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1

Kinematics of Disease Progression in Bulbar ALS  

ERIC Educational Resources Information Center

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…

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

2010-01-01

2

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

PubMed Central

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

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

2009-01-01

3

EGFR Inhibitor Erlotinib Delays Disease Progression but Does Not Extend Survival in the SOD1 Mouse Model of ALS  

PubMed Central

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive paralysis due to motor neuron death. Several lines of published evidence suggested that inhibition of epidermal growth factor receptor (EGFR) signaling might protect neurons from degeneration. To test this hypothesis in vivo, we treated the SOD1 transgenic mouse model of ALS with erlotinib, an EGFR inhibitor clinically approved for oncology indications. Although erlotinib failed to extend ALS mouse survival it did provide a modest but significant delay in the onset of multiple behavioral measures of disease progression. However, given the lack of protection of motor neuron synapses and the lack of survival extension, the small benefits observed after erlotinib treatment appear purely symptomatic, with no modification of disease course. PMID:23638043

Le Pichon, Claire E.; Dominguez, Sara L.; Solanoy, Hilda; Ngu, Hai; Lewin-Koh, Nicholas; Chen, Mark; Eastham-Anderson, Jeffrey; Watts, Ryan; Scearce-Levie, Kimberly

2013-01-01

4

Progression of Liver Disease  

MedlinePLUS

... Handouts Education Resources Support Services Helpful Links For Liver Health Information Call 1-800-GO-LIVER (1- ... The Progression of Liver Disease The Progression of Liver Disease There are many different types of liver ...

5

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

PubMed Central

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

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

2013-01-01

6

Protective effects of heat shock protein 27 in a model of ALS occur in the early stages of disease progression.  

PubMed

Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disorder, characterised by progressive motor neuron degeneration and muscle paralysis. Heat shock proteins (HSPs) have significant cytoprotective properties in several models of neurodegeneration. To investigate the therapeutic potential of heat shock protein 27 (HSP27) in a mouse model of ALS, we conducted an extensive characterisation of transgenic mice generated from a cross between HSP27 overexpressing mice and mice expressing mutant superoxide dismutase (SOD1(G93A)). We report that SOD1(G93A)/HSP27 double transgenic mice showed delayed decline in motor strength, a significant improvement in the number of functional motor units and increased survival of spinal motor neurons compared to SOD1(G93A) single transgenics during the early phase of disease. However, there was no evidence of sustained neuroprotection affecting long-term survival. Marked down-regulation of HSP27 protein occurred during disease progression that was not associated with a reduction in HSP27 mRNA, indicating a translational dysfunction due to the presence of mutant SOD1 protein. This study provides further support for the therapeutic potential of HSPs in ALS and other motor neuron disorders. PMID:18255302

Sharp, Paul S; Akbar, Mohammed T; Bouri, Sonia; Senda, Atsushi; Joshi, Kieran; Chen, Han-Jou; Latchman, David S; Wells, Dominic J; de Belleroche, Jacqueline

2008-04-01

7

Inflammation and disease progression  

Microsoft Academic Search

Inflammation is a physiological response to a foreign organism such as bacteria, dust particles, and viruses. Recent studies have enlightened the role of inflammation in the progression of a variety of diseases such as cancer, atherosclerosis, asthma, and psoriasis. This article is a brief overview of the inflammatory processes involved in the progression of these common diseases. Knowledge about these

Sriram Krishnamoorthy; Kenneth V. Honn

2006-01-01

8

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

PubMed Central

Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s 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

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

2014-01-01

9

ALS-Linked SOD1 Mutant G85R Mediates Damage to Astrocytes and Promotes Rapidly Progressive Disease with SOD1-Containing Inclusions  

Microsoft Academic Search

High levels of familial Amyotrophic Lateral Sclerosis (ALS)-linked SOD1 mutants G93A and G37R were previously shown to mediate disease in mice through an acquired toxic property. We report here that even low levels of another mutant, G85R, cause motor neuron disease characterized by an extremely rapid clinical progression, without changes in SOD1 activity. Initial indicators of disease are astrocytic inclusions

L. I. Bruijn; M. W. Becher; M. K. Lee; K. L. Anderson; N. A. Jenkins; N. G. Copeland; S. S. Sisodia; J. D. Rothstein; D. R. Borchelt; D. L. Price; D. W. Cleveland

1997-01-01

10

Plasma Neurofilament Heavy Chain Levels Correlate to Markers of Late Stage Disease Progression and Treatment Response in SOD1G93A Mice that Model ALS  

PubMed Central

Background Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder characterised by progressive degeneration of motor neurons leading to death, typically within 3–5 years of symptom onset. The diagnosis of ALS is largely reliant on clinical assessment and electrophysiological findings. Neither specific investigative tools nor reliable biomarkers are currently available to enable an early diagnosis or monitoring of disease progression, hindering the design of treatment trials. Methodology/Principal Findings In this study, using the well-established SOD1G93A mouse model of ALS and a new in-house ELISA method, we have validated that plasma neurofilament heavy chain protein (NfH) levels correlate with both functional markers of late stage disease progression and treatment response. We detected a significant increase in plasma levels of phosphorylated NfH during disease progression in SOD1G93A mice from 105 days onwards. Moreover, increased plasma NfH levels correlated with the decline in muscle force, motor unit survival and, more significantly, with the loss of spinal motor neurons in SOD1 mice during this critical period of decline. Importantly, mice treated with the disease modifying compound arimoclomol had lower plasma NfH levels, suggesting plasma NfH levels could be validated as an outcome measure for treatment trials. Conclusions/Significance These results show that plasma NfH levels closely reflect later stages of disease progression and therapeutic response in the SOD1G93A mouse model of ALS and may potentially be a valuable biomarker of later disease progression in ALS. PMID:22815892

Lu, Ching-Hua; Petzold, Axel; Kalmar, Bernadett; Dick, James; Malaspina, Andrea; Greensmith, Linda

2012-01-01

11

Quantifying Disease Progression in Amyotrophic Lateral Sclerosis  

PubMed Central

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

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

2014-01-01

12

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

PubMed

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

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

2012-01-01

13

A Novel Acylaminoimidazole Derivative, WN1316, Alleviates Disease Progression via Suppression of Glial Inflammation in ALS Mouse Model  

PubMed Central

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 µg/kg/day) WN1316 in ALS(SOD1H46R) and ALS(SOD1G93A) 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

Yanagisawa, Yoshiko; Yasutake, Kaori; Inoue, Satoshi; Hirayama, Noriaki; Ikeda, Joh-E

2014-01-01

14

Immunization with a Myelin-Derived Antigen Activates the Brain's Choroid Plexus for Recruitment of Immunoregulatory Cells to the CNS and Attenuates Disease Progression in a Mouse Model of ALS.  

PubMed

Amyotrophic lateral sclerosis (ALS) is a devastating fatal motor neuron disease, for which there is currently no cure or effective treatment. In this disease, local neuroinflammation develops along the disease course and contributes to its rapid progression. In several models of CNS pathologies, circulating immune cells were shown to display an indispensable role in the resolution of the neuroinflammatory response. The recruitment of such cells to the CNS involves activation of the choroid plexus (CP) of the brain for leukocyte trafficking, through a mechanism that requires IFN-? signaling. Here, we found that in the mutant SOD1(G93A) (mSOD1) mouse model of ALS, the CP does not support leukocyte trafficking during disease progression, due to a local reduction in IFN-? levels. Therapeutic immunization of mSOD1 mice with a myelin-derived peptide led to CP activation, and was followed by the accumulation of immunoregulatory cells, including IL-10-producing monocyte-derived macrophages and Foxp3(+) regulatory T cells, and elevation of the neurotrophic factors IGF-1 and GDNF in the diseased spinal cord parenchyma. The immunization resulted in the attenuation of disease progression and an increased life expectancy of the mSOD1 mice. Collectively, our results demonstrate that recruitment of immunoregulatory cells to the diseased spinal cord in ALS, needed for fighting off the pathology, can be enhanced by transiently boosting peripheral immunity to myelin antigens. PMID:25904790

Kunis, Gilad; Baruch, Kuti; Miller, Omer; Schwartz, Michal

2015-04-22

15

Rab11 in Disease Progression  

PubMed Central

Abstract: 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.

Bhuin, Tanmay; Roy, Jagat Kumar

2015-01-01

16

The clinical progression of Parkinson's disease.  

PubMed

Parkinson's disease (PD) is known as a chronic neurodegenerative disorder with a relentlessly progressive course of illness. Although in recent decades there have been many advances in symptomatic therapy, there is still no established therapy that will halt or slow progression in a clinically meaningful way. So far, disease-modification trials have focused on indices of progression of cardinal motor features such as bradykinesia, rigidity and tremor as captured by the Unified Parkinson's Disease Rating Scale, and the emerging need for effective symptomatic dopaminergic therapy. Progression of global disability in PD, however, is driven by additional factors beyond progressive nigrostriatal denervation, leading to increasing severity of cardinal motor features. Progressive pathology in extranigral sites inevitably leads to poorly L-dopa-responsive motor symptoms such as postural instability, freezing and falls, or non-motor symptoms. Furthermore, treatment-induced motor complications also contribute to PD disability. Progression of PD is multidimensional with superimposed age-related co-morbidities. Hence there is no consensus on how to best implement more clinically meaningful end-points for disease progression trials that would reflect these complex interactions impacting on the evolution of global disability in PD. There is an urgent need for biomarkers identifying preclinical stages of illness and describing disease progression--thus faithfully reflecting early and advancing neurodegeneration--that could be used in short-term clinical trials testing putative disease-modifying agents. PMID:20123553

Poewe, Werner; Mahlknecht, Philipp

2009-12-01

17

Complement activation in progressive renal disease  

PubMed Central

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

Fearn, Amy; Sheerin, Neil Stephen

2015-01-01

18

Friends, social networks, and progressive chronic kidney disease.  

PubMed

A report by Dunkler et al. reminds us that social factors are relevant for today's clinical scientist and practitioner. They report that an increasing number of friends reduces the incidence and progression of chronic kidney disease in type 2 diabetes. The observation that 'friends don't let friends' develop kidney disease suggests that social factors, as well as biomarkers, may be relevant in developing 'personalized renal medicine' and may identify areas for future nephrology research and education. PMID:25826543

McClellan, William M; Doran, John J

2015-04-01

19

Mechanisms of progression of chronic kidney disease  

Microsoft Academic Search

Chronic kidney disease (CKD) occurs in all age groups, including children. Regardless of the underlying cause, CKD is characterized\\u000a by progressive scarring that ultimately affects all structures of the kidney. The relentless progression of CKD is postulated\\u000a to result from a self-perpetuating vicious cycle of fibrosis activated after initial injury. We will review possible mechanisms\\u000a of progressive renal damage, including

Agnes B. Fogo

2007-01-01

20

Levodopa and the Progression of Parkinson's Disease  

Microsoft Academic Search

background Despite the known benefit of levodopa in reducing the symptoms of Parkinson's dis- ease, concern has been expressed that its use might hasten neurodegeneration. This study assessed the effect of levodopa on the rate of progression of Parkinson's disease. methods In this randomized, double-blind, placebo-controlled trial, we evaluated 361 patients with early Parkinson's disease who were assigned to receive

Stanley Fahn; Ira Shoulson; Karl Kieburtz; Alice Rudolph; Anthony Lang; C. Warren Olanow; Caroline Tanner

2009-01-01

21

Caffeine and Progression of Parkinson Disease  

PubMed Central

Objective Caffeine use is negatively associated with the risk of developing Parkinson disease (PD) and is protective in animal models of PD, but the relationship between caffeine intake and rate of progression of PD is unknown. We assessed this relationship using data from 2 recent clinical trials of PD. Methods Data were ascertained from 2 recent 1-year clinical trials that together included 413 early PD subjects who did not require symptomatic therapy at the time of study entry. Exploratory analyses compared caffeine intake with rate of progression of PD, as measured by either the likelihood of progression to the point of requiring symptomatic therapy or by change in the total Unified Parkinson Disease Rating Scale score. Results Rate of progression of PD did not differ significantly between those in the highest and lowest quartiles for caffeine use for either of the primary measures or for secondary analyses of changes in scores on the motor or activities of daily living subsections of the Unified Parkinson Disease Rating Scale. Other secondary analyses yielded variable results. Conclusions These data do not reveal a consistent relationship between caffeine intake and rate of progression of PD by these measures, although a larger study is required for sufficient power to more fully assess this relationship. PMID:18670242

Simon, David K.; Swearingen, Christopher J.; Hauser, Robert A.; Trugman, Joel M.; Aminoff, Michael J.; Singer, Carlos; Truong, Daniel; Tilley, Barbara C.

2011-01-01

22

Exotic emerging viral diseases: progress and challenges  

Microsoft Academic Search

The agents causing viral hemorrhagic fever (VHF) are a taxonomically diverse group of viruses that may share commonalities in the process whereby they produce systemic and frequently fatal disease. Significant progress has been made in understanding the biology of the Ebola virus, one of the best known examples. This knowledge has guided our thinking about other VHF agents, including Marburg,

Thomas W Geisbert; Peter B Jahrling

2004-01-01

23

The Axis of Progression of Disease  

PubMed Central

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

Tartakoff, Alan M; Wu, Di

2014-01-01

24

Progression of Glomerular and Tubular Disease  

PubMed Central

Chronic kidney disease may be stimulated by many different etiologies, but its progression involves a common, yet complex, series of events that lead to the replacement of normal tissue with scar. These events include altered physiology within the kidney leading to abnormal hemodynamics, chronic hypoxia, inflammation, cellular dysfunction and activation of fibrogenic biochemical pathways. The end result is the replacement of normal structures with extracellular matrix. Treatments are presently focused on delaying or preventing such progression, and are largely nonspecific. In pediatrics, such therapy is further complicated by both pathophysiological issues that render children a unique population. PMID:19615562

Woroniecki, Robert P.; Schnaper, H. William

2015-01-01

25

Serum Immune Responses Predict Rapid Disease Progression among Children with Crohn's Disease: Immune Responses Predict Disease Progression  

Microsoft Academic Search

BACKGROUND AND AIM:Crohn's disease (CD) is a heterogeneous disorder characterized by diverse clinical phenotypes. Childhood-onset CD has been described as a more aggressive phenotype. Genetic and immune factors may influence disease phenotype and clinical course. We examined the association of immune responses to microbial antigens with disease behavior and prospectively determined the influence of immune reactivity on disease progression in

Marla C. Dubinsky; Ying-Chao Lin; Debra Dutridge; Yoana Picornell; Carol J. Landers; Sharmayne Farrior; Iwona Wrobel; Antonio Quiros; Eric A. Vasiliauskas; Bruce Grill; David Israel; Ron Bahar; Dennis Christie; Ghassan Wahbeh; Gary Silber; Saied Dallazadeh; Praful Shah; Danny Thomas; Drew Kelts; Robert M. Hershberg; Charles O. Elson; Stephan R. Targan; Kent D. Taylor; Jerome I. Rotter; Huiying Yang

2006-01-01

26

Rapidly progressive Alzheimer's disease: a multicenter update.  

PubMed

The objective was to characterize a rapidly progressive subtype of Alzheimer's disease (rpAD). Multicenter (France, Germany, Japan, Spain) retrospective analyses of neuropathologically confirmed rpAD cases initially classified as prion disease due to their clinical phenotype were performed. Genetic properties, cerebrospinal fluid biomarkers, neuropathology, and clinical features were examined. Eighty-nine patients were included (median survival 10 months). APOE and PRNP codon 129 genotype distribution paralleled a healthy control group. APOE ?4 homozygosity was absent. Cerebrospinal fluid biomarkers were abnormal, but within a range as expected for classic AD, except for proteins 14-3-3, which were detectable in 42%. Thus, evidence of the existence of rpAD is accumulating. The APOE profile is intriguing, suggesting that this very rapid disease form might represent a distinct subtype of Alzheimer's disease. PMID:22460329

Schmidt, Christian; Haïk, Stephane; Satoh, Katsuya; Rábano, Alberto; Martinez-Martin, Pablo; Roeber, Sigrun; Brandel, Jean-Philippe; Calero-Lara, Miguel; de Pedro-Cuesta, Jesús; Laplanche, Jean-Louis; Hauw, Jean-Jaques; Kretzschmar, Hans; Zerr, Inga

2012-01-01

27

Mechanisms of progression of chronic kidney disease  

PubMed Central

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 renin–angiotensin–aldosterone 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

2007-01-01

28

Smoking and Disease Progression in Multiple Sclerosis  

PubMed Central

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: 16–75) and disease duration of 9.4 years (range: 0–50.4) -- 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

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

29

Gene therapy: progress in childhood disease.  

PubMed

The recent sequencing of the human genome combined with the development of massively high throughput genetic analysis technologies is driving unprecedented growth in our knowledge of the molecular basis of disease. While this has already had a major impact on our diagnostic power, the therapeutic benefits remain largely unrealised. This review examines progress in the exciting and challenging field of gene therapy. In particular we focus on the treatment of genetic disease in infants and children where the most significant successes have been observed to date, despite the majority of trial participants being adults. Notably, gene transfer to the haematopoietic compartment has provided the clearest examples of therapeutic benefit, particularly in the context of primary immunodeficiencies. The triumphs and tribulations of these successes are explored, and the key challenges confronting researchers as they seek to further advance the field are defined and discussed. PMID:22017270

Ginn, Samantha L; Alexander, Ian E

2012-06-01

30

[Pharmacotherapy of Parkinson's disease: progress or regress?].  

PubMed

Parkinson's disease (PD) is a chronic, progressive disease of the central nervous system (CNS), characterized by a slow loss of dopaminergic neurons in the substantia nigra, leading to significant decrease in dopamine (DA) levels in the striatum. Currently used drugs, such as levodopa (L-DOPA), amantadine, dopamine agonists (D) or anticholinergic drugs, are not effective enough, and do not eliminate the causes of disease. Many research centers are conducting research on new forms of currently used drugs (e.g. Duodopa, XP21279, IPX066), new drugs of already known groups (e.g. safinamide), medicines that suppress side effects of L-DOPA (e.g. AFQ056, fipamezole), and, finally, compounds with a novel mechanism of action (e.g. PMY50028, A2A receptor antagonists). A lot of scientific reports indicate an important role of A2A receptors in the regulation of the central movement system, so a new group of compounds - selective antagonists of A2A receptors (e.g. istradefylline, preladenant, SYN115) - has been developed and their potential use in PD has been examined. Clinical studies of A2A receptor antagonists have shown that this group of compounds can shorten off periods and at the same time they do not worsen dyskinesias in patients with PD. Moreover, there is ongoing research on new forms of treatment, such as gene therapy. Attempts to apply the viral vector AAV-2, which will be able to infect neurons with a variety of genes, including the gene of glutamate decarboxylase (GAD), neurturin (NTN), or aromatic L-amino acid decarboxylase, are currently being carried out. The results of phase I and II clinical studies showed some efficacy of this form of treatment, but the method requires further studies. An analysis of potential future therapies of Parkinson's disease suggests that some progress in this field has been made. PMID:24018435

Pytka, Karolina; Zygmunt, Ma?gorzata; Filipek, Barbara

2013-01-01

31

INTRODUCTION Huntington's disease (HD) is an autosomal dominant, progressive  

E-print Network

INTRODUCTION Huntington's disease (HD) is an autosomal dominant, progressive neurodegenerative protein, huntingtin (Htt) (The Huntington's Disease Collaborative Research Group, 1993). The polyQ tract in HD (The Huntington's Disease Collaborative Research Group, 1993). Numerous studies have demonstrated

Perrimon, Norbert

32

Crevicular Fluid Biomarkers and Periodontal Disease Progression  

PubMed Central

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

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

2014-01-01

33

Measuring disease progression in corticobasal syndrome.  

PubMed

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

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

2014-08-01

34

Disease Progression Analysis: Towards Mechanism-Based Models  

Microsoft Academic Search

\\u000a Sustained disturbances of the biological homeostasis can result in chronic progressive diseases. The respective disease status\\u000a as well as the corresponding effect of drug treatment on disease progression can be characterized at different levels of complexity,\\u000a ranging from data-driven and descriptive to fully mechanistic approaches. Most of the currently employed disease progression\\u000a models are mechanism-based and represent a mixture of

Stephan Schmidt; Teun M. Post; Massoud A. Boroujerdi; Charlotte Kesteren; Bart A. Ploeger; Oscar E. Della Pasqua; Meindert Danhof

35

rotein aggregation appears to be linked to the progression of Alzheimer's disease.  

E-print Network

rotein aggregation appears to be linked to the progression of Alzheimer's disease. (AD that these proteins bind to and prevent the aggregation of A. Shuvaev et al. immobilized A using amine coupling of Alzheimer's disease. For applications in which protein-protein interactions must be minimized

Cairo, Christopher W.

36

Sporadic Jakob-Creutzfeldt Disease Presenting as Primary Progressive Aphasia  

PubMed Central

Objective To report the clinical, neuropsychological, linguistic, imaging, and neuropathological features of a unique case of sporadic Jakob-Creutzfeldt disease in which the patient presented with a logopenic variant of primary progressive aphasia. Design Case report. Setting Large referral center for atypical memory and aging disorders, particularly Jakob-Creutzfeldt disease. Patient Patient presenting with logopenic variant primary progressive aphasia initially thought to be due to Alzheimer disease. Results Despite the long, slow 3.5-year course, the patient was shown to have pathology-proven sporadic Jakob-Creutzfeldt disease. Conclusions These findings expand the differential of primary progressive aphasia to include prion disease. PMID:23400721

Johnson, David Y.; Dunkelberger, Diana L.; Henry, Maya; Haman, Aissatou; Greicius, Michael D.; Wong, Katherine; DeArmond, Stephen J.; Miller, Bruce L.; Gorno-Tempini, Maria Luisa; Geschwind, Michael D.

2015-01-01

37

Alzheimer disease: progress or profit? Claire Mount & Christian Downton  

E-print Network

Alzheimer disease: progress or profit? Claire Mount & Christian Downton Alzheimer disease people worldwide currently have dementia;Alzheimer disease affects about 18 million of them1. Increasing age is the greatest risk factor for Alzheimer disease. Its prevalence approxi- mately doubles every

Cai, Long

38

Emerging risk factors and markers of chronic kidney disease progression  

Microsoft Academic Search

Chronic kidney disease (CKD) is a common condition with an increasing prevalence. A number of comorbidities are associated with CKD and prognosis is poor, with many patients experiencing disease progression. Recognizing the factors associated with CKD progression enables high-risk patients to be identified and given more intensive treatment if necessary. The identification of new predictive markers might improve our understanding

Florian Kronenberg

2009-01-01

39

ALZHEIMER'S DISEASE: MRI IMAGING OF PROGRESSIVE BRAIN CHANGE  

E-print Network

, and widely available. MRI scans of AD patients reveal profound anatomical changes: severe cortical decline. If patients are scanned repeatedly with MRI as their disease progresses, dynamic maps can scanning can be used to monitor disease progression in individual patients, and can evaluate how drugs

Thompson, Paul

40

Therapeutic strategies to slow chronic kidney disease progression  

Microsoft Academic Search

Childhood chronic kidney disease commonly progresses toward end-stage renal failure, largely independent of the underlying\\u000a disorder, once a critical impairment of renal function has occurred. Hypertension and proteinuria are the most important independent\\u000a risk factors for renal disease progression. Therefore, current therapeutic strategies to prevent progression aim at controlling\\u000a blood pressure and reducing urinary protein excretion. Renin-angiotensin-system (RAS) antagonists preserve

Elke Wühl; Franz Schaefer

2008-01-01

41

Structural imaging biomarkers of Alzheimer's disease: predicting disease progression  

E-print Network

1 Structural imaging biomarkers of Alzheimer's disease: predicting disease the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (www of Alzheimer's disease (AD) may allow earlier detection and refined pre- diction

Paris-Sud XI, Université de

42

Progressive supranuclear palsy (Steele-Richardson-Olszewski disease)  

PubMed Central

Progressive supranuclear palsy is a neurodegenerative disease which affects the brainstem and basal ganglia. Patients present with disturbance of balance, a disorder of downward gaze and L-DOPA-unresponsive parkinsonism and usually develop progressive dysphagia and dysarthria leading to death from the complications of immobility and aspiration. Treatment remains largely supportive but, potentially, treatments based on cholinergic therapy may be useful. As in Alzheimer's disease, the neuronal degeneration is associated with the deposition of hyperphosphorylated tau protein as neurofibrillary tangles but there are important distinctions between the two diseases. Evidence from familial fronto-temporal dementia with parkinsonism linked to chromosome 17 suggests that tau protein deposition is a primary pathogenic event in some neurodegenerative diseases. The understanding of the mechanism of tau deposition in progressive supranuclear palsy is likely to be of importance in unravelling its aetiology.???Keywords: progressive supranuclear palsy; Steele-Richardson-Olszewski disease; tau protein PMID:10621897

Morris, H.; Wood, N.; Lees, A.

1999-01-01

43

Progress and prospects: stem cells and neurological diseases  

Microsoft Academic Search

The central nervous system has limited capacity of regenerating lost tissue in slowly progressive, degenerative neurological conditions such as Parkinson's disease (PD), Alzheimer's disease or Huntington's disease (HD), or in acute injuries resulting in rapid cell loss for example, in cerebrovascular damage (for example, stroke) or spinal cord injury. Although the adult brain contains small numbers of stem cells in

S Gögel; M Gubernator; S L Minger

2011-01-01

44

Cardiac magnetic resonance imaging illustrating Anderson–Fabry disease progression  

PubMed Central

Anderson–Fabry disease is an X-linked lysosomal storage disorder resulting from a deficiency of the enzyme ?-galactosidase A (?-Gal A) and subsequent cellular storage of the enzyme's substrate globotriaosylceramide (Gb3) and related glycosphingolipids. We report a case of Anderson–Fabry disease with cardiac involvement evaluated with cardiovascular MRI. Disease progression was observed despite enzyme replacement therapy. PMID:21088081

Imbriaco, M; Messalli, G; Avitabile, G; Cuocolo, A; Maurea, S; Soscia, F; Pisani, A

2010-01-01

45

Cardiac magnetic resonance imaging illustrating Anderson-Fabry disease progression.  

PubMed

Anderson-Fabry disease is an X-linked lysosomal storage disorder resulting from a deficiency of the enzyme ?-galactosidase A (?-Gal A) and subsequent cellular storage of the enzyme's substrate globotriaosylceramide (Gb3) and related glycosphingolipids. We report a case of Anderson-Fabry disease with cardiac involvement evaluated with cardiovascular MRI. Disease progression was observed despite enzyme replacement therapy. PMID:21088081

Imbriaco, M; Messalli, G; Avitabile, G; Cuocolo, A; Maurea, S; Soscia, F; Pisani, A

2010-12-01

46

A Century of Progress: Milestones in Sickle Cell Disease  

E-print Network

A Century of Progress: Milestones in Sickle Cell Disease Research and Care Introduction In 1910 to be known as sickle cell disease. One hundred years later we know that the sickle-shaped cells are due take the characteristic "C"-shape that is the hallmark of sickle cell disease. What is Sickle Cell

Bandettini, Peter A.

47

Pyruvate slows disease progression in a G93A SOD1 mutant transgenic mouse model.  

PubMed

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by selective motor neuron death, and currently no effective treatment is available for ALS. In this study, we investigated the neuroprotective effects of pyruvate, which acts as an anti-oxidant and as an energy source. We treated G93A SOD1 transgenic mice with pyruvate (from 70 days of age, i.p., at 1000 mg/kg/week), and found that it prolonged average lifespan by 12.3 days (10.5%), slowed disease progression, and improved motor performance, but did not delay disease onset. Pyruvate treatment was also associated with reduced nitrotyrosine immunoreactivity, gliosis, and increased Bcl-2 expression in the spinal cords of G93A SOD1 transgenic mice. These results suggest that pyruvate treatment may be a potential therapeutic strategy in ALS. PMID:17174029

Park, Jong-Ha; Hong, Yoon-Ho; Kim, Hyun-Jung; Kim, Sung-Min; Kim, Min-Jeong; Park, Kyung-Seok; Sung, Jung-Joon; Lee, Kwang-Woo

2007-02-21

48

Deciphering early development of complex diseases by progressive module network.  

PubMed

There is no effective cure nowadays for many complex diseases, and thus it is crucial to detect and further treat diseases in earlier stages. Generally, the development and progression of complex diseases include three stages: normal stage, pre-disease stage, and disease stage. For diagnosis and treatment, it is necessary to reveal dynamical organizations of molecular modules during the early development of the disease from the pre-disease stage to the disease stage. Thus, we develop a new framework, i.e. we identify the modules presenting at the pre-disease stage (pre-disease module) based on dynamical network biomarkers (DNBs), detect the modules observed at the advanced stage (disease-responsive module) by cross-tissue gene expression analysis, and finally find the modules related to early development (progressive module) by progressive module network (PMN). As an application example, we used this new method to analyze the gene expression data for NOD mouse model of Type 1 diabetes mellitus (T1DM). After the comprehensive comparison with the previously reported milestone molecules, we found by PMN: (1) the critical transition point was identified and confirmed by the tissue-specific modules or DNBs relevant to the pre-disease stage, which is considered as an earlier event during disease development and progression; (2) several key tissues-common modules related to the disease stage were significantly enriched on known T1DM associated genes with the rewired association networks, which are marks of later events during T1DM development and progression; (3) the tissue-specific modules associated with early development revealed several common essential progressive genes, and a few of pathways representing the effect of environmental factors during the early T1DM development. Totally, we developed a new method to detect the critical stage and the key modules during the disease occurrence and progression, and show that the pre-disease modules can serve as warning signals for the pre-disease state (e.g. T1DM early diagnosis) whereas the progressive modules can be used as the therapy targets for the disease state (e.g. advanced T1DM), which were also validated by experimental data. PMID:24561825

Zeng, Tao; Zhang, Chuan-chao; Zhang, Wanwei; Liu, Rui; Liu, Juan; Chen, Luonan

2014-06-01

49

Research Finds Link Between Statin Use and Progressive Muscle Disease  

MedlinePLUS

... necrotizing myopathy, a progressive muscle wasting disease of unknown cause. Further investigation revealed that as many as three-fourths of these patients had previously used statins, leading the researchers to suspect from ...

50

Why is proteinuria an ominous biomarker of progressive kidney disease?  

Microsoft Academic Search

Why is proteinuria an ominous biomarker of progressive kidney disease? Progressive tubule injury and interstitial fibrosis frequently accompany glomerulopathies associated with proteinuria. Clinical experience indicates that higher levels of proteinuria prior to, as well as after initiation of treatment predict more rapid decline in renal function and more pronounced tubulointerstitial injury.It has been proposed that filtration of potentially tubulotoxic plasma

KAMBIZ ZANDI-NEJAD; Allison A. Eddy; Richard J. Glassock; Barry M. Brenner

2004-01-01

51

A Multi-Task Learning Formulation for Predicting Disease Progression  

E-print Network

, The Biodesign Institute, Arizona State University, Tempe, AZ 85287 {Jiayu.Zhou, Lei.Yuan, Jun.Liu, Jieping impairment of neurons and their connections resulting in loss of cognitive function and ultimately death [20 to slow or prevent AD progressing, the need for markers that can track the progress of the disease

Ye, Jieping

52

Progressive Neuronal Degeneration of Childhood (PNDC) with Liver Disease  

Microsoft Academic Search

Thirteen children with progressive neuronal degeneration and liver disease are reported. Clinical features included developmental delay after a normal initial period with later onset of intractable epilepsy. The EEG showed an unusual but characteristic pattern, and visual evoked responses (VER) were abnormal. Rapidly progressive cerebral atrophy was seen on computerized axial tomography (CAT). Inheritance was consistent with an autosomal recessive

J. Egger; B. N. Harding; S. G. Boyd; J. Wilson; M. Erdohazi

1987-01-01

53

Biomarkers of inflammation and progression of chronic kidney disease  

Microsoft Academic Search

Biomarkers of inflammation and progression of chronic kidney disease.BackgroundChronic kidney disease is associated with higher levels of inflammatory biomarkers. Statins have anti-inflammatory properties and may attenuate loss of kidney function. Although inflammation may mediate progressive renal injury, the relation between statin use, markers of inflammation, and the rate of kidney function loss has not been elucidated. We examined the association

MARCELLO TONELLI; FRANK SACKS; MARC PFEFFER; GIAN S JHANGRI; GARY CURHAN

2005-01-01

54

2006 Nature Publishing Group Alzheimer's disease is characterized by progressive  

E-print Network

© 2006 Nature Publishing Group Alzheimer's disease is characterized by progressive memory deficits tangles are formed by neuronal intracellular deposition of Tau protein and result in the collapse of microtubules (FIG. 1). Although most cases of Alzheimer's disease are sporadic, a small fraction of cases have

Cai, Long

55

Recent achievements in restorative neurology: Progressive neuromuscular diseases  

SciTech Connect

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.

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

1986-01-01

56

Suppressed autophagy flux in skeletal muscle of an amyotrophic lateral sclerosis mouse model during disease progression  

PubMed Central

Abstract Accumulation of abnormal protein inclusions is implicated in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Autophagy, an intracellular process targeting misfolded proteins and damaged organelles for lysosomal degradation, plays crucial roles in survival and diseased conditions. Efforts were made to understand the role of autophagy in motor neuron degeneration and to target autophagy in motor neuron for ALS treatment. However, results were quite contradictory. Possible autophagy defects in other cell types may also complicate the results. Here, we examined autophagy activity in skeletal muscle of an ALS mouse model G93A. Through overexpression of a fluorescent protein LC3?RFP, we found a basal increase in autophagosome formation in G93A muscle during disease progression when the mice were on a regular diet. As expected, an autophagy induction procedure (starvation plus colchicine) enhanced autophagy flux in skeletal muscle of normal mice. However, in response to the same autophagy induction procedure, G93A muscle showed significant reduction in the autophagy flux. Immunoblot analysis revealed that increased cleaved caspase?3 associated with apoptosis was linked to the cleavage of several key proteins involved in autophagy, including Beclin?1, which is an essential molecule connecting autophagy and apoptosis pathways. Taking together, we provide the evidence that the cytoprotective autophagy pathway is suppressed in G93A skeletal muscle and this suppression may link to the enhanced apoptosis during ALS progression. The abnormal autophagy activity in skeletal muscle likely contributes muscle degeneration and disease progression in ALS. PMID:25602021

Xiao, Yajuan; Ma, Changling; Yi, Jianxun; Wu, Shaoping; Luo, Guo; Xu, Xiulong; Lin, Pei?Hui; Sun, Jun; Zhou, Jingsong

2015-01-01

57

Predictors of the progression of renal disease in the Modification of Diet in Renal Disease Study  

Microsoft Academic Search

Predictors of the progression of renal disease in the Modification of Diet in Renal Disease Study. The Modification of Diet in Renal Disease (MDRD) Study examined the effects of dietary protein restriction and strict blood pressure control on the decline in glomerular filtration rate (GFR) in 840 patients with diverse renal diseases. We describe a systematic analysis to determine baseline

Lawrence G Hunsicker; Sharon Adler; Arlene Caggiula; Brian K England; Tom Greene; John W Kusek; Nancy L Rogers; Paul E Teschan; Gerald Beck

1997-01-01

58

Markers predicting progression of human immunodeficiency virus-related disease.  

PubMed Central

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

Tsoukas, C M; Bernard, N F

1994-01-01

59

Aortic regurgitation: disease progression and management  

Microsoft Academic Search

Aortic regurgitation (AR) is a common valvular heart disease that unless appropriately managed is associated with morbidity and mortality. Left ventricular (LV) mechanics and aortic impedance are the main determinants of outcome in patients with AR and govern clinical management. Mild and moderate AR in individuals with normal LV dimensions are both generally benign. In the absence of symptoms and

Jonathan L Halperin; Seth H Goldbarg

2008-01-01

60

Clinical features at first visit and rapid disease progression in Parkinson's disease  

Microsoft Academic Search

We report a retrospective multivariable analysis of the association between patient characteristics at first clinic visit and rapid disease progression in 1411 Parkinson's disease patients treated between 1985 and 2006. At first visit rapid progression was positively associated with age at onset?70 years (OR=5.77), rigidity (OR=1.94), bradykinesia (OR=1.73), dementia (OR=2.61), and levodopa use (OR=1.74). Rapid progression was negatively associated with

Leslie W. Ferguson; Michele L. Rajput; Nazeem Muhajarine; Syed M. Shah; Alexander Rajput

2008-01-01

61

[New approaches in progressive kidney diseases].  

PubMed

Renal fibrosis, i.e. the replacement of functional tissue with scar tissue, represents the pathological correlate for chronic kidney disease (CKD). A great number of renal diseases lead to CKD and thereby to renal fibrosis. Therefore, renal fibrosis represents an excellent treatment option for patients with CKD. Here we discuss the problems with the preclinical identification and testing of potential factors and therapeutic approaches for renal fibrosis as well as obstacles in the translation of these results to clinical practice. We present the preclinical evidence for the role of novel molecules involved in renal fibrosis, e.g. platelet-derived growth factors (PDGF), C5a or peroxisome proliferator-activated receptor-? (PPAR-?). PMID:22935783

Boor, P

2012-11-01

62

Drug Development for Alzheimer's Disease: Recent Progress  

PubMed Central

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

Ji, Wonjin

2010-01-01

63

Lipid-Altering Therapies and the Progression of Atherosclerotic Disease  

SciTech Connect

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.

Wierzbicki, Anthony S. [St. Thomas' Hospital, Department of Chemical Pathology (United Kingdom)], E-mail: Anthony.Wierzbicki@kcl.ac.uk

2007-04-15

64

Inflammasome activation and metabolic disease progression.  

PubMed

Innate pattern recognition receptors NLRs are cytosolic sensors that detect endogenous metabolic stress and form a multiprotein complex called the inflammasome, that recruits and activates caspase enzymes mediating the activation of the cytokines IL-1? and IL-18. The innate immune system and metabolic system are evolutionarily conserved, intimately integrated, and functionally dependent. In recent decades, obesity-associated metabolic diseases have been become a worldwide epidemic. Here we review recent evidence that demonstrates the important roles of NLRs and inflammasomes in response to metabolic stress in different tissues. PMID:25156419

Li, Hua-Bing; Jin, Chengcheng; Chen, Yuanyuan; Flavell, Richard A

2014-12-01

65

Modelling the natural history of Huntington’s disease progression  

E-print Network

, et al. Natural history of Huntington’s disease. JAMA Neurol 2013; 70: 1520-30. 10. Huntington study group. The Unified Huntington's Disease Rating Scale: Reliability and Consistency. Mov Disord 1996; 11: 136-42. 11. Carignano A, Yuan Y, Dalchau N...

Kuan, W. L.; Kasis, A.; Yuan, Y.; Mason, S. L.; Lazar, A. S.; Barker, R. A.; Gonçalves, J.

2014-12-16

66

[Progress in PDE4 targeted therapy for inflammatory diseases].  

PubMed

cAMP-specific phosphodiesterase type 4 (PDE4) is one of the hot targets for treatment of inflammatory diseases. PDE4 inhibitors can suppress inflammation by increasing the concentration of cAMP in inflammatory cells. The efficacy and safety evaluations of several PDE4 inhibitors are currently carried on in clinical trials, for example GSK256066 in asthma, roflumilast and GSK256066 in chronic obstructive pulmonary disease, tetomilast in inflammatory bowel disease, and apremilast in dermatitis and arthritis etc. This article reviews the recent progress on PDE4-targeted therapy for inflammatory diseases. PMID:24998661

Song, Shun-de; Tang, Hui-fang

2014-05-01

67

State of progress in treating cystic fibrosis respiratory disease  

PubMed Central

Since the discovery of the gene associated with cystic fibrosis (CF), there has been tremendous progress in the care of patients with this disease. New therapies have entered the market and are part of the standard treatment of patients with CF, and have been associated with marked improvement in survival. Now there are even more promising therapies directed at different components of the pathophysiology of this disease. In this review, our current knowledge of the pathophysiology of lung disease in patients with CF is described, along with the current treatment of CF lung disease, and the therapies in development that offer great promise to our patients. PMID:22883684

2012-01-01

68

ALS Multicenter Cohort Study of Oxidative Stress (ALS COSMOS): The study methodology, recruitment, and baseline demographic and disease characteristics  

PubMed Central

Objective In a multicenter study of newly diagnosed ALS patients without a reported family history of ALS, we are prospectively investigating whether markers of oxidative stress (OS) are associated with disease progression. Methods An extensive structured telephone interview ascertained environmental, lifestyle, dietary and psychological risk factors associated with OS. Detailed assessments were performed at baseline and at 3 to 6 month intervals during the ensuing 30 months. Our biorepository includes DNA, plasma, urine, and skin. Results 355 patients were recruited. Subjects were enrolled over a 36 month-period at 16 sites. To meet the target number of subjects, the recruitment period was prolonged and additional sites were included. Demographic and disease characteristics were similar between 477 eligible/non-enrolled and enrolled patients, with the only difference being type of health insurance among enrolled patients. Sites were divided into 3 groups by the number of enrolled subjects. Comparing these 3 groups, the Columbia site had fewer “definite ALS” diagnoses. Conclusion This is the first prospective, interdisciplinary, in-depth, multicenter epidemiological investigation of OS related to ALS progression and was accomplished by an aggressive recruitment process. The baseline demographic and disease features of the study sample are now fully characterized. PMID:24564738

Mitsumoto, Hiroshi; Factor-Litvak, Pam; Andrews, Howard; Goetz, Raymond R.; Andrews, Leslie; Rabkin, Judith G.; McElhiney, Martin; Nieves, Jeri; Santella, Regina M.; Murphy, Jennifer; Hupf, Jonathan; Singleton, Jess; Merle, David; Kilty, Mary; Heitzman, Daragh; Bedlack, Richard S.; Miller, Robert G; Katz, Jonathan S.; Forshew, Dallas; Barohn, Richard J.; Sorenson, Eric J.; Oskarsson, Bjorn; Filho, J Americo M. Fernandes; Kasarskis, Edward J.; Lomen-Hoerth, Catherine; Mozaffar, Tahseen; Rollins, Yvonne D.; Nations, Sharon P.; Swenson, Andrea J.; Shefner, Jeremy M.; Andrews, Jinsy A.; Koczon-Jaremko, Boguslawa A.

2015-01-01

69

[ALS disease modeling and drug screening using patient-specific iPS cells].  

PubMed

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder in which motor neuron (MN) loss in the spinal cord leads to progressive paralysis and death. Cytosolic aggregations in ALS MNs are composed of Tar DNA-binding protein-43 (TDP-43). Genetic analysis has identified more than twenty mutations of TDP-43 in ALS cases. Although accumulating evidence provides several hypotheses of disease mechanism, it is still needed to discover effective cure for ALS. We aimed to reveal cellular phenotypes in ALS MNs for identifying a drug-screening target for ALS using patient-specific induced pluripotent stem cells (iPSCs). To generate patient-specific iPSCs, dermal fibroblasts were obtained by biopsy from ALS patients carrying mutant TDP-43. The fibroblasts were reprogrammed by retrovirus or episomal vectors. Disease-specific iPSCs were differentiated into MNs expressing HB9 and SMI-32. Despite short culture period, ALS MNs recapitulated several disease phenotypes including detergent-insoluble TDP-43, shortened neurites and cellular vulnerability that observed in patient and animal models. Anacardic acid treatment reverted those phenotypes. Disease-specific iPSCs might provide a first step for drug-screening platform for ALS using patient-specific iPSCs. PMID:24291866

Egawa, Naohiro; Inoue, Haruhisa

2013-01-01

70

Fibrosis and progression of Autosomal Dominant Polycystic Kidney Disease (ADPKD)  

PubMed Central

The age on onset of decline in renal function and end-stage renal disease (ESRD) in autosomal polycystic kidney disease (ADPKD) is highly variable and there are currently no prognostic tools to identify patients who will progress rapidly to ESRD. In ADPKD, expansion of cysts and loss of renal function is associated with progressive fibrosis. Similar to the correlation between tubulointerstitial fibrosis and progression of CKD, in ADPKD, fibrosis has been identified as the most significant manifestation associated with an increased rate of progression to ESRD. Fibrosis in CKD has been studied extensively. In contrast, little is known about the mechanisms underlying progressive scarring in ADPKD although some commonality may be anticipated. Current data suggest that fibrosis associated with ADPKD shares at least some of the “classical” features of fibrosis in CKD (increased interstitial collagens, changes in MMPs, over-expression of TIMP-1, over-expression of PAI-1 and increased TGF?) but that there are also some unique and stage-specific features. Epithelial changes appear to precede and to drive interstitial changes leading to the proposal that development of fibrosis in ADPKD is biphasic with alterations in cystic epithelia precipitating changes in interstitial fibroblasts and that reciprocal interactions between these cell types drives progressive accumulation of ECM. Since fibrosis is a major component of ADPKD it follows that preventing or slowing fibrosis should retard disease progression with obvious therapeutic benefits. The development of effective anti-fibrotic strategies in ADPKD is dependent on understanding the precise mechanisms underlying initiation and progression of fibrosis in ADPKD and the role of the intrinsic genetic defect in these processes. PMID:21745567

Norman, Jill

2011-01-01

71

Modeling Disease Progression via Fused Sparse Group Lasso  

E-print Network

neurodegen- erative disorder associated with aging. Understanding how the disease progresses and identifying set of biomarkers for multiple time points and specific sets of biomarkers for different time points copies of all or part of this work for personal or classroom use is granted without fee provided

Ye, Jieping

72

Sudden Oak Death Disease Progression in Oaks and Tanoaks1  

E-print Network

of sudden oak death symptoms in coast live oak (Quercus agrifolia), California black oak (Q. kelloggii379 Sudden Oak Death Disease Progression in Oaks and Tanoaks1 Brice A. McPherson2 , Sylvia R. Mori3 words: California black oak, coast live oak, Phytophthora ramorum, survival analysis, tanoak Abstract

Standiford, Richard B.

73

Rosuvastatin-Induced Arrest in Progression of Renal Disease  

Microsoft Academic Search

Preclinical and limited clinical data suggest that statins decrease the progressive decline in renal function that occurs in patients with renal disease. Pooled analysis of data obtained from a population of hyperlipidemic patients enrolled in the rosuvastatin (Crestor®) clinical development program permitted assessment of its effects on renal function both early and later in the course of treatment. Study participants

Donald G. Vidt; Michael D. Cressman; Susan Harris; John S. Pears; Howard G. Hutchinson

2004-01-01

74

Predictors of disease progression in HIV infection: a review  

PubMed Central

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

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

2007-01-01

75

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 ...

76

Targeting the Progression of Parkinson’s Disease  

PubMed Central

By the time a patient first presents with symptoms of Parkinson’s disease at the clinic, a significant proportion (50-70%) of the cells in the substantia nigra (SN) has already been destroyed. This degeneration progresses until, within a few years, most of the cells have died. Except for rare cases of familial PD, the initial trigger for cell loss is unknown. However, we do have some clues as to why the damage, once initiated, progresses unabated. It would represent a major advance in therapy to arrest cell loss at the stage when the patient first presents at the clinic. Current therapies for Parkinson’s disease focus on relieving the motor symptoms of the disease, these unfortunately lose their effectiveness as the neurodegeneration and symptoms progress. Many experimental approaches are currently being investigated attempting to alter the progression of the disease. These range from replacement of the lost neurons to neuroprotective therapies; each of these will be briefly discussed in this review. The main thrust of this review is to explore the interactions between dopamine, alpha synuclein and redox-active metals. There is abundant evidence suggesting that destruction of SN cells occurs as a result of a self-propagating series of reactions involving dopamine, alpha synuclein and redox-active metals. A potent reducing agent, the neurotransmitter dopamine has a central role in this scheme, acting through redox metallo-chemistry to catalyze the formation of toxic oligomers of alpha-synuclein and neurotoxic metabolites including 6-hydroxydopamine. It has been hypothesized that these feed the cycle of neurodegeneration by generating further oxidative stress. The goal of dissecting and understanding the observed pathological changes is to identify therapeutic targets to mitigate the progression of this debilitating disease. PMID:19721815

George, J.L; Mok, S; Moses, D; Wilkins, S; Bush, A.I; Cherny, R.A; Finkelstein, D.I

2009-01-01

77

Predictors of autosomal dominant polycystic kidney disease progression.  

PubMed

Autosomal dominant polycystic kidney disease is a genetic disorder associated with substantial variability in its natural course within and between affected families. Understanding predictors for rapid progression of this disease has become increasingly important with the emergence of potential new treatments. This systematic review of the literature since 1988 evaluates factors that may predict and/or effect autosomal dominant polycystic kidney disease progression. Predicting factors associated with early adverse structural and/or functional outcomes are considered. These factors include PKD1 mutation (particularly truncating mutation), men, early onset of hypertension, early and frequent gross hematuria, and among women, three or more pregnancies. Increases in total kidney volume and decreases in GFR and renal blood flow greater than expected for a given age also signify rapid disease progression. Concerning laboratory markers include overt proteinuria, macroalbuminuria, and perhaps, elevated serum copeptin levels in affected adults. These factors and others may help to identify patients with autosomal dominant polycystic kidney disease who are most likely to benefit from early intervention with novel treatments. PMID:24925719

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

2014-11-01

78

Rapidly progressive dementias and the treatment of human prion diseases  

PubMed Central

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

Lyketsos, Constantine G

2012-01-01

79

Disease Progression and Pharmacodynamics in Parkinson Disease – Evidence for Functional Protection with Levodopa and Other Treatments  

Microsoft Academic Search

We have modelled the Unified Parkinson’s Disease Rating Scale (UPDRS) scores collected in 800 subjects followed for 8 years. Newly diagnosed and previously untreated subjects were initially randomized to treatment with placebo, deprenyl, tocopherol or both and, when clinical disability required, received one or more dopaminergic agents (levodopa (carbidopa \\/ levodopa), bromocriptine, or pergolide). Using models for disease progression and pharmacodynamic

Nicholas H. G. Holford; Phylinda L. S. Chan; John G. Nutt; Karl Kieburtz; Ira Shoulson

2006-01-01

80

A systematic review of biomarkers for disease progression in Parkinson’s disease  

PubMed Central

Background Using surrogate biomarkers for disease progression as endpoints in neuroprotective clinical trials may help differentiate symptomatic effects of potential neuroprotective agents from true disease-modifying effects. A systematic review was undertaken to determine what biomarkers for disease progression in Parkinson’s disease (PD) exist. Methods MEDLINE and EMBASE (1950–2010) were searched using five search strategies. Abstracts were assessed to identify papers meriting review in full. Studies of participants with idiopathic PD diagnosed by formal criteria or clearly described clinical means were included. We made no restriction on age, disease duration, drug treatment, or study design. We included studies which attempted to draw associations between any tests used to investigate disease progression and any clinical measures of disease progression. The electronic search was validated by hand-searching the two journals from which most included articles came. Results 183 studies were included: 163 (89%) cross-sectional, 20 (11%) longitudinal. The electronic search strategy had a sensitivity of 71.4% (95% CI 51.1-86.0) and a specificity of 97.1% (95% CI 96.5-97.7). In longitudinal studies median follow-up was 2.0 years (IQR 1.1-3.5). Included studies were generally poor quality - cross-sectional with small numbers of participants, applying excessive inclusion/exclusion criteria, with flawed methodologies and simplistic statistical analyses. Conclusion We found insufficient evidence to recommend the use of any biomarker for disease progression in PD clinical trials, which may simply reflect the poor quality of research in this area. We therefore present a provisional ‘roadmap’ for conducting future disease progression biomarker studies, and recommend new quality criteria by which future studies may be judged. PMID:23587062

2013-01-01

81

Alzheimer's disease: a mathematical model for onset and progression  

E-print Network

In this paper we propose a mathematical model for the onset and progression of Alzheimer's disease based on transport and diffusion equations. We regard brain neurons as a continuous medium, and structure them by their degree of malfunctioning. Two different mechanisms are assumed to be relevant for the temporal evolution of the disease: i) diffusion and agglomeration of soluble polymers of amyloid, produced by damaged neurons; ii) neuron-to-neuron prion-like transmission. We model these two processes by a system of Smoluchowski equations for the amyloid concentration, coupled to a kinetic-type transport equation for the distribution function of the degree of malfunctioning of neurons. The second equation contains an integral term describing the random onset of the disease as a jump process localized in particularly sensitive areas of the brain. Even though we deliberately neglect many aspects of the complexity of the brain and the disease, numerical simulations are in good qualitative agreement with clinical...

Bertsch, Michiel; Marcello, Norina; Tesi, Maria Carla; Tosin, Andrea

2015-01-01

82

DJ-1 Knockout Augments Disease Severity and Shortens Survival in a Mouse Model of ALS  

PubMed Central

Amyotrophic lateral sclerosis (ALS) is a progressive, lethal, neurodegenerative disorder, characterized by the degeneration of motor neurons. Oxidative stress plays a central role in the disease progression, in concert with an enhanced glutamate excitotoxicity and neuroinflammation. DJ-1 mutations, leading to the loss of functional protein, cause familial Parkinson’s disease and motor neuron disease in several patients. DJ-1 responds to oxidative stress and plays an important role in the cellular defense mechanisms. We aimed to investigate whether loss of functional DJ-1 alters the disease course and severity in an ALS mouse model. To this end we used mice that express the human SOD1G93A mutation, the commonly used model of ALS and knockout of DJ-1 mice to generate SOD1 DJ-1 KO mice. We found that knocking out DJ-1in the ALS model led to an accelerated disease course and shortened survival time. DJ-1 deficiency was found to increase neuronal loss in the spinal cord associated with increased gliosis in the spinal cord and reduced antioxidant response that was regulated by the Nrf2 mechanism.The importance of DJ-1 in ALS was also illustrated in a motor neuron cell line that was exposed to glutamate toxicity and oxidative stress. Addition of the DJ-1 derived peptide, ND-13, enhanced the resistance to glutamate and SIN-1 induced toxicity. Thus, our results maintain that DJ-1 plays a role in the disease process and promotes the necessity of further investigation of DJ-1 as a therapeutic target for ALS. PMID:25822630

Lev, Nirit; Barhum, Yael; Lotan, Itay; Steiner, Israel; Offen, Daniel

2015-01-01

83

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

PubMed

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-? and rates of clinical decline in Alzheimer's disease. Using novel biophysical methods, we analysed levels, particle size, and conformational characteristics of amyloid-? 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-?42 particles that differ in size, display of N-terminal and C-terminal domains, and conformational stability. In contrast, amyloid-?40 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-?42, with higher levels of distinctly structured amyloid-?42 particles composed of 30-100 monomers, and fewer particles composed of < 30 monomers. The link between rapid clinical decline and levels of amyloid-?42 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-?42 structural states and imply the existence of prion-like conformational strains. PMID:25688081

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

84

Glutathione dysregulation and the etiology and progression of human diseases  

PubMed Central

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

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

2009-01-01

85

Patterns of Change in Symptom Clusters with HIV Disease Progression  

PubMed Central

Context With better antiretroviral treatments (ART), persons living with HIV (PLWH) are living longer, healthier lives. Therefore, they also experience more medical comorbidities that come with normal aging, as well as side effects of multiple treatments and long-term sequelae of HIV. It can be hard to know whether symptoms reported by PLWH are related to comorbidities or are signs of HIV disease progression and possible treatment failure. Objectives The current study was designed to disentangle these issues by examining within-person symptom changes in data collected from a cohort of PLWH before the advent of highly efficacious ART. Methods This study was a secondary analysis of symptom reports in longitudinal data collected from 246 PLWH in 1992–1994. Multilevel modeling was used to test for changes over time in HIV-related symptom clusters. Analyses also tested the effects of person-level demographic covariates and co-occurring mental health symptoms on HIV symptoms, and examined the magnitude of within-person versus between-person variations in reported symptom severity. Results Two of six HIV-related symptom clusters, malaise/fatigue and nausea/vomiting, increased over time in the context of HIV disease progression, while the other four did not. Changes were independent of baseline disease severity or psychological covariates. There was substantial within-person variability in absolute symptom severity. Conclusion Relatively small but consistent changes in symptoms related to nausea or fatigue may suggest HIV disease progression, while changes in other HIV symptom clusters may instead be related to comorbidities or normal aging. Further research is recommended on symptom progression in PLWH. PMID:21429701

Cook, Paul F.; Sousa, Karen H.; Matthews, Ellyn E.; Meek, Paula M.; Kwong, Jeffrey

2011-01-01

86

Biomarkers of progression of chronic obstructive pulmonary disease (COPD)  

PubMed Central

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

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

2014-01-01

87

Chitotriosidase and lysosomal enzymes as potential biomarkers of disease progression in amyotrophic lateral sclerosis: a survey clinic-based study.  

PubMed

The aim of this study was to determine if blood chitotriosidase (Chit) activity and lysosomal enzyme levels might represent markers of disease activity and progression in amyotrophic lateral sclerosis (ALS). It is a survey clinic-based study performed in a tertiary ALS centre. Blood samples were obtained from 76 patients with ALS in different stages of the disease and from 106 healthy individuals serving as controls. Chit activity and the levels of acid alpha-glucosidase, acid alpha-galattosidase A, beta-glucocerebrosidase, and alpha-l-iduronidase were detected using the dried blood spots (DBS) technique. The CHIT1 genotype for exon 10 duplication and for the p.G102S variant was also determined. Chit activity was significantly higher in ALS patients than in healthy individuals. This difference was independent of the genotypes at CHIT1 functional variants. Chit were significantly higher in 34 rapidly progressing patients as compared to 42 with slowly progressive disease. Acid alpha-glucosidase was higher than normal and significantly correlated with the severity of the disease. Glucocerebrosidase and alpha-l-iduronidase activity were significantly lower in patients than in the controls. Alpha-galactosidase A was higher than normal only in rapidly progressing patients. We have employed a very simple and affordable laboratory test to measure blood Chit and lysosomal enzymes activity which could be easily included in the screening of ALS patients recruited in clinical trials. Remarkably, high levels of chitinase and alpha-galactosidase A could help to distinguish patients with fast progression from those with slow progression of the disease and possibly to follow the effects of treatments on neuroinflammation and autophagy. PMID:25563799

Pagliardini, Veronica; Pagliardini, Severo; Corrado, Lucia; Lucenti, Ausiliatrice; Panigati, Laura; Bersano, Enrica; Servo, Serena; Cantello, Roberto; D'Alfonso, Sandra; Mazzini, Letizia

2015-01-15

88

Imaging nigral pathology and clinical progression in Parkinson's disease.  

PubMed

The pattern of dopamine cell loss in Parkinson's disease (PD) is known to be prominent in the ventrolateral and caudal substantia nigra (SN), but less severe in the dorsal and rostral region. Both diffusion tensor imaging (DTI) and R2* relaxometry of the SN have been reported as potential markers for PD, but their relative ability to mark disease progression and differences in pathophysiological bases remains unclear. High-resolution T2-weighted, R2*, and DTI were obtained from 28 controls and 40 PD subjects [15 early stage [disease duration ?1 year], 14 mid stage [duration 2-5 years], and 11 late stage [duration >5 years]). Fractional anisotropy and R2* values in both rostral and caudal SN were obtained for all subjects, and clinical measures (e.g., disease duration, levodopa-equivalent daily dosage, and "off"-drug UPDRS motor score) were obtained for Parkinson's subjects. There was no correlation between fractional anisotropy and clinical measures, whereas R2* was strongly associated with disease progression. Compared to controls, fractional anisotropy in caudal SN was significantly decreased in PD patients of all stages, whereas in rostral SN, it was decreased significantly only in the late-stage group. R2* in both SN regions was significantly increased in the mid- and late-stage, but not early-stage, of PD subjects. These findings suggest that fractional anisotropy changes may mark early pathological changes in caudal SN, whereas the changes in R2* may more closely track PD's clinical progression after symptom onset. PMID:23008179

Du, Guangwei; Lewis, Mechelle M; Sen, Suman; Wang, Jianli; Shaffer, Michele L; Styner, Martin; Yang, Qing X; Huang, Xuemei

2012-11-01

89

A yeast functional screen predicts new candidate ALS disease genes  

PubMed Central

Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of these genes, TAF15, in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila, with the ALS-linked variants having a more severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery. PMID:22065782

Couthouis, Julien; Hart, Michael P.; Shorter, James; DeJesus-Hernandez, Mariely; Erion, Renske; Oristano, Rachel; Liu, Annie X.; Ramos, Daniel; Jethava, Niti; Hosangadi, Divya; Epstein, James; Chiang, Ashley; Diaz, Zamia; Nakaya, Tadashi; Ibrahim, Fadia; Kim, Hyung-Jun; Solski, Jennifer A.; Williams, Kelly L.; Mojsilovic-Petrovic, Jelena; Ingre, Caroline; Boylan, Kevin; Graff-Radford, Neill R.; Dickson, Dennis W.; Clay-Falcone, Dana; Elman, Lauren; McCluskey, Leo; Greene, Robert; Kalb, Robert G.; Lee, Virginia M.-Y.; Trojanowski, John Q.; Ludolph, Albert; Robberecht, Wim; Andersen, Peter M.; Nicholson, Garth A.; Blair, Ian P.; King, Oliver D.; Bonini, Nancy M.; Van Deerlin, Vivianna; Rademakers, Rosa; Mourelatos, Zissimos; Gitler, Aaron D.

2011-01-01

90

Predicting Progression of Alzheimer’s Disease Using Ordinal Regression  

PubMed Central

We propose a novel approach to predicting disease progression in Alzheimer’s 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 Alzheimer’s 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 (12–24 months) and late converters (24–36 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

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

91

Angiotensinogen Expression Is Enhanced in the Progression of Glomerular Disease.  

PubMed

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 (H(2)O(2)) induced an increase in the AGT expression in primary rat mesangial cells. Furthermore, the H(2)O(2)-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

Urushihara, Maki; Kobori, Hiroyuki

2011-09-01

92

Aluminum involvement in the progression of Alzheimer's disease.  

PubMed

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

Walton, J R

2013-01-01

93

PNPLA3 I148M polymorphism and progressive liver disease.  

PubMed

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

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

2013-11-01

94

A transcriptional network underlies susceptibility to kidney disease progression  

PubMed Central

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

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

2012-01-01

95

Tracking motor impairments in the progression of Huntington's disease.  

PubMed

The Unified Huntington's Disease Rating Scale is used to characterize motor impairments and establish motor diagnosis. Little is known about the timing of diagnostic confidence level categories and the trajectory of motor impairments during the prodromal phase. Goals of this study were to estimate the timing of categories, model the prodromal trajectory of motor impairments, estimate the rate of motor impairment change by category, and provide required sample size estimates for a test of efficacy in clinical trials. In total, 1010 gene-expanded participants from the Neurobiological Predictors of Huntington's Disease (PREDICT-HD) trial were analyzed. Accelerated failure time models were used to predict the timing of categories. Linear mixed effects regression was used to model the longitudinal motor trajectories. Age and length of gene expansion were incorporated into all models. The timing of categories varied significantly by gene expansion, with faster progression associated with greater expansion. For the median expansion, the third diagnostic confidence level category was estimated to have a first occurrence 1.5 years before diagnosis, and the second and first categories were estimated to occur 6.75 years and 19.75 years before diagnosis, respectively. Motor impairments displayed a nonlinear prodromal course. The motor impairment rate of change increased as the diagnostic confidence level increased, with added acceleration for higher progression scores. Motor items can detect changes in motor impairments before diagnosis. Given a sufficiently high progression score, there is evidence that the diagnostic confidence level can be used for prodromal staging. Implications for Huntington's disease research and the planning of clinical trials of efficacy are discussed. PMID:24150908

Long, Jeffery D; Paulsen, Jane S; Marder, Karen; Zhang, Ying; Kim, Ji-In; Mills, James A

2014-03-01

96

Connected speech as a marker of disease progression in autopsy-proven Alzheimer’s disease  

PubMed Central

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

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

2013-01-01

97

Lack of sigma-1 receptor exacerbates ALS progression in mice.  

PubMed

The function of the sigma-1 receptor (S1R) has been implicated in modulating the activity of various ion channels. In the CNS S1R is enriched in cholinergic postsynaptic densities in spinal cord motoneurons (MNs). 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

Mavlyutov, T A; Epstein, M L; Verbny, Y I; Huerta, M S; Zaitoun, I; Ziskind-Conhaim, L; Ruoho, A E

2013-06-14

98

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

PubMed

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

Bradley, Walter G; Mash, Deborah C

2009-01-01

99

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

PubMed Central

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

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

1996-01-01

100

Cellular Transplantation Alters the Disease Progression in Becker's Muscular Dystrophy  

PubMed Central

Becker's Muscular Dystrophy (BMD) is a dystrophinopathy manifested as progressive muscle degeneration. Autologous Bone Marrow Mononuclear Cells (BMMNCs) have shown some myogenic potential. The paracrine effects of the BMMNCs reduce the inflammation and are thought to reduce muscle degeneration. We treated a 39 year old dental surgeon suffering from BMD. Muscle strength was reduced when measured using modified Medical Research Council's Manual Muscle Testing (mMRC-MMT). Static sitting balance was poor. He was wheelchair dependent for ambulation and moderately independent in Activities of Daily Living (ADL). Functional Independence Measure (FIM) score was 93. Musculoskeletal Magnetic Resonance Imaging (MRI-MSK) showed moderate fatty infiltration in the muscles. Three cellular transplantations were carried out. Clinical assessment and the investigations were repeated. Progressive increase in the muscle strength was noted. Ambulation was independent using push-knee splints and minimal assistance when weary. Static and dynamic balance in sitting and standing improved. FIM score increased from 93 to 105. There was no increase in the degree of fatty infiltration, as seen on the MRI-MSK. The case study provides evidence for the putative benefits of cellular therapy in altering the disease progression in BMD. It also suggests augmented clinical benefits of combination of cellular therapy and rehabilitation. PMID:23841012

Sharma, Alok; Sane, Hemangi; Bhagawanani, Khushboo; Gokulchandran, Nandini; Badhe, Prerna

2013-01-01

101

Slowing chronic kidney disease progression: results of prospective clinical trials in adults  

Microsoft Academic Search

Chronic kidney disease is generally thought to be a progressive disorder regardless of etiology. Over the past 15 years, investigations\\u000a into the mechanisms of disease progression and treatment designed to slow or halt disease progression have been conducted,\\u000a largely in the adult kidney disease population. Intervention trials have demonstrated that lowering blood pressure in hypertensive\\u000a patients and administration of drugs that

Robert D. Toto

2008-01-01

102

[Salt intake and the progression of chronic renal diseases].  

PubMed

To what extent dietary salt intake is involved in the pathogenesis of progressive renal diseases has never been fully understood in humans. To this aim, we investigated the relationship between urinary sodium excretion (under a low salt & low protein diet) and urinary protein excretion/renal function in patients with three major renal diseases: chronic glomerulonephritis(GN), diabetic nephropathy(DN) and nephrosclerosis(NS). The results were as follows; 1) A significant positive correlation was found between urinary sodium excretion (equivalent to the daily salt intake) and daily urinary protein excretion in patients with a GN and DN. However, no relationship was found between the two parameters in patients with NS. 2) Reduction in salt intake led to a significant decrease in daily protein excretion, the effect of which was prominent in patients with GN and DN. 3) A significant positive correlation was found between urinary sodium excretion and estimated protein intake(EPI) in all three groups. 4) There was a significant positive correlation between EPI and urinary protein excretion in DN, but not in GN. 5) Reduction in salt and protein intake(calculated as an EPI) ameliorates the slope of reciprocal creatinine concentration(1/Cr) in patients with GN and DN. These results indicate that slat restriction is strongly associated with the preservation of renal function in patients with GN and DN, suggesting that this dietary strategy can be a useful measure for retarding the progressive nature of these diseases. Of note is that both salt and protein restriction was renoprotective only in patients with DN. Thus, patients with GN and DN must be followed-up on the basis of a salt-restricted diet throughout their clinical course. PMID:14737992

Kuriyama, Satoru; Tomonari, Haruo; Ohtsuka, Yasushi; Yamagishi, Hiroko; Ohkido, Ichiro; Hosoya, Tatsuo

2003-01-01

103

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

PubMed

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 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

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

104

ABCA4 disease progression and a proposed strategy for gene therapy  

E-print Network

ABCA4 disease progression and a proposed strategy for gene therapy Artur V. Cideciyan1,Ã?- retinal gene therapy will aim to arrest disease progression in the extramacular retina. In 66 individuals in ABCA4 disease. INTRODUCTION Human ocular gene therapy success in a rare autosomal reces- sive blindness

Palczewski, Krzysztof

105

Smart garments in chronic disease management: progress and challenges  

NASA Astrophysics Data System (ADS)

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.

Khosla, Ajit

2012-10-01

106

Distinct patterns of sirtuin expression during progression of Alzheimer's disease.  

PubMed

Aging is one of the major risk factors for Alzheimer's disease (AD). Sirtuins are associated with prolonged life span. To examine whether the expression levels of sirtuins associate with the progression of AD or not, we performed a comparative immunoblotting and immunohistochemical study of SIRT1, 3, and 5 in the entorhinal cortex and hippocampal subregions and white matter in 45 cases grouped according to Braak and Braak stages of neurofibrillary degeneration. In addition, we compared the expression levels with the local load of tau and amyloid-beta deposits, evaluated using morphometry. Our study revealed that (1) the neuronal subcellular redistribution of SIRT1 parallels the decrease in its expression, suggesting stepwise loss of neuroprotection dependent on the neuronal population; (2) in contrast to SIRT1 and 3, expression of SIRT5 increases during the progression of AD; (3) which might be related to its appearance in activated microglial cells. The complex patterns of the expression of sirtuins in relation to tissue damage should be taken into account when searching for therapies interacting with sirtuins. PMID:24464653

Lutz, Mirjam I; Milenkovic, Ivan; Regelsberger, Günther; Kovacs, Gabor G

2014-06-01

107

Effects of lowering LDL cholesterol on progression of kidney disease.  

PubMed

Lowering LDL cholesterol reduces the risk of developing atherosclerotic events in CKD, but the effects of such treatment on progression of kidney disease remain uncertain. Here, 6245 participants with CKD (not on dialysis) were randomly assigned to simvastatin (20 mg) plus ezetimibe (10 mg) daily or matching placebo. The main prespecified renal outcome was ESRD (defined as the initiation of maintenance dialysis or kidney transplantation). During 4.8 years of follow-up, allocation to simvastatin plus ezetimibe resulted in an average LDL cholesterol difference (SEM) of 0.96 (0.02) mmol/L compared with placebo. There was a nonsignificant 3% reduction in the incidence of ESRD (1057 [33.9%] cases with simvastatin plus ezetimibe versus 1084 [34.6%] cases with placebo; rate ratio, 0.97; 95% confidence interval [95% CI], 0.89 to 1.05; P=0.41). Similarly, allocation to simvastatin plus ezetimibe had no significant effect on the prespecified tertiary outcomes of ESRD or death (1477 [47.4%] events with treatment versus 1513 [48.3%] events with placebo; rate ratio, 0.97; 95% CI, 0.90 to 1.04; P=0.34) or ESRD or doubling of baseline creatinine (1189 [38.2%] events with treatment versus 1257 [40.2%] events with placebo; rate ratio, 0.93; 95% CI, 0.86 to 1.01; P=0.09). Exploratory analyses also showed no significant effect on the rate of change in eGFR. Lowering LDL cholesterol by 1 mmol/L did not slow kidney disease progression within 5 years in a wide range of patients with CKD. PMID:24790178

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

2014-08-01

108

Multimodality molecular imaging of disease progression in living subjects.  

PubMed

The enormous advances in our understanding of the progression of diseases at the molecular level have been supplemented by the new field of 'molecular imaging', which provides for in vivo visualization of molecular events at the cellular level in living organisms. Molecular imaging is a noninvasive assessment of gene and protein function, protein-protein interaction and or signal transduction pathways in animal models of human disease and in patients to provide insights into molecular pathogenesis. Five major imaging techniques are currently available to assess the structural and functional alterations in vivo in small animals. These are (i) optical bioluminescence and fluorescence imaging techniques, (ii) radionuclide-based positron emission tomography (PET) and single photon emitted computed tomography (SPECT), (iii) X-ray-based computed tomography (CT), (iv) magnetic resonance imaging (MRI) and (v) ultrasound imaging (US). Functional molecular imaging requires an imaging probe that is specific for a given molecular event. In preclinical imaging, involving small animal models, the imaging probe could be an element of a direct ('direct imaging') or an indirect ('indirect imaging') event. Reporter genes are essential for indirect imaging and provide a general integrated platform for many different applications. Applications of multimodality imaging using combinations of bioluminescent, fluorescent and PET reporter genes in unified fusion vectors developed by us for recording events from single live cells to whole animals with high sensitivity and accurate quantification are discussed. Such approaches have immense potential to track progression of metastasis, immune cell trafficking, stem cell therapy, transgenic animals and even molecular interactions in living subjects. PMID:21799261

Ray, Pritha

2011-08-01

109

Differential progression of proprioceptive and visual information processing deficits in Parkinson's disease  

E-print Network

Medical Center St Radboud, Nijmegen, The Netherlands Keywords: disease severity, Parkinson's disease that patients with Parkinson's disease (PD) have deficits not only in motor performance, but also in patients with Parkinson's Disease (PD) (Adamovich et al., 2001; Ketcham et al., 2003). PD patients have

Gielen, C.C.A.M.

110

Progression of coronary disease in a Behcet’s patient in remission  

PubMed Central

Behcet’s disease is characterised histologically by vasculitis. In the heart this can lead to aneurysm formation and thrombosis. There is also accelerated atherosclerosis, the mechanism of which is unclear. Patients with external disease from Behcet’s disease are treated with immunosuppression. The authors present a case of aneurysmal disease in a Behcet’s patient. This case demonstrates that coronary disease may progress in Behcet’s patients despite external disease remission. Therefore, internal disease may progress in the absence of external symptoms when immunosuppressive therapy is usually stopped. This case raises the issue of whether immunosuppression should be continued in Behcet’s patients with coronary disease to suppress disease progression or included in a treatment protocol for patients with Behcet’s related coronary disease. Clinical trials on the use of immunosuppressive therapy for coronary disease in Behcet’s patients are needed. PMID:22761229

Abeyewickreme, Anil; Ramoutar, Anil; Kabir, Alamgir

2012-01-01

111

Pulmonary veno-occlusive disease: recent progress and current challenges.  

PubMed

Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary arterial hypertension characterised by a progressive obstruction of small pulmonary veins that leads to elevation in pulmonary vascular resistance and right ventricular failure. Despite improved understanding and more efficacious treatment options for PAH overall, the prognosis of PVOD remains dismal. Without therapeutic intervention few patients would be expected to survive more than two years. PVOD may occur in both idiopathic and heritable forms, or develop in association with connective tissue disease, chronic respiratory disease, malignancy or bone marrow transplantation, among other causes. A widespread fibrous intimal proliferation that predominantly involves the pulmonary venules and small veins is the key histopathological hallmark. Surgical lung biopsy is considered the definitive diagnostic test but is associated with significant risk and is not recommended. Distinguishing PVOD from PAH on clinical grounds alone is generally not possible, although PVOD is characterised by a higher male/female ratio and higher tobacco exposure. Instead, non-invasive tests may be helpful and the diagnosis is usually based on an integrated assessment that incorporates high resolution computed tomography (septal lines, ground-glass opacities and lymph node enlargement), pulmonary function testing (lower DLCO), arterial blood gas analysis (lower PaO(2) at rest) and bronchoalveolar lavage (occult alveolar haemorrhage). Treatment of PVOD remains challenging as exposure to pulmonary vasodilators and PAH-specific agents may precipitate acute pulmonary oedema. Nonetheless, a number of successful outcomes describing cautious use of prostanoids, endothelin antagonists and phosphodiesterase type-5 inhibitors have been described. Unfortunately, the long term effects of these agents are variable and lung transplantation remains the treatment of choice. PMID:20456932

Montani, David; O'Callaghan, Dermot S; Savale, Laurent; Jaïs, Xavier; Yaïci, Azzedine; Maitre, Sophie; Dorfmuller, Peter; Sitbon, Olivier; Simonneau, Gérald; Humbert, Marc

2010-07-01

112

Blood Platelets in the Progression of Alzheimer’s Disease  

PubMed Central

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

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

113

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

PubMed Central

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

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

2013-01-01

114

Predicting progression from cognitive impairment to Alzheimer's disease with the Disease State Index.  

PubMed

We evaluated the performance of the Disease State Index (DSI) method when predicting progression to Alzheimer's disease (AD) in patients with subjective cognitive impairment (SCI), amnestic or non-amnestic mild cognitive impairment (aMCI, naMCI). The DSI model measures patients' similarity to diagnosed cases based on available data, such as cognitive tests, the APOE genotype, CSF biomarkers and MRI. We applied the DSI model to data from the DESCRIPA cohort, where non-demented patients (N=775) with different subtypes of cognitive impairment were followed for 1 to 5 years. Classification accuracies for the subgroups were calculated with the DSI using leave-one-out crossvalidation. The DSI's classification accuracy in predicting progression to AD was 0.75 (AUC=0.83) in the total population, 0.70 (AUC=0.77) for aMCI and 0.71 (AUC=0.76) for naMCI. For a subset of approximately half of the patients with high or low DSI values, accuracy reached 0.86 (all), 0.78 (aMCI), and 0.85 (naMCI). For patients with MRI or CSF biomarker data available, theywere 0.78 (all), 0.76 (aMCI) and 0.76 (naMCI), while for clear cases the accuracies rose to 0.90 (all), 0.83 (aMCI) and 0.91 (naMCI). The results show that the DSI model can distinguish between clear and ambiguous cases, assess the severity of the disease and also provide information on the effectiveness of different biomarkers. While a specific test or biomarker may confound analysis for an individual patient, combining several different types of tests and biomarkers could be able to reveal the trajectory of the disease and improve the prediction of AD progression. PMID:25523428

Hall, Anette; Mattila, Jussi; Koikkalainen, Juha; Lötjonen, Jyrki; Wolz, Robin; Scheltens, Philip; Frisoni, Giovanni; Tsolaki, Magdalini; Nobili, Flavio; Freund-Levi, Yvonne; Minthon, Lennart; Frölich, Lutz; Hampel, Harald; Visser, Pieter Jelle; Soininen, Hilkka

2015-01-01

115

In silico regulatory analysis for exploring human disease progression  

PubMed Central

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

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

2008-01-01

116

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

PubMed

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

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

2015-02-01

117

FTD and ALS: a tale of two diseases  

PubMed Central

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

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

2012-01-01

118

Effects of HMG-CoA reductase inhibitors (statins) on progression of kidney disease  

Microsoft Academic Search

Chronic kidney disease, especially in the setting of proteinuria, is characterized by hyperlipidemia. In animal models, hyperlipidemia causes glomerular foam cells and glomerulosclerosis. Treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) ameliorates kidney disease in these models. The data of the role of hyperlipidemia in progression of human kidney disease are less clear. Data from small studies in glomerular disease

Linda F Fried

2008-01-01

119

Re exive and volitional saccades: Biomarkers of Huntington disease severity and progression  

E-print Network

Re exive and volitional saccades: Biomarkers of Huntington disease severity and progression Saumil Neurological disease Background: Huntington disease (HD) is a genetic, neurodegenerative disorder characterized. Methods: Eleven HD subjects were evaluated with the motor subscale of the Uni ed Huntington Disease Rating

Sereno, Anne B.

120

Amyloid generation and dysfunctional immunoproteasome activation with disease progression in animal model of familial Alzheimer's disease.  

PubMed

Double-transgenic amyloid precursor protein/presenilin 1 (APP/PS1) mice express a chimeric mouse/human APP bearing the Swedish mutation (Mo/HuAPP695swe) and a mutant human PS1-dE9 both causative of familial Alzheimer's disease (FAD). Transgenic mice show impaired memory and learning performance from the age of 6 months onwards. Double-transgenic APP/PS1 mice express altered APP and PS1 mRNAs and proteins, reduced ?-secretase 1 (BACE1) mRNA and normal BACE1 protein, all of which suggest a particular mechanism of amyloidogenesis when compared with sporadic AD. The first ?-amyloid plaques in APP/PS1 mice appear at 3 months, and they increase in number and distribution with disease progression in parallel with increased levels of brain soluble ?-amyloid 1-42 and 1-40, but also with reduced 1-42/1-40 ratio with age. Amyloid deposition in plaques is accompanied by altered mitochondria and increased oxidative damage, post-translational modifications and accumulation of altered proteins at the dystrophic neurites surrounding plaques. Degradation pathways are also modified with disease progression including activation of the immunoproteasome together with variable alterations of the different protease activities of the ubiquitin-proteasome system. Present observations show modifications in the production of ?-amyloid and activation and malfunction of the subcellular degradation pathways that have general implications in the pathogenesis of AD and more particularly in specificities of FAD amyloidogenesis. PMID:22188425

Aso, Ester; Lomoio, Selene; López-González, Irene; Joda, Laura; Carmona, Margarita; Fernández-Yagüe, Núria; Moreno, Jesús; Juvés, Salvador; Pujol, Aurora; Pamplona, Reinald; Portero-Otin, Manuel; Martín, Virginia; Díaz, Mario; Ferrer, Isidro

2012-09-01

121

MEMORY PRESERVATION DIET™ © 2005 TO REDUCE RISK AND SLOW PROGRESSION OF ALZHEIMER'S DISEASE (AD)  

Microsoft Academic Search

The Memory Preservation Diet™ (MPD), developed by a multidisciplinary, multi-university team is expected to reduce risk, or delay onset, of Alzheimer's disease (AD) in adults, reduce conversion of persons with progressive Mild Cognitive Impairment (MCI) to AD, and help slow progression of disease in persons who already have symptomatic AD. The MPD is an evidence- based comprehensive diet whose 6

N. B. EMERSON LOMBARDO; L. VOLICER; A. MARTIN; B. WU; X. W. ZHANG

122

Bicarbonate therapy for prevention of chronic kidney disease progression.  

PubMed

Kidney injury in chronic kidney disease (CKD) is likely multifactorial, but recent data support that a component is mediated by mechanisms used by the kidney to increase acidification in response to an acid challenge to systemic acid-base status. If so, systemic alkalization might attenuate this acid-induced component of kidney injury. An acid challenge to systemic acid-base status increases nephron acidification through increased production of endothelin, aldosterone, and angiotensin II, each of which can contribute to kidney inflammation and fibrosis that characterizes CKD. Systemic alkalization that ameliorates an acid challenge might attenuate the contributions of angiotensin II, endothelin, and aldosterone to kidney injury. Some small clinical studies support the efficacy of alkalization in attenuating kidney injury and slowing glomerular filtration rate decline in CKD. This review focuses on the potential that orally administered NaHCO? prevents CKD progression and additionally addresses its mechanism of action, side effects, possible complications, dosage, interaction, galenic form description, and contraindications. Current National Kidney Foundation guidelines recommend oral alkali, including NaHCO?(-), in CKD patients with serum HCO?(-) <22 mmol/l. Although oral alkali can be provided by other medications and by base-inducing dietary constituents, oral NaHCO? will be the focus of this review because of its relative safety and apparent efficacy, and its comparatively low cost. PMID:24107852

?oniewski, Igor; Wesson, Donald E

2014-03-01

123

Progress on thermobrachytherapy surface applicator for superficial tissue disease  

NASA Astrophysics Data System (ADS)

This work reports the ongoing development of a combination applicator for simultaneous heating of superficial tissue disease using a 915 MHz DCC (dual concentric conductor) array and High Dose Rate (HDR) brachytherapy delivered via an integrated conformal catheter array. The progress includes engineering design changes in the waterbolus, DCC configurations and fabrication techniques of the conformal multilayer applicator. The dosimetric impact of the thin copper DCC array is also assessed. Steady state fluid dynamics of the new waterbolus bag indicates nearly uniform flow with less than 1°C variation across a large (19×32cm) bolus. Thermometry data of the torso phantom acquired with computer controlled movement of fiberoptic temperature probes inside thermal mapping catheters indicate feasibility of real time feedback control for the DCC array. MR (magnetic resonance) scans of a torso phantom indicate that the waterbolus thickness across the treatment area is controlled by the pressure applied by the surrounding inflatable airbladder and applicator securing straps. The attenuation coefficient of the DCC array was measured as 3+/- 0.001% and 2.95+/-0.03 % using an ion chamber and OneDose dosimeters respectively. The performance of the combination applicator on patient phantoms provides valuable feedback to optimize the applicator prior use in the patient clinic.

Arunachalam, Kavitha; Craciunescu, Oana I.; Maccarini, Paolo F.; Schlorff, Jaime L.; Markowitz, Edward; Stauffer, Paul R.

2009-02-01

124

Virus phenotype switching and disease progression in HIV-1 infection.  

PubMed Central

One of the phenotypic distinctions between different strains of human immunodeficiency virus type 1 (HIV-1) has to do with the ability to cause target cells to form large multinucleate bodies known as syncytia. There are two phenotypes according to this characterization: syncytium-inducing (SI) and non-syncytium-inducing (NSI). NSI strains are usually present throughout infection, while SI strains are typically seen at the beginning of the infection and near the onset of AIDS. The late emergence of SI strains is referred to as phenotype switching. In this paper we analyse the factors that lead to phenotype switching and contribute to the dynamics of disease progression. We show that a strong immune system selects for NSI strains while a weak immune system favours SI strains. The model explicitly accounts for the fact that CD4+ cells are both targets of HIV infection and crucial for activating immune responses against HIV In such a model, SI strains can emerge after a long and variable period of NSI dominated infection. Furthermore, versions of the model which do not explicitly account for HIV-specific, activated CD4+ cells do not exhibit phenotype switching, emphasizing the critical importance of this pool of cells. PMID:10693824

Callaway, D S; Ribeiro, R M; Nowak, M A

1999-01-01

125

Antisense oligonucleotide therapy for the treatment of C9ORF72 ALS/FTD diseases.  

PubMed

Motor neuron disorders, and particularly amyotrophic lateral sclerosis (ALS), are fatal diseases that are due to the loss of motor neurons in the brain and spinal cord, with progressive paralysis and premature death. It has been recently shown that the most frequent genetic cause of ALS, frontotemporal dementia (FTD), and other neurological diseases is the expansion of a hexanucleotide repeat (GGGGCC) in the non-coding region of the C9ORF72 gene. The pathogenic mechanisms that produce cell death in the presence of this expansion are still unclear. One of the most likely hypotheses seems to be the gain-of-function that is achieved through the production of toxic RNA (able to sequester RNA-binding protein) and/or toxic proteins. In recent works, different authors have reported that antisense oligonucleotides complementary to the C9ORF72 RNA transcript sequence were able to significantly reduce RNA foci generated by the expanded RNA, in affected cells. Here, we summarize the recent findings that support the idea that the buildup of "toxic" RNA containing the GGGGCC repeat contributes to the death of motor neurons in ALS and also suggest that the use of antisense oligonucleotides targeting this transcript is a promising strategy for treating ALS/frontotemporal lobe dementia (FTLD) patients with the C9ORF72 repeat expansion. These data are particularly important, given the state of the art antisense technology, and they allow researchers to believe that a clinical application of these discoveries will be possible soon. PMID:24809691

Riboldi, Giulietta; Zanetta, Chiara; Ranieri, Michela; Nizzardo, Monica; Simone, Chiara; Magri, Francesca; Bresolin, Nereo; Comi, Giacomo P; Corti, Stefania

2014-12-01

126

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

PubMed

H63D HFE is associated with iron dyshomeostasis and oxidative stress; each of which plays an important role in amyotrophic lateral sclerosis (ALS) pathogenesis. To examine the role of H63D HFE in ALS, we generated a double transgenic mouse line (SOD1/H67D) carrying the H67D HFE (homologue of human H63D) and SOD1(G93A) mutations. We found double transgenic mice have shorter survival and accelerated disease progression. We examined parameters in the lumbar spinal cord of double transgenic mice at 90days (presymptomatic), 110days (symptomatic) and end-stage. Transferrin receptor and L-ferritin expression, both indicators of iron status, were altered in double transgenic and SOD1 mice starting at 90days, indicating loss of iron homeostasis in these mice. However, double transgenic mice had higher L-ferritin expression than SOD1 mice. Double transgenic mice exhibited increased Iba-1 immunoreactivity and caspase-3 levels, indicating increased microglial activation which would be consistent with the higher L-ferritin levels. Although both SOD1 and double transgenic mice had increased GFAP expression, the magnitude of the increase was higher in double transgenic mice at 110days, suggesting increased gliosis in these mice. Increased hemeoxygenase-1 and decreased nuclear factor E2-related factor 2 levels in double transgenic mice strongly suggest the accelerated disease process could be associated with increased oxidative stress. There was no evidence of TAR-DNA-binding protein 43 mislocalization to the cytoplasm in double transgenic mice; however, there was evidence suggesting neurofilament disruption, which has been reported in ALS. Our findings indicate H63D HFE modifies ALS pathophysiology via pathways involving oxidative stress, gliosis and disruption of cellular functions. PMID:25283820

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

2014-12-01

127

Obesity and preterm birth: additive risks in the progression of kidney disease in children  

Microsoft Academic Search

Preterm birth is associated with decreased nephron mass and obesity that may impact on kidney disease progression in later\\u000a life. Our objectives were to examine the relative risks of obesity and preterm birth on the progression of kidney disease\\u000a in children. In a retrospective cohort study, 80 (44 obese and 36 non-obese) patients with proteinuric kidney disease were\\u000a studied for

Carolyn L. Abitbol; Jayanthi Chandar; Maria M. Rodríguez; Mariana Berho; Wacharee Seeherunvong; Michael Freundlich; Gastón Zilleruelo

2009-01-01

128

Autoimmune BSEP Disease: Disease Recurrence After Liver Transplantation for Progressive Familial Intrahepatic Cholestasis.  

PubMed

Severe cholestasis may result in end-stage liver disease with the need of liver transplantation (LTX). In children, about 10 % of LTX are necessary because of cholestatic liver diseases. Apart from bile duct atresia, three types of progressive familial intrahepatic cholestasis (PFIC) are common causes of severe cholestasis in children. The three subtypes of PFIC are defined by the involved genes: PFIC-1, PFIC-2, and PFIC-3 are due to mutations of P-type ATPase ATP8B1 (familial intrahepatic cholestasis 1, FIC1), the ATP binding cassette transporter ABCB11 (bile salt export pump, BSEP), or ABCB4 (multidrug resistance protein 3, MDR3), respectively. All transporters are localized in the canalicular membrane of hepatocytes and together mediate bile salt and phospholipid transport. In some patients with PFIC-2 disease, recurrence has been observed after LTX, which mimics a PFIC phenotype. It could be shown by several groups that inhibitory anti-BSEP antibodies emerge, which most likely cause disease recurrence. The prevalence of severe BSEP mutations (e.g., splice site and premature stop codon mutations) is very high in this group of patients. These mutations often result in the complete absence of BSEP, which likely accounts for an insufficient auto-tolerance against BSEP. Although many aspects of this "new" disease are not fully elucidated, the possibility of anti-BSEP antibody formation has implications for the pre- and posttransplant management of PFIC-2 patients. This review will summarize the current knowledge including diagnosis, pathomechanisms, and management of "autoimmune BSEP disease." PMID:25342496

Kubitz, Ralf; Dröge, Carola; Kluge, Stefanie; Stross, Claudia; Walter, Nathalie; Keitel, Verena; Häussinger, Dieter; Stindt, Jan

2015-06-01

129

Urine Podocyte mRNAs, Proteinuria, and Progression in Human Glomerular Diseases  

PubMed Central

Model systems demonstrate that progression to ESRD is driven by progressive podocyte depletion (the podocyte depletion hypothesis) and can be noninvasively monitored through measurement of urine pellet podocyte mRNAs. To test these concepts in humans, we analyzed urine pellet mRNAs from 358 adult and pediatric kidney clinic patients and 291 controls (n=1143 samples). Compared with controls, urine podocyte mRNAs increased 79-fold (P<0.001) in patients with biopsy-proven glomerular disease and a 50% decrease in kidney function or progression to ESRD. An independent cohort of patients with Alport syndrome had a 23-fold increase in urinary podocyte mRNAs (P<0.001 compared with controls). Urinary podocyte mRNAs increased during active disease but returned to baseline on disease remission. Furthermore, urine podocyte mRNAs increased in all categories of glomerular disease evaluated, but levels ranged from high to normal, consistent with individual patient variability in the risk for progression. In contrast, urine podocyte mRNAs did not increase in polycystic kidney disease. The association between proteinuria and podocyturia varied markedly by glomerular disease type: a high correlation in minimal-change disease and a low correlation in membranous nephropathy. These data support the podocyte depletion hypothesis as the mechanism driving progression in all human glomerular diseases, suggest that urine pellet podocyte mRNAs could be useful for monitoring risk for progression and response to treatment, and provide novel insights into glomerular disease pathophysiology. PMID:24052633

Wickman, Larysa; Afshinnia, Farsad; Wang, Su Q.; Yang, Yan; Wang, Fei; Chowdhury, Mahboob; Graham, Delia; Hawkins, Jennifer; Nishizono, Ryuzoh; Tanzer, Marie; Wiggins, Jocelyn; Escobar, Guillermo A.; Rovin, Bradley; Song, Peter; Gipson, Debbie; Kershaw, David

2013-01-01

130

Slowing the progression of kidney disease in patients with diabetes  

Microsoft Academic Search

Diabetic nephropathy is a leading cause of renal failure requiring replacement therapy. Diabetic nephropathy is typically characterized by persistent microalbuminuria progressing to nephrotic syndrome, a progressive decline in glomerular filtration rate, and hypertension. Diabetic nephropathy prevention strategies may involve early angiotensin-converting enzyme (ACE) inhibitor treatment and the control of diabetes to reduce glomerular hypertension and hyperfiltration. Treatment strategies include the

Ellen Burgess

2008-01-01

131

Glomerular hypertrophy in minimal change disease predicts subsequent progression to focal glomerular sclerosis  

Microsoft Academic Search

Glomerular hypertrophy in minimal change disease predicts subsequent progression to focal glomerular sclerosis. The study sought a diagnostic clue to identify the group of pediatric patients with apparent minimal change disease who subsequently develop focal glomerular sclerosis (FGS). Review of all renal biopsy material at our institutions identified 42 pediatric patients who met the standard criteria for minimal change disease

Agnes Fogo; Edith P Hawkins; Phillip L Berry; Alan D Glick; Myra L Chiang; Robert C MacDonell; Iekuni Ichikawa; Fogo

1990-01-01

132

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...

133

Re exive and volitional saccades: Biomarkers of Huntington disease severity and progression  

E-print Network

Re exive and volitional saccades: Biomarkers of Huntington disease severity and progression Saumil Background: Huntington disease (HD) is a genetic, neurodegenerative disorder characterized by chorea, behav: Eleven HD subjects were evaluated with the motor subscale of the Uni ed Huntington Disease Rating Scale

Sereno, Anne B.

134

Evaluating the Predictive Power of Multivariate Tensor-based Morphometry in Alzheimers Disease Progression via Convex  

E-print Network

Evaluating the Predictive Power of Multivariate Tensor-based Morphometry in Alzheimers Disease ABSTRACT Prediction of Alzheimers disease (AD) progression based on baseline measures allows us. They showed that this can be used in predicting cognitive outcomes of Alzheimers Disease Neuroimaging

Wang, Yalin

135

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

PubMed Central

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

Skodda, Sabine; Grönheit, Wenke; Schlegel, Uwe

2012-01-01

136

Implementation of a population-based epidemiological rare disease registry: study protocol of the amyotrophic lateral sclerosis (ALS) - registry Swabia  

PubMed Central

Background The social and medical impact of rare diseases is increasingly recognized. Amyotrophic lateral sclerosis (ALS) is the most prevalent of the motor neuron diseases. It is characterized by rapidly progressive damage to the motor neurons with a survival of 2–5 years for the majority of patients. The objective of this work is to describe the study protocol and the implementation steps of the amyotrophic lateral sclerosis (ALS) registry Swabia, located in the South of Germany. Methods/Design The ALS registry Swabia started in October 2010 with both, the retrospective (01.10.2008-30.09.2010) and prospective (from 01.10.2010) collection of ALS cases, in a target population of 8.6 million persons in Southern Germany. In addition, a population based case–control study was implemented based on the registry that also included the collection of various biological materials. Retrospectively, 420 patients (222 men and 198 women) were identified. Prospectively data of ALS patients were collected, of which about 70% agreed to participate in the population-based case–control study. All participants in the case–control study provided also a blood sample. The prospective part of the study is ongoing. Discussion The ALS registry Swabia has been implemented successfully. In rare diseases such as ALS, the collaboration of registries, the comparison with external samples and biorepositories will facilitate to identify risk factors and to further explore the potential underlying pathophysiological mechanisms. PMID:23414001

2013-01-01

137

Status and progress in coral reef disease research.  

PubMed

Recent findings on the ecology, etiology and pathology of coral pathogens, host resistance mechanisms, previously unknown disease/syndromes and the global nature of coral reef diseases have increased our concern about the health and future of coral reef communities. Much of what has been discovered in the past 4 years is presented in this special issue. Among the significant findings, the role that various Vibrio species play in coral disease and health, the composition of the 'normal microbiota' of corals, and the possible role of viruses in the disease process are important additions to our knowledge. New information concerning disease resistance and vectors, variation in pathogen composition for both fungal diseases of gorgonians and black band disease across oceans, environmental effects on disease susceptibility and resistance, and temporal and spatial disease variations among different coral species is presented in a number of papers. While the Caribbean may still be the 'disease hot spot' for coral reefs, it is now clear that diseases of coral reef organisms have become a global threat to coral reefs and a major cause of reef deterioration. PMID:16703761

Weil, Ernesto; Smith, Garriet; Gil-Agudelo, Diego L

2006-03-23

138

In vivo parahippocampal white matter pathology as a biomarker of disease progression to Alzheimer's disease.  

PubMed

Noninvasive diagnostic tests for Alzheimer's disease (AD) are limited. Postmortem diagnosis is based on density and distribution of neurofibrillary tangles (NFTs) and amyloid-rich neuritic plaques. In preclinical stages of AD, the cells of origin for the perforant pathway within the entorhinal cortex are among the first to display NFTs, indicating its compromise in early stages of AD. We used diffusion tensor imaging (DTI) to assess the integrity of the parahippocampal white matter in mild cognitive impairment (MCI) and AD, as a first step in developing a noninvasive tool for early diagnosis. Subjects with AD (N = 9), MCI (N = 8), or no cognitive impairment (NCI; N = 20) underwent DTI-MRI. Fractional anisotropy (FA) and mean (MD) and radial (RD) diffusivity measured from the parahippocampal white matter in AD and NCI subjects differed greatly. Discriminant analysis in the MCI cases assigned statistical membership of 38% of MCI subjects to the AD group. Preliminary data 1 year later showed that all MCI cases assigned to the AD group either met the diagnostic criteria for probable AD or showed significant cognitive decline. Voxelwise analysis in the parahippocampal white matter revealed a progressive change in the DTI patterns in MCI and AD subjects: whereas converted MCI cases showed structural changes restricted to the anterior portions of this region, in AD the pathology was generalized along the entire anterior-posterior axis. The use of DTI for in vivo assessment of the parahippocampal white matter may be useful for identifying individuals with MCI at highest risk for conversion to AD and for assessing disease progression. PMID:23839862

Solodkin, Ana; Chen, E Elinor; Van Hoesen, Gary W; Heimer, Lennart; Shereen, Ahmed; Kruggel, Frithjof; Mastrianni, James

2013-12-15

139

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

PubMed

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

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

2015-04-01

140

Association of survival and disease progression with chromosomal instability: A genomic exploration of colorectal cancer  

E-print Network

During disease progression the cells that comprise solid malignancies undergo significant changes in gene copy number and chromosome structure. Colorectal cancer provides an excellent model to study this process. To indentify ...

Sheffer, Michal

141

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

PubMed

We present a new image registration based method for monitoring regional disease progression in longitudinal image studies of lung disease. A free-form image registration technique is used to match a baseline 3D CT lung scan onto a following scan. Areas with lower intensity in the following scan compared with intensities in the deformed baseline image indicate local loss of lung tissue that is associated with progression of emphysema. To account for differences in lung intensity owing to differences in the inspiration level in the two scans rather than disease progression, we propose to adjust the density of lung tissue with respect to local expansion or compression such that the total weight of the lungs is preserved during deformation. Our method provides a good estimation of regional destruction of lung tissue for subjects with a significant difference in inspiration level between CT scans and may result in a more sensitive measure of disease progression than standard quantitative CT measures. PMID:18982686

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

2008-01-01

142

Fabry disease: progression of nephropathy, and prevalence of cardiac and cerebrovascular events before enzyme replacement therapy  

Microsoft Academic Search

Background. In Fabry disease, progressive glycolipid accumulation leads to organ damage and early demise, but the incidence of renal, cardiac and cerebrovascular events has not been well characterized. Methods. We conducted a retrospective chart review of 279 affected males and 168 females from 27 sites (USA, Canada, Europe). The pre-defined study endpoints included progression of renal, cardiac and cerebrovascular involvement

R. Schiffmann; D. G. Warnock; M. Banikazemi; J. Bultas; G. E. Linthorst; S. Packman; S. A. Sorensen; W. R. Wilcox; R. J. Desnick

2009-01-01

143

Chemokines and chemokine receptors are involved in the resolution or progression of renal disease  

Microsoft Academic Search

Chemokines and chemokine receptors are involved in the resolution or progression of renal disease. Locally secreted chemokines mediate leukocyte recruitment during the initiation and amplification phase of renal inflammation. In turn, the infiltrating leukocytes contribute to renal damage by releasing inflammatory and profibrotic factors. Rapid down modulation of the chemokine signal will support resolution of acute inflammation, whereas progression occurs

Hans-Joachim Anders; Volker Vielhauer; Detlef Schlöndorff

2003-01-01

144

A conceptual framework for the molecular pathogenesis of progressive kidney disease  

Microsoft Academic Search

The data regarding the pathogenesis of progressive kidney disease implicate cytokine effects, physiological factors, and myriad\\u000a examples of relatively nonspecific cellular dysfunction. The sheer volume of information being generated on this topic threatens\\u000a to overwhelm our efforts to understand progression in chronic kidney disease or to derive rational strategies to treat it.\\u000a Here, a conceptual framework is offered for organizing

H. William Schnaper; Susan C. Hubchak; Constance E. Runyan; James A. Browne; Gal Finer; Xiaoying Liu; Tomoko Hayashida

2010-01-01

145

Disease progression and evolution of the HIV1 env gene in 24 infected infants  

Microsoft Academic Search

We have studied the relationship between disease progression and HIV-1 evolution in 24 infants classified as rapid or non-rapid progressors, during nearly the entire disease progression cycle from infection to AIDS. Specifically, we examined the temporal relationship between clinical status and changes in genetic diversity, divergence, selection and recombination at the C2V3C3 region of the env gene during a period

Antonio Carvajal-Rodríguez; David Posada; Marcos Pérez-Losada; Emily Keller; Elaine J. Abrams; Raphael P. Viscidi; Keith A. Crandall

2008-01-01

146

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)

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.

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

2014-03-01

147

Gender Differences in HIV Progression to AIDS and Death in Industrialized Countries: Slower Disease Progression Following HIV Seroconversion in Women  

Microsoft Academic Search

To evaluate sex differences in human immunodeficiency virus (HIV) disease progression before (pre-1997) and after (1997-2006) introduction of highly active antiretroviral therapy, the authors used data from a collaboration of 23 HIV seroconverter cohort studies from Europe, Australia, and Canada restricted to the 6,923 seroconverters infected through injecting drug use and sex between men and women. Within a competing risk

Inmaculada Jarrin; Ronald Geskus; Krishnan Bhaskaran; Maria Prins; Roberto Muga; Ildefonso Hernandez-Aguado; Laurence Meyer

148

Whole brain atrophy rate predicts progression from MCI to Alzheimer's disease.  

PubMed

For both clinical and research reasons, it is essential to identify which mild cognitive impairment (MCI) subjects subsequently progress to Alzheimer's disease (AD). The prediction may be facilitated by accelerated whole brain atrophy exhibited by AD subjects. Iterative principal component analysis (IPCA) was used to characterize whole brain atrophy rates using sequential MRI scans for 102 MCI subjects from the Kuopio University Hospital. We modelled the likelihood of progression to probable AD, and found that each additional percent of annualized whole brain atrophy rate was associated with a higher odds ratio (OR) of progression (OR=1.30, p=0.01, 95% CI=1.05-1.60). Our study demonstrates an association between whole brain atrophy rate and subsequent rate of clinical progression from MCI to AD. These findings suggest that IPCA could be an effective brain-imaging marker of progression to AD and useful tool for the evaluation of disease-modifying treatments. PMID:18829136

Spulber, Gabriela; Niskanen, Eini; MacDonald, Stuart; Smilovici, Oded; Chen, Kewei; Reiman, Eric M; Jauhiainen, Anne M; Hallikainen, Merja; Tervo, Susanna; Wahlund, Lars-Olof; Vanninen, Ritva; Kivipelto, Miia; Soininen, Hilkka

2010-09-01

149

Progress in Early Diagnosis of Sickle Cell Disease  

ERIC Educational Resources Information Center

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)

Pearson, Howard A.

1971-01-01

150

Progress and prospects: graft-versus-host disease  

Microsoft Academic Search

Graft-versus-host disease (GvHD) is one of the major complications of allogeneic hematopoietic stem cell transplantation, an otherwise highly effective therapeutic modality for patients affected by hematological diseases. The main inducers of GvHD are alloreactive donor T cells, which recognize host antigens presented by recipient cells. The critical role of lymphocytes in GvHD is well documented by the observation that T-cell

S Mastaglio; M T L Stanghellini; C Bordignon; A Bondanza; F Ciceri; C Bonini

2010-01-01

151

Cellular Lipid Metabolism and the Role of Lipids in Progressive Renal Disease  

Microsoft Academic Search

Dyslipidemia contributes to the rate of progression of atherosclerosis and chronic kidney disease. Also, chronic kidney disease leads to the development of secondary abnormalities in lipid metabolism that contribute to increased cardiovascular morbidity and mortality. This review presents the mechanisms that underlie this risk. The mechanisms of normal cellular lipid metabolism and the abnormalities that develop in association with inflammation

Christine K. Abrass

2004-01-01

152

Assessing the progression of mild cognitive impairment to Alzheimer's disease: current trends and future directions  

Microsoft Academic Search

ABSTRACT: 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

Larry G Brooks; David A Loewenstein

2010-01-01

153

Neuropsychological Predictors of Rapidly Progressing Patients with Alzheimer’s Disease  

Microsoft Academic Search

Background: Alzheimer disease (AD) has heterogeneous clinical manifestations. Different neuropsychological profiles in AD patients might be indicative of the diffusion of the pathological process and might be associated with differences in rates of disease progression. Methods: We studied 154 newly diagnosed AD patients (65.6% women; mean age: 73 years). Performance in memory, executive functions, praxis and language domains was categorized

Massimo Musicco; Giovanna Salamone; Carlo Caltagirone; Luca Cravello; Lucia Fadda; Federica Lupo; Serena Mosti; Roberta Perri; Katie Palmer

2010-01-01

154

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

Microsoft Academic Search

Industry and academia are devoting a tremendous amount of resources to the testing of anti-inflammatory drugs for the treatment of Alzheimer's disease (AD). This trend is the result of the growing consensus supporting the inflammatory hypothesis of AD. If anti-inflammatory strategies succeed in slowing the rate of disease progression, the impact on patients and families could be enormous. However, given

Giulio Maria Pasinetti

2001-01-01

155

Letter to the Editor Underestimation of Disease Progress Rates with the Logistic, Monomolecular, and Gompertz Models  

E-print Network

Letter to the Editor Underestimation of Disease Progress Rates with the Logistic, Monomolecular. One of the five assumptions listed by Campbell and (rG), and logistic (rL) models. Equivalent rates, a disease intensity of 100% Gompertz, and logistic models, respectively [21]). Values for K can be achieved

Neher, Deborah A.

156

Progress in Blood Pressure Control in Autosomal Dominant Polycystic Kidney Disease  

Microsoft Academic Search

Hypertension occurs commonly in autosomal dominant polycystic kidney disease (ADPKD) and is an important factor in the progression of the disease and cardiovascular mortality. The aim of this prospective 15-year study is to report the rate of blood pressure control and the potential effect of a 10-point education program developed by our center for ADPKD patients and their physicians. The

Tevfik Ecder; Charles L. Edelstein; Godela M. Fick-Brosnahan; Ann M. Johnson; Irene T. Duley; Patricia A. Gabow; Robert W. Schrier

2000-01-01

157

Bilateral, tumorlike diabetic mastopathy-progression and regression of the disease during 5-year follow up  

Microsoft Academic Search

Diabetic mastopathy is a recently described collection of radiographical and histological features found in dense fibrous masses of the breast in long standing Type I diabetes. We describe the first case of bilateral disease with the alternate progression and regression of the disease over a 5 year period. A 45-year-old woman has been affected of insulin dependent diabetes mellitus (IDDM)

Ute Bayer; L.-C Horn; H.-G Schulz

1998-01-01

158

Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years  

Microsoft Academic Search

BackgroundPatients with non-alcoholic steatohepatitis (NASH) have increased mortality and liver-related complications. In contrast, simple steatosis is considered benign and non-progressive.ObjectiveTo investigate disease progression in patients with different degrees of non-alcoholic fatty liver disease (NAFLD) activity.DesignProspective longitudinal hospital-based cohort study.PatientsFifty-two patients (age 44±9 years) with biopsy-proven NAFLD had liver biopsies repeated at month 36.ResultsAmong 13 patients with simple steatosis at baseline,

Vincent Wai-Sun Wong; Grace Lai-Hung Wong; Paul Cheung-Lung Choi; Anthony Wing-Hung Chan; Mia Ka-Po Li; Hoi-Yun Chan; Angel Mei-Ling Chim; Jun Yu; Joseph Jao-Yiu Sung; Henry Lik-Yuen Chan

2010-01-01

159

Deletion of galectin-3 exacerbates microglial activation and accelerates disease progression and demise in a SOD1G93A mouse model of amyotrophic lateral sclerosis  

PubMed Central

Galectins are pleiotropic carbohydrate-binding lectins involved in inflammation, growth/differentiation, and tissue remodeling. The functional role of galectins in amyotrophic lateral sclerosis (ALS) is unknown. Expression studies revealed increases in galectin-1 mRNA and protein in spinal cords from SOD1G93A mice, and in galectin-3 and -9 mRNAs and proteins in spinal cords of both SOD1G93A mice and sporadic ALS patients. As the increase in galectin-3 appeared in early presymptomatic stages and increased progressively through to end stage of disease in the mouse, it was selected for additional study, where it was found to be mainly expressed by microglia. Galectin-3 antagonists are not selective and do not readily cross the blood–brain barrier; therefore, we generated SOD1G93A/Gal-3?/? transgenic mice to evaluate galectin-3 deletion in a widely used mouse model of ALS. Disease progression, neurological symptoms, survival, and inflammation were assessed to determine the effect of galectin-3 deletion on the SOD1G93A disease phenotype. Galectin-3 deletion did not change disease onset, but resulted in more rapid progression through functionally defined disease stages, more severely impaired neurological symptoms at all stages of disease, and expiration, on average, 25 days earlier than SOD1G93A/Gal-3+/+ cohorts. In addition, microglial staining, as well as TNF-?, and oxidative injury were increased in SOD1G93A/Gal-3?/? mice compared with SOD1G93A/Gal-3+/+ cohorts. These data support an important functional role for microglial galectin-3 in neuroinflammation during chronic neurodegenerative disease. We suggest that elevations in galectin-3 by microglia as disease progresses may represent a protective, anti-inflammatory innate immune response to chronic motor neuron degeneration. PMID:23139902

Lerman, Bruce J; Hoffman, Eric P; Sutherland, Margaret L; Bouri, Khaled; Hsu, Daniel K; Liu, Fu-Tong; Rothstein, Jeffrey D; Knoblach, Susan M

2012-01-01

160

Disseminated oligodendroglial-like leptomeningeal tumor with anaplastic progression and presumed extraneural disease: case report.  

PubMed

We report the neuroimaging and histopathologic findings of a 12-year-old female patient with a disseminated oligodendroglial-like leptomeningeal tumor with anaplastic progression and presumed extraneural metastatic disease. These tumors may represent distinct pathology primarily seen in pediatric patients. Neuroimaging demonstrates diffuse, progressive enhancement of the leptomeninges often with interval development of intraparenchymal lesions on follow-up. Disease is typically confined to the central nervous system, though diffuse peritoneal disease was seen in our case, possibly through metastatic seeding of the abdomen via ventriculoperitoneal shunt. PMID:25518979

Kessler, Brice A; Bookhout, Christine; Jaikumar, Sivakumar; Hipps, John; Lee, Yueh Z

2015-01-01

161

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

PubMed Central

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

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

2014-01-01

162

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

PubMed

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

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

2013-04-01

163

Progression of Chronic Kidney Disease: Adrenergic Genetic Influence on Glomerular Filtration Rate Decline in Hypertensive Nephrosclerosis  

Microsoft Academic Search

Background: African-Americans are likely to develop hypertension and hypertensive nephrosclerosis. This grave prognosis, coupled with familial aggregation of end-stage renal disease (ESRD) in Blacks, prompts a search for genetic risk factors for ESRD. Recent evidence implicates a crucial role for the sympathetic nervous system in progressive renal disease. Methods: We used the African-American Study of Kidney Disease to probe whether

Yuqing Chen; Michael S. Lipkowitz; Rany M. Salem; Maple M. Fung; Vibha Bhatnagar; Manjula Mahata; Caroline M. Nievergelt; Fangwen Rao; Sushil K. Mahata; Nicholas J. Schork; Pamela J. Hicks; Donald W. Bowden; Barry I. Freedman; Victoria H. Brophy; Daniel T. O’Connor

2010-01-01

164

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

PubMed

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 ?-Al2O3 at an extraordinarily low temperature (below 300 °C), but this ?-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 ?-phase. PMID:23557087

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

2013-04-15

165

Chronic renal disease progression: treatment strategies and potassium intake.  

PubMed

Disordered potassium homeostasis is a common complication of chronic kidney disease and traditional management focuses on restricting potassium intake to avoid hyperkalemia. Permissive potassium intake carries the risk of hyperkalemia and hyperphosphatemia, and possibly may contribute to the development of uremic neuropathy. Excessive potassium restriction and removal by dialysis carries the risk of worsened chronic hypertension, intradialytic hypotension, renal fibrosis and cyst formation, and ventricular arrhythmias. Cohort studies have associated both hypokalemia and hyperkalemia with increased mortality in CKD. A single study of potassium intake in hemodialysis patients found increased intake associated with increased mortality despite adjustment for serum potassium concentration. We recommend avoiding mandatory potassium restriction in early chronic kidney disease. We endorse routine potassium restriction in advanced chronic kidney disease requiring hemodialysis and close monitoring of serum potassium concentration in any patients receiving renin-angiotensin-aldosterone system blockers. PMID:23953806

Sinha, Arjun D; Agarwal, Rajiv

2013-05-01

166

Herpes virus in Alzheimer's disease: relation to progression of the disease.  

PubMed

Studies regarding different viruses of the herpes family, such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), or human herpes virus 6 (HHV-6) in Alzheimer's disease (AD) are scarce. DNA from peripheral blood leukocytes (PBL) and brain samples were analyzed for the presence of CMV, EBV, or HHV-6. All samples were negative for CMV. EBV positivity was 6% in AD brains, whereas 45% of PBL samples from AD patients and 31% from controls were positive for EBV (p = 0.05). HHV-6 showed a 23% positivity in PBL samples from AD and 4% from controls (p = 0.002). 17% of AD brains were HHV-6 positive. Within a group of elderly individuals, followed up for 5 years, EBV-positive or HHV-6-positive PBL increased in those who developed clinical AD. Virus serological positivity was also investigated, and IgG levels for CMV and EBV antigens were also increased in those subjects who developed AD during the follow-up. Our findings suggest that EBV and HHV-6 may be environmental risk factors for cognitive deterioration and progression to AD in elderly persons. PMID:23916950

Carbone, Ilaria; Lazzarotto, Tiziana; Ianni, Manuela; Porcellini, Elisa; Forti, Paola; Masliah, Eliezer; Gabrielli, Liliana; Licastro, Federico

2014-01-01

167

Analysis of neurological disease in four dimensions: insight from ALS-PDC epidemiology and animal models  

Microsoft Academic Search

The causal factor(s) responsible for sporadic neurological diseases are unknown and the stages of disease progression remain undefined and poorly understood. We have developed an animal model of amyotrophic lateral sclerosis-parkinsonism dementia complex which mimics all the essential features of the disease with the initial neurological insult arising from neurotoxins contained in washed cycad seeds. Animals fed washed cycad develop

C. A Shaw; J. M. B Wilson

2003-01-01

168

Cytolethal Distending Toxin in Isolates of Aggregatibacter actinomycetemcomitans from Ghanaian Adolescents and Association with Serotype and Disease Progression  

PubMed Central

Background and Objectives The cytolethal distending toxin (Cdt) is a highly conserved exotoxin that are produced by a number of Gram negative bacteria, including Aggregatibacter actinomycetemcomitans, and affects mammalian cells by inhibiting cell division and causing apoptosis. A complete cdt-operon is present in the majority of A. actinomycetemcomitans, but the proportion of isolates that lack cdt-encoding genes (A, B and C) varies according to the population studied. The objectives of this study were to examine serotype, Cdt-genotype, and Cdt-activity in isolates of A. actinomycetemcomitans collected from an adolescent West African population and to examine the association between the carrier status of A. actinomycetemcomitans and the progression of attachment loss (AL). Materials and Methods A total of 249 A. actinomycetemcomitans isolates from 200 Ghanaian adolescents were examined for serotype and cdt-genotype by PCR. The activity of the Cdt-toxin was examined by DNA-staining of exposed cultured cells and documented with flow cytometry. The periodontal status of the participants was examined at baseline and at a two-year follow-up. Results Presence of all three cdt-encoding genes was detected in 79% of the examined A. actinomycetemcomitans isolates. All these isolates showed a substantial Cdt-activity. The two different cdt-genotypes (with and without presence of all three cdt-encoding genes) showed a serotype-dependent distribution pattern. Presence of A. actinomycetemcomitans was significantly associated with progression of AL (OR?=?5.126; 95% CI?=?[2.994–8.779], p<0.001). Conclusion A. actinomycetemcomitans isolated from the Ghanaian adolescents showed a distribution of serotype and cdt-genotype in line with results based on other previously studied populations. Presence of A. actinomycetemcomitans was significantly associated with disease progression, in particular the b serotype, whereas the association with disease progression was not particularly related to cdt-genotype, and Cdt-activity. PMID:23922633

Höglund Åberg, Carola; Antonoglou, Georgios; Haubek, Dorte; Kwamin, Francis; Claesson, Rolf; Johansson, Anders

2013-01-01

169

Clinical features and predictors for disease natural progression in adults with Pompe disease: a nationwide prospective observational study  

PubMed Central

Background Due partly to physicians’ unawareness, many adults with Pompe disease are diagnosed with great delay. Besides, it is not well known which factors influence the rate of disease progression, and thus disease outcome. We delineated the specific clinical features of Pompe disease in adults, and mapped out the distribution and severity of muscle weakness, and the sequence of involvement of the individual muscle groups. Furthermore, we defined the natural disease course and identified prognostic factors for disease progression. Methods We conducted a single-center, prospective, observational study. Muscle strength (manual muscle testing, and hand-held dynamometry), muscle function (quick motor function test), and pulmonary function (forced vital capacity in sitting and supine positions) were assessed every 3–6 months and analyzed using repeated-measures ANOVA. Results Between October 2004 and August 2009, 94 patients aged between 25 and 75 years were included in the study. Although skeletal muscle weakness was typically distributed in a limb-girdle pattern, many patients had unfamiliar features such as ptosis (23%), bulbar weakness (28%), and scapular winging (33%). During follow-up (average 1.6 years, range 0.5-4.2 years), skeletal muscle strength deteriorated significantly (mean declines of ?1.3% point/year for manual muscle testing and of ?2.6% points/year for hand-held dynamometry; both p<0.001). Longer disease duration (>15 years) and pulmonary involvement (forced vital capacity in sitting position <80%) at study entry predicted faster decline. On average, forced vital capacity in supine position deteriorated by 1.3% points per year (p=0.02). Decline in pulmonary function was consistent across subgroups. Ten percent of patients declined unexpectedly fast. Conclusions Recognizing patterns of common and less familiar characteristics in adults with Pompe disease facilitates timely diagnosis. Longer disease duration and reduced pulmonary function stand out as predictors of rapid disease progression, and aid in deciding whether to initiate enzyme replacement therapy, or when. PMID:23147228

2012-01-01

170

From Pasteur to genomics: progress and challenges in infectious diseases  

Microsoft Academic Search

Over the past decade, microbiology and infectious disease research have undergone the most profound revolution since the times of Pasteur. Genomic sequencing has revealed the much-awaited blueprint of most pathogens. Screening blood for the nucleic acids of infectious agents has blunted the spread of pathogens by transfusion, the field of antiviral therapeutics has exploded and technologies for the development of

Rino Rappuoli

2004-01-01

171

From disease genes to cellular pathways: a progress report  

E-print Network

and Visual Sciences, {Biomedical Engineering, }Biostatistics, }Statistics and kHuman Genetics, University of gene-based therapies; nonetheless, all of these diseases result in the same fate, i.e. the death of the photoreceptors. A number of innovative strategies have been employed with the objectives of slowing down

Hero, Alfred O.

172

Environmental Factors Affecting Inflammatory Bowel Disease: Have We Made Progress?  

Microsoft Academic Search

The pathogenesis of inflammatory bowel disease (IBD) is only partially understood; various environmental and host (e.g. genetic, epithelial, immune, and nonimmune) factors are involved. The critical role for environmental factors is strongly supported by recent worldwide trends in IBD epidemiology. One important environmental factor is smoking. A meta-analysis partially confirms previous findings that smoking was found to be protective against

Peter Laszlo Lakatos

2009-01-01

173

Inflammatory Leukocyte Phenotypes Correlate with Disease Progression in Idiopathic Pulmonary Fibrosis  

PubMed Central

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive deposition of extracellular matrix, worsening dyspnea, and eventual mortality. Pathogenesis of IPF is poorly understood and the role inflammation and activated leukocytes play in the disease process is controversial. Previous studies demonstrated that activated leukocyte subsets characterize IPF patients. We sought to validate this observation in a well-defined cohort of 35 IPF patients and to correlate the observed leukocyte phenotypes with robust parameters of disease progression. We demonstrate that in univariate and multivariate analyses, increases in the CD14hi, CD16hi subset of monocytes measured at baseline correlated with disease progression, with a threshold value >0.5% of the total peripheral blood mononuclear cells being a significant predictor for worse outcome. In addition, several?T cell subsets, including CD25 expressing CD4 cells, and CXCR3 expressing CD4 and CD8 subsets correlated with disease progression when found in increased percentages in the peripheral blood of IPF patients when sampled at baseline. Somewhat surprising in comparison to previous literature, the CD4?T cells did not appear to have lost expression of the co-stimulatory molecule, CD28, but the CD8 T cells did. Taken together, these results are consistent with the presence of an inflammatory process in IPF patients who eventually progress. However, when longitudinal measurements of these same markers were examined, there was significant heterogeneity of expression and these biomarkers did not necessarily remain elevated in IPF patients with progressive disease. We interpret this heterogeneity to suggest that IPF patients experience episodic inflammatory events that once triggered, may lead to disease progression. This longitudinal heterogeneity in biomarker analyses may explain why such markers are not consistently measured in all IPF cohorts. PMID:25580363

Moore, Bethany B.; Fry, Chris; Zhou, Yueren; Murray, Susan; Han, MeiLan K.; Martinez, Fernando J.; Flaherty, Kevin R.

2014-01-01

174

Orexin antagonists for neuropsychiatric disease: progress and potential pitfalls  

PubMed Central

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

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

2014-01-01

175

Optical Assessment of Vascular Disease Progression and Treatment  

NASA Astrophysics Data System (ADS)

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.

Samuels, Joshua A.

176

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

PubMed

We evaluated whether lysyl oxidase-like 2 (LOXL2), which promotes cross-linking of collagen in pathological stroma, was detectable in serum from idiopathic pulmonary fibrosis (IPF) patients, and assessed its relationship with IPF disease progression. Patients from the ARTEMIS-IPF (n=69) and the Genomic and Proteomic Analysis of Disease Progression in IPF (GAP) (n=104) studies were analysed. Baseline serum LOXL2 (sLOXL2) levels were compared with baseline clinical and physiological surrogates of disease severity, and the association with IPF disease progression was assessed using a classification and regression tree (CART) method. sLOXL2 correlated weakly with forced vital capacity and carbon monoxide diffusion capacity (r -0.24-0.05) in both cohorts. CART-determined thresholds were similar: ARTEMIS-IPF 800 pg·mL(-1) and GAP 700 pg·mL(-1). In ARTEMIS-IPF, higher sLOXL2 (>800 pg·mL(-1)) was associated with increased risk for disease progression (hazard ratio (HR) 5.41, 95% CI 1.65-17.73). Among GAP subjects with baseline spirometric data (n=70), higher sLOXL2 levels (>700 pg·mL(-1)) were associated with more disease progression events (HR 1.78, 95% CI 1.01-3.11). Among all GAP subjects, higher sLOXL2 levels were associated with increased risk for mortality (HR 2.28, 95% CI 1.18-4.38). These results suggest that higher sLOXL2 levels are associated with increased risk for IPF disease progression. However, due to multiple limitations, these results require validation. PMID:24177001

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

2014-05-01

177

Progressive decline of glucocerebrosidase in aging and Parkinson's disease  

PubMed Central

The principal risk factor for developing most adult onset neurodegenerative diseases is aging, with incidence rising significantly after age 50. Despite research efforts, the causes of Parkinson's disease (PD) remain unknown. As neurons age, they show signs of diminished lysosomal and mitochondrial function, including increased oxidative stress and accumulation of misfolded proteins, and these changes become exacerbated PD. We show that activity of the lysosomal hydrolase glucocerebrosidase gradually diminishes with age in the substantia nigra and putamen of healthy controls. This reduction is comparable to glucocerebrosidase activity in GBA1-mutation carrier PD patients. These data, demonstrate for the first time that an age-dependent reduction in glucocerebrosidase activity may lower the threshold for developing PD.

Rocha, Emily M; Smith, Gaynor A; Park, Eric; Cao, Hongmei; Brown, Eilish; Hallett, Penelope; Isacson, Ole

2015-01-01

178

Mutations in TJP2 cause progressive cholestatic liver disease  

PubMed Central

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

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

179

The Kidney Disease Center Progress Report 2007-2008 The Kidney Disease Center (KDC) was established July 1, 2005 under the direction of Richard  

E-print Network

The Kidney Disease Center Progress Report 2007-2008 The Kidney Disease Center (KDC) was established and breadth of its research programs. The research focus includes: the prevention of chronic kidney disease for the treatment of polycystic kidney disease, renal ischemia reperfusion injury and renal stone disease. #12

180

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

NASA Astrophysics Data System (ADS)

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.

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

2014-12-01

181

Enzyme replacement therapy attenuates disease progression in a canine model of late-infantile neuronal ceroid lipofuscinosis (CLN2 disease)  

PubMed Central

Using a canine model of classical late-infantile neuronal ceroid lipofuscinosis (CLN2 disease), a study was conducted to evaluate the potential pharmacological activity of recombinant human tripeptidyl peptidase-1 (rhTPP1) enzyme replacement therapy administered directly to the cerebrospinal fluid (CSF). CLN2 disease is a hereditary neurodegenerative disorder resulting from mutations in CLN2, which encodes the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Infants with mutations in both CLN2 alleles develop normally but in the late-infantile/early-childhood period undergo progressive neurological decline accompanied by pronounced brain atrophy. The disorder, a form of Batten disease, is uniformly fatal, with clinical signs starting between 2 and 4 years of age and death usually occurring by the early teenage years. Dachshunds homozygous for a null mutation in the canine ortholog of CLN2 (TPP1) exhibit a similar disorder that progresses to end stage at 10.5–11 months of age. Administration of rhTPP1 via infusion into the CSF every other week, starting at approximately 2.5 months of age, resulted in dose-dependent significant delays in disease progression, as measured by delayed onset of neurologic deficits, improved performance on a cognitive function test, reduced brain atrophy, and increased life span. Based on these findings, a clinical study evaluating the potential therapeutic value of rhTPP1 administration into the CSF of children with CLN2 disease has been initiated. PMID:24938720

Katz, Martin L; Coates, Joan R; Sibigtroth, Christine M; Taylor, Jacob D; Carpentier, Melissa; Young, Whitney M; Wininger, Fred A; Kennedy, Derek; Vuillemenot, Brian R; O'Neill, Charles A

2014-01-01

182

Enzyme replacement therapy attenuates disease progression in a canine model of late-infantile neuronal ceroid lipofuscinosis (CLN2 disease).  

PubMed

Using a canine model of classical late-infantile neuronal ceroid lipofuscinosis (CLN2 disease), a study was conducted to evaluate the potential pharmacological activity of recombinant human tripeptidyl peptidase-1 (rhTPP1) enzyme replacement therapy administered directly to the cerebrospinal fluid (CSF). CLN2 disease is a hereditary neurodegenerative disorder resulting from mutations in CLN2, which encodes the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Infants with mutations in both CLN2 alleles develop normally but in the late-infantile/early-childhood period undergo progressive neurological decline accompanied by pronounced brain atrophy. The disorder, a form of Batten disease, is uniformly fatal, with clinical signs starting between 2 and 4 years of age and death usually occurring by the early teenage years. Dachshunds homozygous for a null mutation in the canine ortholog of CLN2 (TPP1) exhibit a similar disorder that progresses to end stage at 10.5-11 months of age. Administration of rhTPP1 via infusion into the CSF every other week, starting at approximately 2.5 months of age, resulted in dose-dependent significant delays in disease progression, as measured by delayed onset of neurologic deficits, improved performance on a cognitive function test, reduced brain atrophy, and increased life span. Based on these findings, a clinical study evaluating the potential therapeutic value of rhTPP1 administration into the CSF of children with CLN2 disease has been initiated. PMID:24938720

Katz, Martin L; Coates, Joan R; Sibigtroth, Christine M; Taylor, Jacob D; Carpentier, Melissa; Young, Whitney M; Wininger, Fred A; Kennedy, Derek; Vuillemenot, Brian R; O'Neill, Charles A

2014-11-01

183

Overview of 50 years' progress in upper gastrointestinal diseases.  

PubMed

There have been numerous and dramatic advances in our understanding of the mechanisms, causes and treatments of upper gastrointestinal diseases in the past 50 years. This review focuses on a few, not dealt with elsewhere in this special issue of the Journal. The early history of the recognition that nonsteroidal anti-inflammatory drugs are a major cause of peptic ulcer is described, with particular attention to the work of the pioneering Australian investigators. The story of the development of the histamine H(2)-receptor antagonists and the proton pump inhibitors is also outlined. PMID:19799693

Yeomans, Neville D

2009-10-01

184

4-hydroxynonenal in the pathogenesis and progression of human diseases  

PubMed Central

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

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

2014-01-01

185

[Progress in the treatment of and research on Hirschsprung's disease].  

PubMed

Hirschsprung's disease (HD) is a relatively common cause of intestinal obstruction in the newborn. The disease is named after Harald Hirschsprung, who first described two infants with the condition in 1888. It is characterized by the absence of ganglionic cells in the distal bowel beginning at the internal sphincter and extending proximally for varying distances. The aganglionosis is confined to the rectosigmoid in 80% of patients. HD occurs in about one in 5,000 Japanese children. The most accepted theory of the cause of HD is a defect in the craniocaudal migration of neuroblasts originating from the neural crest which occurs during the first 10 weeks of gestation, as proposed by Okamoto in 1967. The RET protooncogene accounts for the highest proportion of both familial and sporadic cases. Diagnostic techniques involve anorectal manometry, barium enema, and rectal biopsy. The treatment of HD consists of surgical removal (resection) of the abnormal section of the colon, followed by reanastomosis. Definitive surgery for HD has been performed for many years using one of the techniques developed by Swenson, Duhamel, or Soave. Recently, minimally invasive laparoscopic procedures have been introduced for the treatment of HD. PMID:25702510

Fukuzawa, Masahiro

2014-11-01

186

Bidirectional Translational Research: Progress in Understanding Addictive Diseases  

PubMed Central

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

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

2009-01-01

187

A Network Diffusion Model of Disease Progression in Dementia  

PubMed Central

SUMMARY 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

Raj, Ashish; Kuceyeski, Amy; Weiner, Michael

2013-01-01

188

Prion protein polymorphisms affect chronic wasting disease progression.  

PubMed

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

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

2011-01-01

189

Prion Protein Polymorphisms Affect Chronic Wasting Disease Progression  

PubMed Central

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

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

2011-01-01

190

Serum microRNA-125a-5p, a useful biomarker in liver diseases, correlates with disease progression.  

PubMed

It has been demonstrated that liver microRNA-125a-5p (miR-125a-5p) is correlated with disease progression in different liver diseases, including liver fibrosis and hepatocellular carcinoma (HCC). The present study investigated whether serum miR?125a?5p correlated with the progression of different liver diseases. Serum samples were obtained from healthy individuals, patients with chronic hepatitis B who had undergone a liver biopsy, and patients with HCC and were analyzed for the levels of miR?125a?5p. Compared with the healthy controls, the serum levels of miR?125a?5p were significantly higher in the liver fibrosis serum, and were reduced in HCC. With the development of liver fibrosis, there was a significant increase in the expression of miR?125a?5p (P<0.05). In comparing histological activity index (HAI) scores, higher expression levels of miR?125a?5p were observed in the high HAI score group (P<0.05). Furthermore, correlation between serum miR?125a?5p and viral replication (P<0.001) was observed. Notably, miR?125a?5p demonstrated significant correlation with other markers in the liver fibrosis group (P<0.001). In the patients with HCC, lower serum levels of miR?125a?5p were correlated with a poor prognosis, determined by Kaplan?Meier curve analysis (P=0.009). In the liver fibrosis and HCC groups, different expression levels of serum miR?125a?5p were observed, and were correlated with disease progression. The results of the present study suggested that serum miR-125a-5p may be used as a non?invasive biomarker for monitoring disease progression in liver diseases. PMID:25815788

Zheng, Jianjian; Zhou, Zhenxu; Xu, Ziqiang; Li, Guojun; Dong, Peihong; Chen, Zhanguo; Lin, Dezhao; Chen, Bicheng; Yu, Fujun

2015-07-01

191

Clinical and laboratory markers of autosomal dominant polycystic kidney disease (ADPKD) progression: an overview.  

PubMed

Autosomal dominant polycystic kidney (ADPKD) is the most common inherited renal cystic disease and it occurs in all races, the reported prevalence is between 1:400 and 1:1000. It is characterized by development of cysts in both kidneys and progressive renal function loss. Among most Autosomal Dominant Polycystic Kidney patients, renal function remains intact until the fourth decade of life. It is very important to identify early markers of disease progression to recognize patients with a worse prognosis. The aim of this study is to review the clinical and laboratory markers of ADPKD progression. The early clinical parameters evaluated seem to be directly correlated with the volume of the cysts that determine the kidney volume. From a clinical point of view, total kidney volume (TKV) appears to be the best marker of early ADPKD progression. This review evaluated several ADPKD progression markers comparing the early consolidated clinical and the new promising laboratory indicators. From a laboratory point of view, copeptin has a potential role between the serum biomarkers of ADPKD progression. However, further studies are necessary to validate the potential predictive value of its serum level and to adopt it for routine use. The combination of biomarkers could probably predict ADPKD progression with more accuracy than the use of a single biomarker. PMID:25300895

Corradi, V; Gastaldon, F; Virzì, G M; Caprara, C; Martino, F; Ronco, C

2015-02-01

192

Dispositional optimism and the mechanisms by which it predicts slower disease progression in HIV: proactive behavior, avoidant coping, and depression  

Microsoft Academic Search

The issue of whether optimism may prospectively protect against disease progression is one that has generated much interest,\\u000a with mixed results in the literature. The purpose of this study was to determine whether dispositional optimism predicts slower\\u000a disease progression in HIV. Two indicators of disease progression, CD4 counts and viral load, were assessed over 2 years in\\u000a a diverse group

Gail Ironson; Elizabeth Balbin; Rick Stuetzle; Mary Ann Fletcher; Conall O’Cleirigh; J. P. Laurenceau; Neil Schneiderman; George Solomon

2005-01-01

193

The utility of cerebral blood flow imaging in patients with the unique syndrome of progressive dementia with motor neuron disease  

SciTech Connect

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.

Ohnishi, T.; Hoshi, H.; Jinnouchi, S.; Nagamachi, S.; Watanabe, K.; Mituyama, Y. (Miyazaki Medical College (Japan))

1990-05-01

194

Urine Protein Analysis and Correlation of Urinary Biomarkers with Renal Disease Progression in Dogs with X-Linked Hereditary Nephropathy  

E-print Network

URINE PROTEIN ANALYSIS AND CORRELATION OF URINARY BIOMARKERS WITH RENAL DISEASE PROGRESSION IN DOGS WITH X-LINKED HEREDITARY NEPHROPATHY A Dissertation by MARY B. NABITY Submitted to the Office of Graduate Studies of Texas A... with Renal Disease Progression in Dogs with X-Linked Hereditary Nephropathy Copyright 2010 Mary B. Nabity URINE PROTEIN ANALYSIS AND CORRELATION OF URINARY BIOMARKERS WITH RENAL DISEASE PROGRESSION IN DOGS WITH X-LINKED HEREDITARY NEPHROPATHY A...

Nabity, Mary B.

2012-02-14

195

Assessment of threatened flora susceptibility to Phytophthora cinnamomi by analysis of disease progress curves in shadehouse and natural environments  

Microsoft Academic Search

Disease progress curves were evaluated for the assessment of the susceptibility of the flora of the South-West Botanical Province\\u000a of Western Australia threatened by Phytophthora cinnamomi infection. Disease progress was analysed with the logistic model because this model describes numerous observed disease progress\\u000a curves. In addition, the three logistic model parameters, upper asymptote (Kmax), lag time (t1\\/2K) and intrinsic rate

B. L. Shearer; C. E. Crane; S. Barrett; A. Cochrane

2007-01-01

196

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

PubMed Central

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

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

2014-01-01

197

Postradiation imaging changes in the CNS: how can we differentiate between treatment effect and disease progression?  

PubMed Central

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

Walker, Amanda J; Ruzevick, Jake; Malayeri, Ashkan A; Rigamonti, Daniele; Lim, Michael; Redmond, Kristin J; Kleinberg, Lawrence

2015-01-01

198

Branched chain amino acid metabolism profiles in progressive human nonalcoholic fatty liver disease.  

PubMed

Nonalcoholic fatty liver disease (NAFLD) is a globally widespread disease of increasing clinical significance. The pathological progression of the disease from simple steatosis to nonalcoholic steatohepatitis (NASH) has been well defined, however, the contribution of altered branched chain amino acid metabolomic profiles to the progression of NAFLD is not known. The three BCAAs: leucine, isoleucine and valine are known to mediate activation of several important hepatic metabolic signaling pathways ranging from insulin signaling to glucose regulation. The purpose of this study is to profile changes in hepatic BCAA metabolite levels with transcriptomic changes in the progression of human NAFLD to discover novel mechanisms of disease progression. Metabolomic and transcriptomic data sets representing the spectrum of human NAFLD (normal, steatosis, NASH fatty, and NASH not fatty livers) were utilized for this study. During the transition from steatosis to NASH, increases in the levels of leucine (127 % of normal), isoleucine (139 %), and valine (147 %) were observed. Carnitine metabolites also exhibited significantly elevated profiles in NASH fatty and NASH not fatty samples and included propionyl, hexanoyl, lauryl, acetyl and butyryl carnitine. Amino acid and BCAA metabolism gene sets were significantly enriched among downregulated genes during NASH. These cumulative alterations in BCAA metabolite and amino acid metabolism gene profiles represent adaptive physiological responses to disease-induced hepatic stress in NASH patients. PMID:25534430

Lake, April D; Novak, Petr; Shipkova, Petia; Aranibar, Nelly; Robertson, Donald G; Reily, Michael D; Lehman-McKeeman, Lois D; Vaillancourt, Richard R; Cherrington, Nathan J

2015-03-01

199

Minimally invasive treatment of Peyronie's disease: evidence-based progress.  

PubMed

Peyronie's disease (PD) is often physically and psychologically devastating for patients, and the goal of treatment is to improve symptoms and sexual function without adding treatment-related morbidity. The potential for treatment-related morbidity after more invasive interventions, e.g. surgery, creates a need for effective minimally invasive treatments. We critically examined the available literature using levels of evidence to determine the reported support for each treatment. Most available minimally invasive treatments lack critical support for effectiveness due to the absence of randomised, placebo-controlled trials (RCTs) or non-significant results after RCTs. Iontophoresis, oral therapies (vitamin E, potassium para-aminobenzoate, tamoxifen, carnitine, and colchicine), extracorporeal shockwave therapy, and intralesional injection with verapamil or nicardipine have shown mixed or negative results. Treatments that have decreased penile curvature deformity in Level 1 or Level 2 evidence-based, placebo-controlled studies include intralesional injection with interferon ?-2b or collagenase clostridium histolyticum. PMID:24447536

Jordan, Gerald H; Carson, Culley C; Lipshultz, Larry I

2014-07-01

200

Apoptosis as a Mechanism for Liver Disease Progression  

PubMed Central

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

Guicciardi, Maria Eugenia; Gores, Gregory J.

2011-01-01

201

Hepatic inflammation and progressive liver fibrosis in chronic liver disease  

PubMed Central

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

Czaja, Albert J

2014-01-01

202

Progress on conformal microwave array applicators for heating chestwall disease  

NASA Astrophysics Data System (ADS)

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.

Stauffer, P. R.; Maccarini, P. F.; Juang, T.; Jacobsen, S. K.; Gaeta, C. J.; Schlorff, J. L.; Milligan, A. J.

2007-02-01

203

Connections between vascular calcification and progression of chronic kidney disease: Therapeutic alternatives  

Microsoft Academic Search

Connections between vascular calcification and progression of chronic kidney disease: Therapeutic alternatives We have shown that renal injury and chronic kidney disease (CKD) directly inhibit skeletal anabolism, and that stimulation of bone formation decreases the serum phosphate. Most recently, these observations were rediscovered in low-density lipoprotein receptor null mice fed high-fat\\/cholesterol diets, a model of the metabolic syndrome (hypertension, obesity,

KEITH A HRUSKA; SURESH MATHEW; MATTHEW M DAVIES; RICHARD R LUND

2005-01-01

204

Progression of relapsing-remitting demyelinating disease does not require increased TCR affinity or epitope spread.  

PubMed

In this study, we investigate the basis of T cell recognition of myelin that governs the progression from acute symptoms into disease remission, relapse, and chronic progression in a secondary progressive model of demyelinating disease. Until now, the frequency and affinity of myelin-reactive CD4 T cells that elicit relapsing-remitting disease have not been quantified. The micropipette adhesion frequency assay was used to obtain a sensitive and physiologically relevant two-dimensional measurement of frequency and TCR affinity for myelin, as the inherent low affinity does not allow the use of specific peptide:MHC-II tetramers for this purpose. We found the highest affinity and frequency of polyclonal myelin oligodendrocyte glycoprotein-reactive cells infiltrate the CNS during acute disease, whereas affinities during remission, relapse, and chronic disease are not significantly different from each other. Frequency analysis revealed that the vast majority of CNS-infiltrating CD4 T cells are myelin oligodendrocyte glycoprotein reactive at all time points, demonstrating epitope spread is not a predominant factor for disease progression. Furthermore, time points at which mice were symptomatic were characterized by an infiltration of Th17 cells in the CNS, whereas symptom remission showed an enrichment of cells producing IFN-?. Also, the ratio of regulatory T cells to Foxp3(-) CD4 T cells was significantly higher in the CNS at remission than during acute disease. The results of this study indicate that a high frequency of T cells specific for a single myelin Ag, rather than increased TCR affinity or epitope spread, governs the transition from acute symptoms through remission, relapse, and chronic disease states. PMID:25267971

Kersh, Anna E; Edwards, Lindsay J; Evavold, Brian D

2014-11-01

205

Dyslipidemia and progression of cardiovascular calcification (CVC) in patients with end-stage renal disease (ESRD)  

Microsoft Academic Search

Dyslipidemia and progression of cardiovascular calcification (CVC) in patients with end-stage renal disease (ESRD).Cardiovascular calcification (CVC) is commonly encountered both in the general population as well as in patients with end-stage renal disease (ESRD). The etiology of CVC in patients with ESRD is multifactorial. Despite that, current debate remains narrowly focused on the role of calcium loading from calcium-based phosphate

Wajeh Y. Qunibi

2005-01-01

206

Proton magnetic resonance spectroscopic imaging in progressive supranuclear palsy, Parkinson's disease and corticobasal degeneration  

Microsoft Academic Search

Summary We used proton magnetic resonance spectroscopic imaging semiovale, and significantly reduced NA\\/Cho in the lentiform nucleus and parietal cortex. There were no significant (1H-MRSI) to assess the in vivo cortical and subcortical differences between Parkinson's disease patients and control neuronal involvement in progressive supranuclear palsy, subjects, or between patients groups in any individual region Parkinson's disease and corticobasal degeneration.

G. Tedeschi; I. Litvan; S. Bonavita; A. Bertolino; N. Lundbom; N. J. Patronas; M. Hallett

1997-01-01

207

Renal Parenchymal Hypoxia, Hypoxia Response and the Progression of Chronic Kidney Disease  

Microsoft Academic Search

Renal parenchymal hypoxia, documented under a variety of clinical conditions, conceivably contributes to the progression chronic kidney disease. In this review, normal physiologic medullary hypoxia and abnormal profiles of renal pO2 in chronic kidney diseases are presented, and the mechanisms leading to anomalous renal tissue oxygenation are discussed. Direct measurements of pO2 with oxygen electrodes, immunostaining with pimonidazole (which binds

Samuel N. Heyman; Mogher Khamaisi; Seymour Rosen; Christian Rosenberger

2008-01-01

208

HCV Genome-Wide Genetic Analyses in Context of Disease Progression and Hepatocellular Carcinoma  

PubMed Central

Hepatitis C virus (HCV) is a major cause of hepatitis and hepatocellular carcinoma (HCC) world-wide. Most HCV patients have relatively stable disease, but approximately 25% have progressive disease that often terminates in liver failure or HCC. HCV is highly variable genetically, with seven genotypes and multiple subtypes per genotype. This variation affects HCV’s sensitivity to antiviral therapy and has been implicated to contribute to differences in disease. We sequenced the complete viral coding capacity for 107 HCV genotype 1 isolates to determine whether genetic variation between independent HCV isolates is associated with the rate of disease progression or development of HCC. Consensus sequences were determined by sequencing RT-PCR products from serum or plasma. Positions of amino acid conservation, amino acid diversity patterns, selection pressures, and genome-wide patterns of amino acid covariance were assessed in context of the clinical phenotypes. A few positions were found where the amino acid distributions or degree of positive selection differed between in the HCC and cirrhotic sequences. All other assessments of viral genetic variation and HCC failed to yield significant associations. Sequences from patients with slow disease progression were under a greater degree of positive selection than sequences from rapid progressors, but all other analyses comparing HCV from rapid and slow disease progressors were statistically insignificant. The failure to observe distinct sequence differences associated with disease progression or HCC employing methods that previously revealed strong associations with the outcome of interferon ?-based therapy implies that variable ability of HCV to modulate interferon responses is not a dominant cause for differential pathology among HCV patients. This lack of significant associations also implies that host and/or environmental factors are the major causes of differential disease presentation in HCV patients. PMID:25079603

Donlin, Maureen J.; Lomonosova, Elena; Kiss, Alexi; Cheng, Xiaohong; Cao, Feng; Curto, Teresa M.; Di Bisceglie, Adrian; Tavis, John E.

2014-01-01

209

Genetic Deficiency of Complement Component 3 Does Not Alter Disease Progression in a Mouse Model of Huntington's Disease.  

PubMed

Several genes and proteins of the complement cascade are present at elevated levels in brains of patients with Huntington's disease (HD). The complement cascade is well characterized as an effector arm of the immune system, and in the brain it is important for developmental synapse elimination. We hypothesized that increased levels of complement in HD brains contributes to disease progression, perhaps by contributing to synapse elimination or inflammatory signaling. We tested this hypothesis in the R6/2 mouse model of HD by crossing mice deficient in complement component 3 (C3), a crucial complement protein found at increased levels in HD brains, to R6/2 mice and monitoring behavioral and neuropathological disease progression. We found no alterations in multiple behavioral assays, weight or survival in R6/2 mice lacking C3. We also quantified the expression of several complement cascade genes in R6/2 brains and found that the large scale upregulation of complement genes observed in HD brains is not mirrored in R6/2 brains. These data show that C3 deficiency does not alter disease progression in the R6/2 mouse model of HD. PMID:23097680

Larkin, Paul B; Muchowski, Paul J

2012-01-01

210

Genetic Deficiency of Complement Component 3 Does Not Alter Disease Progression in a Mouse Model of Huntington's Disease  

PubMed Central

Several genes and proteins of the complement cascade are present at elevated levels in brains of patients with Huntington's disease (HD). The complement cascade is well characterized as an effector arm of the immune system, and in the brain it is important for developmental synapse elimination. We hypothesized that increased levels of complement in HD brains contributes to disease progression, perhaps by contributing to synapse elimination or inflammatory signaling. We tested this hypothesis in the R6/2 mouse model of HD by crossing mice deficient in complement component 3 (C3), a crucial complement protein found at increased levels in HD brains, to R6/2 mice and monitoring behavioral and neuropathological disease progression. We found no alterations in multiple behavioral assays, weight or survival in R6/2 mice lacking C3. We also quantified the expression of several complement cascade genes in R6/2 brains and found that the large scale upregulation of complement genes observed in HD brains is not mirrored in R6/2 brains. These data show that C3 deficiency does not alter disease progression in the R6/2 mouse model of HD. PMID:23097680

Larkin, Paul B.; Muchowski, Paul J.

2012-01-01

211

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

PubMed

Immunological responses may contribute to disease progression and clinical heterogeneity in neurodegenerative dementia, for example, Alzheimer's disease (AD) and Creutzfeldt-Jakob disease (CJD). Recently, a rapidly progressive form of AD (rpAD) has been described. On neuropathological grounds classical AD and rpAD are not distinguishable at present. All those protein aggregopathies show a state of chronic inflammation with microglia activation and production of proinflammatory cytokines. In this context, it is hypothesized that the severity of the surrounding inflammation substantially contributes to disease progression and accelerated disease courses as seen in rpAD. PMID:25315814

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

2014-01-01

212

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

PubMed Central

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

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

213

The tubulointerstitium in progressive diabetic kidney disease: More than an aftermath of glomerular injury?  

Microsoft Academic Search

The tubulointerstitium in progressive diabetic kidney disease: More than an aftermath of glomerular injury?Although the glomerulus, particularly the mesangium, has been the focus of intense investigation in diabetes, tubulointerstitial injury is also a major feature of diabetic nephropathy and an important predictor of renal dysfunction. The renal tubule in diabetes is subject to both direct and indirect pathogenetic influences as

Richard E. Gilbert; Mark E. Cooper

1999-01-01

214

Matrix metalloproteinases and matrix receptors in progression and reversal of kidney disease: therapeutic perspectives  

Microsoft Academic Search

Remodeling of extracellular matrix (ECM) is a key event in progression and reversal of kidney disease. This process results from synthesis of ECM components and their degradation, mostly by matrix metalloproteinases (MMPs). However, because of both the multiplicity of their targets that include non-matrix substrates, and the complexity of their regulation, MMPs may exert different, and even opposite, effects during

Pierre Ronco; Christos Chatziantoniou

2008-01-01

215

Chronic hypoxia as a mechanism of progression of chronic kidney diseases: from hypothesis to novel therapeutics  

Microsoft Academic Search

In chronic kidney disease, functional impairment correlates with tubulointerstitial fibrosis characterised by inflammation, accumulation of extracellular matrix, tubular atrophy and rarefaction of peritubular capillaries. Loss of the microvasculature implies a hypoxic milieu and suggested an important role for hypoxia when the “chronic hypoxia hypothesis” was proposed a decade ago as an explanation for the progressive nature of fibrosis. Recent data

Leon G Fine; Jill T Norman

2008-01-01

216

The Functional Transitions Model: Maximizing Ability in the Context of Progressive Disability Associated with Alzheimer's Disease  

ERIC Educational Resources Information Center

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…

Slaughter, Susan; Bankes, Jane

2007-01-01

217

Brain Substrates of Learning and Retention in Mild Cognitive Impairment Diagnosis and Progression to Alzheimer's Disease  

ERIC Educational Resources Information Center

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)…

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

218

Chemokine Receptor CCR1: A New Target for Progressive Kidney Disease  

Microsoft Academic Search

Infiltrating leukocytes are thought to contribute to the progression of kidney disease. Locally produced chemokines guide circulating leukocytes into the kidney, which renders therapeutic blockade of respective chemokine receptors on the leukocyte surface as potential targets for the inhibition of renal leukocyte recruitment. By using mutant mice and specific antagonists, we found that chemokine receptor CCR1 has non-redundant functions for

Volha Ninichuk; Hans-Joachim Anders

2005-01-01

219

ACE inhibition reduces glomerulosclerosis and regenerates glomerular tissue in a model of progressive renal disease  

Microsoft Academic Search

Today angiotensin II inhibition is primarily used to slow the rate of progression of kidney diseases. There is evidence that these therapies can induce a partial regression of glomerular lesions. However, we do not know yet the extent of sclerotic lesion regression and whether new glomerular tissue is formed to help support the renal function. We used male Munich Wistar

A Remuzzi; E Gagliardini; F Sangalli; M Bonomelli; M Piccinelli; A Benigni; G Remuzzi

2006-01-01

220

Influence of social support on progression of coronary artery disease in women  

Microsoft Academic Search

There is strong and consistent evidence across numerous studies that social isolation or lack of social support is an independent risk factor for incident coronary heart disease. However, the impact of social isolation or lack of social support on the progression of coronary atherosclerosis in women has not been well documented. Among 292 women, aged 30–65 years, consecutively hospitalized with

Hui-Xin Wang; Murray A. Mittleman; Kristina Orth-Gomer

2005-01-01

221

Category and Letter Fluency in Semantic Dementia, Primary Progressive Aphasia, and Alzheimer's Disease  

ERIC Educational Resources Information Center

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…

Marczinski, Cecile A.; Kertesz, Andrew

2006-01-01

222

Assessment of neuroimaging techniques as biomarkers of the progression of Parkinson's disease  

Microsoft Academic Search

A major goal of research in Parkinson's disease (PD) has been the development of treatments to slow the progressive degeneration of the nigrostriatal dopaminergic system and to reduce the functional decline of patients. Because of the uncertainty in the ability of the clinical evaluation to reflect the status of the nigrostriatal dopaminergic system once dopaminergic therapy has commenced, investigators in

D. J Brooks; K. A Frey; K. L Marek; D Oakes; D Paty; R Prentice; C. W Shults; A. J Stoessl

2003-01-01

223

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

Microsoft Academic Search

Major clinical features and global measures were systematically evaluated and compared in progressive supranu- clear 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 pa- tients with this disorder from PD. For PSP,

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

2006-01-01

224

Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most frequent cause of dementia, affecting more than 5% of the population over the age 65 years. In  

E-print Network

, Parkinson's disease, diabetes, etc but with very limited success. However, the power of stem cells shouldAlzheimer's disease (AD) is a progressive neurodegenerative disease and the most frequent cause of dementia, affecting more than 5% of the population over the age 65 years. In Alzheimer's disease

Giri, Ranjit K.

225

Rapid Disease Progression With Delay in Treatment of Non-Small-Cell Lung Cancer  

SciTech Connect

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.

Mohammed, Nasiruddin [Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI (United States); Kestin, Larry Llyn, E-mail: lkestin@beaumont.ed [Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI (United States); Grills, Inga Siiner; Battu, Madhu; Fitch, Dwight Lamar [Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI (United States); Wong, Ching-yee Oliver [Department of Nuclear Medicine, William Beaumont Hospital, Royal Oak, MI (United States); Margolis, Jeffrey Harold [Department of Medical Oncology, William Beaumont Hospital, Royal Oak, MI (United States); Chmielewski, Gary William; Welsh, Robert James [Department of Thoracic Surgery, William Beaumont Hospital, Royal Oak, MI (United States)

2011-02-01

226

Altered neuronal nitric oxide synthase expression contributes to disease progression in Huntington’s disease transgenic mice  

Microsoft Academic Search

Reduced neuronal NOS (nNOS) expression and biochemical activity was found in the striatum (P<0.05) and cerebellum P<0.05) of late-stage R6\\/1 Huntington’s disease (HD) mice. The changes in NOS biochemical activity correlated with body weight (P<0.001), abnormal clasping (P<0.05) and motor functioning (P<0.05) scores. HD transgenic mice missing both copies of the nNOS gene showed accelerated disease progression relative to HD

A. Wallace Deckel; Vinsee Tang; Diane Nuttal; Keith Gary; Robert Elder

2002-01-01

227

Features of cell death in brain and liver, the target tissues of progressive neuronal degeneration of childhood with liver disease (Alpers-Huttenlocher disease)  

Microsoft Academic Search

Alpers-Huttenlocher disease (AHD) is a rare encephalopathy of infancy and childhood characterized by myoclonic seizures and progressive neurological deterioration, usually associated with signs and symptoms of liver dysfunction. There is no biological marker of the disease, and ultimate diagnosis still relies on pathological examination. Features of clinical progression and pathological findings suggest AHD to be secondary to a genetically determined

Alessandro Simonati; Massimiliano Filosto; Chiara Savio; Giuliano Tomelleri; Paola Tonin; Bernardo Dalla Bernardina; Nicolo' Rizzuto

2003-01-01

228

Endothelial Activation Biomarkers Increase after HIV-1 Acquisition: Plasma VCAM-1 Predicts Disease Progression  

PubMed Central

Objective We aimed to determine whether endothelial activation biomarkers increase after HIV-1 acquisition, and whether biomarker levels measured in chronic infection would predict disease progression and death in HIV-1 seroconverters. Design HIV-1-seronegative Kenyan women were monitored monthly for seroconversion, and followed prospectively after HIV-1 acquisition. Methods Plasma levels of angiopoietins-1 and -2 (ANG-1, ANG-2) and soluble vascular cell adhesion marker-1 (VCAM-1), intercellular adhesion marker-1 (ICAM-1), and E-selectin were tested in stored samples from before infection, acute infection, and at two points during chronic infection. We used non-parametric tests to compare biomarkers before and after HIV-1 acquisition, and Cox proportional-hazards regression to analyze associations with disease progression (CD4 <200 cells/?L, Stage IV disease, or ART initiation) or death. Results Soluble ICAM-1 and VCAM-1 were elevated relative to baseline in all post-infection periods assessed (p<0.0001). Soluble E-selectin and the ANG-2:ANG-1 ratio increased in acute infection (p=0.0001), and ANG-1 decreased in chronic infection (p=0.0004). Among 228 subjects followed over 1,028 person-years, 115 experienced disease progression or death. Plasma VCAM-1 levels measured during chronic infection were independently associated with time to HIV progression or death (aHR 5.36, 95% confidence interval 1.99–14.44 per log10 increase), after adjustment for set point plasma viral load, age at infection, and soluble ICAM-1 levels. Conclusions HIV-1 acquisition was associated with endothelial activation, with sustained elevations of soluble ICAM-1 and VCAM-1 post-infection. Soluble VCAM-1 may be an informative biomarker for predicting the risk of HIV-1 disease progression, morbidity, and mortality. PMID:23807276

GRAHAM, Susan M.; RAJWANS, Nimerta; JAOKO, Walter; ESTAMBALE, Benson B.A.; MCCLELLAND, R. Scott; OVERBAUGH, Julie; LILES, W. Conrad

2013-01-01

229

Quantitative evaluation of disease progression in a longitudinal mild cognitive impairment cohort.  

PubMed

Several neuropsychological tests and biomarkers of Alzheimer's disease (AD) have been validated and their evolution over time has been explored. In this study, multiple heterogeneous predictors of AD were combined using a supervised learning method called Disease State Index (DSI). The behavior of DSI values over time was examined to study disease progression quantitatively in a mild cognitive impairment (MCI) cohort. The DSI method was applied to longitudinal data from 140 MCI cases that progressed to AD and 149 MCI cases that did not progress to AD during the follow-up. The data included neuropsychological tests, brain volumes from magnetic resonance imaging, cerebrospinal fluid samples, and apolipoprotein E from the Alzheimer's Disease Neuroimaging Initiative database. Linear regression of the longitudinal DSI values (including the DSI value at the point of MCI to AD conversion) was performed for each subject having at least three DSI values available (147 non-converters, 126 converters). Converters had five times higher slopes and almost three times higher intercepts than non-converters. Two subgroups were found in the group of non-converters: one group with stable DSI values over time and another group with clearly increasing DSI values suggesting possible progression to AD in the future. The regression parameters differentiated between the converters and the non-converters with classification accuracy of 76.9% for the slopes and 74.6% for the intercepts. In conclusion, this study demonstrated that quantifying longitudinal patient data using the DSI method provides valid information for follow-up of disease progression and support for decision making. PMID:24121959

Runtti, Hilkka; Mattila, Jussi; van Gils, Mark; Koikkalainen, Juha; Soininen, Hilkka; Lötjönen, Jyrki

2014-01-01

230

Assembly and interrogation of Alzheimer's disease genetic networks reveal novel regulators of progression.  

PubMed

Alzheimer's disease (AD) is a complex multifactorial disorder with poorly characterized pathogenesis. Our understanding of this disease would thus benefit from an approach that addresses this complexity by elucidating the regulatory networks that are dysregulated in the neural compartment of AD patients, across distinct brain regions. Here, we use a Systems Biology (SB) approach, which has been highly successful in the dissection of cancer related phenotypes, to reverse engineer the transcriptional regulation layer of human neuronal cells and interrogate it to infer candidate Master Regulators (MRs) responsible for disease progression. Analysis of gene expression profiles from laser-captured neurons from AD and controls subjects, using the Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe), yielded an interactome consisting of 488,353 transcription-factor/target interactions. Interrogation of this interactome, using the Master Regulator INference algorithm (MARINa), identified an unbiased set of candidate MRs causally responsible for regulating the transcriptional signature of AD progression. Experimental assays in autopsy-derived human brain tissue showed that three of the top candidate MRs (YY1, p300 and ZMYM3) are indeed biochemically and histopathologically dysregulated in AD brains compared to controls. Our results additionally implicate p53 and loss of acetylation homeostasis in the neurodegenerative process. This study suggests that an integrative, SB approach can be applied to AD and other neurodegenerative diseases, and provide significant novel insight on the disease progression. PMID:25781952

Aubry, Soline; Shin, William; Crary, John F; Lefort, Roger; Qureshi, Yasir H; Lefebvre, Celine; Califano, Andrea; Shelanski, Michael L

2015-01-01

231

Utility of quantitative ultrasound for tracking the progression of polycystic kidney disease  

NASA Astrophysics Data System (ADS)

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.

Hall, Timothy J.; Khant, Htet A.; Insana, Michael F.; Wood, John G.; Zhu, Yanning; Preston, David; Cowley, Benjamin D.

2000-04-01

232

Inflammatory risk factors and pathologies promoting Alzheimer's disease progression: is RAGE the key?  

PubMed

Epidemiological studies reveal growing evidence that most cases of Alzheimer`s Disease (AD) likely involve a combination of genetic and environmental risk factors. Identifying and validating these risk factors remains one of the most critical scientific challenges. Several diseases appear to have strong implications for neurodegeneration leading to dementia. This risk encompasses different forms of cardiovascular disease, carotid atherosclerosis, history of hypertension or high cholesterol, Type II diabetes, stroke or transient ischemic attack and brain trauma. However, the molecular pathways that are common and central in the progression of these diseases and AD are not yet elucidated. Unveiling these critical mechanisms at the molecular level is necessary for the development of therapeutic strategies aimed at preventing AD progression. The Receptor for Advanced Glycation Endproducts (RAGE) plays a key role in all the diseases that represent a risk for AD. RAGE-mediated signaling also contributes to neurodegeneration in AD, suggesting that it may mediate the effect of risk factors in promoting AD. We will summarize the current knowledge on the role of RAGE in pathologies promoting AD and in AD progression. We will also provide evidence showing the relevance of RAGE-induced inflammation as a risk pathway that is implicated in AD pathophysiology. PMID:25014735

Matrone, Carmela; Djelloul, Mehdi; Taglialatela, Giulio; Perrone, Lorena

2015-02-01

233

Assembly and Interrogation of Alzheimer’s Disease Genetic Networks Reveal Novel Regulators of Progression  

PubMed Central

Alzheimer’s disease (AD) is a complex multifactorial disorder with poorly characterized pathogenesis. Our understanding of this disease would thus benefit from an approach that addresses this complexity by elucidating the regulatory networks that are dysregulated in the neural compartment of AD patients, across distinct brain regions. Here, we use a Systems Biology (SB) approach, which has been highly successful in the dissection of cancer related phenotypes, to reverse engineer the transcriptional regulation layer of human neuronal cells and interrogate it to infer candidate Master Regulators (MRs) responsible for disease progression. Analysis of gene expression profiles from laser-captured neurons from AD and controls subjects, using the Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe), yielded an interactome consisting of 488,353 transcription-factor/target interactions. Interrogation of this interactome, using the Master Regulator INference algorithm (MARINa), identified an unbiased set of candidate MRs causally responsible for regulating the transcriptional signature of AD progression. Experimental assays in autopsy-derived human brain tissue showed that three of the top candidate MRs (YY1, p300 and ZMYM3) are indeed biochemically and histopathologically dysregulated in AD brains compared to controls. Our results additionally implicate p53 and loss of acetylation homeostasis in the neurodegenerative process. This study suggests that an integrative, SB approach can be applied to AD and other neurodegenerative diseases, and provide significant novel insight on the disease progression. PMID:25781952

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

2015-01-01

234

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

PubMed

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

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

2014-11-24

235

Long-term outcome of enzyme-replacement therapy in advanced Fabry disease: evidence for disease progression towards serious complications  

PubMed Central

Objective The long-term effects of enzyme-replacement therapy (ERT) in Fabry disease are unknown. Thus, the aim of this study was to determine whether ERT in patients with advanced Fabry disease affects progression towards ‘hard’ clinical end-points in comparison with the natural course of the disease. Methods A total of 40 patients with genetically proven Fabry disease (mean age 40 ± 9 years; n = 9 women) were treated prospectively with ERT for 6 years. In addition, 40 subjects from the Fabry Registry, matched for age, sex, chronic kidney disease stage and previous transient ischaemic attack (TIA), served as a comparison group. The main outcome was a composite of stroke, end-stage renal disease (ESRD) and death. Secondary outcomes included changes in myocardial left ventricular (LV) wall thickness and replacement fibrosis, change in glomerular filtration rate (GFR), new TIA and change in neuropathic pain. Results During a median follow-up of 6.0 years (bottom and top quartiles: 5.1, 7.2), 15 events occurred in 13 patients (n = 7 deaths, n = 4 cases of ESRD and n = 4 strokes). Sudden death occurred (n = 6) only in patients with documented ventricular tachycardia and myocardial replacement fibrosis. The annual progression of myocardial LV fibrosis in the entire cohort was 0.6 ± 0.7%. As a result, posterior end-diastolic wall thinning was observed (baseline, 13.2 ± 2.0 mm; follow-up, 11.4 ± 2.1 mm; P < 0.01). GFR decreased by 2.3 ± 4.6 mL min?1 per year. Three patients experienced a TIA. The major clinical symptom was neuropathic pain (n = 37), and this symptom improved in 25 patients. The event rate was not different between the ERT group and the untreated (natural history) group of the Fabry Registry. Conclusion Despite ERT, clinically meaningful events including sudden cardiac death continue to develop in patients with advanced Fabry disease. PMID:23586858

Weidemann, F; Niemann, M; Störk, S; Breunig, F; Beer, M; Sommer, C; Herrmann, S; Ertl, G; Wanner, C

2013-01-01

236

Dependence of reversibility and progression of mouse neuronopathic Gaucher disease on acid ?-glucosidase residual activity levels  

PubMed Central

Genetic and chemically induced neuronopathic mouse models of Gaucher disease were developed to facilitate understanding of the reversibility and/or progression of CNS involvement. The lethality of the skin permeability barrier defect of the complete gene knock out [gba, (glucocerebrosidase) GCase] was avoided by conditional reactivation of a low activity allele (D409H) in keratinocytes (kn-9H). In kn-9H mice, progressive CNS disease and massive glucosylceramide storage in tissues led to death from CNS involvement by the age of 14 days. Conduritol B epoxide (CBE, a covalent inhibitor of GCase) treatment (for 8–12 days) of wild type, D409H, D409V or V394L homozygotes recapitulated the CNS phenotype of the kn-9H mice with seizures, tail arching, shaking, tremor, quadriparesis, extensive neuronal degeneration loss and apoptosis, and death by the age of 14 days. Minor CNS abnormalities occurred after daily CBE injections of 100 mg/kg/day for 6 doses, but neuronal degeneration was progressive and glucosylceramide storage persisted in D409V homozygotes in the 2 to 5 months after CBE cessation; wild type and D409H mice had persistent neurological damage without progression. The persistent CNS deterioration, histologic abnormalities, and glucosylceramide storage in the CBE-treated D409V mice revealed a threshold level of GCase activity necessary for the prevention of progression of CNS involvement. PMID:18346921

Xu, You-Hai; Reboulet, Rachel; Quinn, Brian; Huelsken, Joerg; Witte, David; Grabowski, Gregory A.

2008-01-01

237

The Relationship between Uric Acid Levels and Huntington’s Disease Progression  

PubMed Central

Uric acid (UA) may be associated with the progression of Parkinson’s disease and related neurodegenerative conditions; however, its association with Huntington’s disease (HD) progression has not been explored. A secondary analysis of 347 subjects from the CARE-HD clinical trial was performed to examine the relationship between baseline UA levels and the level of functional decline in HD. Outcomes included change in scores at 30 months for the Unified Huntington’s Disease Rating Scale components. There was less worsening of total functional capacity over time with increasing baseline UA levels (adjusted mean worsening in scores: 3.17, 2.99, 2.95, 2.28, 2.21, from lowest to highest UA quintile, p=0.03). These data suggest a possible association between higher UA levels and slower HD progression, particularly as measured by total functional capacity. If confirmed, UA could be an important predictor and potentially modifiable factor affecting the rate of HD progression. PMID:20063429

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

2009-01-01

238

13q deletion anatomy and disease progression in patients with chronic lymphocytic leukemia.  

PubMed

Historically, genes targeted by recurrent chromosomal deletions have been identified within the smallest genomic region shared in all patients, the minimally deleted region (MDR). However, deletions this small do not occur in all patients and are a simplification of the impact larger heterogeneous deletions have during carcinogenesis. We use the example of 13q14 deletions in chronic lymphocytic leukemia to show that genes outside MDRs are associated with disease progression. Genomic profiling of 224 patients identified 205 copy number alterations on chromosome 13 in 132 cases. Deletions including DLEU2 were heterogeneous (845?Kb-96.2?Mb) and identified two breakpoint cluster regions within short interspersed nuclear elements proximal to DLEU2 and within long interspersed nuclear elements/L1 repeats distal to GUCY1B2. After defining a deletion class on the basis of size and location, we show that (a) at diagnosis, larger deletions (class II) were associated with a significantly increased risk of disease progression (odds ratio=12.3; P=0.005), (b) in progressive patients, class II deletions were enriched (P=0.02) and (c) this association was independent of IgVH mutational status, ZAP70 expression and ATM/TP53 deletion. Deletion of a 1?Mb gene cluster (48.2-49.2?Mb), including SETDB2, PHF11 and RCBTB1, was significantly associated (P<0.01) with disease progression. Here, we show that the deletion of genes outside MDRs can influence clinical outcome. PMID:21151023

Parker, H; Rose-Zerilli, M J J; Parker, A; Chaplin, T; Wade, R; Gardiner, A; Griffiths, M; Collins, A; Young, B D; Oscier, D G; Strefford, J C

2011-03-01

239

Early Energy Deficit in Huntington Disease: Identification of a Plasma Biomarker Traceable during Disease Progression  

Microsoft Academic Search

Huntington disease (HD) is a fatal neurodegenerative disorder, with no effective treatment. The pathogenic mechanisms underlying HD have not been elucidated, but weight loss, associated with chorea and cognitive decline, is a characteristic feature of the disease that is accessible to investigation. We, therefore, performed a multiparametric study exploring body weight and the mechanisms of its loss in 32 presymptomatic

Fanny Mochel; Perrine Charles; François Seguin; Julie Barritault; Christiane Coussieu; Laurence Perin; Yves Le Bouc; Christiane Gervais; Guislaine Carcelain; Anne Vassault; Josué Feingold; Daniel Rabier; Alexandra Durr; Ulrich Mueller

2007-01-01

240

Disease-related and drug-induced changes in dopamine transporter expression might undermine the reliability of imaging studies of disease progression in Parkinson's disease  

Microsoft Academic Search

Parkinson's disease (PD) is a progressive neurodegenerative disorder. Standard therapeutic interventions are aimed at replenishment of empty dopamine stores with levodopa or substitution with dopamine receptor agonists. However, in the long term this symptomatic therapy fails. Currently, various neuroprotective agents are being developed, with the intention to slow down the degeneration of dopaminergic neurons. In this context, the early identification

A. Winogrodzka; J. Booij; E. C. M. J. Wolters

2005-01-01

241

Vitamin-D pathway genes and HIV-1 disease progression in injection drug users.  

PubMed

Vitamin-D has pleiotropic effects on calcium and bone metabolism, cellular growth control, cell differentiation and modulation of both innate and acquired immune response. Previous studies revealed the association of vitamin-D receptor gene (VDR) polymorphism with infection diseases including HIV-1 infection. To assess for association between polymorphisms of vitamin-D pathway genes CYP27B1, vitamin-D binding protein (VDBP) and VDR with HIV-1 infection, disease progression to acquired immunodeficiency syndrome (AIDS) was analysed according to CDC93 criteria in a cohort of 185 HIV-1 seroprevalent patients belonging to the injection drug users. Genotype data was obtained from rs10877012, rs3782130 and rs4646536 markers at CYP27B1 locus; rs7041 and rs4588 at VDBP locus; and rs11568820, rs4516035, rs2228570, rs1544410 and rs17878969 at VDR locus. Distribution of genotypes between patients grouped by outcome was compared by contingency table analysis. Marker-marker interaction was assessed by a MDR analysis. Assuming an additive model for VDR markers, a Kaplan-Meier survival analysis was employed to evaluate association with disease progression. Among vitamin-D pathway genes, VDR locus reveals specific 5'UTR and 3'UTR diplotype combinations associated with both, slower and faster progression to AIDS. Marker-marker interaction analysis indicates a strong interaction between VDR markers and a redundant effect for CYP27B1 markers. According to our results, VDR locus association follows an additive model in which increased genetic risk score for the VDR is directly correlated with AIDS progression rates. Our data supports a role of vitamin-D pathway gene variability on HIV-1 disease progression. PMID:24768180

Laplana, Marina; Sánchez-de-la-Torre, Manuel; Puig, Teresa; Caruz, Antonio; Fibla, Joan

2014-07-15

242

Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease  

SciTech Connect

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.

Lake, April D. [University of Arizona, Department of Pharmacology and Toxicology, Tucson, AZ 85721 (United States); Novak, Petr [Biology Centre ASCR, Institute of Plant Molecular Biology, Ceske Budejovice 37001 (Czech Republic); Shipkova, Petia; Aranibar, Nelly; Robertson, Donald; Reily, Michael D. [Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Co., Princeton, NJ 08543 (United States); Lu, Zhenqiang [The Arizona Statistical Consulting Laboratory, University of Arizona, Tucson, AZ 85721 (United States); Lehman-McKeeman, Lois D. [Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Co., Princeton, NJ 08543 (United States); Cherrington, Nathan J., E-mail: cherrington@pharmacy.arizona.edu [University of Arizona, Department of Pharmacology and Toxicology, Tucson, AZ 85721 (United States)

2013-04-15

243

Asymptomatic spinal cord lesions predict disease progression in radiologically isolated syndrome  

PubMed Central

Background: Technological advancements in neuroimaging and the increased use of these diagnostic modalities are responsible for the discovery of incidentally identified anomalies within the CNS. In addition to the identification of unanticipated brain MRI abnormalities suggestive of demyelinating disease in patients undergoing neuroimaging for a medical reason other than evaluation for multiple sclerosis (MS), asymptomatic spinal cord lesions are periodically identified. Objective: To determine if asymptomatic spinal cord lesions are associated with clinical progression in subjects with radiologically isolated syndrome (RIS). Methods: A retrospective review of RIS cases at the University of California, San Francisco Multiple Sclerosis Center was performed. The presence of asymptomatic cervical spinal cord MRI lesions was analyzed as a potential predictor for clinical progression. Results: Twenty-five of 71 subjects with RIS possessed findings within the cervical spine that were highly suggestive of demyelinating disease. Of these subjects, 21 (84%) progressed clinically to clinically isolated syndrome (n = 19) or primary progressive multiple sclerosis (n = 2) over a median time of 1.6 years from the date of RIS identification (interquartile range 0.8–3.8). The sensitivity, specificity, and positive predictive value of an asymptomatic spinal cord lesion for subsequent development of either a first demyelinating attack or primary progressive MS were 87.5%, 91.5%, and 84%, respectively. The odds ratio of clinical progression was 75.3 (95% confidence interval 16.1–350.0, p < 0.0001). This association remained significant after adjusting for potential confounders. Conclusion: These findings suggest that the presence of asymptomatic spinal cord lesions place subjects with RIS at substantial risk for clinical conversion to either an acute or progressive event, a risk that is independent of brain lesions on MRI. PMID:21270417

Mowry, E.M.; Cree, B.A.C.; Crabtree, E.C.; Goodin, D.S.; Waubant, E.; Pelletier, D.

2011-01-01

244

Progression of autoimmune inner ear disease to labyrinthitis ossificans: Clinical and radiologic correlation.  

PubMed

We report the case of a 42-year-old man who presented with fluctuating bilateral sensorineural hearing loss that subsequently progressed to a complete hearing loss, and we describe the correlation between the clinical and radiologic features of this case. To the best of our knowledge, this is the first report to demonstrate imaging evidence of progression from autoimmune inner ear disease to labyrinthitis ossificans. This is also the first reported case of a reversal of a loss of labyrinthine CISS (constructive interference in a steady state) signal, suggesting that T2-weighted hyposignal may be attributable to an alteration in labyrinthine fluid content and not to fibrosis only. PMID:25738715

Khoo, Jenn Nee; Tan, Tiong Yong

2015-03-01

245

Progressive cortical thinning and subcortical atrophy in dementia with Lewy bodies and Alzheimer's disease  

E-print Network

MAK 1 Progressive cortical thinning and subcortical atrophy in dementia with Lewy 1 bodies and Alzheimer’s disease 2 3 Mak E1 , Su L1 , Williams GB2 , Watson R3,4 , Firbank MJ4 , Blamire AM5, O’Brien JT 4 1. 5 6 1 Department... by the Sir Jules Thorn Charitable Trust. 32 33 34 35 36 37 MAK 2 ABSTRACT 1 2 Patterns of progressive cortical thinning in dementia with Lewy bodies (DLB) 3 remains poorly understood. We examined spatiotemporal patterns of cortical thinning...

Mak, E; Williams, GB; Watson, R; Firbank, MJ; Blamire, AM; O’Brien, JT

2015-01-08

246

Disease progression model for Clinical Dementia Rating–Sum of Boxes in mild cognitive impairment and Alzheimer’s subjects from the Alzheimer’s Disease Neuroimaging Initiative  

PubMed Central

Background The objective of this analysis was to develop a nonlinear disease progression model, using an expanded set of covariates that captures the longitudinal Clinical Dementia Rating Scale–Sum of Boxes (CDR–SB) scores. These were derived from the Alzheimer’s Disease Neuroimaging Initiative ADNI-1 study, of 301 Alzheimer’s disease and mild cognitive impairment patients who were followed for 2–3 years. Methods The model describes progression rate and baseline disease score as a function of covariates. The covariates that were tested fell into five groups: a) hippocampal volume; b) serum and cerebrospinal fluid (CSF) biomarkers; c) demographics and apolipoprotein Epsilon 4 (ApoE4) allele status; d) baseline cognitive tests; and e) disease state and comedications. Results Covariates associated with baseline disease severity were disease state, hippocampal volume, and comedication use. Disease progression rate was influenced by baseline CSF biomarkers, Trail-Making Test part A score, delayed logical memory test score, and current level of impairment as measured by CDR–SB. The rate of disease progression was dependent on disease severity, with intermediate scores around the inflection point score of 10 exhibiting high disease progression rate. The CDR–SB disease progression rate in a typical patient, with late mild cognitive impairment and mild Alzheimer’s disease, was estimated to be approximately 0.5 and 1.4 points/year, respectively. Conclusions In conclusion, this model describes disease progression in terms of CDR–SB changes in patients and its dependency on novel covariates. The CSF biomarkers included in the model discriminate mild cognitive impairment subjects as progressors and nonprogressors. Therefore, the model may be utilized for optimizing study designs, through patient population enrichment and clinical trial simulations. PMID:24926196

Samtani, Mahesh N; Raghavan, Nandini; Novak, Gerald; Nandy, Partha; Narayan, Vaibhav A

2014-01-01

247

A retrospective analysis of hand tapping as a longitudinal marker of disease progression in Huntington’s disease  

PubMed Central

Background Current clinical assessments of motor function in Huntington’s Disease (HD) rely on subjective ratings such as the Unified Huntington’s 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 14 years we have routinely collected, using a simple device, the number of taps made by the right and left hand over 30 seconds 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

2014-01-01

248

Phosphodiesterase 5 inhibition at disease onset prevents experimental autoimmune encephalomyelitis progression through immunoregulatory and neuroprotective actions.  

PubMed

In addition to detrimental inflammation, widespread axon degeneration is an important feature of multiple sclerosis (MS) pathology and a major correlate for permanent clinical deficits. Thus, treatments that combine immunomodulatory and neuroprotective effects are beneficial for MS. Using myelin oligodendrocyte glycoprotein peptide 35-55 (MOG)-induced experimental autoimmune encephalomyelitis (EAE) as a model of MS, we recently showed that daily treatment with the phosphodiesterase 5 (PDE5) inhibitor sildenafil at peak disease rapidly ameliorates clinical symptoms and neuropathology (Pifarre et al., 2011). We have now investigated the immunomodulatory and neuroprotective actions of sildenafil treatment from the onset of EAE when the immune response prevails and show that early administration of the drug prevents disease progression. Ultrastructural analysis of spinal cord evidenced that sildenafil treatment preserves axons and myelin and increases the number of remyelinating axons. Immunostaining of oligodendrocytes at different stages of differentiation showed that sildenafil protects immature and mature myelinating oligodendrocytes. Brain-derived neurotrophic factor (BDNF), a recognized neuroprotectant in EAE, was up-regulated by sildenafil in immune and neural cells suggesting its implication in the beneficial effects of the drug. RNA microarray analysis of spinal cord revealed that sildenafil up-regulates YM-1, a marker of the alternative macrophage/microglial M2 phenotype that has neuroprotective and regenerative properties. Immunostaining confirmed up-regulation of YM-1 while the classical macrophage/microglial activation marker Iba-1 was down-regulated. Microarray analysis also showed a notable up-regulation of several members of the granzyme B cluster (GrBs). Immunostaining revealed expression of GrBs in Foxp3+-T regulatory cells (Tregs) suggesting a role for these proteases in sildenafil-induced suppression of T effector cells (Teffs). In vitro analysis of splenocytes from sildenafil-treated animals showed down-regulation of Th1/Th2/Th17 responses while Tregs were up-regulated. Additionally, sildenafil treatment prevented MOG-specific IgG2b accumulation in serum. Taken together these data demonstrates that daily sildenafil treatment from the initiation of EAE symptoms prevents further clinical deterioration by stimulating immunomodulatory and neuroprotective mechanisms. Importantly, we also show here that sildenafil enhances the ability of human Tregs from healthy donors to down-regulate the proliferation of Teffs in vitro, strongly supporting the potential of sildenafil for therapeutic intervention in MS. PMID:24211383

Pifarré, Paula; Gutierrez-Mecinas, María; Prado, Judith; Usero, Lorena; Roura-Mir, Carme; Giralt, Mercedes; Hidalgo, Juan; García, Agustina

2014-01-01

249

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

PubMed

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

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

2015-02-01

250

Does study partner type impact the rate of Alzheimer’s disease progression?  

PubMed Central

Most patients with Alzheimer’s disease (AD) do not have a spouse. Despite this, the majority of AD research participants enroll with a spouse study partner. It remains unclear if differences between AD patients who do and do not have a spouse may bias study results. In this study, we examined whether AD patients with different study partner types (spouse vs adult child) demonstrate different rates of disease progression over two years on three outcome measures commonly used in AD research, including clinical trials. We used data from the National Alzheimer’s Coordinating Center Uniform Data Set to examine disease progression in participants age 55–90 with probable AD dementia. We examined disease progression as measured by the Clinical Dementia Rating Scale-Sum of the Boxes score, the Mini Mental Status Examination, and the Functional Assessment Questionnaire. Analyses were performed on data for all available eligible participants from the NACC UDS and after performing a propensity-matching model to better account for inherent differences between the populations of interest. Propensity matching was successful only when models did not include age and gender. For both propensity-matched analyses and those of all available data, we did not observe any differences between the study partner populations for any outcome measure. These results suggest that, if investigators can improve in recruiting AD patients with adult child caregivers to research, the implications to study results may be minimal. PMID:23985417

Grill, Joshua D.; Zhou, Yan; Karlawish, Jason; Elashoff, David

2013-01-01

251

Ventricular enlargement as a possible measure of Alzheimer's disease progression validated using the Alzheimer's disease neuroimaging initiative database  

PubMed Central

Ventricular enlargement may be an objective and sensitive measure of neuropathological change associated with mild cognitive impairment (MCI) and Alzheimer's disease (AD), suitable to assess disease progression for multi-centre studies. This study compared (i) ventricular enlargement after six months in subjects with MCI, AD and normal elderly controls (NEC) in a multi-centre study, (ii) volumetric and cognitive changes between Apolipoprotein E genotypes, (iii) ventricular enlargement in subjects who progressed from MCI to AD, and (iv) sample sizes for multi-centre MCI and AD studies based on measures of ventricular enlargement. Three dimensional T1-weighted MRI and cognitive measures were acquired from 504 subjects (NEC n = 152, MCI n = 247 and AD n = 105) participating in the multi-centre Alzheimer's Disease Neuroimaging Initiative. Cerebral ventricular volume was quantified at baseline and after six months using semi-automated software. For the primary analysis of ventricle and neurocognitive measures, between group differences were evaluated using an analysis of covariance, and repeated measures t-tests were used for within group comparisons. For secondary analyses, all groups were dichotomized for Apolipoprotein E genotype based on the presence of an ?4 polymorphism. In addition, the MCI group was dichotomized into those individuals who progressed to a clinical diagnosis of AD, and those subjects that remained stable with MCI after six months. Group differences on neurocognitive and ventricle measures were evaluated by independent t-tests. General sample size calculations were computed for all groups derived from ventricle measurements and neurocognitive scores. The AD group had greater ventricular enlargement compared to both subjects with MCI (P = 0.0004) and NEC (P < 0.0001), and subjects with MCI had a greater rate of ventricular enlargement compared to NEC (P = 0.0001). MCI subjects that progressed to clinical AD after six months had greater ventricular enlargement than stable MCI subjects (P = 0.0270). Ventricular enlargement was different between Apolipoprotein E genotypes within the AD group (P = 0.010). The number of subjects required to demonstrate a 20% change in ventricular enlargement was substantially lower than that required to demonstrate a 20% change in cognitive scores. Ventricular enlargement represents a feasible short-term marker of disease progression in subjects with MCI and subjects with AD for multi-centre studies. PMID:18669512

Nestor, Sean M.; Rupsingh, Raul; Borrie, Michael; Smith, Matthew; Accomazzi, Vittorio; Wells, Jennie L.; Fogarty, Jennifer

2008-01-01

252

Inflammation in chronic kidney disease: role in the progression of renal and cardiovascular disease  

Microsoft Academic Search

Inflammation is the response of the vasculature or tissues to various stimuli. An acute and chronic pro-inflammatory state\\u000a exists in patients with chronic kidney disease (CKD), contributing substantially to morbidity and mortality. There are many\\u000a mediators of inflammation in adults with CKD and end-stage kidney disease (ESKD), including hypoalbuminemia\\/malnutrition,\\u000a atherosclerosis, advanced oxidation protein products, the peroxisome proliferators-activated receptor, leptin, the

Douglas M. Silverstein

2009-01-01

253

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

PubMed Central

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 (A?) 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 A? is critical to A?-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

Swomley, Aaron M.; Sultana, Rukhsana

2013-01-01

254

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

PubMed

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

Weiner, Howard L

2008-03-01

255

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

PubMed Central

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 8–22 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

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

2011-01-01

256

HIV-1 DNA predicts disease progression and post-treatment virological control.  

PubMed

In HIV-1 infection, a population of latently infected cells facilitates viral persistence despite antiretroviral therapy (ART). With the aim of identifying individuals in whom ART might induce a period of viraemic control on stopping therapy, we hypothesised that quantification of the pool of latently infected cells in primary HIV-1 infection (PHI) would predict clinical progression and viral replication following ART. We measured HIV-1 DNA in a highly characterised randomised population of individuals with PHI. We explored associations between HIV-1 DNA and immunological and virological markers of clinical progression, including viral rebound in those interrupting therapy. In multivariable analyses, HIV-1 DNA was more predictive of disease progression than plasma viral load and, at treatment interruption, predicted time to plasma virus rebound. HIV-1 DNA may help identify individuals who could safely interrupt ART in future HIV-1 eradication trials. PMID:25217531

Williams, James P; Hurst, Jacob; Stöhr, Wolfgang; Robinson, Nicola; Brown, Helen; Fisher, Martin; Kinloch, Sabine; Cooper, David; Schechter, Mauro; Tambussi, Giuseppe; Fidler, Sarah; Carrington, Mary; Babiker, Abdel; Weber, Jonathan; Koelsch, Kersten K; Kelleher, Anthony D; Phillips, Rodney E; Frater, John

2014-01-01

257

HIV-1 DNA predicts disease progression and post-treatment virological control  

PubMed Central

In HIV-1 infection, a population of latently infected cells facilitates viral persistence despite antiretroviral therapy (ART). With the aim of identifying individuals in whom ART might induce a period of viraemic control on stopping therapy, we hypothesised that quantification of the pool of latently infected cells in primary HIV-1 infection (PHI) would predict clinical progression and viral replication following ART. We measured HIV-1 DNA in a highly characterised randomised population of individuals with PHI. We explored associations between HIV-1 DNA and immunological and virological markers of clinical progression, including viral rebound in those interrupting therapy. In multivariable analyses, HIV-1 DNA was more predictive of disease progression than plasma viral load and, at treatment interruption, predicted time to plasma virus rebound. HIV-1 DNA may help identify individuals who could safely interrupt ART in future HIV-1 eradication trials. DOI: http://dx.doi.org/10.7554/eLife.03821.001 PMID:25217531

Williams, James P; Hurst, Jacob; Stöhr, Wolfgang; Robinson, Nicola; Brown, Helen; Fisher, Martin; Kinloch, Sabine; Cooper, David; Schechter, Mauro; Tambussi, Giuseppe; Fidler, Sarah; Carrington, Mary; Babiker, Abdel; Weber, Jonathan

2014-01-01

258

Disease progression by infecting HIV-1 subtype in a seroconverter cohort in sub-Saharan Africa  

PubMed Central

Objective: To describe immunologic, virologic, and clinical HIV disease progression by HIV-1 subtype among Africans with well documented estimated dates of HIV infection (EDIs). Design: Prospective cohort. Methods: Adults and youth with documented HIV-1 infection in the past 12 months were recruited from seroincidence cohorts in East and Southern Africa and followed at 3–6 month intervals. Blood for lymphocyte subset and viral load determination was collected at each visit. Pol was sequenced from the first positive specimen to ascertain subtype. Preantiretroviral therapy disease progression was measured by three time-to-event endpoints: CD4+ cell count 350?cells/?l or less, viral load measurement at least 1?×?105?copies/ml, and clinical AIDS. Results: From 2006 to 2011, 615 participants were enrolled at nine research centers in Kenya, Rwanda, South Africa, Uganda, and Zambia; 579 (94.1%) had viral subtyping completed. Predominant subtypes were C (256, 44.2%), A (209, 36.1%), and D (84, 14.5%). After adjustment for age, sex, and human leukocyte antigen alleles in Cox regression analyses, subtype C-infected participants progressed faster than subtype A to all three endpoints [CD4+ hazard ratio 1.60, 95% (confidence interval) CI 1.16, 2.20; viral load hazard ratio 1.59, 95% CI 1.12, 2.25; and AIDS hazard ratio 1.60, 95% CI 1.11, 2.31). Subtype D-infected participants reached high viral load more rapidly (hazard ratio 1.61, 95% CI 1.01, 2.57) and progressed nearly twice as fast to AIDS compared to subtype A (hazard ratio 1.93, 95% CI 1.21, 3.09). Conclusion: Subtype-specific differences in HIV disease progression suggest that the local subtype distribution be considered when planning HIV programs and designing and defining clinical endpoints for HIV prevention trials. PMID:24113395

Amornkul, Pauli N.; Karita, Etienne; Kamali, Anatoli; Rida, Wasima N.; Sanders, Eduard J.; Lakhi, Shabir; Price, Matt A.; Kilembe, William; Cormier, Emmanuel; Anzala, Omu; Latka, Mary H.; Bekker, Linda-Gail; Allen, Susan A.; Gilmour, Jill; Fast, Patricia E.

2013-01-01

259

Serum Bicarbonate Levels and the Progression of Kidney Disease: A Cohort Study  

PubMed Central

Background Animal models of kidney disease have linked metabolic acidosis with renal damage. The role of low serum bicarbonate levels in kidney disease progression in humans has not been studied. Study Design Retrospective cohort study. Setting & Participants: Adults visiting a medical clinic in the Bronx, NY from 01/01/01 to 12/31/03 were included in the study (n=5,422) and followed until 6/30/07 Predictor Serum bicarbonate levels Outcomes Kidney disease progression was defined as either a decline in the estimated glomerular filtration rate (eGFR) by 50% or reaching an eGFR of <15 ml/min/1.73m2 (n=337). Measurements Patients’ baseline demographics, comorbidities, laboratory data and socioeconomic status were recorded. Serial outpatient serum creatinines were collected (median, 5 measurements/ person). Results The mean age was 52 years, 69% were women, 45% were African-American, 31% were Hispanic, 21% had diabetes mellitus, 41% had hypertension, and 9% had a baseline eGFR <60 ml/min/1.73m2. Kidney disease progressed by the definition above in 337 patients (6.2%). Compared to the reference group (bicarbonate level 25-26 mEq/L), the hazard ratio for progression after adjustment for potential confounders was 1.54 (95% CI 1.13-2.09) for bicarbonate levels ?22 mEq/L, 0.97 (95% CI 0.70-1.35) for levels 23-24 mEq/L and 1.14 (95% CI 0.84-1.55) for levels ?27 mEq/L. (Global p-value for inclusion of serum bicarbonate in the model, 0.01). These results remained similar when using different definitions of the outcome (an eGFR decline by 30%, 1288 outcomes (24%)) or doubling of serum creatinine (268 outcomes (4.9%)). Limitations Data used in study was collected for clinical, not research, purposes. Conclusions Low serum bicarbonate is associated with the progression of kidney disease, independent of baseline eGFR and other clinical, demographic and socioeconomic factors. Prospective studies are needed to confirm this relationship and to evaluate the efficacy of alkali supplements for slowing progression. PMID:19394734

Shah, Samir N.; Abramowitz, Matthew; Hostetter, Thomas H.; Melamed, Michal L.

2015-01-01

260

Review of psychotherapeutic interventions on depression in cancer patients and their impact on disease progression.  

PubMed

Depression, ranging from mild to severe, is the most frequently found psychological symptom among individuals with cancer. Depression in cancer patients has been known to mitigate emotional distress, quality of life, adherence to medical treatment, and overall health outcomes. Specifically, depression has been associated with impaired immune response and with poorer survival in patients with cancer. Various studies have found that psychotherapeutic interventions are effective in reducing symptoms of depression, which in turn could affect disease progression and mortality. This paper provides updated information on psychotherapeutic interventions geared towards cancer patients suffering from depressive disorders, and its impact on disease progression. PubMed, Cochrane Library database, PsycINFO and PsycARTICLES databases were searched from January 1980 through August 2013 using key words: psychotherapy, treatment, oncology, cancer, psycho-oncology, psychosocial issues, psychosocial stress, depression, mood disorder, and psychoneuroimmunology. PMID:24716499

Barrera, Ingrid; Spiegel, David

2014-02-01

261

Do BRAF inhibitors select for populations with different disease progression kinetics?  

PubMed Central

Ipilimumab, an anti-CTLA-4 monoclonal antibody, has been shown to improve overall survival in patients with metastatic melanoma. Preliminary data suggest that patients who fail BRAF inhibitor treatment experience a very rapid progression of disease. Such selectivity for more rapid disease progression may mean these patients do not receive the same benefit from subsequent treatment with ipilimumab as patients without prior BRAF inhibitor treatment. The current challenge is focused on how to identify and approach the two populations of fast and slow progressors and recent hypothesis suggest that treatment choice could be guided by baseline risk factors. However, no data have yet defined which the best sequence is and more research is needed to identify predictors of response in patients with metastatic melanoma to help guide whether a BRAF inhibitor or ipilimumab should be used first in sequential therapy. PMID:23497384

2013-01-01

262

Gut Microbiota in HIV Infection: Implication for Disease Progression and Management  

PubMed Central

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

Nwosu, Felix Chinweije; Avershina, Ekaterina; Wilson, Robert; Rudi, Knut

2014-01-01

263

The role of renin-angiotensin-aldosterone system in the progression of chronic kidney disease  

Microsoft Academic Search

The role of renin-angiotensin-aldosterone system in the progression of chronic kidney disease The renin-angiotensin-aldosterone system (RAAS) is a well known regulator of blood pressure (BP) and determinant of target-organ damage. It controls fluid and electrolyte balance through coordinated effects on the heart, blood vessels, and Kidneys. Angiotensin II (AII) is the main effector of the RAAS and exerts its vasoconstrictor

GIUSEPPE REMUZZI; NORBERTO PERICO; MANUEL MACIA; PIERO RUGGENENTI

2005-01-01

264

Mass General study finds transition in cell type parallels treatment response, disease progression in breast cancer  

Cancer.gov

A process that normally occurs in developing embryos – the changing of one basic cell type into another – has also been suspected of playing a role in cancer metastasis. Now a study from researchers at the Massachusetts General Hospital Cancer Center, a component of the Dana-Farber Cancer Institute, has associated this process, called epithelial-mesenchymal transition or EMT, with disease progression and treatment response in breast cancer patients. The report also identifies underlying mechanisms that someday may become therapeutic targets.

265

Neurofibrillary tangles in Alzheimer's disease and progressive supranuclear palsy: antigenic similarities and differences  

Microsoft Academic Search

The antigenic profile of neurofibrillary tangles (NFT) in Alzheimer's disease (AD), senile dementia of Alzheimer type (SDAT), progressive supranuclear palsy (PSP) and in non-demented aged humans was investigated by light and electron microscopic immunocytochemistry using antisera and monoclonal antibodies to tubulin, microtubule-associated proteins (MAP1, MAP2 and tau), neurofilament proteins and determinants unique to Alzheimer paired helical filaments (PHF). Antibodies to

C. Bancher; H. Lassmann; H. Budka; I. Grundke-Iqbal; K. Iqbal; G. Wiche; F. Seitelberger; H. M. Wisniewski

1987-01-01

266

Progress in peripheral nerve disease research in the last two years.  

PubMed

Peripheral nerve disorders have been a Cinderella subspecialty for neurologists because of the limited treatment options and difficulties in obtaining a genetic diagnosis. In the last decade, there has been great progress in the management of patients with peripheral nerve disease. In this paper, we review a selection of diagnostic and therapeutic papers in this area published in the Journal of Neurology over the last 24 months. PMID:24154508

Evans, Matthew; Manji, Hadi

2013-12-01

267

Serum Cholesterol and the Progression of Parkinson's Disease: Results from DATATOP  

Microsoft Academic Search

BackgroundRecent studies have suggested that higher serum cholesterol may be associated with lower occurrence of Parkinson's disease (PD). This study is to test the hypothesis that higher serum cholesterol correlates with slower PD progression.MethodsBaseline non-fasting serum total cholesterol was measured in 774 of the 800 subjects with early PD enrolled between 1987 and 1988 in the Deprenyl and Tocopherol Antioxidative

Xuemei Huang; Peggy Auinger; Shirley Eberly; David Oakes; Michael Schwarzschild; Alberto Ascherio; Richard Mailman; Honglei Chen

2011-01-01

268

Characterization of Progressive Motor Deficits in Mice Transgenic for the Human Huntington's Disease Mutation  

Microsoft Academic Search

Transgenic mice expressing exon 1 of the human Huntington's disease (HD) gene carrying a 141-157 CAG repeat (line R6\\/2) develop a progressive neurological phenotype with motor symptoms resembling those seen in HD. We have character- ized the motor deficits in R6\\/2 mice using a battery of behav- ioral tests selected to measure motor aspects of swimming, fore- and hindlimb coordination,

Rebecca J. Carter; Lisa A. Lione; Trevor Humby; Laura Mangiarini; Amarbirpal Mahal; Gillian P. Bates; Stephen B. Dunnett; A. Jennifer Morton

1999-01-01

269

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

PubMed

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

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

2015-03-01

270

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

USGS Publications Warehouse

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.

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

2001-01-01

271

The APOE locus advances disease progression in late onset familial Alzheimer`s disease but is not causative  

SciTech Connect

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.

Crawford, F.; Bennett, C.; Osborne, A. [Univ. of South Florida, Tampa, FL (United States)] [and others

1994-09-01

272

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

PubMed

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

Trias, Emiliano; Díaz-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

273

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

PubMed

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

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

2009-11-01

274

Emergent early markers of renal progression in autosomal-dominant polycystic kidney disease patients: implications for prevention and treatment.  

PubMed

Autosomal-dominant polycystic kidney disease (ADPKD) is the most common single cause of end-stage renal disease after diabetes, hypertension and glomerulonephritis. The clinical course of ADPKD is highly variable. Even with optimal care and therapy monitoring, currently the progression of ADPKD is slowed but not stopped. Newer treatments will no doubt become available in the future, but their side effect profiles will always need to be considered. Therefore, markers to distinguish ADPKD patients with a poor versus a good prognosis will be helpful. Several risk factors influencing kidney disease progression in ADPKD have been identified in the current era. The present review will discuss the spectrum of early markers of ADPKD renal disease progression. Specifically, the volume of total kidney, hypertension, glomerular hyperfiltration, renal blood flow, microalbuminuria, uric acid, and urinary molecular markers will be discussed. On this background, implications for the prevention and treatment of kidney disease progression in ADPKD are also discussed. PMID:22846584

Helal, Imed; Reed, Berenice; Schrier, Robert W

2012-01-01

275

Postural reactions to soleus muscle vibration in Parkinson's disease: Scaling deteriorates as disease progresses  

Microsoft Academic Search

Previous research has shown that Parkinson's disease (PD) patients, especially those with postural instability, respond hyperactively to visual, vestibular, and neck proprioceptive sensory manipulation. To determine if this impairment of the sensory information scaling holds true for the lower leg proprioceptive system, we studied postural responses to mechanical vibration (which affects the muscle spindle Ia afferents) applied to the soleus

Peter Valkovi?; Siegbert Krafczyk; Kai Bötzel

2006-01-01

276

Temporal Profile of the Renal Transcriptome of HIV-1 Transgenic Mice during Disease Progression  

PubMed Central

Profiling of temporal changes of gene expression in the same kidney over the course of renal disease progression is challenging because repeat renal biopsies are rarely indicated in clinical practice. Here, we profiled the temporal change in renal transcriptome of HIV-1 transgenic mice (Tg26), an animal model for human HIV-associated nephropathy (HIVAN), and their littermates at three different time points (4, 8, and 12 weeks of age) representing early, middle, and late stages of renal disease by serial kidney biopsy. We analyzed both static levels of gene expression at three stages of disease and dynamic changes in gene expression between different stages. Analysis of static and dynamic changes in gene expression revealed that up-regulated genes at the early and middle stages are mostly involved in immune response and inflammation, whereas down-regulated genes mostly related to fatty acid and retinoid metabolisms. We validated the expression of a selected panel of genes that are up-regulated at the early stage (CCL2, CCL5, CXCL11, Ubd, Anxa1, and Spon1) by real-time PCR. Among these up-regulated genes, Spon1, which is a previously identified candidate gene for hypertension, was found to be up-regulated in kidney of human with diabetic nephropathy. Immunostaining of human biopsy samples demonstrated that protein expression of Spon1 was also markedly increased in kidneys of patients with both early and late HIVAN and diabetic nephropathy. Our studies suggest that analysis of both static and dynamic changes of gene expression profiles in disease progression avails another layer of information that could be utilized to gain a more comprehensive understanding of disease progression and identify potential biomarkers and drug targets. PMID:24667548

Fan, Ying; Wei, Chengguo; Xiao, Wenzhen; Zhang, Weijia; Wang, Niansong; Chuang, Peter Y.; He, John Cijiang

2014-01-01

277

Pharmacokinetic-Pharmacodynamic Disease Progression Model for Effect of Etanercept in Lewis Rats with Collagen-Induced Arthritis  

Microsoft Academic Search

Purpose  To develop a pharmacokinetic-pharmacodynamic disease progression (PK\\/PD\\/DIS) model to characterize the effect of etanercept\\u000a in collagen-induced arthritis (CIA) rats on rheumatoid arthritis (RA) progression.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  The CIA rats received either 5 mg\\/kg intravenous (IV), 1 mg\\/kg IV, or 5 mg\\/kg subcutaneous (SC) etanercept at day 21 post-disease\\u000a induction. Effect on disease progression was measured by paw swelling. Plasma concentrations of etanercept

Hoi-Kei Lon; Dongyang Liu; Qi Zhang; Debra C. DuBois; Richard R. Almon; William J. Jusko

2011-01-01

278

The fundamental role of mechanical properties in the progression of cancer disease and inflammation  

NASA Astrophysics Data System (ADS)

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.

Mierke, Claudia Tanja

2014-07-01

279

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

PubMed

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

González-Domínguez, Raúl; García-Barrera, Tamara; Gómez-Ariza, José Luis

2014-02-01

280

Effect of Intrastriatal Mesenchymal Stromal Cell Injection on Progression of a Murine Model of Krabbe Disease  

PubMed Central

One of a family of devastating lysosomal storage disorders, Krabbe disease is characterized by demyelination, psychosine accumulation, and inflammation. Affected infants rarely survive longer than two years. Using the twitcher mouse model of the disease, this study evaluated the potential of intrastriatal injection of adipose or bone marrow-derived mesenchymal stromal cells (MSCs) as a treatment option. Neonatal pups were injected with MSCs at 3–4 days of age and subjected to a battery of behavioral tests beginning at 15 days. While MSC injection failed to increase lifespan of twitchers, improvements in rotarod performance and twitching severity were observed at 27–38 days of age using MSCs derived from bone marrow. This study tested several different tasks developed in adult mice for evaluation of disease progression in immature twitchers. Rotarod was both reliable and extremely sensitive. Automated gait analysis using the Treadscan program was also useful for early evaluation of differences prior to overt gait dysfunction. Finally, this study represents the first use of the Stone T-maze in immature mice. Validation of rotarod and automated gait analysis for detection of subtle differences in disease progression is important for early stage efforts to develop treatments for juvenile disorders. PMID:21840342

Wicks, Shawna E.; Londot, Heaven E.; Zhang, Bo; Dowden, Jennifer; Klopf-Eiermann, Jessica; Fisher-Perkins, Jeanne M.; Trygg, Cynthia B.; Scruggs, Brittni A.; Zhang, Xiujuan; Gimble, Jeffrey M.; Bunnell, Bruce A.; Pistell, Paul J.

2011-01-01

281

Markers of and risk factors for the development and progression of diabetic kidney disease.  

PubMed

Diabetic kidney disease (DKD) occurs in 25%-40% of patients with diabetes. Given the dual problems of a significant risk of progression from DKD to end-stage renal disease (ESRD) and increased cardiovascular morbidity and mortality, it is important to identify patients at risk of DKD and ESRD and initiate protective renal and cardiovascular therapies. The importance of preventive therapy is emphasized further by worldwide increases in the incidence of diabetes. This review summarizes the evidence regarding the prognostic value and benefits of targeting established and novel risk markers for DKD development and progression. Family history of DKD, smoking history, and glycemic, blood pressure, and plasma lipid level control are established factors for identifying people at greatest risk of DKD development and progression. Absolute albumin excretion rate (AER) and glomerular filtration rate (GFR) measurements also are important, although AER categorization generally lacks the necessary specificity and sensitivity, and estimates of declining GFR are compromised by methodological limitations for GFRs in the normal-to-high range. Emerging risk markers for progressive loss of kidney function include markers of oxidation and inflammation, profibrotic cytokines, uric acid, advanced glycation end products, functional and structural markers of vascular dysfunction, kidney structural changes, and tubular biomarkers. Among these, the most promising are serum uric acid and soluble tumor necrosis factor receptor (type 1 and type 2) levels, especially in relation to GFR changes. At present, these can only be considered as risk markers because they only identify an individual at increased risk of progressive DKD and not necessarily related to the causal pathway promoting kidney damage. Further work is needed to establish whether modulating these factors improves the prognosis in DKD. Although change in urinary peptidome levels also is a promising marker, there currently is neither a clinical assay nor adequate studies defining its prognostic value. Until these or other novel markers become available for clinical use, predictive accuracy often may be increased with greater attention to established markers. PMID:24461729

Macisaac, Richard J; Ekinci, Elif I; Jerums, George

2014-02-01

282

A longitudinal study of CEACAM1 expression in melanoma disease progression.  

PubMed

The present study characterized the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) expression profile in a longitudinal study during melanoma progression, in lesions obtained from the same patients: a primary skin lesion, a lymph node and a distant metastasis. The present study is expected to increase our understanding of the expression patterns of CEACAM1 in melanoma development. We identified 20 patients who could be analyzed for CEACAM1 expression over the course of disease progression. The pathology blocks were cut, and two slides were generated for each specimen. One underwent standard hematoxylin and eosin (H&E) staining and a corresponding slide underwent immunohistochemical staining for the detection of CEACAM1. For 13 patients who were able to be followed up serially from primary lesion, lymph node and distant metastasis, a borderline significant increase in the staining of the membrane was noted (P=0.06). In contrast, there was no equivalent increase in cytoplasmic CEACAM1 in the same group of patients. For the cohort of 20 patients with primary and distant metastasis, a significant increase in the membrane staining was noted (P=0.026) and again, no equivalent significant increase in cytoplasmic staining was observed. We report that CEACAM1 expression increases along the course of disease development and progression of a patient. CEACAM1 represents a novel area of research which may have profound influence in future methods of harnessing cellular immunity to combat this disease. The results of the present study confirm that CEACAM1 is potentially an extremely useful target in arresting melanoma progression. PMID:25573088

Zippel, Douglas; Barlev, Hani; Ortenberg, Rona; Barshack, Iris; Schachter, Jacob; Markel, Gal

2015-03-01

283

Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism  

PubMed Central

Progressive HIV infection is characterized by dysregulation of the intestinal immune barrier, translocation of immunostimulatory microbial products, and chronic systemic inflammation that is thought to drive progression of disease to AIDS. Elements of this pathologic process persist despite viral suppression during highly active antiretroviral therapy (HAART) and drivers of these phenomena remain poorly understood. Disrupted intestinal immunity can precipitate dysbiosis that induces chronic inflammation in the mucosa and periphery of mice. However, putative microbial drivers of HIV-associated immunopathology versus recovery have not been identified in humans. Using high-resolution bacterial community profiling, we identified a dysbiotic mucosal-adherent community enriched in Proteobacteria and depleted of Bacteroidia members that was associated with markers of mucosal immune disruption, T cell activation, and chronic inflammation in HIV-infected subjects. Furthermore, this dysbiosis was evident among HIV-infected subjects undergoing HAART, and the extent of dysbiosis correlated with activity of the kynurenine pathway of tryptophan metabolism and plasma concentrations of the inflammatory cytokine interleukin-6 (IL-6), two established markers of disease progression. Gut-resident bacteria with capacity to metabolize tryptophan through the kynurenine pathway were found to be enriched in HIV-infected subjects, strongly correlated with kynurenine levels in HIV-infected subjects, and capable of kynurenine production in vitro. These observations demonstrate a link between mucosal-adherent colonic bacteria and immunopathogenesis during progressive HIV infection, which is apparent even in the setting of viral suppression during HAART. This link suggests that gut-resident microbial populations may influence intestinal homeostasis during HIV disease. PMID:23843452

Vujkovic-Cvijin, Ivan; Dunham, Richard M.; Iwai, Shoko; Maher, M. Cyrus; Albright, Rebecca G.; Broadhurst, Mara J.; Hernandez, Ryan D.; Lederman, Michael M.; Huang, Yong; Somsouk, Ma; Deeks, Steven G.; Hunt, Peter W.; Lynch, Susan V.; McCune, Joseph M.

2014-01-01

284

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

PubMed Central

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-?1 (TGF-?1). 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-?, 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 ?-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 ?-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-?1 and decreased expression of VDR and Klotho protein observed in VDD+IRI animals. Conclusion Through inflammatory pathways and involvement of TGF-?1 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

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

285

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

PubMed Central

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 1.76–4.55), to Stage 2 (HR 8.06, 95% CI 4.91–13.2), to Stage 3 (HR 23.5, 95% CI 13.7–40.1) (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

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

2013-01-01

286

Research progress on flavonoids isolated from traditional Chinese medicine in treatment of Alzheimer's disease  

PubMed Central

Summary Alzheimer's disease (AD) is a severe condition in aging countries. The currently used drugs including donepezil, rivastigmine, galantamine, and memantine are effective in managing the symptoms. However, they are hardly capable of preventing, halting, or reversing the disease. In the long history of development of traditional Chinese medicine, much experience has accumulated and is summarized in treatment of diseases that correspond to the concept of AD. In recent years, exploration of natural active ingredients from medicinal herbs for treatment of AD has attracted substantial attention. Some flavonoids have been revealed to have a variety of biological actions such as scavenging free radicals, inhibiting neuron apoptosis, and nurturing neuronal cells that constitute the basis for treatment of AD. In this article, we review recent research progress on flavonoids isolated from traditional Chinese medicine against AD and their underlying mechanisms. PMID:25343094

Gao, Jianjun; Inagaki, Yoshinori; Liu, Yang

2013-01-01

287

[Overweight and obesity--risk factors in the development and progression of renal disease].  

PubMed

Overweight/obesity represent an underestimated risk factor of renal disease. The incidence of obesity-related glomerulopathy (ORG) tremendously increased within the last decade. The first sign of renal damage in overweight conditions is microalbuminuria or proteinuria, indicating the potential risk of its progression to renal insufficiency and the development of premature cardiovascular events. In the early stage of obesity renal hemodynamics are characterized by a renal hypercirculation and glomerular hyperfiltration, particularly in the presence of hypertension. The hyperfiltration is especially harmful in patients with pre-existing inflammatory and metabolic renal disease, or under the conditions of reduced renal mass. Histopathologically, ORG is characterized by glomerulomegaly with/without signs of focal segmental glomerulosclerosis. Pathogenetically, numerous factors are involved, e.g. enhanced glomerular capillary pressure, adrenergic nerve overactivity, inappropriate activation of the renin-angiotensin-aldosterone system, insulin resistance, hyperinsulinemia and hyperleptinemia, dyslipidemia, enhanced clotting tendency and sodium retention. Diabetic nephropathy is one of the most serious complications of obesity-induced diabetes. In the industrial nations type 2 diabetes is the single most frequent cause of end-stage renal disease. After kidney transplantation, overweight/obesity is associated with a less favourable prognosis for the survival of the graft and the patient. Incidence of renal cell carcinomas is enhanced in overweight/obesity. Obesity-related renal disease may be prevented/postponed by an early weight reduction, by dietary intervention combined with physical exercise. In the advanced stages of renal disease benefits of weight reduction are minimal. Concomitant administration of angiotensin-converting-enzyme inhibitors or angiotensin II receptor 1 blockers exerts antiproteinuric effects and thereby aid in retarding the disease progression. Aimed prevention and treatment of obesity represent a challenge for the healthcare system. The concerted action of physicians, patients and the public health authorities is needed. PMID:15323263

Sebeková, K; Klassen, A; Bahner, U; Heidland, A

2004-07-01

288

Helminthic infection and the risk of neurologic disease progression in HTLV-1  

PubMed Central

Background Infection with the human T-cell lymphotropic virus, type 1 (HTLV-1) has been associated with an increased Th1 response. Interestingly, a higher prevalence of helminthic coinfection has been observed among infected individuals, and subsequent modulation of the immune response typically associated with helminths may influence clinical outcomes among HTLV-1 coinfected individuals. Objective This study was conducted to elucidate the association between helminthic coinfection and the development of clinically characterized neurologic disease that occurs in HTLV-1 infection. Study design In a cohort analysis, incidence of HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) was recorded. Incidence of clinical outcomes and disease-free survival of several neurologic outcomes associated with HTLV-1 were estimated using the Kaplan–Meier method with log-rank tests. The relationships between helminthic infection and risk of HTLV-1 neurologic outcomes were assessed by Cox proportional hazard modeling. Results Seventy-four coinfected and 79 non-coinfected patients were followed, with 92 helminthic infections observed in the coinfected group. One patient per group developed HAM/TSP and the risk of progression to neurologic disease outcomes did not differ among those with and without helminthic coinfection (p > 0.45). A significant difference was noted in the prevalence of neurologic disease outcomes among all patients at the conclusion of the study (p < 0.01). Conclusions These data suggest that treated helminthic infection does not affect risk of development of neurologic disease in HTLV-1 infection, and reinforce that treatment of helminths does not adversely affect patients with HTLV-1. Importantly, among all patients, an overall progression of neurologic disease was observed. PMID:22237002

Sundberg, Michael A.; Costa, Davi; Orge, Gloria; Castro, Néviton M.; Muniz, André; Glesby, Marshall J.; Carvalho, Edgar M.

2012-01-01

289

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

PubMed Central

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 Förster 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

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

2013-01-01

290

Pharmacological Treatment of Alzheimer’s Disease: Is it Progressing Adequately?  

PubMed Central

Introduction: Between 1993 and 2000 four acetylcholinesterase inhibitors were marketed as a symptomatic treatment for Alzheimer’s 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 disease’s 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 disease’s 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

Robles, Alfredo

2009-01-01

291

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

PubMed Central

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 ?0.05 ± 0.21 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

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

2015-01-01

292

Accelerated Disease Progression after Discontinuation of Sorafenib in a Patient with Metastatic Papillary Thyroid Cancer  

PubMed Central

Distant metastases from papillary thyroid carcinoma (PTC) are rare and are associated with a poor prognosis. Here, we describe a patient with metastatic PTC who was treated with a tyrosine kinase inhibitor (TKI, sorafenib) for several months that was acutely exacerbated by discontinuation. A 43-year-old male was diagnosed with PTC in February 2004 and underwent total thyroidectomy followed by two courses of high-dose radioactive iodine (RAI) therapy. Despite two additional courses of high-dose RAI therapy, lung and muscle metastases were developed. Treatment with sorafenib was begun in September 2010. After 11 months treatment of sorafenib, newly developed metastatic lesions were found in mediastinal lymph nodes, liver, and bones. Considered as treatment failure, the administration of sorafenib was discontinued. Two weeks after sorafenib treatment was stopped, the disease progressed abruptly and caused death of the patient by respiratory failure. In our patient, PTC progressed rapidly after the cessation of sorafenib treatment. Patients with several other types of cancer have also experienced such rapid disease progression, termed "flare-ups." Physicians should be aware that flare-ups may occur in advanced PTC patients following the cessation of TKI therapy. PMID:25309799

Yun, Kyung-Jin; Kim, Woohyeon; Kim, Eun Hee; Lim, Dong-Jun; Kang, Moo-Il; Cha, Bong-Yun

2014-01-01

293

Cerebrospinal fluid ?-synuclein predicts cognitive decline in Parkinson disease progression in the DATATOP cohort.  

PubMed

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 -0.05 ± 0.21 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

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

2014-04-01

294

Short Communication: Fc Gamma Receptors IIa and IIIa Genetic Polymorphisms Do Not Predict HIV-1 Disease Progression in Kenyan Women.  

PubMed

Genetic polymorphisms of the Fc gamma receptors (Fc?R) IIa and IIIa have been implicated in the rate of HIV-1 disease progression, but results are inconsistent. We aimed to determine the association between these polymorphisms and disease progression in a cohort of HIV-1 seroconverters from Mombasa, Kenya. Neither Fc?RIIa nor Fc?RIIIa genotypes were predictive of set point viral load, viral load increase, CD4 decline, or HIV-1 disease progression (time to CD4 count <200 cells/mm(3), death, or treatment initiation). Our results suggest that Fc?R polymorphisms might not be an important indicator of viral control and disease progression in this population. PMID:25312792

Weis, Julie F; McClelland, R Scott; Jaoko, Walter; Mandaliya, Kishor N; Overbaugh, Julie; Graham, Susan M

2015-03-01

295

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...

296

MR of brain involvement in progressive facial hemiatrophy (Romberg disease): Reconsideration of a syndrome  

SciTech Connect

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.

Terstegge, K.; Hosten, N. (Universitaetsklinikum Rudolf Virchow, Berlin (Germany)); Kunath, B. (Klinik und Poliklinik fuer Neurologie, Dresden (Germany)); Felber, S.; Henkes, H. (Universitaetskliniken der Universitaet Homburg (Germany)); Speciali, J.G. (Universidade de Sao Paolo (Brazil))

1994-01-01

297

Potential Drugs and Methods for Preventing or Delaying the Progression of Huntington’s Disease  

PubMed Central

Huntington’s disease (HD) is an autosomal dominant inherited and progressive neurodegenerative disorder with motor dysfunction and cognitive deficits. Although, there are no treatments to delay the appearance and the progression of HD, there are potential drugs currently in preclinical and clinical trials that are focused on HD therapy. The signaling pathways involved in HD are not yet clearly elucidated; however, expression of mutant huntingtin protein is considered a key factor in the induction and/or progression of HD. The demonstration that the onset and progression of HD in models of transgenic mice, in particular, are delayed or improved by the application of neurotrophic factors has emphasized their importance in neuroprotection in HD. In addition, other compounds targeting the HD gene or mutant huntingtin protein are currently in preclinical and clinical testing and may show promising neuroprotective effects. There are current patented drugs that are currently being considered as potential therapeutics for HD. These patented drugs may provide promising therapy for HD. PMID:21585328

Sari, Youssef

2012-01-01

298

Predicting the Impact of CD8+ T Cell Polyfunctionality on HIV Disease Progression  

PubMed Central

ABSTRACT During the chronic phase of HIV-1 infection, polyfunctional CD8+ T cell responses, which are characterized by a high frequency of cells able to secrete multiple cytokines simultaneously, are associated with lower virus loads and slower disease progression. This relationship may arise for different reasons. Polyfunctional responses may simply be stronger. Alternatively, it could be that the increased functional diversity in polyfunctional responses leads to lower virus loads and slower disease progression. Lastly, polyfunctional responses could contain more CD8+ T cells that mediate a specific key function that is primarily responsible for viral control. Disentangling the influences of overall strength, functional diversity, and specific function on viral control and disease progression is very relevant for the rational design of vaccines and immunotherapy using cellular immune responses. We developed a mathematical model to study how polyfunctional CD8+ T cell responses mediating lytic and nonlytic effector functions affect the CD4+ T cell count and plasma viral load. We based our model on in vitro data on the efficacy of gamma interferon (IFN-?) and macrophage inflammatory protein 1? (MIP-1?)/RANTES against HIV. We find that the strength of the response is a good predictor of disease progression, while functional diversity has only a minor influence. In addition, our model predicts for realistic levels of cytotoxicity that immune responses dominated by nonlytic effector functions most positively influence disease outcome. IMPORTANCE It is an open question in HIV research why polyfunctional CD8+ T cell responses are associated with better viral control, while individual functional correlates of protection have not been identified so far. Identifying the role of CD8+ T cells in HIV-1 infection has important implications for the potential development of effective T cell-based vaccines. Our analysis provides new ways to think about a causative role of CD8+ T cells by studying different hypotheses regarding why polyfunctional CD8+ T cells might be more advantageous. We identify measurements that have to be obtained in order to evaluate the role of CD8+ T cells in HIV-1 infection. In addition, our method shows how individual cell functionality data can be used in population-based virus dynamics models. PMID:24965450

Regoes, Roland R.

2014-01-01

299

Associations of Extracranial Carotid Atherosclerosis Progression With Coronary Status and Risk Factors in Patients With and Without Coronary Artery Disease  

Microsoft Academic Search

Background—Intimal medial thickness of the extracranial carotid arteries (IMT) is related to coronary artery disease (CAD) and CAD risk factors. Few studies have explored the association of risk factors with progression of IMT, and none have evaluated their associations with IMT progression specifically in patients with and without CAD. Methods and Results—We used coronary angiography to identify 280 patients equally

John R. Crouse III; Rong Tang; Mark A. Espeland; James G. Terry; Timothy Morgan; Michele Mercuri

300

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

NASA Astrophysics Data System (ADS)

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, 30.5°C) 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 30.5°C/high-light treatment and least (3.2 mm d-1) in the 28°C/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.

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

2011-09-01

301

Elevated sphingosine-1-phosphate promotes sickling and sickle cell disease progression  

PubMed Central

Sphingosine-1-phosphate (S1P) is a bioactive lipid that regulates multicellular functions through interactions with its receptors on cell surfaces. S1P is enriched and stored in erythrocytes; however, it is not clear whether alterations in S1P are involved in the prevalent and debilitating hemolytic disorder sickle cell disease (SCD). Here, using metabolomic screening, we found that S1P is highly elevated in the blood of mice and humans with SCD. In murine models of SCD, we demonstrated that elevated erythrocyte sphingosine kinase 1 (SPHK1) underlies sickling and disease progression by increasing S1P levels in the blood. Additionally, we observed elevated SPHK1 activity in erythrocytes and increased S1P in blood collected from patients with SCD and demonstrated a direct impact of elevated SPHK1-mediated production of S1P on sickling that was independent of S1P receptor activation in isolated erythrocytes. Together, our findings provide insights into erythrocyte pathophysiology, revealing that a SPHK1-mediated elevation of S1P contributes to sickling and promotes disease progression, and highlight potential therapeutic opportunities for SCD. PMID:24837436

Zhang, Yujin; Berka, Vladimir; Song, Anren; Sun, Kaiqi; Wang, Wei; Zhang, Weiru; Ning, Chen; Li, Chonghua; Zhang, Qibo; Bogdanov, Mikhail; Alexander, Danny C.; Milburn, Michael V.; Ahmed, Mostafa H.; Lin, Han; Idowu, Modupe; Zhang, Jun; Kato, Gregory J.; Abdulmalik, Osheiza Y.; Zhang, Wenzheng; Dowhan, William; Kellems, Rodney E.; Zhang, Pumin; Jin, Jianping; Safo, Martin; Tsai, Ah-Lim; Juneja, Harinder S.; Xia, Yang

2014-01-01

302

Do Positive Psychosocial Factors Predict Disease Progression in HIV-1? A Review of the Evidence  

PubMed Central

Adding to a traditional stress perspective, behavioral medicine has been focusing increasingly on investigating the potential impact of positive psychosocial factors on disease course in HIV. Dispositional optimism, active coping, and spirituality show the most evidence for predicting slower disease progression, although the data are not entirely consistent. Findings for the role of social support are mixed, although indications are that it may be particularly helpful at later stages of illness. Many of the other constructs (positive affect, finding meaning, emotional expression/processing, openness, extraversion, conscientiousness, altruism, and self-efficacy) have only been examined in one or two studies; results are preliminary but suggestive of protective effects. Plausible behavioral and biological mechanisms are discussed (including health behaviors, neurohormones, and immune measures) as well as suggestions for clinicians, limitations, future directions, and a discussion of whether these constructs can be changed. In conclusion, investigating the importance and usefulness of positive psychosocial factors in predicting disease progression in HIV is in its beginning scientific stages and shows good initial evidence and future promise. PMID:18541905

Ironson, Gail H.; Hayward, H’sien

2008-01-01

303

Elevated sphingosine-1-phosphate promotes sickling and sickle cell disease progression.  

PubMed

Sphingosine-1-phosphate (S1P) is a bioactive lipid that regulates multicellular functions through interactions with its receptors on cell surfaces. S1P is enriched and stored in erythrocytes; however, it is not clear whether alterations in S1P are involved in the prevalent and debilitating hemolytic disorder sickle cell disease (SCD). Here, using metabolomic screening, we found that S1P is highly elevated in the blood of mice and humans with SCD. In murine models of SCD, we demonstrated that elevated erythrocyte sphingosine kinase 1 (SPHK1) underlies sickling and disease progression by increasing S1P levels in the blood. Additionally, we observed elevated SPHK1 activity in erythrocytes and increased S1P in blood collected from patients with SCD and demonstrated a direct impact of elevated SPHK1-mediated production of S1P on sickling that was independent of S1P receptor activation in isolated erythrocytes. Together, our findings provide insights into erythrocyte pathophysiology, revealing that a SPHK1-mediated elevation of S1P contributes to sickling and promotes disease progression, and highlight potential therapeutic opportunities for SCD. PMID:24837436

Zhang, Yujin; Berka, Vladimir; Song, Anren; Sun, Kaiqi; Wang, Wei; Zhang, Weiru; Ning, Chen; Li, Chonghua; Zhang, Qibo; Bogdanov, Mikhail; Alexander, Danny C; Milburn, Michael V; Ahmed, Mostafa H; Lin, Han; Idowu, Modupe; Zhang, Jun; Kato, Gregory J; Abdulmalik, Osheiza Y; Zhang, Wenzheng; Dowhan, William; Kellems, Rodney E; Zhang, Pumin; Jin, Jianping; Safo, Martin; Tsai, Ah-Lim; Juneja, Harinder S; Xia, Yang

2014-06-01

304

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

PubMed

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-ABL1-negative 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

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; Eaves, Connie J

2015-01-15

305

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

PubMed Central

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-ABL1–negative 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

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

306

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

PubMed

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

Wagner, M; Greten, F R; Weber, C K; Koschnick, S; Mattfeldt, T; Deppert, W; Kern, H; Adler, G; Schmid, R M

2001-02-01

307

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

PubMed Central

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

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

2001-01-01

308

Indexing Disease Progression at Study Entry with Individuals At-Risk for Huntington Disease  

PubMed Central

The identification of clinical and biological markers of disease in persons at risk for Huntington Disease (HD) has increased in efforts to better quantify and characterize the epoch of prodrome prior to clinical diagnosis. Such efforts are critical in the design and implementation of clinical trials for HD so that interventions can occur at a time most likely to increase neuronal survival and maximize daily functioning. A prime consideration in the examination of prodromal individuals is their proximity to diagnosis. It is necessary to quantify proximity so that individual differences in key marker variables can be properly interpreted. We take a data-driven approach to develop an index that can be viewed as a proxy for time to HD diagnosis known as the CAG-Age Product Scaled or CAPS. CAPS is an observed utility variable computed for all genetically at-risk individuals based on age at study entry and CAG repeat length. Results of a longitudinal receiver operating characteristic (ROC) analysis showed that CAPS had a relatively strong ability to predict individuals who became diagnosed, especially in the first 2 years. Bootstrap validation provided evidence that CAPS computed on a new sample from the same population could have similar discriminatory power. Cutoffs for the empirical CAPS distribution can be used to create a classification for mutation-positive individuals (Low-Med-High) that is useful for comparison with the naturally occurring mutation-negative Control group. The classification is an improvement over the one currently in use as it is based on observed data rather than model-based estimated values. PMID:21858921

Zhang, Ying; Long, Jeffrey D.; Mills, James A.; Warner, John H.; Lu, Wenjing; Paulsen, Jane S.

2011-01-01

309

A predictable sequential determinant spreading cascade invariably accompanies progression of experimental autoimmune encephalomyelitis: a basis for peptide-specific therapy after onset of clinical disease  

PubMed Central

The development of autoimmune disease is accompanied by the acquired recognition of new self-determinants, a process commonly referred to as determinant spreading. In this study, we addressed the question of whether determinant spreading is pathogenic for progression of chronic- relapsing experimental autoimmune encephalomyelitis (EAE), a disease with many similarities to multiple sclerosis (MS). Our approach involved a systematic epitope mapping of responses to myelin proteolipid protein (PLP) as well as assaying responses to known encephalitogenic determinants of myelin basic protein (MBP 87-89) and myelin oligodendrocyte glycoprotein (MOG 92-106) at various times after induction of EAE in (SWR X SJL)F1 mice immunized with PLP 139-151. We found that the order in which new determinants are recognized during the course of disease follows a predictable sequential pattern. At monthly intervals after immunization with p139-151, responses to PLP 249-273, MBP 87-99, and PLP 137-198 were sequentially accumulated in al mice examined. Three lines of evidence showed that determinant spreading is pathogenic for disease progression: (a) spreading determinants mediate passive transfer of acute EAE in naive (SWR X SJL)F1 recipients; (b) an invariant relationship exists between the development of relapse/progression and the spreading of recognition to new immunodominant encephalitogenic determinants; and (c) after EAE onset, the induction of peptide-specific tolerance to spreading but not to nonspreading encephalitogenic determinants prevents subsequent progression of EAE. Thus, the predictability of acquired self- determinant recognition provides a basis for sequential determinant- specific therapeutic intervention after onset of the autoimmune disease process. PMID:8666934

1996-01-01

310

Chronic Alcohol Abuse and HIV Disease Progression: Studies with the Non-Human Primate Model  

PubMed Central

The populations at risk for HIV infection, as well as those living with HIV, overlap with populations that engage in heavy alcohol consumption. Alcohol use has been associated with high-risk sexual behavior and an increased likelihood of acquiring HIV, as well as poor outcome measures of disease such as increased viral loads and declines in CD4+ T lymphocytes among those living with HIV-infections. It is difficult to discern the biological mechanisms by which alcohol use affects the virus:host interaction in human populations due to the numerous variables introduced by human behavior. The rhesus macaque infected with simian immunodeficiency virus has served as an invaluable model for understanding HIV disease and transmission, and thus, provides an ideal model to evaluate the effects of chronic alcohol use on viral infection and disease progression in a controlled environment. In this review, we describe the different macaque models of chronic alcohol consumption and summarize the studies conducted with SIV and alcohol. Collectively, they have shown that chronic alcohol consumption results in higher levels of plasma virus and alterations in immune cell populations that potentiate SIV replication. They also demonstrate a significant impact of chronic alcohol use on SIV-disease progression and survival. These studies highlight the utility of the rhesus macaque in deciphering the biological effects of alcohol on HIV disease. Future studies with this well-established model will address the biological influence of alcohol use on susceptibility to HIV, as well as the efficacy of anti-retroviral therapy. PMID:25053367

Amedee, Angela M.; Nichols, Whitney A.; Robichaux, Spencer; Bagby, Gregory J.; Nelson, Steve

2015-01-01

311

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

PubMed Central

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

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

2014-01-01

312

Quantification of rate of coronary artery disease progression by a new method of angiographic analysis.  

PubMed

To assess the rate and variability of atherostenosis progression in patients with coronary artery disease at baseline angiography, we used a simplified quantitative method of analysis to study single angiograms in 54 patients and paired angiograms in 29 patients. All discrete lesions were identified, then traced and digitized to determine lumen diameter (LD), and summed to give the total LD; the differences in LD for paired angiograms were summed to give total stenosis change (TSC). The following results were obtained: Correlation between LD measured by our method and LD determined by the Brown/Dodge method was excellent (r = 0.99, N = 54). There also was a high correlation between interobserver (r = 0.98, N = 54) and intraobserver (r = 0.99, N = 54) findings. Short-term TSC (N = 9, angiograms paired at less than 1 week) was negligible (0.03 +/- 0.38 mm). Long-term (N = 20, angiograms paired at 0.6 to 4.3 years) total LD differed significantly from baseline total LD (4.1 +/- 2.5 mm vs 6.0 +/- 3 mm; p less than 0.001), and TSC (2.0 +/- 1.3 mm) in long-term patients differed significantly from TSC in short-term patients (p less than 0.001). These results show that true coronary disease progression occurring over 1 to 4 years can be distinguished from intraobserver, interobserver, and interstudy variability by means of a simplified method and provide approximate rates and variability of progression. These results will be useful for power calculations in therapeutic trials aimed at slowing progression. Further prospective studies with the use of this method appear indicated. PMID:2008827

Moreno, F L; Stoops, K L; Hackworthy, R A; Menlove, R L; van Bree, R; Anderson, J L

1991-04-01

313

Neurodegenerative Diseases  

Microsoft Academic Search

The neurodegenerative disorders, which include Amyotrophic Lateral Sclerosis (ALS), Alzheimer Disease (AD), Parkinson Disease\\u000a (PD), and Huntington Disease (HD), are clinically heterogeneous. Medications can ameliorate some symptoms, but none reverse\\u000a the relentless progression of the illnesses. The past several decades have seen a dramatic increase in the understanding of\\u000a the complex pathophysiology underlying the diseases. Overlapping features at the cellular

Jinsy A. Andrews; Paul H. Gordon

314

Metabolomic profiling of serum in the progression of Alzheimer's disease by capillary electrophoresis-mass spectrometry.  

PubMed

There is high interest in the discovery of early diagnostic biomarkers of Alzheimer's disease, for which metabolomics exhibits a great potential. In this work, a metabolomic approach based on ultrafiltration and analysis by CE-MS has been used to obtain representative fingerprints of polar metabolites from serum samples in order to distinguish between patients with Alzheimer's disease, mild cognitive impairment, and healthy controls. By the use of partial least squares discriminant analysis it was possible to classify patients according to the disease stage and then identify potential markers. Significant increase was observed with progression of disease in levels of choline, creatinine, asymmetric dimethyl-arginine, homocysteine-cysteine disulfide, phenylalanyl-phenylalanine, and different medium chain acylcarnitines. On the other hand, asparagine, methionine, histidine, carnitine, acetyl-spermidine, and C5-carnitine were reduced in these serum samples. In this way, multiple essential pathways were found implicated in the underlying pathology, such as oxidative stress or defects in energy metabolism. However, the most interesting results are related to the association of several vascular risk factors with Alzheimer's disease. PMID:25136972

González-Domínguez, Raúl; García, Antonia; García-Barrera, Tamara; Barbas, Coral; Gómez-Ariza, José Luis

2014-12-01

315

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

PubMed Central

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

Mehrotra, R; Norris, K

2011-01-01

316

Host Genetic Factors Associated with Symptomatic Primary HIV Infection and Disease Progression among Argentinean Seroconverters  

PubMed Central

Background Variants in HIV-coreceptor C-C chemokine receptor type 5 (CCR5) and Human leukocyte antigen (HLA) genes are the most important host genetic factors associated with HIV infection and disease progression. Our aim was to analyze the association of these genetic factors in the presence of clinical symptoms during Primary HIV Infection (PHI) and disease progression within the first year. Methods Seventy subjects diagnosed during PHI were studied (55 symptomatic and 15 asymptomatic). Viral load (VL) and CD4 T-cell count were evaluated. HIV progression was defined by presence of B or C events and/or CD4 T-cell counts <350 cell/mm3. CCR5 haplotypes were characterized by polymerase chain reaction and SDM-PCR-RFLP. HLA-I characterization was performed by Sequencing. Results Symptoms during PHI were significantly associated with lower frequency of CCR5-CF1 (1.8% vs. 26.7%, p?=?0.006). Rapid progression was significantly associated with higher frequency of CCR5-CF2 (16.7% vs. 0%, p?=?0.024) and HLA-A*11 (16.7% vs. 1.2%, p?=?0.003) and lower frequency of HLA-C*3 (2.8% vs. 17.5%, p?=?0.035). Higher baseline VL was significantly associated with presence of HLA-A*11, HLA-A*24, and absence of HLA-A*31 and HLA-B*57. Higher 6-month VL was significantly associated with presence of CCR5-HHE, HLA-A*24, HLA-B*53, and absence of HLA-A*31 and CCR5-CF1. Lower baseline CD4 T-cell count was significantly associated with presence of HLA-A*24/*33, HLA-B*53, CCR5-CF2 and absence of HLA-A*01/*23 and CCR5-HHA. Lower 6-month CD4 T-cell count was associated with presence of HLA-A*24 and HLA-B*53, and absence of HLA-A*01 and HLA-B*07/*39. Moreover, lower 12-month CD4 T-cell count was significantly associated with presence of HLA-A*33, HLA-B*14, HLA-C*08, CCR5-CF2, and absence of HLA-B*07 and HLA-C*07. Conclusion Several host factors were significantly associated with disease progression in PHI subjects. Most results agree with previous studies performed in other groups. However, some genetic factor associations are being described for the first time, highlighting the importance of genetic studies at a local level. PMID:25406087

Coloccini, Romina Soledad; Dilernia, Dario; Ghiglione, Yanina; Turk, Gabriela; Laufer, Natalia; Rubio, Andrea; Socías, María Eugenia; Figueroa, María Inés; Sued, Omar; Cahn, Pedro; Salomón, Horacio; Mangano, Andrea; Pando, María Ángeles

2014-01-01

317

Tracking Motor Impairments in the Progression of Huntington’s Disease  

PubMed Central

The Unified Huntington’s Disease Rating Scale is used to characterize motor impairments and establish motor diagnosis. Little is known about the timing of diagnostic confidence level categories and the trajectory of motor impairments during the prodromal phase. Goals of this study were to estimate the timing of categories, model the prodromal trajectory of motor impairments, estimate the rate of motor impairment change by category, and provide required sample size estimates for a test of efficacy in clinical trials. In total, 1010 gene-expanded participants from the Neurobiological Predictors of Huntington’s Disease (PREDICT-HD) trial were analyzed. Accelerated failure time models were used to predict the timing of categories. Linear mixed effects regression was used to model the longitudinal motor trajectories. Age and length of gene expansion were incorporated into all models. The timing of categories varied significantly by gene expansion, with faster progression associated with greater expansion. For the median expansion, the third diagnostic confidence level category was estimated to have a first occurrence 1.5 years before diagnosis, and the second and first categories were estimated to occur 6.75 years and 19.75 years before diagnosis, respectively. Motor impairments displayed a nonlinear prodromal course. The motor impairment rate of change increased as the diagnostic confidence level increased, with added acceleration for higher progression scores. Motor items can detect changes in motor impairments before diagnosis. Given a sufficiently high progression score, there is evidence that the diagnostic confidence level can be used for prodromal staging. Implications for Huntington’s disease research and the planning of clinical trials of efficacy are discussed. PMID:24150908

Long, Jeffery D.; Paulsen, Jane S.; Marder, Karen; Zhang, Ying; Kim, Ji-In; Mills, James A.

2014-01-01

318

Variable course of primary simian immunodeficiency virus infection in lymph nodes: relation to disease progression.  

PubMed Central

To investigate the dynamics of spread of simian immunodeficiency virus (SIV) in the lymphoid organs, we sequentially analyzed the viral burden in lymph nodes (LN) of eight rhesus macaques inoculated intravenously with a high or low dose of the pathogenic SIVmac 251 isolate. For each animal, four axillary or inguinal LN were collected during the first weeks of infection and a fifth LN was taken 6 or 8 months later to estimate disease progression. Measurement of SIV RNA by in situ hybridization showed that all of the macaques studied had a phase of acute viral replication in LN between 7 and 14 days postinoculation which paralleled that observed in the blood. In a second phase, productive infection was controlled and viral particles were trapped in the germinal centers that developed in LN. While the peaks of productive infection were similar for the eight animals, marked differences in the numbers of productively infected cells that persisted in LN after primary infection were seen. Differences were less pronounced in the blood, where productive infection was efficiently controlled in all cases. The persistence of productively infected cells in LN after primary infection was found to be associated with more rapid disease progression, as measured by the decrease of the T4/T8 ratio and the occurrence of clinical signs. However, the persistence of a significant level of viral particles in germinal centers was observed even in animals that remained healthy over a 1- to 2-year observation period. This study indicates that the course of primary SIV infection in LN is variable, and it suggests that the initial capacity of the host to control productive infection in LN may determine the rate of disease progression. Images PMID:7916061

Chakrabarti, L; Cumont, M C; Montagnier, L; Hurtrel, B

1994-01-01

319

Effect of progression of disease on cognitive performance in HIV/AIDS.  

PubMed Central

BACKGROUND: HIV infection causes a range of cognitive and behavioral symptoms that become more frequent and severe as the immune system deteriorates and symptomatic illness ensues. OBJECTIVE: To determine the impact of disease progression on cognitive abilities of Nigerian Africans who present in the HIV/AIDS clinic of the University Teaching Hospital, Benin City, Nigeria, using the CD4 levels as the measure of disease progression. METHODS: A total of 288 subjects comprising 96 randomly selected symptomatic AIDS patients, 96 randomly selected asymptomatic HIV-positive patients and 96 HIV-negative controls participated in the study. Enzyme-linked immunosorbent assay (ELISA) method was used to detect HIV infection, and CD4 levels were obtained for all subjects. The Community Screening Interview for Dementia (CSI 'D') was used to assess cognitive performance of subjects. Subjects were matched for age, sex and level of education. RESULTS: Each category of subjects comprised 48 males and 48 females. The mean ages were 32.94 +/- 8.0 years, 31.47 +/- 6.7 years and 33.56 +/- 7.1 years for the controls, asymptomoatic HIV-positive and symptomatic AIDS subjects respectively (p = 0.127). The mean CD4 levels were 684 +/- 44/microL (controls), 284 +/- 62/microL (asymptomatic HIV positive) and 142 +/- 36/microL (symptomatic AIDS). The mean CS1 'D' scores were 66.46 +/- 1.90 (controls), 66.31 +/- 2.14 (asymptomatic HIV positive) and 56.62 +/- 4.23 (symptomatic AIDS). CONCLUSION: Cognitive abilities of HIV/AIDS patients decline as the disease progresses. This is reflected in the cognitive performances of the symptomatic AIDS patients. The lower the CD4 levels, the worse the cognitive deficits. There was, however, no significant difference in the performance of asymptomatic HIV-positive patients and the controls. PMID:16916122

Odiase, Francis; Ogunrin, Olubunmi; Ogunniyi, Adesola

2006-01-01

320

P2Y2 receptor deficiency aggravates chronic kidney disease progression  

PubMed Central

Purinergic signaling is involved in a variety of physiological states. P2 receptors are mainly activated by adenosine triphosphate (ATP). Activation of specific P2Y receptor subtypes might influence progression of kidney disease. To investigate the in vivo effect of a particular P2 receptor subtype on chronic kidney disease progression, subtotal nephrectomy was performed on wild type (WT) and P2Y2 receptor knockout (KO) mice. During the observational period of 56 ± 2 days, survival of KO mice was inferior compared to WT mice after SNX. Subtotal nephrectomy reduced creatinine clearance in both groups of mice, but the decrease was significantly more pronounced in KO compared to WT mice (53.9 ± 7.7 vs. 84.3 ± 8.7?l/min at day 56). The KO mice also sustained a greater increase in systolic blood pressure after SNX compared to WT mice (177 ± 2 vs. 156 ± 7 mmHg) and a 2.5-fold increase in albuminuria compared to WT. In addition, WT kidneys showed a significant increase in remnant kidney mass 56 days after SNX, but significant attenuation of hypertrophy in KO mice was observed. In line with the observed hypertrophy in WT SNX mice, a significant dose-dependent increase in DNA synthesis, a marker of proliferation, was present in cultured WT glomerular epithelial cells upon ATP stimulation. Markers for tissue damage (TGF-? 1, PAI-1) and proinflammatory target genes (MCP1) were significantly upregulated in KO mice after SNX compared to WT SNX mice. In summary, deletion of the P2Y2 receptor leads to greater renal injury after SNX compared to WT mice. Higher systolic blood pressure and inability of compensatory hypertrophy in KO mice are likely causes for the accelerated progression of chronic kidney disease. PMID:24065922

Potthoff, Sebastian A.; Stegbauer, Johannes; Becker, Jan; Wagenhaeuser, P. Johannes; Duvnjak, Blanka; Rump, Lars C.; Vonend, Oliver

2013-01-01

321

Role of Oxidative Stress in Disease Progression in Stage B Heart Failure  

PubMed Central

Oxidative stress represents a persistent imbalance between the production and the compensation of reactive oxygen species. While predominantly found in advanced heart failure, the majority of “at risk” condition has been associated with underlying oxidative stress. It is therefore conceivable that timely detection and early intervention to reduce oxidative stress processes provide an opportunity to prevent disease progression to overt heart failure. This paper reviews our current understanding of the current evidence of oxidative stress involvement in the pathophysiology of human heart failure and its potential therapeutic interventions in patients with Stage A and B heart failure. PMID:22108730

Bhimaraj, Arvind; Wilson Tang, W. H.

2011-01-01

322

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

PubMed Central

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

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

2014-01-01

323

Levodopa Slows Progression of Parkinson’s Disease. External Validation by Clinical Trial Simulation  

Microsoft Academic Search

Purpose  To externally validate the model predictions of a DATATOP cohort analysis through application of clinical trial simulation\\u000a with the study design of the ELLDOPA trial.\\u000a \\u000a \\u000a \\u000a Methods  The stochastic pharmacokinetic-pharmacodynamic and disease progress model was developed from the large DATATOP cohort of patients\\u000a followed for 8 years. ELLDOPA was designed to detect a difference between placebo and levodopa treated arms in the total

Phylinda L. S. Chan; John G. Nutt; Nicholas H. G. Holford

2007-01-01

324

Bacterial Toxins Fuel Disease Progression in Cutaneous T-Cell Lymphoma  

PubMed Central

In patients with cutaneous T-cell lymphoma (CTCL) bacterial infections constitute a major clinical problem caused by compromised skin barrier and a progressive immunodeficiency. Indeed, the majority of patients with advanced disease die from infections with bacteria, e.g., Staphylococcus aureus. Bacterial toxins such as staphylococcal enterotoxins (SE) have long been suspected to be involved in the pathogenesis in CTCL. Here, we review links between bacterial infections and CTCL with focus on earlier studies addressing a direct role of SE on malignant T cells and recent data indicating novel indirect mechanisms involving SE- and cytokine-driven cross-talk between malignant- and non-malignant T cells. PMID:23949004

Willerslev-Olsen, Andreas; Krejsgaard, Thorbjørn; Lindahl, Lise M.; Bonefeld, Charlotte Menne; A. Wasik, Mariusz; B. Koralov, Sergei; Geisler, Carsten; Kilian, Mogens; Iversen, Lars; Woetmann, Anders; Odum, Niels

2013-01-01

325

FGF23, Albuminuria, and Disease Progression in Patients with Chronic IgA Nephropathy  

PubMed Central

Summary Background and objectives Fibroblast growth factor-23 (FGF23) regulates mineral metabolism. Circulatory FGF23 levels are increased and predict outcomes in CKD. However, the relation of FGF23 to albuminuria and disease progression in patients with CKD and one underlying diagnosis is unknown. Design, setting, participants, & measurements Prospective, observational study in 180 patients with IgA nephropathy (IgAN), CKD stage 1–4, and median 55-month follow-up (range, 12–177 months). Primary outcomes were (1) time-averaged albuminuria, (2A) progression to CKD stage 5 or ?50% loss of estimated GFR, (2B) progression to CKD stage 5 or ?25% loss of estimated GFR within 10 years, and (3) annual loss of estimated GFR. Results FGF23 was independently associated with baseline and time-averaged albuminuria (change in 1 g/24 hour albuminuria per increase in log FGF23: ? = 0.26; P=0.02). Log FGF23 predicted CKD progression in crude models and after adjustment for mineral metabolites (endpoints 2A and 2B). It remained significant after adjustments for age, sex, serum albumin, calcium, phosphate, parathyroid hormone, 25-hydroxyvitamin D, baseline albuminuria, baseline estimated GFR, mean arterial BP, body mass index, and angiotensin-converting enzyme inhibitors/angiotensin-receptor blocker use in endpoint 2B (hazard ratio, 2.53; P=0.02) but not endpoint 2A (hazard ratio, 2.01; P=0.43). Log FGF23 predicted annual loss of estimated GFR in the same model (change in ml/min per 1.73 m2 per increase in log FGF23, 1.50; P=0.008). Conclusions In patients with CKD and IgAN, FGF23 was associated with albuminuria and CKD progression, a finding that suggests its role as a potential biomarker in IgAN. PMID:22383747

Qureshi, Abdul Rashid; Olivecrona, Sara; Gunnarsson, Iva; Jacobson, Stefan H.; Larsson, Tobias E.

2012-01-01

326

Primarily chronic progressive and relapsing/remitting multiple sclerosis: two immunogenetically distinct disease entities.  

PubMed Central

HLA class II gene polymorphism was investigated in 100 patients with clinically definite multiple sclerosis (MS) by restriction fragment length polymorphism analysis of Taq I-digested DNA using DRB, DQA, and DQB cDNA probes. Twenty-six patients had primarily chronic progressive MS and 74 had relapsing/remitting MS. The latter group included patients with a secondary progressive evolution of symptoms. Both clinical forms of MS were found to be associated with the DRw15,DQw6 haplotype. In addition, primarily chronic progressive MS was positively associated with the DQB1 restriction fragment pattern seen in DR4,DQw8, DR7,DQw9, and DRw8, DQw4 haplotypes, as well as negatively associated with the Taq I DQB1 allelic pattern corresponding to the serological specificity DQw7. Relapsing/remitting MS was positively associated with the DQB1 allelic pattern observed in the DRw17,DQw2 haplotype. These three DQB1 alleles are in strong negative linkage disequilibria with DRw15. The two susceptibility markers of each clinical form of MS act additively in determining the genetic susceptibility, as the relative risks for individuals carrying both markers roughly equal the sum of respective risks. Different alleles of the DQB1 locus defined by restriction fragment length polymorphisms contribute to susceptibility and resistance to primarily chronic progressive MS as well as to susceptibility to relapsing/remitting MS. The observed immunogenetic heterogeneity between the different clinical forms of MS favors the hypothesis that primarily chronic progressive MS and relapsing/remitting MS are two distinct disease entities. Images PMID:2571150

Olerup, O; Hillert, J; Fredrikson, S; Olsson, T; Kam-Hansen, S; Möller, E; Carlsson, B; Wallin, J

1989-01-01

327

The Trail Making Test in Prodromal Huntington Disease: Contributions of Disease Progression to Test Performance  

PubMed Central

We examined the Trail Making Test (TMT) in a sample of 767 participants with prodromal Huntington disease (prodromal HD) and 217 healthy comparisons to determine the contributions of motor, psychiatric, and cognitive changes to TMT scores. Eight traditional and derived TMT scores were also evaluated for their ability to differentiate prodromal participants closer to estimated age of diagnosis from those farther away and prodromal individuals from healthy comparisons. Results indicate that motor signs only mildly affected part A, and psychiatric symptoms did not affect either part. Tests of perceptual processing, visual scanning, and attention were primarily associated with part A, and executive functioning (response inhibition, set-shifting), processing speed, and working memory were associated with part B. Additionally, TMT scores differentiated between healthy comparisons and prodromal HD individuals as far as 9–15 years before estimated diagnosis. In participants manifesting prodromal motor signs and psychiatric symptoms, the TMT primarily measures cognition and is able to discriminate between groups based on health status and estimated time to diagnosis. PMID:21302170

O’Rourke, Justin J.F.; Beglinger, Leigh J.; Smith, Megan M.; Mills, James; Moser, David J.; Rowe, Kelly C.; Langbehn, Douglas R.; Duff, Kevin; Stout, Julie C.; Harrington, Deborah L.; Carlozzi, Noelle; Paulsen, Jane S.

2011-01-01

328

Identity experience among progressive gay Muslims in North America: A qualitative study within Al?Fatiha  

Microsoft Academic Search

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,

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

2005-01-01

329

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

SciTech Connect

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.

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

2008-02-13

330

Current progresses on nanodelivery systems for the treatment of neuropsychiatric diseases: Alzheimer's and schizophrenia.  

PubMed

Currently Alzheimer's disease and schizophrenia are both well-established neuropsychiatric diseases. Nonetheless, the treatment of these disorders is not unanimous and fully effective. As a consequence, several approaches have been studied to improve patient's conditions. In this context, the development of new drug nanodelivery systems to increase drug bioavailability and reduce adverse effects has been claimed as a good option. Among these systems we focus on the ones that seem to be most promising, such as lipidbased systems (e.g. liposomes, nanoemulsions and lipid nanoparticles), drug nanocrystals, polymeric nanoparticles and micelles. Moreover, the application of these systems by means of alternative administration routes is also discussed. Regardless of the satisfactory results and the associated progresses that have been done in the last years, more studies are required to quickly licence the application of drug nanodelivery systems in human medicines. PMID:23489198

Silva, A C; González-Mira, E; Lobo, J M Sousa; Amaral, M H

2013-01-01

331

Role of testosterone in the pathogenesis, progression, prognosis and comorbidity of men with chronic kidney disease.  

PubMed

Testosterone deficiency and hypogonadism are common conditions in men with chronic kidney disease (CKD). A disturbed hypothalamic-pituitary-gonadal axis due to CKD is thought to contribute to androgen deficiency. Data from experimental studies support the hypothesis that exogenous administration of testosterone may induce the activation of the renin-angiotensin system (RAS), the production of endothelin and the regulation of anti- or/and proinflammatory cytokines involved in the pathogenesis of hypertension and kidney damage. On the other hand, low testosterone levels in male patients with CKD are paradoxically associated with a higher risk of morbidity and mortality, possibly explained by anemia, osteoporosis and cardiovascular disease. In this article, we present an overview of clinical and experimental studies of the impact of testosterone on the progression and prognosis of male patients with CKD; even today, this remains a controversial issue. PMID:24119223

Dousdampanis, Periklis; Trigka, Konstantina; Fourtounas, Costas; Bargman, Joanne M

2014-06-01

332

Caspase inhibition reduces tubular apoptosis and proliferation and slows disease progression in polycystic kidney disease  

PubMed Central

We have previously demonstrated an increase in proapoptotic caspase-3 in the kidney of Han:SPRD rats with polycystic kidney disease (PKD). The aim of the present study was to determine the effect of caspase inhibition on tubular cell apoptosis and proliferation, cyst formation, and renal failure in the Han:SPRD rat model of PKD. Heterozygous (Cy/+) and littermate control (+/+) male rats were weaned at 3 weeks of age and then treated with the caspase inhibitor IDN-8050 (10 mg/kg per day) by means of an Alzet (Palo Alto, CA) minipump or vehicle [polyethylene glycol (PEG 300)] for 5 weeks. The two-kidney/total body weight ratio more than doubled in Cy/+ rats compared with +/+ rats. IDN-8050 significantly reduced the kidney enlargement by 44% and the cyst volume density by 29% in Cy/+ rats. Cy/+ rats with PKD have kidney failure as indicated by a significant increase in blood urea nitrogen. IDN-8050 significantly reduced the increase in blood urea nitrogen in the Cy/+ rats. The number of proliferating cell nuclear antigen-positive tubular cells and apoptotic tubular cells in non-cystic and cystic tubules was significantly reduced in IDN-8050-treated Cy/+ rats compared with vehicle-treated Cy/+ rats. On immunoblot, the active form of caspase-3 (20 kDa) was significantly decreased in IDN-8050-treated Cy/+ rats compared with vehicle-treated Cy/+ rats. In summary, in a rat model of PKD, caspase inhibition with IDN-8050 (i) decreases apoptosis and proliferation in cystic and noncystic tubules; (ii) inhibits renal enlargement and cystogenesis, and (iii) attenuates the loss of kidney function. PMID:15863619

Tao, Yunxia; Kim, Jun; Faubel, Sarah; Wu, Joe C.; Falk, Sandor A.; Schrier, Robert W.; Edelstein, Charles L.

2005-01-01

333

Validating Predictors of Disease Progression in a Large Cohort of Primary-Progressive Multiple Sclerosis Based on a Systematic Literature Review  

PubMed Central

Background New agents with neuroprotective or neuroregenerative potential might be explored in primary-progressive Multiple Sclerosis (PPMS) - the MS disease course with leading neurodegenerative pathology. Identification of patients with a high short-term risk for progression may minimize study duration and sample size. Cohort studies reported several variables as predictors of EDSS disability progression but findings were partially contradictory. Objective To analyse the impact of published predictors on EDSS disease progression in a large cohort of PPMS patients. Methods A systematic literature research was performed to identify predictors for disease progression in PPMS. Individual case data from the Sylvia Lawry Centre (SLC) and the Hamburg MS patient database (HAPIMS) was pooled for a retrospective validation of these predictors on the annualized EDSS change. Results The systematic literature analysis revealed heterogeneous data from 3 prospective and 5 retrospective natural history cohort studies. Age at onset, gender, type of first symptoms and early EDSS changes were available for validation. Our pooled cohort of 597 PPMS patients (54% female) had a mean follow-up of 4.4 years and mean change of EDSS of 0.35 per year based on 2503 EDSS assessments. There was no significant association between the investigated variables and the EDSS-change. Conclusion None of the analysed variables were predictive for the disease progression measured by the annualized EDSS change. Whether PPMS is still unpredictable or our results may be due to limitations of cohort assessments or selection of predictors cannot be answered. Large systematic prospective studies with new endpoints are needed. PMID:24651401

Stellmann, Jan-Patrick; Neuhaus, Anneke; Lederer, Christian; Daumer, Martin; Heesen, Christoph

2014-01-01

334

Beryllium-Specific CD4+ T Cells in Blood as a Biomarker of Disease Progression  

PubMed Central

Background CD4+ T cells are responsible for the progressive lung damage seen in patients with chronic beryllium disease (CBD), a granulomatous lung disorder in which antigen-specific, Th1-type cytokine-secreting T cells have been characterized. Compared to beryllium (Be)-sensitized subjects, an increased number of Be-responsive T cells are present in the blood of CBD patients. Objective The aim of this study was to determine whether the number of Be-specific T cells in blood predicted the development of CBD in a cohort of Be-exposed subjects. Methods Using IFN-? ELISPOT and proliferation-based assays, we determined the frequency and proliferative capacity of Be-responsive T cells in blood. Results Compared with the Be lymphocyte proliferation test which detected an abnormal Be-induced proliferative response in 11 of 260 (4.2%) workers from a Be-machining facility, IFN-? ELISPOT detected a sensitization rate of 10% (?2 = 55.7; P < 0.0001). A significant positive correlation was also noted between the number of Be-responsive CD4+ T cells in blood and lung of CBD patients. Importantly, the transition from Be sensitization to CBD was associated with an increased number of antigen-specific T cells in blood. Conclusion These findings have important implications for Be-induced disease and potentially other immune-mediated disorders, suggesting that the frequency of antigen-specific T cells in blood can serve as a noninvasive biomarker to predict disease development and severity of the Be-specific CD4+ T cell alveolitis. Clinical implications These findings suggest that the number of Be-responsive T cells in the circulation can serve as a biomarker of disease progression and as an estimate of the severity of Be-induced lung inflammation. PMID:21943943

Martin, Allison K.; Mack, Douglas G.; Falta, Michael T.; Mroz, Margaret M.; Newman, Lee S; Maier, Lisa A.; Fontenot, Andrew P.

2011-01-01

335

Melatonin inhibits the caspase-1/cytochrome c/caspase-3 cell death pathway, inhibits MT1 receptor loss and delays disease progression in a mouse model of amyotrophic lateral sclerosis  

PubMed Central

Caspase-mediated cell death contributes to the pathogenesis of motor neuron degeneration in the mutant SOD1G93A transgenic mouse model of amyotrophic lateral sclerosis (ALS), along with other factors such as inflammation and oxidative damage. By screening a drug library, we found that melatonin, a pineal hormone, inhibited cytochrome c release in purified mitochondria and prevented cell death in cultured neurons. In this study, we evaluated whether melatonin would slow disease progression in SOD1G93A mice. We demonstrate that melatonin significantly delayed disease onset, neurological deterioration and mortality in ALS mice. ALS-associated ventral horn atrophy and motor neuron death were also inhibited by melatonin treatment. Melatonin inhibited Rip2/caspase-1 pathway activation, blocked the release of mitochondrial cytochrome c, and reduced the overexpression and activation of caspase-3. Moreover, for the first time, we determined that disease progression was associated with the loss of both melatonin and the melatonin receptor 1A (MT1) in the spinal cord of ALS mice. These results demonstrate that melatonin is neuroprotective in transgenic ALS mice, and this protective effect is mediated through its effects on the caspase-mediated cell death pathway. Furthermore, our data suggest that melatonin and MT1 receptor loss may play a role in the pathological phenotype observed in ALS. The above observations indicate that melatonin and modulation of Rip2/caspase-1/cytochrome c or MT1 pathways may be promising therapeutic approaches for ALS. PMID:23537713

Zhang, Yi; Cook, Anna; Kim, Jinho; Baranov, Sergei V.; Jiang, Jiying; Smith, Karen; Cormier, Kerry; Bennett, Erik; Browser, Robert P.; Day, Arthur L.; Carlisle, Diane; Ferrante, Robert J.; Wang, Xin; Friedlander, Robert M.

2013-01-01

336

The Effect of Mild Hyperuricemia on Urinary Transforming Growth Factor Beta and the Progression of Chronic Kidney Disease  

Microsoft Academic Search

Although mild hyperuricemia is common in patients with renal disease, it has usually been considered a marker of reduced nephron mass rather than a risk factor for progression of kidney disease. On the other hand, experiments in a rat model demonstrated important deleterious effects of mild hyperuricemia on several aspects of renal structure and function. In the present investigation, the

Khaled M. Talaat; Amira R. El-Sheikh

2007-01-01

337

Rituximab Retreatment after Disease Progression Is Comparable to Rituximab Maintenance Therapy in Patients with Low-Tumor Burden Follicular Lymphoma  

Cancer.gov

In a randomized clinical trial, patients with low–tumor burden follicular lymphoma whose cancer responded to initial treatment with rituximab (Rituxan®) experienced similar disease control regardless of whether they subsequently received maintenance therapy with rituximab or were retreated with rituximab only when there was evidence of disease progression.

338

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

PubMed Central

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

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

2013-01-01

339

Targeting connexin 43 protects against the progression of experimental chronic kidney disease in mice.  

PubMed

Excessive recruitment of monocytes and progression of fibrosis are hallmarks of chronic kidney disease (CKD). Recently we reported that the expression of connexin 43 (Cx43) was upregulated in the kidney during experimental nephropathy. To investigate the role of Cx43 in the progression of CKD, we interbred RenTg mice, a genetic model of hypertension-induced CKD, with Cx43+/- mice. The renal cortex of 5-month-old RenTgCx43+/- mice showed a marked decrease of cell adhesion markers leading to reduced monocyte infiltration and interstitial renal fibrosis compared with their littermates. In addition, functional and histological parameters such as albuminuria and glomerulosclerosis were ameliorated in RenTgCx43+/- mice. Interestingly, treatment with Cx43 antisense produced remarkable improvement of renal function and structure in 1-year-old RenTg mice. Similar results were found in Cx43+/- or wild-type mice treated with Cx43 antisense after obstructive nephropathy. Furthermore, in these mice, Cx43 antisense attenuated E-cadherin downregulation and phosphorylation of the transcription factor Sp1 by the ERK pathway resulting in decreased transcription of type I collagen gene. Interestingly, Cx43-specific blocking peptide inhibited monocyte adhesion in activated endothelium and profibrotic pathways in tubular cells. Cx43 was highly increased in biopsies of patients with CKD. Thus, Cx43 may represent a new therapeutic target against the progression of CKD. PMID:24850151

Abed, Ahmed; Toubas, Julie; Kavvadas, Panagiotis; Authier, Florence; Cathelin, Dominique; Alfieri, Carlo; Boffa, Jean-Jacques; Dussaule, Jean-Claude; Chatziantoniou, Christos; Chadjichristos, Christos E

2014-10-01

340

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

PubMed

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

Muroyama, Akiko

2013-01-01

341

Brain ERP components predict which individuals progress to Alzheimer’s disease and which do not  

PubMed Central

Predicting which individuals will progress to Alzheimer’s 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 70–78%, 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

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

2009-01-01

342

Traditional and novel dietary interventions for preventing progression of chronic kidney disease.  

PubMed

Treatment of chronic kidney disease (CKD) and its complications remain largely unresolved. Currently used treatments include blood pressure control and the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), which can slow down the progression of CKD but are unable to halt or reverse it. Dietary protein restriction represents an additional therapeutic measure used to slow the progression of CKD. The putative mechanisms of action responsible for its therapeutic effects include beneficial hemodynamic effects and the limitation of absorbable protein breakdown products that could lead to the accumulation of uremic waste and consequent various deleterious effects. The practical implementation of protein restriction through dietary intervention has been hindered on multiple levels, including patient nonadherence, lack of health care resources, and concerns related to adverse effects associated with the development of protein-energy wasting (PEW). As a result, alternative interventions have been designed to address some or all of these shortcomings and concerns. One such intervention is the administration of medications that prevent the absorption of protein catabolic products from the gut. This article reviews the various interventions using such a strategy to prevent or slow the progression of CKD, with special focus on recent advances in this field. PMID:23611554

Kovesdy, Csaba P

2013-05-01

343

Features of alpha-synuclein that could explain the progression and irreversibility of Parkinson's disease  

PubMed Central

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

Gallegos, Scarlet; Pacheco, Carla; Peters, Christian; Opazo, Carlos M.; Aguayo, Luis G.

2015-01-01

344

Dispositional Optimism and the Mechanisms by Which It Predicts Slower Disease Progression in HIV: Proactive Behavior, Avoidant Coping, and Depression  

PubMed Central

The issue of whether optimism may prospectively protect against disease progression is one that has generated much interest, with mixed results in the literature. The purpose of this study was to determine whether dispositional optimism predicts slower disease progression in HIV. Two indicators of disease progression, CD4 counts and viral load, were assessed over 2 years in a diverse group (men, women, White, African American, Hispanic) of 177 people with HIV in the midrange of disease at entry to the study. Optimism predicted slower disease progression (less decrease in CD4 and less increase in viral load) controlling for baseline CD4 and viral load, antiretroviral treatment, gender, race, education, and drug use. Those low on optimism (25th percentile) lost CD4 cells at a rate 1.55 times faster than those high on optimism (75th percentile). Optimists had higher proactive behavior, less avoidant coping, and less depression: These variables mediated the linear optimism–disease progression relationship. Thus, optimists may reap health benefits partly through behavioral (proactive behavior), cognitive (avoidant coping), and affective (depression) pathways. Implications, limitations, and interpretations are discussed. PMID:15901217

Ironson, Gail; Balbin, Elizabeth; Stuetzle, Rick; Fletcher, Mary Ann; O’Cleirigh, Conall; Laurenceau, J. P.; Schneiderman, Neil; Solomon, George

2008-01-01

345

Hormone mediation of immune responses in the progression of diabetes, rheumatoid arthritis and periodontal diseases.  

PubMed

The crucial role of the immune response is common to diabetes mellitus (DM), rheumatoid arthritis (RA) and periodontal disease. This review identifies advances in this field and exciting paradigms in their management. Uncontrolled hyperglycaemia in diabetic patients results in the formation of advanced glycation end products (AGEs), which are detrimental to cell structure and function. Altered host resistance such as defective migration of PMN, impaired phagocytosis and an exaggerated inflammatory response to microbial products also compromises healing in uncontrolled diabetic patients, further compromised in smokers. Nicotine has well documented effects on the immune response, cell adhesion proteins and apoptosis which affect the severity of disease presentation and response to treatment. Rheumatoid arthritis is a multifactorial disease that results in severe destruction of synovial cartilage and bone. Local secretion of large amounts of TNF-alpha and IL-1 due to activation of immunocompetent cells characterises the pathophysiology of RA. This has lead to the emergence of TNF-alpha inhibitors such as etanercept and infliximab in its management. Periodontal disease has a microbial aetiology. But it is similar to RA, in its cyclical pattern of destruction associated with high levels of pro-inflammatory cytokines, which can persist after removal of the antigenic stimulus. Non steroidal anti-inflammatory agents (NSAIDs) have been used as an adjunct to mechanical removal of bacterial antigen, in the management of periodontal disease. The non-reproductive functions of steroid hormones include effects on immunocompetent cells, fibroblasts and osteoblasts, which affect the initiation and progression of inflammatory diseases. Hormone replacement therapy could be another facet in a multifaceted treatment approach in these patients, where indicated. PMID:12477294

Soory, M

2002-04-01

346

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

PubMed

Cerebrovascular impairment is frequent in patients with Alzheimer disease and is believed to influence clinical manifestation and severity of the disease. Cardiovascular risk factors, especially hypertension, have been associated with higher risk of developing Alzheimer disease. To investigate the mechanisms underlying the hypertension, Alzheimer disease cross talk, we established a mouse model of dual pathology by infusing hypertensive doses of angiotensin II into transgenic APPPS1 mice overexpressing mutated human amyloid precursor and presenilin 1 proteins. At 4.5 months, at the early stage of disease progression, only hypertensive APPPS1 mice presented impairment of temporal order memory performance in the episodic-like memory task. This cognitive deficit was associated with an increased number of cortical amyloid deposits (223±5 versus 207±5 plaques/mm(2); P<0.05) and a 2-fold increase in soluble amyloid levels in the brain and in plasma. Hypertensive APPPS1 mice presented several cerebrovascular alterations, including a 25% reduction in cerebral microvessel density and a 30% to 40% increase in cerebral vascular amyloid deposits, as well as a decrease in vascular endothelial growth factor A expression in the brain, compared with normotensive APPPS1 mice. Moreover, the brain levels of nitric oxide synthase 1 and 3 and the nitrite/nitrate levels were reduced in hypertensive APPPS1 mice (by 49%, 34%, and 33%, respectively, compared with wild-type mice; P<0.05). Our results indicate that hypertension accelerates the development of Alzheimer disease-related structural and functional alterations, partially through cerebral vasculature impairment and reduced nitric oxide production. PMID:25331846

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

2015-01-01

347

Upregulation of SATB1 is associated with prostate cancer aggressiveness and disease progression.  

PubMed

Disease aggressiveness remains a critical factor to the progression of prostate cancer. Transformation of epithelial cells to mesenchymal lineage, associated with the loss of E-cadherin, offers significant invasive potential and migration capability. Recently, Special AT-rich binding protein (SATB1) has been linked to tumor progression. SATB1 is a cell-type restricted nuclear protein, which functions as a tissue-specific organizer of DNA sequences during cellular differentiation. Our results demonstrate that SATB1 plays significant role in prostate tumor invasion and migration and its nuclear localization correlates with disease aggressiveness. Clinical specimen analysis showed that SATB1 was predominantly expressed in the nucleus of high-grade tumors compared to low-grade tumor and benign tissue. A progressive increase in the nuclear levels of SATB1 was observed in cancer tissues compared to benign specimens. Similarly, SATB1 protein levels were higher in a number of prostate cancer cells viz. HPV-CA-10, DU145, DUPro, PC-3, PC-3M, LNCaP and C4-2B, compared to non-tumorigenic PZ-HPV-7 cells. Nuclear expression of SATB1 was higher in biologically aggressive subclones of prostate cancer cells with their respective parental cell lines. Furthermore, ectopic SATB1 transfection conferred increased cell motility and invasiveness in immortalized human prostate epithelial PZ-HPV-7 cells which correlated with the loss of E-cadherin expression. Consequently, knockdown of SATB1 in highly aggressive human prostate cancer PC-3M cells inhibited invasiveness and tumor growth in vivo along with increase in E-cadherin protein expression. Our findings demonstrate that SATB1 has ability to promote prostate cancer aggressiveness through epithelial-mesenchymal transition. PMID:23308245

Shukla, Sanjeev; Sharma, Haripaul; Abbas, Ata; MacLennan, Gregory T; Fu, Pingfu; Danielpour, David; Gupta, Sanjay

2013-01-01

348

Mechanism-based disease progression modeling of type 2 diabetes in Goto-Kakizaki rats  

PubMed Central

The dynamics of aging and type 2 diabetes (T2D) disease progression were investigated in normal [Wistar-Kyoto (WKY)] and diabetic [Goto-Kakizaki (GK)] rats and a mechanistic disease progression model was developed for glucose, insulin, and glycosylated hemoglobin (HbA1c) changes over time. The study included 30 WKY and 30 GK rats. Plasma glucose and insulin, blood glucose and HbA1c concentrations and hematological measurements were taken at ages 4, 8, 12, 16 and 20 weeks. A mathematical model described the development of insulin resistance (IR) and ?-cell function with age/growth and diabetes progression. The model utilized transit compartments and an indirect response model to quantitate biomarker changes over time. Glucose, insulin and HbA1c concentrations in WKY rats increased to a steady-state at 8 weeks due to developmental changes. Glucose concentrations at 4 weeks in GK rats were almost twice those of controls, and increased to a steady-state after 8 weeks. Insulin concentrations at 4 weeks in GK rats were similar to controls, and then hyperinsulinemia occurred until 12–16 weeks of age indicating IR. Subsequently, insulin concentrations in GK rats declined to slightly below WKY controls due to ?-cell failure. HbA1c showed a delayed increase relative to glucose. Modeling of HbA1c was complicated by age-related changes in hematology in rats. The diabetes model quantitatively described the glucose/insulin inter-regulation and HbA1c production and reflected the underlying pathogenic factors of T2D—IR and ?-cell dysfunction. The model could be extended to incorporate other biomarkers and effects of various anti-diabetic drugs. PMID:21127951

Gao, Wei; Bihorel, Sébastien; DuBois, Debra C.; Almon, Richard R.

2013-01-01

349

The fundamental role of mechanical properties in the progression of cancer disease and inflammation.  

PubMed

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. PMID:25006689

Mierke, Claudia Tanja

2014-07-01

350

Metabolic Tumor Burden Predicts for Disease Progression and Death in Lung Cancer  

SciTech Connect

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.

Lee, Percy; Weerasuriya, Dilani K. [Department of Radiation Oncology, Stanford University, Stanford, CA (United States); Lavori, Philip W. [Department of Health Research and Policy, Stanford University, Stanford, CA (United States); Quon, Andrew [Department of Radiology, Division of Nuclear Medicine, Stanford University, Stanford, CA (United States); Hara, Wendy; Maxim, Peter G.; Le, Quynh-Thu [Department of Radiation Oncology, Stanford University, Stanford, CA (United States); Wakelee, Heather A. [Department of Medicine, Division of Oncology, Stanford University, Stanford, CA (United States); Donington, Jessica S. [Department of Cardiothoracic Surgery, Stanford University, Stanford, CA (United States); Graves, Edward E. [Department of Radiation Oncology, Stanford University, Stanford, CA (United States); Loo, Billy W. [Department of Radiation Oncology, Stanford University, Stanford, CA (United States)], E-mail: BWLoo@Stanford.edu

2007-10-01

351

Significance of intracellular localization of survivin in cervical squamous cell lesions: Correlation with disease progression.  

PubMed

Survivin is a member of the inhibitor of apoptosis protein family. Under normal circumstances, survivin is expressed in embryonic and fetal tissues, but is completely downregulated in normal adult tissues. Notably, this protein has been found to be prominently expressed in a variety of human malignant tumors. The present study was designed to evaluate the possible role of survivin in the tumorigenesis of cervical intraepithelial neoplasia and invasive squamous cell carcinoma (SCC) of the uterine cervix. In addition, it was investigated whether the nuclear or cytoplasmic expression of survivin is associated with tumor progression. In total, 71 samples of cervical squamous tissue were obtained, including 15 normal squamous epithelia, 25 high-grade squamous intraepithelial lesions (HSILs) and 31 SCCs, from cone biopsy and hysterectomy specimens and stained for survivin expression by immunohistochemistry. The intensity of survivin expression tended to increase with tumor progression (60.0% of normal mucosa, 76.0% of HSIL and 80.6% of SCC samples demonstrated high intensity survivin expression), but this correlation was not found to be statistically significant. However, a statistically significant difference was identified in the intracellular localization of survivin among the normal mucosa, HSIL and SCC samples (P<0.001). In total, 72% (18/25) of HSIL and 54.8% (17/31) of SCC cases expressed cytoplasmic staining in contrast to the nuclear staining of the normal mucosa. In addition, 64% (16/25) of HSIL and 42% (13/31) of SCC cases showed coexpression in the nucleus and cytoplasm. An inverse correlation was identified between the decrement of nuclear survivin expression and tumor progression, but was not statistically significant (P=0.08). These results indicated that analysis of the intracellular expression of survivin (particularly cytoplasmic expression) is a marker for predicting disease progression in the uterine cervix. PMID:24765182

Kim, Soo-Ah; Hong, Ran

2014-05-01

352

Significance of intracellular localization of survivin in cervical squamous cell lesions: Correlation with disease progression  

PubMed Central

Survivin is a member of the inhibitor of apoptosis protein family. Under normal circumstances, survivin is expressed in embryonic and fetal tissues, but is completely downregulated in normal adult tissues. Notably, this protein has been found to be prominently expressed in a variety of human malignant tumors. The present study was designed to evaluate the possible role of survivin in the tumorigenesis of cervical intraepithelial neoplasia and invasive squamous cell carcinoma (SCC) of the uterine cervix. In addition, it was investigated whether the nuclear or cytoplasmic expression of survivin is associated with tumor progression. In total, 71 samples of cervical squamous tissue were obtained, including 15 normal squamous epithelia, 25 high-grade squamous intraepithelial lesions (HSILs) and 31 SCCs, from cone biopsy and hysterectomy specimens and stained for survivin expression by immunohistochemistry. The intensity of survivin expression tended to increase with tumor progression (60.0% of normal mucosa, 76.0% of HSIL and 80.6% of SCC samples demonstrated high intensity survivin expression), but this correlation was not found to be statistically significant. However, a statistically significant difference was identified in the intracellular localization of survivin among the normal mucosa, HSIL and SCC samples (P<0.001). In total, 72% (18/25) of HSIL and 54.8% (17/31) of SCC cases expressed cytoplasmic staining in contrast to the nuclear staining of the normal mucosa. In addition, 64% (16/25) of HSIL and 42% (13/31) of SCC cases showed coexpression in the nucleus and cytoplasm. An inverse correlation was identified between the decrement of nuclear survivin expression and tumor progression, but was not statistically significant (P=0.08). These results indicated that analysis of the intracellular expression of survivin (particularly cytoplasmic expression) is a marker for predicting disease progression in the uterine cervix. PMID:24765182

KIM, SOO-AH; HONG, RAN

2014-01-01

353

Determining immune components necessary for progression of pigment dispersing disease to glaucoma in DBA/2J mice  

PubMed Central

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

2014-01-01

354

Skin Autofluorescence Is Associated with the Progression of Chronic Kidney Disease: A Prospective Observational Study  

PubMed Central

Background Advanced glycation end product (AGE) accumulation is thought to be a measure of cumulative metabolic stress that has been reported to independently predict cardiovascular disease in diabetes and renal failure. The aim of this study was to evaluate the association between AGE accumulation, measured as skin autofluorescence, and the progression of renal disease in pre-dialysis patients with chronic kidney disease (CKD). Methods Skin autofluorescence was measured noninvasively with an autofluorescence reader at baseline in 449 pre-dialysis patients with CKD. The primary end point was defined as a doubling of serum creatinine and/or need for dialysis. Results Thirty-three patients were lost to follow-up. Forty six patients reached the primary end point during the follow-up period (Median 39 months). Kaplan-Meier analysis showed a significantly higher risk of development of the primary end points in patients with skin autofluorescence levels above the optimal cut-off level of 2.31 arbitrary units, derived by receiver operator curve analysis. Cox regression analysis revealed that skin autofluorescence was an independent predictor of the primary end point, even after adjustment for age, gender, smoking history, diabetes, estimated glomerular filtration rate and proteinuria (adjusted hazard ratio 2.58, P?=?0.004). Conclusions Tissue accumulation of AGEs, measured as skin autofluorescence, is a strong and independent predictor of progression of CKD. Skin autofluorescence may be useful for risk stratification in this group of patients; further studies should clarify whether AGE accumulation could be one of the therapeutic targets to improve the prognosis of CKD. PMID:24349550

Tanaka, Kenichi; Nakayama, Masaaki; Kanno, Makoto; Kimura, Hiroshi; Watanabe, Kimio; Tani, Yoshihiro; Kusano, Yuki; Suzuki, Hodaka; Hayashi, Yoshimitsu; Asahi, Koichi; Sato, Keiji; Miyata, Toshio; Watanabe, Tsuyoshi

2013-01-01

355

TNF gene polymorphisms in cystic fibrosis patients: contribution to the disease progression  

PubMed Central

Background It is well known that the disease progression in cystic fibrosis (CF) patients may be diverse in subjects with identical mutation in CFTR gene. It is quite possible that such heterogeneity is associated with TNF-? and/or LT-? gene polymorphisms since their products play a key role in inflammation. The aim of the study was to investigate the possible roles of TNF gene polymorphisms in CF disease phenotype and progression. Methods 198 CF patients and 130 control subjects were genotyped for both TNF-?–308GA and LT-??+?252AG polymorphisms. Results The carriers of the TNF-?–308A allele more frequently had asthma as compared to patients homozygous for the TNF-?–308 G allele. In 9 of 108 (8.3%) of LT??+?252AA carriers, tuberculosis infection has been documented, whereas there was no case of tuberculosis among patients, either homozygous or heterozygous for LT? +252 G alleles (p?=?0.01). We never observed virus hepatitis among LT??+?252GA carriers. The genotypes TNF-?–308GG – LT-??+?252AA and TNF-?–308GA – LT-??+?252AG were unfavorable with regard to liver disease development (both p?

2013-01-01

356

Evolutionary dynamics of Staphylococcus aureus during progression from carriage to disease  

PubMed Central

Whole-genome sequencing offers new insights into the evolution of bacterial pathogens and the etiology of bacterial disease. Staphylococcus aureus is a major cause of bacteria-associated mortality and invasive disease and is carried asymptomatically by 27% of adults. Eighty percent of bacteremias match the carried strain. However, the role of evolutionary change in the pathogen during the progression from carriage to disease is incompletely understood. Here we use high-throughput genome sequencing to discover the genetic changes that accompany the transition from nasal carriage to fatal bloodstream infection in an individual colonized with methicillin-sensitive S. aureus. We found a single, cohesive population exhibiting a repertoire of 30 single-nucleotide polymorphisms and four insertion/deletion variants. Mutations accumulated at a steady rate over a 13-mo period, except for a cluster of mutations preceding the transition to disease. Although bloodstream bacteria differed by just eight mutations from the original nasally carried bacteria, half of those mutations caused truncation of proteins, including a premature stop codon in an AraC-family transcriptional regulator that has been implicated in pathogenicity. Comparison with evolution in two asymptomatic carriers supported the conclusion that clusters of protein-truncating mutations are highly unusual. Our results demonstrate that bacterial diversity in vivo is limited but nonetheless detectable by whole-genome sequencing, enabling the study of evolutionary dynamics within the host. Regulatory or structural changes that occur during carriage may be functionally important for pathogenesis; therefore identifying those changes is a crucial step in understanding the biological causes of invasive bacterial disease. PMID:22393007

Young, Bernadette C.; Golubchik, Tanya; Batty, Elizabeth M.; Fung, Rowena; Larner-Svensson, Hanna; Votintseva, Antonina A.; Miller, Ruth R.; Godwin, Heather; Knox, Kyle; Everitt, Richard G.; Iqbal, Zamin; Rimmer, Andrew J.; Cule, Madeleine; Ip, Camilla L. C.; Didelot, Xavier; Harding, Rosalind M.; Donnelly, Peter; Peto, Tim E.; Crook, Derrick W.; Bowden, Rory; Wilson, Daniel J.

2012-01-01

357

Clonal evolution in chronic lymphocytic leukemia: impact of subclonality on disease progression.  

PubMed

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

Sutton, Lesley-Ann; Rosenquist, Richard

2015-02-01

358

Direct evidence of progressive cardiac dysfunction in a transgenic mouse model of Huntington's disease.  

PubMed

The gene carrying the mutation causing Huntington's disease (HD) is not brain specific, and there is increasing evidence for peripheral, as well as brain pathology in this disorder. Here, we used in vivo and ex vivo techniques to assess the cardiac function of mice transgenic for the HD mutation. Using magnetic resonance imaging (MRI) of the beating heart, we show that abnormalities previously reported in end-stage mice are present by the mid-stages of the disease. We also found abnormalities that have not been hitherto reported, including changes in cardiac efficiency and a mechanical distortion of the beating heart. Using the Langendorff preparation, we show reduced coronary blood flow, impaired myocardial contractility and reduced left ventricular developed pressure in HD mouse hearts. Together, our findings suggest that there is significant pathology of the HD mouse heart, even by the mid stages of disease. These are likely to contribute not only to the demise, but also to the progressive decline of the HD mouse. HD is characterised by cognitive as well as motor impairments. Given that previous clinical research has demonstrated that cardiac failure is a major risk factor for HD patients, and the risk of cognitive symptoms markedly increases in patients with heart failure, we suggest that closer attention should be paid to cardiovascular symptoms in HD patients. PMID:24339845

Wood, Nigel I; Sawiak, Stephen J; Buonincontri, Guido; Niu, Youguo; Kane, Andrew D; Carpenter, T Adrian; Giussani, Dino A; Morton, A Jennifer

2012-01-01

359

Chronic follicular bronchiolitis requires antigen-specific regulatory T cell control to prevent fatal disease progression  

PubMed Central

In order 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 (mHEL) and a hemoglobin (Hb) epitope tag under the control of the Clara cell secretory protein (CCSP) promoter, which largely limited transgene expression to the respiratory bronchioles. When CCSP-mHEL/Hb transgenic mice were crossed to N3.L2 TCR transgenic mice that recognize the Hb 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 antigen-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

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.

2014-01-01

360

8OHdG as a marker for Huntington disease progression.  

PubMed

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

Long, Jeffrey D; Matson, Wayne R; Juhl, Andrew R; Leavitt, Blair R; Paulsen, Jane S

2012-06-01

361

Direct evidence of progressive cardiac dysfunction in a transgenic mouse model of Huntington’s disease  

PubMed Central

The gene carrying the mutation causing Huntington’s disease (HD) is not brain specific, and there is increasing evidence for peripheral, as well as brain pathology in this disorder. Here, we used in vivo and ex vivo techniques to assess the cardiac function of mice transgenic for the HD mutation. Using magnetic resonance imaging (MRI) of the beating heart, we show that abnormalities previously reported in end-stage mice are present by the mid-stages of the disease. We also found abnormalities that have not been hitherto reported, including changes in cardiac efficiency and a mechanical distortion of the beating heart. Using the Langendorff preparation, we show reduced coronary blood flow, impaired myocardial contractility and reduced left ventricular developed pressure in HD mouse hearts. Together, our findings suggest that there is significant pathology of the HD mouse heart, even by the mid stages of disease. These are likely to contribute not only to the demise, but also to the progressive decline of the HD mouse. HD is characterised by cognitive as well as motor impairments. Given that previous clinical research has demonstrated that cardiac failure is a major risk factor for HD patients, and the risk of cognitive symptoms markedly increases in patients with heart failure, we suggest that closer attention should be paid to cardiovascular symptoms in HD patients. PMID:24339845

Wood, Nigel I.; Sawiak, Stephen J.; Buonincontri, Guido; Niu, Youguo; Kane, Andrew D.; Carpenter, T. Adrian; Giussani, Dino A.; Morton, A. Jennifer

2013-01-01

362

8OHdG as a marker for Huntington disease progression  

PubMed Central

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

Long, Jeffrey D.; Matson, Wayne R.; Juhl, Andrew R.; Leavitt, Blair R.; Paulsen, Jane S.

2013-01-01

363

Compassionate Love as a Predictor of Reduced HIV Disease Progression and Transmission Risk  

PubMed Central

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

Ironson, Gail; Stuetzle, Rick; Fletcher, Mary A.

2013-01-01

364

Distinctive cytokine, chemokine, and antibody responses in Echinococcus multilocularis-infected patients with cured, stable, or progressive disease.  

PubMed

Metacestode larvae of the tapeworm Echinococcus multilocularis can cause alveolar echinococcosis (AE), a severe parasitic disease in man, which, if it remains untreated, may cause organ failure and death. Spontaneous and parasite antigen-induced cellular responses were studied in patients with cured, stable, and progressive AE to differentiate the response profiles between the distinct states of infection. Antibody reactivity was evaluated in AE patients with cured, stable, and progressive disease. The spontaneous cellular release of pro-inflammatory IL-31 and IL-33 was clearly depressed in all AE patients, while regulatory IL-27, anti-inflammatory SDF-1/CXCL12, and eosinophil granulocyte attracting Eotaxin-1, Eotaxin-2, and Eotaxin-3 (CCL11, CCL24, CCL26) were enhanced with disease progression. Such distinctive response profiles could be applied for monitoring of AE disease progression or regression. E. multilocularis metacestode (Em) antigens (entire metacestode EmAg as well as EmVesicles) stimulated in vitro IL-31, IL-33, Eotaxin-1, Eotaxin-3, and CXCL12 cytokine and chemokine responses, which were similarly present in all AE patient groups, while regulatory IL-27 was suppressed and pro-inflammatory Eotaxin-2 was enhanced. E. multilocularis metacestode-specific IgG1, IgG3, and IgE responses progressively diminished with regression from active to stable and cured AE. IgG2 and IgG4 reactivity remained similarly high in stable and progressive cases, and lessened only with cured AE. Antibody reactivity against E. multilocularis vesicle antigen distinctively separated between cured, stable, or progressive AE, with the exception of IgG4. In sum, the combined and longitudinal study of several cytokines and chemokines, together with the evaluation of E. multilocularis vesicle-specific antibody responses, should provide a better understanding of the immune response during progression and regression of AE, and may help to improve the staging of AE patients. PMID:24509604

Huang, Xiangsheng; Grüner, Beate; Lechner, Christian J; Kern, Peter; Soboslay, Peter T

2014-06-01

365

Rapid progressive interstitial lung disease as initial manifestation of primary Sjögren’s syndrome: a case report  

PubMed Central

Primary Sjögren’s syndrome is a chronic inflammatory disorder with many extraglandular organ systems involved, including the lungs. Diffuse interstitial lung disease is the most serious form of lung involvement. Parenchymal lung involvement in primary Sjögren’s syndrome is usually manifested by cough and/or slowly progressive dyspnea and most of the cases present as chronic course. We describe here a case of primary Sjögren’s syndrome who presented as rapid progressive interstitial lung disease. Improvement was obtained with treatment of corticosteroids and ventilatory support at early time. To the best of our knowledge, this is the first report documenting primary Sjögren’s syndrome initially presenting as rapid progressive interstitial lung disease and it enriches our understanding of the clinical manifestations of primary Sjögren’s syndrome. PMID:25664130

Lin, Yihua; Yi, Qun; Cheng, Deyun

2014-01-01

366

Cytokine profile in Egyptian hepatitis C virus genotype-4 in relation to liver disease progression  

PubMed Central

AIM: To observe the imbalance between T helper cell Th1 and Th2 cytokines in several chronic hepatitis disease at different stages of disease progression. METHODS: We measured the cytokine levels of Th1 (IL-2 and IL-2R), Th2 (IL-10) and the pro-inflammatory cytokines (IL-6 and IL-6R and TNF and TNF-RI and II) by the ELISA technique in the sera of 33 hepatocellular carcinoma (HCC) patients and 20 chronic liver disease (CLD) patients. In addition, 20 asymptomatic hepatitis C virus carriers and 20 healthy subjects negative for hepatitis C virus(HCV) markers served as controls. RESULTS: Anti-HCV antibodies were found to be positive in 94% of HCC cases and 75% of CLD cases. On the other hand, HCV viremia was detected using RT-PCR in 67% of HCC cases and 65% of CLD cases. HBsAg was positive in 9% of HCC cases and 30% of CLD cases. Also bilharzial-Ab was positive in 55% of HCC cases, 65% of CLD cases and in 70% of asymptomatic carriers (ASC). HCC patients had significantly higher values of IL-2R, TNF-RII (P<0.001), and TNF-RI (P>0.05), but lower TNF? (P<0.001) and IL-6 (P = 0.032) in comparison to ASC. But, in comparison to non-cancer controls, HCC patients had higher values of IL-2R, IL-6R, TNF-RI and TNF-RII, but lower TNF-? (P<0.001). CLD patients had higher IL-2R, TNF-RI, and TNF-RII (P<0.001) than ASC. But, in comparison to non-cancer controls, CLD patients had higher values of IL-2R, TNF-RI and TNF-RII, but lower TNF-? (P<0.001). IL-10 was higher (though not significantly) in HCC and CLD patients than in symptomatic carriers and non-cancer controls. CONCLUSION: Liver disease progression from CLD to HCC due to HCV genotype-4 infection is associated with an imbalance between Th1 and Th2 cytokines. IL-2R, TNF-RI, and TNF-RII could be used as potential markers. PMID:16425355

Zekri, Abdel-Rahman N; Ashour, Mohammed S El-Din; Hassan, Ahmed; El-Din, Hanaa M Alam; El-Shehaby, Amal MR; Abu-Shady, Maha A

2005-01-01

367

Rac1b Increases with Progressive Tau Pathology within Cholinergic Nucleus Basalis Neurons in Alzheimer's Disease  

PubMed Central

Cholinergic basal forebrain (CBF) nucleus basalis (NB) neurons display neurofibrillary tangles (NFTs) during Alzheimer's disease (AD) progression, yet the mechanisms underlying this selective vulnerability are currently unclear. Rac1, a member of the Rho family of GTPases, may interact with the proapoptotic pan-neurotrophin receptor p75NTR to induce neuronal cytoskeletal abnormalities in AD NB neurons. Herein, we examined the expression of Rac1b, a constitutively active splice variant of Rac1, in NB cholinergic neurons during AD progression. CBF tissues harvested from people who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment, or AD were immunolabeled for both p75NTR and Rac1b. Rac1b appeared as cytoplasmic diffuse granules, loosely aggregated filaments, or compact spheres in p75NTR-positive NB neurons. Although Rac1b colocalized with tau cytoskeletal markers, the percentage of p75NTR-immunoreactive neurons expressing Rac1b was significantly increased only in AD compared with both mild cognitive impairment and NCI. Furthermore, single-cell gene expression profiling with custom-designed microarrays showed down-regulation of caveolin 2, GNB4, and lipase A in AD Rac1b-positive/p75NTR-labeled NB neurons compared with Rac1b-negative/p75NTR-positive perikarya in NCI. These proteins are involved in Rac1 pathway/cell cycle progression and lipid metabolism. These data suggest that Rac1b expression acts as a modulator or transducer of various signaling pathways that lead to NFT formation and membrane dysfunction in a subgroup of CBF NB neurons in AD. PMID:22142809

Perez, Sylvia E.; Getova, Damianka P.; He, Bin; Counts, Scott E.; Geula, Changiz; Desire, Laurent; Coutadeur, Severine; Peillon, Helene; Ginsberg, Stephen D.; Mufson, Elliott J.

2012-01-01

368

Epigenetic changes associated with disease progression in a mouse model of childhood allergic asthma  

PubMed Central

SUMMARY Development of asthma in childhood is linked to viral infections of the lower respiratory tract in early life, with subsequent chronic exposure to allergens. Progression to persistent asthma is associated with a Th2-biased immunological response and structural remodelling of the airways. The underlying mechanisms are unclear, but could involve epigenetic changes. To investigate this, we employed a recently developed mouse model in which self-limited neonatal infection with a pneumovirus, followed by sensitisation to ovalbumin via the respiratory tract and low-level chronic challenge with aerosolised antigen, leads to development of an asthmatic phenotype. We assessed expression of microRNA by cells in the proximal airways, comparing changes over the period of disease progression, and used target prediction databases to identify genes likely to be up- or downregulated as a consequence of altered regulation of microRNA. In parallel, we assessed DNA methylation in pulmonary CD4+ T cells. We found that a limited number of microRNAs exhibited marked up- or downregulation following early-life infection and sensitisation, for many of which the levels of expression were further changed following chronic challenge with the sensitizing antigen. Targets of these microRNAs included genes involved in immune or inflammatory responses (e.g. Gata3, Kitl) and in tissue remodelling (e.g. Igf1, Tgfbr1), as well as genes for various transcription factors and signalling proteins. In pulmonary CD4+ T cells, there was significant demethylation at promoter sites for interleukin-4 and interferon-?, the latter increasing following chronic challenge. We conclude that, in this model, progression to an asthmatic phenotype is linked to epigenetic regulation of genes associated with inflammation and structural remodelling, and with T-cell commitment to a Th2 immunological response. Epigenetic changes associated with this pattern of gene activation might play a role in the development of childhood asthma. PMID:23611895

Collison, Adam; Siegle, Jessica S.; Hansbro, Nicole G.; Kwok, Chau-To; Herbert, Cristan; Mattes, Joerg; Hitchins, Megan; Foster, Paul S.; Kumar, Rakesh K.

2013-01-01

369

Proteoglycans in health and disease: New concepts for heparanase function in tumor progression and metastasis  

PubMed Central

Heparanase is an endo-?-D-glucuronidase capable of cleaving heparan sulfate (HS) side chains at a limited number of sites, yielding HS fragments of still appreciable size. Importantly, heparanase activity correlates with the metastatic potential of tumor-derived cells, attributed to enhance cell dissemination as a consequence of HS cleavage and remodeling of the extracellular matrix (ECM) and basement membrane underlying epithelial and endothelial cells. Similarly, heparanase activity is implicated in neovascularization, inflammation and autoimmunity, involving migration of vascular endothelial cells and activated cells of the immune system. The cloning of a single human heparanase cDNA 10 years ago enabled researchers to critically approve the notion that HS cleavage by heparanase is required for structural remodeling of the ECM, thereby facilitating cell invasion. Progress in the field has expanded the scope of heparanase function and its significance in tumor progression and other pathologies. Notably, while heparanase inhibitors attenuated tumor progression and metastasis in several experimental systems, other studies revealed that heparanase also functions in an enzymatic activity-independent manner. Thus, inactive heparanase was noted to facilitate adhesion and migration of primary endothelial cells and to promote phosphorylation of signaling molecules such as Akt and Src, facilitating gene transcription (i.e., VEGF) and phosphorylation of selected Src substrates (i.e., EGF-receptor). The concept of enzymatic activity-independent function of heparanase gained substantial support by the recent identification of the heparanase C-terminus domain as the molecular determinant behind its signaling capacity. Identification and characterization of a human heparanase splice variant (T5) devoid of enzymatic activity and endowed with pro-tumorigenic characteristics, elucidation of a cross-talk between heparanase and other ECM-degrading enzymes, and identification of single nucleotide polymorphism associated with heparanase expression and increased risk of GVHD add other layers of complexity to heparanase function in health and disease. PMID:20840586

Barash, Uri; Cohen-Kapaln, Victoria; Dowek, Ilana; Sanderson, Ralph D.; Ilan, Neta; Vlodavsky, Israel

2010-01-01

370

The contribution of biotechnology toward progress in diagnosis, management, and treatment of allergic diseases.  

PubMed

'Biotechnology' has been intuitively used by humans since thousands of years for the production of foods, beverages, and drugs based on the experience without any scientific background. However, the golden era of this discipline emerged only during the second half of the last century. Incredible progresses have been achieved on all fields starting from the industrialization of the production of foods to the discovery of antibiotics, the decipherment of the genetic code, and rational approaches to understand and define the status we now call 'healthy'. The extremely complex interactions between genetic background, life style, and environmental factors influencing our continuously increasing life span have become more and more evident and steadily generate new questions which are only partly answered. Here, we try to summarize the contribution of biotechnology to our understanding, control, and cure of IgE-mediated allergic diseases. We are aware that a review of such a vast topic can never cover all aspects of the progress achieved in the different fields. PMID:25307026

Palomares, O; Crameri, R; Rhyner, C

2014-12-01

371

AST-120 for the management of progression of chronic kidney disease  

PubMed Central

Uremic toxins such as indoxyl sulfate contribute to the pathogenesis of chronic kidney disease (CKD) by promoting glomerulosclerosis and interstitial fibrosis with loss of nephrons and vascular damage. AST-120, an orally administered intestinal sorbent, adsorbs indole, a precursor of indoxyl sulfate, thereby reducing serum and urinary concentrations of indoxyl sulfate. AST-120 has been available in Japan since 1991, and subsequently Korea (2005), and the Philippines (2010) as an agent to prolong the time to initiation of hemodialysis and for improvement of uremic symptoms in patients with CKD. A Medline search was performed to identify data supporting clinical experience with AST-120 for managing CKD. Prospective open-label and double-blind trials as well as retrospective analyses were included. In prospective trials and retrospective analyses, AST-120 has been shown to prolong the time to initiation of hemodialysis, and slow decline in glomerular filtration rate and the increase serum creatinine. In an initial randomized, double-blind, placebo-controlled trial in the United States, AST-120 was associated with a significant dose-dependent reduction in serum indoxyl sulfate levels and a decrease in uremia-related malaise. The Evaluating Prevention of Progression in CKD (EPPIC) trials, two double-blind, placebo-controlled trials undertaken in North America/Latin America and Europe, are evaluating the efficacy of AST-120 for preventing the progression of CKD. The results of the EPPIC trials will further define the role of AST-120 in this debilitating condition. PMID:24501542

Schulman, Gerald; Vanholder, Raymond; Niwa, Toshimitsu

2014-01-01

372

Contingent Negative Variation Is Associated with Cognitive Dysfunction and Secondary Progressive Disease Course in Multiple Sclerosis  

PubMed Central

Background and Purpose The relationship between contingent negative variation (CNV), which is an event-related potential, and cognition in multiple sclerosis (MS) has not been examined previously. The primary objective of the present study was thus to determine the association between CNV and cognition in a sample of MS patients. Methods The subjects of this study comprised 66 MS patients [50 with relapsing-remitting MS (RRMS) and 16 with secondary progressive MS (SPMS)] and 40 matched healthy volunteers. A neuropsychological battery was administered to all of the subjects; CNV recordings were made from the Cz, Fz, and Pz electrodes, and the amplitude and area under the curve (AUC) were measured at each electrode. Results RRMS patients exhibited CNVs with lower amplitudes and smaller AUCs than the controls at Pz. SPMS patients exhibited CNVs with lower amplitudes and smaller AUCs than the controls, and CNVs with a smaller amplitude than the RRMS patients at both Cz and Pz. After correcting for multiple comparisons, a lower CNV amplitude at Pz was significantly associated with worse performance on measures of speed of information processing, verbal fluency, verbal learning, and verbal recall. Conclusions CNV may serve as a marker for disease progression and cognitive dysfunction in MS. Further studies with larger samples and wider electrode coverage are required to fully assess the value of CNV in these areas. PMID:25324878

Idiman, Fethi; Idiman, Egemen; Ozakbas, Serkan; Karakas, Sirel; Bruce, Jared

2014-01-01

373

Glomerular Hyperfiltration and Renal Progression in Children with Autosomal Dominant Polycystic Kidney Disease  

PubMed Central

Summary Background and objectives The purpose of this study was to determine whether glomerular hyperfiltration (GH) occurring early in autosomal dominant polycystic kidney disease (ADPKD) is indicative of more rapid disease progression in children. Design, setting, participants, & measurements One hundred eighty children with ADPKD (ages 4 to 18 years) with normal renal function were examined by renal ultrasound. Renal volume was calculated using a standard formula for a modified ellipsoid. Creatinine clearance was calculated from serum creatinine and 24-hour urine creatinine. GH was defined as creatinine clearance ?140 ml/min per 1.73 m2. Results Thirty-two children had GH (mean age 11.4 ± 3.6 years) and 148 had normal renal function (mean age 10.8 ± 3.9 years). Patients with GH at baseline demonstrated an increased rate of total renal volume growth (?: rate of change = +19.3 ± 10.8 cm3/year) over 5 years compared with those without GH at baseline (? = ?4.3 ± 7.7 cm3/year), P = 0.008. Those with GH at baseline experienced a faster decline in creatinine clearance in subsequent years (? = ?5.0 ± 0.8 ml/min per 1.73 m2 per year) compared with those without GH at baseline (? = +1.0 ± 0.4 ml/min per 1.73 m2 per year), P < 0.0001. Conclusions This study revealed that occurrence of GH in ADPKD children is associated with a significantly faster decline in renal function and higher rate of kidney enlargement over time. GH combined with the increased renal volume may therefore be used as an early marker for a more severe progression of ADPKD in children. PMID:21903987

Helal, Imed; Reed, Berenice; McFann, Kim; Yan, Xiang-Dong; Fick-Brosnahan, Godela M.; Cadnapaphornchai, Melissa

2011-01-01

374

Synaptic change in the posterior cingulate gyrus in the progression of Alzheimer's disease.  

PubMed

Mild cognitive impairment (MCI) is considered to be an early stage in the progression of Alzheimer's disease (AD) providing an opportunity to investigate brain pathogenesis prior to the onset of dementia. Neuroimaging studies have identified the posterior cingulate gyrus (PostC) as a cortical region affected early in the onset of AD. This association cortex is involved in a variety of different cognitive tasks and is intimately connected with the hippocampal/entorhinal cortex region, a component of the medial temporal memory circuit that displays early AD pathology. We quantified the total number of synapses in lamina 3 of the PostC using unbiased stereology coupled with electron microscopy from short postmortem autopsy tissue harvested from cases at different stage of AD progression. Individuals in the early stages of AD showed a significant decline in synaptic numbers compared to individuals with no cognitive impairment (NCI). Subjects with MCI exhibited synaptic numbers that were between the AD and NCI cohorts. Adjacent tissue was evaluated for changes in both pre and postsynaptic proteins levels. Individuals with MCI demonstrated a significant loss in presynaptic markers synapsin-1 and synaptophysin and postsynaptic markers PSD-95 and SAP-97. Levels of [3H]PiB binding was significantly increased in MCI and AD and correlated strongly with levels of synaptic proteins. All synaptic markers showed a significant association with Mini-Mental Status Examination scores. These results support the idea that the PostC synaptic function is affected during the prodromal stage of the disease and may underlie some of the early clinical sequelae associated with AD. PMID:25147118

Scheff, Stephen W; Price, Douglas A; Ansari, Mubeen A; Roberts, Kelly N; Schmitt, Frederick A; Ikonomovic, Milos D; Mufson, Elliott J

2015-01-01

375

Angiotensinogen gene G-6A polymorphism influences idiopathic pulmonary fibrosis disease progression  

PubMed Central

Angiotensin II is a growth factor that plays a key role in the physiopathology of idiopathic pulmonary fibrosis (IPF). A nucleotide substitution of an adenine instead of a guanine (G-6A) in the proximal promoter region of angiotensinogen (AGT), the precursor of angiotensin II, has been associated with an increased gene transcription rate. In order to investigate whether the G-6A polymorphism of the AGT gene is associated with IPF development, severity and progression, the present study utilised a case–control study design and genotyped G-6A in 219 patients with IPF and 224 control subjects. The distribution of G-6A genotypes and alleles did not significantly differ between cases and controls. The G-6A polymorphism of the AGT gene was not associated with disease severity at diagnosis. The presence of the A allele was strongly associated with increased alveolar arterial oxygen tension difference during follow-up, after controlling for the confounding factors. Higher alveolar arterial oxygen tension changes over time were observed in patients with the AA genotype (0.37 ± 0.7 mmHg (0.049 ± 0.093 kPa) per month) compared to GA genotype (0.12 ± 1 mmHg (0.016 ± 0.133 kPa) per month) and GG genotype (0.2 ± 0.6 mmHg (0.027 ± 0.080 kPa) per month). G-6A polymorphism of the angiotensinogen gene is associated with idiopathic pulmonary fibrosis progression but not with disease predisposition. This polymorphism could have a predictive significance in idiopathic pulmonary fibrosis patients. PMID:18508830

Molina-Molina, M.; Xaubet, A.; Li, X.; Abdul-Hafez, A.; Friderici, K.; Jernigan, K.; Fu, W.; Ding, Q.; Pereda, J.; Serrano-Mollar, A.; Casanova, A.; Rodríguez-Becerra, E.; Morell, F.; Ancochea, J.; Picado, C.; Uhal, B.D.

2012-01-01

376

Progression of monoaminergic dysfunction in Parkinson's disease: a longitudinal 18F-dopa PET study.  

PubMed

Post-mortem and neuroimaging studies in Parkinson's disease (PD) have shown involvement of the brain serotoninergic, noradrenergic and cholinergic pathways alongside the characteristic degeneration of nigrostriatal dopamine neurons. The rate of progression of the degenerative process in these extrastriatal areas is still unclear. We used (18)F-dopa PET, a marker of aromatic aminoacid decarboxylase activity in monoaminergic neurons, to assess longitudinal changes in tracer uptake in brain noradrenergic, serotoninergic and extrastriatal dopaminergic structures over a 3-year period in a group of early PD patients. Ten PD patients had (18)F-dopa PET twice: at baseline and again after 37.1±21.5 months follow up. A standard object map was used to extract tracer influx constants (Ki) in 11 striatal and extrastriatal regions. Progressive decreases in (18)F-dopa Ki occurred over the follow-up period in the majority of the investigated areas, the fastest annual declines occurring in putamen (8.1%), locus coeruleus (7.8%), and globus pallidus interna (7.7%). Caudate and hypothalamus showed 6.3% and 6.1% annual Ki declines, respectively. At baseline, some structures showed increased levels of (18)F-dopa uptake in PD compared to controls (internal pallidum, locus coeruleus), indicating possible compensatory upregulation of monoamine turnover. These increased levels had normalised (globus pallidus interna) or become subnormal (locus coeruleus) at follow-up suggesting exhaustion of these mechanisms within the first years of disease. Loss of monoaminergic function in extrastriatal regions, as reflected by(18)F-dopa PET, is delayed and occurs independently from nigrostriatal degeneration. When assessing the efficacy of novel neuroprotective agents on nigrostriatal dysfunction in PD, (18)F-dopa PET could provide supplementary information concerning function of extrastriatal monoaminergic structures. PMID:21396455

Pavese, Nicola; Rivero-Bosch, Maria; Lewis, Stephanie J; Whone, Alan L; Brooks, David J

2011-06-01

377

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

PubMed Central

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

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

2008-01-01

378

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

PubMed Central

IMPORTANCE There are no treatments available to slow or prevent the progression of Parkinson disease, despite its global prevalence and significant health care burden. The National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson Disease program was established to promote discovery of potential therapies. OBJECTIVE To determine whether creatine monohydrate was more effective than placebo in slowing long-term clinical decline in participants with Parkinson disease. DESIGN, SETTING, AND PATIENTS The Long-term Study 1, a multicenter, double-blind, parallel-group, placebo-controlled, 1:1 randomized efficacy trial. Participants were recruited from 45 investigative sites in the United States and Canada and included 1741 men and women with early (within 5 years of diagnosis) and treated (receiving dopaminergic therapy) Parkinson disease. Participants were enrolled from March 2007 to May 2010 and followed up until September 2013. INTERVENTIONS Participants were randomized to placebo or creatine (10 g/d) monohydrate for a minimum of 5 years (maximum follow-up, 8 years). MAIN OUTCOMES AND MEASURES The primary outcome measure was a difference in clinical decline from baseline to 5-year follow-up, compared between the 2 treatment groups using a global statistical test. Clinical status was defined by 5 outcome measures: Modified Rankin Scale, Symbol Digit Modalities Test, PDQ-39 Summary Index, Schwab and England Activities of Daily Living scale, and ambulatory capacity. All outcomes were coded such that higher scores indicated worse outcomes and were analyzed by a global statistical test. Higher summed ranks (range, 5–4775) indicate worse outcomes. RESULTS The trial was terminated early for futility based on results of a planned interim analysis of participants enrolled at least 5 years prior to the date of the analysis (n = 955). The median follow-up time was 4 years. Of the 955 participants, the mean of the summed ranks for placebo was 2360 (95% CI, 2249–2470) and for creatine was 2414 (95% CI, 2304–2524). The global statistical test yielded t1865.8 = ?0.75 (2-sided P = .45). There were no detectable differences (P < .01 to partially adjust for multiple comparisons) in adverse and serious adverse events by body system. CONCLUSIONS AND RELEVANCE Among patients with early and treated Parkinson disease, treatment with creatine monohydrate for at least 5 years, compared with placebo did not improve clinical outcomes. These findings do not support the use of creatine monohydrate in patients with Parkinson disease. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00449865 PMID:25668262

2015-01-01

379

Exon skipping restores dystrophin expression, but fails to prevent disease progression in later stage dystrophic dko mice.  

PubMed

Antisense therapy with both chemistries of phosphorodiamidate morpholino oligomers (PMOs) and 2'-O-methyl phosphorothioate has demonstrated the capability to induce dystrophin expression in Duchenne muscular dystrophy (DMD) patients in phase II-III clinical trials with benefit in muscle functions. However, potential of the therapy for DMD at different stages of the disease progression is not understood. In this study, we examined the effect of peptide-conjugated PMO (PPMO)-mediated exon skipping on disease progression of utrophin-dystrophin-deficient mice (dko) of four age groups (21-29, 30-39, 40-49 and 50+ days), representing diseases from early stage to advanced stage with severe kyphosis. Biweekly intravenous (i.v.) administration of the PPMO restored the dystrophin expression in nearly 100% skeletal muscle fibers in all age groups. This was associated with the restoration of dystrophin-associated proteins including functional glycosylated dystroglycan and neuronal nitric synthase. However, therapeutic outcomes clearly depended on severity of the disease at the time the treatment started. The PPMO treatment alleviated the disease pathology and significantly prolonged the life span of the mice receiving treatment at younger age with mild phenotype. However, restoration of high levels of dystrophin expression failed to prevent disease progression to the mice receiving treatment when disease was already at advanced stage. The results could be critical for design of clinical trials with antisense therapy to DMD. PMID:24942628

Wu, B; Cloer, C; Lu, P; Milazi, S; Shaban, M; Shah, S N; Marston-Poe, L; Moulton, H M; Lu, Q L

2014-09-01

380

Diseases of the kidney in medieval Persia the--Hidayat of Al-Akawayni.  

PubMed

The centralization of socioeconomic resources following the rise of the Islamic empire in the 7th century nurtured an initial gathering and translation into Arabic of extant medical texts in Greek, Syriac, Hindu and Chinese. As Arabic became the lingua franca of scholarship, there followed a second period of assimilation, original observations, commentary and systematization of medical knowledge in Arabic texts, which became the basis of revival and learned medicine in the West in the 12th century. However, not all medical texts of the period were written in Arabic. As central power eroded, provincial principalities arose, and regional cultures flourished, medical texts began to be written in local dialects, particularly in Persia. Notable amongst those and probably the oldest is the Hidayat al-Muallimin fi-al-Tibb (Learner's; guide to medicine) written by Abubakr al-Akawayni al-Bokhari in the closing decades of the 10th century. Written in Farsi and dedicated to his son and other students of medicine, the Hidayat is a relatively short and simplified pandect of medicine at the time and provides a glimpse of the teaching of medicine of the period. The present article is a translation of the sections of the Hidayat related to the kidney and urinary tract and their diseases. These early writings provide insight into the care of patients with kidney disease during the Middle Ages in general, and in Persia in particular. PMID:17855422

Ardalan, Mohammad R; Shoja, Mohammadali M; Tubbs, R Shane; Eknoyan, Garabed

2007-12-01

381

A double-labeling immunohistochemical study of tau exon 10 in Alzheimer’s disease, progressive supranuclear palsy and Pick’s disease  

Microsoft Academic Search

Neurofibrillary tangles (NFT), one of the histopathological hallmarks of Alzheimer’s disease (AD) and progressive supranuclear\\u000a palsy (PSP), and Pick bodies in Pick’s disease (PiD) are composed of microtubule-associated protein tau, which is the product\\u000a of alternative splicing of a gene on chromosome 17. Alternative expression of exon 10 leads to formation of three- or four-repeat\\u000a tau isoforms. To study the

K. Ishizawa; H. Ksiezak-Reding; P. Davies; A. Delacourte; P. Tiseo; S.-H. Yen; D. W. Dickson

2000-01-01

382

Diabetes, cardiovascular disease, selected cardiovascular disease risk factors, and the 5-year incidence of age-related cataract and progression of lens opacities: the beaver dam eye study  

Microsoft Academic Search

PURPOSE: To describe the relationships of diabetes mellitus, cardiovascular disease, and selected cardiovascular disease risk factors to cumulative incidence of age-related cataract and to progression of lens opacities over a 5-year interval.METHODS: A follow-up examination of the Beaver Dam Eye Study cohort was performed 5 years after the baseline evaluation. Ages at the census prior to baseline ranged from 43

Barbara E. K Klein; Ronald Klein; Kristine E Lee

1998-01-01

383

JOANNES M.O et al. HLA polymorphism and sickle cell disease 1 Abstract: 150 words Text: 1988 words  

E-print Network

JOANNES M.O et al. HLA polymorphism and sickle cell disease 1 Abstract: 150 words Text: 1988 words References: 23 (568 words) Table: 3 Title: Infectious complications in sickle cell disease and HLA association, HLA class II alleles Abbreviated title: HLA polymorphism and sickle cell disease hal-00387082

Paris-Sud XI, Université de

384

Progress in the Modeling of NiAl-Based Alloys Using the BFS Method  

NASA Technical Reports Server (NTRS)

The BFS method has been applied to the study of NiAl-based materials to assess the effect of alloying additions on structure. Ternary, quaternary and even pent-alloys based on Ni-rich NiAl with additions of Ti, Cr and Cu were studied. Two approaches were used, Monte Carlo simulations to determine ground state structures and analytical calculations of high symmetry configurations which give physical insight into preferred bonding. Site occupancy energetics for ternary and the more complicated case of quaternary additions were determined, and solubility limits and precipitate formation with corresponding information concerning structure and lattice parameter were also 'observed' computationally. The method was also applied to determine the composition of alloy surfaces and interfaces. Overall, the results demonstrate that the BFS method for alloys is a powerful tool for alloy design and with its simplicity and obvious advantages can be used to complement any experimental alloy design program.

Bozzolo, Guillermo; Noebe, Ronald D.; Ferrante, John; Garg, Anita

1997-01-01

385

Injectable and oral contraception and the incidence and progression of cervical disease in HIV-infected women in South Africa  

PubMed Central

Background Few data exist regarding the effect of hormonal contraception (HC) on incidence and progression of cervical disease (e.g., cervical dysplasia, squamous intraepithelial lesions, cervical intraepithelial neoplasia) in HIV-infected African women. Study Design We conducted an observational study of HIV-seropositive women in Johannesburg, South Africa. The effect of individual HC types on the incidence and progression of cervical disease was determined using Poisson regression to obtain adjusted incidence rate ratios (IRR). Results We evaluated 594 HIV-infected women, with median follow-up time of 445 days; 75 of these women were receiving some form of hormonal contraception (largely DMPA, NET-EN, or COCs) at baseline. Risks of incidence and progression of cervical disease were similar comparing women not receiving HCs to women receiving DMPA, NET-EN, or COCs both individually by HC-type and considering all HC together. Conclusions There was no statistically significant effect of particular HC methods or of HC use in general on rates of incidence or progression of cervical disease in this study. These results should reassure us that use of HC is unlikely to substantially increase risks of cervical disease among HIV-positive women. PMID:24485095

Westreich, Daniel; Jamal, Naiomi; Smith, Jennifer S.; Schulze, Doreen; Williams, Sophie; Michelow, Pam; Levin, Simon; Firnhaber, Cynthia

2014-01-01

386

Variability in Zucker diabetic fatty rats: differences in disease progression in hyperglycemic and normoglycemic animals.  

PubMed

Both obesity and chronic inflammation are often associated with insulin resistance and type 2 diabetes. The Zucker diabetic fatty (ZDF) rat (fa/fa) is an obese animal model frequently used in type 2 diabetes research. The current study determines whether chronic administration (from 5 weeks of age through 24 weeks of age) of salsalate, a salicylate with anti-inflammatory properties, would be effective in mitigating diabetes disease progression in ZDF rats. Although a trend existed for lower blood glucose in the salsalate-treated group, significant differences were obscured by high animal-level variability. However, even in the non-drug-treated group, not all ZDF rats became diabetic as expected. Therefore, animals were parsed into two groups, regardless of drug treatment: normoglycemic ZDF rats, which maintained blood glucose profiles identical to nondiabetic Zucker lean rats (ZLRs), and hyperglycemic ZDF rats, which exhibited progressive elevation in blood glucose. To ascertain the differences between ZDF rats that became hyperglycemic and those that did not, relevant physiological indices and expression levels of adiponectin, tumor necrosis factor-?, interleukin-6, and glucocorticoid-induced leucine zipper messenger RNAs in adipose tissue were measured at sacrifice. Plasma C-reactive protein concentrations and expression levels of cytokine and glucocorticoid-induced leucine zipper messenger RNAs suggested more prevalent chronic inflammation in hyperglycemic animals. Early elevation of the insulin-sensitizing adipokine, adiponectin, was present in both ZDF groups, with the rate of its age-related decline faster in hyperglycemic animals. The most marked difference between the two groups of ZDF animals was in insulin output. Although the two ZDF populations had very similar elevated plasma insulin concentrations for the first 10 weeks, after that time, plasma insulin decreased markedly in the animals that became hyperglycemic, whereas it remained high in the normoglycemic ZDF rats. Thus, hyperglycemic ZDF animals exhibit both insulin resistance and progressive beta cell failure, whereas normoglycemic ZDF rats exhibit a lesser degree of insulin resistance that does not progress to beta cell failure. In these respects, the normoglycemic ZDF rats appear to revert back to a phenotype that strongly resembles that of nondiabetic Zucker fatty rats from which they were derived. PMID:25419150

Wang, Xi; DuBois, Debra C; Sukumaran, Siddharth; Ayyar, Vivaswath; Jusko, William J; Almon, Richard R

2014-01-01

387

Variability in Zucker diabetic fatty rats: differences in disease progression in hyperglycemic and normoglycemic animals  

PubMed Central

Both obesity and chronic inflammation are often associated with insulin resistance and type 2 diabetes. The Zucker diabetic fatty (ZDF) rat (fa/fa) is an obese animal model frequently used in type 2 diabetes research. The current study determines whether chronic administration (from 5 weeks of age through 24 weeks of age) of salsalate, a salicylate with anti-inflammatory properties, would be effective in mitigating diabetes disease progression in ZDF rats. Although a trend existed for lower blood glucose in the salsalate-treated group, significant differences were obscured by high animal-level variability. However, even in the non-drug-treated group, not all ZDF rats became diabetic as expected. Therefore, animals were parsed into two groups, regardless of drug treatment: normoglycemic ZDF rats, which maintained blood glucose profiles identical to nondiabetic Zucker lean rats (ZLRs), and hyperglycemic ZDF rats, which exhibited progressive elevation in blood glucose. To ascertain the differences between ZDF rats that became hyperglycemic and those that did not, relevant physiological indices and expression levels of adiponectin, tumor necrosis factor-?, interleukin-6, and glucocorticoid-induced leucine zipper messenger RNAs in adipose tissue were measured at sacrifice. Plasma C-reactive protein concentrations and expression levels of cytokine and glucocorticoid-induced leucine zipper messenger RNAs suggested more prevalent chronic inflammation in hyperglycemic animals. Early elevation of the insulin-sensitizing adipokine, adiponectin, was present in both ZDF groups, with the rate of its age-related decline faster in hyperglycemic animals. The most marked difference between the two groups of ZDF animals was in insulin output. Although the two ZDF populations had very similar elevated plasma insulin concentrations for the first 10 weeks, after that time, plasma insulin decreased markedly in the animals that became hyperglycemic, whereas it remained high in the normoglycemic ZDF rats. Thus, hyperglycemic ZDF animals exhibit both insulin resistance and progressive beta cell failure, whereas normoglycemic ZDF rats exhibit a lesser degree of insulin resistance that does not progress to beta cell failure. In these respects, the normoglycemic ZDF rats appear to revert back to a phenotype that strongly resembles that of nondiabetic Zucker fatty rats from which they were derived. PMID:25419150

Wang, Xi; DuBois, Debra C; Sukumaran, Siddharth; Ayyar, Vivaswath; Jusko, William J; Almon, Richard R

2014-01-01