Science.gov

Sample records for als disease progression

  1. Kinematics of Disease Progression in Bulbar ALS

    ERIC Educational Resources Information Center

    Yunusova, Yana; Green, Jordan R.; Lindstrom, Mary J.; Ball, Laura J.; Pattee, Gary L.; Zinman, Lorne

    2010-01-01

    The goal of this study was to investigate the deterioration of lip and jaw movements during speech longitudinally in three individuals diagnosed with bulbar amyotrophic lateral sclerosis (ALS). The study was motivated by the need to understand the relationship between physiologic changes in speech movements and clinical measures of speech

  2. Kinematics of Disease Progression in Bulbar ALS

    ERIC Educational Resources Information Center

    Yunusova, Yana; Green, Jordan R.; Lindstrom, Mary J.; Ball, Laura J.; Pattee, Gary L.; Zinman, Lorne

    2010-01-01

    The goal of this study was to investigate the deterioration of lip and jaw movements during speech longitudinally in three individuals diagnosed with bulbar amyotrophic lateral sclerosis (ALS). The study was motivated by the need to understand the relationship between physiologic changes in speech movements and clinical measures of speech…

  3. Effect of fluoxetine on disease progression in a mouse model of ALS

    PubMed Central

    Koschnitzky, J. E.; Quinlan, K. A.; Lukas, T. J.; Kajtaz, E.; Kocevar, E. J.; Mayers, W. F.; Siddique, T.

    2014-01-01

    Selective serotonin reuptake inhibitors (SSRIs) and other antidepressants are often prescribed to amyotrophic lateral sclerosis (ALS) patients; however, the impact of these prescriptions on ALS disease progression has not been systematically tested. To determine whether SSRIs impact disease progression, fluoxetine (Prozac, 5 or 10 mg/kg) was administered to mutant superoxide dismutase 1 (SOD1) mice during one of three age ranges: neonatal [postnatal day (P)5–11], adult presymptomatic (P30 to end stage), and adult symptomatic (P70 to end stage). Long-term adult fluoxetine treatment (started at either P30 or P70 and continuing until end stage) had no significant effect on disease progression. In contrast, neonatal fluoxetine treatment (P5-11) had two effects. First, all animals (mutant SOD1G93A and control: nontransgenic and SOD1WT) receiving the highest dose (10 mg/kg) had a sustained decrease in weight from P30 onward. Second, the high-dose SOD1G93A mice reached end stage ∼8 days (∼6% decrease in life span) sooner than vehicle and low-dose animals because of an increased rate of motor impairment. Fluoxetine increases synaptic serotonin (5-HT) levels, which is known to increase spinal motoneuron excitability. We confirmed that 5-HT increases spinal motoneuron excitability during this neonatal time period and therefore hypothesized that antagonizing 5-HT receptors during the same time period would improve disease outcome. However, cyproheptadine (1 or 5 mg/kg), a 5-HT receptor antagonist, had no effect on disease progression. These results show that a brief period of antidepressant treatment during a critical time window (the transition from neonatal to juvenile states) can be detrimental in ALS mouse models. PMID:24598527

  4. Therapeutic AAV9-mediated Suppression of Mutant SOD1 Slows Disease Progression and Extends Survival in Models of Inherited ALS

    PubMed Central

    Foust, Kevin D; Salazar, Desirée L; Likhite, Shibi; Ferraiuolo, Laura; Ditsworth, Dara; Ilieva, Hristelina; Meyer, Kathrin; Schmelzer, Leah; Braun, Lyndsey; Cleveland, Don W; Kaspar, Brian K

    2013-01-01

    Mutations in superoxide dismutase 1 (SOD1) are linked to familial amyotrophic lateral sclerosis (ALS) resulting in progressive motor neuron death through one or more acquired toxicities. Involvement of wild-type SOD1 has been linked to sporadic ALS, as misfolded SOD1 has been reported in affected tissues of sporadic patients and toxicity of astrocytes derived from sporadic ALS patients to motor neurons has been reported to be reduced by lowering the synthesis of SOD1. We now report slowed disease onset and progression in two mouse models following therapeutic delivery using a single peripheral injection of an adeno-associated virus serotype 9 (AAV9) encoding an shRNA to reduce the synthesis of ALS-causing human SOD1 mutants. Delivery to young mice that develop aggressive, fatal paralysis extended survival by delaying both disease onset and slowing progression. In a later-onset model, AAV9 delivery after onset markedly slowed disease progression and significantly extended survival. Moreover, AAV9 delivered intrathecally to nonhuman primates is demonstrated to yield robust SOD1 suppression in motor neurons and glia throughout the spinal cord and therefore, setting the stage for AAV9-mediated therapy in human clinical trials. PMID:24008656

  5. Synergistic Effects of GDNF and VEGF on Lifespan and Disease Progression in a Familial ALS Rat Model

    PubMed Central

    Krakora, Dan; Mulcrone, Patrick; Meyer, Michael; Lewis, Christina; Bernau, Ksenija; Gowing, Genevieve; Zimprich, Chad; Aebischer, Patrick; Svendsen, Clive N; Suzuki, Masatoshi

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons in the brain and spinal cord. We have recently shown that human mesenchymal stem cells (hMSCs) modified to release glial cell line-derived neurotrophic factor (GDNF) decrease disease progression in a rat model of ALS when delivered to skeletal muscle. In the current study, we determined whether or not this effect could be enhanced by delivering GDNF in concert with other trophic factors. hMSC engineered to secrete GDNF (hMSC-GDNF), vascular endothelial growth factor (hMSC-VEGF), insulin-like growth factor-I (hMSC-IGF-I), or brain-derived neurotrophic factor (hMSC-BDNF), were prepared and transplanted bilaterally into three muscle groups. hMSC-GDNF and hMSC-VEGF prolonged survival and slowed the loss of motor function, but hMSC-IGF-I and hMSC-BDNF did not have any effect. We then tested the efficacy of a combined ex vivo delivery of GDNF and VEGF in extending survival and protecting neuromuscular junctions (NMJs) and motor neurons. Interestingly, the combined delivery of these neurotrophic factors showed a strong synergistic effect. These studies further support ex vivo gene therapy approaches for ALS that target skeletal muscle. PMID:23712039

  6. Metabolic Therapy with Deanna Protocol Supplementation Delays Disease Progression and Extends Survival in Amyotrophic Lateral Sclerosis (ALS) Mouse Model

    PubMed Central

    Ari, Csilla; Poff, Angela M.; Held, Heather E.; Landon, Carol S.; Goldhagen, Craig R.; Mavromates, Nicholas; DAgostino, Dominic P.

    2014-01-01

    Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrigs disease, is a neurodegenerative disorder of motor neurons causing progressive muscle weakness, paralysis, and eventual death from respiratory failure. There is currently no cure or effective treatment for ALS. Besides motor neuron degeneration, ALS is associated with impaired energy metabolism, which is pathophysiologically linked to mitochondrial dysfunction and glutamate excitotoxicity. The Deanna Protocol (DP) is a metabolic therapy that has been reported to alleviate symptoms in patients with ALS. In this study we hypothesized that alternative fuels in the form of TCA cycle intermediates, specifically arginine-alpha-ketoglutarate (AAKG), the main ingredient of the DP, and the ketogenic diet (KD), would increase motor function and survival in a mouse model of ALS (SOD1-G93A). ALS mice were fed standard rodent diet (SD), KD, or either diets containing a metabolic therapy of the primary ingredients of the DP consisting of AAKG, gamma-aminobutyric acid, Coenzyme Q10, and medium chain triglyceride high in caprylic triglyceride. Assessment of ALS-like pathology was performed using a pre-defined criteria for neurological score, accelerated rotarod test, paw grip endurance test, and grip strength test. Blood glucose, blood beta-hydroxybutyrate, and body weight were also monitored. SD+DP-fed mice exhibited improved neurological score from age 116 to 136 days compared to control mice. KD-fed mice exhibited better motor performance on all motor function tests at 15 and 16 weeks of age compared to controls. SD+DP and KD+DP therapies significantly extended survival time of SOD1-G93A mice by 7.5% (p?=?0.001) and 4.2% (p?=?0.006), respectively. Sixty-three percent of mice in the KD+DP and 72.7% of the SD+DP group lived past 125 days, while only 9% of the control animals survived past that point. Targeting energy metabolism with metabolic therapy produces a therapeutic effect in ALS mice which may prolong survival and quality of life in ALS patients. PMID:25061944

  7. Quantifying Disease Progression in Amyotrophic Lateral Sclerosis

    PubMed Central

    Simon, Neil G; Turner, Martin R; Vucic, Steve; Al-Chalabi, Ammar; Shefner, Jeremy; Lomen-Hoerth, Catherine; Kiernan, Matthew C

    2014-01-01

    Amyotrophic lateral sclerosis (ALS) exhibits characteristic variability of onset and rate of disease progression, with inherent clinical heterogeneity making disease quantitation difficult. Recent advances in understanding pathogenic mechanisms linked to the development of ALS impose an increasing need to develop strategies to predict and more objectively measure disease progression. This review explores phenotypic and genetic determinants of disease progression in ALS, and examines established and evolving biomarkers that may contribute to robust measurement in longitudinal clinical studies. With targeted neuroprotective strategies on the horizon, developing efficiencies in clinical trial design may facilitate timely entry of novel treatments into the clinic. PMID:25223628

  8. A novel acylaminoimidazole derivative, WN1316, alleviates disease progression via suppression of glial inflammation in ALS mouse model.

    PubMed

    Tanaka, Kazunori; Kanno, Takuya; Yanagisawa, Yoshiko; Yasutake, Kaori; Inoue, Satoshi; Hirayama, Noriaki; Ikeda, Joh-E

    2014-01-01

    Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron degenerative disease. Given that oxidative stress and resulting chronic neuronal inflammation are thought to be central pathogenic, anti-oxidative agents and modulators of neuronal inflammation could be potential therapies for ALS. We report here that the novel small molecular compound, 2-[mesityl(methyl)amino]-N-[4-(pyridin-2-yl)-1H-imidazol-2-yl] acetamide trihydrochloride (WN1316) selectively suppresses oxidative stress-induced cell death and neuronal inflammation in the late-stage ALS mice. WN1316 has high blood-brain-barrier permeability and water solubility, and boosts both neuronal apoptosis inhibitory protein (NAIP) and NF-E2-related factor 2 (Nrf2) which governed glutathione (GSH)-related anti-oxidation pathway protecting motor neurons against oxidative injuries. Post-onset oral administration of low dose (1-100 g/kg/day) WN1316 in ALS(SOD1(H46R)) and ALS(SOD1(G93A)) mice resulted in sustained improved motor function and post onset survival rate. Immunohistochemical analysis revealed less DNA oxidative damage and motor neuronal inflammation as well as repression of both microgliosis and astrocytosis, concomitant down regulation of interleukin-1? and inducible nitric oxide synthase, and preservation of the motoneurons in anterior horn of lumbar spinal cord and skeletal muscle (quadriceps femoris). Thus, WN1316 would be a novel therapeutic agent for ALS. PMID:24498180

  9. A Pilot Trial of Pioglitazone HCl and Tretinoin in ALS: Cerebrospinal Fluid Biomarkers to Monitor Drug Efficacy and Predict Rate of Disease Progression

    PubMed Central

    Levine, Todd D.; Bowser, Robert; Hank, Nicole C.; Gately, Stephen; Stephan, Dietrich; Saperstein, David S.; Van Keuren-Jensen, Kendall

    2012-01-01

    Objectives. To determine if therapy with pioglitazone HCl and tretinoin could slow disease progression in patients with ALS. Levels of tau and pNFH in the cerebrospinal fluid were measured to see if they could serve as prognostic indicators. Methods. 27 subjects on stable doses of riluzole were enrolled. Subjects were randomized to receive pioglitazone 30?mg/d and tretinoin 10?mg/BID for six months or two matching placebos. ALSFRS-R scores were followed monthly. At baseline and at the final visit, lumbar punctures (LPs) were performed to measure cerebrospinal fluid (CSF) biomarker levels. Results. Subjects treated with tretinoin, pioglitazone, and riluzole had an average rate of decline on the ALSFRS-R scale of ?1.02 points per month; subjects treated with placebo and riluzole had a rate of decline of ?.86 (P = .18). Over six months of therapy, CSF tau levels decreased in subjects randomized to active treatment and increased in subjects on placebo. Further higher levels of pNF-H at baseline correlated with a faster rate of progression. Conclusion. ALS patients who were treated with tretinoin and pioglitazone demonstrated no slowing on their disease progression. Interestingly, the rate of disease progression was strongly correlated with levels of pNFH in the CSF at baseline. PMID:22830016

  10. 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

  11. Lou Gehrig's Disease (ALS)

    MedlinePLUS

    ... works: If you want to make a fist, your brain first sends signals through upper motor neurons to ... in your spinal cord signal the muscles in your hand to move and make a fist. Over time, Lou Gehrig's disease causes these motor neurons in the brain and spinal cord to shrink and disappear, so ...

  12. Rab11 in disease progression.

    PubMed

    Bhuin, Tanmay; Roy, Jagat Kumar

    2015-01-01

    Membrane/protein trafficking in the secretory/biosynthetic and endocytic pathways is mediated by vesicles. Vesicle trafficking in eukaryotes is regulated by a class of small monomeric GTPases: the Rab protein family. Rab proteins represent the largest branch of the Ras superfamily GTPases, and have been concerned in a variety of intracellular vesicle trafficking and different intracellular signalling pathways. Rab11 (a subfamily of the Ypt/Rab gene family), an evolutionarily conserved ubiquitously expressed subfamily of Rab GTPases, has been implicated in regulating vesicular trafficking through the recycling of endosomes. Rabs have been grouped into different subfamilies based on the distinct unambiguous sequence motifs. Three members: Rab11a, Rab11b and Rab25 make up the Rab11 GTPase subfamily. In this review article, we describe an overview over Rab11 subfamily with a brief structural aspect and its roles in implicating different disease progression. PMID:25815277

  13. Rab11 in Disease Progression

    PubMed Central

    Bhuin, Tanmay; Roy, Jagat Kumar

    2015-01-01

    Membrane/protein trafficking in the secretory/biosynthetic and endocytic pathways is mediated by vesicles. Vesicle trafficking in eukaryotes is regulated by a class of small monomeric GTPases: the Rab protein family. Rab proteins represent the largest branch of the Ras superfamily GTPases, and have been concerned in a variety of intracellular vesicle trafficking and different intracellular signalling pathways. Rab11 (a subfamily of the Ypt/Rab gene family), an evolutionarily conserved ubiquitously expressed subfamily of Rab GTPases, has been implicated in regulating vesicular trafficking through the recycling of endosomes. Rabs have been grouped into different subfamilies based on the distinct unambiguous sequence motifs. Three members: Rab11a, Rab11b and Rab25 make up the Rab11 GTPase subfamily. In this review article, we describe an overview over Rab11 subfamily with a brief structural aspect and its roles in implicating different disease progression. PMID:25815277

  14. 2013-2014 Alzheimer's Disease Progress Report

    MedlinePLUS

    Alzheimer's Go4Life Espaol NIHSeniorHealth Publications Text Resize - A + A Search form Search ADEAR Center Home Home > Alzheimer's > 2013-2014 Alzheimer's Disease Progress Report 2013-2014 Alzheimer's Disease ...

  15. Amyotrophic Lateral Sclerosis: A Focus on Disease Progression

    PubMed Central

    Calvo, Ana C.; Manzano, Raquel; Mendona, Deise M. F.; Muoz, Mara 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

  16. Impact of cholesterol on disease progression.

    PubMed

    Lin, Chun-Jung; Lai, Cheng-Kuo; Kao, Min-Chuan; Wu, Lii-Tzu; Lo, U-Ging; Lin, Li-Chiung; Chen, Yu-An; Lin, Ho; Hsieh, Jer-Tsong; Lai, Chih-Ho; Lin, Chia-Der

    2015-06-01

    Cholesterol-rich microdomains (also called lipid rafts), where platforms for signaling are provided and thought to be associated with microbe-induced pathogenesis and lead to cancer progression. After treatment of cells with cholesterol disrupting or usurping agents, raft-associated proteins and lipids can be dissociated, and this renders the cell structure nonfunctional and therefore mitigates disease severity. This review focuses on the role of cholesterol in disease progression including cancer development and infectious diseases. Understanding the molecular mechanisms of cholesterol in these diseases may provide insight into the development of novel strategies for controlling these diseases in clinical scenarios. PMID:26048694

  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. Glatiramer acetate has no impact on disease progression in ALS at 40 mg/day: a double- blind, randomized, multicentre, placebo-controlled trial.

    PubMed

    Meininger, Vincent; Drory, Vivian E; Leigh, P Nigel; Ludolph, Albert; Robberecht, Wim; Silani, Vincenzo

    2009-01-01

    Our objective was to assess the efficacy and safety of 40 mg/day glatiramer acetate (GA) in patients with ALS. We conducted a double-blind, randomized, placebo-controlled, multicentre trial. Three hundred and sixty-six patients with definite, probable or probable laboratory supported ALS and a slow vital capacity > or = 70% were randomly assigned to treatment with placebo or 40 mg GA daily. The primary intention-to-treat analysis was the comparison between the two treated groups of the rates of deterioration on the ALSFRSR scale. The secondary outcome measure was time to death, tracheostomy or permanent assisted ventilation. Safety and tolerability of GA were evaluated. After 52 weeks of follow-up, the slope of the ALSFRSR score was comparable in the both groups (placebo, -1.00+/-0.06/month; GA, -1.05+/-0.06/month; p=0.48). The secondary endpoint was non-significant with 159 patients (87.4%) alive in the placebo group and 162 patients (88.1%) in the GA group (log rank, p=0.75). The most common events were the injection site reactions (76.1% in the GA group, 14.8% in the placebo group), comparable to the known profile of 20 mg GA. In conclusion, GA at a dose of 40 mg/day did not show any beneficial effect in ALS patients, and safety and tolerability of GA were good in this population. PMID:19922128

  19. Alteration of familial ALS-linked mutant SOD1 solubility with disease progression: its modulation by the proteasome and Hsp70.

    PubMed

    Koyama, Shingo; Arawaka, Shigeki; Chang-Hong, Ren; Wada, Manabu; Kawanami, Toru; Kurita, Keiji; Kato, Masaaki; Nagai, Makiko; Aoki, Masashi; Itoyama, Yasuto; Sobue, Gen; Chan, Pak H; Kato, Takeo

    2006-05-12

    Accumulation of misfolded Cu/Zn superoxide dismutase (SOD1) occurs in patients with a subgroup of familial amyotrophic lateral sclerosis (fALS). To identify the conversion of SOD1 from a normally soluble form to insoluble aggregates, we investigated the change of SOD1 solubility with aging in fALS-linked H46R SOD1 transgenic mice. Mutant SOD1 specifically altered to insoluble forms, which were sequentially separated into Triton X-100-insoluble/sodium dodecyl sulfate (SDS)-soluble and SDS-insoluble/formic acid-soluble species. In spinal cords, the levels of SDS-dissociable soluble SOD1 monomers and SDS-stable soluble dimers were significantly elevated before motor dysfunction onset. In COS-7 cells expressing H46R SOD1, treatment with proteasome inhibitors recapitulated the alteration of SOD1 solubility in transgenic mice. In contrast, overexpression of Hsp70 reduced accumulation of mutant-specific insoluble SOD1. SDS-soluble low molecular weight species of H46R SOD1 may appear as early misfolded intermediates when their concentration exceeds the capacity of the proteasome and molecular chaperones. PMID:16563356

  20. Regionality of disease progression predicts prognosis in amyotrophic lateral sclerosis.

    PubMed

    van der Kleij, Lisa A; Jones, Ashley R; Steen, I Nick; Young, Carolyn A; Shaw, Pamela J; Shaw, Christopher E; Leigh, P Nigel; Turner, Martin R; Al-Chalabi, Ammar

    2015-12-01

    Amyotrophic lateral sclerosis (ALS) is a devastating neurological syndrome in which motor neurons degenerate relentlessly. Although the site of onset and the rate of spread have been studied extensively, little is known about whether focal as opposed to diffuse disease affects prognosis. We therefore tested the hypothesis that regionality of disease burden is a prognostic factor in ALS. We analysed clinical data from two large multicentre, longitudinal trials. Regionality was defined as the difference in progression rates in three domains as measured by the revised ALS Functional Rating Scale, omitting the respiratory domain from analysis. We used death by trial end as the outcome variable and tested this by logistic regression against predictor variables including regionality and overall rate of disease progression. There were 561 patients. Regionality of disease was independently associated with significantly higher chance of death by study end (odds ratio most diffuse against most focal category 0.354 (0.191, 0.657), p = 0.001), with a direct relationship between degree of regionality and odds of death. We have shown using clinical trial data that focal disease is associated with a worse prognosis in ALS. Measures of regionality warrant further independent consideration in the development of future prognostic models. PMID:26083873

  1. MAPK Usage in Periodontal Disease Progression

    PubMed Central

    Li, Qiyan; Valerio, Michael S.; Kirkwood, Keith L.

    2012-01-01

    In periodontal disease, host recognition of bacterial constituents, including lipopolysaccharide (LPS), induces p38 MAPK activation and subsequent inflammatory cytokine expression, favoring osteoclastogenesis and increased net bone resorption in the local periodontal environment. In this paper, we discuss evidence that the p38/MAPK-activated protein kinase-2 (MK2) signaling axis is needed for periodontal disease progression: an orally administered p38α inhibitor reduced the progression of experimental periodontal bone loss by reducing inflammation and cytokine expression. Subsequently, the significance of p38 signaling was confirmed with RNA interference to attenuate MK2-reduced cytokine expression and LPS-induced alveolar bone loss. MAPK phosphatase-1 (MKP-1), a negative regulator of MAPK activation, was also critical for periodontal disease progression. In MPK-1-deficient mice, p38-sustained activation increased osteoclast formation and bone loss, whereas MKP-1 overexpression dampened p38 signaling and subsequent cytokine expression. Finally, overexpression of the p38/MK2 target RNA-binding tristetraprolin (TTP) decreased mRNA stability of key inflammatory cytokines at the posttranscriptional level, thereby protecting against periodontal inflammation. Collectively, these studies highlight the importance of p38 MAPK signaling in immune cytokine production and periodontal disease progression. PMID:22315682

  2. The Axis of Progression of Disease

    PubMed Central

    Tartakoff, Alan M; Wu, Di

    2014-01-01

    Starting with genetic or environmental perturbations, disease progression can involve a linear sequence of changes within individual cells. More often, however, a labyrinth of branching consequences emanates from the initial events. How can one repair an entity so fine and so complex that its organization and functions are only partially known? How, given the many redundancies of metabolic pathways, can interventions be effective before the last redundant element has been irreversibly damaged? Since progression ultimately proceeds beyond a point of no return, therapeutic goals must target earlier events. A key goal is therefore to identify early changes of functional importance. Moreover, when several distinct genetic or environmental causes converge on a terminal phenotype, therapeutic strategies that focus on the shared features seem unlikely to be useful precisely because the shared events lie relatively downstream along the axis of progression. We therefore describe experimental strategies that could lead to identification of early events, both for cancer and for other diseases. PMID:25374458

  3. 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

  4. Huntington's disease progression. PET and clinical observations.

    PubMed

    Andrews, T C; Weeks, R A; Turjanski, N; Gunn, R N; Watkins, L H; Sahakian, B; Hodges, J R; Rosser, A E; Wood, N W; Brooks, D J

    1999-12-01

    Using serial [(11)C]SCH 23390- and [11C]raclopride-PET, we have measured the rate of loss of striatal dopamine D1 and D2 receptor binding over a mean of 40 months in nine asymptomatic adult Huntington's disease mutation carriers, four patients with symptomatic disease, seven mutation-negative controls and three subjects at risk for the disease. Eight of the nine asymptomatic Huntington's disease mutation carriers had serial [11C]raclopride-PET and showed a mean annual loss of striatal D2 binding of 4.0%. Only five of these eight, however, showed active progression, and they had a mean annual loss of D2 binding of 6.5%. All nine asymptomatic mutation carriers had serial [11C]SCH 23390-PET and showed a mean annual loss of striatal D1 binding of 2. 0%. Four of these subjects demonstrated active progression and they had a mean annual loss of 4.5%. Our four symptomatic Huntington's disease patients showed a mean annual loss of D2 binding of 3.0% and of D1 binding of 5.0%. Loss of striatal D1 and D2 binding was significantly greater in the known mutation carriers than in the combined at-risk and gene-negative groups (P < 0.05). At follow-up PET all subjects were clinically assessed using the Unified Huntington's Disease Rating Scale. Scores for motor function and total functional capacity correlated with PET measures of striatal dopamine receptor binding both in the asymptomatic mutation carriers (D1, P < 0.01) and across the combined asymptomatic and clinically affected Huntington's disease mutation carrier group (D1 and D2, P < 0.001). We conclude that PET measures of striatal D1 and D2 dopamine binding can be used to identify asymptomatic Huntington's disease mutation carriers who are actively progressing and who would thus be suitable for putative neuroprotective therapies. Measures of disease progression rates in Huntington's disease patients and asymptomatic mutation carriers will be of critical importance in future trials of experimental restorative treatments. PMID:10581228

  5. 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. PMID:25114068

  6. Mechanisms of progression of chronic kidney disease

    PubMed Central

    2007-01-01

    Chronic kidney disease (CKD) occurs in all age groups, including children. Regardless of the underlying cause, CKD is characterized by progressive scarring that ultimately affects all structures of the kidney. The relentless progression of CKD is postulated to result from a self-perpetuating vicious cycle of fibrosis activated after initial injury. We will review possible mechanisms of progressive renal damage, including systemic and glomerular hypertension, various cytokines and growth factors, with special emphasis on the reninangiotensinaldosterone system (RAAS), podocyte loss, dyslipidemia and proteinuria. We will also discuss possible specific mechanisms of tubulointerstitial fibrosis that are not dependent on glomerulosclerosis, and possible underlying predispositions for CKD, such as genetic factors and low nephron number. PMID:17647026

  7. Smoking and Disease Progression in Multiple Sclerosis

    PubMed Central

    Healy, Brian C.; Ali, Eman; Guttmann, Charles R.G.; Chitnis, Tanuja; Glanz, Bonnie I.; Buckle, Guy; Houtchens, Maria; Stazzone, Lynn; Moodie, Jennifer; Berger, Annika M.; Duan, Yang; Bakshi, Rohit; Khoury, Samia; Weiner, Howard; Ascherio, Alberto

    2009-01-01

    Context Although cigarette smokers have an increased risk of developing multiple sclerosis (MS), the effect of smoking on MS progression remains uncertain. Objectives To establish the relationship between cigarette smoking and MS progression using clinical and MRI outcomes Design Cross-sectional survey and longitudinal follow-up for an average of 3.29 years, ending January 15, 2008. Setting Partners MS Center (Boston, MA), a referral center for MS patients Patients 1465 patients with clinically definite MS (25.1% men) with mean baseline age of 42.0 years (range: 1675) and disease duration of 9.4 years (range: 050.4) -- 780 (53.2%) patients were never smokers, 428 (29.2%) ex-smokers, and 257 (17.5%) were current smokers. Main Outcome Measures Smoking groups were compared in terms of baseline clinical and MRI characteristics as well as progression and sustained progression on the expanded disability status scale (EDSS) at 2 years and 5 years and the time until conversion to secondary progressive MS. In addition, the rate of on-study change in the brain parenchymal fraction (BPF) and T2 hyperintense lesion volume was compared. Results Current smokers had significantly worse disease at baseline than never-smokers in terms of EDSS (adjusted p<0.0001), multiple sclerosis severity score (adjusted p<0.0001), and BPF (adjusted p=0.004). In addition, current smokers were significantly more likely to have primary progressive MS (adjusted odds ratio=2.41; 95% CI: 1.09, 5.34). In longitudinal analyses, smokers converted from relapsing remitting MS to secondary progressive MS faster than never-smokers (HR for current smokers versus never smokers, =2.50, 95% CI: 1.42, 4.41) and had a faster rate of increase in the T2 lesion volume (p=0.017) and a faster rate of decrease in BPF (p=0.021). Conclusion Our data suggest that cigarette smoke has an adverse influence on MS progression and accelerates the conversion from a relapsing-remitting to a progressive course. PMID:19597087

  8. Alcohol Use Accelerates HIV Disease Progression

    PubMed Central

    Rafie, Carlin; Lai, Shenghan; Sales, Sabrina; Page, John Bryan; Campa, Adriana

    2010-01-01

    Abstract The effects of alcohol abuse on HIV disease progression have not been definitively established. A prospective, 30-month, longitudinal study of 231 HIV+ adults included history of alcohol and illicit drug use, adherence to antiretroviral therapy (ART), CD4+ cell count, and HIV viral load every 6 months. Frequent alcohol users (two or more drinks daily) were 2.91 times (95% CI: 1.236.85, p?=?0.015) more likely to present a decline of CD4 to ?200 cells/?l, independent of baseline CD4+ cell count and HIV viral load, antiretroviral use over time, time since HIV diagnosis, age, and gender. Frequent alcohol users who were not on ART also increased their risk for CD4 cell decline to ?200 cells/mm3 (HR?=?7.76: 95% CI: 1.249.2, p?=?0.03). Combined frequent alcohol use with crack-cocaine showed a significant risk of CD4+ cell decline (HR?=?3.57: 95% CI: 1.2410.31, p?=?0.018). Frequent alcohol intake was associated with higher viral load over time (??=?0.259, p?=?0.038). This significance was maintained in those receiving ART (??=?0.384, p?=?0.0457), but not in those without ART. Frequent alcohol intake and the combination of frequent alcohol and crack-cocaine accelerate HIV disease progression. The effect of alcohol on CD4+ cell decline appears to be independent of ART, through a direct action on CD4 cells, although alcohol and substance abuse may lead to unmeasured behaviors that promote HIV disease progression. The effect of alcohol abuse on viral load, however, appears to be through reduced adherence to ART. PMID:20455765

  9. 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

  10. Excess Circulating Alternatively Activated Myeloid (M2) Cells Accelerate ALS Progression While Inhibiting Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Miller, Omer; Butovsky, Oleg; Bukshpan, Shay; Beers, David R.; Henkel, Jenny S.; Yoles, Eti; Appel, Stanley H.; Schwartz, Michal

    2011-01-01

    Background Circulating immune cells including autoreactive T cells and monocytes have been documented as key players in maintaining, protecting and repairing the central nervous system (CNS) in health and disease. Here, we hypothesized that neurodegenerative diseases might be associated, similarly to tumors, with increased levels of circulating peripheral myeloid derived suppressor cells (MDSCs), representing a subset of suppressor cells that often expand under pathological conditions and inhibit possible recruitment of helper T cells needed for fighting off the disease. Methods and Findings We tested this working hypothesis in amyotrophic lateral sclerosis (ALS) and its mouse model, which are characterized by a rapid progression once clinical symptoms are evident. Adaptive transfer of alternatively activated myeloid (M2) cells, which homed to the spleen and exhibited immune suppressive activity in G93A mutant superoxide dismutase-1 (mSOD1) mice at a stage before emergence of disease symptoms, resulted in earlier appearance of disease symptoms and shorter life expectancy. The same protocol mitigated the inflammation-induced disease model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), which requires circulating T cells for disease induction. Analysis of whole peripheral blood samples obtained from 28 patients suffering from sporadic ALS (sALS), revealed a two-fold increase in the percentage of circulating MDSCs (LIN?/LowHLA-DR?CD33+) compared to controls. Conclusions Taken together, these results emphasize the distinct requirements for fighting the inflammatory neurodegenerative disease, multiple sclerosis, and the neurodegenerative disease, ALS, though both share a local inflammatory component. Moreover, the increased levels of circulating MDSCs in ALS patients indicates the operation of systemic mechanisms that might lead to an impairment of T cell reactivity needed to overcome the disease conditions within the CNS. This high level of suppressive immune cells might represent a risk factor and a novel target for therapeutic intervention in ALS at least at the early stage. PMID:22073221

  11. Research Progress of Moyamoya Disease in Children

    PubMed Central

    Piao, Jianmin; Wu, Wei; Yang, Zhongxi; Yu, Jinlu

    2015-01-01

    During the onset of Moyamoya disease (MMD), progressive occlusion occurs at the end of the intracranial internal carotid artery, and compensatory net-like abnormal vessels develop in the skull base, generating the corresponding clinical symptoms. MMD can affect both children and adults, but MMD in pediatric patients exhibits distinct clinical features, and the treatment prognoses are different from adult patients. Children are the group at highest risk for MMD. In children, the disease mainly manifests as ischemia, while bleeding is the primary symptom in adults. The pathogenesis of MMD in children is still unknown, and some factors are distinct from those in adults. MMD in children could result in progressive, irreversible nerve functional impairment, and an earlier the onset corresponds to a worse prognosis. Therefore, active treatment at an early stage is highly recommended. The treatment methods for MMD in children mainly include indirect and direct surgeries. Indirect surgeries mainly include multiple burr-hole surgery (MBHS), encephalomyosynangiosis (EMS), and encephaloduroarteriosynangiosis (EDAS); direct surgeries mainly include intra- and extracranial vascular reconstructions that primarily consist of superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis. Indirect surgery, as a treatment for MMD in children, has shown a certain level of efficacy. However, a standard treatment approach should combine both indirect and direct procedures. Compared to MMD in adults, the treatment and prognosis of MMD in children has higher clinical significance. If the treatment is adequate, a satisfactory outcome is often achieved. PMID:26180513

  12. Experimental Progress on the NIST ^27Al^+ Optical Clock

    NASA Astrophysics Data System (ADS)

    Chou, Chin-Wen; Hume, David B.; Koelemeij, Jeroen C. J.; Rosenband, Till; Bergquist, James C.; Wineland, Dave J.

    2009-05-01

    A recent measurement of the frequency ratio between single-ion optical clocks based on ^27Al^+ and ^199Hg^+ at NIST showed a combined statistical and systematic uncertainty of 5.2 x 10-17[1]. Here we report progress on improving both the accuracy and stability of the ^27Al^+ optical clock. We have developed a new trap and laser systems that enable the use of ^25Mg^+ for sympathetic cooling and clock-state detection of ^27Al^+. These developments should reduce time-dilation shifts caused by harmonic motion of the ions and thus lower the dominant systematic uncertainty below 10-17. In the new clock apparatus we have demonstrated spectroscopy of the ^27Al^+ ^1S0 to ^3P0 transition with a quality factor of Q = 3.5 x 10^14 and simultaneously a contrast approaching unity. In addition, we have developed techniques for the sympathetic laser cooling and quantum logic spectroscopy of multiple aluminum ions with the goal of further improving measurement stability [2]. *supported by ONR and NIST [1] T. Rosenband et al., Science 319, 1808 (2008) [2] D. B. Hume et al., Phys. Rev. Lett. 99, 120502 (2007)

  13. 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?disease progression. Serial diffusion data may be useful as an additional objective in vivo biomarker for motor progression in PD. PMID:26871779

  14. Genetic architecture of human fibrotic diseases: disease risk and disease progression

    PubMed Central

    Gardet, Agns; Zheng, Timothy S.; Viney, Joanne L.

    2013-01-01

    Genetic studies of human diseases have identified multiple genetic risk loci for various fibrotic diseases. This has provided insights into the myriad of biological pathways potentially involved in disease pathogenesis. These discoveries suggest that alterations in immune responses, barrier function, metabolism and telomerase activity may be implicated in the genetic risks for fibrotic diseases. In addition to genetic disease-risks, the identification of genetic disease-modifiers associated with disease complications, severity or prognosis provides crucial insights into the biological processes implicated in disease progression. Understanding the biological processes driving disease progression may be critical to delineate more effective strategies for therapeutic interventions. This review provides an overview of current knowledge and gaps regarding genetic disease-risks and genetic disease-modifiers in human fibrotic diseases. PMID:24391588

  15. Electrical impedance myography as a biomarker to assess ALS progression

    PubMed Central

    Rutkove, Seward B.; Caress, James B.; Cartwright, Michael S.; Burns, Ted M.; Warder, Judy; David, William S.; Goyal, Namita; Maragakis, Nicholas J.; Clawson, Lora; Benatar, Michael; Usher, Sharon; Sharma, Khema R.; Gautam, Shiva; Narayanaswami, Pushpa; Raynor, Elizabeth M.; Watson, Mary Lou; Shefner, Jeremy M.

    2012-01-01

    Electrical impedance myography (EIM), a non-invasive, electrophysiological technique, has preliminarily shown value as an ALS biomarker. Here we perform a multicenter study to further assess EIMs potential for tracking ALS. ALS patients were enrolled across eight sites. Each subject underwent EIM, handheld dynamometry (HHD), and the ALS Functional Rating Scale-revised (ALSFRS-R) regularly. Techniques were compared by assessing the coefficient of variation (CoV) in the rate of decline and each techniques correlation to survival. Results showed that in the 60 patients followed for one year, EIM phase measured from the most rapidly progressing muscle in each patient had a CoV in the rate of decline of 0.62, compared to HHD (0.82) and the ALSFRS-R (0.74). Restricting the measurements to the first six months gave a CoV of 0.55 for EIM, 0.93 for HHD, and 0.84 for ALSFRS-R. For both time-periods, all three measures correlated with survival. Based on these data, a six-month clinical trial designed to detect a 20% treatment effect with 80% power using EIM would require only 95 patients/arm compared to the ALSFRS-R, which would require 220 subjects/arm. In conclusion, EIM can serve as a useful ALS biomarker that offers the prospect of greatly accelerating phase 2 clinical trials. PMID:22670883

  16. 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

  17. Celiac disease: diagnostic criteria in progress

    PubMed Central

    Volta, U; Villanacci, V

    2011-01-01

    Until a few years ago, celiac disease (CD) was thought to be a rare food intolerance that was confined to childhood and characterized by severe malabsorption and flat intestinal mucosa. Currently, CD is regarded as an autoimmune disorder that is common in the general population (affecting 1 in 100 individuals), with possible onset at any age and with many possible presentations. The identification of CD is challenging because it can begin not only with diarrhea and weight loss but also with atypical gastrointestinal (constipation and recurrent abdominal pain) and extra-intestinal symptoms (anemia, raised transaminases, osteoporosis, recurrent miscarriages, aphthous stomatitis and associated autoimmune disorders), or it could be completely symptomless. Over the last 20 years, the diagnostic accuracy of serology for CD has progressively increased with the development of highly reliable tests, such as the detection of IgA tissue transglutaminase and antiendomysial and IgG antideamidated gliadin peptide antibodies. The routine use of antibody markers has allowed researchers to discover a very high number of borderline' cases, characterized by positive serology and mild intestinal lesions or normal small intestine architecture, which can be classified as potential CD. Therefore, it is evident that the old celiac disease' with flat mucosa is only a part of the spectrum of CD. It is possible that serology could identify CD in its early stages, before the appearance of severe intestinal damage. In cases with a positive serology but with mild or absent intestinal lesions, the detection of HLA-DQ2 and HLA-DQ8 can help reinforce or exclude the diagnosis of gluten sensitivity. PMID:21278763

  18. 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…

  19. Hypokinesia without decrement distinguishes progressive supranuclear palsy from Parkinson's disease

    PubMed Central

    Massey, Luke A.; Lees, Andrew J.; Brown, Peter; Day, Brian L.

    2012-01-01

    Repetitive finger tapping is commonly used to assess bradykinesia in Parkinson's disease. The Queen Square Brain Bank diagnostic criterion of Parkinson's disease defines bradykinesia as slowness of initiation with progressive reduction in speed and amplitude of repetitive action. Although progressive supranuclear palsy is considered an atypical parkinsonian syndrome, it is not known whether patients with progressive supranuclear palsy have criteria-defined bradykinesia. This study objectively assessed repetitive finger tap performance and handwriting in patients with Parkinson's disease (n?=?15), progressive supranuclear palsy (n?=?9) and healthy age- and gender-matched controls (n?=?16). The motion of the hand and digits was recorded in 3D during 15-s repetitive index finger-to-thumb tapping trials. The main finding was hypokinesia without decrement in patients with progressive supranuclear palsy, which differed from the finger tap pattern in Parkinson's disease. Average finger separation amplitude in progressive supranuclear palsy was less than half of that in controls and Parkinson's disease (P?progressive supranuclear palsy was nearly zero (0.01/cycle) indicating a lack of decrement, which differed from the negative slope in patients with Parkinson's disease OFF levodopa (?0.20/cycle, P?=?0.002). Hypokinesia, defined as <50% of control group's mean amplitude, combined with absence of decrement, defined as mean positive amplitude slope, were identified in 87% of finger tap trials in the progressive supranuclear palsy group and only 12% in the Parkinson's disease OFF levodopa group. In progressive supranuclear palsy, the mean amplitude was not correlated with disease duration or other clinimetric scores. In Parkinson's disease, finger tap pattern was compatible with criteria-defined bradykinesia, characterized by slowness with progressive reduction in amplitude and speed and increased variability in speed throughout the tap trial. In Parkinson's disease, smaller amplitude, slower speed and greater speed variability were all associated with a more severe Unified Parkinson's Disease Rating Scale motor score. Analyses of handwriting showed that micrographia, defined as smaller than 50% of the control group's mean script size, was present in 75% of patients with progressive supranuclear palsy and 15% of patients with Parkinson's disease (P?=?0.022). Most scripts performed by patients with progressive supranuclear palsy did not exhibit decrements in script size. In conclusion, patients with progressive supranuclear palsy have a specific finger tap pattern of hypokinesia without decrement and they do not have criteria-defined limb bradykinesia. Similarly, micrographia and lack of decrement in script size are also more common in progressive supranuclear palsy than in Parkinson's disease. PMID:22396397

  20. Progressive myoclonic epilepsy due to Gaucher's disease in an adult.

    PubMed Central

    King, J O

    1975-01-01

    A 39 year old Jewish male with a 22 year history of progressive myoclonic epilepsy was found to have Gaucher cells in his sternal bone marrow. The diagnosis of Gaucher's disease was confirmed by the demonstration of beta-glucosidase deficiency in fibroblasts. Although neurological involvement is extremely rare in adults with Gaucher's disease, this disease is another lipidosis which should be considered in patients with progressive myoclonic epilepsy. Images PMID:1185223

  1. Metabolic acidosis and the progression of chronic kidney disease

    PubMed Central

    2014-01-01

    Metabolic acidosis is a common complication of chronic kidney disease. Accumulating evidence identifies acidosis not only as a consequence of, but as a contributor to, kidney disease progression. Several mechanistic pathways have been identified in this regard. The dietary acid load, even in the absence of overt acidosis, may have deleterious effects. Several small trials now suggest that the treatment of acidosis with oral alkali can slow the progression of kidney disease. PMID:24708763

  2. Cortical Processing of Swallowing in ALS Patients with Progressive Dysphagia A Magnetoencephalographic Study

    PubMed Central

    Teismann, Inga K.; Warnecke, Tobias; Suntrup, Sonja; Steinstrter, Olaf; Kronenberg, Linda; Ringelstein, E. Bernd; Dengler, Reinhard; Petri, Susanne; Pantev, Christo; Dziewas, Rainer

    2011-01-01

    Amyotrophic lateral sclerosis (ALS) is a rare disease causing degeneration of the upper and lower motor neuron. Involvement of the bulbar motor neurons often results in fast progressive dysphagia. While cortical compensation of dysphagia has been previously shown in stroke patients, this topic has not been addressed in patients suffering from ALS. In the present study, we investigated cortical activation during deglutition in two groups of ALS patients with either moderate or severe dysphagia. Whole-head MEG was employed on fourteen patients with sporadic ALS using a self-paced swallowing paradigm. Data were analyzed by means of time-frequency analysis and synthetic aperture magnetometry (SAM). Group analysis of individual SAM data was performed using a permutation test. We found a reduction of cortical swallowing related activation in ALS patients compared to healthy controls. Additionally a disease-related shift of hemispheric lateralization was observed. While healthy subjects showed bilateral cortical activation, the right sensorimotor cortex was predominantly involved in ALS patients. Both effects were even stronger in the group of patients with severe dysphagia. Our results suggest that bilateral degeneration of the upper motor neuron in the primary motor areas also impairs further adjusted motor areas, which leads to a strong reduction of swallowing related cortical activation. While both hemispheres are affected by the degeneration a relatively stronger activation is seen in the right hemisphere. This right hemispheric lateralization of volitional swallowing observed in this study may be the only sign of cortical plasticity in dysphagic ALS patients. It may demonstrate compensational mechanisms in the right hemisphere which is known to predominantly coordinate the pharyngeal phase of deglutition. These results add new aspects to our understanding of the pathophysiology of dysphagia in ALS patients and beyond. The compensational mechanisms observed could be relevant for future research in swallowing therapies. PMID:21625445

  3. Early intranasal insulin therapy halts progression of neurodegeneration: progress in Alzheimers disease therapeutics

    PubMed Central

    de la Monte, Suzanne M.

    2015-01-01

    Evaluation of Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, et al. Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment: A Pilot Clinical Trial. Arch Neurol. 2011 Sep 12. Alzheimers disease is associated with brain insulin deficiency and insulin resistance, similar to the problems in diabetes. If insulin could be supplied to the brain in the early stages of Alzheimers, subsequent neurodegeneration might be prevented. Administering systemic insulin to elderly non-diabetics poses unacceptable risks of inadvertant hypoglycemia. However, intranasal delivery directs the insulin into the brain, avoiding systemic side-effects. This pilot study demonstrates both efficacy and safety of using intranasal insulin to treat early Alzheimers and mild cognitive impairment, i.e. the precursor to Alzheimers. Significant improvements in learning, memory, and cognition occured within a few months, but without intranasal insulin, brain function continued to deteriorate in measurable degrees. Intranasal insulin therapy holds promise for halting progression of Alzheimers disease.

  4. Frontal deficits differentiate progressive supranuclear palsy from Parkinson's disease.

    PubMed

    Lee, Young-Eun C; Williams, David R; Anderson, Jacqueline F I

    2016-03-01

    The clinical differentiation of progressive supranuclear palsy from Parkinson's disease can be challenging, due to overlapping clinical features and a lack of diagnostic markers. Abnormalities in cognitive function form part of the clinical spectrums of these diseases and distinctive cognitive profiles may be helpful in differentiating these diseases in the diagnostic period. A comprehensive neuropsychological test battery was administered to 12 patients with clinically diagnosed progressive supranuclear palsy and 12 patients with Parkinson's disease matched for age and disease duration. Effect size (Cohen's d) was calculated for cognitive tests that were significantly different between groups. Patients with progressive supranuclear palsy performed significantly worse than those with Parkinson's disease on measures of processing speed, verbal fluency, planning, verbal abstract reasoning, verbal memory, and made more perseverative responses on a set shifting task. Measures of executive function, manual dexterity and processing speed were most diagnostically useful (Cohen's d > 2.0) in differentiating between progressive supranuclear palsy and Parkinson's disease. These findings suggest that more severe and prominent 'frontal' cognitive deficits in patients with progressive parkinsonism would be helpful in predicting progressive supranuclear palsy rather than Parkinson's disease and these findings may contribute to the development of diagnostic criteria. PMID:25223526

  5. 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.

  6. 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…

  7. 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

  8. Quitting Smoking After MS Diagnosis May Delay Disease Progression

    MedlinePLUS

    ... nih.gov/medlineplus/news/fullstory_154524.html Quitting Smoking After MS Diagnosis May Delay Disease Progression Accelerates about 5 percent for each additional year of smoking, study finds To use the sharing features on ...

  9. Animal models of regression/progression of kidney disease

    PubMed Central

    Lim, Beom Jin; Yang, Hai-Chun; Fogo, Agnes B.

    2014-01-01

    Current medical therapies may delay chronic kidney disease progression. However, increasing experimental evidence indicates remission or even regression can be achieved. In order to study mechanisms progression vs. regression by different interventions, appropriate animal models and research design must be implemented. We review key information of selected models, including etiology, pathogenesis, procedure, time course and assessment of potential regression. PMID:25722733

  10. A prediction model for progressive disease in systemic sclerosis

    PubMed Central

    Meijs, Jessica; Schouffoer, Anne A; Ajmone Marsan, Nina; Stijnen, Theo; Putter, Hein; Ninaber, Maarten K; Huizinga, Tom W J; de Vries-Bouwstra, Jeska K

    2015-01-01

    Objective To develop a model that assesses the risk for progressive disease in patients with systemic sclerosis (SSc) over the short term, in order to guide clinical management. Methods Baseline characteristics and 1 year follow-up results of 163 patients with SSc referred to a multidisciplinary healthcare programme were evaluated. Progressive disease was defined as: death, ≥10% decrease in forced vital capacity, ≥15% decrease in diffusing capacity for carbon monoxide, ≥10% decrease in body weight, ≥30% decrease in estimated-glomerular filtration rate, ≥30% increase in modified Rodnan Skin Score (with Δ≥5) or ≥0.25 increase in Scleroderma Health Assessment Questionnaire. The number of patients with progressive disease was determined. Univariable and multivariable logistic regression analyses were used to assess the probability of progressive disease for each individual patient. Performance of the prediction model was evaluated using a calibration plot and area under the receiver operating characteristic curve. Results 63 patients had progressive disease, including 8 patients who died ≤18 months after first evaluation. Multivariable analysis showed that friction rubs, proximal muscular weakness and decreased maximum oxygen uptake as % predicted, adjusted for age, gender and use of immunosuppressive therapy at baseline, were significantly associated with progressive disease. Using the prediction model, the predicted chance for progressive disease increased from a pretest chance of 37% to 67–89%. Conclusions Using the prediction model, the chance for progressive disease for individual patients could be doubled. Friction rubs, proximal muscular weakness and maximum oxygen uptake as % predicted were identified as relevant parameters. PMID:26688749

  11. 2014-2015 Alzheimer's Disease Progress Report

    MedlinePLUS

    ... will rise exponentially as the population ages. The Economic Impact of Alzheimer’s Alzheimer’s disease has a major impact on the U.S. economy. Recent investigations into the national—and personal—costs ...

  12. Predictors of Disease Progression in Pediatric Dilated Cardiomyopathy

    PubMed Central

    Molina, Kimberly M.; Shrader, Peter; Colan, Steven D.; Mital, Seema; Margossian, Renee; Sleeper, Lynn A.; Shirali, Girish; Barker, Piers; Canter, Charles E.; Altmann, Karen; Radojewski, Elizabeth; Selamet Tierney, Elif Seda; Rychik, Jack; Tani, Lloyd Y.

    2014-01-01

    Background Despite medical advances, children with dilated cardiomyopathy (DCM) remain at high risk of death or need for cardiac transplantation. We sought to identify predictors of disease progression in pediatric DCM. Methods and Results The Pediatric Heart Network evaluated chronic DCM patients with prospective echocardiographic and clinical data collection during an 18-month follow-up. Inclusion criteria were age <22 years and DCM disease duration >2 months. Patients requiring intravenous inotropic/mechanical support or listed status 1A/1B for transplant were excluded. Disease progression was defined as an increase in transplant listing status, hospitalization for heart failure, intravenous inotropes, mechanical support, or death. Predictors of disease progression were identified using Cox proportional hazards modeling and classification and regression tree analysis. Of the 127 patients, 28 (22%) had disease progression during the 18-month follow-up. Multivariable analysis identified older age at diagnosis (hazard ratio=1.14 per year; P<0.001), larger left ventricular (LV) end-diastolic M-mode dimension z-score (hazard ratio=1.49; P<0.001), and lower septal peak systolic tissue Doppler velocity z-score (hazard ratio=0.81; P=0.01) as independent predictors of disease progression. Classification and regression tree analysis stratified patients at risk of disease progression with 89% sensitivity and 94% specificity based on LV end-diastolic M-mode dimension z-score ?7.7, LV ejection fraction <39%, LV inflow propagation velocity (color M-mode) z-score <-0.28, and age at diagnosis ?8.5 months. Conclusions In children with chronic stable DCM, a combination of diagnosis after late infancy and echocardiographic parameters of larger LV size and systolic and diastolic function predicted disease progression. PMID:24132734

  13. Microglial Activation Correlates with Disease Progression and Upper Motor Neuron Clinical Symptoms in Amyotrophic Lateral Sclerosis

    PubMed Central

    Brettschneider, Johannes; Toledo, Jon B.; Van Deerlin, Vivianna M.; Elman, Lauren; McCluskey, Leo; Lee, Virginia M.-Y.; Trojanowski, John Q.

    2012-01-01

    Background/Aims We evaluated clinicopathological correlates of upper motor neuron (UMN) damage in amyotrophic lateral sclerosis (ALS), and analyzed if the presence of the C9ORF72 repeat expansion was associated with alterations in microglial inflammatory activity. Methods Microglial pathology was assessed by IHC with 2 different antibodies (CD68, Iba1), myelin loss by Kluver-Barrera staining and myelin basic protein (MBP) IHC, and axonal loss by neurofilament protein (TA51) IHC, performed on 59 autopsy cases of ALS including 9 cases with C9ORF72 repeat expansion. Results Microglial pathology as depicted by CD68 and Iba1 was significantly more extensive in the corticospinal tract (CST) of ALS cases with a rapid progression of disease. Cases with C9ORF72 repeat expansion showed more extensive microglial pathology in the medulla and motor cortex which persisted after adjusting for disease duration in a logistic regression model. Higher scores on the clinical UMN scale correlated with increasing microglial pathology in the cervical CST. TDP-43 pathology was more extensive in the motor cortex of cases with rapid progression of disease. Conclusions This study demonstrates that microglial pathology in the CST of ALS correlates with disease progression and is linked to severity of UMN deficits. PMID:22720079

  14. 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.

  15. [Various pathways leading to the progression of chronic liver diseases].

    PubMed

    Egresi, Anna; Lengyel, Gabriella; Somogyi, Anik; Blzovics, Anna; Hagymsi, Krisztina

    2016-02-01

    As the result of various effects (viruses, metabolic diseases, nutritional factors, toxic agents, autoimmune processes) abnormal liver function, liver steatosis and connective tissue remodeling may develop. Progression of this process is complex including various pathways and a number of factors. The authors summarize the factors involved in the progression of chronic liver disease. They describe the role of cells and the produced inflammatory mediators and cytokines, as well as the relationship between the disease and the intestinal flora. They emphasize the role of oxidative stress, mitochondrial dysfunction and cell death in disease progression. Insulin resistance and micro-elements (iron, copper) in relation to liver damage are also discussed, and genetic and epigenetic aspects underlying disease progression are summarized. Discovery of novel treatment options, assessment of the effectiveness of treatment, as well as the success and proper timing of liver transplantation may depend on a better understanding of the process of disease progression. Orv. Hetil., 2016, 157(8), 290-297. PMID:26876265

  16. 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

  17. 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

  18. [Progression factors for chronic kidney disease. Secondary prevention].

    TOXLINE Toxicology Bibliographic Information

    Garca de Vinuesa S

    2008-01-01

    The natural history of most chronic kidney diseases (CKD) indicates that glomerular filtration gradually declines over time, progressing to more advanced stages of kidney failure. Since the publication of the first studies by the Modification of Diet in Renal Disease (MDRD) Study Group, numerous factors have been identified that can accelerate this progression. Some are dependent on the etiology, but other are common to all and may accelerate progression of kidney disease: Non-modifiable progression factors for CKD: - Etiology of kidney disease - Degree of initial kidney function - Gender - Age - Ethnicity/Other genetic factors - Birth weight Modifiable progression factors for CKD: - Proteinuria - High blood pressure - Poor glycemic control in diabetes - Smoking - Obesity - Metabolic syndrome/Insulin resistance - Dyslipidemia - Anemia - Metabolic factors (Ca/P, uric acid) - Use of nephrotoxic drugs. Therapeutic intervention on these factors has shown that it reduce the rate of progression of CKD (Strength of Recommendation A).There is no clear evidence that correction of these factors slows CKD (Strength of Recommendation C), although it has been shown to have a beneficial effect on cardiovascular risk at other levels.

  19. Predicting the severity of motor neuron disease progression using electronic health record data with a cloud computing Big Data approach

    PubMed Central

    Ko, Kyung Dae; El-Ghazawi, Tarek; Kim, Dongkyu; Morizono, Hiroki

    2014-01-01

    Motor neuron diseases (MNDs) are a class of progressive neurological diseases that damage the motor neurons. An accurate diagnosis is important for the treatment of patients with MNDs because there is no standard cure for the MNDs. However, the rates of false positive and false negative diagnoses are still very high in this class of diseases. In the case of Amyotrophic Lateral Sclerosis (ALS), current estimates indicate 10% of diagnoses are false-positives, while 44% appear to be false negatives. In this study, we developed a new methodology to profile specific medical information from patient medical records for predicting the progression of motor neuron diseases. We implemented a system using Hbase and the Random forest classifier of Apache Mahout to profile medical records provided by the Pooled Resource Open-Access ALS Clinical Trials Database (PRO-ACT) site, and we achieved 66% accuracy in the prediction of ALS progress. PMID:25580472

  20. Primary progressive multiple sclerosis: part of the MS disease spectrum or separate disease entity?

    PubMed

    Antel, Jack; Antel, Samson; Caramanos, Zografos; Arnold, Douglas L; Kuhlmann, Tanja

    2012-05-01

    Multiple sclerosis (MS), the most frequent demyelinating disease, is characterized by a variable disease course. The majority of patients starts with relapsing remitting (RR) disease; approximately 50-60% of these patients progress to secondary progressive (SP) disease. Only about 15% of the patients develop a progressive disease course from onset, termed primary progressive multiple sclerosis (PPMS); the underlying pathogenic mechanisms responsible for onset of the disease with either PPMS or relapsing remitting multiple sclerosis (RRMS) are unknown. Patients with PPMS do not show a female predominance and usually have a later onset of disease compared to patients with RRMS. Monozygous twins can be concordant or discordant for disease courses indicating that the disease course is not only genetically determined. Primary progressive multiple sclerosis and secondary progressive multiple sclerosis (SPMS) share many similarities in imaging and pathological findings. Differences observed among the different disease courses are more of a quantitative than qualitative nature suggesting that the different phenotypes are part of a disease spectrum modulated by individual genetic predisposition and environmental influences. In this review, we summarize the knowledge regarding the clinical, epidemiological, imaging, and pathological characteristics of PPMS and compare those characteristics with RRMS and SPMS. PMID:22327362

  1. Recent progress on small vessel disease with cognitive impairment.

    PubMed

    Gong, Li; Liu, Xue-Yuan; Fang, Min

    2015-01-01

    Vascular cognitive impairment (VCI) refers to different degrees of cognitive dysfunction syndrome caused by all kinds of cerebral vascular disease and vascular factors. Before in the development of vascular dementia (VaD), early diagnosis and intervention can prevent and delay the progress of VCI, even reverse cognitive impairment. In this review, we summarized the research progress of vascular cognitive impairment in pathophysiology, biomarkers and treatments, etc. PMID:26221320

  2. Recent progress on small vessel disease with cognitive impairment

    PubMed Central

    Gong, Li; Liu, Xue-Yuan; Fang, Min

    2015-01-01

    Vascular cognitive impairment (VCI) refers to different degrees of cognitive dysfunction syndrome caused by all kinds of cerebral vascular disease and vascular factors. Before in the development of vascular dementia (VaD), early diagnosis and intervention can prevent and delay the progress of VCI, even reverse cognitive impairment. In this review, we summarized the research progress of vascular cognitive impairment in pathophysiology, biomarkers and treatments, etc. PMID:26221320

  3. 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.

  4. 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

  5. Plasma neurofilament heavy chain levels and disease progression in amyotrophic lateral sclerosis: insights from a longitudinal study

    PubMed Central

    Lu, Ching-Hua; Petzold, Axel; Topping, Jo; Allen, Kezia; Macdonald-Wallis, Corrie; Clarke, Jan; Pearce, Neil; Kuhle, Jens; Giovannoni, Gavin; Fratta, Pietro; Sidle, Katie; Fish, Mark; Orrell, Richard; Howard, Robin; Greensmith, Linda; Malaspina, Andrea

    2015-01-01

    Objective To investigate the role of longitudinal plasma neurofilament heavy chain protein (NfH) levels as an indicator of clinical progression and survival in amyotrophic lateral sclerosis (ALS). Methods A cross-sectional study involving 136 clinically heterogeneous patients with ALS and 104 healthy and neurological controls was extended to include a prospective analysis of 74 of these ALS cases, with samplings at approximately 3-month intervals in a follow-up period of up to 3 years. We analysed the correlation between longitudinal NfH-phosphoform levels and disease progression. Temporal patterns of NfH changes were evaluated using multilevel linear regression. Results Baseline plasma NfH levels were higher than controls only in patients with ALS with short disease duration to baseline sampling. Compared with controls, fast-progressing patients with ALS, particularly those with a short diagnostic latency and disease duration, had higher plasma NfH levels at an early stage and lower levels closer to end-stage disease. Lower NfH levels between visits were associated with rapid functional deterioration. We also detected antibodies against NfH, NfH aggregates and NfH cleavage products. Conclusions Disease progression in ALS involves defined trajectories of plasma NfH levels, reflecting speed of neurological decline and survival. Intervisit plasma NfH changes are also indicative of disease progression. This study confirms that longitudinal measurements of NfH plasma levels are more informative than cross-sectional studies, where the time of sampling may represent a bias in the interpretation of the results. Autoantibodies against NfH aggregates and NfH cleavage products may explain the variable expression of plasma NfH with disease progression. Trail registration number NIHRID6160. PMID:25009280

  6. LACK OF SIGMA-1 RECEPTOR EXACERBATES ALS PROGRESSION IN MICE

    PubMed Central

    Mavlyutov, Timur A.; Epstein, Miles L.; Verbny, Yakov I.; Huerta, Maria S.; Zaitoun, Ismail; Ziskind-Conhaim, Lea; Ruoho, Arnold E.

    2013-01-01

    The function of the sigma-1 receptor (S1R) has been implicated in modulating the activity of various ion channels. In the Central Nervous System (CNS) S1R is enriched in cholinergic postsynaptic densities in spinal cord motoneurons (MN). Mutations in S1R have been found in familial cases of Amyotrophic Lateral Sclerosis (ALS). In this study we show that a knockout of S1R in the SOD1*G93A mouse model of ALS significantly reduces longevity (end stage). Electrophysiological experiments demonstrate that MN of mice lacking S1R exhibit increased excitability. Taken together the data suggest the S1R acts as a brake on excitability, an effect that might enhance longevity in an ALS mouse model. PMID:23458708

  7. 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 ...

  8. 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. PMID:26697982

  9. 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

  10. Disruption of gut homeostasis by opioids accelerates HIV disease progression

    PubMed Central

    Meng, Jingjing; Sindberg, Gregory M.; Roy, Sabita

    2015-01-01

    Cumulative studies during the past 30 years have established the correlation between opioid abuse and human immunodeficiency virus (HIV) infection. Further studies also demonstrate that opioid addiction is associated with faster progression to AIDS in patients. Recently, it was revealed that disruption of gut homeostasis and subsequent microbial translocation play important roles in pathological activation of the immune system during HIV infection and contributes to accelerated disease progression. Similarly, opioids have been shown to modulate gut immunity and induce gut bacterial translocation. This review will explore the mechanisms by which opioids accelerate HIV disease progression by disrupting gut homeostasis. Better understanding of these mechanisms will facilitate the search for new therapeutic interventions to treat HIV infection especially in opioid abusing population. PMID:26167159

  11. Induced pluripotent stem cells from ALS patients for disease modeling.

    PubMed

    Richard, Jean-Philippe; Maragakis, Nicholas J

    2015-05-14

    The ability to reprogram adult somatic cells into pluripotent stem cells that can differentiate into all three germ layers of the developing human has fundamentally changed the landscape of biomedical research. For a neurodegenerative disease like Amyotrophic Lateral Sclerosis (ALS), which does not manifest itself until adulthood and is a heterogeneous disease with few animal models, this technology may be particularly important. Induced pluripotent stem cells (iPSC) have been created from patients with several familial forms of ALS as well as some sporadic forms of ALS. These cells have been differentiated into ALS-relevant cell subtypes including motor neurons and astrocytes, among others. ALS-relevant pathologies have also been identified in motor neurons from these cells and may provide a window into understanding disease mechanisms in vitro. Given that this is a relatively new field of research, numerous challenges remain before iPSC methodologies can fulfill their potential as tools for modeling ALS as well as providing a platform for the investigation of ALS therapeutics. This article is part of a Special Issue entitled ALS complex pathogenesis. PMID:25223906

  12. Cerebrospinal Fluid Biomarkers for Parkinson Disease Diagnosis and Progression

    PubMed Central

    Shi, Min; Bradner, Joshua; Hancock, Aneeka M.; Chung, Kathryn A.; Quinn, Joseph F.; Peskind, Elaine R.; Galasko, Douglas; Jankovic, Joseph; Zabetian, Cyrus P.; Kim, Hojoong M.; Leverenz, James B.; Montine, Thomas J.; Ginghina, Carmen; Kang, Un Jung; Cain, Kevin C.; Wang, Yu; Aasly, Jan; Goldstein, David S.; Zhang, Jing

    2011-01-01

    Background There is a clear need to develop biomarkers for Parkinson disease (PD) diagnosis, differential diagnosis of parkinsonian disorders, and monitoring disease progression. We and others have demonstrated that a decrease in DJ-1 and/or ?-synuclein in the cerebrospinal fluid (CSF) is a potential index for PD diagnosis, but not for PD severity. Methods Using highly sensitive and quantitative Luminex assays, we measured total tau, phosphorylated tau, amyloid beta peptide 1-42 (A?1-42), Flt3 ligand and fractalkine levels in CSF in a large cohort of PD patients at different stages as well as healthy and diseased controls. The utility of these five markers was evaluated for disease diagnosis and severity/progression correlation alone, as well as in combination with DJ-1 and ?-synuclein. The major results were further validated in an independent cohort of cross-sectional PD patients as well as in PD cases with CSF samples collected longitudinally. Findings The results demonstrated that combinations of these biomarkers could differentiate PD patients not only from normal controls but also from patients with Alzheimer disease and multiple system atrophy. Particularly, with CSF Flt3 ligand, PD could be clearly differentiated from multiple system atrophy, a disease that overlaps with PD clinically, with excellent sensitivity (99%) and specificity (95%). In addition, we identified CSF fractalkine/A?1-42 that positively correlated with PD severity in cross-sectional samples as well as with PD progression in longitudinal samples. Interpretation We have demonstrated that this panel of seven CSF proteins could aid in PD diagnosis, differential diagnosis, and correlation with disease severity and progression. PMID:21400565

  13. Predictors of disease progression in HIV infection: a review.

    PubMed

    Langford, Simone E; Ananworanich, Jintanat; Cooper, David A

    2007-01-01

    During the extended clinically latent period associated with Human Immunodeficiency Virus (HIV) infection the virus itself is far from latent. This phase of infection generally comes to an end with the development of symptomatic illness. Understanding the factors affecting disease progression can aid treatment commencement and therapeutic monitoring decisions. An example of this is the clear utility of CD4+ T-cell count and HIV-RNA for disease stage and progression assessment. Elements of the immune response such as the diversity of HIV-specific cytotoxic lymphocyte responses and cell-surface CD38 expression correlate significantly with the control of viral replication. However, the relationship between soluble markers of immune activation and disease progression remains inconclusive. In patients on treatment, sustained virological rebound to >10,000 copies/mL is associated with poor clinical outcome. However, the same is not true of transient elevations of HIV RNA (blips). Another virological factor, drug resistance, is becoming a growing problem around the globe and monitoring must play a part in the surveillance and control of the epidemic worldwide. The links between chemokine receptor tropism and rate of disease progression remain uncertain and the clinical utility of monitoring viral strain is yet to be determined. The large number of confounding factors has made investigation of the roles of race and viral subtype difficult, and further research is needed to elucidate their significance. Host factors such as age, HLA and CYP polymorphisms and psychosocial factors remain important, though often unalterable, predictors of disease progression. Although gender and mode of transmission have a lesser role in disease progression, they may impact other markers such as viral load. Finally, readily measurable markers of disease such as total lymphocyte count, haemoglobin, body mass index and delayed type hypersensitivity may come into favour as ART becomes increasingly available in resource-limited parts of the world. The influence of these, and other factors, on the clinical progression of HIV infection are reviewed in detail, both preceding and following treatment initiation. PMID:17502001

  14. 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 Parkinsons disease. PMID:25977680

  15. Progress in screening and treatment of common congenital eye diseases.

    PubMed

    Li, Yan; Lin, Haotian

    2013-09-01

    Congenital eye illnesses are caused by congenital ocular malformations and are a primary cause of poor visual acuity and blindness in infants. Early diagnosis and treatment of congenital eye illnesses are of great significance for affected infants, their families, and even society as a whole. This study describes the current situation for prenatal and infant screening for congenital eye diseases and briefly summarizes novel progress in the treatment of the five most common eye diseases (congenital dacryocystitis, congenital cataract, retinopathy of prematurity, congenital glaucoma and retinoblastoma). Current programs are now aimed at improvements in the prevention and treatment of congenital eye diseases in China. PMID:24579559

  16. gems: An R Package for Simulating from Disease Progression Models

    PubMed Central

    Blaser, Nello; Vizcaya, Luisa Salazar; Estill, Janne; Zahnd, Cindy; Kalesan, Bindu; Egger, Matthias; Gsponer, Thomas; Keiser, Olivia

    2015-01-01

    Mathematical models of disease progression predict disease outcomes and are useful epidemiological tools for planners and evaluators of health interventions. The 𝖱 package gems is a tool that simulates disease progression in patients and predicts the effect of different interventions on patient outcome. Disease progression is represented by a series of events (e.g., diagnosis, treatment and death), displayed in a directed acyclic graph. The vertices correspond to disease states and the directed edges represent events. The package gems allows simulations based on a generalized multistate model that can be described by a directed acyclic graph with continuous transition-specific hazard functions. The user can specify an arbitrary hazard function and its parameters. The model includes parameter uncertainty, does not need to be a Markov model, and may take the history of previous events into account. Applications are not limited to the medical field and extend to other areas where multistate simulation is of interest. We provide a technical explanation of the multistate models used by gems, explain the functions of gems and their arguments, and show a sample application. PMID:26064082

  17. What is the new target inhibiting the progression of Alzheimer's disease

    PubMed Central

    Zhang, Lin; Yang, Jing; Cao, Yunpeng

    2013-01-01

    To stop the progression of Alzheimer's disease in the early stage, it is necessary to identify new therapeutic targets. We examined striatal-enriched phosphatase 61 expression in the brain tissues of 12-month-old APPswe/PSEN1dE9 transgenic mice. Immunohistochemistry showed that al-enriched phosphatase 61 protein expression was significantly increased but phosphorylated N-methyl-D-aspartate receptor 2B levels were significantly decreased in the cortex and hippocampus of APPswe/PSEN1dE9 transgenic mice. Western blotting of a cell model of Alzheimer's disease consisting of amyloid-beta peptide (142)-treated C57BL/6 mouse cortical neurons in vitro showed that valeric acid (AP5), an N-methyl-D-aspartate receptor antagonist, significantly inhibited amyloid-beta 142-induced increased activity of striatal-enriched phosphatase 61. In addition, the phosphorylation of N-methyl-D-aspartate receptor 2B at Tyr1472 was impaired in amyloid-beta 142-treated cortical neurons, but knockdown of striatal-enriched phosphatase 61 enhanced the phosphorylation of N-methyl-D-aspartate receptor 2B. Collectively, these findings indicate that striatal-enriched phosphatase 61 can disturb N-methyl-D-aspartate receptor transport and inhibit the progression of learning and study disturbances induced by Alzheimer's disease. Thus, al-enriched phosphatase 61 may represent a new target for inhibiting the progression of Alzheimer's disease. PMID:25206502

  18. Coping with amyotrophic lateral sclerosis; from diagnosis and during disease progression.

    PubMed

    Jakobsson Larsson, Birgitta; Nordin, Karin; Nygren, Ingela

    2016-02-15

    To evaluate coping strategies among patients with Amyotrophic lateral sclerosis starting with diagnosis and during the disease progression, as well as investigate changes and correlations between coping strategies, emotional well-being and physical function. A total of 36 patients participated in the study. The patients filled out the Hospital Anxiety and Depression Scale and the Motor Neuron Disease Coping Scale. Physical function was measured using the revised ALS functional rating scale. Data were collected regularly from diagnosis and over a two years period. As a way to cope with the disease patients relied on both problem focused and emotional focused strategies. The use of coping strategies remained stable. Both physical disabilities and emotional well-being was related to some coping strategies, with some variation during the disease progression. Moreover, some coping strategies were related to symptoms of anxiety and depression. Irrespective of whether the coping strategies affect the emotional well-being or vice versa, the results show the importance of early and continuous evaluation of coping and emotional well-being to ease the emotional distress and provide support to the patient so that he/she can cope with the disease during the disease progression. PMID:26810549

  19. Fabrication, phase transformation studies and characterization of SiC-AlN-Al{sub 2}OC ceramics. Progress report

    SciTech Connect

    Virkar, A.V.

    1992-01-12

    SiC and AlN are two of the important high temperature structural ceramics. AlN and the 2H polytype of SiC are isostructural. Prior work has shown that they form an extension solid solution at temperatures {ge} 2000{degrees}C. At lower temperatures, the solid solution can undergo phase separation. Additionally, Al{sub 2}OC is also isostructural and can form extensive solid solutions with SiC and AlN. The formation of solid solutions in such refractory materials as well as the tendency to undergo diffusional phase transformations suggests that a potential exists to improve properties through alloying. The principal objective of the proposed work is to examine phase relations, phase transformations, the resulting precipitate morphologies and their influence on mechanical properties of SiC-AlN-Al{sub 2}OC ceramics. Formation of modulated structures have been documented in SiC-AlN ceramics in our work. It has been shown that modulations occur along directions other than the [0001] direction and this results in the formation of a tweed type of a microstructure. In the AlN-Al{sub 2}OC system, the occurrence of cellular precipitates as well as coherent, disc-shaped precipitates has been observed. During the past year, work has progressed in the following areas: (1) Phase separation in SiC-AlN system: The effect of coherency strain energy on the precipitate morphology. (2) High temperature creep of SiC-AlN ceramics containing modulated structures and SiC-Al{sub 2}OC ceramics. (3) Fabrication and characterization of damage-resistant SiC-AlN ceramics. Three manuscripts have been submitted for publication.

  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. 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

  2. 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

  3. 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

  4. Antagonistic molecular interactions of photosynthetic pigments with molecular disease targets: a new approach to treat AD and ALS.

    PubMed

    Krishnaraj, R Navanietha; Kumari, S S Sreeja; Mukhopadhyay, Sudit Sekhar

    2016-02-01

    Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) are progressive neurodegenerative diseases that affect the neurons in the brain and the spinal cord. Neuroinflamation and apoptosis are key players in the progressive damage of the neurons in AD and ALS. Currently, there is no drug to offer complete cure for both these diseases. Riluzole is the only available drug that can prolong the life time of the ALS patients for nearly 3 months. Molecules that offer good HIT to the molecular targets of ALS will help to treat AD and ALS patients. P53 kinase receptor (4AT3), EphA4 (3CKH) and histone deacetylase (3SFF) are the promising disease targets of AD and ALS. This paper discusses on a new approach to combat neurodegenerative diseases using photosynthetic pigments. The docking studies were performed with the Autodock Vina algorithm to predict the binding of the natural pigments such as β carotene, chlorophyll a, chlorophyll b, phycoerythrin and phycocyanin on these targets. The β carotene, phycoerythrin and phycocyanin had higher binding energies indicating the antagonistic activity to the disease targets. These pigments serve as a potential therapeutic molecule to treat neuroinflammation and apoptosis in the AD and ALS patients. PMID:26053508

  5. Current Progress in Therapeutic Gene Editing for Monogenic Diseases.

    PubMed

    Prakash, Versha; Moore, Marc; Yáñez-Muñoz, Rafael J

    2016-03-01

    Programmable nucleases allow defined alterations in the genome with ease-of-use, efficiency, and specificity. Their availability has led to accurate and widespread genome engineering, with multiple applications in basic research, biotechnology, and therapy. With regard to human gene therapy, nuclease-based gene editing has facilitated development of a broad range of therapeutic strategies based on both nonhomologous end joining and homology-dependent repair. This review discusses current progress in nuclease-based therapeutic applications for a subset of inherited monogenic diseases including cystic fibrosis, Duchenne muscular dystrophy, diseases of the bone marrow, and hemophilia and highlights associated challenges and future prospects. PMID:26765770

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

    PubMed

    Manuel, Ivn; Gonzlez de San Romn, Estbaliz; Giralt, M Teresa; Ferrer, Isidro; Rodrguez-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. PMID:24946872

  7. Glutathione dysregulation and the etiology and progression of human diseases

    PubMed Central

    Ballatori, Nazzareno; Krance, Suzanne M.; Notenboom, Sylvia; Shi, Shujie; Tieu, Kim; Hammond, Christine L.

    2009-01-01

    Glutathione (GSH) plays an important role in a multitude of cellular processes, including cell differentiation, proliferation, and apoptosis, and as a result, disturbances in GSH homeostasis are implicated in the etiology and/or progression of a number of human diseases, including cancer, diseases of aging, cystic fibrosis, and cardiovascular, inflammatory, immune, metabolic, and neurodegenerative diseases. Because of GSH’s pleiotropic effects on cell functions, it has been quite difficult to define the role of GSH in the onset and/or the expression of human diseases, although significant progress is being made. GSH levels, turnover rates and/or oxidation state can be compromised by inherited or aquired defects in the enzymes, transporters, signaling molecules, or transcription factors that are involved in its homeostasis, or from exposure to reactive chemicals or metabolic intermediates. GSH deficiency or a decrease in the GSH/glutathione disulfide (GSSG) ratio manifests itself largely through an increased susceptibility to oxidative stress, and the resulting damage is thought to be involved in diseases such as cancer, Parkinson’s disease, and Alzheimer’s disease. In addition, imbalances in GSH levels affect immune system function, and are thought to play a role in the aging process. Just as low intracellular GSH levels decrease cellular antioxidant capacity, elevated GSH levels generally increase antioxidant capacity and resistance to oxidative stress, and this is observed in many cancer cells. The higher GSH levels in some tumor cells are also typically associated with higher levels of GSH-related enzymes and transporters. Although neither the mechanism nor the implications of these changes are well defined, the high GSH content makes cancer cells chemoresistant, which is a major factor that limits drug treatment. The present report highlights and integrates the growing connections between imbalances in GSH homeostasis and a multitude of human diseases. PMID:19166318

  8. Reversal of progressive nyctalopia in a patient with Crohn's disease.

    TOXLINE Toxicology Bibliographic Information

    Gans M; Taylor C

    1990-04-01

    A 51-year-old man who had undergone several partial bowel resections for Crohn's disease presented with progressively decreased night vision. Electroretinography showed a flat scotopic response and a diminished, delayed photopic response. Measurement of stool fat showed marked fat malabsorption. Treatment with parenteral nutrition, including administration of vitamin A, resulted in marked improvement in the scotopic and photopic response and subjective improvement in his night vision. Patients with malabsorption states should be followed to avoid irreversible visual loss.

  9. Reversal of progressive nyctalopia in a patient with Crohn's disease.

    PubMed

    Gans, M; Taylor, C

    1990-04-01

    A 51-year-old man who had undergone several partial bowel resections for Crohn's disease presented with progressively decreased night vision. Electroretinography showed a flat scotopic response and a diminished, delayed photopic response. Measurement of stool fat showed marked fat malabsorption. Treatment with parenteral nutrition, including administration of vitamin A, resulted in marked improvement in the scotopic and photopic response and subjective improvement in his night vision. Patients with malabsorption states should be followed to avoid irreversible visual loss. PMID:2113831

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

    PubMed Central

    Vaughan, Annalicia; Dent, Annette G.; OHare, 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 ? (TNF-?)] 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

  11. Tumour necrosis factor-? 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)-?, 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-? antagonist therapeutics in reports available in the literature. We found that TNF-? 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-? inhibition has proven useful for patients with progressive vitiligo, where TNF-? 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. PMID:26149498

  12. Beyond Guam: the cyanobacteria/BMAA hypothesis of the cause of ALS and other neurodegenerative diseases.

    PubMed

    Bradley, Walter G; Mash, Deborah C

    2009-01-01

    Excitement about neurogenetics in the last two decades has diverted attention from environmental causes of sporadic ALS. Fifty years ago endemic foci of ALS with a frequency one hundred times that in the rest of the world attracted attention since they offered the possibility of finding the cause for non-endemic ALS throughout the world. Research on Guam suggested that ALS, Parkinson's disease and dementia (the ALS/PDC complex) was due to a neurotoxic non-protein amino acid, beta-methylamino-L-alanine (BMAA), in the seeds of the cycad Cycas micronesica. Recent discoveries that found that BMAA is produced by symbiotic cyanobacteria within specialized roots of the cycads; that the concentration of protein-bound BMAA is up to a hundred-fold greater than free BMAA in the seeds and flour; that various animals forage on the seeds (flying foxes, pigs, deer), leading to biomagnification up the food chain in Guam; and that protein-bound BMAA occurs in the brains of Guamanians dying of ALS/PDC (average concentration 627 microg/g, 5 mM) but not in control brains have rekindled interest in BMAA as a possible trigger for Guamanian ALS/PDC. Perhaps most intriguing is the finding that BMAA is present in brain tissues of North American patients who had died of Alzheimer's disease (average concentration 95 microg/g, 0.8mM); this suggests a possible etiological role for BMAA in non-Guamanian neurodegenerative diseases. Cyanobacteria are ubiquitous throughout the world, so it is possible that all humans are exposed to low amounts of cyanobacterial BMAA, that protein-bound BMAA in human brains is a reservoir for chronic neurotoxicity, and that cyanobacterial BMAA is a major cause of progressive neurodegenerative diseases including ALS worldwide. Though Montine et al., using different HPLC method and assay techniques from those used by Cox and colleagues, were unable to reproduce the findings of Murch et al., Mash and colleagues using the original techniques of Murch et al. have recently confirmed the presence of protein-bound BMAA in the brains of North American patients dying with ALS and Alzheimer's disease (concentrations >100 microg/g) but not in the brains of non-neurological controls or Huntington's disease. We hypothesize that individuals who develop neurodegenerations may have a genetic susceptibility because of inability to prevent BMAA accumulation in brain proteins and that the particular pattern of neurodegeneration that develops depends on the polygenic background of the individual. PMID:19929726

  13. 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

  14. 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

  15. Peripheral Biomarkers of Parkinson's Disease Progression and Pioglitazone Effects.

    PubMed

    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

    2015-10-01

    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-1? 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

  16. Predicting Progression of Alzheimers Disease Using Ordinal Regression

    PubMed Central

    Doyle, Orla M.; Westman, Eric; Marquand, Andre F.; Mecocci, Patrizia; Vellas, Bruno; Tsolaki, Magda; K?oszewska, Iwona; Soininen, Hilkka; Lovestone, Simon; Williams, Steve C. R.; Simmons, Andrew

    2014-01-01

    We propose a novel approach to predicting disease progression in Alzheimers disease (AD) multivariate ordinal regression which inherently models the ordered nature of brain atrophy spanning normal aging (CTL) to mild cognitive impairment (MCI) to AD. Ordinal regression provides probabilistic class predictions as well as a continuous index of disease progression the ORCHID (Ordinal Regression Characteristic Index of Dementia) score. We applied ordinal regression to 1023 baseline structural MRI scans from two studies: the US-based Alzheimers Disease Neuroimaging Initiative (ADNI) and the European based AddNeuroMed program. Here, the acquired AddNeuroMed dataset was used as a completely independent test set for the ordinal regression model trained on the ADNI cohort providing an optimal assessment of model generalizability. Distinguishing CTL-like (CTL and stable MCI) from AD-like (MCI converters and AD) resulted in balanced accuracies of 82% (cross-validation) for ADNI and 79% (independent test set) for AddNeuroMed. For prediction of conversion from MCI to AD, balanced accuracies of 70% (AUC of 0.75) and 75% (AUC of 0.81) were achieved. The ORCHID score was computed for all subjects. We showed that this measure significantly correlated with MMSE at 12 months (??=?0.64, ADNI and ??=?0.59, AddNeuroMed). Additionally, the ORCHID score can help fractionate subjects with unstable diagnoses (e.g. reverters and healthy controls who later progressed to MCI), moderately late converters (1224 months) and late converters (2436 months). A comparison with results in the literature and direct comparison with a binary classifier suggests that the performance of this framework is highly competitive. PMID:25141298

  17. Angiotensinogen Expression Is Enhanced in the Progression of Glomerular Disease

    PubMed Central

    Urushihara, Maki; Kobori, Hiroyuki

    2011-01-01

    Intrarenal renin-angiotensin system (RAS) activation plays a critical role in the development and progression of renal injury. In the kidney, all of the RAS components are present and intrarenal angiotensin II (Ang II) is formed by multiple independent mechanisms. Angiotensinogen (AGT) is the only known substrate for renin that is a rate-limiting enzyme of the RAS. Recently, enhanced intrarenal AGT levels have been shown to reflect the intrarenal RAS status in hypertension, chronic glomerular disease and diabetic nephropathy. In this review, we focus on AGT expression of the diseased glomeruli in the progression of glomerular disease. An anti-glomerular basement membrane nephritis rat model developed progressive proteinuria and glomerular crescent formation, accompanied by increased macrophage infiltration and glomerular expression of AGT and Ang II. The addition of Ang II type 1 receptor blocker to CC-chemokine recaptor 2 antagonist markedly attenuated the induction of macrophage infiltration, AGT and Ang II, and reduced glomerular crescent formation. Next, the levels of glomerular AGT expression and marker of reactive oxygen species in Zucker diabetic fatty (ZDF) obese rats were higher than those in ZDF lean rats. Hydrogen peroxide (H2O2) induced an increase in the AGT expression in primary rat mesangial cells. Furthermore, the H2O2-induced upregulation of AGT was inhibited by a mitogen-activated protein kinase kinase and a c-Jun N-terminal kinase inhibitor. These data suggest the potential contribution of enhanced AGT expression in glomeruli to the intrarenal RAS activation for the development of glomerular disease. PMID:22247811

  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. PMID:23380995

  19. Biomarkers of Renal Disease and Progression in Patients with Diabetes

    PubMed Central

    Hojs, Radovan; Ekart, Robert; Bevc, Sebastjan; Hojs, Nina

    2015-01-01

    Diabetes prevalence is increasing worldwide, mainly due to the increase in type 2 diabetes. Diabetic nephropathy occurs in up to 40% of people with type 1 or type 2 diabetes. It is important to identify patients at risk of diabetic nephropathy and those who will progress to end stage renal disease. In clinical practice, most commonly used markers of renal disease and progression are serum creatinine, estimated glomerular filtration rate and proteinuria or albuminuria. Unfortunately, they are all insensitive. This review summarizes the evidence regarding the prognostic value and benefits of targeting some novel risk markers for development of diabetic nephropathy and its progression. It is focused mainly on tubular biomarkers (neutrophil-gelatinase associated lipocalin, kidney injury molecule 1, liver-fatty acid-binding protein, N-acetyl-beta-d-glucosaminidase), markers of inflammation (pro-inflammatory cytokines, tumour necrosis factor-α and tumour necrosis factor-α receptors, adhesion molecules, chemokines) and markers of oxidative stress. Despite the promise of some of these new biomarkers, further large, multicenter prospective studies are still needed before they can be used in everyday clinical practice. PMID:26239462

  20. PNPLA3 I148M polymorphism and progressive liver disease.

    PubMed

    Dongiovanni, Paola; Donati, Benedetta; Fares, Roberta; Lombardi, Rosa; Mancina, Rosellina Margherita; Romeo, Stefano; Valenti, Luca

    2013-11-01

    The 148 Isoleucine to Methionine protein variant (I148M) of patatin-like phospholipase domain-containing 3 (PNPLA3), a protein is expressed in the liver and is involved in lipid metabolism, has recently been identified as a major determinant of liver fat content. Several studies confirmed that the I148M variant predisposes towards the full spectrum of liver damage associated with fatty liver: from simple steatosis to steatohepatitis and progressive fibrosis. Furthermore, the I148M variant represents a major determinant of progression of alcohol related steatohepatitis to cirrhosis, and to influence fibrogenesis and related clinical outcomes in chronic hepatitis C virus hepatitis, and possibly chronic hepatitis B virus hepatitis, hereditary hemochromatosis and primary sclerosing cholangitis. All in all, studies suggest that the I148M polymorphism may represent a general modifier of fibrogenesis in liver diseases. Remarkably, the effect of the I148M variant on fibrosis was independent of that on hepatic steatosis and inflammation, suggesting that it may affect both the quantity and quality of hepatic lipids and the biology of non-parenchymal liver cells besides hepatocytes, directly promoting fibrogenesis. Therefore, PNPLA3 is a key player in liver disease progression. Assessment of the I148M polymorphism will possibly inform clinical practice in the future, whereas the determination of the effect of the 148M variant will reveal mechanisms involved in hepatic fibrogenesis. PMID:24222941

  1. A transcriptional network underlies susceptibility to kidney disease progression

    PubMed Central

    Laouari, Denise; Burtin, Martine; Phelep, Aurlie; Bienaime, Frank; Noel, Laure-Hlne; Lee, David C; Legendre, Christophe; Friedlander, Grard; 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-?, 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

  2. High Degree of Heterogeneity in Alzheimer's Disease Progression Patterns

    PubMed Central

    Komarova, Natalia L.; Thalhauser, Craig J.

    2011-01-01

    There have been several reports on the varying rates of progression among Alzheimer's Disease (AD) patients; however, there has been no quantitative study of the amount of heterogeneity in AD. Obtaining a reliable quantitative measure of AD progression rates and their variances among the patients for each stage of AD is essential for evaluating results of any clinical study. The Global Deterioration Scale (GDS) and Functional Assessment Staging procedure (FAST) characterize seven stages in the course of AD from normal aging to severe dementia. Each GDS/FAST stage has a published mean duration, but the variance is unknown. We use statistical analysis to reconstruct GDS/FAST stage durations in a cohort of 648 AD patients with an average follow-up time of 4.78 years. Calculations for GDS/FAST stages 4–6 reveal that the standard deviations for stage durations are comparable with their mean values, indicating the presence of large variations in the AD progression among patients. Such amount of heterogeneity in the course of progression of AD is consistent with the existence of several sub-groups of AD patients, which differ by their patterns of decline. PMID:22072952

  3. Initial letter and semantic category fluency in Alzheimer's disease, Huntington's disease, and progressive supranuclear palsy.

    PubMed Central

    Rosser, A; Hodges, J R

    1994-01-01

    Ten patients with dementia of Alzheimer's type, 10 patients with progressive supranuclear palsy, and 10 patients with Huntington's disease were compared on two types of verbal fluency task--namely, initial letter fluency and category (semantic) fluency. The groups were carefully matched for overall level of dementia on the dementia rating scale, and were compared with 25 age matched normal controls. The controls found letter fluency more difficult than category fluency, and this relative pattern of performance was repeated in the progressive supranuclear palsy and Huntington's disease groups, although both groups were significantly impaired on both tasks. By contrast, patients with Alzheimer's disease performed just as poorly as the progressive supranuclear palsy and Huntington's disease groups on the category tasks, but were significantly less impaired at letter fluency, performing at near normal levels on this task. From these results, it is suggested that the performances of patients with progressive supranuclear palsy and Huntington's disease relate largely to initiation and retrieval problems secondary to disruption of frontostriatal circuits, whereas in Alzheimer's disease, the poorer performance on category fluency is due principally to the breakdown of semantic knowledge, which probably reflects temporal neocortical involvement. Images PMID:7964817

  4. Epigenetics of Progression of Chronic Kidney Disease: Fact or Fantasy?

    PubMed Central

    Wing, Maria R.; Ramezani, Ali; Gill, Harindarpal S.; Devaney, Joseph M.; Raj, Dominic S.

    2013-01-01

    Summary Epigenetic modifications are important in the normal functioning of the cell, from regulating dynamic expression of essential genes and associated proteins to repressing those that are unneeded. Epigenetic changes are essential for development and functioning of the kidney, and aberrant methylation, histone modifications, and expression of microRNA could lead to chronic kidney disease (CKD). Here, epigenetic modifications modulate transforming growth factor β signaling, inflammation, profibrotic genes, and the epithelial-to-mesenchymal transition, promoting renal fibrosis and progression of CKD. Identification of these epigenetic changes is important because they are potentially reversible and may serve as therapeutic targets in the future to prevent subsequent renal fibrosis and CKD. In this review we discuss the different types of epigenetic control, methods to study epigenetic modifications, and how epigenetics promotes progression of CKD. PMID:24011578

  5. Staging Alzheimer’s Disease Progression with Multimodality Neuroimaging

    PubMed Central

    Ewers, Michael; Frisoni, Giovanni B.; Teipel, Stefan J.; Grinberg, Lea T.; Amaro, Edson; Heinsen, Helmut; Thompson, Paul M.; Hampel, Harald

    2011-01-01

    Rapid developments in medical neuroimaging have made it possible to reconstruct the trajectory of Alzheimer’s disease (AD) as it spreads through the living brain. The current review focuses on the progressive signature of brain changes throughout the different stages of AD. We integrate recent findings on changes in cortical gray matter volume, white matter fiber tracts, neuropathological alterations, and brain metabolism assessed with molecular positron emission tomography (PET). Neurofibrillary tangles accumulate first in transentorhinal and cholinergic brain areas, and 4-D maps of cortical volume changes show early progressive temporo-parietal cortical thinning. Findings from diffusion tensor imaging (DTI) for assessment fiber tract integrity show cortical disconnection in corresponding brain networks. Importantly, the developmental trajectory of brain changes is not uniform and may be modulated by several factors such as onset of disease mechanisms, risk-associated and protective genes, converging comorbidity, and individual brain reserve. There is a general agreement between in vivo brain maps of cortical atrophy and amyloid pathology assessed through PET, reminiscent of post mortem histopathology studies that paved the way in the staging of AD. The association between in vivo and post mortem findings will clarify the temporal dynamics of pathophysiological alterations in the development of preclinical AD. This will be important in designing effective treatments that target specific underlying disease AD mechanisms. PMID:21718750

  6. Evolution in health and disease: work in progress.

    PubMed

    Stearns, S C; Ebert, D

    2001-12-01

    This article surveys progress in Darwinian medicine since 1991. Evolutionary thinking has been providing an increasing flow of fresh ideas into medical science, ideas that would not be suggested by other perspectives. Recent contributions have shed new light on the evolution of virulence, of antibiotic resistance, of oocytic atresia, of menopause, of the timing of the expression of genetic disease, of links between mate choice and disease resistance, and of genomic conflict between mother and fetus over resource provisioning. An important consequence of changes from the environment of evolutionary adaptedness concerns reproductive cancers; the incidence of reproductive cancers may be linked to changes in the frequency of menstruation in postindustrial societies. Other intriguing developments include some unanticipated and undesirable consequences of good hygiene, hope from an unexpected quarter for progress on nerve and muscle regeneration, evolutionary interpretations of mental disease, and insights from functional genomics into the nature of tradeoffs. The application of evolutionary thinking to problems in medical research and practice has thus yielded an abundant and growing harvest of insights. Some are well founded, others remain speculative. The field is moving from an initial phase dominated by speculation and hypothesis formation into a more rigorous phase of experimental testing of explicit alternatives. Currently the most promising areas, those in which experimental rigor can be applied efficiently, include experimental evolution and functional genomics. The pioneers can be proud of what they have set in motion. PMID:11783396

  7. 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.

  8. Homeostasis of metals in the progression of Alzheimer's disease.

    PubMed

    Gonzlez-Domnguez, Ral; Garca-Barrera, Tamara; Gmez-Ariza, Jos Luis

    2014-06-01

    In order to study the involvement of metals in the progression of Alzheimer's disease, serum samples from patients with Alzheimer and mild cognitive impairment were investigated. For this purpose, metal content was analyzed after size-fractionation of species and then, inter-element and inter-fraction ratios were computed. In this way, the analysis allowed discovering changes that could be used as markers of disease, but also provided a new insight into the interactions in the homeostasis of elements in neurodegeneration and its progression. Aluminum and labile forms of iron and copper were increased in demented patients, while manganese, zinc and selenium were reduced. Interestingly, levels of different elements, principally iron, aluminum and manganese, were closely inter-related, which could evidence a complex interdependency between the homeostasis of the different metals in this disorder. On the other hand, imbalances in metabolism of copper, zinc and selenium could be associated to abnormal redox status. Therefore, this study may contribute to our understanding of the pathological mechanisms related to metals in Alzheimer's disease. PMID:24668390

  9. 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

    2016-01-01

    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

  10. Gene therapy for primary immunodeficiency diseases: recent progress and misgivings.

    PubMed

    Ariga, Tadashi

    2006-01-01

    The progress of clinical gene therapy trials during the last two decades has been remarkable, and its application has also expanded into various fields of human diseases. Among them, hereditary diseases such as the primary immunodeficiency diseases (PID) were considered suitable candidates for gene therapy because the therapeutic strategy was very simple, therefore, effective gene therapy may be obtained without significant difficulty compared to other more complex diseases such as cancer. Indeed, the first clinical gene therapy trial was safely performed and was in part, effective for adenosine deaminase (ADA) deficiency patients, a type of severe combined immunodeficiency diseases (SCID). However, because of certain unforeseen obstacles, it took approximately 10 years until the first curative effects were obtained for gene therapy in patients with X-linked SCID (X-SCID). Here, I review and discuss the background and historical events leading up to PID gene therapy, the safety issues, which unexpectedly arose after the successful report, and finally I will attempt to predict the future trends in this form of gene therapy. PMID:16472146

  11. 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

  12. Vitamin A and HIV infection: disease progression, mortality, and transmission.

    PubMed

    Kennedy, C M; Kuhn, L; Stein, Z

    2000-10-01

    Among HIV-infected individuals, many nutritional factors that influence disease progress, mortality, and transmission are not well understood. Of particular interest is the role of vitamin A. The benefits of vitamin A have been recognized since ancient times by Egyptian physicians who successfully treated night blindness with vitamin A. Contemporary scientists have since recognized the importance of vitamin A and have provided evidence that it may help in repairing damaged mucosal surfaces; what remains unclear, however, is its role during HIV infection. In this review, we examine the evidence provided in both observational studies and randomized controlled trials that assessed the effect of vitamin A during HIV infection. PMID:11127968

  13. Neurologic markers of the progression of Alzheimer's disease.

    PubMed

    Franssen, E H; Reisberg, B

    1997-01-01

    This article describes the results of studies conducted to determine the usefulness of reflex changes as markers of disease severity in Alzheimer's disease (AD). Standardized and quantified muscle stretch reflexes, cutaneous reflexes, and developmental (primitive) reflexes were studied in normal older adults, in individuals with mild memory impairment, and in patients with AD, in all clinical severity stages as assessed with the Global Deterioration Scale (GDS), the Mini-Mental State Examination (MMSE), and the Functional Assessment Staging (FAST) procedure. Changes in frequency and intensity of these individual reflex variables, as well as of variables consisting of combinations of these individual reflexes, appeared to be sensitive indicators of the progression of AD. These neurological reflex variables showed high Pearson correlations with the GDS (.72), the MMSE (.74), and the FAST (.80). Standardized quantified neurological reflex measures are useful as noncognitive, education-independent, and culture-independent markers of the course of AD. PMID:9447450

  14. 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

  15. Connected speech as a marker of disease progression in autopsy-proven Alzheimer's disease.

    PubMed

    Ahmed, Samrah; Haigh, Anne-Marie F; de Jager, Celeste A; Garrard, Peter

    2013-12-01

    Although an insidious history of episodic memory difficulty is a typical presenting symptom of Alzheimer's disease, detailed neuropsychological profiling frequently demonstrates deficits in other cognitive domains, including language. Previous studies from our group have shown that language changes may be reflected in connected speech production in the earliest stages of typical Alzheimer's disease. The aim of the present study was to identify features of connected speech that could be used to examine longitudinal profiles of impairment in Alzheimer's disease. Samples of connected speech were obtained from 15 former participants in a longitudinal cohort study of ageing and dementia, in whom Alzheimer's disease was diagnosed during life and confirmed at post-mortem. All patients met clinical and neuropsychological criteria for mild cognitive impairment between 6 and 18 months before converting to a status of probable Alzheimer's disease. In a subset of these patients neuropsychological data were available, both at the point of conversion to Alzheimer's disease, and after disease severity had progressed from the mild to moderate stage. Connected speech samples from these patients were examined at later disease stages. Spoken language samples were obtained using the Cookie Theft picture description task. Samples were analysed using measures of syntactic complexity, lexical content, speech production, fluency and semantic content. Individual case analysis revealed that subtle changes in language were evident during the prodromal stages of Alzheimer's disease, with two-thirds of patients with mild cognitive impairment showing significant but heterogeneous changes in connected speech. However, impairments at the mild cognitive impairment stage did not necessarily entail deficits at mild or moderate stages of disease, suggesting non-language influences on some aspects of performance. Subsequent examination of these measures revealed significant linear trends over the three stages of disease in syntactic complexity, semantic and lexical content. The findings suggest, first, that there is a progressive disruption in language integrity, detectable from the prodromal stage in a subset of patients with Alzheimer's disease, and secondly that measures of semantic and lexical content and syntactic complexity best capture the global progression of linguistic impairment through the successive clinical stages of disease. The identification of disease-specific language impairment in prodromal Alzheimer's disease could enhance clinicians' ability to distinguish probable Alzheimer's disease from changes attributable to ageing, while longitudinal assessment could provide a simple approach to disease monitoring in therapeutic trials. PMID:24142144

  16. Natural Progression of Canine Glycogen Storage Disease Type IIIa.

    PubMed

    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

  17. Progressive biparietal atrophy: an atypical presentation of Alzheimer's disease.

    PubMed Central

    Ross, S J; Graham, N; Stuart-Green, L; Prins, M; Xuereb, J; Patterson, K; Hodges, J R

    1996-01-01

    OBJECTIVES: To define the clinical, neuropsychological, and radiological features of bilateral parietal lobe atrophy. METHODS: Four patients underwent a comprehensive longitudinal neuropsychological assessment, as well as MRI and HMPAO-SPECT. RESULTS: The consistent findings in the patients were early visuospatial problems, agraphia of a predominantly peripheral (or apraxic) type, and difficulty with bimanual tasks, all of which outweighted deficits in memory and language until later in the course of the illness. As the disease progressed, impairments in the phonological aspects of language and in auditory-verbal short term memory were often striking, perhaps reflecting spread from the parietal lobe to perisylvian language areas. Three patients went on to develop a global dementia and fulfilled the criteria for a clinical diagnosis of probable Alzheimer's disease; the fourth patient has only recently been identified. Neuroimaging disclosed bilateral parietal lobe atrophy (MRI) and hypoperfusion (SPECT), which was out of proportion to that seen elsewhere in the brain. One patient has died and had pathologically confirmed Alzheimer's disease with particular concentration in both superior parietal lobes. CONCLUSIONS: Bilateral biparietal atrophy is a recognisable clinical syndrome which can be the presenting feature of Alzheimer's disease. Although the label "posterior cortical atrophy" has been applied to such cases, review of the medical literature suggests that this broad rubric actually consists of two main clinical syndromes with features reflecting involvement of the occipitotemporal (ventral) and biparietal (dorsal) cortical areas respectively. Images PMID:8890778

  18. 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

  19. FTD and ALS: a tale of two diseases

    PubMed Central

    Ferrari, Raffaele; Kapogiannis, Dimitrios; Huey, Edward D.; Momeni, Parastoo

    2012-01-01

    The first reports of disorders that in terms of cognitive and behavioral symptoms resemble frontotemporal dementia (FTD) and in terms of motor symptoms resemble amyotrophic lateral sclerosis (ALS) bring us back to the second half of the 1800s. Over the last 150 years, and especially in the last two decades, there has been growing evidence that FTD signs can be seen in patients primarily diagnosed with ALS, implying clinical overlap among these two disorders. In the last decade pathological investigations and genetic screening have contributed tremendously in elucidating the pathology and genetic variability associated with FTD and ALS. To the most important recentdiscoveries belong TAR DNA binding protein [TARDBP or TDP-43] and the fused in sarcoma gene [FUS] and their implication in these disorders. FTD and ALS are the focus of this review which aims to 1. summarize clinical features by describing the diagnostic criteria and specific symptomatology, 2. describe the morphological aspects and related pathology, 3. describe the genetic factors associated with the diseases and 4. summarize the current status of clinical trials and treatment options. A better understanding of the clinical, pathological and genetic features characterizing FTD and ALS will shed light into overlaps among these two disorders and the underpinning mechanisms that contribute to the onset and development. Nevertheless, advancements in the knowledge of the biology of these two disorders will help developing novel and, hopefully, more effective diagnostic and treatment options. PMID:21222600

  20. CSF biomarkers and clinical progression of Parkinson disease

    PubMed Central

    Surova, Yulia; hrfelt, Annika; Zetterberg, Henrik; Lindqvist, Daniel; Hansson, Oskar

    2015-01-01

    Objective: To investigate whether certain CSF biomarkers at baseline can predict future progression of motor symptoms and cognitive decline in patients with Parkinson disease (PD). Methods: Patients and controls were recruited from hospitals in southern Sweden as part of the prospective and longitudinal Swedish BioFinder Study. In the present study, we included 42 patients with PD and 69 controls who had clinical assessment and lumbar puncture at baseline. Baseline CSF samples were analyzed for ?-synuclein (?Syn), ?-amyloid 142 (A?42), tau, phosphorylated tau, and neurofilament light. Associations between CSF markers at baseline and change in clinical characteristics after 2 years of follow-up were investigated using multivariate models adjusting for age, sex, disease duration, and levodopa-equivalent daily dose. Results: Higher levels of ?Syn within the PD group were associated with progression of motor symptoms and cognitive decline over 2 years, indicated by significant relationships between ?Syn and change in Hoehn and Yahr (? = 0.394, p = 0.043), Unified Parkinson's Disease Rating Scale, Part III (UPDRS-III) (? = 0.449, p = 0.013), Timed Up and Go (? = 0.406, p = 0.023), and A Quick Test of Cognitive Speed (? = 0.423, p = 0.018). Lower levels of A?42 were associated with worsening of performance on delayed memory recall (F = 5.834, p = 0.022). Finally, high levels of phosphorylated tau were associated with worsening in motor symptoms (UPDRS-III, ? = 0.350, p = 0.045; Hoehn and Yahr, ? = 0.366, p = 0.038). Conclusion: We found evidence of a link between higher levels of ?Syn at baseline and worsening of motor symptoms and cognitive speed over 2 years in PD. Increased ?Syn might be a marker of more intense synaptic degeneration in PD. The results indicate that cortical amyloid pathology (low CSF A?42) is associated with memory decline. PMID:25411441

  1. [An autopsied case of progressive supranuclear palsy presenting with slow progression and unusually prolonged disease duration].

    PubMed

    Iwasaki, Yasushi; Mori, Keiko; Ito, Masumi; Mimuro, Maya; Yoshida, Mari

    2012-01-01

    A 55-year-old Japanese female with no family history of neurological disease showed gait disturbance with rigidity and resting tremor. She was initially diagnosed with Parkinson's disease, but neither laterality of symptoms nor levodopa benefit were observed. The parkinsonism and gait freezing progressed unusually slowly and she experienced frequent falls 17 years after the onset of symptoms. When neurologic examination revealed vertical gaze palsy, masked face, bradykinesia and dominant axial rigidity, the diagnosis was modified to progressive supranuclear palsy (PSP). Retrocollis, grasp reflex, and bilateral Babinski's sign developed, but resting tremor disappeared. Gastrostomy was performed 22 years after onset, after which she was still capable of walking with assistance. Tracheotomy was not performed. The patient died of an acute subarachnoid hemorrhage 24 years after onset at the age of 79. On autopsy, the brain weighed 1,050 g and showed frontal lobe atrophy. Coronal cerebral slices showed atrophy of the globus pallidus and subthalamic nucleus. Tegmental atrophy of the brainstem and depigmentation of the substantia nigra were observed. Neuropathologic examination showed severe neuron loss with gliosis in the globus pallidus, subthalamic nucleus, substantia nigra, and tegmentum of the brainstem. The Purkinje neuron layer and cerebellar dentate nucleus showed mild neuron loss. Globose-type neurofibrillary tangles were widespread, particularly in the globus pallidus, subthalamic nucleus, substantia nigra, nucleus of oculomotor nerve, locus ceruleus, and cerebellar dentate nucleus. Glial fibrillary tangles (coiled body and tuft-shaped astrocyte) and argyrophilic threads were also widespread, particularly in the frontal lobe and basal ganglia. Lewy bodies were not observed. Although, the pathologic findings were consistent with PSP, Gallyas-positive and tau-positive structures were generally small in number. According to the clinicopathological findings, we speculate that this case showed a distinct subtype of PSP with a slowly progressive clinical course and generally mild tau deposition. PMID:22453039

  2. Magnetic resonance imaging in the monitoring of disease progression in multiple sclerosis.

    PubMed

    Stevenson, V L; Miller, D H

    1999-08-01

    Disease progression and irreversible disability in multiple sclerosis results from incomplete recovery from relapses, but most importantly from insidious disease progression. Although magnetic resonance imaging parameters, such as new lesion rate and gadolinium enhancement, reflect inflammation and disease activity they have no bearing on disease progression. Until now the T2 lesion load or disease burden has been relied upon for this, despite its poor relationship with disability measures. This paper looks at the mechanisms responsible for disease progression and discusses the MR techniques now available to reflect these pathological processes. PMID:10467387

  3. Disease steps in multiple sclerosis: a longitudinal study comparing disease steps and EDSS to evaluate disease progression.

    PubMed

    Hohol, M J; Orav, E J; Weiner, H L

    1999-10-01

    Clinical assessment of outcome in multiple sclerosis (MS) patients is problematic since the disease can affect different aspects of the central nervous system and follow a variable course. Recently, we developed Disease Steps, a simple approach for evaluating disease progression. Previously, we found that Disease Steps was easy to use, had uniformly distributed scores and low inter-rater variability. Our current objective was to test the long-term use of Disease Steps together with the most widely utilized clinical outcome measure in MS, the Expanded Disability Status Scale (EDSS) in assessing clinical progression. Over 4 years, 804 patients were classified using both EDSS and Disease Steps. Each patient was assessed at least twice. Follow-up results included annual status and time-to-event analysis examining median staying times within a level of Disease Steps or EDSS. We found that the two scales behaved similarly and correlated strongly with each other. For both Disease Steps and EDSS, patients with milder levels of disability and relapsing-remitting disease demonstrated a higher likelihood of changing scores over time and shorter median staying times compared to more disabled, chronic progressive patients. These findings have important implications for patient selection in clinical trials and for the design of future measurements of clinical outcome in MS. Furthermore, Disease Steps may serve as a simple, practical tool for the nonspecialty neurologist to follow patients over time and serve as a guide in therapeutic decision making. Our findings further document the general progressive nature of MS when a large cohort is followed in an MS specialty clinic over time. PMID:10516779

  4. Progressive increase of inflammatory biomarkers in chronic kidney disease and end-stage renal disease.

    PubMed

    Sharain, Korosh; Hoppensteadt, Debra; Bansal, Vinod; Singh, Ajay; Fareed, Jawed

    2013-06-01

    Chronic kidney disease (CKD) has reached epidemic levels. It is a multisystem disease associated with elevated systemic inflammatory and hypercoagulable states. Most concerning are the cardiovascular risks associated with all stages of kidney disease. It is difficult to assess kidney disease stage progression and cardiovascular risk with current indicators such as estimated glomerular filtration rate and conventional cardiovascular risk factors. However, the use of biomarkers to assess the underlying pathological disease state may bridge the gap. This study evaluated biomarkers of inflammation including C-reactive protein, d-dimer, neuron-specific enolase, neutrophil gelatinase-associated lipocalin, tumor necrosis factor receptor I, and thrombomodulin in 3 groups of patients: CKD stages 2-4, end-stage renal disease (ESRD), and age-matched controls. The study demonstrated a statistically significant progressive upregulation in mean concentration of all markers when comparing controls to CKD and ESRD. Therefore, biomarkers may be able to evaluate the inflammatory state in kidney disease and potentially predict the cardiovascular risk. PMID:22865783

  5. Neuronal loss in the pedunculopontine tegmental nucleus in Parkinson disease and in progressive supranuclear palsy.

    PubMed Central

    Hirsch, E C; Graybiel, A M; Duyckaerts, C; Javoy-Agid, F

    1987-01-01

    In the brains of humans and other mammals, there are two principal groups of cholinergic nuclei aside from those forming the cranial motor nuclei. One group lies in the forebrain and includes the nucleus basalis of Meynert. The second group lies in the hindbrain and includes the nucleus tegmenti pedunculopontinus (NPP), identified by Mesulam et al. [Mesulam, M.-M., Mufson, E. J., Wainer, B. H. & Levey, A. I. (1983) Neuroscience 10, 1185-1201] as cholinergic cell group Ch5. The basal forebrain cholinergic cell groups, which innervate widespread areas of the neocortex, undergo degeneration in Alzheimer disease and also in parkinsonism associated with dementia. We here report that the hindbrain NPP Ch5 cell group, thought to innervate many nuclei of the extrapyramidal motor system, the superior colliculus, and the substantia innominata, undergoes degeneration in idiopathic Parkinson disease and in the parkinsonian syndrome of progressive supranuclear palsy. These findings strongly suggest that degeneration in the brainstem in Parkinson disease is not confined to catecholamine-containing neurons, but that cholinergic neurons of the NPP are also vulnerable. The findings further raise the possibility that certain symptoms of Parkinson disease and progressive supranuclear palsy have their genesis in pathology of these cholinergic neurons. Images PMID:3475716

  6. Predictors of progression in hypertensive renal disease in children.

    PubMed

    Lurbe, Empar; Alvarez, Vicente; Redon, Josep

    2004-04-01

    In hypertensive renal disease in children, several risk factors influence the development and the rate of progression of renal damage, including blood pressure levels, proteinuria, lipid disorders, and genetic differences. The impact of blood pressure on renal structures, the most important of the factors, depends not only on blood pressure levels, but also on the persistence of the blood pressure levels over time, mainly during the hours when the patient is resting or sleeping. Abnormal circadian variability is frequently observed in patients with renal damage, and nocturnal blood pressure reduction should be a major therapeutic objective to protect against a decline in renal function. Proteinuria is a guide for establishing targets and for monitoring treatment. It should be reduced as much as possible to obtain maximal renoprotective effect. The role of the other factors, such as lipid disorders and genetics, remains elusive. PMID:15073472

  7. 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

  8. 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.

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

    PubMed Central

    Schnaper, H. William

    2013-01-01

    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. 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. PMID:23715783

  10. Role of Genetic Changes in the Progression of Cardiovascular Diseases

    PubMed Central

    Sheweita, S. A.; Baghdadi, H.; Allam, A. R.

    2011-01-01

    This review aims to investigate the role of genetic changes in the development of cardiovascular diseases [CVD]. Oxidation of Low density Lipoprotein (LDL) and mutations in LDL receptors gene are a trigger for numerous of atherogenic events. Also, endothelial nitric oxide synthase (eNOS) plays an important role in vasodilatation of blood vessels through synthesis of nitric oxide. Three single base pair changes, 786T/C, 922A/G, and 1468T/A, have been identified in the promoter region of the eNOS gene and are associated with coronary spasm. Moreover, two distinct variable nucleotide tandem repeats (VNTRs) in introns 4 and 13 have been detected. The presence of a minimum of 38 CA repeats in intron 13 has been associated with an independent 2.2-fold increase in the risk of coronary artery disease [CAD]. Plasma glutathione peroxidase (GPx-3) maintains the vascular bioavailability of nitric oxide (NO), through depletion of reactive oxygen species. Mutation(s) or polymorphism(s) in the plasma GPx-3 gene promoter may predispose to a thrombotic disorder, and constitute a genetic risk factor for thrombotic cerebrovascular disease. Hyperhomocysteinemia is another independent risk factor for atherosclerosis and arterial thrombosis. Severe hyperhomocysteinemia could be caused by cystathionine-?-synthase enzyme deficiency but it could be due to homozygosity of a common 677C/T point mutation in the coding region of the methylenetetrahydrofolate reductase (MTHFR) gene as a 3-fold increase in risk of CAD is associated with the MTHFR 677TT genotype. A second common variant in MTHFR 1298A/C is associated with decreased enzyme activity in vitro and in vivo, especially when occurring simultaneously with the 677 C/T polymorphism. Elevated fibrinogen, an essential component of the coagulation system, has been most consistently associated with arterial thrombotic disorders. Several polymorphisms (148C/T, 455G/A, and -854G/A) have been identified in the genes encoding the 3 pairs of fibrinogen polypeptide chains. The -455G/A, and -854G/A substitutions are the most physiologically relevant mutations. In addition the -455A allele has been associated with the progression of atheroma, and also with a 2.5-fold increase in risk of multiple lacunar infarcts in a cohort of elderly patients with stroke. It is concluded that genetic changes in the previously mentioned genes could play a significant role in the initiation and progression of CVD. This review provides useful information for both physicians and medical students whom are interested in human genetics which is related to cardiovascular diseases. PMID:23675242

  11. Arterial Stiffness, Kidney Function, and Chronic Kidney Disease Progression

    PubMed Central

    Townsend, Raymond R.; Tomiyama, Hirofumi

    2013-01-01

    Arterial stiffness can nowadays be measured easily and noninvasively around the globe. Although well established as an independent predictor of cardiovascular events, less is known about the role of arterial stiffness in the progressive loss of kidney function once chronic kidney disease (CKD) is established. In addition to measures of arterial stiffness, a number of devices now noninvasively record the pulse profile from sites such as the radial artery and, using internal algorithms, are able to estimate central pressure profiles. Although these devices have generated much data on the prediction of cardiovascular events, e.g. measures of arterial stiffness, there is much less known about the predictive utility of these measures in CKD progression. In this review, we cover approaches to arterial stiffness as measured by pulse wave velocity and discuss measures of the systolic and diastolic contour of the pulse waveform vis--vis their relationship to declines in kidney function over time. We restrict our coverage to studies that have longitudinal data, but we also include a table of studies, which, to our knowledge, have only published cross-sectional data at this time. PMID:26587431

  12. Oxidative Stress in Fanconi Anemia Hematopoiesis and Disease Progression

    PubMed Central

    Adam, Zsuzsanna; Rani, Reena; Zhang, Xiaoling; Pang, Qishen

    2008-01-01

    Abstract Patients with the genomic instability syndrome Fanconi anemia (FA) commonly develop progressive bone marrow failure and have a high risk of cancer. The prominent role of the FA protein family involves DNA damage response and/or repair. Oxidative stress, defined as an imbalance between the production of reactive oxygen species and antioxidant defense, is considered to be an important pathogenic factor in leukemia-prone bone marrow diseases such as FA. Cellular responses inducing resistance to oxidative stress are important for cellular survival, organism lifespan, and cancer prevention, but until recently, mammalian factors regulating resistance to oxidative stress have not been well characterized. Significant evidence supports excessive apoptosis of hematopoietic stem/progenitor cells, induced by stresses, most significantly oxidative stress, as a critical factor in the pathogenesis of bone marrow failure and leukemia progression in FA. In this brief review, we discuss the functional link between FA proteins and oxidative DNA damage response/repair, with emphasis on the implication of oxidative stress in the pathophysiology and abnormal hematopoiesis in FA. Antioxid. Redox Signal. 10, 19091921. PMID:18627348

  13. 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. PMID:26499077

  14. 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 ?-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

  15. 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

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

    PubMed

    Poredos, P; Zizek, B

    1996-03-01

    Increased blood and plasma viscosity has been described in patients with coronary and peripheral arterial disease. However, the relation of viscosity to the extent of arterial wall deterioration--the most important determinant of clinical manifestation and prognosis of the disease--is not well known. Therefore, the authors studied plasma viscosity as one of the major determinants of blood viscosity in patients with different stages of arterial disease of lower limbs (according to Fontaine) and its relation to the presence of some risk factors of atherosclerosis. The study encompassed four groups of subjects: 19 healthy volunteers (group A), 18 patients with intermittent claudication up to 200 m (stage II; group B), 15 patients with critical ischemia of lower limbs (stage III and IV; group C), and 16 patients with recanalization procedures on peripheral arteries. Venous blood samples were collected from an antecubital vein without stasis for the determination of plasma viscosity (with a rotational capillary microviscometer, PAAR), fibrinogen, total cholesterol, alpha-2-macroglobulin, and glucose concentrations. In patients with recanalization procedure local plasma viscosity was also determined from blood samples taken from a vein on the dorsum of the foot. Plasma viscosity was most significantly elevated in the patients with critical ischemia (1.78 mPa.sec) and was significantly higher than in the claudicants (1.68 mPa.sec), and the claudicants also had significantly higher viscosity than the controls (1.58 mPa.sec). In patients in whom a recanalization procedure was performed, no differences in systemic and local plasma viscosity were detected, neither before nor after recanalization of the diseased artery. In all groups plasma viscosity was correlated with fibrinogen concentration (r=0.70, P < 0.01) and total cholesterol concentration (r=0.24, P < 0.05), but in group C (critical ischemia) plasma viscosity was most closely linked to the concentration of alpha-2-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. PMID:8638868

  17. The Myth of Schizophrenia as a Progressive Brain Disease

    PubMed Central

    Zipursky, Robert B.

    2013-01-01

    Schizophrenia has historically been considered to be a deteriorating disease, a view reinforced by recent MRI findings of progressive brain tissue loss over the early years of illness. On the other hand, the notion that recovery from schizophrenia is possible is increasingly embraced by consumer and family groups. This review critically examines the evidence from longitudinal studies of (1) clinical outcomes, (2) MRI brain volumes, and (3) cognitive functioning. First, the evidence shows that although approximately 25% of people with schizophrenia have a poor long-term outcome, few of these show the incremental loss of function that is characteristic of neurodegenerative illnesses. Second, MRI studies demonstrate subtle developmental abnormalities at first onset of psychosis and then further decreases in brain tissue volumes; however, these latter decreases are explicable by the effects of antipsychotic medication, substance abuse, and other secondary factors. Third, while patients do show cognitive deficits compared with controls, cognitive functioning does not appear to deteriorate over time. The majority of people with schizophrenia have the potential to achieve long-term remission and functional recovery. The fact that some experience deterioration in functioning over time may reflect poor access, or adherence, to treatment, the effects of concurrent conditions, and social and financial impoverishment. Mental health professionals need to join with patients and their families in understanding that schizophrenia is not a malignant disease that inevitably deteriorates over time but rather one from which most people can achieve a substantial degree of recovery. PMID:23172002

  18. 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. 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

  19. Rootstock effects on progression of Pierce's disease symptom development and possible mechanisms

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Rootstocks are utilized to reduce incidence and severity of root-associated diseases. However, the ability of rootstocks to limit progression of stem-afflicting diseases has not been studied extensively. Rootstocks potentially could slow progression of scion-afflicting diseases such as Pierce’s dise...

  20. Blood Platelets in the Progression of Alzheimer’s Disease

    PubMed Central

    Gowert, Nina S.; Donner, Lili; Chatterjee, Madhumita; Eisele, Yvonne S.; Towhid, Seyda T.; Münzer, Patrick; Walker, Britta; Ogorek, Isabella; Borst, Oliver; Grandoch, Maria; Schaller, Martin; Fischer, Jens W.; Gawaz, Meinrad; Weggen, Sascha; Lang, Florian; Jucker, Mathias; Elvers, Margitta

    2014-01-01

    Alzheimer’s disease (AD) is characterized by neurotoxic amyloid-ß plaque formation in brain parenchyma and cerebral blood vessels known as cerebral amyloid angiopathy (CAA). Besides CAA, AD is strongly related to vascular diseases such as stroke and atherosclerosis. Cerebrovascular dysfunction occurs in AD patients leading to alterations in blood flow that might play an important role in AD pathology with neuronal loss and memory deficits. Platelets are the major players in hemostasis and thrombosis, but are also involved in neuroinflammatory diseases like AD. For many years, platelets were accepted as peripheral model to study the pathophysiology of AD because platelets display the enzymatic activities to generate amyloid-ß (Aß) peptides. In addition, platelets are considered to be a biomarker for early diagnosis of AD. Effects of Aß peptides on platelets and the impact of platelets in the progression of AD remained, however, ill-defined. The present study explored the cellular mechanisms triggered by Aß in platelets. Treatment of platelets with Aß led to platelet activation and enhanced generation of reactive oxygen species (ROS) and membrane scrambling, suggesting enhanced platelet apoptosis. More important, platelets modulate soluble Aß into fibrillar structures that were absorbed by apoptotic but not vital platelets. This together with enhanced platelet adhesion under flow ex vivo and in vivo and platelet accumulation at amyloid deposits of cerebral vessels of AD transgenic mice suggested that platelets are major contributors of CAA inducing platelet thrombus formation at vascular amyloid plaques leading to vessel occlusion critical for cerebrovascular events like stroke. PMID:24587388

  1. 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 phagocytes, most likely microglia, and slows disease progression in ALS. Targeting this receptor might be therapeutically useful. PMID:26744351

  2. 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

  3. Optical coherence tomography findings in Huntington's disease: a potential biomarker of disease progression.

    PubMed

    Kersten, Hannah M; Danesh-Meyer, Helen V; Kilfoyle, Dean H; Roxburgh, Richard H

    2015-11-01

    Previous reports of ocular abnormalities in Huntington's disease (HD) have detailed eye movement disorders. The objective of this case-control study was to investigate optic nerve and macular morphology in HD using optical coherence tomography (OCT). A total of 26 HD patients and 29 controls underwent a thorough ophthalmic examination including spectral domain OCT scans of the macula and peripapillary retinal nerve fibre layer (RNFL). Genetic testing results, disease duration, HD disease burden scores and Unified HD Rating Scale motor scores were acquired for HD patients. Temporal RNFL thickness was significantly reduced in the HD group (62.3 vs. 69.8 ?m, p = 0.005), and there was a significant negative correlation between temporal RNFL thickness and disease duration (R (2) = -0.51, p = 0.04). Average peripapillary RNFL thickness was not significantly different between the HD and control groups. There was a significant negative correlation between macular volume and disease duration (R (2) = -0.71, p = 0.002), and motor scores (R (2) = -0.56, p = 0.01). Colour vision was significantly poorer in the HD group. Temporal RNFL is preferentially thinned in HD patients, possibly implicating mitochondrial dysfunction as the temporal RNFL is reduced in the patients with some mitochondrial disorders, including Leber's hereditary optic neuropathy. The correlation between the decrease in macular volume and temporal RNFL, and increasing disease severity suggests that OCT may be a useful biomarker for disease progression in HD. Larger, longitudinal studies are required. PMID:26233693

  4. 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 develop classifiers for the determination of new regulatory targets. Many predicted targets are consistent with the known biology of their regulators, and new targets for the Wilms' tumor regulator, WT1, are proposed. We speculate that Wilms' tumor development is mediated by chromosomal rearrangements in the location of WT1 targets. Reviewers This article was reviewed by Trey Ideker, Vladimir A. Kuznetsov(nominated by Frank Eisenhaber), and Tzachi Pilpel. PMID:18564415

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

    PubMed Central

    Drechsler, Christiane; Kollerits, Barbara; Meinitzer, Andreas; Mrz, Winfried; Ritz, Eberhard; Knig, 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 2.545.19) 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 4713 years old and 65% were male. Meanstandard deviation of homoarginine concentrations were 2.51.1 mol/L and concentrations were incrementally lower at lower levels of GFR with mean concentrations of 2.901.02 mol/L (GFR>90 ml/min), 2.641.06 mol/L (GFR 6090 ml/min), 2.521.24 mol/L (GFR 3060 ml/min) and 2.050.78 mol/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 mol/L) of homoarginine (HR 1.62, 95% CI 1.162.27, p?=?0.005). This association was independent of proteinuria (HR 1.56, 95% CI 1.112.20, p?=?0.01), and was slightly attenuated when adjusting for GFR (HR 1.40 (95% CI 0.981.98, p?=?0.06). Conclusions Homoarginine concentrations are directly correlated with kidney function and are significantly associated with the progression of CKD. Low homoarginine concentrations might be an early indicator of kidney failure and a potential target for the prevention of disease progression which needs further investigations. PMID:23691067

  6. 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?disease progression. Serial diffusion data may be useful as an additional objective in vivo biomarker for motor progression in PD. PMID:26871779

  7. Progression of autosomal dominant kidney disease: measurement of the stage transitions of chronic kidney disease

    PubMed Central

    Blanchette, Christopher M; Liang, Caihua; Lubeck, Deborah P; Newsome, Britt; Rossetti, Sandro; Gu, Xiangmei; Gutierrez, Benjamin; Lin, Nancy D

    2015-01-01

    Background: Autosomal dominant polycystic kidney disease (ADPKD) is a progressive genetic disorder characterized by the development of numerous kidney cysts that result in kidney failure. Little is known regarding the key patient characteristics and utilization of healthcare resources for ADPKD patients along the continuum of disease progression. This observational study was designed to describe the characteristics of ADPKD patients and compare them with those of patients with other chronic kidney diseases. Methods: This retrospective cohort study involved patients with a claim for ADPKD or PKD unspecified from 1/1/20002/28/2013 and ?6 months of previous continuous enrollment (baseline) within a large database of administrative claims in the USA. A random sample of chronic kidney disease (CKD) patients served as comparators. For a subset of ADPKD patients who had only a diagnosis code of unspecified PKD, abstraction of medical records was undertaken to estimate the proportion of patients who had medical chart-confirmed ADPKD. In patients with linked electronic laboratory data, the estimated glomerular filtration rate was calculated via serum creatinine values to determine CKD stage at baseline and during follow-up. Proportions of patients transitioning to another stage and the mean age at transition were calculated. Results: ADPKD patients were, in general, younger and had fewer physician visits, but had more specific comorbidities at observation start compared with CKD patients. ADPKD patients had a longer time in the milder stages and longer duration before recorded transition to a more severe stage compared with CKD patients. Patients with ADPKD at risk of rapid progression had a shorter time-to-end-stage renal disease than patients with CKD and ADPKD patients not at risk, but stage duration was similar between ADPKD patients at risk and those not at risk. Conclusions: These results suggest that distribution of patients by age at transition to next stage may be useful for identification of ADPKD patients at risk of rapid progression. The results also suggest that medical claims with diagnosis codes for unspecified PKD, in absence of a diagnosis code for autosomal recessive polycystic kidney disease, may be a good proxy for ADPKD. PMID:25922609

  8. High Resolution Discovery Proteomics Reveals Candidate Disease Progression Markers of Alzheimer's Disease in Human Cerebrospinal Fluid.

    PubMed

    Hendrickson, Ronald C; 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; Yates, Nathan A

    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

  9. 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. PMID:23761459

  10. 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. PMID:26208584

  11. Verbal repetition in primary progressive aphasia and Alzheimer's disease.

    PubMed

    Leyton, Cristian E; Savage, Sharon; Irish, Muireann; Schubert, Samantha; Piguet, Olivier; Ballard, Kirrie J; Hodges, John R

    2014-01-01

    We aimed to explore the nature of verbal repetition deficits and infer the cognitive systems involved in primary progressive aphasia (PPA) and Alzheimer's disease (AD). A total of 63 patients (13 semantic variant (sv-PPA), 17 nonfluent/agrammatic variant (nfv-PPA), 10 logopenic variant (lv-PPA), 23 AD) and 13 matched healthy controls completed a battery of tests that included naming, word comprehension, digit span, repetition of multisyllabic single words, monosyllabic word span presented under similar and dissimilar phonological conditions, and sentence repetition. All patient groups displayed some level of impairment, however, specific patterns emerged in each variant. Participants with sv-PPA were the least impaired, showing marginal difficulties exclusively for sentence repetition, whereas those with lv-PPA had the worst overall performance. Cases with nfv-PPA showed compromised repetition of multisyllabic and phonologically similar words. The deficit in cases with AD was confined to span tasks. These distinctive patterns of language impairments can assist in the differential diagnosis of PPA variants and point toward the vulnerability of specific cognitive systems in each syndrome. PMID:24662100

  12. 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

  13. Low-level laser therapy ameliorates disease progression in a mouse model of Alzheimer's disease.

    PubMed

    Farfara, Dorit; Tuby, Hana; Trudler, Dorit; Doron-Mandel, Ella; Maltz, Lidya; Vassar, Robert J; Frenkel, Dan; Oron, Uri

    2015-02-01

    Low-level laser therapy (LLLT) has been used to treat inflammation, tissue healing, and repair processes. We recently reported that LLLT to the bone marrow (BM) led to proliferation of mesenchymal stem cells (MSCs) and their homing in the ischemic heart suggesting its role in regenerative medicine. The aim of the present study was to investigate the ability of LLLT to stimulate MSCs of autologous BM in order to affect neurological behavior and ?-amyloid burden in progressive stages of Alzheimer's disease (AD) mouse model. MSCs from wild-type mice stimulated with LLLT showed to increase their ability to maturate towards a monocyte lineage and to increase phagocytosis activity towards soluble amyloid beta (A?). Furthermore, weekly LLLT to BM of AD mice for 2 months, starting at 4 months of age (progressive stage of AD), improved cognitive capacity and spatial learning, as compared to sham-treated AD mice. Histology revealed a significant reduction in A? brain burden. Our results suggest the use of LLLT as a therapeutic application in progressive stages of AD and imply its role in mediating MSC therapy in brain amyloidogenic diseases. PMID:24994540

  14. 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

    2015-01-01

    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

  15. The Progress of Induced Pluripotent Stem Cells as Models of Parkinson's Disease

    PubMed Central

    Kang, Ji-feng; Tang, Bei-sha; Guo, Ji-feng

    2016-01-01

    In recent years, induced pluripotent stem cells (iPSCs) were widely used for investigating the mechanisms of Parkinson's disease (PD). Somatic cells from patients with SNCA (α-synuclein), LRRK2 (leucine-rich repeat kinase 2), PINK1 (PTEN induced putative kinase 1), Parkin mutations, and at-risk individuals carrying GBA (β-glucocerebrosidase) mutations have been successfully induced to iPSCs and subsequently differentiated into dopaminergic (DA) neurons. Importantly, some PD-related cell phenotypes, including α-synuclein aggregation, mitophagy, damaged mitochondrial DNA, and mitochondrial dysfunction, have been described in these iPSCs models, which further investigated the pathogenesis of PD. In 2007, Takahashi et al. and Vodyanik et al. generated iPSCs from human somatic cells for the first time. Since then, patients derived iPSCs were applied for disease modeling, drug discovery and screening, autologous cell replacement therapy, and other biological applications. iPSC research has now become a hot topic in a wide range of fields. This review summarizes the recent progress of PD patients derived iPSC models in pathogenic mechanism investigation and potential clinical applications, especially their promising strategy in pharmacological study and DA neurons transplantation therapy. However, the challenges of iPSC transplantation still exist, and it has a long way to go before it can be used in clinical application. PMID:26880962

  16. Abnormal Olfaction in Parkinson's Disease Is Related to Faster Disease Progression

    PubMed Central

    Cavaco, Sara; Gonçalves, Alexandra; Mendes, Alexandre; Vila-Chã, Nuno; Moreira, Inês; Fernandes, Joana; Damásio, Joana; Teixeira-Pinto, Armando; Bastos Lima, António

    2015-01-01

    Introduction. A possible association between olfactory dysfunction and Parkinson's disease (PD) severity has been a topic of contention for the past 40 years. Conflicting reports may be partially explained by procedural differences in olfactory assessment and motor symptom evaluation. Methods. One hundred and sixty-six nondemented PD patients performed the Brief-Smell Identification Test and test scores below the estimated 20th percentile as a function of sex, age, and education (i.e., 80% specificity) were considered demographically abnormal. Patients underwent motor examination after 12 h without antiparkinsonian medication. Results. Eighty-two percent of PD patients had abnormal olfaction. Abnormal performance on the Brief-Smell Identification Test was associated with higher disease severity (i.e., Hoehn and Yahr, Unified Parkinson's Disease Rating Scale-III, Freezing of Gait questionnaire, and levodopa equivalent dose), even when disease duration was taken into account. Conclusions. Abnormal olfaction in PD is associated with increased severity and faster disease progression. PMID:26136625

  17. Haematuria Increases Progression of Advanced Proteinuric Kidney Disease

    PubMed Central

    Yuste, Claudia; Rubio-Navarro, Alfonso; Barraca, Daniel; Aragoncillo, Ins; Vega, Almudena; Abad, Soraya; Santos, Alba; Macias, Nicols; Mahillo, Ignacio; Gutirrez, Eduardo; Praga, Manuel; Egido, Jess

    2015-01-01

    Background Haematuria has been traditionally considered as a benign hallmark of some glomerular diseases; however new studies show that haematuria may decrease renal function. Objective To determine the influence of haematuria on the rate of chronic kidney disease (CKD) progression in 71 proteinuric patients with advanced CKD (baseline eGFR <30 mL/min) during 12 months of follow-up. Results The mean rate of decline in eGFR was higher in patients with both haematuria and proteinuria (haemoproteinuria, HP, n=31) than in patients with proteinuria alone (P patients, n=40) (-3.88.9 vs 0.99.5 mL/min/1.73m2/year, p<0.05, respectively). The deleterious effect of haematuria on rate of decline in eGFR was observed in patients <65 years (-6.89.9 (HP) vs. 0.111.7 (P) mL/min/1.73m2/year, p<0.05), but not in patients >65 years (-1.26.8 (HP) vs. 1.57.7 (P) mL/min/1.73m2/year). Furthermore, the harmful effect of haematuria on eGFR slope was found patients with proteinuria >0.5 g/24 h (-5.86.4 (HP) vs. -1.37 7.9 (P) mL/min/1.73m2/year, p<0.05), whereas no significant differences were found in patients with proteinuria < 0.5 g/24 h (-0.627.4 (HP) vs. 3.411.1 (P) mL/min/1.73m2/year). Multivariate analysis reported that presence of haematuria was significantly and independently associated with eGFR deterioration after adjusting for traditional risk factors, including age, serum phosphate, mean proteinuria and mean serum PTH (?=-4.316, p=0.025). Conclusions The presence of haematuria is closely associated with a faster decrease in renal function in advanced proteinuric CKD patients, especially in younger CKD patients with high proteinuria levels; therefore this high risk subgroup of patients would benefit of intensive medical surveillance and treatment. PMID:26016848

  18. 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

  19. ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease.

    PubMed

    Montecchiani, Celeste; Pedace, Lucia; Lo Giudice, Temistocle; Casella, Antonella; Mearini, Marzia; Gaudiello, Fabrizio; Pedroso, Jos L; Terracciano, Chiara; Caltagirone, Carlo; Massa, Roberto; St George-Hyslop, Peter H; Barsottini, Orlando G P; Kawarai, Toshitaka; Orlacchio, Antonio

    2016-01-01

    Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes. Hundreds of causative DNA changes have been found, but much of the genetic basis of the disease is still unexplained. Mutations in the ALS5/SPG11/KIAA1840 gene are a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy, and account for ?40% of autosomal recessive juvenile amyotrophic lateral sclerosis. The overlap of axonal Charcot-Marie-Tooth disease with both diseases, as well as the common autosomal recessive inheritance pattern of thin corpus callosum and axonal Charcot-Marie-Tooth disease in three related patients, prompted us to analyse the ALS5/SPG11/KIAA1840 gene in affected individuals with autosomal recessive axonal Charcot-Marie-Tooth disease. We investigated 28 unrelated families with autosomal recessive axonal Charcot-Marie-Tooth disease defined by clinical, electrophysiological, as well as pathological evaluation. Besides, we screened for all the known genes related to axonal autosomal recessive Charcot-Marie-Tooth disease (CMT2A2/HMSN2A2/MFN2, CMT2B1/LMNA, CMT2B2/MED25, CMT2B5/NEFL, ARCMT2F/dHMN2B/HSPB1, CMT2K/GDAP1, CMT2P/LRSAM1, CMT2R/TRIM2, CMT2S/IGHMBP2, CMT2T/HSJ1, CMTRID/COX6A1, ARAN-NM/HINT and GAN/GAN), for the genes related to autosomal recessive hereditary spastic paraplegia with thin corpus callosum and axonal peripheral neuropathy (SPG7/PGN, SPG15/ZFYVE26, SPG21/ACP33, SPG35/FA2H, SPG46/GBA2, SPG55/C12orf65 and SPG56/CYP2U1), as well as for the causative gene of peripheral neuropathy with or without agenesis of the corpus callosum (SLC12A6). Mitochondrial disorders related to Charcot-Marie-Tooth disease type 2 were also excluded by sequencing POLG and TYMP genes. An additional locus for autosomal recessive Charcot-Marie-Tooth disease type 2H on chromosome 8q13-21.1 was excluded by linkage analysis. Pedigrees originated in Italy, Brazil, Canada, England, Iran, and Japan. Interestingly, we identified 15 ALS5/SPG11/KIAA1840 mutations in 12 families (two sequence variants were never reported before, p.Gln198* and p.Pro2212fs*5). No large deletions/duplications were detected in these patients. The novel mutations seemed to be pathogenic since they co-segregated with the disease in all pedigrees and were absent in 300 unrelated controls. Furthermore, in silico analysis predicted their pathogenic effect. Our results indicate that ALS5/SPG11/KIAA1840 is the causative gene of a wide spectrum of clinical features, including autosomal recessive axonal Charcot-Marie-Tooth disease.media-1vid110.1093/brain/awv320_video_abstractawv320_video_abstract. PMID:26556829

  20. 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 microvascular inflammation occur in 5xFAD mice concomitantly to parenchymal plaque deposition. The prospect of cerebrovascular pharmacology in AD is discussed. PMID:26774030

  1. Impairment of Vowel Articulation as a Possible Marker of Disease Progression in Parkinson's Disease

    PubMed Central

    Skodda, Sabine; Grnheit, Wenke; Schlegel, Uwe

    2012-01-01

    Purpose The aim of the current study was to survey if vowel articulation in speakers with Parkinson's disease (PD) shows specific changes in the course of the disease. Method 67 patients with PD (42 male) and 40 healthy speakers (20 male) were tested and retested after an average time interval of 34 months. Participants had to read a given text as source for subsequent calculation of the triangular vowel space area (tVSA) and vowel articulation index (VAI). Measurement of tVSA and VAI were based upon analysis of the first and second formant of the vowels /?/, /i/and /u/ extracted from defined words within the text. Results At first visit, VAI values were reduced in male and female PD patients as compared to the control group, and showed a further decrease at the second visit. Only in female Parkinsonian speakers, VAI was correlated to overall speech impairment based upon perceptual impression. VAI and tVSA were correlated to gait impairment, but no correlations were seen between VAI and global motor impairment or overall disease duration. tVSA showed a similar reduction in the PD as compared to the control group and was also found to further decline between first and second examination in female, but not in male speakers with PD. Conclusions Measurement of VAI seems to be superior to tVSA in the description of impaired vowel articulation and its further decline in the course of the disease in PD. Since impairment of vowel articulation was found to be independent from global motor function but correlated to gait dysfunction, measurement of vowel articulation might have a potential to serve as a marker of axial disease progression. PMID:22389682

  2. [Progress in neuropathology changes the understanding of neurodegenerative diseases].

    PubMed

    Duyckaerts, Charles; Seilhean, Danielle

    2013-05-01

    Improvement of the analytical methods and routine use of immunohistochemistry have demonstrated that most neurodegenerative diseases, known to-day, are characterized by the accumulation of one or several specific proteins for example Abeta peptide and Tau protein in Alzheimer disease, alpha-synuclein in Parkinson disease and dementia with Lewy bodies, TDP-43 in a large group of fronto-temporal dementia. In the case of Alzheimer and Lewy body disease, recent data suggest that misfolding of Abeta peptide, of Tau protein or of alpha-synuclein may propagate to the normal protein of the host in a way that reminds the propagation observed in prion diseases. PMID:23789492

  3. 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

  4. 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...

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

    PubMed Central

    Riwanto, Meliana; Kapoor, Sarika; Rodriguez, Daniel; Edenhofer, Ilka; Segerer, Stephan; Wthrich, 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 (1.980.67 vs 1.410.37 ml/min), BUN (0.690.26 vs 0.400.10 ml/min) and uric acid (0.380.20 vs 0.210.10 ml/min), and reduced albuminuria. Immunoblotting analysis of kidney tissues harvested from 2DG-treated Cy/+ rats showed increased phosphorylation of AMPK-?, 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

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

    PubMed

    Riwanto, Meliana; Kapoor, Sarika; Rodriguez, Daniel; Edenhofer, Ilka; Segerer, Stephan; Wthrich, 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 (1.980.67 vs 1.410.37 ml/min), BUN (0.690.26 vs 0.400.10 ml/min) and uric acid (0.380.20 vs 0.210.10 ml/min), and reduced albuminuria. Immunoblotting analysis of kidney tissues harvested from 2DG-treated Cy/+ rats showed increased phosphorylation of AMPK-?, 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

  7. ALS as a distal axonopathy: molecular mechanisms affecting neuromuscular junction stability in the presymptomatic stages of the disease

    PubMed Central

    Moloney, Elizabeth B.; de Winter, Fred; Verhaagen, Joost

    2014-01-01

    Amyotrophic Lateral Sclerosis (ALS) is being redefined as a distal axonopathy, in that many molecular changes influencing motor neuron degeneration occur at the neuromuscular junction (NMJ) at very early stages of the disease prior to symptom onset. A huge variety of genetic and environmental causes have been associated with ALS, and interestingly, although the cause of the disease can differ, both sporadic and familial forms of ALS show a remarkable similarity in terms of disease progression and clinical manifestation. The NMJ is a highly specialized synapse, allowing for controlled signaling between muscle and nerve necessary for skeletal muscle function. In this review we will evaluate the clinical, animal experimental and cellular/molecular evidence that supports the idea of ALS as a distal axonopathy. We will discuss the early molecular mechanisms that occur at the NMJ, which alter the functional abilities of the NMJ. Specifically, we focus on the role of axon guidance molecules on the stability of the cytoskeleton and how these molecules may directly influence the cells of the NMJ in a way that may initiate or facilitate the dismantling of the neuromuscular synapse in the presymptomatic stages of ALS. PMID:25177267

  8. Does increased water intake prevent disease progression in autosomal dominant polycystic kidney disease?

    PubMed Central

    Higashihara, Eiji; Nutahara, Kikuo; Tanbo, Mitsuhiro; Hara, Hidehiko; Miyazaki, Isao; Kobayashi, Kuninori; Nitatori, Toshiaki

    2014-01-01

    Background The clinical effects of increased water intake on autosomal dominant polycystic kidney disease (ADPKD) progression are unknown. Methods ADPKD patients with creatinine clearance ?50 mL/min/1.73 m2 were divided into high (H-, n = 18) and free (F-, n = 16) water-intake groups, mainly according to their preference. Prior to the study, 30 patients underwent annual evaluation of total kidney volume (TKV) and 24-h urine for an average of 33 months. During the 1-year study period, TKV and 24-h urine were analyzed at the beginning and end of the study and every 4 months, respectively. Results During the pre-study period, urine volume (UV) in the H-group was higher (P = 0.034), but TKV and kidney function and their slopes were not significantly different between the two groups. After the study commenced, UV further increased (P < 0.001) in the H-group but not in the F-group. During the study period, TKV and kidney function slopes were not significantly different between the two groups (primary endpoint). Plasma copeptin was lower (P = 0.024) in the H-group than in the F-group. TKV and kidney function slopes became worse (P = 0.047 and 0.011, respectively) after high water intake (H-group) but not in the F-group. High UV was associated with increased urine sodium, and urine sodium positively correlated with the % TKV slope (P = 0.014). Conclusions Although the main endpoint was not significant, high water intake enhanced disease progression in the H-group when compared with the pre-study period. These findings necessitate a long-term randomized study before drawing a final conclusion. PMID:24739484

  9. PROGRESSION OF ACUTE KIDNEY INJURY TO CHRONIC KIDNEY DISEASE: CLINICAL AND EXPERIMENTAL INSIGHTS AND QUERIES

    PubMed Central

    Zager, Richard A.

    2014-01-01

    There are an increasing number of clinical suggestions that acute kidney injury (AKI) can be complicated by the onset of progressive renal disease. Indeed, given the frequency of AKI in hospitalized patients, were AKI to initiate disease progression, it could potentially be a leading cause of, or contributor to, end stage renal disease. Insights into the natural history of AKI, and potential mechanisms for disease progression, can be gleaned for experimental studies. Although such studies underscore the principle that AKI can “heal with defects”, whether ongoing renal disease develops remains a subject of debate. Indeed, in the aftermath of AKI, a variety of secondary renal protective pathways are activated which may retard or prevent severe, chronic kidney disease (CKD). Furthermore, the onset of acute uremia, per se, may exert surprisingly potent renal protective effects. The purpose of this brief report is to review some of the clinical and experimental data that deal with these complex issues. PMID:25343820

  10. Multi-stage Biomarker Models for Progression Estimation in Alzheimer's Disease.

    PubMed

    Schmidt-Richberg, Alexander; Guerrero, Ricardo; Ledig, Christian; Molina-Abril, Helena; Frangi, Alejandro F; Rueckert, Daniel

    2015-01-01

    The estimation of disease progression in Alzheimer's disease (AD) based on a vector of quantitative biomarkers is of high interest to clinicians, patients, and biomedical researchers alike. In this work, quantile regression is employed to learn statistical models describing the evolution of such biomarkers. Two separate models are constructed using (1) subjects that progress from a cognitively normal (CN) stage to mild cognitive impairment (MCI) and (2) subjects that progress from MCI to AD during the observation window of a longitudinal study. These models are then automatically combined to develop a multi-stage disease progression model for the whole disease course. A probabilistic approach is derived to estimate the current disease progress (DP) and the disease progression rate (DPR) of a given individual by fitting any acquired biomarkers to these models. A particular strength of this method is that it is applicable even if individual biomarker measurements are missing for the subject. Employing cognitive scores and image-based biomarkers, the presented method is used to estimate DP and DPR for subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Further, the potential use of these values as features for different classification tasks is demonstrated. For example, accuracy of 64% is reached for CN vs. MCI vs. AD classification. PMID:26221689

  11. Edaravone, a Free Radical Scavenger, Delayed Symptomatic and Pathological Progression of Motor Neuron Disease in the Wobbler Mouse.

    PubMed

    Ikeda, Ken; Iwasaki, Yasuo

    2015-01-01

    Edaravone, a free radical scavenger is used widely in Japanese patients with acute cerebral infarction. This antioxidant could have therapeutic potentials for other neurological diseases. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the upper and the lower motor neuron, leading to death within 3-5 years after onset. A phase III clinical trial of edaravone suggested no significant effects in ALS patients. However, recent 2nd double-blind trial has demonstrated therapeutic benefits of edaravone in definite patients diagnosed by revised El Escorial diagnostic criteria of ALS. Two previous studies showed that edaravone attenuated motor symptoms or motor neuron degeneration in mutant superoxide dismutase 1-transgenic mice or rats, animal models of familial ALS. Herein we examined whether this radical scavenger can retard progression of motor dysfunction and neuropathological changes in wobbler mice, sporadic ALS-like model. After diagnosis of the disease onset at the postnatal age of 3-4 weeks, wobbler mice received edaravone (1 or 10 mg/kg, n = 10/group) or vehicle (n = 10), daily for 4 weeks by intraperitoneal administration. Motor symptoms and neuropathological changes were compared among three groups. Higher dose (10 mg/kg) of edaravone treatment significantly attenuated muscle weakness and contracture in the forelimbs, and suppressed denervation atrophy in the biceps muscle and degeneration in the cervical motor neurons compared to vehicle. Previous and the present studies indicated neuroprotective effects of edaravone in three rodent ALS-like models. This drug seems to be worth performing the clinical trial in ALS patients in the United States of American and Europe, in addition to Japan. PMID:26469273

  12. Edaravone, a Free Radical Scavenger, Delayed Symptomatic and Pathological Progression of Motor Neuron Disease in the Wobbler Mouse

    PubMed Central

    2015-01-01

    Edaravone, a free radical scavenger is used widely in Japanese patients with acute cerebral infarction. This antioxidant could have therapeutic potentials for other neurological diseases. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the upper and the lower motor neuron, leading to death within 35 years after onset. A phase III clinical trial of edaravone suggested no significant effects in ALS patients. However, recent 2nd double-blind trial has demonstrated therapeutic benefits of edaravone in definite patients diagnosed by revised El Escorial diagnostic criteria of ALS. Two previous studies showed that edaravone attenuated motor symptoms or motor neuron degeneration in mutant superoxide dismutase 1-transgenic mice or rats, animal models of familial ALS. Herein we examined whether this radical scavenger can retard progression of motor dysfunction and neuropathological changes in wobbler mice, sporadic ALS-like model. After diagnosis of the disease onset at the postnatal age of 34 weeks, wobbler mice received edaravone (1 or 10 mg/kg, n = 10/group) or vehicle (n = 10), daily for 4 weeks by intraperitoneal administration. Motor symptoms and neuropathological changes were compared among three groups. Higher dose (10 mg/kg) of edaravone treatment significantly attenuated muscle weakness and contracture in the forelimbs, and suppressed denervation atrophy in the biceps muscle and degeneration in the cervical motor neurons compared to vehicle. Previous and the present studies indicated neuroprotective effects of edaravone in three rodent ALS-like models. This drug seems to be worth performing the clinical trial in ALS patients in the United States of American and Europe, in addition to Japan. PMID:26469273

  13. Public health impact of disease-behavior dynamics. Comment on "Coupled disease-behavior dynamics on complex networks: A review" by Z. Wang et al.

    NASA Astrophysics Data System (ADS)

    Wells, Chad R.; Galvani, Alison P.

    2015-12-01

    In a loop of dynamic feedback, behavior such as the decision to vaccinate, hand washing, or avoidance influences the progression of the epidemic, yet behavior is driven by the individual's and population's perceived risk of infection during an outbreak. In what we believe will become a seminal paper that stimulates future research as well as an informative teaching aid, Wang et. al. comprehensively review methodological advances that have been used to incorporate human behavior into epidemiological models on the effects of coupling disease transmission and behavior on complex social networks [1]. As illustrated by the recent outbreaks of measles and Middle Eastern Respiratory Syndrome (MERS), here we highlight the importance of coupling behavior and disease transmission that Wang et al. address.

  14. Association of foot and ankle characteristics with progression of venous disease.

    PubMed

    Kim, Tanner I; Forbang, Nketi I; Criqui, Michael H; Allison, Matthew A

    2015-04-01

    Although risk factors have been identified for the cross-sectional prevalence of venous disease, few studies have investigated risk factors for venous disease progression. Therefore, the aim of this study was to investigate the relationship between foot and ankle characteristics and the progression of venous disease. A total of 1025 participants from the San Diego Population Study were assessed at baseline and at follow-up 11 years later. Risk factors were assessed by questionnaire and physical measurements, while venous disease was determined by physical examination and Duplex ultrasound. Change in venous disease from baseline to 11-year follow-up was characterized as stable or progression. Those with venous disease progression were less likely to spend increased time lying per day, more likely to have a history of hypertension, lie supine for a surgical procedure greater than an hour, and report an occupation that was professional, technical, administrative, or management. Those with a normal arch reported the greatest degree of plantar flexion. In multivariable logistic regression, including adjustment for weight-bearing arch characteristics, greater dorsiflexion (per 5 degrees) was significantly associated with progression of venous disease (OR = 1.11, p = 0.01). A weight-bearing flat arch compared to a weight-bearing normal arch was of borderline significance as a protective factor against progression of venous disease with adjustment for dorsiflexion (OR = 0.56, p = 0.07). Our results indicate that the ability to have higher levels of dorsiflexion is a risk factor for the progression of venous disease, and suggest a role for connective tissue laxity in the pathogenesis of venous disease. PMID:25832598

  15. Key pathways in renal disease progression of experimental diabetes.

    PubMed

    Zoja, Carlamaria; Zanchi, Cristina; Benigni, Ariela

    2015-08-01

    Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes mellitus and the leading cause of end-stage kidney disease. Both diabetes and chronic kidney disease are risk factors for cardiovascular disease, and diabetic patients with renal involvement are three times more likely to eventually die of cardiovascular disease than diabetic patients without signs of renal failure. In type 2 diabetes, microalbuminuria is a marker of renal dysfunction and a crucial predictor of cardiovascular disease. Inhibitors of angiotensin II synthesis/activity, while preventing micro- or macroalbuminuria, also reduced cardiovascular events in diabetic patients. However, the effectiveness of renin angiotensin system blocking agents depends on the time when treatment is started, and imperfect renoprotection may occur if therapy begins at an advanced disease phase. This raises the need to identify novel multidrug approaches that simultaneously inhibit additional pathways other than angiotensin II for those diabetic patients who remain at high risk of both poor renal and cardiovascular outcomes. Studies in animal models of diabetes have contributed to defining relevant cellular mechanisms underlying the pathogenesis of DN that could represent possible targets for therapies. The pathogenesis of DN is multifactorial, involving a complex series of molecular processes. In this review, we report evidence obtained in experimental models of DN on some specific processes and pathways implicated in DN that may be crucial for managing this disease. PMID:26209738

  16. Rapid progressive bilateral hearing loss due to granulomatous otitis media in Lyme disease.

    PubMed

    Maniu, Alma; Damian, Laura

    2013-01-01

    We report on a patient with Lyme disease who presented with chronic bilateral otitis media and cranial neuropathy with rapid progressive hearing loss. After ceftriaxone and high-dose intravenous immunoglobulins, the disease was controlled only with methylprednisolone and cyclophosphamide. The relationship between Lyme disease and granulomatous vasculitis is discussed. Lyme disease should be kept in mind in the differential diagnosis of various otolaryngological and neurological presentations. PMID:23313123

  17. 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)

  18. Long-term progression of Menière's disease.

    PubMed

    Stahle, J; Friberg, U; Svedberg, A

    1989-05-01

    A retrospective study of 161 patients with Menière's disease followed up for 9 years or more is presented. The development, with respect to hearing, caloric response, vertigo, and ability to work, was analyzed. The main functional loss was found to take place early in the course of the disease. There was an increase in bilaterality with time. A spontaneous relief in vertigo over the years has been noticed. PMID:2750865

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

    PubMed

    Dreke, 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/?-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

  20. Progress toward novel treatments for chronic kidney disease.

    PubMed

    Shah, Sudhir V

    2010-09-01

    Chronic kidney failure remains a major health problem worldwide. Although current treatment is focused on the renin-angiotensin system, it is essential that new treatments targeted toward novel pathophysiological mechanisms are developed if we are to make significant progress in this area. In this review, we have outlined several promising new areas while emphasizing that large, randomized, well-controlled clinical trials are essential to reach a meaningful conclusion about the efficacy and safety of novel treatment. PMID:20797560

  1. Effects of erythropoietin receptors and erythropoiesis-stimulating agents on disease progression in cancer

    PubMed Central

    Aapro, M; Jelkmann, W; Constantinescu, S N; Leyland-Jones, B

    2012-01-01

    Erythropoiesis-stimulating agents (ESAs) increase red blood cell (RBC) production in bone marrow by activating the erythropoietin receptor (EpoR) on erythrocytic-progenitor cells. Erythropoiesis-stimulating agents are approved in the United States and Europe for treating anaemia in cancer patients receiving chemotherapy based on randomised, placebo-controlled trials showing that ESAs reduce RBC transfusions. Erythropoiesis-stimulating agent-safety issues include thromboembolic events and concerns regarding whether ESAs increase disease progression and/or mortality in cancer patients. Several trials have reported an association between ESA use and increased disease progression and/or mortality, whereas other trials in the same tumour types have not provided similar findings. This review thoroughly examines available evidence regarding whether ESAs affect disease progression. Both clinical-trial data on ESAs and disease progression, and preclinical data on how ESAs could affect tumour growth are summarised. Preclinical topics include (i) whether tumour cells express EpoR and could be directly stimulated to grow by ESA exposure and (ii) whether endothelial cells express EpoR and could be stimulated by ESA exposure to undergo angiogenesis and indirectly promote tumour growth. Although assessment and definition of disease progression vary across studies, the current clinical data suggest that ESAs may have little effect on disease progression in chemotherapy patients, and preclinical data indicate a direct or indirect effect of ESAs on tumour growth is not strongly supported. PMID:22395661

  2. Evaluating the predictive power of multivariate tensor-based morphometry in Alzheimer's disease progression via convex fused sparse group Lasso

    NASA Astrophysics Data System (ADS)

    Tsao, Sinchai; Gajawelli, Niharika; Zhou, Jiayu; Shi, Jie; Ye, Jieping; Wang, Yalin; Lepore, Natasha

    2014-03-01

    Prediction of Alzheimers disease (AD) progression based on baseline measures allows us to understand disease progression and has implications in decisions concerning treatment strategy. To this end we combine a predictive multi-task machine learning method1 with novel MR-based multivariate morphometric surface map of the hippocampus2 to predict future cognitive scores of patients. Previous work by Zhou et al.1 has shown that a multi-task learning framework that performs prediction of all future time points (or tasks) simultaneously can be used to encode both sparsity as well as temporal smoothness. They showed that this can be used in predicting cognitive outcomes of Alzheimers Disease Neuroimaging Initiative (ADNI) subjects based on FreeSurfer-based baseline MRI features, MMSE score demographic information and ApoE status. Whilst volumetric information may hold generalized information on brain status, we hypothesized that hippocampus specific information may be more useful in predictive modeling of AD. To this end, we applied Shi et al.2s recently developed multivariate tensor-based (mTBM) parametric surface analysis method to extract features from the hippocampal surface. We show that by combining the power of the multi-task framework with the sensitivity of mTBM features of the hippocampus surface, we are able to improve significantly improve predictive performance of ADAS cognitive scores 6, 12, 24, 36 and 48 months from baseline.

  3. Evaluating the Predictive Power of Multivariate Tensor-based Morphometry in Alzheimers Disease Progression via Convex Fused Sparse Group Lasso.

    PubMed

    Tsao, Sinchai; Gajawelli, Niharika; Zhou, Jiayu; Shi, Jie; Ye, Jieping; Wang, Yalin; Lepore, Natasha

    2014-03-21

    Prediction of Alzheimers disease (AD) progression based on baseline measures allows us to understand disease progression and has implications in decisions concerning treatment strategy. To this end we combine a predictive multi-task machine learning method(1) with novel MR-based multivariate morphometric surface map of the hippocampus(2) to predict future cognitive scores of patients. Previous work by Zhou et al.(1) has shown that a multi-task learning framework that performs prediction of all future time points (or tasks) simultaneously can be used to encode both sparsity as well as temporal smoothness. They showed that this can be used in predicting cognitive outcomes of Alzheimers Disease Neuroimaging Initiative (ADNI) subjects based on FreeSurfer-based baseline MRI features, MMSE score demographic information and ApoE status. Whilst volumetric information may hold generalized information on brain status, we hypothesized that hippocampus specific information may be more useful in predictive modeling of AD. To this end, we applied Shi et al.(2)s recently developed multivariate tensor-based (mTBM) parametric surface analysis method to extract features from the hippocampal surface. We show that by combining the power of the multi-task framework with the sensitivity of mTBM features of the hippocampus surface, we are able to improve significantly improve predictive performance of ADAS cognitive scores 6, 12, 24, 36 and 48 months from baseline. PMID:25076826

  4. Evaluating the Predictive Power of Multivariate Tensor-based Morphometry in Alzheimers Disease Progression via Convex Fused Sparse Group Lasso

    PubMed Central

    Tsao, Sinchai; Gajawelli, Niharika; Zhou, Jiayu; Shi, Jie; Ye, Jieping; Wang, Yalin; Lepore, Natasha

    2014-01-01

    Prediction of Alzheimers disease (AD) progression based on baseline measures allows us to understand disease progression and has implications in decisions concerning treatment strategy. To this end we combine a predictive multi-task machine learning method1 with novel MR-based multivariate morphometric surface map of the hippocampus2 to predict future cognitive scores of patients. Previous work by Zhou et al.1 has shown that a multi-task learning framework that performs prediction of all future time points (or tasks) simultaneously can be used to encode both sparsity as well as temporal smoothness. They showed that this can be used in predicting cognitive outcomes of Alzheimers Disease Neuroimaging Initiative (ADNI) subjects based on FreeSurfer-based baseline MRI features, MMSE score demographic information and ApoE status. Whilst volumetric information may hold generalized information on brain status, we hypothesized that hippocampus specific information may be more useful in predictive modeling of AD. To this end, we applied Shi et al.2s recently developed multivariate tensor-based (mTBM) parametric surface analysis method to extract features from the hippocampal surface. We show that by combining the power of the multi-task framework with the sensitivity of mTBM features of the hippocampus surface, we are able to improve significantly improve predictive performance of ADAS cognitive scores 6, 12, 24, 36 and 48 months from baseline. PMID:25076826

  5. Prognostic models based on patient snapshots and time windows: Predicting disease progression to assisted ventilation in Amyotrophic Lateral Sclerosis.

    PubMed

    Carreiro, Andr V; Amaral, Pedro M T; Pinto, Susana; Toms, Pedro; de Carvalho, Mamede; Madeira, Sara C

    2015-12-01

    Amyotrophic Lateral Sclerosis (ALS) is a devastating disease and the most common neurodegenerative disorder of young adults. ALS patients present a rapidly progressive motor weakness. This usually leads to death in a few years by respiratory failure. The correct prediction of respiratory insufficiency is thus key for patient management. In this context, we propose an innovative approach for prognostic prediction based on patient snapshots and time windows. We first cluster temporally-related tests to obtain snapshots of the patient's condition at a given time (patient snapshots). Then we use the snapshots to predict the probability of an ALS patient to require assisted ventilation after k days from the time of clinical evaluation (time window). This probability is based on the patient's current condition, evaluated using clinical features, including functional impairment assessments and a complete set of respiratory tests. The prognostic models include three temporal windows allowing to perform short, medium and long term prognosis regarding progression to assisted ventilation. Experimental results show an area under the receiver operating characteristics curve (AUC) in the test set of approximately 79% for time windows of 90, 180 and 365days. Creating patient snapshots using hierarchical clustering with constraints outperforms the state of the art, and the proposed prognostic model becomes the first non population-based approach for prognostic prediction in ALS. The results are promising and should enhance the current clinical practice, largely supported by non-standardized tests and clinicians' experience. PMID:26455265

  6. Paget's Disease of Bone: Progress Towards Remission and Prevention.

    PubMed

    Healy, C M; Woods, C; Heffeman, E; McKenna, M J

    2015-01-01

    Paget's disease of bone is a focal disorder of bone remodelling leading to areas of enlarged weakened bone manifesting with chronic pain, bone deformity, and fracture. Predominantly a disease of older adults, its prevalence is strongly linked to European ancestry. Pre-disposing factors include exposure to viruses such as measles and mutations in the SQSTM1 gene. PDB is diagnosed on plain radiograph, the extent of disease is delineated by radionuclide bone imaging, the degree of activity is quantified biochemically, and it is treated with a nitrogen-containing bisphosphonate, most effectively by a single intravenous infusion of zoledronate 5mg. Lifelong specialist follow-up is advocated because some patients require repeated infusions. Current clinical research is focusing on genetic factors in order to identify patients suitable for prevention. PMID:26817293

  7. 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. PMID:23592957

  8. Sertraline Slows Disease Progression and Increases Neurogenesis in N171-82Q mouse model of Huntingtons 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

    Huntingtons 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 Huntingtons 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

  9. Orexin antagonists for neuropsychiatric disease: progress and potential pitfalls

    PubMed Central

    Yeoh, Jiann Wei; Campbell, Erin J.; James, Morgan H.; Graham, Brett A.; Dayas, Christopher V.

    2014-01-01

    The tight regulation of sleep/wake states is critical for mental and physiological wellbeing. For example, dysregulation of sleep/wake systems predisposes individuals to metabolic disorders such as obesity and psychiatric problems, including depression. Contributing to this understanding, the last decade has seen significant advances in our appreciation of the complex interactions between brain systems that control the transition between sleep and wake states. Pivotal to our increased understanding of this pathway was the description of a group of neurons in the lateral hypothalamus (LH) that express the neuropeptides orexin A and B (hypocretin, Hcrt-1 and Hcrt-2). Orexin neurons were quickly placed at center stage with the demonstration that loss of normal orexin function is associated with the development of narcolepsy—a condition in which sufferers fail to maintain normal levels of daytime wakefulness. Since these initial seminal findings, much progress has been made in our understanding of the physiology and function of the orexin system. For example, the orexin system has been identified as a key modulator of autonomic and neuroendocrine function, arousal, reward and attention. Notably, studies in animals suggest that dysregulation of orexin function is associated with neuropsychiatric states such as addiction and mood disorders including depression and anxiety. This review discusses the progress associated with therapeutic attempts to restore orexin system function and treat neuropsychiatric conditions such as addiction, depression and anxiety. We also highlight potential pitfalls and challenges associated with targeting this system to treat these neuropsychiatric states. PMID:24616658

  10. 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. PMID:24277717

  11. 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 work represents an improvement over gold standard qualitative assessments of vascular health and the results obtained promise to develop new clinically relevant and quantitative techniques using non-invasive optical modalities.

  12. 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

  13. Disease Progression in Chronic Hepatitis B Patients under Long-Term Antiviral Therapy

    PubMed Central

    Moon, Jin Chang; Kim, Seong Hun; Kim, In Hee; Lee, Chang Hun; Kim, Sang Wook; Lee, Seung Ok; Lee, Soo Teik; Kim, Dae-Ghon

    2015-01-01

    Background/Aims We investigated factors associated with the disease progression and development of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients during long-term oral nucleos(t)ide analog (NA) therapy. Methods This retrospective study included 524 naive CHB patients who received oral NA therapy for more than 48 weeks between January 2003 and December 2007. The primary outcome was 5-year cumulative probability of disease progression and HCC development. Disease progression was defined as cirrhosis development, cirrhotic complications, HCC or liver-related mortality. Results For the 524 patients, the cumulative probabilities of disease progression and HCC development at 1, 2, 3, 4 and 5 years were 1.1%, 6.3%, 9.0%, 11.6%, and 16.2% and 0.2%, 1.8%, 3.6%, 5.8%, and 9.3%, respectively. In multivariate analysis, age >50 years (hazard ratio [HR], 1.05) and cirrhosis (HR, 2.95) were significant factors for disease progression. Similarly, age >50 years (HR, 1.05), family history of HCC (HR, 5.48), and cirrhosis (HR, 17.16) were significant factors for HCC development. Importantly, longer duration (>12 months) of maintained virological response (<20 IU/mL) reduced the risks of disease progression (HR, 0.19) and HCC development (HR, 0.09). Conclusions Longer duration of maintained virological response significantly reduces the risk of disease progression or HCC development in CHB patients undergoing long-term oral NA therapy. PMID:25473072

  14. Comparison of gait in progressive supranuclear palsy, Parkinsons disease and healthy older adults

    PubMed Central

    2012-01-01

    Background Progressive supranuclear palsy and Parkinsons disease have characteristic clinical and neuropathologic profiles, but also share overlapping clinical features. This study aimed to analyze the gait of people with progressive supranuclear palsy (n=19) and compare it with people with Parkinsons disease (n=20) and healthy older adults (n=20). Methods Gait was recorded at self-selected preferred, fast, very fast, slow and very slow speeds. Stride length was normalized to leg length. Linear regression analyses were carried out between cadence and stride length. Other gait variables were compared for each participants walk which had stride length closest to 1.4. Results All groups showed a strong linear relationship between stride length and cadence with no difference between groups (p>0.05). The intercept between cadence and stride length was lowest in the progressive supranuclear palsy group and highest for older adults (p<0.001). The progressive supranuclear palsy group had higher cadence than older adults (p>0.05), and greater step width and greater double support phase compared with the other two groups (p<0.05). Conclusions The temporal-spatial gait characteristics of progressive supranuclear palsy and Parkinsons disease are largely similar, with similar disruption to scaling of stride length. The additional findings of increased step width and double support percentage suggest increased severity of gait abnormality compared to Parkinsons disease, despite similar disease duration. The findings are consistent with the clinical features of greater instability and more rapid disease progression in progressive supranuclear palsy compared to Parkinsons disease and implicates the early pathological involvement of brain regions involved in gait control. PMID:23031506

  15. Mutations in TJP2 cause progressive cholestatic liver disease

    PubMed Central

    Sambrotta, Melissa; Strautnieks, Sandra; Papouli, Efterpi; Rushton, Peter; Clark, Barnaby E.; Parry, David A.; Logan, Clare V.; Newbury, Lucy J.; Kamath, Binita M.; Ling, Simon; Grammatikopoulos, Tassos; Wagner, Bart E.; Magee, John C.; Sokol, Ronald J.; Mieli-Vergani, Giorgina; Smith, Joshua D.; Johnson, Colin A.; McClean, Patricia; Simpson, Michael A.; Knisely, A.S.; Bull, Laura N.; Thompson, Richard J.

    2014-01-01

    The elucidation of genetic causes of cholestasis has proved to be important in understanding the physiology and pathophysiology of the liver. Protein-truncating mutations in the tight junction protein 2 gene (TJP2) are shown to cause failure of protein localisation, with disruption of tight-junction structure leading to severe cholestatic liver disease. This contrasts with the embryonic-lethal knockout mouse, highlighting differences in redundancy in junctional complexes between organs and species. PMID:24614073

  16. Long-term progression of Meniére's disease.

    PubMed

    Stahle, J; Friberg, U; Svedberg, A

    1991-01-01

    A retrospective study of 161 Meniére patients followed up for 9 years or more is presented. The development with respect to hearing, caloric response, vertigo and ability to work was analysed. The main functional loss was found to take place early in the course of the disease. There was an increase in bilaterality with time. Spontaneous relief in vertigo over the years has been noticed. PMID:1843175

  17. Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia

    PubMed Central

    Iordanskaia, Tatiana; Malesevic, Miroslav; Fischer, Gunter; Pushkarsky, Tatiana; Bukrinsky, Michael; Nadler, Evan P

    2015-01-01

    Biliary atresia (BA) is a devastating liver disease of unknown etiology affecting children generally within the first 3 months of life. The disease is manifested by inflammation and subsequent obstruction of the extrahepatic bile ducts, fibrosis and liver failure. The mechanisms responsible for disease pathogenesis are not fully understood, but a number of factors controlled by the SMAD signaling pathway have been implicated. In this study, we investigated the role of a known proinflammatory factor, extracellular cyclophilin A (CypA), in the pathogenesis of biliary atresia using the rhesus rotavirus (RRV) murine model. We used a unique cyclosporine A derivative, MM284, which does not enter cells and therefore inactivates exclusively extracellular cyclophilins, as a potential treatment. We demonstrated that levels of CypA in plasma of RRV-infected mice were increased significantly, and that treatment of mice with MM284 prior to or one day after disease initiation by RRV infection significantly improved the status of mice with experimental BA: weight gain was restored, bilirubinuria was abrogated, liver infiltration by inflammatory cells was reduced and activation of the SMAD pathway and SMAD-controlled fibrosis mediators and tissue inhibitor of metalloproteinases (TIMP)-4 and matrix metalloproteinase (MMP)-7 was alleviated. Furthermore, treatment of human hepatic stellate cells with recombinant cyclophilin recapitulated SMAD2/3 activation, which was also suppressed by MM284 treatment. Our data provide the first evidence that extracellular cyclophilins activate the SMAD pathway and promote inflammation in experimental BA, and suggest that MM284 may be a promising therapeutic agent for treating BA and possibly other intrahepatic chronic disorders. PMID:26225831

  18. [Recent progress in clinical trials for rheumatic diseases].

    PubMed

    Tanaka, Yoshiya

    2009-03-01

    Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease that causes significant morbidity and mortality. RA patients should be started with DMARD represented by methotrexate (MTX) as early as possible. However, even use of MTX often fails to control disease activity and to prevent structural damage and, thereby, more effective treatment strategies are needed. Since TNF-alpha and IL-6 play a pivotal role in the pathological processes of RA, biologics targeting these cytokines with MTX, have revolutionized the treatment of RA, producing significant improvement in clinical, radiographic and functional outcomes not seen previously. However, even with these drugs the frequency and degree of responses are restricted. Therefore, new agents targeting cell surface molecules which are involved in cellular interaction and/or signaling on immune cells have been emerging, in order to increase response rates and to achieve high frequencies of remission or even cure. Two biologics abatacept, a CTLA4-Ig fusion protein, and rituximab, an anti-CD20 antibody, were launched in US and EU for the treatment of RA and many biologics are under the clinical trials from the similar concept. Thus, certain biologics have brought about paradigm shift in the treatment of rheumatic diseases, but an economical issue remains unsolved. In order to overcome the concern, low molecular weight chemical products have been rethought. Not a few agents targeting intracellular activation signaling in immune cells such as Jak and Syk are under clinical examinations and some of them appear to show wonderful results, which are comparable to biologics in the context of the treatment of rheumatic diseases. The prospects are here. PMID:19280942

  19. Progress in the Diagnosis and Control of Ebola Disease.

    PubMed

    Wo?niak-Kosek, Agnieszka; Kosek, Jaros?aw; Mierzejewski, Jerzy; Rapiejko, Piotr

    2015-01-01

    Ebola hemorrhagic fever is one of numerous viral hemorrhagic fevers. It is a severe, often fatal disease in humans and nonhuman primates (gorillas and chimpanzees). This article discusses the history of Ebola disease, already known routes of infection together with defining prevention methods and treatment trials. The importance of increasing awareness of the risk of disease among people who do not inhabit endemic regions is emphasized. This risk is associated especially with the increasing popularity of tourism to African countries, even to those where the virus is endemic. The research conducted over the years shows that three species of frugivorous bats are subjected to contamination by Ebola, but the infection is asymptomatic in them. It is believed that the saliva of these mammals and other body fluids may be a potential source of infection for primates and humans. In the laboratory, infection through small-particle aerosols has been demonstrated in primates, and airborne spread among humans is strongly suspected, although it has not yet been conclusively demonstrated. The importance of this route of transmission remains unclear. Poor hygienic conditions can aid the spread of the virus. These observations suggest approaches to the study of routes of transmission to and among humans. PMID:25724796

  20. Are Sonographic Characteristics Associated With Progression to Surgery in Men With Peyronies Disease?

    PubMed Central

    Breyer, Benjamin N.; Shindel, Alan W.; Huang, Yun-Ching; Eisenberg, Michael L.; Weiss, Dana A.; Lue, Tom F.; Smith, James F.

    2013-01-01

    Purpose Traditionally, diagnosis and treatment plans for Peyronies disease have been based on history and physical examination. Penile ultrasound provides rapid, anatomical information to establish disease severity, and to monitor progression and response to medical therapy. We determined the relationship between ultrasound characteristics and progression to surgical intervention in men with Peyronies disease. Materials and Methods We conducted a retrospective cohort study of 518 patients with Peyronies disease. Patients completed a Peyronies disease specific questionnaire detailing medical history, health related behaviors and Peyronies disease characteristics, and underwent sonographic evaluation of the penis. Measurements of subtunical calcifications, septal fibrosis, tunical thickening (tunica thickness greater than 2 mm) and intracavernous fibrosis were made. Progression to surgery was determined from the medical record. Results In this cohort (mean patient age 53.8 years, range 20 to 78) 31% of patients had calcifications, 50% had tunical thickening, 20% had septal fibrosis and 15% had intracavernous fibrosis. Overall 25% of the cohort progressed to surgical intervention after an average followup of 1.25 years (range 0 to 7.6). Patients who underwent surgery were more likely to have subtunical calcifications present at the first clinic visit (OR 1.75, 95% CI 1.162.62). No other sonographic characteristics were associated with progression to surgery. After adjustment for age, marital status, degree of curvature, additional penile deformity, difficulty with penetration, ability to have intercourse and prior treatment for Peyronies disease, calcifications were strongly associated with progression to surgery (OR 2.75, 95% CI 1.253.45). Conclusions In a large cohort of patients with Peyronies disease the presence of sonographically detected sub-tunical calcifications during the initial office evaluation was independently associated with subsequent surgical intervention. PMID:20171694

  1. Serial surveillance of carcinoid heart disease: factors associated with echocardiographic progression and mortality

    PubMed Central

    Dobson, R; Burgess, M I; Valle, J W; Pritchard, D M; Vora, J; Wong, C; Chadwick, C; Keevi, B; Adaway, J; Hofmann, U; Poston, G J; Cuthbertson, D J

    2014-01-01

    Background: Carcinoid heart disease is a complication of metastatic neuroendocrine tumours (NETs). We sought to identify factors associated with echocardiographic progression of carcinoid heart disease and death in patients with metastatic NETs. Methods: Patients with advanced non-pancreatic NETs and documented liver metastases and/or carcinoid syndrome underwent prospective serial clinical, biochemical, echocardiographic and radiological assessment. Patients were categorised as carcinoid heart disease progressors, non-progressors or deceased. Multinomial regression was used to assess the univariate association between variables and carcinoid heart disease progression. Results: One hundred and thirty-seven patients were included. Thirteen patients (9%) were progressors, 95 (69%) non-progressors and 29 (21%) patients deceased. Baseline median levels of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) and plasma 5-hydroxyindoleacetic acid (5-HIAA) were significantly higher in the progressors. Every 100 nmol l−1 increase in 5-HIAA yielded a 5% greater odds of disease progression (OR 1.05, 95% CI: 1.01, 1.09; P=0.012) and a 7% greater odds of death (OR 1.07, 95% CI: 1.03, 1.10; P=0.001). A 100 ng l−1 increase in NT-proBNP did not increase the risk of progression, but did increase the risk of death by 11%. Conclusions: The biochemical burden of disease, in particular baseline plasma 5-HIAA concentration, is independently associated with carcinoid heart disease progression and death. Clinical and radiological factors are less useful prognostic indicators of carcinoid heart disease progression and/or death. PMID:25211656

  2. Autoimmune disease leading to pulmonary AL amyloidosis and pulmonary hypertension

    PubMed Central

    Ellender, Claire M; McLean, Catriona; Williams, Trevor J; Snell, Gregory I; Whitford, Helen M

    2015-01-01

    A 33-year-old woman with past history of Sjgren's syndrome and systemic lupus erythematosus presented with dyspnea and syncope secondary to pulmonary hypertension. After progressive symptoms over 4 years, she received bilateral lung transplantation. Histopathology of the explanted lungs showed isolated pulmonary amyloid light-chain amyloidosis and pulmonary cysts. No evidence of systemic amyloidosis was found at the time of transplantation. Seven years post lung transplantation, she remains well with no evidence of systemic amyloidosis recurrence. PMID:26090118

  3. Respiratory Syncytial Virus in Hematopoietic Cell Transplant Recipients: Factors Determining Progression to Lower Respiratory Tract Disease

    PubMed Central

    Kim, Yae-Jean; Guthrie, Katherine A.; Waghmare, Alpana; Walsh, Edward E.; Falsey, Ann R.; Kuypers, Jane; Cent, Anne; Englund, Janet A.; Boeckh, Michael

    2014-01-01

    Background. Respiratory syncytial virus (RSV) lower respiratory tract disease (LRD) is a life-threatening complication in hematopoietic cell transplant (HCT) recipients. Lymphopenia has been associated with an increased risk of progression from upper respiratory tract infection (URI) to LRD. Methods. This study retrospectively analyzed the significance of lymphocyte engraftment dynamics, lung function, smoking history, corticosteroids, antiviral treatment, viral subtypes, and RSV-specific neutralizing antibodies for the progression to LRD in 181 HCT recipients with RSV URI. Results. In multivariable models, smoking history, conditioning with high-dose total body irradiation, and an absolute lymphocyte count (ALC) ≤100/mm3 at the time of URI onset were significantly associated with disease progression. No progression occurred in patients with ALCs of >1000/mm3 at URI onset. Lymphocyte engraftment dynamics were similar in progressors and nonprogressors. Pre- and posttransplant donor and posttransplant recipient RSV subtype-specific neutralizing antibody levels, RSV viral subtypes, and corticosteroids also were not significantly associated with LRD progression. Conclusions. Host and transplant related factors appear to determine the risk of progression to LRD more than viral factors. Dysfunctional cell-mediated immunity appears to be important in the pathogenesis of progressive RSV disease after HCT. A characterization of RSV-specific T-cell immunity is warranted. PMID:24368837

  4. Multiple sclerosis: assessment of disease progression and effects of treatment.

    PubMed

    Paty, D W

    1987-08-01

    MS could well be a two stage disease. The first stage involves the sequential development of multiple small lesions, mostly inflammatory, that accumulate at a given rate. The second stage could be that of consolidation and confluence of lesions that involves not only demyelination but gliosis. MRI now gives us an opportunity to watch the evolution of these processes and also to monitor treatment effects. It is only after the evolution of this process is understood that we can design rational therapies directed toward the prevention of spasticity in MS. PMID:3315154

  5. Five-year follow-up of angiographic disease progression after medicine, angioplasty, or surgery

    PubMed Central

    2010-01-01

    Background Progression of atherosclerosis in coronary artery disease is observed through consecutive angiograms. Prognosis of this progression in patients randomized to different treatments has not been established. This study compared progression of coronary artery disease in native coronary arteries in patients undergoing surgery, angioplasty, or medical treatment. Methods Patients (611) with stable multivessel coronary artery disease and preserved ventricular function were randomly assigned to CABG, PCI, or medical treatment alone (MT). After 5-year follow-up, 392 patients (64%) underwent new angiography. Progression was considered a new stenosis of ≥ 50% in an arterial segment previously considered normal or an increased grade of previous stenosis > 20% in nontreated vessels. Results Of the 392 patients, 136 underwent CABG, 146 PCI, and 110 MT. Baseline characteristics were similar among treatment groups, except for more smokers and statin users in the MT group, more hypertensives and lower LDL-cholesterol levels in the CABG group, and more angina in the PCI group at study entry. Analysis showed greater progression in at least one native vessel in PCI patients (84%) compared with CABG (57%) and MT (74%) patients (p < 0.001). LAD coronary territory had higher progression compared with LCX and RCA (P < 0.001). PCI treatment, hypertension, male sex, and previous MI were independent risk factors for progression. No statistical difference existed between coronary events and the development of progression. Conclusion The angioplasty treatment conferred greater progression in native coronary arteries, especially in the left anterior descending territories and treated vessels. The progression was independently associated with hypertension, male sex, and previous myocardial infarction. PMID:20977758

  6. 4-hydroxynonenal in the pathogenesis and progression of human diseases

    PubMed Central

    Shoeb, Mohammad; Ansari, Naseem H; Srivastava, Satish K; Ramana, Kota V

    2014-01-01

    Metastable aldehydes produced by lipid peroxidation act as 'toxic second messengers' that extend the injurious potential of free radicals. 4-hydroxy 2-nonenal (HNE), a highly toxic and most abundant stable end product of lipid peroxidation, has been implicated in the tissue damage, dysfunction, injury associated with aging and other pathological states such as cancer, Alzheimer, diabetes, cardiovascular and inflammatory complications. Further, HNE has been considered as a oxidative stress marker and it act as a secondary signaling molecule to regulates a number of cell signaling pathways. Biological activity of HNE depends on its intracellular concentration, which can differentially modulate cell death, growth and differentiation. Therefore, the mechanisms responsible for maintaining the intracellular levels of HNE are most important, not only in the defense against oxidative stress but also in the pathophysiology of a number of disease processes. In this review, we discusse the significance of HNE in mediating various disease processes and how regulation of its metabolism could be therapeutically effective. PMID:23848536

  7. A network diffusion model of disease progression in dementia.

    PubMed

    Raj, Ashish; Kuceyeski, Amy; Weiner, Michael

    2012-03-22

    Patterns of dementia are known to fall into dissociated but dispersed brain networks, suggesting that the disease is transmitted along neuronal pathways rather than by proximity. This view is supported by neuropathological evidence for "prion-like" transsynaptic transmission of disease agents like misfolded tau and beta amyloid. We mathematically model this transmission by a diffusive mechanism mediated by the brain's connectivity network obtained from tractography of 14 healthy-brain MRIs. Subsequent graph theoretic analysis provides a fully quantitative, testable, predictive model of dementia. Specifically, we predict spatially distinct "persistent modes," which, we found, recapitulate known patterns of dementia and match recent reports of selectively vulnerable dissociated brain networks. Model predictions also closely match T1-weighted MRI volumetrics of 18 Alzheimer's and 18 frontotemporal dementia subjects. Prevalence rates predicted by the model strongly agree with published data. This work has many important implications, including dimensionality reduction, differential diagnosis, and especially prediction of future atrophy using baseline MRI morphometrics. PMID:22445347

  8. Prion Protein Polymorphisms Affect Chronic Wasting Disease Progression

    PubMed Central

    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. PMID:21445256

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

    PubMed Central

    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. PMID:24765074

  10. Low-level laser therapy ameliorates disease progression in a mouse model of multiple sclerosis.

    PubMed

    Gonçalves, Elaine D; Souza, Priscila S; Lieberknecht, Vicente; Fidelis, Giulia S P; Barbosa, Rafael I; Silveira, Paulo C L; de Pinho, Ricardo A; Dutra, Rafael C

    2016-03-01

    Multiple sclerosis (MS) is an autoimmune demyelinating inflammatory disease characterized by recurrent episodes of T cell-mediated immune attack on central nervous system (CNS) myelin, leading to axon damage and progressive disability. The existing therapies for MS are only partially effective and are associated with undesirable side effects. Low-level laser therapy (LLLT) has been clinically used to treat inflammation, and to induce tissue healing and repair processes. However, there are no reports about the effects and mechanisms of LLLT in experimental autoimmune encephalomyelitis (EAE), an established model of MS. Here, we report the effects and underlying mechanisms of action of LLLT (AlGaInP, 660 nm and GaAs, 904 nm) irradiated on the spinal cord during EAE development. EAE was induced in female C57BL/6 mice by immunization with MOG35-55 peptide emulsified in complete Freund's adjuvant. Our results showed that LLLT consistently reduced the clinical score of EAE and delayed the disease onset, and also prevented weight loss induced by immunization. Furthermore, these beneficial effects of LLLT seem to be associated with the down-regulation of NO levels in the CNS, although the treatment with LLLT failed to inhibit lipid peroxidation and restore antioxidant defense during EAE. Finally, histological analysis showed that LLLT blocked neuroinflammation through a reduction of inflammatory cells in the CNS, especially lymphocytes, as well as preventing demyelination in the spinal cord after EAE induction. Together, our results suggest the use of LLLT as a therapeutic application during autoimmune neuroinflammatory responses, such as MS. PMID:26703077

  11. Baseline Predictors of Renal Disease Progression in the African American Study of Hypertension and Kidney Disease

    PubMed Central

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

    2013-01-01

    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 m2 GFR decline or ESRD among 1094 black patients with hypertensive nephrosclerosis (GFR 20 to 65 ml/min per 1.73 m2). 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. PMID:16959828

  12. Aberrant autophagy and parkinsonism: does correction rescue from disease progression?

    PubMed

    Mishra, Abhishek Kumar; ur Rasheed, Mohd Sami; Shukla, Saurabh; Tripathi, Manish Kumar; Dixit, Anubhuti; Singh, Mahendra Pratap

    2015-01-01

    Information generated from animal models, genome sequencing, and high-throughput technologies provide valuable sequence of events to understand the Parkinson's disease (PD) pathogenesis. A dynamic equilibrium between biosynthesis and biodegradation of sub-cellular components by ubiquitin proteasome system and autophagy is found to be responsible for sustaining the homeostasis of tyrosine hydroxylase-positive neurons. Autophagy degrades and eliminates ?-synuclein, Parkin, ubiquitin, etc., proteins along with damaged cellular components to maintain the homeostasis of the nigrostriatal dopaminergic neurons. Aberrant type II apoptosis is widely implicated in dopaminergic neurodegeneration leading to PD. The current article reviews the elementary role of autophagy in the degradation and elimination of superfluous and aggregated proteins and impaired mitochondria. The article also recapitulates the information, which implicated the role of aberrant autophagy in toxin-induced Parkinsonism. Moreover, the review sheds light on whether or not targeting the defective autophagy could reinstate the normal functioning of dopaminergic neurons, which could ultimately rescue from PD pathogenesis. PMID:24833602

  13. 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

  14. Pathomechanisms: homeostatic chemokines in health, tissue regeneration, and progressive diseases.

    PubMed

    Anders, Hans-Joachim; Romagnani, Paola; Mantovani, Alberto

    2014-03-01

    Homeostatic chemokines control stem and progenitor cell migration and activation during vasculogenesis and organ development. They orchestrate hematopoietic stem cell (HSC) homing to their bone marrow niches and direct immature lymphocytes to a series of maturation sites within lymphoid organs. Along these lines, homeostatic chemokines regulate the niches of peripheral committed progenitor cell populations for tissue renewal. These biological functions support neovascularization and wound healing, including the recruitment of endothelial and other progenitor cells from the bone marrow. Here, we summarize the roles of homeostatic chemokines, their signaling receptors, and atypical decoy receptors during homeostasis and tissue regeneration in order to better understand their pathogenic roles in disease, for example, in diabetes complications, cancer, autoimmunity, epithelial hyperplasia, or hypertrophic scarring and fibrosis. PMID:24440002

  15. 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

  16. Hippocampal plasticity during the progression of Alzheimer's disease.

    PubMed

    Mufson, E J; Mahady, L; Waters, D; Counts, S E; Perez, S E; DeKosky, S T; Ginsberg, S D; Ikonomovic, M D; Scheff, S W; Binder, L I

    2015-11-19

    Neuroplasticity involves molecular and structural changes in central nervous system (CNS) throughout life. The concept of neural organization allows for remodeling as a compensatory mechanism to the early pathobiology of Alzheimer's disease (AD) in an attempt to maintain brain function and cognition during the onset of dementia. The hippocampus, a crucial component of the medial temporal lobe memory circuit, is affected early in AD and displays synaptic and intraneuronal molecular remodeling against a pathological background of extracellular amyloid-beta (A?) deposition and intracellular neurofibrillary tangle (NFT) formation in the early stages of AD. Here we discuss human clinical pathological findings supporting the concept that the hippocampus is capable of neural plasticity during mild cognitive impairment (MCI), a prodromal stage of AD and early stage AD. PMID:25772787

  17. 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, the CMA applicator resulting from these enhancements should expand the number of patients that can benefit from effective heating of superficial disease in combination with radiation or chemotherapy.

  18. TWEAK and the progression of renal disease: clinical translation

    PubMed Central

    Sanz, Ana B.; Izquierdo, M. Concepcion; Sanchez-Nio, Maria Dolores; Ucero, Alvaro C.; Egido, Jesus; Ruiz-Ortega, Marta; Ramos, Adrin Mario; Putterman, Chaim; Ortiz, Alberto

    2014-01-01

    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. PMID:24493870

  19. Effect of organic solvent exposure on chronic kidney disease progression: the GN-PROGRESS cohort study

    PubMed Central

    Jacob, Sophie; Héry, Michel; Protois, Jean-Claude; Rossert, Jérôme; Stengel, Bénédicte

    2007-01-01

    It has been suggested that solvent exposure may have a role in the progression of glomerulonephritis (GN) to end-stage renal failure (ESRD), but this has never been tested with an appropriate cohort study design. We included 338 nonESRD patients with a first biopsy for primary GN between 1994 and 2001: 194 IgA nephropathies (IgAN), 75 membranous nephropathies (MN) and 69 focal and segmental glomerulosclerosis (FSGS). ESRD, defined as an estimated glomerular filtration rate < 15 mL/min/1.73m2 or dialysis, was registered over a mean follow-up period of 5 years. Patients’ lifelong solvent exposures before and after diagnosis were recorded by interview and assessed by industrial hygienist experts. We used Cox models to estimate adjusted hazard ratios (HR) of ESRD related to exposures. Overall, 15% of the patients had been exposed at a low level before diagnosis and 14% at a high level. Forty-two with IgA N reached ESRD, 12 with MN, and 22 with FSGS. A graded relationship was observed for MN: age- and gender-adjusted HR [95% confidence interval] for low exposure vs none 3.1 [0.5–18.2], and for high exposure vs none 8.2 [1.9–34.7], as well as for IgA N: 1.6 [0.7–3.9] and 2.2 [1.0–4.8], respectively, but not for FSGS. Solvent risk was only partly mediated by baseline proteinuria: adjusted HR for high exposure vs none = 5.5 [1.3 – 23.9] for MN and 1.8 [0.8 – 3.9] for IgA N. In patients with IgA N, there was a trend in increasing HR with exposure duration before and its persistence after diagnosis. These findings support the hypothesized association of solvent exposure with the progression of GN to ESRD. They should prompt clinicians to give greater attention to patients’ occupational exposures and possibly to consider professional reclassification. PMID:17135394

  20. Chronic temporal lobe epilepsy: a neurodevelopmental or progressively dementing disease?

    PubMed

    Helmstaedter, C; Elger, C E

    2009-10-01

    To what degree does the so-called 'initial hit' of the brain versus chronic epilepsy contribute towards the memory impairment observed in chronic temporal lobe epilepsy (TLE) patients? We examined cross-sectional comparisons of age-related regressions of verbal learning and memory in 1156 patients with chronic TLE (age range 6-68 years, mean epilepsy onset 14 +/- 11 years) versus 1000 healthy control subjects (age range 6-80 years) and tested the hypothesis that deviations of age regressions (i.e. slowed rise, accelerated decline) will reveal critical phases during which epilepsy interferes with cognitive development. Patients were recruited over a 20-year period at the Department of Epileptology, University of Bonn. Healthy subjects were drawn from an updated normative population of the Verbaler Lern- und Merkfhigkeitstest, the German pendant to the Rey Auditory Verbal learning Test. A significant divergence of age regressions indicates that patients fail to build up adequate learning and memory performance during childhood and particularly during adolescence. The learning peak (i.e. crossover into decline) is seen earlier in patients (at about the age of 16-17 years) than for controls (at about the age of 23-24 years). Decline in performance with ageing in patients and controls runs in parallel, but due to the initial distance between the groups, patients reach very poor performance levels much earlier than controls. Patients with left and right TLEs performed worse in verbal memory than controls. In addition, patients with left TLE performed worse than those with right TLE. However, laterality differences were evident only in adolescent and adult patients, and not (or less so) in children and older patients. Independent of age, hippocampal sclerosis was associated with poorer performance than other pathologies. The results indicate developmental hindrance plus a negative interaction of cognitive impairment with mental ageing, rather than a progressively dementing decline in chronic TLE patients. During childhood, and even more so during the decade following puberty, the critical phases for establishing episodic memory deficits appear. This increases the risk of premature 'dementia' later on, even in the absence of an accelerated decline. Material specific verbal memory impairment in left TLE is a characteristic of the mature brain and seems to disappear at an older age. The findings suggest that increased attention is to be paid to the time of epilepsy onset and thereafter. Early control of epilepsy is demanded to counteract developmental hindrance and damage at a younger age. PMID:19635728

  1. 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.

  2. [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

  3. 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

  4. CaregiverRecipient Closeness and Symptom Progression in Alzheimer Disease. The Cache County Dementia Progression Study

    PubMed Central

    Piercy, Kathleen W.; Rabins, Peter V.; Green, Robert C.; Breitner, John C. S.; stbye, Truls; Corcoran, Christopher; Welsh-Bohmer, Kathleen A.; Lyketsos, Constantine G.; Tschanz, JoAnn T.

    2009-01-01

    Applying Rusbult's investment model of dyadic relationships, we examined the effect of caregivercare recipient relationship closeness (RC) on cognitive and functional decline in Alzheimer's disease. After diagnosis, 167 participants completed up to six visits, observed over an average of 20 months. Participants were 64% women, had a mean age of 86 years, and mean dementia duration of 4 years. Caregiver-rated closeness was measured using a six-item scale. In mixed models adjusted for dementia severity, dyads with higher levels of closeness (p < .05) and with spouse caregivers (p = .01) had slower cognitive decline. Effect of higher RC on functional decline was greater with spouse caregivers (p = .007). These findings of attenuated Alzheimer's dementia (AD) decline with closer relationships, particularly with spouse caregivers, are consistent with investment theory. Future interventions designed to enhance the caregiving dyadic relationship may help slow decline in AD. PMID:19564210

  5. Osteoarthritis disease progression model using six year follow-up data from the osteoarthritis initiative.

    PubMed

    Passey, Chaitali; Kimko, Holly; Nandy, Partha; Kagan, Leonid

    2014-09-11

    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. PMID:25212288

  6. Ketogenic diet prevents epileptogenesis and disease progression in adult mice and rats.

    PubMed

    Lusardi, Theresa A; Akula, Kiran K; Coffman, Shayla Q; Ruskin, David N; Masino, Susan A; Boison, Detlev

    2015-12-01

    Epilepsy is a highly prevalent seizure disorder which tends to progress in severity and become refractory to treatment. Yet no therapy is proven to halt disease progression or to prevent the development of epilepsy. Because a high fat low carbohydrate ketogenic diet (KD) augments adenosine signaling in the brain and because adenosine not only suppresses seizures but also affects epileptogenesis, we hypothesized that a ketogenic diet might prevent epileptogenesis through similar mechanisms. Here, we tested this hypothesis in two independent rodent models of epileptogenesis. Using a pentylenetetrazole kindling paradigm in mice, we first show that a KD, but not a conventional antiepileptic drug (valproic acid), suppressed kindling-epileptogenesis. Importantly, after treatment reversal, increased seizure thresholds were maintained in those animals kindled in the presence of a KD, but not in those kindled in the presence of valproic acid. Next, we tested whether a KD can halt disease progression in a clinically relevant model of progressive epilepsy. Epileptic rats that developed spontaneous recurrent seizures after a pilocarpine-induced status epilepticus were treated with a KD or control diet (CD). Whereas seizures progressed in severity and frequency in the CD-fed animals, KD-fed animals showed a prolonged reduction of seizures, which persisted after diet reversal. KD-treatment was associated with increased adenosine and decreased DNA methylation, the latter being maintained after diet discontinuation. Our findings demonstrate that a KD prevented disease progression in two mechanistically different models of epilepsy, and suggest an epigenetic mechanism underlying the therapeutic effects. PMID:26256422

  7. Computational fluid dynamics tools can be used to predict the progression of coronary artery disease

    NASA Astrophysics Data System (ADS)

    Co?kun, A. mit; Chen, Caixia; Stone, Peter H.; Feldman, Charles L.

    2006-03-01

    Atherosclerosis is focal and individual plaques evolve in an independent manner. The endothelium regulates arterial behavior by responding to its local shear stress. In vitro studies indicate that low endothelial shear stress (ESS) upregulates the genetic and molecular responses leading to the initiation and progression of atherosclerosis and promotes inflammation and formation of other features characteristic of vulnerable plaque. Physiologic ESS is vasculoprotective and fosters quiescence of the endothelium and vascular wall. High ESS promotes platelet aggregation. ESS and vascular wall morphology along the course of human coronary arteries can now be characterized in vivo, and may predict the focal areas in which atherosclerosis progression occurs. Rapidly evolving methodologies are able to characterize the arterial wall and the local hemodynamic factors likely responsible for progression of coronary disease in man. These new diagnostic modalities allow for identification of plaque progression. Accurate identification of arterial segments at high-risk for progression may permit pre-emptive intervention strategies to avoid adverse coronary events.

  8. Identifying informative risk factors and predicting bone disease progression via deep belief networks.

    PubMed

    Li, Hui; Li, Xiaoyi; Ramanathan, Murali; Zhang, Aidong

    2014-10-01

    Osteoporosis is a common disease which frequently causes death, permanent disability, and loss of quality of life in the geriatric population. Identifying risk factors for the disease progression and capturing the disease characteristics have received increasing attentions in the health informatics research. In data mining area, risk factors are features of the data and diagnostic results can be regarded as the labels to train a model for a regression or classification task. We develop a general framework based on the heterogeneous electronic health records (EHRs) for the risk factor (RF) analysis that can be used for informative RF selection and the prediction of osteoporosis. The RF selection is a task designed for ranking and explaining the semantics of informative RFs for preventing the disease and improving the understanding of the disease. Predicting the risk of osteoporosis in a prospective and population-based study is a task for monitoring the bone disease progression. We apply a variety of well-trained deep belief network (DBN) models which inherit the following good properties: (1) pinpointing the underlying causes of the disease in order to assess the risk of a patient in developing a target disease, and (2) discriminating between patients suffering from the disease and without the disease for the purpose of selecting RFs of the disease. A variety of DBN models can capture characteristics for different patient groups via a training procedure with the use of different samples. The case study shows that the proposed method can be efficiently used to select the informative RFs. Most of the selected RFs are validated by the medical literature and some new RFs will attract interests across the medical research. Moreover, the experimental analysis on a real bone disease data set shows that the proposed framework can successfully predict the progression of osteoporosis. The stable and promising performance on the evaluation metrics confirms the effectiveness of our model. PMID:24979059

  9. Hepatitis C virus infection: establishment of chronicity and liver disease progression

    PubMed Central

    Kwon, Young-Chan; Ray, Ratna B.; Ray, Ranjit

    2014-01-01

    Hepatitis C virus (HCV) often causes persistent infection, and is an important factor in the etiology of fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). There are no preventive or therapeutic vaccines available against HCV. Treatment strategies of HCV infection are likely to improve with recently discovered direct antiviral agents (DAAs). However, a proportion of patients still progress to liver failure and/or HCC despite having been cured of the infection. Thus, there is a need for early diagnosis and therapeutic modalities for HCV related end stage liver disease prevention. HCV genome does not integrate into its host genome, and has a predominantly cytoplasmic life cycle. Therefore, HCV mediated liver disease progression appears to involve indirect mechanisms from persistent infection of hepatocytes. Studying the underlying mechanisms of HCV mediated evasion of immune responses and liver disease progression is challenging due to the lack of a naturally susceptible small animal model. We and other investigators have used a number of experimental systems to investigate the mechanisms for establishment of chronic HCV infection and liver disease progression. HCV infection modulates immune systems. Further, HCV infection of primary human hepatocytes promotes growth, induces phenotypic changes, modulates epithelial mesenchymal transition (EMT) related genes, and generates tumor initiating stem-like cells (TISCs). HCV infection also modulates microRNAs (miRNAs), and influences growth by overriding normal death progression of primary human hepatocytes for disease pathogenesis. Understanding these ob-servations at the molecular level should aid in developing strategies for additional effective therapies against HCV mediated liver disease progression. PMID:26417315

  10. Integrative analysis reveals disease-associated genes and biomarkers for prostate cancer progression

    PubMed Central

    2014-01-01

    Background Prostate cancer is one of the most common complex diseases with high leading cause of death in men. Identifications of prostate cancer associated genes and biomarkers are thus essential as they can gain insights into the mechanisms underlying disease progression and advancing for early diagnosis and developing effective therapies. Methods In this study, we presented an integrative analysis of gene expression profiling and protein interaction network at a systematic level to reveal candidate disease-associated genes and biomarkers for prostate cancer progression. At first, we reconstructed the human prostate cancer protein-protein interaction network (HPC-PPIN) and the network was then integrated with the prostate cancer gene expression data to identify modules related to different phases in prostate cancer. At last, the candidate module biomarkers were validated by its predictive ability of prostate cancer progression. Results Different phases-specific modules were identified for prostate cancer. Among these modules, transcription Androgen Receptor (AR) nuclear signaling and Epidermal Growth Factor Receptor (EGFR) signalling pathway were shown to be the pathway targets for prostate cancer progression. The identified candidate disease-associated genes showed better predictive ability of prostate cancer progression than those of published biomarkers. In context of functional enrichment analysis, interestingly candidate disease-associated genes were enriched in the nucleus and different functions were encoded for potential transcription factors, for examples key players as AR, Myc, ESR1 and hidden player as Sp1 which was considered as a potential novel biomarker for prostate cancer. Conclusions The successful results on prostate cancer samples demonstrated that the integrative analysis is powerful and useful approach to detect candidate disease-associate genes and modules which can be used as the potential biomarkers for prostate cancer progression. The data, tools and supplementary files for this integrative analysis are deposited at http://www.ibio-cn.org/HPC-PPIN/. PMID:25080090

  11. A Clinical Index to Predict Progression from Mild Cognitive Impairment to Dementia Due to Alzheimer's Disease

    PubMed Central

    Lee, Sei J.; Ritchie, Christine S.; Yaffe, Kristine; Stijacic Cenzer, Irena; Barnes, Deborah E.

    2014-01-01

    Background Mild cognitive impairment is often a precursor to dementia due to Alzheimer's disease, but many patients with mild cognitive impairment never develop dementia. New diagnostic criteria may lead to more patients receiving a diagnosis of mild cognitive impairment. Objective To develop a prediction index for the 3-year risk of progression from mild cognitive impairment to dementia relying only on information that can be readily obtained in most clinical settings. Design and Participants 382 participants diagnosed with amnestic mild cognitive impairment enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI), a multi-site, longitudinal, observational study. Main Predictors Measures Demographics, comorbid conditions, caregiver report of participant symptoms and function, and participant performance on individual items from basic neuropsychological scales. Main Outcome Measure Progression to probable Alzheimer's disease. Key Results Subjects had a mean (SD) age of 75 (7) years and 43% progressed to probable Alzheimer's disease within 3 years. Important independent predictors of progression included being female, resisting help, becoming upset when separated from caregiver, difficulty shopping alone, forgetting appointments, number of words recalled from a 10-word list, orientation and difficulty drawing a clock. The final point score could range from 0 to 16 (mean [SD]: 4.2 [2.9]). The optimism-corrected Harrell's c-statistic was 0.71(95% CI: 0.68–0.75). Fourteen percent of subjects with low risk scores (0–2 points, n = 124) converted to probable Alzheimer's disease over 3 years, compared to 51% of those with moderate risk scores (3–8 points, n = 223) and 91% of those with high risk scores (9–16 points, n = 35). Conclusions An index using factors that can be obtained in most clinical settings can predict progression from amnestic mild cognitive impairment to probable Alzheimer's disease and may help clinicians differentiate between mild cognitive impairment patients at low vs. high risk of progression. PMID:25486250

  12. Depressive symptoms increase risk of HIV disease progression and mortality among women in Tanzania.

    PubMed

    Antelman, Gretchen; Kaaya, Sylvia; Wei, Ruilan; Mbwambo, Jessie; Msamanga, Gernard I; Fawzi, Wafaie W; Fawzi, Mary C Smith

    2007-04-01

    The effect of depression on HIV disease progression was examined among 996 HIV-positive Tanzanian women participating in a trial on micronutrients and pregnancy outcomes, vertical transmission, and disease progression. Depression and social support were measured 2 months after HIV screening and every 6 to 12 months thereafter. Depression measures from pregnancy and more than 12 months postpartum were included in this analysis. Participants' clinical condition and access to supportive individual or group counseling was assessed throughout the 6 to 8 years of follow-up. Cox proportional hazard models were used to estimate the time-varying effect of depression on progression to HIV clinical stage III/IV (World Health Organization) and all-cause mortality. Participation in group or individual counseling and baseline social support were also examined. More than half (57%) of the study sample had symptoms comparable with depression at least once during the follow-up period. Controlling for sociodemographic variables, psychosocial support, and clinical condition at enrollment, depression was associated with an increased risk of disease progression (HIV clinical stage III/IV [hazard ratio (HR) = 1.61, 95% confidence interval (CI): 1.28 to 2.03] and mortality [HR = 2.65, 95% CI: 1.89 to 3.71]). Depression is common among HIV-infected Tanzanian women and increases the risk of disease progression. Screening for depression and providing psychosocial interventions should be considered part of comprehensive HIV care. PMID:17179766

  13. 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

  14. Cerebellar Transcriptome Profiles of ATXN1 Transgenic Mice Reveal SCA1 Disease Progression and Protection Pathways.

    PubMed

    Ingram, Melissa; Wozniak, Emily A L; Duvick, Lisa; Yang, Rendong; Bergmann, Paul; Carson, Robert; O'Callaghan, Brennon; Zoghbi, Huda Y; Henzler, Christine; Orr, Harry T

    2016-03-16

    SCA1, a fatal neurodegenerative disorder, is caused by a CAG expansion encoding a polyglutamine stretch in the protein ATXN1. We used RNA sequencing to profile cerebellar gene expression in Pcp2-ATXN1[82Q] mice with ataxia and progressive pathology and Pcp2-ATXN1[30Q]D776 animals having ataxia in absence of Purkinje cell progressive pathology. Weighted Gene Coexpression Network Analysis of the cerebellar expression data revealed two gene networks that significantly correlated with disease and have an expression profile correlating with disease progression in ATXN1[82Q] Purkinje cells. The Magenta Module provides a signature of suppressed transcriptional programs reflecting disease progression in Purkinje cells, while the Lt Yellow Module reflects transcriptional programs activated in response to disease in Purkinje cells as well as other cerebellar cell types. Furthermore, we found that upregulation of cholecystokinin (Cck) and subsequent interaction with the Cck1 receptor likely underlies the lack of progressive Purkinje cell pathology in Pcp2-ATXN1[30Q]D776 mice. PMID:26948890

  15. Activation of NK cells is associated with HIV-1 disease progression.

    PubMed

    Kuri-Cervantes, Leticia; de Oca, Gonzalo Salgado-Montes; Avila-Ros, Santiago; Hernndez-Juan, Ramn; Reyes-Tern, Gustavo

    2014-07-01

    The main predictor of HIV-1 disease progression is CD8(+) T cell activation, characterized by elevated expression of CD38 and HLA-DR. NK cells are also activated in viremic HIV-1-infected individuals. However, the relationship between NK cell activation and HIV-1 disease progression remains undefined. We characterized NK cell activation and its association with disease progression in treatment of naive HIV-1-infected individuals, who naturally maintained low/undetectable viremia (elite and viremic controllers), compared with progressors and AIDS subjects, and treated individuals. Our results show that CD38 expression on NK cells, predominantly in the cytotoxic CD56(dim)CD16(+) subset, is associated with HIV-1 disease progression (CD4(+) T cell count and pVL), T cell activation (percentage of CD38(+)HLA-DR(+) T cells), sCD14, inflammation, and innate immune activation. Moreover, NK cell activation is increased in HIV-1-infected subjects progressing to AIDS but not in elite and viremic controllers. ART partially reduces the proportion of activated NK cells. Furthermore, our results show that individuals, who naturally control viremia, maintain low levels of innate immune activation similar to those of uninfected controls. PMID:24399837

  16. Estimating premorbid functioning in huntington's disease: the relationship between disease progression and the wide range achievement test reading subtest.

    PubMed

    O'Rourke, Justin J F; Adams, William H; Duff, Kevin; Byars, Joanne; Nopoulos, Peg; Paulsen, Jane S; Beglinger, Leigh J

    2011-02-01

    The estimation of premorbid abilities is an essential part of a neuropsychological evaluation, especially in neurodegenerative conditions. Although word pronunciation tests are one standard method for estimating the premorbid level, research suggests that these tests may not be valid in neurodegenerative diseases. Therefore, the current study sought to examine two estimates of premorbid intellect, the Wide Range Achievement Test (WRAT) Reading subtest and the Barona formula, in 93 patients with mild to moderate Huntington's disease (HD) to determine their utility and to investigate how these measures relate to signs and symptoms of disease progression. In 89% of participants, WRAT estimates were below the Barona estimates. WRAT estimates were related to worsening memory and motor functioning, whereas the Barona estimates had weaker relationships. Neither estimate was related to depression or functional capacity. Irregular wordreading tests appear to decline with HD progression, whereas estimation methods based on demographic factors may be more robust but overestimate premorbid functioning. PMID:21147861

  17. [Progressive multifocal leukoencephalopathy following azathioprine and steroid treatment of pulmonary sarcoid disease].

    PubMed

    Franzen, Damian; Mathys, Christian; Vesper, Jan; Malzkorn, Bastian; Bohlen, Heribert; Seitz, Rdiger J

    2015-08-01

    Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system following reactivation of the John-Cunningham-Virus (JVC) in an immunocompromised host. This rare condition is characterized by rapid progressing neurologic symptoms often leading to death. In the following, we report on a rapid evolving deterioration of mental status due to PML in an 53-year-old man during treatment of pulmonary sarcoid disease using azathioprine and steroids. In contrast to reported lethal outcomes, our patient experienced a slow recovery of his cognitive impairment and later on of his palsy following termination of immunosuppression. PMID:26306018

  18. Magnetic resonance markers for early diagnosis and progression of Alzheimer's disease.

    PubMed

    Kantarci, Kejal

    2005-09-01

    With increasing life expectancy, the early diagnosis and treatment of Alzheimer's disease has become critical in sustaining a healthy society. Noninvasive markers of disease progression starting from the earliest stages of pathologic involvement are required for determining the effectiveness of putative disease-modifying therapies that are under development. Cross-sectional and longitudinal studies indicate that magnetic resonance-based volume measurements of atrophy are potential markers of the progression of Alzheimer's disease, starting from the preclinical stages. Other magnetic resonance techniques that are sensitive to the different aspects of Alzheimer's disease pathology, such as biochemical ((proton) magnetic resonance spectroscopy), microstructural (diffusion magnetic resonance imaging), functional (functional magnetic resonance imaging) and blood flow (perfusion magnetic resonance imaging) changes, have not been as extensively studied longitudinally. Recent efforts of imaging amyloid plaques with magnetic resonance imaging generate the prospect for in vivo imaging of the pathologic substrate of Alzheimer's disease in the future. In order for magnetic resonance modalities to qualify as surrogate markers for early diagnosis and progression of Alzheimer's disease, multicenter longitudinal studies are needed. PMID:16162090

  19. Differential susceptibility to excitotoxic stress in YAC128 mouse models of Huntington disease between initiation and progression of disease.

    PubMed

    Graham, Rona K; Pouladi, Mahmoud A; Joshi, Prasad; Lu, Ge; Deng, Yu; Wu, Nan-Ping; Figueroa, Bryan E; Metzler, Martina; Andr, Vronique M; Slow, Elizabeth J; Raymond, Lynn; Friedlander, Robert; Levine, Michael S; Leavitt, Blair R; Hayden, Michael R

    2009-02-18

    Huntington disease (HD) is a neurodegenerative disorder caused by an expanded CAG tract in the HD gene. Polyglutamine expansion of huntingtin (htt) results in early, progressive loss of medium spiny striatal neurons, as well as cortical neurons that project to the striatum. Excitotoxicity has been postulated to play a key role in the selective vulnerability of striatal neurons in HD. Early excitotoxic neuropathological changes observed in human HD brain include increased quinolinate (QUIN) concurrent with proliferative changes such as increased spine density and dendritic length. In later stages of the disease, degenerative-type changes are apparent, such as loss of dendritic arborization, a reduction in spine density and reduced levels of 3-hydroxykynurenine and QUIN. It is currently unknown whether sensitivity to excitotoxic stress varies between initiation and progression of disease. Here, we have assessed the excitotoxic phenotype in the YAC128 mouse model of HD by examining the response to excitotoxic stress at different stages of disease. Our results demonstrate that YAC128 mice display enhanced sensitivity to NMDA ex vivo and QUIN in vivo before obvious phenotypic changes. In contrast, 10-month-old symptomatic YAC128 mice are resistant to QUIN-induced neurotoxicity. These findings are paralleled by a significant increase in NMDAR-mediated membrane currents in presymptomatic YAC128 dissociated medium spiny neurons progressing to reduced NMDAR-mediated membrane currents with disease progression. These data highlight the dynamic nature of the mutant htt-mediated excitotoxic phenotype and suggests that therapeutic approaches to HD may need to be altered, depending on the stage and development of the disease. PMID:19228972

  20. Quantitative Micro-Computed Tomography Imaging of Vascular Dysfunction in Progressive Kidney Diseases

    PubMed Central

    Ehling, Josef; Bb?kov, Janka; Gremse, Felix; Klinkhammer, Barbara M.; Baetke, Sarah; Knuechel, Ruth; Kiessling, Fabian; Floege, Jrgen; Lammers, Twan; Boor, Peter

    2015-01-01

    Progressive kidney diseases and renal fibrosis are associated with endothelial injury and capillary rarefaction. However, our understanding of these processes has been hampered by the lack of tools enabling the quantitative and noninvasive monitoring of vessel functionality. Here, we used micro-computed tomography (?CT) for anatomical and functional imaging of vascular alterations in three murine models with distinct mechanisms of progressive kidney injury: ischemia-reperfusion (I/R, days 156), unilateral ureteral obstruction (UUO, days 110), and Alport mice (68 weeks old). Contrast-enhanced in vivo ?CT enabled robust, noninvasive, and longitudinal monitoring of vessel functionality and revealed a progressive decline of the renal relative blood volume in all models. This reduction ranged from ?20% in early disease stages to ?61% in late disease stages and preceded fibrosis. Upon Microfil perfusion, high-resolution ex vivo ?CT allowed quantitative analyses of three-dimensional vascular networks in all three models. These analyses revealed significant and previously unrecognized alterations of preglomerular arteries: a reduction in vessel diameter, a prominent reduction in vessel branching, and increased vessel tortuosity. In summary, using ?CT methodology, we revealed insights into macro-to-microvascular alterations in progressive renal disease and provide a platform that may serve as the basis to evaluate vascular therapeutics in renal disease. PMID:26195818

  1. Quantitative Micro-Computed Tomography Imaging of Vascular Dysfunction in Progressive Kidney Diseases.

    PubMed

    Ehling, Josef; Bábíčková, Janka; Gremse, Felix; Klinkhammer, Barbara M; Baetke, Sarah; Knuechel, Ruth; Kiessling, Fabian; Floege, Jürgen; Lammers, Twan; Boor, Peter

    2016-02-01

    Progressive kidney diseases and renal fibrosis are associated with endothelial injury and capillary rarefaction. However, our understanding of these processes has been hampered by the lack of tools enabling the quantitative and noninvasive monitoring of vessel functionality. Here, we used micro-computed tomography (µCT) for anatomical and functional imaging of vascular alterations in three murine models with distinct mechanisms of progressive kidney injury: ischemia-reperfusion (I/R, days 1-56), unilateral ureteral obstruction (UUO, days 1-10), and Alport mice (6-8 weeks old). Contrast-enhanced in vivo µCT enabled robust, noninvasive, and longitudinal monitoring of vessel functionality and revealed a progressive decline of the renal relative blood volume in all models. This reduction ranged from -20% in early disease stages to -61% in late disease stages and preceded fibrosis. Upon Microfil perfusion, high-resolution ex vivo µCT allowed quantitative analyses of three-dimensional vascular networks in all three models. These analyses revealed significant and previously unrecognized alterations of preglomerular arteries: a reduction in vessel diameter, a prominent reduction in vessel branching, and increased vessel tortuosity. In summary, using µCT methodology, we revealed insights into macro-to-microvascular alterations in progressive renal disease and provide a platform that may serve as the basis to evaluate vascular therapeutics in renal disease. PMID:26195818

  2. 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

  3. Progress and problems in the biology, diagnostics, and therapeutics of prion diseases

    PubMed Central

    Aguzzi, Adriano; Heikenwalder, Mathias; Miele, Gino

    2004-01-01

    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

  4. Tubular Deficiency of von Hippel-Lindau Attenuates Renal Disease Progression in Anti-GBM Glomerulonephritis

    PubMed Central

    Theilig, Franziska; Enke, Anne Kathrin; Scolari, Brigitte; Polzin, Danny; Bachmann, Sebastian; Koesters, Robert

    2011-01-01

    In many kidney diseases, the original insult primarily involves the glomerulus and may then pass onto the tubulointerstitium. Several hypotheses link glomerular disease to tubular injury; perhaps the foremost hypothesis involves chronic tubular hypoxia. The reported effects of hypoxia and consecutive stabilization of hypoxia-inducible factors (HIFs), however, are controversial. Hypoxia induces interstitial fibrosis but also has beneficial effects on renal disease progression when HIF is activated pharmacologically. To analyze the impact of HIF on tubulointerstitial disease development in primary glomerular disease, transgenic von Hippel Lindau (VHL)-knockout mice were generated and null expression was induced before the onset of autoimmune IgG-mediated antiglomerular basement membrane glomerulonephritis (GN). Tubular VHL knockout and, thus, local HIF-? stabilization increased renal production of vascular endothelial growth factor, tumor growth factor?1, and platelet-derived growth factor-B, resulting in augmented formation of capillaries and interstitial matrix, and conversion of fibroblasts to myofibroblasts. Within the glomerular disease, VHL knockout reduced the glomerular damage and attenuated tubulointerstitial injury. Likewise, proteinuria, plasma urea concentration, and tubulointerstitial matrix were decreased in VHL knockout with GN. These findings shown that tubular HIF-? stabilization in glomerular disease is beneficial for disease outcome. In comparison with VHL knockout alone, GN is a much stronger activator of fibrosis such that stimuli other than hypoxia may be considered important for renal disease progression. PMID:21925138

  5. 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

  6. 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

  7. p-Cresyl sulphate and indoxyl sulphate predict progression of chronic kidney disease

    PubMed Central

    Wu, I-Wen; Hsu, Kuang-Hung; Lee, Chin-Chan; Sun, Chiao-Yin; Hsu, Heng-Jung; Tsai, Chi-Jen; Tzen, Chin-Yuan; Wang, Yen-Chih; Lin, Ching-Yuang; Wu, Mai-Szu

    2011-01-01

    Background. Indoxyl sulphate (IS) and p-cresyl sulphate (PCS) are uraemic toxins that have similar protein binding, dialytic clearance and proinflammatory features. However, only a few prospective studies have evaluated possible associations between these two retained solutes and renal disease progression in chronic kidney disease (CKD) patients. Methods. This prospective observational study evaluated independent associations between serum total IS and PCS with renal progression in a selected cohort of patients having different stages of CKD. Baseline PCS and IS were correlated with renal progression [defined as decrements in estimated glomerular filtration rate (eGFR) >?50% from baseline or progression to end-stage renal disease (ESRD)] and death during a follow-up period of 24months. Results. Of 268 patients, 35 (13.1%) had renal progression and 14 (5.2%) died after a mean follow-up of 21 3months. Univariate Cox regression analysis followed by multivariate analysis showed that high-serum PCS levels were associated with renal progression and all-cause mortality independent of age, gender, diabetes status, albumin levels, serum IS, serum creatinine, Ca P product, intact parathyroid hormone, haemoglobin or high-sensitivity C-reactive protein level. Serum IS was only associated with renal progression; however, the predictive power of serum IS was weakened when serum PCS was also present in the analytical model. Conclusions. In addition to traditional and uraemia-related risk factors such as renal function, serum IS and PCS levels may help in predicting the risk of renal progression in patients having different stages of CKD. PMID:20884620

  8. 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.

  9. Failure to thrive, interstitial lung disease, and progressive digital necrosis with onset in infancy.

    PubMed

    Chia, Justin; Eroglu, Fehime Kara; zen, Seza; Orhan, Dicle; Montealegre-Sanchez, Gina; de Jesus, Adriana A; Goldbach-Mansky, Raphaela; Cowen, Edward W

    2016-01-01

    Key teaching points SAVI is a recently described interferonopathy resulting from constitutive action of STING and up-regulation of IFN-? signaling. SAVI is characterized by facial erythema with telangiectasia, acral/cold-sensitive tissue ulceration and amputations, and interstitial lung disease. It has overlapping features with Aicardi-Goutires syndrome and familial chilblain lupus. Traditional immunosuppressive medications and biologic therapies appear to be of limited benefit, but JAK inhibitors may impact disease progression. PMID:26584874

  10. Early HLA-B*57-Restricted CD8+ T Lymphocyte Responses Predict HIV-1 Disease Progression

    PubMed Central

    Ibarrondo, F. Javier; Sugar, Catherine A.; Hausner, Mary Ann; Shih, Roger; Ng, Hwee L.; Detels, Roger; Margolick, Joseph B.; Rinaldo, Charles R.; Phair, John; Jacobson, Lisa P.; Yang, Otto O.

    2012-01-01

    Although HLA-B*57 (B57) is associated with slow progression to disease following HIV-1 infection, B57 heterozygotes display a wide spectrum of outcomes, including rapid progression, viremic slow progression, and elite control. Efforts to identify differences between B57-positive (B57+) slow progressors and B57+ rapid progressors have largely focused on cytotoxic T lymphocyte (CTL) phenotypes and specificities during chronic stages of infection. Although CTL responses in the early months of infection are likely to be the most important for the long-term rate of HIV-1 disease progression, few data on the early CTL responses of eventual slow progressors have been available. Utilizing the Multicenter AIDS Cohort Study (MACS), we retrospectively examined the early HIV-1-specific CTL responses of 14 B57+ individuals whose time to development of disease ranged from 3.5 years to longer than 25 years after infection. In general, a greater breadth of targeting of epitopes from structural proteins, especially Gag, as well as of highly conserved epitopes from any HIV-1 protein, correlated with longer times until disease. The single elite controller in the cohort was an outlier on several correlations of CTL targeting and time until disease, consistent with reports that elite control is typically not achieved solely by protective HLA-mediated CTLs. When targeting of individual epitopes was analyzed, we found that early CTL responses to the IW9 (ISPRTLNAW) epitope of Gag, while generally subdominant, correlated with delayed progression to disease. This is the first study to identify early CTL responses to IW9 as a correlate of protection in persons with HLA-B*57. PMID:22811521

  11. [Exploration of pathogenesis and therapy development for ALS employing sporadic disease model].

    PubMed

    Tanaka, Fumiaki; Waza, Masahiro; Yamamoto, Masahiko; Sobue, Gen

    2009-11-01

    The mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis (ALS) remain poorly understood even now 140 years after the first description of the disease in 1869 by Jean-Martin Charcot. Exploration of pathogenesis of ALS has long been dependent on transgenic animal models with mutations in the copper/ zinc superoxide dismutase 1 (SOD1) gene. However, the lack of therapeutic concordance between these animal models and human sporadic ALS patients is troubling. The reasons include that there might exist the differences of pathogenesis between sporadic and familial ALS and/or the disease models for sporadic ALS have not been established. We have been working on screening motor neuron-specific genes critical for pathogenesis of sporadic ALS using cDNA microarray and laser capture microdissection techniques. Many of the resultant genes are of intense interest and may provide a powerful tool for determining the molecular mechanisms of sporadic ALS. In particular, dynactin-1, a major component of dynein/dynactin complex and several cell cycle-related genes are the targets of our research. Development and analysis of new disease models for sporadic ALS based on these genes will open an avenue for novel therapeutics. PMID:20030217

  12. Iron homeostasis and progression to pulmonary tuberculosis disease among household contacts.

    PubMed

    Minchella, Peter A; Donkor, Simon; McDermid, Joann M; Sutherland, Jayne S

    2015-05-01

    Early identification of individuals at risk for progressing to active tuberculosis (TB) disease may limit new transmission and improve clinical outcomes. Evidence indicates altered iron homeostasis may identify those at greater risk of disease progression in HIV co-infection. We aimed to investigate iron homeostasis biomarkers as risk factors for progression to TB. Archived plasma samples were analyzed from household contacts of pulmonary TB index cases in The Gambia. Contacts were classified as asymptomatic non-progressors (n = 17) or TB-progressors (n = 10), which included two HIV-infected participants. Iron homeostasis (hemoglobin, ferritin, hepcidin, soluble transferrin receptor, transferrin) was assessed in all contacts at study recruitment. Plasma was collected a median of 910 days prior to TB diagnosis. Low transferrin around the time of known exposure to infectious TB was a disease progression risk factor among all TB-progressors (Poisson incidence rate ratio: 0.55; 95% CI: 0.35-0.89). Iron homeostasis also differed between early and delayed TB-progressors, with higher ferritin and hepcidin concentrations observed among early TB-progressors (mean ferritin 50.2 vs. 26.2 ng/ml; P = 0.027; mean hepcidin 37.7 vs. 5.6 ng/ml; P = 0.036). Iron homeostasis is associated with progression to TB among household contacts. Further studies are needed to elucidate mechanisms and determine the clinical utility of monitoring iron homeostasis biomarkers. PMID:25764944

  13. Association of apolipoprotein E with the progression of hepatitis B virus-related liver disease

    PubMed Central

    Shen, Yueshuang; li, Meng; Ye, Xiongwei; Bi, Qihua

    2015-01-01

    Hepatitis B virus (HBV) infection increases the risk of liver decompensation, cirrhosis and hepatocellular carcinoma (HCC). Apolipoprotein E (ApoE), one of the major cholesterol carriers, plays important role in the metabolism of lipoprotein and the regulation of immune response. The present study was aimed to explore whether the genetic variation in ApoE gene affected disease progression in HBV infected individuals. We collected sera samples from healthy volunteers (n=40), inactive HBV carriers (n=30), and patients with acute hepatitis (n=60), severe hepatitis (n=12), HBV-related liver cirrhosis (n=58) or primary HCC (n=39). We found that ApoE and interlukin-6 (IL-6) was progressively increased, while IL-2 was gradually decreased with the increasing grade of disease severity. Furthermore, high ApoE levels in HBV infected individuals were correlated with increased IL-6 and decreased IL-2 levels, indicating immune abnormalities in these patients. The frequency of E3/3 genotype was progressively increased from carriers group, hepatitis group to progressive group (cirrhosis and HCC). The serum levels of low-density lipoprotein cholesterol (LDL-C) differed among ApoE phenotypes, with E3/4, E4/4> E3/3>E2/3. Our study suggested that ApoE may have a role in the pathogenesis and progression of HBV-related liver disease and indicated the possible underlying mechanisms. PMID:26823800

  14. Direct Lineage Reprogramming Reveals Disease-Specific Phenotypes of Motor Neurons from Human ALS Patients.

    PubMed

    Liu, Meng-Lu; Zang, Tong; Zhang, Chun-Li

    2016-01-01

    Subtype-specific neurons obtained from adult humans will be critical to modeling neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). Here, we show that adult human skin fibroblasts can be directly and efficiently converted into highly pure motor neurons without passing through an induced pluripotent stem cell stage. These adult human induced motor neurons (hiMNs) exhibit the cytological and electrophysiological features of spinal motor neurons and form functional neuromuscular junctions (NMJs) with skeletal muscles. Importantly, hiMNs converted from ALS patient fibroblasts show disease-specific degeneration manifested through poor survival, soma shrinkage, hypoactivity, and an inability to form NMJs. A chemical screen revealed that the degenerative features of ALS hiMNs can be remarkably rescued by the small molecule kenpaullone. Taken together, our results define a direct and efficient strategy to obtain disease-relevant neuronal subtypes from adult human patients and reveal their promising value in disease modeling and drug identification. PMID:26725112

  15. Direct lineage reprogramming reveals disease-specific phonotypes of motor neurons from human ALS patients

    PubMed Central

    Liu, Meng-Lu; Zang, Tong; Zhang, Chun-Li

    2015-01-01

    SUMMARY Subtype-specific neurons obtained from adult humans will be critical to modeling neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). Here we show that adult human skin fibroblasts can be directly and efficiently converted into highly pure motor neurons without passing through an induced pluripotent stem cell stage. These adult human induced motor neurons (hiMNs) exhibit the cytological and electrophysiological features of spinal motor neurons and form functional neuromuscular junctions (NMJs) with skeletal muscles. Importantly, hiMNs converted from ALS-patient fibroblasts show disease-specific degeneration manifested through poor survival, soma shrinkage, hypoactivity, and an inability to form NMJs. A chemical screen revealed that the degenerative features of ALS-hiMNs can be remarkably rescued by the small molecule kenpaullone. Taken together, our results define a direct and efficient strategy to obtain disease-relevant neuronal subtypes from adult human patients and reveal their promising value in disease modeling and drug identification. PMID:26725112

  16. 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

  17. Prediction, progression, and outcomes of chronic kidney disease in older adults.

    PubMed

    Anderson, Sharon; Halter, Jeffrey B; Hazzard, William R; Himmelfarb, Jonathan; Horne, Frances McFarland; Kaysen, George A; Kusek, John W; Nayfield, Susan G; Schmader, Kenneth; Tian, Ying; Ashworth, John R; Clayton, Charles P; Parker, Ryan P; Tarver, Erika D; Woolard, Nancy F; High, Kevin P

    2009-06-01

    Chronic kidney disease is a large and growing problem among aging populations. Although progression of chronic kidney disease to end-stage renal disease (ESRD) is a costly and important clinical event with substantial morbidity, it appears less frequently in aging people compared with cardiovascular mortality. The measurement of kidney function and management of kidney disease in older individuals remain challenging, partly because the pathophysiologic mechanisms underlying age-related decline in kidney function, the interactions between age and other risk factors in renal progression, and the associations of chronic kidney disease with other comorbidities in older people are understudied and poorly understood. The Association of Specialty Professors, the American Society of Nephrology, the American Geriatrics Society, the National Institute on Aging, and the National Institute of Diabetes and Digestive and Kidney Diseases held a workshop, summarized in this article, to review what is known about chronic kidney disease, identify research gaps and resources available to address them, and identify priority areas for future research. Answers to emerging research questions will support the integration of geriatrics and nephrology and thus improve care for older patients at risk for chronic kidney disease. PMID:19470680

  18. Tnni3k modifies disease progression in murine models of cardiomyopathy.

    PubMed

    Wheeler, Ferrin C; Tang, Hao; Marks, Odessa A; Hadnott, Tracy N; Chu, Pei-Lun; Mao, Lan; Rockman, Howard A; Marchuk, Douglas A

    2009-09-01

    The Calsequestrin (Csq) transgenic mouse model of cardiomyopathy exhibits wide variation in phenotypic progression dependent on genetic background. Seven heart failure modifier (Hrtfm) loci modify disease progression and outcome. Here we report Tnni3k (cardiac Troponin I-interacting kinase) as the gene underlying Hrtfm2. Strains with the more susceptible phenotype exhibit high transcript levels while less susceptible strains show dramatically reduced transcript levels. This decrease is caused by an intronic SNP in low-transcript strains that activates a cryptic splice site leading to a frameshifted transcript, followed by nonsense-mediated decay of message and an absence of detectable protein. A transgenic animal overexpressing human TNNI3K alone exhibits no cardiac phenotype. However, TNNI3K/Csq double transgenics display severely impaired systolic function and reduced survival, indicating that TNNI3K expression modifies disease progression. TNNI3K expression also accelerates disease progression in a pressure-overload model of heart failure. These combined data demonstrate that Tnni3k plays a critical role in the modulation of different forms of heart disease, and this protein may provide a novel target for therapeutic intervention. PMID:19763165

  19. Non-monotonic reorganization of brain networks with Alzheimer's disease progression

    PubMed Central

    Kim, HyoungKyu; Yoo, Kwangsun; Na, Duk L.; Seo, Sang Won; Jeong, Jaeseung; Jeong, Yong

    2015-01-01

    Background: Identification of stage-specific changes in brain network of patients with Alzheimer's disease (AD) is critical for rationally designed therapeutics that delays the progression of the disease. However, pathological neural processes and their resulting changes in brain network topology with disease progression are not clearly known. Methods: The current study was designed to investigate the alterations in network topology of resting state fMRI among patients in three different clinical dementia rating (CDR) groups (i.e., CDR = 0.5, 1, 2) and amnestic mild cognitive impairment (aMCI) and age-matched healthy subject groups. We constructed density networks from these 5 groups and analyzed their network properties using graph theoretical measures. Results: The topological properties of AD brain networks differed in a non-monotonic, stage-specific manner. Interestingly, local and global efficiency and betweenness of the network were rather higher in the aMCI and AD (CDR 1) groups than those of prior stage groups. The number, location, and structure of rich-clubs changed dynamically as the disease progressed. Conclusions: The alterations in network topology of the brain are quite dynamic with AD progression, and these dynamic changes in network patterns should be considered meticulously for efficient therapeutic interventions of AD. PMID:26106325

  20. Tnni3k Modifies Disease Progression in Murine Models of Cardiomyopathy

    PubMed Central

    Wheeler, Ferrin C.; Tang, Hao; Marks, Odessa A.; Hadnott, Tracy N.; Chu, Pei-Lun; Mao, Lan; Rockman, Howard A.; Marchuk, Douglas A.

    2009-01-01

    The Calsequestrin (Csq) transgenic mouse model of cardiomyopathy exhibits wide variation in phenotypic progression dependent on genetic background. Seven heart failure modifier (Hrtfm) loci modify disease progression and outcome. Here we report Tnni3k (cardiac Troponin I-interacting kinase) as the gene underlying Hrtfm2. Strains with the more susceptible phenotype exhibit high transcript levels while less susceptible strains show dramatically reduced transcript levels. This decrease is caused by an intronic SNP in low-transcript strains that activates a cryptic splice site leading to a frameshifted transcript, followed by nonsense-mediated decay of message and an absence of detectable protein. A transgenic animal overexpressing human TNNI3K alone exhibits no cardiac phenotype. However, TNNI3K/Csq double transgenics display severely impaired systolic function and reduced survival, indicating that TNNI3K expression modifies disease progression. TNNI3K expression also accelerates disease progression in a pressure-overload model of heart failure. These combined data demonstrate that Tnni3k plays a critical role in the modulation of different forms of heart disease, and this protein may provide a novel target for therapeutic intervention. PMID:19763165

  1. [Research progress on the efficacy, metabolism and bioavailability of mebendazole in hydatid disease].

    PubMed

    Liu, Cong-Shan; Zhang, Hao-Bing

    2009-12-01

    Mebendazole is currently used in the treatment of hydatid disease. Its poor absorption from the gastrointestinal tract and low bioavailability aroused further research on new formulations of mebendazole to increase the bioavailability and improve the therapeutic efficacy. This review summarizes the recent research progress. PMID:20232637

  2. 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)…

  3. 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…

  4. 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-nave 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. PMID:25413642

  5. 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

  6. 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

  7. 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)

  8. 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

  9. 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.

  10. Unveiling Clusters of RNA Transcript Pairs Associated with Markers of Alzheimer’s Disease Progression

    PubMed Central

    Arefin, Ahmed Shamsul; Mathieson, Luke; Johnstone, Daniel; Berretta, Regina; Moscato, Pablo

    2012-01-01

    Background One primary goal of transcriptomic studies is identifying gene expression patterns correlating with disease progression. This is usually achieved by considering transcripts that independently pass an arbitrary threshold (e.g. p<0.05). In diseases involving severe perturbations of multiple molecular systems, such as Alzheimer’s disease (AD), this univariate approach often results in a large list of seemingly unrelated transcripts. We utilised a powerful multivariate clustering approach to identify clusters of RNA biomarkers strongly associated with markers of AD progression. We discuss the value of considering pairs of transcripts which, in contrast to individual transcripts, helps avoid natural human transcriptome variation that can overshadow disease-related changes. Methodology/Principal Findings We re-analysed a dataset of hippocampal transcript levels in nine controls and 22 patients with varying degrees of AD. A large-scale clustering approach determined groups of transcript probe sets that correlate strongly with measures of AD progression, including both clinical and neuropathological measures and quantifiers of the characteristic transcriptome shift from control to severe AD. This enabled identification of restricted groups of highly correlated probe sets from an initial list of 1,372 previously published by our group. We repeated this analysis on an expanded dataset that included all pair-wise combinations of the 1,372 probe sets. As clustering of this massive dataset is unfeasible using standard computational tools, we adapted and re-implemented a clustering algorithm that uses external memory algorithmic approach. This identified various pairs that strongly correlated with markers of AD progression and highlighted important biological pathways potentially involved in AD pathogenesis. Conclusions/Significance Our analyses demonstrate that, although there exists a relatively large molecular signature of AD progression, only a small number of transcripts recurrently cluster with different markers of AD progression. Furthermore, considering the relationship between two transcripts can highlight important biological relationships that are missed when considering either transcript in isolation. PMID:23029078

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

    PubMed Central

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

    2014-01-01

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

  12. Recent progress in the discovery of small molecules for the treatment of amyotrophic lateral sclerosis (ALS)

    PubMed Central

    Limpert, Allison S; Mattmann, Margrith E

    2013-01-01

    Summary Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with few therapeutic options. While several gene mutations have been implicated in ALS, the exact cause of neuronal dysfunction is unknown and motor neurons of affected individuals display numerous cellular abnormalities. Ongoing efforts to develop novel ALS treatments involve the identification of small molecules targeting specific mechanisms of neuronal pathology, including glutamate excitotoxicity, mutant protein aggregation, endoplasmic reticulum (ER) stress, loss of trophic factors, oxidative stress, or neuroinflammation. Herein, we review recent advances in the discovery and preclinical characterization of lead compounds that may ultimately provide novel drugs to treat patients suffering from ALS. PMID:23766784

  13. Assembly and Interrogation of Alzheimers Disease Genetic Networks Reveal Novel Regulators of Progression

    PubMed Central

    Crary, John F.; Lefort, Roger; Qureshi, Yasir H.; Lefebvre, Celine; Califano, Andrea; Shelanski, Michael L.

    2015-01-01

    Alzheimers 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. PMID:25781952

  14. 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.

  15. Phenotypic transition of microglia into astrocyte-like cells associated with disease onset in a model of inherited ALS

    PubMed Central

    Trias, Emiliano; Daz-Amarilla, Pablo; Olivera-Bravo, Silvia; Isasi, Eugenia; Drechsel, Derek A.; Lopez, Nathan; Bradford, C. Samuel; Ireton, Kyle E.; Beckman, Joseph S.; Barbeito, Luis

    2013-01-01

    Microglia and reactive astrocytes accumulate in the spinal cord of rats expressing the Amyotrophic lateral sclerosis (ALS)-linked SOD1 G93A mutation. We previously reported that the rapid progression of paralysis in ALS rats is associated with the appearance of proliferative astrocyte-like cells that surround motor neurons. These cells, designated as Aberrant Astrocytes (AbA cells) because of their atypical astrocytic phenotype, exhibit high toxicity to motor neurons. However, the cellular origin of AbA cells remains unknown. Because AbA cells are labeled with the proliferation marker Ki67, we analyzed the phenotypic makers of proliferating glial cells that surround motor neurons by immunohistochemistry. The number of Ki67 +AbA cells sharply increased in symptomatic rats, displaying large cell bodies with processes embracing motor neurons. Most were co-labeled with astrocytic marker GFAP concurrently with the microglial markers Iba1 and CD163. Cultures of spinal cord prepared from symptomatic SOD1 G93A rats yielded large numbers of microglia expressing Iba1, CD11b, and CD68. Cells sorted for CD11b expression by flow cytometry transformed into AbA cells within two weeks. During these two weeks, the expression of microglial markers largely disappeared, while GFAP and S100? expression increased. The phenotypic transition to AbA cells was stimulated by forskolin. These findings provide evidence for a subpopulation of proliferating microglial cells in SOD1 G93A rats that undergo a phenotypic transition into AbA cells after onset of paralysis that may promote the fulminant disease progression. These cells could be a therapeutic target for slowing paralysis progression in ALS. PMID:24399933

  16. Transgenic over-expression of mammalian heparanase delays prion disease onset and progression.

    PubMed

    Kovalchuk Ben-Zaken, O; Nissan, I; Tzaban, S; Taraboulos, A; Zcharia, E; Matzger, S; Shafat, I; Vlodavsky, I; Tal, Y

    2015-08-28

    Cellular heparan sulfate (HS) has a dual role in scrapie pathogenesis; it is required for PrP(Sc) (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 PrP(Sc). Moreover, disease onset and progression were dramatically delayed in scrapie infected transgenic mice over-expressing heparanase. Together, our results provide direct invivo 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

  17. Huntington's disease biomarker progression profile identified by transcriptome sequencing in peripheral blood

    PubMed Central

    Mastrokolias, Anastasios; Ariyurek, Yavuz; Goeman, Jelle J; van Duijn, Erik; Roos, Raymund AC; van der Mast, Roos C; van Ommen, GertJan B; den Dunnen, Johan T; 't Hoen, Peter AC; van Roon-Mom, Willeke MC

    2015-01-01

    With several therapeutic approaches in development for Huntington's disease, there is a need for easily accessible biomarkers to monitor disease progression and therapy response. We performed next-generation sequencing-based transcriptome analysis of total RNA from peripheral blood of 91 mutation carriers (27 presymptomatic and, 64 symptomatic) and 33 controls. Transcriptome analysis by DeepSAGE identified 167 genes significantly associated with clinical total motor score in Huntington's disease patients. Relative to previous studies, this yielded novel genes and confirmed previously identified genes, such as H2AFY, an overlap in results that has proven difficult in the past. Pathway analysis showed enrichment of genes of the immune system and target genes of miRNAs, which are downregulated in Huntington's disease models. Using a highly parallelized microfluidics array chip (Fluidigm), we validated 12 of the top 20 significant genes in our discovery cohort and 7 in a second independent cohort. The five genes (PROK2, ZNF238, AQP9, CYSTM1 and ANXA3) that were validated independently in both cohorts present a candidate biomarker panel for stage determination and therapeutic readout in Huntington's disease. Finally we suggest a first empiric formula predicting total motor score from the expression levels of our biomarker panel. Our data support the view that peripheral blood is a useful source to identify biomarkers for Huntington's disease and monitor disease progression in future clinical trials. PMID:25626709

  18. 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. PMID:25730155

  19. Huntington's disease biomarker progression profile identified by transcriptome sequencing in peripheral blood.

    PubMed

    Mastrokolias, Anastasios; Ariyurek, Yavuz; Goeman, Jelle J; van Duijn, Erik; Roos, Raymund A C; van der Mast, Roos C; van Ommen, GertJan B; den Dunnen, Johan T; 't Hoen, Peter A C; van Roon-Mom, Willeke M C

    2015-10-01

    With several therapeutic approaches in development for Huntington's disease, there is a need for easily accessible biomarkers to monitor disease progression and therapy response. We performed next-generation sequencing-based transcriptome analysis of total RNA from peripheral blood of 91 mutation carriers (27 presymptomatic and, 64 symptomatic) and 33 controls. Transcriptome analysis by DeepSAGE identified 167 genes significantly associated with clinical total motor score in Huntington's disease patients. Relative to previous studies, this yielded novel genes and confirmed previously identified genes, such as H2AFY, an overlap in results that has proven difficult in the past. Pathway analysis showed enrichment of genes of the immune system and target genes of miRNAs, which are downregulated in Huntington's disease models. Using a highly parallelized microfluidics array chip (Fluidigm), we validated 12 of the top 20 significant genes in our discovery cohort and 7 in a second independent cohort. The five genes (PROK2, ZNF238, AQP9, CYSTM1 and ANXA3) that were validated independently in both cohorts present a candidate biomarker panel for stage determination and therapeutic readout in Huntington's disease. Finally we suggest a first empiric formula predicting total motor score from the expression levels of our biomarker panel. Our data support the view that peripheral blood is a useful source to identify biomarkers for Huntington's disease and monitor disease progression in future clinical trials. PMID:25626709

  20. Activation of Notch3 in Glomeruli Promotes the Development of Rapidly Progressive Renal Disease.

    PubMed

    El Machhour, Fala; Keuylian, Zela; Kavvadas, Panagiotis; Dussaule, Jean-Claude; Chatziantoniou, Christos

    2015-07-01

    Notch3 expression is found in the glomerular podocytes of patients with lupus nephritis or focal segmental GN but not in normal kidneys. Here, we show that activation of the Notch3 receptor in the glomeruli is a turning point inducing phenotypic changes in podocytes promoting renal inflammation and fibrosis and leading to disease progression. In a model of rapidly progressive GN, Notch3 expression was induced by several-fold in podocytes concurrently with disease progression. By contrast, mice lacking Notch3 expression were protected because they exhibited less proteinuria, uremia, and inflammatory infiltration. Podocyte outgrowth from glomeruli isolated from wild-type mice during the early phase of the disease was higher than outgrowth from glomeruli of mice lacking Notch3. In vitro studies confirmed that podocytes expressing active Notch3 reorganize their cytoskeleton toward a proliferative/migratory and inflammatory phenotype. We then administered antisense oligodeoxynucleotides targeting Notch3 or scramble control oligodeoxynucleotides in wild-type mice concomitant to disease induction. Both groups developed chronic renal disease, but mice injected with Notch3 antisense had lower values of plasma urea and proteinuria and inflammatory infiltration. The improvement of renal function was accompanied by fewer deposits of fibrin within the glomeruli and by decreased peritubular inflammation. Finally, abnormal Notch3 staining was observed in biopsy samples of patients with crescentic GN. These results demonstrate that abnormal activation of Notch3 may be involved in the progression of renal disease by promoting migratory and proinflammatory pathways. Inhibiting Notch3 activation could be a novel, promising approach to treat GN. PMID:25421557

  1. C57BL/6J congenic Prp-TDP43A315T mice develop progressive neurodegeneration in the myenteric plexus of the colon without exhibiting key features of ALS.

    PubMed

    Hatzipetros, Theo; Bogdanik, Laurent P; Tassinari, Valerie R; Kidd, Joshua D; Moreno, Andy J; Davis, Crystal; Osborne, Melissa; Austin, Andrew; Vieira, Fernando G; Lutz, Cathleen; Perrin, Steve

    2014-10-10

    ALS therapy development has been hindered by the lack of rodent animal models. The discovery of TDP-43, a transcription factor that accumulates in the cytoplasm of motor neurons (MNs) in most cases of ALS, prompted attempts to develop TDP-43-based models of the disease. The current study sought to examine, in extensive detail, the emerging disease phenotype of a transgenic mouse model that overexpresses a mutant human TDP-43 (hTDP-43) gene under mouse prion promoter control. Careful attention was given to ALS-like characteristics to determine the appropriateness of this model for testing therapies for ALS. In light of previous reports that gastrointestinal (GI) dysfunction is responsible for early death in these mice, gut immunohistochemistry (IHC) and longitudinal gut motility assays were used to identify the onset and the progression of these defects. IHC studies revealed that site-specific overexpression of the hTDP-43 transgene in colonic myenteric plexes resulted in progressive neurodegeneration in this region. This change was associated with progressively reduced GI motility, culminating in frank stasis that was primarily responsible for decreasing longevity in these mice. The disease phenotype was gender- and genetic background-dependent, with congenic C57BL/6J male mice exhibiting the most aggressive form of the disease. Spinal cord IHC revealed ubiquitin-positive inclusions, but not TDP-43 aggregates, in the cytoplasm of MNs. Neither gender exhibited compelling ALS-like neuromuscular deficits, irrespective of age. While this model may be useful for studying GI tract neurodegeneration, in its present state it does not display a phenotype suitable for testing ALS therapeutics. PMID:24141148

  2. 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. PMID:25713992

  3. The Relationship between Uric Acid Levels and Huntingtons Disease Progression

    PubMed Central

    Auinger, Peggy; Kieburtz, Karl; McDermott, Michael P.

    2009-01-01

    Uric acid (UA) may be associated with the progression of Parkinsons disease and related neurodegenerative conditions; however, its association with Huntingtons 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 Huntingtons 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

  4. Inflammation in sputum relates to progression of disease in subjects with COPD: a prospective descriptive study

    PubMed Central

    Parr, David G; White, Andrew J; Bayley, Darren L; Guest, Peter J; Stockley, Robert A

    2006-01-01

    Background Inflammation is considered to be of primary pathogenic importance in COPD but the evidence on which current understanding is based does not distinguish between cause and effect, and no single mechanism can account for the complex pathology. We performed a prospective longitudinal study of subjects with COPD that related markers of sputum inflammation at baseline to subsequent disease progression. Methods A cohort of 56 patients with chronic bronchitis was characterized in the stable state at baseline and after an interval of four years, using physiological measures and CT densitometry. Sputum markers of airway inflammation were quantified at baseline from spontaneously produced sputum in a sub-group (n = 38), and inflammation severity was related to subsequent disease progression. Results Physiological and CT measures indicated disease progression in the whole group. In the sub-group, sputum myeloperoxidase correlated with decline in FEV1 (rs = -0.344, p = 0.019, n = 37). LTB4 and albumin leakage correlated with TLCO decline (rs = -0.310, p = 0.033, rs = -0.401, p = 0.008, respectively, n = 35) and IL-8 correlated with progression of lung densitometric indices (rs = -0.464, p = 0.005, n = 38). Conclusion The data support a principal causative role for neutrophilic inflammation in the pathogenesis of COPD and suggest that the measurement of sputum inflammatory markers may have a predictive role in clinical practice. PMID:17112387

  5. High resolution radiographic and fine immunologic definition of TB disease progression in the rhesus macaque.

    PubMed

    Lewinsohn, David M; Tydeman, Ian S; Frieder, Marisa; Grotzke, Jeff E; Lines, Rebecca A; Ahmed, Sheela; Prongay, Kamm D; Primack, Steven L; Colgin, Lois M A; Lewis, Anne D; Lewinsohn, Deborah A

    2006-09-01

    Mycobacterium tuberculosis infection in non-human primates parallels human tuberculosis, and provides a valuable vaccine evaluation model. However, this model is limited by the availability of real-time, non-invasive information regarding disease progression. Consequently, we have combined computed tomography scanning with enumeration of antigen-specific T cell responses. Four rhesus monkeys were infected with M. tuberculosis strain H37Rv (1000 cfu) in the right lower lobe via a bronchoscope. All uniformly developed progressive tuberculosis, and required euthanasia at 12 weeks. Computed tomography scanning provided detailed real-time imaging of disease progression. At necropsy, computed tomography and pathohistologic findings were tightly correlated, and characteristic of human disease. Immunologic monitoring demonstrated progressive evolution of high frequency M. tuberculosis-specific CD4(+) and CD8(+) T cell responses. Peripheral blood effector cell frequencies were similar to those observed in tissues. In summary, computed tomography scanning in conjunction with immunologic monitoring provides a non-invasive, accurate, and rapid assessment of tuberculosis in the non-human primate. PMID:16952476

  6. 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 are observed in NASH. ► Hepatic bile acid synthesis shifts toward the alternative pathway in NASH.

  7. CTSH regulates ?-cell function and disease progression in newly diagnosed type 1 diabetes patients

    PubMed Central

    Flyel, Tina; Brorsson, Caroline; Nielsen, Lotte B.; Miani, Michela; Bang-Berthelsen, Claus Heiner; Friedrichsen, Martin; Overgaard, Anne Julie; Berchtold, Lukas A.; Wiberg, Anna; Poulsen, Pernille; Hansen, Lars; Rosinger, Silke; Boehm, Bernhard O.; Ram, Ramesh; Nguyen, Quang; Mehta, Munish; Morahan, Grant; Concannon, Patrick; Bergholdt, Regine; Nielsen, Jens H.; Reinheckel, Thomas; von Herrath, Matthias; Vaag, Allan; Eizirik, Decio Laks; Mortensen, Henrik B.; Strling, Joachim; Pociot, Flemming

    2014-01-01

    Over 40 susceptibility loci have been identified for type 1 diabetes (T1D). Little is known about how these variants modify disease risk and progression. Here, we combined in vitro and in vivo experiments with clinical studies to determine how genetic variation of the candidate gene cathepsin H (CTSH) affects disease mechanisms and progression in T1D. The T allele of rs3825932 was associated with lower CTSH expression in human lymphoblastoid cell lines and pancreatic tissue. Proinflammatory cytokines decreased the expression of CTSH in human islets and primary rat ?-cells, and overexpression of CTSH protected insulin-secreting cells against cytokine-induced apoptosis. Mechanistic studies indicated that CTSH exerts its antiapoptotic effects through decreased JNK and p38 signaling and reduced expression of the proapoptotic factors Bim, DP5, and c-Myc. CTSH overexpression also up-regulated Ins2 expression and increased insulin secretion. Additionally, islets from Ctsh?/? mice contained less insulin than islets from WT mice. Importantly, the TT genotype was associated with higher daily insulin dose and faster disease progression in newly diagnosed T1D patients, indicating agreement between the experimental and clinical data. In line with these observations, healthy human subjects carrying the T allele have lower ?-cell function, which was evaluated by glucose tolerance testing. The data provide strong evidence that CTSH is an important regulator of ?-cell function during progression of T1D and reinforce the concept that candidate genes for T1D may affect disease progression by modulating survival and function of pancreatic ?-cells, the target cells of the autoimmune assault. PMID:24982147

  8. CTSH regulates ?-cell function and disease progression in newly diagnosed type 1 diabetes patients.

    PubMed

    Flyel, Tina; Brorsson, Caroline; Nielsen, Lotte B; Miani, Michela; Bang-Berthelsen, Claus Heiner; Friedrichsen, Martin; Overgaard, Anne Julie; Berchtold, Lukas A; Wiberg, Anna; Poulsen, Pernille; Hansen, Lars; Rosinger, Silke; Boehm, Bernhard O; Ram, Ramesh; Nguyen, Quang; Mehta, Munish; Morahan, Grant; Concannon, Patrick; Bergholdt, Regine; Nielsen, Jens H; Reinheckel, Thomas; von Herrath, Matthias; Vaag, Allan; Eizirik, Decio Laks; Mortensen, Henrik B; Strling, Joachim; Pociot, Flemming

    2014-07-15

    Over 40 susceptibility loci have been identified for type 1 diabetes (T1D). Little is known about how these variants modify disease risk and progression. Here, we combined in vitro and in vivo experiments with clinical studies to determine how genetic variation of the candidate gene cathepsin H (CTSH) affects disease mechanisms and progression in T1D. The T allele of rs3825932 was associated with lower CTSH expression in human lymphoblastoid cell lines and pancreatic tissue. Proinflammatory cytokines decreased the expression of CTSH in human islets and primary rat ?-cells, and overexpression of CTSH protected insulin-secreting cells against cytokine-induced apoptosis. Mechanistic studies indicated that CTSH exerts its antiapoptotic effects through decreased JNK and p38 signaling and reduced expression of the proapoptotic factors Bim, DP5, and c-Myc. CTSH overexpression also up-regulated Ins2 expression and increased insulin secretion. Additionally, islets from Ctsh(-/-) mice contained less insulin than islets from WT mice. Importantly, the TT genotype was associated with higher daily insulin dose and faster disease progression in newly diagnosed T1D patients, indicating agreement between the experimental and clinical data. In line with these observations, healthy human subjects carrying the T allele have lower ?-cell function, which was evaluated by glucose tolerance testing. The data provide strong evidence that CTSH is an important regulator of ?-cell function during progression of T1D and reinforce the concept that candidate genes for T1D may affect disease progression by modulating survival and function of pancreatic ?-cells, the target cells of the autoimmune assault. PMID:24982147

  9. A case of biopsy-proven chronic kidney disease on progression from acute phosphate nephropathy

    PubMed Central

    Joo, Woo Chul; Lee, Seoung Woo; Yang, Dong Hyuk; Han, Jee Young; Kim, Moon-Jae

    2012-01-01

    Acute phosphate nephropathy (APhN) following oral sodium phosphate solution (OSP) ingestion as a bowel purgative has been frequently reported. It was recently suggested that APhN could progress to chronic kidney disease (CKD) and a history of APhN might be considered as one of the causes of CKD. However, there are few reports proving APhN as a cause of CKD. Here, we report a case of APhN that progressed to CKD, as proven by renal biopsy.

  10. Baseline Kidney Function as Predictor of Mortality and Kidney Disease Progression in HIV-Positive Patients

    PubMed Central

    Ibrahim, Fowzia; Hamzah, Lisa; Jones, Rachael; Nitsch, Dorothea; Sabin, Caroline; Post, Frank A.

    2012-01-01

    Background Chronic kidney disease (CKD) is associated with increased all-cause mortality and kidney disease progression. Decreased kidney function at baseline may identify human immunodeficiency virus (HIV)-positive patients at increased risk of death and kidney disease progression. Study Design Observational cohort study. Setting & Participants 7 large HIV cohorts in the United Kingdom with kidney function data available for 20,132 patients. Predictor Baseline estimated glomerular filtration rate (eGFR). Outcomes Death and progression to stages 4-5 CKD (eGFR <30 mL/min/1.73 m2 for >3 months) in Cox proportional hazards and competing-risk regression models. Results Median age at baseline was 34 (25th-75th percentile, 30-40) years, median CD4 cell count was 350 (25th-75th percentile, 208-520) cells/?L, and median eGFR was 100 (25th-75th percentile, 87-112) mL/min/1.73 m2. Patients were followed up for a median of 5.3 (25th-75th percentile, 2.0-8.9) years, during which 1,820 died and 56 progressed to stages 4-5 CKD. A U-shaped relationship between baseline eGFR and mortality was observed. After adjustment for potential confounders, eGFRs <45 and >105 mL/min/1.73 m2 remained associated significantly with increased risk of death. Baseline eGFR <90 mL/min/1.73 m2 was associated with increased risk of kidney disease progression, with the highest incidence rates of stages 4-5 CKD (>3 events/100 person-years) observed in black patients with eGFR of 30-59 mL/min/1.73 m2 and those of white/other ethnicity with eGFR of 30-44 mL/min/1.73 m2. Limitations The relatively small numbers of patients with decreased eGFR at baseline and low rates of progression to stages 4-5 CKD and lack of data for diabetes, hypertension, and proteinuria. Conclusions Although stages 4-5 CKD were uncommon in this cohort, baseline eGFR allowed the identification of patients at increased risk of death and at greatest risk of kidney disease progression. PMID:22521282

  11. The CJD Neurological Status Scale: A New Tool for Evaluation of Disease Severity and Progression in Creutzfeldt - Jakob disease

    PubMed Central

    Cohen, Oren S.; Prohovnik, Isak; Korczyn, Amos D.; Ephraty, Lilach; Nitsan, Zeev; Tsabari, Rakefet; Appel, Shmuel; Rosenmann, Hanna; Kahana, Ester; Chapman, Joab

    2011-01-01

    Objectives To develop a scale sensitive for the neurological manifestations of Creutzfeldt-Jakob disease (CJD). Methods A 26-item CJD neurological status scale (CJD-NS) was created based on characteristic disease manifestations. Each sign was assigned to one of eight neurological systems to calculate a total scale score (TSS) and a system involvement score (SIS). The scale was administered to 37 CJD patients, 101 healthy first-degree relatives of the patients and 14 elderly patients with Parkinson's disease (PD). Results The mean TSS (SD) was significantly higher in patients with CJD (13.195.63) compared to normal controls (0.410.78) and PD patients (9.713.05). The mean SIS was also significantly different between the CJD (5.191.22) and PD (2.781.18 p<0.01) groups reflecting the disseminated nature of neurological involvement in CJD. Using a cutoff of TSS>4 yielded a sensitivity of 97% for CJD, and specificity of 100% against healthy controls. All individual items showed excellent specificity against healthy subjects, but sensitivity was highly variable. Repeat assessments of CJD patients over 3-9 months revealed a time-dependent increase of both the TSS and the SIS reflecting the scale's ability to track disease progression. Conclusions The CJD-NS scale is sensitive to neurological signs and their progression in CJD patients. PMID:21303352

  12. Hypothesis: Chronic Progressive Nephropathy in Rodents as a Disease Caused by an Expanding Somatic Mutant Clone.

    PubMed

    Manskikh, V N

    2015-05-01

    Chronic progressive nephropathy is a common noninfectious disease in aging (mice, rats) and non-aging (naked mole rat) rodents, sometimes resulting in death. The etiology and pathogenesis of the disease remain mysterious. For instance, it remains unclear what is the immediate cause of the disease and where exactly in the kidneys, glomerular or tubulointerstitial compartment, do primary and secondary changes occur. Here, I propose a potential scenario for development of progressive nephropathy that is based on an assumption that the disease is caused by occurrence and spread of mutant cellular clones from tubular epithelium secreting proinflammatory and prosclerotic cytokines. The hypothesis considers some features of the disease that have never been discussed earlier. According to the proposed concept, a clone of mutant cells secretes cytokines inducing chronic inflammation, proliferation of fibroblasts, and active collagen production that eventually results in sclerosis and thickening of tubular basement membranes. Sclerosis of interstitium and thickening of tubular basement membranes cause narrowing of some parts of the nephron, especially collecting ducts, which hinders passage of the urine, elevates tubular hydrostatic pressure, and impairs filtration and reabsorption in the kidneys. High hydrostatic pressure and reabsorption-induced elevated concentration of macromolecular substances in the primary urine result in development of large cysts and glomerular hyalinosis followed by renal failure. Based on this, it might be concluded that chronic progressive nephropathy in rodents represents a special type of tubulointerstitial dysplasia (or "non-tumorous neoplasia") in kidneys with secondary glomerular disorder at late stage of the disease. The concept for development of the disease proposed here may be of special importance from the viewpoint of toxicological pathology and gerontology, particularly for analysis of pathological features resulting in death of non-aging animals (naked mole rats). PMID:26071776

  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. PMID:15855643

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

    PubMed

    Popp, Julius; Wolfsgruber, Steffen; Heuser, Isabella; Peters, Oliver; Hll, Michael; Schrder, Johannes; Mller, Hans-Jrgen; Lewczuk, Piotr; Schneider, Anja; Jahn, Holger; Luckhaus, Christian; Perneczky, Robert; Frlich, Lutz; Wagner, Michael; Maier, Wolfgang; Wiltfang, Jens; Kornhuber, Johannes; Jessen, Frank

    2015-02-01

    Increased peripheral and central nervous system cortisol levels have been reported in Alzheimer's disease (AD) and may reflect dysfunction of cerebral components of the hypothalamic-pituitary-adrenal (HPA) axis. However, brain exposure to high cortisol concentrations may also accelerate disease progression and cognitive decline. The objectives of this study were to investigate whether HPA-axis dysregulation occurs at early clinical stages of AD and whether plasma and CSF cortisol levels are associated with clinical disease progression. Morning plasma and CSF cortisol concentrations were obtained from the subjects with AD dementia, mild cognitive impairment of AD type (MCI-AD), MCI of other type (MCI-O), and controls with normal cognition included in a multicenter study from the German Dementia Competence Network. A clinical and neuropsychological follow-up was performed in a subgroup of participants with MCI-AD, MCI-O, and AD dementia. CSF cortisol concentrations were increased in the subjects with AD dementia or MCI-AD compared with subjects with MCI-O or normal cognition. After controlling for possible confounders including CSF measures of amyloid beta1-42 and total tau, higher baseline CSF cortisol levels were associated with faster clinical worsening and cognitive decline in MCI-AD. The findings suggest that HPA-axis dysregulation occurs at the MCI stage of AD and may accelerate disease progression and cognitive decline. PMID:25435336

  15. MAPPING THE PROGRESSION OF ATROPHY IN EARLY AND LATE ONSET ALZHEIMERS 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 Alzheimers 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

  16. Mapping the Progression of Atrophy in Early- and Late-Onset Alzheimer's Disease.

    PubMed

    Migliaccio, Raffaella; Agosta, Federica; Possin, Katherine L; Canu, Elisa; Filippi, Massimo; Rabinovici, Gil D; Rosen, Howard J; Miller, Bruce L; Gorno-Tempini, Maria Luisa

    2015-01-01

    The term early-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 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

  17. Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease

    PubMed Central

    Thambisetty, Madhav; Simmons, Andrew; Velayudhan, Latha; Hye, Abdul; Campbell, James; Zhang, Yi; Wahlund, Lars-Olof; Westman, Eric; Kinsey, Anna; Gentert, Andreas; Proitsi, Petra; Powell, John; Causevic, Mirsada; Killick, Richard; Lunnon, Katie; Lynham, Steven; Broadstock, Martin; Choudhry, Fahd; Howlett, David R.; Williams, Robert J.; Sharp, Sally I.; Mitchelmore, Cathy; Tunnard, Catherine; Leung, Rufina; Foy, Catherine; O'Brien, Darragh; Breen, Gerome; Furney, Simon; Ward, Malcolm; Kloszewska, Iwona; Mecocci, Patrizia; Soininen, Hilkka; Tsolaki, Magda; Vellas, Bruno; Hodges, Angela; Murphy, Declan; Parkins, Sue; Richardson, Jill; Resnick, Susan M.; Ferrucci, Luigi; Wong, Dean F.; Zhou, Yun; Muehlboeck, Sebastian; Evans, Alan; Francis, Paul T.; Spenger, Christian; Lovestone, Simon

    2010-01-01

    Context Blood-based analytes as indicators of pathological processes in Alzheimer's disease (AD). Objective Combined proteomic and neuroimaging approach to identify plasma proteins associated with AD pathology. Design Discovery-phase proteomic experiments to identify plasma proteins associated with correlates of AD pathology including evidence of atrophy using neuroimaging and more rapid clinical progression, followed by replication using quantitative immunoassay. Extension studies in older non-demented humans using 11C-PiB amyloid imaging and transgenic mice with amyloid pathology. Setting Multi-center European study, AddNeuroMed, and the Baltimore Longitudinal Study of Aging (BLSA) in United States. Participants AD patients, mild cognitive impairment (MCI) subjects and healthy controls with standardized clinical assessments and structural neuroimaging. Plasma samples from non-demented older BLSA participants with brain amyloid imaging by PET. Main outcome measures Association of plasma proteins with brain atrophy, disease severity and rate of clinical progression. Extension studies in man and transgenic mice tested association between plasma proteins and brain amyloid. Results Clusterin/apolipoprotein-J was associated with atrophy of the entorhinal cortex, baseline disease severity and rapid clinical progression in AD. Increased plasma concentration of clusterin was predictive of greater beta amyloid (A?) burden in the medial temporal lobe. Subjects with AD had increased clusterin mRNA in blood but there was no effect of SNPs in the gene encoding clusterin (CLU) with gene or protein expression. Finally, APP/PS1 transgenic mice showed increased plasma clusterin, age-dependent increase in brain clusterin and amyloid and clusterin co-localisation in plaques. Conclusions Clusterin/apolipoprotein-J is a known amyloid chaperone associated with Alzheimer's disease severity, pathology and progression. Increased plasma concentration of clusterin is also associated with greater burden of fibrillar A? in the brain. These results demonstrate an important role of clusterin in the pathogenesis of AD and suggest that alterations in amyloid chaperone proteins may be a biologically relevant peripheral signature of Alzheimer's disease. PMID:20603455

  18. A retrospective analysis of hand tapping as a longitudinal marker of disease progression in Huntingtons disease

    PubMed Central

    2014-01-01

    Background Current clinical assessments of motor function in Huntingtons Disease (HD) rely on subjective ratings such as the Unified Huntingtons Disease Rating scale (UHDRS). The ability to track disease progression using simple, objective, inexpensive, and robust measures would be beneficial. Methods One objective measure of motor performance is hand-tapping. Over the last 14years we have routinely collected, using a simple device, the number of taps made by the right and left hand over 30seconds in HD patients attending our NHS clinics. Results Here we report on a longitudinal cohort of 237 patients, which includes patients at all stages of the disease on a wide range of drug therapies. Hand tapping in these patients declines linearly at a rate of 5.1 taps per year (p?progressed at a faster rate of 0.45 fewer taps per year (CAG by time interaction: p?=?0.008; 95% CI?=?0.12 to 0.78 taps). In addition, for each unit decrease in Total Functional Capacity (TFC) within individuals, the number of taps decreased by 6.3 (95% CI?=?5.4 to 7.1, p?disease progression. As such, this simple motor task could be a useful tool by which to assess disease progression as well therapies designed to slow it down. PMID:24564568

  19. Disease progression subtype discovery from longitudinal EMR data with a majority of missing values and unknown initial time points

    PubMed Central

    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. PMID:25954377

  20. 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

  1. Progression of calcifications in breast arteries in women at high risk for coronary heart disease events

    PubMed Central

    Maas, A.H.E.M.; van der Schouw, Y.T.; Mali, W.P.Th.M.; van der Graaf, Y.

    2006-01-01

    Objective To study changes in breast artery calcifications (BAC) over time and its relation with coronary heart disease (CHD) risk factors. Methods Breast arterial calcifications were studied at baseline and after five years follow-up in 453 women participating in the Raloxifene Use for The Heart (RUTH) study. All mammograms were scored by two observers. With logistic regression analysis the independent effect of risk factors on the progression of BAC was evaluated. Results BAC was present in 94 of 453 (21%) women at baseline and in 116 of 453 (26%) women after 5.01.04 years. Progression of BAC was seen in 44 of 453 (10%) women. In 22 participants (5%) BAC was not present at baseline, while in 22 participants (5%) the severity of BAC merely changed from grade 1 to grade 2 calcification. Age was significantly associated with progression of BAC (OR 1.09, 95% CI 1.03 to 1.14). Multivariate regression analysis with adjustment for age and the duration of follow-up showed no association between CHD risk factors and the progression of BAC. Lipid-lowering drugs protected for progression (adjusted OR 0.5, 95% CI 0.22 to 0.98). The strongest determinant in the progression of BAC was BAC at baseline (adjusted OR 4.2, 95% CI 2.10 to 8.27). Conclusion Progression of BAC is not associated with CHD risk factors, but with increasing age and BAC at baseline. Lipid-lowering drugs protect against progression of BAC. PMID:25696661

  2. Amyloid β-Peptide (1–42)-Induced Oxidative Stress in Alzheimer Disease: Importance in Disease Pathogenesis and Progression

    PubMed Central

    Swomley, Aaron M.; Sultana, Rukhsana

    2013-01-01

    Abstract Significance: Alzheimer disease (AD) is an age-related neurodegenerative disease. AD is characterized by progressive cognitive impairment. One of the main histopathological hallmarks of AD brain is the presence of senile plaques (SPs) and another is elevated oxidative stress. The main component of SPs is amyloid beta-peptide (Aβ) that is derived from the proteolytic cleavage of amyloid precursor protein. Recent Advances: Recent studies are consistent with the notion that methionine present at 35 position of Aβ is critical to Aβ-induced oxidative stress and neurotoxicity. Further, we also discuss the signatures of oxidatively modified brain proteins, identified using redox proteomics approaches, during the progression of AD. Critical Issues: The exact relationships of the specifically oxidatively modified proteins in AD pathogenesis require additional investigation. Future Directions: Further studies are needed to address whether the therapies directed toward brain oxidative stress and oxidatively modified key brain proteins might help delay or prevent the progression of AD. Antioxid. Redox Signal. 19, 823–835. PMID:23249141

  3. Sialoadhesin promotes neuroinflammation-related disease progression in two mouse models of CLN disease.

    PubMed

    Groh, Janos; Ribechini, Eliana; Stadler, David; Schilling, Tim; Lutz, Manfred B; Martini, Rudolf

    2016-05-01

    CLN diseases are mostly fatal lysosomal storage diseases that lead to neurodegeneration in the CNS. We have previously shown that CD8+ T-lymphocytes contribute to axonal perturbation and neuron loss in the CNS of Ppt1(-/-) mice, a model of CLN1 disease. We now investigated the role of the inflammation-related cell adhesion molecule sialoadhesin (Sn) in Ppt1(-/-) and Cln3(-/-) mice, a model of the most frequent form, CLN3 disease. Microglia/macrophages in the CNS of both models showed an upregulation of Sn and markers for proinflammatory M1 polarization and antigen presentation. Sn+ microglia/macrophages associated with SMI32+ axonal spheroids and CD8+ T-lymphocytes. To analyze their pathogenic impact, we crossbred both models with Sn-deficient mice and scored axonal degeneration and neuronal integrity using immunohistochemistry, electron microscopy and optical coherence tomography. Degenerative alterations in the retinotectal pathway of Ppt1(-/-) Sn(-/-) and Cln3(-/-) Sn(-/-) mice were significantly reduced. Ppt1(-/-) Sn(-/-) mice also showed a substantially improved clinical phenotype and extended lifespan, attenuated numbers of M1-polarized microglia/macrophages and reduced expression levels of proinflammatory cytokines. This was accompanied by an increased frequency of CD8+CD122+ T-lymphocytes in the CNS of Ppt1(-/-) Sn(-/-) mice, the regulatory phenotype of which was demonstrated by impaired survival of CD8+CD122- effector T-lymphocytes in co-culture experiments. We show for the first time that increased Sn expression on microglia/macrophages contributes to neural perturbation in two distinct models of CLN disease. Our data also indicate that a rarely described CD8+CD122+ T-cell population can regulate the corresponding diseases. These studies provide insights into CLN pathogenesis and may guide in designing immuno-regulatory treatment strategies. GLIA 2016;64:792-809. PMID:26775238

  4. A shift from adaptive to innate immunity: a potential mechanism of disease progression in multiple sclerosis.

    PubMed

    Weiner, Howard L

    2008-03-01

    Multiple sclerosis is postulated to be a T cell-mediated autoimmune disease characterised by a relapsing-remitting stage followed by a secondary progressive phase. The relapsing remitting phase may involve waves of proinflammatory Th1 and Th17 cells that infiltrate the nervous system, provoking a clinical attack. The activity of these cells is modulated by other populations of regulatory T cells and the balance between the pro-inflammatory and regulatory T cells is critical for determining disease activity. Promoting the activity of regulatory cells is a potentially beneficial therapeutic strategy, and probably contributes to the action of glatiramer acetate. The progressive phase of multiple sclerosis is believed to be secondary to neurodegenerative changes triggered by inflammation. The status of the innate immune system and its relationship to the stages of multiple sclerosis has been poorly defined until recently. However, recent data suggest that these results demonstrate abnormalities of dendritic cell activation or maturation may underlie the transition to the progressive phase of the disease. Preventing this transition, perhaps by acting at the level of the innate immune system, is an important treatment goal. The identification of biomarkers to predict disease course and treatment response is a major challenge in multiple sclerosis research. Studies using antigen arrays have identified antibody patterns related to CNS antigens and heat-shock proteins that are associated with different disease stages and with response to therapy. In the future, such antibody repertoires could be used as biomarkers for the diagnosis and evaluation of patients with multiple sclerosis, for matching treatments to individual patients and, potentially, to identify healthy individuals at risk for this autoimmune disease. PMID:18317671

  5. Association Between Lung Microbiome and Disease Progression in IPF: A Prospective Cohort Study

    PubMed Central

    Han, MeiLan K.; Zhou, Yueren; Murray, Susan; Tayob, Nabihah; Noth, Imre; Lama, Vibha N.; Moore, Bethany B.; White, Eric S.; Flaherty, Kevin R.; Huffnagle, Gary B.; Martinez, Fernando J.

    2014-01-01

    Background The lung microbiomes contribution to IPF pathogenesisis unknown. Using COMET-IPF (Correlating Outcomes with biochemical Markers to Estimate Time-progression in Idiopathic Pulmonary Fibrosis), the goal of this study was to determine whether unique microbial signatures would associate with disease progression. Methods IPF subjects within four years of diagnosis aged 3580 were eligible for inclusion. Subjects were followed for up to a maximum of 80 weeks. This completed observational study is registered with ClinicalTrials.gov, number NCT01071707. Progression-free survival was defined as death, acute exacerbation, lung transplant, or decline in FVC of 10% or DLCO of 15%.DNA was isolated from 55 bronchoscopic alveolar lavage (BAL) samples. 454 pyrosequencing was used to assign operational taxonomic units (OTUs) based on a 3% sequence divergence. Adjusted Cox models identified OTUs significantly associated with progression-free survival at a p<010 level. These OTUs were then used in principal components (PC) analysis. The association between PCs and microbes with high factor loadings from the PC analysis and progression-free survival were examined via Cox regression analyses. Findings Mean FVC was 701% and mean DLCO 423 %predicted. Significant associations with disease progression were noted with increased % relative abundance of two OTUs identified by PC analysis, a Streptococcus OTU. (p<00009) and a Staphylococcus OTU(p=001). Strength of associations using PCs versus two OTUs alone was similar. Threshold analysis helped define a cut point for % relative abundance for each OTU associated with progression-free survival, >39% for the Streptococcus OTU, HR 1019 (95% CI 294, 3535; p=00002) and >18% for the Staphylococcus OTU, HR 506 (171, 1493; p=0003). Interpretation These preliminary data suggest IPF disease progression is associated with presence of specific members within the Staphylococcus and Streptococcus genera. PMID:24767767

  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. Effect of statin therapy on disease progression in pediatric ADPKD: Design and baseline characteristics of participants

    PubMed Central

    Cadnapaphornchai, Melissa A.; George, Diana M.; Masoumi, Amirali; McFann, Kim; Strain, John D.; Schrier, Robert W.

    2011-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney condition and is associated with important renal and cardiovascular manifestations in childhood. Renal cystic disease can be documented in some cases as early as in utero. Early intervention is critical if the long-term complications of this condition, including end-stage renal disease, are to be ameliorated. Here we describe our ongoing randomized double-blind placebo-controlled phase III clinical trial to assess the effect of pravastatin treatment on renal and cardiovascular disease progression in 107 children and young adults age 822 years with ADPKD who are receiving the angiotensin converting enzyme inhibitor lisinopril. Baseline demographic and laboratory data are provided. Results of this study could markedly impact the standard of care for evaluation and treatment of ADPKD in this population. PMID:21266204

  8. 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

  9. Role of levetiracetam in refractory seizures due to a rare progressive myoclonic epilepsy: Lafora body disease

    PubMed Central

    Hashmi, Mubashira; Saleem, Feroza; Mustafa, Muhammad Shahid; Sheerani, Mughis; Ehtesham, Zeeshan; Siddiqui, Khurram

    2010-01-01

    Lafora disease is one of the rare, most fatal progressive myoclonic epilepsies reported. We present a case of a teenager with intractable seizures and progressive mental decline, diagnosed as Lafora body disease on axillary skin biopsy. He was admitted with status epilepticus with refractory myoclonic and generalised tonic clonic seizures. Despite on maximum doses of multiple antiepileptic drugs and infusions of propofol and midazolam, his seizures were refractory to all forms of medical therapy tried. Levetiracetam (LEV), a pyrrolidine derivative, was introduced; he showed a prompt response and was weaned off successfully from infusions of anticonvulsants and mechanical ventilation within 48 h of introduction of LEV, followed by an almost seizure-free status. PMID:22791845

  10. 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

  11. Evaluation of Vascular Disease Progression in Retinopathy of Prematurity using Static and Dynamic Retinal Images

    PubMed Central

    Myung, Jane S.; Gelman, Rony; Aaker, Grant D.; Radcliffe, Nathan M.; Chan, R.V. Paul; Chiang, Michael F.

    2011-01-01

    Purpose To measure accuracy and speed for detection of vascular progression in retinopathy of prematurity (ROP) from serial images. Two strategies are compared: static side-by-side presentation vs. dynamic flickering of superimposed image pairs. Design Prospective comparative study. Methods Fifteen de-identified, wide-angle retinal image pairs were taken from infants who eventually developed plus disease. Image pairs representing vascular disease progression were taken ?1 week apart, and control images without progression were taken on same day. Dynamic flickering pairs were created by digital image registration. Ten experts independently reviewed each image pair on a secure website using both strategies, and were asked to identify progression or state that images were identical. Accuracy and speed were measured, using examination date and ophthalmoscopic findings as a reference standard. Results Using static images, experts were accurate in a mean (%) standard deviation (SD) of 11.4/15 (76%) 1.7 image pairs. Using dynamic flickering images, experts were accurate in a mean (%) SD of 11.3/15 (75%) 1.7 image pairs. There was no significant difference in accuracy between these strategies (p=0.420). Diagnostic speed was faster using dynamic flickering (24.78.3 seconds) versus static side-by-side images (40.318.3 seconds) (p=0.002). Experts reported higher confidence when interpreting dynamic flickering images (p=0.001). Conclusions Retinal imaging provides objective documentation of vascular appearance, with potentially improved ability to recognize ROP progression compared to standard ophthalmoscopy. Speed of identifying vascular progression was faster by review of dynamic flickering image pairs than by static side-by-side images, although there was no difference in accuracy. PMID:22019222

  12. Lipocalin 2 is essential for chronic kidney disease progression in mice and humans

    PubMed Central

    Viau, Amandine; El Karoui, Khalil; Laouari, Denise; Burtin, Martine; Nguyen, Clment; Mori, Kiyoshi; Pillebout, Evangline; Berger, Thorsten; Mak, Tak Wah; Knebelmann, Bertrand; Friedlander, Grard; Barasch, Jonathan; Terzi, Fabiola

    2010-01-01

    Mechanisms of progression of chronic kidney disease (CKD), a major health care burden, are poorly understood. EGFR stimulates CKD progression, but the molecular networks that mediate its biological effects remain unknown. We recently showed that the severity of renal lesions after nephron reduction varied substantially among mouse strains and required activation of EGFR. Here, we utilized two mouse strains that react differently to nephron reduction FVB/N mice, which develop severe renal lesions, and B6D2F1 mice, which are resistant to early deterioration coupled with genome-wide expression to elucidate the molecular nature of CKD progression. Our results showed that lipocalin 2 (Lcn2, also known as neutrophil gelatinaseassociated lipocalin [NGAL]), the most highly upregulated gene in the FVB/N strain, was not simply a marker of renal lesions, but an active player in disease progression. In fact, the severity of renal lesions was dramatically reduced in Lcn2/ mice. We discovered that Lcn2 expression increased upon EGFR activation and that Lcn2 mediated its mitogenic effect during renal deterioration. EGFR inhibition prevented Lcn2 upregulation and lesion development in mice expressing a dominant negative EGFR isoform, and hypoxia-inducible factor 1? (Hif-1?) was crucially required for EGFR-induced Lcn2 overexpression. Consistent with this, cell proliferation was dramatically reduced in Lcn2/ mice. These data are relevant to human CKD, as we found that LCN2 was increased particularly in patients who rapidly progressed to end-stage renal failure. Together our results uncover what we believe to be a novel function for Lcn2 and a critical pathway leading to progressive renal failure and cystogenesis. PMID:20921623

  13. Lipocalin 2 is essential for chronic kidney disease progression in mice and humans.

    PubMed

    Viau, Amandine; El Karoui, Khalil; Laouari, Denise; Burtin, Martine; Nguyen, Clment; Mori, Kiyoshi; Pillebout, Evangline; Berger, Thorsten; Mak, Tak Wah; Knebelmann, Bertrand; Friedlander, Grard; Barasch, Jonathan; Terzi, Fabiola

    2010-11-01

    Mechanisms of progression of chronic kidney disease (CKD), a major health care burden, are poorly understood. EGFR stimulates CKD progression, but the molecular networks that mediate its biological effects remain unknown. We recently showed that the severity of renal lesions after nephron reduction varied substantially among mouse strains and required activation of EGFR. Here, we utilized two mouse strains that react differently to nephron reduction--FVB/N mice, which develop severe renal lesions, and B6D2F1 mice, which are resistant to early deterioration--coupled with genome-wide expression to elucidate the molecular nature of CKD progression. Our results showed that lipocalin 2 (Lcn2, also known as neutrophil gelatinase-associated lipocalin [NGAL]), the most highly upregulated gene in the FVB/N strain, was not simply a marker of renal lesions, but an active player in disease progression. In fact, the severity of renal lesions was dramatically reduced in Lcn2-/- mice. We discovered that Lcn2 expression increased upon EGFR activation and that Lcn2 mediated its mitogenic effect during renal deterioration. EGFR inhibition prevented Lcn2 upregulation and lesion development in mice expressing a dominant negative EGFR isoform, and hypoxia-inducible factor 1? (Hif-1?) was crucially required for EGFR-induced Lcn2 overexpression. Consistent with this, cell proliferation was dramatically reduced in Lcn2-/- mice. These data are relevant to human CKD, as we found that LCN2 was increased particularly in patients who rapidly progressed to end-stage renal failure. Together our results uncover what we believe to be a novel function for Lcn2 and a critical pathway leading to progressive renal failure and cystogenesis. PMID:20921623

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

    PubMed Central

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

    2014-01-01

    Despite vast improvements in treatment of Philadelphia chromosomepositive 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

  15. Progress in defining clinically meaningful changes for clinical trials in nonrenal manifestations of SLE disease activity.

    PubMed

    Choi, Chan-Bum; Liang, Matthew H; Bae, Sang-Cheol

    2016-01-01

    Since the 2002 Dusseldorf meeting, one new agent, Benlysta, has been approved by the US Food and Drug Administration for systemic lupus erythematosus. Experiences from the field in conducting trials of all the agents tested during this period have provided valuable practical insights. There has been incremental progress in defining the minimal clinically important difference (MCID) of key disease manifestations and the view is largely that of the health care providers and not that of the person suffering the disease. This basic methodological work on the MCID should improve the efficiency and the clinical relevance of future trials and their design. PMID:26732314

  16. Genetic algorithm with logistic regression for prediction of progression to Alzheimer's disease

    PubMed Central

    2014-01-01

    Background Assessment of risk and early diagnosis of Alzheimer's disease (AD) is a key to its prevention or slowing the progression of the disease. Previous research on risk factors for AD typically utilizes statistical comparison tests or stepwise selection with regression models. Outcomes of these methods tend to emphasize single risk factors rather than a combination of risk factors. However, a combination of factors, rather than any one alone, is likely to affect disease development. Genetic algorithms (GA) can be useful and efficient for searching a combination of variables for the best achievement (eg. accuracy of diagnosis), especially when the search space is large, complex or poorly understood, as in the case in prediction of AD development. Results Multiple sets of neuropsychological tests were identified by GA to best predict conversions between clinical categories, with a cross validated AUC (area under the ROC curve) of 0.90 for prediction of HC conversion to MCI/AD and 0.86 for MCI conversion to AD within 36 months. Conclusions This study showed the potential of GA application in the neural science area. It demonstrated that the combination of a small set of variables is superior in performance than the use of all the single significant variables in the model for prediction of progression of disease. Variables more frequently selected by GA might be more important as part of the algorithm for prediction of disease development. PMID:25521394

  17. Have we made progress in the management of chronic graft-vs-host disease?

    PubMed Central

    Lee, Stephanie J.

    2010-01-01

    Chronic graft-vs-host disease (GVHD) is a common long-term complication of allogeneic hematopoietic cell transplant that is associated with very high morbidity and mortality. In order to understand whether we have made progress in the management of chronic GVHD, it is helpful to first propose a definition of meaningful “progress.” The following can be considered to be indicators of improved management of chronic GVHD: a decrease in the incidence or severity of chronic GVHD, better efficacy or decreased toxicity of therapies, better quality of life despite chronic GVHD, and improved overall and disease-free survival rates. However, to date, real progress has not been made in these areas, though there are promising new preventive strategies and treatments. Furthermore, a consensus has been reached in the research community about many different issues surrounding chronic GVHD definitions, management, and the conduct of clinical trials. These consensus documents will help to standardize efforts and data collection so that true comparisons can be made in the future and real clinical progress achieved. PMID:21130418

  18. TLR4 mutant mice are protected from renal fibrosis and chronic kidney disease progression.

    PubMed

    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

    2015-09-01

    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

  19. 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

  20. Different Scales of Cortical Organization are Selectively Targeted in the Progression to Alzheimer's Disease.

    PubMed

    Romero-Garcia, Rafael; Atienza, Mercedes; Cantero, Jose L

    2016-03-01

    Previous studies have shown that the topological organization of the cerebral cortex is altered in Alzheimer's disease (AD). However, it remains unknown whether different levels of the cortical hierarchy are homogeneously affected during disease progression, and which of these levels are mostly involved in the breakdown of metabolic (functional) connectivity. To fulfill these goals, we acquired structural magnetic resonance images (MRI) and positron emission tomography (PET) with the radiotracer 18F-fludeoxyglucose (FDG) in 29 healthy old (HO) adults, 29 amnestic mild cognitive impairment (aMCI) and 29 mild AD patients. Structural and metabolic connections were obtained from inter-regional correlations of cortical thickness and glucose consumption, respectively. Results showed that AD and HO groups differed at all levels of cortical organization (i.e. whole cortex, hemisphere, lobe and node), whereas differences among the three groups were only evident at the lobe and node levels. The correlation between structural and metabolic connectivity (F-S coupling) was also disturbed during AD progression, affecting to different connectivity scales: it decreased at the local level, revealing a progressive increase of metabolic connections in those local communities with fewer structural connections; whereas it increased at the global level, likely due to a parallel reduction of cortical thickness and glucose consumption between long-distance cortical regions. Collectively, these results reveal that different levels of cortical organization are selectively affected during the transition from normal aging to dementia, which could be helpful to track cortical dysfunctions in the progression to AD. PMID:26790483

  1. Rapidly progressive Alzheimer's disease features distinct structures of amyloid-β.

    PubMed

    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; Safar, Jiri G

    2015-04-01

    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

  2. Current progress in nanotechnology applications for diagnosis and treatment of kidney diseases.

    PubMed

    Lee, Sue Hyun; Lee, Jung Bok; Bae, Min Soo; Balikov, Daniel A; Hwang, Amy; Boire, Timothy C; Kwon, Il Keun; Sung, Hak-Joon; Yang, Jae Won

    2015-09-16

    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

  3. AlSb photonic detectors for gamma-ray spectroscopy. Progress report, October 1994--August 1995

    SciTech Connect

    Becla, P.; Witt, A.F.

    1995-12-31

    Aluminum antimony (AlSb) is an indirect band gap semiconductor with Eg of about 1.62 eV at 300 K and about 1.75 eV at 77 K. This material, is extremely difficult to obtain in single crystal form because of the very high reactivity of aluminum with oxygen, and the high volatility of antimony. Moreover, molten AlSb reacts with nearly all crucible materials available. Since Welker`s first attempts in 1952, only very few different experimental approaches have been used to grow single crystals of AlSb, e.g. by Bridgman, Czochralski and MBE. All experimental results, however, indicate that many of the properties of AlSb, e.g. carrier concentration, electron-hole mobility and carrier life-time, differ significantly from the theoretically predicted values. The main objective of this research period has been to develop a method leading to improved crystallographic and electronic quality of AlSb crystals, making them more suitable for device applications. The research program was aimed along the following two directions: (1) study the growth of AlSb via Bridgman, Czochralski and THM techniques; (2) comprehensive characterization of grown material, related to the use of compounds for high energy gamma detectors. Variables in the growth study were growth temperature, equilibrium pressure, growth rate, doping, crucible material, seeding and encapsulation. The characterization study included crystallographic quality (grain size, etch pits, precipitates, inclusions), electronic quality (conductivity type, carrier concentration and mobility), optical properties (spectral absorption, photoconductivity, persistent absorption) and others (SIMS, EPR).

  4. 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

  5. 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

  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. A longitudinal EEG study of Alzheimer's disease progression based on a complex network approach.

    PubMed

    Morabito, Francesco Carlo; Campolo, Maurizio; Labate, Domenico; Morabito, Giuseppe; Bonanno, Lilla; Bramanti, Alessia; de Salvo, Simona; Marra, Angela; Bramanti, Placido

    2015-03-01

    A complex network approach is combined with time dynamics in order to conduct a space-time analysis applicable to longitudinal studies aimed to characterize the progression of Alzheimer's disease (AD) in individual patients. The network analysis reveals how patient-specific patterns are associated with disease progression, also capturing the widespread effect of local disruptions. This longitudinal study is carried out on resting electroence phalography (EEGs) of seven AD patients. The test is repeated after a three months' period. The proposed methodology allows to extract some averaged information and regularities on the patients' cohort and to quantify concisely the disease evolution. From the functional viewpoint, the progression of AD is shown to be characterized by a loss of connected areas here measured in terms of network parameters (characteristic path length, clustering coefficient, global efficiency, degree of connectivity and connectivity density). The differences found between baseline and at follow-up are statistically significant. Finally, an original topographic multiscale approach is proposed that yields additional results. PMID:25655033

  8. The genetics of human autoimmune disease: A perspective on progress in the field and future directions.

    PubMed

    Seldin, Michael F

    2015-11-01

    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 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

  9. UCHL1 is a biomarker of aggressive multiple myeloma required for disease progression

    PubMed Central

    Hussain, Sajjad; Bedekovics, Tibor; Chesi, Marta; Bergsagel, P. Leif; Galardy, Paul J.

    2015-01-01

    The success of proteasome inhibition in multiple myeloma highlights the critical role for the ubiquitin-proteasome system (UPS) in this disease. However, there has been little progress in finding more specific targets within the UPS involved in myeloma pathogenesis. We previously found the ubiquitin hydrolase UCH-L1 to be frequently over-expressed in B-cell malignancies, including myeloma, and showed it to be a potent oncogene in mice. Here we show that UCH-L1 is a poor prognostic factor that is essential for the progression of myeloma. We found high levels of UCHL1 to predict early progression in newly diagnosed patients; a finding reversed by the inclusion of bortezomib. We also found high UCHL1 levels to be a critical factor in the superiority of bortezomib over high-dose dexamethasone in relapsed patients. High UCHL1 partially overlaps with, but is distinct from, known genetic risks including 4p16 rearrangement and 1q21 amplification. Using an orthotopic mouse model, we found UCH-L1 depletion delays myeloma dissemination and causes regression of established disease. We conclude that UCH-L1 is a biomarker of aggressive myeloma that may be an important marker of bortezomib response, and may itself be an effective target in disseminated disease. PMID:26513019

  10. 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. PMID:26601739

  11. 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.

  12. Alzheimer's disease and infection: do infectious agents contribute to progression of Alzheimer's disease?

    PubMed

    Honjo, Kie; van Reekum, Robert; Verhoeff, Nicolaas P L G

    2009-07-01

    Infection with several important pathogens could constitute risk factors for cognitive impairment, dementia, and Alzheimer's disease (AD) in particular. This review summarizes the data related to infectious agents that appear to have a relationship with AD. Infections with herpes simplex virus type 1, picornavirus, Borna disease virus, Chlamydia pneumoniae, Helicobacter pylori, and spirochete were reported to contribute to the pathophysiology of AD or to cognitive changes. Based on these reports, it may be hypothesized that central nervous system or systemic infections may contribute to the pathogenesis or pathophysiology of AD, and chronic infection with several pathogens should be considered a risk factor for sporadic AD. If this hypothesis holds true, early intervention against infection may delay or even prevent the future development of AD. PMID:19560105

  13. The Progression of Cardiometabolic Disease: Validation of a New Cardiometabolic Disease Staging System Applicable to Obesity

    PubMed Central

    Guo, Fangjian; Moellering, Douglas R; Garvey, W. Timothy

    2013-01-01

    Objective To validate a Cardiometabolic Disease Staging (CMDS) system for assigning risk level for diabetes, and all-cause and cardiovascular disease (CVD) mortality. Design, and Methods Two large national cohorts, CARDIA and NHANES III, were used to validate CMDS. CMDS: Stage 0: metabolically healthy; Stage 1: 1 or 2 Metabolic Syndrome risk factors (other than IFG); Stage 2: IFG or IGT or Metabolic Syndrome (without IFG); Stage 3: 2 of 3 (IFG, IGT, and/or Metabolic Syndrome); Stage 4: T2DM/CVD. Results In the CARDIA study, compared with Stage 0 metabolically healthy subjects, adjusted risk for diabetes exponentially increased from Stage 1 (HR 2.83, 95% CI 1.764.55), to Stage 2 (HR 8.06, 95% CI 4.9113.2), to Stage 3 (HR 23.5, 95% CI 13.740.1) (p for trend <0.001). In NHANES III, both cumulative incidence and multivariable adjusted hazard ratios markedly increased for both all-cause and CVD mortality with advancement of the risk stage from Stage 0 to 4. Adjustment for BMI minimally affected the risks for diabetes and all-cause/CVD mortality using CMDS. Conclusion CMDS can discriminate a wide range of risk for diabetes, CVD mortality, and all-cause mortality independent of BMI, and should be studied as a risk assessment tool to guide interventions that prevent and treat cardiometabolic disease. PMID:23894121

  14. Mortality model based on delays in progression of chronic diseases: alternative to cause elimination model.

    PubMed Central

    Manton, K G; Patrick, C H; Stallard, E

    1980-01-01

    For the analysis of the impact of major chronic diseases on a population, a life table model is proposed in which the age at death due to specific cause (chronic disease) is postponed. Even though many of the major causes of death related to intrinsic aging processes are impossible to eliminate, these causes might be significantly delayed or retarded. To illustrate the use of this model, the effects of a delay of 5, 10, and 15 years in deaths due to three chronic degenerative diseases (cancer, ischemic heart disease, and stroke) are calculated for specific race-sex components of the U.S. population in 1969. These calculations show that even moderate delays in the progression of major chronic diseases will yield a sizable portion of the total gain in longevity that would be available if the diseases were totally eliminated. Thus, they demonstrate that a life table model based on cause delay provides a more biomedically plausible representation of the health impact of a chronic disease on a population than does the cause elimination life table model. Additionally, the cause-delay model provides a mechanism for incorporating the likely effects of medical innovation on survival. PMID:7433613

  15. Phase progression of γ-Al2O3 nanoparticles synthesized in a solvent-deficient environment.

    PubMed

    Smith, Stacey J; Amin, Samrat; Woodfield, Brian F; Boerio-Goates, Juliana; Campbell, Branton J

    2013-04-15

    Our simple and uniquely cost-effective solvent-deficient synthetic method produces 3-5 nm Al2O3 nanoparticles which show promise as improved industrial catalyst-supports. While catalytic applications are sensitive to the details of the atomic structure, a diffraction analysis of alumina nanoparticles is challenging because of extreme size/microstrain-related peak broadening and the similarity of the diffraction patterns of various transitional Al2O3 phases. Here, we employ a combination of X-ray pair-distribution function (PDF) and Rietveld methods, together with solid-state NMR and thermogravimetry/differential thermal analysis-mass spectrometry (TG/DTA-MS), to characterize the alumina phase-progression in our nanoparticles as a function of calcination temperature between 300 and 1200 °C. In the solvent-deficient synthetic environment, a boehmite precursor phase forms which transitions to γ-Al2O3 at an extraordinarily low temperature (below 300 °C), but this γ-Al2O3 is initially riddled with boehmite-like stacking-fault defects that steadily disappear during calcination in the range from 300 to 950 °C. The healing of these defects accounts for many of the most interesting and widely reported properties of the γ-phase. PMID:23557087

  16. 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 particular the understanding of mechano-coupling and mechano-regulating functions in cell invasion, appears as an important step in cancer progression and inflammatory response to injuries. This may lead to novel insights into cancer disease and inflammatory diseases and will overcome classical views on cancer and inflammation. In addition, this review will discuss how the physics of cancer and inflammation can help to reveal whether cancer cells will invade connective tissue and metastasize or how leukocytes extravasate and migrate through the tissue. In this review, the physical concepts of cancer progression, including the tissue basement membrane a cancer cell is crossing, its invasion and transendothelial migration as well as the basic physical concepts of inflammatory processes and the cellular responses to the mechanical stress of the microenvironment such as external forces and matrix stiffness, are presented and discussed. In conclusion, this review will finally show how physical measurements can improve classical approaches that investigate cancer and inflammatory diseases, and how these physical insights can be integrated into classical tumor biological approaches.

  17. 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.

  18. Characterization of metal profiles in serum during the progression of Alzheimer's disease.

    PubMed

    Gonzlez-Domnguez, Ral; Garca-Barrera, Tamara; Gmez-Ariza, Jos Luis

    2014-02-01

    Metal dyshomeostasis is closely related to Alzheimer's disease, so the characterization of the metal profiles in these patients is of special interest for studying associated neurodegenerative processes and to discover potential markers of disease. An analytical approach, based on non-denaturing precipitation of proteins, has been optimized for the fractionation of high molecular mass (HMM) and low molecular mass (LMM) metal-species from serum, which were subjected to multielemental analysis by inductively coupled plasma mass spectrometry (ICP-MS). This methodology was applied to healthy controls, Alzheimer's disease (AD) and mild cognitive impairment (MCI) patients in order to study the progression of dementia. Thus, it was found that some metals, such as iron, copper, zinc and aluminium, suffer progressive changes along the advance of neurodegeneration, suggesting that these imbalances could be related to the decline of cognitive functions. On the other hand, elements such as manganese, lithium or vanadium allow discriminating between controls and diseased subjects, both AD and MCI, but no differences were found between these two clinical stages, so they could be considered as precursors in the early development of neurodegenerative failures. In addition, it should be noted the important role that low molecular mass fractions of iron, copper, aluminium and cobalt appear to play in pathogenesis of Alzheimer. Finally, correlation analysis indicated that these metal abnormalities can be interrelated, participating in common processes such as oxidative stress, altered homeostasis and uptake into brain, as well as impaired glucose metabolism. PMID:24343096

  19. Estimation and Validation of a Multi-Attribute Model of Alzheimer's Disease Progression

    PubMed Central

    Stallard, Eric; Kinosian, Bruce; Zbrozek, Arthur S.; Yashin, Anatoliy I.; Glick, Henry A.; Stern, Yaakov

    2015-01-01

    Objectives To estimate and validate a multi-attribute model of the clinical course of Alzheimer's Disease (AD) from mild AD to death in a high-quality prospective cohort study; to estimate the impact of hypothetical modifications to AD progression rates on costs associated with Medicare and Medicaid services. Data and Methods We estimated sex-specific longitudinal Grade of Membership (GoM) models for AD patients (103 males; 149 females) in the initial cohort of the Predictors Study (19892001) based on 80 individual measures obtained every six months for 10 years. We replicated these models for AD patients (106 males; 148 females) in the second Predictors Study cohort (19972007). Model validation required that the disease-specific transition parameters be identical for both Predictors Study cohorts. Medicare costs were estimated from the National Long Term Care Survey. Results Sex-specific models were validated using the second Predictors Study cohort with the GoM transition parameters constrained to the values estimated for the first Predictors Study cohort; 5761 of the 80 individual measures contributed significantly to the GoM models. Simulated, cost-free interventions in the rate of progression of AD indicated that large potential cost offsets could occur for patients at the earliest stages of AD. Conclusions AD progression is characterized by a small number of parameters governing changes in large numbers of correlated indicators of AD severity. The analysis confirmed that the progression of AD represents a complex multidimensional physiological process that is similar across different study cohorts. The estimates suggested that there could be large cost offsets to Medicare and Medicaid from the slowing of AD progression among patients with mild AD. The methodology appears generally applicable in AD modeling. PMID:21183754

  20. Vitamin D Deficiency Aggravates Chronic Kidney Disease Progression after Ischemic Acute Kidney Injury

    PubMed Central

    Gonçalves, Janaína Garcia; de Bragança, Ana Carolina; Canale, Daniele; Shimizu, Maria Heloisa Massola; Sanches, Talita Rojas; Moysés, Rosa Maria Affonso; Andrade, Lúcia; Seguro, Antonio Carlos; Volpini, Rildo Aparecido

    2014-01-01

    Background Despite a significant improvement in the management of chronic kidney disease (CKD), its incidence and prevalence has been increasing over the years. Progressive renal fibrosis is present in CKD and involves the participation of several cytokines, including Transforming growth factor-β1 (TGF-β1). Besides cardiovascular diseases and infections, several studies show that Vitamin D status has been considered as a non-traditional risk factor for the progression of CKD. Given the importance of vitamin D in the maintenance of essential physiological functions, we studied the events involved in the chronic kidney disease progression in rats submitted to ischemia/reperfusion injury under vitamin D deficiency (VDD). Methods Rats were randomized into four groups: Control; VDD; ischemia/reperfusion injury (IRI); and VDD+IRI. At the 62 day after sham or IRI surgery, we measured inulin clearance, biochemical variables and hemodynamic parameters. In kidney tissue, we performed immunoblotting to quantify expression of Klotho, TGF-β, and vitamin D receptor (VDR); gene expression to evaluate renin, angiotensinogen, and angiotensin-converting enzyme; and immunohistochemical staining for ED1 (macrophages), type IV collagen, fibronectin, vimentin, and α-smooth mucle actin. Histomorphometric studies were performed to evaluate fractional interstitial area. Results IRI animals presented renal hypertrophy, increased levels of mean blood pressure and plasma PTH. Furthermore, expansion of the interstitial area, increased infiltration of ED1 cells, increased expression of collagen IV, fibronectin, vimentin and α-actin, and reduced expression of Klotho protein were observed. VDD deficiency contributed to increased levels of plasma PTH as well as for important chronic tubulointerstitial changes (fibrosis, inflammatory infiltration, tubular dilation and atrophy), increased expression of TGF-β1 and decreased expression of VDR and Klotho protein observed in VDD+IRI animals. Conclusion Through inflammatory pathways and involvement of TGF-β1 growth factor, VDD could be considered as an aggravating factor for tubulointerstitial damage and fibrosis progression following acute kidney injury induced by ischemia/reperfusion. PMID:25222475

  1. An estrogen-induced endometrial hyperplasia mouse model recapitulating human disease progression and genetic aberrations

    PubMed Central

    Yang, Chieh-Hsiang; Almomen, Aliyah; Wee, Yin Shen; Jarboe, Elke A; Peterson, C Matthew; Jant-Amsbury, Margit M

    2015-01-01

    Endometrial hyperplasia (EH) is a condition originating from uterine endometrial glands undergoing disordered proliferation including the risk to progress to endometrial adenocarcinoma. In recent years, a steady increase in EH cases among younger women of reproductive age accentuates the demand of therapeutic alternatives, which emphasizes that an improved disease model for therapeutic agents evaluation is concurrently desired. Here, a new hormone-induced EH mouse model was developed using a subcutaneous estradiol (E2)-sustained releasing pellet, which elevates the serum E2 level in mice, closely mimicking the effect known as estrogen dominance with underlying, pathological E2 levels in patients. The onset and progression of EH generated within this model recapitulate a clinically relevant, pathological transformation, beginning with disordered proliferation developing to simple EH, advancing to atypical EH, and then progressing to precancerous stages, all following a chronologic manner. Although a general increase in nuclear progesterone receptor (PR) expression occurred after E2 expression, a total loss in PR was noted in some endometrial glands as disease advanced to simple EH. Furthermore, estrogen receptor (ER) expression in the nucleus of endometrial cells was reduced in disordered proliferation and increased when EH progressed to atypical EH and precancerous stages. This EH model also resembles other pathological patterns found in human disease such as leukocytic infiltration, genetic aberrations in ?-catenin, and joint phosphatase and tensin homolog/paired box gene 2 (PTEN/PAX2) silencing. In summary, this new and comprehensively characterized EH model is cost-effective, easily reproducible, and may serve as a tool for preclinical testing of therapeutic agents and facilitate further investigation of EH. PMID:25809780

  2. Progressive resistance training in Parkinson's disease: a systematic review and meta-analysis

    PubMed Central

    Saltychev, Mikhail; Bärlund, Esa; Paltamaa, Jaana; Katajapuu, Niina; Laimi, Katri

    2016-01-01

    Objectives To investigate if there is evidence on effectiveness of progressive resistance training in rehabilitation of Parkinson disease. Design Systematic review and meta-analysis. Data sources: Central, Medline, Embase, Cinahl, Web of Science, Pedro until May 2014. Randomised controlled or controlled clinical trials. The methodological quality of studies was assessed according to the Cochrane Collaboration's domain-based evaluation framework. Data synthesis: random effects meta-analysis with test for heterogeneity using the I² and pooled estimate as the raw mean difference. Participants Adults with primary/idiopathic Parkinson's disease of any severity, excluding other concurrent neurological condition. Interventions Progressive resistance training defined as training consisting of a small number of repetitions until fatigue, allowing sufficient rest between exercises for recovery, and increasing the resistance as the ability to generate force improves. Comparison Progressive resistance training versus no treatment, placebo or other treatment in randomised controlled or controlled clinical trials. Primary and secondary outcome measures Any outcome. Results Of 516 records, 12 were considered relevant. Nine of them had low risk of bias. All studies were randomised controlled trials conducted on small samples with none or 1 month follow-up after the end of intervention. Of them, six were included in quantitative analysis. Pooled effect sizes of meta-analyses on fast and comfortable walking speed, the 6 min walking test, Timed Up and Go test and maximal oxygen consumption were below the level of minimal clinical significance. Conclusions There is so far no evidence on the superiority of progressive resistance training compared with other physical training to support the use of this technique in rehabilitation of Parkinson's disease. Systematic review registration number PROSPERO 2014:CRD42014009844. PMID:26743698

  3. Lysosomal and phagocytic activity is increased in astrocytes during disease progression in the SOD1 G93A mouse model of amyotrophic lateral sclerosis

    PubMed Central

    Baker, David J.; Blackburn, Daniel J.; Keatinge, Marcus; Sokhi, Dilraj; Viskaitis, Paulius; Heath, Paul R.; Ferraiuolo, Laura; Kirby, Janine; Shaw, Pamela J.

    2015-01-01

    Astrocytes are key players in the progression of amyotrophic lateral sclerosis (ALS). Previously, gene expression profiling of astrocytes from the pre-symptomatic stage of the SOD1G93A model of ALS has revealed reduced lactate metabolism and altered trophic support. Here, we have performed microarray analysis of symptomatic and late-stage disease astrocytes isolated by laser capture microdissection (LCM) from the lumbar spinal cord of the SOD1G93A mouse to complete the picture of astrocyte behavior throughout the disease course. Astrocytes at symptomatic and late-stage disease show a distinct up-regulation of transcripts defining a reactive phenotype, such as those involved in the lysosome and phagocytic pathways. Functional analysis of hexosaminidase B enzyme activity in the spinal cord and of astrocyte phagocytic ability has demonstrated a significant increase in lysosomal enzyme activity and phagocytic activity in SOD1G93A vs. littermate controls, validating the findings of the microarray study. In addition to the increased reactivity seen at both stages, astrocytes from late-stage disease showed decreased expression of many transcripts involved in cholesterol homeostasis. Staining for the master regulator of cholesterol synthesis, SREBP2, has revealed an increased localization to the cytoplasm of astrocytes and motor neurons in late-stage SOD1G93A spinal cord, indicating that down-regulation of transcripts may be due to an excess of cholesterol in the CNS during late-stage disease possibly due to phagocytosis of neuronal debris. Our data reveal that SOD1G93A astrocytes are characterized more by a loss of supportive function than a toxic phenotype during ALS disease progression and future studies should focus upon restorative therapies. PMID:26528138

  4. Plasma concentrations of transforming growth factor beta 1 in non-progressive HIV-1 infection correlates with markers of disease progression.

    PubMed

    Maina, Edward K; Abana, C Z; Bukusi, E A; Sedegah, M; Lartey, M; Ampofo, W K

    2016-05-01

    The human immunodeficiency virus (HIV) infection shows variable rate of disease progression. The underlying biological and molecular mechanisms involved in determining progression of HIV infection are not fully understood. The aims of this study were to determine plasma concentrations of active TGF β 1, Th1 and Th2 cytokines in patients with non-progressive and those with progressive HIV-1 infection, as well as to determine if there is an association of these cytokines to disease progression. In a cross-sectional study of 61 HIV-1 infected individuals categorized according to disease progression as having non-progressive HIV-1 infection (n=14) and progressive infection (n=47), plasma levels of active TGF β 1, INF-γ, TNF-α, IL-10, IL-1β, IL-12p70 and IL-13 were compared with HIV uninfected healthy controls (n=12). Plasma concentration of these cytokines was measured using a highly sensitive luminex200 XMAP assay. Pearson correlation test was used to assess the correlation of cytokines with CD4+ and CD8+ T cells, CD4:CD8 ratio and plasma HIV-1 RNA in the different study groups. Plasma concentrations of TGF β 1 and IL-10 were significantly decreased while IL-1β, IL-12p70 and TNF-α were increased in patients with non-progressive HIV-1 infection compared to patients with progressive infection. Plasma levels of TGF β 1 and IL-10 showed an inverse correlation with CD8+ T cell counts and CD4:CD8 ratios in patients with non-progressive HIV-1 infection, while plasma HIV-1 RNA positively correlated with CD4+ T cell counts. Plasma levels of TNF-α, IL-1β, IL-12p70 and IL-13 positively correlated with CD4+ T cell counts and inversely correlated with plasma HIV-1 RNA, CD8+ T cell count and CD4:CD8 ratio in patients with non-progressive infection. The correlation of cytokines to the state of T-lymphocyte and plasma HIV-1 RNA found in this study may provide insight into the role of cytokines in both progressive and non-progressive HIV-1 infection. Additionally, these findings may have implications for systemic cytokine-based therapies in HIV-1 infection. PMID:26986868

  5. A computational method for computing an Alzheimer’s Disease Progression Score; experiments and validation with the ADNI dataset

    PubMed Central

    Jedynak, Bruno M.; Liu, Bo; Lang, Andrew; Gel, Yulia; Prince, Jerry L.

    2014-01-01

    Understanding the time-dependent changes of biomarkers related to Alzheimer’s disease (AD) is a key to assessing disease progression and to measuring the outcomes of disease-modifying therapies. In this paper, we validate an Alzheimer’s disease progression score model which uses multiple biomarkers to quantify the AD progression of subjects following three assumptions: (1) there is a unique disease progression for all subjects, (2) each subject has a different age of onset and rate of progression, and (3) each biomarker is sigmoidal as a function of disease progression. Fitting the parameters of this model is a challenging problem which we approach using an alternating least squares optimization algorithm. In order to validate this optimization scheme under realistic conditions, we use the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. With the help of Monte Carlo simulations, we show that most of the global parameters of the model are tightly estimated, thus enabling an ordering of the biomarkers that fit the model well, ordered as: the Rey auditory verbal learning test with 30 minutes delay, the sum of the two lateral hippocampal volumes divided by the intra-cranial volume, followed by (the clinical dementia rating sum of boxes score and the mini mental state examination score) in no particular order and lastly the Alzheimer’s disease assessment scale-cognitive subscale. PMID:25444605

  6. Severe hyponatraemia with absence of hyperkalaemia in rapidly progressive Addison's disease.

    PubMed

    Thompson, Michael D; Kalmar, Eileen; Bowden, Sasigarn A

    2015-01-01

    We present a case of rapidly progressing Addison's disease in adrenal crisis with severe hyponatraemia and absence of hyperkalaemia in a 10-year-old girl. She presented with 2?weeks of vomiting, fatigue and weight loss. Her serum electrolytes obtained 1?week prior to presentation were normal, except for mild hyponatraemia at 131?mmol/L, which dropped to 112?mmol/L on admission. She had normal serum potassium, low-serum osmolality, with elevated urine sodium and osmolality, indistinguishable from syndrome of inappropriate antidiuretic hormone (SIADH). Subsequently, Addison's disease was diagnosed on the basis of gingival hyperpigmentation and undetectable cortisol on adrenocorticotropic hormone stimulation test. She rapidly responded to stress dose hydrocortisone, followed by hydrocortisone and fludrocortisone replacement therapy. The absence of hyperkalaemia in the presence of severe hyponatraemia cannot rule out Addison's disease in children. The mechanism of hypo-osmolar hyponatraemia in primary adrenal insufficiency and clinical clues to differentiate it from SIADH are discussed. PMID:26021383

  7. Does selegiline delay progression of Parkinson's disease? A critical re-evaluation of the DATATOP study.

    PubMed Central

    Ward, C D

    1994-01-01

    The deprenyl and tocopherol antioxidative treatment (DATATOP) study has shown that selegiline (deprenyl), with or without tocopherol, reduces physical and psychological deficits in patients with Parkinson's disease within one month of treatment and reduces the probability of reaching a primary endpoint, the decision to treat with levodopa. This paper critically re-evaluates the inference that selegiline has a neuroprotective effect and thus delays progression of Parkinson's disease. Analysis is based on a simple model which assumes that clinically measured impairment is proportional to degree of cellular dysfunction in Parkinson's disease. The analysis suggests that the reduced probability of reaching an endpoint was due to a direct treatment effect rather than to neuroprotection. PMID:8126510

  8. Pharmacological Treatment of Alzheimers Disease: Is it Progressing Adequately?

    PubMed Central

    Robles, Alfredo

    2009-01-01

    Introduction: Between 1993 and 2000 four acetylcholinesterase inhibitors were marketed as a symptomatic treatment for Alzheimers disease (AD), as well as memantine in 2003. Current research is focused on finding drugs that favorably modify the course of the disease. However, their entrance into the market does not seem to be imminent. Research Development: The aim of AD research is to find substances that inhibit certain elements of the AD pathogenic chain (beta- and gamma-secretase inhibitors, alpha-secretase stimulants, beta-amyloid aggregability reducers or disaggregation and elimination inductors, as well as tau-hyperphosphorylation, glutamate excitotoxicity, oxidative stress and mitochondrial damage reducers, among other action mechanisms). Demonstrating a diseases retarding effect demands longer trials than those necessary to ascertain symptomatic improvement. Besides, a high number of patients (thousands of them) is necessary, all of which turns out to be difficult and costly. Furthermore, it would be necessary to count on diagnosis and progression markers in the diseases pre-clinical stage, markers for specific phenotypes, as well as high-selectivity molecules acting only where necessary. In order to compensate these difficulties, drugs acting on several defects of the pathogenic chain or showing both symptomatic and neuroprotective action simultaneously are being researched. Conclusions: There are multiple molecules used in research to modify AD progression. Although it turns out to be difficult to obtain drugs with sufficient efficacy so that their marketing is approved, if they were achieved they would lead to a reduction of AD prevalence. PMID:19461897

  9. Cerebellar Soluble Mutant Ataxin-3 Level Decreases during Disease Progression in Spinocerebellar Ataxia Type 3 Mice

    PubMed Central

    Weber, Jonasz Jeremiasz; Grueninger, Stephan; Riess, Olaf; Weiss, Andreas

    2013-01-01

    Spinocerebellar Ataxia Type 3 (SCA3), also known as Machado-Joseph disease, is an autosomal dominantly inherited neurodegenerative disease caused by an expanded polyglutamine stretch in the ataxin-3 protein. A pathological hallmark of the disease is cerebellar and brainstem atrophy, which correlates with the formation of intranuclear aggregates in a specific subset of neurons. Several studies have demonstrated that the formation of aggregates depends on the generation of aggregation-prone and toxic intracellular ataxin-3 fragments after proteolytic cleavage of the full-length protein. Despite this observed increase in aggregated mutant ataxin-3, information on soluble mutant ataxin-3 levels in brain tissue is lacking. A quantitative method to analyze soluble levels will be a useful tool to characterize disease progression or to screen and identify therapeutic compounds modulating the level of toxic soluble ataxin-3. In the present study we describe the development and application of a quantitative and easily applicable immunoassay for quantification of soluble mutant ataxin-3 in human cell lines and brain samples of transgenic SCA3 mice. Consistent with observations in Huntington disease, transgenic SCA3 mice reveal a tendency for decrease of soluble mutant ataxin-3 during disease progression in fractions of the cerebellum, which is inversely correlated with aggregate formation and phenotypic aggravation. Our analyses demonstrate that the time-resolved Frster resonance energy transfer immunoassay is a highly sensitive and easy method to measure the level of soluble mutant ataxin-3 in biological samples. Of interest, we observed a tendency for decrease of soluble mutant ataxin-3 only in the cerebellum of transgenic SCA3 mice, one of the most affected brain regions in Spinocerebellar Ataxia Type 3 but not in whole brain tissue, indicative of a brain region selective change in mutant ataxin-3 protein homeostasis. PMID:23626768

  10. Identification of Major Signaling Pathways in Prion Disease Progression Using Network Analysis

    PubMed Central

    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 immunological pathways occupy influential positions in the PFNs (protein functional networks) that are related to prion disease. Importantly, this functional network involvement is prevalent in all the five different mouse strain-prion strain combinations that we studied. We also conclude that the dysregulation of the core elements of the bow-tie structure, which belongs to PI3K-Akt signaling pathway, leads to dysregulation of the downstream components corresponding to other biological pathways. PMID:26646948

  11. 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

  12. Identity experience among progressive gay Muslims in North America: a qualitative study within Al-Fatiha.

    PubMed

    Minwalla, Omar; Rosser, B R Simon; Feldman, Jamie; Varga, Christine

    2005-03-01

    This qualitative study aims to document the identity experience of progressive gay Muslim men in a North American context. Six in-depth interviews, supplemented with participant observation, were conducted of gay Muslim men who attended an international conference for lesbian, gay, bisexual, transgendered, and questioning (LGBTQ) Muslims. For progressive gay Muslims such as these, a Muslim identity appears three-dimensional (religious, ethno-cultural, and color) when integrated with a gay identity. As a religious identity, gay Muslim's relationship to Allah (God) and a reinterpretation of the Qur'an and traditional condemnation of homosexuality appears necessary. As a cultural identity, East-West ethno-cultural differences that impact on homo-sociality and gay identity construction, marriage and the impact of coming out on the Eastern family and siblings emerged as critical issues. As a color identity, internalized racism, dating relationships and social dynamics within gay subculture as Muslims of color in a white dominant context appear key challenges. PMID:16864192

  13. Modulation of TGF-beta signaling during progression of chronic liver diseases.

    PubMed

    Matsuzaki, Koichi

    2009-01-01

    A large body of work has established roles for epithelial cells as important mediators of progressive fibrosis and carcinogenesis. Transforming growth factor-beta (TGF-beta) and pro-inflammatory cytokines are important inducers of fibro-carcinogenesis. TGF-beta signaling involves phosphorylation of Smad3 at middle linker and/or C-terminal regions. Reversible shifting of Smad3-dependent signaling between tumor-suppression and oncogenesis in hyperactive Ras-expressing epithelial cells indicates that Smad3 phosphorylated at the C-terminal region (pSmad3C) transmits a tumor-suppressive TGF-beta signal, while oncogenic activities such as cell proliferation and invasion are promoted by Smad3 phosphorylated at the linker region (pSmad3L). Notably, pSmad3L-mediated signaling promotes extracellular matrix deposition by activated mesenchymal cells. During progression of chronic liver diseases, hepatic epithelial hepatocytes undergo transition from the tumor-suppressive pSmad3C pathway to the fibrogenic/oncogenic pSmad3L pathway, accelerating liver fibrosis and increasing risk of hepatocellular carcinoma. c-Jun N-terminal kinase activated by pro-inflammatory cytokines is mediating this perturbed hepatocytic TGF-beta signaling. Thus, TGF-beta signaling of hepatocytes affected by chronic inflammation offers a general framework for understanding the molecular mechanisms of human fibro-carcinogenesis during progression of chronic liver diseases. PMID:19273245

  14. 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

  15. Cerebrospinal Fluid ?-Synuclein Predicts Cognitive Decline in Parkinson Disease Progression in the DATATOP Cohort

    PubMed Central

    Stewart, Tessandra; Liu, Changqin; Ginghina, Carmen; Cain, Kevin C.; Auinger, Peggy; Cholerton, Brenna; Shi, Min; Zhang, Jing

    2015-01-01

    Most patients with Parkinson disease (PD) develop both cognitive and motor impairment, and biomarkers for progression are urgently needed. Although ?-synuclein is altered in cerebrospinal fluid of patients with PD, it is not known whether it predicts motor or cognitive deterioration. We examined clinical data and ?-synuclein in >300 unmedicated patients with PD who participated in the deprenyl and tocopherol antioxidative therapy of parkinsonism (DATATOP) study, with up to 8 years of follow-up. Longitudinal measures of motor and cognitive function were studied before (phase 1) and during (phase 2) levodopa therapy; cerebrospinal fluid was collected at the beginning of each phase. Correlations and linear mixed models were used to assess ?-synuclein association with disease severity and prediction of progression in the subsequent follow-up period. Despite decreasing ?-synuclein (phase 1 to phase 2 change of ?0.050.21 log-transformed values, P<0.001), no correlations were observed between ?-synuclein and motor symptoms. Longitudinally, lower ?-synuclein predicted better preservation of cognitive function by several measures [Selective Reminding Test total recall ?-synuclein time interaction effect coefficient, ?0.12 (P=0.037); delayed recall, ?0.05 (P=0.002); New Dot Test, ?0.03 (P=0.002)]. Thus, ?-synuclein, although not clinically useful for motor progression, might predict cognitive decline, and future longitudinal studies should include this outcome for further validation. PMID:24625392

  16. Atheroprotection through SYK inhibition fails in established disease when local macrophage proliferation dominates lesion progression.

    PubMed

    Lindau, Alexandra; Hrdtner, 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 Mhlen, 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 8weeks 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. PMID:26891724

  17. Reconsidering harbingers of dementia: Progression of parietal lobe white matter hyperintensities predicts Alzheimer's disease incidence

    PubMed Central

    Brickman, Adam M.; Zahodne, Laura B.; Guzman, Vanessa A.; Narkhede, Atul; Meier, Irene B.; Griffith, Erica Y.; Provenzano, Frank A.; Schupf, Nicole; Manly, Jennifer J.; Stern, Yaakov; Luchsinger, José A.; Mayeux, Richard

    2014-01-01

    Accumulating evidence implicates small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMH) on T2-weighted MRI, in the pathogenesis and diagnosis of Alzheimer's disease (AD). Cross-sectional volumetric measures of WMH, particularly in the parietal lobes, are associated with increased risk of AD. In the current study, we sought to determine whether the longitudinal regional progression of WMH predicts incident AD above-and-beyond traditional radiological markers of neurodegeneration (i.e., hippocampal atrophy, cortical thickness). Three hundred three non-demented older adults (mean age = 79.24±5.29) received high-resolution MRI at baseline and then again 4.6 years (SD=1.01) later. Over the follow-up interval 26 participants progressed to AD. Using structural equation modeling (SEM), we calculated latent difference scores of parietal/non-parietal WMH, hippocampus volumes, and cortical thickness values in AD-related regions. Within the SEM framework, we determined whether baseline or change scores or both predicted AD conversion, while controlling for several time-invariant relevant variables. Smaller baseline hippocampus volume, change in hippocampus volume (i.e., atrophy), higher baseline parietal lobe WMH, and increasing parietal lobe WMH volume but not WMH in other regions or measures of cortical thickness, independently predicted progression to AD. The findings provide strong evidence that regionally accumulating WMH, in addition to degenerative changes in the medial temporal lobe, predict AD onset in addition to hallmark neurodegenerative changes typically associated with AD. PMID:25155654

  18. Reconsidering harbingers of dementia: progression of parietal lobe white matter hyperintensities predicts Alzheimer's disease incidence.

    PubMed

    Brickman, Adam M; Zahodne, Laura B; Guzman, Vanessa A; Narkhede, Atul; Meier, Irene B; Griffith, Erica Y; Provenzano, Frank A; Schupf, Nicole; Manly, Jennifer J; Stern, Yaakov; Luchsinger, Jos A; Mayeux, Richard

    2015-01-01

    Accumulating evidence implicates small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMH) on T2-weighted magnetic resonance imaging, in the pathogenesis and diagnosis of Alzheimer's disease (AD). Cross-sectional volumetric measures of WMH, particularly in the parietal lobes, are associated with increased risk of AD. In the present study, we sought to determine whether the longitudinal regional progression of WMH predicts incident AD above-and-beyond traditional radiological markers of neurodegeneration (i.e., hippocampal atrophy and cortical thickness). Three hundred three nondemented older adults (mean age = 79.24 5.29) received high-resolution magnetic resonance imaging at baseline and then again 4.6 years (standard deviation = 1.01) later. Over the follow-up interval 26 participants progressed to AD. Using structural equation modeling, we calculated latent difference scores of parietal and nonparietal WMH, hippocampus volumes, and cortical thickness values in AD-related regions. Within the structural equation modeling framework, we determined whether baseline or change scores or both predicted AD conversion, while controlling for several time-invariant relevant variables. Smaller baseline hippocampus volume, change in hippocampus volume (i.e., atrophy), higher baseline parietal lobe WMH, and increasing parietal lobe WMH volume but not WMH in other regions or measures of cortical thickness, independently predicted progression to AD. The findings provide strong evidence that regionally accumulating WMH predict AD onset in addition to hallmark neurodegenerative changes typically associated with AD. PMID:25155654

  19. 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

  20. 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 the striatum, the substantia nigra and, finally, hippocampal and cortical regions. The slowly progressive nature of this model, together with its construct, face and predictive validity, make it ideal for the screening of potential neuroprotective therapies for the treatment of PD. PMID:26439489

  1. ALS Patient Stem Cells for Unveiling Disease Signatures of Motoneuron Susceptibility: Perspectives on the Deadly Mitochondria, ER Stress and Calcium Triad

    PubMed Central

    Kaus, Anjoscha; Sareen, Dhruv

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a largely sporadic progressive neurodegenerative disease affecting upper and lower motoneurons (MNs) whose specific etiology is incompletely understood. Mutations in superoxide dismutase-1 (SOD1), TAR DNA-binding protein 43 (TARDBP/TDP-43) and C9orf72, have been identified in subsets of familial and sporadic patients. Key associated molecular and neuropathological features include ubiquitinated TDP-43 inclusions, stress granules, aggregated dipeptide proteins from mutant C9orf72 transcripts, altered mitochondrial ultrastructure, dysregulated calcium homeostasis, oxidative and endoplasmic reticulum (ER) stress, and an unfolded protein response (UPR). Such impairments have been documented in ALS animal models; however, whether these mechanisms are initiating factors or later consequential events leading to MN vulnerability in ALS patients is debatable. Human induced pluripotent stem cells (iPSCs) are a valuable tool that could resolve this “chicken or egg” causality dilemma. Relevant systems for probing pathophysiologically affected cells from large numbers of ALS patients and discovering phenotypic disease signatures of early MN susceptibility are described. Performing unbiased ‘OMICS and high-throughput screening in relevant neural cells from a cohort of ALS patient iPSCs, and rescuing mitochondrial and ER stress impairments, can identify targeted therapeutics for increasing MN longevity in ALS. PMID:26635528

  2. 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.

  3. 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

  4. EEG Synchronization Evaluation: A New Diagnostic Tool for Predicting the Progression of Alzheimer's disease.

    PubMed

    Yi, Ran; Zhan, Xiao-Rong; Tang, Jing; Zhang, Li-Ming; Liu, Xiao-Min; Dong, Qi

    2015-04-01

    Alzheimer's disease (AD) is known as a leading cause of dementia in elderly persons. It is a chronic neurodegenerative disorder characterized by progressive cognitive dysfunction. AD can disrupt functional connectivity in distributed cortical networks. The S-estimator, which is a measure of multivariate intraregional synchronization, was analyzed in this study. Twenty patients with AD and 20 age-matched controls were tested at baseline and after 1 year to evaluate the potential of synchronization to be a possible marker of AD progression. All the subjects had clinical evaluations and electroencephalography (EEG) at baseline and post 1 year. Hyposynchronization had an important effect in the medial temporal and frontal regions, while there were no significant effects for hypersynchronization. Hypersynchronized clusters changed more slowly with time (P = .067), whereas hyposynchronized clusters changed more quickly (P = .032). Hyposynchronized cluster-averaged S-estimator correlated negatively with progression of AD (r = -0.98769, P = .0103). In conclusion, the present study provides a whole-brain, AD-specific phenotype of temporal coordination in distributed cortical networks, which is an early diagnostic tool for progression of AD. PMID:24590871

  5. PACAP signaling exerts opposing effects on neuroprotection and neuroinflammation during disease progression in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis?

    PubMed Central

    Ringer, Cornelia; Bning, Luisa-Sybille; Schfer, Martin K.H.; Eiden, Lee E.; Weihe, Eberhard; Schtz, Burkhard

    2014-01-01

    Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic peptide with autocrine neuroprotective and paracrine anti-inflammatory properties in various models of acute neuronal damage and neurodegenerative diseases. Therefore, we examined a possible beneficial role of endogenous PACAP in the superoxide dismutase 1, SOD1(G93A), mouse model of amyotrophic lateral sclerosis (ALS), a lethal neurodegenerative disease particularly affecting somatomotor neurons. In wild-type mice, somatomotor and visceromotor neurons in brain stem and spinal cord were found to express the PACAP specific receptor PAC1, but only visceromotor neurons expressed PACAP as a potential autocrine source of regulation of these receptors. In SOD1(G93A) mice, only a small subset of the surviving somatomotor neurons showed induction of PACAP mRNA, and somatomotor neuron degeneration was unchanged in PACAP-deficient SOD1(G93A) mice. Pre-ganglionic sympathetic visceromotor neurons were found to be resistant in SOD1(G93A) mice, while pre-ganglionic parasympathetic neurons degenerated during ALS disease progression in this mouse model. PACAP-deficient SOD1(G93A) mice showed even greater pre-ganglionic parasympathetic neuron loss compared to SOD1(G93A) mice, and additional degeneration of pre-ganglionic sympathetic neurons. Thus, constitutive expression of PACAP and PAC1 may confer neuroprotection to central visceromotor neurons in SOD1(G93A) mice via autocrine pathways. Regarding the progression of neuroinflammation, the switch from amoeboid to hypertrophic microglial phenotype observed in SOD1(G93A) mice was absent in PACAP-deficient SOD1(G93A) mice. Thus, endogenous PACAP may promote microglial cytodestructive functions thought to drive ALS disease progression. This hypothesis was consistent with prolongation of life expectancy and preserved tongue motor function in PACAP-deficient SOD1(G93A) mice, compared to SOD1(G93A) mice. Given the protective role of PACAP expression in visceromotor neurons and the opposing effect on microglial function in SOD1(G93A) mice, both PACAP agonism and antagonism may be promising therapeutic tools for ALS treatment, if stage of disease progression and targeting the specific auto- and paracrine signaling pathways are carefully considered. PMID:23466699

  6. Adipokines and Osteoarthritis: Novel Molecules Involved in the Pathogenesis and Progression of Disease

    PubMed Central

    Conde, Javier; Scotece, Morena; Gmez, Rodolfo; Lopez, Veronica; Gmez-Reino, Juan Jesus; Gualillo, Oreste

    2011-01-01

    Obesity has been considered a risk factor for osteoarthritis and it is usually accepted that obesity contributes to the development and progression of osteoarthritis by increasing mechanical load of the joints. Nevertheless, recent advances in the physiology of white adipose tissue evidenced that fat cells produce a plethora of factors, called adipokines, which have a critical role in the development of ostearthritis, besides to mechanical effects. In this paper, we review the role of adipokines and highlight the cellular and molecular mechanisms at play in osteoarthritis elicited by adipokines. We also emphasize how defining the role of adipokines has broadned our understanding of the diversity of factors involved in the genesis and progression of osteoarthritis in the hope of modifying it to prevent and treat diseases. PMID:22046513

  7. Human Respiratory Syncytial Virus: Role of Innate Immunity in Clearance and Disease Progression.

    PubMed

    Farrag, Mohamed A; Almajhdi, Fahad N

    2016-01-01

    Human respiratory syncytial virus (HRSV) infections have worldwide records. The virus is responsible for bronchiolitis, pneumonia, and asthma in humans of different age groups. Premature infants, young children, and immunocompromised individuals are prone to severe HRSV infection that may lead to death. Based on worldwide estimations, millions of cases were reported in both developed and developing countries. In fact, HRSV symptoms develop mainly as a result of host immune response. Due to inability to establish long lasting adaptive immunity, HRSV infection is recurrent and hence impairs vaccine development. Once HRSV attached to the airway epithelia, interaction with the host innate immune components starts. HRSV interaction with pulmonary innate defenses is crucial in determining the disease outcome. Infection of alveolar epithelial cells triggers a cascade of events that lead to recruitment and activation of leukocyte populations. HRSV clearance is mediated by a number of innate leukocytes, including macrophages, natural killer cells, eosinophils, dendritic cells, and neutrophils. Regulation of these cells is mediated by cytokines, chemokines, and other immune mediators. Although the innate immune system helps to clear HRSV infection, it participates in disease progression such as bronchiolitis and asthma. Resolving the mechanisms by which HRSV induces pathogenesis, different possible interactions between the virus and immune components, and immune cells interplay are essential for developing new effective vaccines. Therefore, the current review focuses on how the pulmonary innate defenses mediate HRSV clearance and to what extent they participate in disease progression. In addition, immune responses associated with HRSV vaccines will be discussed. PMID:26679242

  8. Efficient Learning of Continuous-Time Hidden Markov Models for Disease Progression

    PubMed Central

    Liu, Yu-Ying; Li, Shuang; Li, Fuxin; Song, Le; Rehg, James M.

    2016-01-01

    The Continuous-Time Hidden Markov Model (CT-HMM) is an attractive approach to modeling disease progression due to its ability to describe noisy observations arriving irregularly in time. However, the lack of an efficient parameter learning algorithm for CT-HMM restricts its use to very small models or requires unrealistic constraints on the state transitions. In this paper, we present the first complete characterization of efficient EM-based learning methods for CT-HMM models. We demonstrate that the learning problem consists of two challenges: the estimation of posterior state probabilities and the computation of end-state conditioned statistics. We solve the first challenge by reformulating the estimation problem in terms of an equivalent discrete time-inhomogeneous hidden Markov model. The second challenge is addressed by adapting three approaches from the continuous time Markov chain literature to the CT-HMM domain. We demonstrate the use of CT-HMMs with more than 100 states to visualize and predict disease progression using a glaucoma dataset and an Alzheimer’s disease dataset.

  9. Cell cycle proteins in brain in mild cognitive impairment: insights into progression to Alzheimer disease.

    PubMed

    Keeney, Jeriel T R; Swomley, Aaron M; Harris, Jessica L; Fiorini, Ada; Mitov, Mihail I; Perluigi, Marzia; Sultana, Rukhsana; Butterfield, D Allan

    2012-10-01

    Recent studies have demonstrated the re-emergence of cell cycle proteins in brain as patients progress from the early stages of mild cognitive impairment (MCI) into Alzheimer's disease (AD). Oxidative stress markers present in AD have also been shown to be present in MCI brain suggesting that these events occur in early stages of the disease. The levels of key cell cycle proteins, such as CDK2, CDK5, cyclin G1, and BRAC1 have all been found to be elevated in MCI brain compared to age-matched control. Further, peptidyl prolyl cis-trans isomerase (Pin1), a protein that plays an important role in regulating the activity of key proteins, such as CDK5, GSK3-β, and PP2A that are involved in both the phosphorylation state of Tau and in the cell cycle, has been found to be oxidatively modified and downregulated in both AD and MCI brain. Hyperphosphorylation of Tau then results in synapse loss and the characteristic Tau aggregation as neurofibrillary tangles, an AD hallmark. In this review, we summarized the role of cell cycle dysregulation in the progression of disease from MCI to AD. Based on the current literature, it is tempting to speculate that a combination of oxidative stress and cell cycle dysfunction conceivably leads to neurodegeneration. PMID:22083458

  10. Disruption of IKAROS activity in primitive chronic-phase CML cells mimics myeloid disease progression

    PubMed Central

    Beer, Philip A.; Knapp, David J. H. F.; Miller, Paul H.; Kannan, Nagarajan; Sloma, Ivan; Heel, Kathy; Babovic, Sonja; Bulaeva, Elizabeth; Rabu, Gabrielle; Terry, Jefferson; Druker, Brian J.; Loriaux, Marc M.; Loeb, Keith R.; Radich, Jerald P.; Erber, Wendy N.

    2015-01-01

    Without effective therapy, chronic-phase chronic myeloid leukemia (CP-CML) evolves into an acute leukemia (blast crisis [BC]) that displays either myeloid or B-lymphoid characteristics. This transition is often preceded by a clinically recognized, but biologically poorly characterized, accelerated phase (AP). Here, we report that IKAROS protein is absent or reduced in bone marrow blasts from most CML patients with advanced myeloid disease (AP or BC). This contrasts with primitive CP-CML cells and BCR-ABL1negative acute myeloid leukemia blasts, which express readily detectable IKAROS. To investigate whether loss of IKAROS contributes to myeloid disease progression in CP-CML, we examined the effects of forced expression of a dominant-negative isoform of IKAROS (IK6) in CP-CML patients CD34+ cells. We confirmed that IK6 disrupts IKAROS activity in transduced CP-CML cells and showed that it confers on them features of AP-CML, including a prolonged increased output in vitro and in xenografted mice of primitive cells with an enhanced ability to differentiate into basophils. Expression of IK6 in CD34+ CP-CML cells also led to activation of signal transducer and activator of transcription 5 and transcriptional repression of its negative regulators. These findings implicate loss of IKAROS as a frequent step and potential diagnostic harbinger of progressive myeloid disease in CML patients. PMID:25370416

  11. Progress of mesenchymal stem cell therapy for neural and retinal diseases.

    PubMed

    Ng, Tsz Kin; Fortino, Veronica R; Pelaez, Daniel; Cheung, Herman S

    2014-04-26

    Complex circuitry and limited regenerative power make central nervous system (CNS) disorders the most challenging and difficult for functional repair. With elusive disease mechanisms, traditional surgical and medical interventions merely slow down the progression of the neurodegenerative diseases. However, the number of neurons still diminishes in many patients. Recently, stem cell therapy has been proposed as a viable option. Mesenchymal stem cells (MSCs), a widely-studied human adult stem cell population, have been discovered for more than 20 years. MSCs have been found all over the body and can be conveniently obtained from different accessible tissues: bone marrow, blood, and adipose and dental tissue. MSCs have high proliferative and differentiation abilities, providing an inexhaustible source of neurons and glia for cell replacement therapy. Moreover, MSCs also show neuroprotective effects without any genetic modification or reprogramming. In addition, the extraordinary immunomodulatory properties of MSCs enable autologous and heterologous transplantation. These qualities heighten the clinical applicability of MSCs when dealing with the pathologies of CNS disorders. Here, we summarize the latest progress of MSC experimental research as well as human clinical trials for neural and retinal diseases. This review article will focus on multiple sclerosis, spinal cord injury, autism, glaucoma, retinitis pigmentosa and age-related macular degeneration. PMID:24772238

  12. Progress of mesenchymal stem cell therapy for neural and retinal diseases

    PubMed Central

    Ng, Tsz Kin; Fortino, Veronica R; Pelaez, Daniel; Cheung, Herman S

    2014-01-01

    Complex circuitry and limited regenerative power make central nervous system (CNS) disorders the most challenging and difficult for functional repair. With elusive disease mechanisms, traditional surgical and medical interventions merely slow down the progression of the neurodegenerative diseases. However, the number of neurons still diminishes in many patients. Recently, stem cell therapy has been proposed as a viable option. Mesenchymal stem cells (MSCs), a widely-studied human adult stem cell population, have been discovered for more than 20 years. MSCs have been found all over the body and can be conveniently obtained from different accessible tissues: bone marrow, blood, and adipose and dental tissue. MSCs have high proliferative and differentiation abilities, providing an inexhaustible source of neurons and glia for cell replacement therapy. Moreover, MSCs also show neuroprotective effects without any genetic modification or reprogramming. In addition, the extraordinary immunomodulatory properties of MSCs enable autologous and heterologous transplantation. These qualities heighten the clinical applicability of MSCs when dealing with the pathologies of CNS disorders. Here, we summarize the latest progress of MSC experimental research as well as human clinical trials for neural and retinal diseases. This review article will focus on multiple sclerosis, spinal cord injury, autism, glaucoma, retinitis pigmentosa and age-related macular degeneration. PMID:24772238

  13. Identification of MMP-9 as a biomarker for detecting progression of chronic obstructive pulmonary disease.

    PubMed

    Abd El-Fatah, Marwa F; Ghazy, Mohamed A; Mostafa, Mohamed S; El-Attar, May M; Osman, Ahmed

    2015-12-01

    Chronic obstructive pulmonary disease (COPD) is a complex immunological disease with multiple pathological features that is primarily induced by smoking together with additional genetic risk factors. COPD is frequently underdiagnosed; forced expiratory volume in the first second (FEV1) is considered to be the main diagnostic measure for COPD, yet it is insufficiently sensitive to monitor disease progression. Biomarkers capable of monitoring COPD progression and severity are needed. In this report, we evaluated matrix metalloproteinase-9 (MMP-9) as an early marker for the detection and staging of COPD, by assessing the mRNA levels of MMP-9 in peripheral blood samples collected from 22 COPD patients, 6 asymptomatic smokers, and 5 healthy controls. Our results demonstrate that the mRNA levels of MMP-9 increased more than two-fold in severe COPD relative to non-COPD smokers or moderate COPD groups. Moreover, in the very severe COPD group, MMP-9 mRNA levels showed a 4-fold increase relative to the non-COPD smokers or the moderate COPD groups, while there was a mild increase (?40%) when compared to the severe COPD group. Taken together, our results suggest that MMP-9 serves as a biomarker for the grade and severity of COPD. PMID:26291981

  14. Chronic Kidney Disease Progression in Elderly Iranian Patients: A Cohort Study

    PubMed Central

    Shojamoradi, Mohammad Hossein; Saberi Isfeedvajani, Mohsen; Mahdavi-Mazdeh, Mitra; Ahmadi, Farrokhlagha; Gatmiri, Seyed Mansour; Abbasi Larki, Rozina

    2014-01-01

    Background: In the past few decades, Chronic Kidney Disease (CKD) - a disease with progressive decline in renal function - has become an important problem of global public health, not only in developed countries, but also in developing countries with less economic power. Objectives: In this study, CKD progression to death or End Stage Renal Disease (ESRD) in elderly Iranian patients was compared with younger counterparts. Patients and Methods: This retrospective cohort study was conducted on CKD patients with estimated Glomerular Filtration Rate (eGFR) < 60 mL/min, in a nephrology clinic in Tehran from December of 2006 until December of 2012. eGFR trend, death and need to renal replacement therapy (RRT) were evaluated as outcomes and compared between patients younger and older than 60 years. Data were analyzed using SPSS version 13. Results: Five-hundred and two patients were enrolled and followed up for an average of 37.6 months. Two thirds of the patients were older than 60 years. The incidence density of ESRD in patients younger and older than 60 years were 6.3 and 3.6 for 100 persons per year, respectively. Younger ones showed more rapid decline in their eGFR, while older patients had more stable renal function. Conclusions: It seems necessary to conduct more researches in order to redefine CKD and identify its prognostic markers in elderly population. PMID:25695035

  15. Longitudinal deformation models, spatial regularizations and learning strategies to quantify Alzheimer's disease progression

    PubMed Central

    Fiot, Jean-Baptiste; Raguet, Hugo; Risser, Laurent; Cohen, Laurent D.; Fripp, Jurgen; Vialard, Franois-Xavier

    2014-01-01

    In the context of Alzheimer's disease, two challenging issues are (1) the characterization of local hippocampal shape changes specific to disease progression and (2) the identification of mild-cognitive impairment patients likely to convert. In the literature, (1) is usually solved first to detect areas potentially related to the disease. These areas are then considered as an input to solve (2). As an alternative to this sequential strategy, we investigate the use of a classification model using logistic regression to address both issues (1) and (2) simultaneously. The classification of the patients therefore does not require any a priori definition of the most representative hippocampal areas potentially related to the disease, as they are automatically detected. We first quantify deformations of patients' hippocampi between two time points using the large deformations by diffeomorphisms framework and transport these deformations to a common template. Since the deformations are expected to be spatially structured, we perform classification combining logistic loss and spatial regularization techniques, which have not been explored so far in this context, as far as we know. The main contribution of this paper is the comparison of regularization techniques enforcing the coefficient maps to be spatially smooth (Sobolev), piecewise constant (total variation) or sparse (fused LASSO) with standard regularization techniques which do not take into account the spatial structure (LASSO, ridge and ElasticNet). On a dataset of 103 patients out of ADNI, the techniques using spatial regularizations lead to the best classification rates. They also find coherent areas related to the disease progression. PMID:24936423

  16. Serum protein electrophoresis under effective control of HIV-1 disease progression

    PubMed Central

    Adedeji, Adebayo Lawrence; Adenikinju, Rufus Omotayo; Ajele, Joshua Olufemi; Olawoye, Theophilus Ladapo

    2014-01-01

    In this report, we compared the serum protein electrophoresis (SPE) patterns in a subset of HIV-1-infected subjects who did not progress to AIDS without antiretroviral treatment with those in whose control of disease progression was achieved by highly active antiretroviral therapy (HAART). SPE and immunofixation electrophoresis were performed on Helena Electrophoresis System according to manufacturers instructions. The percentage of SPE abnormalities, resembling chronic inflammation, was significantly higher in HIV-1-infected subject without HAART compared with those under HAART (p = 0.001). The majority of individuals under HAART showed evidence of oligoclonal bands on the ?-band against a polyclonal background compared with those without HAART but -?-band bridging was more evident. Immunofixation pattern was consistent with oligoclonal hypergammaglobulinaemia of IgG kappa type, which was found to be more intense in group without HAART. HIV clinical status did not show appreciable effect on the SPE pattern in subjects without HAART. However, under effective HAART, subjects with better CD4 T-cell count were associated with higher ?-globulin band. In group without HAART, acute infection was found to be associated the higher ?-globulin fraction compared with chronic infection. The opposite was the case under effective HAART. HIV infected subjects that did not progress to AIDS were associated with markedly abnormal SPE pattern. Overall results reflect the host ability compensate defective cellular immunity in HIV-1 infection with humoral immune responses. These findings underscore the usefulness of SPE monitoring HIV disease management and identifying individuals that may not progress to full-blown AIDS in the absence of treatment. PMID:26417299

  17. PROGRESSION OF DISEASES CAUSED BY THE OYSTER PARASITES, PERKINSUS MARINUS AND HAPLOSPORIDIUM NELSONI IN CRASSOSTREA VIRGINICA ON CONSTRUCTED INTERTIDAL REEFS

    EPA Science Inventory

    The progression of diseases caused by the oyster parasites, Perkinsus marinus and Haplosporidium nelsoni, were evaluated by periodic sampling (May 1994 - December 1995) of oysters, Crassostrea virginica, on an artificial reef located in the Piankatank River, Virginia. The infecti...

  18. Progression of mild Alzheimers disease: knowledge and prediction models required for future treatment strategies

    PubMed Central

    2013-01-01

    Introduction Knowledge of longitudinal progression in mild Alzheimers disease (AD) is required for the evaluation of disease-modifying therapies. Our aim was to observe the effects of long-term cholinesterase inhibitor (ChEI) therapy in mild AD patients in a routine clinical setting. Methods This was a prospective, open-label, non-randomized, multicenter study of ChEI treatment (donepezil, rivastigmine or galantamine) conducted during clinical practice. The 734 mild AD patients (Mini-Mental State Examination (MMSE) score 20 to 26) were assessed at baseline and then semi-annually over three years. Outcome measures included the MMSE, Alzheimers Disease Assessment Scale-cognitive subscale (ADAS-cog), Clinicians Interview-Based Impression of Change (CIBIC) and Instrumental Activities of Daily Living (IADL) scale. Results After three years of ChEI therapy, 31% (MMSE) and 33% (ADAS-cog) of the patients showed improved/unchanged cognitive ability, 33% showed improved/unchanged global performance and 14% showed improved/unchanged IADL capacity. Higher mean dose of ChEI and lower educational level were both predictors of more positive longitudinal cognitive and functional outcomes. Older participants and those with a better IADL score at baseline exhibited a slower rate of cognitive decline, whereas younger participants and those with higher cognitive status showed more preserved IADL ability over time. Gender and apolipoprotein E (APOE) genotype showed inconsistent results. Prediction models using the abovementioned scales are presented. Conclusions In naturalistic mild AD patients, a marked deterioration in IADL compared with cognitive and global long-term outcomes was observed, indicating the importance of functional assessments during the early stages of the disease. The participants time on ChEI treatment before inclusion in studies of new therapies might affect their rate of decline and thus the comparisons of changes in scores between various studies. An increased understanding of expected disease progression in different domains and potential predictors of disease progression is essential for assessment of future therapies in AD. PMID:24099236

  19. Letter Report Documenting Progress of Second Generation ATF FeCrAl Alloy Fabrication

    SciTech Connect

    Yamamoto,, Y.; Yang, Y.; Field, K. G.; Terrani, K.; Pint, B. A.; Snead, L. L.

    2014-06-10

    Development of the 2nd generation ATF FeCrAl alloy has been initiated, and a candidate alloy was selected for trial tube fabrication through hot-extrusion and gun-drilling processes. Four alloys based on Fe-13Cr-4.5Al-0.15Y in weight percent were newly cast with minor alloying additions of Mo, Si, Nb, and C to promote solid-solution and second-phase precipitate strengthening. The alloy compositions were selected with guidance from computational thermodynamic tools. The lab-scale heats of ~ 600g were arc-melted and drop-cast, homogenized, hot-forged and -rolled, and then annealed producing plate shape samples. An alloy with Mo and Nb additions (C35MN) processed at 800°C exhibits very fine sub-grain structure with the sub-grain size of 1-3μm which exhibited more than 25% better yield and tensile strengths together with decent ductility compared to the other FeCrAl alloys at room temperature. It was found that the Nb addition was key to improving thermal stability of the fine sub-grain structure. Optimally, grains of less than 30 microns are desired, with grains up to and order of magnitude in desired produced through Nb addition. Scale-up effort of the C35MN alloy was made in collaboration with a commercial cast company who has a capability of vacuum induction melting. A 39lb columnar ingot with ~81mm diameter and ~305mm height (with hot-top) was commercially cast, homogenized, hot-extruded, and annealed providing 10mm-diameter bar-shape samples with the fine sub-grain structure. This commercial heat proved consistent with materials produced at ORNL at the lab-scale. Tubes and end caps were machined from the bar sample and provided to another work package for the ATF-1 irradiation campaign in the milestone M3FT-14OR0202251.

  20. An abnormal resting-state functional brain network indicates progression towards Alzheimer's disease.

    PubMed

    Xiang, Jie; Guo, Hao; Cao, Rui; Liang, Hong; Chen, Junjie

    2013-10-25

    Brain structure and cognitive function change in the temporal lobe, hippocampus, and prefrontal cortex of patients with mild cognitive impairment and Alzheimer's disease, and brain network-connection strength, network efficiency, and nodal attributes are abnormal. However, existing research has only analyzed the differences between these patients and normal controls. In this study, we constructed brain networks using resting-state functional MRI data that was extracted from four populations (normal controls, patients with early mild cognitive impairment, patients with late mild cognitive impairment, and patients with Alzheimer's disease) using the Alzheimer's Disease Neuroimaging Initiative data set. The aim was to analyze the characteristics of resting-state functional neural networks, and to observe mild cognitive impairment at different stages before the transformation to Alzheimer's disease. Results showed that as cognitive deficits increased across the four groups, the shortest path in the resting-state functional network gradually increased, while clustering coefficients gradually decreased. This evidence indicates that dementia is associated with a decline of brain network efficiency. In addition, the changes in functional networks revealed the progressive deterioration of network function across brain regions from healthy elderly adults to those with mild cognitive impairment and Alzheimer's disease. The alterations of node attributes in brain regions may reflect the cognitive functions in brain regions, and we speculate that early impairments in memory, hearing, and language function can eventually lead to diffuse brain injury and other cognitive impairments. PMID:25206600

  1. Hypovitaminosis D, neighborhood poverty, and progression of chronic kidney disease in disadvantaged populations

    PubMed Central

    Mehrotra, R; Norris, K

    2011-01-01

    In the United States, there are significant racial disparities in the incidence and prevalence of end-stage renal disease. The disparities are greatest for the Blacks and the magnitude of disparity is significantly greater than is evident from the incidence and prevalence data of end-stage renal disease – early stage chronic kidney disease is less common in Blacks and during that stage, mortality rate is significantly higher for that racial group. Recent studies have identified a genetic predisposition for non-diabetic renal disease among Blacks. However, genetic factors explain only part of the higher risk and the racial disparities are a result of a complex interplay of biology and sociology. Herein we focus on two factors and their role in explaining the higher risk for progression of chronic kidney disease among Blacks – one biologic (vitamin D deficiency) and one sociologic (neighborhood poverty). A greater Understanding of these factors is important in order to reduce the racial disparities in the United States. PMID:20979972

  2. Variation in black and white band disease progression in corals of the Gulf of Mannar and Palk Bay, Southeastern India.

    PubMed

    Thinesh, T; Mathews, G; Raj, K Diraviya; Patterson Edward, J K

    2014-08-11

    Information on the progression of coral diseases and transmission to live corals is scarce despite the fact that coral disease poses one of the most lethal threats to the survival of coral reefs. In this study, in situ progression rates of lesions similar to black band disease (BBD) and white band disease (WBD) were measured in different species of corals from the Gulf of Mannar (GoM) and Palk Bay, southeastern India, during the period between January and December of 2009. Maximum progression rates of 3 and 1.6 cm mo-1 for BBD and WBD, respectively, were observed during May, when the temperature exceeded 30C. The annual progression rate was 10.9 and 4.9 cm yr-1 for BBD at GoM and Palk Bay, respectively. Significant variation in the progression rate (p < 0.001) was observed between months in all the examined species. Significant correlation between temperature and disease progression rates for BBD (R2 = 0.875, p ? 0.001) and WBD (R2 = 0.776, p ? 0.001) was recorded. Rates of disease progression were higher in Palk Bay than in GoM. This could be attributed to the higher temperature coupled with higher anthropogenic activities in Palk Bay. Severe mortality was observed due to both BBD and WBD. No sign of recovery was noticed in the disease-affected colonies at either study site. Anthropogenic activities should be checked, and further research on both the transmission and progression rate and role of the diseases in reef dynamics should be carried out to understand the causal factors in reef degradation and generate a plan to manage the reef properly. PMID:25114046

  3. Effects of temperature and light on the progression of black band disease on the reef coral, Montipora hispida

    NASA Astrophysics Data System (ADS)

    Sato, Y.; Bourne, D. G.; Willis, B. L.

    2011-09-01

    Understanding environmental drivers of black band disease (BBD), a virulent disease affecting corals worldwide, is critical to managing coral populations. Field monitoring studies have implicated seasonally elevated temperature and light as drivers of annual BBD outbreaks on the Great Barrier Reef, but do not distinguish their relative impacts. Here, we compare progression of BBD lesions on Montipora hispida among three controlled temperature (28.0, 29.0, 30.5C) and two controlled light treatments (170, 440 ?mol m-2 s-1) within normal seasonal ranges at the site. BBD progression rates were greatest (5.2 mm d-1) in the 30.5C/high-light treatment and least (3.2 mm d-1) in the 28C/low-light treatment. High light significantly enhanced BBD progression, whereas increases in disease progression under high temperatures were not statistically significant, identifying the greater role of light in driving BBD dynamics within the temperature range examined. Greater BBD progression during daytime compared with nighttime (by 2.2-3.6-fold across temperature and light treatments) corroborates our conclusion that light is the pre-eminent factor driving BBD progression at typical summer temperatures. Decreased photochemical efficiency of algal endosymbionts in the high-temperature/high-light treatments suggests that compromised health of the coral holobiont contributes to enhanced disease progression, highlighting the complexity of disease dynamics in host-pathogen systems responding to environmental changes.

  4. Involvement of ‘stress-response’ kinase pathways in Alzheimer’s disease progression

    PubMed Central

    Mairet-Coello, Georges

    2014-01-01

    Alzheimer’s disease (AD) is the most prevalent cause of dementia, affecting more than 25 million people worldwide. Current models of the pathophysiological mechanisms of AD suggest that the accumulation of soluble oligomeric forms of amyloid-β (Aβ) peptides causes early loss of excitatory synapses and impairs synaptic plasticity. The signaling pathways mediating Aβ oligomer-induced impairment of synaptic plasticity and loss of excitatory synapses are only beginning to be unraveled. Here, we review recent evidence supporting the critical contribution of conserved ‘stress-response’ kinase pathways in AD progression. PMID:24709372

  5. Using palliative care in progressive neuromuscular disease to maximize quality of life.

    PubMed

    Carter, Gregory T; Joyce, Nanette C; Abresch, Allison L; Smith, Amanda E; VandeKeift, Gregg K

    2012-11-01

    This article discusses the role of palliative care in the treatment pathway of patients with progressive neuromuscular disease (NDM), including amyotrophic lateral sclerosis and Duchenne muscular dystrophy (DMD). People with severe NMDs like DMD are now living much longer, well in to adulthood. This makes them suitable for the medical model of palliative care. Yet palliative medicine is a new area, especially for "adults" with DMD. Strategies for identifying the most effective modalities to alleviate suffering in patients with an NMD receiving palliative services and creating best practice standards in pain and symptom management for this patient population are discussed. PMID:23137745

  6. Comparison of motor, cognitive, and behavioral features in progressive supranuclear palsy and Parkinson's disease.

    PubMed

    Cordato, Nicholas J; Halliday, Glenda M; Caine, Diana; Morris, John G L

    2006-05-01

    Major clinical features and global measures were systematically evaluated and compared in progressive supranuclear palsy (PSP) and Parkinson's disease (PD). In addition to gaze palsy and early postural instability in PSP, absence of levodopa-induced dyskinesia, frontalis muscle overactivity, primitive reflexes, visuospatial impairment, and substantial frontal behavioral disturbances differentiated almost all patients with this disorder from PD. For PSP, behavioral changes related to severity of general disability, thereby challenging previous models of relationships between behavior, motor, and cognitive disturbance for this disorder. PMID:16353177

  7. Applying Proteomics to the Diagnosis and Treatment of ALS and Related Diseases

    PubMed Central

    Lacomis, David

    2010-01-01

    Protein-based biomarkers for amyotrophic lateral sclerosis (ALS) and other motor neuron diseases (MNDs) have many potential clinical utilities, including diagnostic, prognostic, and drug development indications. During the past decade a number of potential protein biomarkers have been proposed for MNDs. Further verification studies, followed by large validation and qualification studies, are required to advance these initial discoveries toward clinical use. Study of additional patient populations, including disease mimics, is required during the validation phase of biomarker development. Important regulatory issues are discussed that will affect the timing and strategy for biomarker assay development in ALS and other MNDs. The continued development of protein biomarkers for MNDs requires extensive collaboration between academic clinicians and scientists in conjunction with the biotechnology and pharmaceutical industries. PMID:19670321

  8. A computational method for computing an Alzheimer's disease progression score; experiments and validation with the ADNI data set.

    PubMed

    Jedynak, Bruno M; Liu, Bo; Lang, Andrew; Gel, Yulia; Prince, Jerry L

    2015-01-01

    Understanding the time-dependent changes of biomarkers related to Alzheimer's disease (AD) is a key to assessing disease progression and measuring the outcomes of disease-modifying therapies. In this article, we validate an AD progression score model which uses multiple biomarkers to quantify the AD progression of subjects following 3 assumptions: (1) there is a unique disease progression for all subjects; (2) each subject has a different age of onset and rate of progression; and (3) each biomarker is sigmoidal as a function of disease progression. Fitting the parameters of this model is a challenging problem which we approach using an alternating least squares optimization algorithm. To validate this optimization scheme under realistic conditions, we use the Alzheimer's Disease Neuroimaging Initiative cohort. With the help of Monte Carlo simulations, we show that most of the global parameters of the model are tightly estimated, thus enabling an ordering of the biomarkers that fit the model well, ordered as: the Rey auditory verbal learning test with 30 minutes delay, the sum of the 2 lateral hippocampal volumes divided by the intracranial volume, followed (by the clinical dementia rating sum of boxes score and the mini-mental state examination score) in no particular order and at last the AD assessment scale-cognitive subscale. PMID:25444605

  9. Spliceosome integrity is defective in the motor neuron diseases ALS and SMA.

    PubMed

    Tsuiji, Hitomi; Iguchi, Yohei; Furuya, Asako; Kataoka, Ayane; Hatsuta, Hiroyuki; Atsuta, Naoki; Tanaka, Fumiaki; Hashizume, Yoshio; Akatsu, Hiroyasu; Murayama, Shigeo; Sobue, Gen; Yamanaka, Koji

    2013-02-01

    Two motor neuron diseases, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are caused by distinct genes involved in RNA metabolism, TDP-43 and FUS/TLS, and SMN, respectively. However, whether there is a shared defective mechanism in RNA metabolism common to these two diseases remains unclear. Here, we show that TDP-43 and FUS/TLS localize in nuclear Gems through an association with SMN, and that all three proteins function in spliceosome maintenance. We also show that in ALS, Gems are lost, U snRNA levels are up-regulated and spliceosomal U snRNPs abnormally and extensively accumulate in motor neuron nuclei, but not in the temporal lobe of FTLD with TDP-43 pathology. This aberrant accumulation of U snRNAs in ALS motor neurons is in direct contrast to SMA motor neurons, which show reduced amounts of U snRNAs, while both have defects in the spliceosome. These findings indicate that a profound loss of spliceosome integrity is a critical mechanism common to neurodegeneration in ALS and SMA, and may explain cell-type specific vulnerability of motor neurons. PMID:23255347

  10. Rapidly progressive glomerulonephritis due to coexistent anti-glomerular basement membrane disease and fibrillary glomerulonephritis

    PubMed Central

    Cheungpasitporn, Wisit; Zacharek, Claudia C.; Fervenza, Fernando C.; Cornell, Lynn D.; Sethi, Sanjeev; Herrera Hernandez, Loren P.; Nasr, Samih H.; Alexander, Mariam P.

    2016-01-01

    Anti-glomerular basement membrane (anti-GBM) disease is a major cause of rapidly progressive glomerulonephritis (RPGN). On the other hand, fibrillary glomerulonephritis (GN) typically presents as proteinuria, hematuria and renal insufficiency, but rarely as RPGN. Without electron microscopy, the diagnosis of fibrillary GN can be missed. We report a 68-year-old white woman who presented with RPGN with kidney biopsy demonstrating diffuse crescentic GN on light microscopy. By immunofluorescence, there was bright linear staining of the GBMs and smudgy mesangial staining for immunoglobulin G, C3, and kappa and lambda light chain. Electron microscopy revealed fibrillary deposits in the GBM and mesangium. A serum test for anti-GBM antibody was positive. To our knowledge, this is the first report of coexistence of fibrillary GN in a patient with anti-GBM disease. Electron microscopy is critical to identify the coexistence of other GN in patients presenting with crescentic GN. PMID:26798468

  11. Predicting disease progression from short biomarker series using expert advice algorithm

    NASA Astrophysics Data System (ADS)

    Morino, Kai; Hirata, Yoshito; Tomioka, Ryota; Kashima, Hisashi; Yamanishi, Kenji; Hayashi, Norihiro; Egawa, Shin; Aihara, Kazuyuki

    2015-05-01

    Well-trained clinicians may be able to provide diagnosis and prognosis from very short biomarker series using information and experience gained from previous patients. Although mathematical methods can potentially help clinicians to predict the progression of diseases, there is no method so far that estimates the patient state from very short time-series of a biomarker for making diagnosis and/or prognosis by employing the information of previous patients. Here, we propose a mathematical framework for integrating other patients' datasets to infer and predict the state of the disease in the current patient based on their short history. We extend a machine-learning framework of ``prediction with expert advice'' to deal with unstable dynamics. We construct this mathematical framework by combining expert advice with a mathematical model of prostate cancer. Our model predicted well the individual biomarker series of patients with prostate cancer that are used as clinical samples.

  12. Rapidly progressive glomerulonephritis due to coexistent anti-glomerular basement membrane disease and fibrillary glomerulonephritis.

    PubMed

    Cheungpasitporn, Wisit; Zacharek, Claudia C; Fervenza, Fernando C; Cornell, Lynn D; Sethi, Sanjeev; Herrera Hernandez, Loren P; Nasr, Samih H; Alexander, Mariam P

    2016-02-01

    Anti-glomerular basement membrane (anti-GBM) disease is a major cause of rapidly progressive glomerulonephritis (RPGN). On the other hand, fibrillary glomerulonephritis (GN) typically presents as proteinuria, hematuria and renal insufficiency, but rarely as RPGN. Without electron microscopy, the diagnosis of fibrillary GN can be missed. We report a 68-year-old white woman who presented with RPGN with kidney biopsy demonstrating diffuse crescentic GN on light microscopy. By immunofluorescence, there was bright linear staining of the GBMs and smudgy mesangial staining for immunoglobulin G, C3, and kappa and lambda light chain. Electron microscopy revealed fibrillary deposits in the GBM and mesangium. A serum test for anti-GBM antibody was positive. To our knowledge, this is the first report of coexistence of fibrillary GN in a patient with anti-GBM disease. Electron microscopy is critical to identify the coexistence of other GN in patients presenting with crescentic GN. PMID:26798468

  13. The Progress of Mitophagy and Related Pathogenic Mechanisms of the Neurodegenerative Diseases and Tumor

    PubMed Central

    Song, Ying; Ding, Wei; Xiao, Yan; Lu, Kong-jun

    2015-01-01

    Mitochondrion, an organelle with two layers of membrane, is extremely vital to eukaryotic cell. Its major functions are energy center and apoptosis censor inside cell. The intactness of mitochondrial membrane is important to maintain its structure and function. Mitophagy is one kind of autophagy. In recent years, studies of mitochondria have shown that mitophagy is regulated by various factors and is an important regulation mechanism for organisms to maintain their normal state. In addition, abnormal mitophagy is closely related to several neurodegenerative diseases and tumor. However, the related signal pathway and its regulation mechanism still remain unclear. As a result, summarizing the progress of mitophagy and its related pathogenic mechanism not only helps to reveal the complicated molecular mechanism, but also helps to find a new target to treat the related diseases. PMID:26779531

  14. Delayed Disease Progression in Cynomolgus Macaques Infected with Ebola Virus Makona Strain

    PubMed Central

    Marzi, Andrea; Feldmann, Friederike; Hanley, Patrick W.; Scott, Dana P.; Gnther, Stephan

    2015-01-01

    In late 2013, the largest documented outbreak of Ebola hemorrhagic fever started in Guinea and has since spread to neighboring countries, resulting in almost 27,000 cases and >11,000 deaths in humans. In March 2014, Ebola virus (EBOV) was identified as the causative agent. This study compares the pathogenesis of a new EBOV strain, Makona, which was isolated in Guinea in 2014 with the prototype strain from the 1976 EBOV outbreak in the former Zaire. Both strains cause lethal disease in cynomolgus macaques with similar pathologic changes and hallmark features of Ebola hemorrhagic fever. However, disease progression was delayed in EBOV-Makonainfected animals, suggesting decreased rather than increased virulence of this most recent EBOV strain. PMID:26402165

  15. Mechanisms of disease: epithelial-mesenchymal transition and back again: does cellular plasticity fuel neoplastic progression?

    SciTech Connect

    Bissell, Mina J; Turley, Eva A.; Veiseh, Mandana; Radisky, Derek C.; Bissell, Mina J.

    2008-02-13

    Epithelial-mesenchymal transition (EMT) is a conversion that facilitates organ morphogenesis and tissue remodeling in physiological processes such as embryonic development and wound healing. A similar phenotypic conversion is also detected in fibrotic diseases and neoplasia, which is associated with disease progression. EMT in cancer epithelial cells often seems to be an incomplete and bi-directional process. In this Review, we discuss the phenomenon of EMT as it pertains to tumor development, focusing on exceptions to the commonly held rule that EMT promotes invasion and metastasis. We also highlight the role of the RAS-controlled signaling mediators, ERK1, ERK2 and PI3-kinase, as microenvironmental responsive regulators of EMT.

  16. TDP-43 Proteinopathy and ALS: Insights into Disease Mechanisms and Therapeutic Targets.

    PubMed

    Scotter, Emma L; Chen, Han-Jou; Shaw, Christopher E

    2015-04-01

    Therapeutic options for patients with amyotrophic lateral sclerosis (ALS) are currently limited. However, recent studies show that almost all cases of ALS, as well as tau-negative frontotemporal dementia (FTD), share a common neuropathology characterized by the deposition of TAR-DNA binding protein (TDP)-43-positive protein inclusions, offering an attractive target for the design and testing of novel therapeutics. Here we demonstrate how diverse environmental stressors linked to stress granule formation, as well as mutations in genes encoding RNA processing proteins and protein degradation adaptors, initiate ALS pathogenesis via TDP-43. We review the progressive development of TDP-43 proteinopathy from cytoplasmic mislocalization and misfolding through to macroaggregation and the addition of phosphate and ubiquitin moieties. Drawing from cellular and animal studies, we explore the feasibility of therapeutics that act at each point in pathogenesis, from mitigating genetic risk using antisense oligonucleotides to modulating TDP-43 proteinopathy itself using small molecule activators of autophagy, the ubiquitin-proteasome system, or the chaperone network. We present the case that preventing the misfolding of TDP-43 and/or enhancing its clearance represents the most important target for effectively treating ALS and frontotemporal dementia. PMID:25652699

  17. Long-Term Nonsense Suppression Therapy Moderates MPS I-H Disease Progression

    PubMed Central

    Gunn, Gwen; Dai, Yanying; Du, Ming; Belakhov, Valery; Kandasamy, Jeyakumar; Schoeb, Trenton R.; Baasov, Timor; Bedwell, David M.; Keeling, Kim M.

    2014-01-01

    Nonsense suppression therapy is a therapeutic approach aimed at treating genetic diseases caused by in-frame premature termination codons (PTCs; also commonly known as nonsense mutations). This approach utilizes compounds that suppress translation termination at PTCs, which allows translation to continue and partial levels of deficient protein function to be restored. We hypothesize that suppression therapy can attenuate the lysosomal storage disease mucopolysaccharidosis type I-Hurler (MPS I-H), the severe form of ?-L-iduronidase deficiency. ?-L-iduronidase participates in glycosaminoglycan (GAG) catabolism and its insufficiency causes progressive GAG accumulation and onset of the MPS I-H phenotype, which consists of multiple somatic and neurological defects. 60-80% of MPS I-H patients carry a nonsense mutation in the IDUA gene. We previously showed that 2-week treatment with the designer aminoglycoside NB84 restored enough ?-L-iduronidase function via PTC suppression to reduce tissue GAG accumulation in the Iduatm1Kmke MPS I-H mouse model, which carries a PTC homologous to the human IDUA-W402X nonsense mutation. Here we report that long-term NB84 administration maintains ?-L-iduronidase activity and GAG reduction in Iduatm1Kmke mice throughout a 28-week treatment period. Examination of more complex MPS I-H phenotypes in Iduatm1Kmke mice following 28-week NB84 treatment revealed significant moderation of the disease in multiple tissues, including the brain, heart and bone, that are resistant to current MPS I-H therapies. This study represents the first demonstration that long-term nonsense suppression therapy can moderate progression of a genetic disease. PMID:24411223

  18. Mixed connective tissue disease presenting with progressive scleroderma symptoms in a 10-year-old girl

    PubMed Central

    Latu?kiewicz-Potemska, Joanna; Biernacka-Zieli?ska, Ma?gorzata; Sta?czyk, Jerzy; Smolewska, El?bieta

    2013-01-01

    Mixed connective tissue disease (MCTD) is a systemic inflammatory disease affecting connective tissue with the underlying autoimmunological mechanism. The core of MCTD is an appearance of symptoms of several other inflammatory diseases of connective tissue systemic lupus erythematosus, systemic scleroderma, poly- or dermatomyositis, rheumatoid arthritis at the same time, accompanied by a high level of anti-ribonucleoprotein antibodies (anti-U1RNP). The disease was described more than 40 years ago by Sharp et al. During recent years, many efforts to better understand clinical and serological features of MCTD have been made. Diagnosis of MCTD can be difficult. Obligatory international diagnostic criteria are required to be fulfilled. Several versions of such criteria have been proposed, but the most widely used one was described by Kasukawa. There is no consensus about treatment a choice of drugs depends on symptoms. We present a case of a 10-year-old girl with sclerodactyly and trophic damages of fingers accompanied by symptoms of Raynaud's phenomenon. After an almost 2-year course of the disease, a diagnosis of MCTD has been established. PMID:24353496

  19. Progress on PEEM3 - An Aberration Corrected X-Ray PhotoemissionElectron Microscope at the ALS

    SciTech Connect

    MacDowell, Alastair A.; Feng, J.; DeMello, A.; Doran, A.; Duarte,R.; Forest, E.; Kelez, N.; Marcus, M.A.; Miller, T.; Padmore, H.A.; Raoux, S.; Robin, D.; Scholl, A.; Schlueter, R.; Schmid, P.; Stohr, J.; Wan, W.; Wei, D.H.; Wu, Y.

    2006-05-20

    A new ultrahigh-resolution photoemission electron microscope called PEEM3 is being developed and built at the Advanced Light Source (ALS). An electron mirror combined with a much-simplified magnetic dipole separator is to be used to provide simultaneous correction of spherical and chromatic aberrations. It is installed on an elliptically polarized undulator (EPU) beamline, and will be operated with very high spatial resolution and high flux to study the composition, structure, electric and magnetic properties of complex materials. The instrument has been designed and is described. The instrumental hardware is being deployed in 2 phases. The first phase is the deployment of a standard PEEM type microscope consisting of the standard linear array of electrostatic electron lenses. The second phase will be the installation of the aberration corrected upgrade to improve resolution and throughput. This paper describes progress as the instrument enters the commissioning part of the first phase.

  20. Ventilatory Control in ALS

    PubMed Central

    Nichols, Nicole L.; Van Dyke, J.; Nashold, L.; Satriotomo, I.; Suzuki, M.; Mitchell, G.S.

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease. ALS selectively causes degeneration in upper and lower (spinal) motor neurons, leading to muscle weakness, paralysis and death by ventilatory failure. Although ventilatory failure is generally the cause of death in ALS, little is known concerning the impact of this disorder on respiratory motor neurons, the consequences of respiratory motor neuron cell death, or the ability of the respiratory control system to fight back via mechanisms of compensatory respiratory plasticity. Here we review known effects of ALS on breathing, including possible effects on rhythm generation, respiratory motor neurons, and their target organs: the respiratory muscles. We consider evidence for spontaneous compensatory plasticity, preserving breathing well into disease progression despite dramatic loss of spinal respiratory motor neurons. Finally, we review current and potential therapeutic approaches directed toward preserving the capacity to breathe in ALS patients. PMID:23692930

  1. An alternative medical approach for the neuroprotective therapy to slow the progression of Parkinson's disease.

    PubMed

    Muroyama, Akiko

    2013-01-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the core symptoms such as bradykinesia, resting tremor, rigidity and postural instability. Currently, pharmacotherapy and surgical approaches for the treatments of PD can only improve the neurological symptoms. Therefore, to search neuroprotective therapies using pharmacological and nonpharmacological approaches could be important to delay the progression of pathogenesis in PD. Coenzyme Q10 (CoQ10) is a component of the electron transport chain as well as an important antioxidant in mitochondrial and lipid membranes. The central role of CoQ10 in two areas implicated in the pathogenesis of PD, mitochondrial dysfunction and oxidative damages, suggest that it may be useful for treatment to slow the progression of PD. The neuroprotective effect of CoQ10 has been reported in several in vivo and in vitro models of neurodegenerative disorders. Although CoQ10 attenuated the toxin-induced reduction of dopamine content and tyrosine hydroxylase-immunoreactive neurons in the striatum of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model, it is still unknown how this nutrition affects the mitochondrial function. We demonstrated that oral administration of CoQ10 significantly attenuated the loss of dopaminergic nerve terminals induced by MPTP treatment. Furthermore, our experimental data indicate that an inhibition of mitochondrial cytochrome c release is one of the primary targets for CoQ10 and may lead to a potent neuroprotection. PMID:23903224

  2. Distinctive Pattern of Serum Elements During the Progression of Alzheimer's Disease.

    PubMed

    Paglia, Giuseppe; Miedico, Oto; Cristofano, Adriana; Vitale, Michela; Angiolillo, Antonella; Chiaravalle, Antonio Eugenio; Corso, Gaetano; Di Costanzo, Alfonso

    2016-01-01

    Element profiling is an interesting approach for understanding neurodegenerative processes, considering that compelling evidences show that element toxicity might play a crucial role in the onset and progression of Alzheimer's disease (AD). Aim of this study was to profile 22 serum elements in subjects with or at risk of AD. Thirtyfour patients with probable AD, 20 with mild cognitive impairment (MCI), 24 with subjective memory complaint (SMC) and 40 healthy subjects (HS) were included in the study. Manganese, iron, copper, zinc, selenium, thallium, antimony, mercury, vanadium and molybdenum changed significantly among the 4 groups. Several essential elements, such as manganese, selenium, zinc and iron tended to increase in SMC and then progressively to decrease in MCI and AD. Toxic elements show a variable behavior, since some elements tended to increase, while others tended to decrease in AD. A multivariate model, built using a panel of six essential elements (manganese, iron, copper, zinc, selenium and calcium) and their ratios, discriminated AD patients from HS with over 90% accuracy. These findings suggest that essential and toxic elements contribute to generate a distinctive signature during the progression of AD, and their monitoring in elderly might help to detect preclinical stages of AD. PMID:26957294

  3. Distinctive Pattern of Serum Elements During the Progression of Alzheimer’s Disease

    PubMed Central

    Paglia, Giuseppe; Miedico, Oto; Cristofano, Adriana; Vitale, Michela; Angiolillo, Antonella; Chiaravalle, Antonio Eugenio; Corso, Gaetano; Di Costanzo, Alfonso

    2016-01-01

    Element profiling is an interesting approach for understanding neurodegenerative processes, considering that compelling evidences show that element toxicity might play a crucial role in the onset and progression of Alzheimer’s disease (AD). Aim of this study was to profile 22 serum elements in subjects with or at risk of AD. Thirtyfour patients with probable AD, 20 with mild cognitive impairment (MCI), 24 with subjective memory complaint (SMC) and 40 healthy subjects (HS) were included in the study. Manganese, iron, copper, zinc, selenium, thallium, antimony, mercury, vanadium and molybdenum changed significantly among the 4 groups. Several essential elements, such as manganese, selenium, zinc and iron tended to increase in SMC and then progressively to decrease in MCI and AD. Toxic elements show a variable behavior, since some elements tended to increase, while others tended to decrease in AD. A multivariate model, built using a panel of six essential elements (manganese, iron, copper, zinc, selenium and calcium) and their ratios, discriminated AD patients from HS with over 90% accuracy. These findings suggest that essential and toxic elements contribute to generate a distinctive signature during the progression of AD, and their monitoring in elderly might help to detect preclinical stages of AD. PMID:26957294

  4. Brain ERP components predict which individuals progress to Alzheimers disease and which do not

    PubMed Central

    Chapman, Robert M.; McCrary, John W.; Gardner, Margaret N.; Sandoval, Tiffany C.; Guillily, Maria D.; Reilly, Lindsey A.; DeGrush, Elizabeth

    2009-01-01

    Predicting which individuals will progress to Alzheimers disease (AD) is important in both clinical and research settings. We used brain Event-Related Potentials (ERPs) obtained in a perceptual/cognitive paradigm with various processing demands to predict which individual Mild Cognitive Impairment (MCI) subjects will develop AD versus which will not. ERP components, including P3, memory storage component, and other earlier and later components, were identified and measured by Principal Components Analysis. When measured for particular task conditions, a weighted set of eight ERP component_conditions performed well in discriminant analysis at predicting later AD progression with good accuracy, sensitivity, and specificity. The predictions for most individuals (79%) had high posterior probabilities and were accurate (88%). This method, supported by a cross-validation where the prediction accuracy was 7078%, features the posterior probability for each individual as a method of determining the likelihood of progression to AD. Empirically obtained prediction accuracies rose to 94% when the computed posterior probabilities for individuals were 0.90 or higher (which was found for 40% of our MCI sample). PMID:20005599

  5. Predictors of progression to severe Alzheimer’s disease in an incidence sample

    PubMed Central

    Rabins, Peter V.; Schwartz, Sarah; Black, Betty S.; Corcoran, Christopher; Fauth, Elizabeth; Mielke, Michele; Christensen, Jessica; Lyketsos, Constantine; Tschanz, JoAnn

    2013-01-01

    Background Little is known about factors influencing time to severe Alzheimer’s disease (AD). Methods Incident cases of AD in the Cache County Memory Study were identified. Severe AD was defined as Mini-Mental State Examination score of ≤10 or Clinical Dementia Rating Scale score of 3; cases with either Mini-Mental State Examination score of ≥16 or Clinical Dementia Rating <2 were not categorized as severe AD. Kaplan–Meier, log-rank tests, and Cox analyses were used to identify demographic, clinical, and genetic correlates of time to progression to severe AD. Results Sixty-eight of 335 cases of incident AD developed severe dementia. In bivariate analyses, female gender, less than high school education, at least one clinically significant Neuropsychiatric Inventory domain at baseline, and the youngest and oldest ages exhibited shorter time to severe AD. In competing risk analysis, subjects with mild or at least one clinically significant Neuropsychiatric Inventory domain score, and subjects with worse health were more likely to progress to severe dementia or death. Conclusions Demographic and clinical variables predict progression to severe AD. Further study should examine whether these relationships are causal or correlational. PMID:23123228

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

    PubMed Central

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

    2016-01-01

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

  7. Cervical intraepithelial neoplasia disease progression is associated with increased vaginal microbiome diversity.

    PubMed

    Mitra, A; MacIntyre, D A; Lee, Y S; Smith, A; Marchesi, J R; Lehne, B; Bhatia, R; Lyons, D; Paraskevaidis, E; Li, J V; Holmes, E; Nicholson, J K; Bennett, P R; Kyrgiou, M

    2015-01-01

    Persistent infection with oncogenic Human Papillomavirus (HPV) is necessary for cervical carcinogenesis. Although evidence suggests that the vaginal microbiome plays a functional role in the persistence or regression of HPV infections, this has yet to be described in women with cervical intra-epithelial neoplasia (CIN). We hypothesised that increasing microbiome diversity is associated with increasing CIN severity. llumina MiSeq sequencing of 16S rRNA gene amplicons was used to characterise the vaginal microbiota of women with low-grade squamous intra-epithelial lesions (LSIL; n?=?52), high-grade (HSIL; n?=?92), invasive cervical cancer (ICC; n?=?5) and healthy controls (n?=?20). Hierarchical clustering analysis revealed an increased prevalence of microbiomes characterised by high-diversity and low levels of Lactobacillus spp. (community state type-CST IV) with increasing disease severity, irrespective of HPV status (Normal?=?2/20,10%; LSIL?=?11/52,21%; HSIL?=?25/92,27%; ICC?=?2/5,40%). Increasing disease severity was associated with decreasing relative abundance of Lactobacillus spp. The vaginal microbiome in HSIL was characterised by higher levels of Sneathia sanguinegens (P?disease severity is associated with increasing vaginal microbiota diversity and may be involved in regulating viral persistence and disease progression. PMID:26574055

  8. No paradox, no progress: inverse cancer comorbidity in people with other complex diseases.

    PubMed

    Tabars-Seisdedos, Rafael; Dumont, Nancy; Baudot, Anas; Valderas, Jose M; Climent, Joan; Valencia, Alfonso; Crespo-Facorro, Benedicto; Vieta, Eduard; Gmez-Beneyto, Manuel; Martnez, Salvador; Rubenstein, John L

    2011-06-01

    In the past 5 years, several leading groups have attempted to explain why individuals with Down's syndrome have a reduced risk of many solid tumours and an increased risk of leukaemia and testicular cancer. Niels Bohr, the Danish physicist, noted that a paradox could initiate progress. We think that the paradox of a medical disorder protecting against cancer could be formalised in a new model of inverse cancer morbidity in people with other serious diseases. In this Personal View, we review evidence from epidemiological and clinical studies that supports a consistently lower than expected occurrence of cancer in patients with Down's syndrome, Parkinson's disease, schizophrenia, diabetes, Alzheimer's disease, multiple sclerosis, and anorexia nervosa. Intriguingly, most comorbidities are neuropsychiatric or CNS disorders. We provide a brief overview of evidence indicating genetic and molecular connections between cancer and these complex diseases. Inverse comorbidity could be a valuable model to investigate common or related pathways or processes and test new therapies, but, most importantly, to understand why certain people are protected from the malignancy. PMID:21498115

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

    PubMed Central

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

    2013-01-01

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

  10. Expression of Muscle-Specific MiRNA 206 in the Progression of Disease in a Murine SMA Model

    PubMed Central

    Valsecchi, Valeria; Boido, Marina; De Amicis, Elena; Piras, Antonio; Vercelli, Alessandro

    2015-01-01

    Spinal muscular atrophy (SMA) is a severe neuromuscular disease, the most common in infancy, and the third one among young people under 18 years. The major pathological landmark of SMA is a selective degeneration of lower motor neurons, resulting in progressive skeletal muscle denervation, atrophy, and paralysis. Recently, it has been shown that specific or general changes in the activity of ribonucleoprotein containing micro RNAs (miRNAs) play a role in the development of SMA. Additionally miRNA-206 has been shown to be required for efficient regeneration of neuromuscular synapses after acute nerve injury in an ALS mouse model. Therefore, we correlated the morphology and the architecture of the neuromuscular junctions (NMJs) of quadriceps, a muscle affected in the early stage of the disease, with the expression levels of miRNA-206 in a mouse model of intermediate SMA (SMAII), one of the most frequently used experimental model. Our results showed a decrease in the percentage of type II fibers, an increase in atrophic muscle fibers and a remarkable accumulation of neurofilament (NF) in the pre-synaptic terminal of the NMJs in the quadriceps of SMAII mice. Furthermore, molecular investigation showed a direct link between miRNA-206-HDAC4-FGFBP1, and in particular, a strong up-regulation of this pathway in the late phase of the disease. We propose that miRNA-206 is activated as survival endogenous mechanism, although not sufficient to rescue the integrity of motor neurons. We speculate that early modulation of miRNA-206 expression might delay SMA neurodegenerative pathway and that miRNA-206 could be an innovative, still relatively unexplored, therapeutic target for SMA. PMID:26030275

  11. Current and Future Disease Progression of the Chronic HCV Population in the United States

    PubMed Central

    Zalesak, Martin; Francis, Kevin; Gedeon, Alex; Gillis, John; Hvidsten, Kyle; Kidder, Phyllis; Li, Hong; Martyn, Derek; Orne, Leslie; Smith, Amanda; Kwong, Ann

    2013-01-01

    Chronic hepatitis C virus (HCV) infection can lead to advanced liver disease (AdvLD), including cirrhosis, decompensated cirrhosis, and liver cancer. The aim of this study was to determine recent historical rates of HCV patient progression to AdvLD and to project AdvLD prevalence through 2015. We first determined total 2008 US chronic HCV prevalence from the National Health and Nutrition Evaluation Surveys. Next, we examined disease progression and associated non-pharmacological costs of diagnosed chronic HCV-infected patients between 20072009 in the IMS LifeLink and CMS Medicare claims databases. A projection model was developed to estimate AdvLD population growth through 2015 in patients diagnosed and undiagnosed as of 2008, using the 20072009 progression rates to generate a worst case projection of the HCV-related AdvLD population (i.e., scenario where HCV treatment is the same in the forecasted period as it was before 2009). We found that the total diagnosed chronic HCV population grew from 983,000 to 1.19 million in 20072009, with patients born from 19451964 accounting for 75.0% of all patients, 83.7% of AdvLD patients, and 79.2% of costs in 2009, indicating that HCV is primarily a disease of the baby boomer population. Non-pharmacological costs grew from $7.22 billion to $8.63 billion, with the majority of growth derived from the 60,000 new patients that developed AdvLD in 20072009, 91.5% of whom were born between 1945 and 1964. The projection model estimated the total AdvLD population would grow from 195,000 in 2008 to 601,000 in 2015, with 73.5% of new AdvLD cases from patients undiagnosed as of 2008. AdvLD prevalence in patients diagnosed as of 2008 was projected to grow 6.5% annually to 303,000 patients in 2015. These findings suggest that strategies to diagnose and treat HCV-infected patients are urgently needed to increase the likelihood that progression is interrupted, particularly for patients born from 19451964. PMID:23704962

  12. Current and future disease progression of the chronic HCV population in the United States.

    PubMed

    Zalesak, Martin; Francis, Kevin; Gedeon, Alex; Gillis, John; Hvidsten, Kyle; Kidder, Phyllis; Li, Hong; Martyn, Derek; Orne, Leslie; Smith, Amanda; Kwong, Ann

    2013-01-01

    Chronic hepatitis C virus (HCV) infection can lead to advanced liver disease (AdvLD), including cirrhosis, decompensated cirrhosis, and liver cancer. The aim of this study was to determine recent historical rates of HCV patient progression to AdvLD and to project AdvLD prevalence through 2015. We first determined total 2008 US chronic HCV prevalence from the National Health and Nutrition Evaluation Surveys. Next, we examined disease progression and associated non-pharmacological costs of diagnosed chronic HCV-infected patients between 2007-2009 in the IMS LifeLink and CMS Medicare claims databases. A projection model was developed to estimate AdvLD population growth through 2015 in patients diagnosed and undiagnosed as of 2008, using the 2007-2009 progression rates to generate a "worst case" projection of the HCV-related AdvLD population (i.e., scenario where HCV treatment is the same in the forecasted period as it was before 2009). We found that the total diagnosed chronic HCV population grew from 983,000 to 1.19 million in 2007-2009, with patients born from 1945-1964 accounting for 75.0% of all patients, 83.7% of AdvLD patients, and 79.2% of costs in 2009, indicating that HCV is primarily a disease of the "baby boomer" population. Non-pharmacological costs grew from $7.22 billion to $8.63 billion, with the majority of growth derived from the 60,000 new patients that developed AdvLD in 2007-2009, 91.5% of whom were born between 1945 and 1964. The projection model estimated the total AdvLD population would grow from 195,000 in 2008 to 601,000 in 2015, with 73.5% of new AdvLD cases from patients undiagnosed as of 2008. AdvLD prevalence in patients diagnosed as of 2008 was projected to grow 6.5% annually to 303,000 patients in 2015. These findings suggest that strategies to diagnose and treat HCV-infected patients are urgently needed to increase the likelihood that progression is interrupted, particularly for patients born from 1945-1964. PMID:23704962

  13. [Urological procedures for progressive renal dysfunction due to polycystic kidney disease].

    PubMed

    Nakatani, T; Kishimoto, T; Tsujino, T; Sugimura, T; Oyama, A; Kato, T; Higashihara, E

    2000-09-01

    Urological procedures for progressive renal dysfunction due to polycystic kidney disease (PKD) such as percutaneous puncture of renal cysts are merely symptomatic treatments and have little effect on renal function. At present, the two most effective methods of preventing renal dysfunction are blood pressure management and dietetic therapy, which are more effective with early initiation. Moreover, as PKD is an autosomal dominant disease, there is a high risk that family members of the patient may have asymptomatic PKD. It is essential to identify and treat such potential patients at an early stage in order to prevent progressive renal dysfunction. In place of the traditional nephrectomy, we attempted transcutaneous renal arterial embolization (TRAE) for hemorrhage into renal cysts, hematuria and obstruction of intestine due to proliferation of cysts after the introduction of hemodialysis. When TRAE was carried out on one kidney, the cysts in the other kidney proliferated and even though the renal arteries were completely embolized, it required 5 to 6 weeks for the kidney to contract. Our conclusions are TRAE is effective with no adverse reactions for PKD. These results suggest that in the future TRAE may become the preferred treatment for PKD in place of nephrectomy. PMID:11107537

  14. Loss of Peripheral Tolerance in Emphysema. Phenotypes, Exacerbations, and Disease Progression.

    PubMed

    Bhavani, Sivasubramanium; Yuan, Xiaoyi; You, Ran; Shan, Ming; Corry, David; Kheradmand, Farrah

    2015-11-01

    Heterogeneity in the development and progression of cigarette smoke-induced lung diseases strongly argues for a need to improve the clinical and phenotypic characterization of patients with chronic obstructive lung disease and emphysema. Smokers with emphysema are at a much higher risk for accelerated loss of lung function, increased cardiovascular morbidity, and development of lung cancer. Recent evidence in human translational studies and animal models suggests that emphysema is associated with activation of specialized antigen-presenting cells and that cigarette smoke can disrupt the induction of immune tolerance in the lungs. Quantitative assessment of cytokines expressed by autoreactive T lymphocytes in response to human lung elastin fragments has shown a strong positive correlation between T helper Type 1 (Th1) and Th17 cells' immune responses and emphysema. In search of factors that could reduce the threshold for induction of autoimmune inflammation, we have discovered that cleavage of complement protein 3 (C3) generates bioactive molecules (e.g., C3a) and activates lung antigen-presenting cells. The autocrine and paracrine function of C3a and its receptor are required in T cell-mediated inflammatory responses to cigarette smoke in both human and preclinical models of emphysema. Targeting upstream molecules that reduce the potential for generation of autoreactive T cells could lead to the development of novel therapeutics to prevent progression of emphysema in smokers. PMID:26595734

  15. Tubular Obstruction Leads to Progressive Proximal Tubular Injury and Atubular Glomeruli in Polycystic Kidney Disease

    PubMed Central

    Galarreta, Carolina I.; Grantham, Jared J.; Forbes, Michael S.; Maser, Robin L.; Wallace, Darren P.; Chevalier, Robert L.

    2015-01-01

    In polycystic kidney disease (PKD), renal parenchyma is destroyed by cysts, hypothesized to obstruct nephrons. A signature of unilateral ureteral obstruction, proximal tubular atrophy leads to formation of atubular glomeruli. To determine whether this process occurs in PKD, kidneys from pcy mice (moderately progressive PKD), kidneys from cpk mice (rapidly progressive PKD), and human autosomal dominant PKD were examined in early and late stages. Integrity of the glomerulotubular junction and proximal tubular mass were determined in sections stained with Lotus tetragonolobus lectin. Development of proximal tubular atrophy and atubular glomeruli was determined in serial sections of individual glomeruli. In pcy mice, most glomerulotubular junctions were normal at 20 weeks, but by 30 weeks, 56% were atrophic and 25% of glomeruli were atubular; glomerulotubular junction integrity decreased with increasing cyst area (r=0.83, P<0.05). In cpk mice, all glomerulotubular junctions were normal at 10 days, but by 19 days, 26% had become abnormal. In early-stage autosomal dominant PKD kidneys, 50% of glomeruli were atubular or attached to atrophic tubules; in advanced disease, 100% were abnormal. Thus, proximal tubular injury in cystic kidneys closely parallels that observed with ureteral obstruction. These findings support the hypothesis that, in renal cystic disorders, cyst-dependent obstruction of medullary and cortical tubules initiates a process culminating in widespread destruction of proximal convoluted tubules at the glomerulotubular junction. PMID:24815352

  16. High STAT5 levels mediate imatinib resistance and indicate disease progression in chronic myeloid leukemia.

    PubMed

    Warsch, Wolfgang; Kollmann, Karoline; Eckelhart, Eva; Fajmann, Sabine; Cerny-Reiterer, Sabine; Hlbl, Andrea; Gleixner, Karoline V; Dworzak, Michael; Mayerhofer, Matthias; Hoermann, Gregor; Herrmann, Harald; Sillaber, Christian; Egger, Gerda; Valent, Peter; Moriggl, Richard; Sexl, Veronika

    2011-03-24

    In BCR-ABL1(+) leukemia, drug resistance is often associated with up-regulation of BCR-ABL1 or multidrug transporters as well as BCR-ABL1 mutations. Here we show that the expression level of the transcription factor STAT5 is another parameter that determines the sensitivity of BCR-ABL1(+) cells against tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, or dasatinib. Abelson-transformed cells, expressing high levels of STAT5, were found to be significantly less sensitive to TKI-induced apoptosis in vitro and in vivo but not to other cytotoxic drugs, such as hydroxyurea, interferon-?, or Aca-dC. The STAT5-mediated protection requires tyrosine phosphorylation of STAT5 independent of JAK2 and transcriptional activity. In support of this concept, under imatinib treatment and with disease progression, STAT5 mRNA and protein levels increased in patients with Ph(+) chronic myeloid leukemia. Based on our data, we propose a model in which disease progression in BCR-ABL1(+) leukemia leads to up-regulated STAT5 expression. This may be in part the result of clonal selection of cells with high STAT5 levels. STAT5 then accounts for the resistance against TKIs, thereby explaining the dose escalation frequently required in patients reaching accelerated phase. It also suggests that STAT5 may serve as an attractive target to overcome imatinib resistance in BCR-ABL1(+) leukemia. PMID:21220747

  17. Features of alpha-synuclein that could explain the progression and irreversibility of Parkinson's disease

    PubMed Central

    Gallegos, Scarlet; Pacheco, Carla; Peters, Christian; Opazo, Carlos M.; Aguayo, Luis G.

    2015-01-01

    Alpha-synuclein is a presynaptic protein expressed throughout the central nervous system, and it is the main component of Lewy bodies, one of the histopathological features of Parkinson's disease (PD) which is a progressive and irreversible neurodegenerative disorder. The conformational flexibility of ?-synuclein allows it to adopt different conformations, i.e., bound to membranes or form aggregates, the oligomers are believed to be the more toxic species. In this review, we will focus on two major features of ?-synuclein, transmission and toxicity, that could help to understand the pathological characteristics of PD. One important feature of ?-synuclein is its ability to be transmitted from neuron to neuron using mechanisms such as endocytosis, plasma membrane penetration or through exosomes, thus propagating the Lewy body pathology to different brain regions thereby contributing to the progressiveness of PD. The second feature of ?-synuclein is that it confers cytotoxicity to recipient cells, principally when it is in an oligomeric state. This form causes mitochondrial dysfunction, endoplasmic reticulum stress, oxidative stress, proteasome impairment, disruption of plasma membrane and pore formation that lead to apoptosis pathway activation and consequent cell death. The complexity of ?-synuclein oligomerization and formation of toxic species could be a major factor for the irreversibility of PD and could also explain the lack of successful therapies to halt the disease. PMID:25805964

  18. Assessing the progression of mild cognitive impairment to Alzheimer's disease: current trends and future directions.

    PubMed

    Brooks, Larry G; Loewenstein, David A

    2010-01-01

    With the advent of advances in biomarker detection and neuropsychological measurement, prospects have improved for identifying and tracking the progression of Alzheimer's disease (AD) from its earliest stages through dementia. While new diagnostic techniques have exciting implications for initiating treatment earlier in the disease process, much work remains to be done to optimize the contributions of the expanding range of tools at the disposal of researchers and clinicians. The present paper examines recent work in cerebrospinal fluid biomarkers, magnetic resonance imaging, positron emission tomography, neuropsychological measures, and functional assessment. The strengths and weaknesses of current methodologies are explored and discussed. It is concluded that AD from its mild cognitive impairment state through dementia represents a continuous process, and that progression over time can best be accomplished by interval-level variables. Biomarkers that are most sensitive to early AD may not be the most optimal for monitoring longitudinal change, and it is likely that multivariate models incorporating cognitive measures, functional variables and biomarker data will be the most fruitful avenues for future research. PMID:20920147

  19. Repeated treatment with a low dose of reserpine as a progressive model of Parkinson's disease.

    PubMed

    Fernandes, Valria S; Santos, Jos R; Leo, Anderson H F F; Medeiros, Andr M; Melo, Thieza G; Izdio, Geison S; Cabral, Alicia; Ribeiro, Rosana A; Ablio, Vanessa C; Ribeiro, Alessandra M; Silva, Regina H

    2012-05-16

    Animal models are widely used to study alterations caused by Parkinson's disease (PD). However, in general, pharmacological models do not express the progressive nature of the disease, being characterized by immediate severe motor impairment after a single dose of the drug. Reserpine administration in rodents has been suggested as a pharmacological model of PD based on the effects of this monoamine-depleting agent on motor activity. Here, we describe that repeated administration with a low dose (0.1 mg/kg) of reserpine in rats induces a gradual appearance of motor signs, evaluated by catalepsy behavior. Furthermore, these motor signs are accompanied by increased levels of striatal lipid peroxidation. However, treatment with reserpine failed to induce memory impairments (evaluated by novel object recognition and discriminative avoidance tasks) and alterations in hippocampal lipid peroxidation. Thus, repeated treatment with low doses of reserpine progressively induces alterations in motor function and an increase in striatal oxidative stress, indicating a possible application of this model in the study of the neuroprogressive nature of the motor signs in PD. PMID:22446059

  20. Impeded progression of Friend disease in mice by an inhibitor of retroviral proteases.

    PubMed

    Lai, M H; Tang, J; Wroblewski, V; Dee, A G; Margolin, N; Vlahos, C; Bowdon, B; Buckheit, R; Colacino, J; Hui, K Y

    1993-01-01

    The protease of the human immunodeficiency virus type 1 (HIV-1) is essential for the processing of GAG and POL polyproteins and maturation of the virus particles. Using recombinant protease and a truncated GAG polyprotein as substrate, we developed a Western blot assay for the evaluation of inhibitors of the enzyme. Two statine-based inhibitors of the enzyme, KH161 and KH164, were effective in blocking the replication of HIV-1 in acutely infected human T4 lymphoid cells, with potency approaching that of zidovudine (ZDV) when tested in parallel. In chronically infected cells, the production of infectious virus was inhibited by KH161 and KH164, while ZDV was ineffective. Both KH161 and KH164 were also active as antivirals against the replication of murine leukemia virus (MLV) in cultured mouse cells. In an animal model of a murine retroviral disease, KH164 was shown to inhibit in a dose-dependent manner the progression of the disease induced by Friend virus complex (a mixture of Friend MLV and spleen focus-forming virus). The results suggest that the progression of the acquired immune deficiency syndrome (AIDS) may be impeded by inhibitors of HIV-1 protease. PMID:8093263

  1. New Insights about Treg and Th17 Cells in HIV Infection and Disease Progression

    PubMed Central

    Valverde-Villegas, Jacqueline María; Matte, Maria Cristina Cotta; de Medeiros, Rúbia Marília; Chies, José Artur Bogo

    2015-01-01

    Treg and Th17 cell subsets are characterized by the expression of specific transcriptional factors and chemokine receptor as well as by secretion of specific cytokine and chemokines. These subsets are important to the differentiation, expansion, homing capacity, and recruitment of several different immune cell populations to the site of infection. Whereas Treg cells maintain self-tolerance and control the activation and expansion of autoreactive CD4+ T effector cells through an anti-inflammatory response, Th17 cells, in an exacerbated unregulated proinflammatory response, can promote autoimmunity. Despite such apparently opposite functions, Th17 and Treg cells share common characteristics, and their differentiation pathways are interconnected. Recent studies have revealed quite intricate relations between Treg and Th17 cells in HIV infection and progression to AIDS. Considering Treg cells, different subsets were already investigated in the context of HIV infection, indicating a fluctuation in the total number and frequency throughout the disease course. This review focuses on the recent findings regarding the role of regulatory T and Th17 cells in the context of HIV infection, highlighting the importance of the balance between these two subsets on disease progression. PMID:26568963

  2. Cytokine Response Signatures in Disease Progression and Development of Severe Clinical Outcomes for Leptospirosis

    PubMed Central

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

    2013-01-01

    Background The role of the immune response in influencing leptospirosis clinical outcomes is not yet well understood. We hypothesized that acute-phase serum cytokine responses may play a role in disease progression, risk for death, and severe pulmonary hemorrhage syndrome (SPHS). Methodology/Principal Findings We performed a case-control study design to compare cytokine profiles in patients with mild and severe forms of leptospirosis. Among patients hospitalized with severe disease, we compared those with fatal and nonfatal outcomes. During active outpatient and hospital-based surveillance we prospectively enrolled 172 patients, 23 with mild disease (outpatient) and 149 with severe leptospirosis (hospitalized). Circulating concentrations of pro- and anti-inflammatory cytokines at the time of patient presentation were measured using a multiplex bead array assay. Concentrations of IL-1?, IL-2, IL-4, IL-6, IL-8, IL-10, IL-17A, and TNF-? were significantly higher (P<0.05) in severe disease compared to mild disease. Among severe patients, levels of IL-6 (P<0.001), IL-8 (P?=?0.0049) and IL-10 (P<0.001), were higher in fatal compared to non-fatal cases. High levels of IL-6 and IL-10 were independently associated (P<0.05) with case fatality after adjustment for age and days of symptoms. IL-6 levels were higher (P?=?0.0519) among fatal cases who developed SPHS than among who did not. Conclusion/Significance This study shows that severe cases of leptospirosis are differentiated from mild disease by a cytokine storm process, and that IL-6 and IL-10 may play an immunopathogenic role in the development of life-threatening outcomes in human leptospirosis. PMID:24069500

  3. Heterogeneity of Regional Brain Atrophy Patterns Associated with Distinct Progression Rates in Alzheimer’s Disease

    PubMed Central

    Byun, Min Soo; Kim, Song E.; Park, Jinsick; Yi, Dahyun; Choe, Young Min; Sohn, Bo Kyung; Choi, Hyo Jung; Baek, Hyewon; Han, Ji Young; Woo, Jong Inn; Lee, Dong Young

    2015-01-01

    We aimed to identify and characterize subtypes of Alzheimer’s disease (AD) exhibiting different patterns of regional brain atrophy on MRI using age- and gender-specific norms of regional brain volumes. AD subjects included in the Alzheimer's Disease Neuroimaging Initiative study were classified into subtypes based on standardized values (Z-scores) of hippocampal and regional cortical volumes on MRI with reference to age- and gender-specific norms obtained from 222 cognitively normal (CN) subjects. Baseline and longitudinal changes of clinical characteristics over 2 years were compared across subtypes. Whole-brain-level gray matter (GM) atrophy pattern using voxel-based morphometry (VBM) and cerebrospinal fluid (CSF) biomarkers of the subtypes were also investigated. Of 163 AD subjects, 58.9% were classified as the “both impaired” subtype with the typical hippocampal and cortical atrophy pattern, whereas 41.1% were classified as the subtypes with atypical atrophy patterns: “hippocampal atrophy only” (19.0%), “cortical atrophy only” (11.7%), and “both spared” (10.4%). Voxel-based morphometric analysis demonstrated whole-brain-level differences in overall GM atrophy across the subtypes. These subtypes showed different progression rates over 2 years; and all subtypes had significantly lower CSF amyloid-β1–42 levels compared to CN. In conclusion, we identified four AD subtypes exhibiting heterogeneous atrophy patterns on MRI with different progression rates after controlling the effects of aging and gender on atrophy with normative information. CSF biomarker analysis suggests the presence of Aβ neuropathology irrespective of subtypes. Such heterogeneity of MRI-based neuronal injury biomarker and related heterogeneous progression patterns should be considered in clinical trials and practice with AD patients. PMID:26618360

  4. The association between hepatitis C virus genotype and human immunodeficiency virus disease progression in a cohort of hemophilic men.

    PubMed

    Sabin, C A; Telfer, P; Phillips, A N; Bhagani, S; Lee, C A

    1997-01-01

    Patients coinfected with both hepatitis C virus (HCV) and the human immunodeficiency virus (HIV) have more rapid progression of HCV infection; however, little is known about the effect of coinfection with HCV on the progression of HIV disease. This study assessed the association between infection with different HCV genotypes on progression to AIDS and death in a cohort of men with hemophilia. Patients infected with HCV type 1 experienced a more rapid progression to both AIDS (P = .009) and death (P = .007) than did those infected with other types. This effect was largely independent of age at seroconversion, hemophilia diagnosis, and changes in CD4 cell count over the follow-up period. These results suggest an association between HCV genotype and progression of HIV disease, which, if confirmed, could have important implications for the treatment and care of patients coinfected with both HIV and HCV. PMID:8985212

  5. Metabolic Tumor Burden Predicts for Disease Progression and Death in Lung Cancer

    SciTech Connect

    Lee, Percy; Weerasuriya, Dilani K.; Lavori, Philip W.; Quon, Andrew; Hara, Wendy; Maxim, Peter G.; Le, Quynh-Thu; Wakelee, Heather A.; Donington, Jessica S.; Graves, Edward E.; Loo, Billy W.

    2007-10-01

    Purpose: In lung cancer, stage is an important prognostic factor for disease progression and survival. However, stage may be simply a surrogate for underlying tumor burden. Our purpose was to assess the prognostic value of tumor burden measured by {sup 18}F-fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging. Patients and Methods: We identified 19 patients with lung cancer who had staging PET-CT scans before any therapy, and adequate follow-up (complete to time of progression for 18, and death for 15 of 19). Metabolically active tumor regions were segmented on pretreatment PET scans semi-automatically using custom software. We determined the relationship between times to progression (TTP) and death (OS) and two PET parameters: total metabolic tumor volume (MTV), and standardized uptake value (SUV). Results: The estimated median TTP and OS for the cohort were 9.3 months and 14.8 months. On multivariate Cox proportional hazards regression analysis, an increase in MTV of 25 ml (difference between the 75th and 25th percentiles) was associated with increased hazard of progression and of death (5.4-fold and 7.6-fold), statistically significant (p = 0.0014 and p = 0.001) after controlling for stage, treatment intent (definitive or palliative), age, Karnofsky performance status, and weight loss. We did not find a significant relationship between SUV and TTP or OS. Conclusions: In this study, high tumor burden assessed by PET MTV is an independent poor prognostic feature in lung cancer, promising for stratifying patients in randomized trials and ultimately for selecting risk-adapted therapies. These results will need to be validated in larger cohorts with longer follow-up, and evaluated prospectively.

  6. Progressive nigrostriatal terminal dysfunction and degeneration in the engrailed1 heterozygous mouse model of Parkinson's disease.

    PubMed

    Nordström, Ulrika; Beauvais, Geneviève; Ghosh, Anamitra; Pulikkaparambil Sasidharan, Baby Chakrapani; Lundblad, Martin; Fuchs, Julia; Joshi, Rajiv L; Lipton, Jack W; Roholt, Andrew; Medicetty, Satish; Feinstein, Timothy N; Steiner, Jennifer A; Escobar Galvis, Martha L; Prochiantz, Alain; Brundin, Patrik

    2015-01-01

    Current research on Parkinson's disease (PD) pathogenesis requires relevant animal models that mimic the gradual and progressive development of neuronal dysfunction and degeneration that characterizes the disease. Polymorphisms in engrailed 1 (En1), a homeobox transcription factor that is crucial for both the development and survival of mesencephalic dopaminergic neurons, are associated with sporadic PD. This suggests that En1 mutant mice might be a promising candidate PD model. Indeed, a mouse that lacks one En1 allele exhibits decreased mitochondrial complex I activity and progressive midbrain dopamine neuron degeneration in adulthood, both features associated with PD. We aimed to further characterize the disease-like phenotype of these En1(+/-) mice with a focus on early neurodegenerative changes that can be utilized to score efficacy of future disease modifying studies. We observed early terminal defects in the dopaminergic nigrostriatal pathway in En1(+/-) mice. Several weeks before a significant loss of dopaminergic neurons in the substantia nigra could be detected, we found that striatal terminals expressing high levels of dopaminergic neuron markers TH, VMAT2, and DAT were dystrophic and swollen. Using transmission electron microscopy, we identified electron dense bodies consistent with abnormal autophagic vacuoles in these terminal swellings. In line with these findings, we detected an up-regulation of the mTOR pathway, concurrent with a downregulation of the autophagic marker LC3B, in ventral midbrain and nigral dopaminergic neurons of the En1(+/-) mice. This supports the notion that autophagic protein degradation is reduced in the absence of one En1 allele. We imaged the nigrostriatal pathway using the CLARITY technique and observed many fragmented axons in the medial forebrain bundle of the En1(+/-) mice, consistent with axonal maintenance failure. Using in vivo electrochemistry, we found that nigrostriatal terminals in the dorsal striatum were severely deficient in dopamine release and reuptake. Our findings support a progressive retrograde degeneration of En1(+/-) nigrostriatal neurons, akin to what is suggested to occur in PD. We suggest that using the En1(+/-) mice as a model will provide further key insights into PD pathogenesis, and propose that axon terminal integrity and function can be utilized to estimate dopaminergic neuron health and efficacy of experimental PD therapies. PMID:25281317

  7. Different decision deficits impair response inhibition in progressive supranuclear palsy and Parkinson's disease.

    PubMed

    Zhang, Jiaxiang; Rittman, Timothy; Nombela, Cristina; Fois, Alessandro; Coyle-Gilchrist, Ian; Barker, Roger A; Hughes, Laura E; Rowe, James B

    2016-01-01

    Progressive supranuclear palsy and Parkinson's disease have distinct underlying neuropathology, but both diseases affect cognitive function in addition to causing a movement disorder. They impair response inhibition and may lead to impulsivity, which can occur even in the presence of profound akinesia and rigidity. The current study examined the mechanisms of cognitive impairments underlying disinhibition, using horizontal saccadic latencies that obviate the impact of limb slowness on executing response decisions. Nineteen patients with clinically diagnosed progressive supranuclear palsy (Richardson's syndrome), 24 patients with clinically diagnosed Parkinson's disease and 26 healthy control subjects completed a saccadic Go/No-Go task with a head-mounted infrared saccadometer. Participants were cued on each trial to make a pro-saccade to a horizontal target or withhold their responses. Both patient groups had impaired behavioural performance, with more commission errors than controls. Mean saccadic latencies were similar between all three groups. We analysed behavioural responses as a binary decision between Go and No-Go choices. By using Bayesian parameter estimation, we fitted a hierarchical drift-diffusion model to individual participants' single trial data. The model decomposes saccadic latencies into parameters for the decision process: decision boundary, drift rate of accumulation, decision bias, and non-decision time. In a leave-one-out three-way classification analysis, the model parameters provided better discrimination between patients and controls than raw behavioural measures. Furthermore, the model revealed disease-specific deficits in the Go/No-Go decision process. Both patient groups had slower drift rate of accumulation, and shorter non-decision time than controls. But patients with progressive supranuclear palsy were strongly biased towards a pro-saccade decision boundary compared to Parkinson's patients and controls. This indicates a prepotency of responding in combination with a reduction in further accumulation of evidence, which provides a parsimonious explanation for the apparently paradoxical combination of disinhibition and severe akinesia. The combination of the well-tolerated oculomotor paradigm and the sensitivity of the model-based analysis provides a valuable approach for interrogating decision-making processes in neurodegenerative disorders. The mechanistic differences underlying participants' poor performance were not observable from classical analysis of behavioural data, but were clearly revealed by modelling. These differences provide a rational basis on which to develop and assess new therapeutic strategies for cognition and behaviour in these disorders. PMID:26582559

  8. Knocking down metabotropic glutamate receptor 1 improves survival and disease progression in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis.

    PubMed

    Milanese, Marco; Giribaldi, Francesco; Melone, Marcello; Bonifacino, Tiziana; Musante, Ilaria; Carminati, Enrico; Rossi, Pia I A; Vergani, Laura; Voci, Adriana; Conti, Fiorenzo; Puliti, Aldamaria; Bonanno, Giambattista

    2014-04-01

    Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disease reflecting degeneration of upper and lower motoneurons (MNs). The cause of ALS and the mechanisms of neuronal death are still largely obscure, thus impairing the establishment of efficacious therapies. Glutamate (Glu)-mediated excitotoxicity plays a major role in MN degeneration in ALS. We recently demonstrated that the activation of Group I metabotropic Glu autoreceptors, belonging to both type 1 and type 5 receptors (mGluR1 and mGluR5), at glutamatergic spinal cord nerve terminals, produces excessive Glu release in mice over-expressing human superoxide-dismutase carrying the G93A point mutation (SOD1(G93A)), a widely used animal model of human ALS. To establish whether these receptors are implicated in ALS, we generated mice expressing half dosage of mGluR1 in the SOD1(G93A) background (SOD1(G93A)Grm1(crv4/+)), by crossing the SOD1(G93A) mutant mouse with the Grm1(crv4/+) mouse, lacking mGluR1 because of a spontaneous recessive mutation. SOD1(G93A)Grm1(crv4/+) mice showed prolonged survival probability, delayed pathology onset, slower disease progression and improved motor performances compared to SOD1(G93A) mice. These effects were associated to reduction of mGluR5 expression, enhanced number of MNs, decreased astrocyte and microglia activation, normalization of metallothionein and catalase mRNA expression, reduced mitochondrial damage, and decrease of abnormal Glu release in spinal cord of SOD1(G93A)Grm1(crv4/+)compared to SOD1(G93A) mice. These results demonstrate that a lower constitutive level of mGluR1 has a significant positive impact on mice with experimental ALS, thus providing the rationale for future pharmacological approaches to ALS by selectively blocking Group I metabotropic Glu receptors. PMID:24361555

  9. Familial and primary (AL) cardiac amyloidosis: echocardiographically similar diseases with distinctly different clinical outcomes.

    PubMed Central

    Dubrey, S. W.; Cha, K.; Skinner, M.; LaValley, M.; Falk, R. H.

    1997-01-01

    OBJECTIVE: To determine whether patients with myocardial amyloidosis due either to AL (primary) amyloid or familial amyloid have distinguishing echocardiographic or electrocardiographic features; and to compare the prevalence of heart failure and survival in the two types of amyloidosis in relation to echocardiographic findings. DESIGN: Blinded group comparison of randomly selected cases of cardiac amyloidosis. SETTING: International referral centre for amyloid research and treatment. PATIENTS: 36 patients with cardiac amyloid heart disease, of whom 12 had familial and 24 had primary AL amyloidosis. RESULTS: Familial and AL echocardiograms were morphologically indistinguishable, with similar left ventricular wall thickness, mean (SD) 15.4 (2.3) nu 15.8 (2.5) mm, respectively; right ventricular wall thickness was also similar between amyloid types: 9.6 (2.8) nu 9.7 (6.5) mm, respectively. Doppler indices of left and right ventricular function, left ventricular volume, and ejection fraction were also similar. Low voltage electrocardiograms (< 0.5 mV) were more common in the AL (16/24, 67%) than in the familial group (4/12, 25%), P < 0.05. The one year survival for familial and AL forms was 92% (11/12) nu 38% (6/24), respectively, with virtually all deaths due to cardiac causes. CONCLUSIONS: Although cardiac involvement is echocardiographically indistinguishable, cardiac mortality is very different between the two forms of amyloidosis. Preservation of electrocardiographic voltage in familial amyloidosis suggests that the particular biochemical characteristics of distinct types of amyloid fibril have different pathological effects on the myocardium. This distinction becomes critical in the evaluation, treatment, and management of patients who have a diagnosis within the spectrum of the protein deposition diseases. Images PMID:9290406

  10. Hyperperfusion in progressive multifocal leukoencephalopathy is associated with disease progression and absence of immune reconstitution inflammatory syndrome

    PubMed Central

    Khoury, Michael N.; Gheuens, Sarah; Ngo, Long; Wang, Xiaoen; Alsop, David C.

    2013-01-01

    We sought to characterize perfusion patterns of progressive multifocal leukoencephalopathy lesions by arterial spin labelling perfusion magnetic resonance imaging and to analyse their association with immune reconstitution inflammatory syndrome, and survival. A total of 22 patients with progressive multifocal leukoencephalopathy underwent a clinical evaluation and magnetic resonance imaging of the brain within 190 days of symptom onset. The presence of immune reconstitution inflammatory syndrome was determined based on clinical and laboratory criteria. Perfusion within progressive multifocal leukoencephalopathy lesions was determined by arterial spin labelling magnetic resonance imaging. We observed intense hyperperfusion within and at the edge of progressive multifocal leukoencephalopathy lesions in a subset of subjects. This hyperperfusion was quantified by measuring the fraction of lesion volume showing perfusion in excess of twice normal appearing grey matter. Hyperperfused lesion fraction was significantly greater in progressive multifocal leukoencephalopathy progressors than in survivors (12.8% versus 3.4% P = 0.02) corresponding to a relative risk of progression for individuals with a hyperperfused lesion fraction ≥ 4.0% of 9.1 (95% confidence interval of 1.4–59.5). The presence of hyperperfusion was inversely related to the occurrence of immune reconstitution inflammatory syndrome at the time of scan (P = 0.03). Indeed, within 3 months after symptom onset, hyperperfusion had a positive predictive value of 88% for absence of immune reconstitution inflammatory syndrome. Arterial spin labelling magnetic resonance imaging recognized regions of elevated perfusion within lesions of progressive multifocal leukoencephalopathy. These regions might represent virologically active areas operating in the absence of an effective adaptive immune response and correspond with a worse prognosis. PMID:24088807

  11. A longitudinal model for disease progression was developed and applied to multiple sclerosis

    PubMed Central

    Lawton, Michael; Tilling, Kate; Robertson, Neil; Tremlett, Helen; Zhu, Feng; Harding, Katharine; Oger, Joel; Ben-Shlomo, Yoav

    2015-01-01

    Objectives To develop a model of disease progression using multiple sclerosis (MS) as an exemplar. Study Design and Settings Two observational cohorts, the University of Wales MS (UoWMS), UK (1976), and British Columbia MS (BCMS) database, Canada (1980), with longitudinal disability data [the Expanded Disability Status Scale (EDSS)] were used; individuals potentially eligible for MS disease-modifying drugs treatments, but who were unexposed, were selected. Multilevel modeling was used to estimate the EDSS trajectory over time in one data set and validated in the other; challenges addressed included the choice and function of time axis, complex observation-level variation, adjustments for MS relapses, and autocorrelation. Results The best-fitting model for the UoWMS cohort (404 individuals, and 2,290 EDSS observations) included a nonlinear function of time since onset. Measurement error decreased over time and ad hoc methods reduced autocorrelation and the effect of relapse. Replication within the BCMS cohort (978 individuals and 7,335 EDSS observations) led to a model with similar time (years) coefficients, time [0.22 (95% confidence interval {CI}: 0.19, 0.26), 0.16 (95% CI: 0.10, 0.22)] and log time [−0.13 (95% CI: −0.39, 0.14), −0.15 (95% CI: −0.70, 0.40)] for BCMS and UoWMS, respectively. Conclusion It is possible to develop robust models of disability progression for chronic disease. However, explicit validation is important given the complex methodological challenges faced. PMID:26071892

  12. Alterations in urine, serum and brain metabolomic profiles exhibit sexual dimorphism during malaria disease progression

    PubMed Central

    2010-01-01

    Background Metabolic changes in the host in response to Plasmodium infection play a crucial role in the pathogenesis of malaria. Alterations in metabolism of male and female mice infected with Plasmodium berghei ANKA are reported here. Methods 1H NMR spectra of urine, sera and brain extracts of these mice were analysed over disease progression using Principle Component Analysis and Orthogonal Partial Least Square Discriminant Analysis. Results Analyses of overall changes in urinary profiles during disease progression demonstrate that females show a significant early post-infection shift in metabolism as compared to males. In contrast, serum profiles of female mice remain unaltered in the early infection stages; whereas that of the male mice changed. Brain metabolite profiles do not show global changes in the early stages of infection in either sex. By the late stages urine, serum and brain profiles of both sexes are severely affected. Analyses of individual metabolites show significant increase in lactate, alanine and lysine, kynurenic acid and quinolinic acid in sera of both males and females at this stage. Early changes in female urine are marked by an increase of ureidopropionate, lowering of carnitine and transient enhancement of asparagine and dimethylglycine. Several metabolites when analysed individually in sera and brain reveal significant changes in their levels in the early phase of infection mainly in female mice. Asparagine and dimethylglycine levels decrease and quinolinic acid increases early in sera of infected females. In brain extracts of females, an early rise in levels is also observed for lactate, alanine and glycerol, kynurenic acid, ureidopropionate and 2-hydroxy-2-methylbutyrate. Conclusions These results suggest that P. berghei infection leads to impairment of glycolysis, lipid metabolism, metabolism of tryptophan and degradation of uracil. Characterization of early changes along these pathways may be crucial for prognosis and better disease management. Additionally, the distinct sexual dimorphism exhibited in these responses has a bearing on the understanding of the pathophysiology of malaria. PMID:20412601

  13. M2 Macrophages Play Critical Roles in Progression of Inflammatory Liver Disease in Hepatitis C Virus Transgenic Mice

    PubMed Central

    Ohtsuki, Takahiro; Kimura, Kiminori; Tokunaga, Yuko; Tsukiyama-Kohara, Kyoko; Tateno, Chise; Hayashi, Yukiko; Hishima, Tsunekazu

    2015-01-01

    ABSTRACT Macrophages in liver tissue are widely defined as important inflammatory cells in chronic viral hepatitis due to their proinflammatory activity. We reported previously that interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-?) play significant roles in causing chronic hepatitis in hepatitis C virus (HCV) transgenic mice (S. Sekiguchi et al., PLoS One 7:e51656, 2012, http://dx.doi.org/10.1371/journal.pone.0051656). In addition, we showed that recombinant vaccinia viruses expressing an HCV nonstructural protein (rVV-N25) could protect against the progression of chronic hepatitis by suppression of macrophage activation. Here, we focus on the role of macrophages in liver disease progression in HCV transgenic mice and examine characteristic features of macrophages following rVV-N25 treatment. The number of CD11b+ F4/80+ CD11c? CD206+ (M2) macrophages in the liver of HCV transgenic mice was notably increased compared to that of age-matched control mice. These M2 macrophages in the liver produced elevated levels of IL-6 and TNF-?. rVV-N25 infection suppressed the number and activation of M2 macrophages in liver tissue. These results suggested that inflammatory cytokines produced by M2-like macrophages contribute to the induction of chronic liver inflammation in HCV transgenic mice. Moreover, the therapeutic effect of rVV-N25 might be induced by the suppression of the number and activation of hepatic macrophages. IMPORTANCE HCV causes persistent infections that can lead to chronic liver diseases, liver fibrosis, and hepatocellular carcinoma; the search for an HCV curative is the focus of ongoing research. Recently, effective anti-HCV drugs have been developed; however, vaccine development still is required for the prevention and therapy of infection by this virus. We demonstrate here that M2 macrophages are important for the pathogenesis of HCV-caused liver diseases and additionally show that M2 macrophages contribute to the therapeutic mechanism observed following rVV-N25 treatment. PMID:26468521

  14. Crosstalk between the Unfolded Protein Response and NF-κB-Mediated Inflammation in the Progression of Chronic Kidney Disease

    PubMed Central

    Cruz, Gaile L.; Dickhout, Jeffrey G.

    2015-01-01

    The chronic inflammatory response is emerging as an important therapeutic target in progressive chronic kidney disease. A key transcription factor in the induction of chronic inflammation is NF-κB. Recent studies have demonstrated that sustained activation of the unfolded protein response (UPR) can initiate this NF-κB signaling phenomenon and thereby induce chronic kidney disease progression. A key factor influencing chronic kidney disease progression is proteinuria and this condition has now been demonstrated to induce sustained UPR activation. This review details the crosstalk between the UPR and NF-κB pathways as pertinent to chronic kidney disease. We present potential tools to study this phenomenon as well as potential therapeutics that are emerging to regulate the UPR. These therapeutics may prevent inflammation specifically induced in the kidney due to proteinuria-induced sustained UPR activation. PMID:25977931

  15. Mapping Progressive Brain Structural Changes in Early Alzheimers Disease and Mild Cognitive Impairment

    PubMed Central

    Apostolova, Liana G.; Thompson, Paul M.

    2009-01-01

    Alzheimers disease (AD), the most common neurodegenerative disorder of the elderly, ranks third in health care cost after heart disease and cancer. Given the disproportionate aging of the population in all developed countries, the socio-economic impact of AD will continue to rise. Mild cognitive impairment (MCI), a transitional state between normal aging and dementia, carries a 46-fold increased risk of future diagnosis of dementia. As complete drug-induced reversal of AD symptoms seems unlikely, researchers are now focusing on the earliest stages of AD where a therapeutic intervention is likely to realize the greatest impact. Recently neuroimaging has received significant scientific consideration as a promising in vivo disease-tracking modality that can also provide potential surrogate biomarkers for therapeutic trials. While several volumetric techniques laid the foundation of the neuroimaging research in AD and MCI, more precise computational anatomy techniques have recently become available. This new technology detects and visualizes discrete changes in cortical and hippocampal integrity and tracks the spread of AD pathology throughout the living brain. Related methods can visualize regionally specific correlations between brain atrophy and important proxy measures of disease such as neuropsychological tests, age of onset or factors that may influence disease progression. We describe extensively validated cortical and hippocampal mapping techniques that are sensitive to clinically relevant changes even in the single individual, and can identify group differences in epidemiological studies or clinical treatment trials. We give an overview of some recent neuroimaging advances in AD and MCI and discuss strengths and weaknesses of the various analytic approaches. PMID:18395760

  16. Mapping progressive brain structural changes in early Alzheimer's disease and mild cognitive impairment.

    PubMed

    Apostolova, Liana G; Thompson, Paul M

    2008-01-01

    Alzheimer's disease (AD), the most common neurodegenerative disorder of the elderly, ranks third in health care cost after heart disease and cancer. Given the disproportionate aging of the population in all developed countries, the socio-economic impact of AD will continue to rise. Mild cognitive impairment (MCI), a transitional state between normal aging and dementia, carries a four- to sixfold increased risk of future diagnosis of dementia. As complete drug-induced reversal of AD symptoms seems unlikely, researchers are now focusing on the earliest stages of AD where a therapeutic intervention is likely to realize the greatest impact. Recently neuroimaging has received significant scientific consideration as a promising in vivo disease-tracking modality that can also provide potential surrogate biomarkers for therapeutic trials. While several volumetric techniques laid the foundation of the neuroimaging research in AD and MCI, more precise computational anatomy techniques have recently become available. This new technology detects and visualizes discrete changes in cortical and hippocampal integrity and tracks the spread of AD pathology throughout the living brain. Related methods can visualize regionally specific correlations between brain atrophy and important proxy measures of disease such as neuropsychological tests, age of onset or factors that may influence disease progression. We describe extensively validated cortical and hippocampal mapping techniques that are sensitive to clinically relevant changes even in the single individual, and can identify group differences in epidemiological studies or clinical treatment trials. We give an overview of some recent neuroimaging advances in AD and MCI and discuss strengths and weaknesses of the various analytic approaches. PMID:18395760

  17. Natural history of atherosclerotic disease progression as assessed by (18)F-FDG PET/CT.

    PubMed

    Hetterich, Holger; Rominger, Axel; Walter, Lisa; Habs, Maximilian; Volpers, Sarah; Hacker, Marcus; Reiser, Maximilian F; Bartenstein, Peter; Saam, Tobias

    2016-01-01

    The aim of this study was to assess the impact of cardiovascular risk factors and plaque inflammation on the progression of atherosclerosis as assessed by positron emission tomography/computed tomography (PET/CT) imaging with (18)F-radiolabled fluorodeoxyglucose ((18)F-FDG). This study was designed as a retrospective cohort study. Patients who received a (18)F-FDG PET/CT scan and follow-up scan 9-24months later without systemic inflammation or steroid medication were eligible for the study. (18)F-FDG PET/CT included a full diagnostic contrast enhanced CT scan. Cardiovascular risk factors and medication were documented. Calcified plaque volume, lumen area and (18)F-FDG uptake, quantified by the target-to-background ratio (TBR), were measured in the carotid arteries, aorta and iliac arteries. Influence of cardiovascular risk factors and vessel wall inflammation on atherosclerotic disease progression was analyzed. Ninety-four patients underwent baseline and follow-up whole body (18)F-FDG PET/CT (mean follow-up time 14.53.5months). Annualized calcified plaque volume increased by 15.4% (p<0.0001), carotid and aortic lumen area decreased by 10.5 % (p<0.0001) and 1.7% (p=0.045). There was no significant difference in (18)F-FDG uptake at baseline and follow-up (mean TBR 1.440.18 vs. 1.420.19, p=0.18). Multiple linear regression analysis identified hypertension as an independent predictor for total, aortic and iliac calcified plaque volume progression (all p<0.04). Carotid lumen reduction was predicted by hypercholesterolemia (p=0.008) while aortic lumen reduction was associated with BMI and mean (18)F-FDG uptake (p?0.005). Furthermore we observed a dose response relationship between the number of cardiovascular risk factors and calcified plaque volume progression in the aorta (p=0.03). Findings from this study provide data on the natural history of atherosclerotic disease burden in multiple vascular beds and emphasize the value of morphological and physiologic information provided by (18)F-FDG PET/CT imaging. PMID:25898891

  18. Determining immune components necessary for progression of pigment dispersing disease to glaucoma in DBA/2J mice

    PubMed Central

    2014-01-01

    Background The molecular mechanisms causing pigment dispersion syndrome (PDS) and the pathway(s) by which it progresses to pigmentary glaucoma are not known. Mutations in two melanosomal protein genes (Tyrp1 b and Gpnmb R150X ) are responsible for pigment dispersing iris disease, which progresses to intraocular pressure (IOP) elevation and subsequent glaucoma in DBA/2J mice. Melanosomal defects along with ocular immune abnormalities play a role in the propagation of pigment dispersion and progression to IOP elevation. Here, we tested the role of specific immune components in the progression of the iris disease and high IOP. Results We tested the role of NK cells in disease etiology by genetically modifying the B6.D2-Gpnmb R150X Tyrp1 b strain, which develops the same iris disease as DBA/2J mice. Our findings demonstrate that neither diminishing NK mediated cytotoxic activity (Prf1 mutation) nor NK cell depletion (Il2rg mutation) has any influence on the severity or timing of Gpnmb R150X Tyrp1 b mediated iris disease. Since DBA/2J mice are deficient in CD94, an important immune modulator that often acts as an immune suppressor, we generated DBA/2J mice sufficient in CD94. Sufficiency of CD94 failed to alter either the iris disease or the subsequent IOP elevation. Additionally CD94 status had no detected effect on glaucomatous optic nerve damage. Conclusion Our previous data implicate immune components in the manifestation of pigment dispersion and/or IOP elevation in DBA/2J mice. The current study eliminates important immune components, specifically NK cells and CD94 deficiency, as critical in the progression of iris disease and glaucoma. This narrows the field of possible immune components responsible for disease progression. PMID:24678736

  19. RTN1 mediates progression of kidney disease by inducing ER stress.

    PubMed

    Fan, Ying; Xiao, Wenzhen; Li, Zhengzhe; Li, Xuezhu; Chuang, Peter Y; Jim, Belinda; Zhang, Weijia; Wei, Chengguo; Wang, Niansong; Jia, Weiping; Xiong, Huabao; Lee, Kyung; He, John C

    2015-01-01

    Identification of new biomarkers and drug targets for chronic kidney disease (CKD) is required for the development of more effective therapy. Here we report an association between expression of reticulon 1 (RTN1) and severity of CKD. An isoform-specific increase in the expression of RTN1A is detected in the diseased kidneys from mice and humans, and correlates inversely with renal function in patients with diabetic nephropathy. RTN1 overexpression in renal cells induces ER stress and apoptosis, whereas RTN1 knockdown attenuates tunicamycin-induced and hyperglycaemia-induced ER stress and apoptosis. RTN1A interacts with PERK through its N-terminal and C-terminal domains, and mutation of these domains prevents this effect on ER stress. Knockdown of Rtn1a expression in vivo attenuates ER stress and renal fibrosis in mice with unilateral ureteral obstruction, and also attenuates ER stress, proteinuria, glomerular hypertrophy and mesangial expansion in diabetic mice. Together, these data indicate that RTN1A contributes to progression of kidney disease by inducing ER stress. PMID:26227493

  20. RTN1 mediates progression of kidney disease by inducing ER stress

    PubMed Central

    Fan, Ying; Xiao, Wenzhen; Li, Zhengzhe; Li, Xuezhu; Chuang, Peter Y.; Jim, Belinda; Zhang, Weijia; Wei, Chengguo; Wang, Niansong; Jia, Weiping; Xiong, Huabao; Lee, Kyung; He, John C.

    2015-01-01

    Identification of new biomarkers and drug targets for chronic kidney disease (CKD) is required for the development of more effective therapy. Here we report an association between expression of reticulon 1 (RTN1) and severity of CKD. An isoform-specific increase in the expression of RTN1A is detected in the diseased kidneys from mice and humans, and correlates inversely with renal function in patients with diabetic nephropathy. RTN1 overexpression in renal cells induces ER stress and apoptosis, whereas RTN1 knockdown attenuates tunicamycin-induced and hyperglycaemia-induced ER stress and apoptosis. RTN1A interacts with PERK through its N-terminal and C-terminal domains, and mutation of these domains prevents this effect on ER stress. Knockdown of Rtn1a expression in vivo attenuates ER stress and renal fibrosis in mice with unilateral ureteral obstruction, and also attenuates ER stress, proteinuria, glomerular hypertrophy and mesangial expansion in diabetic mice. Together, these data indicate that RTN1A contributes to progression of kidney disease by inducing ER stress. PMID:26227493

  1. Fatal Progression of Gorham Disease: A Case Report and Review of the Literature.

    PubMed

    Kim, Min-Keun; Hong, Jong-Rak; Kim, Seong-Gon; Lee, Seok-Keun

    2015-12-01

    Gorham disease is an idiopathic massive osteolysis, and maxillofacial involvement is rare. This report describes a case of a 12-year-old boy with severe progressive osteolysis in the mandible, hyoid bone, mastoid process, and cervical spine. Radiation therapy and interferon-? therapy were followed by bisphosphonate therapy. The patient died of respiratory failure. To describe the clinicopathologic features of Gorham disease of the jaws with an emphasis on the fatal types, 64 cases in the literature were reviewed (female-to-male ratio, 1:1.78; average age, 33.02 19.38yr). Most lesions were located only in the mandible or in other locations in combination with the mandible, except for 3 cases. During follow-up, there were 7 cases of disease-specific death, resulting in a mortality rate of 10.94%. The main causes of death were chylothorax, rib fractures secondary to osteolysis, or spinal fractures. Although most patients received surgical treatment (43.75%), the type of treatment was not related to prognosis. PMID:26169484

  2. Speech disorders reflect differing pathophysiology in Parkinson's disease, progressive supranuclear palsy and multiple system atrophy.

    PubMed

    Rusz, Jan; Bonnet, Cecilia; Klempíř, Jiří; Tykalová, Tereza; Baborová, Eva; Novotný, Michal; Rulseh, Aaron; Růžička, Evžen

    2015-01-01

    Although speech disorder is frequently an early and prominent clinical feature of Parkinson's disease (PD) as well as atypical parkinsonian syndromes (APS) such as progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), there is a lack of objective and quantitative evidence to verify whether any specific speech characteristics allow differentiation between PD, PSP and MSA. Speech samples were acquired from 77 subjects including 15 PD, 12 PSP, 13 MSA and 37 healthy controls. The accurate differential diagnosis of dysarthria subtypes was based on the quantitative acoustic analysis of 16 speech dimensions. Dysarthria was uniformly present in all parkinsonian patients but was more severe in PSP and MSA than in PD. Whilst PD speakers manifested pure hypokinetic dysarthria, ataxic components were more affected in MSA whilst PSP subjects demonstrated severe deficits in hypokinetic and spastic elements of dysarthria. Dysarthria in PSP was dominated by increased dysfluency, decreased slow rate, inappropriate silences, deficits in vowel articulation and harsh voice quality whereas MSA by pitch fluctuations, excess intensity variations, prolonged phonemes, vocal tremor and strained-strangled voice quality. Objective speech measurements were able to discriminate between APS and PD with 95% accuracy and between PSP and MSA with 75% accuracy. Dysarthria severity in APS was related to overall disease severity (r = 0.54, p = 0.006). Dysarthria with various combinations of hypokinetic, spastic and ataxic components reflects differing pathophysiology in PD, PSP and MSA. Thus, motor speech examination may provide useful information in the evaluation of these diseases with similar manifestations. PMID:25683763

  3. High Serum GFAP Levels in SCA3/MJD May Not Correlate with Disease Progression.

    PubMed

    Shi, Yuting; Wang, Chunrong; Huang, Fengzhen; Chen, Zhao; Sun, Zhanfang; Wang, Junling; Tang, Beisha; Ashizawa, Tetsuo; Klockgether, Thomas; Jiang, Hong

    2015-12-01

    Spinocerebellar ataxia type 3(SCA3), also known as Machado-Joseph disease (MJD), is the most frequent subtype of autosomal dominant inherited spinocerebellar ataxias, which caused by the expansion of CAG repeats in the ATXN3 gene. The number of CAG repeats of the abnormal allele determines the rate of disease progression in patients with SCA3/MJD. Markers to assess the clinical severity, to predict the course of illness and to monitor the efficacy of therapeutic measures, can be clinical, biological, and radiological. Here, we aimed to explore whether the serum glial fibrillary acidic protein (GFAP) may act as a biomarker in SCA3/MJD patients and to evaluate the correlation between some markers with the number of CAG repeats in SCA3/MJD patients. We showed that the serum levels of GFAP were significantly higher in SCA3/MJD patients than in controls. There was a strong positive correlation between the age-adjusted GFAP levels with the number of CAG repeats. Age-adjusted International Cooperative Ataxia Rating Scale (ICARS) scores and Scale for the Assessment and Rating of Ataxia (SARA) scores correlated with the number of CAG repeats. Raw scores and disease duration-adjusted GFAP levels, ICARS scores, and SARA scores were not correlated with the number of CAG repeats. Our results reveal novel evidence for the role of the triplet expansion in SCA3/MJD-associated neuronal damage. PMID:25869927

  4. Effect of Treatment for CHC on Liver Disease Progression and Hepatocellular Carcinoma Development in African Americans

    PubMed Central

    Reddy, Naveen; Naylor, Paul; Hakim, Zaher; Asbahi, Redwan; Ravindran, Karthik; May, Elizabeth; Ehrinpreis, Murray; Mutchnick, Milton

    2015-01-01

    Background and Aims: African Americans (AA) historically have a low response rate to hepatitis C therapies, and there is limited information available for this patient population regarding the development and treatment of chronic hepatitis C (CHC). The aim of this study was to evaluate liver disease progression and hepatocellular carcinoma (HCC) development in AA with CHC. Methods: Between 1995 and 2008, 246 AA patients with CHC were identified from a database of patients and followed until 2012-2013 (average 8 years) or the development of HCC after 2008. Results: Viral clearance (intent to treat; sustained virus response (SVR)) was achieved in 15% of patients with interferon based therapies with or without ribavirin. AA patients who achieved an SVR (n=22) did not develop HCC or new onset cirrhosis, whereas the HCC incidence in untreated AA patients was 23% (51/203). Patients who achieved an SVR also had improved fibrosis, as defined by the AST Platelet Ratio Index (APRI) and Fibrosis-4 (FIB-4) score, relative to nonresponders and untreated patients. Conclusions: The severity of liver disease at the first visit (except for cirrhosis) correlated with the development of HCC, but because of the overlap in values between patients, these measurements were not useful for predicting individual risk. Since cirrhosis at the first visit was not a predictive factor, treatment with newer antiviral therapies is the best option for reducing the incidence of advanced liver disease and its harmful outcomes in the AA population. PMID:26623262

  5. Chronic follicular bronchiolitis requires antigen-specific regulatory T cell control to prevent fatal disease progression.

    PubMed

    Schmitt, Erica G; Haribhai, Dipica; Jeschke, Jonathan C; Co, Dominic O; Ziegelbauer, Jennifer; Yan, Ke; Iwakura, Yoichiro; Mishra, Manoj K; Simpson, Pippa; Salzman, Nita H; Williams, Calvin B

    2013-12-01

    To study regulatory T (Treg) cell control of chronic autoimmunity in a lymphoreplete host, we created and characterized a new model of autoimmune lung inflammation that targets the medium and small airways. We generated transgenic mice that express a chimeric membrane protein consisting of hen egg lysozyme and a hemoglobin epitope tag under the control of the Clara cell secretory protein promoter, which largely limited transgene expression to the respiratory bronchioles. When Clara cell secretory protein-membrane hen egg lysozyme/hemoglobin transgenic mice were crossed to N3.L2 TCR transgenic mice that recognize the hemoglobin epitope, the bigenic progeny developed dense, pseudo-follicular lymphocytic peribronchiolar infiltrates that resembled the histological pattern of follicular bronchiolitis. Aggregates of activated IFN-?- and IL-17A-secreting CD4(+) T cells as well as B cells surrounded the airways. Lung pathology was similar in Ifng(-/-) and Il17a(-/-) mice, indicating that either cytokine is sufficient to establish chronic disease. A large number of Ag-specific Treg cells accumulated in the lesions, and Treg cell depletion in the affected mice led to an interstitial spread of the disease that ultimately proved fatal. Thus, Treg cells act to restrain autoimmune responses, resulting in an organized and controlled chronic pathological process rather than a progressive disease. PMID:24163409

  6. Clonal evolution in chronic lymphocytic leukemia: impact of subclonality on disease progression.

    PubMed

    Sutton, Lesley-Ann; Rosenquist, Richard

    2015-02-01

    In recent years, next-generation sequencing has unraveled the molecular landscape in chronic lymphocytic leukemia with the discovery of a number of recurrently mutated genes. Mutations in several of these genes, such as NOTCH1, SF3B1 and BIRC3, are linked to a more aggressive disease with early disease progression, short time-to-first-treatment and even chemorefractoriness. Although in its infancy, we have also begun to understand the complex dynamics of subclonal diversity and its impact on disease outcome. From pioneering studies, we know that certain genetic events are found in the majority of chronic lymphocytic leukemia cells and are considered as 'clonal driver mutations' (e.g., +12, 13q-), whereas others, present only in a fraction of the tumor, are deemed to be 'subclonal driver mutations' for example, TP53 and SF3B1. Over the coming years, we need to gain a deeper insight into the dynamics of this subclonal architecture to understand how, at an individual level, chronic lymphocytic leukemia patients should be followed, which will be particularly relevant as novel targeted therapies begin to emerge. PMID:25345442

  7. 8OHdG as a marker for Huntington disease progression

    PubMed Central

    Long, Jeffrey D.; Matson, Wayne R.; Juhl, Andrew R.; Leavitt, Blair R.; Paulsen, Jane S.

    2013-01-01

    Leukocyte 8-hydroxydeoxyguanosine (8OHdG) is an indicator of oxidative stress, impaired metabolism, and mitochondrial dysfunction, features that have been implicated in Huntington disease (HD). Increased levels of 8OHdG have been reported in the caudate, parietal cortex, and peripherally in the serum and leukocytes, in patients diagnosed with HD. However, little is known about levels in prodromal patients and changes that might occur as the disease progresses. To address these issues, 8OHdG was tracked over time for a subset of participants enrolled in the PREDICT-HD study. Participants were stratified into four groups based on proximity to HD diagnosis at study entry: Controls (gene-negative individuals), Low (low probability of near future diagnosis), Medium, and High. Blood samples were analyzed using Liquid Chromatography Electrochemical Array, and for comparison purposes, a separate cross-sectional sample was analyzed using liquid chromatography coupled with multiple-reaction-monitoring mass spectrometry. Longitudinal data analysis showed that initial status (at study entry) and annual rate of change varied as a function of proximity group, adjusting for sex, education, age at study entry, and site effects. Overall levels were lowest for the Control group and highest for the High group, and the rate of increase varied in a similar manner. The finding that 8OHdG concentrations increased as a function of proximity to projected disease diagnosis and duration indicates support for the continued assessment of 8OHdG as a robust clinical HD biomarker. PMID:22414782

  8. Compassionate Love as a Predictor of Reduced HIV Disease Progression and Transmission Risk.

    PubMed

    Kremer, Heidemarie; Ironson, Gail; Kaplan, Lauren; Stuetzle, Rick; Fletcher, Mary A

    2013-01-01

    Objectives. This study examined if compassionate love (CL) predicts HIV disease progression and transmission risk. Scientific study of CL emerged with Underwood's working model of other-centered CL, defining five criteria: free choice, cognitive understanding, valuing/empowering, openness/receptivity for spirituality, and response of the heart. Method. This 10-year cohort study collected 6-monthly interviews/essays on coping with HIV and trauma of 177 people with HIV in South Florida. Secondary qualitative content analysis on other-centered CL inductively added the component of CL towards self. Deductively, we coded the presence of the five criteria of CL and rated the benefit of CL for the recipient on a 6-point Likert scale. Growth-curve modeling (reduced to 4 years due to cohort effects) investigated if CL predicts CD4 slope (HIV disease progression) and cumulative viral load detection (transmission risk). Results. Valuing/empowering and cognitive understanding were the essential criteria for CL to confer long-term benefits. CL had a higher benefit for recipients if given out of free choice. High scores of CL towards self were reciprocal with receiving (93%) and giving (77%) other-centered CL. Conversely, those rated low on CL towards self were least likely to score high on receiving (38%) and giving (49%) other-centered CL. Growth-curve modeling showed that CL towards self predicted 4-year cumulative undetectable viral load (independent from sociocultural differences, substance use disorder, baseline CD4 and viral load). Those high versus low on CL self were 2.25 times more likely to have undetectable viral load at baseline and 1.49 times more likely to maintain undetectable viral load over time. CL towards self predicted CD4 preservation after controlling for differences in CL giving. Conclusions. CL towards self is potentially the seed of being expressive and receptive of CL. Health care professionals prepared to walk the extra mile for those who neglect and isolate themselves may break a vicious circle since those lacking CL self were least likely to receive CL from others. Future studies should examine whether any enhancement of CL towards self may translate into slower disease progression and reduction of transmission risk. PMID:24348722

  9. Modifications of the mouse bone marrow microenvironment favor angiogenesis and correlate with disease progression from asymptomatic to symptomatic multiple myeloma

    PubMed Central

    Calcinotto, Arianna; Ponzoni, Maurilio; Ria, Roberto; Grioni, Matteo; Cattaneo, Elena; Villa, Isabella; Sabrina Bertilaccio, Maria Teresa; Chesi, Marta; Rubinacci, Alessandro; Tonon, Giovanni; Bergsagel, P Leif; Vacca, Angelo; Bellone, Matteo

    2015-01-01

    While multiple myeloma (MM) is almost invariably preceded by asymptomatic monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering MM (SMM), the alterations of the bone marrow (BM) microenvironment that establish progression to symptomatic disease are circumstantial. Here we show that in Vk*MYC mice harboring oncogene-driven plasma cell proliferative disorder, disease appearance associated with substantial modifications of the BM microenvironment, including a progressive accumulation of both CD8+ and CD4+ T cells with a dominant T helper type 1 (Th1) response. Progression from asymptomatic to symptomatic MM was characterized by further BM accrual of T cells with reduced Th1 and persistently increased Th2 cytokine production, which associated with accumulation of CD206+Tie2+ macrophages, and increased pro-angiogenic cytokines and microvessel density (MVD). Notably, MVD was also increased at diagnosis in the BM of MGUS and SMM patients that subsequently progressed to MM when compared with MGUS and SMM that remained quiescent. These findings suggest a multistep pathogenic process in MM, in which the immune system may contribute to angiogenesis and disease progression. They also suggest initiating a large multicenter study to investigate MVD in asymptomatic patients as prognostic factor for the progression and outcome of this disease. PMID:26155424

  10. Discordant Impact of HLA on Viral Replicative Capacity and Disease Progression in Pediatric and Adult HIV Infection

    PubMed Central

    Adland, Emily; Paioni, Paolo; Thobakgale, Christina; Laker, Leana; Mori, Luisa; Muenchhoff, Maximilian; Csala, Anna; Clapson, Margaret; Flynn, Jacquie; Novelli, Vas; Hurst, Jacob; Naidoo, Vanessa; Shapiro, Roger; Huang, Kuan-Hsiang Gary; Frater, John; Prendergast, Andrew; Prado, Julia G.; Ndungu, Thumbi; Walker, Bruce D.; Carrington, Mary; Jooste, Pieter; Goulder, Philip J. R.

    2015-01-01

    HLA class I polymorphism has a major influence on adult HIV disease progression. An important mechanism mediating this effect is the impact on viral replicative capacity (VRC) of the escape mutations selected in response to HLA-restricted CD8+ T-cell responses. Factors that contribute to slow progression in pediatric HIV infection are less well understood. We here investigate the relationship between VRC and disease progression in pediatric infection, and the effect of HLA on VRC and on disease outcome in adult and pediatric infection. Studying a South African cohort of >350 ART-nave, HIV-infected children and their mothers, we first observed that pediatric disease progression is significantly correlated with VRC. As expected, VRCs in mother-child pairs were strongly correlated (p = 0.004). The impact of the protective HLA alleles, HLA-B*57, HLA-B*58:01 and HLA-B*81:01, resulted in significantly lower VRCs in adults (p<0.0001), but not in children. Similarly, in adults, but not in children, VRCs were significantly higher in subjects expressing the disease-susceptible alleles HLA-B*18:01/45:01/58:02 (p = 0.007). Irrespective of the subject, VRCs were strongly correlated with the number of Gag CD8+ T-cell escape mutants driven by HLA-B*57/58:01/81:01 present in each virus (p = 0.0002). In contrast to the impact of VRC common to progression in adults and children, the HLA effects on disease outcome, that are substantial in adults, are small and statistically insignificant in infected children. These data further highlight the important role that VRC plays both in adult and pediatric progression, and demonstrate that HLA-independent factors, y