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1

Kinematics of Disease Progression in Bulbar ALS  

PubMed Central

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 performance such as speaking rate and speech intelligibility. Movements of the lip and jaw were quantified with respect to their size (i.e., path distance measure), speed, and duration. The data revealed several changes in lip and jaw movement that coincided with ALS progression. In two out of three speakers, the changes in measures of path distance and speed anticipated the drop in speech intelligibility by approximately 3 months. With disease progression, increases in movement duration coincided with declines in speech intelligibility. Overall, the movement measures appeared to be sensitive to disease progression in ALS. Learning outcomes By the end of the manuscript, the reader should be able to: (1) describe the changes that occur in articulatory movements of the jaw and lower lip in ALS; (2) understand the relationship between physiologic measures of movement and speech intelligibility and speaking rate; (3) identify critical points in the disease progression and understand which quantitative measures reveal the state of the bulbar system at these time points.

Yunusova, Yana; Green, Jordan; Lindstrom, Mary; Ball, Laura; Pattee, Gary; Zinman, Lorne

2009-01-01

2

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

3

The crucial role of caspase-9 in the disease progression of a transgenic ALS mouse model  

PubMed Central

Mutant copper/zinc superoxide dismutase (SOD1)-overexpressing transgenic mice, a mouse model for familial amyotrophic lateral sclerosis (ALS), provides an excellent resource for developing novel therapies for ALS. Several observations suggest that mitochondria-dependent apoptotic signaling, including caspase-9 activation, may play an important role in mutant SOD1-related neurodegeneration. To elucidate the role of caspase-9 in ALS, we examined the effects of an inhibitor of X chromosome-linked inhibitor of apoptosis (XIAP), a mammalian inhibitor of caspase-3, -7 and -9, and p35, a baculoviral broad caspase inhibitor that does not inhibit caspase-9. When expressed in spinal motor neurons of mutant SOD1 mice using transgenic techniques, XIAP attenuated disease progression without delaying onset. In contrast, p35 delayed onset without slowing disease progression. Moreover, caspase-9 was activated in spinal motor neurons of human ALS subjects. These data strongly suggest that caspase-9 plays a crucial role in disease progression of ALS and constitutes a promising therapeutic target.

Inoue, Haruhisa; Tsukita, Kayoko; Iwasato, Takuji; Suzuki, Yasuyuki; Tomioka, Masanori; Tateno, Minako; Nagao, Masahiro; Kawata, Akihiro; Saido, Takaomi C.; Miura, Masayuki; Misawa, Hidemi; Itohara, Shigeyoshi; Takahashi, Ryosuke

2003-01-01

4

The CMAP scan as a tool to monitor disease progression in ALS and PMA.  

PubMed

Amyotrophic lateral sclerosis (ALS) and progressive muscular atrophy (PMA) are characterized by a loss of motor units (MUs), reinnervation and, eventually, muscle fibre loss. These three aspects are all reflected in the compound muscle action potential scan (CMAP scan, a high-detail stimulus response curve), which visualizes large MU potentials as 'steps'. We explored changes in the CMAP scan over time, combined the information on steps and CMAP amplitude into a CMAP scan-based progression score (CSPS), and correlated this score with motor unit number estimates (MUNE). Ten patients (three PMA, seven ALS; age 37-77 years) were included. CMAP scan and MUNE measurements were performed five times during a three-month period. Nine patients had additional measurements. The follow-up period was 3-24 months. Results demonstrated that abnormalities in steps preceded a decline in maximum CMAP amplitude during follow-up. Usually, both steps and maximum CMAP amplitude changed between recordings. The correlation between the CSPS and MUNE was -0.80 (p < 0.01). In conclusion, the CMAP scan can be used to visualize and quantify disease progression in a muscle affected by MND. The CSPS is a measure of MU loss that is quick and easy to obtain and that, in contrast to MUNE, has no sample bias. PMID:23134509

Maathuis, Ellen M; Drenthen, Judith; van Doorn, Pieter A; Visser, Gerhard H; Blok, Joleen H

2012-10-22

5

EGFR inhibitor erlotinib delays disease progression but does not extend survival in the SOD1 mouse model of ALS.  

PubMed

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

2013-04-26

6

Hdac6 deletion delays disease progression in the SOD1G93A mouse model of ALS.  

PubMed

Defects in axonal transport are thought to contribute to the pathogenesis of neurodegenerative disease. Because ?-tubulin acetylation facilitates axonal transport, inhibition of the ?-tubulin deacetylating enzymes, histone deacetylase 6 (Hdac6) and silent information regulator 2 (Sirt2), is thought to be an interesting therapeutic strategy for these conditions. Amyotrophic lateral sclerosis (ALS) is a one such rapidly progressive and fatal neurodegenerative disorder, in which axonal transport defects have been found in vitro and in vivo. To establish whether the inhibition of Hdac6 or Sirt2 may be of interest for ALS treatment, we investigated whether deleting Hdac6 or Sirt2 from the superoxide dismutase 1, SOD1(G93A) mouse affects the motor neuron degeneration in this ALS model. Deletion of Hdac6 significantly extended the survival of SOD1(G93A) mice without affecting disease onset, and maintained motor axon integrity. This protective effect was associated with increased ?-tubulin acetylation. Deletion of Sirt2 failed to affect the disease course, but also did not modify ?-tubulin acetylation. These findings show that Hdac6, rather than Sirt2, is a therapeutic target for the treatment of ALS. Moreover, Sirt2 appears not to be a major ?-tubulin deacetylase in the nervous system. PMID:23364049

Taes, Ines; Timmers, Mieke; Hersmus, Nicole; Bento-Abreu, André; Van Den Bosch, Ludo; Van Damme, Philip; Auwerx, Johan; Robberecht, Wim

2013-01-30

7

Synergistic effects of GDNF and VEGF on lifespan and disease progression in a familial ALS rat model.  

PubMed

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

2013-05-28

8

Electrophysiologic Biomarkers for Assessing Disease Progression and the Effect of Riluzole in SOD1 G93A ALS Mice  

PubMed Central

Objective To compare electrical impedance myography (EIM) 50 kHz phase to weight, motor score, paw grip endurance (PGE), CMAP amplitude, and MUNE for the identification of disease progression and the effect of riluzole in the SOD1 G93A mouse. Methods Twenty-three animals received 8 mg/kg/day riluzole in the drinking water starting at 6 weeks of age; 22 animals served as controls. Weight, motor score, PGE, CMAP, MUNE, and EIM were performed weekly to evaluate disease progression. Results No difference in clinical disease onset or survival was found between treated and untreated groups. In addition, all methods failed to identify any beneficial effect of riluzole. Thus, data from all animals were combined for additional analyses. Of the 4 parameters, EIM phase showed the earliest change from baseline and the most linear decline throughout the entire measurement period. In addition, EIM phase correlated with PGE, CMAP amplitude, and MUNE (Spearman r?=?0.92, 0.90, and 0.72, respectively, p<0.01 for all). The rate of EIM phase decline also correlated with individual animal survival (Spearman r?=??0.31, p<0.05). Conclusions At this dose, riluzole is ineffective in slowing progression of ALS. However, EIM phase shows early linear declines, supporting its potential as a useful new biomarker for preclinical drug testing.

Li, Jia; Sung, Minhee; Rutkove, Seward B.

2013-01-01

9

Overexpression of HGF retards disease progression and prolongs life span in a transgenic mouse model of ALS.  

PubMed

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motoneurons and degeneration of motor axons. We show that overexpression of hepatocyte growth factor (HGF) in the nervous system attenuates motoneuron death and axonal degeneration and prolongs the life span of transgenic mice overexpressing mutated Cu2+/Zn2+ superoxide dismutase 1. HGF prevented induction of caspase-1 and inducible nitric oxide synthase (iNOS) in motoneurons and retained the levels of the glial-specific glutamate transporter (excitatory amino acid transporter 2/glutamate transporter 1) in reactive astrocytes. We propose that HGF may be the first example of an endogenous growth factor that can alleviate the symptoms of ALS by direct neurotrophic activities on motoneurons and indirect activities on glial cells, presumably favoring a reduction in glutamatergic neurotoxicity. PMID:12151533

Sun, Woong; Funakoshi, Hiroshi; Nakamura, Toshikazu

2002-08-01

10

Astrocyte loss of mutant SOD1 delays ALS disease onset and progression in G85R transgenic mice.  

PubMed

Approximately 10% of patients with amyotrophic lateral sclerosis (ALS) have familial ALS (FALS), and 20% of FALS are caused by mutations of superoxide dismutase type 1 (MTSOD1). The fact that some MTSOD1s that cause FALS have full dismutase activity (e.g. G37R) and others no dismutase activity (e.g. G85R) suggests that MTSOD1 causes FALS due to toxicity of the protein rather than a loss in enzymatic function. Compelling data have demonstrated that motor neuron (MN) degeneration can result from a non-cell autonomous effect of the MTSOD1. In order to clarify the role of astrocytes in FALS, we deleted MTSOD1 in astrocytes of G85R transgenic mice. In contrast to a similar study using G37R mice in which astrocyte MTSOD1 loss affected only the late phase of ALS disease, we found that astrocyte MTSOD1 loss in G85R mice delayed disease onset and prolonged the early phase of disease progression, without affecting the late phase. In addition, astrocyte G85R knockdown resulted in decreased microgliosis, decreased SOD1-immunoreactive inclusions and preservation of GLT-1 transporter expression. The differential effects of astrocyte G85R versus G37R knockdown on MN death demonstrate SOD1 mutation-specific effects on ALS pathogenesis; these differences may be a result of the different dismutase activities of the two mutants. The effect of the knockdown of G85R expression in astrocytes on onset as well as disease duration highlights the importance of this cell type in FALS. PMID:20962037

Wang, Lijun; Gutmann, David H; Roos, Raymond P

2010-10-20

11

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.

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

2012-01-01

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 Central

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.

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

2012-01-01

13

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

2012-06-28

14

Progress in Autoimmune Diseases Research.  

National Technical Information Service (NTIS)

This progress report is organized around the four major themes identified in the 2002 Autoimmune Diseases Coordinating Committee (ADCC) Autoimmune Diseases Research Plan: (1) Epidemiology and Burden of Autoimmune Diseases; (2) Etiology of Autoimmune Disea...

2005-01-01

15

Lou Gehrig's Disease (ALS)  

MedlinePLUS

... about 50 years — ever since his diagnosis at age 21. He is the most famous long-term survivor of the disease. Born in England, Hawking is a famous physicist who furthered our understanding of the universe. He has written a lot of books, including ...

16

Progress Report on Alzheimer's Disease.  

National Technical Information Service (NTIS)

Alzheimer's disease (AD) is an irreversible, progressive brain disorder that occurs gradually and results in memory loss, behavior and personality changes, and a decline in thinking abilities. These losses are related to the death of brain cells and the b...

1999-01-01

17

Onset and Progression in Inherited ALS Determined by Motor Neurons and Microglia  

Microsoft Academic Search

Dominant mutations in superoxide dismutase cause amyotrophic lateral sclerosis (ALS), a progressive paralytic disease characterized by loss of motor neurons. With the use of mice carrying a deletable mutant gene, expression within motor neurons was shown to be a primary determinant of disease onset and of an early phase of disease progression. Diminishing the mutant levels in microglia had little

Séverine Boillée; Koji Yamanaka; Christian S. Lobsiger; Neal G. Copeland; Nancy A. Jenkins; George Kassiotis; George Kollias; Don W. Cleveland

2006-01-01

18

Al Qaeda's Scorecard: A Progress Report on Al Qaeda's Objectives  

Microsoft Academic Search

Terrorism scholars are divided over whether terrorism is an effective tactic. Disagreement derives from the fact that the objectives of terrorist groups are often highly contested. Nowhere is this clearer than in contemporary statements on Al Qaeda. This article explores the most common interpretations for why Al Qaeda attacked the United States on 11 September 2001, and then analyzes their

Max Abrahms

2006-01-01

19

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

Microsoft Academic Search

Amyotrophic lateral sclerosis (ALS) is a rare disease causing degeneration of the upper and lower motor neuron. Involvement of the bulbar motor neurons often results in fast progressive dysphagia. While cortical compensation of dysphagia has been previously shown in stroke patients, this topic has not been addressed in patients suffering from ALS. In the present study, we investigated cortical activation

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

2011-01-01

20

Shading reduces coral-disease progression  

NASA Astrophysics Data System (ADS)

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

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

2009-09-01

21

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

22

Imatinib 'Treatment Holiday' Risks Disease Progression  

Cancer.gov

Patients whose advanced gastrointestinal stromal tumors (GIST) are controlled with the drug imatinib (Gleevec®) risk rapid progression of disease if treatment is interrupted, according to the March 20, 2007, Journal of Clinical Oncology.

23

Fibrogenesis in progressive renal disease  

Microsoft Academic Search

Molecular biology offers new opportunities for experimental and clinical medicine. Promising clinical applications for patient care include identification of mRNA expression patterns (gene profiling) in diseased organs in correlation with diagnosis, prognosis, and responsiveness to different treatments. The development of novel technologies, such as microarray analysis and real-time PCR, allows study of gene expression networks, even in small renal biopsies.

H. Baelde

2005-01-01

24

Celiac Disease: A Progress Report  

Microsoft Academic Search

Celiac disease (CD) has a wide range of clinical presentations and is being diagnosed with increasing frequency in patients in the 4th and 5th decades of life. The diagnosis of CD is confirmed by a combination of clinical, serological, and morphological findings associated with a response to a gluten-free diet. In small-bowel mucosal biopsy specimens, abnormalities range from minimal (increased

Donald A. Antonioli

2003-01-01

25

Chronic myelogenous leukemia: mechanisms underlying disease progression  

Microsoft Academic Search

Chronic myelogenous leukemia (CML), characterized by the BCR-ABL gene rearrangement, has been extensively studied. Significant progress has been made in the area of BCR-ABL-mediated intracellular signaling, which has led to a better understanding of BCR-ABL-mediated clinical features in chronic phase CML. Disease progression and blast crisis CML is associated with characteristic non-random cytogenetic and molecular events. These can be viewed

AS Shet; BN Jahagirdar; CM Verfaillie

2002-01-01

26

Progress in Alzheimer’s disease  

Microsoft Academic Search

After more than one century from Alois Alzheimer and Gaetano Perusini’s first report, progress has been made in understanding\\u000a the pathogenic steps of Alzheimer’s disease (AD), as well as in its early diagnosis. This review discusses recent findings\\u000a leading to the formulation of novel criteria for diagnosis of the disease even in a preclinical phase, by using biological\\u000a markers. In

Daniela Galimberti; Elio Scarpini

27

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.

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

28

MAPK Usage in Periodontal Disease Progression  

PubMed Central

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

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

2012-01-01

29

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

PubMed Central

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

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

2011-01-01

30

Gray matter perfusion correlates with disease severity in ALS  

PubMed Central

Objective: The goal of this study is to determine if regional brain perfusion, as measured by arterial spin labeling (ASL) MRI, is correlated with clinical measures of amyotrophic lateral sclerosis (ALS) disease severity. The presence of such a relationship would indicate a possible role for ASL perfusion as a marker of disease severity and upper motor neuron involvement in ALS. Methods: Disease severity was assessed in 16 subjects with ALS (age 54 ± 11) using the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) and the pulmonary function measure, forced vital capacity (FVC). Upper motor neuron involvement was assessed by testing rapid tapping of the fingers and feet. Magnetic resonance perfusion images were coregistered with structural T1-weighted MRI, corrected for partial volume effects using the structural images and normalized to a study-specific atlas. Correlations between perfusion and ALS disease severity were analyzed, using statistical parametric mapping, and including age as a factor. Analyses were adjusted for multiple clusters. Result: ALS severity, as measured by the ALSFRS and FVC, was correlated with gray matter perfusion. This correlation was predominantly observed in the hemisphere contralateral to the more affected limbs. ALSFRS scores correlated with perfusion in the contralateral frontal and parietal lobe (p < 0.001) and ipsilateral frontal lobe (p < 0.02). FVC scores correlated with gray matter perfusion in contralateral frontal lobe (p < 0.001). Upper motor neuron involvement, as measured by rapid finger tapping, correlated bilaterally with perfusion in the middle cingulate gyrus (p < 0.001). Conclusion: Amyotrophic lateral sclerosis (ALS) severity is correlated with brain perfusion as measured by arterial spin labeling (ASL) perfusion. This correlation appears to be independent of brain atrophy. ASL perfusion may be a useful tool for monitoring disease progression and assessing treatment effects in ALS. GLOSSARY ALS = amyotrophic lateral sclerosis; ALSFRS = Amyotrophic Lateral Sclerosis Functional Rating Scale; ASL = arterial spin labeling; BA = Brodmann areas; FDG PET = fluorodeoxyglucose PET; FVC = forced vital capacity; HMPAO SPECT = Tc-hexamethylpropyleneamine oxime SPECT; NAA = N-acetylaspartate; VBM = voxel-based morphometry.

Rule, Randall R.; Schuff, Norbert; Miller, Robert G.; Weiner, Michael W.

2010-01-01

31

Electrical impedance myography as a biomarker to assess ALS progression.  

PubMed

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

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

2012-06-07

32

Electrical impedance myography as a biomarker to assess ALS progression  

PubMed Central

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

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

2012-01-01

33

Dose-Response Thresholds for Progressive Diseases  

PubMed Central

Many diseases, including cancers, heart diseases, and lung diseases, can usefully be viewed as arising from disruption of feedback control systems that normally maintain homeostasis of tissues and cell populations. Excessive exposure can destabilize feedback control loops, leading to sustained elevation of variables to saturated levels and clinical consequences such as chronic unresolved inflammation, destruction of tissue (as in emphysema), proliferation of cell populations (as in lung cancer), and increases in reactive oxygen species and protease levels (as in coronary heart diseases and chronic obstructive lung disease). We propose a framework for understanding how exposure can destabilize normally homeostatic feedback control systems and create sustained imbalances and elevated levels of disease-related variables, by creating a new, locally stable, alternative equilibrium for the dynamic system, in addition to its normal (homeostatic) equilibrium. The resulting model, which we call alternative-equilibria (AE) theory, implies the existence of an exposure threshold below which transition to the alternative equilibrium (potential disease) state will not occur. Once this threshold is exceeded, progression to the alternative equilibrium continues spontaneously, even without further exposure. These predictions may help to explain patterns observed in experimental and epidemiological data for diseases such as COPD, silicosis, and inflammation-mediated lung cancer.

Cox, Louis Anthony (Tony)

2012-01-01

34

Soluble Beta-Amyloid Precursor Protein Is Related to Disease Progression in Amyotrophic Lateral Sclerosis  

PubMed Central

Background Biomarkers of disease progression in amyotrophic lateral sclerosis (ALS) could support the identification of beneficial drugs in clinical trials. We aimed to test whether soluble fragments of beta-amyloid precursor protein (sAPP? and sAPPß) correlated with clinical subtypes of ALS and were of prognostic value. Methodology/Principal Findings In a cross-sectional study including patients with ALS (N?=?68) with clinical follow-up data over 6 months, Parkinson's disease (PD, N?=?20), and age-matched controls (N?=?40), cerebrospinal fluid (CSF) levels of sAPP? a, sAPPß and neurofilaments (NfHSMI35) were measured by multiplex assay, Progranulin by ELISA. CSF sAPP? and sAPPß levels were lower in ALS with a rapidly-progressive disease course (p?=?0.03, and p?=?0.02) and with longer disease duration (p?=?0.01 and p?=?0.01, respectively). CSF NfHSMI35 was elevated in ALS compared to PD and controls, with highest concentrations found in patients with rapid disease progression (p<0.01). High CSF NfHSMI3 was linked to low CSF sAPP? and sAPPß (p?=?0.001, and p?=?0.007, respectively). The ratios CSF NfHSMI35/CSF sAPP?,-ß were elevated in patients with fast progression of disease (p?=?0.002 each). CSF Progranulin decreased with ongoing disease (p?=?0.04). Conclusions This study provides new CSF candidate markers associated with progression of disease in ALS. The data suggest that a deficiency of cellular neuroprotective mechanisms (decrease of sAPP) is linked to progressive neuro-axonal damage (increase of NfHSMI35) and to progression of disease.

Steinacker, Petra; Fang, Lubin; Kuhle, Jens; Petzold, Axel; Tumani, Hayrettin; Ludolph, Albert C.; Otto, Markus; Brettschneider, Johannes

2011-01-01

35

Disease progression in amyotrophic lateral sclerosis  

Microsoft Academic Search

This study reports the results of a long-term economic evaluation of riluzole in the treatment of amyotrophic lateral sclerosis\\u000a (ALS) versus best supportive care in the United Kingdom. The analysis included in this contribution aims to provide an update\\u000a of the determination of the phase of the disease that is prolonged by riluzole and also to assess the quality of

Manouche Tavakoli

2002-01-01

36

Quantification of disease progression and dropout for Alzheimer's disease.  

PubMed

This research aimed to quantitatively describe the natural progression of Alzheimer's disease (AD) based on ADAScog scores in patients with mild-to-moderate AD. ADAS-cog data from 10 placebo-controlled clinical trials including more than 2,400 patients with up to 72 weeks of treatment were used. Different models describing the time course of ADAS-cog were evaluated. Patient characteristics potentially affect score changes were assessed. Furthermore, patient dropout patterns were characterized using parametric survival models. Covariate selection was performed to identify the risk factors associated with a higher dropout rate. ADAS-cog time course in mild-tomoderate AD patients receiving placebo was best described by a log-linear model, where the intercept represents the log-transformed ADAS-cog score at Week 10, the slope is the disease progression (i.e., natural increase of ADAS-cog score) on the log scale. Covariates influencing the intercept were baseline ADAS-cog score and baseline Mini Mental State Exam score. No covariates influenced the disease progression slope. A parametric log-normal model fit the dropout data best. Baseline ADAS-cog score and age were found to be significant predictors for dropout. AD disease and dropout models were both established. These models set up a quantitative basis for future clinical trial design and endpoint selection. PMID:23211395

William-Faltaos, Demiana; Chen, Ying; Wang, Yaning; Gobburu, Jogarao; Zhu, Hao

2013-02-01

37

Sexual differences in onset of disease and response to exercise in a transgenic model of ALS  

Microsoft Academic Search

Transgenic mice that overexpress the mutant human SOD1 gene (hSOD1) serve as an animal model for amyotrophic lateral sclerosis (ALS). Age and sex are recognized as risk factors for ALS, but physical activity remains controversial. Therefore, we investigated the effect of exercise on the phenotype of male and female hSOD1 mice. Onset of disease, progression of disease and survival were

J. H. Veldink; P. R. Bär; E. A. J. Joosten; M. Otten; J. H. J. Wokke; L. H. van den Berg

2003-01-01

38

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

2011-10-21

39

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

2013-07-24

40

Vascular burden and Alzheimer disease pathologic progression  

PubMed Central

Objective: To investigate the vascular contribution to longitudinal changes in Alzheimer disease (AD) biomarkers. Methods: The Alzheimer's Disease Neuroimaging Initiative is a clinic based, longitudinal study with CSF, PET, and MRI biomarkers repeatedly measured in participants with normal cognition (NC), mild cognitive impairment (MCI), and mild AD. Participants with severe cerebrovascular risks were excluded. Cardiovascular risk scores and MRI white matter hyperintensities (WMHs) were treated as surrogate markers for vascular burden. Generalized estimating equations were applied, and both vascular burden and its interaction with time (vascular burden × time) or time-varying WMHs were entered into regression models to assess whether biomarker rates of change were modified by vascular burden. Results: Cardiovascular risk profiles were not predictive of progression in CSF ?42-amyloid, [18F]fluorodeoxyglucose (FDG) PET uptake, and MRI hippocampal atrophy. Greater baseline cardiovascular risks or WMHs were generally associated with cognitive impairment, particularly poor executive function. WMHs increased over time with a faster rate in MCI and AD than in NC. Increased time-varying WMH was associated with faster decline in executive function and lower FDG uptake in NC. Otherwise, WMH was not associated with CSF and MRI biomarkers in the 3 groups. These findings remained unchanged after accounting for APOE4. Conclusion: Increased WMHs are associated with aging, decreased glucose metabolism, and decline in executive function but do not affect AD-specific pathologic progression, suggesting that the vascular contribution to dementia is probably additive although not necessarily independent of the amyloid pathway.

Jagust, William J.

2012-01-01

41

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

PubMed Central

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

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

2011-01-01

42

Antioxidants and progression of human immunodeficiency virus (HIV) disease  

Microsoft Academic Search

HIV infection is thought to lead to increased oxidative stress which may in turn lead to faster progression of HIV disease. Therefore, antioxidants may have a role in the treatment of HIV disease. We review the data on the relations of selected antioxidants to HIV disease progression. Results from observational epidemiologic studies suggest that vitamin A deficiency may accelerate HIV

Miriam Garland; Wafaie W. Fawzi

1999-01-01

43

Bromocriptine methylate suppresses glial inflammation and moderates disease progression in a mouse model of amyotrophic lateral sclerosis  

Microsoft Academic Search

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by a selective loss of upper and lower motor neurons. Since oxidative stress plays a crucial role in the progression of motor neuron loss observed in ALS, anti-oxidative agents could be an important therapeutic means for the ALS treatment. We have previously developed a drug screening system allowing the identification

Kazunori Tanaka; Takuya Kanno; Yoshiko Yanagisawa; Kaori Yasutake; Shinji Hadano; Fumihito Yoshii; Joh-E Ikeda

2011-01-01

44

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

PubMed Central

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 pediatric CD patients. METHODS Sera were collected from 196 pediatric CD cases and tested for immune responses: anti-I2, anti-outer membrane protein C (anti-OmpC), anti-CBir1 flagellin (anti-CBir1), and anti-Saccharomyces-cerevisiae (ASCA) using ELISA. Associations between immune responses and clinical phenotype were evaluated. RESULTS Fifty-eight patients (28%) developed internal penetrating and/or stricturing (IP/S) disease after a median follow-up of 18 months. Both anti-OmpC (p < 0.0006) and anti-I2 (p < 0.003) were associated with IP/S disease. The frequency of IP/S disease increased with increasing number of immune responses (p trend = 0.002). The odds of developing IP/S disease were highest in patients positive for all four immune responses (OR (95% CI): 11 (1.5–80.4); p = 0.03). Pediatric CD patients positive for ?1 immune response progressed to IP/S disease sooner after diagnosis as compared to those negative for all immune responses (p < 0.03). CONCLUSIONS The presence and magnitude of immune responses to microbial antigens are significantly associated with more aggressive disease phenotypes among children with CD. This is the first study to prospectively demonstrate that the time to develop a disease complication in children is significantly faster in the presence of immune reactivity, thereby predicting disease progression to more aggressive disease phenotypes among pediatric CD patients.

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

2007-01-01

45

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

46

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

47

When Progressive Disease Does Not Mean Treatment Failure: Reconsidering the Criteria for Progression  

PubMed Central

Although progression-based endpoints, such as progression-free survival, are often key clinical trial endpoints for anticancer agents, the clinical meaning of “objective progression” is much less certain. As scrutiny of progression-based endpoints in clinical trials increases, it should be remembered that the Response Evaluation Criteria In Solid Tumors (RECIST) progression criteria were not developed as a surrogate for survival. Now that progression-free survival has come to be an increasingly important trial endpoint, the criteria that define progression deserve critical evaluation to determine whether alternate definitions of progression might facilitate the development of stronger surrogate endpoints and more meaningful trial results. In this commentary, we review the genesis of the criteria for progression, highlight recent data that question their value as a marker of treatment failure, and advocate for several research strategies that could lay the groundwork for a clinically validated definition of disease progression in solid tumor oncology.

2012-01-01

48

Progress Report on Alzheimer Disease: Volume III.  

ERIC Educational Resources Information Center

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

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

49

Progress Report on Alzheimer Disease: Volume III.  

ERIC Educational Resources Information Center

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

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

50

Motor Unit Number Estimation in Evaluating Disease Progression in Patients with Amyotrophic Lateral Sclerosis  

PubMed Central

We investigated the availability of motor unit number estimation (MUNE) as a quantitative method to assess the severity and clinical progression of amyotrophic lateral sclerosis (ALS). The 143 ALS patients were evaluated by statistical MUNE and the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R). By using mean values of MUNE according to disease duration, regression equation between mean MUNE and disease duration was presented as a formula. The individual MUNE ratio was calculated by dividing individual MUNE value by mean MUNE value. All patients were classified into 2 groups (MUNE ratio <1 vs. MUNE ratio ?1) according to the MUNE ratio. Comparison between the 2 groups revealed that the patients in MUNE ratio <1 group or MUNE ratio ?1 group were respectively assigned to rapid progression or slow progression. We recommended informative mean values of MUNE and best regression equation in ALS patients according to disease duration. These values allow us to evaluate the severity and rapidity of progression in ALS.

Ahn, Suk-Won; Kim, Su-Hyun; Oh, Dong-Hoon; Kim, Sung-Min; Park, Kyung Seok; Hong, Yoon-Ho; Kwon, Oh-Sang; Sung, Jung-Joon

2010-01-01

51

Progress Report on Alzheimer's Disease 1995.  

National Technical Information Service (NTIS)

Alzheimer's disease (AD) is the most common cause of dementia, or mental deterioration, among people 65 and older. A slowly degenerative brain disease, AD is marked by changes in behavior and personality and by an irreversible decline in intellectual abil...

1995-01-01

52

Ischemic Heart Disease SCOR Progress Reports.  

National Technical Information Service (NTIS)

A summary of scientific accomplishments during the past year on the subject of ischemic heart disease is presented. The report presents results from comprehensive clinical and fundamental research programs encompassing all facets of ischemic heart disease...

1975-01-01

53

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

54

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

PubMed Central

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

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

2012-01-01

55

Brain plasticity in the motor network is correlated with disease progression in amyotrophic lateral sclerosis.  

PubMed

Objective: To test the influence of functional cerebral reorganization in amyotrophic lateral sclerosis (ALS) on disease progression. Methods: Nineteen predominantly right-handed ALS patients and 21 controls underwent clinical evaluation, functional Magnetic Resonance Imaging (fMRI), and diffusion tensor imaging. Patients were clinically re-evaluated 1 year later and followed until death. For fMRI, subjects executed and imagined a simple hand-motor task. Between-group comparisons were performed, and correlations were searched with motor deficit arm Medical Research Council (MRC) score, disease progression ALS Functional Rating Scale (ALSFRS), and survival time. Results: By the MRC score, the hand strength was lowered by 12% in the ALS group predominating on the right side in accordance with an abnormal fractional anisotropy (FA) limited to the left corticospinal tract (37.3% reduction vs. controls P < 0.01). Compared to controls, patients displayed overactivations in the controlateral parietal (P < 0.004) and somatosensory (P < 0.004) cortex and in the ipsilateral parietal (P < 0.01) and somatosensory (P < 0.01) cortex to right-hand movement. Movement imagination gave similar results while no difference occurred with left-hand tasks. Stepwise regression analysis corrected for multiple comparisons showed that controlateral parietal activity was inversely correlated with disease progression (R(2) = 0.43, P = 0.001) and ipsilateral somatosensory activations with the severity of the right-arm deficit (R(2) = 0.48, P = 0.001). Conclusions: Cortical Blood Oxygen Level Dependent (BOLD) signal changes occur in the brain of ALS patients during a simple hand-motor task when the motor deficit is still moderate. It is correlated with the rate of disease progression suggesting that brain functional rearrangement in ALS may have prognostic implications. Hum Brain Mapp 34:2391-2401, 2013. © 2012 Wiley Periodicals, Inc. PMID:22461315

Poujois, Aurélia; Schneider, Fabien C; Faillenot, Isabelle; Camdessanché, Jean-Philippe; Vandenberghe, Nadia; Thomas-Antérion, Catherine; Antoine, Jean-Christophe

2012-03-28

56

Global progress in infectious disease control.  

PubMed

There is both good news and bad news concerning infectious disease control globally. The good news is that smallpox has been eradicated, eradication of poliomyelitis and guinea worm disease is on track, and many infectious diseases are under effective control in much of the world. The advances are primarily the result of improved sanitation, effective use of vaccines, and introduction and use of specific therapies (whose impact has primarily been on mortality, rather than incidence). The bad news is that infectious diseases are still the leading cause of death world-wide, new diseases are emerging, old diseases are re-emerging, there are ominous interactions between diseases, and antibiotic resistance is emerging as a major problem. There are many promising developments for the future, including new and improved vaccines, new specific therapies, and new strategies to deal with infectious disease. However, unless eradicated, infectious diseases remain a threat and require continuous efforts to be kept under control. Given the ability of infectious agents to evolve, it is certain that the future will also hold new problems and new diseases. PMID:9682367

Hinman, A R

1998-07-01

57

Dopamine Transporter Imaging Assessment of Parkinson's Disease Progression.  

National Technical Information Service (NTIS)

The primary goal of this study is to investigate whether sequential dopamine transporter imaging using 123Ib-CIT and SPECT, a marker of dopamine terminal integrity, will provide a quantitative biomarker of Parkinson's disease progression in subjects with ...

K. Marek

2000-01-01

58

Bladder cancer: the molecular progression to invasive disease  

Microsoft Academic Search

Recent investigations have given a clearer insight into the genetic progression of bladder cancer. In this review we identify the clinical courses of bladder cancer, review the basic concepts of carcinogenesis, and focus on the specific cytogenetic and molecular alterations observed in bladder cancer. Progression models to superficial and invasive disease are discussed.

A. R. Simoneau; P. A. Jones

1994-01-01

59

Alcohol and HIV Disease Progression: Weighing the Evidence  

Microsoft Academic Search

Heavy alcohol use is commonplace among HIV-infected individuals; however, the extent that alcohol use adversely impacts HIV\\u000a disease progression has not been fully elucidated. Fairly strong evidence suggests that heavy alcohol consumption results\\u000a in behavioral and biological processes that likely increase HIV disease progression, and experimental evidence of the biological\\u000a effect of heavy alcohol on simian immunodeficiency virus in macaques

Judith A. Hahn; Jeffrey H. Samet

2010-01-01

60

Progress Report on Alzheimer's Disease: Volume II.  

ERIC Educational Resources Information Center

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

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

61

Progress Report on Alzheimer's Disease: Volume II.  

ERIC Educational Resources Information Center

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

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

62

Parkinson's Disease: Challenges, Progress, and Promise.  

National Technical Information Service (NTIS)

Ever since PD was first described in 1817, scientists have pursued the causes and treatment of the disease. In the early 1960s, scientists identified the primary problem underlying the disease: the loss of brain cells that produce a chemical called dopami...

2004-01-01

63

Posttraumatic Growth and HIV Disease Progression  

ERIC Educational Resources Information Center

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

Milam, Joel

2006-01-01

64

Posttraumatic Growth and HIV Disease Progression  

Microsoft Academic Search

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

Joel Milam

2006-01-01

65

Repeat expansion disease: progress and puzzles in disease pathogenesis  

Microsoft Academic Search

Repeat expansion mutations cause at least 22 inherited neurological diseases. The complexity of repeat disease genetics and pathobiology has revealed unexpected shared themes and mechanistic pathways among the diseases, such as RNA toxicity. Also, investigation of the polyglutamine diseases has identified post-translational modification as a key step in the pathogenic cascade and has shown that the autophagy pathway has an

J. Paul Taylor; Albert R. La Spada

2010-01-01

66

Progress and frustration in inflammatory bowel disease.  

PubMed Central

Advances -- and lack of them -- in our understanding of the aetiology, nature, and treatment of ulcerative colitis and Crohn's disease during the past 30 years are reviewed with special reference to personal experience.

Brooke, B. N.

1980-01-01

67

Elevated Levels of Methylmalonate and Homocysteine in Parkinson’s Disease, Progressive Supranuclear Palsy and Amyotrophic Lateral Sclerosis  

Microsoft Academic Search

Background\\/Aims: Increasing evidence suggests that elevated levels of homocysteine (Hcy) and methylmalonate (MMA) may be involved in the pathogenesis of neurodegenerative diseases. Methods: The urine levels of MMA and serum levels of Hcy as well as folic acid and vitamin B12 were measured in patients suffering from the distinct neurodegenerative diseases progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis (ALS) and

Johannes Levin; Kai Bötzel; Armin Giese; Michael Vogeser; Stefan Lorenzl

2010-01-01

68

Nonsteroidal Antiinflammatory Drugs as Inhibitors of Periodontal Disease Progression  

Microsoft Academic Search

Recent interest in the control and modulation of periodontal disease has focused on the potential benefits of blocking the host response mechanisms involved in the progression of the disease. In addition to recent advances in the identification and control of etiologic bacteria, investigators have indicated promising results using nonsteroidal antiinflammatory drugs (NSAIDs) as inhibitors of the inflammatory destruction in periodontal

T. Howard Howell; Ray C. Williams

1993-01-01

69

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

70

Central Blood Pressure and Chronic Kidney Disease Progression  

PubMed Central

Hypertension, diabetes, and proteinuria are well-recognized risk factors for progressive kidney function loss. However, despite excellent antihypertensive and antidiabetic drug therapies, which also often lower urinary protein excretion, there remains a significant reservoir of patients with chronic kidney disease who are at high risk for progression to end-stage kidney disease. This has led to the search for less traditional cardiovascular risk factors that will help stratify patients at risk for more rapid kidney disease progression. Among these are noninvasive estimates of vascular structure and function. Arterial stiffness, manifested by the pulse wave velocity in the aorta, has been established in a number of studies as a significant risk factor for kidney disease progression and cardiovascular endpoints. Much less well studied in chronic kidney disease are measures of central arterial pressures. In this paper we cover the physiology behind the generation of the central pulse wave contour and the studies available using these approaches and conclude with some speculations on the rationale for why measurements of central pressure may be informative for the study of chronic kidney disease progression.

Cohen, Debbie L.; Townsend, Raymond R.

2011-01-01

71

Factors affecting the progression of renal disease in autosomal-dominant polycystic kidney disease  

Microsoft Academic Search

Factors affecting the progression of renal disease in autosomal-dominant polycystic kidney disease. Autosomal-dominant polycystic kidney disease results in renal failure at a varying age from childhood to old age. We postulated that factors other than the culprit gene alone contribute to the course of progression of the renal failure. We studied 580 subjects with autosomal-dominant polycystic kidney disease and 194

Patricia A Gabow; Ann M Johnson; William D Kaehny; William J Kimberling; Dennis C Lezotte; Irene T Duley; Richard H Jones

1992-01-01

72

AUTONOMIC DYSFUNCTION AND PROGRESSION OF PARKINSON'S DISEASE  

Microsoft Academic Search

An exact quantitative evaluation method of autonomic dysfunction in Parkinson's disease (PD) for everyday clinical use has not been developed yet. The aim of this study was to evaluate autonomic cardiovascular regulation in mild and advanced stages of PD with the use of heart rate variability (HRV) examination. Twenty-five patients entered the study and passed short-term HRV examination in supine

73

Fibrosis and progression of autosomal dominant polycystic kidney disease (ADPKD).  

PubMed

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 are associated with progressive fibrosis. Similar to the correlation between tubulointerstitial fibrosis and progression of chronic kidney disease (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 matrix metalloproteinases (MMPs), over-expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), over-expression of plasminogen activator inhibitor-1 (PAI-1) and increased transforming growth factor beta (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 extracellular matrix (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. This article is part of a Special Issue entitled: Polycystic Kidney Disease. PMID:21745567

Norman, Jill

2011-07-01

74

Radiological diagnostic progress in skeletal diseases.  

PubMed

High-resolution bone imaging has made tremendous progress in the recent past. Both imaging modalities, computed tomography as well as MR imaging, have improved image quality. New developments such as HR-pQCT now make it possible to acquire in vivo images at peripheral sites with isotropic voxel size in a very short time. Further enhancements in the MR field have made it possible to image more central body sites such as the proximal femur with very high spatial resolution. New analysis methods can obtain direct estimates of biomechanical properties and important information related to bone's topology, as well as parameters of scale and orientation. These accomplishments will be essential in the noninvasive assessment of osteoporosis and fracture risk, will provide insight into the mechanisms behind bone loss, and will increasingly play a role as a tool for assessing treatment efficacy. PMID:22461797

Guglielmi, Giuseppe; Nasuto, Michelangelo; La Porta, Michele

2011-01-01

75

Radiological diagnostic progress in skeletal diseases  

PubMed Central

High-resolution bone imaging has made tremendous progress in the recent past. Both imaging modalities, computed tomography as well as MR imaging, have improved image quality. New developments such as HR-pQCT now make it possible to acquire in vivo images at peripheral sites with isotropic voxel size in a very short time. Further enhancements in the MR field have made it possible to image more central body sites such as the proximal femur with very high spatial resolution. New analysis methods can obtain direct estimates of biomechanical properties and important information related to bone’s topology, as well as parameters of scale and orientation. These accomplishments will be essential in the noninvasive assessment of osteoporosis and fracture risk, will provide insight into the mechanisms behind bone loss, and will increasingly play a role as a tool for assessing treatment efficacy.

Guglielmi, Giuseppe; Nasuto, Michelangelo; La Porta, Michele

2011-01-01

76

Monitoring of disease progression of HIV infection  

Microsoft Academic Search

\\u000a The CD4 T lymphocyte is one of the central targets for HIV infection. It is the selective deletion and depletion of this population\\u000a that appears largely responsible for the increasing range and severity of opportunistic infections and tumours that characterize\\u000a the later stages of the natural history of this disease. Decline over time of CD4 counts in patient populations has

A. G. Bird

77

An update on 'progression promoters' in renal diseases.  

PubMed Central

AIM: This paper reviews progression in renal diseases. METHODS: An English language literature search using Medline (1980 January-2001 July) was done to assess research and review articles on progression in renal diseases. RESULTS: Factors that increase the risk of progression in renal diseases are hypertension, dyslipidaemia, underlying nephropathy, high dietary protein intake and proteinuria. Others are smoking, hyperglycemia, low birth weight, obesity, metabolic syndrome X, genetic factors such as angiotensin converting enzyme 'DD' genotype and chromosome 1q21, and exposure to lead. Hypertension induces arteriolar nephrosclerosis. The mechanisms whereby lipids contribute to vascular and renal injury are incompletely understood. Glomerular hyperperfusion and increased proteinuria may explain the adverse effects of increased protein intake on renal disease progression. Proteinuria contains numerous toxic/inflammatory systems that promote progression. Cigarette smoking has vasoconstrictive, thrombotic and direct toxic effects on the vascular epithelium. Hyperglycemia is strongly implicated in the progression of complications in diabetics. Oligonephropathy in low birth weight has been suggested to increase the risk for systemic and glomerular hypertension in adult life. In obesity, the combination of hyperfiltration, glomerular hypertrophy and glomerular hypertension is a primary initiating event for glomerular injury manifesting as glomerulomegally and focal and segmental glomerulosclerosis and proteinuria. Angiotensin I, with enzyme insertion/deletion polymorphism, especially the "DD" genotype, predisposes to a rapid decline in renal function. Finally, long-term exposure to low levels of environmental lead affects renal function. CONCLUSION: The control of hypertension, dyslipidaemia, proteinuria, obesity, avoidance of low birth weight, smoking and heavy metals such as lead are intervention strategies for preventing progression of renal diseases.

Alebiosu, C. O.

2003-01-01

78

Estimating disease progression using panel data.  

PubMed

Continuous-time Markov processes are frequently used to describe the evolution of a disease over different phases. Such modeling can provide estimates for important parameters that are defined on the paths of the process. A simple example is the mean first hitting time to a set of states. However, more interesting events are defined by several time points such as the first time the process stays in state j for at least Delta time units. These kinds of events are very important in relapsing-remitting diseases such as in multiple sclerosis (MS) where the focus is on a sustained worsening that lasts 6 months or longer. The current paper considers data on independent continuous Markov processes that are only observed intermittently. It reviews modeling and estimation, presents a new general concept of hitting times, and provides point and interval estimates for it. The methodology is applied to data from a phase III clinical trial of Avonex--a drug given to MS patients. PMID:20064845

Mandel, Micha

2010-01-11

79

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

80

Risk factor reduction in progression of angiographic coronary artery disease  

PubMed Central

Introduction To investigate differences between outpatients with progressive and nonprogressive coronary artery disease (CAD) measured by coronary angiography. Material and methods Chart reviews were performed in patients in an outpatient cardiology practice having ? 2 coronary angiographies ? 1 year apart. Progressive CAD was defined as 1) new non-obstructive or obstructive CAD in a previously disease-free vessel; or 2) new obstruction in a previously non-obstructive vessel. Coronary risk factors, comorbidities, cardiovascular events, medication use, serum low-density lipoprotein cholesterol (LDL-C), and blood pressure were used for analysis. Results The study included 183 patients, mean age 71 years. Mean follow-up duration was 11 years. Mean follow-up between coronary angiographies was 58 months. Of 183 patients, 108 (59%) had progressive CAD, and 75 (41%) had nonprogressive CAD. The use of statins, ?-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and aspirin was not significantly different in patient with progressive CAD or nonprogressive CAD Mean arterial pressure was higher in patients with progressive CAD than in patients with nonprogressive CAD (97±13 mm Hg vs. 92±12 mm Hg) (p<0.05). Serum LDL-C was insignificantly higher in patients with progressive CAD (94±40 mg/dl) than in patients with nonprogressive CAD (81±34 mg/dl) (p=0.09). Conclusions Our data suggest that in addition to using appropriate medical therapy, control of blood pressure and serum LDL-C level may reduce progression of CAD.

Lai, Hoang M.; Mercando, Anthony D.; Kalen, Phoenix; Desai, Harit V.; Gandhi, Kaushang; Sharma, Mala; Amin, Harshad; Lai, Trung M.

2012-01-01

81

Progress update: Pharmacological treatment of Alzheimer's disease  

PubMed Central

A number of drugs have been approved for the treatment of Alzheimer’s disease (AD) and a larger number are being studied as possible therapies. The current mainstays of the pharmacotherapy of AD are the cholinesterase inhibitors (donepezil, galantamine, rivastigmine) and memantine. They collectively have acceptable tolerability and proven but modest efficacy. The agents being studied include dietary supplements (eg, vitamin E), herbal preparations (eg, Ginkgo biloba), medications approved for other indications (eg, HMG-CoA reductase enzyme inhibitors) and research drugs. In this review we discuss in detail the approved agents and review a number of the unapproved therapies that are currently available to the practitioner. While our era offers much more in the way of therapeutics for AD, it is clear that more work still needs to be done.

Hogan, David B

2007-01-01

82

Innate immune receptors: key regulators of metabolic disease progression.  

PubMed

The study of the intersection of immunology and metabolism is a growing field fueled by the increased prevalence of obesity-associated pathologies. Importantly, the capacity of the innate immune system to sense metabolic stress induced by nutritional surplus has been linked with the progression of obesity, insulin resistance, type 2 diabetes mellitus, nonalcoholic fatty liver disease, and atherosclerosis. Moreover, it is clear that the innate immune system regulates the composition of the intestinal microbiota, which impacts multiple host metabolic processes. Here we review recent studies in this emerging field with an emphasis on how innate immune receptors determine metabolic disease progression. PMID:23747246

Jin, Chengcheng; Henao-Mejia, Jorge; Flavell, Richard A

2013-06-01

83

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.

Norman, Jill

2011-01-01

84

An event-based model for disease progression and its application in familial Alzheimer's disease and Huntington's disease.  

PubMed

Understanding the progression of neurological diseases is vital for accurate and early diagnosis and treatment planning. We introduce a new characterization of disease progression, which describes the disease as a series of events, each comprising a significant change in patient state. We provide novel algorithms to learn the event ordering from heterogeneous measurements over a whole patient cohort and demonstrate using combined imaging and clinical data from familial Alzheimer's and Huntington's disease cohorts. Results provide new detail in the progression pattern of these diseases, while confirming known features, and give unique insight into the variability of progression over the cohort. The key advantage of the new model and algorithms over previous progression models is that they do not require a priori division of the patients into clinical stages. The model and its formulation extend naturally to a wide range of other diseases and developmental processes and accommodate cross-sectional and longitudinal input data. PMID:22281676

Fonteijn, Hubert M; Modat, Marc; Clarkson, Matthew J; Barnes, Josephine; Lehmann, Manja; Hobbs, Nicola Z; Scahill, Rachael I; Tabrizi, Sarah J; Ourselin, Sebastien; Fox, Nick C; Alexander, Daniel C

2012-01-16

85

Prostate Cancer Susceptibility Variants Confer Increased Risk of Disease Progression  

PubMed Central

Background Genome-wide association studies have identified numerous single nucleotide polymorphisms (SNPs) associated with the risk of prostate cancer. Our objective was to determine whether these SNPs impact progression of prostate cancer. Methods We genotyped 26 SNPs previously associated with prostate cancer risk among 788 aggressive prostate cancer patients who were treated by radical prostatectomy (RP) or radiation therapy (RT). Prostate cancer progression was defined as biochemical recurrence based on post-treatment prostate specific antigen levels >0.3 ng/ml for RP patients or 2 ng/ml increase above the nadir for RT patients, initiation of hormone treatment, or metastases. We assessed the association between independent and combined SNPs and disease progression by Cox proportional hazard regression. Results Five SNPs demonstrated independent associations with prostate cancer progression (rs12621278, rs629242, rs9364554, rs4430796, rs5945572) based on stepwise regression analysis. The strongest SNP was rs12621278 in the ITGA6 locus, which was associated with a 2.4-fold increased risk of progression (P = 0.0003). When considering the sum of risk alleles across these five SNPs, each additional allele was associated with a 29% increase in risk of progression (95% CI = 1.12-1-47). Conclusions We found that five of the recently highlighted prostate cancer susceptibility loci also influence prostate cancer progression beyond known clinicopathological predictors. If confirmed, these genetic variants may help clarify which tumors are likely to progress and require more aggressive treatment in contrast to those that may not have substantial impact on morbidity or mortality. Impact Genetic susceptibility variants for prostate cancer development may also inform disease progression.

Cheng, Iona; Plummer, Sarah J.; Neslund-Dudas, Christine; Klein, Eric A.; Casey, Graham; Rybicki, Benjamin A.; Witte, John S.

2010-01-01

86

Computational Approaches for Translational Clinical Research in Disease Progression  

PubMed Central

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

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

2011-01-01

87

Beryllium Sensitization Progresses to Chronic Beryllium Disease A Longitudinal Study of Disease Risk  

Microsoft Academic Search

The blood beryllium lymphocyte proliferation test is used in medical surveillance to identify both beryllium sensitization and chronic beryllium disease. Approximately 50% of individuals with beryllium sensitization have chronic beryllium disease at the time of their initial clinical evaluation; however, the rate of progression from beryllium sensitization to chronic beryllium disease is unknown. We monitored a cohort of beryllium-sensitized patients

Lee S. Newman; Margaret M. Mroz; Ronald Balkissoon; Lisa A. Maier

2004-01-01

88

Rate of progression differs in frontotemporal dementia and Alzheimer disease  

Microsoft Academic Search

Objective: To compare survival and rates of cognitive and functional decline in patients with autopsy- confirmed frontotemporal dementia (FTD) and Alzheimer disease (AD) in a large multicenter study. Background: Despite advances in the clinical characterization of FTD, little is known about its rate of progression. Characterizing survival and rate of decline in FTD is important because it can provide prognostic

K. Rascovsky; D. P. Salmon; A. M. Lipton; J. B. Leverenz; C. DeCarli; W. J. Jagust; C. M. Clark; M. F. Mendez; D. F. Tang-Wai; N. R. Graff-Radford; D. Galasko

2005-01-01

89

Vascular factors predict rate of progression in Alzheimer disease  

Microsoft Academic Search

Background: While there is considerable epidemiologic evidence that cardiovascular risk factors increase risk of incident Alzheimer disease (AD), few studies have examined their effect on pro- gression after an established AD diagnosis. Objective: To examine the effect of vascular factors, and potential age modification, on rate of progression in a longitudinal study of incident dementia. Methods: A total of 135

M. M. Mielke; P. B. Rosenberg; J. Tschanz; L. Cook; C. Corcoran; K. M. Hayden; M. Norton; P. V. Rabins; R. C. Green; K. A. Welsh-Bohmer; J. C. S. Breitner; R. Munger; C. G. Lyketsos

2007-01-01

90

Primary hyperaldosteronism, a mediator of progressive renal disease in cats  

Microsoft Academic Search

In recent years, there has been renewed interest in primary hyperaldosteronism, particularly because of its possible role in the progression of kidney disease. While most studies have concerned humans and experimental animal models, we here report on the occurrence of a spontaneous form of (non-tumorous) primary hyperaldosteronism in cats. At presentation, the main physical features of 11 elderly cats were

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

2005-01-01

91

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.

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

2007-01-01

92

Cerebrospinal Fluid Biomarkers for Parkinson Disease Diagnosis and Progression  

PubMed Central

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

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

2011-01-01

93

HIV-1 Transmission, Replication Fitness and Disease Progression  

PubMed Central

Upon transmission, human immunodeficiency virus type 1 (HIV-1) establishes infection of the lymphatic reservoir, leading to profound depletion of the memory CD4+ T cell population, despite the induction of the adaptive immune response. The rapid evolution and association of viral variants having distinct characteristics with different stages of infection, the level of viral burden, and rate of disease progression suggest a role for viral variants in this process. Here, we review the literature on HIV-1 variants and disease and discuss the importance of viral fitness for transmission and disease.

Biesinger, Tasha; Kimata, Jason T.

2009-01-01

94

Amyotrophic Lateral Sclerosis (ALS)  

MedlinePLUS

... progressive, invariably fatal neurological disease that attacks the nerve cells (neurons) responsible for controlling voluntary muscles. In ALS, ... Information New gene mutations linked to ALS and nerve cell growth dysfunction Researchers have linked newly discovered gene ...

95

Plasma sphingomyelins are associated with cognitive progression in Alzheimer's Disease  

PubMed Central

Plasma sphingolipids have been shown to predict cognitive impairment and hippocampal volume loss, but there is little research in patients with Alzheimer’s disease dementia (AD). In this study we sought to determine whether plasma ceramides, dihydroceramides (DHCer), sphingomyelins (SM), or dihydrosphingomyelin (DHSM) levels and ratios of SM/ceramide or DHSM/DHCer were predictive of progression in AD. Probable AD patients (n=120) were enrolled in the Alzheimer’s Disease and Memory Disorders Center at Baylor College of Medicine. Plasma sphingolipids were assessed using ESI/MS/MS. Linear mixed effects models were used to examine the relation between baseline plasma sphingolipid levels and cross-sectional and longitudinal performance on the Mini-Mental State Exam (MMSE), Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and Clinical Dementia Rating-Sum of Boxes (CDR-Sum). Participants were followed a mean of 4.2 visits and 2.3 years. There were no cross-sectional associations. In longitudinal analyses, high levels of DHCer and ceramide were associated with greater progression, but findings did not reach significance (p>0.05). In contrast, higher plasma levels of SM, DHSM, SM/ceramide and DHSM/DHCer ratios were associated with less progression on the MMSE and ADAS-Cog; the ratios were the strongest predictors of clinical progression. Compared to the lowest tertiles, the highest tertiles of DHSM/DHCer and SM/ceramide ratios declined 1.35 points (p=0.001) and 1.19 (p=0.004) less per year on the MMSE and increased 3.18 points (p=0.001) and 2.42 (p=0.016) less per year on the ADAS-Cog. These results suggest that increased SM/ceramide and DHSM/DHCer ratios dose-dependently predict slower progression among AD patients and may be sensitive blood-based biomarkers for clinical progression.

Mielke, Michelle M.; Haughey, Norman J.; Bandaru, Veera Venkata Ratnam; Weinberg, Danielle D.; Darby, Eveleen; Zaidi, Noman; Pavlik, Valory; Doody, Rachelle S.; Lyketsos, Constantine G.

2011-01-01

96

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.

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

2012-01-01

97

The beneficial role of intensive exercise on Parkinson disease progression.  

PubMed

In the last decade, a considerable number of articles has shown that exercise is effective in improving motor performance in Parkinson disease. In particular, recent studies have focused on the efficacy of intensive exercise in achieving optimal results in the rehabilitation of patients with Parkinson disease. The effects of intensive exercise in promoting cell proliferation and neuronal differentiation in animal models are reported in a large cohort of studies, and these neuroplastic effects are probably related to increased expression of a variety of neurotrophic factors. The authors outline the relation between intensive exercises and neuroplastic activity on animal models of Parkinson disease and discuss the clinical results of different intensive strategies on motor performance and disease progression in patients with Parkinson disease. PMID:23552330

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

2013-06-01

98

Imaging and CFD in the analysis of vascular disease progression  

NASA Astrophysics Data System (ADS)

Conventional evaluation of the significance of vascular disease has focused on estimates of geometric factors. There is now substantial interest in investigating whether the onset and progression of vascular pathology can be related to hemodynamic factors. Current imaging modalities have excellent capabilities in delineating the geometric boundaries of the vascular lumen. Advanced non-invasive imaging modalities such as Multi Detector CT and MRI are also able to define the extent of disease within the vessel wall and to provide information on the composition of thrombotic and atherosclerotic components. Finally, it is also possible to use imaging techniques to measure flow velocities across the lumen of vessels of interest, and to determine the pulsatile variation of these velocities through the cardiac cycle. Despite these advanced capabilities, imaging alone is unable to determine important features of the vascular hemodynamics such as wall shear stress or pressure distributions. However, the information on lumenal geometry and the inlet and outlet flow conditions can be used as input into numerical simulation models that are able to predict those quantities. These Computational Fluid Dynamics models can be used to predict hemodynamic parameters on a patient-specific basis. It is therefore possible to use non-invasive imaging methods to follow the progression of vascular disease over time, and to relate changes in lumenal and wall structure to calculated hemodynamic descriptors. This approach can be used not only to understand the natural progression of vascular disease, but as a tool to predict the likely outcome of a surgical intervention.

Saloner, David; Acevedo-Bolton, Gabriel; Rayz, Vitaliy; Wintermark, Max; Martin, Alastair; Dispensa, Brad; Young, William; Lawton, Michael; Rapp, Joseph; Jou, Liang-Der

2006-03-01

99

Nutrient enrichment enhances black band disease progression in corals  

NASA Astrophysics Data System (ADS)

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

Voss, Joshua D.; Richardson, Laurie L.

2006-11-01

100

Exosomes-associated neurodegeneration and progression of Parkinson's disease  

PubMed Central

Growing evidence indicates the role of exosomes in a variety of physiological pathways as conveyors of biological materials from cell-to-cell. However the molecular mechanism(s) of secretion and their interaction with receiving cells are yet unclear. Recently, it is emerging that exosomes are involved in pathological processes as potential carriers in the progression of neurodegenerative pathologies associated with misfolded proteins. In the current review we will discuss some recent findings on the key role of exosomes in the spreading of the aggregated products of ?-synuclein from neuron-to-neuron and of inflammatory response propagation from immune cell-to-cell; we will highlight the implication of exosomes in the neurodegeneration and progression of the disease and the their potential interplay with genes related to Parkinson’s disease. Increasing our knowledge on the cell-to-cell transmissions might provide new insights into mechanism of disease onset and progression and identify novel strategies for diagnosis and therapeutic intervention in Parkinson and other neurodegenerative diseases.

Russo, Isabella; Bubacco, Luigi; Greggio, Elisa

2012-01-01

101

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.

Robles, Alfredo

2009-01-01

102

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

PubMed Central

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

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

2010-01-01

103

Disease-modifying treatments for progressive multiple sclerosis.  

PubMed

The last 20 years have seen major progress in the treatment of relapsing-remitting multiple sclerosis (RRMS) using a variety of drugs targeting immune dysfunction. In contrast, all clinical trials of such agents in primary progressive multiple sclerosis (PPMS) have failed and there is limited evidence of their efficacy in secondary progressive disease. Evolving concepts of the complex interplay between inflammatory and neurodegenerative processes across the course of multiple sclerosis (MS) may explain this discrepancy. This paper will provide an up-to-date overview of the rationale and results of the published clinical trials that have sought to alter the trajectory of both primary and secondary MS, considering studies involving drugs with a primary immune target and also those aiming for neuroprotection. Future areas of study will be discussed, building on these results combined with the experience of treating RRMS and new concepts emerging from laboratory science and animal models. PMID:24062415

Comi, Giancarlo

2013-10-01

104

No benefit of dietary restriction on disease onset or progression in amyotrophic lateral sclerosis Cu\\/Zn-superoxide dismutase mutant mice  

Microsoft Academic Search

Amyotrophic lateral sclerosis (ALS) is a fatal disease in which spinal cord motor neurons degenerate resulting in progressive paralysis. Some cases of ALS are caused by mutations in the antioxidant enzyme Cu\\/Zn-superoxide dismutase (SOD). Transgenic mice expressing ALS-linked Cu\\/Zn-SOD mutations (SODMutM) exhibit a phenotype analogous to that of human ALS patients. Dietary restriction (DR) is a well-established means of extending

Ward A. Pedersen; Mark P. Mattson

1999-01-01

105

Exercise and disease progression in multiple sclerosis: can exercise slow down the progression of multiple sclerosis?  

PubMed Central

It has been suggested that exercise (or physical activity) might have the potential to have an impact on multiple sclerosis (MS) pathology and thereby slow down the disease process in MS patients. The objective of this literature review was to identify the literature linking physical exercise (or activity) and MS disease progression. A systematic literature search was conducted in the following databases: PubMed, SweMed+, Embase, Cochrane Library, PEDro, SPORTDiscus and ISI Web of Science. Different methodological approaches to the problem have been applied including (1) longitudinal exercise studies evaluating the effects on clinical outcome measures, (2) cross-sectional studies evaluating the relationship between fitness status and MRI findings, (3) cross-sectional and longitudinal studies evaluating the relationship between exercise/physical activity and disability/relapse rate and, finally, (4) longitudinal exercise studies applying the experimental autoimmune encephalomyelitis (EAE) animal model of MS. Data from intervention studies evaluating disease progression by clinical measures (1) do not support a disease-modifying effect of exercise; however, MRI data (2), patient-reported data (3) and data from the EAE model (4) indicate a possible disease-modifying effect of exercise, but the strength of the evidence limits definite conclusions. It was concluded that some evidence supports the possibility of a disease-modifying potential of exercise (or physical activity) in MS patients, but future studies using better methodologies are needed to confirm this.

Stenager, Egon

2012-01-01

106

State-space size considerations for disease-progression models.  

PubMed

Markov models of disease progression are widely used to model transitions in patients' health state over time. Usually, patients' health status may be classified according to a set of ordered health states. Modelers lump together similar health states into a finite and usually small, number of health states that form the basis of a Markov chain disease-progression model. This increases the number of observations used to estimate each parameter in the transition probability matrix. However, lumping together observably distinct health states also obscures distinctions among them and may reduce the predictive power of the model. Moreover, as we demonstrate, precision in estimating the model parameters does not necessarily improve as the number of states in the model declines. This paper explores the tradeoff between lumping error introduced by grouping distinct health states and sampling error that arises when there are insufficient patient data to precisely estimate the transition probability matrix. Copyright © 2013 John Wiley & Sons, Ltd. PMID:23609629

Regnier, Eva D; Shechter, Steven M

2013-04-23

107

Assessment of coronary heart diseases in diabetics in al-Madinah al-Munawarah  

PubMed Central

Background Coronary heart disease is highly prevalent and a major cause of morbidity and mortality in diabetic patients. The aim of this study was to assess the major risk factors and their predictor score for coronary heart diseases in diabetic patients. Methods The present study was conducted in al-Madinah, Kingdom of Saudi Arabia. Using a cross-sectional case control study, 262 outpatient diabetics and 264 matched control subjects were examined for the risk factors and risk predictor scores for ischemic heart disease. The mean age of the patient and control groups was 49.61 ± 12.93 years and 48.39 ± 11.60 years, respectively. Results Diabetic patients had significantly higher positive family history of diabetes, but no significant difference regarding their family history of hypertension. There was a significantly higher body mass index (33.67 kg/m2), glycosylated hemoglobin (7.26%), significantly higher cholesterol, low-density lipoprotein, and triglyceride in diabetics compared to control. Diabetic patients had higher risk for developing coronary heart disease with a mean risk score of 6.07 while the control subject risk score was ?6.81. However, females showed significantly higher risk for coronary heart diseases than did males. Conclusion Our study replicates the known fact of higher risk in diabetes, but higher risk of coronary heart disease in female diabetics compared with male diabetics.

al-Nozha, Omar; Mojadadi, Moaz; Mosaad, Mohamed; El-Bab, Mohamed F

2012-01-01

108

Contributions of Muhadhdhab Al-Deen Al-Baghdadi to the progress of medicine and urology. A study and translations from his book Al-Mukhtar.  

PubMed

This study of the Arabic 4-volume book of Al-Mukhtar Fi Al-Tibb (Choice Book on Medicine) written by the Muslim physician Muhadhdhab Al-Deen Al-Baghdadi (515-610 H, 1117-1213 AD) aimed at evaluating his contributions to the progress of medicine and urology along with providing English translations of relevant excerpts. Al-Baghdadi laid emphasis on the morals of medical practice and the principles of medical education describing how to select medical students and how to evaluate graduates. He stressed on the need for a long training program directly supervised by skilled expert doctors both in hospitals (Al-Bimaristanat) and during home visits. A good part of volume 1 was allocated to preventive medicine and the whole of volume 2 was devoted to the pharmacy section, which he restricted to what was proven by the experience of his teacher and by his own experiments. Same as all his predecessors in the Islamic era, Al-Baghdadi stressed the importance of clinical medicine and gave more details related to history taking, physical examination, differential diagnosis and prognosis. Similar to them, he also, emphasized that a doctor should be quite knowledgeable in anatomy. Furthermore, the presence of anatomical drawings in Kitab Al-Mukhtar Fi Al-Tibb is a further step forward in illustrating medical text books; a trend that flourished in the Islamic era reflecting the role of direct observations and experience. The detailed description of the functional anatomy of the uretero-vesical junction and the antireflux and micturition mechanisms given by Al-Baghdadi is contrary to that of Galen (130-200 AD) but conforms well to our contemporary understanding. In the conservative management of urinary stones, he described 70 simple and 13 compound drugs while those described by Pulus of Aegina (625-690 AD) were only 20 simple and 3 compound drugs. Furthermore, Al-Baghdadi's description of the instruments and techniques of urethral catheterization, perineal cystolithotomy and perineal cystolithotripsy using Al-Zahrawi's lithotrite is meticulous and reveals originality, dexterity and experience. PMID:17106533

Abdel-Halim, Rabie E

2006-11-01

109

Progress in Mining the Human Proteome for Disease Applications  

PubMed Central

Abstract Currently available technologies allow in-depth analysis of multiple facets of the proteome that have clinical relevance and that complement current genomics-based approaches. Although some progress has been made in our knowledge of the human proteome in health and in disease, there is an urgent need to chart a coherent road map with clearly defined milestones to guide proteomics efforts. Areas of emphasis include: (1) building resources, (2) filling gaps in our understanding of biological variation, and (3) systematically characterizing proteome alterations that occur in well-defined disease states, all of which require an organized and collaborative effort.

2011-01-01

110

Progressive Multifocal Leukoencephalopathy after Natalizumab Therapy for Crohn's Disease  

Microsoft Academic Search

The prior diagnosis of fatal astrocytoma in a 60-year-old man with Crohn's disease treated with natalizumab, a monoclonal antibody against a 4 integrins, was reclassified as JC virus-related progressive multifocal leukoencephalopathy (PML). Analysis of fro- zen serum samples showed that JC virus DNA had appeared in the serum three months after the initiation of open-label natalizumab monotherapy and two months

Gert Van Assche; Marc Van Ranst; Raf Sciot; Bénédicte Dubois; Séverine Vermeire; Maja Noman; Jannick Verbeeck; Karel Geboes; Wim Robberecht; Paul Rutgeerts

2005-01-01

111

Modification of disease progression in rats with inherited polycystic kidney disease  

Microsoft Academic Search

The most common inherited form of human polycystic kidney disease (PKD), autosomal dominant PKD (ADPKD), is a leading cause of chronic renal failure, but has a variable clinical presentation, with end-stage renal disease occurring in only 25% to 75%. Several findings are consistent with the idea that factors in addition to the primary mutation can affect the progression of cystic

B. D. Cowley; J. J. Grantham; M. J. Muessel; A. L. Kraybill; V. H. Gattone

1996-01-01

112

How to detect disease progression in pulmonary arterial hypertension.  

PubMed

Pulmonary arterial hypertension (PAH) is a rapidly progressive disease, ultimately leading to right heart failure and death. Accumulating evidence indicates that intervention early in disease progression results in better outcomes than delaying treatment. In this review we will discuss the assessments and strategies that can be used to monitor disease progression and guide clinical management. Many tools, such as symptoms, functional classification, exercise capacity, haemodynamic measures, findings on cardiac imaging and levels of biomarkers, have shown to be prognostic for survival both at diagnosis and during treatment. However, attempts to define goal thresholds have produced a variety of results. Several groups have developed risk calculators to estimate individual patients' mortality risk, but the accuracy of these tools across different patient populations remains unknown. What is clear is the importance of regularly assessing a range of parameters and then tailoring treatment goals to each patient. In addition, the use of a multidisciplinary team approach is crucial in order to support patients through all aspects of managing their condition. There is still an urgent need for prospective collaborative initiatives to assess novel goals and improve treatment strategies that would allow physicians to personalise and optimise clinical management for their patients with PAH. PMID:22379173

Vachiéry, J-L; Yerly, P; Huez, S

2012-03-01

113

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

114

Radiation therapy in Hodgkin's disease - decades of steady progress.  

PubMed

The treatment of lymphoproliferative diseases has changed dramatically during the last decades. The improved therapeutic results for this disease group are included among the most important achievements of modern oncohaematology. They are due to better disease staging, use of new markers for risk assessment, patient stratification in separate risk groups, implementation of highly effective chemotherapy (CHT), progress of targeted therapies using monoclonal antibodies, proteasome inhibitors, modern radiation therapy (RT) and supportive care. The achieved progress, especially in the treatment of Hodgkin's disease (HD), is an example of the fundamental dependence of clinical practice on the scientific achievements, mainly in the field of diagnostics and in the two pure anticancer therapeutic modalities: chemo- and radiotherapy. The aim of this article was to discuss the basic variants of RT in the multimodal treatment of HD and the clinical experience accumulated during the last decades. The experience gained in the area of involved field RT (IFRT) and extended field RT (EFRT), both alone or as a part of the combined-therapy protocols, is considered in detail. The role of RT is also discussed as a part of the dose-escalated CHT combined programmes for patients recurring, progressing or partially responding to treatment, carried out mainly as IFRT, total lymphoid irradiation (TLI) or total body irradiation (TBI). Regardless of the already attained achievements of the combined treatment at the present stage of development of oncological knowledge, there is still no consensus with respect to the optimal therapy of HD in children and in adult patients. New trials addressing issues of the best modality, best RT technique, optimal dose of RT, optimal number of cycles and timing of CHT are still needed. The contemporary challenge is to optimize treatment so that it can be accomplished with the least toxicity, lowest cost, and greatest efficiency possible. PMID:20658714

Gocheva, L

115

2-Hydroxyestradiol slows progression of experimental polycystic kidney disease  

PubMed Central

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

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

2012-01-01

116

Progressive bradykinesia and hypokinesia of ocular pursuit in Parkinson's disease  

PubMed Central

OBJECTIVES—Patients with Parkinson's disease characteristically have difficulty in sustaining repetitive motor actions. The purpose of this study was to establish if parkinsonian difficulty with sustaining repetitive limb movements also applies to smooth ocular pursuit and to identify any pursuit abnormalities characteristic of Parkinson's disease.?METHODS—Ocular pursuit in seven patients with moderate to severe bradykinesia predominant Parkinson's disease was compared with seven age matched controls. Predictive and non-predictive pursuit of constant velocity target ramps were examined. Subjects pursued intermittently illuminated 400/s ramps sweeping to the left or right with an exposure duration of 480 ms and average interval of 1.728 s between presentations. To examine for any temporal changes in peak eye velocity, eye displacement or anticipatory smooth pursuit the 124 s duration of each record was divided into four epochs (E1, E2, E3, E4), each lasting 31 s and containing 18 ramp stimuli. Three test conditions were examined in each subject: predictive (PRD1), non-predictive (NPD), and predictive (PRD2) in that order.?RESULTS—Both patients and controls initiated appropriate anticipatory pursuit before target onset in the PRD1 and PRD2 conditions that enhanced the response compared with the NPD condition. The distinctive findings in patients with Parkinson's disease were a reduction in response magnitude compared with controls and a progressive decline of response with stimulus repetition. The deficits were explained on the basis of easy fatiguability in Parkinson's disease.?CONCLUSIONS—Ocular pursuit shows distinct anticipatory movements in Parkinson's disease but peak velocity and displacement are reduced and progressively decline with repetition as found with limb movements.??

Lekwuwa, G; Barnes, G; Collins, C; Limousin, P

1999-01-01

117

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.

Laouari, Denise; Burtin, Martine; Phelep, Aurelie; Bienaime, Frank; Noel, Laure-Helene; Lee, David C; Legendre, Christophe; Friedlander, Gerard; Pontoglio, Marco; Terzi, Fabiola

2012-01-01

118

High Degree of Heterogeneity in Alzheimer's Disease Progression Patterns  

PubMed Central

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

Komarova, Natalia L.; Thalhauser, Craig J.

2011-01-01

119

The Omega-3 Fatty Acid Eicosapentaenoic Acid Accelerates Disease Progression in a Model of Amyotrophic Lateral Sclerosis  

PubMed Central

Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease characterised by loss of motor neurons that currently has no cure. Omega-3 polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA), have many health benefits including neuroprotective and myoprotective potential. We tested the hypothesis that a high level of dietary EPA could exert beneficial effects in ALS. The dietary exposure to EPA (300 mg/kg/day) in a well-established mouse model of ALS expressing the G93A superoxide dismutase 1 (SOD1) mutation was initiated at a pre-symptomatic or symptomatic stage, and the disease progression was monitored until the end stage. Daily dietary EPA exposure initiated at the disease onset did not significantly alter disease presentation and progression. In contrast, EPA treatment initiated at the pre-symptomatic stage induced a significantly shorter lifespan. In a separate group of animals sacrificed before the end stage, the tissue analysis showed that the vacuolisation detected in G93A-SOD1 mice was significantly increased by exposure to EPA. Although EPA did not alter motor neurone loss, EPA reversed the significant increase in activated microglia and the astrocytic activation seen in G93A-SOD1 mice. The microglia in the spinal cord of G93A-SOD1 mice treated with EPA showed a significant increase in 4-hydroxy-2-hexenal, a highly toxic aldehydic oxidation product of omega-3 fatty acids. These data show that dietary EPA supplementation in ALS has the potential to worsen the condition and accelerate the disease progression. This suggests that great caution should be exerted when considering dietary omega-3 fatty acid supplements in ALS patients.

Gladman, Stacy; Biggio, Maria Luigia; Marino, Marianna; Jayasinghe, Maduka; Ullah, Farhan; Dyall, Simon C.; Malaspina, Andrea; Bendotti, Caterina; Michael-Titus, Adina

2013-01-01

120

Epigenetics of progression of chronic kidney disease: fact or fantasy?  

PubMed

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

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

2013-07-01

121

Allopurinol for prevention of progression of kidney disease with hyperuricemia  

PubMed Central

Hyperuricemia is associated with hypertension and progressive chronic renal disease. This is a retrospective cohort study in chronic kidney disease (CKD) patients with hyperuricemia from 1998 to 2008. Patients were divided into two groups: treatment group who received allopurinol in a dose of 100 mg/day and the other group remained untreated. Clinical, hematologic, biochemical parameters and outcome were measured at baseline and 6 months, 1 year, and 2 years of treatment. A total of 183 patients were enrolled. Mean age of the allopurinol group was 50.15 ± 14.42 years and control group was 53.23 ± 13.86 years. Male-female ratios were 2.57:1 and 2.21:1 for the treatment and control groups, respectively. Baseline characteristics and the laboratory parameters were similar in both groups. Patients who received allopurinol had lower blood pressure at 6 months, 1 year, and 2 years when compared to baseline. There was a significant decrease in the serum uric acid (UA) levels in the treatment group at the end of 6 months, 1 year, and 2 years with respect to base line. An inverse correlation as noted between serum UA levels and the estimated glomerular filtration rate at 6 months, 1 year, and 2 years. Allopurinol treatment decreases blood UA levels and is associated with better blood pressure control and decreased progression of renal disease in CKD patients with hyperuricemia.

Pai, B. H. Santhosh; Swarnalatha, G.; Ram, R.; Dakshinamurty, K. V.

2013-01-01

122

The genetics of Parkinson's disease: progress and therapeutic implications.  

PubMed

The past 15 years has witnessed tremendous progress in our understanding of the genetic basis for Parkinson's disease (PD). Notably, whereas most mutations, such as those in SNCA, PINK1, PARK2, PARK7, PLA2G6, FBXO7, and ATP13A2, are a rare cause of disease, one particular mutation in LRRK2 has been found to be common in certain populations. There has been considerable progress in finding risk loci. To date, approximately 16 such loci exist; notably, some of these overlap with the genes known to contain disease-causing mutations. The identification of risk alleles has relied mostly on the application of revolutionary technologies; likewise, second-generation sequencing methods have facilitated the identification of new mutations in PD. These methods will continue to provide novel insights into PD. The utility of genetics in therapeutics relies primarily on leveraging findings to understand the pathogenesis of PD. Much of the investigation into the biology underlying PD has used these findings to define a pathway, or pathways, to pathogenesis by trying to fit disparate genetic defects onto the same network. This work has had some success, particularly in the context of monogenic disease, and is beginning to provide clues about potential therapeutic targets. Approaches toward therapies are also being provided more directly by genetics, notably by the reduction and clearance of alpha-synuclein and inhibition of Lrrk2 kinase activity. We believe this has been an exciting, productive time for PD genetics and, furthermore, that genetics will continue to drive the etiologic understanding and etiology-based therapeutic approaches in this disease. PMID:23389780

Singleton, Andrew B; Farrer, Matthew J; Bonifati, Vincenzo

2013-01-01

123

Effect of Maraviroc on HIV Disease Progression-Related Biomarkers  

PubMed Central

The potential effect of blocking the CCR5 receptor on HIV disease progression biomarkers is not well understood. We showed that an 8-day maraviroc (MVC) monotherapy clinical test (MCT) can be used in selecting patients to receive MVC-containing combined antiretroviral therapy (cART). Using this MCT model, we assessed the effect of MVC on several HIV disease progression biomarkers during the MCT (MVC-specific effect) and following short-term (12-week) cART. We compared 45 patients on MVC monotherapy with a control group of 25 patients on MVC-sparing cART. We found that MVC did not modify any biomarkers in patients that had no virological response after the MCT. MVC-specific effects in patients with virological responses included increased CD8+ T-cell activation and senescence levels, preservation of an increase in soluble CD14 (sCD14), and a decrease in D dimer levels. After 12 weeks, MVC-containing cART increased CD8+ T-cell counts and preserved CD4+ T-cell senescence levels compared with MVC-sparing cART. Moreover, there was a decrease in sCD14 levels in patients that received MVC-containing cART. In conclusion, effects compatible with CD8+ T-cell redistribution in peripheral blood were observed after MVC therapy. However, MVC was associated with a favorable profile in HIV disease progression biomarkers only in patients with a virological response. These results support a potential clinical benefit of a therapy which includes MVC in HIV-infected patients.

Romero-Sanchez, M. Concepcion; Machmach, Kawthar; Gonzalez-Serna, Alejandro; Genebat, Miguel; Pulido, Ildefonso; Garcia-Garcia, Maria; Alvarez-Rios, Ana Isabel; Ferrando-Martinez, Sara

2012-01-01

124

The Impact of Gender on Progression of Renal Disease  

PubMed Central

Male gender is associated with a more rapid progression of renal disease independent of blood pressure, dietary protein intake, or serum lipid levels. Recently, we reported a key role for the intrarenal vasculature in progressive renal disease (Kang D-H, Kanellis J, Hugo C, Truong L, Anderson S, Kerjaschki D, Schreiner GF, Johnson RJ: Role of endothelium in progressive renal disease. J Am Soc Nephrol 2002, 13:806–816). We hypothesized that estrogen-mediated preservation of the renal vasculature could account for the better renal outcome in female rats. We analyzed micro- and macrovascular changes in the 5/6 remnant kidney (RK) models both in male (n = 24) and female (n = 24) Sprague-Dawley rats up to 12 weeks after renal mass reduction. At 12 weeks, male and female RK rats had equivalent blood pressure, glomerular tuft area, and RK/body weight, but male rats showed worse renal function, proteinuria, glomerulosclerosis (%), and tubulointerstitial fibrosis. At 12 weeks peritubular capillary (PTC) EC proliferation and PTC density were higher in female RK rats whereas macrovascular changes in preglomerular vessels (smooth muscle cell proliferation, medial wall thickening, and adventitial fibrosis) were less prominent. The expression of vascular endothelial growth factor (VEGF) and VEGF type 2 receptor (flk-1) in renal cortex assessed by immunostaining were higher in female RK rats. To dissect the mechanism of sex hormone-induced vascular remodeling and VEGF regulation, we investigated the in vitro effect of 17?-estradiol (17?E, 10 nmol/L) on proliferation and VEGF expression of renal tubular cells (rat proximal tubular cells), vascular smooth muscle cells (VSMCs), and human umbilical vein endothelial cells (HUVECs). 17?E directly stimulated the proliferation of HUVECs, whereas it inhibited serum-induced proliferation of VSMCs. 17?E stimulated VEGF mRNA expression both in renal tubular cells and VSMCs. However, when cells were pretreated with a nitric oxide donor to simulate the in vivo condition, 17?E inhibited VEGF mRNA expression and protein release in VSMCs. In conclusion, female RK rats developed less glomerulosclerosis and renal failure compared to male RK rats in association with greater preservation of PTC and less preglomerular arteriopathy. Estrogen stimulated basal VEGF expression in renal tubular cells. We propose that estrogen may protect female rats in progressive renal disease by stimulating VEGF expression and maintaining a healthy intrarenal vasculature.

Kang, Duk-Hee; Yu, Eun Sun; Yoon, Kyun-Il; Johnson, Richard

2004-01-01

125

Prevalence and progression of diabetes in mitochondrial disease  

Microsoft Academic Search

Aims\\/Hypothesis  The aims of this study were (1) to determine the prevalence and rate of progression in diabetes secondary to mitochondrial\\u000a DNA (mtDNA) mutations; and (2) to determine whether percentage heteroplasmy predicts clinical outcome in patients carrying\\u000a the m.3243A>G mutation.\\u000a \\u000a \\u000a \\u000a Methods  We prospectively assessed 242 patients attending a specialist neuromuscular clinic using a validated mitochondrial disease\\u000a rating scale. Retrospective clinical data on

R. G. Whittaker; A. M. Schaefer; R. McFarland; R. W. Taylor; M. Walker; D. M. Turnbull

2007-01-01

126

Fabrication, phase transformation studies and characterization of SiC-AlN-Al2OC ceramics. Progress report.  

National Technical Information Service (NTIS)

The research effort conducted to date had two specific objectives: (1) to determine phase relations and phase transformations in SiC-AlN, AlN-Al(sub 2)OC, and SiC-Al(sub 2)OC pseudobinary systems and in SiC-AlN-Al(sub 2)OC pseudoternary system, and (2) to...

A. V. Virkar

1990-01-01

127

Network biomarkers reveal dysfunctional gene regulations during disease progression.  

PubMed

Extensive studies have been conducted on gene biomarkers by exploring the increasingly accumulated gene expression and sequence data generated from high-throughput technology. Here, we briefly report on the state-of-the-art research and application of biomarkers from single genes (i.e. gene biomarkers) to gene sets (i.e. group or set biomarkers), gene networks (i.e. network biomarkers) and dynamical gene networks (i.e. dynamical network biomarkers). In particular, differential and dynamical network biomarkers are used as representative examples to demonstrate their effectiveness in both detecting early signals for complex diseases and revealing essential mechanisms on disease initiation and progression at a network level. PMID:24107168

Zeng, Tao; Sun, Shao-Yan; Wang, Yong; Zhu, Hailong; Chen, Luonan

2013-10-22

128

Lipoproteins and apolipoproteins during the progression of chronic renal disease.  

PubMed

The association between lipoprotein and apolipoprotein levels and the degree of renal failure was investigated in 72 conservatively treated patients with chronic renal disease. The progression of renal insufficiency was attended by marked increases in total triglycerides, and very-low-density (VLDL), low-density (LDL) and high-density (HDL) lipoprotein triglycerides. Total cholesterol was slightly elevated due to a rise in VLDL cholesterol. There was no change in LDL cholesterol, whereas HDL cholesterol decreased. Apo C-II and C-III showed distinct increases, their mass ratio decreasing only insignificantly. Apo B and A-I were unaffected by the degree of renal insufficiency, whereas apo A-II decreased. The findings reflect compositional changes within HDL and the accumulation to triglyceride-rich lipoproteins in chronic renal disease. The alterations in the plasma lipoprotein pattern were demonstrable even in early stages of renal failure and, therefore, may bear a serious risk for the acceleration of atherosclerosis. PMID:3221949

Grützmacher, P; März, W; Peschke, B; Gross, W; Schoeppe, W

1988-01-01

129

Nicotine signaling and progression of chronic kidney disease in smokers.  

PubMed

The deleterious health effects of cigarette smoking are far reaching, and it remains the most important modifiable risk factor for improving overall morbidity and mortality. In addition to being a risk factor for cancer, cardiovascular disease and lung disease, there is strong evidence, both from human and animal studies, demonstrating a role for cigarette smoking in the progression of chronic kidney disease (CKD). Clinical studies have shown a strong correlation between cigarette smoking and worsening CKD in patients with diabetes, hypertension, polycystic kidney disease, and post kidney transplant. Nicotine, in addition to its role in the addictive properties of cigarette smoking, has other biological effects via activation of non-neuronal nicotinic acetylcholine receptors (nAChRs). Several nAChR subunits are expressed in the normal kidney and blockade of the ?7-nAChR subunit ameliorates the effects of nicotine in animal models of CKD. Nicotine increases the severity of renal injury in animal models including acute kidney injury, diabetes, acute nephritis and subtotal nephrectomy. The renal effects of nicotine are also linked to increased generation of reactive oxygen species and activation of pro-fibrotic pathways. In humans, nicotine induces transitory increases in blood pressure accompanied by reductions in glomerular filtration rate and effective renal plasma flow. In summary, clinical and experimental evidence indicate that nicotine is at least in part responsible for the deleterious effects of cigarette smoking in the progression of CKD. The mechanisms involved are the subject of active investigation and may result in novel strategies to ameliorate the effects of cigarette smoking in CKD. PMID:23892062

Jain, Gaurav; Jaimes, Edgar A

2013-07-26

130

Genetic Biomarkers for ALS Disease in Transgenic SOD1G93A Mice  

PubMed Central

The pathophysiological mechanisms of both familial and sporadic Amyotrophic Lateral Sclerosis (ALS) are unknown, although growing evidence suggests that skeletal muscle tissue is a primary target of ALS toxicity. Skeletal muscle biopsies were performed on transgenic SOD1G93A mice, a mouse model of ALS, to determine genetic biomarkers of disease longevity. Mice were anesthetized with isoflurane, and three biopsy samples were obtained per animal at the three main stages of the disease. Transcriptional expression levels of seventeen genes, Ankrd1, Calm1, Col19a1, Fbxo32, Gsr, Impa1, Mef2c, Mt2, Myf5, Myod1, Myog, Nnt, Nogo A, Pax7, Rrad, Sln and Snx10, were tested in each muscle biopsy sample. Total RNA was extracted using TRIzol Reagent according to the manufacturer's protocol, and variations in gene expression were assayed by real-time PCR for all of the samples. The Pearson correlation coefficient was used to determine the linear correlation between transcriptional expression levels throughout disease progression and longevity. Consistent with the results obtained from total skeletal muscle of transgenic SOD1G93A mice and 74-day-old denervated mice, five genes (Mef2c, Gsr, Col19a1, Calm1 and Snx10) could be considered potential genetic biomarkers of longevity in transgenic SOD1G93A mice. These results are important because they may lead to the exploration of previously unexamined tissues in the search for new disease biomarkers and even to the application of these findings in human studies.

Calvo, Ana C.; Manzano, Raquel; Atencia-Cibreiro, Gabriela; Olivan, Sara; Munoz, Maria J.; Zaragoza, Pilar; Cordero-Vazquez, Pilar; Esteban-Perez, Jesus; Garcia-Redondo, Alberto; Osta, Rosario

2012-01-01

131

Elevated 4-hydroxyhexenal in Alzheimer's disease (AD) progression  

PubMed Central

Multiple studies have demonstrated elevations of ?, ?-unsaturated aldehydes including, 4-hydroxynonenal (HNE) and acrolein, in vulnerable regions of mild cognitive impairment (MCI), preclinical Alzheimer’s disease (PCAD), and late-stage Alzheimer’s disease (LAD) brain. However, there has been limited study of a third member, 4-hydroxyhexenal (HHE), a diffusible lipid peroxidation product of the ?-3 polyunstataturated fatty acids (PUFAs). In the present study levels of extractable and protein-bound HHE were quantified in the hippocampus/parahippocampal gyrus (HPG), superior and middle temporal gyri (SMTG), and cerebellum (CER) of MCI, PCAD, LAD, and normal control (NC) subjects. Levels of extractable and protein-bound HHE were increased in multiple regions in the progression of AD. Extractable HHE was significantly elevated in the hippocampus/parahippocampal gyrus (HPG) of PCAD and LAD subjects and protein-bound HHE was significantly higher in MCI, PCAD, and LAD HPG. A time- and concentration-dependent decrease in survival and a concentration dependent decrease in glucose uptake were observed in primary cortical cultures treated with HHE. Together these data support a role for lipid peroxidation in the progression of AD.

Bradley, M. A.; Xiong-Fister, S.; Markesbery, W. R.; Lovell, M. A.

2010-01-01

132

Aminopeptidase A (= angiotensinase A) in human progressive renal disease.  

PubMed

To elucidate factors possibly involved in adaptive cell responses due to progressive deterioration of glomerular structure and function, the activity of angiotensinase A (ATA), a glycoprotein of the glomerular tuft and of the proximal tubule, was analyzed on human kidney sections applying quantitative image analysis. Based on the software the exclusive glomerular expression of ATA was assessed in normal controls and 34 kidneys of patients with various stages of renal insufficiency (1.3-12 mg/dl serum creatinine). The data from diseased kidneys revealed a reduced total ATA-positive glomerular compartment, a larger area of remaining glomeruli, and a rise of the ATA-negative renal interstitium. Irrespective of the progression of the disease, hypertrophic glomeruli of remnant nephrons exhibited a high and homogeneous expression of ATA. Survival of glomeruli in patients with chronic renal failure correlated with the capability of glomerular cells to synthesize ATA at an increased rate, which may prevent angiotensin II-mediated growth effects, the accumulation of extracellular matrix proteins, etc., thus escaping final glomerulosclerosis. PMID:1465088

Scherberich, J E; Matthess, A; Remelius, W; Schoeppe, W

1992-01-01

133

Low-dose weekly methotrexate for progressive neuropsychiatric manifestations in Behcet's disease  

Microsoft Academic Search

The most serious central nervous system (CNS) manifestation in Behcet's disease is a slowly progressive dementia (progressive NB), which may ultimately lead to the deterioration of the personality of patients. An open trial was designed to investigate the efficacy of low dose weekly methotrexate (MTX) therapy for progressive NB. Six patients with Behcet's disease, whose neuropsychiatric manifestations were judged to

Shunsei Hirohata; Hiroko Suda; Takashi Hashimoto

1998-01-01

134

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

2013-04-04

135

Voice characteristics in the progression of Parkinson's disease.  

PubMed

This study examined the acoustic and perceptual voice characteristics of patients with Parkinson's disease according to disease severity. The perceptual and acoustic voice characteristics of 30 patients with early stage PD and 30 patients with later stage PD were compared with data from 30 normal control subjects. Voice recordings consisted of prolongation of the vowel /a/, scale singing, and a 1-min monologue. In comparison with controls and previously published normative data, both early and later stage PD patients' voices were characterized perceptually by limited pitch and loudness variability, breathiness, harshness and reduced loudness. High modal pitch levels also characterized the voices of males in both early and later stages of PD. Acoustically, the voices of both groups of PD patients demonstrated lower mean intensity levels and reduced maximum phonational frequency ranges in comparison with normative data. Although less clear, the present data also suggested that the PD patients' voices were characterized by excess jitter, a high-speaking fundamental frequency for males and a reduced fundamental frequency variability for females. While several of these voice features did not appear to deteriorate with disease progression (i.e. harshness, high modal pitch and speaking fundamental frequency in males, fundamental frequency variability in females, low intensity and jitter), breathiness, monopitch and monoloudness, low loudness and reduced maximum phonational frequency range were all worse in the later stages of PD. Tremor was the sole voice feature which was associated only with later stage PD. PMID:10963022

Holmes, R J; Oates, J M; Phyland, D J; Hughes, A J

136

Mechanisms of prion disease progression: a chemical reaction network approach.  

PubMed

Fatal neurodegenerative diseases such as bovine spongiform encephalopathy in cattle, scrapie in sheep and Creutzfeldt-Jakob disease in humans are caused by prions. Prion is a protein encoded by a normal cellular gene. The cellular form of the prion, namely PrP(C), is benign but can be converted into a disease-causing form (named scrapie), PrP(Sc), by a conformational change from -helix to -sheets. Prions replicate by this conformational change; that is, PrP(Sc) interacts with PrP(C) producing a new molecule of PrP(Sc). This kind of replication is modelled in this contribution as an autocatalytic process. The kinetic model accounts for two of the three epidemiological manifestations: sporadic and infectious. By assuming irreversibility of the PrP(Sc) replication and describing a first-order reaction for the degradation of cellular tissue, the authors explore dynamical scenarios for prion progression, such as oscillations and conditions for multiplicity of equilibria. Feinberg's chemical reaction network theory is exploited to identify multiple steady states and their associate kinetic constants. PMID:22129030

Méndez, J M; Femat, R

2011-11-01

137

Disease specificity and pathologic progression of tau pathology in brainstem nuclei of Alzheimer's disease and progressive supranuclear palsy  

PubMed Central

Previous studies have shown tau pathology in the inferior colliculus (IC) and superior colliculus (SC) in Alzheimer’s disease (AD); however, it has not been compared to other tauopathies, such as progressive supranuclear palsy (PSP), or characterized with respect to progression of tau pathology in AD. The main purpose of this study was to investigate frequency, neuroanatomical selectivity and disease specificity of tau pathology in visual and auditory nuclei (SC and lateral geniculate body (LGB); IC and medial geniculate body (MGB), respectively). We measured phospho-tau burden with immunohistochemistry and image analysis in 26 cases of AD, 37 PSP and 11 normal controls. Tau burden was also assessed in two unrelated brainstem nuclei (substantia nigra (SN) and pedunculopontine nucleus (PPN)) of the same cases. We found tau burden to be greater in the SC of PSP compared to AD and controls. Conversely, tau burden was greater in the IC of AD compared to PSP and controls. The MGB and LGB had sparse tau pathology in both AD and PSP. This disease selectivity parallels known deficits in visual reflexes in PSP and auditory reflexes in AD. Tau burden was greater in the SC, IC, and PPN in both PSP and AD compared to controls, and greater in the SN in PSP compared to AD and controls. Although present at early Braak neurofibrillary tangle stages, the SC, IC, PPN and SN did not accumulate tau consistently until later stages. These findings support a concept of tau pathology affecting the brainstem at mid-to-late stage AD.

Dugger, Brittany N.; Tu, Michael; Murray, Melissa E.; Dickson, Dennis W.

2011-01-01

138

Human immunodeficiency virus type 1 subtypes differ in disease progression.  

PubMed

At least 10 different genetic human immunodeficiency virus type 1 (HIV-1) subtypes (A-J) are responsible for the AIDS pandemic. Much of the understanding of HIV-1 disease progression derives from studies in the developed world where HIV infection is almost exclusively subtype B. This has led many to question whether the properties and consequences of HIV-1 infection can be generalized across subtypes that afflict the majority of infected persons in the developing world. From 1985 to 1997, a prospective study of registered female sex workers in Senegal tracked the introduction and spread of HIV-1 subtypes A, C, D, and G. In clinical follow-up, the AIDS-free survival curves differed by HIV-1 subtype. Women infected with a non-A subtype were 8 times more likely to develop AIDS than were those infected with subtype A (hazard ratio=8.23; P=. 009), the predominant subtype in the study. These data suggest that HIV-1 subtypes may differ in rates of progression to AIDS. PMID:9841824

Kanki, P J; Hamel, D J; Sankalé, J L; Hsieh, C c; Thior, I; Barin, F; Woodcock, S A; Guèye-Ndiaye, A; Zhang, E; Montano, M; Siby, T; Marlink, R; NDoye, I; Essex, M E; MBoup, S

1999-01-01

139

Subthalamic Nucleus Neuronal Firing Rate Increases with Parkinson's Disease Progression  

PubMed Central

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic cells in the central nervous system, in particular the substantia nigra, resulting in an unrelenting loss of motor and non-motor function. Animal models of PD reveal hyperactive neurons in the subthalamic nucleus (STN) that have increased firing rates and bursting activity compared to controls. Although STN activity has been characterized in advanced stage PD patients, it has not been described in early stage PD patients. Here we present the results of STN neuronal recordings from early stage PD patients (Hoehn and Yahr stage II) enrolled in an ongoing clinical trial compared to recordings from age and sex matched advanced PD patients. STN neurons had a significantly lower firing rate in early versus advanced PD (28.7Hz vs. 36.3Hz; p<0.01). The overall activity of the STN was also significantly lower in early versus late PD, as measured by background neuronal noise (12.4mV vs. 14.0mV; p <0.05). No significant difference was identified between groups in the bursting or variability of neuronal firing in the STN, as measured by a burst index or the interspike interval coefficient of variability. The results suggest that neuronal firing in STN increases with PD progression.

Remple, Michael S.; Bradenham, Courtney H.; Kao, C. Chris; Charles, P. David; Neimat, Joseph S.; Konrad, Peter E.

2011-01-01

140

Prevention of progressive fibrosis in chronic renal diseases: antifibrotic agents.  

PubMed

Renal fibrogenesis can be induced by several injury mechanisms in different renal diseases, but ultimately produces identical fibrotic changes in the kidney. Recently, a number of agents that can inhibit extracellular matrix (ECM) accumulation have been studied, suggesting a therapeutic utility in the treatment of fibrotic renal disease. Pirfenidone (PFD) is a small molecule that has shown efficacy in various models of renal damage with progressive disease. The apparent absence of toxicity in PFD suggests that it does not affect the normal ECM turnover. Relaxin, a hormone belonging to the insulin-like growth factor (IGF) family, has antifibrotic properties and has been used for a long time to induce transient remissions in patients with scleroderma. Only recently it has been shown to drastically reduce corticomedular scarring in animal models. Bone morphogenetic protein 7 (BMP-7), a member of the transforming growth factor beta (TGF-beta) superfamily, has been shown to reduce glomerular and interstitial area, and prevent glomerular sclerosis even more effectively than enalapril. Finally, hepatocyte growth factor (HGF), with its multiple biological activities on a wide variety of cells, has an organotrophic role in the regeneration and protection of various organs including the kidney. Both endogenous and exogenous HGF have shown suppressive effects on renal fibrosis and chronic renal damage in various animal models. The inhibition of pathological ECM accumulation and the modulation of fibrotic mechanisms with these new antifibrotic agents is an achievable goal and could confer further benefits beyond the current therapies used in the treatment of chronic renal diseases. PMID:15372410

Negri, Armando Luis

141

ALS2\\/Alsin Knockout Mice and Motor Neuron Diseases  

Microsoft Academic Search

Autosomal recessive mutations in the ALS2 gene have been linked to juvenile-onset amyotrophic lateral sclerosis (ALS2), primary lateral sclerosis and juvenile-onset ascending hereditary spastic paraplegia. Except for two recently identified missense mutations, all other mutations in the ALS2 gene lead to a premature stop codon and likely abrogate all the potential functions of alsin, the protein encoded by the ALS2

Huaibin Cai; Hoon Shim; Chen Lai; Chengsong Xie; Xian Lin; Wan Jou Yang; Jayanth Chandran

2008-01-01

142

Do HIV Disease Progression and HAART Response Vary among Injecting Drug Users in Europe?  

Microsoft Academic Search

Prior to HAART availability, there was no evidence of a geographical variation in HIV disease progression among injecting drug users (IDU) from different European regions. Nowadays, factors of importance regarding HIV disease progression in the face of HAART availability, such as HAART access, adherence, and the organization of care for IDU may differ across Europe. Therefore we studied HIV disease

Liselotte van Asten; Robert Zangerle; Ildefonso Hernández Aguado; Faroudy Boufassa; Barbara Broers; Raymond P. Brettle; J. Roy Robertson; Jim McMenamin; Roel A. Coutinho; Maria Prins

2005-01-01

143

Plasma viscosity increase with progression of peripheral arterial atherosclerotic disease.  

PubMed

Increased blood and plasma viscosity has been described in patients with coronary and peripheral arterial disease. However, the relation of viscosity to the extent of arterial wall deterioration--the most important determinant of clinical manifestation and prognosis of the disease--is not well known. Therefore, the authors studied plasma viscosity as one of the major determinants of blood viscosity in patients with different stages of arterial disease of lower limbs (according to Fontaine) and its relation to the presence of some risk factors of atherosclerosis. The study encompassed four groups of subjects: 19 healthy volunteers (group A), 18 patients with intermittent claudication up to 200 m (stage II; group B), 15 patients with critical ischemia of lower limbs (stage III and IV; group C), and 16 patients with recanalization procedures on peripheral arteries. Venous blood samples were collected from an antecubital vein without stasis for the determination of plasma viscosity (with a rotational capillary microviscometer, PAAR), fibrinogen, total cholesterol, alpha-2-macroglobulin, and glucose concentrations. In patients with recanalization procedure local plasma viscosity was also determined from blood samples taken from a vein on the dorsum of the foot. Plasma viscosity was most significantly elevated in the patients with critical ischemia (1.78 mPa.sec) and was significantly higher than in the claudicants (1.68 mPa.sec), and the claudicants also had significantly higher viscosity than the controls (1.58 mPa.sec). In patients in whom a recanalization procedure was performed, no differences in systemic and local plasma viscosity were detected, neither before nor after recanalization of the diseased artery. In all groups plasma viscosity was correlated with fibrinogen concentration (r=0.70, P < 0.01) and total cholesterol concentration (r=0.24, P < 0.05), but in group C (critical ischemia) plasma viscosity was most closely linked to the concentration of alpha-2-macroglobulin (r=0.78, P < 0.01). These results indicate that in patients with peripheral arterial disease plasma viscosity increases with the progression of the atherosclerotic process and is correlated with the clinical stages of the disease. PMID:8638868

Poredos, P; Zizek, B

1996-03-01

144

The area under the disease progress stairs: calculation, advantage, and application.  

PubMed

The area under the disease progress curve (AUDPC) is frequently used to combine multiple observations of disease progress into a single value. However, our analysis shows that this approach severely underestimates the effect of the first and last observation. To get a better estimate of disease progress, we have developed a new formula termed the area under the disease progress stairs (AUDPS). The AUDPS approach improves the estimation of disease progress by giving a weight closer to optimal to the first and last observations. Analysis of real data indicates that AUDPS outperforms AUDPC in most of the tested trials and may be less precise than AUDPC only when assessments in the first or last observations have a comparatively large variance. We propose using AUDPS and its standardized (sAUDPS) and relative (rAUDPS) forms when combining multiple observations from disease progress experiments into a single value. PMID:22122266

Simko, Ivan; Piepho, Hans-Peter

2012-04-01

145

The Myth of Schizophrenia as a Progressive Brain Disease  

PubMed Central

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

Zipursky, Robert B.

2013-01-01

146

The myth of schizophrenia as a progressive brain disease.  

PubMed

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

Zipursky, Robert B; Reilly, Thomas J; Murray, Robin M

2012-11-20

147

Elevation of myoinositol is associated with disease containment in progressive multifocal leukoencephalopathy.  

PubMed

MRI, 1H-MR spectroscopy, immunologic, and virologic studies were performed in search of prognostic factors of disease evolution in patients with progressive multifocal leukoencephalopathy (PML). Acute lesions of PML survivors showed twofold higher standard score of the ratio of myoinositol (a glial marker) to creatine compared with lesions in patients whose disease progressed. Concomitantly, JC virus-specific cytotoxic T lymphocytes were only detected in the blood of PML survivors. These results suggest that inflammation limits disease progression. PMID:15365144

Katz-Brull, Rachel; Lenkinski, Robert E; Du Pasquier, Renaud A; Koralnik, Igor J

2004-09-14

148

Cardiac autoantibodies in dilated cardiomyopathy become undetectable with disease progression.  

PubMed Central

OBJECTIVE: To determine the relation of cardiac autoantibody and disease status in a consecutive series of patients with dilated cardiomyopathy by prospective antibody testing at diagnosis and at follow up. METHODS: Antibody status was assessed by indirect immunofluorescence in 110 patients with dilated cardiomyopathy (85 male, mean (SD) age 44 (13) years) at diagnosis and at follow up (mean (SD) 14 (12) months); in 57 of them cardiac specific anti-alpha myosin antibody titres were also measured by an enzyme-linked immunosorbent assay (ELISA). Patients underwent complete evaluation at diagnosis and clinical and non-invasive assessment at follow up, including exercise testing with maximal oxygen consumption measurements. RESULTS: The frequency of cardiac specific antibodies by immunofluorescence was lower at follow up than at diagnosis (28 (25%) v 11 (10%), P = 0.002). Mean (SEM) anti-alpha myosin antibody titres at follow up were also lower than at diagnosis (0.24 (0.02) v 0.30 (0.02), P = 0.038); 24% of patients at diagnosis and 14% at follow up had an abnormal ELISA result. None of the patients who were negative by immunofluorescence or ELISA at diagnosis became positive at follow up. Presence of antibody at diagnosis was associated with milder symptoms and greater exercise capacity at follow up and persistence of antibody at follow up was associated with stable disease and milder symptoms at diagnosis. CONCLUSIONS: Cardiac specific autoantibodies in dilated cardiomyopathy become undetectable with disease progression; this is a recognised feature of other autoimmune conditions, such as type 1 diabetes. Detection of these antibodies at diagnosis and at follow up may provide a non-invasive marker of early dilated cardiomyopathy.

Caforio, A. L.; Goldman, J. H.; Baig, M. K.; Haven, A. J.; Dalla Libera, L.; Keeling, P. J.; McKenna, W. J.

1997-01-01

149

Phenotypic Heterogeneity in a SOD1 G93D Italian ALS Family: An Example of Human Model to Study a Complex Disease  

Microsoft Academic Search

We report different clinical expression in seven members of a large family with amyotrophic lateral sclerosis (ALS) and the\\u000a G93D mutation in exon 4 of the Cu\\/Zn superoxide dismutase (SOD1) gene. The ALS clinical course in the proband showed an unusually fast progression of the disease compared to the paucisymptomatic\\u000a presentation associated to this mutation in the two previously Italian

Silvana Penco; Christian Lunetta; Lorena Mosca; Eleonora Maestri; Francesca Avemaria; Claudia Tarlarini; Maria Cristina Patrosso; Alessandro Marocchi; Massimo Corbo

2011-01-01

150

ALS2/alsin knockout mice and motor neuron diseases.  

PubMed

Autosomal recessive mutations in the ALS2 gene have been linked to juvenile-onset amyotrophic lateral sclerosis (ALS2), primary lateral sclerosis and juvenile-onset ascending hereditary spastic paraplegia. Except for two recently identified missense mutations, all other mutations in the ALS2 gene lead to a premature stop codon and likely abrogate all the potential functions of alsin, the protein encoded by the ALS2 gene. To study the pathologic mechanisms of ALS2 deficiency, four different lines of ALS2 knockout (ALS2(-/-)) mice have been generated by independent groups. The loss of ALS2/alsin does not have a drastic effect on the survival or function of motor neurons in mice. However, subtle deficits observed in the behavior and pathology of these mice have aided in our understanding of the relationship between alsin and motor neuron dysfunction. In this review, we summarize and reconcile major findings of ALS2(-/-) mice and attempt to place these results within the larger context of modeling recessive movement disorders in mice. PMID:18714162

Cai, Huaibin; Shim, Hoon; Lai, Chen; Xie, Chengsong; Lin, Xian; Yang, Wan Jou; Chandran, Jayanth

2008-08-20

151

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

PubMed Central

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 carriers and HD patients in the early stages of the disease, compared to 21 controls. We combined this study with a multivariate statistical analysis of plasma components quantified by proton nuclear magnetic resonance (1H NMR) spectroscopy. We report evidence of an early hypermetabolic state in HD. Weight loss was observed in the HD group even in presymptomatic carriers, although their caloric intake was higher than that of controls. Inflammatory processes and primary hormonal dysfunction were excluded. 1H NMR spectroscopy on plasma did, however, distinguish HD patients at different stages of the disease and presymptomatic carriers from controls. This distinction was attributable to low levels of the branched chain amino acids (BCAA), valine, leucine and isoleucine. BCAA levels were correlated with weight loss and, importantly, with disease progression and abnormal triplet repeat expansion size in the HD1 gene. Levels of IGF1, which is regulated by BCAA, were also significantly lower in the HD group. Therefore, early weight loss in HD is associated with a systemic metabolic defect, and BCAA levels may be used as a biomarker, indicative of disease onset and early progression. The decreased plasma levels of BCAA may correspond to a critical need for Krebs cycle energy substrates in the brain that increased metabolism in the periphery is trying to provide.

Mochel, Fanny; Charles, Perrine; Seguin, Francois; Barritault, Julie; Coussieu, Christiane; Perin, Laurence; Le Bouc, Yves; Gervais, Christiane; Carcelain, Guislaine; Vassault, Anne; Feingold, Josue; Rabier, Daniel; Durr, Alexandra

2007-01-01

152

Polymorphism in RANTES chemokine promoter affects HIV-1 disease progression  

PubMed Central

RANTES (regulated on activation normal T cell expressed and secreted) is one of the natural ligands for the chemokine receptor CCR5 and potently suppresses in vitro replication of the R5 strains of HIV-1, which use CCR5 as a coreceptor. Previous studies showed that peripheral blood mononuclear cells or CD4+ lymphocytes obtained from different individuals had wide variations in their ability to secrete RANTES. These findings prompted us to analyze the upstream noncoding region of the RANTES gene, which contains cis-acting elements involved in RANTES promoter activity, in 272 HIV-1-infected and 193 non-HIV-1-infected individuals in Japan. Our results showed that there were two polymorphic positions, one of which was associated with reduced CD4+ lymphocyte depletion rates during untreated periods in HIV-1-infected individuals. This mutation, RANTES?28G, occurred at an allele frequency of ?17% in the non-HIV-1-infected Japanese population and exerted no influence on the incidence of HIV-1 infection. Functional analyses of RANTES promoter activity indicated that the RANTES?28G mutation increases transcription of the RANTES gene. Taken together, these data suggest that the RANTES?28G mutation increases RANTES expression in HIV-1-infected individuals and thus delays the progression of the HIV-1 disease.

Liu, Huanliang; Chao, David; Nakayama, Emi E.; Taguchi, Hitomi; Goto, Mieko; Xin, Xiaomi; Takamatsu, Jun-ki; Saito, Hidehiko; Ishikawa, Yoshihide; Akaza, Tatsuya; Juji, Takeo; Takebe, Yutaka; Ohishi, Takeshi; Fukutake, Katsuyuki; Maruyama, Yoshikazu; Yashiki, Shinji; Sonoda, Shunro; Nakamura, Tetsuya; Nagai, Yoshiyuki; Iwamoto, Aikichi; Shioda, Tatsuo

1999-01-01

153

Saliva/Pathogen Biomarker Signatures and Periodontal Disease Progression  

PubMed Central

The purpose of this study was to determine the role of saliva-derived biomarkers and periodontal pathogens during periodontal disease progression (PDP). One hundred human participants were recruited into a 12-month investigation. They were seen bi-monthly for saliva and clinical measures and bi-annually for subtraction radiography, serum and plaque biofilm assessments. Saliva and serum were analyzed with protein arrays for 14 pro-inflammatory and bone turnover markers, while qPCR was used for detection of biofilm. A hierarchical clustering algorithm was used to group study participants based on clinical, microbiological, salivary/serum biomarkers, and PDP. Eighty-three individuals completed the six-month monitoring phase, with 44 exhibiting PDP, while 39 demonstrated stability. Participants assembled into three clusters based on periodontal pathogens, serum and salivary biomarkers. Cluster 1 members displayed high salivary biomarkers and biofilm; 82% of these individuals were undergoing PDP. Cluster 2 members displayed low biofilm and biomarker levels; 78% of these individuals were stable. Cluster 3 members were not discriminated by PDP status; however, cluster stratification followed groups 1 and 2 based on thresholds of salivary biomarkers and biofilm pathogens. The association of cluster membership to PDP was highly significant (p < 0.0002). The use of salivary and biofilm biomarkers offers potential for the identification of PDP or stability (ClinicalTrials.gov number, CT00277745).

Kinney, J.S.; Morelli, T.; Braun, T.; Ramseier, C.A.; Herr, A.E.; Sugai, J.V.; Shelburne, C.E.; Rayburn, L.A.; Singh, A.K.; Giannobile, W.V.

2011-01-01

154

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

155

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

156

Effect of lipid reduction on the progression of renal disease: A meta-analysis  

Microsoft Academic Search

Effect of lipid reduction on the progression of renal disease: A meta-analysis.BackgroundIt has been proposed that hyperlipidemia contributes to the progression of renal disease. A large trial has not been performed; however, a number of small, controlled trials have been reported. We examined the effects of antilipemic agents on glomerular filtration rate and proteinuria or albuminuria in patients with renal

Linda F Fried; Trevor J Orchard; Bertram L Kasiske

2001-01-01

157

Fabrication, phase transformation studies and characterization of SiC-AlN-Al2OC ceramics. Progress report.  

National Technical Information Service (NTIS)

SiC and AlN are two of the important high temperature structural ceramics. AlN and the 2H polytype of SiC are isostructural. Prior work has shown that they form an extension solid solution at temperatures = or > 2000(degrees)C. At lower temperatures, the ...

A. V. Virkar

1992-01-01

158

Occupational therapy for patients with chronic diseases: CVA, rheumatoid arthritis and progressive diseases of the central nervous system  

Microsoft Academic Search

A substantial proportion of the patients treated by occupational therapists have a chronic disease. The aim of this study was to describe the outlines of occupational therapy treatment for three specific groups of chronic diseases: progressive neurological diseases, cerebrovascular accident and rheumatoid arthritis. A total of 143 therapists, working in 49 occupational therapy departments in The Netherlands, were asked to

M.-J. Driessen; J. Dekker; G. Lankhorst; J. van der Zee

1997-01-01

159

Late-onset frontotemporal dementia associated with progressive supranuclear palsy\\/argyrophilic grain disease\\/Alzheimer’s disease pathology  

Microsoft Academic Search

Progressive supranuclear palsy (PSP) is typically manifested by vertical supranuclear gaze palsy, frequent falls early in the disease course, axial rigidity and poor response to levodopa. Prominent anterograde memory dysfunction with subsequent impairment in other cognitive domains is characteristic of Alzheimer’s disease (AD). No clear clinical syndrome has been identified in argyrophilic grain disease (AGD). Frontotemporal dementia (FTD) is characterized

G. A. Rippon; B. F. Boeve; J. E. Parisi; D. W. Dickson; R. I. Ivnik; C. R. Jack; M. Hutton; M. Baker; K. A. Josephs; D. S. Knopman; R. C. Petersen

2005-01-01

160

Dietary Manipulation and Social Isolation Alter Disease Progression in a Murine Model of Coronary Heart Disease  

PubMed Central

Background Mice with a deficiency in the HDL receptor SR-BI and low expression of a modified apolipoprotein E gene (SR-BI KO/ApoeR61h/h) called ‘HypoE’ when fed an atherogenic, ‘Paigen’ diet develop occlusive, atherosclerotic coronary arterial disease (CHD), myocardial infarctions (MI), and heart dysfunction and die prematurely (50% mortality ?40 days after initiation of this diet). Because few murine models share with HypoE mice these cardinal, human-like, features of CHD, HypoE mice represent a novel, small animal, diet-inducible and genetically tractable model for CHD. To better describe the properties of this model, we have explored the effects of varying the composition and timing of administration of atherogenic diets, as well as social isolation vs. group housing, on these animals. Methodology/Principal Findings HypoE mice were maintained on a standard lab chow diet (control) until two months of age. Subsequently they received one of three atherogenic diets (Paigen, Paigen without cholate, Western) or control diet for varying times and were housed in groups or singly, and we determined the plasma cholesterol levels, extent of cardiomegaly and/or survival. The rate of disease progression could be reduced by lowering the severity of the atherogenic diet and accelerated by social isolation. Disease could be induced by Paigen diets either containing or free of cholate. We also established conditions under which CHD could be initiated by an atherogenic diet and then subsequently, by replacing this diet with standard lab chow, hypercholesterolemia could be reduced and progression to early death prevented. Conclusions/Significance HypoE mice provide a powerful, surgery-free, diet-‘titratable’ small animal model that can be used to study the onset of recovery from occlusive, atherosclerotic CHD and heart failure due to MI. HypoE mice can be used for the analysis of the effects of environment (diet, social isolation) on a variety of features of cardiovascular disease.

Krieger, Monty

2012-01-01

161

Commentary: Progressive inflammation as a contributing factor to early development of Parkinson's disease.  

PubMed

Parkinson's disease (PD) is a progressive neurodegenerative disorder with three cardinal features of pathology: 1. Aggregation of ?-synuclein into intraneuronal structures called Lewy bodies and Lewy neurites. 2. Dysregulated immune activation in the substantia nigra (SN). 3. Degeneration of dopaminergic neurons in the nigrostriatal circuit. The largely correlative nature of evidence in humans has precluded a decisive verdict on the relationship between ?-synuclein pathology, inflammation, and neuronal damage. Furthermore, it is unclear whether inflammation plays a role in the early prodromal stages of PD before neuronal damage has occurred and Parkinsonian motor symptoms become apparent. To gain insight into the interaction between the inflammatory response and the development of neuronal pathology in PD, Watson et al. characterized neuroinflammation in a wild-type ?-synuclein overexpressing mouse model of prodromal PD. They demonstrate, for the first time, the existence of early and sustained microglial mediated innate inflammation that precedes damage to the nigrostriatal circuit. Additionally they observe the spread of inflammation from the striatum to the SN. This study suggests that early dysregulated inflammation may contribute to progressive nigrostriatal pathology in PD, although the initiating factor that triggers the inflammatory response remains elusive. The novel concept of an early inflammatory response in the development of PD has important implications for preventive and therapeutic strategies for PD. PMID:23261765

Pradhan, Suraj; Andreasson, Katrin

2012-12-21

162

ABCA4 disease progression and a proposed strategy for gene therapy  

Microsoft Academic Search

Autosomal recessive retinal diseases caused by mutations in the ABCA4 gene are being considered for gene replacement therapy. All individuals with ABCA4-disease show macular degeneration, but only some are thought to progress to retina-wide blindness. It is currently not predictable if or when specific ABCA4 geno- types will show extramacular disease, and how fast it will progress thereafter. Early clinical

Artur V. Cideciyan; Malgorzata Swider; Tomas S. Aleman; Yaroslav Tsybovsky; Sharon B. Schwartz; Elizabeth A. M. Windsor; Alejandro J. Roman; Alexander Sumaroka; Janet D. Steinberg; Samuel G. Jacobson; Edwin M. Stone; Krzysztof Palczewski

2009-01-01

163

A combination of genetic polymorphisms increases the risk of progressive disease in chronic hepatitis C  

PubMed Central

Background: There is increasing interest in the influence of host genetic factors on hepatic fibrosis, and whether genetic markers can reliably identify subjects at risk of developing severe disease. We hypothesised that hepatitis C virus (HCV) infected subjects with progressive fibrosis, classified using strict criteria based on histology at biopsy in addition to disease duration would be more likely to inherit several genetic polymorphisms associated with disease progression compared with subjects with a low rate of disease progression. Methods: We examined polymorphisms in eight genes that have been reported to have an association with hepatic fibrosis. Results: Associations between polymorphisms in six genes and more rapidly progressing fibrosis were observed, with individual adjusted odds ratios ranging from 2.1 to 4.5. The relationship between rapidly progressing fibrosis and possession of ?3, ?4, or ?5 progression associated alleles was determined and the adjusted odds ratios increased with increasing number of progression associated alleles (9.1, 15.5, and 24.1, respectively). Using logistic regression analysis, a predictive equation was developed and tested using a second cohort of patients with rapidly progressing fibrosis. The predictive equation correctly classified 80% of patients in this second cohort. Conclusions: This approach may allow determination of a genetic profile predictive of rapid disease progression in HCV and identify patients warranting more aggressive therapeutic management.

Richardson, M; Powell, E; Barrie, H; Clouston, A; Purdie, D; Jonsson, J

2005-01-01

164

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

PubMed

This study was performed to evaluate the incidence of seizures with its implications on disease progression and the diagnostic value of post-ictal magnetic resonance images (MRI) during the management of high-grade gliomas (HGGs). A total of 406 consecutive patients with newly diagnosed HGGs were retrospectively reviewed. The incidence of seizures during the management was investigated. In patients who experienced a seizure, the causality between seizures and disease progression was assessed by pre-ictal, post-ictal (<1 month), and follow-up (<3 months) MRI. After a median follow-up of 17.4 months (range 0.1-88.3), seizures developed in 127 patients (31 %). Of the 127 patients, radiological progression at the post-ictal MRI was found in 83 patients (65 %) and the follow-up MRI confirmed progression in 79 patients (62 %). Four other patients (3 %) were shown to be progression-free. Among those without radiological progression at the post-ictal MRI, the follow-up MRI confirmed progression-free in 31 patients (24 %); however, 13 patients (10 %) revealed eventual progression. In the patients with a seizure, absence of preoperative seizures (p = 0.003), <95 % tumor resection (p = 0.001), and pre-ictal Karnofsky Performance Scale score ? 70 (p = 0.025) were significantly associated with disease progression. During the management of HGG, 31 % of patients experienced seizures; of these patients, 72 % harbored progressive disease. The post-ictal MRI is useful for detecting disease progression; however, there are pitfalls. Clinical settings should be considered together for diagnosing disease progression in patients with seizures. PMID:23459994

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

2013-03-04

165

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

PubMed Central

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

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

1996-01-01

166

Research Finds Link Between Statin Use and Progressive Muscle Disease  

MedlinePLUS

... 2004 2003 2002 2001 2000 1999 Spotlight on Research 2011 September 2011 Research Finds Link Between Statin Use and Progressive Muscle ... as the drugs are taken. New NIAMS-supported research has found that for a subset of patients, ...

167

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.

Skodda, Sabine; Gronheit, Wenke; Schlegel, Uwe

2012-01-01

168

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

PubMed

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

Duyckaerts, Charles; Seilhean, Danielle

2013-05-01

169

ABCA4 disease progression and a proposed strategy for gene therapy  

PubMed Central

Autosomal recessive retinal diseases caused by mutations in the ABCA4 gene are being considered for gene replacement therapy. All individuals with ABCA4-disease show macular degeneration, but only some are thought to progress to retina-wide blindness. It is currently not predictable if or when specific ABCA4 genotypes will show extramacular disease, and how fast it will progress thereafter. Early clinical trials of focal subretinal gene therapy will aim to arrest disease progression in the extramacular retina. In 66 individuals with known disease-causing ABCA4 alleles, we defined retina-wide disease expression by measuring rod- and cone-photoreceptor-mediated vision. Serial measurements over a mean period of 8.7 years were consistent with a model wherein a normal plateau phase of variable length was followed by initiation of retina-wide disease that progressed exponentially. Once initiated, the mean rate of disease progression was 1.1 log/decade for rods and 0.45 log/decade for cones. Spatio-temporal progression of disease could be described as the sum of two components, one with a central-to-peripheral gradient and the other with a uniform retina-wide pattern. Estimates of the age of disease initiation were used as a severity metric and contributions made by each ABCA4 allele were predicted. One-third of the non-truncating alleles were found to cause more severe disease than premature truncations supporting the existence of a pathogenic component beyond simple loss of function. Genotype-based inclusion/exclusion criteria and prediction of the age of retina-wide disease initiation will be invaluable for selecting appropriate candidates for clinical trials in ABCA4 disease.

Cideciyan, Artur V.; Swider, Malgorzata; Aleman, Tomas S.; Tsybovsky, Yaroslav; Schwartz, Sharon B.; Windsor, Elizabeth A.M.; Roman, Alejandro J.; Sumaroka, Alexander; Steinberg, Janet D.; Jacobson, Samuel G.; Stone, Edwin M.; Palczewski, Krzysztof

2009-01-01

170

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. J. Comp. Neurol. 521:4300-4317, 2013. © 2013 Wiley Periodicals, Inc. PMID:23839862

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

2013-12-15

171

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

172

Brain muscarinic receptors in progressive supranuclear palsy and Parkinson's disease: a positron emission tomographic study  

PubMed Central

OBJECTIVES—To assess muscarinic acetylcholine receptors (mAChRs) in the brains of patients with progressive supranuclear palsy and Parkinson's disease, and to correlate the cholinergic system with cognitive function in progressive supranuclear palsy and Parkinson's disease.?METHODS— Positron emission tomography (PET) and [11C]N-methyl-4-piperidyl benzilate ([11C]NMPB) was used to measure mAChRs in the brain of seven patients with progressive supranuclear palsy, 12 patients with Parkinson's disease, and eight healthy controls. All of the patients with progressive supranuclear palsy were demented. The Parkinson's disease group consisted of 11 non-demented patients and one demented patient. The mini mental state examination (MMSE) was used to assess the severity of cognitive dysfunction in all of the subjects. The modified Wisconsin card sorting test (WCST) was used to evaluate frontal cognitive function in the non-demented patients with Parkinson's disease and controls.?RESULTS—The mean K3 value, an index of mAChR binding, was significantly higher for the frontal cortex in the patients with Parkinson's disease than in the controls (p<0.01). By contrast, the patients with progressive supranuclear palsy had no significant changes in the K3 values of any cerebral cortical regions. The mean score of the MMSE in the progressive supranuclear palsy group was significantly lower than that in the control group. Although there was no difference between the Parkinson's disease and control groups in the MMSE, the non-demented patients with Parkinson's disease showed significant frontal lobe dysfunction in the WCST.?CONCLUSIONS—The increased mAChR binding in the frontal cortex of the patients with Parkinson's disease may reflect denervation hypersensitivity caused by loss of the ascending cholinergic input to that region from the basal forebrain and may be related to frontal lobe dysfunction in Parkinson's disease. The cerebral cortical cholinergic system may not have a major role in cognitive dysfunction in progressive supranuclear palsy.??

Asahina, M.; Suhara, T.; Shinotoh, H.; Inoue, O.; Suzuki, K.; Hattori, T.

1998-01-01

173

Caspase Gene Expression in the Brain as a Function of the Clinical Progression of Alzheimer Disease  

Microsoft Academic Search

Background: Caspase gene expression has previously been reported in terminal Alzheimer disease (AD) brain, but, currently, little is known about the temporal pat- tern of caspase gene expression relative to the onset and clinical progression of AD. Objective: To derive a profile of caspase gene expres- sion and proapoptotic indexes as a function of the clinical and neuropathologic progression of

Patrick N. Pompl; Shrishailam Yemul; Zhongmin Xiang; Lap Ho; Varham Haroutunian; Dushyant Purohit; Richard Mohs; Giulio Maria Pasinetti

2003-01-01

174

Progress and prospects: Cell based regenerative therapy for cardiovascular disease  

Microsoft Academic Search

Experimental and clinical studies are progressing simultaneously to investigate the mechanisms and efficacy of progenitor cell treatment after an acute myocardial infarction and in chronic congestive heart failure. Multipotent progenitor cells appear to be capable of improving cardiac perfusion and\\/or function; however, the mechanisms still are unclear, and the issue of whether or not trans-differentiation occurs remains unsettled. Both experimentally

E D de Muinck; C Thompson; M Simons

2006-01-01

175

A specific endothelin subtype A receptor antagonist protects against injury in renal disease progression  

Microsoft Academic Search

A specific endothelin subtype A receptor antagonist protects against injury in renal disease progression. We have recently reported that renal preproendothelin-1 gene is up-regulated in rats with renal mass reduction (RMR) and that time-dependent increase in urinary excretion of the corresponding peptide correlates with renal disease progression. Here we evaluated whether a specific endothelin subtype A (ETA) receptor antagonist, FR139317,

Ariela Benigni; Carla Zoja; Daniela Corna; Silvia Orisio; Lorena Longaretti; Tullio Bertani; Giuseppe Remuzzi

1993-01-01

176

Progressive renal fibrosis in murine polycystic kidney disease: An immunohistochemical observation  

Microsoft Academic Search

Progressive renal fibrosis in murine polycystic kidney disease: An immunohistochemical observation.BackgroundThe appearance of interstitial fibrosis in polycystic kidneys is emblematic of progressive disease. Matrix forming this scar tissue is derived from local renal cells in response to cystogenesis. We investigated the phenotype of collagen-producing cells in the cystic kidneys of DBA\\/2-pcy mice to better characterize the spectrum of interstitial cells

Hirokazu Okada; Shinichi Ban; Shizuko Nagao; Hisahide Takahashi; Hiromichi Suzuki; Eric G Neilson

2000-01-01

177

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

178

ALS-parkinsonism-dementia complex of Kii and other related diseases in Japan.  

PubMed

The ALS/parkinsonism-dementia complex (PDC) of Kii is an endemic disease with a diverse phenotypic expression characteristic of classical ALS, parkinsonism and dementia. Its clinical and neuropathological manifestations are similar to a syndrome found in Guam, sharing classical ALS pathology together with many neurofibrillary tangles in the brain. The incidence rates of ALS declined dramatically between the 1950s and 1980s. In the 1990 s, Kuzuhara found a high incidence of PDC with abundant neurofibrillary tangles, similar to Guamanian PDC. The incidence rates of PDC dramatically rose during the 1980s and 1990 s, and PDC replaced ALS. More than 70% of patients in the endemic region had a family history of ALS or PDC. We recently found a new gene OPTN causing ALS, and have extended its clinical survey in Japan. Two autopsied cases showed involvement of basal ganglia and/or cerebral cortex with neurofibrillary tangles. A few family members also showed dementia and parkinsonism without evidence of motor neuron disease. Moreover the penetrance seems to be incomplete. Despite these similarities, OPTN mutations were not found in the Kii patients. We speculate that the Kii/ALS-PDC could primarily be a genetic disease, and its clinical manifestation is modified by other genes or environmental factors. PMID:22166431

Kaji, Ryuji; Izumi, Yishin; Adachi, Yoshiki; Kuzuhara, Shigeki

2012-01-01

179

The Alzheimer's Disease Neuroimaging Initiative: Progress report and future plans  

Microsoft Academic Search

The Alzheimer's Disease Neuroimaging Initiative (ADNI) beginning in October 2004, is a 6-year research project that studies changes of cognition, function, brain structure and function, and biomarkers in elderly controls, subjects with mild cognitive impairment, and subjects with Alzheimer's disease (AD). A major goal is to determine and validate MRI, PET images, and cerebrospinal fluid (CSF)\\/blood biomarkers as predictors and

Michael W. Weiner; Paul S. Aisen; Clifford R. Jack Jr.; William J. Jagust; John Q. Trojanowski; Leslie Shaw; Andrew J. Saykin; John C. Morris; Nigel Cairns; Laurel A. Beckett; Arthur Toga; Robert Green; Sarah Walter; Holly Soares; Peter Snyder; Eric Siemers; William Potter; Patricia E. Cole; Mark Schmidt

2010-01-01

180

Immunotherapeutic approaches in prion disease: progress, challenges and potential directions.  

PubMed

Therapeutic trials utilizing animal models of prion disease have explored a variety of compounds and a number of approaches with varying success, including several immunotherapeutic strategies, such as passive immunization through the delivery of viruses carrying nucleic acid inserts encoding prion protein-specific immunoglobulin. Targeted, organ-specific cellular production of therapeutic proteins is a relatively unexplored approach in the treatment of neurodegeneration despite many successful experimental outcomes in animal models and human trials of other diseases of the CNS. Emphasizing studies utilizing mouse models of disease, this review outlines developments and limitations of immunological approaches to the treatment of prion diseases. In addition, the authors discuss the potential of an experimental therapeutic strategy, utilizing hybridoma cells injected directly into the CNS to establish long-term production of anti-prion antibodies in vivo within the organ associated with the greatest pathogenic change in prion disease, the brain. PMID:23647278

Brazier, Marcus W; Mot, Alexandra I; White, Anthony R; Collins, Steven J

2013-05-01

181

Decreased Metabolism in the Cerebral Cortex in Early-Stage Huntington's Disease: A Possible Biomarker of Disease Progression?  

PubMed Central

Background and Purpose Huntington's disease (HD) is an autosomal-dominant inherited neurodegenerative disorder. Genetic analysis of abnormal CAG expansion in the IT15 gene allows disease confirmation even in the preclinical stage. However, because there is no treatment to cure or delay the progression of this disease, monitoring of biological markers that predict progression is warranted. Methods FDG-PET was applied to 13 patients with genetically confirmed HD in the early stage of the disease. We recorded the initial and follow-up statuses of patients using the Independence Scale (IS) of the Unified Huntington's Disease Rating Scale. The progression rate (PR) was calculated as the annual change in the IS. The patients were divided into two groups with faster and slower progression, using the median value of the PR as the cut-off. FDG-PET data were analyzed using regions of interest, and compared among the two patient groups and 11 age- and sex-matched controls. Results The mean CAG repeat size in patients was 44.7. The CAG repeat length was inversely correlated with the age at onset as reported previously, but was not correlated with the clinical PR. Compared with normal controls, hypometabolism was observed even at very early stages of the disease in the bilateral frontal, temporal, and parietal cortices on FDG-PET. The decreases in metabolism in the bilateral frontal, parietal, and right temporal cortices were much greater in the faster-progression group than in the slower-progression group. Conclusions A decrease in cortical glucose metabolism is suggested as a predictor for identifying a more rapid form of progression in patients with early-stage HD.

Shin, Hyeeun; Kim, Man Ho; Lee, Su Jin; Lee, Kyung-Han; Kim, Mi-Jung; Kim, Ji Sun

2013-01-01

182

Medicare Patients with Cardiovascular Disease Have a High Prevalence of Chronic Kidney Disease and a High Rate of Progression to End-Stage Renal Disease  

Microsoft Academic Search

The risk of progression to ESRD among individuals with cardiovascular disease and chronic kidney disease (CKD) is not well defined. The purpose of this study was to describe the risk of ESRD among patients with cardiovascular disease. Charts were abstracted for randomly selected hospitalized Medicare beneficiaries with a diagnosis of either congestive heart failure (CHF) or acute myocardial infarction (AMI).

WILLIAM M. MCCLELLAN; ROBERT D. LANGSTON; RODNEY PRESLEY

2004-01-01

183

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.

Hoglund Aberg, Carola; Antonoglou, Georgios; Haubek, Dorte; Kwamin, Francis; Claesson, Rolf; Johansson, Anders

2013-01-01

184

Progress in developing disease control strategies for hybrid poplars  

Treesearch

... failures resulting in poplars being labeled the universal host to many damaging pathogens. ... affecting poplars and in gaining knowledge of the underlying genetic mechanisms of disease resistance in poplars. ... Last Modified: July 21, 2013.

185

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

PubMed

A significant amount of research has been focused on the relationship between hormones and Alzheimer's disease. However, the majority of this work has been on estrogen and more recently testosterone. A serendipitous patient encounter led one of us (RLB) to question whether other hormones of the hypothalamic-pituitary-gonadal axis could be playing a role in the pathogenesis of Alzheimer's disease. The age-related decline in reproductive function results in a dramatic decrease in serum estrogen and testosterone concentrations and an equally dramatic compensatory increase in serum luteinizing hormone concentrations. Indeed, there is growing evidence that the gonadotropin, luteinizing hormone, which regulates serum estrogen and testosterone concentrations, could be an important causative factor in the development of Alzheimer's disease. This review provides information supporting the "gonadotropin hypothesis," puts forth a novel mechanism of how changes in serum luteinizing hormone concentrations could contribute to the pathogenesis of Alzheimer's disease, and discusses potential therapeutic anti-gonadotropin compounds. PMID:16472158

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

2006-01-01

186

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

187

Therapeutic targets for prevention and regression of progressive fibrosing renal diseases.  

PubMed

Renal fibrosis complicates most chronic renal diseases, leading to a progressive loss of function and ultimately resulting in terminal renal failure. Molecular mechanisms underlying the development and progression of renal fibrosis have been increasingly identified, and much progress has been made towards a better understanding of the roles of different growth factors/cytokines and regulators of matrix turnover, as well as of the interactions between renal inflammation and fibrosis. This review focuses on recent advances in the identification of novel targets, as well as the development of new therapeutic tools for use in the treatment of progressive fibrosing renal diseases. Using our growing knowledge, treatment strategies need to be identified that prevent progression more effectively, as well as inducing regression of developed renal fibrosis. This is likely by combining compounds that interfere with a variety of targets simultaneously. PMID:15816501

Eitner, Frank; Floege, Jürgen

2005-03-01

188

Mutation in the senataxin gene found in a patient affected by familial ALS with juvenile onset and slow progression.  

PubMed

We report an Italian male with juvenile onset familial disease characterized by progressive weakness and wasting of four limbs and prolonged survival. Diagnostic work-up revealed the diffuse involvement of central and peripheral motor neurons. Genetic analysis revealed a L389S mutation in the senataxin (SETX) gene. PMID:21438761

Avemaria, Francesca; Lunetta, Christian; Tarlarini, Claudia; Mosca, Lorena; Maestri, Eleonora; Marocchi, Alessandro; Melazzini, Mario; Penco, Silvana; Corbo, Massimo

2011-03-28

189

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

190

Mechanisms of Disease: epithelial–mesenchymal transition—does cellular plasticity fuel neoplastic progression?  

Microsoft Academic Search

Epithelial–mesenchymal transition (EMT) is a phenotypic 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, and is associated with disease progression. EMT in cancer epithelial cells often seems to be an incomplete and bidirectional process. In this Review, we

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

2008-01-01

191

Volume Progression in Autosomal Dominant Polycystic Kidney Disease: The Major Factor Determining Clinical Outcomes  

Microsoft Academic Search

Autosomal dominant polycystic kidney disease (PKD) is a hereditary condition characterized by the progressive enlargement of innumerable renal cysts that contribute to life-altering morbidity early in the course of the disease. Evidence indicates that the rate of increase in kidney volume can be reliably measured by magnetic resonance or computed tomography imaging, thus providing objective means to judge the effectiveness

Jared J. Grantham; Arlene B. Chapman; Vicente E. Torres

2006-01-01

192

Predicting initiation and progression of chronic kidney disease: Developing renal risk scores  

Microsoft Academic Search

Epidemiological studies have raised awareness of the problem of undiagnosed chronic kidney disease (CKD) and suggest that early identification and treatment will reduce the global burden of patients requiring dialysis. This has highlighted the twin problems of how to identify subjects for screening and target intervention to those with CKD most likely to progress to end-stage renal disease. Prospective studies

M W Taal; B M Brenner

2006-01-01

193

The tau gene A0 polymorphism in progressive supranuclear palsy and related neurodegenerative diseases  

Microsoft Academic Search

Progressive supranuclear palsy is characterised pathologically by the deposition of neurofibrillary tangles consisting of tau protein. Patients with the disease have been reported to have a more frequent occurrence of one allele of an intronic polymorphism of thetau gene. Other diseases which may involve tau deposition include frontotemporal dementia and corticobasal degeneration. This polymorphism has been studied in a series

H R Morris; J C Janssen; O Bandmann; S E Daniel; M N Rossor; A J Lees; N W Wood

1999-01-01

194

Estimating prevalence in single-gene kidney diseases progressing to renal failure  

Microsoft Academic Search

Estimating prevalence in single-gene kidney diseases progressing to renal failure. Incidence and prevalence, the measures of “frequency,” are often confused. While in a nonhereditary situation, the useful parameter is the incidence rate, evaluating the impact of an etiologic factor, it is prevalence that is considered useful in a hereditary disease. Prevalence may concern either the whole population or a fraction

Micheline Levy; Josué Feingold

2000-01-01

195

Influence of Obesity on Progression of Non-Diabetic Chronic Kidney Disease: A Retrospective Cohort Study  

Microsoft Academic Search

Background: There is increasing awareness of the impact of obesity on chronic diseases including chronic kidney disease (CKD). Until recently, a limited number of epidemiologic studies have examined the association between obesity and CKD. We conducted a retrospective cohort study to evaluate whether obesity impacts on the rate of non-diabetic CKD progression. Methods: The medical records of 125 non-diabetic CKD

Muftah Othman; Bisher Kawar; A. Meguid El Nahas

2009-01-01

196

Progress in hematopoietic stem cell transplantation for autoimmune diseases.  

PubMed

An international co-ordinated Phase I/II program commenced 8 years ago to study the role of profound immunoablation with hematopoietic stem cell transplantation in the treatment of severe, refractory autoimmune disease. Almost 700 patients have been treated for a variety of autoimmune diseases, mostly multiple sclerosis, systemic sclerosis, also referred to as scleroderma, systemic lupus erythematosis, rheumatoid arthritis and juvenile idiopathic arthritis. An overall treatment-related mortality of 7% was observed, with significant differences between diseases; 11% in systemic lupus erythematosis and only one patient with rheumatoid arthritis. Although outcomes are disparate in different diseases, there were significant durable, clinically useful remissions, relapses, and nonresponders in all groups. Although different protocols were employed, a clear advantage from the more intensive myeloablative regimens was not observed, although an increased toxicity did occur. The Phase I/II data was exploited in designing the Phase III randomized, comparative trials that are running in systemic sclerosis, multiple sclerosis and rheumatoid arthritis in Europe, and at the advanced planning stage in systemic sclerosis, multiple sclerosis and systemic lupus erythematosis in the USA. In parallel, a basic science program is proceeding with the prospective studies to improve understanding of the mechanisms of autoimmune disease activity and remission. PMID:20477663

Tyndall, Alan; Farge, Dominique

2005-05-01

197

Glomerular Hyperfiltration and Renal Disease Progression in Type 2 Diabetes  

PubMed Central

OBJECTIVE To describe the prevalence and determinants of hyperfiltration (glomerular filtration rate [GFR] ?120 mL/min/1.73 m2), GFR decline, and nephropathy onset or progression in type 2 diabetic patients with normo- or microalbuminuria. RESEARCH DESIGN AND METHODS We longitudinally studied 600 hypertensive type 2 diabetic patients with albuminuria <200 ?g/min and who were retrieved from two randomized trials testing the renal effect of trandolapril and delapril. Target blood pressure (BP) was <120/80 mmHg, and HbA1c was <7%. GFR, albuminuria, and glucose disposal rate (GDR) were centrally measured by iohexol plasma clearance, nephelometry in three consecutive overnight urine collections, and hyperinsulinemic euglycemic clamp, respectively. RESULTS Over a median (range) follow-up of 4.0 (1.7–8.1) years, GFR declined by 3.37 (5.71–1.31) mL/min/1.73 m2 per year. GFR change was bimodal over time: a larger reduction at 6 months significantly predicted slower subsequent decline (coefficient: ?0.0054; SE: 0.0009), particularly among hyperfiltering patients. A total of 90 subjects (15%) were hyperfiltering at inclusion, and 11 of 47 (23.4%) patients with persistent hyperfiltration progressed to micro- or macroalbuminuria versus 53 (10.6%) of the 502 who had their hyperfiltration ameliorated at 6 months or were nonhyperfiltering since inclusion (hazard ratio 2.16 [95% CI 1.13–4.14]). Amelioration of hyperfiltration was independent of baseline characteristics or ACE inhibition. It was significantly associated with improved BP and metabolic control, amelioration of GDR, and slower long-term GFR decline on follow-up. CONCLUSIONS Despite intensified treatment, patients with type 2 diabetes have a fast GFR decline. Hyperfiltration affects a subgroup of patients and may contribute to renal function loss and nephropathy onset or progression. Whether amelioration of hyperfiltration is renoprotective is worth investigating.

Ruggenenti, Piero; Porrini, Esteban L.; Gaspari, Flavio; Motterlini, Nicola; Cannata, Antonio; Carrara, Fabiola; Cella, Claudia; Ferrari, Silvia; Stucchi, Nadia; Parvanova, Aneliya; Iliev, Ilian; Dodesini, Alessandro Roberto; Trevisan, Roberto; Bossi, Antonio; Zaletel, Jelka; Remuzzi, Giuseppe

2012-01-01

198

Racial differences in the incidence and progression of renal diseases.  

PubMed

There is an excess incidence of ESRD treatment among non-White North Americans that is not completely explained by the racial prevalences of the underlying diseases, including hypertension, which can potentially cause renal disease. The racial difference is particularly striking for presumed nephrosclerosis from hypertension and for nephropathy from Type II diabetes, but is not yet substantiated for ESRD attributed to polycystic kidney disease or Type I diabetes. The existing data are insufficient to support the notion that poorer blood pressure control alone is responsible for the racial differences in incident ESRD. Black race (and possibly Mexican or Native American heritage) may be a specific risk factor for ESRD, independent of hypertension and its treatment. PMID:1762285

Smith, S R; Svetkey, L P; Dennis, V W

1991-11-01

199

Immunoprotection against toxic biomarkers is retained during Parkinson's disease progression.  

PubMed

The aim was to ascertain any possible linkage between humoral immune responses to principal biomarkers (?-synuclein monomers, its toxic oligomers or fibrils, dopamine and S100B) and cellular immunity in Parkinson's disease development. There were elevated autoantibody titers to ?-synuclein monomers, oligomers plus fibrils in 72%, 56%, and 17% of Parkinsonian patients respectively with a 5-year disease duration. Additionally, there were increased titers to dopamine and S100B (96% and 89%) in the 5-year patient group. All of these values subsided in 10-year sufferers. Furthermore, CD3+, CD4+, CD8+ T-lymphocyte and B-lymphocyte subsets declined in the patient cohort during Parkinsonism indicating disease associated reductions in these lymphocyte subsets. PMID:21239064

Gruden, Marina A; Sewell, Robert D E; Yanamandra, Kiran; Davidova, Tatyana V; Kucheryanu, Valery G; Bocharov, Evgeny V; Bocharova, Olga R; Polyschuk, Vsevolod V; Sherstnev, Vladimir V; Morozova-Roche, Ludmilla A

2011-01-15

200

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

201

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

PubMed Central

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

Limpert, Allison S; Mattmann, Margrith E

2013-01-01

202

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

2013-08-03

203

Cross-sectional and longitudinal correlations between disease progression and different health-related quality of life domains in persons with amyotrophic lateral sclerosis.  

PubMed

In ALS it would be expected that quality of life (QoL) would be decreased. However, studies to date show diverging results. Our study focuses on how ALS affects QoL on the different domains of the SF-36 cross-sectionally and during progression. The method used was a prospective cohort study, with assessments at baseline, at six months, and at one year. Patients were included with possible, probable or definite ALS according to the revised El Escorial criteria and were between 30 and 70 years of age. ALS functional rating scale was used to establish disease status, SF-36 as QoL scale. At baseline 73 completed ALSFRS forms were available and 62 completed SF-36 forms. The ALSFRS showed disease progression. SF-36 scores showed lower QoL scores of persons with ALS compared to the general population both in cross-sectional and longitudinal aspects in the domains of Physical Functioning, Role Physical, and Social Functioning, but similar compared with the general population in the Mental Health and Role Emotional domains. This study shows deteriorating physical health but stable mental health, thereby illustrating the diverging correlations between ALS severity and HRQoL. The diverging pattern of physical and mental health suggests a frame-shift in the experience of HRQoL. PMID:18033593

De Groot, Imelda J M; Post, Marcel W M; van Heuveln, Tineke; Van den Berg, Leonard H; Lindeman, Eline

2007-12-01

204

Changes in network activity with the progression of Parkinson's disease  

Microsoft Academic Search

Parkinson's disease (PD) is associated with abnormal activity in spatially distributed neural systems mediating the motor and cognitive manifestations of this disorder. Metabolic PET studies have demonstrated that this illness is characterized by a set of reproducible functional brain networks that correlate with these clinical features.The time at which these abnormalities appear is unknown, as is their relationship to concurrent

Chaorui Huang; Chengke Tang; Andrew Feigin; Martin Lesser; Yilong Ma; Michael Pourfar; Vijay Dhawan; David Eidelberg

2007-01-01

205

Progress toward Vaccines against Viruses that Cause Heart Disease  

Microsoft Academic Search

Of the numerous viruses that have been implicated as causes of viral inflammatory cardiomyopathy, only the 6 serotypes of the group B coxsackieviruses (CVB 1-,6) and adenovirus type 2 (Ad2) have been regularly linked to heart disease on the basis of both clinical investigations as well as animal models (in the case of the coxsackieviruses). Of these, only the coxsackieviruses

Katja Höfling; Kyung-Soo Kim; J. Smith Leser; Nora M. Chapman; Sandra Willian; Charles J. Gauntt; Steven Tracy

2000-01-01

206

Krabbe Disease: Genetic Aspects and Progress toward Therapy  

Microsoft Academic Search

Krabbe disease or globoid cell leukodystrophy is a disorder involving the white matter of the peripheral and central nervous systems. Mutations in the gene for the lysosomal enzyme galactocerebrosidase (GALC) result in low enzymatic activity and decreased ability to degrade galactolipids found almost exclusively in myelin. The pathological changes observed, including the presence of globoid cells and decreased myelin, appear

David A. Wenger; Mohammad A. Rafi; Paola Luzi; Jeffrey Datto; Elvira Costantino-Ceccarini

2000-01-01

207

Progress Report on Alzheimer's Disease, 2003: Research Advances at NIH.  

National Technical Information Service (NTIS)

The National Institute on Aging (NIA), part of the Federal Government's National Institutes of Health (NIH), has primary responsibility for basic research in Alzheimer's disease (AD) as well as research aimed at finding ways to prevent and treat AD. The I...

2004-01-01

208

Pharmacogenetics: Progress, pitfalls and clinical potential for coronary heart disease  

Microsoft Academic Search

Much has been written about the potential of pharmacogenetic testing to inform therapy based on an individual's genetic makeup, and to decide the most effective choice of available drugs, or to avoid dangerous side effects. Currently, there is little hard data for either in the field of cardiovascular disease. The usual approach has been opportunistic use of drug trials in

Steve E. Humphries; Aroon Hingorani

2006-01-01

209

Serum Metabolomics of Slow vs. Rapid Motor Progression Parkinson's Disease: a Pilot Study  

PubMed Central

Progression of Parkinson’s disease (PD) is highly variable, indicating that differences between slow and rapid progression forms could provide valuable information for improved early detection and management. Unfortunately, this represents a complex problem due to the heterogeneous nature of humans in regards to demographic characteristics, genetics, diet, environmental exposures and health behaviors. In this pilot study, we employed high resolution mass spectrometry-based metabolic profiling to investigate the metabolic signatures of slow versus rapidly progressing PD present in human serum. Archival serum samples from PD patients obtained within 3 years of disease onset were analyzed via dual chromatography-high resolution mass spectrometry, with data extraction by xMSanalyzer and used to predict rapid or slow motor progression of these patients during follow-up. Statistical analyses, such as false discovery rate analysis and partial least squares discriminant analysis, yielded a list of statistically significant metabolic features and further investigation revealed potential biomarkers. In particular, N8-acetyl spermidine was found to be significantly elevated in the rapid progressors compared to both control subjects and slow progressors. Our exploratory data indicate that a fast motor progression disease phenotype can be distinguished early in disease using high resolution mass spectrometry-based metabolic profiling and that altered polyamine metabolism may be a predictive marker of rapidly progressing PD.

Roede, James R.; Uppal, Karan; Park, Youngja; Lee, Kichun; Tran, Vilinh; Walker, Douglas; Strobel, Frederick H.; Rhodes, Shannon L.; Ritz, Beate; Jones, Dean P.

2013-01-01

210

A network diffusion model of disease progression in dementia.  

PubMed

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

2012-03-21

211

Epidemic progression on networks based on disease generation time  

PubMed Central

We investigate the time evolution of disease spread on a network and present an analytical framework using the concept of disease generation time. Assuming a susceptible–infected–recovered epidemic process, this network-based framework enables us to calculate in detail the number of links (edges) within the network that are capable of producing new infectious nodes (individuals), the number of links that are not transmitting the infection further (non-transmitting links), as well as the number of contacts that individuals have with their neighbours (also known as degree distribution) within each epidemiological class, for each generation period. Using several examples, we demonstrate very good agreement between our analytical calculations and the results of computer simulations.

Davoudi, Bahman; Moser, Flavia; Brauer, Fred; Pourbohloul, Babak

2013-01-01

212

Linear Clinical Progression, Independent of Age of Onset, in Niemann-Pick Disease, type C  

PubMed Central

Niemann-Pick Disease, type C is a neurodegenerative, lysosomal storage disorder with a broad clinical spectrum and a variable age of onset. The absence of a universally accepted clinical outcome measure is an impediment to the design of a therapeutic trial for NPC. Thus, we developed a clinical severity scale to characterize and quantify disease progression. Clinical signs and symptoms in nine major (ambulation, cognition, eye movement, fine motor, hearing, memory, seizures, speech, swallowing,) and eight minor (auditory brainstem response, behavior, gelastic cataplexy, hyperreflexia, incontinence, narcolepsy, psychiatric, respiratory problems) domains were scored. Data were collected from 18 current NPC patients and were extracted from records of 19 patients. Both patient cohorts showed a linear increase in severity scores over time. Cross-sectional evaluation of current patients showed a linear increase in the severity score. Longitudinal chart review of historical data demonstrated that although age of onset varied significantly, the rate of progression appeared linear, independent of age of onset, and similar in all patients. Combining the data from both cohorts, disease progression could be modeled by the following equation: ?t0+x = ?t0 + 1.87x; where ?t0 is the initial score and ?t0+x is the predicted future score after x years. Our observation that disease progression is similar across patients and independent of age of onset is consistent with a biphasic pathological model for NPC. This scale may prove useful in the characterization of potential biomarkers, and as an outcome measure to monitor disease progression in NPC patients.

Yanjanin, Nicole M.; Velez, Jorge I.; Gropman, Andrea; King, Kelly; Bianconi, Simona E.; Conley, Sandra K.; Brewer, Carmen C.; Solomon, Beth; Pavan, William J.; Arcos-Burgos, Mauricio; Patterson, Marc C.; Porter, Forbes D.

2009-01-01

213

Triclosan-containing dentifrice may slow periodontal disease progression  

Microsoft Academic Search

Design The study was a double-blind randomised controlled trail of a general population (members of which were not at risk for periodontal disease).Intervention Subjects in the test group were given a dentifrice containing 0.3% triclosan, 2% copolymer and 0.243% sodium fluoride (Colgate Total; Colgate Palmolive, Sydney, NSW, Australia), whereas members of the control group were supplied with a placebo dentifrice

Richard Niederman

2004-01-01

214

Mechanisms of Copper Ion Mediated Huntington's Disease Progression  

Microsoft Academic Search

Huntington's disease (HD) is caused by a dominant polyglutamine expansion within the N-terminus of huntingtin protein and results in oxidative stress, energetic insufficiency and striatal degeneration. Copper and iron are increased in the striata of HD patients, but the role of these metals in HD pathogenesis is unknown. We found, using inductively-coupled-plasma mass spectroscopy, that elevations of copper and iron

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

2007-01-01

215

HIV infection in Haiti: natural history and disease progression  

Microsoft Academic Search

Objective: A study was conducted to define the natural history and disease progres- sion of HIV infection in a developing country. Design: A prospective longitudinal cohort study. Methods: Forty-two patients with documented dates of HIV seroconversion were followed in Port-au-Prince, Haiti. Patients were seen at 3 month intervals or when ill. Patients were treated for bacterial, mycobacterial, parasitic, and fungal

Marie-Marcelle Deschamps; Daniel W. Fitzgerald; Jean William Pape; Warren D. Johnson Jr

2000-01-01

216

Disease manifestations of progressive systemic sclerosis: sensitivity and specificity  

Microsoft Academic Search

Summary  The authors conducted a study of 47 patients with a diagnosis of systemic sclerosis in order to determine the sensitivity,\\u000a specificity and Youden index and consequently the diagnostic value of the generally accepted criteria and of some other common\\u000a disease features. The control population consisted of 324 patients with rheumatoid arthritis and 35 patients with systemic\\u000a lupus erythematosus. In addition

X. Janssens; L. Herman; H. Mielants; G. Verbruggen; E. M. Veys

1987-01-01

217

[Research progress of anemia associated with inflammatory bowel diseases].  

PubMed

Anemia is a frequent and serious complication in patients with inflammatory bowel disease (IBD). One third of patients with inflammatory bowel disease suffers from recurrent anemia. Anemia is associated with a decrease in the quality of life and an increased rate of hospitalization. A number of studies have been conducted and the most relevant conclusions obtained are:(1)anemia is quite common in IBD; (2)although in many cases anemia parallels the clinical activity of the disease, many patients in remission have anemia, and iron, vitamin B12 and/or folic acid deficiency;(3)anemia, and also iron deficiency without anemia, have important consequences in the clinical status and quality of life of the patients;(4)oral iron supplement is limited by poor absorption, intolerance, and induction of oxidative stress at the site of bowel inflammation; (5) intravenous iron sucrose has a high efficiency and a significant improvement in the quality of life; (6)erythropoietin is needed in a significant number of cases to achieve normal hemoglobin levels. Combination therapy with erythropoietin leads to a faster and larger hemoglobin increase. Thus, clinicians caring for IBD patients should have a comprehensive knowledge of anemia, and apply recently published guidelines in clinical practice. PMID:22736141

Hong, Zhi-wu; Ren, Jian-an

2012-06-01

218

[Progress on dynamic neutralization system in treating lumbar degenerative diseases].  

PubMed

Dynamic stabilization technology has increasingly become the hot spot in basic and clinical research for treating lumbar degenerative diseases. As one kind of dynamic stabilization technology,dynamic neutralization system (Dynesys) keeps the spinal motion ability and improve clinical symptoms of patients, moreover, it shows a certain advantage in delaying the degeneration of adjacent segments. From the available documents,the preliminary biomechanical and clinical results of Dynesys were optimistically, it has become another choice in treating the lumbar degenerative diseases besides the lumbar fusion, and it primarily applies to the treatment of mild to moderate lumbar degenerative disease. However, it lacks a mechanism to maintain and restore the lumbar lordosis and patients need active stretching to achieve lordosis. What's more, how to extend the service life and prevent complications remain to be solved, the long-term effect and the mechanism of delaying the adjacent segment degeneration need further investigation. In this article, the design principle, biomechanical research, clinical outcome and clinical application of Dynesys was reviewed. PMID:24015664

Chen, Xi-Jun; Fan, Shun-Wu

2013-06-01

219

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.

2012-01-01

220

Modelling Disease Progression in Alzheimer's Disease: A Review of Modelling Methods used for Cost-Effectiveness Analysis  

Microsoft Academic Search

The literature reporting economic evaluations related to the treatment of Alzheimer's disease (AD) has developed over the last decade. Most analyses have used economic models to estimate the cost effectiveness of drugs for the treatment of AD. This review considers the range of methods used in the published cost-effectiveness literature to model AD progression and the effect of interventions on

Colin Green

2007-01-01

221

Research progress on natural products from traditional Chinese medicine in treatment of Alzheimer's disease.  

PubMed

Alzheimer's disease (AD) is a severe condition in aging societies. Although research on this disease is advancing rapidly, thus far few very effective drugs are available for AD patients. The currently widely used medicines such as donepezil and galantamine transiently improve the symptoms of patients with mild to moderate AD. They are hardly capable of preventing, halting or reversing the progression of this disease. In the long history of development of traditional Chinese medicine, many herbs have been discovered and employed to treat dementia diseases in clinics in China. In recent decades, a number of agents were isolated from these herbs and their efficacies against AD were tested. Some flavonoids, alkaloids, phenylpropanoids, triterpenoid saponins, and polysaccharides were demonstrated to have potential efficacies against AD via targeting multiple pathological changes of this disease. In this article, we reviewed research progress on the efficacies and underlying mechanisms of these agents. PMID:23715502

Gao, Jianjun; Inagaki, Yoshinori; Li, Xuan; Kokudo, Norihiro; Tang, Wei

2013-04-01

222

Does the Season or Month of Birth Influence Disease Progression in Multiple Sclerosis?  

Microsoft Academic Search

We investigated the influence of season and birth month on sustained progression to Expanded Disability Status Scale 6 (requires a cane) through a database review of 2,319 definite multiple sclerosis (MS) patients followed for a mean 19.3 years, until July 2003 in British Columbia, Canada. The season of birth had a marginal effect on disease progression (p = 0.051), with

Helen L. Tremlett; Virginia A. Devonshire

2006-01-01

223

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 ac- cumulation 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).Thepre-definedstudyendpointsincluded progression of renal, cardiac and cerebrovascular involve- ment and\\/or death before the

Raphael J. Schiffmann; David G. Warnock; Maryam Banikazemi; Jan Bultas; Gabor E. Linthorst; Seymour Packman; Sven Asger Sorensen; William R. Wilcox; Robert J. Desnick

224

Transcriptomic indices of fast and slow disease progression in two mouse models of amyotrophic lateral sclerosis.  

PubMed

Amyotrophic lateral sclerosis is heterogeneous with high variability in the speed of progression even in cases with a defined genetic cause such as superoxide dismutase 1 (SOD1) mutations. We reported that SOD1(G93A) mice on distinct genetic backgrounds (C57 and 129Sv) show consistent phenotypic differences in speed of disease progression and life-span that are not explained by differences in human SOD1 transgene copy number or the burden of mutant SOD1 protein within the nervous system. We aimed to compare the gene expression profiles of motor neurons from these two SOD1(G93A) mouse strains to discover the molecular mechanisms contributing to the distinct phenotypes and to identify factors underlying fast and slow disease progression. Lumbar spinal motor neurons from the two SOD1(G93A) mouse strains were isolated by laser capture microdissection and transcriptome analysis was conducted at four stages of disease. We identified marked differences in the motor neuron transcriptome between the two mice strains at disease onset, with a dramatic reduction of gene expression in the rapidly progressive (129Sv-SOD1(G93A)) compared with the slowly progressing mutant SOD1 mice (C57-SOD1(G93A)) (1276 versus 346; Q-value ? 0.01). Gene ontology pathway analysis of the transcriptional profile from 129Sv-SOD1(G93A) mice showed marked downregulation of specific pathways involved in mitochondrial function, as well as predicted deficiencies in protein degradation and axonal transport mechanisms. In contrast, the transcriptional profile from C57-SOD1(G93A) mice with the more benign disease course, revealed strong gene enrichment relating to immune system processes compared with 129Sv-SOD1(G93A) mice. Motor neurons from the more benign mutant strain demonstrated striking complement activation, over-expressing genes normally involved in immune cell function. We validated through immunohistochemistry increased expression of the C3 complement subunit and major histocompatibility complex I within motor neurons. In addition, we demonstrated that motor neurons from the slowly progressing mice activate a series of genes with neuroprotective properties such as angiogenin and the nuclear factor (erythroid-derived 2)-like 2 transcriptional regulator. In contrast, the faster progressing mice show dramatically reduced expression at disease onset of cell pathways involved in neuroprotection. This study highlights a set of key gene and molecular pathway indices of fast or slow disease progression which may prove useful in identifying potential disease modifiers responsible for the heterogeneity of human amyotrophic lateral sclerosis and which may represent valid therapeutic targets for ameliorating the disease course in humans. PMID:24065725

Nardo, Giovanni; Iennaco, Raffaele; Fusi, Nicolò; Heath, Paul R; Marino, Marianna; Trolese, Maria C; Ferraiuolo, Laura; Lawrence, Neil; Shaw, Pamela J; Bendotti, Caterina

2013-09-24

225

Bromocriptine methylate suppresses glial inflammation and moderates disease progression in a mouse model of amyotrophic lateral sclerosis.  

PubMed

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by a selective loss of upper and lower motor neurons. Since oxidative stress plays a crucial role in the progression of motor neuron loss observed in ALS, anti-oxidative agents could be an important therapeutic means for the ALS treatment. We have previously developed a drug screening system allowing the identification of small chemical compounds that upregulate endogenous neuronal apoptosis inhibitory protein (NAIP), an oxidative stress-induced cell death suppressor. Using this system, we identified the dopamine D2 receptor agonist bromocriptine (BRC) as one of NAIP-upregulating compounds. In this study, to prove the efficacy of BRC in ALS, we conducted a set of preclinical studies using a transgenic ALS mouse model carrying the H46R mutation in the human Cu/Zn superoxide dismutase (SOD1) gene ALS(SOD1(H46R)) by the post-onset administration of BRC. ALS(SOD1(H46R)) mice receiving BRC showed sustained motor functions and modest prolonged survival after onset. Further, BRC treatment delayed anterior horn cell loss, and reduced the number of reactive astrocytes and the level of inflammatory factors such as inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF)-? in the spinal cord of late symptomatic mice. In vitro study showed the reduced level of extracellular TNF-? after lipopolysaccharide (LPS) exposure in BRC-treated mouse astrocytes. BRC-treated ALS(SOD1(H46R)) mice also showed a reduced level of oxidative damage in the spinal cord. Notably, BRC treatment resulted in an upregulation of anti-oxidative stress genes, activating transcription factor 3 (ATF3) and heme oxygenase-1 (HO-1), and the generation of a glutathione (GSH) in SH-SY5Y cultured neuronal cells in a dopamine receptor-independent manner. These results imply that BRC protects motor neurons from the oxidative injury via suppression of astrogliosis in the spinal cord of ALS(SOD1(H46R)) mice. Thus, BRC might be a promising therapeutic agent for the treatment of ALS. PMID:21867702

Tanaka, Kazunori; Kanno, Takuya; Yanagisawa, Yoshiko; Yasutake, Kaori; Hadano, Shinji; Yoshii, Fumihito; Ikeda, Joh-E

2011-08-16

226

SPARC Accelerates Disease Progression in Experimental Crescentic Glomerulonephritis  

PubMed Central

Podocytopenia characterizes many forms of glomerular disease, preceding the development of glomerulosclerosis. While detachment of viable podocytes from the underlying glomerular basement membrane is an important mechanism of podocyte loss, the underlying factors involved remain unclear. Secreted protein acidic and rich in cysteine (SPARC), a matricellular protein with counteradhesive properties, is normally expressed at low levels by the podocyte but is markedly increased following podocyte injury. Accordingly, we elucidate the role of SPARC in mediating experimental crescentic glomerulonephritis by inducing passive nephrotoxic nephritis in SPARC+/+ and SPARC?/? mice. By days 4, 7, and 21 following disease induction, podocyte number is better preserved, glomerulosclerosis is ameliorated, and proteinuria is reduced in SPARC?/? mice as compared with SPARC+/+ littermates. Moreover, the preserved podocyte number in SPARC?/? mice correlates with reduced urinary levels of both nephrin and podocin. To establish a causal role for SPARC in mediating detachment, cultured SPARC+/+ and SPARC?/? podocytes were subjected to mechanical strain as well as trypsin digestion, and detachment assays were performed. While podocytes lacking SPARC were more resistant to stretch-induced detachment, stable re-expression of SPARC restored detachment rates to levels comparable with SPARC+/+ podocytes. Taken together, this study proves that SPARC plays a causal role in mediating podocyte detachment and accelerating glomerulosclerosis in experimental crescentic glomerulonephritis.

Sussman, Amy N.; Sun, Tong; Krofft, Ronald M.; Durvasula, Raghu V.

2009-01-01

227

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.

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

2009-01-01

228

Serum cysteine proteases and their inhibitors in rheumatoid arthritis: relation to disease activity and radiographic progression.  

PubMed

This study aims to investigate the serum levels of cysteine proteases cathepsins B and H and their inhibitors stefin A, stefin B, and cystatin C, as well as traditional inflammatory markers such as C-reactive protein in patients with rheumatoid arthritis and to correlate these markers with scores of disease activity and radiographic progression. Seventy-two patients with rheumatoid arthritis were included from two previously described cohorts of patients with chronic polyarthritis. At inclusion, disease activity was assessed by a 28-joint count, patient global assessment, and serum C-reactive protein. Erosive status of hands and wrists was expressed by the Larsen score and recorded at inclusion and after 1 year. Serum levels of cathepsin B, cathepsin H, stefin A, stefin B, and cystatin C were determined by enzyme-linked immunosorbent assay. Neither cathepsin B nor cathepsin H serum levels were associated with disease activity, presence or progression of erosive disease. Number of swollen joints correlated with serum levels of stefin A and B and correlated negatively with cystatin C serum levels. Erosive disease was associated with high serum levels of C-reactive protein and stefin A and low serum levels of cystatin C. Progression of radiographic destruction was associated with high serum levels of C-reactive protein, stefin A and B, whereas serum levels of cystatin C were not associated with radiographic progression. The findings in this study support further investigation in the regulation of the activity of cathepsins and their inhibitors in erosive rheumatoid arthritis. PMID:20924627

Jørgensen, Iben; Kos, Janko; Krašovec, Marta; Troelsen, Lone; Klarlund, Mette; Jensen, Trine W; Hansen, Michael S; Jacobsen, Søren

2010-10-06

229

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

230

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

PubMed Central

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

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

2011-01-01

231

An economic model of Parkinson's disease: implications for slowing progression in the United States.  

PubMed

Multiple studies describe progression, dementia rates, direct and indirect costs, and health utility by Hoehn and Yahr (H&Y) stage, but research has not incorporated these data into a model to evaluate possible economic consequences of slowing progression. This study aimed to model the course of Parkinson's disease (PD) and describe the economic consequences of slower rates of progression. A Markov model was developed to show the net monetary benefits of slower rates of progression. Four scenarios assuming hypothetical slower rates of progression were compared to a base case scenario. A systematic literature review identified published longitudinal H&Y progression rates. Direct and indirect excess costs (i.e., healthcare costs beyond what similar patients without PD would incur), mortality rates, dementia rates, and health utility were derived from the literature. Ten publications (N = 3,318) were used to model longitudinal H&Y progression. Base case results indicate average excess direct costs of $303,754, life-years of 12.8 years and quality-adjusted life-years of 6.96. A scenario where PD progressed 20% slower than the base case resulted in net monetary benefits of $60,657 ($75,891 including lost income) per patient. The net monetary benefit comes from a $37,927 decrease in direct medical costs, 0.45 increase in quality-adjusted life-years, and $15,235 decrease in lost income. The scenario where PD progression was arrested resulted in net monetary benefits of $442,429 per patient. Reducing progression rates could produce significant economic benefit. This benefit is strongly dependent on the degree to which progression is slowed. PMID:23404374

Johnson, Scott J; Diener, Melissa D; Kaltenboeck, Anna; Birnbaum, Howard G; Siderowf, Andrew D

2013-02-12

232

6. Asthma: Factors underlying inception, exacerbation, and disease progression.  

PubMed

Asthma is a heterogeneous disorder that is characterized by variable airflow obstruction, airway inflammation and hyperresponsiveness, and reversibility either spontaneously or as a result of treatment. Multiple causes no doubt exist for both its inception and symptom exacerbation once the disease is established. Factors underlying inception can range from viral respiratory tract infections in infancy to occupational exposures in adults. Factors underlying asthma exacerbations include allergen exposure in sensitized individuals, viral infections, exercise, irritants, and ingestion of nonsteroidal anti-inflammatory agents among others. Exacerbating factors might include one or all of these exposures and vary both among and within patients. Asthma treatment is determined to a large extent after an assessment of severity, which can be variable over time and assessed in 2 domains: impairment (current) and risk (long-term consequences). Unfortunately, despite the availability of effective therapies, suboptimal asthma control exists in many patients on a worldwide basis. The future development of novel therapies and treatment paradigms should address these disparities. PMID:16455346

Lemanske, Robert F; Busse, William W

2006-02-01

233

Folate-Conjugated Rapamycin Slows Progression of Polycystic Kidney Disease  

PubMed Central

Activation of the mammalian target of rapamycin (mTOR) signaling pathway is aberrant in autosomal-dominant polycystic kidney disease (ADPKD). The mTOR inhibitors, such as rapamycin, ameliorate PKD in rodent models, but clinical trials have not shown benefit, possibly as a result of low tissue concentrations of rapamycin at clinically tolerable doses. To overcome this limitation, we synthesized a folate-conjugated form of rapamycin (FC-rapa) that is taken up by folate receptor–mediated endocytosis and cleaved intracellularly to reconstitute the active drug. We found that renal cyst-lining cells highly express the folate receptor in ADPKD and mouse models. In vitro, FC-rapa inhibited mTOR activity in a dose- and folate receptor–dependent manner. Treatment of a PKD mouse model with FC-rapa inhibited mTOR in the target tissue, strongly attenuated proliferation and growth of renal cysts and preserved renal function. Furthermore, FC-rapa inhibited mTOR activity in the kidney but not in other organs. In summary, these results suggest that targeting the kidney using FC-rapa may overcome the significant side effects and lack of renal efficacy observed in clinical trials with mTOR inhibitors in ADPKD.

Shillingford, Jonathan M.; Leamon, Christopher P.; Vlahov, Iontcho R.

2012-01-01

234

Theoretical and Practical Progress of New Heliostat by Chen et al  

Microsoft Academic Search

Recently, Chen and his team were active in the theoretical and practical study of a new heliostat for the use of solar energy. This work represents the first innovation in the area of heliostats after many years of little progress. The mathematical development of the tracking and concentration optics principles, and the practical implementation and demonstration of the technology, are

A. Kribus

2006-01-01

235

Pharmacogenetics: progress, pitfalls and clinical potential for coronary heart disease.  

PubMed

Much has been written about the potential of pharmacogenetic testing to inform therapy based on an individual's genetic makeup, and to decide the most effective choice of available drugs, or to avoid dangerous side effects. Currently, there is little hard data for either in the field of cardiovascular disease. The usual approach has been opportunistic use of drug trials in unrelated patients, and to look for differences in response or outcome by "candidate gene" genotype, for example genes coding for drug metabolising enzymes (activators and metabolisers), and enzymes and receptors involved in lipid metabolism, adrenergic response, etc. As with all association studies, initially promising results have often failed the test of replication in larger studies, and the relationship between the CETP Taq-I variant and response to statins has now been disproved. The strongest data to date is the report [Chasman, D.I., Posada, D., Subrahmanyan, L., Cook, N.R., Stanton Jr., V.P., Ridker, P.M., 2004. Pharmacogenetic study of statin therapy and cholesterol reduction. J. Am. Med. Assoc. 291, 2821-2827] of a poorer cholesterol-lowering response to Pravastatin in the 7% of patients carrying a certain haplotype of the HMG CoA reductase gene (14% fall versus 19%), but if this is overcome simply by a higher dose, it is of little clinical relevance. Currently, the best example of avoiding side effects is determining genotype at the CYP2C9 locus with respect of warfarin treatment, since carriers for functional variants (>20% of the population) require lower doses for optimal anticoagulation, and homozygotes, although rare, may well experience serious bleeding if given a usual dose. The full potential of this field will only be realised with much further work. PMID:16359930

Humphries, Steve E; Hingorani, Aroon

2005-12-15

236

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

PubMed Central

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

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

2011-01-01

237

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

PubMed Central

The term “prion” was introduced by Stanley Prusiner in 1982 to describe the atypical infectious agent that causes transmissible spongiform encephalopathies, a group of infectious neurodegenerative diseases that include scrapie in sheep, Creutzfeldt-Jakob disease in humans, chronic wasting disease in cervids, and bovine spongiform encephalopathy in cattle. Over the past twenty years, the word “prion” has been taken to signify various subtly different concepts. In this article, we refer to the prion as the transmissible principle underlying prion diseases, without necessarily implying any specific biochemical or structural identity. When Prusiner started his seminal work, the study of transmissible spongiform encephalopathies was undertaken by only a handful of scientists. Since that time, the “mad cow” crisis has put prion diseases on the agenda of both politicians and the media. Significant progress has been made in prion disease research, and many aspects of prion pathogenesis are now understood. And yet the diagnostic procedures available for prion diseases are not nearly as sensitive as they ought to be, and no therapeutic intervention has been shown to reliably affect the course of the diseases. This article reviews recent progress in the areas of pathogenesis of, diagnostics of, and therapy for prion diseases and highlights some conspicuous problems that remain to be addressed in each of these fields.

Aguzzi, Adriano; Heikenwalder, Mathias; Miele, Gino

2004-01-01

238

Cognitive and SPECT characteristics predict progression of Parkinson’s disease in newly diagnosed patients  

Microsoft Academic Search

Objective To identify features in cognitive functioning and regional cerebral blood flow (rCBF) in newly diagnosed Parkinson’s disease (PD) patients and to determine whether these factors are able to predict the progression of the disease in general and the development of cognitive decline in particular. Methods 50 previously treatment-naive PD patients participated in the study. Cognitive assessment and SPECT were

Kathy Dujardin; Luc Defebvre; Alain Duhamel; Pascal Lecouffe; Pascal Rogelet; Marc Steinling; Alain Destée

2004-01-01

239

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

240

A protective effect of breastfeeding on the progression of non-alcoholic fatty liver disease  

Microsoft Academic Search

Objective:Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disease characterised by accumulation of large-droplet fat in hepatocytes with possible progression to inflammation and fibrosis. Breastfeeding has benefits for child health, both during infancy and later in life, reducing the risk of manifestations of the metabolic syndrome. Here we investigated the association between early type of feeding (breastfed versus

V Nobili; G Bedogni; A Alisi; A Pietrobattista; A Alterio; C Tiribelli; C Agostoni

2009-01-01

241

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

242

Persistent treatment with cholinesterase inhibitors and\\/or memantine slows clinical progression of Alzheimer disease  

Microsoft Academic Search

INTRODUCTION: There are no empiric data to support guidelines for duration of therapy with antidementia drugs. This study examined whether persistent use of antidementia drugs slows clinical progression of Alzheimer disease (AD) assessed by repeated measures on serial tests of cognition and function. METHODS: Six hundred forty-one probable AD patients were followed prospectively at an academic center over 20 years.

Susan D Rountree; Wenyaw Chan; Valory N Pavlik; Eveleen J Darby; Samina Siddiqui; Rachelle S Doody

2009-01-01

243

Methylprednisolone retards the progression of inherited polycystic kidney disease in rodents  

Microsoft Academic Search

Polycystic kidney disease in adult laboratory animals and humans is associated with enlarged kidneys and a progressive decline of renal function, resulting in death from uremia. Interstitial inflammation and fibrosis typically are observed in association with the development of renal insufficiency. To determine whether amelioration of interstitial inflammation and fibrosis may diminish cyst expansion\\/kidney enlargement and stabilize renal function, we

Vincent H. Gattone; Benjamin D. Cowley; Brian D. Barash; Shizuko Nagao; Hisahide Takahashi; Tamio Yamaguchi; Jared J. Grantham

1995-01-01

244

Use of predictive markers of HIV disease progression in vaccine trials  

Microsoft Academic Search

Generating broadly neutralizing antibodies with candidate vaccines has remained an elusive goal. Consequently, vaccine candidates developed have aimed at eliciting cell-mediated immune effector activities (CMI) that could delay disease progression, and maybe also limit secondary transmission, by controlling virus replication. There is considerable discussion about what types of endpoints would constitute definable standardized clinical benefit to the individual that would

S. Gurunathan; R. El Habib; L. Baglyos; C. Meric; S. Plotkin; B. Dodet; L. Corey; J. Tartaglia

2009-01-01

245

Advancing Drug Innovation for Neglected Diseases—Criteria for Lead Progression  

Microsoft Academic Search

The current drug R&D pipeline for most neglected diseases remains weak, and unlikely to support registration of novel drug classes that meet desired target product profiles in the short term. This calls for sustained investment as well as greater emphasis in the risky upstream drug discovery. Access to technologies, resourc- es, and strong management as well as clear compound progression

Solomon Nwaka; Bernadette Ramirez; Reto Brun; Louis Maes; Frank Douglas; Robert Ridley

2009-01-01

246

A Randomized Trial of Multivitamin Supplements and HIV Disease Progression and Mortality  

Microsoft Academic Search

background Results from observational studies suggest that micronutrient status is a determinant of the progression of human immunodeficiency virus (HIV) disease. methods We enrolled 1078 pregnant women infected with HIV in a double-blind, placebo-con- trolled trial in Dar es Salaam, Tanzania, to examine the effects of daily supplements of vitamin A (preformed vitamin A and beta carotene), multivitamins (vitamins B,

Wafaie W. Fawzi; Gernard I. Msamanga; Donna Spiegelman; Ruilan Wei; Saidi Kapiga; Eduardo Villamor; Davis Mwakagile; Ferdinand Mugusi; Ellen Hertzmark; Max Essex; David J. Hunter

2004-01-01

247

Progressive abnormalities in skeletal muscle and neuromuscular junctions of transgenic mice expressing the Huntington's disease mutation  

Microsoft Academic Search

Huntington's disease (HD) is a neurodegenerative disorder with complex symptoms dominated by progressive motor dysfunction. Skeletal muscle atrophy is common in HD patients. Because the HD mutation is expressed in skeletal muscle as well as brain, we wondered whether the muscle changes arise from primary pathology. We used R6 ? 2 transgenic mice for our studies. Unlike denervation atrophy, skeletal

Richard R. Ribchester; Derek Thomson; Nigel I. Wood; Tim Hinks; Thomas H. Gillingwater; Thomas M. Wishart; Felipe A. Court; A. Jennifer Morton

2004-01-01

248

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…

Slaughter, Susan; Bankes, Jane

2007-01-01

249

Regression and Non-Progression of Coronary Artery Disease with Exercise  

Microsoft Academic Search

Metabolic interventions using low-fat diets and lipid level-lowering drugs were successful in controlling the progression rate of coronary artery disease and reduced the number of clinical events. Only a few studies have examined the role of regular physical exercise as a therapeutic instrument to enhance these beneficial effects. The design of the available studies did not permit differentiation among the

Gerhard Schuler; Rainer Hambrecht

1996-01-01

250

Parkinson's disease symptoms are differentially affected by massage therapy vs. progressive muscle relaxation: a pilot study  

Microsoft Academic Search

Sixteen adults diagnosed with idiopathic Parkinson's disease (M age=58) received 30-min massage therapy or progressive muscle relaxation exercise sessions twice a week for 5 weeks (10 sessions total). Physicians rated participants in the massage therapy group as improved in daily living activities by the end of the study. The massaged group also rated themselves as improved in daily functioning, and

Maria Hernandez-Reif; Tiffany Field; Shay Largie; Christy Cullen; Julia Beutler; Chris Sanders; William Weiner; Dinorah Rodriguez-Bateman; Lisette Zelaya; Saul Schanber; Cynthia Kuhn

2002-01-01

251

Dynamics of naive and memory CD4+ T lymphocytes in HIV-1 disease progression.  

PubMed

Understanding the dynamics of naive and memory CD4+ T cells in the immune response to HIV-1 infection can help elucidate typical disease progression patterns observed in HIV-1 patients. Although infection markers such as CD4+ T-cell count and viral load are monitored in patient blood, the lymphatic tissues (LT) have been shown to be an important viral reservoir. Here, we introduce the first comprehensive theoretical model of disease progression based on T-cell subsets and virus circulating between the two compartments of LT and blood. We use this model to predict several trademarks observed in adult HIV-1 disease progression such as the establishment of a setpoint in the asymptomatic stage. Our model predicts that both host and viral elements play a role in determining different disease progression patterns. Viral factors include viral infectivity and production rates, whereas host factors include elements of specific immunity. We also predict the effect of highly active antiretroviral therapy and treatment cessation on cellular and viral dynamics in both blood and LT. PMID:12048362

Bajaria, Seema H; Webb, Glenn; Cloyd, Miles; Kirschner, Denise

2002-05-01

252

The role of leptin in progression of non-alcoholic fatty liver disease  

Microsoft Academic Search

Since non-alchoholic steatohepatitis (NASH) is often accompanied with metabolic syndrome comprising obesity, type-2 diabetes and hypertension, it is hypothesized that adipocytokines, insulin resistance and autonomic nervous system play crucial roles in disease progression of NASH. On the other hand, hepatic stellate cells (HSCs) have been shown to produce leptin when they get activated during hepatic fibrogenesis. Therefore, we investigated the

Kenichi Ikejima; Kyoko Okumura; Tie Lang; Hajime Honda; Wataru Abe; Shunhei Yamashina; Nobuyuki Enomoto; Yoshiyuki Takei; Nobuhiro Sato

2005-01-01

253

Progressive podocyte injury and globotriaosylceramide (GL3) accumulation in young patients with Fabry disease  

Microsoft Academic Search

Progressive renal failure often complicates Fabry disease, the pathogenesis of which is not well understood. To further explore this we applied unbiased stereological quantitative methods to electron microscopic changes of Fabry nephropathy and the relationship between parameters of glomerular structure and renal function in 14 young Fabry patients (median age 12 years). Renal biopsies were obtained shortly before enzyme replacement

Behzad Najafian; Einar Svarstad; Leif Bostad; Marie-Claire Gubler; Camilla Tøndel; Chester Whitley; Michael Mauer

2011-01-01

254

Physical therapy assessment tools to evaluate disease progression and phenotype variability in Golden Retriever muscular dystrophy.  

PubMed

Dogs suffering from Golden Retriever muscular dystrophy (GRMD) present symptoms that are similar to human patients with Duchenne muscular dystrophy (DMD). Phenotypic variability is common in both cases and correlates with disease progression and response to therapy. Physical therapy assessment tools were used to study disease progression and assess phenotypic variability in dogs with GRMD. At 5 (T0), 9 (T1), 13 (T2) and 17 (T3)months of age, the physical features, joint ranges of motion (ROM), limb and thorax circumferences, weight and creatine kinase (CK) levels were assessed in 11 dogs with GRMD. Alterations of physical features were higher at 13 months, and different disease progression rates were observed. Passive ROM decreased until 1 year old, which was followed by a decline of elbow and tarsal ROM. Limb and thorax circumferences, which were corrected for body weight, decreased significantly between T0 and T3. These measurements can be used to evaluate disease progression in dogs with GRMD and to help discover new therapies for DMD patients. PMID:21315399

Gaiad, T P; Silva, M B; Silva, G C A; Caromano, F A; Miglino, M A; Ambrósio, C E

2011-02-18

255

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

PubMed

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

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

2009-05-21

256

Unveiling Clusters of RNA Transcript Pairs Associated with Markers of Alzheimer's Disease Progression  

PubMed Central

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

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

2012-01-01

257

Vitamin D Related Host Genetic Variants Alter HIV Disease Progression in Children.  

PubMed

BACKGROUND:: Vitamin D deficiency is common in HIV infection and has been associated with advanced disease. This study investigated whether vitamin D related genetic variants were associated with disease progression in HIV-infected children. METHODS:: The Fok-I (C/T), Bsm-I (G/A), GC (A/C), DHCR7 (G/T) and CYP2R1 (G/A) genetic variants were detected by RT-PCR in HIV-infected children who participated in the PACTG P152 and P300 protocols which pre-dated the availability of effective combination antiretroviral therapy. The primary endpoints included time to progression to the first HIV-related disease end-point (?2 OI's, weight-growth failure) or death, which constituted the progression-free-survival. Analyses were performed for age >2 years and <2 years separately adjusting for race and treatment effect. RESULTS:: Of the 998 children evaluated, 139 experienced HIV disease progression. For children >2 years, rapid disease progression was associated with the DHCR7 G allele compared to the T allele (G/G vs. T/T: HR=5.0, p=0.035, G/T vs. T/T: HR=4.5, p=0.042, G/G+G/T vs. T/T: HR=4.8, p=0.036), and the Bsm-I A allele compared to the G allele (A/G vs. G/G: HR=2.2, p=0.014 and A/G+A/A vs. G/G: HR=2.0, p=0.026). In children ?2 years, the Bsm-I A allele increased the risk of disease progression in Hispanics (A/A vs. G/A+G/G: HR=2.8, p=0.03; A/A vs. G/G: HR=2.8, p=0.046) and whites (A/A vs. G/G: HR=6.6, p=0.025; A/A vs. G/A+G/G: HR=3.6, p=0.038). CONCLUSIONS:: Vitamin D related host genetic variants that alter the availability and activity of vitamin D are associated with risk of HIV disease progression in children, and may vary by age and race. PMID:23736144

Moodley, Amaran; Qin, Min; Singh, Kumud K; Spector, Stephen A

2013-06-01

258

In vivo bioluminescence imaging for early detection and monitoring of disease progression in a murine model of neuroblastoma  

Microsoft Academic Search

BackgroundWe evaluated the potential of bioluminescence imaging (BLI) for early tumor detection, demonstrating occult sites of disseminated disease and assessing disease progression in a murine model of neuroblastoma.

Paxton V. Dickson; Blair Hamner; Catherine Y. C. Ng; Marshall M. Hall; Junfang Zhou; Phillip W. Hargrove; M. Beth McCarville; Andrew M. Davidoff

2007-01-01

259

Genome integrity of myeloproliferative neoplasms in chronic phase and during disease progression.  

PubMed

Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are clonal myeloid disorders with increased production of terminally differentiated cells. The disease course is generally chronic, but some patients show disease progression (secondary myelofibrosis or accelerated phase) and/or leukemic transformation. We investigated chromosomal aberrations in 408 MPN samples using high-resolution single-nucleotide polymorphism microarrays to identify disease-associated somatic lesions. Of 408 samples, 37.5% had a wild-type karyotype and 62.5% harbored at least 1 chromosomal aberration. We identified 25 recurrent aberrations that were found in 3 or more samples. An increased number of chromosomal lesions was significantly associated with patient age, as well as with disease progression and leukemic transformation, but no association was observed with MPN subtypes, Janus kinase 2 (JAK2) mutational status, or disease duration. Aberrations of chromosomes 1q and 9p were positively associated with disease progression to secondary myelofibrosis or accelerated phase. Changes of chromosomes 1q, 7q, 5q, 6p, 7p, 19q, 22q, and 3q were positively associated with post-MPN acute myeloid leukemia. We mapped commonly affected regions to single target genes on chromosomes 3p (forkhead box P1 [FOXP1]), 4q (tet oncogene family member 2 [TET2]), 7p (IKAROS family zinc finger 1 [IKZF1]), 7q (cut-like homeobox 1 [CUX1]), 12p (ets variant 6 [ETV6]), and 21q (runt-related transcription factor 1 [RUNX1]). Our data provide insight into the genetic complexity of MPNs and implicate new genes involved in disease progression. PMID:21531982

Klampfl, Thorsten; Harutyunyan, Ashot; Berg, Tiina; Gisslinger, Bettina; Schalling, Martin; Bagienski, Klaudia; Olcaydu, Damla; Passamonti, Francesco; Rumi, Elisa; Pietra, Daniela; Jäger, Roland; Pieri, Lisa; Guglielmelli, Paola; Iacobucci, Ilaria; Martinelli, Giovanni; Cazzola, Mario; Vannucchi, Alessandro M; Gisslinger, Heinz; Kralovics, Robert

2011-04-29

260

Advanced fuel cell development. Progress Report, April-June 1980. [LiAl  

Microsoft Academic Search

Advanced fuel cell research and development activities at Argonne National Laboratory (ANL) during the period April-June 1980 are described. These efforts have been directed toward understanding and improving components of molten carbonate fuel cells and have included operation of a 10-cm square cell. Studies have continued on the development of electrolyte structures (LiAlOâ and LiâCOâ-KâCOâ). This effort is being concentrated

R. D. Pierce; R. M. Arons; J. T. Dusek; A. V. Fraioli; G. H. Kucera; R. B. Poeppel; J. W. Sim; J. L. Smith

1980-01-01

261

Overview of the epidemiology, diagnosis, and disease progression associated with multiple sclerosis.  

PubMed

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system that affects approximately 400,000 people in the United States. The etiology of MS is unknown, but it is likely the result of a complex interaction between genetic and environmental factors and the immune system. The clinical manifestations of MS are highly variable, but most patients initially experience a relapsing-remitting course. Patients accumulate disability as a result of incomplete recovery from acute exacerbations and/or gradual disease progression. This article briefly reviews the immunopathology of MS, the symptoms and natural course of the disease, and the recently revised MS diagnostic criteria. PMID:23544716

Tullman, Mark J

2013-02-01

262

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

263

Theoretical and Practical Progress of New Heliostat by Chen et al.  

NASA Astrophysics Data System (ADS)

Recently, Chen and his team were active in the theoretical and practical study of a new heliostat for the use of solar energy. This work represents the first innovation in the area of heliostats after many years of little progress. The mathematical development of the tracking and concentration optics principles, and the practical implementation and demonstration of the technology, are both very interesting advances in this field. Many applications are possible for this technology such as generation of solar electricity and solar industrial process heat.

Kribus, A.

2006-01-01

264

The SETX missense variation spectrum as evaluated in patients with ALS4-like motor neuron diseases.  

PubMed

Mutations in the senataxin (SETX) gene can cause amyotrophic lateral sclerosis 4 (ALS4), an autosomal dominant form of juvenile onset amyotrophic lateral sclerosis, or result in autosomal recessive ataxia with oculomotor apraxia type 2. Great caution regarding the possible disease causation, especially of missense variations, has to be taken. Here, we evaluated the significance of all previously reported SETX missense mutations as well as six newly identified variations in 54 patients suspected of having ALS4. Yet, epidemiologic and in silico evidence indicates that all newly identified variations and two previously published ALS4-related missense variations (C1554G and I2547T) are most likely non-pathogenic, demonstrating the problems of interpretation of SETX missense alleles in the absence of functional assays. PMID:23129421

Arning, Larissa; Epplen, Jörg T; Rahikkala, Elisa; Hendrich, Corinna; Ludolph, Albert C; Sperfeld, Anne-Dorte

2012-11-06

265

A Mechanism-based Disease Progression Model for Comparison of Long-term Effects of Pioglitazone, Metformin and Gliclazide on Disease Processes Underlying Type 2 Diabetes Mellitus  

Microsoft Academic Search

Effective long-term treatment of Type 2 Diabetes Mellitus (T2DM) implies modification of the disease processes that cause this progressive disorder. This paper proposes a mechanism-based approach to disease progression modeling of T2DM that aims to provide the ability to describe and quantify the effects of treatment on the time-course of the progressive loss of ?-cell function and insulin-sensitivity underlying T2DM.

Willem de Winter; Joost DeJongh; Teun Post; Bart Ploeger; Richard Urquhart; Ian Moules; David Eckland; Meindert Danhof

2006-01-01

266

Progress on stem cell research towards the treatment of Parkinson's disease  

PubMed Central

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive accumulation of Lewy body inclusions along with selective destruction of dopaminergic (DA) neurons in the nigrostriatal tract of the brain. Genetic studies have revealed much about the pathophysiology of PD, enabling the identification of both biomarkers for diagnosis and genetic targets for therapeutic treatment, which are evolved in tandem with the development of stem cell technologies. The discovery of induced pluripotent stem (iPS) cells facilitates the derivation of stem cells from adult somatic cells for personalized treatment and thus overcomes not only the limited availability of human embryonic stem cells but also ethical concerns surrounding their use. Non-viral, non-integration, or non-DNA-mediated reprogramming technologies are being developed. Protocols for generating midbrain DA neurons are undergoing constant refinement. The iPS cell-derived DA neurons provide cellular models for investigating disease progression in vitro and for screening molecules of novel therapeutic potential and have beneficial effects on improving the behavior of parkinsonian animals. Further progress in the development of safer non-viral/non-biased reprogramming strategies and the subsequent generation of homogenous midbrain DA neurons shall pave the way for clinical trials. A combined approach of drugs, cell replacement, and gene therapy to stop disease progression and to improve treatment may soon be within our reach.

2012-01-01

267

Progress on stem cell research towards the treatment of Parkinson's disease.  

PubMed

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive accumulation of Lewy body inclusions along with selective destruction of dopaminergic (DA) neurons in the nigrostriatal tract of the brain. Genetic studies have revealed much about the pathophysiology of PD, enabling the identification of both biomarkers for diagnosis and genetic targets for therapeutic treatment, which are evolved in tandem with the development of stem cell technologies. The discovery of induced pluripotent stem (iPS) cells facilitates the derivation of stem cells from adult somatic cells for personalized treatment and thus overcomes not only the limited availability of human embryonic stem cells but also ethical concerns surrounding their use. Non-viral, non-integration, or non-DNA-mediated reprogramming technologies are being developed. Protocols for generating midbrain DA neurons are undergoing constant refinement. The iPS cell-derived DA neurons provide cellular models for investigating disease progression in vitro and for screening molecules of novel therapeutic potential and have beneficial effects on improving the behavior of parkinsonian animals. Further progress in the development of safer non-viral/non-biased reprogramming strategies and the subsequent generation of homogenous midbrain DA neurons shall pave the way for clinical trials. A combined approach of drugs, cell replacement, and gene therapy to stop disease progression and to improve treatment may soon be within our reach. PMID:22494990

Gibson, Stuart A J; Gao, Guo-Dong; McDonagh, Katya; Shen, Sanbing

2012-04-03

268

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

PubMed Central

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

Lacomis, David

2010-01-01

269

Cerebrospinal fluid evidence of increased extra-mitochondrial glucose metabolism implicates mitochondrial dysfunction in multiple sclerosis disease progression  

Microsoft Academic Search

In contrast to relapse, the mechanisms of multiple sclerosis (MS) disease progression are less understood and appear not to be exclusively inflammatory in nature. In this pilot study we investigated the relationship between disturbed CNS energy metabolism and MS disease progression. We tested the hypothesis that cerebrospinal fluid (CSF) concentrations of sorbitol, fructose, and lactate, all metabolites of extra-mitochondrial glucose

William T. Regenold; Pornima Phatak; Michael J. Makley; Roger D. Stone; Mitchel A. Kling

2008-01-01

270

Predicting Disease Progression After Nephrectomy for Localized Renal Cell Carcinoma: The Utility of Prognostic Models and Molecular Biomarkers  

PubMed Central

Disease progression after nephrectomy for pathologically localized renal cell carcinoma (RCC) is associated with a significant mortality rate, given the limited efficacy of available treatment regimens for metastatic disease. As such, several adjuvant trials have been designed to treat patients at particularly high risk for post-surgical RCC progression. Several different prognostic models designed to identify patients at high risk of disease progression are available. Although these available predictive models provide a reasonable assessment of patients’ risks of disease progression, the accuracy of these models may further be improved via the incorporation of molecular prognostic biomarkers. Although numerous candidate molecules have been described, few have been specifically assessed for the association with disease progression after nephrectomy. IMP-3, CXCR3, p53, Survivin, cIAP1, B7-H1, and B7-H4 have all been associated with disease progression after nephrectomy. The incorporation of 1 or several of these biomarkers may increase the accuracy of currently available prognostic models and thereby facilitate the appropriate use of adjuvant therapies aimed at preventing future disease progression. As such, the authors review the current prognostic tools for predicting disease progression for localized RCC, and detail studies to date that have evaluated various biomarkers in this setting.

Crispen, Paul L.; Boorjian, Stephen A.; Lohse, Christine M.; Leibovich, Bradley C.; Kwon, Eugene D.

2009-01-01

271

Hierarchical kernel mixture models for the prediction of AIDS disease progression using HIV structural gp120 profiles  

Microsoft Academic Search

Changes to the glycosylation profile on HIV gp120 can influence viral pathogenesis and alter AIDS disease progression. The characterization of glycosylation differences at the sequence level is inadequate as the placement of carbohydrates is structurally complex. However, no structural framework is available to date for the study of HIV disease progression. In this study, we propose a novel machine-learning based

Paul D Yoo; Yung Shwen Ho; Jason Ng; Michael Charleston; Nitin K Saksena; Pengyi Yang; Albert Y Zomaya

2010-01-01

272

Memory impairment, but not cerebrovascular disease, predicts progression of MCI to dementia  

PubMed Central

Background Mild cognitive impairment (MCI) is widely viewed as the transition phase between normal aging and Alzheimer disease (AD). Given that MCI can also result from cerebrovascular disease (CVD), the authors used clinical, MRI, and cognitive measures of AD and CVD to test the hypothesis that CVD increases the likelihood of progression from MCI to dementia within 3 years. Objective To examine the impact of CVD on progression of MCI to dementia. Methods Fifty-two consecutive patients with MCI (71% men) including many with symptomatic CVD were longitudinally evaluated for 3.1 ± 1.3 years. MCI was defined as a Clinical Dementia Rating Scale (CDR) score of 0.5. Dementia was defined as progression to a CDR score of ?1.0. Results Forty-four percent of the MCI patients had MRI infarcts, 50% of which were symptomatic. Thirty-three percent of patients progressed to dementia, and 37.8% of these had MRI infarcts. Clinically probable or possible AD was diagnosed in approximately 82% of converters. Of the clinical and MRI measures, only hippocampal volume was associated with increased risk to progression (hazard ratio [HR] = 0.31 [95% CI 0.1 to 0.92], p = 0.03). When neuropsychological measures were included in the analysis, memory (HR = 0.90 [95% CI 0.84 to 0.96], p = 0.002) and executive function (HR = 0.96 [95% CI 0.92 to 1.0], p = 0.045) were associated with increased risk of dementia progression, whereas APOE genotype, cerebrovascular risk factors, clinical stroke, presence or absence of lacunes, and extent of white matter hyperintensities did not predict progression. Conclusion Within a heterogenous group of MCI patients, including many with clinically significant CVD, baseline memory and executive performance significantly predicted likelihood to develop dementia.

DeCarli, C.; Mungas, D.; Harvey, D.; Reed, B.; Weiner, M.; Chui, H.; Jagust, W.

2007-01-01

273

Faster HIV-1 Disease Progression among Brazilian Individuals Recently Infected with CXCR4-Utilizing Strains  

PubMed Central

Introduction Primary HIV infection is usually caused by R5 viruses, and there is an association between the emergence of CCXR4-utilizing strains and faster disease progression. We characterized HIV-1 from a cohort of recently infected individuals in Brazil, predicted the virus's co-receptor use based on the env genotype and attempted to correlate virus profiles with disease progression. Methods A total of 72 recently infected HIV patients were recruited based on the Serologic Testing Algorithm for Recent HIV Seroconversion and were followed every three to four months for up to 78 weeks. The HIV-1 V3 region was characterized by sequencing nine to twelve weeks after enrollment. Disease progression was characterized by CD4+ T-cell count decline to levels consistently below 350 cells/µL. Results Twelve out of 72 individuals (17%) were predicted to harbor CXCR4-utilizing strains; a baseline CD4<350 was more frequent among these individuals (p?=?0.03). Fifty-seven individuals that were predicted to have CCR5-utilizing viruses and 10 individuals having CXCR4-utilizing strains presented with baseline CD4>350; after 78 weeks, 33 individuals with CCR5 strains and one individual with CXCR4 strains had CD4>350 (p?=?0.001). There was no association between CD4 decline and demographic characteristics or HIV-1 subtype. Conclusions Our findings confirm the presence of strains with higher in vitro pathogenicity during early HIV infection, suggesting that even among recently infected individuals, rapid progression may be a consequence of the early emergence of CXCR4-utilizing strains. Characterizing the HIV-1 V3 region by sequencing may be useful in predicting disease progression and guiding treatment initiation decisions.

Sucupira, Maria Cecilia Araripe; Sanabani, Sabri; Cortes, Rodrigo M.; Giret, Maria Teresa M.; Tomiyama, Helena; Sauer, Mariana M.; Sabino, Ester Cerdeira; Janini, Luiz Mario; Kallas, Esper Georges; Diaz, Ricardo Sobhie

2012-01-01

274

Benefit from autologous stem cell transplantation in primary refractory myeloma? Different outcomes in progressive versus stable disease  

PubMed Central

Background Several studies of autologous stem cell transplantation in primary refractory myeloma have produced encouraging results. However, the outcome of primary refractory patients with stable disease has not been analyzed separately from the outcome of patients with progressive disease. Design and Methods In the Spanish Myeloma Group 2000 trial, 80 patients with primary refractory myeloma (49 with stable disease and 31 with progressive disease), i.e. who were refractory to initial chemotherapy, were scheduled for tandem transplants (double autologous transplant or a single autologous transplant followed by an allogeneic transplant). Patients with primary refractory disease included those who never achieved a minimal response (?25% M-protein decrease) or better. Responses were assessed using the European Bone Marrow Transplant criteria. Results There were no significant differences in the rates of partial response or better between patients with stable or progressive disease. However, 38% of the patients with stable disease at the time of transplantation remained in a stable condition or achieved a minimal response after transplantation versus 7% in the group with progressive disease (P=0.0017) and the rate of early progression after transplantation was significantly higher among the group with progressive disease at the time of transplantation (22% versus 2%; P=0.0043). After a median follow-up of 6.6 years, the median survival after first transplant of the whole series was 2.3 years. Progression-free and overall survival from the first transplant were shorter in patients with progressive disease (0.6 versus 2.3 years, P=0.00004 and 1.1 versus 6 years, P=0.00002, respectively). Conclusions Our results show that patients with progressive refractory myeloma do not benefit from autologous transplantation, while patients with stable disease have an outcome comparable to those with chemosensitive disease. (ClinicalTrials.gov:NCT00560053)

Rosinol, Laura; Garcia-Sanz, Ramon; Lahuerta, Juan Jose; Hernandez-Garcia, Miguel; Granell, Miquel; de la Rubia, Javier; Oriol, Albert; Hernandez-Ruiz, Belen; Rayon, Consuelo; Navarro, Isabel; Garcia-Ruiz, Juan Carlos; Besalduch, Joan; Gardella, Santiago; Jimenez, Javier Lopez; Diaz-Mediavilla, Joaquin; Alegre, Adrian; Miguel, Jesus San; Blade, Joan

2012-01-01

275

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

PubMed Central

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

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

2010-01-01

276

Identification of serological biomarkers of infection, disease progression and treatment efficacy for leprosy.  

PubMed

Although leprosy is curable with drug treatment, the identification of biomarkers of infection, disease progression and treatment efficacy would greatly help to reduce the overall prevalence of the disease. Reliable biomarkers would also reduce the incidence of grade-2 disability by ensuring that those who are most at risk are diagnosed and treated early or offered repeated treatments in the case of relapse. In this study, we examined the reactivity of sera from lepromatous and tuberculoid leprosy patients (LPs) against a panel of 12 recombinant Mycobacterium leprae proteins and found that six proteins were strongly recognised by multibacillary (MB) patients, while only three were consistently recognised by paucibacillary patients. To better understand the dynamics of patient antibody responses during and after drug therapy, we measured antibody titres to four recombinant proteins, phenolic glycolipid-I and lipoarabinomannan at baseline and up to two years after diagnosis to investigate the temporal changes in the antibody titres. Reactivity patterns to individual antigens and decreases in antibody titres were patient-specific. Antibody titres to proteins declined more rapidly vs. those to carbohydrate and glycolipid antigens. Compared to baseline values, increases in antibody titres were observed during reactional episodes in one individual. Additionally, antibody responses against a subset of antigens that provided a good prognostic indicator of disease progression were analysed in 51 household contacts of MB index cases for up to two years. Although the majority of these contacts showed no change or exhibited decreases in antibody titres, seven individuals developed higher titres towards one or more of these antigens and one individual with progressively higher titres was diagnosed with borderline lepromatous leprosy 19 months after enrolment. The results of this study indicate that antibody titres to specific M. leprae antigens can be used to monitor treatment efficacy in LPs and assess disease progression in those most at risk for developing this disease. PMID:23283458

Spencer, John S; Duthie, Malcolm S; Geluk, Annemieke; Balagon, Marivic F; Kim, Hee Jin; Wheat, William H; Chatterjee, Delphi; Jackson, Mary; Li, Wei; Kurihara, Jade N; Maghanoy, Armi; Mallari, Irene; Saunderson, Paul; Brennan, Patrick J; Dockrell, Hazel M

2012-12-01

277

Cavitation phenomenon in superplastic creep. Progress report, November 1, 1984-November 30, 1985. [7475 Al  

SciTech Connect

The deformation mechanisms during superplastic flow of a fine grained 7475 Al alloy was investigated between 437 and 517/sup 0/C and strain rates from 10/sup -5/ to 5 x 10/sup -3/ s/sup -1/. The mechanical data were analyzed in order to establish the stress, temperature and grain size dependence of the strain rate. It was found that the activation energy is equal to that for grain boundary diffusion and stress exponent = 2.00. This indicates that the dominant mechanism of superplasticity could be grain boundary sliding accommodated by dislocation motion. A comparison of the experimentally determined rate parameters for superplastic flow with the predictions of theoretical models supports this conclusion. The topological features with respect to grain size and shape are explained using the grain emerging model, as proposed by Gifkins.

Mukherjee, A.K.

1984-01-01

278

Blood pressure, proteinuria, and phosphate as risk factors for progressive kidney disease: a hypothesis.  

PubMed

Chronic kidney disease (CKD) affects approximately 500 million people worldwide and is increasingly common in both industrialized and emerging countries. Although the mechanisms underlying the inexorable progression of CKD are incompletely defined, recent discoveries may pave the way to a more comprehensive understanding of the pathophysiology of CKD progression and the development of new therapeutic strategies. In particular, there is accumulating evidence indicating a key role for the complex and yet incompletely understood system of divalent cation regulation, which includes phosphate metabolism and the recently discovered fibroblast growth factor 23 (FGF-23)/klotho system, which seems inextricably associated with vitamin D deficiency. The aim of this review is to discuss the links between high blood pressure, proteinuria, phosphate levels, and CKD progression and explore new therapeutic strategies to win the fight against CKD. PMID:23664548

Cozzolino, Mario; Gentile, Giorgio; Mazzaferro, Sandro; Brancaccio, Diego; Ruggenenti, Piero; Remuzzi, Giuseppe

2013-05-10

279

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

SciTech Connect

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

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

2006-05-20

280

Estimation of renal cell carcinoma treatment effects from disease progression modeling.  

PubMed

To improve future drug development efficiency in renal cell carcinoma (RCC), a disease-progression model was developed with longitudinal tumor size data from a phase III trial of sorafenib in RCC. The best-fit model was externally evaluated on 145 placebo-treated patients in a phase III trial of pazopanib; the model incorporated baseline tumor size, a linear disease-progression component, and an exponential drug effect (DE) parameter. With the model-estimated effect of sorafenib on RCC growth, we calculated the power of randomized phase II trials between sorafenib and hypothetical comparators over a range of effects. A hypothetical comparator with 80% greater DE than sorafenib would have 82% power (one-sided ? = 0.1) with 50 patients per arm. Model-based quantitation of treatment effect with computed tomography (CT) imaging offers a scaffold on which to develop new, more efficient, phase II trial end points and analytic strategies for RCC. PMID:23443753

Maitland, M L; Wu, K; Sharma, M R; Jin, Y; Kang, S P; Stadler, W M; Karrison, T G; Ratain, M J; Bies, R R

2012-12-27

281

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

PubMed Central

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

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

2010-01-01

282

Advancing Drug Innovation for Neglected Diseases--Criteria for Lead Progression  

PubMed Central

The current drug R&D pipeline for most neglected diseases remains weak, and unlikely to support registration of novel drug classes that meet desired target product profiles in the short term. This calls for sustained investment as well as greater emphasis in the risky upstream drug discovery. Access to technologies, resources, and strong management as well as clear compound progression criteria are factors in the successful implementation of any collaborative drug discovery effort. We discuss how some of these factors have impacted drug discovery for tropical diseases within the past four decades, and highlight new opportunities and challenges through the virtual North–South drug discovery network as well as the rationale for greater participation of institutions in developing countries in product innovation. A set of criteria designed to facilitate compound progression from screening hits to drug candidate selection is presented to guide ongoing efforts.

Nwaka, Solomon; Ramirez, Bernadette; Brun, Reto; Maes, Louis; Douglas, Frank; Ridley, Robert

2009-01-01

283

Estimation of renal cell carcinoma treatment effects from disease progression modeling  

PubMed Central

To improve future drug development efficiency in renal cell carcinoma (RCC), a disease progression model was developed with longitudinal tumor size data from a phase III trial of sorafenib in RCC. The best fit model was externally evaluated on 145 placebo-treated patients in a phase III trial of pazopanib, and incorporated baseline tumor size, a linear disease progression component, and an exponential drug effect parameter. With the model-estimated effect of sorafenib on RCC growth we calculated the power of randomized phase II trials between sorafenib and hypothetical comparators over a range of effects. A hypothetical comparator with 80% greater drug effect than sorafenib would have 82% power (one-sided ? = 0.1) with 50 patients per arm. Model-based quantitation of treatment effect with CT imaging offers a scaffold on which to develop new, more efficient, phase II trial endpoints and analytic strategies for RCC.

Maitland, Michael L.; Wu, Kehua; Sharma, Manish R.; Jin, Yuyan; Kang, Soonmo Peter; Stadler, Walter M.; Karrison, Theodore G.; Ratain, Mark J.; Bies, Robert R.

2013-01-01

284

Atypical presentation of Creutzfeldt-Jakob disease: a rare but important cause of rapidly progressive dementia.  

PubMed

We report an atypical presentation of sporadic Creutzfeldt-Jakob disease (CJD) in a 74-year-old woman that illustrates the difficulty in diagnosing this rare, but important, cause of rapidly progressive dementia. Despite well-established criteria, this diagnosis is often missed or substantially delayed (Table 1). In this case, a precipitous cognitive decline associated with a urinary tract infection initiallysuggested delirium. Although atypical CJD was considered as a cause when symptoms persisted, a definitive diagnosis was established postmortem when the cerebrospinal fluid (CSF) prion protein 14-3-3 tested positive. Creutzfeldt-Jakob disease must be considered in the differential diagnosis of rapidly progressive dementia as Connecticut accounts for approximately three of the more than 200 cases diagnosed nationally. PMID:21980678

Taillefer, Marguerite S; Tangarorang, Glendo L; Kuchel, George A; Menkes, Daniel L

2011-09-01

285

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.

2013-01-01

286

Personal Factors Involved in Onset or Progression of Ménière’s Disease and Low-Tone Sensorineural Hearing Loss  

Microsoft Academic Search

Purpose: To identify personal causative factors for Ménière’s disease. Procedures: Patterns of hearing loss progression were studied in patients with Ménière’s disease and low-tone sensorineural hearing loss, and the involvement of stress and the relation of stressors to the onset or progression of the disease were analyzed. Results: Low-tone loss recurred in 40% of patients even after hearing was restored,

Masahiro Takahashi; Kyoko Odagiri; Ririko Sato; Ryoko Wada; Junichi Onuki; M. Tsubota; S. Yasumura; R. A. Lima; C. Cernea; S. Moralioglu; R. Karabulut; S. Iwasaki; M. Zähringer; O. Guntinas-Lichius; J. Wustrow

2005-01-01

287

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.

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

2011-01-01

288

The role of oxidative stress in disease progression in individuals infected by the human immunodeficiency virus  

Microsoft Academic Search

This review describes the potential role of ox- idative stress as a cofactor of disease progression from asymptomatic human immunodeficiency virus (H!V) in- fection to the acquired immunodeficiency syndrome (AIDS). Oxidative stress is a known activator of H!V replication in vitro through the activation of a factor that binds to a DNA-binding protein, NF-xB, which in turn stimulates H!V gene

Sylvain Baruchel; Mark A. Wainberg

289

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

Microsoft Academic Search

Post-traumatic stress disorder (PTSD) is a common psychological outcome of any disaster. The purpose of this study was to examine the effects of PTSD on disease progression among HIV-infected persons in metropolitan New Orleans post-hurricane Katrina. One-year post-storm, a convenience sample of 145 HIV-infected patients who returned to care at the HIV Outpatient Program clinic in New Orleans were interviewed.

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

2009-01-01

290

Serum cysteine proteases and their inhibitors in rheumatoid arthritis: relation to disease activity and radiographic progression  

Microsoft Academic Search

This study aims to investigate the serum levels of cysteine proteases cathepsins B and H and their inhibitors stefin A, stefin\\u000a B, and cystatin C, as well as traditional inflammatory markers such as C-reactive protein in patients with rheumatoid arthritis\\u000a and to correlate these markers with scores of disease activity and radiographic progression. Seventy-two patients with rheumatoid\\u000a arthritis were included

Iben Jørgensen; Janko Kos; Marta Krašovec; Lone Troelsen; Mette Klarlund; Trine W. Jensen; Michael S. Hansen; Søren Jacobsen

2011-01-01

291

Clinical Reactivations of Herpes Simplex Virus Type 2 Infection and Human Immunodeficiency Virus Disease Progression Markers  

Microsoft Academic Search

BackgroundThe natural history of HSV-2 infection and role of HSV-2 reactivations in HIV disease progression are unclear.MethodsClinical symptoms of active HSV-2 infection were used to classify 1,938 HIV\\/HSV-2 co-infected participants of the Women's Interagency HIV Study (WIHS) into groups of varying degree of HSV-2 clinical activity. Differences in plasma HIV RNA and CD4+ T cell counts between groups were explored

Bulbulgul Aumakhan; Charlotte A. Gaydos; Thomas C. Quinn; Chris Beyrer; Lorie Benning; Howard Minkoff; Daniel J. Merenstein; Mardge Cohen; Ruth Greenblatt; Marek Nowicki; Kathryn Anastos; Stephen J. Gange

2010-01-01

292

Grapevine Susceptibility to Pierce's Disease II: The Progression of Anatomical Symptoms  

Microsoft Academic Search

The progression of anatomical symptoms of Pierce's disease in susceptible Vitis vinifera cv. Chardonnay grapevines was studied over a time course following controlled inoculation of Y-shaped, two-shooted plants with Xylella fastidiosa. Leaf, petiole, and stem tissue samples collected from locations on inoculated and non-inoculated shoots were taken at ten, fourteen, and eighteen weeks following inoculation. After ten weeks, leaf necrosis

JOSHUA F. STEVENSON; MARK A. MATTHEWS; L. CARL GREVE; JOHN M. LABAVITCH

2004-01-01

293

The Renin-Angiotensin System and Progression of Renal Disease: From Hemodynamics to Cell Biology  

Microsoft Academic Search

The renal community is faced with an ever increasing number of patients reaching end-stage renal failure. Clinical studies have provided clear evidence that angiotensin-converting enzyme (ACE) inhibitors, and probably also AT1 receptor antagonists, at least in patients suffering from type 2 diabetes, slow disease progression to end-stage renal failure. This protective effect of drugs interfering with the renin-angiotensin system (RAS)

Gunter Wolf; Ulrike Butzmann; Ulrich O. Wenzel

2003-01-01

294

Comparison of Intravascular Ultrasound and Quantitative Coronary Angiography for the Assessment of Coronary Artery Disease Progression  

Microsoft Academic Search

Background—The relative merits of quantitative coronary analysis (QCA) and intravascular ultrasound (IVUS) for the assessment of progression\\/regression in coronary artery disease are uncertain. To explore this subject further, we analyzed the angiographic and IVUS data derived from a contemporary clinical trial population. Methods and Results—We investigated the relationships between QCA and IVUS at single time points (n525) and also for

Colin Berry; Philippe L. L'Allier; Jean Grégoire; Jacques Lespérance; Sylvie Levesque; Reda Ibrahim; Jean-Claude Tardif

2010-01-01

295

Immunophilin ligands can prevent progressive dopaminergic degeneration in animal models of Parkinson's disease  

Microsoft Academic Search

Slowing or halting the progressive dopaminergic (DA) degeneration in Parkinson's disease (PD) would delay the onset and development of motor symptoms, prolong the efficacy of pharmacotherapies and decrease drug-induced side-effects. We tested the potential of two orally administered novel immunophilin ligands to protect against DA degeneration in two animal models of PD. First, in an MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model, we

Lauren C. Costantini; Douglas Cole; Ole Isacson

2001-01-01

296

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

Microsoft Academic Search

Human immunodeficiency virus (HIV)-specific CD8+ T-cell proliferation is consistently correlated with enhanced host HIV immune control, but whether proliferative responses are a cause or consequence of immune protection is unclear. We measured Env-specific CD8+ T-cell proliferation and interferon (IFN)-? secretion in HIV-infected participants with CD4 counts >200, who then completed 121 person-years of prospective follow-up to monitor HIV disease progression.

Lyle R McKinnon; Rupert Kaul; Joshua Kimani; Nico J Nagelkerke; Charles Wachihi; Keith R Fowke; Terry Blake Ball; Francis A Plummer

2012-01-01

297

Effects of breathing supplemental oxygen before progressive exercise in patients with chronic obstructive lung disease  

Microsoft Academic Search

A study was carried out to determine whether supplemental oxygen before exercise would improve maximum exercise performance and relieve exertional dyspnoea in 20 patients with chronic obstructive lung disease (mean FEV1 0.79 l; forced vital capacity 2.30 l). Patients performed two progressive treadmill exercise tests to a symptom limited maximum, with at least 30 minutes rest between tests. They received

J L McKeon; K Murree-Allen; N A Saunders

1988-01-01

298

Recent cigarette smoking and HIV disease progression: no evidence of an association  

Microsoft Academic Search

The association between smoking and HIV disease progression has been examined in several studies; however, findings have been inconsistent. We examined the effect of recent cigarette smoking on CD4 T cell count\\/µl (CD4 count) and HIV RNA concentration (HIV viral load (VL)) among two HIV-infected cohorts with alcohol problems in Massachusetts in the periods 1997–2001 and 2001–2006 using a prospective

Conrad Kabali; Debbie M. Cheng; Daniel Brooks; Carly Bridden; Robert Horsburgh Jr; Jeffrey H. Samet

2011-01-01

299

Differential progression of brain atrophy in Parkinson's disease with and without visual hallucinations  

Microsoft Academic Search

ObjectiveTo determine the course of cognitive deficits and the regional progression of brain atrophy in patients with Parkinson's disease (PD) with and without visual hallucinations (VH).MethodsThe authors performed MRI and neuropsychological assessment at entry to the study and at follow-up (mean±SD=29.91±5.74 months) in a sample of initially non-demented 12 PD patients with VH, 14 PD patients without VH and 12

Naroa Ibarretxe-Bilbao; Blanca Ramirez-Ruiz; Carme Junque; Maria Jose Marti; Francesc Valldeoriola; Nuria Bargallo; Silvia Juanes; Eduardo Tolosa

2010-01-01

300

Participation of bile ductular cells in the pathological progression of non-alcoholic fatty liver disease  

Microsoft Academic Search

AimsNon-alcoholic fatty liver disease (NAFLD) represents a spectrum of pathological conditions, ranging from simple steatosis to hepatic fibrosis with progression to cirrhosis. While activated hepatic stellate cells (HSC) are known to be involved in intralobular, perisinuosidal fibrosis, the mechanisms of portal and bridging fibrosis remain speculative. This study investigated the roles of bile ductules in portal and septal fibrosis.Methods48 liver

Mayumi Chiba; Motoko Sasaki; Seiko Kitamura; Hiroko Ikeda; Yasunori Sato; Yasuni Nakanuma

2011-01-01

301

Positive Thought Induction for Arresting Disease Progression: A Hypnotherapeutic Application in HIV\\/AIDS  

Microsoft Academic Search

The present research aimed to investigate the effect of positive thought induction through hypnotherapeutic strategies, e.g.,\\u000a package of relaxation, guided imagery, positive suggestions, etc., on the coping strategies, clinical and immune parameters\\u000a of disease progression in people living with HIV\\/AIDS(PLWHA). Data were collected from 20 adults HIV+ patients having CD4\\u000a count above 250 and plasma viral load less than 5000,

Urmi Nanda Biswas

2011-01-01

302

Longitudinal association of alcohol use with HIV disease progression and psychological health of women with HIV  

Microsoft Academic Search

We evaluated the association of alcohol consumption and depression, and their effects on HIV disease progression among women with HIV. The study included 871 women with HIV who were recruited from 1993–1995 in four US cities. The participants had physical examination, medical record extraction, and venipuncture, CD4+T-cell counts determination, measurement of depression symptoms (using the self-report Center for Epidemiological Studies-Depression

Musie Ghebremichael; Elijah Paintsil; Jeannette R. Ickovics; David Vlahov; Paula Schuman; Robert Boland; Ellie Schoenbaum; Janet Moore; Heping Zhang

2009-01-01

303

Disease progression and recurrence in women treated for vulvovaginal intraepithelial neoplasia  

PubMed Central

Objective The malignant potential of intraepithelial neoplasia of the vulva and vagina after treatment is not well defined. Our objective was to examine risk factors for recurrence and invasive disease. Methods Four hundred sixty-four women with biopsy proven high-grade intraepithelial neoplasia of the vulva and vagina were identified in the electronic databases of four colposcopy clinics. Inclusion criteria were a follow-up of more than one year, no history of invasive cancer and no invasive cancer within the first year after initial treatment. We investigated the potential factors associated with recurrence and progression using a logistic regression analysis to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results Of the 411 eligible patients, 123 patients (29.9%) recurred later than one year after initial treatment and 24 patients (5.8%) progressed to invasive disease. According to multivariate analyses, the risk factors associated with recurrence were multifocality (OR, 3.33; 95% CI, 2.02 to 5.51), immunosuppression (OR, 2.51; 95% CI, 1.09 to 5.81), excision as initial treatment (vs. laser evaporation; OR, 1.79; 95% CI, 1.11 to 2.91) and smoking (OR, 1.61; 95% CI, 1.02 to 2.55). Risk factors for progression to invasive disease were immunosuppression (OR, 4.00; 95% CI, 1.30 to 12.25), multifocality (OR, 3.05; 95% CI, 1.25 to 7.43) and smoking (OR, 2.97; 95% CI, 1.16 to 7.60), but not treatment modality. Conclusion Laser evaporation combined with extensive biopsy is at least as efficacious as initial treatment of intraepithelial neoplasia with excision. Smoking is a risk factor for both recurrence and progression to invasive disease. Hence, smoking cessation should be advised and maintaining a long follow-up period due to late relapses is necessary.

Baumann, Marc; Mueller, Michael; Fink, Daniel; Heinzl, Siegfried; Imesch, Patrick; Dedes, Konstantin

2013-01-01

304

Podocyte Injury and GL-3 Accumulation are Progressive in Young Patients with Fabry Disease  

PubMed Central

Progressive renal failure often complicates Fabry’s disease. However, the pathogenesis of Fabry nephropathy is not well understood. We applied unbiased stereological methods to the study of the electron microscopic changes of Fabry nephropathy and the relationship between glomerular structural parameters and renal function in young Fabry patients. Renal biopsies from 14 (M/F=8/6) enzyme replacement therapy (ERT)-naive Fabry patients (median age 12 years; range 4–19 years) and 9 (M/F=6/3) normal living kidney donor control subjects were studied. Podocyte GL-3 inclusion volume density [Vv(Inc/PC)] increased progressively with age, while there was no significant relationship between age and endothelial [Vv(Inc/Endo)] or mesangial [Vv(Inc/Mes)] inclusion volume densities. Foot process width which was greater in male Fabry patients vs. controls also progressively increased with age, and correlated directly with proteinuria. Endothelial fenestration was reduced in Fabry patients vs. controls. These studies are the first to show relationships between quantitative glomerular structural parameters of Fabry nephropathy and urinary protein excretion. The parallel progression with increasing age in podocyte GL-3 accumulation, foot process widening and proteinuria, strongly suggest that podocyte injury may play a pivotal role in the development and progression of Fabry nephropathy.

Najafian, Behzad; Svarstad, Einar; Bostad, Leif; Gubler, Marie-Claire; T?ndel, Camilla; Whitley, Chester; Mauer, Michael

2013-01-01

305

Renovascular disease, microcirculation, and the progression of renal injury: role of angiogenesis  

PubMed Central

Emerging evidence supports the pivotal role of renal microvascular disease as a determinant of tubulo-interstitial and glomerular fibrosis in chronic kidney disease. An intact microcirculation is vital to restore blood flow to the injured tissues, which is a crucial step to achieve a successful repair response. The purpose of this review is to discuss the impact and mechanisms of the functional and structural changes of the renal microvascular network, as well as the role of these changes in the progression and irreversibility of renal injury. Damage of the renal microcirculation and deterioration of the angiogenic response may constitute early steps in the complex pathways involved in progressive renal injury. There is limited but provocative evidence that stimulation of vascular proliferation and repair may stabilize renal function and slow the progression of renal disease. The feasibility of novel potential therapeutic interventions for stabilizing the renal microvasculature is also discussed. Targeted interventions to enhance endogenous renoprotective mechanisms focused on the microcirculation, such as cell-based therapy or the use of angiogenic cytokines have shown promising results in some experimental and clinical settings.

2011-01-01

306

Hypertension and progression of nephropathy in diabetic and non-diabetic chronic kindney disease patients  

PubMed Central

Background: Hypertension is associated with more rapid progression of chronic kidney disease. Several studies have shown that treating hypertension in patients with chronic kidney disease and proteinuria may attenuate the decline in glomerular filtration rate. Study objective: The study evaluates the prevalence of hypertension and its association with chronic kidney disease progression in patients without and with diabetic nephropathy. Methods: Patients with CKD stage 2-4 were followed up by a nephrologist for 12-52 months. A total of 137 patients were included in the study, 70 with non-diabetic CKD and 67 with type 2 diabetes and diabetic nephropathy. Demographic and clinical parameters were recorded at initiation and during follow-up. Glomerular filtration rate was estimated by the Cockroft-Gault formula and progression of CKD by the slope of the estimated GFR decline . Results: Out of 70 patients in the non-diabetic group, 34 were males, (mean age 50.37±12.2 years). Out of 67 diabetic patients, 30 were (males, mean age 57.8±8.4 years). 77% in the non-diabetic group had SBP above 140 mmHg. The higher SBP was associated with older age, (53.16±10.8 vs 40.9±12.2 years, p<0.0001). Diastolic blood pressure above 90 was present in 73%. Pulse pressure above 80 had 5.7% and was associated with older age (p<0.02). Progression of chronic kidney disease correlated inversely with age, and positively with diastolic blood pressure and proteinuria (p=0.005, p=0.019 and p=0.02 respectively). Multiple regression analysis showed that only younger age and higher proteinuria were predictive for chronic kidney disease progression (p=0.00002). 6% of pts in the diabetic group had SBP below 140, 19% between 140 and 160, and 75% above 160 mmHg. Diastolic blood pressure below 80 had only 6% of patients, between 80 and 90 had 37% and above 90 mmHg had 57%. Pulse pressure below 80 mmHg had 55% and it was correlated positively with age, p=0.009. Progression of chronic kidney disease in the diabetic group correlated positively with mean arterial pressure, systolic blood pressure and proteinuria, (p=0.017, 0.036 and 0.000000 respectively) and inversely with age (p=0.0003). Multiple regression analysis showed that proteinuria, age and SBP were the only predictors for chronic kidney disease progression in diabetics. Conclusion: Isolated systolic hypertension predominates the older age groups, proteinuria and age significantly correlate with GFR decline in both groups, and SBP is associated with more rapid progression of CKD in the diabetic patients.

Stojceva-Taneva, O; Selim, G; Stojkovski, L; Ivanovski, N

2007-01-01

307

The Chronic Kidney Disease Model: A General Purpose Model of Disease Progression and Treatment  

Microsoft Academic Search

Background  Chronic kidney disease (CKD) is the focus of recent national policy efforts; however, decision makers must account for multiple\\u000a therapeutic options, comorbidities and complications. The objective of the Chronic Kidney Disease model is to provide guidance\\u000a to decision makers. We describe this model and give an example of how it can inform clinical and policy decisions.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  Monte Carlo simulation of

Lori A Orlando; Eric J Belasco; Uptal D Patel; David B Matchar

2011-01-01

308

-374 T/A RAGE Polymorphism Is Associated with Chronic Kidney Disease Progression in Subjects Affected by Nephrocardiovascular Disease  

PubMed Central

Background Chronic kidney disease (CKD) patients present elevated advanced glycation end products (AGEs) blood levels. AGEs promote inflammation through binding to their receptor (RAGE), located on the membrane of mesangial cells, endothelial cells and macrophages. Several genetic polymorphisms influence RAGE transcription, expression and activity, including the substitution of a thymine with an adenine (T/A) in the position -374 of the gene promoter of RAGE. Our study investigates the role of -374 T/A RAGE polymorphism in CKD progression in subjects affected by nephrocardiovascular disease. Methods 174 patients (119 males (68.4%) mean age 67.2±0.88 years; 55 females (31.6%): mean age 65.4±1.50 years) affected by mild to moderate nephrocardiovascular CKD were studied. Each subject was prospectively followed for 84 months, every 6–9 months. The primary endpoint of the study was a rise of serum creatinine concentrations above 50% of basal values or end stage renal disease. Results Carriers of the A/A and T/A genotype presented higher plasma levels of interleukin 6 (A/A 29.5±15.83; T/A 30.0±7.89, vs T/T 12.3±5.04 p?=?0.01 for both) and Macrophages chemoattractant protein 1 (A/A 347.1±39.87; T/A 411.8±48.41, vs T/T 293.5±36.20, p?=?0.04 for both) than T/T subjects. Carriers of the A allele presented a faster CKD progression than wild type patients (Log-Rank test: Chi square?=?6.84, p?=?0,03). Cox regression showed that -374 T/A RAGE polymorphism (p?=?0.037), albuminuria (p?=?0.01) and LDL cholesterol (p?=?0.038) were directly associated with CKD progression. HDL cholesterol (p?=?0.022) and BMI (p?=?0.04) were inversely related to it. No relationship was found between circulating RAGE and renal function decline. Conclusions -374 T/A RAGE polymorphism could be associated with CKD progression and inflammation. Further studies should confirm this finding and address whether inhibiting RAGE downstream signalling would be beneficial for CKD progression.

Baragetti, Ivano; Norata, Giuseppe Danilo; Sarcina, Cristina; Baragetti, Andrea; Rastelli, Francesco; Buzzi, Laura; Grigore, Liliana; Garlaschelli, Katia; Pozzi, Claudio; Catapano, Alberico Luigi

2013-01-01

309

Comparison of progression of macrovascular diseases after kidney or pancreas and kidney transplantation in diabetic patients with end-stage renal disease  

Microsoft Academic Search

Aims\\/hypothesis\\u000a \\u000a . The aim of the study was to examine the effect of pancreas-kidney transplantation on the progression of macrovascular diseases\\u000a in Type I diabetic patients with end-stage renal disease.¶Methods\\u000a \\u000a . The progression of cerebrovascular disease, coronary heart disease and peripheral vascular disease in uraemic patients with\\u000a Type I (insulin-dependent) diabetes mellitus and who had had simultaneous pancreas-kidney transplantation was

G. Biesenbach; R. Margreiter; A. Königsrainer; C. Bösmüller; O. Janko; P. Brücke; C. Gross; J Zazgornik

2000-01-01

310

Exacerbations and Progression of Disease in Asthma and Chronic Obstructive Pulmonary Disease  

Microsoft Academic Search

Exacerbations, characterized by an increase in patients' symptoms above baseline, are characteristic of both chronic obstructive pul- monary disease (COPD) and asthma. Prevention of exacerbations and their expedient treatment are major goals for reducing the morbidity and cost of both conditions. Exacerbations, however, may also adversely affect the natural history of these disorders, perhaps by contributing to increased rates of

Stephen I. Rennard; Stephen G. Farmer

2004-01-01

311

Statins and peripheral arterial disease: effects on claudication, disease progression, and prevention of cardiovascular events.  

PubMed

Peripheral arterial disease (PAD) of the lower limbs is the third most important site of atherosclerotic disease alongside coronary heart disease (CHD) and cerebrovascular disease (CVD). Best medical treatment is beneficial even in patients who eventually need invasive treatment, as the safety, immediate success, and durability of intervention is greatly improved in patients who adhere to best medical treatment. In recent years, a number of studies have suggested that the ACE-inhibitor ramipril and different statins, together with antiplatelet drugs, reduce cardiovascular morbidity and mortality in PAD. Patients with PAD are really a category of patients with a very high cardiovascular risk burden for fatal and nonfatal cerebrovascular and cardiovascular events; therefore, they need to be treated not only for local problems deriving from arteriopathy (intermittent claudication, rest pain and/or ulcers) but, above all, for preventing vascular events. Statins not only lower the risk of vascular events, but they also improve the symptoms associated with PAD. Statins exert beneficial pleiotropic effects on hemostasis, vasculature and inflammatory markers; there is also evidence that statins improve renal function considering that the plasma creatinine level is considered as an emerging vascular risk factor. PMID:17560452

Coppola, Giuseppe; Novo, Salvatore

2007-07-01

312

The Trail Making Test in prodromal Huntington disease: Contributions of disease progression to test performance  

Microsoft Academic Search

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

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

2011-01-01

313

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

314

Phenotypic heterogeneity in a SOD1 G93D Italian ALS family: an example of human model to study a complex disease.  

PubMed

We report different clinical expression in seven members of a large family with amyotrophic lateral sclerosis (ALS) and the G93D mutation in exon 4 of the Cu/Zn superoxide dismutase (SOD1) gene. The ALS clinical course in the proband showed an unusually fast progression of the disease compared to the paucisymptomatic presentation associated to this mutation in the two previously Italian families described. The remaining mutation carriers did not show the aggressive clinical course displayed by the proband. We selected few genes known to be ALS modifiers searching for genetic variants that could explain the wide phenotypic diversity within the family. Exclusion of causative genes such as TDP43, FUS, PGRN and VAPB was performed too. We believe that this kind of family with contrasting phenotypes of ALS may be considered an excellent human model to study the relationship between a wider genetic profile, including modifier genes, and the clinical expression of the disease. Therefore, the novelty of our approach is also represented by the study of a single family to reproduce a composite structure in which search for possible modifier genes/genetic variants linked to SOD1 mutated. PMID:21120636

Penco, Silvana; Lunetta, Christian; Mosca, Lorena; Maestri, Eleonora; Avemaria, Francesca; Tarlarini, Claudia; Patrosso, Maria Cristina; Marocchi, Alessandro; Corbo, Massimo

2010-12-01

315

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

2012-07-26

316

Novel White Matter Tract Integrity Metrics Sensitive to Alzheimer Disease Progression.  

PubMed

BACKGROUND AND PURPOSE:Along with cortical abnormalities, white matter microstructural changes such as axonal loss and myelin breakdown are implicated in the pathogenesis of Alzheimer disease. Recently, a white matter model was introduced that relates non-Gaussian diffusional kurtosis imaging metrics to characteristics of white matter tract integrity, including the axonal water fraction, the intra-axonal diffusivity, and the extra-axonal axial and radial diffusivities.MATERIALS AND METHODS:This study reports these white matter tract integrity metrics in subjects with amnestic mild cognitive impairment (n = 12), Alzheimer disease (n = 14), and age-matched healthy controls (n = 15) in an effort to investigate their sensitivity, diagnostic accuracy, and associations with white matter changes through the course of Alzheimer disease.RESULTS:With tract-based spatial statistics and region-of-interest analyses, increased diffusivity in the extra-axonal space (extra-axonal axial and radial diffusivities) in several white matter tracts sensitively and accurately discriminated healthy controls from those with amnestic mild cognitive impairment (AUC = 0.82-0.95), while widespread decreased axonal water fraction discriminated amnestic mild cognitive impairment from Alzheimer disease (AUC = 0.84). Additionally, these white matter tract integrity metrics in the body of the corpus callosum were strongly correlated with processing speed in amnestic mild cognitive impairment (r = |0.80-0.82|, P < .001).CONCLUSIONS:These findings have implications for the course and spatial progression of white matter degeneration in Alzheimer disease, suggest the mechanisms by which these changes occur, and demonstrate the viability of these white matter tract integrity metrics as potential neuroimaging biomarkers of the earliest stages of Alzheimer disease and disease progression. PMID:23764722

Fieremans, E; Benitez, A; Jensen, J H; Falangola, M F; Tabesh, A; Deardorff, R L; Spampinato, M V S; Babb, J S; Novikov, D S; Ferris, S H; Helpern, J A

2013-06-13

317

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.

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

318

APOL1 risk variants predict histopathology and progression to ESRD in HIV-related kidney disease.  

PubMed

With earlier institution of antiretroviral therapy, kidney diseases other than HIV-associated nephropathy (HIVAN) predominate in HIV-infected persons. Outcomes for these diseases are typically worse among those infected with HIV, but the reasons for this are not clear. Here, we examined the role of APOL1 risk variants in predicting renal histopathology and progression to ESRD in 98 HIV-infected African Americans with non-HIVAN kidney disease on biopsy. We used survival analysis to determine time to ESRD associated with APOL1 genotype. Among the 29 patients with two APOL1 risk alleles, the majority (76%) had FSGS and 10% had hypertensive nephrosclerosis. In contrast, among the 54 patients with one APOL1 risk allele, 47% had immune-complex GN as the predominant lesion and only 23% had FSGS. Among the 25 patients with no APOL1 risk allele, 40% had immune-complex GN and 12% had FSGS. In 310 person-years of observation, 29 patients progressed to ESRD. In adjusted analyses, individuals with two APOL1 risk alleles had a nearly three-fold higher risk for ESRD compared with those with one or zero risk alleles (P=0.03). In summary, these data demonstrate an association between APOL1 variants and renal outcomes in non-HIVAN kidney disease, suggesting a possible use for APOL1 genotyping to help guide the care of HIV-infected patients. PMID:22135313

Fine, Derek M; Wasser, Walter G; Estrella, Michelle M; Atta, Mohamed G; Kuperman, Michael; Shemer, Revital; Rajasekaran, Arun; Tzur, Shay; Racusen, Lorraine C; Skorecki, Karl

2011-12-01

319

APOL1 Risk Variants Predict Histopathology and Progression to ESRD in HIV-Related Kidney Disease  

PubMed Central

With earlier institution of antiretroviral therapy, kidney diseases other than HIV-associated nephropathy (HIVAN) predominate in HIV-infected persons. Outcomes for these diseases are typically worse among those infected with HIV, but the reasons for this are not clear. Here, we examined the role of APOL1 risk variants in predicting renal histopathology and progression to ESRD in 98 HIV-infected African Americans with non-HIVAN kidney disease on biopsy. We used survival analysis to determine time to ESRD associated with APOL1 genotype. Among the 29 patients with two APOL1 risk alleles, the majority (76%) had FSGS and 10% had hypertensive nephrosclerosis. In contrast, among the 54 patients with one APOL1 risk allele, 47% had immune-complex GN as the predominant lesion and only 23% had FSGS. Among the 25 patients with no APOL1 risk allele, 40% had immune-complex GN and 12% had FSGS. In 310 person-years of observation, 29 patients progressed to ESRD. In adjusted analyses, individuals with two APOL1 risk alleles had a nearly three-fold higher risk for ESRD compared with those with one or zero risk alleles (P=0.03). In summary, these data demonstrate an association between APOL1 variants and renal outcomes in non-HIVAN kidney disease, suggesting a possible use for APOL1 genotyping to help guide the care of HIV-infected patients.

Wasser, Walter G.; Estrella, Michelle M.; Atta, Mohamed G.; Kuperman, Michael; Shemer, Revital; Rajasekaran, Arun; Tzur, Shay; Racusen, Lorraine C.; Skorecki, Karl

2012-01-01

320

Effect of intrastriatal mesenchymal stromal cell injection on progression of a murine model of Krabbe disease.  

PubMed

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 2 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; 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

2011-08-05

321

Kidney transplants with progressing chronic diseases express high levels of acute kidney injury transcripts.  

PubMed

We previously reported that kidney transplants with early acute injury express transcripts indicating injury repair--the acute kidney injury signal. This study investigated the significance of this signal in transplants with other conditions, including rejection and recurrent disease. The injury signal was elevated in biopsies in many different conditions, including T cell-mediated rejection and potentially progressive diseases such as antibody-mediated rejection and glomerulonephritis. A high injury signal correlated with poor function and with inflammation in areas of fibrosis, but not with fibrosis without inflammation. In multivariate survival analysis, the injury signal in late kidney transplant biopsies strongly predicted future graft loss, similar to a published molecular risk score derived in late kidneys. Indeed, the injury signal shared many individual transcripts with the risk score, e.g. ITGB6, VCAN, NNMT. The injury signal was a better predictor of future graft loss than fibrosis, inflammation or expression of collagen genes. Thus the acute injury signal, first defined in early reversible injury, is present in many diseases as a reflection of parenchymal distress, where its significance is dictated by the inducing insult, i.e. treatable/self-limited versus untreatable and sustained. Progression in troubled transplants is primarily a function of ongoing parenchymal injury by disease, not fibrogenesis. PMID:23356967

Famulski, K S; Reeve, J; de Freitas, D G; Kreepala, C; Chang, J; Halloran, P F

2013-01-28

322

Unstable mutants in the peripheral endosomal membrane component ALS2 cause early-onset motor neuron disease.  

PubMed

Mutations in ALS2, carrying three putative guanine exchange factor (GEF) domains, are causative for a juvenile, autosomal recessive form of amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, and infantile-ascending hereditary spastic paralysis. Endogenous ALS2 is shown here to be enriched in nervous tissue and to be peripherally bound to the cytoplasmic face of endosomal membranes, an association that requires the amino-terminal "RCC1 (regulator of chromatin condensation)-like" GEF domain. Disease-causing mutants and a naturally truncated isoform of ALS2 are shown to be rapidly degraded when expressed in cultured human cells, including lymphocytes derived from patients with ALS2 mutations. Thus, mutations in the ALS2 gene linked to early-onset motor neuron disease uniformly produce loss of activity through decreased protein stability of this endosomal GEF. PMID:14668431

Yamanaka, Koji; Vande Velde, Christine; Eymard-Pierre, Eleonore; Bertini, Enrico; Boespflug-Tanguy, Odile; Cleveland, Don W

2003-12-10

323

The mild form of menkes disease: a 34 year progress report on the original case.  

PubMed

Classical Menkes disease is a neurodegenerative disorder caused by mutations in the copper-transporting ATPase ATP7A gene which, when untreated, is usually fatal in early childhood. A mild form of Menkes disease was originally reported in 1981 and clinical progress of the patient at 10 years described subsequently. The causative mutation is c.4085C>T in exon 21, causing an alanine to valine substitution in the highly conserved TM7 domain at the C-terminal end of the Menkes protein. Here we report his status at 34 years of age. Intellectual impairment is mild. Ataxia has nearly resolved but motor retardation, dysarthria and an extreme slow speech rate remain. In contrast to patients with the occipital horn syndrome, there have been no connective tissue complications of his mild Menkes disease. He has been under long-term copper therapy for more than 30 years and he continues to enjoy a good quality of life. PMID:23430551

Tchan, M C; Wilcken, B; Christodoulou, J

2012-10-13

324

Using biomarkers to stage disease progression in a lethal mousepox model treated with CMX001  

PubMed Central

Background The emergence of human monkeypox and the potential use of recombinant variola and monkeypox viruses as biological terrorist agents have necessitated the development of therapeutic and prophylactic therapies. The primary, or index, cases of smallpox and/or human monkeypox will likely be identified by a characteristic rash. Effective biomarkers will be required to monitor disease progression, guide the choice of therapeutic intervention strategies and evaluate their efficacies. To address this we have evaluated several biomarkers of disease in a lethal mousepox model. Methods The efficacy of a single dose of a hexadecyloxypropyl ester of cidofovir (CMX001) at 20, 25 and 30 mg/ kg doses administered on days 4, 5, 6 and 7 post-infection was evaluated in A/Ncr mice intranasally infected with low doses of ectromelia virus (<20 plaque-forming units). Mice were monitored for weight loss, blood interferon-? levels, alanine aminotransferase (ALT), aspartate aminotransferase, viral DNA copies and neutrophilia levels to stage disease progression. Results We have used these biomarkers to establish the optimal dosing regimen for treatment and reveal that a single dose of 25 mg/kg of CMX001 can be efficacious at treating lethal mousepox when administered on days 4 or 5 post-infection. This dose significantly reduces ALT, interferon-? and DNA copies found in the blood of infected animals. Conclusions A single dose regimen of CMX001 is efficacious at treating mousepox. Disease progression and antiviral efficacy can be monitored using several biomarkers that could readily be used in the case of a human monkeypox or smallpox outbreak.

Parker, Scott; Schriewer, Jill; Oberle, Christina; Robertson, Alice; Lanier, Randall; Painter, George; Buller, R Mark

2013-01-01

325

Progression of Parkinson's disease following thalamic deep brain stimulation for tremor.  

PubMed

We assessed the long-term effect of thalamic deep brain stimulation (DBS) on motor symptoms and progression of Parkinson's disease (PD) in PD patients treated for resting and postural/action tremor. Thalamic DBS was performed in 17 patients with treatment-resistant resting and postural/action tremor. Nine patients were available for follow-up examination a mean of 5.5 years after surgery. Three had tremor-dominant PD. DBS produced marked improvement in resting and postural/action tremor in target upper extremity in all 9 patients, which persisted unchanged at the time of the last follow-up visit 5.5 years after surgery. PD severity with DBS 'on' and 'off' 1 year after surgery was compared to PD severity at the last follow-up visit using UPDRS (Unified Parkinson's Disease Rating Scale) III motor scores and individual motor item subscores. Patients were tested while on medication. There was no significant worsening of tremor, rigidity, speech, postural stability, gait, or axial bradykinesia with DBS either on or off at the last follow-up visit compared to the 12-month visit. UPDRS III motor scores were unchanged. However, global assessment of PD progression and increased mean L-dopa dose and L-dopa equivalent daily dose at the time of last follow-up visit indicated that a progression of PD had occurred. PMID:16534254

Tarsy, Daniel; Scollins, Lisa; Corapi, Kristin; O'Herron, Siobhan; Apetauerova, Diana; Norregaard, Thorkild

2006-03-08

326

Parkinson's Disease Progression: Implicit Acquisition, Cognitive and Motor Impairments, and Medication Effects  

PubMed Central

Parkinson’s disease (PD) symptoms have been collectively ascribed to malfunctioning of dopamine-related nigro-striatal and cortico-striatal loops. However, some doubts about this proposition are raised by controversies about the temporal progression of the impairments, and whether they are concomitant or not. The present study consists of a systematic revision of literature data on both functional PD impairments and dopaminergic medication effects in order to draw a coherent picture about the disease progression. It was done in terms of an explanatory model for the disruption of implicit knowledge acquisition, motor and cognitive impairments, and the effects of dopaminergic medication on these functions. Cognitive impairments arise at early stages of PD and stabilizes while disruption of implicit knowledge acquisition and motor impairments, are still in progression; additionally, dopaminergic medication reduces motor impairments and increases disruption of implicit knowledge acquisition. Since this model revealed consistency and plausibility when confronted with data of others studies not included in model’s formulation, it may turn out to be a useful tool for understanding the multifaceted characteristics of PD.

Pavao, Rodrigo; Helene, Andre Frazao; Xavier, Gilberto Fernando

2012-01-01

327

The effect of progressive glomerular disease on megalin-mediated endocytosis in the kidney  

PubMed Central

Background. A well-characterized dog model of the X-linked collagen disease Alport syndrome (XLAS) was used to study the effect of progressive glomerular disease on megalin-mediated endocytosis. In XLAS, altered structure and function of the glomerular basement membrane induces a progressive proteinuric nephropathy. Methods. The investigation was performed in male XLAS dogs and age-matched normal male littermates. The urine profile and megalin-mediated endocytosis in the proximal tubule of six healthy and six XLAS dogs were examined at 2, 4, 6, 8 and 10 months of age using SDS–PAGE, immunoblotting and immunohistochemistry. Results. Gradually increasing urinary excretion of proteins over time and a reduced content of the same proteins in proximal tubule cells were found. Besides the glomerular component of the proteinuria, a significant tubular component was seen, which is due to a progressive change in the uptake of low-molecular-weight (LMW) ligands by megalin. Furthermore, the protein overload present in the lumen of the proximal tubule exceeds the reabsorption capacity of megalin and the co-receptor cubilin and results in a combined low- and high-molecular-weight (HMW) proteinuria. Also, a shift in the distribution of lysosomes was seen in the XLAS dogs suggesting changes in the lysosomal degradation pattern in response to the altered endocytosis. Conclusions. The present study shows that the increased glomerular permeability and the subsequently altered megalin-mediated and megalin-dependent cubilin-mediated endocytosis lead to a partial LMW proteinuria and partial HMW proteinuria.

Lees, George E.; Nielsen, Rikke; Kashtan, Clifford E.; Bahr, Anne; Christensen, Erik I.

2010-01-01

328

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.

1996-01-01

329

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.

Sari, Youssef

2012-01-01

330

Atg4b-Dependent Autophagic Flux Alleviates Huntington's Disease Progression  

PubMed Central

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

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

2013-01-01

331

Is there a common mechanism for the progression of different types of renal diseases other than proteinuria? Towards the unifying theme of chronic hypoxia  

Microsoft Academic Search

Is there a common mechanism for the progression of different types of renal diseases other than proteinuria? Towards the unifying theme of chronic hypoxia. The question of why chronic renal diseases progress is a topic only recently investigated. Putative causes such as proteinuria do not account for all aspects of progressive renal disease. An alternative mechanism, chronic hypoxia, is proposed

Leon G. Fine; Debasish Bandyopadhay; Jill T. Norman

2000-01-01

332

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...

333

Disease stabilization of progressive olfactory neuroblastoma (esthesioneuroblastoma) under treatment with sunitinib mesylate.  

PubMed

Olfactory neuroblastoma (esthesioneuroblastoma) is a rare neoplasm of the olfactory epithelium in the upper nasal cavity. Here, we report the case of a 69-year-old man who presented with massive progression of a metastatic esthesioneuroblastoma after endonasal resection, functional neck dissection, and radiotherapy of local and distant tumor relapses. After exhaustion of all conventional therapeutic options, we initiated treatment with the oral multityrosinekinase inhibitor sunitinib mesylate. Using this drug, significant improvement of clinical symptoms, disease stabilization, and recovery from Karnofsky index of 40% to 70% could be achieved in the absence of significant adverse drug effects. The patient died 15 months after initiation of sunitinib therapy due to complications of a traumatic femoral neck fracture without evidence of tumor progression. Immunohistochemical analysis of tumor tissue specimens obtained at initial surgery revealed ample expression of platelet-derived growth factor receptor (PDGFR)-b on stromal and endothelial cells. Sunitinib should be considered for palliative therapy of advanced esthesioneuroblastoma. PMID:19820899

Preusser, M; Hutterer, M; Sohm, M; Koperek, O; Elandt, K; Dieckmann, K; Prayer, D; Marosi, C

2009-10-10

334

miRNAs and their putative roles in the development and progression of Parkinson's disease  

PubMed Central

Small regulatory RNAs, such as miRNAs, are increasingly being recognized not only as regulators of developmental processes but contributors to pathological states. The number of miRNAs determined experimentally to be involved in Parkinson's disease (PD) development and progression is small and includes regulators of pathologic proteins, neurotrophic factors, and xenobiotic metabolizing enzymes. PD gene-association studies have also indicated miRNAs in the pathology. In this review, we present known miRNAs and their validated targets that contribute to PD development and progression. We also incorporate data mining methods to link additional miRNAs with non-experimentally validated targets and propose additional roles of miRNAs in neurodegenerative processes. Furthermore, we present the potential contribution of next-generation-sequencing approaches to elucidate mechanisms and etiology of PD through discovery of novel miRNAs and other non-coding RNA classes.

Wong, Garry; Nass, Richard

2012-01-01

335

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.

Ironson, Gail H.; Hayward, H'sien

2008-01-01

336

Slowing the progression of chronic kidney disease: comparison between predialysis and dialysis Jordanian patients.  

PubMed

Abstract Background: The prevalence of chronic kidney disease (CKD) and end-stage renal disease (ESRD) has increased worldwide; however, data regarding the prevalence of CKD in Jordan are limited. Therefore, the present study investigated the associated risk factors of both CKD and ESRD in Jordanian patients. Methods: A convenience sample of 161 patients with CKD (n?=?92) and ESRD (n?=?69) was recruited through randomly selected hospitals from the governmental, private and educational sectors in Jordan. A sociodemographic data and behavioral variables (exercise frequency per week, body mass index, and smoking status) were collected and compared between the two groups to obtain the needed information. Results: ESRD in amounted to relatively 68% in males and 52% in the unmarried patients (p?=?0.01). In addition, patients with poor physical activity were more likely to be on the postdialysis phase. Patients with ESRD were characterized with low BMI when compared with patients CKD (t?=?3.1, p?=?0.004). Conclusion: National CKD and ESRD risk assessment is important in considering primary prevention for CKD progression. At the front line in health care, the nurse can play a vital role in assessing patient's risk for renal disease progression. PMID:23992491

Alramly, Manal; Darawad, Muhammad Waleed; Khalil, Amani A

2013-09-02

337

Disease Progression Mediated by Egr-1 Associated Signaling in Response to Oxidative Stress  

PubMed Central

When cellular reducing enzymes fail to shield the cell from increased amounts of reactive oxygen species (ROS), oxidative stress arises. The redox state is misbalanced, DNA and proteins are damaged and cellular transcription networks are activated. This condition can lead to the initiation and/or to the progression of atherosclerosis, tumors or pulmonary hypertension; diseases that are decisively furthered by the presence of oxidizing agents. Redox sensitive genes, like the zinc finger transcription factor early growth response 1 (Egr-1), play a pivotal role in the pathophysiology of these diseases. Apart from inducing apoptosis, signaling partners like the MEK/ERK pathway or the protein kinase C (PKC) can activate salvage programs such as cell proliferation that do not ameliorate, but rather worsen their outcome. Here, we review the currently available data on Egr-1 related signal transduction cascades in response to oxidative stress in the progression of epidemiologically significant diseases. Knowing the molecular pathways behind the pathology will greatly enhance our ability to identify possible targets for the development of new therapeutic strategies.

Pagel, Judith-Irina; Deindl, Elisabeth

2012-01-01

338

Mechanisms and consequences of TGF-ß overexpression by podocytes in progressive podocyte disease.  

PubMed

In patients with progressive podocyte disease, such as focal segmental glomerulosclerosis (FSGS) and membranous nephropathy, upregulation of transforming growth factor-ß (TGF-ß) is observed in podocytes. Mechanical pressure or biomechanical strain in podocytopathies may cause overexpression of TGF-ß and angiotensin II (Ang II). Oxidative stress induced by Ang II may activate the latent TGF-ß, which then activates Smads and Ras/extracellular signal-regulated kinase (ERK) signaling pathways in podocytes. Enhanced TGF-ß activity in podocytes may lead to thickening of the glomerular basement membrane (GBM) by overproduction of GBM proteins and impaired GBM degradation in podocyte disease. It may also lead to podocyte apoptosis and detachment from the GBM, and epithelial-mesenchymal transition (EMT) of podocytes, initiating the development of glomerulosclerosis. Furthermore, activated TGF-ß/Smad signaling by podocytes may induce connective tissue growth factor and vascular endothelial growth factor overexpression, which could act as a paracrine effector mechanism on mesangial cells to stimulate mesangial matrix synthesis. In proliferative podocytopathies, such as cellular or collapsing FSGS, TGF-ß-induced ERK activation may play a role in podocyte proliferation, possibly via TGF-ß-induced EMT of podocytes. Collectively, these data bring new mechanistic insights into our understanding of the TGF-ß overexpression by podocytes in progressive podocyte disease. PMID:21541658

Lee, Hyun Soon

2011-05-04

339

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

340

HLA Alleles are Associated with Altered Risk for Disease Progression and Central Nervous System Impairment of HIV-Infected Children  

PubMed Central

Objective To examine the effects of human leukocyte antigen (HLA) alleles on HIV-1-related disease progression and central nervous system (CNS) impairment in children. Design 572 HIV-1-infected children, identified as disease progressors or non-progressors, were selected from PACTG P152 and P300 through a case-cohort sampling scheme. Study endpoints were HIV-1-related disease progression-free survival and time to CNS impairment. Methods DNA was genotyped for HLA alleles using a Luminex 100 platform. Weighted Kaplan-Meier methods and Cox proportional hazards models were used to assess the effects of HLA alleles on study endpoints. Results Presence of the B-27 allele (n=20) was associated with complete protection against disease progression and CNS impairment over the median follow-up of 26 months (P<0.0001 for both). These findings held in multivariate analyses controlling for baseline covariates including race, gender, age, log HIV-1 RNA, CD4+ lymphocyte count and percent, weight for age z-score and treatment, and for other genotypes shown to affect HIV-1-related disease progression. Also, while the Cw-2 allele protected against disease progression (HR, 0.48; 95% CI: 0.28–0.81; P= 0.006), the A-24 allele was associated with more rapid CNS impairment (HR: 2.01; 95% CI: 1.04–3.88; P= 0.04). The HLA class II DQB1-2 allele was associated with a delayed disease progression (HR: 0.66; 95% CI: 0.47–0.92; P= 0.01) and CNS impairment (HR: 0.58; 95% CI: 0.36–0.93; P= 0.02). Conclusions Presence of B-27, Cw-2, or DQB1-2 alleles was associated with delayed HIV-1 disease progression, while B-27, A-24, and DQB1-2 alleles were associated with altered progression to CNS impairment in children.

Singh, Kumud K.; Gray, P. Kathryn; Wang, Yan; Fenton, Terence; Trout, Rodney; Spector, Stephen A.

2011-01-01

341

C868T single nucleotide polymorphism and HIV type 1 disease progression among postpartum women in Kenya.  

PubMed

The C868T single nucleotide polymorphism in the CD4 receptor encodes an amino acid substitution of tryptophan for arginine in the third domain. Previous studies suggest that C868T increases the risk of HIV-1 acquisition; however, the influence of this single nucleotide polymorphism (SNP) on disease progression has not been established. The presence of the C868T polymorphism was not statistically significantly associated with HIV-1 disease progression outcomes in a cohort of postpartum Kenyan women. PMID:21902583

Choi, Robert Y; Fowke, Keith R; Juno, Jennifer; Lohman-Payne, Barbara; Oyugi, Julius O; Brown, Elizabeth R; Bosire, Rose; John-Stewart, Grace; Farquhar, Carey

2011-09-27

342

C868T Single Nucleotide Polymorphism and HIV Type 1 Disease Progression Among Postpartum Women in Kenya  

PubMed Central

Abstract The C868T single nucleotide polymorphism in the CD4 receptor encodes an amino acid substitution of tryptophan for arginine in the third domain. Previous studies suggest that C868T increases the risk of HIV-1 acquisition; however, the influence of this single nucleotide polymorphism (SNP) on disease progression has not been established. The presence of the C868T polymorphism was not statistically significantly associated with HIV-1 disease progression outcomes in a cohort of postpartum Kenyan women.

Fowke, Keith R.; Juno, Jennifer; Lohman-Payne, Barbara; Oyugi, Julius O.; Brown, Elizabeth R.; Bosire, Rose; John-Stewart, Grace; Farquhar, Carey

2012-01-01

343

Progressive tumefactive inflammatory central nervous system demyelinating disease in an acquired immunodeficiency syndrome patient treated with highly active antiretroviral therapy  

Microsoft Academic Search

We report here a case of progressive tumefactive inflammatory central nervous system (CNS) demyelinating disease in a human\\u000a immunodeficiency virus (HIV)-seropositive patient treated with highly active antiretroviral therapy (HAART). Biopsy revealed\\u000a diffuse macrophage and perivascular T-lymphocytic infiltrates with severe demyelination and relative axonal sparing. The disease\\u000a progressed in a centrifugal fashion, to involve bihemispheric cerebral white matter, with subsequent central

Eric Lindzen; Valerie Jewells; Thomas Bouldin; Danielle Speer; Walter Royal III; Silva Markovic-Plese

2008-01-01

344

Progress towards understanding disease mechanisms in small vertebrate models of neuronal ceroid lipofuscinosis.  

PubMed

Model systems provide an invaluable tool for investigating the molecular mechanisms underlying the NCLs, devastating neurodegenerative disorders that affect the relatively inaccessible tissues of the central nervous system. These models have enabled the assessment of behavioural, pathological, cellular, and molecular abnormalities, and also allow for development and evaluation of novel therapies. This review highlights the relative advantages of the two available small vertebrate species, the mouse and zebrafish, in modelling NCL disease, summarising how these have been useful in NCL research and their potential for the development and testing of prospective disease treatments. A panel of mouse mutants is available representing all the cloned NCL gene disorders (Cathepsin D, CLN1, CLN2, CLN3, CLN5, CLN6, CLN8). These NCL mice all have progressive neurodegenerative phenotypes that closely resemble the pathology of human NCL. The analysis of these models has highlighted several novel aspects underlying NCL pathogenesis including the selective nature of neurodegeneration, evidence for glial responses that precede neuronal loss and identification of the thalamus as an important pathological target early in disease progression. Studies in mice have also highlighted an unexpected heterogeneity underlying NCL phenotypes, and novel potential NCL-like mouse models have been described including mice with mutations in cathepsins, CLC chloride channels, and other lysosome-related genes. These new models are likely to provide significant new information on the spectrum of NCL disease. Information on NCL mice is available in the NCL Mouse Model Database (). There are homologs of most of the NCL genes in zebrafish, and NCL zebrafish models are currently in development. This model system provides additional advantages to those provided by NCL mouse models including high-throughput mutational, pharmacogenetic and therapeutic technique analyses. Mouse and zebrafish models are an important shared resource for NCL research, offering a unique possibility to dissect disease mechanisms and to develop therapeutic approaches. PMID:17023146

Cooper, Jonathan D; Russell, Claire; Mitchison, Hannah M

2006-08-10

345

Timing of progression from Chlamydia trachomatis infection to pelvic inflammatory disease: a mathematical modelling study  

PubMed Central

Background Pelvic inflammatory disease (PID) results from the ascending spread of microorganisms from the vagina and endocervix to the upper genital tract. PID can lead to infertility, ectopic pregnancy and chronic pelvic pain. The timing of development of PID after the sexually transmitted bacterial infection Chlamydia trachomatis (chlamydia) might affect the impact of screening interventions, but is currently unknown. This study investigates three hypothetical processes for the timing of progression: at the start, at the end, or throughout the duration of chlamydia infection. Methods We develop a compartmental model that describes the trial structure of a published randomised controlled trial (RCT) and allows each of the three processes to be examined using the same model structure. The RCT estimated the effect of a single chlamydia screening test on the cumulative incidence of PID up to one year later. The fraction of chlamydia infected women who progress to PID is obtained for each hypothetical process by the maximum likelihood method using the results of the RCT. Results The predicted cumulative incidence of PID cases from all causes after one year depends on the fraction of chlamydia infected women that progresses to PID and on the type of progression. Progression at a constant rate from a chlamydia infection to PID or at the end of the infection was compatible with the findings of the RCT. The corresponding estimated fraction of chlamydia infected women that develops PID is 10% (95% confidence interval 7-13%) in both processes. Conclusions The findings of this study suggest that clinical PID can occur throughout the course of a chlamydia infection, which will leave a window of opportunity for screening to prevent PID.

2012-01-01

346

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.

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

2012-01-01

347

Pathogenicity of infectious bursal disease virus variant AL2 in young chickens.  

PubMed

Limited information is available on the effects of the recently emerged infectious bursal disease virus (IBDV) variant AL2. In this study, the effects of inoculation of 4-day-old chickens with increasing doses of IBDV AL2 were characterized. IBDV AL2 induced neither overt clinical signs nor mortality. Infected chickens showed reduced bursa indices (BI) and bursa lymphocytic depletion, as determined by histomorphometry. However, histomorphometry and BI values differed during the early stages of the infection. Because data from bursa histomorphometry were consistent with viral RNA detection, such values seem to be more appropriate for the assessment of AL2 viral infectivity in chickens. Both the histomorphometry and BI data indicated a dose-effect pattern. However, with time, even low doses of the virus ultimately resulted in significant damage to the bursa. Samples of spleen were used to assess B- (IgM+) and T- (CD4+ and CD8+) cell populations by flow cytometry. Infected chickens showed a significant increase of splenic IgM+ cells at 5 and 8 days postinoculation (PI). On day 8 PI, the number of total IgM+ cells in the spleen was inversely related to the virus concentration. Others have shown that cell-mediated immunity is essential for protection against IBDV. Our results indicate a significant increase (P < 0.05) of total spleen CD4+ cell counts on day 8 PI in birds that received higher virus concentrations, indicating a role for these cells in protective immunity, while CD8 cell counts remained unchanged. We speculate that the changes in splenic CD4+ and IgM+ cell populations are associated with protective immune responses against IBDV in the host. PMID:19432007

Toro, H; Effler, J C; Hoerr, F J; van Ginkel, F W

2009-03-01

348

Characterization of LEDGF/p75 Genetic Variants and Association with HIV-1 Disease Progression  

PubMed Central

Background As Lens epithelium-derived growth factor (LEDGF/p75) is an important co-factor involved in HIV-1 integration, the LEDGF/p75-IN interaction is a promising target for the new class of allosteric HIV integrase inhibitors (LEDGINs). Few data are available on the genetic variability of LEDGF/p75 and the influence on HIV disease in vivo. This study evaluated the relation between LEDGF/p75 genetic variation, mRNA expression and HIV-1 disease progression in order to guide future clinical use of LEDGINs. Methods Samples were derived from a therapy-naïve cohort at Ghent University Hospital and a Spanish long-term-non-progressor cohort. High-resolution melting curve analysis and Sanger sequencing were used to identify all single nucleotide polymorphisms (SNPs) in the coding region, flanking intronic regions and full 3?UTR of LEDGF/p75. In addition, two intronic tagSNPs were screened based on previous indication of influencing HIV disease. LEDGF/p75 mRNA was quantified in patient peripheral blood mononuclear cells (PBMC) using RT-qPCR. Results 325 samples were investigated from patients of Caucasian (n?=?291) and African (n?=?34) origin, including Elite (n?=?49) and Viremic controllers (n?=?62). 21 SNPs were identified, comprising five in the coding region and 16 in the non-coding regions and 3?UTR. The variants in the coding region were infrequent and had no major impact on protein structure according to SIFT and PolyPhen score. One intronic SNP (rs2737828) was significantly under-represented in Caucasian patients (P<0.0001) compared to healthy controls (HapMap). Two SNPs showed a non-significant trend towards association with slower disease progression but not with LEDGF/p75 expression. The observed variation in LEDGF/p75 expression was not correlated with disease progression. Conclusions LEDGF/p75 is a highly conserved protein. Two non-coding polymorphisms were identified indicating a correlation with disease outcome, but further research is needed to clarify phenotypic impact. The conserved coding region and the observed variation in LEDGF/p75 expression are important characteristics for clinical use of LEDGINs.

Messiaen, Peter; De Spiegelaere, Ward; Alcami, Jose; Vervisch, Karen; Van Acker, Petra; Verhasselt, Bruno; Meuwissen, Pieter; Calonge, Esther; Gonzalez, Nuria; Gutierrez-Rodero, Felix; Rodriguez-Martin, Carmen; Sermijn, Erica; Poppe, Bruce; Vogelaers, Dirk; Verhofstede, Chris; Vandekerckhove, Linos

2012-01-01

349

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.

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

2013-01-01

350

P2Y2 receptor deficiency aggravates chronic kidney disease progression.  

PubMed

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

2013-09-19

351

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

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

1994-01-01

352

Bacterial toxins fuel disease progression in cutaneous T-cell lymphoma.  

PubMed

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; Wasik, Mariusz A; Koralov, Sergei B; Geisler, Carsten; Kilian, Mogens; Iversen, Lars; Woetmann, Anders; Odum, Niels

2013-08-14

353

Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes in an interferon-dependent autoimmune disease.  

PubMed

The type I interferon (IFN) response initiated by detection of nucleic acids is important for antiviral defense but is also associated with specific autoimmune diseases. Mutations in the human 3' repair exonuclease 1 (Trex1) gene cause Aicardi-Goutières syndrome (AGS), an IFN-associated autoimmune disease. However, the source of the type I IFN response and the precise mechanisms of disease in AGS remain unknown. Here, we demonstrate that Trex1 is an essential negative regulator of the STING-dependent antiviral response. We used an in vivo reporter of IFN activity in Trex1-deficient mice to localize the initiation of disease to nonhematopoietic cells. These IFNs drove T cell-mediated inflammation and an autoantibody response that targeted abundant, tissue-restricted autoantigens. However, B cells contributed to mortality independently of T cell-mediated tissue damage. These findings reveal a stepwise progression of autoimmune disease in Trex1-deficient mice, with implications for the treatment of AGS and related disorders. PMID:22284419

Gall, Alevtina; Treuting, Piper; Elkon, Keith B; Loo, Yueh-Ming; Gale, Michael; Barber, Glen N; Stetson, Daniel B

2012-01-27

354

The Trail Making Test in prodromal Huntington disease: contributions of disease progression to test performance.  

PubMed

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

2011-02-07

355

ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43  

PubMed Central

Transactivating response region DNA binding protein (TDP-43) is the major protein component of ubiquitinated inclusions found in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitinated inclusions. Two ALS-causing mutants (TDP-43Q331K and TDP-43M337V), but not wild-type human TDP-43, are shown here to provoke age-dependent, mutant-dependent, progressive motor axon degeneration and motor neuron death when expressed in mice at levels and in a cell type-selective pattern similar to endogenous TDP-43. Mutant TDP-43-dependent degeneration of lower motor neurons occurs without: (i) loss of TDP-43 from the corresponding nuclei, (ii) accumulation of TDP-43 aggregates, and (iii) accumulation of insoluble TDP-43. Computational analysis using splicing-sensitive microarrays demonstrates alterations of endogenous TDP-43–dependent alternative splicing events conferred by both human wild-type and mutant TDP-43Q331K, but with high levels of mutant TDP-43 preferentially enhancing exon exclusion of some target pre-mRNAs affecting genes involved in neurological transmission and function. Comparison with splicing alterations following TDP-43 depletion demonstrates that TDP-43Q331K enhances normal TDP-43 splicing function for some RNA targets but loss-of-function for others. Thus, adult-onset motor neuron disease does not require aggregation or loss of nuclear TDP-43, with ALS-linked mutants producing loss and gain of splicing function of selected RNA targets at an early disease stage.

Arnold, Eveline S.; Ling, Shuo-Chien; Huelga, Stephanie C.; Lagier-Tourenne, Clotilde; Polymenidou, Magdalini; Ditsworth, Dara; Kordasiewicz, Holly B.; McAlonis-Downes, Melissa; Platoshyn, Oleksandr; Parone, Philippe A.; Da Cruz, Sandrine; Clutario, Kevin M.; Swing, Debbie; Tessarollo, Lino; Marsala, Martin; Shaw, Christopher E.; Yeo, Gene W.; Cleveland, Don W.

2013-01-01

356

Chronic graft-versus-host disease mimicking rapid progressive rheumatoid arthritis with atlantoaxial subluxation  

PubMed Central

Chronic graft-versus-host disease (cGVHD) may mimic clinical and serological features of various autoimmune diseases. We present a case of a 23-year-old man who developed vitiligo, symmetric polyarthritis, high titre rheumatoid factor, antinuclear antibodies and anti-double stranded DNA antibodies after allogenic peripheral blood stem cell transplantation for severe aplastic anaemia. He was treated with low dose oral steroids, non-steroid anti-inflammatory drugs and azathioprine and clinical improvement of polyarthritis were observed initially. However, atlantoaxial subluxation (C1-C2) and rapid progression of symmetrical joint space narrowing in knees and wrists developed within 1 year. cGVHD mimicking rheumatoid arthritis with unusual presentations was observed in this patient.

Lee, Hui-Ting; Chen, Wei-Sheng; Chou, Chung-Tei; Chen, Ming-Han; Tsai, Chang-Youh

2009-01-01

357

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

358

Rate of progression and predictive factors for pulmonary outcome in children and adults with Pompe disease.  

PubMed

Respiratory insufficiency is a serious threat to patients with Pompe disease, a neuromuscular disorder caused by lysosomal acid alpha-glucosidase deficiency. Innovative therapeutic options which may stabilize pulmonary function have recently become available. We therefore determined proportion and severity of pulmonary involvement in patients with Pompe disease, the rate of progression of pulmonary dysfunction, and predictive factors for poor respiratory outcome. In a single-center, prospective, cohort study, we measured vital capacity (VC) in sitting and supine positions, as well as maximum inspiratory (MIP) and expiratory (MEP) mouth pressures, and end expiratory CO(2) in 17 children and 75 adults with Pompe disease (mean age 42.7 years, range 5-76 years). Seventy-four percent of all patients, including 53% of the children, had some degree of respiratory dysfunction. Thirty-eight percent had obvious diaphragmatic weakness. Males appeared to have more severe pulmonary involvement than females: at a group level, their mean VC was significantly lower than that of females (p<0.001), they used mechanical ventilation more often than females (p=0.042) and the decline over the course of the disease was significantly different between males and females (p=0.003). Apart from male gender, severe skeletal muscle weakness and long disease duration were the most important predictors of poor respiratory status. During follow-up (average 1.6 years, range 0.5-4.2 years), three patients became ventilator dependent. Annually, there were average decreases in VC in upright position of 0.9% points (p=0.09), VC in supine position of 1.2% points (p=0.049), MIP of 3.2% points (p=0.018) and MEP of 3.8% points (p<0.01). We conclude that pulmonary dysfunction in Pompe disease is much more common than generally thought. Males, patients with severe muscle weakness, and those with advanced disease duration seem most at risk. PMID:21763167

van der Beek, N A M E; van Capelle, C I; van der Velden-van Etten, K I; Hop, W C J; van den Berg, B; Reuser, A J J; van Doorn, P A; van der Ploeg, A T; Stam, H

2011-06-24

359

Progression of lung disease in primary ciliary dyskinesia: is spirometry less accurate than CT?  

PubMed

Despite its extensive use, there is no evidence that spirometry is useful in the assessment of progression of lung disease in primary ciliary dyskinesia (PCD). We hypothesize that high-resolution computed tomography (HRCT) is a better indicator of PCD lung disease progression than spirometry. We retrospectively evaluated two paired spirometry and HRCT examinations from 20 PCD patients (age, 11.6 years; range, 6.5-27.5 years). The evaluations were performed in stable state and during unstable lung disease. HRCT scans were scored blind by two raters. Compared to the first assessment, at the second evaluation spirometry did not change while HRCT scores significantly worsened (P?disease may worsen despite spirometry being stable. PMID:22006708

Maglione, Marco; Bush, Andrew; Montella, Silvia; Mollica, Carmine; Manna, Angelo; Esposito, Antonietta; Santamaria, Francesca

2011-10-17

360

Comparative evaluations of neuroperformance and clinical outcome assessments in chronic progressive multiple sclerosis: I. Reliability, validity and sensitivity to disease progression. Multiple Sclerosis Study Group.  

PubMed

There remains controversy regarding the most sensitive and valid outcome assessments to use in multiple sclerosis (MS) clinical trials. A double blind, placebo controlled, parallel group multicenter clinical trial to evaluate the clinical efficacy of cyclosporine A in chronic progressive MS incorporated several major clinical and performance outcome assessment modalities and a large sample size, both of which provide a unique opportunity to explore the relationship among MS disease status and the various outcome measures over time. The measures included a structured neurological examination, the Kurtzke Functional System scales and Expanded Disability Status Score, and the Incapacity Status Scale from the MS Minimal Record of Disability, the Harvard Ambulation Index, and neuroperformance testing. A test-retest reliability index, principal component analyses and a signal-to-noise ratio metric were used to comparatively evaluate the reliability, validity and sensitivity to disease progression of the various outcome assessments. The goal was to provide a rational basis for selection of behavioral outcome assessments in future MS clinical trials by identifying the primary dimensions of MS measured by the candidate outcome assessments and providing an objective basis for selecting tests that are most sensitive to MS disease and its progression over a two year trial period. We conclude that the components of the major clinical and performance measures show excellent reliability and cross validation. Principal component analyses of all outcome assessments yielded six primary underlying factors for describing disease status in chronic progressive MS that included lower extremity/pyramidal dysfunction, cerebellar/brainstem and upper extremity dysfunction, somatosensory dysfunction, visual dysfunction, mental or intellectual dysfunction and bowel/bladder problems. Signal-to-noise ratios indicated that upper and lower extremity composites of neuroperformance test items provided the most sensitive indicators of MS disease progression in the placebo group over the 2 year trial period. PMID:9345379

Syndulko, K; Ke, D; Ellison, G W; Baumhefner, R W; Myers, L W; Tourtellotte, W W

1996-10-01

361

Retinal pigment epithelial detachments and tears, and progressive retinal degeneration in light chain deposition disease  

PubMed Central

Background/purpose Light-chain deposition disease (LCDD) is a rare condition characterised by deposition of monoclonal immunoglobulin light chains (LCs) in tissues, resulting in varying degrees of organ dysfunction. This study reports the characteristic clinical ocular findings seen in advanced LCDD upon development of ocular fundus changes. This is the first report to describe this entity in vivo in a series of patients. Methods A case series of ocular fundus changes in three patients with kidney biopsy-proven LCDD. All patients underwent best corrected visual acuity (BCVA) exam, perimetry, colour fundus photography and fluorescein angiography; two patients underwent indocyanine green angiography, optical coherence tomography, ultrasound and electroretinography; and one patient underwent fundus autofluorescence. Results Three patients, 53–60?years old at initial presentation, were studied. All three presented with night blindness, poor dark adaptation, metamorphopsia and visual loss. Examination revealed serous and serohaemorrhagic detachments, multiple retinal pigment epithelial (RPE) tears, diffuse RPE degeneration and progressive fibrotic changes. Neither choroidal neovascularisation nor other vascular abnormalities were present. Final best corrected visual acuity (BCVA) ranged from 20/40 to 20/300. Conclusions Progressive LC deposition in the fundus seems to damage RPE pump function with flow disturbance between choroid and retina. This pathogenesis can explain the evolution to RPE detachments and subsequent rips and progressive retinal malfunction.

Spielberg, Leigh H; Heckenlively, John R; Leys, Anita M

2013-01-01

362

Rotigotine treatment partially protects from MPTP toxicity in a progressive macaque model of Parkinson's disease.  

PubMed

Clinical DA agonist monotherapy trials, which used in vivo imaging of the DA transporter (DAT) to assess the rate of progression of nigrostriatal degeneration, have failed to demonstrate consistent evidence for neuroprotection. The present study aims at reconciling these experimental and clinical data by testing the protective property of the continuously delivered D3/D2/D1 dopamine receptor agonist rotigotine. Using a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned (MPTP) macaque model that mimics the progression of Parkinson's disease in vivo ([99mTc]-TRODAT-1 single photon emission computed tomography (SPECT)) and ex vivo ([125I]-nortropane DAT labelling) endpoints were evaluated. After 38 days of treatment followed by two weeks of washout, rotigotine-treated animals were significantly less parkinsonian than the vehicle-treated ones. Such behavioural difference is the consequence of a partial protection of the DA terminals as could be confirmed by ex vivo DAT labelling. However, the protection of nerve terminals was not detected using SPECT. The data suggest that rotigotine exerts partial protection but that conventional imaging would not be able to identify such protection. PMID:17045989

Scheller, Dieter; Chan, Piu; Li, Qin; Wu, Tao; Zhang, Renling; Guan, Le; Ravenscroft, Paula; Guigoni, Celine; Crossman, Alan R; Hill, Michael; Bezard, Erwan

2006-10-12

363

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

364

Genetic risk score predicting accelerated progression from mild cognitive impairment to Alzheimer's disease.  

PubMed

Aside from APOE, the genetic factors that influence the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) remain largely unknown. We assessed whether a genetic risk score (GRS), based on eight non-APOE genetic variants previously associated with AD risk in genome-wide association studies, is associated with either risk of conversion or with rapid progression from MCI to AD. Among 288 subjects with MCI, follow-up (mean 26.3 months) identified 118 MCI-converters to AD and 170 MCI-nonconverters. We genotyped ABCA7 rs3764650, BIN1 rs744373, CD2AP rs9296559, CLU rs1113600, CR1 rs1408077, MS4A4E rs670139, MS4A6A rs610932, and PICALM rs3851179. For each subject we calculated a cumulative GRS, defined as the number of risk alleles (range 0-16) with each allele weighted by the AD risk odds ratio. GRS was not associated with risk of conversion from MCI to AD. However, MCI-converters to AD harboring six or more risk alleles (second and third GRS tertiles) progressed twofold more rapidly to AD when compared with those with less than six risk alleles (first GRS tertile). Our GRS is a first step toward development of prediction models for conversion from MCI to AD that incorporate aggregate genetic factors. PMID:23180304

Rodríguez-Rodríguez, E; Sánchez-Juan, P; Vázquez-Higuera, J L; Mateo, I; Pozueta, A; Berciano, J; Cervantes, S; Alcolea, D; Martínez-Lage, P; Clarimón, J; Lleó, A; Pastor, P; Combarros, O

2012-11-20

365

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

PubMed

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

2009-12-14

366

Contributions of Ibn Al-Nafis (1210-1288 AD) to the progress of medicine and urology. A study and translations from his medical works.  

PubMed

This primary-source study of 4 medical works of the 13th century Muslim scholar Ibn Al-Nafis confirmed that his Kitab Al-Mujaz Fi Al-Tibb was authored as an independent book meant to be a handbook for medical students and practitioners not as an epitome of Kitab Al-Qanun of Ibn Sina as thought by recent historians. His huge medical encyclopedia, Al-Shamil, represents a wave of intense scientific activity that spread among the scholars of Cairo and Damascus following the massive destruction of books by Hulako's Army during the devastation of Baghdad in 1258. Like his predecessors in the Islamic Era, Ibn Al-Nafis critically appraised the views of scholars before him in the light of his own experimentation and direct observations. Accordingly, in his books Sharh Tashreeh Al-Qanun, Risalat al-Aadaa and Al-Risalah Al-Kameleyyah, we find the first description of the coronary vessels and the true concept of the blood supply of the heart as well as the correct description of the pulmonary circulation and the beginnings of the proper understanding of the systemic circulation. Those discoveries of Ibn Al-Nafis, translated to Latin by Andreas Alpagus printed in Venice in 1547, appeared, 6 years later, in the Christianismi Restituto of Servetus and, in 1555, in the De Fabrica Humani Corporis of Vesalius 2nd edition then in the works of Valvarde 1554, Columbus 1559, Cesalpino 1571, and finally Harvey in 1628. Furthermore, this study documented several other contributions of Ibn Al-Nafis to the progress of human functional anatomy and to advances in medical and surgical practice. PMID:18176669

Abdel-Halim, Rabie E

2008-01-01

367

Vascular Care in Patients With Alzheimer Disease With Cerebrovascular Lesions Slows Progression of White Matter Lesions on MRI The Evaluation of Vascular Care in Alzheimer's Disease (EVA) Study  

Microsoft Academic Search

Background and Purpose-White matter lesions (WMLs) and cerebral infarcts are common findings in Alzheimer disease and may contribute to dementia severity. WMLs and lacunar infarcts may provide a potential target for intervention strategies. This study assessed whether multicomponent vascular care in patients with Alzheimer disease with cerebrovascular lesions slows progression of WMLs and prevents occurrence of new infarcts. Methods-A randomized

E. Richard; A. A. Gouw; P. Scheltens; Gool van W. A

2010-01-01

368

Musical long-term memory throughout the progression of Alzheimer disease.  

PubMed

In Alzheimer patients with a solid musical background, isolated case-reports have reported the maintenance of remarkable musical abilities despite clear difficulties in their verbal memory and linguistic functions. These reports have encouraged a number of scientists to undertake more systematic studies which would allow a rigorous approach to the analysis of musical memory in Alzheimer patients with no formal musical background. Although restricted in number, the latest data are controversial regarding preserved musical capacities in Alzheimer patients. Our current review of the literature addresses this topic and advances the hypothesis that the processes of musical memory are function of illness progression. In the earlier stages, the majority of evaluations concerned musical episodic memory and suggested a dysfunction of this memory whereas in the moderate and severe stages, musical semantic memory and implicit learning are the majority of investigations and seemed more resistant to Alzheimer disease. In summary, our current review bring to understand the memory circuits involved and highlight the necessity to adapted the investigational tools employed to conform with the severity of the signs and symptoms of progressive Alzheimer disease in order to demonstrate the preserved musical capacities. PMID:23508326

Groussard, Mathilde; Mauger, Caroline; Platel, Hervé

2013-03-01

369

Genetic variations in inflammatory mediators influence lung disease progression in cystic fibrosis.  

PubMed

The clinical course of cystic fibrosis (CF) varies considerably among patients carrying the same CF-causing gene mutation. Additional genetic modifiers may contribute to this variability. As airway inflammation is a key component of CF pathophysiology, we investigated whether major cytokine variants represent such modifiers in young CF patients. We tested 13 polymorphisms in 8 genes that play a key role in the inflammatory response: tumor necrosis factor, lymphotoxin alpha, interleukin (IL) 1B, IL1 receptor antagonist, IL6, IL8, IL10 and transforming growth factor beta 1 (TGFB1), for an association with lung disease progression and nutritional status in 329 CF patients. Variants in the TGFB1 gene at position +869T/C demonstrated a significant association with lung function decline. A less pronounced rate of decline in forced expiratory volume in 1 sec (FEV(1)) and forced vital capacity (FVC) were observed in patients heterozygous for TGFB1 +869 (+869CT), when compared to patients carrying either TGFB1 +869TT or +869CC genotypes. These findings support the concept that TGFB1 gene variants appear to be important genetic modifiers of lung disease progression in CF. PMID:19009622

Corvol, Harriet; Boelle, Pierre-Yves; Brouard, Jacques; Knauer, Nicola; Chadelat, Katarina; Henrion-Caude, Alexandra; Flamant, Cyril; Muselet-Charlier, Celine; Boule, Michele; Fauroux, Brigitte; Vallet, Christelle; Feingold, Josue; Ratjen, Felix; Grasemann, Hartmut; Clement, Annick

2008-12-01

370

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

PubMed Central

With the advent of advances in biomarker detection and neuropsychological measurement, prospects have improved for identifying and tracking the progression of Alzheimer's disease (AD) from its earliest stages through dementia. While new diagnostic techniques have exciting implications for initiating treatment earlier in the disease process, much work remains to be done to optimize the contributions of the expanding range of tools at the disposal of researchers and clinicians. The present paper examines recent work in cerebrospinal fluid biomarkers, magnetic resonance imaging, positron emission tomography, neuropsychological measures, and functional assessment. The strengths and weaknesses of current methodologies are explored and discussed. It is concluded that AD from its mild cognitive impairment state through dementia represents a continuous process, and that progression over time can best be accomplished by interval-level variables. Biomarkers that are most sensitive to early AD may not be the most optimal for monitoring longitudinal change, and it is likely that multivariate models incorporating cognitive measures, functional variables and biomarker data will be the most fruitful avenues for future research.

2010-01-01

371

Nijmegen paediatric CDG rating scale: a novel tool to assess disease progression.  

PubMed

Congenital disorders of glycosylation (CDG) are a group of clinically heterogeneous inborn errors of metabolism. At present, treatment is available for only one CDG, but potential treatments for the other CDG are on the horizon. It will be vitally important in clinical trials of such agents to have a clear understanding of both the natural history of CDG and the corresponding burden of disability suffered by patients. To date, no multicentre studies have attempted to document the natural history of CDG. This is in part due to the lack of a reliable assessment tool to score CDG's diverse clinical spectrum. Based on our earlier experience evaluating disease progression in disorders of oxidative phosphorylation, we developed a practical and semi-quantitative rating scale for children with CDG. The Nijmegen Paediatric CDG Rating Scale (NPCRS) has been validated in 12 children, offering a tool to objectively monitor disease progression. We undertook a successful trial of the NPCRS with a collaboration of nine experienced physicians, using video records of physical and neurological examination of patients. The use of NPCRS can facilitate both longitudinal and natural history studies that will be essential for future interventions. PMID:21541726

Achouitar, Samira; Mohamed, Miski; Gardeitchik, Thatjana; Wortmann, Saskia B; Sykut-Cegielska, Jolanta; Ensenauer, Regina; de Baulny, Hélène Ogier; Õunap, Katrin; Martinelli, Diego; de Vries, Maaike; McFarland, Robert; Kouwenberg, Dorus; Theodore, Miranda; Wijburg, Frits; Grünewald, Stephanie; Jaeken, Jaak; Wevers, Ron A; Nijtmans, Leo; Elson, Joanna; Morava, Eva

2011-05-04

372

Behavioral mediation of the relationship between psychosocial factors and HIV disease progression.  

PubMed

The psychological and physical demands of coping with medication side effects and comorbid illnesses can be overwhelming and may influence behaviors, such as medication adherence, substance use, sexual risk behavior, and exercise that, in turn, affect health outcomes. Cross-sectional and prospective studies among diverse populations of persons living with HIV suggest that these behavioral mechanisms may be associated with HIV disease progression. The motivation to change behavior is often highest in the immediate aftermath of a stressor. However, over time the motivation to continue a particular behavior change is often challenged by habits, environmental influences, and psychosocial factors. Furthermore, a number of studies suggest that behavioral mechanisms may mediate the relationship between psychosocial variables (e.g., stress, depression, coping, and social support) and disease progression in HIV. Thus, developing clinical interventions that address these psychosocial factors and enhance protective health behaviors and reduce behaviors that convey risk to health are likely to lessen overall morbidity and mortality among patients living with HIV/AIDS. PMID:18519885

Gore-Felton, Cheryl; Koopman, Cheryl

2008-06-02

373

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

PubMed

Post-traumatic stress disorder (PTSD) is a common psychological outcome of any disaster. The purpose of this study was to examine the effects of PTSD on disease progression among HIV-infected persons in metropolitan New Orleans post-hurricane Katrina. One-year post-storm, a convenience sample of 145 HIV-infected patients who returned to care at the HIV Outpatient Program clinic in New Orleans were interviewed. Clinical factors pre and one and two years post-disaster were abstracted from medical records and compared by PTSD status. Of the 145 participants, 37.2% had PTSD. Those with PTSD were more likely than those without PTSD to have detectable plasma viral loads at both follow-up time points post-disaster and more likely to have CD4 cell counts <200/mm(3) two years post-disaster. They were also more likely to have had medication interruptions immediately post-disaster. Our findings corroborate the findings of others that PTSD accelerates HIV disease progression. Disaster planners should consider the special counseling and medication safeguards needs of HIV-infected persons. PMID:20024706

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

2009-10-01

374

Progression of Tau Pathology in Cholinergic Basal Forebrain Neurons in Mild Cognitive Impairment and Alzheimer's Disease  

PubMed Central

Tau is a microtubule-associated protein that forms neurofibrillary tangles (NFTs) in the selective vulnerable long projection neurons of the cholinergic basal forebrain (CBF) in Alzheimer's disease (AD). Although CBF neurodegeneration correlates with cognitive decline during AD progression, little is known about the temporal changes of tau accumulation in this region. We investigated tau posttranslational modifications during NFT evolution within the CBF neurons of the nucleus basalis (NB) using tissue from subjects with no cognitive impairment, mild cognitive impairment, and AD. The pS422 antibody was used as an early tau pathology marker that labels tau phosphorylated at Ser422; the TauC3 antibody was used to detect later stage tau pathology. Stereologic evaluation of NB tissue immunostained for pS422 and TauC3 revealed an increase in neurons expressing these tau epitopes during disease progression. We also investigated the occurrence of pretangle tau events within cholinergic NB neurons by dual staining for the cholinergic cell marker, p75NTR, which displays a phenotypic down-regulation within CBF perikarya in AD. As pS422+ neurons increased in number, p75NTR+ neurons decreased, and these changes correlated with both AD neuropathology and cognitive decline. Also, NFTs developed slower in the CBF compared with previously examined cortical regions. Taken together, these results suggest that changes in cognition are associated with pretangle events within NB cholinergic neurons before frank NFT deposition.

Vana, Laurel; Kanaan, Nicholas M.; Ugwu, Isabella C.; Wuu, Joanne; Mufson, Elliott J.; Binder, Lester I.

2011-01-01

375

Hepatitis C virus infection, microRNA and liver disease progression  

PubMed Central

Hepatitis C virus (HCV) is a global health problem with an estimated 170-200 million peoples (approximately 3% of world population) are chronically infected worldwide and new infections are predicted to be on rise in coming years. HCV infection remains categorized as a major risk factor for chronic hepatitis, liver cirrhosis and hepatocellular carcinoma worldwide. There has been considerable improvement in our understanding of virus life cycle since, the discovery of HCV two-decades ago. MicroRNAs (miRNAs) are important players in establishment of HCV infection and their propagation in infected hepatocytes. They target crucial host cellular factors needed for productive HCV replication and augmented cell growth. Very first anti-miRNA oligonucleotides, miravirsen has been tested in clinical trial and shown promising results as therapeutic agent in treatment against chronic HCV infection. Deregulated expression of miRNAs has been linked to the pathogenesis associated with HCV infection by controlling signaling pathways such as, proliferation, apoptosis and migration. Circulating miRNAs emerging as growing field in identification of biomarkers in disease progression and their potential as a means of communication between cells inside the liver is an exciting area of research in future. This review focuses on recent studies enforcing the contribution of miRNAs in HCV life cycle and coordinated regulation in HCV mediated liver disease progression.

Shrivastava, Shubham; Mukherjee, Anupam; Ray, Ratna B

2013-01-01

376

Chronic kidney disease progression to end stage renal disease: a single center experience of the role of the underlying kidney disease.  

PubMed

Chronic kidney disease (CKD) is common and several factors affect its progression to end-stage renal disease (ESRD). The main goal of our study was to assess the influence of underlying kidney disease and some other important factors during the time of CKD progression to ESRD. A retrospective study of 91 patients (57 men, 34 women; average age 57.7?±?13.2 years) was carried out. Patients were monitored at least one month before the first renal replacement treatment (RRT). Estimated glomerular filtration rate (eGFR) at first referral to nephrologist was determined by Modification of Diet in Renal Disease equation. Proteinuria was assessed semiquantitatively with dipsticks. Thirty-five patients (38.5%) had diabetic nephropathy (DN), 21 (23.1%) hypertensive nephrosclerosis (HN), 21 (23.1%) adult polycystic kidney disease (APKD) and 14 (15.4%) immunoglobulin A nephropathy (IgAN). Average eGFR at first referral for DN patients was 20.1, and then 23.4 for HN, 35.5 for APKD, and 36.4?mL/min per 1,73?m(2) for IgAN patients. Average time between first nephrological visit and first RRT was 28.4 months for DN patients, 41 for HN, 80.8 for APKD, and 70.1 for IgAN patients. Comparison of all four groups of CKD patients showed that in patients with APKD and IgAN impairment of kidney function to ESRD had progressed statistically significantly slower (P?progression rate of CKD to ESRD. PMID:23931872

Ekart, Robert; Ferjuc, Anita; Furman, Barbara; Gerjevi?, Špela; Bevc, Sebastjan; Hojs, Radovan

2013-08-01

377

Progressive dopaminergic degeneration in the chronic MPTPp mouse model of Parkinson's disease.  

PubMed

Parkinson's disease (PD) is characterized by a progressive degeneration of dopamine (DA) neurons and gradual worsening of motor symptoms. The investigation of progressive degenerative mechanisms and potential neuroprotective strategies relies on experimental models of the chronic neuropathology observed in human. The present study investigated the progressive nature of neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTPp) chronic mouse model of PD. MPTP (25 mg/kg) plus probenecid (250 mg/kg) were administered twice a week for 5 weeks. We evaluated behavioral deficits (olfactory and motor impairment), neurodegeneration (loss of tyrosine hydroxylase (TH)-positive cells in the substantia nigra pars compacta, SNc), biochemical markers of functional impairment in the caudate-putamen (CPu) (striatal enkephalin mRNA, DA and DOPAC levels), and glial reactivity (CD11b and GFAP immunoreactivity in the SNc and CPu) at progressive time-points (after 1, 3, 7, and 10 administrations of MPTPp). Olfactory dysfunction already appeared after the 1st MPTPp injection, whereas motor dysfunction appeared after the 3rd and worsened upon subsequent administrations. Moreover, starting after three MPTPp injections, we observed a gradual decline of TH-positive cells in the SNc, and a gradual raise of enkephalin mRNA in the CPu. Striatal DA levels reduction was not different among all time-points evaluated, whereas DOPAC levels were similarly reduced after 1-7 MPTP injections, but were further decreased after the 10th injection. Reactive microglia and astroglia were observed in both the SNc and CPu from the 1st MPTPp administration. In the SNc, gliosis displayed a gradual increase over the treatment. After 2 months, TH, DA, DOPAC, and reactive glia in the SNc were still altered in MPTPp-treated mice as compared to controls. By showing a progressive development of behavioral deficits and nigral neurodegeneration, together with impairment of biochemical parameters and gradual increase of glial response, results suggest that the chronic MPTPp protocol is a model of progressive PD, which may be suitable to investigate chronic pathological processes and neuroprotective strategies in PD. PMID:19526289

Schintu, Nicoletta; Frau, Lucia; Ibba, Marcello; Garau, Arianna; Carboni, Ezio; Carta, Anna R

2009-05-27

378

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

379

Gene Expression Patterns in Myelodyplasia Underline the Role of Apoptosis and Differentiation in Disease Initiation and Progression  

Microsoft Academic Search

The myelodysplastic syndromes (MDS) are clonal stem cell disorders, characterized by ineffective and dysplastic hematopoiesis. The genetic and epigenetic pathways that determine disease stage and progression are largely unknown. In the current study we used gene expression microarray methodology to examine the gene expression differences between normal hematopoietic cells and hematopoietic cells from patients with MDS at different disease stages,

Merav Bar; Derek Stirewalt; Era Pogosova-Agadjanyan; Vitas Wagner; Ted Gooley; Nissa Abbasi; Ravi Bhatia; H. Joachim Deeg; Jerald Radich

2008-01-01

380

Reverse phase protein microarrays which capture disease progression show activation of pro-survival pathways at the cancer invasion front  

Microsoft Academic Search

Protein arrays are described for screening of molecular markers and pathway targets in patient matched human tissue during disease progression. In contrast to previous protein arrays that immobilize the probe, our reverse phase protein array immobilizes the whole repertoire of patient proteins that represent the state of individual tissue cell populations undergoing disease transitions. A high degree of sensitivity, precision

Cloud P Paweletz; Lu Charboneau; Verena E Bichsel; Nicole L Simone; Tina Chen; John W Gillespie; Michael R Emmert-Buck; Mark J Roth; Emanuel F Petricoin III; Lance A Liotta

2001-01-01

381

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

382

Mucosa-associated lymphoid tissue lymphoma with initial supradiaphragmatic presentation: natural history and patterns of disease progression  

Microsoft Academic Search

Purpose: Mucosa-associated lymphoid tissue (MALT) lymphoma commonly presents in the gastrointestinal (GI) tract. Supradiaphragmatic MALT lymphoma is less common and its natural history is not well defined. This study was conducted to understand the natural history, to determine the frequency of synchronous disease in the GI tract, and to understand the patterns of disease progression after treatment for supradiaphragmatic MALT

Zhongxing Liao; Chul S Ha; Peter McLaughlin; John T Manning; Mark Hess; Fernando Cabanillas; James D Cox

2000-01-01

383

[Recessive motor neuron diseases: mutations in the ALS2 gene and molecular pathogenesis for the upper motor neurodegeneration].  

PubMed

We have initially identified a mutation in ALS2 as a causative for a juvenile autosomal recessive form of amyotrophic lateral sclerosis (ALS), termed ALS2 (OMIM 205100). ALS2 mutations also are causative for an autosomal recessive juvenile primary lateral sclerosis, and infantile-ascending hereditary spastic paralysis. To date, nine homozygous ALS2 mutaions from nine independent families have been identified. All of these mutations result in predicted premature translation termination caused by the recessive frameshift or nonsense mutation. ALS2 is a 184-kD protein comprising several putative guanine nucleotide exchange factor (GEF) domains [RLD; RCC1 like domain, DH. PH domain, VPS9; Vacuolar protein sorting 9 domain]. In vitro, ALS2 specifically binds to the small GTPase Rab5 and functions as a GEF for Rab5. Ectopic expression of full-length ALS2 has further implied an association with endosomal membranes mediated by the VPS9 domain, consistent with ALS2 involvement in endosomal trafficking and fusion in conjunction with the activation of Rab5. These results combined with our findings suggest that an obstruction of endosomal dynamics might underlie neuronal dysfunction and degeneration in ALS2, PLSJ, and HSP, as well as in a number of other motor neuron diseases. PMID:15651293

Ikeda, Joh-E

2004-11-01

384

Muscle histone deacetylase 4 upregulation in amyotrophic lateral sclerosis: potential role in reinnervation ability and disease progression.  

PubMed

Amyotrophic lateral sclerosis is a typically rapidly progressive neurodegenerative disorder affecting motor neurons leading to progressive muscle paralysis and death, usually from respiratory failure, in 3-5 years. Some patients have slow disease progression and prolonged survival, but the underlying mechanisms remain poorly understood. Riluzole, the only approved treatment, only modestly prolongs survival and has no effect on muscle function. In the early phase of the disease, motor neuron loss is initially compensated for by collateral reinnervation, but over time this compensation fails, leading to progressive muscle wasting. The crucial role of muscle histone deacetylase 4 and its regulator microRNA-206 in compensatory reinnervation and disease progression was recently suggested in a mouse model of amyotrophic lateral sclerosis (transgenic mice carrying human mutations in the superoxide dismutase gene). Here, we sought to investigate whether the microRNA-206-histone deacetylase 4 pathway plays a role in muscle compensatory reinnervation in patients with amyotrophic lateral sclerosis and thus contributes to disease outcome differences. We studied muscle reinnervation using high-resolution confocal imaging of neuromuscular junctions in muscle samples obtained from 11 patients with amyotrophic lateral sclerosis, including five long-term survivors. We showed that the proportion of reinnervated neuromuscular junctions was significantly higher in long-term survivors than in patients with rapidly progressive disease. We analysed the expression of muscle candidate genes involved in the reinnervation process and showed that histone deacetylase 4 upregulation was significantly greater in patients with rapidly progressive disease and was negatively correlated with the extent of muscle reinnervation and functional outcome. Conversely, the proposed regulator of histone deacetylase 4, microRNA-206, was upregulated in both patient groups, but did not correlate with disease progression or reinnervation. We conclude that muscle expression of histone deacetylase 4 may be a key factor for muscle reinnervation and disease progression in patients with amyotrophic lateral sclerosis. Specific histone deacetylase 4 inhibitors may then constitute a therapeutic approach to enhancing motor performance and slowing disease progression in amyotrophic lateral sclerosis. PMID:23824486

Bruneteau, Gaëlle; Simonet, Thomas; Bauché, Stéphanie; Mandjee, Nathalie; Malfatti, Edoardo; Girard, Emmanuelle; Tanguy, Marie-Laure; Behin, Anthony; Khiami, Frédéric; Sariali, Elhadi; Hell-Remy, Caroline; Salachas, François; Pradat, Pierre-François; Fournier, Emmanuel; Lacomblez, Lucette; Koenig, Jeanine; Romero, Norma Beatriz; Fontaine, Bertrand; Meininger, Vincent; Schaeffer, Laurent; Hantaï, Daniel

2013-07-03

385

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

386

The effect of history of injection drug use and alcoholism on HIV disease progression.  

PubMed

The effectiveness of highly active antiretroviral therapy (HAART) in preventing disease progression can be negatively influenced by the high prevalence of substance use among patients. Here, we quantify the effect of history of injection drug use and alcoholism on virologic and immunologic response to HAART. Clinical and survey data, collected at the start of HAART and at the interview date, were based on the study Longitudinal Investigations into Supportive and Ancillary Health Services (LISA) in British Columbia, Canada. Substance use was a three-level categorical variable, combining information on history of alcohol dependence and of injection drug use, defined as: no history of alcohol and injection drug use; history of alcohol or injection drug use; and history of both alcohol and injection drug use. Virologic response (pVL) was defined by ?2 log10 copy/mL drop in a viral load. Immunologic response was defined as an increase in CD4 cell count percent of ?100%. We used cumulative logit modeling for ordinal responses to address our objective. Of the 537 HIV-infected patients, 112 (21%) were characterized as having a history of both alcohol and injection drug use, 173 (32%) were nonadherent (<95%), 196 (36%) had a CD4(+)/pVL(+) (Best) response, 180 (34%) a CD4(+)/pVL(-) or a CD4(-) /pVL(+) (Incomplete) response, and 161 (30%) a CD4(-) /pVL(-) (Worst) response. For individuals with history of both alcohol and injection drug use, the estimated probability of non-adherence was 0.61, and (0.15, 0.25, 0.60) of Best, Incomplete and Worse responses, respectively. Screening and detection of substance dependence will identify individuals at high-risk for nonadherence and ideally prevent their HIV disease from progressing to advanced stages where HIV disease can become difficult to manage. PMID:23767757

Lima, Viviane Dias; Kerr, Thomas; Wood, Evan; Kozai, Tsubasa; Salters, Kate A; Hogg, Robert S; Montaner, Julio S G

2013-06-14

387

Local ASIC3 modulates pain and disease progression in a rat model of osteoarthritis  

PubMed Central

Background Recent data have suggested a relationship between acute arthritic pain and acid sensing ion channel 3 (ASIC3) on primary afferent fibers innervating joints. The purpose of this study was to clarify the role of ASIC3 in a rat model of osteoarthritis (OA) which is considered a degenerative rather than an inflammatory disease. Methods We induced OA via intra-articular mono-iodoacetate (MIA) injection, and evaluated pain-related behaviors including weight bearing measured with an incapacitance tester and paw withdrawal threshold in a von Frey hair test, histology of affected knee joint, and immunohistochemistry of knee joint afferents. We also assessed the effect of ASIC3 selective peptide blocker (APETx2) on pain behavior, disease progression, and ASIC3 expression in knee joint afferents. Results OA rats showed not only weight-bearing pain but also mechanical hyperalgesia outside the knee joint (secondary hyperalgesia). ASIC3 expression in knee joint afferents was significantly upregulated approximately twofold at Day 14. Continuous intra-articular injections of APETx2 inhibited weight distribution asymmetry and secondary hyperalgesia by attenuating ASIC3 upregulation in knee joint afferents. Histology of ipsilateral knee joint showed APETx2 worked chondroprotectively if administered in the early, but not late phase. Conclusions Local ASIC3 immunoreactive nerve is strongly associated with weight-bearing pain and secondary hyperalgesia in MIA-induced OA model. APETx2 inhibited ASIC3 upregulation in knee joint afferents regardless of the time-point of administration. Furthermore, early administration of APETx2 prevented cartilage damage. APETx2 is a novel, promising drug for OA by relieving pain and inhibiting disease progression.

2012-01-01

388

Hyperperfusion in progressive multifocal leukoencephalopathy is associated with disease progression and absence of immune reconstitution inflammatory syndrome.  

PubMed

We sought to characterize perfusion patterns of progressive multifocal leukoencephalopathy lesions by arterial spin labelling perfusion magnetic resonance imaging and to analyse their association with immune reconstitution inflammatory syndrome, and survival. A total of 22 patients with progressive multifocal leukoencephalopathy underwent a clinical evaluation and magnetic resonance imaging of the brain within 190 days of symptom onset. The presence of immune reconstitution inflammatory syndrome was determined based on clinical and laboratory criteria. Perfusion within progressive multifocal leukoencephalopathy lesions was determined by arterial spin labelling magnetic resonance imaging. We observed intense hyperperfusion within and at the edge of progressive multifocal leukoencephalopathy lesions in a subset of subjects. This hyperperfusion was quantified by measuring the fraction of lesion volume showing perfusion in excess of twice normal appearing grey matter. Hyperperfused lesion fraction was significantly greater in progressive multifocal leukoencephalopathy progressors than in survivors (12.8% versus 3.4% P = 0.02) corresponding to a relative risk of progression for individuals with a hyperperfused lesion fraction ? 4.0% of 9.1 (95% confidence interval of 1.4-59.5). The presence of hyperperfusion was inversely related to the occurrence of immune reconstitution inflammatory syndrome at the time of scan (P = 0.03). Indeed, within 3 months after symptom onset, hyperperfusion had a positive predictive value of 88% for absence of immune reconstitution inflammatory syndrome. Arterial spin labelling magnetic resonance imaging recognized regions of elevated perfusion within lesions of progressive multifocal leukoencephalopathy. These regions might represent virologically active areas operating in the absence of an effective adaptive immune response and correspond with a worse prognosis. PMID:24088807

Khoury, Michael N; Gheuens, Sarah; Ngo, Long; Wang, Xiaoen; Alsop, David C; Koralnik, Igor J

2013-10-01

389

Dietary soya protein during pregnancy and lactation in rats with hereditary kidney disease attenuates disease progression in offspring.  

PubMed

Dietary soya protein substitution for casein initiated at weaning slows disease progression in animal models of chronic renal disease. As there is increasing evidence that fetal programming can have a significant impact on kidney physiology and function in offspring, the objective of the current study was to determine whether exposure to soya protein in the diet earlier than weaning would have further benefits. Han:SPRD-cy (cy/+) breeder rats were fed a casein-based or soya protein-based diet 2 weeks prior to mating, throughout pregnancy and during lactation. Following this maternal period, 3-week-old pups were given either the same or the alternate diet for a 7-week weaning period. Dietary soya protein compared with casein in the maternal or weaning period both independently resulted in less renal inflammation (macrophage infiltration lower by 24% (P=0.0003) and 32% (P<0.001), respectively). When soya protein was given in both feeding periods, the effect was additive. Soya protein substitution for casein resulted in less oxidative damages as indicated by 28% lower oxidized-LDL staining (P=0.013) when present in the maternal period, or in the weaning period (by 56%, P<0.0001). Renal cell proliferation was reduced by 29-33% (P<0.05) in rats given soya protein whether the exposure was during the maternal or weaning period. Soya protein compared with casein in the maternal period also resulted in 33% (P=0.0013) less proteinuria, indicating superior renal function. Dietary soya protein during pregnancy and lactation represents a potential preventative approach in treating for those with congenital kidney diseases. PMID:17217562

Cahill, Leah E; Peng, Claudia Yu-Chen; Bankovic-Calic, Neda; Sankaran, Deepa; Ogborn, Malcolm R; Aukema, Harold M

2007-01-01

390

Mapping Progressive Brain Structural Changes in Early Alzheimer's Disease and Mild Cognitive Impairment  

PubMed Central

Alzheimer’s disease (AD), the most common neurodegenerative disorder of the elderly, ranks third in health care cost after heart disease and cancer. Given the disproportionate aging of the population in all developed countries, the socio-economic impact of AD will continue to rise. Mild cognitive impairment (MCI), a transitional state between normal aging and dementia, carries a 4–6-fold increased risk of future diagnosis of dementia. As complete drug-induced reversal of AD symptoms seems unlikely, researchers are now focusing on the earliest stages of AD where a therapeutic intervention is likely to realize the greatest impact. Recently neuroimaging has received significant scientific consideration as a promising in vivo disease-tracking modality that can also provide potential surrogate biomarkers for therapeutic trials. While several volumetric techniques laid the foundation of the neuroimaging research in AD and MCI, more precise computational anatomy techniques have recently become available. This new technology detects and visualizes discrete changes in cortical and hippocampal integrity and tracks the spread of AD pathology throughout the living brain. Related methods can visualize regionally specific correlations between brain atrophy and important proxy measures of disease such as neuropsychological tests, age of onset or factors that may influence disease progression. We describe extensively validated cortical and hippocampal mapping techniques that are sensitive to clinically relevant changes even in the single individual, and can identify group differences in epidemiological studies or clinical treatment trials. We give an overview of some recent neuroimaging advances in AD and MCI and discuss strengths and weaknesses of the various analytic approaches.

Apostolova, Liana G.; Thompson, Paul M.

2009-01-01

391

R6/2 Huntington's disease mice develop early and progressive abnormal brain metabolism and seizures.  

PubMed

A hallmark feature of Huntington's disease pathology is the atrophy of brain regions including, but not limited to, the striatum. Though MRI studies have identified structural CNS changes in several Huntington's disease (HD) mouse models, the functional consequences of HD pathology during the progression of the disease have yet to be investigated using in vivo functional MRI (fMRI). To address this issue, we first established the structural and functional MRI phenotype of juvenile HD mouse model R6/2 at early and advanced stages of disease. Significantly higher fMRI signals [relative cerebral blood volumes (rCBVs)] and atrophy were observed in both age groups in specific brain regions. Next, fMRI results were correlated with electrophysiological analysis, which showed abnormal increases in neuronal activity in affected brain regions, thus identifying a mechanism accounting for the abnormal fMRI findings. [(14)C] 2-deoxyglucose maps to investigate patterns of glucose utilization were also generated. An interesting mismatch between increases in rCBV and decreases in glucose uptake was observed. Finally, we evaluated the sensitivity of this mouse line to audiogenic seizures early in the disease course. We found that R6/2 mice had an increased susceptibility to develop seizures. Together, these findings identified seizure activity in R6/2 mice and show that neuroimaging measures sensitive to oxygen metabolism can be used as in vivo biomarkers, preceding the onset of an overt behavioral phenotype. Since fMRI-rCBV can also be obtained in patients, we propose that it may serve as a translational tool to evaluate therapeutic responses in humans and HD mouse models. PMID:22573668

Cepeda-Prado, Efrain; Popp, Susanna; Khan, Usman; Stefanov, Dimitre; Rodríguez, Jorge; Menalled, Liliana B; Dow-Edwards, Diana; Small, Scott A; Moreno, Herman

2012-05-01

392

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.

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

393

Snord 3A: A Molecular Marker and Modulator of Prion Disease Progression  

PubMed Central

Since preventive treatments for prion disease require early identification of subjects at risk, we searched for surrogate peripheral markers characterizing the asymptomatic phases of such conditions. To this effect, we subjected blood mRNA from E200K PrP CJD patients and corresponding family members to global arrays and found that the expression of Snord3A, a non-coding RNA transcript, was elevated several times in CJD patients as compared to controls, while asymptomatic carriers presented intermediate Snord3A levels. In the brains of TgMHu2ME199K mice, a mouse model mimicking for E200K CJD, Snord 3A levels were elevated in an age and disease severity dependent manner, as was the case for brains of these mice in which disease was exacerbated by copper administration. Snord3A expression was also elevated in scrapie infected mice, but not in PrP0/0 mice, indicating that while the expression levels of this transcript may reflect diverse prion etiologies, they are not related to the loss of PrPC’s function. Elevation of Snord3A was consistent with the activation of ATF6, representing one of the arms of the unfolded protein response system. Indeed, SnoRNAs were associated with reduced resistance to oxidative stress, and with ER stress in general, factors playing a significant role in this and other neurodegenerative conditions. We hypothesize that in addition to its function as a disease marker, Snord3A may play an important role in the mechanism of prion disease manifestation and progression.

Cohen, Eran; Avrahami, Dana; Frid, Kati; Canello, Tamar; Levy Lahad, Ephrat; Zeligson, Sharon; Perlberg, Shira; Chapman, Joab; Cohen, Oren S.; Kahana, Esther; Lavon, Iris; Gabizon, Ruth

2013-01-01

394

Postmortem Pittsburgh Compound B (PiB) binding increases with Alzheimer's disease progression.  

PubMed

The development of imaging reagents is of considerable interest in the Alzheimer's disease (AD) field. Some of these, such as Pittsburgh Compound B (PiB), were designed to bind to the amyloid-? peptide (A?), the major component of amyloid deposits in the AD brain. Although these agents were designed for imaging amyloid deposits in vivo, a major avenue of evaluation relies on postmortem cross validation with established indices of AD pathology. In this study, we evaluated changes in the postmortem binding of PiB and its relationship to other aspects of A?-related pathology in a series of AD cases and age-matched controls. We also examined cases of preclinical AD (PCAD) and amnestic mild cognitive impairment (MCI), both considered early points in the AD continuum. PiB binding was found to increase with the progression of the disease and paralleled increases in the less soluble forms of A?, including SDS-stable A? oligomers. Increased PiB binding and its relationship to A? was only significant in a brain region vulnerable to the development of AD pathology (the superior and middle temporal gyri) but not in an unaffected region (cerebellum). This implies that the amyloid deposited in disease-affected regions may possess fundamental, brain region specific characteristics that may not as yet be fully appreciated. These data support the idea that PiB is a useful diagnostic tool for AD, particularly in the early stage of the disease, and also show that PiB could be a useful agent for the discovery of novel disease-related properties of amyloid. PMID:22766739

Beckett, Tina L; Webb, Robin L; Niedowicz, Dana M; Holler, Christopher J; Matveev, Sergey; Baig, Irfan; LeVine, Harry; Keller, Jeffrey N; Murphy, M Paul

2012-01-01

395

Postmortem Pittsburgh Compound B (PiB) Binding Increases with Alzheimer's Disease Progression  

PubMed Central

The development of imaging reagents is of considerable interest in the Alzheimer's disease (AD) field. Some of these, such as Pittsburgh Compound B (PiB), were designed to bind to the amyloid-? peptide (A?), the major component of amyloid deposits in the AD brain. Although these agents were designed for imaging amyloid deposits in vivo, a major avenue of evaluation relies on postmortem cross validation with established indices of AD pathology. In this study, we evaluated changes in the postmortem binding of PiB and its relationship to other aspects of A?-related pathology in a series of AD cases and age-matched controls. We also examined cases of preclinical AD (PCAD) and amnestic mild cognitive impairment (MCI), both considered early points in the AD continuum. PiB binding was found to increase with the progression of the disease, and paralleled increases in the less soluble forms of A?, including SDS-stable A? oligomers. Increased PiB binding and its relationship to A? was only significant in a brain region vulnerable to the development of AD pathology (the superior and middle temporal gyri) but not in an unaffected region (cerebellum). This implies that the amyloid deposited in disease affected regions may possess fundamental, brain region specific characteristics that may not as yet be fully appreciated. These data support the idea that PiB is a useful diagnostic tool for AD, particularly in the early stage of the disease, and also show that PiB could be a useful agent for the discovery of novel disease-related properties of amyloid.

Beckett, Tina L.; Webb, Robin L.; Niedowicz, Dana M.; Holler, Christopher J.; Matveev, Sergey; Baig, Irfan; LeVine, Harry; Keller, Jeffrey N.; Murphy, M. Paul

2013-01-01

396

Functional characterization of human immunodeficiency virus type 1 nef genes in patients with divergent rates of disease progression.  

PubMed Central

We have studied the sequence and function of the human immunodeficiency virus type 1 (HIV-1) nef genes from nine patients with highly divergent rates of disease progression enrolled in a longitudinal study of HIV disease