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1

Kinematics of Disease Progression in Bulbar ALS  

ERIC Educational Resources Information Center

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

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

2010-01-01

2

Evaluation of humoral immune response in adaptive immunity in ALS patients during disease progression  

Microsoft Academic Search

In ALS, evidence suggests immune reactions in disease pathogenesis. Although immunological changes point to adaptive immune response, whether humoral or cellular response dominates during disease course is unknown. The study aim was to evaluate humoral immune response in ALS patients during disease progression. Circulating immune complexes (CICs), IgG, and IgM in sera of ALS patients and matching controls were evaluated

Islam A. Saleh; Theresa Zesiewicz; Yong Xie; Kelly L. Sullivan; Amber M. Miller; Nicole Kuzmin-Nichols; Paul R. Sanberg; Svitlana Garbuzova-Davis

2009-01-01

3

Disease progression of human SOD1 (G93A) transgenic ALS model rats.  

PubMed

The recent development of a rat model of amyotrophic lateral sclerosis (ALS) in which the rats harbor a mutated human SOD1 (G93A) gene has greatly expanded the range of potential experiments, because the rats' large size permits biochemical analyses and therapeutic trials, such as the intrathecal injection of new drugs and stem cell transplantation. The precise nature of this disease model remains unclear. We described three disease phenotypes: the forelimb-, hindlimb-, and general-types. We also established a simple, non-invasive, and objective evaluation system using the body weight, inclined plane test, cage activity, automated motion analysis system (SCANET), and righting reflex. Moreover, we created a novel scale, the Motor score, which can be used with any phenotype and does not require special apparatuses. With these methods, we uniformly and quantitatively assessed the onset, progression, and disease duration, and clearly presented the variable clinical course of this model; disease progression after the onset was more aggressive in the forelimb-type than in the hindlimb-type. More importantly, the disease stages defined by our evaluation system correlated well with the loss of spinal motor neurons. In particular, the onset of muscle weakness coincided with the loss of approximately 50% of spinal motor neurons. This study should provide a valuable tool for future experiments to test potential ALS therapies. PMID:16342121

Matsumoto, Arifumi; Okada, Yohei; Nakamichi, Masanori; Nakamura, Masaya; Toyama, Yoshiaki; Sobue, Gen; Nagai, Makiko; Aoki, Masashi; Itoyama, Yasuto; Okano, Hideyuki

2006-01-01

4

Progression of Parkinson's Disease  

MedlinePLUS

... Order Free Materials Today Progression The progression of Parkinson’s disease varies among different individuals. Parkinson's is chronic and ... assess the progression of Parkinson's is the United Parkinson’s Disease Rating Scale (UPDRS). It is more comprehensive than ...

5

Rapid disease progression correlates with instability of mutant SOD1 in familial ALS.  

PubMed

Studies on the clinical course of familial ALS suggest that the duration of illness is relatively consistent for each mutation but variable among the different mutations. The authors analyzed the relative amount of mutant compared with normal SOD1 protein in the erythrocytes from 29 patients with ALS with 22 different mutations. Turnover of mutant SOD1 correlated with a shorter disease survival time. PMID:16291929

Sato, T; Nakanishi, T; Yamamoto, Y; Andersen, P M; Ogawa, Y; Fukada, K; Zhou, Z; Aoike, F; Sugai, F; Nagano, S; Hirata, S; Ogawa, M; Nakano, R; Ohi, T; Kato, T; Nakagawa, M; Hamasaki, T; Shimizu, A; Sakoda, S

2005-12-27

6

From scleredema to AL amyloidosis: disease progression or coincidence? Review of the literature  

Microsoft Academic Search

Scleredema (also called scleredema of Buschke) is a fibromucinous connective tissue disorder of unknown cause that belongs to a group of scleroderma-like disorders. We report the case of a 64-year-old lady with long-standing scleredema, associated with a paraprotein, and progressing to multiple myeloma and AL amyloidosis. The relationship of scleredema with paraprotein and multiple myeloma is well established, but only

Magdalena Dziadzio; Constantinos P. Anastassiades; Philip N. Hawkins; Michael Potter; Armando Gabrielli; Geraldine M. Brough; Carol M. Black; Christopher P. Denton

2006-01-01

7

Progression of Liver Disease  

MedlinePLUS

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

8

The effect of epigallocatechin gallate on suppressing disease progression of ALS model mice  

Microsoft Academic Search

Epigallocatechin gallate (EGCG) is a constituent of green tea, and increasing evidence suggests that EGCG has neuroprotective effects on oxidative stress-injured neuronal cells, especially motoneurons. Although the neuroprotective effects of EGCG have been demonstrated in Parkinson's and Alzheimer's diseases and ischemic stroke models, there has been no report on the effect of EGCG on an in vivo model of amyotrophic

Seong-Ho Koh; Sang Mok Lee; Hyun Young Kim; Kyu-Yong Lee; Young Joo Lee; Hee-Tae Kim; Juhan Kim; Myung-Ho Kim; Myung Sil Hwang; Chiwon Song; Ki-Wha Yang; Kwang Woo Lee; Seung Hyun Kim; Ok-Hee Kim

2006-01-01

9

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

PubMed Central

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

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

2012-01-01

10

Quantifying Disease Progression in Amyotrophic Lateral Sclerosis  

PubMed Central

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

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

2014-01-01

11

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

PubMed

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

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

2012-01-01

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. PMID:22830016

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

2012-01-01

13

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

PubMed Central

Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron degenerative disease. Given that oxidative stress and resulting chronic neuronal inflammation are thought to be central pathogenic, anti-oxidative agents and modulators of neuronal inflammation could be potential therapies for ALS. We report here that the novel small molecular compound, 2-[mesityl(methyl)amino]-N-[4-(pyridin-2-yl)-1H-imidazol-2-yl] acetamide trihydrochloride (WN1316) selectively suppresses oxidative stress-induced cell death and neuronal inflammation in the late-stage ALS mice. WN1316 has high blood-brain-barrier permeability and water solubility, and boosts both neuronal apoptosis inhibitory protein (NAIP) and NF-E2-related factor 2 (Nrf2) which governed glutathione (GSH)-related anti-oxidation pathway protecting motor neurons against oxidative injuries. Post-onset oral administration of low dose (1–100 µg/kg/day) WN1316 in ALS(SOD1H46R) and ALS(SOD1G93A) mice resulted in sustained improved motor function and post onset survival rate. Immunohistochemical analysis revealed less DNA oxidative damage and motor neuronal inflammation as well as repression of both microgliosis and astrocytosis, concomitant down regulation of interleukin-1? and inducible nitric oxide synthase, and preservation of the motoneurons in anterior horn of lumbar spinal cord and skeletal muscle (quadriceps femoris). Thus, WN1316 would be a novel therapeutic agent for ALS. PMID:24498180

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

2014-01-01

14

ALS UPDATE: SIGNS OF PROGRESS, REASONS FOR HOPE  

Microsoft Academic Search

Amyotrophic lateral sclerosis (ALS) was first described 134 years ago. While still incurable, significant progress has been made in understanding the pathophysi- ology of the disease and its management. For example, it is now clear that ALS is not a single disease; there are familial and sporadic subtypes. ALS is not specific for motor neurons; other cell types are involved

Richard S. Bedlack; Swati Aggarwal

2009-01-01

15

Predicting progression of Alzheimer's disease  

PubMed Central

Introduction Clinicians need to predict prognosis of Alzheimer's disease (AD), and researchers need models of progression to develop biomarkers and clinical trials designs. We tested a calculated initial progression rate to see whether it predicted performance on cognition, function and behavior over time, and to see whether it predicted survival. Methods We used standardized approaches to assess baseline characteristics and to estimate disease duration, and calculated the initial (pre-progression) rate in 597 AD patients followed for up to 15 years. We designated slow, intermediate and rapidly progressing groups. Using mixed effects regression analysis, we examined the predictive value of a pre-progression group for longitudinal performance on standardized measures. We used Cox survival analysis to compare survival time by progression group. Results Patients in the slow and intermediate groups maintained better performance on the cognitive (ADAScog and VSAT), global (CDR-SB) and complex activities of daily living measures (IADL) (P values < 0.001 slow versus fast; P values < 0.003 to 0.03 intermediate versus fast). Interaction terms indicated that slopes of ADAScog and PSMS change for the slow group were smaller than for the fast group, and that rates of change on the ADAScog were also slower for the intermediate group, but that CDR-SB rates increased in this group relative to the fast group. Slow progressors survived longer than fast progressors (P = 0.024). Conclusions A simple, calculated progression rate at the initial visit gives reliable information regarding performance over time on cognition, global performance and activities of daily living. The slowest progression group also survives longer. This baseline measure should be considered in the design of long duration Alzheimer's disease clinical trials. PMID:20178566

2010-01-01

16

Lou Gehrig's Disease (ALS)  

MedlinePLUS

... ALS. The official name comes from these Greek words: "a" for without "myo" for muscle "trophic" for nourishment "lateral" for side (of the spinal cord) "sclerosis" for hardening or scarring So, amyotrophic means that the muscles have lost their nourishment. When this happens, they become smaller ...

17

Unsupervised Learning of Disease Progression Models IBM Research  

E-print Network

(DPM) [11], the modeling of the progression of a target disease with computational meth- ods that targets a specific domain. For ex- ample, Jackson et al. [9] presented a general Hidden Markov Model for simultaneously estimating the transition rates and the probabilities of stage misclassification. Ito et al. [8

18

Amyotrophic Lateral Sclerosis: A Focus on Disease Progression  

PubMed Central

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

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

2014-01-01

19

Amyotrophic lateral sclerosis: a focus on disease progression.  

PubMed

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

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

2014-01-01

20

Neurobiology of Disease Progressive Motor Neuronopathy: A Critical Role of the  

E-print Network

.WeconcludethatmotoraxonscriticallydependonaxonaltubulinroutingfromtheGolgiapparatus,aprocessthatinvolvesTBCEand possibly other tubulin chaperones. Key words: motor neuron disease; ALS; axon degeneration; tubulin ALS1, denervation of endplates appears at presymptomatic stage, loss of ventral root axons at disease motor neuron disease characterized by axonal dying back (Schmalbruch et al., 1991) and progressive loss

Boyer, Edmond

21

Clinical pharmacology = disease progression + drug action.  

PubMed

Clinical pharmacology is concerned with understanding how to use medicines to treat disease. Pharmacokinetics and pharmacodynamics have provided powerful methodologies for describing the time course of concentration and effect in individuals and in populations. This population approach may also be applied to describing the progression of disease and the action of drugs to change disease progress. Quantitative models for symptomatic and disease-modifying effects of drugs are valuable not only for describing drugs and diseases but also for identifying criteria to distinguish between types of drug actions, with implications for regulatory decisions and long-term patient care. PMID:23713816

Holford, Nick

2015-01-01

22

Complement activation in progressive renal disease  

PubMed Central

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

Fearn, Amy; Sheerin, Neil Stephen

2015-01-01

23

Progressive scoliosis in central core disease  

Microsoft Academic Search

Central core disease (CCD) is a rare congenital myopathy with autosomal dominant inheritance. Here, we report on two cases of progressive scoliosis in CCD, pointing out the value of a muscle biopsy to establish the correct diagnosis. The first case involves a 13-year-old boy with severe progressive scoliosis and joint contractures. The patient was initially diagnosed with arthropgryposis multiplex congenita.

Kirsten D. Mertz; Bernhard Jost; Markus Glatzel; Kan Min

2005-01-01

24

[Clinical evaluation of Parkinson's disease progression.  

PubMed

Objective. We conducted a prospective study on the dynamics of clinical progression of motor and non-motor impairments in PD from 2009 to 2012. Material and methods. We examined 136 patients with Parkinson's disease, 77 men and 59 women, mean age 63.2±10.4 years, disease duration 7.5±3.8 years, including 50 (36.8%) patients at the mild stage of disease, 67 (49.3%) patients at the moderate stage and 19 (13.9%) patients at the advanced stage. Evaluation of progression was carried out annually using part III UPDRS: an annual increase of 9 scores or more indicated the fast progression; from 5 to 8 scores - moderate progression; up to 4 scores - slow progression. Results. Eighty-five patients (62.5%) had slow progression, 39 patients (27.1%) had moderate progression and 12 patients (10.4%) had fast progression. Conclusion. Older age, severity of axial movement disorders, cognitive impairment and motor fluctuations, orthostatic hypotension and psychotic disorders (hallucinations) predicted the fast progression. PMID:25042501

Smolentseva, I G; Chupina, L P; Amosova, N A; Krivonos, O V

2014-01-01

25

Analysis of factors that modify susceptibility and rate of progression in amyotrophic lateral sclerosis (ALS).  

PubMed

We conducted case-control and prospective longitudinal studies to examine risk factors and predictors of disease progression for ALS. Ninety-five subjects with ALS and 106 healthy control subjects were enrolled. All subjects completed a risk factor questionnaire at enrollment. The ALS subjects were prospectively followed for one year to define factors that influence the rate of disease progression, measured by rate of change in percent predicted forced vital capacity (%FVC) and the ALS functional rating scale (ALSFRS) score. The association of each potential risk factor with ALS was determined using univariate logistic regression. A random slope model was used to determine the association of each risk factor with disease progression. The demographic characteristics of ALS subjects and controls at enrollment did not differ. Significant risk factors for ALS included reported exposure to lead (p = 0.02) and pesticides (p = 0.03). Disease progression was faster in the ALS subjects having bulbar onset and a shorter time period between onset of symptoms and diagnosis. Pertinent variables not associated with either causation or progression of ALS included physical activity, cigarette smoking and a history of physical trauma or other clinical disorders. PMID:16963407

Qureshi, M Muddasir; Hayden, Douglas; Urbinelli, Leo; Ferrante, Kimberly; Newhall, Kristyn; Myers, Daniela; Hilgenberg, Sarah; Smart, Ryan; Brown, Robert H; Cudkowicz, Merit E

2006-09-01

26

[Lafora's disease presenting with progressive myoclonus epilepsy].  

PubMed

Lafora's disease is a progressive myoclonus epilepsy and must be evocated if myoclonus, occipital seizures and progressive cognitive impairment are present. We report the case of a 14-year-old boy who suffered from several occipital seizures and two generalised seizures. The diagnosis of Lafora's disease was made six years after these inaugural symptoms because of occurrence of myoclonus, aggravation of the epilepsy with paharmacoresistance and psychic deterioration. Axila sweat gland duct biopsy was performed to conclude to the disease. A mutation was found on the gene EPM2A. Lafora's disease is a genetic autosomal-recessive pathology. Two genes have been recently identified. They code for two proteins, malin and laforin, involved in glycogen metabolism in the cellular endoplasmic reticulum. Mutations of these genes are responsible for intracytoplasmic polyglucosan inclusions called Lafora bodies and pathognomonic of the disease. PMID:18033035

Béjot, Y; Lemesle-Martin, M; Contégal, F; Graule-Petot, A; Thauvin, C; Aubriot-Lorton, M-H; Moreau, T; Giroud, M

2007-10-01

27

Longitudinal alignment of disease progression in fibrosing interstitial lung disease.  

PubMed

Generating disease progression models from longitudinal medical imaging data is a challenging task due to the varying and often unknown state and speed of disease progression at the time of data acquisition, the limited number of scans and varying scanning intervals. We propose a method for temporally aligning imaging data from multiple patients driven by disease appearance. It aligns follow- up series of different patients in time, and creates a cross-sectional spatio-temporal disease pattern distribution model. Similarities in the disease distribution guide an optimization process, regularized by temporal rigidity and disease volume terms. We demonstrate the benefit of longitudinal alignment by classifying instances of different fibrosing interstitial lung diseases. Classification results (AUC) of Usual Interstitial Pneumonia (UIP) versus non-UIP improve from AUC = 0.71 to 0.78 following alignment, classification of UIP vs. Extrinsic Allergic Alveolitis (EAA) improves from 0.78 to 0.88. PMID:25485367

Vogl, Wolf-Dieter; Prosch, Helmut; Müller-Mang, Christina; Schmidt-Erfurth, Ursula; Langs, Georg

2014-01-01

28

Proteasome inhibitors in progressive renal diseases.  

PubMed

Proteasome (PS) is a sophisticated protein degradation machinery comprising a 20S proteolytic core particle provided with caspase-like, trypsin-like and chymotrypsin-like activities on ubiquitinilated proteins. The products of this selective, complex, controlled and strictly coordinated system play a crucial role in cell cycle progression and apoptosis; activation of transcription factors, cytokines and chemokines; degradation and generation of MHC class I-presented peptides. PS has recently emerged as a promising drug target in cancer therapy, and bortezomib has been approved for refractory multiple myeloma. PS proteolysis is crucial for the degradation of the inhibitory protein IkB of nuclear factor kB (NF-kB), and hence, an interesting field of research has been developed on possible benefits of drugs with anti-PS activity in disease conditions with hyper-expression of NF-kB. PS inhibitors are being adopted in pilot studies in antibody-mediated renal rejection and in AL amyloidosis, with increasing scientific interest in possible applications in lupus, IgA nephropathy, idiopathic nephrotic syndrome and renal fibrosis. The most often used PS inhibitor, bortezomib, has a severe peripheral neurotoxicity, and the search for effective and less toxic PS-targeted drugs is a challenging area also in nephrology. PMID:24493867

Coppo, Rosanna

2014-02-01

29

The Axis of Progression of Disease  

PubMed Central

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

Tartakoff, Alan M; Wu, Di

2014-01-01

30

Genetic determinants of disease progression in Alzheimer’s disease  

PubMed Central

There is a strong genetic basis for late-onset of Alzheimer’s disease (LOAD); thus far 22 genes/loci have been identified that affect the risk of LOAD. However, the relationships among the genetic variations at these loci and clinical progression of the disease have not been fully explored. In the present study, we examined the relationships of 22 known LOAD genes to the progression of AD in 680 AD patients recruited from the University of Pittsburgh Alzheimer’s Disease Research Center. Patients were classified as “rapid progressors” if the MMSE changed ?3 points in 12 months and “slow progressors” if the MMSE changed ?2 points. We also performed a genome-wide association study in this cohort in an effort to identify new loci for AD progression. Association analysis between SNPs and the progression status of the AD cases was performed using logistic regression model controlled for age, gender, dementia medication use, psychosis, and hypertension. While no significant association was observed with either APOE*4 (p=0.94) or APOE*2 (p=0.33) with AD progression, we found multiple nominally significant associations (p<0.05) either within or adjacent to seven known LOAD genes (INPP5D, MEF2C, TREM2, EPHA1, PTK2B, FERMT2 and CASS4) that harbor both risk and protective SNPs. Genome-wide association analyses identified four suggestive loci (PAX3, CCRN4L, PIGQ and ADAM19) at p<1E-05. Our data suggest that short-term clinical disease progression in AD has genetic basis. Better understanding of these genetic factors could help to improve clinical trial design and potentially affect the development of disease modifying therapies. PMID:25114068

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

2014-01-01

31

Genetic determinants of disease progression in Alzheimer's disease.  

PubMed

There is a strong genetic basis for late-onset Alzheimer's disease (LOAD); thus far 22 genes/loci have been identified that affect the risk of LOAD. However, the relationships among the genetic variations at these loci and clinical progression of the disease have not been fully explored. In the present study, we examined the relationships of 22 known LOAD genes to the progression of AD in 680 AD patients recruited from the University of Pittsburgh Alzheimer's Disease Research Center. Patients were classified as "rapid progressors" if the Mini-Mental State Examination (MMSE) changed ?3 points in 12 months and "slow progressors" if the MMSE changed ?2 points. We also performed a genome-wide association study in this cohort in an effort to identify new loci for AD progression. Association analysis between single nucleotide polymorphisms (SNPs) and the progression status of the AD cases was performed using logistic regression model controlled for age, gender, dementia medication use, psychosis, and hypertension. While no significant association was observed with either APOE*4 (p = 0.94) or APOE*2 (p = 0.33) with AD progression, we found multiple nominally significant associations (p < 0.05) either within or adjacent to seven known LOAD genes (INPP5D, MEF2C, TREM2, EPHA1, PTK2B, FERMT2, and CASS4) that harbor both risk and protective SNPs. Genome-wide association analyses identified four suggestive loci (PAX3, CCRN4L, PIGQ, and ADAM19) at p < 1E-05. Our data suggest that short-term clinical disease progression in AD has a genetic basis. Better understanding of these genetic factors could help to improve clinical trial design and potentially affect the development of disease modifying therapies. PMID:25114068

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

2015-01-01

32

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

Microsoft Academic Search

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

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

2006-01-01

33

Slowing progression of chronic kidney disease  

PubMed Central

Early identification of chronic kidney disease (CKD) provides an opportunity to implement therapies to improve kidney function and slow progression. The goal of this article is to review established and developing clinical therapies directed at slowing progression. The importance of controlling blood pressure will be discussed along with the target blood pressure that should be achieved in CKD patients. Therapy directed at inhibiting the renin–angiotensin–aldosterone system remains the mainstay of treatment with single-agent inhibition of this system being as good as dual blockade with fewer adverse effects. Other therapies that may be used include correction of metabolic acidosis, dietary protein restriction, and new models for delivering care to patients with CKD. Emerging therapies targeting endothelin, uric acid, kidney fibrosis, and oxidant stress hold promise for the future. PMID:25019022

Drawz, Paul E; Rosenberg, Mark E

2013-01-01

34

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

PubMed Central

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

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

2013-01-01

35

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

PubMed

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

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

2013-01-01

36

Recent progress in hemorrhagic moyamoya disease.  

PubMed

Moyamoya disease (MMD) is a chronic progressive cerebrovascular disease, which can be divided into three types: ischemic, hemorrhagic, and asymptomatic. Hemorrhagic MMD has attracted considerable attention due to its distinctive imaging features and the controversy over the treatment. This report presents a comprehensive review of the literature on hemorrhagic MMD, focusing on the epidemiological characteristics, etiology and pathogenesis, imaging features, predictors of hemorrhage, and treatment options and their efficacy of hemorrhagic MMD. Hemorrhagic MMD mainly occurs in adult patients in Asian countries, and many factors may contribute to the etiology and development of this disease. Hemorrhagic MMD has two major imaging features: the dilatation and abnormal branching of anterior choroidal artery or posterior communicating artery, and multiple microbleeds, which may predict subsequent hemorrhage. The treatment for hemorrhagic MMD is not standardized, and large sample prospective randomized clinical trials may help to determine which method is better. In hemorrhagic MMD patients, more attention should be paid to cognitive function and quality of life, and these assessments should be included in the evaluation of effectiveness of treatment modalities. PMID:25365664

Wan, Ming; Duan, Lian

2014-11-01

37

Progress and promise in the management of chronic kidney disease  

Microsoft Academic Search

1 for the management of chronic kidney disease provide clear guidance for the co- operative care of patients with chronic kidney disease by all health care providers throughout the spectrum of disease. There are specific stages and recommendations for interven- tions to slow disease progression, prevent complications, and reduce morbidity and mortality. This is a major para- digm shift on

Garabed Eknoyan

2008-01-01

38

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

E-print Network

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

Cai, Long

39

Multifactorial assessment of predictors for prevention of periodontal disease progression  

Microsoft Academic Search

Univariate approaches have identified single factors influencing periodontal disease progression. The aim of this explorative approach was to assess the influence of various predictive factors responsible for the prevention of periodontal disease progression in the same patient sample. Patients with untreated chronic periodontitis underwent subgingival debridement alone or in combination with adjunctive antimicrobial therapy (systemic amoxicillin and metronidazole\\/7 days plus supragingival

Benjamin Ehmke; Thomas Beikler; Imme Haubitz; Helge Karch; ThomasFrank Flemmig

2003-01-01

40

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

PubMed Central

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

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

2012-01-01

41

Prognosis and clinical varieties of ALS disease  

Microsoft Academic Search

210 cases of ALS disease in the period 1955–1979 are considered. Different parameters such as sex, age, duration and clinical course have been correlated with four clinical types: conventional, pseudopolyneuritic, pyramidal and bulbar. The age distribution shows a peak in the fifth decade of life. The sex ratio is 2.08?1. Considering together all the clinical types, the mean duration of

P. Mortara; D. Bardelli; M. Leone; D. Schiffer

1981-01-01

42

Metabolic acidosis and the progression of chronic kidney disease  

PubMed Central

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

2014-01-01

43

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.

44

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

E-print Network

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

Paris-Sud XI, Université de

45

Asymmetric Dimethylarginine and Progression of Chronic Kidney Disease: The Mild to Moderate Kidney Disease Study  

Microsoft Academic Search

Reduced bioavailability of nitric oxide (NO) is thought to play an important role in progression of renal damage. The hypothesis that the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) is involved in progression of kidney disease was tested. Plasma ADMA concentrations and other putative progression factors were assessed in 227 relatively young patients (45.7 12.6 yr) with nondiabetic kidney diseases

Danilo Fliser; Florian Kronenberg; Jan T. Kielstein; Christian Morath; Stefanie M. Bode-Boger; Hermann Haller; Eberhard Ritz

2005-01-01

46

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

E-print Network

only in patients with Alzheimer's disease. The subunit of the amyloid fibrils found in patients that accumulation of amyloid- is the first event in the pathogenesis of Alzheimer's disease and this has led© 2006 Nature Publishing Group Alzheimer's disease is characterized by progressive memory deficits

Cai, Long

47

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

PubMed

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

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

2014-09-16

48

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

E-print Network

??Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease symptomatically characterized by progressive, fatal paralysis resulting from the degeneration of the upper and lower motor… (more)

Arnold, Eveline Sun

2012-01-01

49

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

50

Biomarkers of inflammation and progression of chronic kidney disease  

Microsoft Academic Search

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

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

2005-01-01

51

GLOBAL DYNAMICS OF A STAGED PROGRESSION MODEL FOR INFECTIOUS DISEASES  

Microsoft Academic Search

We analyze a mathematical model for infectious diseases that progress through distinct stages within infected hosts. An example of such a disease is AIDS, which results from HIV infection. For a general n-stage stage-progression (SP) model with bilinear incidences, we prove that the global dynamics are completely determined by the basic reproduction number R0: If R0 • 1; then the

Hongbin Guo; Michael Y. Li

2006-01-01

52

Markers of Immune Cell Activation and Disease Progression  

Microsoft Academic Search

\\u000a Immune cell activation is a feature of infection with the human immunodeficiency virus (HIV). Here we report our studies on\\u000a a cohort of over 400 patients with HIV infection studied cross-sectionally and longitudinally to examine the relationship\\u000a between markers of immune cell activation and disease progression. To examine disease progression, 340 patients with HIV infection\\u000a but without AIDS were followed

M. Peakman; M. Mahalingam; A. Pozniak; T. J. McManus; A. N. Phillips; D. Vergani

53

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.

54

Progression of pulmonary cystic disease during ECMO  

Microsoft Academic Search

Only one of the 65 ECMO patients treated at Thomas Jefferson University Hospital to date has shown progression of pulmonary parenchymal cystic change on serial portable chest radiographs while on ECMO. The radiographic and clinical findings of this unique case are presented.

G. W. Gross; J. Cullen; H. J. Desai

1990-01-01

55

Accurate Telemonitoring of Parkinson's Disease Progression by Noninvasive Speech Tests  

Microsoft Academic Search

Tracking Parkinson's disease (PD) symptom progression often uses the unified Parkinson's disease rating scale (UPDRS) that requires the patient's presence in clinic, and time-consuming physical examinations by trained medical staff. Thus, symptom monitoring is costly and logistically inconvenient for patient and clinical staff alike, also hindering recruitment for future large-scale clinical trials. Here, for the first time, we demonstrate rapid,

Athanasios Tsanas; Max A. Little; Patrick E. McSharry; Lorraine O. Ramig

2010-01-01

56

Progress and challenges in controlling neglected zoonotic diseases.  

PubMed

Suzanne Jarvis reports from the Fourth International Meeting on the Control of Neglected Zoonotic Diseases, hosted by the World Health Organization in Geneva in November. The meeting looked at progress that has been made in controlling these diseases and at what the next steps should be for further control. PMID:25614544

2015-01-24

57

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

PubMed

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

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

2015-01-01

58

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

Microsoft Academic Search

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

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

1997-01-01

59

Markers predicting progression of human immunodeficiency virus-related disease.  

PubMed Central

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

Tsoukas, C M; Bernard, N F

1994-01-01

60

[Research progress with renalase and cardiovascular disease].  

PubMed

Renalase, a novel amine oxidase, is secreted by kidney. It regulates heart function and blood pressure by degrading catecholamines. Hormones secreted by the kidney are associated with cardiovascular disease. Renalase, as a new biomarker of heart and kidney functional correlation, can lower blood pressure, protect ischemic heart muscle, improve heart function and degrade catecholamine. PMID:22659670

Guo, Yunzhong; Jiang, Weihong

2012-05-01

61

Drug Development for Alzheimer's Disease: Recent Progress  

PubMed Central

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

Ji, Wonjin

2010-01-01

62

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

63

Patterns of subregional mesiotemporal disease progression in temporal lobe epilepsy  

PubMed Central

Objective: Evidence for disease progression in the mesiotemporal lobe is mainly derived from global volumetry of the hippocampus. In this study, we tracked progressive structural changes in the hippocampus, amygdala, and entorhinal cortex in drug-resistant temporal lobe epilepsy at a subregional level. Furthermore, we evaluated the relation between disease progression and surgical outcome. Methods: We combined cross-sectional modeling of disease duration in a large cohort of patients (n = 134) and longitudinal analysis in a subset that delayed surgery (n = 31). To track subregional pathology, we applied surface-shape analysis techniques on manual mesiotemporal labels. Results: Longitudinal and cross-sectional designs showed consistent patterns of progressive atrophy in hippocampal CA1, anterolateral entorhinal, and the amygdalar laterobasal group bilaterally. These regions also exhibited more marked age-related volume loss in patients compared with controls. We found a faster progression of hippocampal atrophy in patients with a seizure frequency ?6 per month. High rates of contralateral entorhinal cortex atrophy predicted postsurgical seizure relapse. Conclusion: We observed progressive atrophy in hippocampal, amygdalar, and entorhinal subregions that frequently display neuronal loss on histology. The bilateral character of cumulative atrophy highlights the importance of early surgery. In patients who nevertheless delay this procedure, serial scanning may provide markers of surgical outcome. PMID:24142475

Bernhardt, Boris C.; Kim, Hosung

2013-01-01

64

State of progress in treating cystic fibrosis respiratory disease  

PubMed Central

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

2012-01-01

65

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. PMID:21625445

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

2011-01-01

66

The pedunculopontine nucleus in Parkinson's disease, progressive supranuclear palsy and Alzheimer's disease  

Microsoft Academic Search

Significant loss of neurons in the pedunculopontine nucleus pars compacta (PPNc), a putative cholinergic nucleus involved in modulating somatic motor activities, has been demonstrated in progressive supranuclear palsy (PSP) and Parkinson's disease but not in Alzheimer's disease. A morphometric study of this nucleus was performed in two cases of PSP and in a cohort of cases of Parkinson's disease, Alzheimer's

K Jellinger

1988-01-01

67

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

68

A Systematic Review of Biomarkers for Disease Progression in Alzheimer's Disease  

PubMed Central

Background Using surrogate biomarkers for disease progression as endpoints in neuroprotective clinical trials may help differentiate symptomatic effects of potential neuroprotective agents from true slowing of the neurodegenerative process. A systematic review was undertaken to determine what biomarkers for disease progression in Alzheimer's disease exist and how well they perform. Methods MEDLINE and Embase (1950–2011) were searched using five search strategies. Abstracts were assessed to identify papers meriting review in full. Studies of participants with probable Alzheimer's disease diagnosed by formal criteria were included. We made no restriction on age, disease duration, or drug treatment. We only included studies with a longitudinal design, in which the putative biomarker and clinical measure were both measured at least twice, as this is the only appropriate study design to use when developing a disease progression biomarker. We included studies which attempted to draw associations between the changes over time in the biomarker used to investigate disease progression and a clinical measure of disease progression. Results Fifty-nine studies were finally included. The commonest biomarker modality examined was brain MRI (17/59, 29% of included studies). Median follow-up in included studies was only 1.0 (IQR 0.8–1.7) year and most studies only measured the putative biomarker and clinical measure twice. Included studies were generally of poor quality with small numbers of participants (median 31 (IQR 17 to 64)), applied excessively restrictive study entry criteria, had flawed methodologies and conducted overly simplistic statistical analyses without adjusting for confounding factors. Conclusions We found insufficient evidence to recommend the use of any biomarker as an outcome measure for disease progression in Alzheimer's disease trials. However, further investigation into the efficacy of using MRI measurements of ventricular volume and whole brain volume appeared to be merited. A provisional ‘roadmap’ to improve the quality of future disease progression biomarker studies is presented. PMID:24558437

McGhee, David J. M.; Ritchie, Craig W.; Thompson, Paul A.; Wright, David E.; Zajicek, John P.; Counsell, Carl E.

2014-01-01

69

Sudden Oak Death Disease Progression in Oaks and Tanoaks1  

E-print Network

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

Standiford, Richard B.

70

Rosuvastatin-Induced Arrest in Progression of Renal Disease  

Microsoft Academic Search

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

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

2004-01-01

71

Influence of Spontaneous Platelet Aggregation on Progression of Glomerular Disease  

Microsoft Academic Search

Platelet secretion products may play an important role in the pathogenesis and progression of the kidney disease. Amongst the parameters describing platelet hyperactivity the measurement of spontaneous platelet aggregation (SPA) seems particularly useful. In this study SPA as well as mean platelet volume (MPV), modal platelet volume (PLT Mode) and platelet count (PLT) were investigated in 60 patients with biopsy

Z. Zdrojewski; S. Lizakowski; A. Raszeja-Specht; A. Skibowska; B. Rutkowski

2002-01-01

72

Modeling Disease Progression via Fused Sparse Group Lasso  

E-print Network

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

Ye, Jieping

73

Progressive lymphangiomatosis and Gorham's disease: case report and clinical implications.  

PubMed

Lymphangiomatosis is a rare proliferative disorder of the lymphatic system. The etiology is unknown, rendering it difficult to manage. This case report of lymphangiomatosis with features of Gorham's disease reveals the progressive and unexpected nature of the condition. It highlights the need for further research into the pathophysiology and management of lymphangiomatosis as current treatment options are limited. PMID:22196286

Gordon, K D; Mortimer, P S

2011-01-01

74

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. PMID:21712727

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

2011-01-01

75

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

PubMed

Optimized magnetic resonance imaging (MRI)-based biomarkers of Alzheimer's disease (AD) may allow earlier detection and refined prediction of the disease. In addition, they could serve as valuable tools when designing therapeutic studies of individuals at risk of AD. In this study, we combine (1) a novel method for grading medial temporal lobe structures with (2) robust cortical thickness measurements to predict AD among subjects with mild cognitive impairment (MCI) from a single T1-weighted MRI scan. Using AD and cognitively normal individuals, we generate a set of features potentially discriminating between MCI subjects who convert to AD and those who remain stable over a period of 3 years. Using mutual information-based feature selection, we identify 5 key features optimizing the classification of MCI converters. These features are the left and right hippocampi gradings and cortical thicknesses of the left precuneus, left superior temporal sulcus, and right anterior part of the parahippocampal gyrus. We show that these features are highly stable in cross-validation and enable a prediction accuracy of 72% using a simple linear discriminant classifier, the highest prediction accuracy obtained on the baseline Alzheimer's Disease Neuroimaging Initiative first phase cohort to date. The proposed structural features are consistent with Braak stages and previously reported atrophic patterns in AD and are easy to transfer to new cohorts and to clinical practice. PMID:25260851

Eskildsen, Simon F; Coupé, Pierrick; Fonov, Vladimir S; Pruessner, Jens C; Collins, D Louis

2015-01-01

76

Avoiding permanent atrial fibrillation: treatment approaches to prevent disease progression  

PubMed Central

Atrial fibrillation (AF) is the most common sustained arrhythmia and a major global public health problem due to its associated morbidity, including stroke and heart failure, diminished quality of life, and increased mortality. AF often presents initially in a paroxysmal form and may progress to a more sustained form over time. Evidence from randomized controlled trials suggests that there may be no mortality benefit to using a rhythm control approach in comparison with rate control of AF. Nevertheless, sustained forms of AF may be associated with increased symptoms and cardiovascular morbidity, and consequently they remain an additional target for therapy. The present review evaluates the clinical correlates of arrhythmia progression and risk stratification techniques available to assess probability of AF progression. Further, currently available management options for arrhythmia control in AF are evaluated and their therapeutic effect and efficacy on disease progression are explored. PMID:24379678

Shukla, Ashish; Curtis, Anne B

2014-01-01

77

Dendritic cells in progressive renal disease: some answers, many questions.  

PubMed

Renal disease results from a variety of insults, but whatever its genesis, ongoing inflammation will drive progressive fibrotic disease. Dendritic cells link innate and adaptive immunity by presenting antigens, but they act also in an antigen-independent manner. While systemic dendritic cells (DCs) establish nephritogenic adaptive immunity, DCs are also present in the kidney. The tubulointerstitium is endowed with a network of mononuclear phagocytes, many having dendritic cell characteristics. While the roles of renal DCs are complex, recent evidence demonstrates that in adaptive immune responses affecting the kidney, DCs in the cortical interstitium express the chemokine receptor CX3CR1, are CX3CR1 dependent and are important in ongoing antigen recognition by effector CD4+ T cells, leading to progressive disease. Medullary DCs do not share this potent antigen-presenting function and CX3CR1 dependence. Though macrophages have a pathogenic role in antigen-independent renal fibrosis, whether interstitial DCs have any role is not clear. The participation of local and systemic DCs in progressive renal disease varies according to their involvement as antigen-presenting or local innate cells, the nature of the pathogenic process, and the involvement of the glomerulus, the cortical tubulointerstitium and the medulla in disease. PMID:24739483

Kitching, A Richard

2014-12-01

78

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

PubMed Central

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

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

2015-01-01

79

Rapidly progressive dementias and the treatment of human prion diseases  

PubMed Central

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

Lyketsos, Constantine G

2012-01-01

80

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. PMID:21607144

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

2010-01-01

81

Neuroprotective therapeutics for Alzheimer's disease: progress and prospects.  

PubMed

The number of people with Alzheimer's disease (AD) has never been greater and is set to increase substantially in the decades ahead as the proportion of the population aged 65 years or more rises sharply. There is therefore an urgent need for safe and effective pharmacotherapy to help combat the corresponding and substantial increase in disease burden. Increased understanding of disease aetiology and pathophysiology, particularly in relation to the loss of vulnerable neurons and the formation of plaques and tangles, has increased hope for medications that can slow (or perhaps even halt) the course of the disease. In this article I review the neurobiological basis of AD, current progress towards neuroprotective therapeutics, and prospects for the future. PMID:21256602

Palmer, Alan M

2011-03-01

82

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. PMID:22435073

Stenager, Egon

2012-01-01

83

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

PubMed

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

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

2014-11-01

84

Risk Factors for Progression of Chronic Kidney Disease  

PubMed Central

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

Staples, Amy; Wong, Craig

2010-01-01

85

The Effects of Age on Rate of Progression of Alzheimer Disease and Dementia With Associated Cerebrovascular Disease  

Microsoft Academic Search

Background: Relatively little is known about how ce- rebrovascular disease affects progression of dementia. Pre- vious studies have found no differences in progression of Alzheimer disease and vascular dementia, but these studies have not specifically examined age effects. Objective: To test whether the rate of cognitive de- cline is different in Alzheimer disease compared with dementia with associated cerebrovascular disease

Dan Mungas; Bruce R. Reed; William G. Ellis; William J. Jagust

2001-01-01

86

Progress in molecular genetics of heritable skin diseases: the paradigms of epidermolysis bullosa and pseudoxanthoma elasticum.  

PubMed

The 42nd Annual Symposium on the Biology of the Skin, entitled "The Genetics of Skin Disease", was held in Snowmass Village, Colorado, in July 1993. That meeting presented the opportunity to discuss how modern approaches to molecular genetics and molecular biology could be applied to understanding the mechanisms of skin diseases. The published proceedings of this meeting stated that "It is an opportune time to examine the genetics of skin disease" (Norris et al, 1994). Indeed, this meeting just caught the wave of early pioneering studies that have helped us to understand the molecular basis of a large number of genodermatoses. This overview presented in the 50th Annual Symposium on the biology of the skin, highlights the progress made in the molecular genetics of heritable skin diseases over the past decade. PMID:12518787

Uitto, Jouni; Pulkkinen, Leena; Ringpfeil, Franziska

2002-12-01

87

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

PubMed

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

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

2015-01-15

88

Klinefelter's syndrome associated with progressive muscular atrophy simulating Kennedy's disease.  

PubMed

Kennedy's disease, an X-linked spinal and bulbar muscular atrophy, is characterized by loss of lower motor neurons. Mild sensory deficits, gynecomastia and infertility may be observed. Klinefelter's syndrome is a variation of sex chromosome disorder characterized by hypogonadism, gynecomastia and azoospermia, and the most frequent karyotype is XXY. A 55-year-old man who presented with slowly progressive and diffuse neurogenic muscle atrophy without bulbar or sensory symptoms. He also had Klinefelter's syndrome. Genetic study of Kennedy's disease was normal. Our patient differs from those with Kennedy's disease in the absence of bulbar and sensory symptoms. It is suggested that the X chromosome plays an important role in the biology of motor neurons. PMID:22919202

Caballero, Pedro Enrique Jiménez

2012-07-01

89

Disease progression and evolution of the HIV-1 env gene in 24 infected infants  

E-print Network

Disease progression and evolution of the HIV-1 env gene in 24 infected infants§ Antonio Carvajal Available online 1 November 2007 Abstract We have studied the relationship between disease progression disease progression cycle from infection to AIDS. Specifically, we examined the temporal relationship

Posada, David

90

Predicting Progression of Alzheimer’s Disease Using Ordinal Regression  

PubMed Central

We propose a novel approach to predicting disease progression in Alzheimer’s disease (AD) – multivariate ordinal regression – which inherently models the ordered nature of brain atrophy spanning normal aging (CTL) to mild cognitive impairment (MCI) to AD. Ordinal regression provides probabilistic class predictions as well as a continuous index of disease progression – the ORCHID (Ordinal Regression Characteristic Index of Dementia) score. We applied ordinal regression to 1023 baseline structural MRI scans from two studies: the US-based Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the European based AddNeuroMed program. Here, the acquired AddNeuroMed dataset was used as a completely independent test set for the ordinal regression model trained on the ADNI cohort providing an optimal assessment of model generalizability. Distinguishing CTL-like (CTL and stable MCI) from AD-like (MCI converters and AD) resulted in balanced accuracies of 82% (cross-validation) for ADNI and 79% (independent test set) for AddNeuroMed. For prediction of conversion from MCI to AD, balanced accuracies of 70% (AUC of 0.75) and 75% (AUC of 0.81) were achieved. The ORCHID score was computed for all subjects. We showed that this measure significantly correlated with MMSE at 12 months (??=?–0.64, ADNI and ??=?–0.59, AddNeuroMed). Additionally, the ORCHID score can help fractionate subjects with unstable diagnoses (e.g. reverters and healthy controls who later progressed to MCI), moderately late converters (12–24 months) and late converters (24–36 months). A comparison with results in the literature and direct comparison with a binary classifier suggests that the performance of this framework is highly competitive. PMID:25141298

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

2014-01-01

91

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

92

CNS Infiltration of Peripheral Immune Cells: D-Day for Neurodegenerative Disease?  

E-print Network

ALS) is a rapidly progressive, ultimately fatal neuromuscular diseaseALS have implicated free radical damage, gliosis, and excitotoxicity as disease-disease progression, and modify glial morphology in an animal model of inherited ALS.

Rezai-Zadeh, Kavon; Gate, David; Town, Terrence

2009-01-01

93

A transcriptional network underlies susceptibility to kidney disease progression  

PubMed Central

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

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

2012-01-01

94

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. PMID:23960345

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

2013-01-01

95

Allopurinol for prevention of progression of kidney disease with hyperuricemia.  

PubMed

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. PMID:23960345

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

2013-07-01

96

The MPTP/probenecid model of progressive Parkinson's disease.  

PubMed

Parkinson's disease (PD) is characterized by a progressive degeneration of dopamine (DA) neurons and a chronic loss of motor functions. The investigation of progressive degenerative mechanisms and possible neuroprotective approaches for PD depends upon the development of an experimental animal model that reproduces the neuropathology observed in humans. This chapter describes the generation of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTPp) chronic mouse model of PD. This model displays key features of PD, including impairment of motor and olfactory functions associated with partial loss of tyrosine hydroxylase-positive neurons and DA levels in the brain. The MPTPp mouse model provides an important tool for the study of mechanisms contributing to the pathological dysfunction of PD at the cellular and whole animal level. PMID:23296790

Carta, Anna R; Carboni, Ezio; Spiga, Saturnino

2013-01-01

97

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

98

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

PubMed

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

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

2014-03-01

99

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. PMID:22948867

Romero-Sánchez, M. Concepción; Machmach, Kawthar; Gonzalez-Serna, Alejandro; Genebat, Miguel; Pulido, Ildefonso; García-García, María; Álvarez-Ríos, Ana Isabel; Ferrando-Martinez, Sara

2012-01-01

100

A computational model of the progression of Alzheimer's disease.  

PubMed

Computational modeling allows analysis of the role of network dynamics in the initiation and progression of neuropathology in Alzheimer's disease. The model focuses on a final common breakdown in function, termed runaway synaptic modification. This phenomenon could account for evidence that neuropathological markers associated with neuronal death in Alzheimer's disease first appear and attain their highest concentration in subregions of the hippocampal formation, and then successively spread into the temporal lobe cortex and the cortex of the frontal and parietal lobes. The model demonstrates how the spread of neuropathology from the hippocampus into neocortical structures could result from the mechanisms of consolidation. Initial sensitivity of the hippocampus and entorhinal cortex to the neuropathological process is proposed to result from an imbalance of variables regulating the influence of synaptic transmission on synaptic modification. Memory deficits are described as due to increased interference effects on recent memory caused by runaway synaptic modification, which ultimately leads to impairments of remote and semantic memory. PMID:9151508

Hasselmo, M E

1997-01-01

101

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

Microsoft Academic Search

Ten patients with dementia of Alzheimer's type, 10 patients with progressive supranuclear palsy, and 10 patients with Huntington's disease were compared on two types of verbal fluency task--namely, initial letter fluency and category (semantic) fluency. The groups were carefully matched for overall level of dementia on the dementia rating scale, and were compared with 25 age matched normal controls. The

A Rosser; J R Hodges

1994-01-01

102

Multifactorial assessment of predictors for prevention of periodontal disease progression.  

PubMed

Univariate approaches have identified single factors influencing periodontal disease progression. The aim of this explorative approach was to assess the influence of various predictive factors responsible for the prevention of periodontal disease progression in the same patient sample. Patients with untreated chronic periodontitis underwent subgingival debridement alone or in combination with adjunctive antimicrobial therapy (systemic amoxicillin and metronidazole/7 days plus supragingival CHX irrigation). Supportive periodontal therapy was performed over a 24-month period. As predictors, clinical, microbial, immunological, and genetic parameters were assessed. The primary outcome variable was the percentage of teeth without attachment loss >/=2 mm over the study period (stability of attachment). At 24 months, multiple regression analysis identified adjunctive antimicrobial therapy for teeth with initially at least one site showing a pocket probing depth of >/=7 mm and IgG(4) reactivity against a 110-kDa protein of A. actinomycetemcomitans at teeth with initial pocket probing depths

Ehmke, Benjamin; Beikler, Thomas; Haubitz, Imme; Karch, Helge; Flemmig, Thomas Frank

2003-12-01

103

Progress towards ultra-wideband AlGaN/GaN MMICs  

NASA Astrophysics Data System (ADS)

The AlGaN/GaN material system possesses fundamental properties that make it an ideal candidate for high power microwave devices. This has been known for over 30 years, however, significant device progress has only come recently. This article gives a summary of AlGaN/GaN electronic device progress, outlines future device directions, and discusses the use of these new devices in power amplifier circuits.

Zolper, J. C.

1999-08-01

104

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

Microsoft Academic Search

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

Robert D. Toto

2008-01-01

105

Pathogenesis and disease-modifying therapy in Alzheimer's disease: the flat line of progress.  

PubMed

The lack of progress in the development of disease-modifying therapy in Alzheimer's disease (AD) was highlighted recently by the cessation of a phase 3 clinical trial studying the effects of bapineuzumab on mild to moderate disease. No treatment benefit was apparent, whereas several serious side effects occurred more commonly in the treatment group compared to placebo. This is the latest failure in a now long list of trials targeting lesional proteins believed to be fundamental drivers of the disease process. As the focus of the trial is directly tied to ostensible disease pathogenesis, objectivity compels us yet again to re-examine the amyloid cascade hypothesis as even a marginally significant pathogenic mediator of disease and to perhaps revert back to traditional science where repeated negative data leads one to consider other ideas. In the case of AD, amyloid-? metabolism and tau phosphorylation have been exhaustively studied, both to no avail. Oxidative stress has similarly been examined in detail by multiple mechanisms and targeted for treatment with a similar result. An appeal to the scientific community may be made to consider lesions in a different light. Have we been seduced by so-called hallmark lesions into believing that they are responsible for disease when in fact the reverse is true, and will we genuinely consider a systems biology approach to AD or instead continue on the path of the lesion, which has so far followed a flat line of progress? PMID:23085451

Castellani, Rudy J; Perry, George

2012-11-01

106

ABCA4 disease progression and a proposed strategy for gene therapy  

E-print Network

ABCA4 disease progression and a proposed strategy for gene therapy Artur V. Cideciyan1,Ã? 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 trials of focal sub

Palczewski, Krzysztof

107

Bayesian Modeling of Incidence and Progression of Disease from CrossSectional Data  

E-print Network

Bayesian Modeling of Incidence and Progression of Disease from Cross­Sectional Data David B. Dunson incidence and progression. In this article, Bayesian discrete­time stochastic models are de­ veloped severity having different measure­ ment scales and heterogeneity among individuals in disease progression

West, Mike

108

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

109

Parkinson's disease: 10 years of progress, 1997-2007.  

PubMed

Many people with Parkinson's disease (PD) and their family members ask their physicians "What is happening in research on Parkinson's disease? Is there anything new?" As the initial speaker at the symposium organized by the Parkinson's Disease Foundation in celebration of its 50th anniversary, I sought to address these questions, focusing on research published between the years 1997 and 2007. I cataloged the advances I considered most important in the field, recognizing my viewpoint is a subjective one and most likely differs from similar listings that others would put together. Space limitation allows me to discuss only a tiny fraction of the remarkable new findings that have been discovered during this 10-year span. Nevertheless, I expect the readers of this summation of advances in the field to be as impressed as I am on the wealth, breadth, and excitement stirring in the field of PD research. Included in this overview are highlights in both laboratory science and clinical science of PD research. In the former category are advances in knowledge on the genetics of PD; potential etiologic and pathogenic causes, especially the better understanding of endogenous factors within dopaminergic neurons; pathologic changes including deposition of alpha-synuclein aggregates; and the consequences of altered alpha-synuclein on the degradation of proteins by both the ubiquitin-proteasomal pathway and the lysosome. Clinical science has also been very active and impressively productive with important clinical advances. In this category are new information on the epidemiology of PD, including awareness of additional factors (besides smoking) that might slow the onset and worsening of PD, such as caffeine and urate; neuroimaging with positron emission tomography and single photon emission tomography; keener awareness of nonmotor features of PD and their impact on quality of life for the persons with PD and their family; recognition of behavioral complications of medications utilized to treat PD, such as impulse control problems; appreciation of the natural history of PD with the increasing impairments as the disease relentlessly worsens over time; the many controlled clinical trials attempting to slow the progression of the disease and to provide new symptomatic therapies; and surgical approaches to alleviate symptoms and progression, including cellular and gene therapy as well as deep brain stimulation. PMID:20187239

Fahn, Stanley

2010-01-01

110

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

PubMed

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

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

2015-01-01

111

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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 prog...

112

HIV disease progression: immune activation, microbes, and a leaky gut.  

PubMed

Recent findings indicate that the majority of all CD4+ T lymphocytes are lost during acute HIV infection, with mucosal compartments being most severely affected. The frequency of infection is very high in gut CD4+ T cells, and depletion of these cells persists into the chronic phase of infection. Infection is associated with increased gut permeability, with microbial translocation being evidenced by increased circulating lipopolysaccharide (LPS) levels. Plasma LPS levels correlate with systemic immune activation, which drives chronic HIV infection. Antiretroviral therapy reduces plasma LPS, and greater CD4+ T cell reconstitution is associated with lower LPS levels. These findings have a number of implications for therapeutic strategies. This article summarizes a presentation on HIV disease progression made by Daniel Douek, MD, PhD, at an International AIDS Society-USA Continuing Medical Education course in San Francisco in May 2007. The original presentation is available as a Webcast at www.iasusa.org. PMID:17720995

Douek, Daniel

2007-01-01

113

Effects of lowering LDL cholesterol on progression of kidney disease.  

PubMed

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

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

2014-08-01

114

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

PubMed Central

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

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

1999-01-01

115

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

2013-11-01

116

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

E-print Network

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

Gielen, C.C.A.M.

117

Blood Platelets in the Progression of Alzheimer’s Disease  

PubMed Central

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

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

2014-01-01

118

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

PubMed Central

Background Homoarginine is an amino acid derivative mainly synthesized in the kidney. It is suggested to increase nitric oxide availability, enhance endothelial function and to protect against cardiovascular diseases. We aimed to investigate the relation between homoarginine, kidney function and progression of chronic kidney disease (CKD). Methods We measured plasma homoarginine concentrations in baseline samples of the Mild to Moderate Kidney Disease (MMKD) Study, a prospective cohort study of 227 patients with CKD in Europe. Homoarginine concentrations were available in 182 of the baseline samples and in 139 of the prospectively-followed patients. We correlated homoarginine concentrations to parameters of kidney function. The association between homoarginine and progression of CKD was assessed during a follow-up of up to seven years (median 4.45 years, interquartile range 2.54–5.19) using Cox regression analysis. Progression of CKD was defined as doubling of baseline serum creatinine and/or end-stage renal disease. Results Study participants were at baseline on average 47±13 years old and 65% were male. Mean±standard deviation of homoarginine concentrations were 2.5±1.1 µmol/L and concentrations were incrementally lower at lower levels of GFR with mean concentrations of 2.90±1.02 µmol/L (GFR>90 ml/min), 2.64±1.06 µmol/L (GFR 60–90 ml/min), 2.52±1.24 µmol/L (GFR 30–60 ml/min) and 2.05±0.78 µmol/L (GFR<30 ml/min), respectively (p?=?0.002). The age- and sex-adjusted risk to reach the renal endpoint was significantly higher by 62% with each decrease by one standard deviation (1.1 µmol/L) of homoarginine (HR 1.62, 95% CI 1.16–2.27, p?=?0.005). This association was independent of proteinuria (HR 1.56, 95% CI 1.11–2.20, p?=?0.01), and was slightly attenuated when adjusting for GFR (HR 1.40 (95% CI 0.98–1.98, p?=?0.06). Conclusions Homoarginine concentrations are directly correlated with kidney function and are significantly associated with the progression of CKD. Low homoarginine concentrations might be an early indicator of kidney failure and a potential target for the prevention of disease progression which needs further investigations. PMID:23691067

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

2013-01-01

119

Predicting progression from cognitive impairment to Alzheimer's disease with the disease state index.  

PubMed

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

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

2015-01-01

120

Gene expression fingerprints in human tubulointerstitial inflammation and fibrosis as prognostic markers of disease progression1  

Microsoft Academic Search

Gene expression fingerprints in human tubulointerstitial inflammation and fibrosis as prognostic markers of disease progression.BackgroundGene expression profiling of nephropathies may facilitate development of diagnostic strategies for complex renal diseases as well as provide insight into the molecular pathogenesis of kidney diseases. To test molecular based renal disease categorization, differential gene expression profiles were compared between control and hydronephrotic kidneys showing

ANNA HENGER; MATTHIAS KRETZLER; PETER DORAN; MAHNAZ BONROUHI; HOLGER SCHMID; EVA KISS; Clemens D. Cohen; STEPHEN MADDEN; STEFAN PORUBSKY; Elisabeth F. Grone; DETLEF SCHLÖNDORFF; Peter J. Nelson; HERMANN-JOSEF GRÖNE

2004-01-01

121

Bicarbonate therapy for prevention of chronic kidney disease progression.  

PubMed

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

?oniewski, Igor; Wesson, Donald E

2014-03-01

122

Optimizing disease progression study designs for drug effect discrimination.  

PubMed

Investigate the possibility to directly optimize a clinical trial design for statistical power to detect a drug effect and compare to optimal designs that focus on parameter precision. An improved statistic derived from the general formulation of the Wald approximation was used to predict the statistical power for given trial designs of a disease progression study. The predicted value was compared, together with the classical Wald statistic, to a type I error-corrected model-based power determined via clinical trial simulations. In a second step, a study design for maximal power was determined by directly maximizing the new statistic. The resulting power-optimal designs and their corresponding performance based on empirical power calculations were compared to designs focusing on parameter precision. Comparisons of empirically determined power and the newly developed statistic, showed excellent agreement across all scenarios investigated. This was in contrast to the classical Wald statistic, which consistently over-predicted the reference power with deviations of up to 90 %. Designs maximized using the proposed metric differed from traditional optimal designs and showed equal or up to 20 % higher power in the subsequent clinical trial simulations. Furthermore, the proposed method was used to minimize the number of individuals required to achieve 80 % power through a simultaneous optimization of study size and study design. The targeted power of 80 % was confirmed in subsequent simulation study. A new statistic was developed, allowing for the explicit optimization of a clinical trial design with respect to statistical power. PMID:23979056

Ueckert, Sebastian; Hennig, Stefanie; Nyberg, Joakim; Karlsson, Mats O; Hooker, Andrew C

2013-10-01

123

Chronic progressive renal disease: Rate of change of serum creatinine concentration  

Microsoft Academic Search

Chronic progressive renal disease : Rate of change of serum concentration. The rate of change of the serum creatinine concentrations in 63 patients with chronic progressive renal disease of varied etiology was examined by linear regression analysis using the logarithm or the reciprocal of the serum creatinine concentration versus time. A single straight line was described by one or the

W Ernest Rutherford; Joan Blondin; J Philip Miller; Allen S Greenwalt; John D Vavra

1977-01-01

124

The Effects of Electroshock on Immune Function and Disease Progression in Juvenile Spring Chinook Salmon  

Microsoft Academic Search

Although much is known about the effects of electroshock on fish physiology, consequences to the immune system and disease progression have not received attention. Our objectives were to determine the effects of electroshock on selected immune function in juvenile spring chinook salmon Oncorhynchus tshawytscha, the mechanism of any observed alteration, and the effects of electroshock on disease progression. We found

Scott P. VanderKooi; Alec G. Maule; Carl B. Schreck

2001-01-01

125

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

126

Disease progression model in subjects with mild cognitive impairment from the Alzheimer's disease neuroimaging initiative: CSF biomarkers predict population subtypes  

PubMed Central

AIM The objective is to develop a semi-mechanistic disease progression model for mild cognitive impairment (MCI) subjects. The model aims to describe the longitudinal progression of ADAS-cog scores from the Alzheimer's disease neuroimaging initiative trial that had data from 198 MCI subjects with cerebrospinal fluid (CSF) information who were followed for 3 years. METHOD Various covariates were tested on disease progression parameters and these variables fell into six categories: imaging volumetrics, biochemical, genetic, demographic, cognitive tests and CSF biomarkers. RESULTS CSF biomarkers were associated with both baseline disease score and disease progression rate in subjects with MCI. Baseline disease score was also correlated with atrophy measured using hippocampal volume. Progression rate was also predicted by executive functioning as measured by the Trail B-test. CONCLUSION CSF biomarkers have the ability to discriminate MCI subjects into sub-populations that exhibit markedly different rates of disease progression on the ADAS-cog scale. These biomarkers can therefore be utilized for designing clinical trials enriched with subjects that carry the underlying disease pathology. PMID:22534009

Samtani, Mahesh N; Raghavan, Nandini; Shi, Yingqi; Novak, Gerald; Farnum, Michael; Lobanov, Victor; Schultz, Tim; Yang, Eric; DiBernardo, Allitia; Narayan, Vaibhav A

2013-01-01

127

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

PubMed

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

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

2014-12-01

128

Myeloperoxidase deficiency ameliorates progression of chronic kidney disease in mice.  

PubMed

Myeloperoxidase (MPO) is an enzyme expressed in neutrophils and monocytes/macrophages. Beside its well-defined role in innate immune defence, it may also be responsible for tissue damage. To identify the role of MPO in the progression of chronic kidney disease (CKD), we investigated CKD in a model of renal ablation in MPO knockout and wild-type mice. CKD was induced by 5/6 nephrectomy. Mice were followed for 10 wk to evaluate the impact of MPO deficiency on renal morbidity. Renal ablation induced CKD in wild-type mice with increased plasma levels of MPO compared with controls. No difference was found between MPO-deficient and wild-type mice regarding albuminuria 1 wk after renal ablation, indicating similar acute responses to renal ablation. Over the next 10 wk, however, MPO-deficient mice developed significantly less albuminuria and glomerular injury than wild-type mice. This was accompanied by a significantly lower renal mRNA expression of the fibrosis marker genes plasminogen activator inhibitor-I, collagen type III, and collagen type IV as well as matrix metalloproteinase-2 and matrix metalloproteinase-9. MPO-deficient mice also developed less renal inflammation after renal ablation, as indicated by a lower infiltration of CD3-positive T cells and F4/80-positive monocytes/macrophages compared with wild-type mice. In vitro chemotaxis of monocyte/macrophages isolated from MPO-deficient mice was impaired compared with wild-type mice. No significant differences were observed for mortality and blood pressure after renal ablation. In conclusion, these results demonstrate that MPO deficiency ameliorates renal injury in the renal ablation model of CKD in mice. PMID:24990898

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

2014-08-15

129

Urine podocyte mRNAs, proteinuria, and progression in human glomerular diseases.  

PubMed

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

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

2013-12-01

130

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

PubMed Central

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

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

2013-01-01

131

Markers of Arterial Stiffness Are Risk Factors for Progression to End-Stage Renal Disease among Patients with Chronic Kidney Disease Stages 4 and 5  

Microsoft Academic Search

Background: Factors associated with chronic kidney disease (CKD) contribute to an increased risk of cardiovascular disease and death. The impact of vascular disease on CKD progression is, however, less well studied. Methods: We examined the effect of markers of vascular disease on the risk of progression to end-stage renal disease (ESRD) in 35 patients with CKD stages 4–5. Superficial femoral

Maarten W. Taal; Mhairi K. Sigrist; Apostolos Fakis; Richard J. Fluck; Christopher W. McIntyre

2007-01-01

132

Disentangling the Normal Aging from the Pathological Alzheimer's Disease Progression on  

E-print Network

of patients affected by Alzheimer's disease (AD) is the contribution of different biological processesDisentangling the Normal Aging from the Pathological Alzheimer's Disease Progression on Cross for the Alzheimer's Disease Neuroimaging Initiative 1 Project Team Asclepios, INRIA Sophia Antipolis, France 2

Paris-Sud XI, Université de

133

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

134

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

E-print Network

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

Wang, Yalin

135

Impact of kidney transplantation on the progression of cardiovascular disease  

Microsoft Academic Search

Kidney transplantation, of all the treatment modalities for end-stage renal disease, affords the greatest potential for prolonged survival and improved quality of life. Great strides in immunosuppressant therapy have improved graft survival and forced clinicians to consider other health-care needs of kidney transplant recipients. Chief among these needs is the prevention and treatment of cardiovascular disease. Cardiovascular disease is the

Sangeetha Satyan; Leslie L Rocher

2004-01-01

136

A Computational Neurodegenerative Disease Progression Score: Method and Results with the Alzheimer’s Disease Neuroimaging Initiative Cohort  

PubMed Central

While neurodegenerative diseases are characterized by steady degeneration over relatively long timelines, it is widely believed that the early stages are the most promising for therapeutic intervention, before irreversible neuronal loss occurs. Developing a therapeutic response requires a precise measure of disease progression. However, since the early stages are for the most part asymptomatic, obtaining accurate measures of disease progression is difficult. Longitudinal databases of hundreds of subjects observed during several years with tens of validated biomarkers are becoming available, allowing the use of computational methods. We propose a widely applicable statistical methodology for creating a disease progression score (DPS), using multiple biomarkers, for subjects with a neurodegenerative disease. The proposed methodology was evaluated for Alzheimer’s disease (AD) using the publicly available AD Neuroimaging Initiative (ADNI) database, yielding an Alzheimer’s DPS or ADPS score for each subject and each time-point in the database. In addition, a common description of biomarker changes was produced allowing for an ordering of the biomarkers. The Rey Auditory Verbal Learning Test delayed recall was found to be the earliest biomarker to become abnormal. The group of biomarkers comprising the volume of the hippocampus and the protein concentration amyloid beta and Tau were next in the timeline, and these were followed by three cognitive biomarkers. The proposed methodology thus has potential to stage individuals according to their state of disease progression relative to a population and to deduce common behaviors of biomarkers in the disease itself. PMID:22885136

Jedynak, Bruno M.; Lang, Andrew; Liu, Bo; Katz, Elyse; Zhang, Yanwei; Wyman, Bradley T.; Raunig, David; Jedynak, C. Pierre; Caffo, Brian; Prince, Jerry L.

2012-01-01

137

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

PubMed

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

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

2013-12-15

138

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

PubMed Central

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

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

2014-01-01

139

Contribution of regulatory T cells to immunosuppression and disease progression in multiple myeloma patients  

PubMed Central

Multiple myeloma (MM) patients exhibit consistent degrees of immune dysfunction. Regulatory T cells contribute to the establishment of an immunosuppressive status in MM patients, hence favoring disease progression. PMID:24327932

Raja, Karthick Raja Muthu; Hajek, Roman

2013-01-01

140

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

E-print Network

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

Sheffer, Michal

141

Impaired autophagy: a link between neurodegenerative diseases and progressive myoclonus epilepsies.  

PubMed

In recent years, research into the molecular bases of neurodegenerative diseases has progressed, and therapies have been developed to combat the causative agents. Based on the observation that progressive myoclonus epilepsies (PMEs) and neurodegenerative diseases share common features of neurodegeneration, we propose that the two pathologies share common underlying molecular characteristics. It is well documented that autophagy is overloaded or impaired in neurodegenerative conditions, and it is also impaired in some PMEs, the clearest example being EPM2 (Lafora disease). Although more research into this connection is warranted, we propose that existing therapies for PMEs could be augmented with similar drugs as those used for neurodegenerative diseases. PMID:21482188

Polajnar, Mira; Zerovnik, Eva

2011-06-01

142

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

PubMed Central

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

2013-01-01

143

Molecular sampling of prostate cancer: a dilemma for predicting disease progression  

Microsoft Academic Search

BACKGROUND: Current prostate cancer prognostic models are based on pre-treatment prostate specific antigen (PSA) levels, biopsy Gleason score, and clinical staging but in practice are inadequate to accurately predict disease progression. Hence, we sought to develop a molecular panel for prostate cancer progression by reasoning that molecular profiles might further improve current clinical models. METHODS: We analyzed a Swedish Watchful

Andrea Sboner; Francesca Demichelis; Stefano Calza; Yudi Pawitan; Sunita R Setlur; Yujin Hoshida; Sven Perner; Hans-Olov Adami; Katja Fall; Lorelei A Mucci; Philip W Kantoff; Meir Stampfer; Swen-Olof Andersson; Eberhard Varenhorst; Jan-Erik Johansson; Mark B Gerstein; Todd R Golub; Mark A Rubin; Ove Andrén

2010-01-01

144

A Multi-Task Learning Formulation for Predicting Disease Progression  

E-print Network

.Ye}@asu.edu ABSTRACT Alzheimer's Disease (AD), the most common type of de- mentia, is a severe neurodegenerative/cognitive measures including Mini Men- tal State Examination (MMSE) and Alzheimer's Disease As- sessment Scale have performed extensive evaluations using various types of data at the baseline from the Alzheimer

Ye, Jieping

145

Cytokine gene polymorphism and progression of renal and cardiovascular diseases  

Microsoft Academic Search

Cytokines are important modulators of inflammation. The balance between pro- and anti-inflammatory cytokines determines whether the intensity of inflammatory response is within physiological limits or in the pathological range. The cytokine network is highly complex, containing interactive cascades of gene activation and suppression. Both chronic kidney disease (CKD) and end-stage renal disease (ESRD) are characterized by elevated levels of proinflammatory

M Rao; C Wong; P Kanetsky; M Girndt; P Stenvinkel; M Reilly; D S C Raj; DSC Raj

2007-01-01

146

Surveillance and control of infectious diseases: progress toward the 1990 objectives.  

PubMed Central

Great progress has been made in the United States in reducing infectious disease mortality. However, infectious diseases remain the greatest cause of morbidity in this country. Newer infectious diseases or agents have been recognized, but newer tools for surveillance and control have also been made available. Specific objectives for the reduction of infectious diseases by 1990 have been set by the Public Health Service. The opportunities appear to be good for achieving by 1990 objectives for nosocomial infections, Legionnaires' disease, tuberculosis, and surveillance and control of infectious diseases. Achievement of the 1990 objectives for hepatitis B, pneumococcal pneumonia, and bacterial meningitis, however, will require both scientific advances and additional resources. PMID:6867252

Dowdle, W R

1983-01-01

147

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

NASA Astrophysics Data System (ADS)

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

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

2014-03-01

148

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

149

A Table of Areas Under Disease Progress Curves.  

E-print Network

Experiment Station Tech. Bul. 323. SINGLETON, L.L. 1974. Evaluation of selected moderately resistant oat lines for their ability to reduce disease development and yield losses caused by Puccinia coronata var. avenae. Ph.3. Thesis. University...

Johnson, Dennis A.; Wilcoxson, Roy D.

1980-01-01

150

Apelin beyond kidney failure and hyponatremia: a useful biomarker for cancer disease progression evaluation.  

PubMed

Apelin regulates angiogenesis, stimulating endothelial cell proliferation and migration. It is upregulated during tumor angiogenesis, and its overexpression was reported to increase tumor growth. Furthermore, apelin controls vasopressin release and body fluid homeostasis. The aim of this study was to examine the correlations between apelin expression and clinical outcomes in oncologic patients, such as cancer disease progression and patient's survival. Apelin levels were evaluated in a cohort of 95 patients affected by different varieties of cancer. Partial remission and stable disease were assigned to the 'no progression' group, comparing it with the progressor group. Patients were followed up for 2 years. Receiver operating characteristics analysis was employed for identifying the progression of the oncologic disease and Kaplan-Meier curves assessed the survival. Adjusted risk estimates for progression endpoint were calculated using Cox proportional hazard regression analysis. Oncologic patients had higher apelin levels compared with healthy subjects, and apelin was closely related to the stages of the disease. In the hyponatremia group, apelin values were significantly higher than patients with eunatremia. After the follow-up of 24 months, 41 patients (43 %) reached the endpoint. Progressor subjects presented significantly increased apelin values at baseline compared with non-progressor. Univariate followed by multivariate Cox proportional hazard regression analysis showed that apelin predicted cancer progression independently of other potential confounders. In patients with cancer, apelin closely reflects the stage of the disease and represents a strong and independent risk marker for cancer progression. PMID:24469934

Lacquaniti, Antonio; Altavilla, Giuseppe; Picone, Antonio; Donato, Valentina; Chirico, Valeria; Mondello, Patrizia; Aloisi, Carmela; Marabello, Grazia; Loddo, Saverio; Buemi, Antoine; Lorenzano, Giuseppina; Buemi, Michele

2015-02-01

151

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

152

Cortical Thickness Analysis to Detect Progressive Mild Cognitive Impairment: A Reference to Alzheimer’s Disease  

Microsoft Academic Search

Background\\/Aims: Mild cognitive impairment (MCI) is associated with an increased risk of Alzheimer’s disease (AD). It would be advantageous to be able to distinguish the characteristics of those MCI patients with a high probability to progress to AD if one wishes to monitor the disease development and treatment. Methods: We assessed the baseline MRI and maximum of 7 years clinical

Valtteri Julkunen; Eini Niskanen; Sebastian Muehlboeck; Maija Pihlajamäki; Mervi Könönen; Merja Hallikainen; Miia Kivipelto; Susanna Tervo; Ritva Vanninen; Alan Evans; Hilkka Soininen

2009-01-01

153

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

PubMed

The failure of current strategies to provide an explanation for controversial findings on the pattern of pathophysiological changes in Alzheimer's Disease (AD) motivates the necessity to develop new integrative approaches based on multi-modal neuroimaging data that captures various aspects of disease pathology. Previous studies using [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) and structural magnetic resonance imaging (sMRI) report controversial results about time-line, spatial extent and magnitude of glucose hypometabolism and atrophy in AD that depend on clinical and demographic characteristics of the studied populations. Here, we provide and validate at a group level a generative anatomical model of glucose hypo-metabolism and atrophy progression in AD based on FDG-PET and sMRI data of 80 patients and 79 healthy controls to describe expected age and symptom severity related changes in AD relative to a baseline provided by healthy aging. We demonstrate a high level of anatomical accuracy for both modalities yielding strongly age- and symptom-severity- dependant glucose hypometabolism in temporal, parietal and precuneal regions and a more extensive network of atrophy in hippocampal, temporal, parietal, occipital and posterior caudate regions. The model suggests greater and more consistent changes in FDG-PET compared to sMRI at earlier and the inversion of this pattern at more advanced AD stages. Our model describes, integrates and predicts characteristic patterns of AD related pathology, uncontaminated by normal age effects, derived from multi-modal data. It further provides an integrative explanation for findings suggesting a dissociation between early- and late-onset AD. The generative model offers a basis for further development of individualized biomarkers allowing accurate early diagnosis and treatment evaluation. PMID:23592957

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

2013-04-01

154

A Comparison of the Cingulum Tract in ALS-B Patients and Controls Using Kernel Matching  

E-print Network

.w.a.caan@amc.uva.nl Abstract. Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with poor prognosis Introduction Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease fea- turing upper

van Vliet, Lucas J.

155

Pathological gambling amongst Parkinson's disease and ALS patients in an online community (PatientsLikeMe.com).  

PubMed

Pathological gambling (PG) has been identified in Parkinson's disease (PD), but such gambling behaviors may also occur in amyotrophic lateral sclerosis (ALS). We sought to estimate the prevalence of PG amongst members of a web-based community, PatientsLikeMe.com. A survey was constructed, consisting of demographic information, the South Oaks Gambling Screen (SOGS), the K-6 measure of distress, and items related to motivation for gambling. Data were obtained from 236 ALS patients and 208 PD patients. Of the PD patients, 13% were classified as problem gamblers compared with 3% of ALS patients (chi(2) = 14.005, P ALS patients. Thus, the higher prevalence of compulsive behavior in PD may relate to damaged reward pathways or medication rather than to the effects of living with a chronic progressive neurological disorder per se. PMID:19353722

Wicks, Paul; MacPhee, Graeme J A

2009-05-15

156

Association between mycobacterial genotypes and disease progression in Mycobacterium avium pulmonary infection  

Microsoft Academic Search

Background:Non-tuberculous mycobacterial lung disease, most commonly caused by Mycobacterium avium infection, tends to show variable disease progression, and significant disease predictors have not been adequately established.Methods:Variable numbers of tandem repeats (VNTR) were evaluated in 16 mycobacterial interspersed repetitive unit (MIRU) loci from M avium isolates cultured from respiratory specimens obtained from 2005 to 2007. Specifically, the association between VNTR profiles

T. Kikuchi; A. Watanabe; K. Gomi; T. Sakakibara; K. Nishimori; H. Daito; S. Fujimura; R. Tazawa; A. Inoue; M. Ebina; Y. Tokue; M. Kaku; T. Nukiwa

2009-01-01

157

Risk Factors for the Progression of Cystic Fibrosis Lung Disease throughout Childhood  

PubMed Central

Rationale: Previous studies of risk factors for progression of lung disease in cystic fibrosis (CF) have suffered from limitations that preclude a comprehensive understanding of the determinants of CF lung disease throughout childhood. The epidemiologic component of the 27-year Wisconsin Randomized Clinical Trial of CF Neonatal Screening Project (WI RCT) afforded us a unique opportunity to evaluate the significance of potential intrinsic and extrinsic risk factors for lung disease in children with CF. Objectives: Describe the most important intrinsic and extrinsic risk factors for progression of lung disease in children with CF. Methods: Variables hypothesized at the onset of the WI RCT study to be determinants of the progression of lung disease and potential risk factors previously identified in the WI RCT study were assessed with multivariable generalized estimating equation models for repeated measures of chest radiograph scores and pulmonary function tests in the WI RCT cohort. Measurements and Main Results: Combining all patients in the WI RCT, 132 subjects were observed for a mean of 16 years and contributed 1,579 chest radiographs, and 1,792 pulmonary function tests. The significant determinants of lung disease include genotype, poor growth, hospitalizations, meconium ileus, and infection with mucoid Pseudomonas aeruginosa. The previously described negative effect of female sex was not seen. Conclusions: Modifiable extrinsic risk factors are the major determinants of progression of lung disease in children with CF. Better interventions to prevent or treat these risk factors may lead to improvements in lung health for children with CF. PMID:24261460

Li, Zhanhai; Laxova, Anita; Rock, Michael J.; Levy, Hara; Collins, Jannette; Ferec, Claude; Farrell, Philip M.

2014-01-01

158

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. PMID:22773704

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

159

Modelling the natural history of Huntington’s disease progression  

E-print Network

for the latter two observations. Over the past few years much effort has gone into uncovering potential biomarkers to track HD progression. For example, the level of striatal brain-derived neurotrophic factor (BDNF) was shown to be substantially reduced in HD... patients.15 Therefore the level of plasma BDNF in 398 HD patients was studied, before concluding that neither the serum level of BDNF protein nor mRNA could be reliably matched to stages of HD severity.16 On the other hand, Weiss and colleagues17 have...

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

2014-12-16

160

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. PMID:24167579

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

161

Contributions of Ibn Zuhr (Avenzoar) to the progress of surgery: a study and translations from his book Al-Taisir.  

PubMed

This study of the original Arabic edition of the book Al-Taisir Fil-Mudawat Wal-Tadbeer (Book of Simplification Concerning Therapeutics and Diet) written by the Muslim physician Abu-Marwan Abdel-Malik Ibn Zuhr (Avenzoar, 1093-1162 AD) aimed at evaluating his contributions to the progress of surgery and providing English translations of relevant excerpts. Ibn Zuhr s unique experiment performing a tracheotomy on a goat, proved the safety of this operation in humans and represented a further step in the development of the experimental school started by Al-Razi (Rhazes) of Baghdad in the ninth century who is known to have given monkeys doses of mercury to test it as a drug for human use. Ibn Zuhr also performed post mortems on sheep in the course of his clinical research on treatment of ulcerating diseases of the lungs. Same as all his predecessors in the Islamic Era, he stressed the importance of a practical and sound knowledge of anatomy for surgical trainees. Furthermore, Ibn Zuhr insisted on a well supervised and structured training program for the surgeon-to-be, before allowing him to operate independently. He also drew the red lines at which a physician should stop, during his general management of a surgical condition; a step forward in the evolution of general surgery as a specialty of its own. He believed in prophylaxis against urinary stone disease and reported the importance of dietary management for that purpose. Furthermore, Ibn Zuhr enriched surgical and medical knowledge by describing many diseases and treatment innovations not ever described before him. PMID:16155644

Abdel-Halim, Rabie E

2005-09-01

162

Inflammatory Leukocyte Phenotypes Correlate with Disease Progression in Idiopathic Pulmonary Fibrosis  

PubMed Central

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

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

2014-01-01

163

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

PubMed

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

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

2013-04-01

164

Parkinson's disease progression at 30 years: a study of subthalamic deep brain-stimulated patients.  

PubMed

Clinical findings in Parkinson's disease suggest that most patients progressively develop disabling non-levodopa-responsive symptoms during the course of the disease. Nevertheless, several heterogeneous factors, such as clinical phenotype, age at onset and genetic aspects may influence the long-term clinical picture. In order to investigate the main features of long-term Parkinson's disease progression, we studied a cohort of 19 subjects treated with subthalamic nucleus deep brain stimulation after >20 years of disease, reporting clinical and neuropsychological data up to a mean of 30 years from disease onset. This group of patients was characterized by an early onset of disease, with a mean age of 38.63 years at Parkinson's disease onset, which was significantly lower than in the other long-term subthalamic nucleus deep brain stimulation follow-up cohorts reported in the literature. All subjects were regularly evaluated by a complete Unified Parkinson's Disease Rating Scale, a battery of neuropsychological tests and a clinical interview, intended to assess the rate of non-levodopa-responsive symptom progression. Clinical data were available for all patients at presurgical baseline and at 1, 3 and 5 years from the subthalamic nucleus deep brain stimulation surgical procedure, while follow-up data after >7 years were additionally reported in a subgroup of 14 patients. The clinical and neuropsychological performance progressively worsened during the course of follow-up; 64% of patients gradually developed falls, 86% dysphagia, 57% urinary incontinence and 43% dementia. A progressive worsening of motor symptoms was observed both in 'medication-ON' condition and in 'stimulation-ON' condition, with a parallel reduction in the synergistic effect of 'medication-ON/stimulation-ON' condition. Neuropsychological data also showed a gradual decline in the performances of all main cognitive domains, with an initial involvement of executive functions, followed by the impairment of language, reasoning and memory. Thirty years after the disease onset, most patients presented non-levodopa-responsive symptoms, although the effect of both subthalamic nucleus deep brain stimulation and dopaminergic therapies still showed significant efficacy on the main disease cardinal features. Nevertheless, compared with other subthalamic nucleus deep brain stimulation follow-up studies, which included patients with a shorter disease duration at the time of surgery, a higher prevalence of axial and non-levodopa-responsive symptoms was observed in the long-term evaluations, confirming that several complex aspects underlie the development of non-motor symptoms and other features of Parkinson's disease progression, even in patients with an early disease onset and a prior long-lasting response to dopaminergic therapies. PMID:21666262

Merola, Aristide; Zibetti, Maurizio; Angrisano, Serena; Rizzi, Laura; Ricchi, Valeria; Artusi, Carlo A; Lanotte, Michele; Rizzone, Mario G; Lopiano, Leonardo

2011-07-01

165

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

PubMed Central

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

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

2014-01-01

166

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

167

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

168

Mutations in TJP2 cause progressive cholestatic liver disease  

PubMed Central

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

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

2014-01-01

169

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

PubMed Central

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

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

2014-01-01

170

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

E-print Network

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

171

CYTOMEGALOVIRUS INFECTION AND HIV-1 DISEASE PROGRESSION IN INFANTS BORN TO HIV-1–INFECTED WOMEN  

PubMed Central

Background and Methods Cytomegalovirus (CMV) has been implicated as a cofactor in the progression of human immunodeficiency virus type 1 (HIV-1) disease. We assessed 440 infants (75 of whom were HIV-1–infected and 365 of whom were not) whose CMV status was known, who were born to HIV-1–infected women, and who were followed prospectively. HIV-1 disease progression was defined as the presence of class C symptoms (according to the criteria of the Centers for Disease Control and Prevention [CDC]) or CD4 counts of less than 750 cells per cubic millimeter by 1 year of age and less than 500 cells per cubic millimeter by 18 months of age. Results At birth the frequency of CMV infection was similar in the HIV-1–infected and HIV-1–uninfected infants (4.3 percent and 4.5 percent, respectively), but the HIV-1–infected infants had a higher rate of CMV infection at six months of age (39.9 percent vs. 15.3 percent, P=0.001) and continued to have a higher rate of CMV infection through four years of age (P=0.04). By 18 months of age, the infants with both infections had higher rates of HIV-1 disease progression (70.0 percent vs. 30.4 percent, P=0.001), CDC class C symptoms or death (52.5 percent vs. 21.7 percent, P=0.008), and impaired brain growth or progressive motor deficits (35.6 percent vs. 8.7 percent, P=0.005) than infants infected only with HIV-1. In a Cox regression analysis, CMV infection was associated with an increased risk of HIV-1 disease progression (relative risk, 2.59; 95 percent confidence interval, 1.13 to 5.95). Among children infected with HIV-1 alone, but not among those infected with both viruses, children with rapid progression of HIV-1 disease had higher mean levels of HIV-1 RNA than those with slower or no progression of disease. Conclusions HIV-1–infected infants who acquire CMV infection in the first 18 months of life have a significantly higher rate of disease progression and central nervous system disease than those infected with HIV-1 alone. PMID:10395631

Kovacs, Andrea; Schluchter, Mark; Easley, Kirk; Demmler, Gail; Shearer, William; La Russa, Philip; Pitt, Jane; Cooper, Ellen; Goldfarb, Johanna; Hodes, David; Kattan, Meyer; McIntosh, Kenneth

2014-01-01

172

Rapidly progressive phenotype of Lafora disease associated with a novel NHLRC1 mutation.  

PubMed

Lafora disease is a fatal, autosomal recessive form of progressive myoclonus epilepsy. Patients characteristically exhibit myoclonic and tonic-clonic seizures and cognitive impairment, beginning in their second decade. Alterations in two genes were identified as the cause of the disease. Mutations in the NHL repeat containing 1 (NHLRC1) gene were described in association with a more benign clinical course and later age of death, compared with epilepsy progressive myoclonus type 2A (EPM2A) mutations. We describe a rapidly progressive phenotype of Lafora disease in an adolescent patient with a novel NHLRC1 mutation. He developed severe disability and dementia less than 2 years after the onset of signs. PMID:21555062

Brackmann, Florian A; Kiefer, Alexander; Agaimy, Abbas; Gencik, Martin; Trollmann, Regina

2011-06-01

173

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

NASA Astrophysics Data System (ADS)

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

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

2014-12-01

174

Acute kidney injury: a springboard for progression in chronic kidney disease  

PubMed Central

Recently published epidemiological and outcome analysis studies have brought to our attention the important role played by acute kidney injury (AKI) in the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD). AKI accelerates progression in patients with CKD; conversely, CKD predisposes patients to AKI. This research gives credence to older, well-thought-out wisdom that recovery from AKI is often not complete and is marked by residual structural damage. It also mirrors older experimental observations showing that unilateral nephrectomy, a surrogate for loss of nephrons by disease, compromises structural recovery and worsens tubulointerstitial fibrosis after ischemic AKI. Moreover, review of a substantial body of work on the relationships among reduced renal mass, hypertension, and pathology associated with these conditions suggests that impaired myogenic autoregulation of blood flow in the setting of hypertension, the arteriolosclerosis that results, and associated recurrent ischemic AKI in microscopic foci play important roles in the development of progressively increasing tubulointerstitial fibrosis. How nutrition, an additional factor that profoundly affects renal disease progression, influences these events needs reevaluation in light of information on the effects of calories vs. protein and animal vs. vegetable protein on injury and progression. Considerations based on published and emerging data suggest that a pathology that develops in regenerating tubules after AKI characterized by failure of differentiation and persistently high signaling activity is the proximate cause that drives downstream events in the interstitium: inflammation, capillary rarefaction, and fibroblast proliferation. In light of this information, we advance a comprehensive hypothesis regarding the pathophysiology of AKI as it relates to the progression of kidney disease. We discuss the implications of this pathophysiology for developing efficient therapeutic strategies to delay progression and avert ESRD. PMID:20200097

Griffin, Karen A.; Lan, Rongpei; Geng, Hui; Saikumar, Pothana; Bidani, Anil K.

2010-01-01

175

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

PubMed

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

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

2014-10-01

176

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

PubMed

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

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

2014-11-01

177

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

PubMed Central

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

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

2014-01-01

178

Molecular Signatures of Amyotrophic Lateral Sclerosis Disease Progression in Hind and Forelimb Muscles of an SOD1G93A Mouse Model  

PubMed Central

Abstract Aims: This study utilized proteomics, biochemical and enzymatic assays, and bioinformatics tools that characterize protein alterations in hindlimb (gastrocnemius) and forelimb (triceps) muscles in an amyotrophic lateral sclerosis (ALS) (SOD1G93A) mouse model. The aim of this study was to identify the key molecular signatures involved in disease progression. Results: Both muscle types have in common an early down-regulation of complex I. In the hindlimb, early increases in oxidative metabolism are associated with uncoupling of the respiratory chain, an imbalance of NADH/NAD+, and an increase in reactive oxygen species (ROS) production. The NADH overflow due to complex I inactivation induces TCA flux perturbations, leading to citrate production, triggering fatty acid synthase (FAS), and lipid peroxidation. These early metabolic changes in the hindlimb followed by sustained and comparatively higher metabolic and cytoskeletal derangements over time precede and may catalyze the progressive muscle wasting in this muscle at the late stage. By contrast, in the forelimb, there is an early down-regulation of complexes I and II that is associated with the reduction of oxidative metabolism, which promotes metabolic homeostasis that is accompanied by a greater cytoskeletal stabilization response. However, these early compensatory systems diminish by a later time point. Innovation: The identification of potential early- and late-stage disease molecular signatures in an ALS model: muscle albumin, complex I, complex II, citrate synthase, FAS, and phosphoinositide 3-kinase functions as diagnostic markers and peroxisome proliferator-activated receptor ? co-activator 1? (PGC1?), Sema-3A, and Rho-associated protein kinase 1 (ROCK1) play the role of disease progression markers. Conclusion: The differing pattern of cellular metabolism and cytoskeletal derangements in the hind and forelimb identifies the potential dysmetabolism/hypermetabolism molecular signatures associated with disease progression, which may serve as diagnostic/disease progression markers in ALS patients. Antioxid. Redox Signal. 17, 1333–1350. PMID:22563797

Capitanio, Daniele; Vasso, Michele; Ratti, Antonia; Grignaschi, Giuliano; Volta, Manuela; Moriggi, Manuela; Daleno, Cristina; Bendotti, Caterina; Silani, Vincenzo

2012-01-01

179

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

PubMed Central

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

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

2014-01-01

180

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

PubMed Central

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

2014-01-01

181

Evaluation of monkeypox disease progression by molecular imaging.  

PubMed

Infection of nonhuman primates (NHPs) with monkeypox virus (MPXV) is currently being developed as an animal model of variola infection in humans. We used positron emission tomography and computed tomography (PET/CT) to identify inflammatory patterns as predictors for the outcome of MPXV disease in NHPs. Two NHPs were sublethally inoculated by the intravenous (IV) or intrabronchial (IB) routes and imaged sequentially using fluorine-18 fluorodeoxyglucose ((18)FDG) uptake as a nonspecific marker of inflammation/immune activation. Inflammation was observed in the lungs of IB-infected NHPs, and bilobular involvement was associated with morbidity. Lymphadenopathy and immune activation in the axillary lymph nodes were evident in IV- and IB-infected NHPs. Interestingly, the surviving NHPs had significant (18)FDG uptake in the axillary lymph nodes at the time of MPXV challenge with no clinical signs of illness, suggesting an association between preexisting immune activation and survival. Molecular imaging identified patterns of inflammation/immune activation that may allow risk assessment of monkeypox disease. PMID:22013221

Dyall, Julie; Johnson, Reed F; Chen, Dar-Yeong; Huzella, Louis; Ragland, Dan R; Mollura, Daniel J; Byrum, Russell; Reba, Richard C; Jennings, Gerald; Jahrling, Peter B; Blaney, Joseph E; Paragas, Jason

2011-12-15

182

Disease Severity and Progression in Progressive Supranuclear Palsy and Multiple System Atrophy: Validation of the NNIPPS – PARKINSON PLUS SCALE  

PubMed Central

Background The Natural History and Neuroprotection in Parkinson Plus Syndromes (NNIPPS) study was a large phase III randomized placebo-controlled trial of riluzole in Progressive Supranuclear Palsy (PSP, n?=?362) and Multiple System Atrophy (MSA, n?=?398). To assess disease severity and progression, we constructed and validated a new clinical rating scale as an ancillary study. Methods and Findings Patients were assessed at entry and 6-montly for up to 3 years. Evaluation of the scale's psychometric properties included reliability (n?=?116), validity (n?=?760), and responsiveness (n?=?642). Among the 85 items of the initial scale, factor analysis revealed 83 items contributing to 15 clinically relevant dimensions, including Activity of daily Living/Mobility, Axial bradykinesia, Limb bradykinesia, Rigidity, Oculomotor, Cerebellar, Bulbar/Pseudo-bulbar, Mental, Orthostatic, Urinary, Limb dystonia, Axial dystonia, Pyramidal, Myoclonus and Tremor. All but the Pyramidal dimension demonstrated good internal consistency (Cronbach ??0.70). Inter-rater reliability was high for the total score (Intra-class coefficient?=?0.94) and 9 dimensions (Intra-class coefficient?=?0.80–0.93), and moderate (Intra-class coefficient?=?0.54–0.77) for 6. Correlations of the total score with other clinical measures of severity were good (rho?0.70). The total score was significantly and linearly related to survival (p<0.0001). Responsiveness expressed as the Standardized Response Mean was high for the total score slope of change (SRM?=?1.10), though higher in PSP (SRM?=?1.25) than in MSA (SRM?=?1.0), indicating a more rapid progression of PSP. The slope of change was constant with increasing disease severity demonstrating good linearity of the scale throughout disease stages. Although MSA and PSP differed quantitatively on the total score at entry and on rate of progression, the relative contribution of clinical dimensions to overall severity and progression was similar. Conclusions The NNIPPS-PPS has suitable validity, is reliable and sensitive, and therefore is appropriate for use in clinical studies with PSP or MSA. Trial Registration ClinicalTrials.gov NCT00211224 PMID:21829612

Payan, Christine A. M.; Viallet, François; Landwehrmeyer, Bernhard G.; Bonnet, Anne-Marie; Borg, Michel; Durif, Franck; Lacomblez, Lucette; Bloch, Frédéric; Verny, Marc; Fermanian, Jacques; Agid, Yves; Ludolph, Albert C.

2011-01-01

183

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

E-print Network

Chronic kidney disease (CKD) is a major cause of illness in dogs, and it is commonly caused by glomerular diseases that result in proteinuria and a progressive decline in renal function. Despite the importance of glomerular lesions, tubulointerstitial... of canine chronic kidney disease................................ 1! Current non-invasive methods for detecting renal disease ......... 2! Proteinuria in kidney disease ...................................................... 5! The glomerular capillary...

Nabity, Mary B.

2012-02-14

184

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

PubMed

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

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

2015-02-01

185

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

PubMed Central

Cell death and synapse dysfunction are two likely causes of cognitive decline in AD. As cells die and synapses lose their drive, remaining cells suffer an initial decrease in activity. Neuronal homeostatic synaptic scaling then provides a feedback mechanism to restore activity. This homeostatic mechanism is believed to sense levels of activity-dependent cytosolic calcium within the cell and to adjust neuronal firing activity by increasing the density of AMPA synapses at remaining synapses to achieve balance. The scaling mechanism increases the firing rates of remaining cells in the network to compensate for decreases in network activity. However, this effect can itself become a pathology, as it produces increased imbalance between excitatory and inhibitory circuits, leading to greater susceptibility to further cell loss via calcium-mediated excitotoxicity. Here, we present a mechanistic explanation of how directed brain stimulation might be expected to slow AD progression based on computational simulations in a 470-neuron biomimetic model of a neocortical column. The simulations demonstrate that the addition of low-intensity electrostimulation (neuroprosthesis) to a network undergoing AD-like cell death can raise global activity and break this homeostatic-excitotoxic cascade. The increase in activity within the remaining cells in the column results in lower scaling-driven AMPAR upregulation, reduced imbalances in excitatory and inhibitory circuits, and lower susceptibility to ongoing damage. PMID:24765074

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

2014-01-01

186

What Is ALS?  

MedlinePLUS

... prolong survival. It is important to remember that ALS is a quite variable disease; no two people will have the same journey or experiences. There are medically documented cases of people in whom ALS ‘burns out,’ stops progressing or progresses at a ...

187

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

SciTech Connect

Two patients presenting with progressive dementia coupled with motor neuron disease underwent brain SPECT using N-isopropyl-p iodine-123-iodoamphetamine (({sup 123}I)IMP). The characteristic clinical features of progressive dementia and motor neuron disease were noted. IMP SPECT also revealed reduced uptake in the bilateral frontal and temporal regions, with no reduction of uptake in the parietal, parietal-occipital regions. We conclude that IMP SPECT has potential for the evaluation of progressive dementia with motor neuron disease.

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

1990-05-01

188

TEMPORAL PATTERNS OF ALMOND LEAF SCORCH DISEASE PROGRESS AND ASSOCIATED XYLELLA FASTIDIOSA GENOTYPES.  

Technology Transfer Automated Retrieval System (TEKTRAN)

Almond leaf scorch (ALS) disease has emerged as a potential threat to almond production areas throughout California’s San Joaquin Valley. The disease results from infection by the xylem-limited bacterium, Xylella fastidiosa (Xf), and the pathogen is transmitted by xylophagous insect vectors. Five ...

189

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

PubMed

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

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

2015-03-01

190

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

PubMed Central

A familiar challenge for neuroradiologists and neuro-oncologists is differentiating between radiation treatment effect and disease progression in the CNS. Both entities are characterized by an increase in contrast enhancement on MRI and present with similar clinical signs and symptoms that may occur either in close temporal proximity to the treatment or later in the disease course. When radiation-related imaging changes or clinical deterioration are mistaken for disease progression, patients may be subject to unnecessary surgery and/or a change from otherwise effective therapy. Similarly, when disease progression is mistaken for treatment effect, a potentially ineffective therapy may be continued in the face of progressive disease. Here we describe the three types of radiation injury to the brain based on the time to development of signs and symptoms – acute, subacute and late – and then review specific imaging changes after intensity-modulated radiation therapy, stereotactic radiosurgery and brachytherapy. We provide an overview of these phenomena in the treatment of a wide range of malignant and benign CNS illnesses. Finally, we review the published data regarding imaging techniques under investigation to address this well-known problem. PMID:24947265

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

2015-01-01

191

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

PubMed

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

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

2014-07-01

192

Apoptosis as a Mechanism for Liver Disease Progression  

PubMed Central

Hepatocyte injury is ubiquitous in clinical practice, and the mode of cell death associated with this injury is often apoptosis, especially by death receptors. Information from experimental systems demonstrates that hepatocyte apoptosis is sufficient to cause liver hepatic fibrogenesis. The mechanisms linking hepatocyte apoptosis to hepatic fibrosis remain incompletely understood, but likely relate to engulfment of apoptotic bodies by professional phagocytic cells and stellate cells, and release of mediators by cells undergoing apoptosis. Inhibition of apoptosis with caspase inhibitors has demonstrated beneficial effects in murine models of hepatic fibrosis. Recent studies implicating Toll-like receptor 9 (TLR9) in liver injury and fibrosis are also of particular interest. Engulfment of apoptotic bodies is one mechanism by which the TLR9 ligand (CpG DNA motifs) could be delivered to this intracellular receptor. These concepts suggest therapy focused on interrupting the cellular mechanisms linking apoptosis to fibrosis would be useful in human liver diseases. PMID:20960379

Guicciardi, Maria Eugenia; Gores, Gregory J.

2011-01-01

193

Hepatic inflammation and progressive liver fibrosis in chronic liver disease  

PubMed Central

Chronic liver inflammation drives hepatic fibrosis, and current immunosuppressive, anti-inflammatory, and anti-viral therapies can weaken this driver. Hepatic fibrosis is reversed, stabilized, or prevented in 57%-79% of patients by conventional treatment regimens, mainly by their anti-inflammatory actions. Responses, however, are commonly incomplete and inconsistently achieved. The fibrotic mechanisms associated with liver inflammation have been clarified, and anti-fibrotic agents promise to improve outcomes as adjunctive therapies. Hepatitis C virus and immune-mediated responses can activate hepatic stellate cells by increasing oxidative stress within hepatocytes. Angiotensin can be synthesized by activated hepatic stellate cells and promote the production of reactive oxygen species. Anti-oxidants (N-acetylcysteine, S-adenosyl-L-methionine, and vitamin E) and angiotensin inhibitors (losartin) have had anti-fibrotic actions in preliminary human studies, and they may emerge as supplemental therapies. Anti-fibrotic agents presage a new era of supplemental treatment for chronic liver disease. PMID:24627588

Czaja, Albert J

2014-01-01

194

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

Microsoft Academic Search

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

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

1997-01-01

195

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

PubMed Central

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

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

2014-01-01

196

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

Microsoft Academic Search

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

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

2005-01-01

197

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

PubMed

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

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

2014-11-01

198

Can malondialdehyde be used as a biological marker of progression in neurodegenerative disease?  

Microsoft Academic Search

There is a large body of evidence that free radical-mediated oxidative damage is involved in the pathogenesis of neurodegenerative\\u000a disease. Although it is unlikely that markers of such damage will have any diagnostic value, they might be of considerable\\u000a interest in following disease progression and monitoring the efficacy of different treatments. Among such markers, there is\\u000a evidence for the elevation

Michel Dib; Catherine Garrel; Alain Favier; Valérie Robin; Claude Desnuelle

2002-01-01

199

Alpers syndrome: progressive neuronal degeneration of children with liver disease.  

PubMed

Alpers syndrome was not clearly defined until the link between brain and liver disease was described. Alpers syndrome can now be clearly established as a disorder of oxidative metabolism related to mitochondrial dysfunction, and in most instances with an autosomal mode of inheritance. The symptoms and signs are discussed. The illness occurs in the first years of life with the sudden onset of intractable seizures associated with developmental delay, hypotonia, ataxia, cortical blindness, and hepatic failure, and death occurs within a short time. Treating the seizures with valproic acid can cause the rapid onset of liver failure and must be avoided. To establish a definite diagnosis, liver and muscle biopsies may be needed. The former shows bile duct proliferation with the evidence of cirrhosis, and the latter may support the involvement of the mitochondrial respiratory chain if there are ragged-red fibres. Genetic studies can show an association with mitochondrial DNA depletion and mutations in the polymerase gene. Cytochrome c oxidase deficiency has been demonstrated in some patients. Useful diagnostic tests include liver function tests, lactic acid levels in the blood and cerebrospinal fluid, electroencephalograms, computed tomography, and magnetic resonance imaging. The differential diagnosis will be from other forms of neuronal degeneration and disorders of mitochondrial function. There is no specific treatment, which must await further research into causes. PMID:17109792

Gordon, Neil

2006-12-01

200

Cerebrospinal Fluid Apolipoprotein E Concentration and Progression of Alzheimer's Disease.  

PubMed

Background/Objective: Apolipoprotein E plays a role in the pathogenesis of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) and plasma level alterations have been reported in AD patients. In search of a potential biomarker, which would be predictive of cognitive, functional, or motor decline, we analyzed CSF apolipoprotein E (ApoE) levels of AD patients in this regard. Methods: Subjects with newly diagnosed AD enrolled into an observational study were followed up longitudinally. Neuropsychological testing and physical examination were performed annually. In a sub-cohort of patients, where baseline CSF ApoE concentration values were available, multiple regression analyses were used to determine possible associations of CSF ApoE concentration and speed of decline on different cognitive, functional, and motor scales (MMSE, iADL, bADL, GDS, UPDRSIII) adjusting for possible confounders. Results: No association of CSF ApoE levels and speed of decline on the various scales could be established (p = 0.09 to 0.88). Nevertheless, the use of neuroleptic drugs could be linked to higher velocity of global and extrapyramidal deterioration (p = 0.04 and 0.05 for GDS and UPDRSIII, respectively), but not to other outcomes (MMSE, bADL, and iADL). Conclusion: Herein, CSF ApoE at time of AD diagnosis could not be shown to be a viable biomarker for future cognitive, functional, or motor decline. Expectedly, the use of neuroleptic drugs was associated with detrimental effects. PMID:25125466

Schmidt, Christian; Gerlach, Nicole; Peter, Christoph; Gherib, Kerim; Lange, Katharina; Fride, Tim; Zerr, Inga

2014-08-13

201

Caregiver–Recipient Closeness and Symptom Progression in Alzheimer Disease. The Cache County Dementia Progression Study  

PubMed Central

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

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

2009-01-01

202

Chemokine Receptor CCR1: A New Target for Progressive Kidney Disease  

Microsoft Academic Search

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

Volha Ninichuk; Hans-Joachim Anders

2005-01-01

203

Continuing trastuzumab beyond disease progression: outcomes analysis in patients with metastatic breast cancer  

Microsoft Academic Search

INTRODUCTION: We performed a retrospective analysis of HER2-overexpressing metastatic breast cancer patients to describe clinical outcomes of those who, despite progression of the disease (PD), maintained trastuzumab for multiple chemotherapy lines. We also compared survival of these patients with that of those who halted trastuzumab at first PD. METHODS: We identified 101 patients treated between July 2000 and January 2007.

Giuseppe Cancello; Emilia Montagna; Diego D'Agostino; Mario Giuliano; Antonio Giordano; Giuseppe Di Lorenzo; Monica Plaitano; Sabino De Placido; Michele De Laurentiis

2008-01-01

204

The topographic distribution of brain atrophy in Huntington's disease and progressive supranuclear palsy  

Microsoft Academic Search

The topographic distribution of brain atrophy was quantified by image analysis of fixed coronal brain slices from 12 patients dying with Huntington's disease (HD) and from 4 other patients dying with progressive supranuclear palsy (PSP). In HD, atrophy was maximal within the caudate nucleus, putamen and globus pallidus. However, the cerebral cortex was also atrophied with reductions in cross-sectional area

D. M. A. Mann; R. Oliver; J. S. Snowden

1993-01-01

205

Progress and prospects: Immunobiology of gene therapy for neurodegenerative disease: prospects and risks  

Microsoft Academic Search

Gene therapy for neurological, and in particular neurodegenerative, disease is now a reality. A number of early phase clinical trials have been completed and several are currently in progress. In view of this, it is critically important to evaluate the immunological risk associated with neurological gene therapy, which has clear implications for trial safety and efficacy. Moreover, it is imperative

M M McMenamin; M J A Wood; MJA Wood

2010-01-01

206

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

Microsoft Academic Search

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

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

2006-01-01

207

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

208

CHALKBROOD DISEASE OF HONEY BEES, APIS MELLIFERA L.: A PROGRESS REPORT  

E-print Network

CHALKBROOD DISEASE OF HONEY BEES, APIS MELLIFERA L.: A PROGRESS REPORT Martha GILLIAM, Stephen apis. However, variation in susceptibility of bee colonies appeared to be an important factor and prepupae, but eggs and pupae did not support the growth of A. apis. Infection occured both through

Paris-Sud XI, Université de

209

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

210

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

ERIC Educational Resources Information Center

Understanding the underlying qualitative features of memory deficits in mild cognitive impairment (MCI) can provide critical information for early detection of Alzheimer's disease (AD). This study sought to investigate the utility of both learning and retention measures in (a) the diagnosis of MCI, (b) predicting progression to AD, and (c)…

Chang, Yu-Ling; Bondi, Mark W.; Fennema-Notestine, Christine; McEvoy, Linda K.; Hagler, Donald J., Jr.; Jacobson, Mark W.; Dale, Anders M.

2010-01-01

211

Nonparametric Inference and Uniqueness for Periodically-Observed Progressive Disease Models  

PubMed Central

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

Griffin, Beth Ann; Lagakos, Stephen W.

2010-01-01

212

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

213

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

ERIC Educational Resources Information Center

The Functional Transitions Model (FTM) integrates the theoretical notions of progressive functional decline associated with Alzheimer's disease (AD), excess disability, and transitions occurring intermittently along the trajectory of functional decline. Application of the Functional Transitions Model to clinical practice encompasses the paradox of…

Slaughter, Susan; Bankes, Jane

2007-01-01

214

Salt Intake and Renal Outcome in Patients with Progressive Renal Disease  

Microsoft Academic Search

Experimental studies suggest that salt intake plays a critical role in the progressive glomerular filtration rate (GFR) loss of established renal disease; however, this issue has never been addressed in humans. To this aim, we have retrospectively analyzed the clinical data of patients with chronic renal failure (CRF), in whom a low-protein diet was prescribed, over a period of about

Bruno Cianciaruso; Vincenzo Bellizzi; Roberto Minutolo; Antonello Tavera; Alfredo Capuano; Giuseppe Conte; Luca De Nicola

1998-01-01

215

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

E-print Network

of dementia, affecting more than 5% of the population over the age 65 years. In Alzheimer's diseaseAlzheimer's disease (AD) is a progressive neurodegenerative disease and the most frequent cause, complete replication of Human Alzheimer's disease has not been achieved in these groups of transgenic mice

Giri, Ranjit K.

216

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

PubMed Central

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

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

2014-01-01

217

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

SciTech Connect

Purpose: To assess rate of disease progression from diagnosis to initiation of treatment for Stage I-IIIB non-small-cell lung cancer (NSCLC). Methods and Materials: Forty patients with NSCLC underwent at least two sets of computed tomography (CT) and 18-fluorodeoxyglucose positron emission tomography (PET) scans at various time intervals before treatment. Progression was defined as development of any new lymph node involvement, site of disease, or stage change. Results: Median time interval between first and second CT scans was 13.4 weeks, and between first and second PET scans was 9.0 weeks. Median initial primary maximum tumor dimension (MTD) was 3.5 cm (0.6-8.5 cm) with a median standardized uptake value (SUV) of 13.0 (1.7-38.5). The median MTD increased by a median of 1.0 cm (mean, 1.6 cm) between scans for a median relative MTD increase of 35% (mean, 59%). Nineteen patients (48%) progressed between scans. Rate of any progression was 13%, 31%, and 46% at 4, 8, and 16 weeks, respectively. Upstaging occurred in 3%, 13%, and 21% at these intervals. Distant metastasis became evident in 3%, 13%, and 13% after 4, 8, and 16 weeks, respectively. T and N stage were associated with progression, whereas histology, grade, sex, age, and maximum SUV were not. At 3 years, overall survival for Stage III patients with vs. without progression was 18% vs. 67%, p = 0.05. Conclusions: With NSCLC, treatment delay can lead to disease progression. Diagnosis, staging, and treatment initiation should be expedited. After 4-8 weeks of delay, complete restaging should be strongly considered.

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

2011-02-01

218

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

PubMed

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

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

2014-01-01

219

Towards an expert system for accurate diagnosis and progress monitoring of Parkinson's disease.  

PubMed

While Parkinson's disease is a chronic and progressive movement disorder, no one can predict which symptoms will affect an individual patient. At the present time there is no cure for Parkinson's disease but instead a variety of alternative treatments provide relief from the symptoms. Due to these unpromising factors, we propose a new multi-scale ontology-based modeling technology for the accurate diagnosis of Parkinson's disease and its progress monitoring. The proposed model will be used to assess the status of the patient with PD corresponding treatments using a multilayer neural network. The proposed tool also aims to identify new associated physical and biological biomarkers from heterogeneous patients' data. The architecture of this expert system and its implementation in Protégé is presented in this paper. PMID:25416985

Alexiou, Athanasios; Psiha, Maria; Vlamos, Panayiotis

2015-01-01

220

Neuropsychological follow up in patients with Parkinson's disease, striatonigral degeneration-type multisystem atrophy, and progressive supranuclear palsy  

Microsoft Academic Search

OBJECTIVESImpairment of executive function is frequent in Parkinson's disease (PD), striatonigral degeneration-type multisystem atrophy (SND), and progressive supranuclear palsy (PSP); sometimes frank dementia is also present. However, the progression of cognitive decline has not been adequately studied. The objectives were to delineate the progression of cognitive impairment in these parkinsonisms and to elucidate interdisease differences.METHODSTwenty three patients with SND and

Paola Soliveri; Daniela Monza; Dominga Paridi; Francesco Carella; Silvia Genitrini; Daniela Testa; Floriano Girotti

2000-01-01

221

Factors affecting the age of onset and rate of progression of Alzheimer's disease  

PubMed Central

OBJECTIVES—To assess the role of cerebrovascular disease, sex, education, occupation, year of birth, leukoaraiosis, congophilic angiopathy, family history, and other demographic factors on the reported age of onset and rate of progression of Alzheimer's disease.?METHODS—Analysis of data from the University of Western Ontario Dementia Study, a prospective longitudinal study of dementia patients with clinical and 6 monthly psychometric follow up to postmortem based in a university memory disorders clinic with secondary and tertiary referrals. There were 172 patients with dementia. The main outcome measures were the reported age of onset of cognitive decline as described by the family (available in 168) and rate of progression as measured during the linear phase of the extended scale for dementia, which could be calculated in 66. The cases subdivided into 49 cases of definite Alzheimer's disease without infarcts, 25 cases of otherwise definite Alzheimer's disease with infarcts, 79 cases of probable Alzheimer's disease without infarcts, and 19 such cases with infarcts.?RESULTS—The age of onset was not influenced by the rate of progression, the presence of cerebral infarcts, or congophilic angiopathy. Educational level, occupational level, sex, family history, year of birth, reported age of onset, severity at entry, an ischaemic score, and the presence of leukoariosis, affected neither age of onset nor the rate of progression. An earlier year of birth had a major effect and higher education had a minor effect on earlier age of onset. The earlier the year of birth, the lower the educational level and the greater the accrual of cerebral infarcts.?CONCLUSIONS—Contrary to series without pathological verification, age of onset in this study was not affected by occupation. Education had a modest effect on earlier reported onset, probably reflecting earlier recognition. As birth year has a strong effect on educational level and the occurrence of cerebral infarcts, this must be taken into account when analysing for risk factors for Alzheimer's disease.?? PMID:9703168

Bowler, J.; Munoz, D.; Merskey, H.; Hachinski, V.

1998-01-01

222

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

PubMed Central

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

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

2013-01-01

223

Nonanastomotic biliary strictures after liver transplantation, part 2: Management, outcome, and risk factors for disease progression.  

PubMed

Nonanastomotic biliary strictures (NAS) after orthotopic liver transplantation (OLT) are associated with high retransplant rates. The aim of the present study was to describe the treatment of and identify risk factors for radiological progression of bile duct abnormalities, recurrent cholangitis, biliary cirrhosis, and retransplantation in patients with NAS. We retrospectively studied 81 cases of NAS. Strictures were classified according to severity and location. Management of strictures was recorded. Possible prognostic factors for bacterial cholangitis, radiological progression of strictures, development of severe fibrosis/cirrhosis, graft survival, and patient survival were evaluated. Median follow-up after OLT was 7.9 years. NAS were most prevalent in the extrahepatic bile duct. Twenty-eight patients (35%) underwent some kind of interventional treatment, leading to a marked improvement in biochemistry. Progression of disease was noted in 68% of cases with radiological follow-up. Radiological progression was more prevalent in patients with early NAS and one or more episodes of bacterial cholangitis. Recurrent bacterial cholangitis (>3 episodes) was more prevalent in patients with a hepaticojejunostomy. Severe fibrosis or cirrhosis developed in 23 cases, especially in cases with biliary abnormalities in the periphery of the liver. Graft survival, but not patient survival, was influenced by the presence of NAS. Thirteen patients (16%) were retransplanted for NAS. In conclusion, especially patients with a hepaticojejunostomy, those with an early diagnosis of NAS, and those with NAS presenting at the level of the peripheral branches of the biliary tree, are at risk for progressive disease with severe outcome. PMID:17457935

Verdonk, Robert C; Buis, Carlijn I; van der Jagt, Eric J; Gouw, Annette S H; Limburg, Abraham J; Slooff, Maarten J H; Kleibeuker, Jan H; Porte, Robert J; Haagsma, Elizabeth B

2007-05-01

224

Laterality of Motor Symptom Onset, Disease Progression, and Cognition in Parkinson's Disease  

E-print Network

The current study examined whether laterality of initial motor symptom onset (left-sided onset vs. right-sided onset) in Parkinson's disease (PD) would predict the pattern and/or severity of cognitive deficits measured at various stages of disease...

Chau, Phuong My

2010-08-31

225

Sirolimus attenuates disease progression in an orthologous mouse model of human autosomal dominant polycystic kidney disease  

Microsoft Academic Search

In autosomal dominant polycystic kidney disease (ADPKD), abnormal proliferation of tubular cells drives cyst development and growth. Sirolimus, an inhibitor of the protein kinase mammalian target of rapamycin (mTOR) and a potent anti-proliferative agent, decreases cyst growth in several genetically distinct rodent models of polycystic kidney disease (PKD). We determined here the effect of sirolimus on renal cyst growth in

Iram Zafar; Kameswaran Ravichandran; Franck A Belibi; R Brian; Charles L Edelstein

2010-01-01

226

Disease Progression in Hemodynamically Stable Patients Presenting to the Emergency Department With Sepsis  

PubMed Central

Background Aggressive diagnosis and treatment of patients presenting to the emergency department (ED) with septic shock has been shown to reduce mortality. To enhance the ability to intervene in patients with lesser illness severity, a better understanding of the natural history of the early progression from simple infection to more severe illness is needed. Objectives The objectives were to 1) describe the clinical presentation of ED sepsis, including types of infection and causative microorganisms, and 2) determine the incidence, patient characteristics, and mortality associated with early progression to septic shock among ED patients with infection. Methods This was a multicenter study of adult ED patients with sepsis but no evidence of shock. Multivariable logistic regression was used to identify patient factors for early progression to shock and its association with 30-day mortality. Results Of 472 patients not in shock at ED presentation (systolic blood pressure > 90 mm Hg and lactate < 4 mmol / L), 84 (17.8%) progressed to shock within 72 hours. Independent factors associated with early progression to shock included older age, female sex, hyperthermia, anemia, comorbid lung disease, and vascular access device infection. Early progression to shock (vs. no progression) was associated with higher 30-day mortality (13.1% vs. 3.1%, odds ratio [OR] = 4.72, 95% confidence interval [CI] = 2.01 to 11.1; p ? 0.001). Among 379 patients with uncomplicated sepsis (i.e., no evidence of shock or any end-organ dysfunction), 86 (22.7%) progressed to severe sepsis or shock within 72 hours of hospital admission. Conclusions A significant portion of ED patients with less severe sepsis progress to severe sepsis or shock within 72 hours. Additional diagnostic approaches are needed to risk stratify and more effectively treat ED patients with sepsis. PMID:20370777

Glickman, Seth W.; Cairns, Charles B.; Otero, Ronny M.; Woods, Christopher W.; Tsalik, Ephraim L.; Langley, Raymond J.; van Velkinburgh, Jennifer C.; Park, Lawrence P.; Glickman, Lawrence T.; Fowler, Vance G.; Kingsmore, Stephen F.; Rivers, Emanuel P.

2014-01-01

227

Progression of structural neuropathology in preclinical Huntington's disease: a tensor based morphometry study  

PubMed Central

Background and objectives: Regional cerebral atrophy occurs in carriers of the Huntington's disease (HD) gene mutation before clinical diagnosis is possible. The current inability to reliably measure progression of pathology in this preclinical phase impedes development of therapies to delay clinical onset. We hypothesised that longitudinal statistical imaging would detect progression of structural pathology in preclinical carriers of the HD gene mutation, in the absence of measurable clinical change. Methods: Thirty subjects (17 preclinical mutation positive, 13 mutation negative) underwent serial clinical and magnetic resonance imaging (MRI) assessments over an interval of 2 years. Statistically significant changes in regional grey and white matter volume on MRI were analysed using tensor based morphometry (TBM). This technique derives a voxel-wise estimation of regional tissue volume change from the deformation field required to warp a subject's early to late T1 images. Results: Over 2 years, there was progressive regional grey matter atrophy in mutation-positive relative to negative subjects, without significant clinical progression of disease. Significant grey matter volume loss was limited to bilateral putamen and globus pallidus externa (GPe), left caudate nucleus, and left ventral midbrain in the region of the substantia nigra. Conclusions: While these results are consistent with previous cross sectional pathologic and morphometric studies, significant progression of atrophy in HD before the onset of significant clinical decline is now demonstrable with longitudinal statistical imaging. Such measures could be used to assess the efficacy of potential disease modifying drugs in slowing the progression of pathology before confirmed clinical onset of HD. PMID:15834021

Kipps, C; Duggins, A; Mahant, N; Gomes, L; Ashburner, J; McCusker, E

2005-01-01

228

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

PubMed Central

Objectives To develop a scale sensitive for the neurological manifestations of Creutzfeldt-Jakob disease (CJD). Methods A 26-item CJD neurological status scale (CJD-NS) was created based on characteristic disease manifestations. Each sign was assigned to one of eight neurological systems to calculate a total scale score (TSS) and a system involvement score (SIS). The scale was administered to 37 CJD patients, 101 healthy first-degree relatives of the patients and 14 elderly patients with Parkinson's disease (PD). Results The mean TSS (±SD) was significantly higher in patients with CJD (13.19±5.63) compared to normal controls (0.41±0.78) and PD patients (9.71±3.05). The mean SIS was also significantly different between the CJD (5.19±1.22) and PD (2.78±1.18 p<0.01) groups reflecting the disseminated nature of neurological involvement in CJD. Using a cutoff of TSS>4 yielded a sensitivity of 97% for CJD, and specificity of 100% against healthy controls. All individual items showed excellent specificity against healthy subjects, but sensitivity was highly variable. Repeat assessments of CJD patients over 3-9 months revealed a time-dependent increase of both the TSS and the SIS reflecting the scale's ability to track disease progression. Conclusions The CJD-NS scale is sensitive to neurological signs and their progression in CJD patients. PMID:21303352

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

2011-01-01

229

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

SciTech Connect

Bile acids (BAs) have many physiological roles and exhibit both toxic and protective influences within the liver. Alterations in the BA profile may be the result of disease induced liver injury. Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of chronic liver disease characterized by the pathophysiological progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The hypothesis of this study is that the ‘classical’ (neutral) and ‘alternative’ (acidic) BA synthesis pathways are altered together with hepatic BA composition during progression of human NAFLD. This study employed the use of transcriptomic and metabolomic assays to study the hepatic toxicologic BA profile in progressive human NAFLD. Individual human liver samples diagnosed as normal, steatosis, and NASH were utilized in the assays. The transcriptomic analysis of 70 BA genes revealed an enrichment of downregulated BA metabolism and transcription factor/receptor genes in livers diagnosed as NASH. Increased mRNA expression of BAAT and CYP7B1 was observed in contrast to decreased CYP8B1 expression in NASH samples. The BA metabolomic profile of NASH livers exhibited an increase in taurine together with elevated levels of conjugated BA species, taurocholic acid (TCA) and taurodeoxycholic acid (TDCA). Conversely, cholic acid (CA) and glycodeoxycholic acid (GDCA) were decreased in NASH liver. These findings reveal a potential shift toward the alternative pathway of BA synthesis during NASH, mediated by increased mRNA and protein expression of CYP7B1. Overall, the transcriptomic changes of BA synthesis pathway enzymes together with altered hepatic BA composition signify an attempt by the liver to reduce hepatotoxicity during disease progression to NASH. - Highlights: ? Altered hepatic bile acid composition is observed in progressive NAFLD. ? Bile acid synthesis enzymes are transcriptionally altered in NASH livers. ? Increased levels of taurine and conjugated bile acids are observed in NASH. ? Hepatic bile acid synthesis shifts toward the alternative pathway in NASH.

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

2013-04-15

230

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

PubMed Central

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

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

2014-01-01

231

Progressive, massive osteolysis of mandible (Gorham’s disease): report of a case  

PubMed Central

A rare case of progressive osteolysis of mandible is discussed with clinicoradiological presentation. The purpose of the case report is to make the medical community aware of this rare and fascinating disorder in the maxillofacial region. The disease is characterised by spontaneous progressive osteolysis of one or more skeletal bones. Occurrence in maxillofacial region is rare with fewer than 35 reported cases affecting the facial and jaw bones. The present case report is about the mystery of bilaterally missing ascending rami. An attempt is made to draw attention of the medical fraternity to this unusual and rare entity which can induce instability, dysfunction and cosmetic disturbances. PMID:22605602

Kale, Manuvela Virendra; Gadre, Kiran S; Kulkarni, Adwait Uday

2012-01-01

232

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

PubMed Central

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

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

2014-01-01

233

Identifying progression related disease risk modules based on the human subcellular signaling networks.  

PubMed

Many studies have shown that the structure and dynamics of the human signaling network are disturbed in complex diseases such as coronary artery disease, and gene expression profiles can distinguish variations in diseases since they can accurately reflect the status of cells. Integration of subcellular localization and the human signaling network holds promise for providing insight into human diseases. In this study, we performed a novel algorithm to identify progression-related-disease-risk modules (PRDRMs) among patients of different disease states within eleven subcellular sub-networks from a human signaling network. The functional annotation and literature retrieval showed that the PRDRMs were strongly associated with disease pathogenesis. The results indicated that the PRDRM expression values as classification features had a good classification performance to distinguish patients of different disease states. Our approach compared with the method PageRank had a better classification performance. The identification of the PRDRMs in response to the dynamic gene expression change could facilitate our understanding of the pathological basis of complex diseases. Our strategy could provide new insights into the potential use of prognostic biomarkers and the effective guidance of clinical therapy from the human subcellular signaling network perspective. PMID:25315201

Xie, Ruiqiang; Huang, Hao; Li, Wan; Chen, Binbin; Jiang, Jing; He, Yuehan; Lv, Junjie; ma, Bo; Zhou, Yanyan; Feng, Chenchen; Chen, Lina; He, Weiming

2014-12-01

234

Kinetics of Disease Progression and Host Response in a Rat Model of Bubonic Plague  

PubMed Central

Plague, caused by the gram-negative bacterium Yersinia pestis, primarily affects rodents but is also an important zoonotic disease of humans. Bubonic plague in humans follows transmission by infected fleas and is characterized by an acute, necrotizing lymphadenitis in the regional lymph nodes that drain the intradermal flea bite site. Septicemia rapidly follows with spread to spleen, liver, and other organs. We developed a model of bubonic plague using the inbred Brown Norway strain of Rattus norvegicus to characterize the progression and kinetics of infection and the host immune response after intradermal inoculation of Y. pestis. The clinical signs and pathology in the rat closely resembled descriptions of human bubonic plague. The bacteriology; histopathology; host cellular response in infected lymph nodes, blood, and spleen; and serum cytokine levels were analyzed at various times after infection to determine the kinetics and route of disease progression and to evaluate hypothesized Y. pestis pathogenic mechanisms. Understanding disease progression in this rat infection model should facilitate further investigations into the molecular pathogenesis of bubonic plague and the immune response to Y. pestis at different stages of the disease. PMID:15855643

Sebbane, Florent; Gardner, Donald; Long, Daniel; Gowen, Brian B.; Hinnebusch, B. Joseph

2005-01-01

235

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

PubMed

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

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

2014-10-31

236

Renal CD14 expression correlates with the progression of cystic kidney disease  

PubMed Central

Monocyte and macrophage markers are among the most highly overexpressed genes in cpk mouse kidneys with severely progressive renal cystic disease. We now demonstrate that one of these markers, CD14, is abnormally transcribed, activated and shed in cystic kidneys. However, these abnormalities are not associated with an increased number of interstitial CD14-positive mononuclear cells. Instead, we show that most non-cystic and cystic renal tubular epithelia are CD14-positive and that CD14 can be produced even by distal nephron-derived principal cells. Cd14 overexpression is significant in as early as 5-d old sporadically cystic cpk kidneys and it further increases during the disease progression. Similarly, in a cpk model with variable rates of cystic kidney disease progression, a (C57BL/6J-cpk × CAST/Ei)F1 intercross, Cd14 expression positively correlates with kidney volume in 10-d old mice, exceeding the correlation of a gene encoding an established autosomal dominant polycystic kidney disease (ADPKD) marker, MCP-1 (r=0.94 vs. r=0.79; both p<0.001). Similarly, in a small group of ADPKD patients (n=16), baseline urinary CD14 levels (but not GFR) correlate with a two-year rate of total kidney volume change (overall r=0.43, p=0.09; for males r=0.74, p=0.02) suggesting potential utility of CD14 in predicting ADPKD outcomes. PMID:20555320

Zhou, Juling; Ouyang, Xiaosen; Cui, Xiangqin; Schoeb, Trenton R.; Smythies, Lesley E.; Johnson, Martin R.; Guay-Woodford, Lisa M.; Chapman, Arlene B.; Mrug, Michal

2011-01-01

237

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

PubMed Central

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

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

2013-01-01

238

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. PMID:20603455

Thambisetty, Madhav; Simmons, Andrew; Velayudhan, Latha; Hye, Abdul; Campbell, James; Zhang, Yi; Wahlund, Lars-Olof; Westman, Eric; Kinsey, Anna; Güentert, 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

239

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

Microsoft Academic Search

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

Douglas M. Silverstein

2009-01-01

240

Justine et al., 2009 Manuscript published in Diseases of Aquatic Organisms 1 Manuscript published in Diseases of Aquatic Organisms 85: 245-249, 2009  

E-print Network

Justine et al., 2009 Manuscript published in Diseases of Aquatic Organisms 1 Manuscript published, 3 (2009) 245-249" DOI : 10.3354/dao02082 #12;Justine et al., 2009 Manuscript published in Diseases in Diseases of Aquatic Organisms 85: 245-249, 2009 doi: 10.3354/dao02082 Turbellarian black spot disease

Boyer, Edmond

241

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

PubMed Central

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney condition and is associated with important renal and cardiovascular manifestations in childhood. Renal cystic disease can be documented in some cases as early as in utero. Early intervention is critical if the long-term complications of this condition, including end-stage renal disease, are to be ameliorated. Here we describe our ongoing randomized double-blind placebo-controlled phase III clinical trial to assess the effect of pravastatin treatment on renal and cardiovascular disease progression in 107 children and young adults age 8–22 years with ADPKD who are receiving the angiotensin converting enzyme inhibitor lisinopril. Baseline demographic and laboratory data are provided. Results of this study could markedly impact the standard of care for evaluation and treatment of ADPKD in this population. PMID:21266204

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

2011-01-01

242

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

PubMed Central

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

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

2014-01-01

243

UPDRS activity of daily living score as a marker of Parkinson's disease progression.  

PubMed

The activities of daily living (ADL) subscore of the Unified Parkinson's Disease Rating Scale (UPDRS) captures the impact of Parkinson's disease (PD) on daily function and may be less affected than other subsections by variability associated with drug cycle and motor fluctuations. We examined UPDRS mentation, ADL and motor subscores in 888 patients with idiopathic PD. Multiple linear regression analyses determined the association between disease duration and UPDRS subscores as a function of medication status at examination and in a subset of patients with multiple examinations. Independent of medication status and across cross-sectional and longitudinal analyses, ADL subscores showed a stronger and more stable association with disease duration than other UPDRS subscores after adjusting for age of disease onset. The association between disease duration and the motor subscore depended on medication status. The strong association between ADL subscore and disease duration in PD suggests that this measure may serve as a better marker of disease progression than signs and symptoms assessed in other UPDRS sections. PMID:18951537

Harrison, Madaline B; Wylie, Scott A; Frysinger, Robert C; Patrie, James T; Huss, Diane S; Currie, Lillian J; Wooten, G Frederick

2009-01-30

244

Effectiveness of selective dorsal rhizotomy in 2 patients with progressive spasticity due to neurodegenerative disease.  

PubMed

Selective dorsal rhizotomy at the lumbar level is a neurosurgical procedure, which reduces spasticity in the legs. Its effect has mainly been studied in children with spastic cerebral palsy. Little is known about the outcome of selective dorsal rhizotomy in patients with neurodegenerative disorders. We report the clinical course after selective dorsal rhizotomy in 2 patients with progressive spasticity. Leg spasticity was effectively and persistently reduced in both patients, facilitating care and improving sitting comfort. However, spasticity of the arms and other motor disturbances, such as spontaneous extension spasms and the ataxia, increased gradually in time. Selective dorsal rhizotomy leads to a disappearance of leg spasticity in patients with a neurodegenerative disease. Other motor signs are not influenced and may increase due to the progressive nature of the underlying disease. PMID:18658081

Grunt, Sebastian; van der Knaap, Marjo S; van Ouwerkerk, Willem J R; Strijers, Rob L M; Becher, Jules G; Vermeulen, R Jeroen

2008-07-01

245

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

PubMed Central

Survival rates among HIV patients have significantly improved since the introduction of antiretroviral therapy (ART) in HIV management. However, persistent disease progression and clinical complications in virally suppressed individuals point to additional contributing factors other than HIV replication; microbial translocation is one such factor. The role of underlying commensal microbes and microbial products that traverse the intestinal lumen into systemic circulation in the absence of overt bacteraemia is under current investigation. This review focuses on current knowledge of the complex microbial communities and microbial markers involved in the disruption of mucosal immune T-cells in the promotion of inflammatory processes in HIV infections. Unanswered questions and aims for future studies are addressed. We provide perspective for discussing potential future therapeutic strategies focused on modulating the gut microbiota to abate HIV disease progression. PMID:25024700

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

2014-01-01

246

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. PMID:19707561

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

2009-01-01

247

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

PubMed

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

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

2010-01-01

248

Neural effects of inflammation, cardiovascular disease, and HIV: Parallel, perpendicular, or progressive?  

PubMed

The pervasive reach of the inflammatory system is evidenced by its involvement in numerous disease states. Cardiovascular disease, marked by high levels of circulating inflammatory mediators, affects an estimated 83.6 million Americans. Similarly, human immunodeficiency virus (HIV) produces a paradoxical state of generalized immune activity despite widespread immunosuppression, and affects 35 million people worldwide. Patients living with HIV (PLWH) suffer from inflammatory conditions, including cardiovascular disease (CVD), at a rate exceeding the general population. In this combined disease state, immune mechanisms that are common to both CVD and HIV may interact to generate a progressive condition that contributes to the exacerbated pathogenesis of the other to the net effect of damage to the brain. In this review, we will outline inflammatory cell mediators that promote cardiovascular risk factors and disease initiation and detail how HIV-related proteins may accelerate this process. Finally, we examine the extent to which these comorbid conditions act as parallel, perpendicular, or progressive sequela of events to generate a neurodegenerative environment, and consider potential strategies that can be implemented to reduce the burden of CVD and inflammation in PLWH. PMID:25239371

Nemeth, C L; Bekhbat, M; Neigh, G N

2014-09-17

249

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

PubMed Central

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

2014-01-01

250

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

PubMed Central

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

Lee, Stephanie J.

2010-01-01

251

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

PubMed

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

Lee, Stephanie J

2010-12-01

252

Novel insights into the relationship between glomerular pathology and progressive kidney disease.  

PubMed

Both glomerular and tubulointerstitial damage are important factors in the pathophysiology and progression of nephropathy. Glomerular injury is associated with tubulointerstitial inflammation, and many studies show that tubulointerstitial changes correlate well with progressive renal functional decline. Strong evidence supports the concept that once established, proteinuric glomerular injury can cause tubular injury. This review briefly summarizes the pathophysiological consequences of glomerular damage that are responsible for tubulointerstitial injury. It further focuses on tubule-derived renal injury biomarkers that may be used to monitor the progression of kidney disease. This monitoring is predicted to become increasingly useful as novel therapeutic interventions preventing progressive renal damage are introduced. In particular, biomarkers of kidney dysfunction, such as urinary podocytes, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, hematopoietic growth factor-inducible neurokinin 1, or periostin, might be useful in the diagnosis or detection of early nephropathy and risk assessment of kidney disease. However, these biomarkers require further study before they are used in routine screening or in guiding patient therapy. PMID:22449346

Satirapoj, Bancha; Nast, Cynthia C; Adler, Sharon G

2012-03-01

253

Effects of Ionizing Radiation on Progressive Experimental Renal Disease: A Hemodynamic Approach  

Microsoft Academic Search

In order to evaluate the progression of renal disease, Munich-Wistar rats were submitted to 5\\/6 nephrectomy and given whole-body x- or ?-irradiation with or without remnant kidney protection or were submitted only to remnant kidney irradiation. All groups received a single 6-Gy dose immediately after surgery. Whole-kidney function, glomerular hemodynamics, 24-hour proteinuria and histopathology were assessed 60 days after surgery

Vicente P. C. Teixeira; Helena R. C. Segreto; Mirian A. Boim; Clara V. Razvickas; Nestor Schor

2001-01-01

254

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

255

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

Microsoft Academic Search

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

GIUSEPPE REMUZZI; NORBERTO PERICO; MANUEL MACIA; PIERO RUGGENENTI

2005-01-01

256

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

Microsoft Academic Search

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

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

1987-01-01

257

Proton magnetic resonance spectroscopy in Parkinson's disease and progressive supranuclear palsy  

Microsoft Academic Search

OBJECTIVES: Proton magnetic resonance spectroscopy (1H-MRS) localised to the lentiform nucleus, was carried out in eight patients with idiopathic Parkinson's disease and five patients with progressive supranuclear palsy. The aim of the study was to assess the concentration of N-acetyl-aspartate (NAA), creatine and phosphocreatine (Cr), and choline containing compounds (Cho) in the putamen and globus pallidus of these patients. METHODS:

F Federico; I L Simone; V Lucivero; M De Mari; P Giannini; G Iliceto; D M Mezzapesa; P Lamberti

1997-01-01

258

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. PMID:23875073

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

2013-01-01

259

Development of ALS-like disease in SOD1 mice deficient of B lymphocytes  

Microsoft Academic Search

Several recent studies proposed a role for innate immunity and inflammation in the pathogenesis of amyotrophic lateral sclerosis\\u000a (ALS). However, possible links, if any, between disease and adaptive immunity are poorly understood. The present study probed\\u000a for the role of B cells in ALS disease using the G93A-SOD-1 transgenic mouse model. In agreement with other studies, we show\\u000a here that

Shulamit Naor; Zohar Keren; Tomer Bronshtein; Efrat Goren; Marcelle Machluf; Doron Melamed

2009-01-01

260

Generalizability of the Disease State Index Prediction Model for Identifying Patients Progressing from Mild Cognitive Impairment to Alzheimer's Disease.  

PubMed

Background: The Disease State Index (DSI) prediction model measures the similarity of patient data to diagnosed stable and progressive mild cognitive impairment (MCI) cases to identify patients who are progressing to Alzheimer's disease. Objectives: We evaluated how well the DSI generalizes across four different cohorts: DESCRIPA, ADNI, AddNeuroMed, and the Kuopio MCI study. Methods: The accuracy of the DSI in predicting progression was examined for each cohort separately using 10 × 10-fold cross-validation and for inter-cohort validation using each cohort as a test set for the model built from the other independent cohorts using bootstrapping with 10 repetitions. Altogether 875 subjects were included in the analysis. The analyzed data included a comprehensive set of age and gender corrected magnetic resonance imaging (MRI) features from hippocampal volumetry, multi-template tensor-based morphometry, and voxel-based morphometry as well as Mini-Mental State Examination (MMSE), APOE genotype, and additional cohort specific data from neuropsychological tests and cerebrospinal fluid measurements (CSF). Results: The DSI model was used to classify the patients into stable and progressive MCI cases. AddNeuroMed had the highest classification results of the cohorts, while ADNI and Kuopio MCI exhibited the lowest values. The MRI features alone achieved a good classification performance for all cohorts. For ADNI and DESCRIPA, adding MMSE, APOE genotype, CSF, and neuropsychological data improved the results. Conclusions: The results reveal that the prediction performance of the combined cohort is close to the average of the individual cohorts. It is feasible to use different cohorts as training sets for the DSI, if they are sufficiently similar. PMID:25201784

Hall, Anette; Muñoz-Ruiz, Miguel; Mattila, Jussi; Koikkalainen, Juha; Tsolaki, Magda; Mecocci, Patrizia; Kloszewska, Iwona; Vellas, Bruno; Lovestone, Simon; Visser, Pieter Jelle; Lötjonen, Jyrki; Soininen, Hilkka

2014-09-01

261

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

262

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

USGS Publications Warehouse

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

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

2001-01-01

263

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

PubMed

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

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

2015-03-01

264

Nonparametric network design and analysis of disease genes in oral cancer progression.  

PubMed

Biological networks in living organisms can be seen as the ultimate means of understanding the underlying mechanisms in complex diseases, such as oral cancer. During the last decade, many algorithms based on high-throughput genomic data have been developed to unravel the complexity of gene network construction and their progression in time. However, the small size of samples compared to the number of observed genes makes the inference of the network structure quite challenging. In this study, we propose a framework for constructing and analyzing gene networks from sparse experimental temporal data and investigate its potential in oral cancer. We use two network models based on partial correlations and kernel density estimation, in order to capture the genetic interactions. Using this network construction framework on real clinical data of the tissue and blood at different time stages, we identified common disease-related structures that may decipher the association between disease state and biological processes in oral cancer. Our study emphasizes an altered MET (hepatocyte growth factor receptor) network during oral cancer progression. In addition, we demonstrate that the functional changes of gene interactions during oral cancer progression might be particularly useful for patient categorization at the time of diagnosis and/or at follow-up periods. PMID:24608056

Kalantzaki, K; Bei, E S; Exarchos, K P; Zervakis, M; Garofalakis, M; Fotiadis, D I

2014-03-01

265

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

266

Voxel-based morphometry detects patterns of atrophy that help differentiate progressive supranuclear palsy and Parkinson's disease  

Microsoft Academic Search

Progressive supranuclear palsy (PSP) and Parkinson's disease (PD) are neurodegenerative diseases with distinctive pathological appearances. Early clinical diagnosis can be difficult. MRI may help differentiate PSP from PD, but the differences are often only obvious with advanced disease. It would be useful to have an unbiased assessment of difference to guide visual assessment of MRI as an aid to clinical

Shona Price; Dominic Paviour; Rachael Scahill; John Stevens; Martin Rossor; Andrew Lees; Nick Fox

2004-01-01

267

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

PubMed Central

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

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

2014-01-01

268

Novel White Matter Tract Integrity Metrics Sensitive to Alzheimer Disease Progression  

PubMed Central

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 (area under the receiver operating characteristic curve = 0.82–0.95), while widespread decreased axonal water fraction discriminated amnestic mild cognitive impairment from Alzheimer disease (area under the receiver operating characteristic curve = 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.

2014-01-01

269

Differential Virulence and Disease Progression following Mycobacterium tuberculosis Complex Infection of the Common Marmoset (Callithrix jacchus)  

PubMed Central

Existing small-animal models of tuberculosis (TB) rarely develop cavitary disease, limiting their value for assessing the biology and dynamics of this highly important feature of human disease. To develop a smaller primate model with pathology similar to that seen in humans, we experimentally infected the common marmoset (Callithrix jacchus) with diverse strains of Mycobacterium tuberculosis of various pathogenic potentials. These included recent isolates of the modern Beijing lineage, the Euro-American X lineage, and M. africanum. All three strains produced fulminant disease in this animal with a spectrum of progression rates and clinical sequelae that could be monitored in real time using 2-deoxy-2-[18F]fluoro-d-glucose (FDG) positron emission tomography (PET)/computed tomography (CT). Lesion pathology at sacrifice revealed the entire spectrum of lesions observed in human TB patients. The three strains produced different rates of progression to disease, various extents of extrapulmonary dissemination, and various degrees of cavitation. The majority of live births in this species are twins, and comparison of results from siblings with different infecting strains allowed us to establish that the infection was highly reproducible and that the differential virulence of strains was not simply host variation. Quantitative assessment of disease burden by FDG-PET/CT provided an accurate reflection of the pathology findings at necropsy. These results suggest that the marmoset offers an attractive small-animal model of human disease that recapitulates both the complex pathology and spectrum of disease observed in humans infected with various M. tuberculosis strain clades. PMID:23716617

Via, Laura E.; Weiner, Danielle M.; Schimel, Daniel; Lin, Philana Ling; Dayao, Emmanuel; Tankersley, Sarah L.; Cai, Ying; Coleman, M. Teresa; Tomko, Jaime; Paripati, Praveen; Orandle, Marlene; Kastenmayer, Robin J.; Tartakovsky, Michael; Rosenthal, Alexander; Portevin, Damien; Eum, Seok Yong; Lahouar, Saher; Gagneux, Sebastien; Young, Douglas B.; Flynn, JoAnne L.

2013-01-01

270

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

NASA Astrophysics Data System (ADS)

The role of mechanical properties in cancer disease and inflammation is still underinvestigated and even ignored in many oncological and immunological reviews. In particular, eight classical hallmarks of cancer have been proposed, but they still ignore the mechanics behind the processes that facilitate cancer progression. To define the malignant transformation of neoplasms and finally reveal the functional pathway that enables cancer cells to promote cancer progression, these classical hallmarks of cancer require the inclusion of specific mechanical properties of cancer cells and their microenvironment such as the extracellular matrix as well as embedded cells such as fibroblasts, macrophages or endothelial cells. Thus, this review will present current cancer research from a biophysical point of view and will therefore focus on novel physical aspects and biophysical methods to investigate the aggressiveness of cancer cells and the process of inflammation. As cancer or immune cells are embedded in a certain microenvironment such as the extracellular matrix, the mechanical properties of this microenvironment cannot be neglected, and alterations of the microenvironment may have an impact on the mechanical properties of the cancer or immune cells. Here, it is highlighted how biophysical approaches, both experimental and theoretical, have an impact on the classical hallmarks of cancer and inflammation. It is even pointed out how these biophysical approaches contribute to the understanding of the regulation of cancer disease and inflammatory responses after tissue injury through physical microenvironmental property sensing mechanisms. The recognized physical signals are transduced into biochemical signaling events that guide cellular responses, such as malignant tumor progression, after the transition of cancer cells from an epithelial to a mesenchymal phenotype or an inflammatory response due to tissue injury. Moreover, cell adaptation to mechanical alterations, in particular the understanding of mechano-coupling and mechano-regulating functions in cell invasion, appears as an important step in cancer progression and inflammatory response to injuries. This may lead to novel insights into cancer disease and inflammatory diseases and will overcome classical views on cancer and inflammation. In addition, this review will discuss how the physics of cancer and inflammation can help to reveal whether cancer cells will invade connective tissue and metastasize or how leukocytes extravasate and migrate through the tissue. In this review, the physical concepts of cancer progression, including the tissue basement membrane a cancer cell is crossing, its invasion and transendothelial migration as well as the basic physical concepts of inflammatory processes and the cellular responses to the mechanical stress of the microenvironment such as external forces and matrix stiffness, are presented and discussed. In conclusion, this review will finally show how physical measurements can improve classical approaches that investigate cancer and inflammatory diseases, and how these physical insights can be integrated into classical tumor biological approaches.

Mierke, Claudia Tanja

2014-07-01

271

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

2011-05-01

272

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

2013-03-01

273

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

PubMed Central

Objective To validate a Cardiometabolic Disease Staging (CMDS) system for assigning risk level for diabetes, and all-cause and cardiovascular disease (CVD) mortality. Design, and Methods Two large national cohorts, CARDIA and NHANES III, were used to validate CMDS. CMDS: Stage 0: metabolically healthy; Stage 1: 1 or 2 Metabolic Syndrome risk factors (other than IFG); Stage 2: IFG or IGT or Metabolic Syndrome (without IFG); Stage 3: 2 of 3 (IFG, IGT, and/or Metabolic Syndrome); Stage 4: T2DM/CVD. Results In the CARDIA study, compared with Stage 0 metabolically healthy subjects, adjusted risk for diabetes exponentially increased from Stage 1 (HR 2.83, 95% CI 1.76–4.55), to Stage 2 (HR 8.06, 95% CI 4.91–13.2), to Stage 3 (HR 23.5, 95% CI 13.7–40.1) (p for trend <0.001). In NHANES III, both cumulative incidence and multivariable adjusted hazard ratios markedly increased for both all-cause and CVD mortality with advancement of the risk stage from Stage 0 to 4. Adjustment for BMI minimally affected the risks for diabetes and all-cause/CVD mortality using CMDS. Conclusion CMDS can discriminate a wide range of risk for diabetes, CVD mortality, and all-cause mortality independent of BMI, and should be studied as a risk assessment tool to guide interventions that prevent and treat cardiometabolic disease. PMID:23894121

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

2013-01-01

274

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

PubMed

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

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

2013-07-10

275

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

PubMed Central

Background Despite a significant improvement in the management of chronic kidney disease (CKD), its incidence and prevalence has been increasing over the years. Progressive renal fibrosis is present in CKD and involves the participation of several cytokines, including Transforming growth factor-?1 (TGF-?1). Besides cardiovascular diseases and infections, several studies show that Vitamin D status has been considered as a non-traditional risk factor for the progression of CKD. Given the importance of vitamin D in the maintenance of essential physiological functions, we studied the events involved in the chronic kidney disease progression in rats submitted to ischemia/reperfusion injury under vitamin D deficiency (VDD). Methods Rats were randomized into four groups: Control; VDD; ischemia/reperfusion injury (IRI); and VDD+IRI. At the 62 day after sham or IRI surgery, we measured inulin clearance, biochemical variables and hemodynamic parameters. In kidney tissue, we performed immunoblotting to quantify expression of Klotho, TGF-?, and vitamin D receptor (VDR); gene expression to evaluate renin, angiotensinogen, and angiotensin-converting enzyme; and immunohistochemical staining for ED1 (macrophages), type IV collagen, fibronectin, vimentin, and ?-smooth mucle actin. Histomorphometric studies were performed to evaluate fractional interstitial area. Results IRI animals presented renal hypertrophy, increased levels of mean blood pressure and plasma PTH. Furthermore, expansion of the interstitial area, increased infiltration of ED1 cells, increased expression of collagen IV, fibronectin, vimentin and ?-actin, and reduced expression of Klotho protein were observed. VDD deficiency contributed to increased levels of plasma PTH as well as for important chronic tubulointerstitial changes (fibrosis, inflammatory infiltration, tubular dilation and atrophy), increased expression of TGF-?1 and decreased expression of VDR and Klotho protein observed in VDD+IRI animals. Conclusion Through inflammatory pathways and involvement of TGF-?1 growth factor, VDD could be considered as an aggravating factor for tubulointerstitial damage and fibrosis progression following acute kidney injury induced by ischemia/reperfusion. PMID:25222475

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

2014-01-01

276

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

PubMed Central

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

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

2014-01-01

277

Differential expression and processing of matrix metalloproteinase 19 marks progression of gastrointestinal diseases.  

PubMed

Matrix metalloproteinases (MMPs), responsible for extracellular matrix remodelling and processing of numerous soluble and cell-surface proteins, appear to play important roles in pathogenesis of gastrointestinal diseases. MMPs influence migration of inflammatory cells, mucosal destruction, matrix deposition and degradation. In this study, we analysed the expression of MMP-19 in the main forms of gastrointestinal diseases including inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease, and colorectal carcinoma. We identified prominent MMP-19 expression in unaffected areas of intestinal epithelia and macrophages but not in other cells or tissues. Abundant expression of MMP-19 was also found in the endothelium of blood and lymphatic vessels of inflamed intestinal tissue. High MMP-19 immunoreactivity was also associated with macrophages in inflamed areas and myenteric plexuses. In comparison to the intestinal epithelium, all these cell types and compartments appeared to express MMP-19 irrespective of the disease pathogenesis and progression. Intestinal epithelia exhibited striking differential immunoreactivity for MMP-19. While immunoreactivity of monoclonal antibody recognizing the propeptide domain declined in virtually all IBD and colorectal carcinoma samples, other polyclonal antibodies against the hinge region and propetide domain did not show such an obvious decrease. Additional Western blotting analysis revealed that the antibodies against MMP-19 recognize differently processed forms of this MMP. The disappearance of immunoreactivity of the monoclonal anti-propeptide domain antibody does not mean down-regulation of MMP-19, but processing of the immature form. As this processing likely leads to the activation of this MMP, the differential staining pattern may be an important sign of disease progression. PMID:25056434

Cervinková, M; Horák, P; Kanchev, I; Mat?j, R; Fanta, J; Sequens, R; Kašpárek, P; Sarnová, L; Ture?ková, J; Sedlá?ek, R

2014-01-01

278

Effect of oral alkali supplementation on progression of chronic kidney disease.  

PubMed

Metabolic acidosis is a frequent but asymptomatic complication in chronic kidney disease (CKD). In early stages of CKD acidosis is limited to the renal tissue and progresses to reduced serum bicarbonate levels. Reduced renal tissue pH and increased ammoniagenesis are the key mechanisms of the kidney to enhance acid excretion to the urine. The expressed protein patterns in the proximal tubular epithelial cells change remarkably, the proximal convoluted tubule develops hypertrophy, and an intra-renal enhanced renin-angiotensin-system leads to interstitial fibrosis. Since nephrons are numerically reduced in CKD each remaining functional unit has to progressively increase these mechanisms to keep up the equilibrium. The adverse effects of chronic metabolic acidosis include aside from acceleration of progression of kidney disease, the development or exacerbation of bone disease, increased degradation of muscle with muscle wasting, enhanced protein degradation and inflammation. Genome wide association studies demonstrated that tubular acid-base transporters are involved in the development of arterial hypertension. Several retrospective analyses have indicated that low serum bicarbonate predicts death in cohorts with CKD and cardiovascular disease. All studies confirmed a U-shaped association of mortality and serum bicarbonate, indicating that both, acidosis and alkalosis are associated with increased mortality. Randomized controlled trials showed that base substitution, either by modification of the diet or by simply adding alkalizing agents, might halt the decline of kidney function in subjects with CKD. In 2012 a meta-analysis concluded that alkali therapy might provide a long-term favorable effect on renal function in patients with CKD. PMID:25549843

Gaggl, Martina; Sliber, Christopher; Sunder-Plassmann, Gere

2014-01-01

279

Cerebrospinal fluid detection of interleukin-1? in phase of remission predicts disease progression in multiple sclerosis  

PubMed Central

Background Absence of clinical and radiological activity in relapsing–remitting multiple sclerosis (RRMS) is perceived as disease remission. We explored the role of persisting inflammation during remission in disease evolution. Methods Cerebrospinal fluid (CSF) levels of interleukin 1? (IL-1?), a major proinflammatory cytokine, were measured in 170 RRMS patients at the time of clinical and radiological remission. These patients were then followed up for at least 4 years, and clinical, magnetic resonance imaging (MRI) and optical coherence tomography (OCT) measures of disease progression were recorded. Results Median follow-up of RRMS patients was 5 years. Detection of CSF IL-1? levels at the time of remission did not predict earlier relapse or new MRI lesion formation. Detection of IL-1? in the CSF was instead associated with higher progression index (PI) and Multiple Sclerosis Severity Scale (MSSS) scores at follow-up, and the number of patients with sustained Expanded Disability Status Scale (EDSS) or Multiple Sclerosis Functional Composite worsening at follow-up was higher in individuals with detectable levels of IL-1?. Patients with undetectable IL-1? in the CSF had significantly lower PI and MSSS scores and a higher probability of having a benign MS phenotype. Furthermore, patients with undetectable CSF levels of IL-1? had less retinal nerve fiber layer thickness and macular volume alterations visualized by OCT compared to patients with detectable IL-1?. Conclusions Our results suggest that persistence of a proinflammatory environment in RRMS patients during clinical and radiological remission influences midterm disease progression. Detection of IL-1? in the CSF at the time of remission appears to be a potential negative prognostic factor in RRMS patients. PMID:24548694

2014-01-01

280

Oral health information systems--towards measuring progress in oral health promotion and disease prevention.  

PubMed Central

This article describes the essential components of oral health information systems for the analysis of trends in oral disease and the evaluation of oral health programmes at the country, regional and global levels. Standard methodology for the collection of epidemiological data on oral health has been designed by WHO and used by countries worldwide for the surveillance of oral disease and health. Global, regional and national oral health databanks have highlighted the changing patterns of oral disease which primarily reflect changing risk profiles and the implementation of oral health programmes oriented towards disease prevention and health promotion. The WHO Oral Health Country/Area Profile Programme (CAPP) provides data on oral health from countries, as well as programme experiences and ideas targeted to oral health professionals, policy-makers, health planners, researchers and the general public. WHO has developed global and regional oral health databanks for surveillance, and international projects have designed oral health indicators for use in oral health information systems for assessing the quality of oral health care and surveillance systems. Modern oral health information systems are being developed within the framework of the WHO STEPwise approach to surveillance of noncommunicable, chronic disease, and data stored in the WHO Global InfoBase may allow advanced health systems research. Sound knowledge about progress made in prevention of oral and chronic disease and in health promotion may assist countries to implement effective public health programmes to the benefit of the poor and disadvantaged population groups worldwide. PMID:16211160

Petersen, Poul Erik; Bourgeois, Denis; Bratthall, Douglas; Ogawa, Hiroshi

2005-01-01

281

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

PubMed Central

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

Watanabe, Shoji; Kaneko, Kumi; Yamanaka, Koji

2013-01-01

282

Vgf is a novel biomarker associated with muscle weakness in amyotrophic lateral sclerosis (ALS), with a potential role in disease pathogenesis  

PubMed Central

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Previous proteomic evidence revealed that the content of certain peptide fragments including Vgf-derived peptide aa 398-411 (Vgf398-411) of the precursor Vgf protein in the cerebral spinal fluid (CSF) correctly identified patients with ALS from normal and disease controls. Using quantitative ELISA immunoassay we found that the CSF levels of Vgf decreases with muscle weakness in patients with ALS. In SOD1 G93A transgenic mice, loss of full-length Vgf content in CSF, serum and in SMI-32 immunopositive spinal cord motor neurons is noted in asymptomatic animals (approximately 75 days old) and continues to show a progressive decline as animals weaken. In vitro studies show that viral-mediated exogenous Vgf expression in primary mixed spinal cord neuron cultures attenuates excitotoxic injury. Thus, while Vgf may be a reliable biomarker of progression of muscle weakness in patients with ALS, restoration of Vgf expression in spinal cord motor neurons may therapeutically rescue spinal cord motorneurons against excitotoxic injury. PMID:18432310

Zhao, Zhong; Lange, Dale J.; Ho, Lap; Bonini, Sara; Shao, Belinda; Salton, Stephen R.; Thomas, Sunil; Pasinetti, Giulio Maria

2008-01-01

283

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

PubMed

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

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

2013-01-01

284

Early myeloid dendritic cell dysregulation is predictive of disease progression in simian immunodeficiency virus infection.  

PubMed

Myeloid dendritic cells (mDC) are lost from blood in individuals with human immunodeficiency virus (HIV) infection but the mechanism for this loss and its relationship to disease progression are not known. We studied the mDC response in blood and lymph nodes of simian immunodeficiency virus (SIV)-infected rhesus macaques with different disease outcomes. Early changes in blood mDC number were inversely correlated with virus load and reflective of eventual disease outcome, as animals with stable infection that remained disease-free for more than one year had average increases in blood mDC of 200% over preinfection levels at virus set-point, whereas animals that progressed rapidly to AIDS had significant loss of mDC at this time. Short term antiretroviral therapy (ART) transiently reversed mDC loss in progressor animals, whereas discontinuation of ART resulted in a 3.5-fold increase in mDC over preinfection levels only in stable animals, approaching 10-fold in some cases. Progressive SIV infection was associated with increased CCR7 expression on blood mDC and an 8-fold increase in expression of CCL19 mRNA in lymph nodes, consistent with increased mDC recruitment. Paradoxically, lymph node mDC did not accumulate in progressive infection but rather died from caspase-8-dependent apoptosis that was reduced by ART, indicating that increased recruitment is offset by increased death. Lymph node mDC from both stable and progressor animals remained responsive to exogenous stimulation with a TLR7/8 agonist. These data suggest that mDC are mobilized in SIV infection but that an increase in the CCR7-CCL19 chemokine axis associated with high virus burden in progressive infection promotes exodus of activated mDC from blood into lymph nodes where they die from apoptosis. We suggest that inflamed lymph nodes serve as a sink for mDC through recruitment, activation and death that contributes to AIDS pathogenesis. PMID:21203477

Wijewardana, Viskam; Soloff, Adam C; Liu, Xiangdong; Brown, Kevin N; Barratt-Boyes, Simon M

2010-01-01

285

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

PubMed Central

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

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

2014-01-01

286

Long-term mineralocorticoid receptor blockade ameliorates progression of experimental diabetic renal disease.  

PubMed

The final end point of diabetic renal disease is the accumulation of excess collagen. A number of studies have shown that aldosterone antagonism ameliorates progression of renal fibrosis. This study was designed to examine the effect of the mineralocorticoid receptor blocker eplerenone (EPL) on progression in streptozotocin (STZ)-treated spontaneously hypertensive rats (SHR), an accelerated model of Type I diabetes. STZ-treated SHRs with a blood glucose >18 mmol/L were randomly divided into treatment (100 mg/kg/day EPL) and non-treatment groups. Sham-injected SHR animals were used as a control. Functional parameters were monitored for 16 weeks, with structural parameters assessed at completion. Both hyperglycaemic groups developed progressive albuminuria, but the increase was ameliorated by EPL from Week 12. STZ-SHRs had elevated kidney weight/body weight ratio, glomerular size, glomerular macrophages (ED-1-positive cells), tissue transforming growth factor beta 1 (TGF?1) concentrations and glomerular collagen IV staining (all P < 0.05 versus control animals). EPL reduced glomerular volume, TGF?1 expression and glomerular collagen IV without changing glomerular macrophage infiltration. The ability of EPL to ameliorate these functional and structural changes in hyperglycaemic SHRs suggest that EPL has a renoprotective role in diabetic renal disease. PMID:21908416

Lian, Michael; Hewitson, Tim D; Wigg, Belinda; Samuel, Chrishan S; Chow, Fiona; Becker, Gavin J

2012-03-01

287

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

PubMed

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

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

2009-11-01

288

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...

289

Measuring Disease Progression in Early Parkinson Disease: the National Institutes of Health Exploratory Trials in Parkinson Disease (NET-PD) Experience  

PubMed Central

Importance Optimizing assessments of rate of progression in Parkinson Disease (PD) is important in designing clinical trials, especially of potential disease-modifying agents. Objective To examine the value of measures of impairment, disability, and quality of life in assessing progression in early Parkinson disease. Design, Setting, and Participants Inception cohort analysis of data from 413 early, untreated PD patients, who were enrolled in two multicenter, randomized, double-blind clinical trials. Intervention Participants were randomized into five treatments: 67 received creatine, 66 minocycline, 71 Coenzyme Q10, 71 GPI-1485, and 138 placebo. We assessed the association between the rates of change in measures of impairment, disability, and quality of life and time to initiation of symptomatic treatment. Main Outcome Measure Time between baseline assessment and need for the initiation of symptomatic pharmaceutical treatment for PD was the primary indicator of disease progression. Results After adjusting for baseline confounding variables Unified Parkinson Disease Rating Scale (UPDRS) II, UPDRS III, modified Rankin score (mRS), level of education, and treatment group, the rate of change of the following measurements was assessed: UPDRS II, UPDRS III, Schwab and England ADL (S&E), Total Functional Capacity (TFC), Parkinson’s Disease Quality of Life Questionnaire – 39 (PDQ39) ADL and Summary Index (SI), Short Form -12v2 Health Survey (SF12) Physical Summary (PS), and SF12 Mental Summary (MS). Variables reaching statistical threshold in univariate analysis were entered into a multivariable Cox proportional hazards model using time to symptomatic treatment as the dependent variable. More rapid worsening of UPDRS II (HR 1.15, 95% C.I. 1.08 – 1.22 for 1 scale unit change per 6 months), UPDRS III (HR 1.09; 95% C.I. 1.06 – 1.13 for 1 scale unit change per 6 months), and S&E (HR 1.29 95% C.I. 1.12 – 1.48 for 5 percentage point change per 6 months), was associated with earlier need for symptomatic therapy. Conclusions and Relevance In early PD, UPDRS II and III, and S&E can be used to measure disease progression, while the PDQ39 ADL, PDQ39 SI, TFC, SF12 PH, and SF12 MH are not sensitive to change. Trial Registration clinicaltrials.gov identifiers NCT00063193 and NCT00076492 PMID:24711047

Parashos, Sotirios A.; Luo, Sheng; Biglan, Kevin M.; -Wollner, Ivan Bodis; He, Bo; Liang, Grace S.; Ross, G. Webster; Tilley, Barbara C.; Shulman, Lisa M.

2014-01-01

290

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

PubMed Central

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

Ringer, Cornelia; Büning, Luisa-Sybille; Schäfer, Martin K.H.; Eiden, Lee E.; Weihe, Eberhard; Schütz, Burkhard

2014-01-01

291

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

PubMed

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

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

2014-08-11

292

Circulating TGF-?1 as a reliable biomarker for chronic kidney disease progression in the African-American population  

PubMed Central

Progressive renal fibrosis is common to all chronic kidney diseases (CKD). Suthanthiran and colleagues identified a positive association between transforming growth factor-?1 and several risk factors for CKD progression in African Americans but not in whites. This study offers a possible explanation for the higher prevalence of end-stage renal disease in African Americans and highlights the need for a better therapeutic strategy for this population. PMID:19528989

Lee, Soo Bong; Kanasaki, Keizo; Kalluri, Raghu

2014-01-01

293

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

PubMed

Without effective therapy, chronic-phase chronic myeloid leukemia (CP-CML) evolves into an acute leukemia (blast crisis [BC]) that displays either myeloid or B-lymphoid characteristics. This transition is often preceded by a clinically recognized, but biologically poorly characterized, accelerated phase (AP). Here, we report that IKAROS protein is absent or reduced in bone marrow blasts from most CML patients with advanced myeloid disease (AP or BC). This contrasts with primitive CP-CML cells and BCR-ABL1-negative acute myeloid leukemia blasts, which express readily detectable IKAROS. To investigate whether loss of IKAROS contributes to myeloid disease progression in CP-CML, we examined the effects of forced expression of a dominant-negative isoform of IKAROS (IK6) in CP-CML patients' CD34(+) cells. We confirmed that IK6 disrupts IKAROS activity in transduced CP-CML cells and showed that it confers on them features of AP-CML, including a prolonged increased output in vitro and in xenografted mice of primitive cells with an enhanced ability to differentiate into basophils. Expression of IK6 in CD34(+) CP-CML cells also led to activation of signal transducer and activator of transcription 5 and transcriptional repression of its negative regulators. These findings implicate loss of IKAROS as a frequent step and potential diagnostic harbinger of progressive myeloid disease in CML patients. PMID:25370416

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

2015-01-15

294

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

PubMed Central

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

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

2014-01-01

295

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

PubMed Central

Without effective therapy, chronic-phase chronic myeloid leukemia (CP-CML) evolves into an acute leukemia (blast crisis [BC]) that displays either myeloid or B-lymphoid characteristics. This transition is often preceded by a clinically recognized, but biologically poorly characterized, accelerated phase (AP). Here, we report that IKAROS protein is absent or reduced in bone marrow blasts from most CML patients with advanced myeloid disease (AP or BC). This contrasts with primitive CP-CML cells and BCR-ABL1–negative acute myeloid leukemia blasts, which express readily detectable IKAROS. To investigate whether loss of IKAROS contributes to myeloid disease progression in CP-CML, we examined the effects of forced expression of a dominant-negative isoform of IKAROS (IK6) in CP-CML patients’ CD34+ cells. We confirmed that IK6 disrupts IKAROS activity in transduced CP-CML cells and showed that it confers on them features of AP-CML, including a prolonged increased output in vitro and in xenografted mice of primitive cells with an enhanced ability to differentiate into basophils. Expression of IK6 in CD34+ CP-CML cells also led to activation of signal transducer and activator of transcription 5 and transcriptional repression of its negative regulators. These findings implicate loss of IKAROS as a frequent step and potential diagnostic harbinger of progressive myeloid disease in CML patients. PMID:25370416

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

2015-01-01

296

Moyamoya Disease is a Progressive Occlusive Arteriopathy of the Primitive Internal Carotid Artery  

PubMed Central

Summary The purpose of this literature review is to disclose the relationship between the temporal profile of steno-occlusive changes in the cerebral arteries in moyamoya disease and the embryological evolution of the cerebral arteries. Steno-occlusive changes and progression occur in the sequence of embryological evolution of the primitive internal carotid artery in the early embryological stage. In other words, steno-occlusive changes in the cerebral arteries occur primarily near the bifurcation of the cranial and caudal divisions of the primitive internal carotid artery, evolve from the cranial division to the caudal one, and progress from the bifurcation centrifugally. Steno-occlusive changes do not occur essentially in the distal cortical branches of the primitive internal carotid artery, in any arteries in the external carotid system, which are derived from ventral pharyngeal system and primitive stapedial system, or in any cerebral arteries in the vertebrobasilar system, which are derived from the longitudinal neural arteries. These facts suggest that moyamoya disease is strongly related to the vasculogenesis of the primitive internal carotid artery and genetic factors play a major role in the clinical manifestations of moyamoya disease. PMID:20591301

Komiyama, M.

2003-01-01

297

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

PubMed Central

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

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

2014-01-01

298

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

PubMed

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. PMID:23316214

Wong, Garry; Nass, Richard

2012-01-01

299

Specific anti-gp41 antibodies predict HIV-1 disease progression.  

PubMed

The immunodeficiency-defining AIDS results from a progressive decline of CD4 cell count. We previously showed that 3S, a unique motif of the HIV-1 gp41 envelop protein, is highly conserved in HIV-1 strains and induces expression of NKp44L, rendering CD4 cells sensitive to NK killing. Here we found from a well-characterized cohort of 244 untreated HIV-1 seroconverters that high levels of anti-3S antibodies significantly delay spontaneous disease progression in the first years after seroconversion; this effect was not mediated through baseline viral load or CD4. These results could have important implications both for clinical care and better understanding of pathogenicity. PMID:22732471

Vieillard, Vincent; Crouzet, Joël; Boufassa, Faroudy; Sennepin, Alexis; Ho Tsong Fang, Raphaël; Debré, Patrice; Meyer, Laurence

2012-11-01

300

Involvement of CCR6/CCL20/IL-17 Axis in NSCLC Disease Progression  

PubMed Central

Objectives Autocrine and paracrine chemokine/chemokine receptor-based interactions promote non-small-cell-lung-cancer (NSCLC) carcinogenesis. CCL20/CCR6 interactions are involved in prostatic and colonic malignancy pathogenesis. The expression and function of CCL20/CCR6 and its related Th-17 type immune response in NSCLC is not yet defined. We sought to characterize the role of the CCL20/CCR6/IL-17 axis in NSCLC tumor growth. Methods A specialized histopathologist blindly assessed CCL20/CCR6 expression levels in 49 tissue samples of NSCLC patients operated in our department. Results were correlated to disease progression. Colony assays, ERK signaling and chemokine production were measured to assess cancer cell responsiveness to CCL20 and IL-17 stimulation. Results CCL20 was highly expressed in the majority (38/49, 77.5%) of tumor samples. Only a minority of samples (8/49, 16.5%) showed high CCR6 expression. High CCR6 expression was associated with a shorter disease-free survival (P?=?0.008) and conferred a disease stage-independent 4.87-fold increased risk for disease recurrence (P?=?0.0076, CI 95% 1.52–15.563). Cancerous cell colony-forming capacity was increased by CCL20 stimulation; this effect was dependent in part on ERK phosphorylation and signaling. IL-17 expression was detected in NSCLC; IL-17 potentiated the production of CCL20 by cancerous cells. Conclusion Our findings suggest that the CCL20/CCR6 axis promotes NSCLC disease progression. CCR6 is identified as a potential new prognostic marker and the CCL20/CCR6/IL-17 axis as a potential new therapeutic target. Larger scale studies are required to consolidate these observations. PMID:21949768

Amir, Gail; Demma, Jonathan; Vernea, Fiona; Beider, Katia; Shlomai, Zippora; Wald, Hanna; Zamir, Gideon; Shapira, Oz M.; Peled, Amnon; Wald, Ori

2011-01-01

301

Periodontal disease progression and glycaemic control among Gullah African Americans with type-2 diabetes  

PubMed Central

Aim To evaluate associations between glycaemic control and periodontitis progression among Gullah African Americans with type-2 diabetes mellitus (T2DM). Materials and Methods From an ongoing clinical trial among T2DM Gullah, we extracted a cohort previously in a cross-sectional study (N 5 88). Time from baseline (previous study) to follow-up (trial enrollment, before treatment interventions) ranged 1.93–4.08 years [mean 5 2.99, standard deviation (SD) = 0.36]. We evaluated tooth site-level periodontitis progression [clinical attachment loss (CAL) worsening of ? 2 mm, periodontal probing depth (PPD) increases of ? 2 mm and bleeding on probing (BOP) from none to present] by glycaemic control status (well-controlled = HbA1c < 7%, poorly-controlled = HbA1c ? 7%) using multivariable generalized estimating equations logistic regression, nesting tooth sites/person. Results Poorly-controlled T2DM (68.18%) was more prevalent than well-controlled T2DM (31.82%). Proportions of tooth sites/person with CAL progression between baseline and follow-up ranged 0.00–0.59 (mean = 0.12, SD = 0.12), while PPD and BOP progression ranged 0.00–0.44 (mean = 0.09, SD = 0.11) and 0.00–0.96 (mean = 0.24, SD = 0.18), respectively. Site-level PPD at baseline was a significant effect modifier of associations between poorly-controlled T2DM and site-level CAL and PPD progression [adjusted odds ratios (OR) according to poorly-controlled T2DM among PPD at baseline = 3, 5 and 7 mm, respectively: CAL progression = 1.93, 2.64, and 3.62, PPD progression = 1.98, 2.76, and 3.84; p < 0.05 for all]. Odds of site-level BOP progression were increased (OR = 1.24) for poorly-controlled T2DM, yet the results were not significant (p = 0.32). Conclusions These findings from a distinct, homogenous population further support the clinical relevance of identifying patients with poor glycaemic control and periodontitis, particularly among those with disparities for both diseases. PMID:20507373

Bandyopadhyay, Dipankar; Marlow, Nicole M.; Fernandes, Jyotika K.; Leite, Renata S.

2010-01-01

302

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

PubMed

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

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

2015-01-01

303

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

PubMed Central

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 framework for the prediction of AIDS disease progression in three stages (RP, SP, and LTNP) using the HIV structural gp120 profile. This new intelligent framework proves to be accurate and provides an important benchmark for predicting AIDS disease progression computationally. The model is trained using a novel HIV gp120 glycosylation structural profile to detect possible stages of AIDS disease progression for the target sequences of HIV+ individuals. The performance of the proposed model was compared to seven existing different machine-learning models on newly proposed gp120-Benchmark_1 dataset in terms of error-rate (MSE), accuracy (CCI), stability (STD), and complexity (TBM). The novel framework showed better predictive performance with 67.82% CCI, 30.21 MSE, 0.8 STD, and 2.62 TBM on the three stages of AIDS disease progression of 50 HIV+ individuals. This framework is an invaluable bioinformatics tool that will be useful to the clinical assessment of viral pathogenesis. PMID:21143806

2010-01-01

304

Progression of mild Alzheimer’s disease: knowledge and prediction models required for future treatment strategies  

PubMed Central

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

2013-01-01

305

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

PubMed

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

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

2014-12-01

306

Alzheimer's disease progression model based on integrated biomarkers and clinical measures  

PubMed Central

Aim: Biomarkers and image markers of Alzheimer's disease (AD), such as cerebrospinal fluid A?42 and p-tau, are effective predictors of cognitive decline or dementia. The aim of this study was to integrate these markers with a disease progression model and to identify their abnormal ranges. Methods: The data of 395 participants, including 86 normal subjects, 108 early mild cognitive impairment (EMCI) subjects, 120 late mild cognitive impairment (LMCI) subjects, and 81 AD subjects were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. For the participants, baseline and long-term data on cerebrospinal fluid A?42 and p-tau, hippocampal volume, and ADAS-cog were available. Various linear and nonlinear models were tested to determine the associations among the ratio of A?42 to p-tau (the Ratio), hippocampal volume and ADAS-cog. Results: The most likely models for the Ratio, hippocampal volume, and ADAS-cog (logistic, Emax, and linear models, respectively) were used to construct the final model. Baseline disease state had an impact on all the 3 endpoints (the Ratio, hippocampal volume, and ADAS-cog), while APOE?4 genotype and age only influence the Ratio and hippocampal volume. Conclusion: The Ratio can be used to identify the disease stage for an individual, and clinical measures integrated with the Ratio improve the accuracy of mild cognitive impairment (MCI) to AD conversion forecasting. PMID:25088003

Qiu, Yue; Li, Liang; Zhou, Tian-yan; Lu, Wei

2014-01-01

307

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

PubMed Central

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

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

2014-01-01

308

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

PubMed Central

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

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

2014-01-01

309

Effects of FDA approved medications for Alzheimer’s disease on clinical progression  

PubMed Central

Background Observational studies suggest cholinesterase inhibitors and/or memantine may delay clinical progression of Alzheimer’s disease (AD) in 40% of individuals taking the medications. Given this response and existence of side effects, we sought to quantify medication use and benefits in a population-based study of incident AD cases. Methods The Cache County Dementia Progression study (DPS) enrolled and followed a cohort of 327 incident AD cases up to 9 years. Drug exposure was expressed using a persistency index (PI), calculated as total years of drug use divided by total years of observation. Linear mixed effects models examined PI, and interactions with sex and APOE ?4, as predictors of clinical progression on the Mini-Mental State Exam (MMSE) and Clinical Dementia Rating-Sum of Boxes (CDR-Sum). Results Sixty-nine participants (21.1%) ever used cholinesterase inhibitors or memantine. There was a strong three-way interaction between PI, sex, and time. Among women, a higher PI (i.e. greater duration of use) of cholinesterase inhibitors was associated with slower progression on the MMSE and CDR-Sum, particularly among those with an APOE ?4 allele. In contrast, higher PI was associated with faster progression in males. Conclusion A low percentage of individuals with AD in the community are taking cholinesterase inhibitors or memantine. This study suggests that women, particularly those with an APOE ?4 allele, may receive the most benefit from these medications. With the newly approved increased dose of donepezil, it will be imperative to determine whether a higher dose is needed in men or whether other factors warrant consideration. PMID:22301194

Mielke, Michelle M.; Leoutsakos, Jeannie-Marie; Corcoran, Chris D.; Green, Robert C.; Norton, Maria C.; Welsh-Bohmer, Kathleen A.; Tschanz, JoAnn T.; Lyketsos, Constantine G.

2011-01-01

310

Association between Free Light Chain Levels, and Disease Progression and Mortality in Chronic Kidney Disease  

PubMed Central

Immunoglobulin free light chains (FLCs) form part of the middle molecule group of uremic toxins. Accumulation of FLCs has been observed in patients with chronic kidney disease (CKD). The aim of the present study was to measure FLC levels in patients at different CKD stages and to assess putative associations between FLC levels on one hand and biochemical/clinical parameters and mortality on the other. One hundred and forty patients at CKD stages 2-5D were included in the present study. Routine clinical biochemistry assays and assays for FLC kappa (?) and lambda (?) and other uremic toxins were performed. Vascular calcification was evaluated using radiological techniques. The enrolled patients were prospectively monitored for mortality. Free light chain ? and ? levels were found to be elevated in CKD patients (especially in those on hemodialysis). Furthermore, FLC ? and ? levels were positively correlated with inflammation, aortic calcification and the levels of various uremic toxins levels. A multivariate linear regression analysis indicated that FLC ? and ? levels were independently associated with CKD stages and ?2 microglobulin levels. Elevated FLC ? and ? levels appeared to be associated with mortality. However, this association disappeared after adjustment for a propensity score including age, CKD stage and aortic calcification. In conclusion, our results indicate that FLC ? and ? levels are elevated in CKD patients and are associated with inflammation, vascular calcification and levels of other uremic toxins. The observed link between elevated FLC levels and mortality appears to depend on other well-known factors. PMID:24217396

Desjardins, Lucie; Liabeuf, Sophie; Lenglet, Aurélie; Lemke, Horst-Dieter; Vanholder, Raymond; Choukroun, Gabriel; Massy, Ziad A.

2013-01-01

311

Association between free light chain levels, and disease progression and mortality in chronic kidney disease.  

PubMed

Immunoglobulin free light chains (FLCs) form part of the middle molecule group of uremic toxins. Accumulation of FLCs has been observed in patients with chronic kidney disease (CKD). The aim of the present study was to measure FLC levels in patients at different CKD stages and to assess putative associations between FLC levels on one hand and biochemical/clinical parameters and mortality on the other. One hundred and forty patients at CKD stages 2-5D were included in the present study. Routine clinical biochemistry assays and assays for FLC kappa (?) and lambda (?) and other uremic toxins were performed. Vascular calcification was evaluated using radiological techniques. The enrolled patients were prospectively monitored for mortality. Free light chain ? and ? levels were found to be elevated in CKD patients (especially in those on hemodialysis). Furthermore, FLC ? and ? levels were positively correlated with inflammation, aortic calcification and the levels of various uremic toxins levels. A multivariate linear regression analysis indicated that FLC ? and ? levels were independently associated with CKD stages and ?2 microglobulin levels. Elevated FLC ? and ? levels appeared to be associated with mortality. However, this association disappeared after adjustment for a propensity score including age, CKD stage and aortic calcification. In conclusion, our results indicate that FLC ? and ? levels are elevated in CKD patients and are associated with inflammation, vascular calcification and levels of other uremic toxins. The observed link between elevated FLC levels and mortality appears to depend on other well-known factors. PMID:24217396

Desjardins, Lucie; Liabeuf, Sophie; Lenglet, Aurélie; Lemke, Horst-Dieter; Vanholder, Raymond; Choukroun, Gabriel; Massy, Ziad A

2013-11-01

312

Performance on the dementia rating scale in Parkinson's disease with dementia and dementia with Lewy bodies: comparison with progressive supranuclear palsy and Alzheimer's disease  

Microsoft Academic Search

Background: The relation between dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) is unknown. Objectives: To compare the cognitive profiles of patients with DLB and PDD, and compare those with the performance of patients with a subcortical dementia (progressive supranuclear palsy) and a corti- cal dementia (Alzheimer's disease). Design: Survey of cognitive features. Setting: General community in

D Aarsland; I Litvan; D Salmon; D Galasko; T Wentzel-Larsen; J P Larsen

2003-01-01

313

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

314

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

315

Comparison of the pattern of atrophy of the corpus callosum in frontotemporal dementia, progressive supranuclear palsy, and Alzheimer's disease  

Microsoft Academic Search

OBJECTIVESThe loss of the neurons in layer 3, one of the groups of cortical neurons most vulnerable in various degenerative brain diseases, results in axonal degeneration leading to atrophy of the corpus callosum. Previous studies showed callosal atrophy in three degenerative dementias: frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and Alzheimer's disease (AD). However, it is unclear whether a characteristic

Hiroshi Yamauchi; Hidenao Fukuyama; Yasuhiro Nagahama; Yukinori Katsumi; Takuya Hayashi; Chisako Oyanagi; Junji Konishi; Hideo Shio

2000-01-01

316

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

PubMed Central

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

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

2013-01-01

317

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

PubMed

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

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

2013-01-01

318

Not so rapid progression of peripheral vascular disease after diagnostic angiography.  

PubMed

It was recently reported that peripheral vascular disease may progress so rapidly after diagnostic angiography that most likely the diagnostic procedure is in some way responsible. Because flow-limiting arterial stenoses often become complete occlusions within hours or days of the diagnostic procedure, it was recommended that angioplasty be performed immediately after diagnostic angiography to avoid this complication. The authors attempted to confirm these findings before implementing this recommendation. In fact, they did not confirm the findings. Among 96 flow-limiting stenoses considered for angioplasty, the procedure was performed in 31 on the same day. Among the remaining 65 cases, in 64 the stenosis did not occlude and angioplasty was successfully performed. Only one stenosis was discovered to have thrombosed, and this occurred 3 weeks after diagnostic angiography. These results indicate that there is not such rapid progression of peripheral vascular disease after diagnostic angiography. It is not necessary to perform angioplasty of stenotic lesions emergently, and treatment is not impaired by electively scheduling the patient for the next available day. PMID:1530759

Naidich, J B; Crystal, K S; Stein, H L

1992-01-01

319

Type I interferon responses in rhesus macaques prevent SIV infection and slow disease progression.  

PubMed

Inflammation in HIV infection is predictive of non-AIDS morbidity and death, higher set point plasma virus load and virus acquisition; thus, therapeutic agents are in development to reduce its causes and consequences. However, inflammation may simultaneously confer both detrimental and beneficial effects. This dichotomy is particularly applicable to type I interferons (IFN-I) which, while contributing to innate control of infection, also provide target cells for the virus during acute infection, impair CD4 T-cell recovery, and are associated with disease progression. Here we manipulated IFN-I signalling in rhesus macaques (Macaca mulatta) during simian immunodeficiency virus (SIV) transmission and acute infection with two complementary in vivo interventions. We show that blockade of the IFN-I receptor caused reduced antiviral gene expression, increased SIV reservoir size and accelerated CD4 T-cell depletion with progression to AIDS despite decreased T-cell activation. In contrast, IFN-?2a administration initially upregulated expression of antiviral genes and prevented systemic infection. However, continued IFN-?2a treatment induced IFN-I desensitization and decreased antiviral gene expression, enabling infection with increased SIV reservoir size and accelerated CD4 T-cell loss. Thus, the timing of IFN-induced innate responses in acute SIV infection profoundly affects overall disease course and outweighs the detrimental consequences of increased immune activation. Yet, the clinical consequences of manipulation of IFN signalling are difficult to predict in vivo and therapeutic interventions in human studies should be approached with caution. PMID:25043006

Sandler, Netanya G; Bosinger, Steven E; Estes, Jacob D; Zhu, Richard T R; Tharp, Gregory K; Boritz, Eli; Levin, Doron; Wijeyesinghe, Sathi; Makamdop, Krystelle Nganou; del Prete, Gregory Q; Hill, Brenna J; Timmer, J Katherina; Reiss, Emma; Yarden, Ganit; Darko, Samuel; Contijoch, Eduardo; Todd, John Paul; Silvestri, Guido; Nason, Martha; Norgren, Robert B; Keele, Brandon F; Rao, Srinivas; Langer, Jerome A; Lifson, Jeffrey D; Schreiber, Gideon; Douek, Daniel C

2014-07-31

320

Recurrent ovarian cancer: how important is it to treat to disease progression?  

PubMed

Ovarian cancer is increasingly recognized as a chronic disease whose treatment is often characterized by administration of multiple, sequential active agents, each of which may or may not be accompanied by a tumor response. Despite the large proportion of patients who relapse and undergo longer-term treatment, the question of optimal treatment duration has not been fully addressed to date. For patients who progress on therapy, the answer is straightforward: they are switched to another active agent, presumably having a different mechanism of action from previous therapies with, ideally, limited overlapping toxicities. However, for patients who remain in partial response or who have stable disease, the answer is less apparent and less clear. The majority of oncologists believe that treatment beyond 6 cycles of a given therapy does not provide any additional benefit to patients. There are some data to support that treatment strategy. However, with the advent of new, less toxic agents, treatment to progression should be further explored. Agents that are potentially well suited for extended treatment intervals may include such properties as absence of cumulative toxicity, non-cross-resistance, positive benefit on quality of life, and convenient schedule. A number of active agents in ovarian cancer (platinum, paclitaxel, topotecan, liposomal doxorubicin, docetaxel, gemcitabine, and etoposide) will be reviewed in the context of what is known about cumulative toxicity, potential adverse effects on patients' quality of life, and evidence addressing the potential benefits of longer-term treatment. PMID:15569973

Herzog, Thomas J

2004-11-15

321

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

PubMed

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

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

2015-01-01

322

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

PubMed

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

Soory, M

2002-04-01

323

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

PubMed Central

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

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

2013-01-01

324

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. PMID:20200006

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

2010-01-01

325

MicroRNA-150 Is a Potential Biomarker of HIV/AIDS Disease Progression and Therapy  

PubMed Central

Background The surrogate markers of HIV/AIDS progression include CD4 T cell count and plasma viral load. But, their reliability has been questioned in patients on anti-retroviral therapy (ART). Five microRNAs (miRNAs) - miR-16, miR-146b-5p, miR-150, miR-191 and miR-223 in peripheral blood mononuclear cells (PBMCs) were earlier found to assign HIV/AIDS patients into groups with varying CD4 T cell counts and viral loads. In this pilot study, we profiled the expression of these five miRNAs in PBMCs, and two of these miRNAs (miR-146b-5p and miR-150) in the plasma of HIV/AIDS patients, including those on ART and those who developed ART resistance, to evaluate if these are biomarkers of disease progression and therapy. Results We quantified miRNA levels by quantitative reverse transcription polymerase chain reaction (qRT-PCR) using RNA isolated from PBMCs and plasma of healthy persons or HIV-infected patients who were (1) asymptomatic; (2) symptomatic and ART naïve; (3) on ART; and (4) failing ART. Our results show miR-150 (p<0.01) and to a lesser extent miR-146b-5p (p<0.05) levels in PBMCs to reliably distinguish between ART-naïve AIDS patients, those on ART, and those developing drug resistance and failing ART. The plasma levels of these two miRNAs also varied significantly between patients in these groups and between patients and healthy controls (p values <0.05). Conclusions We report for the first time that PBMC and plasma levels of miR-150 and miR-146b-5p are predictive of HIV/AIDS disease progression and therapy. PMID:24828336

Munshi, Saif Ullah; Panda, Harekrushna; Holla, Prasida; Rewari, Bharat Bhushan; Jameel, Shahid

2014-01-01

326

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

PubMed Central

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

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

2013-01-01

327

Progressive nigrostriatal terminal dysfunction and degeneration in the engrailed1 heterozygous mouse model of Parkinson's disease.  

PubMed

Current research on Parkinson's disease (PD) pathogenesis requires relevant animal models that mimic the gradual and progressive development of neuronal dysfunction and degeneration that characterizes the disease. Polymorphisms in engrailed 1 (En1), a homeobox transcription factor that is crucial for both the development and survival of mesencephalic dopaminergic neurons, are associated with sporadic PD. This suggests that En1 mutant mice might be a promising candidate PD model. Indeed, a mouse that lacks one En1 allele exhibits decreased mitochondrial complex I activity and progressive midbrain dopamine neuron degeneration in adulthood, both features associated with PD. We aimed to further characterize the disease-like phenotype of these En1(+/-) mice with a focus on early neurodegenerative changes that can be utilized to score efficacy of future disease modifying studies. We observed early terminal defects in the dopaminergic nigrostriatal pathway in En1(+/-) mice. Several weeks before a significant loss of dopaminergic neurons in the substantia nigra could be detected, we found that striatal terminals expressing high levels of dopaminergic neuron markers TH, VMAT2, and DAT were dystrophic and swollen. Using transmission electron microscopy, we identified electron dense bodies consistent with abnormal autophagic vacuoles in these terminal swellings. In line with these findings, we detected an up-regulation of the mTOR pathway, concurrent with a downregulation of the autophagic marker LC3B, in ventral midbrain and nigral dopaminergic neurons of the En1(+/-) mice. This supports the notion that autophagic protein degradation is reduced in the absence of one En1 allele. We imaged the nigrostriatal pathway using the CLARITY technique and observed many fragmented axons in the medial forebrain bundle of the En1(+/-) mice, consistent with axonal maintenance failure. Using in vivo electrochemistry, we found that nigrostriatal terminals in the dorsal striatum were severely deficient in dopamine release and reuptake. Our findings support a progressive retrograde degeneration of En1(+/-) nigrostriatal neurons, akin to what is suggested to occur in PD. We suggest that using the En1(+/-) mice as a model will provide further key insights into PD pathogenesis, and propose that axon terminal integrity and function can be utilized to estimate dopaminergic neuron health and efficacy of experimental PD therapies. PMID:25281317

Nordström, Ulrika; Beauvais, Geneviève; Ghosh, Anamitra; Pulikkaparambil Sasidharan, Baby Chakrapani; Lundblad, Martin; Fuchs, Julia; Joshi, Rajiv L; Lipton, Jack W; Roholt, Andrew; Medicetty, Satish; Feinstein, Timothy N; Steiner, Jennifer A; Escobar Galvis, Martha L; Prochiantz, Alain; Brundin, Patrik

2015-01-01

328

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

329

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

PubMed Central

Background The molecular mechanisms causing pigment dispersion syndrome (PDS) and the pathway(s) by which it progresses to pigmentary glaucoma are not known. Mutations in two melanosomal protein genes (Tyrp1 b and Gpnmb R150X ) are responsible for pigment dispersing iris disease, which progresses to intraocular pressure (IOP) elevation and subsequent glaucoma in DBA/2J mice. Melanosomal defects along with ocular immune abnormalities play a role in the propagation of pigment dispersion and progression to IOP elevation. Here, we tested the role of specific immune components in the progression of the iris disease and high IOP. Results We tested the role of NK cells in disease etiology by genetically modifying the B6.D2-Gpnmb R150X Tyrp1 b strain, which develops the same iris disease as DBA/2J mice. Our findings demonstrate that neither diminishing NK mediated cytotoxic activity (Prf1 mutation) nor NK cell depletion (Il2rg mutation) has any influence on the severity or timing of Gpnmb R150X Tyrp1 b mediated iris disease. Since DBA/2J mice are deficient in CD94, an important immune modulator that often acts as an immune suppressor, we generated DBA/2J mice sufficient in CD94. Sufficiency of CD94 failed to alter either the iris disease or the subsequent IOP elevation. Additionally CD94 status had no detected effect on glaucomatous optic nerve damage. Conclusion Our previous data implicate immune components in the manifestation of pigment dispersion and/or IOP elevation in DBA/2J mice. The current study eliminates important immune components, specifically NK cells and CD94 deficiency, as critical in the progression of iris disease and glaucoma. This narrows the field of possible immune components responsible for disease progression. PMID:24678736

2014-01-01

330

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. PMID:23766784

Limpert, Allison S; Mattmann, Margrith E

2013-01-01

331

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

2014-01-01

332

The Effect of History of Injection Drug Use and Alcoholism on HIV Disease Progression  

PubMed Central

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 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 history of both alcohol and injection drug use, 173 (32%) were non adherent (<95%), 196 (36%) had 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 of Best, Incomplete and Worse responses, respectively. Screening and detection of substance dependence will identify individuals at high-risk for non-adherence 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.

2013-01-01

333

Sustained seizure remission on perampanel in progressive myoclonic epilepsy (Lafora disease)?  

PubMed Central

Aim The aim of this report is to provide initial evidence that add-on treatment with perampanel might be highly effective in progressive myoclonic epilepsy such as Lafora disease. Case report We report on a 21-year-old woman suffering from persistent myoclonus and generalized tonic–clonic seizures for more than seven years. Additionally, ataxia, a disturbance in speech and gait, as well as a cognitive decline were rapidly progressing. Subsequently, the diagnosis of Lafora disease was confirmed by the identification of a novel homozygous missense mutation in exon 3 of the EPM2A gene (c.538C>G; p.L180V). Adjunctive therapy with perampanel was started in this patient with advanced Lafora disease and was titrated up to 8 mg/day. A sustained and reproducible remission of myoclonus and GTCS could be achieved for a follow-up of three months. After dosage reduction to 6 mg/day, seizures recurred; however, on increasing the daily dose to 10 mg, seizures stopped for another three months. The patient also regained her ability to walk with help and the aid of a walker. Conclusions Perampanel is a selective, noncompetitive antagonist of AMPA-type glutamate receptors and recently licensed as adjunctive therapy for the treatment of refractory focal onset seizures. There is evidence for its effectiveness in generalized epilepsies, and phase III studies for this indication are on the way. Our case illustrates the possibility that perampanel might be a valuable option for treatment in PME. Considering its impressive efficacy in this case, we suggest a prospective, multicenter study evaluating perampanel in PME.

Schorlemmer, Kathrin; Bauer, Sebastian; Belke, Marcus; Hermsen, Anke; Klein, Karl Martin; Reif, Philipp S.; Oertel, Wolfgang H.; Kunz, Wolfram S.; Knake, Susanne; Rosenow, Felix; Strzelczyk, Adam

2013-01-01

334

Haemostatic alterations in a group of canine cancer patients are associated with cancer type and disease progression  

PubMed Central

Background Haemostatic alterations are commonly detected in human and canine cancer patients. Previous studies have described haemostatic dysfunction in canine patients with haemangiosarcomas and carcinomas, and haemostasis has been assessed in dogs with various malignant and benign neoplasias. Few studies have addressed the effect of cancer type and progression of disease on the presence of haemostatic alterations in canine patients. The objective of the present study was to evaluate haemostatic variables of coagulation and fibrinolysis in a group of canine cancer patients, and to compare haemostatic changes to the cancer type and progression of disease. Methods The study population consisted of 71 dogs with malignant neoplasia presented to the University Hospital for Companion Animals, Faculty of Life Sciences, University of Copenhagen, Denmark. The study was designed as a prospective observational study evaluating the haemostatic function in canine cancer patients stratified according to type of cancer disease and disease progression. The coagulation response was evaluated by thromboelastrography (TEG), platelet count, activated partial thromboplastin time (aPTT), prothombin time (PT), fibrinogen and antithrombin (AT); and fibrinolysis by d-dimer and plasminogen. Results Hypercoagulability was the most common haemostatic dysfunction found. Non mammary carcinomas had increased clot strength (TEG G), aPTT and fibrinogen compared to the other groups. When stratifying the patients according to disease progression dogs with distant metastatic disease exhibited significantly increased fibrinogen, and d-dimer compared to dogs with local invasive and local non-invasive cancers. Conclusion Hypercoagulability was confirmed as the most common haemostatic abnormality in canine cancer patients and haemostatic dysfunction in canine cancer patients was found related to the cancer type and progression of disease. Increase in TEG G, aPTT and fibrinogen were observed in non-mammary carcinomas and were speculated to overall represent a proinflammatory response associated with the disease. Dogs with distant metastatic disease exhibited increased fibrinogen and d-dimer. Future studies are needed to elucidate the clinical importance of these results. PMID:22280938

2012-01-01

335

8OHdG as a marker for Huntington disease progression.  

PubMed

Leukocyte 8-hydroxydeoxyguanosine (8OHdG) is an indicator of oxidative stress, impaired metabolism, and mitochondrial dysfunction, features that have been implicated in Huntington disease (HD). Increased levels of 8OHdG have been reported in the caudate, parietal cortex, and peripherally in the serum and leukocytes, in patients diagnosed with HD. However, little is known about levels in prodromal patients and changes that might occur as the disease progresses. To address these issues, 8OHdG was tracked over time for a subset of participants enrolled in the PREDICT-HD study. Participants were stratified into four groups based on proximity to HD diagnosis at study entry: Controls (gene-negative individuals), Low (low probability of near-future diagnosis), Medium, and High. Blood samples were analyzed using Liquid Chromatography Electrochemical Array, and for comparison purposes, a separate cross-sectional sample was analyzed using liquid chromatography coupled with multiple-reaction-monitoring mass spectrometry. Longitudinal data analysis showed that initial status (at study entry) and annual rate of change varied as a function of proximity group, adjusting for sex, education, age at study entry, and site effects. Overall levels were lowest for the Control group and highest for the High group, and the rate of increase varied in a similar manner. The finding that 8OHdG concentrations increased as a function of proximity to projected disease diagnosis and duration indicates support for the continued assessment of 8OHdG as a robust clinical HD biomarker. PMID:22414782

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

2012-06-01

336

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

PubMed

In recent years, next-generation sequencing has unraveled the molecular landscape in chronic lymphocytic leukemia with the discovery of a number of recurrently mutated genes. Mutations in several of these genes, such as NOTCH1, SF3B1 and BIRC3, are linked to a more aggressive disease with early disease progression, short time-to-first-treatment and even chemorefractoriness. Although in its infancy, we have also begun to understand the complex dynamics of subclonal diversity and its impact on disease outcome. From pioneering studies, we know that certain genetic events are found in the majority of chronic lymphocytic leukemia cells and are considered as 'clonal driver mutations' (e.g., +12, 13q-), whereas others, present only in a fraction of the tumor, are deemed to be 'subclonal driver mutations' for example, TP53 and SF3B1. Over the coming years, we need to gain a deeper insight into the dynamics of this subclonal architecture to understand how, at an individual level, chronic lymphocytic leukemia patients should be followed, which will be particularly relevant as novel targeted therapies begin to emerge. PMID:25345442

Sutton, Lesley-Ann; Rosenquist, Richard

2015-02-01

337

Glycogen phosphomonoester distribution in mouse models of the progressive myoclonic epilepsy, Lafora disease.  

PubMed

Glycogen is a branched polymer of glucose that acts as an energy reserve in many cell types. Glycogen contains trace amounts of covalent phosphate, in the range of one phosphate per 500-2000 glucose residues, depending on the source. The function, if any, is unknown but in at least one genetic disease, the progressive myooclonic epilepsy Lafora disease, excessive phosphorylation of glycogen has been implicated in the pathology by disturbing glycogen structure. Some 90% of Lafora cases are attributed to mutations of the EPM2A or EPM2B genes and mice with either gene disrupted accumulate hyperphosphorylated glycogen. It is therefore of importance to understand the chemistry of glycogen phosphorylation. Rabbit skeletal muscle glycogen contained covalent phosphate as monoesters of C2, C3 and C6 carbons of glucose residues based on analyses of phospho-oligosaccharides by NMR. Furthermore, using a sensitive assay for glucose-6-P in hydrolysates of glycogen coupled with measurement of total phosphate, we determined the proportion of C6 phosphorylation in rabbit muscle glycogen to be ~20%. C6 phosphorylation also accounted for ~20% of the covalent phosphate in wild type mouse muscle glycogen. Glycogen phosphorylation in Epm2a-/- and Epm2b-/- mice was increased eight- and four-fold compared to wild type mice but the proportion of C6 phosphorylation remained unchanged at ~20%. Therefore, our results suggest that C2, C3 and/or C6 phosphate could all contribute to abnormal glycogen structure or to Lafora disease. PMID:25416783

DePaoli-Roach, Anna A; Contreras, Christopher J; Segvich, Dyann M; Heiss, Christian; Ishihara, Mayumi; Azadi, Parastoo; Roach, Peter J

2014-11-21

338

Evaluation of bakanae disease progression caused by Fusarium fujikuroi in Oryza sativa L.  

PubMed

Bakanae disease caused by Fusarium fujikuroi is an important fungal disease in rice. Among the seven strains isolated from symptomatic rice grains in this study, one strain, FfB14, triggered severe root growth inhibition and decay in the crown and root of rice seedlings. The remaining six strains caused typical Bakanae symptoms such as etiolation and abnormal succulent rice growth. To reveal the relationship between mycelial growth in the infected tissues and Bakanae disease progression, we have established a reliable quantification method using real time PCR that employs a primer pair and dual-labeled probe specific to a unigene encoding F. fujikuroi PNG1 (FfPNG1), which is located upstream of the fumonisin biosynthesis gene cluster. Plotting the crossing point (CP) values from the infected tissue DNAs on a standard curve revealed the active fungal growth of FfB14 in the root and crown of rice seedlings, while the growth rate of FfB20 in rice was more than 4 times lower than FfB14. Massive infective mycelial growth of FfB14 was evident in rice stems and crown; however, FfB20 did not exhibit vigorous growth. Our quantitative evaluation system is applicable for the identification of fungal virulence factors other than gibberellin. PMID:24385365

Hwang, In Sun; Kang, Woo-Ri; Hwang, Duk-Ju; Bae, Shin-Chul; Yun, Sung-Hwan; Ahn, Il-Pyung

2013-12-01

339

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

PubMed Central

Objectives. This study examined if compassionate love (CL) predicts HIV disease progression and transmission risk. Scientific study of CL emerged with Underwood's working model of other-centered CL, defining five criteria: free choice, cognitive understanding, valuing/empowering, openness/receptivity for spirituality, and response of the heart. Method. This 10-year cohort study collected 6-monthly interviews/essays on coping with HIV and trauma of 177 people with HIV in South Florida. Secondary qualitative content analysis on other-centered CL inductively added the component of CL towards self. Deductively, we coded the presence of the five criteria of CL and rated the benefit of CL for the recipient on a 6-point Likert scale. Growth-curve modeling (reduced to 4 years due to cohort effects) investigated if CL predicts CD4 slope (HIV disease progression) and cumulative viral load detection (transmission risk). Results. Valuing/empowering and cognitive understanding were the essential criteria for CL to confer long-term benefits. CL had a higher benefit for recipients if given out of free choice. High scores of CL towards self were reciprocal with receiving (93%) and giving (77%) other-centered CL. Conversely, those rated low on CL towards self were least likely to score high on receiving (38%) and giving (49%) other-centered CL. Growth-curve modeling showed that CL towards self predicted 4-year cumulative undetectable viral load (independent from sociocultural differences, substance use disorder, baseline CD4 and viral load). Those high versus low on CL self were 2.25 times more likely to have undetectable viral load at baseline and 1.49 times more likely to maintain undetectable viral load over time. CL towards self predicted CD4 preservation after controlling for differences in CL giving. Conclusions. CL towards self is potentially the seed of being expressive and receptive of CL. Health care professionals prepared to walk the extra mile for those who neglect and isolate themselves may break a vicious circle since those lacking CL self were least likely to receive CL from others. Future studies should examine whether any enhancement of CL towards self may translate into slower disease progression and reduction of transmission risk. PMID:24348722

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

2013-01-01

340

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

PubMed Central

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.

2013-01-01

341

Performance on the dementia rating scale in Parkinson's disease with dementia and dementia with Lewy bodies: comparison with progressive supranuclear palsy and Alzheimer's disease  

PubMed Central

Background: The relation between dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) is unknown. Objectives: To compare the cognitive profiles of patients with DLB and PDD, and compare those with the performance of patients with a subcortical dementia (progressive supranuclear palsy) and a cortical dementia (Alzheimer's disease). Design: Survey of cognitive features. Setting: General community in Rogaland county, Norway, and a university dementia and movement disorder research centre in the USA. Patients: 60 patients with DLB, 35 with PDD, 49 with progressive supranuclear palsy, and 29 with Alzheimer's disease, diagnosed by either standardised clinical procedures and criteria (all PDD and Alzheimer cases and 76% of cases of progressive supranuclear palsy), or necropsy (all DLB cases and 24% of cases of progressive supranuclear palsy). Level of dementia severity was matched using the total score on the dementia rating scale adjusted for age and education. Main outcome measures: Dementia rating scale subscores corrected for age. Results: No significant differences between the dementia rating scale subscores in the PDD and DLB groups were found in the severely demented patients; in patients with mild to moderate dementia the conceptualisation subscore was higher in PDD than in DLB (p = 0.03). Compared with Alzheimer's disease, PDD and DLB had higher memory subscores (p < 0.001) but lower initiation and perseveration (p = 0.008 and p=0.021) and construction subscores (p = 0.009 and p = 0.001). DLB patients had a lower conceptualisation subscore (p = 0.004). Compared with progressive supranuclear palsy, PDD and DLB patients had lower memory subscores (p < 0.001). Conclusions: The cognitive profiles of patients with DLB and PDD were similar, but they differed from those of patients with Alzheimer's disease and progressive supranuclear palsy. The cognitive pattern in DLB and PDD probably reflects the superimposition of subcortical deficits upon deficits typically associated with Alzheimer's disease. PMID:12933921

Aarsland, D; Litvan, I; Salmon, D; Galasko, D; Wentzel-Larsen, T; Larsen, J

2003-01-01

342

Recent progress in AlGaN\\/GaN-based optoelectronic devices  

Microsoft Academic Search

Unique optical and electronic properties of the InGaN\\/GaN\\/AlGaN material system open up numerous opportunities for visible-blind optoelectronic devices. GaN based optoelectronic devices include InGaN-AlGaN light emitting diodes (LEDs), GaN photoconductive, Schottky barrier, and p-n junction ultraviolet detectors, and optoelectronic AlGaN-GaN heterostructure field effect transistors. These devices have a high sensitivity and a large gain-bandwidth product and can be integrated with

M. Asif Khan; Michael S. Shur

1997-01-01

343

Elevated temperature and light enhance progression and spread of black band disease on staghorn corals of the Great Barrier Reef  

Microsoft Academic Search

Rates of progression and transmission of black band disease (BBD) on the staghorn coral, Acropora muricata, were compared between months for seasonal in situ studies and between temperature treatments in experimental aquaria manipulations\\u000a at Lizard Island on the Great Barrier Reef (GBR). In situ field experiments demonstrated that BBD progressed along branches\\u000a approximately twice as fast (1.7–2.4 times) during the

Holly V. Boyett; David G. Bourne; Bette L. Willis

2007-01-01

344

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

PubMed

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

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

2014-06-01

345

A single dopamine pathway underlies progressive locomotor deficits in a Drosophila model of Parkinson disease.  

PubMed

Expression of the human Parkinson-disease-associated protein ?-synuclein in all Drosophila neurons induces progressive locomotor deficits. Here, we identify a group of 15 dopaminergic neurons per hemisphere in the anterior medial region of the brain whose disruption correlates with climbing impairments in this model. These neurons selectively innervate the horizontal ? and ?' lobes of the mushroom bodies, and their connections to the Kenyon cells are markedly reduced when they express ?-synuclein. Using selective mushroom body drivers, we show that blocking or overstimulating neuronal activity in the ?' lobe, but not the ? or ? lobes, significantly inhibits negative geotaxis behavior. This suggests that modulation of the mushroom body ?' lobes by this dopaminergic pathway is specifically required for an efficient control of startle-induced locomotion in flies. PMID:24239353

Riemensperger, Thomas; Issa, Abdul-Raouf; Pech, Ulrike; Coulom, Hélène; Nguy?n, M?-Vân; Cassar, Marlène; Jacquet, Mélanie; Fiala, André; Birman, Serge

2013-11-27

346

Benign metastasising leiomyoma: a progressive disease despite chemical and surgical castration  

PubMed Central

Benign metastasising leiomyoma (BML) is a rare entity characterised by uterine leiomyoma that, later on, develops slow-growing metastasis mainly to the lung. In general, these lung metastases are incidentally discovered, but sometimes can become symptomatic with dyspnoea, cough and chest pain. The expression of oestrogen and progesterone receptors by these tumours supports the idea that they respond to hormone therapy (chemical, with oestrogen receptor modulators, aromatase inhibitors or luteinising hormone releasing hormone analogues and surgical, with bilateral adnexectomy). The authors present a case report of BML with two peculiarities: a less common pattern of metastisation (soft tissue), in addition to lung; and disease progression despite treatment with chemical and surgical castration. PMID:22605795

Silva, Inês; Tomé, Vera; Oliveira, João

2012-01-01

347

[Progress of ultrasound microbubble contrast technology in the diagnosis and treatment of clinical diseases].  

PubMed

Contrast enhanced ultrasound (CEUS) technology has made important developments over the past decade. It has been applied in the clinical diagnosis for various diseases of multiple organs including liver, kidney, thyroid, breast and so on, which greatly improves the accuracy of ultrasound diagnosis. The emergence of targeted ultrasound microbubble makes ultrasound molecular imaging possible. More than the improvement of ultrasound imaging, microbubble contrast agent also could be an effective drug or gene carrier. Microbubble will rupture under the irradiation effect of local ultrasound, and then the carried drugs or genes will be released to achieve the purpose of targeted therapy. We should pay more attention on the progress of ultrasound microbubble contrast technology in clinical and basic research. It will promote better understanding and clinical applications of this novel medical ultrasound technology. PMID:25571727

Qiu, Li; Leng, Qian-ying; Luo, Yan

2014-11-01

348

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

PubMed Central

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

Lin, Yihua; Yi, Qun; Cheng, Deyun

2014-01-01

349

Clinico-pathological investigations of Rasmussen encephalitis suggest multifocal disease progression and associated focal cortical dysplasia.  

PubMed

Rasmussen encephalitis is a devastating neurological disorder characterised by seizures, brain inflammation, and progressive hemispheric atrophy. The objective of the current study was to systematically characterise patterns of structural lesions in children with Rasmussen encephalitis, referred for modified anatomical hemispherectomy at the Tsinghua University Epilepsy Center in Beijing. Seven consecutive patients were investigated with a mean age at operation of 4.5 years, who suffered from medically intractable seizures for a mean of 1.6 years. Foci of abnormally increased T2 signal intensity were observed in all patients. With the exception of one child, all patients presented with progressive unilateral cerebral atrophy. FDG-PET imaging revealed extensive regions of hypometabolism within the affected cerebral hemisphere in 3 of 4 patients. Diagnosis of Rasmussen encephalitis was confirmed histologically, demonstrating CD68 positive microglial nodules, as well as CD3 and CD8 positive T lymphocytes invading the cerebral parenchyma. An intriguing observation was the heterogenous distribution of patterns of lesions throughout the affected hemisphere, suggesting multifocal manifestation and distinct sequences of disease progression, from discrete foci of inflammatory infiltrates (stage 1) to extensive cortical destruction (stage 4). Atypical hippocampal sclerosis (HS), with neuronal cell loss affecting most prominently the CA4 region (HS type 3 or end folium sclerosis), was evident in 5 of 7 cases. Four hippocampi also showed chronic inflammation. In addition, we observed associated focal cortical dysplasia (FCD; ILAE type IIId) in 4 of 7 children, supporting the concept of acquired and postmigratory FCD pathomechanisms. Postsurgical seizure freedom was achieved in all children with a mean follow-up period of 2.7 years and continuous antiepileptic medication. PMID:23531608

Wang, Dandan; Blümcke, Ingmar; Gui, Qiuping; Zhou, Wenjing; Zuo, Huancong; Lin, Jiuluan; Luo, Yang

2013-03-01

350

Smoking is associated with progressive disease course and increased progression in clinical disability in a prospective cohort of people with multiple sclerosis  

Microsoft Academic Search

Background\\u000a   Multiple sclerosis has a variable disease course. The contribution of modifiable lifestyle factors to disease course has not\\u000a been well studied, although one cohort has reported that smoking is associated with conversion to secondary progressive MS\\u000a course and another that smoking is not.\\u000a \\u000a \\u000a \\u000a \\u000a Methods\\u000a   We conducted a prospective cohort study of people with MS in Southern Tasmania from 2002

Fotini Pittas; Anne-Louise Ponsonby; Ingrid A. F. van der Mei; Bruce V. Taylor; Leigh Blizzard; Patricia Groom; Obioha C. Ukoumunne; Terry Dwyer

2009-01-01

351

Demyelination in Mild Cognitive Impairment Suggests Progression Path to Alzheimer’s Disease  

PubMed Central

The preclinical Alzheimer's disease (AD) - amnestic mild cognitive impairment (MCI) - is manifested by phenotypes classified into exclusively memory (single-domain) MCI (sMCI) and multiple-domain MCI (mMCI). We suggest that typical MCI-to-AD progression occurs through the sMCI-to-mMCI sequence as a result of the extension of initial pathological processes. To support this hypothesis, we assess myelin content with a Magnetization Transfer Ratio (MTR) in 21 sMCI and 21 mMCI patients and in 42 age-, sex-, and education-matched controls. A conjunction analysis revealed MTR reduction shared by sMCI and mMCI groups in the medial temporal lobe and posterior structures including white matter (WM: splenium, posterior corona radiata) and gray matter (GM: hippocampus; parahippocampal and lingual gyri). A disjunction analysis showed the spread of demyelination to prefrontal WM and insula GM in executive mMCI. Our findings suggest that demyelination starts in the structures affected by neurofibrillary pathology; its presence correlates with the clinical picture and indicates the method of MCI-to-AD progression. In vivo staging of preclinical AD can be developed in terms of WM/GM demyelination. PMID:24023644

Carmeli, Cristian; Donati, Alessia; Antille, Valérie; Viceic, Dragana; Ghika, Joseph; von Gunten, Armin; Clarke, Stephanie; Meuli, Reto; Frackowiak, Richard S.; Knyazeva, Maria G.

2013-01-01

352

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

PubMed

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

Palomares, O; Crameri, R; Rhyner, C

2014-12-01

353

Decreased expression of GLT-1 in the R6/2 model of Huntington's disease does not worsen disease progression.  

PubMed

Excitotoxicity is thought to be important in the pathogenesis of Huntington's disease (HD). Glutamate is the predominant excitatory neurotransmitter in the brain, and excess activation of glutamate receptors can cause neuronal dysfunction and death. Glutamate transporters regulate the extracellular concentration of glutamate. GLT-1 is the most abundant glutamate transporter, and accounts for most of the glutamate transport in the brain. Administration of ceftriaxone, an antibiotic that increases the functional expression of GLT-1, can improve the behavioral phenotype of the R6/2 mouse model of HD. To test the hypothesis that GLT-1 expression critically affects the HD disease process, we generated a novel mouse model that is heterozygous for the null allele of GLT-1 and carries the R6/2 transgene (double mutation). We demonstrated that the protein expression of total GLT-1, as well as two of its isoforms, is decreased within the cortex and striatum of 12-week-old R6/2 mice, and that the expression of EAAC1 was decreased in the striatum. Protein expression of GLT-1 was further decreased in the cortex and striatum of the double mutation mice compared with the R6/2 mice at 11 weeks. However, the effects of the R6/2 transgene on weight loss, accelerating rotarod, climbing and paw-clasping were not exacerbated in these double mutants. Na(+) -dependent glutamate uptake into synapatosomes isolated from the striatum and cortex of 11-week-old R6/2 mice was unchanged compared with controls. These results suggest that changes in GLT-1 expression or function per se are unlikely to potentiate or ameliorate the progression of HD. PMID:23586612

Petr, Geraldine T; Schultheis, Laurel A; Hussey, Kayla C; Sun, Yan; Dubinsky, Janet M; Aoki, Chiye; Rosenberg, Paul A

2013-08-01

354

Intranasal administration of TAT-haFGF(??????) attenuates disease progression in a mouse model of Alzheimer's disease.  

PubMed

Human acidic fibroblast growth factor (haFGF), a neurotrophin-like growth factor in the brain, plays important roles in the development, differentiation and regeneration of brain neurons, which makes it potential to treat Alzheimer's disease (AD). In this study, haFGF(14-154) and TAT-haFGF(14-154) (haFGF(14-154) fused with the cell-penetrating peptide transactivator of transcription protein transduction domain (TAT-PTD)) were intranasally administrated for 5 weeks to investigate the effects on senescence-accelerated mouse prone-8 (SAMP8) mice (a mouse model of AD). Results showed that TAT-PTD could increase the concentration of haFGF in the brain significantly, and TAT-haFGF(14-154) was more effective than haFGF(14-154) in the same dosage (300 ?g/kg). Importantly, TAT-haFGF(14-154) improved the learning and memory abilities of SAMP8 mice in the behavioral test, and promoted the function of cholinergic system by measuring the relevant biomarkers (acetylcholine (ACh) level, acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) activities). TAT-haFGF(14-154) also significantly reduced ?-amyloid protein(1-42) (A?(1-42)) deposits as well as the levels of A? soluble forms in the mice brains and prevented the neurons from apoptosis. Besides, the oxidative stress impairment in the brain and serum was also ameliorated. The results suggest that TAT-haFGF(14-154) could attenuate the disease progression of SAMP8 AD mice, and the mechanism is related to the regulation of neurons microenvironment including neurotransmitters, A? pathology and oxidative stress. PMID:22885230

Lou, G; Zhang, Q; Xiao, F; Xiang, Q; Su, Z; Zhang, L; Yang, P; Yang, Y; Zheng, Q; Huang, Y

2012-10-25

355

Association of interleukin-10 with hepatitis B virus (HBV) mediated disease progression in Indian population  

PubMed Central

Background & objectives: Interleukin (IL)-10, an anti-inflammatory Th2 cytokine, is one of the key coordinators of the inflammatory responses involved. The present study was designed to evaluate the impact of IL-10 (-819/-592) genotypes, haplotypes, mRNA and the protein levels with risk for hepatitis B virus (HBV) related hepatocellular carcinoma (HCC) development in India. Methods: A total of 390 subjects (145 controls, 62 inactive HBV-carriers, 64 chronic-active HBV patients, 60 HBV related cirrhotics and 59 HBV- HCC subjects) were enrolled in the study. Allele specific (AS)-PCR, ELISA and RT-PCR methods were used for assessing polymorphism, spontaneous blood levels and the mRNA expression, respectively of IL-10. Results: The study revealed that the CC/TA genotype acted as a risk factor for cirrhosis (ORa=2.02; P<0.05) and the subsequent HCC development (ORa=2.20; P<0.05), with controls as reference. However, no significant association was found between the two haplotypes (CC and TA) observed and HCC risk. Moreover, the IL-10 protein and mRNA levels in peripheral blood mono nuclear cells (PBMCs) showed a significant elevation as the disease progressed to cirrhosis. But, no variation was observed in the IL-10 levels in subjects with different IL-10 genotypes. Interpretation & conclusions: These preliminary results suggest a strong association of IL10 (-819/-592) with the HBV infection mediated disease progression, from inactive carrier state to malignancy, in Indian population. PMID:25027084

Saxena, Roli; Chawla, Yogesh Kumar; Verma, Indu; Kaur, Jyotdeep

2014-01-01

356

Integrative EEG biomarkers predict progression to Alzheimer's disease at the MCI stage  

PubMed Central

Alzheimer's disease (AD) is a devastating disorder of increasing prevalence in modern society. Mild cognitive impairment (MCI) is considered a transitional stage between normal aging and AD; however, not all subjects with MCI progress to AD. Prediction of conversion to AD at an early stage would enable an earlier, and potentially more effective, treatment of AD. Electroencephalography (EEG) biomarkers would provide a non-invasive and relatively cheap screening tool to predict conversion to AD; however, traditional EEG biomarkers have not been considered accurate enough to be useful in clinical practice. Here, we aim to combine the information from multiple EEG biomarkers into a diagnostic classification index in order to improve the accuracy of predicting conversion from MCI to AD within a 2-year period. We followed 86 patients initially diagnosed with MCI for 2 years during which 25 patients converted to AD. We show that multiple EEG biomarkers mainly related to activity in the beta-frequency range (13–30 Hz) can predict conversion from MCI to AD. Importantly, by integrating six EEG biomarkers into a diagnostic index using logistic regression the prediction improved compared with the classification using the individual biomarkers, with a sensitivity of 88% and specificity of 82%, compared with a sensitivity of 64% and specificity of 62% of the best individual biomarker in this index. In order to identify this diagnostic index we developed a data mining approach implemented in the Neurophysiological Biomarker Toolbox (http://www.nbtwiki.net/). We suggest that this approach can be used to identify optimal combinations of biomarkers (integrative biomarkers) also in other modalities. Potentially, these integrative biomarkers could be more sensitive to disease progression and response to therapeutic intervention. PMID:24106478

Poil, Simon-Shlomo; de Haan, Willem; van der Flier, Wiesje M.; Mansvelder, Huibert D.; Scheltens, Philip; Linkenkaer-Hansen, Klaus

2013-01-01

357

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

PubMed

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

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

2015-01-01

358

Oxidative Stress Induced Mechanisms in the Progression of Periodontal Diseases and Cancer: A Common Approach to Redox Homeostasis?  

PubMed Central

There is documented evidence of significant associations between cancer of the lung, kidney, pancreas, hematological and oral cancers and periodontal diseases of the supporting structures of the teeth. Enhanced lipid peroxidation, raised levels of TBARS and the oxidative stress marker malondealdehyde have been detected in breast cancer with reduced antioxidant capacity, also characteristic of periodontal diseases. Antioxidants could overcome this deficit and attenuate disease progression by down regulating glutathione detoxification/redox buffering system and inhibiting key transcription factors. Periodontal disease may be a critical marker of a susceptible immune system, or initiate cancer risk with a pro-oxidant inflammatory profile. PMID:24281088

Soory, Mena

2010-01-01

359

A Case of Adventitial Cystic Disease of the Popliteal Artery Progressing Rapidly after Percutaneous Ultrasound-guided Aspiration  

PubMed Central

Adventitial cystic disease is a rare non-atherosclerotic vascular disease. We report a 36-year-old man with right intermittent claudication by adventitial cystic disease. computed tomography (CT) and magnetic resonance imaging (MRI) revealed an ovoid cystic mass compressing the right popliteal artery and causing severe stenosis of the lumen. Percutaneous aspiration was performed, which improved his symptoms. However, he complained of identical intermittent claudication two weeks later. Radiographic findings revealed that the cystic lesion had progressed rapidly. The cystic lesion was resected and the affected arterial segment was interposed. We consider that conventional surgical intervention remains the favored treatment option in the management of adventitial cystic disease. PMID:25593629

Fujii, Hiromichi; Aoyama, Takanobu; Sasako, Yoshikado

2014-01-01

360

Natural progression of renal function in the elderly: analysis of poor prognosis factors associated with chronic kidney disease.  

PubMed

In the last few years a debate has emerged on the range of normal renal function and the rate at which renal disease progresses in the elderly. In this review we analysed, on the basis of the results of the study Ancianos con enfermedad renal crónica del Hospital General de Segovia (Elderly people with chronic kidney disease of the Hospital General de Segovia), the poor prognosis factors associated with this disease: proteinuria, episodes of acute renal failure and heart failure, and the role of uric acid. Elderly people with chronic kidney disease who present these poor prognosis factors may benefit from follow-up by Nephrology. PMID:23897177

Heras, Manuel; García-Cosmes, Pedro; Fernández-Reyes, María J; Sánchez, Rosa

2013-01-01

361

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

PubMed Central

Antisense therapy with both chemistries of phosphorodiamidate morpholino oligomers (PMOs) and 2?-O-methyl phosphorothioate has demonstrated the capability to induce dystrophin expression in Duchenne muscular dystrophy (DMD) patients in phase II–III clinical trials with benefit in muscle functions. However, potential of the therapy for DMD at different stages of the disease progression is not understood. In this study, we examined the effect of peptide-conjugated PMO (PPMO)-mediated exon skipping on disease progression of utrophin-dystrophin-deficient mice (dko) of four age groups (21–29, 30–39, 40–49 and 50+ days), representing diseases from early stage to advanced stage with severe kyphosis. Biweekly intravenous (i.v.) administration of the PPMO restored the dystrophin expression in nearly 100% skeletal muscle fibers in all age groups. This was associated with the restoration of dystrophin-associated proteins including functional glycosylated dystroglycan and neuronal nitric synthase. However, therapeutic outcomes clearly depended on severity of the disease at the time the treatment started. The PPMO treatment alleviated the disease pathology and significantly prolonged the life span of the mice receiving treatment at younger age with mild phenotype. However, restoration of high levels of dystrophin expression failed to prevent disease progression to the mice receiving treatment when disease was already at advanced stage. The results could be critical for design of clinical trials with antisense therapy to DMD. PMID:24942628

Wu, B; Cloer, C; Lu, P; Milazi, S; Shaban, M; Shah, SN; Marston-Poe, L; Moulton, HM; Lu, QL

2014-01-01

362

A double-labeling immunohistochemical study of tau exon 10 in Alzheimer’s disease, progressive supranuclear palsy and Pick’s disease  

Microsoft Academic Search

Neurofibrillary tangles (NFT), one of the histopathological hallmarks of Alzheimer’s disease (AD) and progressive supranuclear\\u000a palsy (PSP), and Pick bodies in Pick’s disease (PiD) are composed of microtubule-associated protein tau, which is the product\\u000a of alternative splicing of a gene on chromosome 17. Alternative expression of exon 10 leads to formation of three- or four-repeat\\u000a tau isoforms. To study the

K. Ishizawa; H. Ksiezak-Reding; P. Davies; A. Delacourte; P. Tiseo; S.-H. Yen; D. W. Dickson

2000-01-01

363

Bone marrow stroma CD40 expression correlates with inflammatory mast cell infiltration and disease progression in splenic marginal zone lymphoma.  

PubMed

Splenic marginal zone lymphoma (SMZL) is a mature B-cell neoplasm characterized by rather indolent clinical course. However, nearly one third of patients experience a rapidly progressive disease with a dismal outcome. Despite the characterization of clone genetics and the recognition of deregulated immunologic stimulation in the pathogenesis of SMZL, little is known about microenvironment dynamics and their potential biological influence on disease outcome. Here we investigate the effect of stroma-intrinsic features on SMZL disease progression by focusing on the microenvironment of the bone marrow (BM), which represents an elective disease localization endorsing diagnostic and prognostic relevance. We show that the quality of the BM stromal meshwork of SMZL infiltrates correlates with time to progression. In particular, we describe the unfavorable prognostic influence of dense CD40 expression by BM stromal cells, which involves the contribution of CD40 ligand (CD40L)-expressing bystander mast cells infiltrating SMZL BM aggregates. The CD40/CD40L-assisted crosstalk between mesenchymal stromal cells and mast cells populating the SMZL microenvironment finds correlation in p53(-/-) mice developing SMZL and contributes to the engendering of detrimental proinflammatory conditions. Our study highlights a dynamic interaction, playing between nonneoplastic elements within the SMZL niche, toward disease progression. PMID:24452203

Franco, Giovanni; Guarnotta, Carla; Frossi, Barbara; Piccaluga, Pier Paolo; Boveri, Emanuela; Gulino, Alessandro; Fuligni, Fabio; Rigoni, Alice; Porcasi, Rossana; Buffa, Salvatore; Betto, Elena; Florena, Ada Maria; Franco, Vito; Iannitto, Emilio; Arcaini, Luca; Pileri, Stefano Aldo; Pucillo, Carlo; Colombo, Mario Paolo; Sangaletti, Sabina; Tripodo, Claudio

2014-03-20

364

Lymphocyte Mitochondria: Towards Identification of Peripheral Biomarkers in Progression of Alzheimer Disease  

PubMed Central

Alzheimer disease is an age-related neurodegenerative condition. AD is histopathologically characterized by the presence of three main hallmarks: senile plaque (SP, rich in amyloid-beta peptide), neuronal fibrillary tangles (NFT, rich in phosphorylated tau protein), and synapse loss. However, definitive biomarkers for this devastating disease in living people are still lacking. In the present study, we showed that levels of oxidative stress markers are significantly increased in the mitochondria isolated from lymphocytes of subjects with mild cognitive impairment (MCI) compared to cognitively normal individuals. Further, increase in mitochondrial oxidative stress in MCI is associated with the MMSE scores, vitamin E components, and beta-carotene. Further, proteomics approach showed that the alterations in the levels of thioredoxin-dependent peroxide reductase, myosin light polypeptide 6, and ATP synthase subunit beta might be important in the progression and pathogenesis of AD. Increased understanding of oxidative stress and protein alterations in easily obtainable peripheral tissues will be helpful in developing biomarkers to combat this devastating disorder. PMID:23933528

Sultana, Rukhsana; Baglioni, Mauro; Cecchetti, Roberta; Cai, Jian; Klein, Jon B; Bastiani, Patrizia; Ruggiero, Carmelinda; Mecocci, Patrizia; Butterfield, D. Allan

2013-01-01

365

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

PubMed Central

The Alzheimer’s Disease Neuroimaging Initiative (ADNI) beginning in October 2004, is a 6-year re-search 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 outcomes for use in clinical trials of AD treatments. Structural MRI, FDG PET, C-11 Pittsburgh compound B (PIB) PET, CSF measurements of amyloid ? (A?) and species of tau, with clinical/cognitive measurements were performed on elderly controls, subjects with mild cognitive impairment, and subjects with AD. Structural MRI shows high rates of brain atrophy, and has high statistical power for determining treatment effects. FDG PET, C-11 Pittsburgh compound B PET, and CSF measurements of A? and tau were significant predictors of cognitive decline and brain atrophy. All data are available at UCLA/LONI/ADNI, without embargo. ADNI-like projects started in Australia, Europe, Japan, and Korea. ADNI provides significant new information concerning the progression of AD. PMID:20451868

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

2010-01-01

366

Multiple sclerosis in Finland: incidence trends and differences in relapsing remitting and primary progressive disease courses  

PubMed Central

Objective: To compare the secular trends and geographical differences in the incidence of relapsing-remitting (RRMS) and primary progressive multiple sclerosis (PPMS) in Finland, and to draw inferences about aetiological differences between the two forms of the disease. Methods: New multiple sclerosis cases in southern Uusimaa and the western districts Vaasa and Seinäjoki of Finland in 1979–1993 were verified from hospital records and classified into RRMS and PPMS. Patients met the Poser criteria for definite multiple sclerosis or otherwise satisfied the criteria for PPMS. Disease course was categorised by the same neurologist. Crude and age adjusted incidence in 1979–1993 was estimated. Results: During 1979–1993 the age adjusted incidence was 5.1 per 100 000 person-years in Uusimaa, 5.2 in Vaasa, and 11.6 in Seinäjoki. The rates in Uusimaa remained stable, while a decrease occurred in Vaasa and an increase in Seinäjoki. Between 1979–86 and 1987–93 the incidence of PPMS increased in Seinäjoki from 2.6 to 3.7 per 105 and decreased in Vaasa from 1.9 to 0.2 per 105; the trends were similar for RRMS. Conclusions: There are significant differences in secular trends for multiple sclerosis incidence in Finland by geographical area, but these are similar for PPMS and RRMS. The recent changes point to locally acting environmental factors. The parallel incidence trends for RRMS and PPMS suggest similar environmental triggers for the two clinical presentations of multiple sclerosis. PMID:12486261

Sumelahti, M; Tienari, P; Hakama, M; Wikstrom, J

2003-01-01

367

Progression of Parkinson's disease pathology is reproduced by intragastric administration of rotenone in mice.  

PubMed

In patients with Parkinson's disease (PD), the associated pathology follows a characteristic pattern involving inter alia the enteric nervous system (ENS), the dorsal motor nucleus of the vagus (DMV), the intermediolateral nucleus of the spinal cord and the substantia nigra, providing the basis for the neuropathological staging of the disease. Here we report that intragastrically administered rotenone, a commonly used pesticide that inhibits Complex I of the mitochondrial respiratory chain, is able to reproduce PD pathological staging as found in patients. Our results show that low doses of chronically and intragastrically administered rotenone induce alpha-synuclein accumulation in all the above-mentioned nervous system structures of wild-type mice. Moreover, we also observed inflammation and alpha-synuclein phosphorylation in the ENS and DMV. HPLC analysis showed no rotenone levels in the systemic blood or the central nervous system (detection limit [rotenone]<20 nM) and mitochondrial Complex I measurements showed no systemic Complex I inhibition after 1.5 months of treatment. These alterations are sequential, appearing only in synaptically connected nervous structures, treatment time-dependent and accompanied by inflammatory signs and motor dysfunctions. These results strongly suggest that the local effect of pesticides on the ENS might be sufficient to induce PD-like progression and to reproduce the neuroanatomical and neurochemical features of PD staging. It provides new insight into how environmental factors could trigger PD and suggests a transsynaptic mechanism by which PD might spread throughout the central nervous system. PMID:20098733

Pan-Montojo, Francisco; Anichtchik, Oleg; Dening, Yanina; Knels, Lilla; Pursche, Stefan; Jung, Roland; Jackson, Sandra; Gille, Gabriele; Spillantini, Maria Grazia; Reichmann, Heinz; Funk, Richard H W

2010-01-01

368

MRI signal and texture features for the prediction of MCI to Alzheimer's disease progression  

NASA Astrophysics Data System (ADS)

An early diagnosis of Alzheimer's disease (AD) confers many benefits. Several biomarkers from different information modalities have been proposed for the prediction of MCI to AD progression, where features extracted from MRI have played an important role. However, studies have focused almost exclusively in the morphological characteristics of the images. This study aims to determine whether features relating to the signal and texture of the image could add predictive power. Baseline clinical, biological and PET information, and MP-RAGE images for 62 subjects from the Alzheimer's Disease Neuroimaging Initiative were used in this study. Images were divided into 83 regions and 50 features were extracted from each one of these. A multimodal database was constructed, and a feature selection algorithm was used to obtain an accurate and small logistic regression model, which achieved a cross-validation accuracy of 0.96. These model included six features, five of them obtained from the MP-RAGE image, and one obtained from genotyping. A risk analysis divided the subjects into low-risk and high-risk groups according to a prognostic index, showing that both groups are statistically different (p-value of 2.04e-11). The results demonstrate that MRI features related to both signal and texture, add MCI to AD predictive power, and support the idea that multimodal biomarkers outperform single-modality biomarkers.

Martínez-Torteya, Antonio; Rodríguez-Rojas, Juan; Celaya-Padilla, José M.; Galván-Tejada, Jorge I.; Treviño, Victor; Tamez-Peña, José G.

2014-03-01

369

Relationship between Serum Levels of Tau Fragments and Clinical Progression of Alzheimer's Disease.  

PubMed

Enzyme-generated fragments of tau have been linked to neuronal death and may serve as serum biomarkers of cognitive loss. Two competitive ELISAs detecting an ADAM10-generated fragment (Tau-A) or a caspase-3-generated fragment (Tau-C) were measured in baseline serum samples from patients with mild to moderate Alzheimer's disease (AD) from a Phase III clinical trial, and correlated to change in the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog11) and Clinical Dementia Rating-Sum of Boxes (CDR-SB) over a 64-week period using an MMRM-analysis. Relationship between the biomarkers and changes in ADAS-Cog11 score as a function of time were observed for Tau-C and change in ADAS-Cog11 (p = 0.06), and for Tau-A and change in CDR-SB (p = 0.04). The correlation of Tau-A/Tau-C ratio with cognitive change assessed by ADAS-Cog11 was even more significant (p < 0.006). These data indicate that measuring the balance between tau fragments in serum may provide a marker of the rate of progression of AD and warrant studies in larger cohorts. PMID:25171717

Henriksen, Kim; Byrjalsen, Inger; Christiansen, Claus; Karsdal, Morten Asser

2015-01-01

370

Alteration of the microRNA network during the progression of Alzheimer's disease  

PubMed Central

An overview of miRNAs altered in Alzheimer's disease (AD) was established by profiling the hippocampus of a cohort of 41 late-onset AD (LOAD) patients and 23 controls, showing deregulation of 35 miRNAs. Profiling of miRNAs in the prefrontal cortex of a second independent cohort of 49 patients grouped by Braak stages revealed 41 deregulated miRNAs. We focused on miR-132-3p which is strongly altered in both brain areas. Downregulation of this miRNA occurs already at Braak stages III and IV, before loss of neuron-specific miRNAs. Next-generation sequencing confirmed a strong decrease of miR-132-3p and of three family-related miRNAs encoded by the same miRNA cluster on chromosome 17. Deregulation of miR-132-3p in AD brain appears to occur mainly in neurons displaying Tau hyper-phosphorylation. We provide evidence that miR-132-3p may contribute to disease progression through aberrant regulation of mRNA targets in the Tau network. The transcription factor (TF) FOXO1a appears to be a key target of miR-132-3p in this pathway. PMID:24014289

Lau, Pierre; Bossers, Koen; Janky, Rekin's; Salta, Evgenia; Frigerio, Carlo Sala; Barbash, Shahar; Rothman, Roy; Sierksma, Annerieke S R; Thathiah, Amantha; Greenberg, David; Papadopoulou, Aikaterini S; Achsel, Tilmann; Ayoubi, Torik; Soreq, Hermona; Verhaagen, Joost; Swaab, Dick F; Aerts, Stein; De Strooper, Bart

2013-01-01

371

Results of total hip arthroplasty in patients who have rapidly progressive hip disease: a systematic review of the literature.  

PubMed

Rapidly progressive hip disease is a rare condition characterized by rapid joint space narrowing (>2 mm in 1 year), chondrolysis and destruction of the femoral head. Although the etiology and pathogenetic mechanism is unclear, subchondral insufficiency fractures in the setting of physiologically weakened bone has recently been implicated as the primary insult. The standard of care has been total hip arthroplasty; however, there is a theoretical risk that the disease process may continue, placing the prosthesis at risk. In order to determine the clinical outcomes and implant survivorship in this population, a systematic search of the literature was conducted. Midterm (mean: 5 years) results following total hip arthroplasty demonstrated mean good-to-excellent clinical results (clinical hip scores >80 points) and a 3% revision rate, making this a valuable treatment option for patients who have rapidly progressive hip disease. The underlying disease process does not appear to compromise implant longevity. PMID:22702256

Pivec, Robert; Johnson, Aaron J; Mont, Michael A

2012-05-01

372

The Effects of Dietary Protein Restriction and Blood-Pressure Control on the Progression of Chronic Renal Disease  

Microsoft Academic Search

Background Restricting protein intake and controlling hypertension delay the progression of renal disease in animals. We tested these interventions in 840 patients with various chronic renal diseases. Abstract Methods In study 1, 585 patients with glomerular filtration rates of 25 to 55 ml per minute per 1.73 m2 of body-surface area were randomly assigned to a usual-protein diet or a

Saulo Klahr; Andrew S. Levey; Gerald J. Beck; Arlene W. Caggiula; Lawrence Hunsicker; John W. Kusek; Gary Striker

1994-01-01

373

Aetiology and causal agents of mango sudden decline disease in the Sultanate A. O. Al Adawi1  

E-print Network

Aetiology and causal agents of mango sudden decline disease in the Sultanate of Oman A. O. Al Adawi and Fisheries, P.O. Box 204 Sohar, 311, Sultanate of Oman; 2 Department of Crop Sciences, Sultan Qaboos University, P.O. Box 34 Al Khod, 123, Sultanate of Oman; 3 University of Nizwa, P.O. Box 33 Barkat Al Muz 616

374

Modeling the impact of H63D HFE polymorphism on amyotrophic lateral sclerosis (ALS).  

E-print Network

??Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig’s disease, is a progressive neurodegenerative disorder characterized by selective degeneration of upper and lower motor neurons… (more)

Nandar, Wint

2013-01-01

375

The rs1800471 Polymorphism of TGFB1 Gene, Serum TGF-Beta1 Level and Chronic Kidney Disease Progression.  

PubMed

The aim of the study was to investigate whether rs1800471 polymorphism in TGFB1 gene is associated with the development and progression of non-diabetic chronic kidney disease. Moreover, we examined the serum TGF-beta1 concentration and its association with that polymorphism and progression of the disease. We applied two different methodological approaches. Firstly, a family based study was carried out, comprised of 109 patients with non-diabetic chronic kidney disease and their 218 healthy parents, using the transmission/disequilibrium test. The rs1800471 polymorphism and serum TGF-beta1 level were determined in all subjects. Serum TGF-beta1 concentration was also measured in 40 healthy controls. Secondly, we performed a case-control orientated study to determine whether rs1800471 polymorphism and other factors influence the progression of renal impairment. We found no relationships between rs1800471 polymorphism allele transfer and the incidence or progression of non-diabetic chronic kidney disease. We found, however, that the serum TGF-beta1 was significantly higher in patients than in controls. In conclusion, rs1800471 polymorphism in TGFB1 gene does not have an impact on the development and progression of non-diabetic chronic kidney disease caused by primary glomerulopathy and chronic interstitial nephritis. The increased serum TGF-beta1 concentration in such patients suggests its role in the pathomechanism of the disease. Circulating TGF-beta1 level is determined in a multifactorial way, not by rs1800471 polymorphism in TGFB1 gene. PMID:25298263

Kili?-Pstrusi?ska, K; Mastalerz-Migas, A; Zwoli?ska, D; Grzeszczak, W; Zachwieja, K; Zachwieja, J; Madziarska, K; Hyla Klekot, L

2015-01-01

376

Persistent endothelial dysfunction turns the frequent exacerbator COPD from respiratory disorder into a progressive pulmonary and systemic vascular disease.  

PubMed

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in developed countries of the world, while the main cause of mortality and morbidity in COPD patients are acute exacerbations and cardiovascular diseases. With regard to the frequency of exacerbations the phenotype «frequent exacerbators» has been defined, which, besides a more severe clinical course and a significantly higher total mortality, is also characterised by an elevated risk of cardiovascular mortality, as some indicators show us. It is notable that during the exacerbation of COPD, next to other changes, a significant aggravation of endothelial function occurs while the ED and COPD relationship seems very complex and is still in greater part unknown. Making the pathophysiological link between the frequency of exacerbations of COPD and ED could change our understanding of the character of this type of pulmonary disease. We hypothesize that frequent exacerbator COPD is a progressive and generalised vascular disease, not only an isolated respiratory disorder with ancillary systemic effects. Our opinion is that differences in COPD phenotype do not only determine the clinical picture but could also be of key importance in defining the progressivity of the disease. ED, which in these patients persists between frequent exacerbations, could be the main cause of the progression of pulmonary disease, and not only of the high cardiovascular risk of these patients. Such a persistent ED in FE COPD, with its pro-inflammatory, vasoconstrictory and prothrombotic mechanisms, could contemporaneously induce new exacerbations of COPD, the progression of pulmonary changes and the development of systemic atherosclerosis as a main extrapulmonary manifestation in these patients. Such a model defines endothelium as a common soil of progressive pulmonary and cardiovascular changes in FE COPD. It can fully explain all the elements of the clinical course and co-morbidity in FE COPD, for which we still do not have adequate explanation. PMID:25539899

Vukic Dugac, A; Ruzic, A; Samarzija, M; Badovinac, S; Kehler, T; Jakopovic, M

2015-02-01

377

Endothelin-A receptor blockade slows the progression of renal injury in experimental renovascular disease  

PubMed Central

Endothelin (ET)-1, a potent renal vasoconstrictor with mitogenic properties, is upregulated by ischemia and has been shown to induce renal injury via the ET-A receptor. The potential role of ET-A blockade in chronic renovascular disease (RVD) has not, to our knowledge, been previously reported. We hypothesized that chronic ET-A receptor blockade would preserve renal hemodynamics and slow the progression of injury of the stenotic kidney in experimental RVD. Renal artery stenosis, a major cause of chronic RVD, was induced in 14 pigs and observed for 6 wk. In half of the pigs, chronic ET-A blockade was initiated (RVD+ET-A, 0.75 mg·kg?1·day?1) at the onset of RVD. Single-kidney renal blood flow, glomerular filtration rate, and perfusion were quantified in vivo after 6 wk using multidetector computer tomography. Renal microvascular density was quantified ex vivo using three-dimensional microcomputer tomography, and growth factors, inflammation, apoptosis, and fibrosis were determined in renal tissue. The degree of stenosis and increase in blood pressure were similar in RVD and RVD+ET-A pigs. Renal hemodynamics, function, and microvascular density were decreased in the stenotic kidney but preserved by ET-A blockade, accompanied by increased renal expression of vascular endothelial growth factor, hepatocyte growth factor, and downstream mediators such as phosphorilated-Akt, angiopoietins, and endothelial nitric oxide synthase. ET-A blockade also reduced renal apoptosis, inflammation, and glomerulosclerosis. This study shows that ET-A blockade slows the progression of renal injury in experimental RVD and preserves renal hemodynamics, function, and microvascular density in the stenotic kidney. These results support a role for ET-1/ET-A as a potential therapeutic target in chronic RVD. PMID:21478482

Kelsen, Silvia; Hall, John E.

2011-01-01

378

A genomic classifier predicting metastatic disease progression in men with biochemical recurrence after prostatectomy  

PubMed Central

BACKGROUND Due to their varied outcomes, men with biochemical recurrence (BCR) following radical prostatectomy (RP) present a management dilemma. Here, we evaluate Decipher, a genomic classifier (GC), for its ability to predict metastasis following BCR. METHODS The study population included 85 clinically high-risk patients who developed BCR after RP. Time-dependent receiver operating characteristic (ROC) curves, weighted Cox proportional hazard models and decision curves were used to compare GC scores to Gleason score (GS), PSA doubling time (PSAdT), time to BCR (ttBCR), the Stephenson nomogram and CAPRA-S for predicting metastatic disease progression. All tests were two-sided with a type I error probability of 5%. RESULTS GC scores stratified men with BCR into those who would or would not develop metastasis (8% of patients with low versus 40% with high scores developed metastasis, P<0.001). The area under the curve for predicting metastasis after BCR was 0.82 (95% CI, 0.76–0.86) for GC, compared to GS 0.64 (0.58–0.70), PSAdT 0.69 (0.61–0.77) and ttBCR 0.52 (0.46–0.59). Decision curve analysis showed that GC scores had a higher overall net benefit compared to models based solely on clinicopathologic features. In multivariable modeling with clinicopathologic variables, GC score was the only significant predictor of metastasis (P = 0.003). CONCLUSIONS When compared to clinicopathologic variables, GC better predicted metastatic progression among this cohort of men with BCR following RP. While confirmatory studies are needed, these results suggest that use of GC may allow for better selection of men requiring earlier initiation of treatment at the time of BCR. PMID:24145624

Ross, AE; Feng, FY; Ghadessi, M; Erho, N; Crisan, A; Buerki, C; Sundi, D; Mitra, AP; Vergara, IA; Thompson, DJS; Triche, TJ; Davicioni, E; Bergstralh, EJ; Jenkins, RB; Karnes, RJ; Schaeffer, EM

2015-01-01

379

FIELD PERFORMANCE AND QPX DISEASE PROGRESS IN CULTURED AND WILD-TYPE STRAINS OF MERCENARIA MERCENARIA IN NEW YORK WATERS  

E-print Network

-1500 ABSTRACT A field experiment was conducted to compare the performance of different hard clam (MercenariaFIELD PERFORMANCE AND QPX DISEASE PROGRESS IN CULTURED AND WILD-TYPE STRAINS OF MERCENARIA MERCENARIA IN NEW YORK WATERS SOREN F. DAHL,1 JOSHUA THIEL2 AND BASSEM ALLAM1 * 1 School of Marine

Allam, Bassem

380

Cognitive deficits in progressive supranuclear palsy, Parkinson's disease, and multiple system atrophy in tests sensitive to frontal lobe dysfunction  

Microsoft Academic Search

Groups of patients with idiopathic Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy or Steele-Richardson-Olszewski syndrome, matched for overall clinical disability, were compared using three computerised cognitive tests previously shown to be sensitive to frontal lobe dysfunction. On a test of planning based on the Tower of London task, all three groups were impaired, but in different ways. The

T W Robbins; M James; A M Owen; K W Lange; A J Lees; P N Leigh; C D Marsden; N P Quinn; B A Summers

1994-01-01

381

Differentiation of idiopathic Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, and healthy controls using magnetization transfer imaging  

Microsoft Academic Search

The differentiation of multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) from idiopathic Parkinson's disease (IPD) is difficult. Magnetization transfer imaging (MTI), a measure that correlates with myelination and axonal density, was employed in this study in the attempt to distinguish between these disorders. Measurements were carried out in 15 patients with IPD, 12 patients with MSA, 10 patients

Thomas Eckert; Michael Sailer; Joern Kaufmann; Christoph Schrader; Thomas Peschel; Nils Bodammer; Hans-Jochen Heinze; Mircea Ariel Schoenfeld

2004-01-01

382

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

Technology Transfer Automated Retrieval System (TEKTRAN)

A genetic tool hypothesized to predict which OPPV infected sheep will progress to debilitating clinical disease is MHC Class II Ovis aries (Ovar)-DRB1. Previously, fifteen Ovar-DRB1 beta 1 expressed alleles were identified in a ewe-lamb flock of 32 originating from an Idaho flock using RT-PCR, clon...

383

Cyclosporine A Slows the Progressive Renal Disease of Alport Syndrome (X-Linked Hereditary Nephritis): Results from a Canine Model  

Microsoft Academic Search

Alport syndrome refers to a hereditary disorder char- acterized by progressive renal disease and a multilaminar ap- pearance to the glomerular basement membrane (GBM). In a small group of patients with Alport syndrome, cyclosporine A was reported to decrease proteinuria and maintain stable renal function over 7 to 10 yr of follow-up. The present study examined the effect of cyclosporine

DILYS CHEN; BARBARA JEFFERSON; SCOTT J. HARVEY; KEQIN ZHENG; CATHY J. GARTLEY; ROBERT M. JACOBS; PAUL S. THORNER

2003-01-01

384

An In-Depth Review of the Evidence Linking Dietary Salt Intake and Progression of Chronic Kidney Disease  

Microsoft Academic Search

Background: Dietary salt has been debated for decades as having a potentially deleterious influence on human health. Objectives: To determine the quality of research and the relationship between dietary salt and markers for progression of kidney disease. Methods: Data sources included 7 electronic databases comprehensively searched for literature published between January 1, 1966, and August 31, 2004, and a manual

Charlotte Jones-Burton; Shiraz I. Mishra; Jeffrey C. Fink; Jeanine Brown; Weyinshet Gossa; George L. Bakris; Matthew R. Weir

2006-01-01

385

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-Dec. 1995) of oysters, Crassostrea virginica, that set on an artificial reef located in the Piankatank River, Virginia, in Augus...

386

JOANNES M.O et al. HLA polymorphism and sickle cell disease 1 Abstract: 150 words Text: 1988 words  

E-print Network

JOANNES M.O et al. HLA polymorphism and sickle cell disease 1 Abstract: 150 words Text: 1988 words References: 23 (568 words) Table: 3 Title: Infectious complications in sickle cell disease and HLA association, HLA class II alleles Abbreviated title: HLA polymorphism and sickle cell disease hal-00387082

Paris-Sud XI, Université de

387

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

2013-02-01

388

Diabetes disease progression in Goto-Kakizaki rats: effects of salsalate treatment  

PubMed Central

This study investigates the antidiabetic effects of salsalate on disease progression of diabetes in non-obese diabetic Goto-Kakizaki (GK) rats, an experimental model of type 2 diabetes. Salsalate was formulated in rat chow (1,000 ppm) and used to feed rats from 5 to 21 weeks of age. At 5 weeks of age, GK and Wistar (WIS) control rats were subdivided into four groups, each composed of six rats: GK rats with standard diet (GK-C); GK rats with salsalate-containing diet (GK-S); WIS rats with standard diet (WIS-C); and WIS rats with salsalate-containing diet (WIS-S). The GK-C rats (167.2±11.6 mg/dL) showed higher blood glucose concentrations than WIS-C rats (133.7±4.9 mg/dL, P<0.001) at the beginning of the experiment, and had substantially elevated blood glucose from an age of 15 weeks until sacrifice at 21 weeks (341.0±133.6 mg/dL). The GK-S rats showed an almost flat profile of blood glucose from 4 weeks (165.1±11.0 mg/dL) until sacrifice at 21 weeks of age (203.7±22.2 mg/dL). While this difference in blood glucose between 4 and 21 weeks in GK-S animals was significant, blood glucose at 21 weeks was significantly lower in GK-S compared to GK-C animals. At sacrifice, salsalate decreased plasma insulin (GK-S =1.0±0.3; GK-C =2.0±0.3 ng/mL, P<0.001) and increased plasma adiponectin concentrations (GK-S =15.9±0.7; GK-C =9.7±2.0 ?g/mL, P<0.001). Salsalate also lowered total cholesterol in GK-S rats (96.1±8.5 mg/dL) compared with GK-C rats (128.0±11.4 mg/dL, P<0.001). Inflammation-related genes (Ifit1 and Iigp1) exhibited much higher mRNA expression in GK-C rats than WIS-C rats in liver, adipose, and muscle tissues, while salsalate decreased the Ifit1 and Iigp1 mRNA only in adipose tissue. These results suggest that salsalate acts to both increase adiponectin and decrease adipose tissue-based inflammation while preventing type 2 diabetes disease progression in GK rats. PMID:25120374

Wang, Xi; DuBois, Debra C; Cao, Yanguang; Jusko, William J; Almon, Richard R

2014-01-01

389

Structure Versus Processing Deficits in Alzheimer's Disease, a Matter of Degree: A Comment on Storms et al. (2003)  

E-print Network

Structure Versus Processing Deficits in Alzheimer's Disease, a Matter of Degree: A Comment-suited for investigating semantic deficits in individ- uals diagnosed with dementia of the Alzheimer type (DAT) because) the inevitable semantic degradation following severe progression of the disease. A framework is presented

390

Soluble receptor for advanced glycation end-products and progression of airway disease  

PubMed Central

Background The receptor for advanced glycation end-products (RAGE) is highly expressed in the lung, where it is believed to have a homeostatic role. Reduced plasma levels of soluble RAGE (sRAGE) have been reported in patients with chronic obstructive pulmonary disease (COPD). The aim of the present study was to evaluate the association of plasma sRAGE levels with a longitudinal decline of lung function. We have also measured plasma levels of high mobility group box 1 (HMGB1), a RAGE ligand which has been associated with chronic inflammatory diseases including COPD. Methods Baseline plasma concentrations of sRAGE and HMGB1 were measured in non-smokers (n =?32), smokers without COPD (n =?212), and smokers with COPD (n =?51), and the associations of the plasma sRAGE and HMGB1 levels with longitudinal declines of lung function during a 4-year follow-up period were analysed. Results The plasma levels of sRAGE were significantly lower in smokers without COPD and in smokers with COPD, as compared to those of non-smokers. Plasma sRAGE levels positively correlated with FVC and FEV1 and inversely correlated with BMI and pack-years. Lower sRAGE levels were associated with greater declines of FEV1/FVC over 4 years in all participants. Moreover, multivariate regression analysis indicated that the baseline plasma sRAGE concentration was an independent predictor of FEV1/FVC decline in all groups. A subgroup analysis showed that decreased sRAGE levels are significantly associated with a more rapid decline of FEV1/FVC in smokers with COPD. There was no significant correlation between plasma HMGB1 levels and longitudinal decline of lung function. Conclusions Lower plasma concentrations of sRAGE were associated with greater progression of airflow limitations over time, especially in smokers with COPD, suggesting that RAGE might have a protective role in the lung. PMID:24758342

2014-01-01

391

Salivary DJ-1 could be an indicator of Parkinson's disease progression  

PubMed Central

Objective: The goal of the current investigation was to explore whether salivary DJ-1 could be a potential biomarker for monitoring disease progression in Parkinson's disease (PD) by evaluating the association between salivary DJ-1 concentrations and nigrostriatal dopaminergic function. Methods: First, in 74 patients with PD and 12 age-matched normal controls, single photon emission computed tomography (SPECT) imaging with labeled dopamine transporters (DAT) (99mTc-TRODAT-1), which has been used for measuring DAT density in PD was prformed. Then, the DJ-1 level in their saliva was analyzed by quantitative and sensitive Luminex assay and compared to caudate or putamen DAT density. Finally, based on the above, our cross-section study was carried out in 376 research volunteers (285 patients with PD and 91 healthy controls) to measure salivary DJ-1 level. Results: From our analysis, we found a correlation between salivary concentration of DJ-1 and putamen nucleus uptake of 99mTc-TRODAT-1 in the PD group. Although salivary DJ-1 levels were not affected by UPDRS scores, gender, age, and pharmacotherapy, DJ-1 levels in H&Y 4 stage of PD were higher than those in H&Y 1-3 stage as well as those in healthy controls. Salivary DJ-1 also decreased significantly in mixed type PD patients compared to the tremor-dominant type (TDT) and akinetic-rigid dominant type (ARDT) PD patients. Conclusions: According to the investigation in a large cohort, we reported for the first time the prognostic potential of the salivary DJ-1 as a biomarker for evaluating nigrostriatal dopaminergic function in PD. PMID:24936184

Kang, Wen-Yan; Yang, Qiong; Jiang, Xu-Feng; Chen, Wei; Zhang, Lin-Yuan; Wang, Xiao-Ying; Zhang, Li-Na; Quinn, Thomas J.; Liu, Jun; Chen, Sheng-Di

2014-01-01

392

Dysregulation of Anti-Inflammatory Annexin A1 Expression in Progressive Crohns Disease  

PubMed Central

Background Development of inflammatory bowel disease (IBD) involves the interplay of environmental and genetic factors with the host immune system. Mechanisms contributing to immune dysregulation in IBD are not fully defined. Development of novel therapeutic strategies is focused on controlling aberrant immune response in IBD. Current IBD therapy utilizes a combination of immunomodulators and biologics to suppress pro-inflammatory effectors of IBD. However, the role of immunomodulatory factors such as annexin A1 (ANXA1) is not well understood. The goal of this study was to examine the association between ANXA1 and IBD, and the effects of anti-TNF-?, Infliximab (IFX), therapy on ANXA1 expression. Methods ANXA1 and TNF-? transcript levels in PBMC were measured by RT PCR. Clinical follow up included the administration of serial ibdQs. ANXA1 expression in the gut mucosa was measured by IHC. Plasma ANXA1 levels were measured by ELISA. Results We found that the reduction in ANXA1 protein levels in plasma coincided with a decrease in the ANXA1 mRNA expression in peripheral blood of IBD patients. ANXA1 expression is upregulated during IFX therapy in patients with a successful intervention but not in clinical non-responders. The IFX therapy also modified the cellular immune activation in the peripheral blood of IBD patients. Decreased expression of ANXA1 was detected in the colonic mucosa of IBD patients with incomplete resolution of inflammation during continuous therapy, which correlated with increased levels of TNF-? transcripts. Gut mucosal epithelial barrier disruption was evident by increased plasma bacterial 16S levels. Conclusion Loss of ANXA1 expression may support inflammation during IBD and can serve as a biomarker of disease progression. Changes in ANXA1 levels may be predictive of therapeutic efficacy. PMID:24130820

Sena, Angela; Grishina, Irina; Thai, Anne; Goulart, Larissa; Macal, Monica; Fenton, Anne; Li, Jay; Prindiville, Thomas; Oliani, Sonia Maria; Dandekar, Satya; Goulart, Luiz; Sankaran-Walters, Sumathi

2013-01-01

393

The influence of renal manifestations to the progression of autosomal dominant polycystic kidney disease  

PubMed Central

Background: Renal stones, urinary tract infections (UTI) and gross hematuria (GH) are the most important renal manifestations of autosomal dominant polycystic kidney disease (ADPKD). They are not only common, but are also frequent cause of morbidity, influencing renal dysfunction. The aim of this study was to evaluate the frequency of these manifestations in our patients with ADPKD and their impact on renal function. Methods: One hundred eighty ADPKD patients were included in the study. Subjects were studied for the presence of UTI, gross hematuria frequency and responsible factors of nephrolithiasis. Survival times were calculated as the time to renal replacement therapy or time of serum creatinine value up to 10 mg/dl. Kaplan-Meier product-limit survival curves were constructed, and log rank test was used to compare the survival curves. Results: Kidney stones were present in 76/180 (42% of pts). The stones were composed of urate (47%) calcium oxalate (39%), and other compounds 14%. UTI was observed in 60% (108 patients). Patients treated with urinary disinfectants had a significant lower frequency of urinary infection (p<0.001) and hematuria (p<0.001) after one year than untreated patients. Gross hematuria was present in 113 patients (63%). In 43 patients hematuria was diagnosed before age 30 (38%), while in 70 patients it was diagnosed after age 30 (62%). Conclusions: UTI is frequent in our ADPKD patients. The correct treatment of UTI decreases its frequency and has beneficial role in the rate of progression to renal failure in ADPKD patients. Patients with recurrent episodes of gross hematuria may be at risk for more severe renal disease. PMID:19918304

Idrizi, A; Barbullushi, M; Petrela, E; Kodra, S; Koroshi, A; Thereska, N

2009-01-01

394

Genetic variants in IL2RA and IL7R affect multiple sclerosis disease risk and progression.  

PubMed

Multiple sclerosis (MS) is a common demyelinating neurodegenerative disease with a strong genetic component. Previous studies have associated genetic variants in IL2RA and IL7R in the pathophysiology of the disease. In this study, we describe the association between IL2RA (rs2104286) and IL7R (rs6897932) in the Canadian population. Genotyping 1,978 MS patients and 830 controls failed to identify any significant association between these variants and disease risk. However, stratified analysis for family history of disease and disease course identified a trend towards association for IL2RA in patients without a family history (p?=?0.05; odds ratio?=?0.77) and a significant association between IL7R and patients who developed progressive MS (PrMS) (p?=?0.002; odds ratio?=?0.73). Although not statistically significant, the effect of IL2RA (rs2104286) in patients without a family history of MS indicates that the genetic components for familial and sporadic disease are perhaps distinct. This data suggests that the onset of sporadic disease is likely determined by a large number of variants of small effect, whereas MS in patients with a family history of disease is caused by a few deleterious variants. In addition, the significant association between PrMS and rs6897932 indicates that IL7R may not be