12. Lesion of the Olfactory Epithelium Accelerates Prion Neuroinvasion and Disease Onset when Prion Replication Is Restricted to Neurons

    PubMed Central

    Crowell, Jenna; Wiley, James A.; Bessen, Richard A.

    2015-01-01

    Natural prion diseases of ruminants are moderately contagious and while the gastrointestinal tract is the primary site of prion agent entry, other mucosae may be entry sites in a subset of infections. In the current study we examined prion neuroinvasion and disease induction following disruption of the olfactory epithelium in the nasal mucosa since this site contains environmentally exposed olfactory sensory neurons that project directly into the central nervous system. Here we provide evidence for accelerated prion neuroinvasion and clinical onset from the olfactory mucosa after disruption and regeneration of the olfactory epithelium and when prion replication is restricted to neurons. In transgenic mice with neuron restricted replication of prions, there was a reduction in survival when the olfactory epithelium was disrupted prior to intranasal inoculation and there was >25% decrease in the prion incubation period. In a second model, the neurotropic DY strain of transmissible mink encephalopathy was not pathogenic in hamsters by the nasal route, but 50% of animals exhibited brain infection and/or disease when the olfactory epithelium was disrupted prior to intranasal inoculation. A time course analysis of prion deposition in the brain following loss of the olfactory epithelium in models of neuron-restricted prion replication suggests that neuroinvasion from the olfactory mucosa is via the olfactory nerve or brain stem associated cranial nerves. We propose that induction of neurogenesis after damage to the olfactory epithelium can lead to prion infection of immature olfactory sensory neurons and accelerate prion spread to the brain. PMID:25822718

  13. Disease origin and progression in amyotrophic lateral sclerosis: an immunology perspective.

    PubMed

    Malaspina, Andrea; Puentes, Fabiola; Amor, Sandra

    2015-03-01

    The immune system is inextricably linked with many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), a devastating neuromuscular disorder affecting motor cell function with an average survival of 3 years from symptoms onset. In ALS, there is a dynamic interplay between the resident innate immune cells, that is, microglia and astrocytes, which may become progressively harmful to motor neurons. Although innate and adaptive immune responses are associated with progressive neurodegeneration, in the early stages of ALS immune activation pathways are primarily considered to be beneficial promoting neuronal repair of the damaged tissues, though a harmful effect of T cells at this stage of disease has also been observed. In addition, although auto-antibodies against neuronal antigens are present in ALS, it is unclear whether these arise as a primary or secondary event to neuronal damage, and whether the auto-antibodies are indeed pathogenic. Understanding how the immune system contributes to the fate of motor cells in ALS may shed light on the triggers of disease as well as on the mechanisms contributing to the propagation of the pathology. Immune markers may also act as biomarkers while pathways involved in immune action may be targets of new therapeutic strategies. Here, we review the modalities by which the immune system senses the core pathological process in motor neuron disorders, focusing on tissue-specific immune responses in the neuromuscular junction and in the neuroaxis observed in affected individuals and in animal models of ALS. We elaborate on existing data on the immunological fingerprint of ALS that could be used to identify clues on the disease origin and patterns of progression.

  14. Disease origin and progression in amyotrophic lateral sclerosis: an immunology perspective.

    PubMed

    Malaspina, Andrea; Puentes, Fabiola; Amor, Sandra

    2015-03-01

    The immune system is inextricably linked with many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), a devastating neuromuscular disorder affecting motor cell function with an average survival of 3 years from symptoms onset. In ALS, there is a dynamic interplay between the resident innate immune cells, that is, microglia and astrocytes, which may become progressively harmful to motor neurons. Although innate and adaptive immune responses are associated with progressive neurodegeneration, in the early stages of ALS immune activation pathways are primarily considered to be beneficial promoting neuronal repair of the damaged tissues, though a harmful effect of T cells at this stage of disease has also been observed. In addition, although auto-antibodies against neuronal antigens are present in ALS, it is unclear whether these arise as a primary or secondary event to neuronal damage, and whether the auto-antibodies are indeed pathogenic. Understanding how the immune system contributes to the fate of motor cells in ALS may shed light on the triggers of disease as well as on the mechanisms contributing to the propagation of the pathology. Immune markers may also act as biomarkers while pathways involved in immune action may be targets of new therapeutic strategies. Here, we review the modalities by which the immune system senses the core pathological process in motor neuron disorders, focusing on tissue-specific immune responses in the neuromuscular junction and in the neuroaxis observed in affected individuals and in animal models of ALS. We elaborate on existing data on the immunological fingerprint of ALS that could be used to identify clues on the disease origin and patterns of progression. PMID:25344935

  15. Acceleration of the loss of the first-phase insulin response during the progression to type 1 diabetes in diabetes prevention trial-type 1 participants.

    PubMed

    Sosenko, Jay M; Skyler, Jay S; Beam, Craig A; Krischer, Jeffrey P; Greenbaum, Carla J; Mahon, Jeffrey; Rafkin, Lisa E; Matheson, Della; Herold, Kevan C; Palmer, Jerry P

    2013-12-01

    We studied the change in the first-phase insulin response (FPIR) during the progression to type 1 diabetes (T1D). Seventy-four oral insulin trial progressors to T1D from the Diabetes Prevention Trial-Type 1 with at least one FPIR measurement after baseline and before diagnosis were studied. The FPIR was examined longitudinally in 26 progressors who had FPIR measurements during each of the 3 years before diagnosis. The association between the change from the baseline FPIR to the last FPIR and time to diagnosis was studied in the remainder (n = 48). The 74 progressors had lower baseline FPIR values than nonprogressors (n = 270), with adjustments made for age and BMI. In the longitudinal analysis of the 26 progressors, there was a greater decline in the FPIR from 1.5 to 0.5 years before diagnosis than from 2.5 to 1.5 years before diagnosis. This accelerated decline was also evident in a regression analysis of the 48 remaining progressors in whom the rate of decline became more marked with the approaching diagnosis. The patterns of decline were similar between the longitudinal and regression analyses. There is an acceleration of decline in the FPIR during the progression to T1D, which becomes especially marked between 1.5 and 0.5 years before diagnosis. PMID:23863814

  16. Acceleration of the loss of the first-phase insulin response during the progression to type 1 diabetes in diabetes prevention trial-type 1 participants.

    PubMed

    Sosenko, Jay M; Skyler, Jay S; Beam, Craig A; Krischer, Jeffrey P; Greenbaum, Carla J; Mahon, Jeffrey; Rafkin, Lisa E; Matheson, Della; Herold, Kevan C; Palmer, Jerry P

    2013-12-01

    We studied the change in the first-phase insulin response (FPIR) during the progression to type 1 diabetes (T1D). Seventy-four oral insulin trial progressors to T1D from the Diabetes Prevention Trial-Type 1 with at least one FPIR measurement after baseline and before diagnosis were studied. The FPIR was examined longitudinally in 26 progressors who had FPIR measurements during each of the 3 years before diagnosis. The association between the change from the baseline FPIR to the last FPIR and time to diagnosis was studied in the remainder (n = 48). The 74 progressors had lower baseline FPIR values than nonprogressors (n = 270), with adjustments made for age and BMI. In the longitudinal analysis of the 26 progressors, there was a greater decline in the FPIR from 1.5 to 0.5 years before diagnosis than from 2.5 to 1.5 years before diagnosis. This accelerated decline was also evident in a regression analysis of the 48 remaining progressors in whom the rate of decline became more marked with the approaching diagnosis. The patterns of decline were similar between the longitudinal and regression analyses. There is an acceleration of decline in the FPIR during the progression to T1D, which becomes especially marked between 1.5 and 0.5 years before diagnosis.

  17. Recent progress in the development of a circular ion induction accelerator for space charge dominated beams at LLNL

    SciTech Connect

    Ahle, L; Autrey, D; Barnard, J; Berners, D; Craig, G; Debeling, A; Eylon, S; Friedman, A; Fritz, W; Grote, D P; Halaxa, E; Hanks, R L; Hernandez, M; Judd, D L; Kirbie, H C; Logan, B G; Lund, S M; Mant, G; Molvik, A W; Reginato, L; Sangster, T C; Sharp, W M

    1998-08-19

    The Heavy Ion Fusion Group at Lawrence Livermore National Laboratory has for several years been developing the world's first circular ion induction accelerator. This machine has recently been extended to 90 degrees, or 10 half-lattice periods (HLP) with full beam transport. In addition, induction cores have been installed on five of the HLP's, each with an independent arbitrary waveform pulser. An arbitrary waveform pulser for the bending electrostatic dipoles has also been enabled. Together, they have allowed the first attempts at coordinated bending and acceleration of the beam. The results of these first attempts will be reported on in the paper by examining the output of various diagnostic devices, such as the capacitive Beam Probes (C-probes), slit scanners, and the Gated Beam Imager(GBI).

  18. The Progressive BSSG Rat Model of Parkinson's: Recapitulating Multiple Key Features of the Human Disease

    PubMed Central

    Van Kampen, Jackalina M.; Baranowski, David C.; Robertson, Harold A.; Shaw, Christopher A.; Kay, Denis G.

    2015-01-01

    The development of effective neuroprotective therapies for Parkinson's disease (PD) has been severely hindered by the notable lack of an appropriate animal model for preclinical screening. Indeed, most models currently available are either acute in nature or fail to recapitulate all characteristic features of the disease. Here, we present a novel progressive model of PD, with behavioural and cellular features that closely approximate those observed in patients. Chronic exposure to dietary phytosterol glucosides has been found to be neurotoxic. When fed to rats, β-sitosterol β-d-glucoside (BSSG) triggers the progressive development of parkinsonism, with clinical signs and histopathology beginning to appear following cessation of exposure to the neurotoxic insult and continuing to develop over several months. Here, we characterize the progressive nature of this model, its non-motor features, the anatomical spread of synucleinopathy, and response to levodopa administration. In Sprague Dawley rats, chronic BSSG feeding for 4 months triggered the progressive development of a parkinsonian phenotype and pathological events that evolved slowly over time, with neuronal loss beginning only after toxin exposure was terminated. At approximately 3 months following initiation of BSSG exposure, animals displayed the early emergence of an olfactory deficit, in the absence of significant dopaminergic nigral cell loss or locomotor deficits. Locomotor deficits developed gradually over time, initially appearing as locomotor asymmetry and developing into akinesia/bradykinesia, which was reversed by levodopa treatment. Late-stage cognitive impairment was observed in the form of spatial working memory deficits, as assessed by the radial arm maze. In addition to the progressive loss of TH+ cells in the substantia nigra, the appearance of proteinase K-resistant intracellular α-synuclein aggregates was also observed to develop progressively, appearing first in the olfactory bulb, then

  19. Identification of Major Signaling Pathways in Prion Disease Progression Using Network Analysis.

    PubMed

    Newaz, Khalique; Sriram, K; Bera, Debajyoti

    2015-01-01

    Prion diseases are transmissible neurodegenerative diseases that arise due to conformational change of normal, cellular prion protein (PrPC) to protease-resistant isofrom (rPrPSc). Deposition of misfolded PrpSc proteins leads to an alteration of many signaling pathways that includes immunological and apoptotic pathways. As a result, this culminates in the dysfunction and death of neuronal cells. Earlier works on transcriptomic studies have revealed some affected pathways, but it is not clear which is (are) the prime network pathway(s) that change during the disease progression and how these pathways are involved in crosstalks with each other from the time of incubation to clinical death. We perform network analysis on large-scale transcriptomic data of differentially expressed genes obtained from whole brain in six different mouse strain-prion strain combination models to determine the pathways involved in prion diseases, and to understand the role of crosstalks in disease propagation. We employ a notion of differential network centrality measures on protein interaction networks to identify the potential biological pathways involved. We also propose a crosstalk ranking method based on dynamic protein interaction networks to identify the core network elements involved in crosstalk with different pathways. We identify 148 DEGs (differentially expressed genes) potentially related to the prion disease progression. Functional association of the identified genes implicates a strong involvement of immunological pathways. We extract a bow-tie structure that is potentially dysregulated in prion disease. We also propose an ODE model for the bow-tie network. Predictions related to diseased condition suggests the downregulation of the core signaling elements (PI3Ks and AKTs) of the bow-tie network. In this work, we show using transcriptomic data that the neuronal dysfunction in prion disease is strongly related to the immunological pathways. We conclude that these

  20. Atheroprotection through SYK inhibition fails in established disease when local macrophage proliferation dominates lesion progression.

    PubMed

    Lindau, Alexandra; Härdtner, Carmen; Hergeth, Sonja P; Blanz, Kelly Daryll; Dufner, Bianca; Hoppe, Natalie; Anto-Michel, Nathaly; Kornemann, Jan; Zou, Jiadai; Gerhardt, Louisa M S; Heidt, Timo; Willecke, Florian; Geis, Serjosha; Stachon, Peter; Wolf, Dennis; Libby, Peter; Swirski, Filip K; Robbins, Clinton S; McPheat, William; Hawley, Shaun; Braddock, Martin; Gilsbach, Ralf; Hein, Lutz; von zur Mühlen, Constantin; Bode, Christoph; Zirlik, Andreas; Hilgendorf, Ingo

    2016-03-01

    Macrophages in the arterial intima sustain chronic inflammation during atherogenesis. Under hypercholesterolemic conditions murine Ly6C(high) monocytes surge in the blood and spleen, infiltrate nascent atherosclerotic plaques, and differentiate into macrophages that proliferate locally as disease progresses. Spleen tyrosine kinase (SYK) may participate in downstream signaling of various receptors that mediate these processes. We tested the effect of the SYK inhibitor fostamatinib on hypercholesterolemia-associated myelopoiesis and plaque formation in Apoe(-/-) mice during early and established atherosclerosis. Mice consuming a high cholesterol diet supplemented with fostamatinib for 8 weeks developed less atherosclerosis. Histologic and flow cytometric analysis of aortic tissue showed that fostamatinib reduced the content of Ly6C(high) monocytes and macrophages. SYK inhibition limited Ly6C(high) monocytosis through interference with GM-CSF/IL-3 stimulated myelopoiesis, attenuated cell adhesion to the intimal surface, and blocked M-CSF stimulated monocyte to macrophage differentiation. In Apoe(-/-) mice with established atherosclerosis, however, fostamatinib treatment did not limit macrophage accumulation or lesion progression despite a significant reduction in blood monocyte counts, as lesional macrophages continued to proliferate. Thus, inhibition of hypercholesterolemia-associated monocytosis, monocyte infiltration, and differentiation by SYK antagonism attenuates early atherogenesis but not established disease when local macrophage proliferation dominates lesion progression.

  1. The Role of Dendritic Cells in Fibrosis Progression in Nonalcoholic Fatty Liver Disease

    PubMed Central

    Almeda-Valdes, Paloma; Aguilar Olivos, Nancy E.; Barranco-Fragoso, Beatriz; Uribe, Misael; Méndez-Sánchez, Nahum

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most frequent cause of chronic liver disease. NAFLD encompasses a wide range of pathologies, from simple steatosis to steatosis with inflammation to fibrosis. The pathogenesis of NAFLD progression has not been completely elucidated, and different liver cells could be implicated. This review focuses on the current evidence of the role of liver dendritic cells (DCs) in the progression from NAFLD to fibrosis. Liver DCs are a heterogeneous population of hepatic antigen-presenting cells; their main function is to induce T-cell mediated immunity by antigen processing and presentation to T cells. During the steady state liver DCs are immature and tolerogenic. However, in an environment of chronic inflammation, DCs are transformed to potent inducers of immune responses. There is evidence about the role of DC in liver fibrosis, but it is not clearly understood. Interestingly, there might be a link between lipid metabolism and DC function, suggesting that immunogenic DCs are associated with liver lipid storage, representing a possible pathophysiological mechanism in NAFLD development. A better understanding of the interaction between inflammatory pathways and the different cell types and the effect on the progression of NAFLD is of great relevance. PMID:26339640

  2. Oral health information systems--towards measuring progress in oral health promotion and disease prevention.

    PubMed Central

    Petersen, Poul Erik; Bourgeois, Denis; Bratthall, Douglas; Ogawa, Hiroshi

    2005-01-01

    This article describes the essential components of oral health information systems for the analysis of trends in oral disease and the evaluation of oral health programmes at the country, regional and global levels. Standard methodology for the collection of epidemiological data on oral health has been designed by WHO and used by countries worldwide for the surveillance of oral disease and health. Global, regional and national oral health databanks have highlighted the changing patterns of oral disease which primarily reflect changing risk profiles and the implementation of oral health programmes oriented towards disease prevention and health promotion. The WHO Oral Health Country/Area Profile Programme (CAPP) provides data on oral health from countries, as well as programme experiences and ideas targeted to oral health professionals, policy-makers, health planners, researchers and the general public. WHO has developed global and regional oral health databanks for surveillance, and international projects have designed oral health indicators for use in oral health information systems for assessing the quality of oral health care and surveillance systems. Modern oral health information systems are being developed within the framework of the WHO STEPwise approach to surveillance of noncommunicable, chronic disease, and data stored in the WHO Global InfoBase may allow advanced health systems research. Sound knowledge about progress made in prevention of oral and chronic disease and in health promotion may assist countries to implement effective public health programmes to the benefit of the poor and disadvantaged population groups worldwide. PMID:16211160

  3. Cerebrospinal Fluid Calbindin D Concentration as a Biomarker of Cerebellar Disease Progression in Niemann-Pick Type C1 Disease.

    PubMed

    Bradbury, Allison; Bagel, Jessica; Sampson, Maureen; Farhat, Nicole; Ding, Wenge; Swain, Gary; Prociuk, Maria; O'Donnell, Patricia; Drobatz, Kenneth; Gurda, Brittney; Wassif, Christopher; Remaley, Alan; Porter, Forbes; Vite, Charles

    2016-08-01

    Niemann-Pick type C (NPC) 1 disease is a rare, inherited, neurodegenerative disease. Clear evidence of the therapeutic efficacy of 2-hydroxypropyl-β-cyclodextrin (HPβCD) in animal models resulted in the initiation of a phase I/IIa clinical trial in 2013 and a phase IIb/III trial in 2015. With clinical trials ongoing, validation of a biomarker to track disease progression and serve as a supporting outcome measure of therapeutic efficacy has become compulsory. In this study, we evaluated calcium-binding protein calbindin D-28K (calbindin) concentrations in the cerebrospinal fluid (CSF) as a biomarker of NPC1 disease. In the naturally occurring feline model, CSF calbindin was significantly elevated at 3 weeks of age, prior to the onset of cerebellar dysfunction, and steadily increased to >10-fold over normal at end-stage disease. Biweekly intrathecal administration of HPβCD initiated prior to the onset of neurologic dysfunction completely normalized CSF calbindin in NPC1 cats at all time points analyzed when followed up to 78 weeks of age. Initiation of HPβCD after the onset of clinical signs (16 weeks of age) resulted in a delayed reduction of calbindin levels in the CSF. Evaluation of CSF from patients with NPC1 revealed that calbindin concentrations were significantly elevated compared with CSF samples collected from unaffected patients. Off-label treatment of patients with NPC1 with miglustat, an inhibitor of glycosphingolipid biosynthesis, significantly decreased CSF calbindin compared with pretreatment concentrations. These data suggest that the CSF calbindin concentration is a sensitive biomarker of NPC1 disease that could be instrumental as an outcome measure of therapeutic efficacy in ongoing clinical trials. PMID:27307499

  4. Cerebrospinal Fluid Calbindin D Concentration as a Biomarker of Cerebellar Disease Progression in Niemann-Pick Type C1 Disease

    PubMed Central

    Bagel, Jessica; Sampson, Maureen; Farhat, Nicole; Ding, Wenge; Swain, Gary; Prociuk, Maria; O’Donnell, Patricia; Drobatz, Kenneth; Gurda, Brittney; Wassif, Christopher; Remaley, Alan; Porter, Forbes; Vite, Charles

    2016-01-01

    Niemann-Pick type C (NPC) 1 disease is a rare, inherited, neurodegenerative disease. Clear evidence of the therapeutic efficacy of 2-hydroxypropyl-β-cyclodextrin (HPβCD) in animal models resulted in the initiation of a phase I/IIa clinical trial in 2013 and a phase IIb/III trial in 2015. With clinical trials ongoing, validation of a biomarker to track disease progression and serve as a supporting outcome measure of therapeutic efficacy has become compulsory. In this study, we evaluated calcium-binding protein calbindin D-28K (calbindin) concentrations in the cerebrospinal fluid (CSF) as a biomarker of NPC1 disease. In the naturally occurring feline model, CSF calbindin was significantly elevated at 3 weeks of age, prior to the onset of cerebellar dysfunction, and steadily increased to >10-fold over normal at end-stage disease. Biweekly intrathecal administration of HPβCD initiated prior to the onset of neurologic dysfunction completely normalized CSF calbindin in NPC1 cats at all time points analyzed when followed up to 78 weeks of age. Initiation of HPβCD after the onset of clinical signs (16 weeks of age) resulted in a delayed reduction of calbindin levels in the CSF. Evaluation of CSF from patients with NPC1 revealed that calbindin concentrations were significantly elevated compared with CSF samples collected from unaffected patients. Off-label treatment of patients with NPC1 with miglustat, an inhibitor of glycosphingolipid biosynthesis, significantly decreased CSF calbindin compared with pretreatment concentrations. These data suggest that the CSF calbindin concentration is a sensitive biomarker of NPC1 disease that could be instrumental as an outcome measure of therapeutic efficacy in ongoing clinical trials. PMID:27307499

  5. Recombinant growth factor mixtures induce cell cycle progression and the upregulation of type I collagen in human skin fibroblasts, resulting in the acceleration of wound healing processes.

    PubMed

    Lee, Do Hyun; Choi, Kyung-Ha; Cho, Jae-We; Kim, So Young; Kwon, Tae Rin; Choi, Sun Young; Choi, Yoo Mi; Lee, Jay; Yoon, Ho Sang; Kim, Beom Joon

    2014-05-01

    Application of growth factor mixtures has been used for wound healing and anti-wrinkles agents. The aim of this study was to evaluate the effect of recombinant growth factor mixtures (RGFM) on the expression of cell cycle regulatory proteins, type I collagen, and wound healing processes of acute animal wound models. The results showed that RGFM induced increased rates of cell proliferation and cell migration of human skin fibroblasts (HSF). In addition, expression of cyclin D1, cyclin E, cyclin-dependent kinase (Cdk)4, and Cdk2 proteins was markedly increased with a growth factor mixtures treatment in fibroblasts. Expression of type I collagen was also increased in growth factor mixtures-treated HSF. Moreover, growth factor mixtures-induced the upregulation of type I collagen was associated with the activation of Smad2/3. In the animal model, RGFM-treated mice showed accelerated wound closure, with the closure rate increasing as early as on day 7, as well as re-epithelization and reduced inflammatory cell infiltration than phosphate-buffered saline (PBS)-treated mice. In conclusion, the results indicated that RGFM has the potential to accelerate wound healing through the upregulation of type I collagen, which is partly mediated by activation of Smad2/3-dependent signaling pathway as well as cell cycle progression in HSF. The topical application of growth factor mixtures to acute and chronic skin wound may accelerate the epithelization process through these molecular mechanisms.

  6. Distinct Changes in Functional Connectivity in Posteromedial Cortex Subregions during the Progress of Alzheimer's Disease.

    PubMed

    Wu, Yan; Zhang, Yaqin; Liu, Yong; Liu, Jieqiong; Duan, Yunyun; Wei, Xuehu; Zhuo, Junjie; Li, Kuncheng; Zhang, Xinqin; Yu, Chunshui; Wang, Jiaojian; Jiang, Tianzi

    2016-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder which causes dementia, especially in the elderly. The posteromedial cortex (PMC), which consists of several subregions involved in distinct functions, is one of the critical regions associated with the progression and severity of AD. However, previous studies always ignored the heterogeneity of the PMC and focused on one stage of AD. Using resting-state functional magnetic resonance imaging, we studied the respective alterations of each subregion within the PMC along the progression of AD. Our data set consisted of 21 healthy controls, 18 patients with mild cognitive impairment (MCI), 17 patients with mild AD (mAD), and 18 patients with severe AD (sAD). We investigated the functional alterations of each subregion within the PMC in different stages of AD. We found that subregions within the PMC have differential vulnerability in AD. Disruptions in functional connectivity began in the transition area between the precuneus and the posterior cingulate cortex (PCC) and then extended to other subregions of the PMC. In addition, each of these subregions was associated with distinct alterations in the functional networks that we were able to relate to AD. Our research demonstrated functional changes within the PMC in the progression of AD and may elucidate potential biomarkers for clinical applications. PMID:27147982

  7. MR of brain involvement in progressive facial hemiatrophy (Romberg disease): Reconsideration of a syndrome

    SciTech Connect

    Terstegge, K.; Hosten, N. ); Kunath, B. ); Felber, S.; Henkes, H. ); Speciali, J.G. )

    1994-01-01

    To gain further insight into the pathogenesis of progressive facial hemiatrophy, a sporadic disease of unclear etiology characterized by shrinking and deformation of one side of the face. We investigated possible brain involvement. MR of the head and face was performed in three female patients with progressive facial hemiatrophy. The central-nervous-system findings were correlated to a clinical protocol and a review of the literature. One patient with epilepsy had abnormal brain findings confined to the cerebral hemisphere homolateral to the facial hemiatrophy. These consisted of monoventricular enlargement, meningocortical dysmorphia, and white-matter changes. These MR findings, and corresponding neuroradiologic data disclosed by the review, indicate that homolateral hemiatrophy occasionally occurs in a subgroup of patients with progressive facial hemiatrophy. The MR features do not seem consistent with an underlying simple or nutritive atrophic process. We propose chronic localized meningoencephalitis with vascular involvement as a possible underlying cause of the occasional brain involvement in progressive facial hemiatrophy. 29 refs., 2 figs.

  8. Progressive synaptic pathology of motor cortical neurons in a BAC transgenic mouse model of Huntington's disease.

    PubMed

    Spampanato, J; Gu, X; Yang, X W; Mody, I

    2008-12-01

    Huntington's disease (HD) is a neurodegenerative disorder caused by a polyglutamine repeat expansion in huntingtin. A newly developed bacterial artificial chromosome transgenic mouse model (BACHD) reproduces phenotypic features of HD including predominantly neuropil-associated protein aggregation and progressive motor dysfunction with selective neurodegenerative pathology. Motor dysfunction has been shown to precede neuropathology in BACHD mice. We therefore investigated the progression of synaptic pathology in pyramidal cells and interneurons of the superficial motor cortex of BACHD mice. Whole-cell patch clamp recordings were performed on layer 2/3 primary motor cortical pyramidal cells and parvalbumin interneurons from BACHD mice at 3 months, when the mice begin to demonstrate mild motor dysfunction, and at 6 months, when the motor dysfunction is more severe. Changes in synaptic variances were detectable at 3 months, and at 6 months BACHD mice display progressive synaptic pathology in the form of reduced cortical excitation and loss of inhibition onto pyramidal cells. These results suggest that progressive alterations of the superficial cortical circuitry may contribute to the decline of motor function in BACHD mice. The synaptic pathology occurs prior to neuronal degeneration and may therefore prove useful as a target for future therapeutic design. PMID:18854207

  9. Indexing Disease Progression at Study Entry with Individuals At-Risk for Huntington Disease

    PubMed Central

    Zhang, Ying; Long, Jeffrey D.; Mills, James A.; Warner, John H.; Lu, Wenjing; Paulsen, Jane S.

    2011-01-01

    The identification of clinical and biological markers of disease in persons at risk for Huntington Disease (HD) has increased in efforts to better quantify and characterize the epoch of prodrome prior to clinical diagnosis. Such efforts are critical in the design and implementation of clinical trials for HD so that interventions can occur at a time most likely to increase neuronal survival and maximize daily functioning. A prime consideration in the examination of prodromal individuals is their proximity to diagnosis. It is necessary to quantify proximity so that individual differences in key marker variables can be properly interpreted. We take a data-driven approach to develop an index that can be viewed as a proxy for time to HD diagnosis known as the CAG-Age Product Scaled or CAPS. CAPS is an observed utility variable computed for all genetically at-risk individuals based on age at study entry and CAG repeat length. Results of a longitudinal receiver operating characteristic (ROC) analysis showed that CAPS had a relatively strong ability to predict individuals who became diagnosed, especially in the first 2 years. Bootstrap validation provided evidence that CAPS computed on a new sample from the same population could have similar discriminatory power. Cutoffs for the empirical CAPS distribution can be used to create a classification for mutation-positive individuals (Low-Med-High) that is useful for comparison with the naturally occurring mutation-negative Control group. The classification is an improvement over the one currently in use as it is based on observed data rather than model-based estimated values. PMID:21858921