Gender differences in HIV progression to AIDS and death in industrialized countries: slower disease progression following HIV seroconversion in women

NARCIS (Netherlands)

Jarrin, Inmaculada; Geskus, Ronald; Bhaskaran, Krishnan; Prins, Maria; Perez-Hoyos, Santiago; Muga, Roberto; Hernández-Aguado, Ildefonso; Meyer, Laurence; Porter, Kholoud; del Amo, Julia; Bucher, Heiner; Chêne, Geneviève; Pillay, Deenan; Rosinska, Magda; Sabin, Caroline; Touloumi, Giota; Walker, Sarah; Babiker, Abdel; Darbyshire, Janet; de Luca, Andrea; Fisher, Martin; Goujard, Cécile; Kaldor, John; Kelleher, Tony; Gelgor, Linda; Ramacciotti, Tim; Cooper, David; Smith, Don; Gill, John; Jørgensen, Louise Bruun; Nielsen, Claus; Pedersen, Court; Lutsar, Irja; Dabis, Francois; Thiebaut, Rodolphe; Masquelier, Bernard; Costagliola, Dominique; Vanhems, Philippe; Boufassa, Faroudy; Hamouda, Osamah; Kucherer, Claudia; Pantazis, Nikos; Hatzakis, Angelos; Paraskevis, Dimitrios; Karafoulidou, Anastasia; Rezza, Giovanni; Dorrucci, Maria; Longo, Benedetta; Balotta, Claudia; Coutinho, Roel

2008-01-01

To evaluate sex differences in human immunodeficiency virus (HIV) disease progression before (pre-1997) and after (1997-2006) introduction of highly active antiretroviral therapy, the authors used data from a collaboration of 23 HIV seroconverter cohort studies from Europe, Australia, and Canada

Pregnancy and HIV Disease Progression in an Early Infection Cohort from Five African Countries.

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Wall, Kristin M; Rida, Wasima; Haddad, Lisa B; Kamali, Anatoli; Karita, Etienne; Lakhi, Shabir; Kilembe, William; Allen, Susan; Inambao, Mubiana; Yang, Annie H; Latka, Mary H; Anzala, Omu; Sanders, Eduard J; Bekker, Linda-Gail; Edward, Vinodh A; Price, Matt A

2017-03-01

Understanding associations between pregnancy and HIV disease progression is critical to provide appropriate counseling and care to HIV-positive women. From 2006 to 2011, women less than age 40 with incident HIV infection were enrolled in an early HIV infection cohort in Kenya, Rwanda, South Africa, Uganda, and Zambia. Time-dependent Cox models evaluated associations between pregnancy and HIV disease progression. Clinical progression was defined as a single CD4 measurement pregnancy. Among 222 women, 63 experienced clinical progression during 783.5 person-years at risk (8.0/100). Among 205 women, 87 experienced immunologic progression during 680.1 person-years at risk (12.8/100). The association between pregnancy and clinical progression was adjusted hazard ratio [aHR] = 0.7; 95% confidence interval (CI): 0.2, 1.8. The association between pregnancy and immunologic progression was aHR = 1.7; 95% CI: 0.9, 3.3. Models controlled for age; human leukocyte antigen alleles A*03:01, B*45, B*57; CD4 set point; and HIV-1 subtype. CD4 measurements before versus after pregnancies were not different. In this cohort, pregnancy was not associated with increased clinical or immunologic HIV progression. Similarly, we did not observe meaningful deleterious associations of pregnancy with CD4s. Our findings suggest that HIV-positive women may become pregnant without harmful health effects occurring during the pregnancy. Evaluation of longer-term impact of pregnancy on progression is warranted.

[Hepatobiliary System Diseases as the Predictors of Psoriasis Progression].

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Smirnova, S V; Barilo, A A; Smolnikova, M V

2016-01-01

To assess the state of the hepatobiliary system in psoriasis andpsoriatic arthritis in order to establish a causal relationship and to identify clinical and functional predictors of psoriatic disease progression. The study includedpatients with extensive psoriasis vulgaris (n = 175) aged 18 to 66 years old and healthy donors (n = 30), matched by sex and age: Group 1--patients with psoriasis (PS, n = 77), group 2--patients with psoriatic arthritis (PsA, n = 98), group 3--control. The evaluation of functional state of the hepatobiliary system was performed by the analysis of the clinical and anamnestic data and by the laboratory-instrumental methods. We identified predictors of psoriasis: triggers (stress and nutritionalfactor), increased total bilirubin, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, eosinophilia, giardiasis, carriers of hepatitis C virus, ductal changes andfocal leisons in the liver, thickening of the walls of the gallbladder detected by ultrasound. Predictors ofpsoriatic arthritis: age over 50 years, dyspeptic complaints, the presence of hepatobiliary system diseases, the positive right hypochondrium syndrome, the clinical symptoms of chronic cholecystitis, excess body weight, high levels of bilirubin, cholesterol and low density lipoprotein, hepatomegaly, non-alcoholic fatty liver disease. High activity of hepatocytes cytolysis, cholestasis, inflammation, metabolic disorders let us considerpsoriatic arthritis as a severe clinical stage psoriatic disease when the hepatobiliary system, in turn, is one of the main target organs in systemic psoriatic process. Non-alcoholic fatty liver disease and chronic cholecystitis are predictors of psoriatic disease progression.

Early intranasal insulin therapy halts progression of neurodegeneration: progress in Alzheimer's disease therapeutics.

Science.gov (United States)

de la Monte, Suzanne M

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

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

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Egresi, Anna; Lengyel, Gabriella; Somogyi, Anikó; Blázovics, Anna; Hagymási, Krisztina

2016-02-21

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

Interleukin-6 and interleukin-10 gene polymorphisms and the risk of further periodontal disease progression.

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Chatzopoulos, Georgios; Doufexi, Aikaterini-Ellisavet; Wolff, Larry; Kouvatsi, Anastasia

2018-03-08

Susceptible genotypes to periodontal disease are associated with disease onset and progression. The aim of this study was to examine the effect of gene polymorphisms on the risk of further disease progression and the need for further treatment among adults with chronic periodontal disease. Sixty-seven patients diagnosed with chronic periodontitis were grouped according to genotype status and risk of further progression of disease and tooth loss. All individuals were clinically evaluated for probing pocket depth, clinical attachment loss and bleeding on probing at baseline and 45 days after treatment. Blood samples were collected at baseline and genotyping of the polymorphisms in IL-6 (rs1800796) and IL-10 (rs1800872) genes were performed by PCR. Following DNA separation and genotyping, 65.7% of the patients were homozygous carriers of the IL-6 -572G and 49.3% were carriers of the IL-10 -592A allele. Individuals at risk of disease progression ranged from 7.5% to 62.7% based on the criteria used. Carriers of the IL-10 -592A allele were significantly associated with BOP ≥ 30% and therefore exhibited a higher risk of further periodontal breakdown (p = 0.018) with an odds ratio of 1.18. None of the other definitions of disease progression were significantly associated with the examined IL-6 and IL-10 genotypes (p > 0.05). IL-10 polymorphism was associated with an increased risk of further disease progression and the potential need for further treatment following non-surgical periodontal treatment. Susceptible IL-6 genotypes were not associated with the risk of persisting or recurrent disease activity.

Site-level progression of periodontal disease during a follow-up period

Science.gov (United States)

Morozumi, Toshiya; Nakagawa, Taneaki; Sugaya, Tsutomu; Kawanami, Masamitsu; Suzuki, Fumihiko; Takahashi, Keiso; Abe, Yuzo; Sato, Soh; Makino-Oi, Asako; Saito, Atsushi; Takano, Satomi; Minabe, Masato; Nakayama, Yohei; Ogata, Yorimasa; Kobayashi, Hiroaki; Izumi, Yuichi; Sugano, Naoyuki; Ito, Koichi; Sekino, Satoshi; Numabe, Yukihiro; Fukaya, Chie; Yoshinari, Nobuo; Fukuda, Mitsuo; Noguchi, Toshihide; Kono, Tomoo; Umeda, Makoto; Fujise, Osamu; Nishimura, Fusanori; Yoshimura, Atsutoshi; Hara, Yoshitaka; Nakamura, Toshiaki; Noguchi, Kazuyuki; Kakuta, Erika; Hanada, Nobuhiro; Takashiba, Shogo; Amitani, Yasuharu; Yoshie, Hiromasa

2017-01-01

Periodontal disease is assessed and its progression is determined via observations on a site-by-site basis. Periodontal data are complex and structured in multiple levels; thus, applying a summary statistical approach (i.e., the mean) for site-level evaluations results in loss of information. Previous studies have shown the availability of mixed effects modeling. However, clinically beneficial information on the progression of periodontal disease during the follow-up period is not available. We conducted a multicenter prospective cohort study. Using mixed effects modeling, we analyzed 18,834 sites distributed on 3,139 teeth in 124 patients, and data were collected 5 times over a 24-month follow-up period. The change in the clinical attachment level (CAL) was used as the outcome variable. The CAL at baseline was an important determinant of the CAL changes, which varied widely according to the tooth surface. The salivary levels of periodontal pathogens, such as Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, were affected by CAL progression. “Linear”- and “burst”-type patterns of CAL progression occurred simultaneously within the same patient. More than half of the teeth that presented burst-type progression sites also presented linear-type progression sites, and most of the progressions were of the linear type. Maxillary premolars and anterior teeth tended to show burst-type progression. The parameters identified in this study may guide practitioners in determining the type and extent of treatment needed at the site and patient levels. In addition, these results show that prior hypotheses concerning "burst" and "linear" theories are not valid. PMID:29206238

Evaluation of keratoconus progression.

Science.gov (United States)

Shajari, Mehdi; Steinwender, Gernot; Herrmann, Kim; Kubiak, Kate Barbara; Pavlovic, Ivana; Plawetzki, Elena; Schmack, Ingo; Kohnen, Thomas

2018-06-01

To define variables for the evaluation of keratoconus progression and to determine cut-off values. In this retrospective cohort study (2010-2016), 265 eyes of 165 patients diagnosed with keratoconus underwent two Scheimpflug measurements (Pentacam) that took place 1 year apart ±3 months. Variables used for keratoconus detection were evaluated for progression and a correlation analysis was performed. By logistic regression analysis, a keratoconus progression index (KPI) was defined. Receiver-operating characteristic curve (ROC) analysis was performed and Youden Index calculated to determine cut-off values. Variables used for keratoconus detection showed a weak correlation with each other (eg, correlation r=0.245 between RPImin and Kmax, pKPI). KPI was defined by logistic regression and consisted of a Pachymin coefficient of -0.78 (p=0.001), a maximum elevation of back surface coefficient of 0.27 and coefficient of corneal curvature at the zone 3 mm away from the thinnest point on the posterior corneal surface of -12.44 (both pKPI: D-index had a cut-off of 0.4175 (70.6% sensitivity) and Youden Index of 0.606. Cut-off for KPI was -0.78196 (84.7% sensitivity) and a Youden Index of 0.747; both 90% specificity. Keratoconus progression should be defined by evaluating parameters that consider several corneal changes; we suggest D-index and KPI to detect progression. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Primary progressive aphasia: from syndrome to disease.

Science.gov (United States)

Matías-Guiu, J A; García-Ramos, R

2013-01-01

Primary progressive aphasia (PPA) is a clinical syndrome characterised by a progressive decline in language and speech of neurodegenerative origin. Major breakthroughs made in recent years have lent us a better understanding of this syndrome, which may be the first manifestation of any of a number of neurodegenerative diseases. We reviewed the main aspects of PPA epidemiology, clinical manifestations, diagnosis, aetiology and treatment. Most cases manifest sporadically and the typical age of onset is between 50 and 70 years. Three clinically distinct variants have been described: nonfluent or agrammatic PPA, semantic PPA and logopenic PPA. Each of these variants tends to be associated with specific histopathological findings, but clinical diagnostic methods are imperfect predictors of underlying pathology. Anatomical and functional neuroimaging can provide useful biomarkers. Several treatments have been proposed, and while no clear benefits have been demonstrated, acetylcholinesterase inhibitors may be useful, especially in the logopenic variant. PPA is an emerging syndrome which may be more prevalent than we might expect. It was previously listed as part of the frontotemporal dementia spectrum, and it is also related to Alzheimer disease. Clinical diagnosis, complemented by a biomarker evaluation, may predict the underlying pathology, which in turn will improve treatment possibilities. Copyright © 2012 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

En Face Spectral-Domain Optical Coherence Tomography for the Monitoring of Lesion Area Progression in Stargardt Disease.

Science.gov (United States)

Melillo, Paolo; Testa, Francesco; Rossi, Settimio; Di Iorio, Valentina; Orrico, Ada; Auricchio, Alberto; Simonelli, Francesca

2016-07-01

We investigated the progression of Stargardt disease (STGD1) over a multiyear follow-up by evaluating the macular lesion area as computed by an automatic algorithm from spectral-domain optical coherence tomography (SD-OCT). We reviewed medical records of STGD1 patients, with a clinical and molecular diagnosis of STGD1 at a single institution, who underwent best-corrected visual acuity (BCVA), fundus photography, SD-OCT, full-field electroretinography, and, when available, fundus autofluorescence (FAF). Regression models were fitted on the selected clinical parameters; in particular, on the macular lesion area computed by SD-OCT, to evaluate the disease progression over a multiyear follow-up. The comparison between SD-OCT and FAF, available for 22 patients, showed that macular lesion area, assessed by SD-OCT, significantly correlated with the area of absent FAF (P disease, showing a significant progression over the follow-up. Our findings suggest that the evaluation of macular lesion area by en face SD-OCT, together with FAF, could drive the choice of the most amenable candidates and the most suitable area to be treated in gene therapy clinical trials.

Progression of Stargardt Disease as Determined by Fundus Autofluorescence in the Retrospective Progression of Stargardt Disease Study (ProgStar Report No. 9).

Science.gov (United States)

Strauss, Rupert W; Muñoz, Beatriz; Ho, Alexander; Jha, Anamika; Michaelides, Michel; Cideciyan, Artur V; Audo, Isabelle; Birch, David G; Hariri, Amir H; Nittala, Muneeswar G; Sadda, SriniVas; West, Sheila; Scholl, Hendrik P N

2017-11-01

Sensitive outcome measures for disease progression are needed for treatment trials of Stargardt disease. To describe the yearly progression rate of atrophic lesions in the retrospective Progression of Stargardt Disease study. A multicenter retrospective cohort study was conducted at tertiary referral centers in the United States and Europe. A total of 251 patients aged 6 years or older at baseline, harboring disease-causing variants in ABCA4 (OMIM 601691), enrolled in the study from 9 centers between August 2, 2013, and December 12, 2014; of these patients, 215 had at least 2 gradable fundus autofluorescence images with atrophic lesion(s) present in at least 1 eye. Areas of definitely decreased autofluorescence (DDAF) and questionably decreased autofluorescence were quantified by a reading center. Progression rates were estimated from linear mixed models with time as the independent variable. Yearly rate of progression using the growth of atrophic lesions measured by fundus autofluorescence. A total of 251 participants (458 study eyes) were enrolled. Images from 386 eyes of 215 participants (126 females and 89 males; mean [SD] age, 29.9 [14.7] years; mean [SD] age of onset of symptoms, 21.9 [13.3] years) showed atrophic lesions present on at least 2 visits and were graded for 2 (156 eyes), 3 (174 eyes), or 4 (57 eyes) visits. A subset of 224 eyes (123 female participants and 101 male participants; mean [SD] age, 33.0 [15.1] years) had areas of DDAF present on at least 2 visits; these eyes were included in the estimation of the progression of the area of DDAF. At the first visit, DDAF was present in 224 eyes (58.0%), with a mean (SD) lesion size of 2.2 (2.7) mm2. The total mean (SD) area of decreased autofluorescence (DDAF and questionably decreased autofluorescence) at first visit was 2.6 (2.8) mm2. Mean progression of DDAF was 0.51 mm2/y (95% CI, 0.42-0.61 mm2/y), and of total decreased fundus autofluorescence was 0.35 mm2/y (95% CI, 0.28-0.43 mm2/y). Rates of

Evaluation of medication treatment for Alzheimer's disease on clinical evidence

Directory of Open Access Journals (Sweden)

Meng-qiu LI

2014-03-01

Full Text Available Objective To formulate the best treatment plan for Alzheimer's disease patients by evaluating the therapeutic efficacy and side effect of various evidence-based programs. Methods Alzheimer's disease, donepezil, rivastigmine, galantamine, memantine, rosiglitazone, etc. were defined as retrieval words. PubMed, Cochrane Library, Wanfang Data and China National Knowledge Infrastructure (CNKI databases were used with applying of manual searching. Systematic reviews, randomized controlled trials (RCT, controlled clinical trials and case-observation studies were collected and evaluated by Jadad Scale. Results After screening, 33 selected resources included 14 systematic reviews, 14 randomized controlled trials, 4 controlled clinical trials and 1 case-observation study. According to Jadad Scale, total 28 articles were evaluated to be high quality (12 with score 4, 10 score 5, 6 score 7, and 5 were low quality with score 3. It was summarized as follows: 1 Alzheimer's disease is a progressive neurodegenerative disease for which no cure exists. To date, only symptomatic treatments with cholinesterase inhibitors (donepezil, rivastigmine, galantamine and an N-methyl-D-aspartate (NMDA receptor noncompetitive antagonist (memantine, are effective and well tolerated to counterbalance the neurotransmitter disturbance, but cannot limit or impact on disease progression. 2 Disease modifying drug is an potential agent, with persistent effect on slowing the progression of structural damage, and can be detected even after withdrawing the treatment. Many types of disease modifying drugs are undergoing clinical trials. Conclusions Using evidence-based medicine methods can provide best clinical evidence on Alzheimer's disease treatment. doi: 10.3969/j.issn.1672-6731.2014.03.009

Evaluating Chagas disease progression and cure through blood-derived biomarkers: a systematic review.

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Requena-Méndez, Ana; López, Manuel Carlos; Angheben, Andrea; Izquierdo, Luis; Ribeiro, Isabela; Pinazo, Maria-Jesús; Gascon, Joaquim; Muñoz, José

2013-09-01

This article reviews the usefulness of various types of blood-derived biomarkers that are currently being studied to predict the progression of Chagas disease in patients with the indeterminate form, to assess the efficacy of antiparasitic drugs and to identify early cardiac and gastrointestinal damage. The authors used a search strategy based on MEDLINE, Cochrane Library Register for systematic review, EmBase, Global Health and LILACS databases. Out of 1716 screened articles, only 166 articles were eligible for final inclusion. The authors classified the biomarkers according to their biochemical structure and primary biological activity in four groups: i) markers of inflammation and cellular injury, ii) metabolic biomakers, iii) prothrombotic biomarkers and iv) markers derived from specific antigens of the parasite. Several potential biomarkers might have clinical potential for the detection of early cardiopathy. Such capacity is imperative in order to detect high-risk patients who require intensive monitoring and earlier therapy. Prospective studies with longer follow-ups are needed for the appraisal of biomarkers assessing clinical or microbiological cure after therapy. At the same time, studies evaluating more than one biomarker are useful to compare the efficacy among them given the lack of a recognized gold standard.

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

International Nuclear Information System (INIS)

Ohnishi, T.; Hoshi, H.; Jinnouchi, S.; Nagamachi, S.; Watanabe, K.; Mituyama, Y.

1990-01-01

Two patients presenting with progressive dementia coupled with motor neuron disease underwent brain SPECT using N-isopropyl-p iodine-123-iodoamphetamine [( 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

Periodontal profile classes predict periodontal disease progression and tooth loss.

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Morelli, Thiago; Moss, Kevin L; Preisser, John S; Beck, James D; Divaris, Kimon; Wu, Di; Offenbacher, Steven

2018-02-01

Current periodontal disease taxonomies have limited utility for predicting disease progression and tooth loss; in fact, tooth loss itself can undermine precise person-level periodontal disease classifications. To overcome this limitation, the current group recently introduced a novel patient stratification system using latent class analyses of clinical parameters, including patterns of missing teeth. This investigation sought to determine the clinical utility of the Periodontal Profile Classes and Tooth Profile Classes (PPC/TPC) taxonomy for risk assessment, specifically for predicting periodontal disease progression and incident tooth loss. The analytic sample comprised 4,682 adult participants of two prospective cohort studies (Dental Atherosclerosis Risk in Communities Study and Piedmont Dental Study) with information on periodontal disease progression and incident tooth loss. The PPC/TPC taxonomy includes seven distinct PPCs (person-level disease pattern and severity) and seven TPCs (tooth-level disease). Logistic regression modeling was used to estimate relative risks (RR) and 95% confidence intervals (CI) for the association of these latent classes with disease progression and incident tooth loss, adjusting for examination center, race, sex, age, diabetes, and smoking. To obtain personalized outcome propensities, risk estimates associated with each participant's PPC and TPC were combined into person-level composite risk scores (Index of Periodontal Risk [IPR]). Individuals in two PPCs (PPC-G: Severe Disease and PPC-D: Tooth Loss) had the highest tooth loss risk (RR = 3.6; 95% CI = 2.6 to 5.0 and RR = 3.8; 95% CI = 2.9 to 5.1, respectively). PPC-G also had the highest risk for periodontitis progression (RR = 5.7; 95% CI = 2.2 to 14.7). Personalized IPR scores were positively associated with both periodontitis progression and tooth loss. These findings, upon additional validation, suggest that the periodontal/tooth profile classes and the derived

Predictors of disease progression in HIV infection: a review

Directory of Open Access Journals (Sweden)

Ananworanich Jintanat

2007-05-01

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

Quantification of disease progression of several microbial pathogens on Arabidopsis thaliana using real-time fluorescence PCR

NARCIS (Netherlands)

Brouwer, M.; Lievens, B.; Hemelrijck, van W.; Ackerveken, van den G.; Cammue, B.P.A.; Thomma, B.P.H.J.

2003-01-01

An accurate monitoring of disease progression is important to evaluate disease susceptibility phenotypes. Over the years, Arabidopsis thaliana has become the model species to serve as a host in plant-pathogen interactions. Despite the efforts to study genetic mechanisms of host defense, little

Natural History of Progression of Chronic Kidney Disease in Stages ...

African Journals Online (AJOL)

Natural History of Progression of Chronic Kidney Disease in Stages 4 and 5. ... Conclusion: Low serum bicarbonate level and high urinary protein excretion at baseline are independent predictors of progression in stage 4 and 5 CKD. Keywords: Chronic kidney disease; End stage renal disease; Glomerular filtration rate; ...

Progress in genetics of coronary artery disease

African Journals Online (AJOL)

Radwa Gamal

To the Editor. Coronary Heart Disease (CHD) is the leading cause of mortality and morbidity worldwide [1] and it is a result of coronary artery disease (CAD). Coronary artery disease refers to the build-up of atherosclerotic plaque in the blood vessels that supply oxygen and nutrients to the heart. Progressive infiltration of the ...

Overlap between age-at-onset and disease-progression determinants in Huntington disease.

Science.gov (United States)

Aziz, N Ahmad; van der Burg, Jorien M M; Tabrizi, Sarah J; Landwehrmeyer, G Bernhard

2018-05-09

A fundamental but still unresolved issue regarding Huntington disease (HD) pathogenesis is whether the factors that determine age at onset are the same as those that govern disease progression. Because elucidation of this issue is crucial for the development as well as optimal timing of administration of novel disease-modifying therapies, we aimed to assess the extent of overlap between age-at-onset and disease-progression determinants in HD. Using observational data from Enroll-HD, the largest cohort of patients with HD worldwide, in this study we present, validate, and apply an intuitive method based on linear mixed-effect models to quantify the variability in the rate of disease progression in HD. A total of 3,411 patients with HD met inclusion criteria. We found that (1) about two-thirds of the rate of functional, motor, and cognitive progression in HD is determined by the same factors that also determine age at onset, with CAG repeat-dependent mechanisms having by far the largest effect; (2) although expanded HTT CAG repeat size had a large influence on average body weight, the rate of weight loss was largely independent of factors that determine age at onset in HD; and (3) about one-third of the factors that determine the rate of functional, motor, and cognitive progression are different from those that govern age at onset and need further elucidation. Our findings imply that targeting of CAG repeat-dependent mechanisms, for example through gene-silencing approaches, is likely to affect the rate of functional, motor, and cognitive impairment, but not weight loss, in manifest HD mutation carriers. Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Highly sensitive measurements of disease progression in rare disorders: Developing and validating a multimodal model of retinal degeneration in Stargardt disease.

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Lambertus, Stanley; Bax, Nathalie M; Fakin, Ana; Groenewoud, Joannes M M; Klevering, B Jeroen; Moore, Anthony T; Michaelides, Michel; Webster, Andrew R; van der Wilt, Gert Jan; Hoyng, Carel B

2017-01-01

Each inherited retinal disorder is rare, but together, they affect millions of people worldwide. No treatment is currently available for these blinding diseases, but promising new options-including gene therapy-are emerging. Arguably, the most prevalent retinal dystrophy is Stargardt disease. In each case, the specific combination of ABCA4 variants (> 900 identified to date) and modifying factors is virtually unique. It accounts for the vast phenotypic heterogeneity including variable rates of functional and structural progression, thereby potentially limiting the ability of phase I/II clinical trials to assess efficacy of novel therapies with few patients. To accommodate this problem, we developed and validated a sensitive and reliable composite clinical trial endpoint for disease progression based on structural measurements of retinal degeneration. We used longitudinal data from early-onset Stargardt patients from the Netherlands (development cohort, n = 14) and the United Kingdom (external validation cohort, n = 18). The composite endpoint was derived from best-corrected visual acuity, fundus autofluorescence, and spectral-domain optical coherence tomography. Weighting optimization techniques excluded visual acuity from the composite endpoint. After optimization, the endpoint outperformed each univariable outcome, and showed an average progression of 0.41° retinal eccentricity per year (95% confidence interval, 0.30-0.52). Comparing with actual longitudinal values, the model accurately predicted progression (R2, 0.904). These properties were largely preserved in the validation cohort (0.43°/year [0.33-0.53]; prediction: R2, 0.872). We subsequently ran a two-year trial simulation with the composite endpoint, which detected a 25% decrease in disease progression with 80% statistical power using only 14 patients. These results suggest that a multimodal endpoint, reflecting structural macular changes, provides a sensitive measurement of disease progression in

Highly sensitive measurements of disease progression in rare disorders: Developing and validating a multimodal model of retinal degeneration in Stargardt disease.

Directory of Open Access Journals (Sweden)

Stanley Lambertus

progression in Stargardt disease. It can be very useful in the evaluation of novel therapeutic modalities in rare disorders.

En Face Spectral-Domain Optical Coherence Tomography for the Monitoring of Lesion Area Progression in Stargardt Disease

Science.gov (United States)

Melillo, Paolo; Testa, Francesco; Rossi, Settimio; Di Iorio, Valentina; Orrico, Ada; Auricchio, Alberto; Simonelli, Francesca

2016-01-01

Purpose We investigated the progression of Stargardt disease (STGD1) over a multiyear follow-up by evaluating the macular lesion area as computed by an automatic algorithm from spectral-domain optical coherence tomography (SD-OCT). Methods We reviewed medical records of STGD1 patients, with a clinical and molecular diagnosis of STGD1 at a single institution, who underwent best-corrected visual acuity (BCVA), fundus photography, SD-OCT, full-field electroretinography, and, when available, fundus autofluorescence (FAF). Regression models were fitted on the selected clinical parameters; in particular, on the macular lesion area computed by SD-OCT, to evaluate the disease progression over a multiyear follow-up. Results The comparison between SD-OCT and FAF, available for 22 patients, showed that macular lesion area, assessed by SD-OCT, significantly correlated with the area of absent FAF (P disease, showing a significant progression over the follow-up. Our findings suggest that the evaluation of macular lesion area by en face SD-OCT, together with FAF, could drive the choice of the most amenable candidates and the most suitable area to be treated in gene therapy clinical trials. PMID:27409479

Disease Progression in a Patient with Nonalcoholic Steatohepatitis

Directory of Open Access Journals (Sweden)

Ping-Huei Tseng

2008-10-01

Full Text Available Nonalcoholic steatohepatitis (NASH is a severe form of nonalcoholic fatty liver disease (NAFLD. The prevalence and clinical significance of NAFLD/NASH have been increasingly recognized in Western countries but much less known in Asian countries, including Taiwan. Here, we report the case of a 43-year-old man who had abnormal liver tests for 18 years. Retrospective evaluation of his initial clinical, laboratory and histologic findings indicated that the hepatic disorder was compatible with the diagnosis of NASH. Although his liver biochemical tests improved after taking lipid-lowering agents, a liver biopsy 17 years later demonstrated histologic progression of intralobular necroinflammation and perivenular fibrosis. These facts suggest that NASH, albeit mild and slowly progressive, indeed exists in Taiwan. After the control of chronic hepatitis B and C and westernization of the lifestyle in Taiwan, an increasing burden of NAFLD/NASH is anticipated and active prophylactic measures should be implemented.

Development and reliability of a multi-modality scoring system for evaluation of disease progression in pre-clinical models of osteoarthritis: celecoxib may possess disease-modifying properties.

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Panahifar, A; Jaremko, J L; Tessier, A G; Lambert, R G; Maksymowych, W P; Fallone, B G; Doschak, M R

2014-10-01

We sought to develop a comprehensive scoring system for evaluation of pre-clinical models of osteoarthritis (OA) progression, and use this to evaluate two different classes of drugs for management of OA. Post-traumatic OA (PTOA) was surgically induced in skeletally mature rats. Rats were randomly divided in three groups receiving either glucosamine (high dose of 192 mg/kg) or celecoxib (clinical dose) or no treatment. Disease progression was monitored utilizing micro-magnetic resonance imaging (MRI), micro-computed tomography (CT) and histology. Pertinent features such as osteophytes, subchondral sclerosis, joint effusion, bone marrow lesion (BML), cysts, loose bodies and cartilage abnormalities were included in designing a sensitive multi-modality based scoring system, termed the rat arthritis knee scoring system (RAKSS). Overall, an inter-observer correlation coefficient (ICC) of greater than 0.750 was achieved for each scored feature. None of the treatments prevented cartilage loss, synovitis, joint effusion, or sclerosis. However, celecoxib significantly reduced osteophyte development compared to placebo. Although signs of inflammation such as synovitis and joint effusion were readily identified at 4 weeks post-operation, we did not detect any BML. We report the development of a sensitive and reliable multi-modality scoring system, the RAKSS, for evaluation of OA severity in pre-clinical animal models. Using this scoring system, we found that celecoxib prevented enlargement of osteophytes in this animal model of PTOA, and thus it may be useful in preventing OA progression. However, it did not show any chondroprotective effect using the recommended dose. In contrast, high dose glucosamine had no measurable effects. Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Embryonic Stem Cells-loaded Gelatin Microcryogels Slow Progression of Chronic Kidney Disease

Science.gov (United States)

Geng, Xiao-Dong; Zheng, Wei; Wu, Cong-Mei; Wang, Shu-Qiang; Hong, Quan; Cai, Guang-Yan; Chen, Xiang-Mei; Wu, Di

2016-01-01

Background: Chronic kidney disease (CKD) has become a public health problem. New interventions to slow or prevent disease progression are urgently needed. In this setting, cell therapies associated with regenerative effects are attracting increasing interest. We evaluated the effect of embryonic stem cells (ESCs) on the progression of CKD. Methods: Adult male Sprague–Dawley rats were subjected to 5/6 nephrectomy. We used pedicled greater omentum flaps packing ESC-loaded gelatin microcryogels (GMs) on the 5/6 nephrectomized kidney. The viability of ESCs within the GMs was detected using in vitro two-photon fluorescence confocal imaging. Rats were sacrificed after 12 weeks. Renal injury was evaluated using serum creatinine, urea nitrogen, 24 h protein, renal pathology, and tubular injury score results. Structural damage was evaluated by periodic acid-Schiff and Masson trichrome staining. Results: In vitro, ESCs could be automatically loaded into the GMs. Uniform cell distribution, good cell attachment, and viability were achieved from day 1 to 7 in vitro. After 12 weeks, in the pedicled greater omentum flaps packing ESC-loaded GMs on 5/6 nephrectomized rats group, the plasma urea nitrogen levels were 26% lower than in the right nephrectomy group, glomerulosclerosis index was 62% lower and tubular injury index was 40% lower than in the 5/6 nephrectomized rats group without GMs. Conclusions: In a rat model of established CKD, we demonstrated that the pedicled greater omentum flaps packing ESC-loaded GMs on the 5/6 nephrectomized kidney have a long-lasting therapeutic rescue function, as shown by the decreased progression of CKD and reduced glomerular injury. PMID:26879011

The applause sign and neuropsychological profile in progressive supranuclear palsy and Parkinson's disease.

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Somme, Johanne; Gómez-Esteban, Juan Carlos; Tijero, Beatriz; Berganzo, Koldo; Lezcano, Elena; Zarranz, Juan Jose

2013-08-01

The applause sign has been associated with various neurodegenerative diseases. We investigate its validity in the differential diagnosis of progressive supranuclear palsy and Parkinson's disease, and its relationship with neuropsychological tests. 23 patients with progressive supranuclear palsy and 106 patients with Parkinson's disease were included and administered the following scales: progressive supranuclear palsy rating scale, unified Parkinson's disease rating scale (UPDRS), mini-mental state examination (MMSE), frontal assessment battery (FAB), neuropsychiatric inventory and three-clap test. 73.9% with progressive supranuclear palsy and 21.7% with Parkinson's disease showed a positive applause sign. Only a positive applause sign, UPDRS II score and disease duration were found to be predictors of progressive supranuclear palsy. Both patient-groups showed statistically significant correlations between the applause sign and neuropsychological tests: in progressive supranuclear palsy patients MMSE correlation coefficient: 0.62 (p: 0.002) and FAB correlation coefficient: 0.48 (p: 0.02), and in Parkinson's disease patients MMSE correlation coefficient: 0.47 (pspecific to progressive supranuclear palsy and may also be observed in Parkinson's disease patients with altered cognition, and it's related to cortical frontal abnormalities such as language disorders and inhibitory control. Copyright © 2012 Elsevier B.V. All rights reserved.

Vascular care in patients with Alzheimer disease with cerebrovascular lesions slows progression of white matter lesions on MRI: the evaluation of vascular care in Alzheimer's disease (EVA) study.

Science.gov (United States)

Richard, Edo; Gouw, Alida A; Scheltens, Philip; van Gool, Willem A

2010-03-01

White matter lesions (WMLs) and cerebral infarcts are common findings in Alzheimer disease and may contribute to dementia severity. WMLs and lacunar infarcts may provide a potential target for intervention strategies. This study assessed whether multicomponent vascular care in patients with Alzheimer disease with cerebrovascular lesions slows progression of WMLs and prevents occurrence of new infarcts. A randomized controlled clinical trial, including 123 subjects, compared vascular care with standard care in patients with Alzheimer disease with cerebrovascular lesions on MRI. Progression of WMLs, lacunes, medial temporal lobe atrophy, and global cortical atrophy were semiquantitatively scored after 2-year follow-up. Sixty-five subjects (36 vascular care, 29 standard care) had a baseline and a follow-up MRI and in 58 subjects, a follow-up scan could not be obtained due to advanced dementia or death. Subjects in the vascular care group had less progression of WMLs as measured with the WML change score (1.4 versus 2.3, P=0.03). There was no difference in the number of new lacunes or change in global cortical atrophy or medial temporal lobe atrophy between the 2 groups. Vascular care in patients with Alzheimer disease with cerebrovascular lesions slows progression of WMLs. Treatment aimed at vascular risk factors in patients with early Alzheimer disease may be beneficial, possibly in an even earlier stage of the disease.

Lipid-Altering Therapies and the Progression of Atherosclerotic Disease

International Nuclear Information System (INIS)

Wierzbicki, Anthony S.

2007-01-01

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

Differential Disease Progression in Atrophic Age-Related Macular Degeneration and Late-Onset Stargardt Disease.

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Lindner, Moritz; Lambertus, Stanley; Mauschitz, Matthias M; Bax, Nathalie M; Kersten, Eveline; Lüning, Anna; Nadal, Jennifer; Schmitz-Valckenberg, Steffen; Schmid, Matthias; Holz, Frank G; Hoyng, Carel B; Fleckenstein, Monika

2017-02-01

To compare the disease course of retinal pigment epithelium (RPE) atrophy secondary to age-related macula degeneratio (AMD) and late-onset Stargardt disease (STGD1). Patients were examined longitudinally by fundus autofluorescence, near-infrared reflectance imaging, and best-corrected visual acuity (BCVA). Areas of RPE atrophy were quantified using semi-automated software, and the status of the fovea was evaluated based on autofluorescence and near-infrared reflectance images. Mixed-effects models were used to compare atrophy progression rates. BCVA loss and loss of foveal integrity were analyzed using Turnbull's estimator. A total of 151 patients (226 eyes) with RPE atrophy secondary to AMD and 38 patients (66 eyes) with RPE atrophy secondary to late-onset STGD1 were examined for a median time of 2.3 years (interquartile range, 2.7). Mean baseline age was 74.2 years (SD, 7.6) in AMD and 63.4 (SD, 9.9) in late-onset STGD1 (P = 1.1 × 10-7). Square root atrophy progression was significantly faster in AMD when compared with late-onset STGD1 (0.28 mm/year [SE, 0.01] vs. 0.23 [SE, 0.03]; P = 0.030). In late-onset STGD1, the median survival of the fovea was significantly longer when compared with eyes with AMD (8.60 vs. 3.35 years; P = 0.005) with a trend to a later BCVA loss of ≥3 lines (5.97 vs. 4.37 years; P = 0.382). These natural history data indicate differential disease progression in AMD versus late-onset STGD1. The results underline the relevance of refined phenotyping in elderly patients presenting with RPE atrophy in regard to prognosis and design of interventional trials.

Metabonomics Research Progress on Liver Diseases.

Science.gov (United States)

Yu, Mengqian; Zhu, Ying; Cong, Qingwei; Wu, Chunyan

2017-01-01

Metabolomics as the new omics technique develops after genomics, transcriptomics, and proteomics and has rapid development at present. Liver diseases are worldwide public health problems. In China, chronic hepatitis B and its secondary diseases are the common liver diseases. They can be diagnosed by the combination of history, virology, liver function, and medical imaging. However, some patients seldom have relevant physical examination, so the diagnosis may be delayed. Many other liver diseases, such as drug-induced liver injury (DILI), alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD), and autoimmune liver diseases, still do not have definite diagnostic markers; the diagnosis consists of history, medical imaging, and the relevant score. As a result, the clinical work becomes very complex. So it has broad prospects to explore the specific and sensitive biomarkers of liver diseases with metabolomics. In this paper, there are several summaries which are related to the current research progress and application of metabolomics on biomarkers of liver diseases.

Crevicular fluid biomarkers and periodontal disease progression.

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Kinney, Janet S; Morelli, Thiago; Oh, Min; Braun, Thomas M; Ramseier, Christoph A; Sugai, Jim V; Giannobile, William V

2014-02-01

Assess the ability of a panel of gingival crevicular fluid (GCF) biomarkers as predictors of periodontal disease progression (PDP). In this study, 100 individuals participated in a 12-month longitudinal investigation and were categorized into four groups according to their periodontal status. GCF, clinical parameters and saliva were collected bi-monthly. Subgingival plaque and serum were collected bi-annually. For 6 months, no periodontal treatment was provided. At 6 months, patients received periodontal therapy and continued participation from 6 to 12 months. GCF samples were analysed by ELISA for MMP-8, MMP-9, Osteoprotegerin, C-reactive Protein and IL-1β. Differences in median levels of GCF biomarkers were compared between stable and progressing participants using Wilcoxon Rank Sum test (p = 0.05). Clustering algorithm was used to evaluate the ability of oral biomarkers to classify patients as either stable or progressing. Eighty-three individuals completed the 6-month monitoring phase. With the exception of GCF C-reactive protein, all biomarkers were significantly higher in the PDP group compared to stable patients. Clustering analysis showed highest sensitivity levels when biofilm pathogens and GCF biomarkers were combined with clinical measures, 74% (95% CI = 61, 86). Signature of GCF fluid-derived biomarkers combined with pathogens and clinical measures provides a sensitive measure for discrimination of PDP (ClinicalTrials.gov NCT00277745). © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Highly sensitive measurements of disease progression in rare disorders: Developing and validating a multimodal model of retinal degeneration in Stargardt disease

Science.gov (United States)

Bax, Nathalie M.; Fakin, Ana; Groenewoud, Joannes M. M.; Klevering, B. Jeroen; Moore, Anthony T.; Michaelides, Michel; Webster, Andrew R.; van der Wilt, Gert Jan; Hoyng, Carel B.

2017-01-01

sensitive measurement of disease progression in Stargardt disease. It can be very useful in the evaluation of novel therapeutic modalities in rare disorders. PMID:28355279

One-Dimensional-Ratio Measures of Atrophy Progression in Multiple Sclerosis as Evaluated by Longitudinal Magnetic Resonance Imaging

International Nuclear Information System (INIS)

Martola, J.; Wiberg Kristoffersen, M.; Aspelin, P.; Stawiarz, L.; Fredrikson, S.; Hillert, J.; Bergstroem, J.; Flodmark, O.

2009-01-01

Background: For decades, normalized one-dimensional (1D) measures have been used in the evaluation of brain atrophy. In multiple sclerosis (MS), the use of normalized linear measures over longitudinal follow-up remains insufficiently documented. Purpose: To evaluate the association between different regional atrophy measures and disability in MS patients over four decades in a longitudinal cross-sectional study. Material and Methods: 37 consecutively selected MS patients were included. At baseline, patients had a range of disease duration (1-33 years) and age (24-65 years). Each patient was followed by magnetic resonance imaging (MRI) for a mean of 9.25 years (range 7.3-10 years). Four 1D measures were applied at three time points on axial 5-mm T1-weighted images. Three clinical MS subgroups were represented: relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS). Results: There were significant changes in all 1D ratios during follow-up. The Evans ratio (ER) and the bifrontal ratio (BFR) were associated with the development of disability. Changes of ER and BFR reflected more aggressive disease progression, as expressed by MS severity score (MSSS). Conclusion: All four normalized ratios showed uniform atrophy progression, suggesting a consistent rate of atrophy over long-term disease duration independent of MS course. Disability status correlated with 1D measures, suggesting that serial evaluation of Evans and bifrontal ratios might contribute to the radiological evaluation of MS patients

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

Science.gov (United States)

Groussard, Mathilde; Mauger, Caroline; Platel, Hervé

2013-03-01

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

Triple pelvic osteotomy: effect on limb function and progression of degenerative joint disease

International Nuclear Information System (INIS)

Johnson, A.L.; Smith, C.W.; Pijanowski, G.J.; Hungerford, L.L.

1998-01-01

The objective of this study was to evaluate prospectively the outcome of 21 clinical patients treated with triple pelvic osteotomies during the year following surgery. Specific aims included documenting the time of and extent of improved limb function as measured by force plate analysis, evaluating the progression of degenerative joint disease (DJD) in the treated and untreated coxofemoral joints, and determining whether or not triple pelvic osteotomy resulted in degenerative joint changes in the ipsilateral stifle and hock. Twelve dogs were treated unilaterally and nine dogs were treated bilaterally with triple pelvic osteotomies. There were no differences in mean anteversion angles, angles of inclination, or preoperative DJD between treated hips and untreated hips. Degenerative joint disease progressed significantly in all hips regardless of treatment. Two cases developed hyperextension of their hocks after the triple pelvic osteotomies. However, no radiographic evidence of DJD was observed for any of the stifles or hocks at any observation time. A significant increase in vertical peak force (VPF) scores was noted for treated legs by two-to-three months after surgery, which continued over time. Untreated legs did not show a significant change in VPF scores over time. No differences were found in progression to higher scores when unilaterally treated legs, first-side treated legs, and second-side treated legs were compared

Lung disease associated with progressive systemic sclerosis. Assessment of interlobar variation by bronchoalveolar lavage and comparison with noninvasive evaluation of disease activity

International Nuclear Information System (INIS)

Miller, K.S.; Smith, E.A.; Kinsella, M.; Schabel, S.I.; Silver, R.M.

1990-01-01

Progressive systemic sclerosis (PSS), or scleroderma, is a disease of unknown etiology that involves many organ systems, including the lungs. The interstitial lung disease of systemic sclerosis is becoming an increasing cause of morbidity and mortality. This process has been previously evaluated with single-site bronchoalveolar lavage (BAL), gallium scanning, pulmonary function testing, and, occasionally, by open lung biopsy. As BAL has been shown to correlate well with open lung biopsy in systemic sclerosis, we sought to determine if single-site BAL accurately reflects alveolitis in a second site in the lung, and if BAL results correlate with other noninvasive tests of lung inflammation: gallium uptake, chest radiography, or arterial blood gas analysis. We performed 17 studies in 13 patients with scleroderma and found no significant lobar differences in lavage results or gallium scanning. By our criteria for normal versus active alveolitis, only two of 17 patient lavages would have been classified as normal by one side and abnormal by the other side. Although percent gallium uptake was equal bilaterally and supported the concept of alveolitis uniformity, gallium uptake intensity did not correlate with activity as measured by BAL. Furthermore, chest radiograph and arterial blood gas analysis did not correlate with BAL results or gallium scanning. We believe these data support the suitability of single-site lavage in the investigation of systemic-sclerosis-associated alveolitis and diminish the importance of gallium scanning in the investigation of systemic sclerosis pulmonary disease

Adverse effect of the CCR5 promoter -2459A allele on HIV-1 disease progression

DEFF Research Database (Denmark)

Knudsen, T B; Kristiansen, T B; Katzenstein, T L

2001-01-01

/G transition that has been discovered recently, have also been shown to influence HIV progression. Since genetic linkages make these polymorphisms interdependent variables, the aim of the present study was to isolate and evaluate the effect on HIV disease progression for each of these mutations independently......HIV positive individuals heterozygous for a 32 basepair deletion in the CCR5 encoding gene (CCR5 Delta32) have a reduced number of CCR5 receptors on the cell surface and a slower progression towards AIDS and death. Other human polymorphisms, such as the CCR2 64I and the CCR5 promoter -2459 A...

Progression of Alzheimer Disease in Europe

DEFF Research Database (Denmark)

Vellas, B; Hausner, L; Frolich, L

2012-01-01

The clinical progression of Alzheimer disease (AD) was studied in European subjects under treatment with AChE inhibitors (AChE-I) in relation to geographical location over a 2-years period. One thousand three hundred and six subjects from 11 European countries were clustered into 3 regions (North...

Radiographic assessment of disease progression in rheumatoid arthritis patients undergoing early disease-modifying anti-rheumatic drug treatment

International Nuclear Information System (INIS)

Wick, M.C.

2002-04-01

Rheumatoid arthritis (RA) is a common systemic disease predominantly involving the joints. Since the pathogenesis, etiology and pathophysiological mechanisms of RA have only been partially elucidated, a definitive therapy has not been established. Precise diagnosis and follow-up therapy requires objective quantification, and radiological analyses are considered to be the most appropriate method. The aim of this study was to retrospectively determine the time-dependent progression of joint damage in patients with pharmacologically-treated RA, and to determine which therapeutic agents demonstrate the highest efficacy. Outpatient records, laboratory values, therapy schemes and radiographs from hands and feet of 150 RA patients were collected, analyzed and statistically evaluated. Radiographs were quantified using the Larsen score and supportively using the 'RheumaCoach-Rheumatology' computer software. Our observations reveal that radiologically-detectable damage is most pronounced during the first year of disease, while mitigated and generally progressing linearly thereafter. Overall Larsen scores linearly increased from year 0 to 10 (r=0.853), during which the mean Larsen score increased 7.93 ± 0.76 per year. During the first year, RA progression was similar regardless of the medication administered (gold-compounds, AU; chloroquine, CQ; methotrexate, MTX; sulfasalazine SSZ). While MTX and CQ treatment showed no difference when examined as mean 5-year increment of Larsen score, AU and SSZ showed up to 3 fold higher RA progression compared with MTX. The Larsen score in year 1 did not correlate with that of years 2 to 5. In contrast, Larsen scores in year 2 were linearly related to each of the subsequent 3 years. Despite similar ESR values in various medication groups, cumulative ESR correlated with RA progression, and its reduction with therapeutic efficacy. In conclusion, this study found that, (i) early DMARD-treated RA progressed more rapidly during the first than

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

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

2008-01-01

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

Volumetric MRI for evaluation of regional pattern and progression of neocortical degeneration in Alzheimer's disease

International Nuclear Information System (INIS)

Leinsinger, G.; Teipel, S.; Pruessner, J.; Hampel, H.; Wismueller, A.; Born, C.; Meindl, T.; Flatz, W.; Schoenberg, S.; Reiser, M.

2003-01-01

Volumetric analysis of the corpus callosum and hippocampus using MRI in Alzheimer's disease (AD) to evaluate the regional pattern and progression of neocortical neurodegeneration. In subsequent studies we investigated patients with AD and healthy controls. Volumetry was based on MRI-data from a sagittal 3D T1w-gradient echo sequence. The corpus callosum (CC) was measured in a midsagittal slice, and subdivided into 5 subregions. Volumetry of the hippocampus/amygdala-formation (HAF) was performed by segmentation in coronary reoriented slices. In AD patients we found a significant atrophy in the rostrum und splenium of CC. The atrophy was correlated with the severity of dementia, but no correlation was found with the load of white matter lesions. In comparison with 18 FDG-PET, we found a significant correlation of regional CC-atrophy with the regional decline of cortical glucose metabolism. A ROC-analysis demonstrated no significant differences in the diagostic accuracy of HAF volumetry and regional CC volumetry of the splenium (region C5) even in mild stages of dementia. Regional atrophy of CC can be used as a marker of neocortical degeneration even in early stages of dementia in AD. (orig.) [de

Occult hepatitis B virus infection is not associated with disease progression of chronic hepatitis C virus infection.

Science.gov (United States)

Cho, Junhyeon; Lee, Sang Soo; Choi, Yun Suk; Jeon, Yejoo; Chung, Jung Wha; Baeg, Joo Yeong; Si, Won Keun; Jang, Eun Sun; Kim, Jin-Wook; Jeong, Sook-Hyang

2016-11-14

To clarify the prevalence of occult hepatitis B virus (HBV) infection (OBI) and the association between OBI and liver disease progression, defined as development of liver cirrhosis or hepatocellular carcinoma (HCC), worsening of Child-Pugh class, or mortality in cases of chronic hepatitis C virus (HCV) infection. This prospective cohort study enrolled 174 patients with chronic HCV infection (chronic hepatitis, n = 83; cirrhosis, n = 47; HCC, n = 44), and evaluated disease progression during a mean follow-up of 38.7 mo. OBI was defined as HBV DNA positivity in 2 or more different viral genomic regions by nested polymerase chain reaction using 4 sets of primers in the S, C, P and X open reading frame of the HBV genome. The overall OBI prevalence in chronic HCV patients at enrollment was 18.4%, with 16.9%, 25.5% and 13.6% in the chronic hepatitis C, liver cirrhosis and HCC groups, respectively ( P = 0.845). During follow-up, 52 patients showed disease progression, which was independently associated with aspartate aminotransferase > 40 IU/L, Child-Pugh score and sustained virologic response (SVR), but not with OBI positivity. In 136 patients who were not in the SVR state during the study period, OBI positivity was associated with neither disease progression, nor HCC development. The prevalence of OBI in chronic HCV patients was 18.4%, and OBI was not associated with disease progression in South Koreans.

Progressive neuronal degeneration of childhood with liver disease

International Nuclear Information System (INIS)

Kendall, B.E.; Boyd, S.G.; Egger, J.; Harding, B.N.

1987-01-01

The clinical, electrophysiological and neuroradiological features of thirteen patients suffering from progressive neuronal degeneration of childhood with liver failure are presented. The disease commonly presents very early in life with progressive mental retardation, followed by intractable epilepsy, and should be suspected clinically especially if there is a family history of similar disorder in a sibling. On computed tomography there are low density regions, particularly in the occipital and posterior temporal lobes, involving both cortex and white matter, combined with or followed by progressive atrophy. Typical EEG findings may be confirmatory. (orig.)

Fluorescence Lifetime Imaging in Stargardt Disease: Potential Marker for Disease Progression

OpenAIRE

Dysli Chantal; Wolf Sebastian; Hatz Katja; Zinkernagel Martin

2016-01-01

PURPOSE The purpose of this study was to describe autofluorescence lifetime characteristics in Stargardt disease (STGD) using fluorescence lifetime imaging ophthalmoscopy (FLIO) and to investigate potential prognostic markers for disease activity and progression. METHODS Fluorescence lifetime data of 16 patients with STGD (mean age, 40 years; range, 22-56 years) and 15 age-matched controls were acquired using a fluorescence lifetime imaging ophthalmoscope based on a Heidelberg Eng...

Sudden oak death disease progression in oaks and tanoaks

Science.gov (United States)

Brice A. McPherson; Sylvia R. Mori; David L. Wood; Andrew J. Storer; Pavel Svihra; N. Maggi Kelly; Richard B. Standiford

2006-01-01

In March 2000, we established twenty disease progression plots in Marin County to monitor the progress of sudden oak death symptoms in coast live oak (Quercus agrifolia), California black oak (Q. kelloggii), and tanoak (Lithocarpus densiflorus) (McPherson and others 2005). Plots were located to encompass a...

Haptocorrin as marker of disease progression in fibrolamellar hepatocellular carcinoma

DEFF Research Database (Denmark)

Lildballe, Dorte Launholt; Nguyen, Khoa Tran; Poulsen, Steen Seier

2011-01-01

No valid markers are routinely available to follow disease progression in patients with fibrolamellar hepatocellular carcinoma (FLHCC). We report data suggesting that the vitamin B12 binding protein haptocorrin (HC) may prove a suitable marker.......No valid markers are routinely available to follow disease progression in patients with fibrolamellar hepatocellular carcinoma (FLHCC). We report data suggesting that the vitamin B12 binding protein haptocorrin (HC) may prove a suitable marker....

Vitamin D deficiency aggravates chronic kidney disease progression after ischemic acute kidney injury.

Directory of Open Access Journals (Sweden)

Janaína Garcia Gonçalves

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

Recent progress in ERCP for biliary and pancreatic diseases

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MIAO Lin

2014-12-01

Full Text Available In recent years, with the continuous development of endoscopic and interventional techniques, many new devices and methods have been used in clinical practice, and the application of endoscopic retrograde cholangiopancreatography (ERCP in biliary and pancreatic diseases has developed rapidly. This paper reviews and summarizes the recent progress in ERCP among patients with biliary and pancreatic diseases, including those with altered gastrointestinal anatomy, pregnant patients, patients with benign and malignant biliary strictures, and patients with pancreatic pseudocysts, as well as the application of SpyGlass, photodynamic therapy, and radiofrequency ablation, the management of ERCP-related duodenal perforation, and the prevention of post-ERCP pancreatitis. All the progress has made a great contribution to the diagnosis and treatment of biliary and pancreatic diseases.

Association between time to disease progression end points and overall survival in patients with neuroendocrine tumors

Directory of Open Access Journals (Sweden)

Singh S

2014-08-01

Full Text Available Simron Singh,1 Xufang Wang,2 Calvin HL Law1 1Sunnybrook Odette Cancer Center, University of Toronto, Toronto, ON, Canada; 2Novartis Oncology, Florham Park, NJ, USA Abstract: Overall survival can be difficult to determine for slowly progressing malignancies, such as neuroendocrine tumors. We investigated whether time to disease progression is positively associated with overall survival in patients with such tumors. A literature review identified 22 clinical trials in patients with neuroendocrine tumors that reported survival probabilities for both time to disease progression (progression-free survival and time to progression and overall survival. Associations between median time to disease progression and median overall survival and between treatment effects on time to disease progression and treatment effects on overall survival were analyzed using weighted least-squares regression. Median time to disease progression was significantly associated with median overall survival (coefficient 0.595; P=0.022. In the seven randomized studies identified, the risk reduction for time to disease progression was positively associated with the risk reduction for overall survival (coefficient on −ln[HR] 0.151; 95% confidence interval −0.843, 1.145; P=0.713. The significant association between median time to disease progression and median overall survival supports the assertion that time to disease progression is an alternative end point to overall survival in patients with neuroendocrine tumors. An apparent albeit not significant trend correlates treatment effects on time to disease progression and treatment effects on overall survival. Informal surveys of physicians’ perceptions are consistent with these concepts, although additional randomized trials are needed. Keywords: neuroendocrine tumors, progression-free survival, disease progression, mortality

Clinical course of nonalcoholic fatty liver disease: an assessment of severity, progression, and outcomes

Directory of Open Access Journals (Sweden)

Simeone JC

2017-12-01

Full Text Available Jason C Simeone,1 Jay P Bae,2 Byron J Hoogwerf,3 Qian Li,1 Axel Haupt,3 Ayad K Ali,4 Marilyn K Boardman,3 Beth L Nordstrom1 1Real-world Evidence, Evidera, Waltham, MA, USA; 2Global Patient Outcomes and Real World Evidence, Eli Lilly and Company, Indianapolis, IN, USA; 3Lily Diabetes, Eli Lilly and Company, Indianapolis, IN, USA; 4Global Patient Safety, Eli Lilly and Company, Indianapolis, IN, USA Purpose: To identify the characteristics and initial disease severity of patients with nonalcoholic fatty liver disease (NAFLD and assess incidence and risk factors for disease progression in a retrospective study.Methods: Patients ≥18 years of age without alcoholism or other liver diseases (eg, hepatitis B/C were selected from Geisinger Health System electronic medical record data from 2004 to 2015. Initial disease stage was stratified into uncomplicated NAFLD, advanced fibrosis, cirrhosis, hepatocellular carcinoma (HCC, and liver transplant using clinical biomarkers, diagnosis, and procedure codes. Disease progression was defined as stage progression or death and analyzed via Kaplan–Meier plots and multistate models.Results: In the NAFLD cohort (N=18,754, 61.5% were women, 39.0% had type 2 diabetes mellitus (T2DM, and the mean body mass index was 38.2±10.2 kg/m2. At index, 69.9% had uncomplicated NAFLD, 11.7% had advanced fibrosis, and 17.8% had cirrhosis. Of 18,718 patients assessed for progression, 17.3% progressed (11.0% had stage progression, 6.3% died without evidence of stage progression during follow-up (median=842 days. Among subgroups, 12.3% of those without diabetes mellitus progressed vs 24.7% of those with T2DM. One-year mortality increased from 0.5% in uncomplicated NAFLD to 22.7% in HCC. After liver transplant, mortality decreased to 5.6% per year.Conclusions: In 2.3 years of follow-up, approximately 17% of patients progressed or died without evidence of stage progression. T2DM was associated with approximately twice the risk of

Reduced serum myostatin concentrations associated with genetic muscle disease progression.

Science.gov (United States)

Burch, Peter M; Pogoryelova, Oksana; Palandra, Joe; Goldstein, Richard; Bennett, Donald; Fitz, Lori; Guglieri, Michela; Bettolo, Chiara Marini; Straub, Volker; Evangelista, Teresinha; Neubert, Hendrik; Lochmüller, Hanns; Morris, Carl

2017-03-01

Myostatin is a highly conserved protein secreted primarily from skeletal muscle that can potently suppress muscle growth. This ability to regulate skeletal muscle mass has sparked intense interest in the development of anti-myostatin therapies for a wide array of muscle disorders including sarcopenia, cachexia and genetic neuromuscular diseases. While a number of studies have examined the circulating myostatin concentrations in healthy and sarcopenic populations, very little data are available from inherited muscle disease patients. Here, we have measured the myostatin concentration in serum from seven genetic neuromuscular disorder patient populations using immunoaffinity LC-MS/MS. Average serum concentrations of myostatin in all seven muscle disease patient groups were significantly less than those measured in healthy controls. Furthermore, circulating myostatin concentrations correlated with clinical measures of disease progression for five of the muscle disease patient populations. These findings greatly expand the understanding of myostatin in neuromuscular disease and suggest its potential utility as a biomarker of disease progression.

Recent achievements in restorative neurology: Progressive neuromuscular diseases

International Nuclear Information System (INIS)

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

1986-01-01

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

Regression of Nonalcoholic Fatty Liver Disease with Zinc and Selenium Co-supplementation after Disease Progression in Rats.

Science.gov (United States)

Shidfar, Farzad; Faghihi, Amirhosein; Amiri, Hamid Lorvand; Mousavi, Seyedeh Neda

2018-01-01

Studies have shown that zinc and selenium deficiency is common in nonalcoholic fatty liver disease (NAFLD). However, the effects of zinc and selenium co-supplementation before and/or after disease progression on NAFLD are not clear enough. The aim of this study was to compare the effects of zinc and selenium co-supplementation before and/or after disease progression on NAFLD prognosis. Forty male Sprague-Dawley rats (197±4 g) were randomly assigned to 4 dietary groups: normal-fat diet (NFD; receiving 9% of calories as fat), high-fat diet (HFD; receiving 82% of calories as fat), supplementation before disease progression (S+HFD), and supplementation after disease progression (HFD+S). The diets were implemented over a 20-week period in all the groups. Biochemical and histologic parameters were compared between the 4 groups, and between-group comparisons were also carried out. There were significant differences in the average food dietary intake (P<0.001), weight (P<0.001), fasting blood sugar (P=0.005), triglyceride (P<0.001), total cholesterol (P<0.001), low-density lipoprotein cholesterol (P=0.002), high-density lipoprotein cholesterol (P=0.001), alanine aminotransferase (P<0.001), and aspartate aminotransferase (P<0.001) between the 4 dietary groups. Serum triglyceride and total cholesterol were significantly lower in the HFD+S Group than in the S+HFD Group (P<0.001 and P=0.003, respectively). Fat accumulation was significantly reduced in the HFD+S Group (P<0.001). Zinc and selenium co-supplementation after disease progression improved biochemical and histologic parameters in an experimental model of NAFLD.

Progression of MDS-UPDRS Scores Over Five Years in De Novo Parkinson Disease from the Parkinson's Progression Markers Initiative Cohort.

Science.gov (United States)

Holden, Samantha K; Finseth, Taylor; Sillau, Stefan H; Berman, Brian D

2018-01-01

The Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UDPRS) is a commonly used tool to measure Parkinson disease (PD) progression. Longitudinal changes in MDS-UPDRS scores in de novo PD have not been established. Determine progression rates of MDS-UPDRS scores in de novo PD. 362 participants from the Parkinson's Progression Markers Initiative, a multicenter longitudinal cohort study of de novo PD, were included. Longitudinal progression of MDS-UPDRS total and subscale scores were modeled using mixed model regression. MDS-UPDRS scores increased in a linear fashion over five years in de novo PD. MDS-UPDRS total score increased an estimated 4.0 points/year, Part I 0.25 points/year, Part II 1.0 points/year, and Part III 2.4 points/year. The expected average progression of MDS-UPDRS scores in de novo PD from this study can assist in clinical monitoring and provide comparative data for detection of disease modification in treatment trials.

Retrospective study of the effect of disease progression on patient reported outcomes in HER-2 negative metastatic breast cancer patients

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Yu Elaine

2011-06-01

Full Text Available Abstract Background This retrospective study evaluated the impact of disease progression and of specific sites of metastasis on patient reported outcomes (PROs that assess symptom burden and health related quality of life (HRQoL in women with metastatic breast cancer (mBC. Methods HER-2 negative mBC patients (n = 102 were enrolled from 7 U.S. community oncology practices. Demographic, disease and treatment characteristics were abstracted from electronic medical records and linked to archived Patient Care Monitor (PCM assessments. The PCM is a self-report measure of symptom burden and HRQoL administered as part of routine care in participating practices. Linear mixed models were used to examine change in PCM scores over time. Results Mean age was 57 years, with 72% of patients Caucasian, and 25% African American. Median time from mBC diagnosis to first disease progression was 8.8 months. Metastasis to bone (60%, lung (28% and liver (26% predominated at initial metastatic diagnosis. Results showed that PCM items assessing fatigue, physical pain and trouble sleeping were sensitive to either general effects of disease progression or to effects associated with specific sites of metastasis. Progression of disease was also associated with modest but significant worsening of General Physical Symptoms, Treatment Side Effects, Acute Distress and Impaired Performance index scores. In addition, there were marked detrimental effects of liver metastasis on Treatment Side Effects, and of brain metastasis on Acute Distress. Conclusions Disease progression has a detrimental impact on cancer-related symptoms. Delaying disease progression may have a positive impact on patients' HRQoL.

Evaluation [corrected] of the "Iceberg Phenomenon" in Johne's disease through mathematical modelling.

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Gesham Magombedze

Full Text Available Johne's disease (JD is a chronic, enteric disease in ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP. Disease progression follows four distinct stages: silent, subclinical, clinical and advanced. Available diagnostic tests have poor sensitivity and cannot detect early stages of the infection; as a result, only animals in the clinical and advanced stages, which represent the tip of the 'iceberg', are identified through testing. The Iceberg Phenomenon is then applied to provide estimates for JD prevalence. For one animal in the advanced stage, it is assumed that there are one to two in the clinical stage, four to eight in the subclinical stage, and ten to fourteen in the silent stage. These ratios, however, are based on little evidence. To evaluate the ratios, we developed a deterministic ordinary differential equation model of JD transmission and disease progression dynamics. When duration periods associated with the natural course of the disease progression are used, the above ratios do not hold. The ratios used to estimate JD prevalence need to be further investigated.

Magnetic resonance imaging-determined synovial membrane volume as a marker of disease activity and a predictor of progressive joint destruction in the wrists of patients with rheumatoid arthritis

DEFF Research Database (Denmark)

Østergaard, Mikkel; Hansen, M; Stoltenberg, M

1999-01-01

OBJECTIVE: To evaluate the synovial membrane volume, determined by magnetic resonance imaging (MRI), as a marker of joint disease activity and a predictor of progressive joint destruction in rheumatoid arthritis (RA). METHODS: Twenty-six patients with RA, randomized to receive disease-modifying a......OBJECTIVE: To evaluate the synovial membrane volume, determined by magnetic resonance imaging (MRI), as a marker of joint disease activity and a predictor of progressive joint destruction in rheumatoid arthritis (RA). METHODS: Twenty-six patients with RA, randomized to receive disease......-Pratt analysis). The rate of erosive progression on MRI was highly correlated with baseline scores and, particularly, with area under the curve (AUC) values of synovial membrane volume (Spearman's sigma = 0.69, P

Carotid artery disease progression and related neurologic events after carotid endarterectomy.

Science.gov (United States)

Avgerinos, Efthymios D; Go, Catherine; Ling, Jennifer; Naddaf, Abdallah; Steinmetz, Amy; Abou Ali, Adham N; Makaroun, Michel S; Chaer, Rabih A

2016-08-01

During the last decade, there has been a dramatic improvement in best medical treatment for patients with vascular disease. Yet, there is a paucity of contemporary long-term data for restenosis and contralateral internal carotid artery (ICA) progression. This study assessed ipsilateral and contralateral disease progression and cerebrovascular events after carotid endarterectomy (CEA). A consecutive cohort of CEAs between January 1, 2000, and December 31, 2010, was retrospectively analyzed. End points were restenosis ≥50% and ≥70%, contralateral carotid disease progression (50%-69%, 70%-99%, or occlusion) and stroke. Survival analysis and Cox regression models were used to assess the effect of baseline predictors. During the 11-year study period, 1639 patients underwent 1782 CEAs (50.0% patch closure, 23.9% primary closure, 26.1% eversion, and 2.5% combined with coronary artery bypass grafting). The combined stroke/death rate was 2.6% overall and 1.8% in the asymptomatic cohort. The rate of restenosis ≥50% at 2, 5, and 10 years was 8.5%, 15.6%, 27.2%, and the rate for restenosis ≥70% was 3.4%, 6.5%, 10.2%, respectively. Restenosis ≥50% was predicted by hypertension (hazard ratio [HR], 2.09; P = .027), female gender (HR, 1.43; P = .042), and younger age (≤65 years; HR, 1.56; P = .016), but not by statins, surgical technique, symptoms, or other baseline risk factors. Restenoses remained asymptomatic in 125 of 148 (84.5%). Progression of contralateral ICA disease at 2, 5, and 10 years was estimated at 5.4%, 15.5%, and 46.8%, respectively. Contralateral progression was only predicted by smoking (HR, 1.74; P = .008). The stroke rate in patients with disease progression of the contralateral ICA was not different compared with those without progression (7.0% vs 3.3%; P = .063). Any-stroke rates at 2, 5, and 10 years were 4.6%, 7.3%, and 15.7%, respectively. Predictors were symptomatic lesion (HR, 1.48; P = .039), renal insufficiency, defined as a

Nondestructive Evaluation Program: Progress in 1986

International Nuclear Information System (INIS)

1987-07-01

The increasing cost of equipment for power generating plants and the potential increases in productivity and safety available through rapidly developing Nondestructive Evaluation (NDE) technology led EPRI to initiate a Nondestructive Evaluation Program in 1974. To date, the major focus has been on light water reactor inspection problems; however, increased application to other systems is now under way. This report presents a comprehensive review of the EPRI effort in the NDE area. Most of the report consists of contractor-supplied progress reports on each current project. An organizational plan of the program is presented in overview. In addition, organization from several viewpoints is presented, e.g., in-service inspection operators, R and D personnel, and utility representatives. The report summarizes significant progress made since the previous EPRI Special Report NP-4315-SR was issued in May 1986. Section 1 contains information about the program organization, and the sections that follow contain contractor-supplied progress reports of each current project. The progress reports are grouped by plant components - pipe, pressure vessel, steam generator and boiler tubes, and turbine. In addition, Part 6 is devoted to discussions of technology transfer

Disruption of gut homeostasis by opioids accelerates HIV disease progression

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Jingjing eMeng

2015-06-01

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

Discontinuing disease-modifying therapy in progressive multiple sclerosis: can we stop what we have started?

LENUS (Irish Health Repository)

Lonergan, Roisin

2012-02-01

Disease-modifying therapy is ineffective in disabled patients (Expanded Disability Status Scale [EDSS] > 6.5) with secondary progressive multiple sclerosis (MS) without relapses, or in primary progressive MS. Many patients with secondary progressive MS who initially had relapsing MS continue to use disease-modifying therapies. The enormous associated costs are a burden to health services. Regular assessment is recommended to guide discontinuation of disease-modifying therapies when no longer beneficial, but this is unavailable to many patients, particularly in rural areas. The objectives of this study are as follows: 1. To observe use of disease-modifying therapies in patients with progressive multiple sclerosis and EDSS > 6.5. 2. To examine approaches used by a group of international MS experts to stopping-disease modifying therapies in patients with secondary progressive MS without relapses. During an epidemiological study in three regions of Ireland (southeast Dublin city, and Wexford and Donegal Counties), we recorded details of disease-modifying therapies in patients with progressive MS and EDSS > 6.5. An e-questionnaire was sent to 26 neurologists with expert knowledge of MS, asking them to share their approach to stopping disease-modifying therapies in patients with secondary progressive MS. Three hundred and thirty-six patients were studied: 88 from southeast Dublin, 99 from Wexford and 149 from Donegal. Forty-four had EDSS > 6.5: 12 were still using disease-modifying therapies. Of the surveyed neurologists, 15 made efforts to stop disease-modifying therapies in progressive multiple sclerosis, but most did not insist. A significant proportion (12 of 44 patients with progressive MS and EDSS > 6.5) was considered to be receiving therapy without benefit. Eleven of the 12 were from rural counties, reflecting poorer access to neurology services. The costs of disease-modifying therapies in this group (>170,000 euro yearly) could be re-directed towards development

Regression of Nonalcoholic Fatty Liver Disease with Zinc and Selenium Co-supplementation after Disease Progression in Rats

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Farzad Shidfar

2018-01-01

Full Text Available Background: Studies have shown that zinc and selenium deficiency is common in nonalcoholic fatty liver disease (NAFLD. However, the effects of zinc and selenium co-supplementation before and/or after disease progression on NAFLD are not clear enough. The aim of this study was to compare the effects of zinc and selenium co-supplementation before and/or after disease progression on NAFLD prognosis. Methods: Forty male Sprague–Dawley rats (197±4 g were randomly assigned to 4 dietary groups: normal-fat diet (NFD; receiving 9% of calories as fat, high-fat diet (HFD; receiving 82% of calories as fat, supplementation before disease progression (S+HFD, and supplementation after disease progression (HFD+S. The diets were implemented over a 20-week period in all the groups. Biochemical and histologic parameters were compared between the 4 groups, and between-group comparisons were also carried out. Results: There were significant differences in the average food dietary intake (P<0.001, weight (P<0.001, fasting blood sugar (P=0.005, triglyceride (P<0.001, total cholesterol (P<0.001, low-density lipoprotein cholesterol (P=0.002, high-density lipoprotein cholesterol (P=0.001, alanine aminotransferase (P<0.001, and aspartate aminotransferase (P<0.001 between the 4 dietary groups. Serum triglyceride and total cholesterol were significantly lower in the HFD+S Group than in the S+HFD Group (P<0.001 and P=0.003, respectively. Fat accumulation was significantly reduced in the HFD+S Group (P<0.001. Conclusion: Zinc and selenium co-supplementation after disease progression improved biochemical and histologic parameters in an experimental model of NAFLD.

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

Science.gov (United States)

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

2013-01-01

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

Progression of Late-Onset Stargardt Disease

OpenAIRE

Lambertus, Stanley; Lindner, Moritz; Bax, Nathalie M.; Mauschitz, Matthias M.; Nadal, Jennifer; Schmid, Matthias; Schmitz-Valckenberg, Steffen; den Hollander, Anneke I.; Weber, Bernhard H. F.; Holz, Frank G.; van der Wilt, Gert Jan; Fleckenstein, Monika; Hoyng, Carel B.

2016-01-01

Purpose: Identification of sensitive biomarkers is essential to determine potential effects of emerging therapeutic trials for Stargardt disease. This study aimed to describe the natural history of late-onset Stargardt, and demonstrates the accuracy of retinal pigment epithelium (RPE) atrophy progression as an outcome measure. Methods: We performed a retrospective cohort study collecting multicenter data from 47 patients (91 eyes) with late-onset Stargardt, defined by clinical phenotype...

NMR-based lipidomic analysis of blood lipoproteins differentiates the progression of coronary heart disease.

Science.gov (United States)

Kostara, Christina E; Papathanasiou, Athanasios; Psychogios, Nikolaos; Cung, Manh Thong; Elisaf, Moses S; Goudevenos, John; Bairaktari, Eleni T

2014-05-02

Abnormal lipid composition and metabolism of plasma lipoproteins play a crucial role in the pathogenesis of coronary heart disease (CHD). A (1)H NMR-based lipidomic approach was used to investigate the correlation of coronary artery stenosis with the atherogenic (non-HDL) and atheroprotective (HDL) lipid profiles in 99 patients with CHD of various stages of disease and compared with 60 patients with normal coronary arteries (NCA), all documented in coronary angiography. The pattern recognition models created from lipid profiles predicted the presence of CHD with a sensitivity of 87% and a specificity of 88% in the HDL model and with 90% and 89% in the non-HDL model, respectively. Patients with mild, moderate, and severe coronary artery stenosis were progressively differentiated from those with NCA in the non-HDL model with a statistically significant separation of severe stage from both mild and moderate. In the HDL model, the progressive differentiation of the disease stages was statistically significant only between patients with mild and severe coronary artery stenosis. The lipid constituents of lipoproteins that mainly characterized the initial stages and then the progression of the disease were the high levels of saturated fatty acids in lipids in both HDL and non-HDL particles, the low levels of HDL-phosphatidylcholine, HDL-sphingomyelin, and omega-3 fatty acids and linoleic acid in lipids in non-HDL particles. The conventional lipid marker, total cholesterol, found in low levels in HDL and in high levels in non-HDL, also contributed to the onset of the disease but with a much lower coefficient of significance. (1)H NMR-based lipidomic analysis of atherogenic and atheroprotective lipoproteins could contribute to the early evaluation of the onset of coronary artery disease and possibly to the establishment of an appropriate therapeutic option.

Voltage-Gated Potassium Channel Antibodies in Slow-Progression Motor Neuron Disease.

Science.gov (United States)

Godani, Massimiliano; Zoccarato, Marco; Beronio, Alessandro; Zuliani, Luigi; Benedetti, Luana; Giometto, Bruno; Del Sette, Massimo; Raggio, Elisa; Baldi, Roberta; Vincent, Angela

2017-01-01

The spectrum of autoimmune neurological diseases associated with voltage-gated potassium channel (VGKC)-complex antibodies (Abs) ranges from peripheral nerve disorders to limbic encephalitis. Recently, low titers of VGKC-complex Abs have also been reported in neurodegenerative disorders, but their clinical relevance is unknown. The aim of the study was to explore the prevalence of VGKC-complex Abs in slow-progression motor neuron disease (MND). We compared 11 patients affected by slow-progression MND with 9 patients presenting typical progression illness. Sera were tested for VGKC-complex Abs by radioimmunoassay. The distribution of VGKC-complex Abs was analyzed with the Mann-Whitney U test. The statistical analysis showed a significant difference between the mean values in the study and control groups. A case with long-survival MND harboring VGKC-complex Abs and treated with intravenous immunoglobulins is described. Although VGKC-complex Abs are not likely to be pathogenic, these results could reflect the coexistence of an immunological activation in patients with slow disease progression. © 2016 S. Karger AG, Basel.

Non-monotonic reorganization of brain networks with Alzheimer’s disease progression

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Hyoungkyu eKim

2015-06-01

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

Differential distribution of striatal [123I]β-CIT in Parkinson's disease and progressive supranuclear palsy, evaluated with single-photon emission tomography

International Nuclear Information System (INIS)

Messa, C.; Volonte, M.A.; Fazio, F.; Zito, F.; Carpinelli, A.; D'Amico, A.; Rizzo, G.; Moresco, R.M.; Paulesu, E.; Franceschi, M.; Lucignani, G.

1998-01-01

Functional imaging of the presynaptic dopaminergic activity using single-photon emission tomography (SPET) and iodine-123 labelled 2-β-carboxymethoxy-3-β-(4-iodophenyl)tropane ([ 123 I]β-CIT) is important for the assessment of disease severity and progression in patients with Parkinson's disease (PD). However, its capability to discriminate between different extrapyramidal disorders has not yet been assessed. The aim of this study was to evaluate the possibility of differentiating patients with PD and with progressive supranuclear palsy (PSP) by means of this method. The distribution of [ 123 I]β-CIT in the basal ganglia was assessed in six normal subjects, 13 petients with PD and five patients with PSP in whom the disease was mild. SPET images were obtained 24±2 h after i.v. injection of the tracer using a brain-dedicated system (CERASPECT). MR and SPET images were co-registered in four normal subjects and used to define a standard set of 16 circular regions of interest (ROIs) on the slice showing the highest striatal activity. The basal ganglia ROIs corresponded to (1) the head of caudate, (2) a region of transition between the head of caudate and the anterior putamen, (3) the anterior putamen and (4) the posterior putamen. A ratio of specific to non-displaceable striatal uptake was calculated normalising the activity of the basal ganglia ROIs to that of the occipital cortex (V3''). ANOVA revealed a global reduction of V3'' in all ROIs of PD and PSP patients compared with normal controls (P 123 I]β-CIT distribution in discrete striatal areas provides information on the relative caudate-putamen damage, with different values being obtained in patients clinically diagnosed as having either PD or PSP. (orig.)

Soluble beta-amyloid precursor protein is related to disease progression in amyotrophic lateral sclerosis.

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Petra Steinacker

Full Text Available BACKGROUND: Biomarkers of disease progression in amyotrophic lateral sclerosis (ALS could support the identification of beneficial drugs in clinical trials. We aimed to test whether soluble fragments of beta-amyloid precursor protein (sAPPα and sAPPß correlated with clinical subtypes of ALS and were of prognostic value. METHODOLOGY/PRINCIPAL FINDINGS: In a cross-sectional study including patients with ALS (N = 68 with clinical follow-up data over 6 months, Parkinson's disease (PD, N = 20, and age-matched controls (N = 40, cerebrospinal fluid (CSF levels of sAPPα a, sAPPß and neurofilaments (NfH(SMI35 were measured by multiplex assay, Progranulin by ELISA. CSF sAPPα and sAPPß levels were lower in ALS with a rapidly-progressive disease course (p = 0.03, and p = 0.02 and with longer disease duration (p = 0.01 and p = 0.01, respectively. CSF NfH(SMI35 was elevated in ALS compared to PD and controls, with highest concentrations found in patients with rapid disease progression (p<0.01. High CSF NfH(SMI3 was linked to low CSF sAPPα and sAPPß (p = 0.001, and p = 0.007, respectively. The ratios CSF NfH(SMI35/CSF sAPPα,-ß were elevated in patients with fast progression of disease (p = 0.002 each. CSF Progranulin decreased with ongoing disease (p = 0.04. CONCLUSIONS: This study provides new CSF candidate markers associated with progression of disease in ALS. The data suggest that a deficiency of cellular neuroprotective mechanisms (decrease of sAPP is linked to progressive neuro-axonal damage (increase of NfH(SMI35 and to progression of disease.

Sodium intake, RAAS-blockade and progressive renal disease

NARCIS (Netherlands)

de Borst, Martin H; Navis, Gerjan

Pharmacological blockade of the renin-angiotensin-aldosterone system (RAAS) by angiotensin converting enzyme inhibitors or angiotensin receptor blockers is the current standard treatment to prevent progressive renal function loss in patients with chronic kidney disease. Yet in many patients the

Mapping Neurodegenerative Disease Onset and Progression.

Science.gov (United States)

Seeley, William W

2017-08-01

Brain networks have been of long-standing interest to neurodegeneration researchers, including but not limited to investigators focusing on conventional prion diseases, which are known to propagate along neural pathways. Tools for human network mapping, however, remained inadequate, limiting our understanding of human brain network architecture and preventing clinical research applications. Until recently, neuropathological studies were the only viable approach to mapping disease onset and progression in humans but required large autopsy cohorts and laborious methods for whole-brain sectioning and staining. Despite important advantages, postmortem studies cannot address in vivo, physiological, or longitudinal questions and have limited potential to explore early-stage disease except for the most common disorders. Emerging in vivo network-based neuroimaging strategies have begun to address these issues, providing data that complement the neuropathological tradition. Overall, findings to date highlight several fundamental principles of neurodegenerative disease anatomy and pathogenesis, as well as some enduring mysteries. These principles and mysteries provide a road map for future research. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.

Chronic Progressive Neurodegeneration in a transgenic mouse model of Prion disease

Directory of Open Access Journals (Sweden)

Nina Fainstein

2016-11-01

Full Text Available Neurodegenerative diseases present pathologically with progressive structural destruction of neurons and accumulation of mis-folded proteins specific for each condition leading to brain atrophy and functional disability. Many animal models exert deposition of pathogenic protein without accompanying neurodegeneration pattern. The lack of a comprehensive model hinders the efforts to develop treatment. We performed longitudinal quantification of cellular, neuronal and synaptic density, as well as of neurogenesis in brains of mice, mimicking for genetic Creutzfeldt-Jacob disease as compared to age matched wild type mice. Mice exhibited a neurodegenerative process indicated by progressive reduction in cortical neurons and synapses, starting at age of 4-6 months, in accordance with neurologic disability. This was accompanied by significant decrease in subventricular/subependymal zone neurogenesis. Although increased hippocampal neurogenesis was detected in mice, a neurodegenerative process of CA1 and CA3 regions associated with impaired hippocampal-dependent memory function was observed. In conclusion, mice exhibit pathological neurodegeneration concomitant with progressive neurological disease, indicating these mice can serve as a model for neurodegenerative diseases.

Chronic Progressive Neurodegeneration in a Transgenic Mouse Model of Prion Disease.

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Fainstein, Nina; Dori, Dvir; Frid, Kati; Fritz, Alexa T; Shapiro, Ilona; Gabizon, Ruth; Ben-Hur, Tamir

2016-01-01

Neurodegenerative diseases present pathologically with progressive structural destruction of neurons and accumulation of mis-folded proteins specific for each condition leading to brain atrophy and functional disability. Many animal models exert deposition of pathogenic proteins without an accompanying neurodegeneration pattern. The lack of a comprehensive model hinders efforts to develop treatment. We performed longitudinal quantification of cellular, neuronal and synaptic density, as well as of neurogenesis in brains of mice mimicking for genetic Creutzfeldt-Jacob disease as compared to age-matched wild-type mice. Mice exhibited a neurodegenerative process of progressive reduction in cortical neurons and synapses starting at age of 4-6 months, in accord with neurologic disability. This was accompanied by significant decrease in subventricular/subependymal zone neurogenesis. Although increased hippocampal neurogenesis was detected in mice, a neurodegenerative process of CA1 and CA3 regions associated with impaired hippocampal-dependent memory function was observed. In conclusion, mice exhibit pathological neurodegeneration concomitant with neurological disease progression, indicating these mice can serve as a model for neurodegenerative diseases.

Glutathione dysregulation and the etiology and progression of human diseases.

NARCIS (Netherlands)

Ballatori, N.; Krance, S.M.; Notenboom, S.; Shi, S.; Tieu, K.; Hammond, C.L.

2009-01-01

Glutathione (GSH) plays an important role in a multitude of cellular processes, including cell differentiation, proliferation, and apoptosis, and as a result, disturbances in GSH homeostasis are implicated in the etiology and/or progression of a number of human diseases, including cancer, diseases

Serum metabolomics of slow vs. rapid motor progression Parkinson's disease: a pilot study.

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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

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.

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

OpenAIRE

Hensman Moss, Davina J; Pardinas, Antonio; Langbehn, Douglas; Lo, Kitty; Leavitt, Blair R; Roos, Raymund; Durr, Alexandra; Mead, Simon; Holmans, Peter; Jones, Lesley; Tabrizi, Sarah J; Coleman, A; Santos, R Dar; Decolongon, J; Sturrock, A

2017-01-01

Background\\ud \\ud Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure.\\ud \\ud Methods\\ud \\ud We generated a progression score on the basis of principal ...

Genome-wide analysis of disease progression in age-related macular degeneration.

Science.gov (United States)

Yan, Qi; Ding, Ying; Liu, Yi; Sun, Tao; Fritsche, Lars G; Clemons, Traci; Ratnapriya, Rinki; Klein, Michael L; Cook, Richard J; Liu, Yu; Fan, Ruzong; Wei, Lai; Abecasis, Gonçalo R; Swaroop, Anand; Chew, Emily Y; Weeks, Daniel E; Chen, Wei

2018-03-01

Family- and population-based genetic studies have successfully identified multiple disease-susceptibility loci for Age-related macular degeneration (AMD), one of the first batch and most successful examples of genome-wide association study. However, most genetic studies to date have focused on case-control studies of late AMD (choroidal neovascularization or geographic atrophy). The genetic influences on disease progression are largely unexplored. We assembled unique resources to perform a genome-wide bivariate time-to-event analysis to test for association of time-to-late-AMD with ∼9 million variants on 2721 Caucasians from a large multi-center randomized clinical trial, the Age-Related Eye Disease Study. To our knowledge, this is the first genome-wide association study of disease progression (bivariate survival outcome) in AMD genetic studies, thus providing novel insights to AMD genetics. We used a robust Cox proportional hazards model to appropriately account for between-eye correlation when analyzing the progression time in the two eyes of each participant. We identified four previously reported susceptibility loci showing genome-wide significant association with AMD progression: ARMS2-HTRA1 (P = 8.1 × 10-43), CFH (P = 3.5 × 10-37), C2-CFB-SKIV2L (P = 8.1 × 10-10) and C3 (P = 1.2 × 10-9). Furthermore, we detected association of rs58978565 near TNR (P = 2.3 × 10-8), rs28368872 near ATF7IP2 (P = 2.9 × 10-8) and rs142450006 near MMP9 (P = 0.0006) with progression to choroidal neovascularization but not geographic atrophy. Secondary analysis limited to 34 reported risk variants revealed that LIPC and CTRB2-CTRB1 were also associated with AMD progression (P < 0.0015). Our genome-wide analysis thus expands the genetics in both development and progression of AMD and should assist in early identification of high risk individuals.

Hdac6 knock-out increases tubulin acetylation but does not modify disease progression in the R6/2 mouse model of Huntington's disease.

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Anna Bobrowska

Full Text Available Huntington's disease (HD is a progressive neurodegenerative disorder for which there is no effective disease modifying treatment. Following-on from studies in HD animal models, histone deacetylase (HDAC inhibition has emerged as an attractive therapeutic option. In parallel, several reports have demonstrated a role for histone deacetylase 6 (HDAC6 in the modulation of the toxicity caused by the accumulation of misfolded proteins, including that of expanded polyglutamine in an N-terminal huntingtin fragment. An important role for HDAC6 in kinesin-1 dependent transport of brain-derived neurotrophic factor (BDNF from the cortex to the striatum has also been demonstrated. To elucidate the role that HDAC6 plays in HD progression, we evaluated the effects of the genetic depletion of HDAC6 in the R6/2 mouse model of HD. Loss of HDAC6 resulted in a marked increase in tubulin acetylation throughout the brain. Despite this, there was no effect on the onset and progression of a wide range of behavioural, physiological, molecular and pathological HD-related phenotypes. We observed no change in the aggregate load or in the levels of soluble mutant exon 1 transprotein. HDAC6 genetic depletion did not affect the efficiency of BDNF transport from the cortex to the striatum. Therefore, we conclude that HDAC6 inhibition does not modify disease progression in R6/2 mice and HDAC6 should not be prioritized as a therapeutic target for HD.

Validating predictors of disease progression in a large cohort of primary-progressive multiple sclerosis based on a systematic literature review.

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Jan-Patrick Stellmann

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

Influence of model assumptions about HIV disease progression after initiating or stopping treatment on estimates of infections and deaths averted by scaling up antiretroviral therapy

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Sucharitakul, Kanes; Boily, Marie-Claude; Dimitrov, Dobromir

2018-01-01

Background Many mathematical models have investigated the population-level impact of expanding antiretroviral therapy (ART), using different assumptions about HIV disease progression on ART and among ART dropouts. We evaluated the influence of these assumptions on model projections of the number of infections and deaths prevented by expanded ART. Methods A new dynamic model of HIV transmission among men who have sex with men (MSM) was developed, which incorporated each of four alternative assumptions about disease progression used in previous models: (A) ART slows disease progression; (B) ART halts disease progression; (C) ART reverses disease progression by increasing CD4 count; (D) ART reverses disease progression, but disease progresses rapidly once treatment is stopped. The model was independently calibrated to HIV prevalence and ART coverage data from the United States under each progression assumption in turn. New HIV infections and HIV-related deaths averted over 10 years were compared for fixed ART coverage increases. Results Little absolute difference (ART coverage (varied between 33% and 90%) if ART dropouts reinitiated ART at the same rate as ART-naïve MSM. Larger differences in the predicted fraction of HIV-related deaths averted were observed (up to 15pp). However, if ART dropouts could only reinitiate ART at CD4ART interruption did not affect the fraction of HIV infections averted with expanded ART, unless ART dropouts only re-initiated ART at low CD4 counts. Different disease progression assumptions had a larger influence on the fraction of HIV-related deaths averted with expanded ART. PMID:29554136

Perspective Insights into Disease Progression, Diagnostics, and Therapeutic Approaches in Alzheimer's Disease: A Judicious Update

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Arif Tasleem Jan

2017-11-01

Full Text Available Alzheimer's disease (AD is a neurodegenerative disorder characterized by the progressive accumulation of β-amyloid fibrils and abnormal tau proteins in and outside of neurons. Representing a common form of dementia, aggravation of AD with age increases the morbidity rate among the elderly. Although, mutations in the ApoE4 act as potent risk factors for sporadic AD, familial AD arises through malfunctioning of APP, PSEN-1, and−2 genes. AD progresses through accumulation of amyloid plaques (Aβ and neurofibrillary tangles (NFTs in brain, which interfere with neuronal communication. Cellular stress that arises through mitochondrial dysfunction, endoplasmic reticulum malfunction, and autophagy contributes significantly to the pathogenesis of AD. With high accuracy in disease diagnostics, Aβ deposition and phosphorylated tau (p-tau are useful core biomarkers in the cerebrospinal fluid (CSF of AD patients. Although five drugs are approved for treatment in AD, their failures in achieving complete disease cure has shifted studies toward a series of molecules capable of acting against Aβ and p-tau. Failure of biologics or compounds to cross the blood-brain barrier (BBB in most cases advocates development of an efficient drug delivery system. Though liposomes and polymeric nanoparticles are widely adopted for drug delivery modules, their use in delivering drugs across the BBB has been overtaken by exosomes, owing to their promising results in reducing disease progression.

Serum metabolomics of slow vs. rapid motor progression Parkinson's disease: a pilot study.

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James R Roede

Full Text Available 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.

Progression of disease preceding lower extremity amputation in Denmark

DEFF Research Database (Denmark)

Jensen, Pia Søe; Petersen, Janne; Kirketerp-Møller, Klaus

2017-01-01

OBJECTIVES: Patients with non-traumatic lower extremity amputation are characterised by high age, multi-morbidity and polypharmacy and long-term complications of atherosclerosis and diabetes. To ensure early identification of patients at risk of amputation, we need to gain knowledge about...... the progression of diseases related to lower extremity amputations during the years preceding the amputation. DESIGN: A retrospective population-based national registry study. SETTING: The study includes data on demographics, diagnoses, surgery, medications and healthcare services from five national registries....... Data were retrieved from 14 years before until 1 year after the amputation. Descriptive statistics were used to describe the progression of diseases and use of medication and healthcare services. PARTICIPANTS: An unselected cohort of patients (≥50 years; n=2883) subjected to a primary non...

Data-driven models of dominantly-inherited Alzheimer's disease progression.

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Oxtoby, Neil P; Young, Alexandra L; Cash, David M; Benzinger, Tammie L S; Fagan, Anne M; Morris, John C; Bateman, Randall J; Fox, Nick C; Schott, Jonathan M; Alexander, Daniel C

2018-03-22

Dominantly-inherited Alzheimer's disease is widely hoped to hold the key to developing interventions for sporadic late onset Alzheimer's disease. We use emerging techniques in generative data-driven disease progression modelling to characterize dominantly-inherited Alzheimer's disease progression with unprecedented resolution, and without relying upon familial estimates of years until symptom onset. We retrospectively analysed biomarker data from the sixth data freeze of the Dominantly Inherited Alzheimer Network observational study, including measures of amyloid proteins and neurofibrillary tangles in the brain, regional brain volumes and cortical thicknesses, brain glucose hypometabolism, and cognitive performance from the Mini-Mental State Examination (all adjusted for age, years of education, sex, and head size, as appropriate). Data included 338 participants with known mutation status (211 mutation carriers in three subtypes: 163 PSEN1, 17 PSEN2, and 31 APP) and a baseline visit (age 19-66; up to four visits each, 1.1 ± 1.9 years in duration; spanning 30 years before, to 21 years after, parental age of symptom onset). We used an event-based model to estimate sequences of biomarker changes from baseline data across disease subtypes (mutation groups), and a differential equation model to estimate biomarker trajectories from longitudinal data (up to 66 mutation carriers, all subtypes combined). The two models concur that biomarker abnormality proceeds as follows: amyloid deposition in cortical then subcortical regions (∼24 ± 11 years before onset); phosphorylated tau (17 ± 8 years), tau and amyloid-β changes in cerebrospinal fluid; neurodegeneration first in the putamen and nucleus accumbens (up to 6 ± 2 years); then cognitive decline (7 ± 6 years), cerebral hypometabolism (4 ± 4 years), and further regional neurodegeneration. Our models predicted symptom onset more accurately than predictions that used familial estimates: root mean squared error of 1

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

Science.gov (United States)

Rosiñol, Laura; García-Sanz, Ramón; Lahuerta, Juan José; Hernández-García, Miguel; Granell, Miquel; de la Rubia, Javier; Oriol, Albert; Hernández-Ruiz, Belén; Rayón, Consuelo; Navarro, Isabel; García-Ruiz, Juan Carlos; Besalduch, Joan; Gardella, Santiago; Jiménez, Javier López; Díaz-Mediavilla, Joaquín; Alegre, Adrián; Miguel, Jesús San; Bladé, Joan

2012-01-01

Background Several studies of autologous stem cell transplantation in primary refractory myeloma have produced encouraging results. However, the outcome of primary refractory patients with stable disease has not been analyzed separately from the outcome of patients with progressive disease. Design and Methods In the Spanish Myeloma Group 2000 trial, 80 patients with primary refractory myeloma (49 with stable disease and 31 with progressive disease), i.e. who were refractory to initial chemotherapy, were scheduled for tandem transplants (double autologous transplant or a single autologous transplant followed by an allogeneic transplant). Patients with primary refractory disease included those who never achieved a minimal response (≥25% M-protein decrease) or better. Responses were assessed using the European Bone Marrow Transplant criteria. Results There were no significant differences in the rates of partial response or better between patients with stable or progressive disease. However, 38% of the patients with stable disease at the time of transplantation remained in a stable condition or achieved a minimal response after transplantation versus 7% in the group with progressive disease (P=0.0017) and the rate of early progression after transplantation was significantly higher among the group with progressive disease at the time of transplantation (22% versus 2%; P=0.0043). After a median follow-up of 6.6 years, the median survival after first transplant of the whole series was 2.3 years. Progression-free and overall survival from the first transplant were shorter in patients with progressive disease (0.6 versus 2.3 years, P=0.00004 and 1.1 versus 6 years, P=0.00002, respectively). Conclusions Our results show that patients with progressive refractory myeloma do not benefit from autologous transplantation, while patients with stable disease have an outcome comparable to those with chemosensitive disease. (ClinicalTrials.gov:NCT00560053) PMID:22058223

Role for transforming growth factor-beta1 in alport renal disease progression.

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Sayers, R; Kalluri, R; Rodgers, K D; Shield, C F; Meehan, D T; Cosgrove, D

1999-11-01

Alport syndrome results from mutations in either the alpha3(IV), alpha4(IV), or alpha5(IV) collagen genes. The disease is characterized by a progressive glomerulonephritis usually associated with a high-frequency sensorineural hearing loss. A mouse model for an autosomal form of Alport syndrome [collagen alpha3(IV) knockout] was produced and characterized. In this study, the model was exploited to demonstrate a potential role for transforming growth factor-beta1 (TGF-beta1) in Alport renal disease pathogenesis. Kidneys from normal and Alport mice, taken at different stages during the course of renal disease progression, were analyzed by Northern blot, in situ hybridization, and immunohistology for expression of TGF-beta1 and components of the extracellular matrix. Normal and Alport human kidney was examined for TGF-beta1 expression using RNase protection. The mRNAs encoding TGF-beta1 (in both mouse and human), entactin, fibronectin, and the collagen alpha1(IV) and alpha2(IV) chains were significantly induced in total kidney as a function of Alport renal disease progression. The induction of these specific mRNAs was observed in the glomerular podocytes of animals with advanced disease. Type IV collagen, laminin-1, and fibronectin were markedly elevated in the tubulointerstitium at 10 weeks, but not at 6 weeks, suggesting that elevated expression of specific mRNAs on Northern blots reflects events associated with tubulointerstitial fibrosis. The concomitant accumulation of mRNAs encoding TGF-beta1 and extracellular matrix components in the podocytes of diseased kidneys may reflect key events in Alport renal disease progression. These data suggest a role for TGF-beta1 in both glomerular and tubulointerstitial damage associated with Alport syndrome.

[Retrospective analysis of influence of differential protein intake on renal prognosis for progressive chronic kidney disease].

Science.gov (United States)

Dai, Wendi; Yin, Daoxin; Cui, Wenying; Liu, Wenhu

2014-01-28

To explore retrospectively the influence of differential protein intake on renal prognosis for progressive chronic kidney disease (CKD). A total of 159 chronic kidney disease patients at stages 2, 3 and 4 were enrolled and a questionnaire survey was conducted from January 2009 to July 2012. They were followed monthly and their clinical data collected, including primary disease, blood pressure, body mass index and adverse events. Laboratory tests were performed every 3 months, including biochemical parameters, protein-energy malnutrition (PEM), diet reviews and daily protein intake (DPI). A simplified MDRD formula was employed to evaluate the level of estimated glomerular filtration rate (eGFR). According to the level of DPI, they were divided into 3 groups of very low protein diet (VLPD): DPI ≤ 0.6 g · kg(-1) · d(-1), low-protein diet (LPD): DPI >0.6-protein diet (NPD): DPI ≥ 0.8 · g · kg(-1) · d(-1). Among them, 4 cases (2.50%) progressed to uremia stage and received renal replacement therapy, 2(1.25%) experienced rapid decline in renal function, 9(5.66%) were hospitalized from cardio-cerebral diseases and the 2-year kidney survival rate was 97.5%. At the end of study, among 9 patients of PEM, 2 subjects had a serum level of albumin under 32 g/L and another 7 with a BMI 0.05). Within a certain range, differential protein intake may not significantly affect the prognosis of kidney for progressive CKD patients.

Effect of mineralocorticoid receptor antagonists on proteinuria and progression of chronic kidney disease

DEFF Research Database (Denmark)

Currie, Gemma; Taylor, Alison H M; Fujita, Toshiro

2016-01-01

BACKGROUND: Hypertension and proteinuria are critically involved in the progression of chronic kidney disease. Despite treatment with renin angiotensin system inhibition, kidney function declines in many patients. Aldosterone excess is a risk factor for progression of kidney disease. Hyperkalaemi...... pressure and urinary protein/albumin excretion with a quantifiable risk of hyperkalaemia above predefined study upper limit....

Serum Levels of Toxic AGEs (TAGE May Be a Promising Novel Biomarker for the Onset/Progression of Lifestyle-Related Diseases

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Masayoshi Takeuchi

2016-06-01

Full Text Available Advanced glycation end-products (AGEs generated with aging or in the presence of diabetes mellitus, particularly AGEs derived from the glucose/fructose metabolism intermediate glyceraldehyde (Glycer-AGEs; termed toxic AGEs (TAGE, were recently shown to be closely involved in the onset/progression of diabetic vascular complications via the receptor for AGEs (RAGE. TAGE also contribute to various diseases, such as cardiovascular disease; nonalcoholic steatohepatitis; cancer; Alzheimer’s disease, and; infertility. This suggests the necessity of minimizing the influence of the TAGE-RAGE axis in order to prevent the onset/progression of lifestyle-related diseases (LSRD and establish therapeutic strategies. Changes in serum TAGE levels are closely associated with LSRD related to overeating, a lack of exercise, or excessive ingestion of sugars/dietary AGEs. We also showed that serum TAGE levels, but not those of hemoglobin A1c, glucose-derived AGEs, or Nε-(carboxymethyllysine, have potential as a biomarker for predicting the progression of atherosclerosis and future cardiovascular events. We herein introduce the usefulness of serum TAGE levels as a biomarker for the prevention/early diagnosis of LSRD and the evaluation of the efficacy of treatments; we discuss whether dietary AGE/sugar intake restrictions reduce the generation/accumulation of TAGE, thereby preventing the onset/progression of LSRD.

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

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

2014-06-01

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

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

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Christopher M Blanchette

2015-04-01

Full Text Available Background: Autosomal dominant polycystic kidney disease (ADPKD is a progressive genetic disorder characterized by the development of numerous kidney cysts that result in kidney failure. Little is known regarding the key patient characteristics and utilization of healthcare resources for ADPKD patients along the continuum of disease progression. This observational study was designed to describe the characteristics of ADPKD patients and compare them with those of patients with other chronic kidney diseases. Methods: This retrospective cohort study involved patients with a claim for ADPKD or PKD unspecified from 1/1/2000–2/28/2013 and ≥6 months of previous continuous enrollment (baseline within a large database of administrative claims in the USA. A random sample of chronic kidney disease (CKD patients served as comparators. For a subset of ADPKD patients who had only a diagnosis code of unspecified PKD, abstraction of medical records was undertaken to estimate the proportion of patients who had medical chart-confirmed ADPKD. In patients with linked electronic laboratory data, the estimated glomerular filtration rate was calculated via serum creatinine values to determine CKD stage at baseline and during follow-up. Proportions of patients transitioning to another stage and the mean age at transition were calculated. Results: ADPKD patients were, in general, younger and had fewer physician visits, but had more specific comorbidities at observation start compared with CKD patients. ADPKD patients had a longer time in the milder stages and longer duration before recorded transition to a more severe stage compared with CKD patients. Patients with ADPKD at risk of rapid progression had a shorter time-to-end-stage renal disease than patients with CKD and ADPKD patients not at risk, but stage duration was similar between ADPKD patients at risk and those not at risk. Conclusions: These results suggest that distribution of patients by age at transition

Motor unit number estimation in the quantitative assessment of severity and progression of motor unit loss in Hirayama disease.

Science.gov (United States)

Zheng, Chaojun; Zhu, Yu; Zhu, Dongqing; Lu, Feizhou; Xia, Xinlei; Jiang, Jianyuan; Ma, Xiaosheng

2017-06-01

To investigate motor unit number estimation (MUNE) as a method to quantitatively evaluate severity and progression of motor unit loss in Hirayama disease (HD). Multipoint incremental MUNE was performed bilaterally on both abductor digiti minimi and abductor pollicis brevis muscles in 46 patients with HD and 32 controls, along with handgrip strength examination. MUNE was re-evaluated approximately 1year after initial examination in 17 patients with HD. The MUNE values were significantly lower in all the tested muscles in the HD group (Pdisease duration (Pmotor unit loss in patients with HD within approximately 1year (P4years. A reduction in the functioning motor units was found in patients with HD compared with that in controls, even in the early asymptomatic stages. Moreover, the motor unit loss in HD progresses gradually as the disease advances. These results have provided evidence for the application of MUNE in estimating the reduction of motor unit in HD and confirming the validity of MUNE for tracking the progression of HD in a clinical setting. Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Periodontal Pocket Depth, Hyperglycemia, and Progression of Chronic Kidney Disease: A Population-Based Longitudinal Study.

Science.gov (United States)

Chang, Jia-Feng; Yeh, Jih-Chen; Chiu, Ya-Lin; Liou, Jian-Chiun; Hsiung, Jing-Ru; Tung, Tao-Hsin

2017-01-01

No large epidemiological study has been conducted to investigate the interaction and joint effects of periodontal pocket depth and hyperglycemia on progression of chronic kidney disease in patients with periodontal diseases. Periodontal pocket depth was utilized for the grading severity of periodontal disease in 2831 patients from January 2002 to June 2013. Progression of chronic kidney disease was defined as progression of color intensity in glomerular filtration rate and albuminuria grid of updated Kidney Disease-Improving Global Outcomes guidelines. Multivariable-adjusted hazard ratios (aHR) in various models were presented across different levels of periodontal pocket depth and hemoglobin A1c (HbA1c) in forest plots and 3-dimensional histograms. During 7621 person-years of follow-up, periodontal pocket depth and HbA1C levels were robustly associated with incremental risks for progression of chronic kidney disease (aHR 3.1; 95% confidence interval [CI], 2.0-4.6 for periodontal pocket depth >4.5 mm, and 2.5; 95% CI, 1.1-5.4 for HbA1C >6.5%, respectively). The interaction between periodontal pocket depth and HbA1C on progression of chronic kidney disease was strong (P periodontal pocket depth (>4.5 mm) and higher HbA1C (>6.5%) had the greatest risk (aHR 4.2; 95% CI, 1.7-6.8) compared with the lowest aHR group (periodontal pocket depth ≤3.8 mm and HbA1C ≤6%). Our study identified combined periodontal pocket depth and HbA1C as a valuable predictor of progression of chronic kidney disease in patients with periodontal diseases. While considering the interaction between periodontal diseases and hyperglycemia, periodontal survey and optimizing glycemic control are warranted to minimize the risk of worsening renal function. Copyright © 2016 Elsevier Inc. All rights reserved.

State of progress in treating cystic fibrosis respiratory disease

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Flume Patrick A

2012-08-01

Full Text Available Abstract 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.

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

NARCIS (Netherlands)

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

1997-01-01

A substantial proportion of the patients treated by occupational therapists have a chronic disease. The aim of this study was to describe the outlines of occupational therapy treatment for three specific groups of chronic diseases: progressive neurological diseases, cerebrovascular accident and

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

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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...

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

Science.gov (United States)

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

2014-03-21

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

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

Science.gov (United States)

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

2014-03-01

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

Serial Noninvasive Assessment of Apoptosis During Right Ventricular Disease Progression in Rats

NARCIS (Netherlands)

Campian, Maria E.; Verberne, Hein J.; Hardziyenka, Maxim; de Bruin, Kora; Selwaness, Mariana; van den Hoff, Maurice J. B.; Ruijter, Jan M.; van Eck-Smit, Berthe L. F.; de Bakker, Jacques M. T.; Tan, Hanno L.

2009-01-01

Right ventricular (RV) function is the major determinant of survival in patients with pulmonary hypertension. Yet, the pathophysiologic basis of RV disease is unresolved. We aimed to study the role of apoptosis in RV disease by monitoring it serially during disease progression using in vivo

Effect of blood pressure lowering on markers of kidney disease progression.

Science.gov (United States)

Udani, Suneel M; Koyner, Jay L

2009-10-01

Hypertension remains a common comorbidity and cause of chronic kidney disease (CKD). As the number of patients with CKD grows, so does the need to identify modifiable risk factors for CKD progression. Data on slowing progression of CKD or preventing end-stage renal disease with aggressive blood pressure control have not yielded definitive conclusions regarding ideal blood pressure targets. Shifting the focus of antihypertensive therapy to alternative markers of end-organ damage, specifically proteinuria, has yielded some promise in preventing the progression of CKD. Nevertheless, proteinuria and decline in estimated GFR may represent an irreversible degree of injury to the kidney that limits the impact of any therapy. The identification and use of novel markers of kidney injury to assess the impact of antihyper-tensive therapy may yield clearer direction with regard to optimal management of hypertension in the setting of CKD.

Normal and mutant HTT interact to affect clinical severity and progression in Huntington disease

DEFF Research Database (Denmark)

Aziz, N A; Jurgens, C K; Landwehrmeyer, G B

2009-01-01

OBJECTIVE: Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the HD gene (HTT). We aimed to assess whether interaction between CAG repeat sizes in the mutant and normal allele could affect disease severity and progression. METHODS: Using...... with less severe symptoms and pathology. CONCLUSIONS: Increasing CAG repeat size in normal HTT diminishes the association between mutant CAG repeat size and disease severity and progression in Huntington disease. The underlying mechanism may involve interaction of the polyglutamine domains of normal...

Characterization of annual disease progression of multiple sclerosis patients: A population-based study

DEFF Research Database (Denmark)

Freilich, Jonatan; Manouchehrinia, Ali; Trusheim, Mark

2017-01-01

Previous research characterizing factors influencing multiple sclerosis (MS) disease progression has typically been based on time to disease milestones (Kaplan-Meier, Cox hazard regression, etc.). A limitation of these methods is the handling of the often large groups of patients not reaching...... the milestone. To characterize clinical factors influencing MS disease progression as annual transitions from each Expanded Disability Status Scale (EDSS). The annual progression of 11,964 patients from the Swedish MS Registry was analysed with 10 multinomial logistic regressions, that is, one for transition...... from each full EDSS with explanatory variables age, sex, age at onset, time in current EDSS, highest prior EDSS, MS course and treatment. All factors (except sex) investigated had statistically significant impacts on transitions from at least one EDSS. However, significance and size of the effect...

Electrophysiology and optical coherence tomography to evaluate Parkinson disease severity.

Science.gov (United States)

Garcia-Martin, Elena; Rodriguez-Mena, Diego; Satue, Maria; Almarcegui, Carmen; Dolz, Isabel; Alarcia, Raquel; Seral, Maria; Polo, Vicente; Larrosa, Jose M; Pablo, Luis E

2014-02-04

To evaluate correlations between visual evoked potentials (VEP), pattern electroretinogram (PERG), and macular and retinal nerve fiber layer (RNFL) thickness measured by optical coherence tomography (OCT) and the severity of Parkinson disease (PD). Forty-six PD patients and 33 age and sex-matched healthy controls were enrolled, and underwent VEP, PERG, and OCT measurements of macular and RNFL thicknesses, and evaluation of PD severity using the Hoehn and Yahr scale to measure PD symptom progression, the Schwab and England Activities of Daily Living Scale (SE-ADL) to evaluate patient quality of life (QOL), and disease duration. Logistical regression was performed to analyze which measures, if any, could predict PD symptom progression or effect on QOL. Visual functional parameters (best corrected visual acuity, mean deviation of visual field, PERG positive (P) component at 50 ms -P50- and negative (N) component at 95 ms -N95- component amplitude, and PERG P50 component latency) and structural parameters (OCT measurements of RNFL and retinal thickness) were decreased in PD patients compared with healthy controls. OCT measurements were significantly negatively correlated with the Hoehn and Yahr scale, and significantly positively correlated with the SE-ADL scale. Based on logistical regression analysis, fovea thickness provided by OCT equipment predicted PD severity, and QOL and amplitude of the PERG N95 component predicted a lower SE-ADL score. Patients with greater damage in the RNFL tend to have lower QOL and more severe PD symptoms. Foveal thicknesses and the PERG N95 component provide good biomarkers for predicting QOL and disease severity.

Progressive atlanto-axial subluxation in Behcet's disease

Energy Technology Data Exchange (ETDEWEB)

Kim, Sang-hyuk [Chonbuk National University Hospital, Department of Neurosurgery, Jeonju City, Jeonbuk (Korea); Eoh, Whan [Sungkyunkwan University School of Medicine, Samsung Medical Center, Department of Neurosurgery, Seoul (Korea)

2010-03-15

Behcet's disease is a chronic inflammatory condition involving several organs, such as the skin, mucous membranes, eyes, joints, intestines, lungs and central nervous system. It rarely affects the spinal column. We describe a case of progressive atlanto-axial subluxation in a 44-year-old woman with Behcet's disease. The patient started complaining of posterior neck pain 10 years after the diagnosis of her Behcet's disease. Initial radiographs showed no abnormal finding, but follow-up radiographs 6 month later demonstrated atlanto-axial subluxation. To the best of our knowledge, this is the second reported case in the worldwide literature of an atlanto-axial instability in a patient with Behcet's disease. (orig.)

Disease progression of acute pancreatitis in pediatric patients.

Science.gov (United States)

Hao, Fabao; Guo, Hongjie; Luo, Qianfu; Guo, Chunbao

2016-05-15

Approximately 10% of patients with acute pancreatitis (AP) progress to chronic pancreatitis. Little is known about the factors that affect recurrence of pancreatitis after an initial episode. We retrospectively investigated patients with AP, focusing on their outcomes and the predictors for disease progression. Between July 2003 and June 2015, we retrospectively enrolled first-time AP patients with medical records on disease etiology, severity (according to the Atlanta classifications), and recurrence of AP. Independent predictors of recurrent AP (RAP) and chronic pancreatitis were identified using the logistic regression model. Of the total 159 patients, 45 (28.3%) developed RAP, including two episodes of RAP in 19 patients, and 9 (5.7%) developed chronic pancreatitis. The median duration from the time of AP to the onset of RAP was 5.6 ± 2.3 months. RAP patients were identified as more common among patients with idiopathic first-time AP. The presence of severe ascites, pancreatic necrosis, and systemic complications was independent predictors of RAP in pediatric patients. Experiencing over two RAP episodes was the predictor for developing chronic pancreatitis. No influence of age or number of AP episodes was found on the occurrence of abdominal pain, pain severity, and the prevalence of any pain. Severity of first-time AP and idiopathic first-time AP are related to RAP. Recurrence increases risk for progression to chronic pancreatitis. The risk of recurrence increased with increasing numbers of AP episodes. Copyright © 2016 Elsevier Inc. All rights reserved.

Disease Progression/Clinical Outcome Model for Castration-Resistant Prostate Cancer in Patients Treated with Eribulin

NARCIS (Netherlands)

Van Hasselt, J. G C; Gupta, A.; Hussein, Z.; Beijnen, J. H.; Schellens, J. H M; Huitema, A. D R

2015-01-01

Frameworks that associate cancer dynamic disease progression models with parametric survival models for clinical outcome have recently been proposed to support decision making in early clinical development. Here we developed such a disease progression clinical outcome model for castration-resistant

Role of rasagiline in treating Parkinson's disease: Effect on disease progression.

Science.gov (United States)

Malaty, Irene A; Fernandez, Hubert H

2009-08-01

Rasagiline is a second generation, selective, irreversible monoamine oxidase type B (MAO-B) inhibitor. It has demonstrated efficacy in monotherapy for early Parkinson's disease (PD) patients in one large randomized, placebo-controlled trial (TVP-1012 in Early Monotherapy for Parkinson's Disease Outpatients), and has shown ability to reduce off time in more advanced PD patients with motor fluctuations in two large placebo-controlled trials (Parkinson's Rasagiline: Efficacy and Safety in the Treatment of "Off", and Lasting Effect in Adjunct Therapy With Rasagiline Given Once Daily). Preclinical data abound to suggest potential for neuroprotection by this compound against a variety of neurotoxic insults in cell cultures and in animals. The lack of amphetamine metabolites provides an advantage over the first generation MAO-B inhibitor selegiline. One large trial has investigated the potential for disease modification in PD patients (Attenuation of Disease progression with Azilect Given Once-daily) and preliminary results maintain some possible advantage to earlier initiation of the 1 mg/day dose. The clinical significance of the difference detected remains a consideration.

Teleosts Genomics: Progress and Prospects in Disease Prevention and Control.

Science.gov (United States)

Munang'andu, Hetron Mweemba; Galindo-Villegas, Jorge; David, Lior

2018-04-04

Genome wide studies based on conventional molecular tools and upcoming omics technologies are beginning to gain functional applications in the control and prevention of diseases in teleosts fish. Herein, we provide insights into current progress and prospects in the use genomics studies for the control and prevention of fish diseases. Metagenomics has emerged to be an important tool used to identify emerging infectious diseases for the timely design of rational disease control strategies, determining microbial compositions in different aquatic environments used for fish farming and the use of host microbiota to monitor the health status of fish. Expounding the use of antimicrobial peptides (AMPs) as therapeutic agents against different pathogens as well as elucidating their role in tissue regeneration is another vital aspect of genomics studies that had taken precedent in recent years. In vaccine development, prospects made include the identification of highly immunogenic proteins for use in recombinant vaccine designs as well as identifying gene signatures that correlate with protective immunity for use as benchmarks in optimizing vaccine efficacy. Progress in quantitative trait loci (QTL) mapping is beginning to yield considerable success in identifying resistant traits against some of the highly infectious diseases that have previously ravaged the aquaculture industry. Altogether, the synopsis put forth shows that genomics studies are beginning to yield positive contribution in the prevention and control of fish diseases in aquaculture.

Teleosts Genomics: Progress and Prospects in Disease Prevention and Control

Directory of Open Access Journals (Sweden)

Hetron Mweemba Munang’andu

2018-04-01

Full Text Available Genome wide studies based on conventional molecular tools and upcoming omics technologies are beginning to gain functional applications in the control and prevention of diseases in teleosts fish. Herein, we provide insights into current progress and prospects in the use genomics studies for the control and prevention of fish diseases. Metagenomics has emerged to be an important tool used to identify emerging infectious diseases for the timely design of rational disease control strategies, determining microbial compositions in different aquatic environments used for fish farming and the use of host microbiota to monitor the health status of fish. Expounding the use of antimicrobial peptides (AMPs as therapeutic agents against different pathogens as well as elucidating their role in tissue regeneration is another vital aspect of genomics studies that had taken precedent in recent years. In vaccine development, prospects made include the identification of highly immunogenic proteins for use in recombinant vaccine designs as well as identifying gene signatures that correlate with protective immunity for use as benchmarks in optimizing vaccine efficacy. Progress in quantitative trait loci (QTL mapping is beginning to yield considerable success in identifying resistant traits against some of the highly infectious diseases that have previously ravaged the aquaculture industry. Altogether, the synopsis put forth shows that genomics studies are beginning to yield positive contribution in the prevention and control of fish diseases in aquaculture.

An alpha-synuclein MRM assay with diagnostic potential for Parkinson's disease and monitoring disease progression

Energy Technology Data Exchange (ETDEWEB)

Yang, Li [Department of Pathology, University of Washington, Seattle WA USA; Stewart, Tessandra [Department of Pathology, University of Washington, Seattle WA USA; Shi, Min [Department of Pathology, University of Washington, Seattle WA USA; Pottiez, Gwenael [Department of Pathology, University of Washington, Seattle WA USA; Dator, Romel [Department of Pathology, University of Washington, Seattle WA USA; Wu, Rui [Department of Pathology, University of Washington, Seattle WA USA; Department of Pathology, No. 3 Hospital of Beijing University, Beijing China; Aro, Patrick [Department of Pathology, University of Washington, Seattle WA USA; Schuster, Robert J. [Department of Pathology, University of Washington, Seattle WA USA; Ginghina, Carmen [Department of Pathology, University of Washington, Seattle WA USA; Pan, Catherine [Department of Pathology, University of Washington, Seattle WA USA; Gao, Yuqian [Pacific Northwest National Laboratory, Richland WA USA; Qian, Weijun [Pacific Northwest National Laboratory, Richland WA USA; Zabetian, Cyrus P. [Parkinson' s Disease Research and Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle WA USA; Department of Neurology, University of Washington School of Medicine, Seattle WA USA; Hu, Shu-Ching [Department of Neurology, University of Washington School of Medicine, Seattle WA USA; Quinn, Joseph F. [Department of Neurology, Oregon Health and Science University, Portland OR USA; Zhang, Jing [Department of Pathology, University of Washington, Seattle WA USA; Department of Pathology, Peking University Health Science Centre and Third Hospital, Beijing 100083 China

2017-04-19

Aim: The alpha-synuclein (α-syn) level in human cerebrospinal fluid (CSF), as measured by immunoassays, is promising as a Parkinson’s disease (PD) biomarker. However, the levels of total α-syn are inconsistent among studies with large cohorts and different measurement platforms. Total α-syn level also does not correlate with disease severity or progression. Here, we developed a highly sensitive Multiple Reaction Monitoring (MRM) method to measure absolute CSF α-syn peptide concentrations without prior enrichment or fractionation, aiming to discover new candidate biomarkers. Results: Six peptides covering 73% of protein sequence were reliably identified, and two were consistently quantified in cross-sectional and longitudinal cohorts. Absolute concentration of α-syn in human CSF was determined to be 2.1ng/mL. A unique α-syn peptide, TVEGAGSIAAATGFVK (81-96), displayed excellent correlation with previous immunoassay results in two independent PD cohorts (p < 0.001), correlated with disease severity, and its changes significantly tracked the disease progression longitudinally. Conclusions: An MRM assay to quantify human CSF α-syn was developed and optimized. Sixty clinical samples from cross-sectional and longitudinal PD cohorts were analyzed with this approach. Although further larger-scale validation is needed, the results suggest that α-syn peptide could serve as a promising biomarker in PD diagnosis and progression.

Biomarkers of Renal Disease and Progression in Patients with Diabetes

Directory of Open Access Journals (Sweden)

Radovan Hojs

2015-05-01

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

Factors That Affect Disease Progression After First Attack of Acute Pancreatitis.

Science.gov (United States)

Bertilsson, Sara; Swärd, Per; Kalaitzakis, Evangelos

2015-09-01

Little is known about recurrence of pancreatitis after an initial episode, and little is known about how the disease progresses or what factors affect progression. We performed a population-based study of patients with acute pancreatitis (AP) to determine their outcomes and associated factors. We performed a retrospective study of patients with first-time AP from 2003 through 2012 in a well-defined area of Sweden. Data were collected from medical records on disease etiology, severity (according to the Atlanta classification), recurrence of AP, subsequent chronic pancreatitis, and mortality. Patients were followed up for a median time of 4.6 years, until death or the end of 2013. We identified 1457 patients with first-time AP (48% biliary disease, 17% alcohol-associated, 9.9% severe); 23% of patients had 1 or more recurrences. Risk for recurrence was significantly higher among smokers (hazard ratio [HR], 1.42; 95% confidence interval [CI], 1.03-1.95; P = .03), patients with alcohol-associated AP (HR, 1.58; 95% CI, 1.25-2.23; P chronic pancreatitis, although alcohol-associated AP progressed most frequently (2.8/100 patient-years). Patients with recurrent AP were at the highest risk for chronic pancreatitis (HR, 6.74; 95% CI, 4.02-11.3; P associated AP (HR, 3.10; 95% CI, 2.05-5.87; P associated only with organ failure (odds ratio, 71.17; 95% CI, 21.14-239.60; P chronic pancreatitis. Recurrence increases the risk for progression to chronic pancreatitis. Most patients who die upon disease recurrence have biliary AP. Copyright © 2015. Published by Elsevier Inc.

Anosognosia in Alzheimer disease: Prevalence, associated factors, and influence on disease progression.

Science.gov (United States)

Castrillo Sanz, A; Andrés Calvo, M; Repiso Gento, I; Izquierdo Delgado, E; Gutierrez Ríos, R; Rodríguez Herrero, R; Rodríguez Sanz, F; Tola-Arribas, M A

2016-06-01

Anosognosia is a frequent symptom in Alzheimer disease (AD). The objective of this article is to describe prevalence of this condition at time of diagnosis and analyse any predisposing factors and their influence on disease progression. Observational, prospective, and analytical multi-centre study in an outpatient setting. Patients recently diagnosed with AD (NINCDS-ADRDA criteria) were included. Each patient underwent two cognitive, functional, and neuropsychiatric assessments separated by an interval of 18 months. The Clinical Insight Rating Scale was employed as a measure of anosognosia (CIR, scored 0-8). Progression was defined as an increase in the Clinical Dementia Rating Scale-sum of boxes of more than 2.5 points. The predictor variables were analysed using binary logistic regression. The study included 127 patients, and 94 completed both assessments. Of the total, 31.5% displayed severe anosognosia (CIR 7-8); 39.4%, altered level of consciousness (CIR 3-6); and 29.1%, normal awareness (CIR 0-2). The median baseline CIR in this cohort was 4 (Q1-Q3: 1-7), and at 18 months, 6 (Q1-Q3: 3-8), Pde Neurología. Published by Elsevier España, S.L.U. All rights reserved.

Quantitative muscle MRI as an assessment tool for monitoring disease progression in LGMD2I

DEFF Research Database (Denmark)

Willis, Tracey A; Hollingsworth, Kieren G; Coombs, Anna

2013-01-01

Outcome measures for clinical trials in neuromuscular diseases are typically based on physical assessments which are dependent on patient effort, combine the effort of different muscle groups, and may not be sensitive to progression over short trial periods in slow-progressing diseases. We hypoth...

Characterization of LEDGF/p75 genetic variants and association with HIV-1 disease progression.

Directory of Open Access Journals (Sweden)

Peter Messiaen

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

Effects of deep brain stimulation on rest tremor progression in early stage Parkinson disease.

Science.gov (United States)

Hacker, Mallory L; DeLong, Mahlon R; Turchan, Maxim; Heusinkveld, Lauren E; Ostrem, Jill L; Molinari, Anna L; Currie, Amanda D; Konrad, Peter E; Davis, Thomas L; Phibbs, Fenna T; Hedera, Peter; Cannard, Kevin R; Drye, Lea T; Sternberg, Alice L; Shade, David M; Tonascia, James; Charles, David

2018-06-29

To evaluate whether the progression of individual motor features was influenced by early deep brain stimulation (DBS), a post hoc analysis of Unified Parkinson's Disease Rating Scale-III (UPDRS-III) score (after a 7-day washout) was conducted from the 2-year DBS in early Parkinson disease (PD) pilot trial dataset. The prospective pilot trial enrolled patients with PD aged 50-75 years, treated with PD medications for 6 months-4 years, and no history of dyskinesia or other motor fluctuations, who were randomized to receive optimal drug therapy (ODT) or DBS plus ODT (DBS + ODT). At baseline and 6, 12, 18, and 24 months, all patients stopped all PD therapy for 1 week (medication and stimulation, if applicable). UPDRS-III "off" item scores were compared between the ODT and DBS + ODT groups (n = 28); items with significant between-group differences were analyzed further. UPDRS-III "off" rest tremor score change from baseline to 24 months was worse in patients receiving ODT vs DBS + ODT ( p = 0.002). Rest tremor slopes from baseline to 24 months favored DBS + ODT both "off" and "on" therapy ( p will be tested in the Food and Drug Administration-approved, phase III, pivotal, multicenter clinical trial evaluating DBS in early PD. This study provides Class II evidence that for patients with early PD, DBS may slow the progression of rest tremor. © 2018 American Academy of Neurology.

A fuzzy logic expert system for evaluating policy progress towards sustainability goals.

Science.gov (United States)

Cisneros-Montemayor, Andrés M; Singh, Gerald G; Cheung, William W L

2017-12-16

Evaluating progress towards environmental sustainability goals can be difficult due to a lack of measurable benchmarks and insufficient or uncertain data. Marine settings are particularly challenging, as stakeholders and objectives tend to be less well defined and ecosystem components have high natural variability and are difficult to observe directly. Fuzzy logic expert systems are useful analytical frameworks to evaluate such systems, and we develop such a model here to formally evaluate progress towards sustainability targets based on diverse sets of indicators. Evaluation criteria include recent (since policy enactment) and historical (from earliest known state) change, type of indicators (state, benefit, pressure, response), time span and spatial scope, and the suitability of an indicator in reflecting progress toward a specific objective. A key aspect of the framework is that all assumptions are transparent and modifiable to fit different social and ecological contexts. We test the method by evaluating progress towards four Aichi Biodiversity Targets in Canadian oceans, including quantitative progress scores, information gaps, and the sensitivity of results to model and data assumptions. For Canadian marine systems, national protection plans and biodiversity awareness show good progress, but species and ecosystem states overall do not show strong improvement. Well-defined goals are vital for successful policy implementation, as ambiguity allows for conflicting potential indicators, which in natural systems increases uncertainty in progress evaluations. Importantly, our framework can be easily adapted to assess progress towards policy goals with different themes, globally or in specific regions.

CCR5Δ32 Polymorphism Associated with a Slower Rate Disease Progression in a Cohort of RR-MS Sicilian Patients

Directory of Open Access Journals (Sweden)

Rosalia D'Angelo

2011-01-01

Full Text Available Multiple sclerosis (MS disease is carried through inflammatory and degenerative stages. Based on clinical feaures, it can be subdivided into three groups: relapsing-remitting MS, secondary progressive MS, and primary progressive MS. Multiple sclerosis has a multifactorial etiology with an interplay of genetic predisposition, environmental factors, and autoimmune inflammatory mechanism in which play a key role CC-chemokines and its receptors. In this paper, we studied the frequency of CCR5 gene Δ32 allele in a cohort of Sicilian RR-MS patients comparing with general Sicilian population. Also, we evaluate the association between this commonly polymorphism and disability development and age of disease onset in the same cohort. Our results show that presence of CCR5Δ32 is significantly associated with expanded disability status scale score (EDSS but not with age of disease onset.

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

Science.gov (United States)

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

2013-01-01

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

JAK2V617F mutation in chronic myeloid leukemia predicts early disease progression

International Nuclear Information System (INIS)

Pahore, Z.A.A.; Shamsi, T.S.; Taj, M.; Farzana, T.; Ansari, S.H.; Nadeem, M.; Ahmad, M.; Naz, A.

2011-01-01

Objective: To determine the association of JAK2V617F mutation along with BCR-ABL translocation or Philadelphia chromosome in chronic myeloid leukemia with early disease progression to advanced stages (accelerated phase or blast crisis) and poor outcome. Study Design: Case series. Place and Duration of Study: National Institute of Blood Diseases and Bone Marrow Transplantation, Karachi, from February 2008 to August 2009. Methodology: All the newly diagnosed cases of BCR-ABL or Philadelphia positive CML were tested for JAK2V617F mutation by Nested PCR. Demographic data, spleen size, hemoglobin levels, white blood cell and platelet counts were recorded. Independent sample t-test was used for age, haemoglobin level and spleen size. Fisher's exact test was applied to compare disease progression in JAK2V617F mutation positive and negative cases. Results: Out of 45 newly diagnosed cases of CML, 40 were in chronic phase, 01 in accelerated phase and 04 in blast crisis. JAK2V617F mutation was detected in 12 (26.7%) patients; 09 (22.5%) in chronic phase, none in accelerated phase and 03 (75%) in blast crisis. During a mean follow-up of 8 months, 03 patients in chronic phase transformed in blast crisis and 02 into accelerated phase. Overall 08 out of 11 (73%) JAK2V617F positive patients either had advanced disease or showed disease progression. Only 2 of 20 (10%) available patients, negative for the mutation, showed disease progression by transforming into blast crisis (p < 0.001). No statistically significant difference was seen in the age, spleen size, haemoglobin levels, white blood cells and platelets counts in JAK2V617F positive patients. Conclusion: JAK2V617F mutation was detected in 26.7% cases of chronic myeloid leukemia. A significant proportion of them showed early disease progression. (author)

Molecular Differentiation of Risk for Disease Progression: Delineating Stage-Specific Therapeutic Targets for Disease Management in Breast Cancer

National Research Council Canada - National Science Library

Worsham, Maria J; Raju, Usha; Chase, Gary; Lu, Mei

2004-01-01

.... The aim of this research is to 1a: identify an informative set of specific genetic alterations that underlie the pathogenesis of disease progression to serve as targets for management of disease at the earliest stages and 1b...

Molecular Differentiation of Risk for Disease Progression: Delineating Stage-Specific Therapeutic Targets for Disease Management in Breast Cancer

National Research Council Canada - National Science Library

Worsham, Maria J; Raju, Usha; Lu, Mei

2006-01-01

.... The aim of this research is to 1a: identify an informative set of specific genetic alterations that underlie the pathogenesis of disease progression to serve as targets for management of disease at the earliest stages and 1b...

Progression of Common Variable Immunodeficiency Interstitial Lung Disease Accompanies Distinct Pulmonary and Laboratory Findings.

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Maglione, Paul J; Overbey, Jessica R; Cunningham-Rundles, Charlotte

2015-01-01

Common variable immunodeficiency may be complicated by interstitial lung disease, which leads to worsened morbidity and mortality in some. Although immunomodulatory treatment has efficacy, choice of patient, duration of treatment, and long-term follow-up are not available. Interstitial lung disease appears stable in certain instances, so it is not known whether all patients will develop progressive disease or require immunomodulatory therapy. This study aims to determine if all common variable immunodeficiency patients with interstitial lung disease have physiological worsening, and if clinical and/or laboratory parameters may correlate with disease progression. A retrospective review of medical records at Mount Sinai Medical Center in New York was conducted for referred patients with common variable immunodeficiency, CT scan-confirmed interstitial lung disease, and periodic pulmonary function testing covering 20 or more months before immunomodulatory therapy. Fifteen patients were identified from the retrospective review and included in this study. Of the 15 patients with common variable immunodeficiency, 9 had physiological worsening of interstitial lung disease adapted from consensus guidelines, associated with significant reductions in forced expiratory volume in 1 second, forced vital capacity, and diffusion capacity of the lung for carbon monoxide. Those with progressive lung disease also had significantly lower mean immunoglobulin G levels, greater increases and highest levels of serum immunoglobulin M (IgM), and more significant thrombocytopenia. Interstitial lung disease resulted in physiological worsening in many, but not all subjects, and was associated with suboptimal immunoglobulin G replacement. Those with worsening pulmonary function tests, elevated IgM, and severe thrombocytopenic episodes appear to be at highest risk for progressive disease. Such patients may benefit from immunomodulatory treatment. Copyright © 2015 American Academy of Allergy

Associations of hormonal contraceptive use with measures of HIV disease progression and antiretroviral therapy effectiveness.

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Whiteman, Maura K; Jeng, Gary; Samarina, Anna; Akatova, Natalia; Martirosyan, Margarita; Kissin, Dmitry M; Curtis, Kathryn M; Marchbanks, Polly A; Hillis, Susan D; Mandel, Michele G; Jamieson, Denise J

2016-01-01

To examine the associations between hormonal contraceptive use and measures of HIV disease progression and antiretroviral treatment (ART) effectiveness. A prospective cohort study of women with prevalent HIV infection in St. Petersburg, Russia, was conducted. After contraceptive counseling, participants chose to use combined oral contraceptives (COCs), depot-medroxyprogesterone acetate (DMPA), a copper intrauterine device (IUD) or male condoms for pregnancy prevention. Among participants not using ART at enrollment, we used multivariate Cox regression to assess the association between current (time-varying) contraceptive use and disease progression, measured by the primary composite outcome of CD4 decline to contraceptive method. During a total of 5233 months follow-up among participants not using ART with enrollment CD4 ≥350 cells/mm(3) (n=315), 97 experienced disease progression. Neither current use of COCs [adjusted hazard ratio (aHR) 0.91, 95% confidence interval (CI) 0.56-1.48] nor DMPA (aHR 1.28, 95% CI 0.71-2.31) was associated with a statistically significant increased risk for disease progression compared with use of nonhormonal methods (IUD or condoms). Among participants using ART at enrollment (n=77), we found no statistically significant differences in the predicted mean changes in CD4 cell count comparing current use of COCs (p=.1) or DMPA (p=.3) with nonhormonal methods. Hormonal contraceptive use was not significantly associated with measures of HIV disease progression or ART effectiveness among women with prevalent HIV infection. Hormonal contraceptive use was not significantly associated with measures of HIV disease progression or ART effectiveness among women with prevalent HIV infection. Published by Elsevier Inc.

Correlation between radiographic, echographic and MRI changes and rheumatoid arthritis progression

Directory of Open Access Journals (Sweden)

G. Garlaschi

2011-09-01

Full Text Available Objectives: To review the imaging methods used for the evaluation of disease progression in rheumatoid arthritis (RA and to evaluate the results of their application in pharmacological trials. Methods: Literature articles dealing with radiology, echography, and magnetic resonance imaging (MRI of patients with RA were evaluated in a non-systematic fashion. Results: Conventional radiology is the gold standard for the evaluation of disease progression in RA because of its diffusion, economy, and standardization. Different techniques have been proposed to evaluate radiological damage of the joints, with the Larsen’s and Sharp’s methods being most widely used. These methods are commonly used for the evaluation of the ability of DMARDs to slow RA progression. Among traditional DMARDs, gold salts, sulphasalazine, methotrexate, cyclosporin, and leflunomide have shown efficacy in slowing the appearance of new erosions. The same effect has been recently demonstrated for infliximab plus methotrexate, anakinra and etanercept. However, conventional radiology has several disadvantages, because it is monoplanar and has a low sensitivity to change. Newer imaging techniques, such as echography and MRI are extensively studied and have been used occasionally in the mediumterm evaluation of DMARDs, with promising results. Conclusions: Although conventional radiology is still the gold standard for the evaluation of disease progression in RA, newer techniques are increasingly studied. In particular, standardization of echographic and MRI imaging of the joints is in progress.

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

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

2014-01-01

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

MMP-7 is a predictive biomarker of disease progression in patients with idiopathic pulmonary fibrosis

Directory of Open Access Journals (Sweden)

Yasmina Bauer

2017-03-01

Full Text Available Idiopathic pulmonary fibrosis (IPF is a progressive interstitial lung disease with poor prognosis, which is characterised by destruction of normal lung architecture and excessive deposition of lung extracellular matrix. The heterogeneity of disease progression in patients with IPF poses significant obstacles to patient care and prevents efficient development of novel therapeutic interventions. Blood biomarkers, reflecting pathobiological processes in the lung, could provide objective evidence of the underlying disease. Longitudinally collected serum samples from the Bosentan Use in Interstitial Lung Disease (BUILD-3 trial were used to measure four biomarkers (metalloproteinase-7 (MMP-7, Fas death receptor ligand, osteopontin and procollagen type I C-peptide, to assess their potential prognostic capabilities and to follow changes during disease progression in patients with IPF. In baseline BUILD-3 samples, only MMP-7 showed clearly elevated protein levels compared with samples from healthy controls, and further investigations demonstrated that MMP-7 levels also increased over time. Baseline levels of MMP-7 were able to predict patients who had higher risk of worsening and, notably, baseline levels of MMP-7 could predict changes in FVC as early as month 4. MMP-7 shows potential to be a reliable predictor of lung function decline and disease progression.

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

International Nuclear Information System (INIS)

Mohammed, Nasiruddin; Kestin, Larry Llyn; Grills, Inga Siiner; Battu, Madhu; Fitch, Dwight Lamar; Wong, Ching-yee Oliver; Margolis, Jeffrey Harold; Chmielewski, Gary William; Welsh, Robert James

2011-01-01

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

Sex differences in progression to mild cognitive impairment and dementia in Parkinson's disease.

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Cholerton, Brenna; Johnson, Catherine O; Fish, Brian; Quinn, Joseph F; Chung, Kathryn A; Peterson-Hiller, Amie L; Rosenthal, Liana S; Dawson, Ted M; Albert, Marilyn S; Hu, Shu-Ching; Mata, Ignacio F; Leverenz, James B; Poston, Kathleen L; Montine, Thomas J; Zabetian, Cyrus P; Edwards, Karen L

2018-05-01

Identification of factors associated with progression of cognitive symptoms in Parkinson's disease (PD) is important for treatment planning, clinical care, and design of future clinical trials. The current study sought to identify whether prediction of cognitive progression is aided by examining baseline cognitive features, and whether this differs according to stage of cognitive disease. Participants with PD in the Pacific Udall Center Clinical Consortium who had longitudinal data available and were nondemented at baseline were included in the study (n = 418). Logistic and Cox regression models were utilized to examine the relationship between cognitive, demographic, and clinical variables with risk and time to progression from no cognitive impairment to mild cognitive impairment (PD-MCI) or dementia (PDD), and from PD-MCI to PDD. Processing speed (OR = 1.05, p = 0.009) and working memory (OR = 1.01, p = 0.03) were associated with conversion to PDD among those with PD-MCI at baseline, over and above demographic variables. Conversely, the primary predictive factor in the transition from no cognitive impairment to PD-MCI or PDD was male sex (OR = 4.47, p = 0.004), and males progressed more rapidly than females (p = 0.01). Further, among females with shorter disease duration, progression was slower than for their male counterparts, and poor baseline performance on semantic verbal fluency was associated with shorter time to cognitive impairment in females but not in males. This study provides evidence for sex differences in the progression to cognitive impairment in PD, while specific cognitive features become more important indicators of progression with impending conversion to PDD. Copyright © 2018 Elsevier Ltd. All rights reserved.

Transgenic Monkey Model of the Polyglutamine Diseases Recapitulating Progressive Neurological Symptoms

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Ishibashi, Hidetoshi; Minakawa, Eiko N.; Motohashi, Hideyuki H.; Takayama, Osamu; Popiel, H. Akiko; Puentes, Sandra; Owari, Kensuke; Nakatani, Terumi; Nogami, Naotake; Yamamoto, Kazuhiro; Yonekawa, Takahiro; Tanaka, Yoko; Fujita, Naoko; Suzuki, Hikaru; Aizawa, Shu; Nagano, Seiichi; Yamada, Daisuke; Wada, Keiji; Kohsaka, Shinichi

2017-01-01

Abstract Age-associated neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and the polyglutamine (polyQ) diseases, are becoming prevalent as a consequence of elongation of the human lifespan. Although various rodent models have been developed to study and overcome these diseases, they have limitations in their translational research utility owing to differences from humans in brain structure and function and in drug metabolism. Here, we generated a transgenic marmoset model of the polyQ diseases, showing progressive neurological symptoms including motor impairment. Seven transgenic marmosets were produced by lentiviral introduction of the human ataxin 3 gene with 120 CAG repeats encoding an expanded polyQ stretch. Although all offspring showed no neurological symptoms at birth, three marmosets with higher transgene expression developed neurological symptoms of varying degrees at 3–4 months after birth, followed by gradual decreases in body weight gain, spontaneous activity, and grip strength, indicating time-dependent disease progression. Pathological examinations revealed neurodegeneration and intranuclear polyQ protein inclusions accompanied by gliosis, which recapitulate the neuropathological features of polyQ disease patients. Consistent with neuronal loss in the cerebellum, brain MRI analyses in one living symptomatic marmoset detected enlargement of the fourth ventricle, which suggests cerebellar atrophy. Notably, successful germline transgene transmission was confirmed in the second-generation offspring derived from the symptomatic transgenic marmoset gamete. Because the accumulation of abnormal proteins is a shared pathomechanism among various neurodegenerative diseases, we suggest that this new marmoset model will contribute toward elucidating the pathomechanisms of and developing clinically applicable therapies for neurodegenerative diseases. PMID:28374014

Clinical neurorestorative progress in Parkinson's disease

Directory of Open Access Journals (Sweden)

Chen L

2015-06-01

Full Text Available Lin Chen,1,2 Hongyun Huang,3–5 Wei-Ming Duan,6 Gengsheng Mao3 1Department of Neurosurgery, Yuquan Hospital, Tsinghua University, 2Department of Neurosurgery, Medical Center, Tsinghua University, 3Department of Neurosurgery, General Hospital of Chinese People's Armed Police Forces, 4Center of Cell Research, Beijing Rehabilitation Hospital of Capital Medical University, 5Beijing Hongtianji Neuroscience Academy, 6Department of Anatomy, Capital Medical University, Beijing, People's Republic of China Abstract: Parkinson’s disease (PD is one of the common neurodegenerative diseases. Besides the symptomatic therapies, the increasing numbers of neurorestorative therapies have shown the potential therapeutic value of reversing the neurodegenerative process and improving the patient's quality of life. Currrently available novel clinical neurorestorative strategies include pharmacological managements (glial cell-line derived neurotrophic factor, selegiline, recombinant human erythropoietin, neuromodulation intervention (deep brain stimulation, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, tissue and cell transplantation (fetal ventral mesencephalic tissue, sympathetic neurons, carotid body cells, bone marrow stromal cells, retinal pigment epithelium cells, gene therapy, and neurorehabilitative therapy. Herein, we briefly review the progress in this field and describe the neurorestorative mechanisms of the above-mentioned therapies for PD. Keywords: Parkinson’s disease, clinical study, neurorestorative treatment, cell transplantation, neuromodulation

Gaucher disease: Progress and ongoing challenges.

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Mistry, Pramod K; Lopez, Grisel; Schiffmann, Raphael; Barton, Norman W; Weinreb, Neal J; Sidransky, Ellen

Over the past decades, tremendous progress has been made in the field of Gaucher disease, the inherited deficiency of the lysosomal enzyme glucocerebrosidase. Many of the colossal achievements took place during the course of the sixty-year tenure of Dr. Roscoe Brady at the National Institutes of Health. These include the recognition of the enzymatic defect involved, the isolation and characterization of the protein, the localization and characterization of the gene and its nearby pseudogene, as well as the identification of the first mutant alleles in patients. The first treatment for Gaucher disease, enzyme replacement therapy, was conceived of, developed and tested at the Clinical Center of the National Institutes of Health. Advances including recombinant production of the enzyme, the development of mouse models, pioneering gene therapy experiments, high throughput screens of small molecules and the generation of induced pluripotent stem cell models have all helped to catapult research in Gaucher disease into the twenty-first century. The appreciation that mutations in the glucocerebrosidase gene are an important risk factor for parkinsonism further expands the impact of this work. However, major challenges still remain, some of which are described here, that will provide opportunities, excitement and discovery for the next generations of Gaucher investigators. Published by Elsevier Inc.

Slow progression of paediatric HIV disease: Selective adaptation or ...

African Journals Online (AJOL)

In the European Caucasian populations, the chemokine-cell receptor variant CCR5 \\"Delta 32\\" is a the genetic determinant of HIV disease progression that is believed to have been selected for in the general population by exposure to antigens closely interlinked to HIV like Yersinia pestis or small pox virus. Among African ...

The Association of Statin Use with Age-Related Macular Degeneration Progression: The Age-Related Eye Disease Study 2 Report Number 9.

Science.gov (United States)

Al-Holou, Shaza N; Tucker, William R; Agrón, Elvira; Clemons, Traci E; Cukras, Catherine; Ferris, Frederick L; Chew, Emily Y

2015-12-01

To evaluate the association of statin use with progression of age-related macular degeneration (AMD). Preplanned, prospective cohort study within a controlled clinical trial of oral supplementation for age-related eye diseases. Age-Related Eye Disease Study 2 (AREDS2) participants, aged 50 to 85 years. Factors, including age, gender, smoking status, aspirin use, and history of diabetes, hypertension, heart disease, angina, and stroke-all known to be associated with statin use-were included in a logistic regression model to estimate propensity scores for each participant. Age-adjusted proportional hazards regression models, with and without propensity score matching, were performed to evaluate the association of statin use with progression to late AMD. Analyses adjusting for the competing risk of death were also performed. Baseline and annual stereoscopic fundus photographs were assessed centrally by masked graders for the development of late AMD, either neovascular AMD or geographic atrophy (GA). Of the 3791 participants (2462 with bilateral large drusen and 1329 with unilateral late AMD at baseline), 1659 (43.8%) were statin users. The overall analysis, with no matching of propensity scores and no adjustment for death as a competing risk, showed that statin use was not associated with progression to late AMD (hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.83-1.41; P = 0.56). When matched for propensity scores and adjusted for death as a competing risk, the result was not statistically significant (HR, 0.81; 95% CI, 0.55-1.20; P = 0.29). Furthermore, subgroup analyses of persons with or without late AMD at baseline and the various components of late AMD (neovascular AMD, central GA, or any GA) also showed no statistically significant association of statin use with progression to AMD. Statin use was not statistically significantly associated with progression to late AMD in the AREDS2 participants, and these findings are consistent with findings in the

The Association of Statin Use with Age-Related Macular Degeneration Progression The Age-Related Eye Disease Study 2 Report Number 9

Science.gov (United States)

Al-Holou, Shaza N.; Tucker, William R.; Agrón, Elvira; Clemons, Traci E.; Cukras, Catherine; Ferris, Frederick L.; Chew, Emily Y.

2015-01-01

Objective/purpose To evaluate the association of statin use with progression of age-related macular degeneration (AMD). Design Preplanned, prospective cohort study within a controlled clinical trial of oral supplementation for age-related eye diseases. Subjects Age-Related Eye Disease Study 2 participants, aged 50 to 85 years. Methods Factors, including age, gender, smoking status, aspirin use, and history of diabetes, hypertension, heart disease, angina, and stroke, all known to be associated with statin use, were included in a logistic regression model to estimate propensity scores for each participant. Age-adjusted proportional hazards regression models, with and without propensity score matching, were performed to evaluate the association of statin use with progression to late AMD. Analyses were also performed adjusting for the competing risk of death. Main Outcome Measures Baseline and annual stereoscopic fundus photographs were assessed centrally by masked graders for the development of late AMD, either neovascular AMD or geographic atrophy (GA). Results Of the 3791 participants (2462 with bilateral large drusen and 1329 with unilateral late AMD at baseline), 1659 (43.8%) were statin users. The overall analysis, with no matching of propensity scores and no adjustment for death as a competing risk, showed that statin use was not associated with progression to late AMD (hazard ratios [HR] of 1.08, 95% confidence intervals [CI] of 0.83–1.41, P=0.56). When matched for propensity scores and adjusted for death as a competing risk, the result was not statistically significant with HR: 0.81, 95% CI: 0.55–1.20, P=0.29. Further subgroup analyses of persons with or without late AMD at baseline to the various components of late AMD (neovascular, central geographic atrophy, or any geographic atrophy) also showed no statistically significant association of statin use with progression to AMD. Conclusions Statin use was not statistically significantly associated with the

Sequential inflammatory processes define human progression from M. tuberculosis infection to tuberculosis disease.

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Scriba, Thomas J; Penn-Nicholson, Adam; Shankar, Smitha; Hraha, Tom; Thompson, Ethan G; Sterling, David; Nemes, Elisa; Darboe, Fatoumatta; Suliman, Sara; Amon, Lynn M; Mahomed, Hassan; Erasmus, Mzwandile; Whatney, Wendy; Johnson, John L; Boom, W Henry; Hatherill, Mark; Valvo, Joe; De Groote, Mary Ann; Ochsner, Urs A; Aderem, Alan; Hanekom, Willem A; Zak, Daniel E

2017-11-01

Our understanding of mechanisms underlying progression from Mycobacterium tuberculosis infection to pulmonary tuberculosis disease in humans remains limited. To define such mechanisms, we followed M. tuberculosis-infected adolescents longitudinally. Blood samples from forty-four adolescents who ultimately developed tuberculosis disease (“progressors”) were compared with those from 106 matched controls, who remained healthy during two years of follow up. We performed longitudinal whole blood transcriptomic analyses by RNA sequencing and plasma proteome analyses using multiplexed slow off-rate modified DNA aptamers. Tuberculosis progression was associated with sequential modulation of immunological processes. Type I/II interferon signalling and complement cascade were elevated 18 months before tuberculosis disease diagnosis, while changes in myeloid inflammation, lymphoid, monocyte and neutrophil gene modules occurred more proximally to tuberculosis disease. Analysis of gene expression in purified T cells also revealed early suppression of Th17 responses in progressors, relative to M. tuberculosis-infected controls. This was confirmed in an independent adult cohort who received BCG re-vaccination; transcript expression of interferon response genes in blood prior to BCG administration was associated with suppression of IL-17 expression by BCG-specific CD4 T cells 3 weeks post-vaccination. Our findings provide a timeline to the different immunological stages of disease progression which comprise sequential inflammatory dynamics and immune alterations that precede disease manifestations and diagnosis of tuberculosis disease. These findings have important implications for developing diagnostics, vaccination and host-directed therapies for tuberculosis. Clincialtrials.gov, NCT01119521.

Inflammation in Lafora Disease: Evolution with Disease Progression in Laforin and Malin Knock-out Mouse Models.

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López-González, Irene; Viana, Rosa; Sanz, Pascual; Ferrer, Isidre

2017-07-01

Lafora progressive myoclonus epilepsy (Lafora disease, LD) is a fatal rare autosomal recessive neurodegenerative disorder characterized by the accumulation of insoluble ubiquitinated polyglucosan inclusions in the cytoplasm of neurons, which is most commonly associated with mutations in two genes: EPM2A, encoding the glucan phosphatase laforin, and EPM2B, encoding the E3-ubiquitin ligase malin. The present study analyzes possible inflammatory responses in the mouse lines Epm2a -/- (laforin knock-out) and Epm2b -/- (malin knock-out) with disease progression. Increased numbers of reactive astrocytes (expressing the GFAP marker) and microglia (expressing the Iba1 marker) together with increased expression of genes encoding cytokines and mediators of the inflammatory response occur in both mouse lines although with marked genotype differences. C3ar1 and CxCl10 messenger RNAs (mRNAs) are significantly increased in Epm2a -/- mice aged 12 months when compared with age-matched controls, whereas C3ar1, C4b, Ccl4, CxCl10, Il1b, Il6, Tnfα, and Il10ra mRNAs are significantly upregulated in Epm2b -/- at the same age. This is accompanied by increased protein levels of IL1-β, IL6, TNFα, and Cox2 particularly in Epm2b -/- mice. The severity of inflammatory changes correlates with more severe clinical symptoms previously described in Epm2b -/- mice. These findings show for the first time increased innate inflammatory responses in a neurodegenerative disease with polyglucosan intraneuronal deposits which increase with disease progression, in a way similar to what is seen in neurodegenerative diseases with abnormal protein aggregates. These findings also point to the possibility of using anti-inflammatory agents to mitigate the degenerative process in LD.

Gender hormones and the progression of experimental polycystic kidney disease.

Science.gov (United States)

Stringer, Kenneth D; Komers, Radko; Osman, Shukri A; Oyama, Terry T; Lindsley, Jessie N; Anderson, Sharon

2005-10-01

Male gender is a risk factor for progression of autosomal-dominant polycystic kidney disease (ADPKD), clinically and in the Han:SPRD rat model. Orchiectomy limits progression, but mechanisms of the detrimental effect of androgen, and/or beneficial effects of estrogen, are not known. This protocol tested the hypothesis that male gender (intact androgen status) promotes progression, while female gender (intact estrogen status) is protective; and that these disease-modifying effects are due to changes in expression of known fibrotic mediators. Studies were performed in male and female noncystic control (+/+) and cystic (+/-) rats subjected to orchiectomy, ovariectomy, or sham operation. At 12 weeks of age, renal function was measured. Blood and kidneys were taken for measurement of plasma and renal renin, endothelin (ET-1), endothelial nitric oxide synthase (eNOS), and vascular endothelial growth factor (VEGF), using biochemical, protein expression, and immunohistochemical methods. Cystic male rats exhibited significantly reduced glomerular filtration (GFR) and effective renal plasma flow (ERPF) rates, with suppression of plasma and renal renin, up-regulation of renal ET-1 and eNOS, and down-regulation of renal VEGF expression. Orchiectomy attenuated the fall in GFR and ERPF, while numerically limiting changes in eNOS and VEGF. Female rats exhibited less cystic growth, with normal renin status, lesser elevation of renal ET-1, and proportionately lesser changes in VEGF and eNOS. Ovariectomy led to higher blood pressure and reduced GFR and ERPF, with a trend toward upregulation of ET-1, and significant down-regulation of VEGF and eNOS. Female gender is protective, but ovariectomy attenuates the protective effect of female gender, in association with changes in renal expression of ET-1, VEGF, and eNOS. The accelerated disease in male rats can be attenuated by orchiectomy and consequent changes in expression of disease mediators.

Role of rasagiline in treating Parkinson’s disease: Effect on disease progression

Science.gov (United States)

Malaty, Irene A; Fernandez, Hubert H

2009-01-01

Rasagiline is a second generation, selective, irreversible monoamine oxidase type B (MAO-B) inhibitor. It has demonstrated efficacy in monotherapy for early Parkinson’s disease (PD) patients in one large randomized, placebo-controlled trial (TVP-1012 in Early Monotherapy for Parkinson’s Disease Outpatients), and has shown ability to reduce off time in more advanced PD patients with motor fluctuations in two large placebo-controlled trials (Parkinson’s Rasagiline: Efficacy and Safety in the Treatment of “Off”, and Lasting Effect in Adjunct Therapy With Rasagiline Given Once Daily). Preclinical data abound to suggest potential for neuroprotection by this compound against a variety of neurotoxic insults in cell cultures and in animals. The lack of amphetamine metabolites provides an advantage over the first generation MAO-B inhibitor selegiline. One large trial has investigated the potential for disease modification in PD patients (Attenuation of Disease progression with Azilect Given Once-daily) and preliminary results maintain some possible advantage to earlier initiation of the 1 mg/day dose. The clinical significance of the difference detected remains a consideration. PMID:19753135

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

Science.gov (United States)

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

2014-01-01

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

The effect of cigarette smoking, tea, and coffee consumption on the progression of Parkinson's disease.

Science.gov (United States)

Kandinov, Boris; Giladi, Nir; Korczyn, Amos D

2007-05-01

Previous epidemiological studies found a negative association between cigarette smoking, tea or coffee drinking with the occurrence of Parkinson's disease (PD). However, it is unknown how these factors affect the rate of progression of the disease. A retrospective study was conducted among 278 consecutive PD patients. Data on smoking and coffee or tea consumption were obtained through direct or proxy interviews, and the time from onset of motor symptoms until reaching Hoehn & Yahr (H&Y) stage 3 was retrieved from the case records. Cox proportional hazards model and Kaplan-Meyer model were used to estimate whether the dependent variables (smoking, drinking coffee or tea) affect the rate of progression of the disease, which was measured by the time it took patients to reach H&Y stage 3. We found that disease progression was not affected by cigarette smoking, tea or coffee consumption. The present study suggests that these variables do not have a disease modifying effect in already diagnosed PD patients.

Effects of Lowering LDL Cholesterol on Progression of Kidney Disease

DEFF Research Database (Denmark)

Haynes, Richard; Lewis, David; Emberson, Jonathan

2014-01-01

Lowering LDL cholesterol reduces the risk of developing atherosclerotic events in CKD, but the effects of such treatment on progression of kidney disease remain uncertain. Here, 6245 participants with CKD (not on dialysis) were randomly assigned to simvastatin (20 mg) plus ezetimibe (10 mg) daily...... or matching placebo. The main prespecified renal outcome was ESRD (defined as the initiation of maintenance dialysis or kidney transplantation). During 4.8 years of follow-up, allocation to simvastatin plus ezetimibe resulted in an average LDL cholesterol difference (SEM) of 0.96 (0.02) mmol/L compared...... with placebo; 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....

High resolution molecular and histological analysis of renal disease progression in ZSF1 fa/faCP rats, a model of type 2 diabetic nephropathy.

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Dower, Ken; Zhao, Shanrong; Schlerman, Franklin J; Savary, Leigh; Campanholle, Gabriela; Johnson, Bryce G; Xi, Li; Nguyen, Vuong; Zhan, Yutian; Lech, Matthew P; Wang, Ju; Nie, Qing; Karsdal, Morten A; Genovese, Federica; Boucher, Germaine; Brown, Thomas P; Zhang, Baohong; Homer, Bruce L; Martinez, Robert V

2017-01-01

ZSF1 rats exhibit spontaneous nephropathy secondary to obesity, hypertension, and diabetes, and have gained interest as a model system with potentially high translational value to progressive human disease. To thoroughly characterize this model, and to better understand how closely it recapitulates human disease, we performed a high resolution longitudinal analysis of renal disease progression in ZSF1 rats spanning from early disease to end stage renal disease. Analyses included metabolic endpoints, renal histology and ultrastructure, evaluation of a urinary biomarker of fibrosis, and transcriptome analysis of glomerular-enriched tissue over the course of disease. Our findings support the translational value of the ZSF1 rat model, and are provided here to assist researchers in the determination of the model's suitability for testing a particular mechanism of interest, the design of therapeutic intervention studies, and the identification of new targets and biomarkers for type 2 diabetic nephropathy.

Caffeine, creatine, GRIN2A and Parkinson's disease progression.

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Simon, David K; Wu, Cai; Tilley, Barbara C; Lohmann, Katja; Klein, Christine; Payami, Haydeh; Wills, Anne-Marie; Aminoff, Michael J; Bainbridge, Jacquelyn; Dewey, Richard; Hauser, Robert A; Schaake, Susen; Schneider, Jay S; Sharma, Saloni; Singer, Carlos; Tanner, Caroline M; Truong, Daniel; Wei, Peng; Wong, Pei Shieen; Yang, Tianzhong

2017-04-15

Caffeine is neuroprotective in animal models of Parkinson's disease (PD) and caffeine intake is inversely associated with the risk of PD. This association may be influenced by the genotype of GRIN2A, which encodes an NMDA-glutamate-receptor subunit. In two placebo-controlled studies, we detected no association of caffeine intake with the rate of clinical progression of PD, except among subjects taking creatine, for whom higher caffeine intake was associated with more rapid progression. We now have analyzed data from 420 subjects for whom DNA samples and caffeine intake data were available from a placebo-controlled study of creatine in PD. The GRIN2A genotype was not associated with the rate of clinical progression of PD in the placebo group. However, there was a 4-way interaction between GRIN2A genotype, caffeine, creatine and the time since baseline. Among subjects in the creatine group with high levels of caffeine intake, but not among those with low caffeine intake, the GRIN2A T allele was associated with more rapid progression (p=0.03). These data indicate that the deleterious interaction between caffeine and creatine with respect to rate of progression of PD is influenced by GRIN2A genotype. This example of a genetic factor interacting with environmental factors illustrates the complexity of gene-environment interactions in the progression of PD. Copyright © 2017 Elsevier B.V. All rights reserved.

The role of acquired immunity and periodontal disease progression.

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Teng, Yen-Tung A

2003-01-01

Our understanding of the pathogenesis in human periodontal diseases is limited by the lack of specific and sensitive tools or models to study the complex microbial challenges and their interactions with the host's immune system. Recent advances in cellular and molecular biology research have demonstrated the importance of the acquired immune system not only in fighting the virulent periodontal pathogens but also in protecting the host from developing further devastating conditions in periodontal infections. The use of genetic knockout and immunodeficient mouse strains has shown that the acquired immune response-in particular, CD4+ T-cells-plays a pivotal role in controlling the ongoing infection, the immune/inflammatory responses, and the subsequent host's tissue destruction. In particular, studies of the pathogen-specific CD4+ T-cell-mediated immunity have clarified the roles of: (i) the relative diverse immune repertoire involved in periodontal pathogenesis, (ii) the contribution of pathogen-associated Th1-Th2 cytokine expressions in periodontal disease progression, and (iii) micro-organism-triggered periodontal CD4+ T-cell-mediated osteoclastogenic factor, 'RANK-L', which is linked to the induction of alveolar bone destruction in situ. The present review will focus on some recent advances in the acquired immune responses involving B-cells, CD8+ T-cells, and CD4+ T-cells in the context of periodontal disease progression. New approaches will further facilitate our understanding of their underlying molecular mechanisms that may lead to the development of new treatment modalities for periodontal diseases and their associated complications.

Impact of HIV Type 1 DNA Levels on Spontaneous Disease Progression: A Meta-Analysis

DEFF Research Database (Denmark)

Tsiara, Chrissa G; Nikolopoulos, Georgios K; Bagos, Pantelis G

2012-01-01

Abstract Several studies have reported the prognostic strength of HIV-1 DNA with variable results however. The aims of the current study were to estimate more accurately the ability of HIV-1 DNA to predict progression of HIV-1 disease toward acquired immunodeficiency syndrome (AIDS) or death...... of primary studies indicated that HIV-1 DNA was a significantly better predictor than HIV-1 RNA of either AIDS alone (ratio of RRs=1.47, 95% CI: 1.05-2.07) or of combined (AIDS or death) progression outcomes (ratio of RRs=1.51, 95% CI: 1.11-2.05). HIV-1 DNA is a strong predictor of HIV-1 disease progression...

Qualitative and quantitative analysis of diffusion-weighted imaging of gestational trophoblastic disease: Can it predict progression of molar pregnancy to persistent form of disease?

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Sefidbakht, Sepideh [Medical imaging research center, Department of Radiology and Imaging, Shiraz University of Medical Sciences, Shiraz (Iran, Islamic Republic of); Hosseini, Fatemeh, E-mail: f.hoseini88@gmail.com [Medical imaging research center, Department of Radiology and Imaging, Shiraz University of Medical Sciences, Shiraz (Iran, Islamic Republic of); Bijan, Bijan [Abdominal Imaging/MR and Nonvascular Interventional Division, University of California, Davis, CA (United States); Hamedi, Bahareh; Azizi, Tayyebeh [Obstetrics& Gynecology Department, Medical School, Shiraz University of Medical Sciences, Shiraz (Iran, Islamic Republic of)

2017-03-15

Highlights: • The incidence of GTD in Iran is significantly higher than America and Europe. • ADC value of GTD is (1.96 ± 0.32 × 10{sup −3} mm{sup 2}/s). • GTD in T1 and T2-weighted images shows heterogeneous “snow-storm” appearance. • Focal intratumoral hemorrhage is bright in DWI and low signal in the ADC map. • ADC value and DWI are not helpful to predict progression of HM to persistent disease. - Abstract: Purpose: To describe the diffusion-weighted imaging (DWI) appearance of gestational trophoblastic disease (GTD) and to determine its apparent diffusion coefficient (ADC) values. To evaluate the feasibility of DWI to predict progression of hydatidiform mole (HM) to persistent disease. Methods: During a period of 6 months, women with preliminary diagnosis of GTD, based on ultrasound and ßhCG levels, underwent 1.5T MRI (T2 high-resolution and DWI; b values 50, 400, 800; sagittal and perpendicular to the endometrium; and T1, T2 Turbo Spin Echo [TSE] axial images). Patients were followed for 6–12 months to monitor progression to persistent form of the disease. ADC values and image characteristics were compared between HM and persistent neoplasia and between GTD and non-molar pregnancy using Mann–Whitney U and Fisher’s exact tests, respectively. Results: Among the 23 studied patients, 19 (83%) were classified as molar and 4 (17%) as non-molar, based on pathology reports. After 6–12 months of follow-up, 5 (26%) cases progressed to persistent disease and 14 (74%) cases were benign HM. There was no significant difference between ADC values for HM (1.93 ± 0.33 × 10{sup −3} mm{sup 2}/s) and persistent neoplasia (2.03 ± 0.28 × 10{sup −3} mm{sup 2}/s) (P = 0.69). The ADC of non-molar pregnancies was (0.96 ± 0.46 × 10{sup −3} mm{sup 2}/s), which was significantly different from GTD (1.96 ± 0.32 × 10{sup −3} mm{sup 2}/s) (P = 0.001). Heterogeneous snowstorm appearance, focal intratumoral hemorrhage, myometrial contraction, and

Evaluation of Probabilistic Disease Forecasts.

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Hughes, Gareth; Burnett, Fiona J

2017-10-01

The statistical evaluation of probabilistic disease forecasts often involves calculation of metrics defined conditionally on disease status, such as sensitivity and specificity. However, for the purpose of disease management decision making, metrics defined conditionally on the result of the forecast-predictive values-are also important, although less frequently reported. In this context, the application of scoring rules in the evaluation of probabilistic disease forecasts is discussed. An index of separation with application in the evaluation of probabilistic disease forecasts, described in the clinical literature, is also considered and its relation to scoring rules illustrated. Scoring rules provide a principled basis for the evaluation of probabilistic forecasts used in plant disease management. In particular, the decomposition of scoring rules into interpretable components is an advantageous feature of their application in the evaluation of disease forecasts.

[Progressive pulmonary hypertension in a patient with type 1 Gaucher disease].

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Ponomarev, R V; Model, S V; Averbukh, O M; Gavrilov, A M; Galstyan, G M; Lukina, E A

Gaucher disease is the most common form of hereditary enzymopathies combined into a group of lysosomal storage diseases. The basis for the disease is a hereditary deficiency of the activity of acid β-glucosidase, a lysosomal enzyme involved in the catabolism of lipids, which results in the accumulation of nonutilized cellular metabolism products in the macrophage lysosomes. The main clinical manifestations of type 1 Gaucher disease are cytopenia, hepatomegaly, and splenomegaly, and bone lesion. One of the atypical clinical manifestations of Gaucher disease is damage to the lungs with the development of pulmonary hypertension, which is usually considered within the underlying disease - the development of pneumosclerosis due to macrophage dysfunction. The paper describes a case of progressive pulmonary hypertension in a patient with type 1 Gaucher disease.

Unveiling clusters of RNA transcript pairs associated with markers of Alzheimer's disease progression.

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Ahmed Shamsul Arefin

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

Evaluation of induced mutants of wheat for resistance to fungal diseases

International Nuclear Information System (INIS)

Barriga B, P.; Fuentes P, R.; Andrade S, N.; Seeman F, P.

1990-01-01

Evaluation of induced mutants of wheat for resistance to fungal diseases. Seeds of spring wheat cultivars Austral and Huenufen were exposed to gamma radiation in doses of 0.10 and 0.25 KGy with the objective of producing genotypes resistant to the main fungal diseases, with a high protein content and grain yield, for the southern region of Chile (39 sup(o)-44 sup(o) Latitude south). The selection process and evaluation up to the generation M sub(8) has made possible to identify mutants with a higher protein content and grain yield. Progress made in improving resistance to Puccinia striiformis and tolerance to Septoria spp., has also been important. Some selected mutants, conditioned to their future performance, could be directly used as commercial varieties and other mutants, on crosses with regionally adapted cultivars. (author)

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

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Felix Chinweije Nwosu

2014-01-01

Full Text Available 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.

Early energy deficit in Huntington disease: identification of a plasma biomarker traceable during disease progression.

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Fanny Mochel

Full Text Available Huntington disease (HD is a fatal neurodegenerative disorder, with no effective treatment. The pathogenic mechanisms underlying HD has not been elucidated, but weight loss, associated with chorea and cognitive decline, is a characteristic feature of the disease that is accessible to investigation. We, therefore, performed a multiparametric study exploring body weight and the mechanisms of its loss in 32 presymptomatic carriers and HD patients in the early stages of the disease, compared to 21 controls. We combined this study with a multivariate statistical analysis of plasma components quantified by proton nuclear magnetic resonance ((1H NMR spectroscopy. We report evidence of an early hypermetabolic state in HD. Weight loss was observed in the HD group even in presymptomatic carriers, although their caloric intake was higher than that of controls. Inflammatory processes and primary hormonal dysfunction were excluded. (1H NMR spectroscopy on plasma did, however, distinguish HD patients at different stages of the disease and presymptomatic carriers from controls. This distinction was attributable to low levels of the branched chain amino acids (BCAA, valine, leucine and isoleucine. BCAA levels were correlated with weight loss and, importantly, with disease progression and abnormal triplet repeat expansion size in the HD1 gene. Levels of IGF1, which is regulated by BCAA, were also significantly lower in the HD group. Therefore, early weight loss in HD is associated with a systemic metabolic defect, and BCAA levels may be used as a biomarker, indicative of disease onset and early progression. The decreased plasma levels of BCAA may correspond to a critical need for Krebs cycle energy substrates in the brain that increased metabolism in the periphery is trying to provide.

Prognostic indicators of renal disease progression in adults with Fabry disease: natural history data from the Fabry Registry

NARCIS (Netherlands)

Wanner, Christoph; Oliveira, João P.; Ortiz, Alberto; Mauer, Michael; Germain, Dominique P.; Linthorst, Gabor E.; Serra, Andreas L.; Maródi, László; Mignani, Renzo; Cianciaruso, Bruno; Vujkovac, Bojan; Lemay, Roberta; Beitner-Johnson, Dana; Waldek, Stephen; Warnock, David G.

2010-01-01

These analyses were designed to characterize renal disease progression in untreated adults with Fabry disease. Data from the Fabry Registry for 462 untreated adults (121 men and 341 women) who had at least two estimated GFR (eGFR) values over a span of ≥12 months before starting enzyme replacement

Role of rasagiline in treating Parkinson’s disease: effect on disease progression

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Irene A Malaty

2009-05-01

Full Text Available Irene A Malaty, Hubert H FernandezUniversity of Florida Movement Disorders Center, Gainesville, FL, USAAbstract: Rasagiline is a second generation, selective, irreversible monoamine oxidase type B (MAO-B inhibitor. It has demonstrated efficacy in monotherapy for early Parkinson’s disease (PD patients in one large randomized, placebo-controlled trial (TVP-1012 in Early Monotherapy for Parkinson’s Disease Outpatients, and has shown ability to reduce off time in more advanced PD patients with motor fluctuations in two large placebo-controlled trials (Parkinson’s Rasagiline: Efficacy and Safety in the Treatment of “Off”, and Lasting Effect in Adjunct Therapy With Rasagiline Given Once Daily. Preclinical data abound to suggest potential for neuroprotection by this compound against a variety of neurotoxic insults in cell cultures and in animals. The lack of amphetamine metabolites provides an advantage over the first generation MAO-B inhibitor selegiline. One large trial has investigated the potential for disease modification in PD patients (Attenuation of Disease progression with Azilect Given Once-daily and preliminary results maintain some possible advantage to earlier initiation of the 1 mg/day dose. The clinical significance of the difference detected remains a consideration.Keywords: rasagiline, Parkinson’s disease, neuroprotection, selegiline

Cysteine 138 mutation in HIV-1 Nef from patients with delayed disease progression

DEFF Research Database (Denmark)

Tolstrup, Martin; Laursen, Alex Lund; Gerstoft, J.

2006-01-01

on the delayed disease status. However, the results demonstrate a high incidence of a single amino acid polymorphism (cysteine 138) in HIV-1 Nef. The allelic frequency of cysteine 138 between the delayed disease progression group and the progressor group was found to be statistically significant (P = 0.......0139). The phylogeny of isolates was investigated and the variants harbouring the cysteine 138 mutation clustered independently. CONCLUSION: The present study describes a viral genetic polymorphism related to AIDS disease progression. The polymorphism (cysteine 138) has previously been reported to confer decreased...... viral replication (Premkumar DR, et al. AIDS Res Hum Retroviruses 1996; 12(4): 337-45). A sequence database search for comparative mutations revealed a high frequency of cysteine 138 in patients with reported SP AIDS...

Usefulness of the computed tomography and magnetic resonance in evaluation of progress of treatment of the neoplasmatic diseases in children

International Nuclear Information System (INIS)

Myga-Porosiło, Jolanta; Borowiak, Hanna; Sraga, Wojciech; Jackowska, Zuzanna; Serafin, Magdalena; Kluczewska, Ewa

2012-01-01

Neoplastmatic diseases constitute about 1% diseases in children in Poland, what makes about 1200 new incidents during one year. Fast diagnosis in those illnesses is crucial in treatment results. The point of this work was to value usefulness of CT and MRI in diagnostics of neoplasmatic diseases in children. The retrospective study involved 121 children examined in CT and MRI because of suspicion or during treatment of neoplasmatic disease. Together 184 CT and 119 MRI examination were performed. Eventually in 106 children neoplasmatic disease was diagnosed. In 16 cases neoplasm was excluded. In the analyzed group of patients acute lymphoblastic and non lymphoblastic leukemia was diagnosed in 68 children (55.7%); among them mycosis was identified after radiological examinations in 7 cases (10.3%). 8 children (6.6%) with non Hodgkin lymphoma and 11 (9%) with Hodgkin lymphoma were examined. Nephroblastoma was found after MRI and CT in 6 cases (4.9%). Presence of tumors, that were classified histopatologically as PNET, was confirmed in 4 children. In 15 cases after MRI and CT neoplasmatic disease was excluded. Depending on the kind of sickness MRI and CT may fulfill basic or subsidiary role in diagnostic and estimating the progress of treatment in neoplasmatic diseases among children

Pregnancy and HIV disease progression: a systematic review and meta-analysis.

Science.gov (United States)

Calvert, Clara; Ronsmans, Carine

2015-02-01

To assess whether pregnancy accelerates HIV disease progression. Studies comparing progression to HIV-related illness, low CD4 count, AIDS-defining illness, HIV-related death, or any death in HIV-infected pregnant and non-pregnant women were included. Relative risks (RR) for each outcome were combined using random effects meta-analysis and were stratified by antiretroviral therapy (ART) availability. 15 studies met the inclusion criteria. Pregnancy was not associated with progression to HIV-related illness [summary RR: 1.32, 95% confidence interval (CI): 0.66-2.61], AIDS-defining illness (summary RR: 0.97, 95% CI: 0.74-1.25) or mortality (summary RR: 0.97, 95% CI: 0.62-1.53), but there was an association with low CD4 counts (summary RR: 1.41, 95% CI: 0.99-2.02) and HIV-related death (summary RR: 1.65, 95% CI: 1.06-2.57). In settings where ART was available, there was no evidence that pregnancy accelerated progress to HIV/AIDS-defining illnesses, death and drop in CD4 count. In settings without ART availability, effect estimates were consistent with pregnancy increasing the risk of progression to HIV/AIDS-defining illnesses and HIV-related or all-cause mortality, but there were too few studies to draw meaningful conclusions. In the absence of ART, pregnancy is associated with small but appreciable increases in the risk of several negative HIV outcomes, but the evidence is too weak to draw firm conclusions. When ART is available, the effects of pregnancy on HIV disease progression are attenuated and there is little reason to discourage healthy HIV-infected women who desire to become pregnant from doing so. © 2014 John Wiley & Sons Ltd.

Scanning laser Doppler imaging may predict disease progression of localized scleroderma in children and young adults.

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Shaw, L J; Shipley, J; Newell, E L; Harris, N; Clinch, J G; Lovell, C R

2013-07-01

Localized scleroderma is a rare but potentially disfiguring and disabling condition. Systemic treatment should be started early in those with active disease in key functional and cosmetic sites, but disease activity is difficult to determine clinically. Superficial blood flow has been shown to correlate with disease activity in localized scleroderma. To examine whether superficial blood flow measured by laser Doppler imaging (LDI) has the potential to predict disease progression and therefore select patients for early systemic treatment. A group of 20 individuals had clinical assessment and scanning LDI blood-flow measurements of 32 affected body sites. After a mean follow-up of 8.7 months their clinical outcome was compared with the results of the initial LDI assessment. Eleven out of 15 patients with an assessment of active LDI had progressed clinically, and 16 out of the 17 scans with inactive LDI assessment had not progressed, giving a positive predictive value of 73% and a negative predictive value of 94%. We believe that LDI can be a useful tool in predicting disease progression in localized scleroderma, and it may help clinicians to decide which patients to treat early. © 2013 The Authors BJD © 2013 British Association of Dermatologists.

Anthesis, the infectious process and disease progress curves for fusarium head blight in wheat

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Erlei Melo Reis

2016-06-01

Full Text Available ABSTRACT Fusarium head blight of wheat (Triticum aestivum, caused by the fungus Gibberella zeae, is a floral infecting disease that causes quantitative and qualitative losses to winter cereals. In Brazil, the sanitary situation of wheat has led to research in order to develop strategies for sustainable production, even under adverse weather conditions. To increase the knowledge of the relationship among the presence of anthesis, the infectious process, the disease progress and the saprophytic fungi present in wheat anthers, studies were conducted in the experimental field of University of Passo Fundo (UPF, using the cultivar Marfim, in the 2011 growing season. The disease incidence in spikes and spikelets was evaluated. The presence of exserted anthers increased the spike exposure time to the inoculum. The final incidence of fusarium head blight, in the field, was dependent on the presence of exserted anthers. The disease followed an aggregation pattern and its evolution increased with time, apparently showing growth according to secondary cycles. The fungi isolated from exserted anthers (Alternaria sp., Fusarium sp., Drechslera spp. and Epicoccum sp. did not compete for the infection site of fusarium head blight in wheat, not interfering with the incidence of F. graminearum.

Personalized biomarkers to monitor disease progression in advanced non-small-cell lung cancer patients treated with icotinib.

Science.gov (United States)

Song, Gaoguang; Liu, Yujie; Wang, Yanying; Ren, Guanjun; Guo, Shuai; Ren, Junling; Zhang, Li; Li, Zhili

2015-02-02

Disease-specific humoral immune response-related protein complexes in blood are associated with disease progression. Thirty-one patients with stage IIIB and IV non-small-cell lung cancer (NSCLC) were administered with oral dose of icotinib hydrochloride (150 mg twice daily or 125 mg 3 times daily) for a 28-continuous-day cycle until diseases progressed or unacceptable toxicity occurred. The levels of immunoinflammation-related protein complexes (IIRPCs) in a series of plasma samples from 31 NSCLC patients treated with icotinib hydrochloride were determined by an optimized native polyacrylamide gel electrophoresis. Three characteristic patterns of the IIRPCs, named as patterns a, b, and c, respectively, were detected in plasma samples from 31 patients. Prior to the treatment, there were 18 patients in pattern a consisting of 5 IIRPCs, 9 in pattern b consisting of six IIRPCs, and 4 in pattern c without the IIRPCs. The levels of the IIRPCs in 27 patients were quantified. Our results indicate that the time length of humoral immune and inflammation response (TLHIIR) was closely associated with disease progression, and the median TLHIIR was 22.0 weeks, 95% confidence interval: 16.2 to 33.0 weeks, with a lead time of median 11 weeks relative to clinical imaging evidence confirmed by computed tomography or magnetic resonance imaging (the median progression-free survival, 34.0 weeks, 95% confidence interval: 27.9 to 49.0 weeks). The complex relationships between humoral immune response, acquired resistance, and disease progression existed. Personalized IIRPCs could be indicators to monitor the disease progression. Copyright © 2014 Elsevier B.V. All rights reserved.

Factors associated with coronary artery disease progression assessed by serial coronary computed tomography angiography

International Nuclear Information System (INIS)

Camargo, Gabriel Cordeiro; Gottlieb, Ilan; Rothstein, Tamara; Derenne, Maria Eduarda; Sabioni, Leticia; Lima, Ronaldo de Souza Leão; Lima, João A. C.

2017-01-01

Background: Coronary computed tomography angiography (CCTA) allows for noninvasive coronary artery disease (CAD) phenotyping. Factors related to CAD progression are epidemiologically valuable. Objective: To identify factors associated with CAD progression in patients undergoing sequential CCTA testing. Methods: We retrospectively analyzed 384 consecutive patients who had at least two CCTA studies between December 2005 and March 2013. Due to limitations in the quantification of CAD progression, we excluded patients who had undergone surgical revascularization previously or percutaneous coronary intervention (PCI) between studies. CAD progression was defined as any increase in the adapted segment stenosis score (calculated using the number of diseased segments and stenosis severity) in all coronary segments without stent (in-stent restenosis was excluded from the analysis). Stepwise logistic regression was used to assess variables associated with CAD progression. Results: From a final population of 234 patients, a total of 117 (50%) had CAD progression. In a model accounting for major CAD risk factors and other baseline characteristics, only age (odds ratio [OR] 1.04, 95% confidence interval [95%CI] 1.01–1.07), interstudy interval (OR 1.03, 95%CI 1.01–1.04), and past PCI (OR 3.66, 95%CI 1.77–7.55) showed an independent relationship with CAD progression. Conclusions: A history of PCI with stent placement was independently associated with a 3.7-fold increase in the odds of CAD progression, excluding in-stent restenosis. Age and interstudy interval were also independent predictors of progression. (author)

Factors associated with coronary artery disease progression assessed by serial coronary computed tomography angiography

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Camargo, Gabriel Cordeiro; Gottlieb, Ilan, E-mail: ilangottlieb@gmail.com [Casa de Saúde São José, Rio de Janeiro, RJ (Brazil); Rothstein, Tamara; Derenne, Maria Eduarda; Sabioni, Leticia; Lima, Ronaldo de Souza Leão [Centro de Diagnóstico por Imagem CDPI, Rio de Janeiro, RJ (Brazil); Lima, João A. C. [Johns Hopkins University, Baltimore (United States)

2017-05-15

Background: Coronary computed tomography angiography (CCTA) allows for noninvasive coronary artery disease (CAD) phenotyping. Factors related to CAD progression are epidemiologically valuable. Objective: To identify factors associated with CAD progression in patients undergoing sequential CCTA testing. Methods: We retrospectively analyzed 384 consecutive patients who had at least two CCTA studies between December 2005 and March 2013. Due to limitations in the quantification of CAD progression, we excluded patients who had undergone surgical revascularization previously or percutaneous coronary intervention (PCI) between studies. CAD progression was defined as any increase in the adapted segment stenosis score (calculated using the number of diseased segments and stenosis severity) in all coronary segments without stent (in-stent restenosis was excluded from the analysis). Stepwise logistic regression was used to assess variables associated with CAD progression. Results: From a final population of 234 patients, a total of 117 (50%) had CAD progression. In a model accounting for major CAD risk factors and other baseline characteristics, only age (odds ratio [OR] 1.04, 95% confidence interval [95%CI] 1.01–1.07), interstudy interval (OR 1.03, 95%CI 1.01–1.04), and past PCI (OR 3.66, 95%CI 1.77–7.55) showed an independent relationship with CAD progression. Conclusions: A history of PCI with stent placement was independently associated with a 3.7-fold increase in the odds of CAD progression, excluding in-stent restenosis. Age and interstudy interval were also independent predictors of progression. (author)

Parkinsonian syndroms: Clinical phenotype, differential diagnosis and disease progression

International Nuclear Information System (INIS)

Storch, A.

2002-01-01

Parkinsonian syndromes include idiopathic Parkinson's disease (IPD), other neurodegenerative diseases with parkinsonism, the so-called atypical parkinsonian syndromes, and symptomatic parkinsonian syndromes, such as Wilson's disease. IPD is the most frequent disease with parkinsonism as the main clinical feature and is responsible for approx. 80% of all parkinsonian syndromes. Atypical parkinsonian syndromes are the most important differential diagnoses of IPD. The two most frequent types are multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). For clinical diagnosis it is essential to take a careful medical history and to examine the patients physically in regular intervals. However, various clinico-pathological studies have shown that approx. 25% of patients with clinical diagnosis of IPD may have other causes of parkinsonism. Selected technical investigations, in particular functional imaging of the central dopaminergic system using PET or SPECT, may help to make clinical diagnosis more secure. This paper reviews the clinical features and diagnostic findings in diseases with parkinsonism and summarises the difficulties in establishing early and differential diagnoses. (orig.) [de

Inhibition of 5-Lipoxygenase inhibitor zileuton in high-fat diet-induced nonalcoholic fatty liver disease progression model

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Kuifen Ma

2017-11-01

Full Text Available Objective(s: Arachidonic Acid/5-lipoxygenase (AA/5-LOX pathway connects lipid metabolism and proinflammatory cytokine, which are both related to the development and progression of nonalcoholic fatty liver disease (NAFLD. Therefore, the present study was designed to investigate the role of AA/5-LOX pathway in progression of NAFLD, and the effect of zileuton, an inhibitor of 5-LOX, in this model. Materials and Methods: Animal model for progression of NAFLD was established via feeding high saturated fat diet (HFD. Liver function, HE staining, NAFLD activity score (NAS were used to evaluate NAFLD progression. We detected the lipid metabolism substrates: free fatty acids (FFA and AA, products: cysteinyl-leukotrienes (CysLTs, and changes in gene and protein level of key enzyme in AA/5-LOX pathway including PLA2 and 5-LOX. Furthermore, we determined whether NAFLD progression pathway was delayed or reversed when zileuton (1-[1-(1-benzothiophen-2-ylethyl]-1-hydroxyurea was administrated. Results: Rat model for progression of NAFLD was well established as analyzed by liver transaminase activities, hematoxylin-eosin (HE staining and NAS. The concentrations of substrates and products in AA/5-LOX pathway were increased with the progression of NAFLD. mRNA and protein expression of PLA2 and 5-LOX were all enhanced. Moreover, administration of zileuton inhibited AA/5-LOX pathway and reversed the increased transamine activities and NAS. Conclusion: AA/5-LOX pathway promotes the progression of NAFLD, which can be reversed by zileuton.

Discordant Impact of HLA on Viral Replicative Capacity and Disease Progression in Pediatric and Adult HIV Infection.

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Emily Adland

2015-06-01

Full Text Available HLA class I polymorphism has a major influence on adult HIV disease progression. An important mechanism mediating this effect is the impact on viral replicative capacity (VRC of the escape mutations selected in response to HLA-restricted CD8+ T-cell responses. Factors that contribute to slow progression in pediatric HIV infection are less well understood. We here investigate the relationship between VRC and disease progression in pediatric infection, and the effect of HLA on VRC and on disease outcome in adult and pediatric infection. Studying a South African cohort of >350 ART-naïve, HIV-infected children and their mothers, we first observed that pediatric disease progression is significantly correlated with VRC. As expected, VRCs in mother-child pairs were strongly correlated (p = 0.004. The impact of the protective HLA alleles, HLA-B*57, HLA-B*58:01 and HLA-B*81:01, resulted in significantly lower VRCs in adults (p<0.0001, but not in children. Similarly, in adults, but not in children, VRCs were significantly higher in subjects expressing the disease-susceptible alleles HLA-B*18:01/45:01/58:02 (p = 0.007. Irrespective of the subject, VRCs were strongly correlated with the number of Gag CD8+ T-cell escape mutants driven by HLA-B*57/58:01/81:01 present in each virus (p = 0.0002. In contrast to the impact of VRC common to progression in adults and children, the HLA effects on disease outcome, that are substantial in adults, are small and statistically insignificant in infected children. These data further highlight the important role that VRC plays both in adult and pediatric progression, and demonstrate that HLA-independent factors, yet to be fully defined, are predominantly responsible for pediatric non-progression.

Evaluation of Quality of Life at Progression in Patients with Soft Tissue Sarcoma

Directory of Open Access Journals (Sweden)

Stacie Hudgens

2017-01-01

Full Text Available Introduction. Soft Tissue Sarcoma (STS is a rare malignancy of mesodermal tissue, with international incidence estimates between 1.8 and 5 per 100,000 per year. Understanding quality of life (QoL and the detrimental impact of disease progression is critical for long-term care and survival. Objectives. The primary objective was to explore the relationship between disease progression and health-related quality of life (HRQoL using data from Eisai’s study (E7389-G000-309. Methods. This was a 1 : 1 randomized, open-label, multicenter, Phase 3 study comparing the efficacy and safety of eribulin versus dacarbazine in patients with advanced STS. The QoL analysis was conducted for the baseline and progression populations using the European Organization for Research and Treatment of Cancer 30-item core QoL questionnaire (EORTC QLQ-C30. Results. There were no statistical differences between the two treatment arms at baseline for any domain (p>0.05; n=452. Of the 399 patients who experienced disease progression (unadjusted and adjusting for histology, dacarbazine patients had significantly lower Global Health Status, Physical Functioning scores, and significantly worse Nausea and Vomiting, Insomnia, and Appetite Loss (p<0.05. Conclusions. These results indicate differences in HRQoL overall and at progression between dacarbazine and eribulin patients, with increases in symptom severity observed among dacarbazine patients.

Role of Diet and Nutritional Supplements in Parkinson’s Disease Progression

Directory of Open Access Journals (Sweden)

Laurie K. Mischley

2017-01-01

Full Text Available Objectives. The goal of this study is to describe modifiable lifestyle variables associated with reduced rate of Parkinson’s disease (PD progression. Methods. The patient-reported outcomes in PD (PRO-PD were used as the primary outcome measure, and a food frequency questionnaire (FFQ was used to assess dietary intake. In this cross-sectional analysis, regression analysis was performed on baseline data to identify the nutritional and pharmacological interventions associated with the rate of PD progression. All analyses were adjusted for age, gender, and years since diagnosis. Results. 1053 individuals with self-reported idiopathic PD were available for analysis. Foods associated with the reduced rate of PD progression included fresh vegetables, fresh fruit, nuts and seeds, nonfried fish, olive oil, wine, coconut oil, fresh herbs, and spices (P<0.05. Foods associated with more rapid PD progression include canned fruits and vegetables, diet and nondiet soda, fried foods, beef, ice cream, yogurt, and cheese (P<0.05. Nutritional supplements coenzyme Q10 and fish oil were associated with reduced PD progression (P=0.026 and P=0.019, resp., and iron supplementation was associated with faster progression (P=0.022. Discussion. These are the first data to provide evidence that targeted nutrition is associated with the rate of PD progression.

A Quick Phenotypic Neurological Scoring System for Evaluating Disease Progression in the SOD1-G93A Mouse Model of ALS.

Science.gov (United States)

Hatzipetros, Theo; Kidd, Joshua D; Moreno, Andy J; Thompson, Kenneth; Gill, Alan; Vieira, Fernando G

2015-10-06

The SOD1-G93A transgenic mouse is the most widely used animal model of amyotrophic lateral sclerosis (ALS). At ALS TDI we developed a phenotypic screening protocol, demonstrated in video herein, which reliably assesses the neuromuscular function of SOD1-G93A mice in a quick manner. This protocol encompasses a simple neurological scoring system (NeuroScore) designed to assess hindlimb function. NeuroScore is focused on hindlimb function because hindlimb deficits are the earliest reported neurological sign of disease in SOD1-G93A mice. The protocol developed by ALS TDI provides an unbiased assessment of onset of paresis (slight or partial paralysis), progression and severity of paralysis and it is sensitive enough to identify drug-induced changes in disease progression. In this report, the combination of a detailed manuscript with video minimizes scoring ambiguities and inter-experimenter variability thus allowing for the protocol to be adopted by other laboratories and enabling comparisons between studies taking place at different settings. We believe that this video protocol can serve as an excellent training tool for present and future ALS researchers.

Hepcidin-25 in diabetic chronic kidney disease is predictive for mortality and progression to end stage renal disease.

Directory of Open Access Journals (Sweden)

Martin Wagner

Full Text Available Anemia is common and is associated with impaired clinical outcomes in diabetic chronic kidney disease (CKD. It may be explained by reduced erythropoietin (EPO synthesis, but recent data suggest that EPO-resistance and diminished iron availability due to inflammation contribute significantly. In this cohort study, we evaluated the impact of hepcidin-25--the key hormone of iron-metabolism--on clinical outcomes in diabetic patients with CKD along with endogenous EPO levels.249 diabetic patients with CKD of any stage, excluding end-stage renal disease (ESRD, were enrolled (2003-2005, if they were not on EPO-stimulating agent and iron therapy. Hepcidin-25 levels were measured by radioimmunoassay. The association of hepcidin-25 at baseline with clinical variables was investigated using linear regression models. All-cause mortality and a composite endpoint of CKD progression (ESRD or doubling of serum creatinine were analyzed by Cox proportional hazards models.Patients (age 67 yrs, 53% male, GFR 51 ml/min, hemoglobin 131 g/L, EPO 13.5 U/L, hepcidin-25 62.0 ng/ml were followed for a median time of 4.2 yrs. Forty-nine patients died (19.7% and forty (16.1% patients reached the composite endpoint. Elevated hepcidin levels were independently associated with higher ferritin-levels, lower EPO-levels and impaired kidney function (all p<0.05. Hepcidin was related to mortality, along with its interaction with EPO, older age, greater proteinuria and elevated CRP (all p<0.05. Hepcidin was also predictive for progression of CKD, aside from baseline GFR, proteinuria, low albumin- and hemoglobin-levels and a history of CVD (all p<0.05.We found hepcidin-25 to be associated with EPO and impaired kidney function in diabetic CKD. Elevated hepcidin-25 and EPO-levels were independent predictors of mortality, while hepcidin-25 was also predictive for progression of CKD. Both hepcidin-25 and EPO may represent important prognostic factors of clinical outcome and have the

Podometry: a critical evaluation of its use in Hansen's disease

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Júlia Maria D'Andréa Greve

Full Text Available The aim of this paper is to evaluate the effectiveness of podometry to measure the pressure developed over the feet and the value of these findings to help in the prevention of the plantar neuropathic ulcer in patients bearing Hansen's disease. We evaluated 13 patients with impaired plantar pain and touch sensations and 17 normal patients. All the patients were submitted to static evaluation using the podometer. The system employed was the "Midcapteur" commercial podometer composed of a platform for acquisition of analogic data capable of registering the segmental pressures applied to the feet. These data are read by a 386 IBM/PC compatible computer that registers the graphic patterns obtained from the pressures developed and also calculates the modes of pressure distribution in the four quadrants of the foot. These data obtained by means of static podometry were compared to the clinical evaluation of pain and touch sensation of the feet in hansenian patients. The results demonstrate that podometery is an efficient method for evaluating the pressure in impaired feet in Hansen's disease and is a progression of neuropathic ulcer; it is sensitive in the identification of the spots of increased pressure in anesthetic and anomalous areas, asymmetries and in correlating the presence of ulcers with increased pressure.

A systematic review of the effect of moderate intensity exercise on function and disease progression in amyotrophic lateral sclerosis.

Science.gov (United States)

Lui, Andrew J; Byl, Nancy N

2009-06-01

Amyotrophic lateral sclerosis (ALS) is an idiopathic disease of adults affecting upper and lower motor neurons. In one to four years, progressive weakness, spasticity, and respiratory insufficiency compromise independence and survival. Current medical treatment is limited to medication and supportive care. The benefit and harm of moderate physical exercise are controversial. This review examined current research related to moderate exercise for maintaining independence without accelerating disease progression in persons with ALS. An evidence-based search was conducted using keywords alone and in combination (ALS, exercise, Lou Gehrig's disease, physical therapy) to search PubMed, PEDro, Hooked on Evidence, Ovid, and Cochrane databases. Human and animal models were included and graded on level of evidence and strength of recommendations for developing guidelines to practice. A secondary reviewer evaluated all selected studies, and statistics were calculated. The search yielded the following nine studies: four small clinical studies, one clinical systematic review, and four randomized, controlled trials based on animal models. In human studies, there were small to moderate effect sizes supporting the benefit of moderate exercise in persons with early-stage ALS, with no adverse affects on disease progression or survival time. In transgenic mice with superoxide dismutase-1 ALS, moderate exercise most often had a moderate effect size for increasing life span. Large randomized clinical trials are needed to develop specific exercise guidelines. However, evidence suggests that moderate exercise is not associated with adverse outcomes in persons with early-stage ALS. Moderate exercise programs can be safely adapted to abilities, interests, specific response to exercise, accessibility, and family support.

CSF neurofilament light chain and phosphorylated tau 181 predict disease progression in PSP.

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Rojas, Julio C; Bang, Jee; Lobach, Iryna V; Tsai, Richard M; Rabinovici, Gil D; Miller, Bruce L; Boxer, Adam L

2018-01-23

To determine the ability of CSF biomarkers to predict disease progression in progressive supranuclear palsy (PSP). We compared the ability of baseline CSF β-amyloid 1-42 , tau, phosphorylated tau 181 (p-tau), and neurofilament light chain (NfL) concentrations, measured by INNO-BIA AlzBio3 or ELISA, to predict 52-week changes in clinical (PSP Rating Scale [PSPRS] and Schwab and England Activities of Daily Living [SEADL]), neuropsychological, and regional brain volumes on MRI using linear mixed effects models controlled for age, sex, and baseline disease severity, and Fisher F density curves to compare effect sizes in 50 patients with PSP. Similar analyses were done using plasma NfL measured by single molecule arrays in 141 patients. Higher CSF NfL concentration predicted more rapid decline (biomarker × time interaction) over 52 weeks in PSPRS ( p = 0.004, false discovery rate-corrected) and SEADL ( p = 0.008), whereas lower baseline CSF p-tau predicted faster decline on PSPRS ( p = 0.004). Higher CSF tau concentrations predicted faster decline by SEADL ( p = 0.004). The CSF NfL/p-tau ratio was superior for predicting change in PSPRS, compared to p-tau ( p = 0.003) or NfL ( p = 0.001) alone. Higher NfL concentrations in CSF or blood were associated with greater superior cerebellar peduncle atrophy (fixed effect, p ≤ 0.029 and 0.008, respectively). Both CSF p-tau and NfL correlate with disease severity and rate of disease progression in PSP. The inverse correlation of p-tau with disease severity suggests a potentially different mechanism of tau pathology in PSP as compared to Alzheimer disease. Copyright © 2017 American Academy of Neurology.

C-Reactive Protein Predicts Progression of Peripheral Arterial Disease in Patients with Type 2 Diabetes: A 5-Year Follow-Up Study

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Popović Ljiljana

2014-09-01

Full Text Available Background: Previous studies have indicated that high sensitivity C-reactive protein (hs-CRP is a risk factor for the peripheral arterial disease (PAD in diabetes. This study aimed to evaluate the possible predictive significance of hs-CRP for the development and progression of PAD in patients with type 2 diabetes (T2D.

Measuring the progression of idiopathic Parkinson's disease with [123I] β-CIT SPECT

International Nuclear Information System (INIS)

Staffen, W.; Mair, A.; Unterrainer, J.; Trinka, E.; Ladurner, G.

2000-01-01

Idiopathic Parkinson's disease (PD) is the most common neuro degenerative disorder. An important step in diagnosing the disease has been achieved with the development of the cocaine derivative [ 123 I] β-CIT for single photon emission computed tomography (SPECT). The aim of this study was to demonstrate the disease progression by repeated measuring presynaptic dopamine transporter density and relating it to clinical data. The presynaptic dopamine, transporter density of 15 PD patients was measured two times with a mean interval of 15 months. All patients were clinically assessed at the time of the experiments according to the classification scheme of Hoehn and Yahr. 11 healthy volunteers were used as a control group. [ 123 I] β-CIT was injected intravenously and measured with a triple-headed camera twenty hours later. The pictures were evaluated semi quantitatively by using the ratio of specific to non-displaceable binding. Presynaptic dopamine transporter density differed significantly between controls and PD patients. A significant correlation between imaging data and clinical stages (H/Y I 27 %, H/Y II -40 %, H/Y III 58 %) was observed for the patient group in the initial experiment. The subsequent decrease of dopamine transporter binding depended on the initial clinical stage (H/Y I -6.81 %; H/Y II -6.05 %; H/Y III -1.25 %) of the patients, and regression analysis revealed that. 91.4 % of the variance of the second measurement were predicted by the initial measurement. No correlations were found for age, gender and disease progression. All patients were treated with L-DOPA and those given a higher dose showed a more rapid decrease of dopamine transporter density. This result could be interpreted as an indication for in vivo neurotoxicity of high concentrations of L-DOPA. We conclude that combining [ 123 I] β-CIT with SPECT imaging is not only a powerful tool for diagnosing PD patients, but may also be used to demonstrate neuro degeneration in vivo. (author)

Cysteine 138 mutation in HIV-1 Nef from patients with delayed disease progression

DEFF Research Database (Denmark)

Tolstrup, Martin; Laursen, Alex Lund; Gerstoft, J.

2006-01-01

.0139). The phylogeny of isolates was investigated and the variants harbouring the cysteine 138 mutation clustered independently. CONCLUSION: The present study describes a viral genetic polymorphism related to AIDS disease progression. The polymorphism (cysteine 138) has previously been reported to confer decreased......-1 isolates from patients in a long-term non-progressor (LTNP) cohort and a slow-progressor (SP) cohort (n = 11) was analysed and compared with isolates from a control patient group of progressors (n = 18). Most of the patients with delayed disease progression had extensive medical records, providing...... an insight into the LTNP disease profile and allowing for the stratification of patients based on their CD4 cell decline. RESULTS: In sequences from nine patients, most of the functional domains of HIV-1 Nef appeared intact, and no major deletions were observed to possibly account for an effect...

View of God as benevolent and forgiving or punishing and judgmental predicts HIV disease progression.

Science.gov (United States)

Ironson, Gail; Stuetzle, Rick; Ironson, Dale; Balbin, Elizabeth; Kremer, Heidemarie; George, Annie; Schneiderman, Neil; Fletcher, Mary Ann

2011-12-01

This study assessed the predictive relationship between View of God beliefs and change in CD4-cell and Viral Load (VL) in HIV positive people over an extended period. A diverse sample of HIVseropositive participants (N = 101) undergoing comprehensive psychological assessment and blood draws over the course of 4 years completed the View of God Inventory with subscales measuring Positive View (benevolent/forgiving) and Negative View of God (harsh/judgmental/punishing). Adjusting for initial disease status, age, gender, ethnicity, education, and antiretroviral medication (at every 6-month visit), a Positive View of God predicted significantly slower disease-progression (better preservation of CD4-cells, better control of VL), whereas a Negative View of God predicted faster disease-progression over 4 years. Effect sizes were greater than those previously demonstrated for psychosocial variables known to predict HIV-disease-progression, such as depression and coping. Results remained significant even after adjusting for church attendance and psychosocial variables (health behaviors, mood, and coping). These results provide good initial evidence that spiritual beliefs may predict health outcomes.

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

International Nuclear Information System (INIS)

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

2000-01-01

Purpose: Mucosa-associated lymphoid tissue (MALT) lymphoma commonly presents in the gastrointestinal (GI) tract. Supradiaphragmatic MALT lymphoma is less common and its natural history is not well defined. This study was conducted to understand the natural history, to determine the frequency of synchronous disease in the GI tract, and to understand the patterns of disease progression after treatment for supradiaphragmatic MALT lymphoma. Patients and Methods: We retrospectively reviewed the medical records of 39 patients who presented with supradiaphragmatic MALT lymphoma between 1991 and 1997. Results: The median age of patients was 58 years (range, 25-90 years) with 16 male and 23 female patients. The most common primary site was salivary gland followed by ocular adnexa, lung, oral cavity, and others. Sixteen patients underwent esophagogastroduodenoscopy and biopsy (EGD + Bx) and 4 were found to have gastric involvement. Ann Arbor stages were the following: IEA, 17; IIEA, 5, IIEB, 1; and IVA, 16. The initial treatments were: involved field radiation therapy (n = 10), chemotherapy (n = 14), combination of radiation therapy and chemotherapy (n = 9), observation after biopsy (n = 4), antibiotics only (n = 1), and patient refusal of further intervention (n = 1). Seven patients received antibiotics as a part of the initial treatment. Every patient except for 1 was alive at a median follow-up of 39.5 months (range, 3-83 months). Thirty-six patients achieved complete response (CR) to the initial treatment. The actuarial 5-year progression-free survival rate was 83%. Progression of the disease occurred in 4 patients, with 2 in the stomach. Salvage attempts were made to 4 and were successful in 3. Of the 2 patients who relapsed in the stomach, 1 had negative EGD + Bx at the time of initial diagnosis. An EGD + Bx was not done in the second patient. Conclusion: Supradiaphragmatic MALT lymphoma appears to have a favorable prognosis. However, routine evaluation of the stomach

Progression and prognostic indicators of bronchial disease in children with sickle cell disease.

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Williams, Sophia N; Nussbaum, Eliezer; Yoonessi, Leila; Morphew, Tricia; Randhawa, Inderpal

2014-06-01

The pulmonary complications of sickle cell disease (SCD) are a leading cause of morbidity and mortality (MacLean et al. Am J Respir Crit Care Med 178:1055-1059, 2008; Klings et al. Am J Respir Crit Care Med 173:1264-1269, 2006; National Heart, Lung, and Blood Institute, 2009). Despite this recognition, predictive markers of lung dysfunction progression remain elusive (Klings et al. Am J Respir Crit Care Med 173:1264-1269, 2006; Platt et al. N Engl J Med 330:1639-1644, 1994; Caboot et al. Curr Opin Pediatr 20:279-287, 2008; Field et al. Am J Hematol 83:574-576, 2008; Shirlo et al. Peadiatr Respir Review 12:78-82, 2011). This study was designed describe the longitudinal progression and identify specific markers that influence bronchial disease in SCD. A retrospective, chart review of 89 patients with SCD was conducted. All patients underwent spirometry in conjunction with body plethysmography as part of routine care. Eleven lung function variables were assessed, five of which were selected to establish patterns of normal, obstructive, restrictive, or mixed obstructive-restrictive physiology (Klings et al. Am J Respir Crit Care Med 173:1264-1269, 2006; Field et al. Am J Hematol 83:574-576, 2008). In the unadjusted model, forced expiratory volume in one second (FEV1)% of predicted trended downward with age, while total lung capacity (TLC)% of predicted showed a bimodal distribution and carbon monoxide diffusion capacity corrected for hemoglobin (DLCOcor)% of predicted remained stable. Adjusting for acute chest syndrome (ACS) episodes, medication status, and growth velocity (GV), the final model demonstrated that the downward trend between FEV1% of predicted with age was further influenced by the latter two factors. Initial decline in FEV1% of predicted is associated with worsening pulmonary dysfunction over time. Independent of ACS episodes, the factors most influential on the progression of FEV1% predicted include the introduction of medications as well as the

Endothelial progenitor cell dysfunction in patients with progressive chronic kidney disease

NARCIS (Netherlands)

Krenning, Guido; Dankers, Patricia Y. W.; Drouven, Johannes W.; Waanders, Femke; Franssen, Casper F. M.; van Luyn, Marja J. A.; Harmsen, Martin C.; Popa, Eliane R.

Krenning G, Dankers PY, Drouven JW, Waanders F, Franssen CF, van Luyn MJ, Harmsen MC, Popa ER. Endothelial progenitor cell dysfunction in patients with progressive chronic kidney disease. Am J Physiol Renal Physiol 296: F1314-F1322, 2009. First published April 1, 2009; doi:

Effect of Sex Hormones on Progression of Diabetic Renal Disease in ...

African Journals Online (AJOL)

Effect of Sex Hormones on Progression of Diabetic Renal Disease in Experimental Model of Streptozotocin Induced Diabetic Rats. ... into five groups 8 rats each, normal control, diabetic, gonadectomized diabetic, 17 beta estradiol is given to female and testosterone propionate to male diabetic and gonadectomized diabetic.

Herpes zoster, immunological deterioration and disease progression in HIV-1 infection

NARCIS (Netherlands)

Veenstra, J.; Krol, A.; van Praag, R. M.; Frissen, P. H.; Schellekens, P. T.; Lange, J. M.; Coutinho, R. A.; van der Meer, J. T.

1995-01-01

OBJECTIVE: To study the incidence of herpes zoster, the relationship between herpes zoster and immunological markers, and the prognostic value of herpes zoster for progression of HIV disease. DESIGN AND METHODS: A total of 966 homosexual participants in The Amsterdam Cohort Study were studied.

Progress on chinese evaluated nuclear parameter library: Pt.5

Energy Technology Data Exchange (ETDEWEB)

Zongdi, Su; Zhongfu, Huang; Jianfeng, Liu [and others

1996-06-01

The progress on chinese evaluated nuclear parameter library (v) was introduced. Six sub-libraries, MCC, DLS, NLD, GDP, FBP and OMP, including their data files and management-retrieval code systems have all been finished. All six sub-libraries have been used in nuclear model calculations, nuclear data evaluations and other fields in China. The applied results show that our evaluated nuclear parameter library is satisfactory and convenient.

An Evaluation of Neuropsychiatric Symptoms in Parkinson's Disease ...

African Journals Online (AJOL)

2017-09-14

Sep 14, 2017 ... Parkinson's disease (PD) is a chronic, progressive, and neurodegenerative disease which may present with complaints of tremor, bradykinesia, rigidity, and postural imbalance. Besides motor symptoms, neuropsychiatric symptoms such as depression, hallucination, anxiety, sleep disorders, and psychosis.

Primate amygdala neurons evaluate the progress of self-defined economic choice sequences.

Science.gov (United States)

Grabenhorst, Fabian; Hernadi, Istvan; Schultz, Wolfram

2016-10-12

The amygdala is a prime valuation structure yet its functions in advanced behaviors are poorly understood. We tested whether individual amygdala neurons encode a critical requirement for goal-directed behavior: the evaluation of progress during sequential choices. As monkeys progressed through choice sequences toward rewards, amygdala neurons showed phasic, gradually increasing responses over successive choice steps. These responses occurred in the absence of external progress cues or motor preplanning. They were often specific to self-defined sequences, typically disappearing during instructed control sequences with similar reward expectation. Their build-up rate reflected prospectively the forthcoming choice sequence, suggesting adaptation to an internal plan. Population decoding demonstrated a high-accuracy progress code. These findings indicate that amygdala neurons evaluate the progress of planned, self-defined behavioral sequences. Such progress signals seem essential for aligning stepwise choices with internal plans. Their presence in amygdala neurons may inform understanding of human conditions with amygdala dysfunction and deregulated reward pursuit.

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

Directory of Open Access Journals (Sweden)

Izumi Masashi

2012-08-01

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

Chronic progressive multiple sclerosis

International Nuclear Information System (INIS)

Buffoli, A.; Micheletti, E.; Capra, R.; Mattioli, F.; Marciano', N.

1991-01-01

A long-lasting immunological suppression action seems to be produced by total lymphoid irradiation; some authors emphasize the favorable effect of this treatment on chronic progressive multiple sclerosis. In order to evaluate the actual role of TLI, 6 patients affected with chronic progressive multiple sclerosis were submitted to TLI with shaped and personalized fields at the Istituto del Radio, University of Brescia, Italy. The total dose delivered was 19.8 Gy in 4 weeks, 1.8 Gy/day, 5d/w; a week elapsed between the first and the second irradiation course. Disability according to Kurtzke scale was evaluated, together with blood lymphocyte count and irradiation side-effects, over a mean follow-up period of 20.8 months (range: 13-24). Our findings indicate that: a) disease progression was not markedly reduced by TLI; b) steroid hormones responsivity was restored after irradiation, and c) side-effects were mild and tolerable

Pulmonary Hypertension Due to Left Ventricular Cardiomyopathy: Is it the Result or Cause of Disease Progression?

Science.gov (United States)

Adusumalli, Srinath; Mazurek, Jeremy A

2017-12-01

The purpose of this review is to define pulmonary hypertension in the setting of left heart disease (PH-LHD), discuss its epidemiology and pathophysiology, and highlight the cause and effect relationship it has with disease progression in the setting of cardiomyopathy. Both pulmonary hypertension (PH) and heart failure are becoming increasingly common. As such, PH-LHD is now the most common form of PH. The pathophysiology of the condition relates to backward transmission of elevated left ventricular filling pressures into the pulmonary circulation and, ultimately, right ventricular (RV) strain/dysfunction. It is evident that these pathophysiologic processes are both the effect and cause of left heart disease progression. In this review, we describe the complex relationship between disease progression in left ventricular cardiomyopathy and PH-LHD. Clinicians and researchers should take note of the importance of PH-LHD and RV dysfunction to appropriately risk stratify patients and develop therapies for the condition.

Naturalism about health and disease: adding nuance for progress.

Science.gov (United States)

Kingma, Elselijn

2014-12-01

The literature on health and diseases is usually presented as an opposition between naturalism and normativism. This article argues that such a picture is too simplistic: there is not one opposition between naturalism and normativism, but many. I distinguish four different domains where naturalist and normativist claims can be contrasted: (1) ordinary usage, (2) conceptually clean versions of "health" and "disease," (3) the operationalization of dysfunction, and (4) the justification for that operationalization. In the process I present new arguments in response to Schwartz (2007) and Hausman (2012) and expose a link between the arguments made by Schwartz (2007) and Kingma (2010). Distinguishing naturalist claims at these four domains will allow us to make progress by (1) providing more nuanced, intermediate positions about a possible role for values in health and disease; and (2) assisting in the addressing of relativistic worries about the value-ladenness of health and disease. © The Author 2014. Published by Oxford University Press, on behalf of the Journal of Medicine and Philosophy Inc. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Considerations on Intervention Goal and Efficacy Evaluation of Traditional Chinese Medicine in the Treatment of Neurological Diseases

Institute of Scientific and Technical Information of China (English)

XIE Ren-ming; DU Bao-xin; HUANG Yan; ZHOU Dao-you; WANG yong-yan; HUANG pei-xin

2007-01-01

In the last several years, traditional Chinese medicine (TCM) has made much progress in the treatment of neurological diseases. The living space of TCM in neurological diseases lies in refractory diseases, aging and chronic diseases caused by multiple factors as well as sub-health state and chronic fatigue state. The effect model of TCM mainly consists of whole effect, self-organization,self-stable model, holographic effect and butterfly effect. The effective point of TCM in neurological diseases lies mainly in end-points and health-related events. Moreover, TCM has advantages in the evaluation of symptoms, syndrome and quality of life (QOL). Some key indexes should be included when evaluating the efficacy of TCM in neurological diseases. Meanwhile, the advantages of TCM such as end-points, health-related events and QOL should be highlighted. Multi-subject researching methods could be adopted to make a comprehensive evaluation of subjective and objective indexes.The clinical evidence on the TCM efficacy evaluation may come from RCTs, and other types of designs can also be considered.

Skin autofluorescence is associated with the progression of chronic kidney disease: a prospective observational study.

Science.gov (United States)

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

2013-01-01

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

Guidelines for the field evaluation of desert tortoise health and disease

Science.gov (United States)

Berry, Kristin H.; Christopher, Mary M.

2001-01-01

Field evaluation of free-ranging wildlife requires the systematic documentation of a variety of environmental conditions and individual parameters of health and disease, particularly in the case of rare or endangered species. In addition, defined criteria are needed for the humane salvage of ill or dying animals. The purpose of this paper is to describe, in detail, the preparation, procedures, and protocols we developed and tested for the field evaluation of wild desert tortoises (Gopherus agassizii). These guidelines describe: preparations for the field, including developing familiarity with tortoise behavior and ecology, and preparation of standardized data sheets; journal notes to document background data on weather conditions, temperature, rainfall, locality, and historic and recent human activities; procedures to prevent the spread of disease and parasites; data sheets for live tortoises to record tortoise identification, location, sex, body measurements and activity; health profile forms for documenting and grading physical abnormalities of tortoise posture and movements, general condition (e.g., lethargy, cachexia), external parasites, and clinical abnormalities associated with shell and upper respiratory diseases; permanent photographic records for the retrospective analysis of progression and regression of upper respiratory and eye diseases, analysis of shell lesions and evaluation of growth and age; and indications and methods for salvaging ill or dying tortoises for necropsy evaluation. These guidelines, tested on 5,000 to 20,000 tortoises over a 10 to 27 yr period, were designed to maximize acquisition of data for demographic, ecological, health and disease research projects; to reduce handling and stress of individual animals; to avoid spread of infectious disease; to promote high quality and consistent data sets; and to reduce the duration and number of field trips. The field methods are adapted for desert tortoise life cycle, behavior, anatomy

Plasma lipid peroxidation and progression of disability in multiple sclerosis

NARCIS (Netherlands)

Koch, M.; Mostert, J.; Arutjunyan, A. V.; Stepanov, M.; Teelken, A.; Heersema, D.; De Keyser, J.

Oxidative stress has been implicated in the pathophysiology of multiple sclerosis (MS), but its relation to disease progression is uncertain. To evaluate the relationship of plasma lipid peroxidation with progression of disability in MS, we measured blood plasma fluorescent lipid peroxidation

Previously Unidentified Single Nucleotide Polymorphisms in HIV/AIDS Cases Associate with Clinical Parameters and Disease Progression

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Vladimir V. Anokhin

2016-01-01

Full Text Available The genetic background of an individual plays an important role in the progression of HIV infection to AIDS. Identifying previously unknown or uncharacterized single nucleotide polymorphisms (SNPs that associate with disease progression may reveal important therapeutic targets and provide a greater understanding of disease pathogenesis. In the present study, we employed ultra-high multiplex PCR on an Ion Torrent next-generation sequencing platform to sequence 23 innate immune genes from 94 individuals with HIV/AIDS. This data was used to identify potential associations of SNPs with clinical parameters and disease progression. SNPs that associated with an increased viral load were identified in the genes for the interleukin 15 receptor (IL15RA, toll-like receptor 7 (TLR7, tripartite motif-containing protein 5 (TRIM5, and two killer-cell immunoglobulin-like receptors (KIR2DL1 and KIR2DL3. Additionally, SNPs that associated with progression from HIV infection to AIDS were identified in two 2′-5′-oligoadenylate synthetase genes (OAS2 and OAS3. In contrast, other SNPs identified in OAS2 and OAS3 genes, as well as in the TRIM5 and KIR2DS4 genes, were associated with a slower progression of disease. Taken together, our data demonstrates the utility of ultra-high multiplex PCR in identifying polymorphisms of potential clinical significance and further,identifies SNPs that may play a role in HIV pathogenesis.

Primary progressive aphasia patients evaluated using diffusion tensor imaging and voxel based volumetry-preliminary results

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Fábio Pascotto de Oliveira

2011-06-01

Full Text Available There are individuals who have a progressive language deficit without presenting cognitive deficits in other areas. One of the diseases related to this presentation is primary progressive aphasia (PPA. OBJECTIVE: Identify by means of diffusion tensor imaging (DTI and measurements of cortical volume, brain areas that lead to dysphasia when presenting signs of impaired connectivity or reduced volume. METHOD: Four patients with PPA were evaluated using DTI, and measurements of cortical volumes in temporal areas. These patients were compared with two normal volunteers. RESULTS: There is a trend to a difference in the number and volume of related fibers between control group and patients with PPA. Comparing cortical volumes in temporal areas between groups yielded a trend to a smaller volume in PPA patients. CONCLUSION: Patients with PPA have a trend to impairment in cortical and subcortical levels regarding relevant areas.

Effect of mineralocorticoid receptor antagonists on proteinuria and progression of chronic kidney disease: A systematic review and meta-analysis

NARCIS (Netherlands)

Currie, G. (Gemma); Taylor, A.H.M. (Alison H. M.); Fujita, T. (Toshiro); Ohtsu, H. (Hiroshi); Lindhardt, M. (Morten); K. Rossing; Boesby, L. (Lene); Edwards, N.C. (Nicola C.); Ferro, C.J. (Charles J.); J. Townend (Jonathan); A.H. van den Meiracker (Anton); Saklayen, M.G. (Mohammad G.); Oveisi, S. (Sonia); Jardine, A.G. (Alan G.); C. Delles (Christian); Preiss, D.J. (David J.); Mark, P.B. (Patrick B.)

2016-01-01

textabstractBackground: Hypertension and proteinuria are critically involved in the progression of chronic kidney disease. Despite treatment with renin angiotensin system inhibition, kidney function declines in many patients. Aldosterone excess is a risk factor for progression of kidney disease.

Large-scale identification of clinical and genetic predictors of motor progression in patients with newly diagnosed Parkinson's disease: a longitudinal cohort study and validation.

Science.gov (United States)

Latourelle, Jeanne C; Beste, Michael T; Hadzi, Tiffany C; Miller, Robert E; Oppenheim, Jacob N; Valko, Matthew P; Wuest, Diane M; Church, Bruce W; Khalil, Iya G; Hayete, Boris; Venuto, Charles S

2017-11-01

-specific epistatic interaction, all indicative of faster motor progression. Genetic variation was the most useful predictive marker of motor progression (2·9%, 95% CI 1·5-4·3). CSF biomarkers at baseline showed a more modest (0·3%, 95% CI 0·1-0·5) but still significant effect on prediction of motor progression. The simulations (n=5000) showed that incorporating the predicted rates of motor progression (as assessed by the annual change in MDS-UPDRS score) into the final models of treatment effect reduced the variability in the study outcome, allowing significant differences to be detected at sample sizes up to 20% smaller than in naive trials. Our model ensemble confirmed established and identified novel predictors of Parkinson's disease motor progression. Improvement of existing prognostic models through machine-learning approaches should benefit trial design and evaluation, as well as clinical disease monitoring and treatment. Michael J Fox Foundation for Parkinson's Research and National Institute of Neurological Disorders and Stroke. Copyright © 2017 Elsevier Ltd. All rights reserved.

Do frequent moderate exacerbations contribute to progression of chronic obstructive pulmonary disease in patients who are ex-smokers?

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Dreyse J

2015-03-01

Full Text Available Jorge Dreyse,1 Orlando Díaz,1 Paula Repetto,2 Arturo Morales,1 Fernando Saldías,1 Carmen Lisboa11Department of Pulmonary Diseases, School of Medicine, 2School of Psychology, Pontificia Universidad Católica de Chile, Santiago, ChileBackground: In addition to smoking, acute exacerbations are considered to be a contributing factor to progression of chronic obstructive pulmonary disease (COPD. However, these findings come from studies including active smokers, while results in ex-smokers are scarce and contradictory. The purpose of this study was to evaluate if frequent acute moderate exacerbations are associated with an accelerated decline in forced expiratory volume in one second (FEV1 and impairment of functional and clinical outcomes in ex-smoking COPD patients.Methods: A cohort of 100 ex-smoking patients recruited for a 2-year follow-up study was evaluated at inclusion and at 6-monthly scheduled visits while in a stable condition. Evaluation included anthropometry, spirometry, inspiratory capacity, peripheral capillary oxygen saturation, severity of dyspnea, a 6-minute walking test, BODE (Body mass index, airflow Obstruction, Dyspnea, Exercise performance index, and quality of life (St George’s Respiratory Questionnaire and Chronic Respiratory Disease Questionnaire. Severity of exacerbation was graded as moderate or severe according to health care utilization. Patients were classified as infrequent exacerbators if they had no or one acute exacerbation/year and frequent exacerbators if they had two or more acute exacerbations/year. Random effects modeling, within hierarchical linear modeling, was used for analysis.Results: During follow-up, 419 (96% moderate acute exacerbations were registered. At baseline, frequent exacerbators had more severe disease than infrequent exacerbators according to their FEV1 and BODE index, and also showed greater impairment in inspiratory capacity, forced vital capacity, peripheral capillary oxygen saturation

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

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

2012-05-09

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

White matter disease correlates with lexical retrieval deficits in primary progressive aphasia

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John P. Powers

2013-12-01

Full Text Available Objective: To relate fractional anisotropy changes associated with the semantic and logopenic variants of primary progressive aphasia to measures of lexical retrieval.Methods: We collected neuropsychological testing, volumetric MRI, and diffusion-weighted imaging on semantic variant primary progressive aphasia (n=11 and logopenic variant primary progressive aphasia (n=13 patients diagnosed using published criteria. We also acquired neuroimaging data on a group of demographically comparable healthy seniors (n=34. Fractional anisotropy was calculated and analyzed using a white matter tract-specific analysis approach. This approach utilizes anatomically guided data reduction to increase sensitivity and localizes results within canonically defined tracts. We used non-parametric, cluster-based statistical analysis to relate language performance to fractional anisotropy and determine regions of reduced fractional anisotropy in patients. Results: We found widespread fractional anisotropy reductions in white matter for both variants of primary progressive aphasia. Fractional anisotropy was related to both confrontation naming and category naming fluency performance in left uncinate fasciculus and corpus callosum in semantic variant primary progressive aphasia and left superior and inferior longitudinal fasciculi in logopenic variant primary progressive aphasia. Conclusions: Semantic variant primary progressive aphasia and logopenic variant primary progressive aphasia are associated with distinct disruptions of a large-scale network implicated in lexical retrieval, and the white matter disease in each phenotype may contribute to language impairments including lexical retrieval.

Repeat interventions as a long-term treatment strategy in the management of progressive coronary artery disease.

NARCIS (Netherlands)

K.G. Lehmann (Kenneth); P.W.J.C. Serruys (Patrick); M.J.B.M. van den Brand (Marcel); P.J. de Feyter (Pim); A.C.P. Maas (Arthur); R.T. van Domburg (Ron)

1996-01-01

textabstractObjectives. This study investigates whether repeat coronary interventions, applied over an extended time period, can successfully curtail the progression of ischemic symptoms and angiographic lumen narrowing. Background. Coronary artery disease is a chronic and generally progressive

Progressive white-matter disease with primary cerebellar involvement: a separate entity?

Energy Technology Data Exchange (ETDEWEB)

Yalcinkaya, C. [Division of Child Neurology, Department of Neurology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul (Turkey); Arslanoglu, I. [Division of Endocrinology, Department of Paediatrics, Goeztepe Hospital, Istanbul (Turkey); Islak, C. [Division of Neuroradiology, Department of Radiology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul (Turkey); Aydin, A. [Division of Metabolic Disease, Department of Paediatrics, Cerrahpasa Medical Faculty, Istanbul University, Istanbul (Turkey); Boltshauser, E. [Division of Paediatric Neurology, University Children' s Hospital, Steinwiesstrasse 75, 8032 Zuerich (Switzerland)

2002-09-01

Although its metabolic basis has not yet been clarified, we report a progressive white-matter disease in a Turkish girl, starting in the cerebellum and spreading to supratentorial white matter. The onset was at the age of 2.5 years with diabetes insipidus, followed by ataxia and pyramidal signs resulting in loss of walking. Aqueduct stenosis was first recognised at the age of 8 years. To our knowledge, this MRI and clinical pattern does not correspond to a recognised, well-defined white-matter disease and may indicate a separate entity. (orig.)

Progressive white-matter disease with primary cerebellar involvement: a separate entity?

International Nuclear Information System (INIS)

Yalcinkaya, C.; Arslanoglu, I.; Islak, C.; Aydin, A.; Boltshauser, E.

2002-01-01

Although its metabolic basis has not yet been clarified, we report a progressive white-matter disease in a Turkish girl, starting in the cerebellum and spreading to supratentorial white matter. The onset was at the age of 2.5 years with diabetes insipidus, followed by ataxia and pyramidal signs resulting in loss of walking. Aqueduct stenosis was first recognised at the age of 8 years. To our knowledge, this MRI and clinical pattern does not correspond to a recognised, well-defined white-matter disease and may indicate a separate entity. (orig.)

Research progress in role of iron overload in non-alcoholic fatty liver disease

OpenAIRE

LI Guangming

2013-01-01

Iron overload is an important research focus in non-alcoholic fatty liver disease (NAFLD). The relationship between iron overload and NAFLD is summarized from the assessment method for iron overload, relationship between iron load and hemochromatosis gene mutations, incidence of iron load in NAFLD, and relationship between iron load and progression of NAFLD; the action mechanism of iron overload in the progression of NAFLD is reviewed from the causes of iron overload, relationship between iro...

Incisor malalignment and the risk of periodontal disease progression.

Science.gov (United States)

Alsulaiman, Ahmed A; Kaye, Elizabeth; Jones, Judith; Cabral, Howard; Leone, Cataldo; Will, Leslie; Garcia, Raul

2018-04-01

The objective of this study was to investigate the association between incisor crowding, irregularity, and periodontal disease progression in the anterior teeth. Data collected over 35 years from men enrolled in the Veterans Affairs Dental Longitudinal Study included information concerning pocket depth and alveolar bone loss. Plaster casts of the maxillary (n = 400) and mandibular (n = 408) arches were available for baseline measurements. Periodontal disease in the anterior teeth was defined as per arch sum of pathologic pocket depth and sum of teeth with any alveolar bone loss in the anterior sextants. Incisor malalignment status was defined by the anterior tooth size-arch length discrepancy index and Little's Irregularity Index. Adjusted mixed effects linear models computed the beta (β) estimates and 95% confidence intervals (95% CI) of the amounts of change in periodontal disease outcomes by the level of malalignment. In the anterior maxillary arch, crowding and spacing were significantly associated with an increased per-arch sum of pathologic pocket depth (β, 0.70 mm; 95% CI, 0.20-1.21, and β, 0.49 mm; 95% CI, 0.06-0.91, respectively). In the anterior mandibular arch, incisor crowding and irregularity were significantly associated with an increased per-arch sum of pathologic pocket depth (mild crowding: β, 0.47 mm; 95% CI, 0.01-0.93; severe irregularity: β, 0.94 mm; 95% CI, 0.50-1.38), and the sum number of teeth with alveolar bone loss (mild and moderate-to-severe crowding: β, 0.45 teeth; 95% CI, 0.08-0.82; and β, 0.45 teeth; 95% CI, 0.13-0.83, respectively; moderate irregularity: β, 0.34 teeth; 95% CI, 0.06-0.62). Certain incisor malalignment traits (ie, maxillary incisor crowding, maxillary incisor spacing, mandibular incisor mild crowding, mandibular incisor moderate-to-severe crowding, mandibular incisor moderate irregularity, and mandibular incisor severe irregularity) are associated with significant periodontal disease progression

Progress of the relationship between serum uric acid and neurodegenerative diseases

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Yang FU

2018-04-01

Full Text Available Serum uric acid (sUA, a natural antioxidant in human body, has been found to be related to the occurrence and development of various neurodegenerative diseases in recent years, including Parkinson's disease (PD, multiple system atrophy (MSA, Alzheimer's disease (AD and amyotrophic lateral sclerosis (ALS. Increasing of sUA level has been found to reduce the incidence of PD and ALS, but the relationship between sUA and AD, MSA remains largely unknown. The in vitro studies and animal experiments revealed that sUA can enhance the antioxidant capacity of neurons and delay neurodegeneration and apoptosis. This paper mainly reviews the progress in epidemiological and basic studies of the relationship between sUA and neurodegenerative diseases in recent years, and aims to provide a reference for future novel prevention and treatment strategies for neurodegenerative diseases. DOI: 10.3969/j.issn.1672-6731.2018.03.010

Retrospective analysis of factors affecting the progression of Chronic Renal Failure in Adult Polycystic Kidney Disease

International Nuclear Information System (INIS)

Ahmed, E.R.; Tashkandi, Muhammed A.; Nahrir, S.; Maulana, A.

2006-01-01

Autosomal dominant polycystic kidney disease (ADPKD) is the commonest congenital cystic renal disease. Factors such as hypertension, urinary tract infection, hematuria and proteinuria may effect the progression to chronic renal failure in ADPKD patients. Therapeutic interventions, such as the use of angiotensin converting enzyme inhibitors (ACEI) or diet modification, may impact the natural progression of the disease. We aim in this study to review a registry of ADPKD patients in order to compare the slow and fast progressors and identify possible predictors of progression and interventions that slow the progression of this disease. Sheffield Kidney Institute (SKI), one of the largest kidney institutes in Northern Europe, has registered a large number of ADPKD patients since 1981. SKI's computer network contains a wide range of information on these patients. We selected 94 adult polycystic patients from the SKI for retrospective analysis of factors affecting progression to chronic renal failure. Patients who doubled their s. creatinine in 3 6 months were considered fast progressors (FP), while those who doubled their s. creatinine in > 36 months were regarded as slow progressors (SP). There 70 patients in the FP group and 24 patients in the SP group. A third group of 137 patients consisted of non-progressors (NP) who ha d stable s. creatinine levels during the same period. We found that the incidence of hypertension, UTI, macroscopic and microscopic hematuria, and overt proteinuria in the FP group was higher than in SP and NP groups. Modification of some factors, such as hypertension and UTI, may decrease the rate of the deterioration of renal function. (author)

A MULTICENTRE STUDY OF ASSESSING THE EFFECTIVENESS OF SALVAGING LYMPHADENECTOMY IN PATIENTS WITH PROSTATE CANCER WITH DISEASE PROGRESSION AFTER THE RADICAL TREATMENT

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B. Y. Alekseev

2016-01-01

Full Text Available Prostate cancer (PC is one of the most urgent problems of modern oncourology because of the continuing high incidence of this pathology. The main methods of radical treatment of patients with localized and locally advanced prostate cancer are radical prostatectomy (RP and radiotherapy – remote (RRT or brachytherapy.  However, the frequency of biochemical markers of disease progression after curative treatment is high and reaches up to 27–53%. It is extremely important to find the tumor lesion that leads to the increase of the marker. The  palliative hormone therapy (PHT was the only accepted method in patients with occurrence of distant metastases in recent time. However, a significant number of patients relapse marker may be associated with the so-called oligo-metastatic disease progression, in which the number of detected metastatic lesions is minimal. As the results of the research, the use of surgical or radiological treatment in selected patients of this cohort can significantly increase the length of time prior to the appointment of HT, and in some cases completely abandon its holding.Purpose. To evaluate the results of the saving pelvic lymphadenectomy in patients with prostate cancer with disease progression after radical therapies.Patients and methods. The article summarizes the results of surgical treatment of patients who have undergone life-saving lymphadenectomy about oligo-nodal metastatic progression of prostate cancer after treatment in 3 centers – P. Hertsen MORI, the branch of NMRRC; N. Petrov Research Institute of Oncology and Russian scientific center of radiology and surgical technologies. In this multicenter study they evaluated the immediate and remote results of surgical treatment of 57 patients.Results. The results performed the high efficiency of the method of the saving pelvic lymphadenectomy in patients with prostate cancer with disease progression after radical treatment. So, response to therapy and reduction

Predictors of high healthcare resource utilization and liver disease progression among patients with chronic hepatitis C.

Science.gov (United States)

LaMori, Joyce; Tandon, Neeta; Laliberté, François; Germain, Guillaume; Pilon, Dominic; Lefebvre, Patrick; Prabhakar, Avinash

2016-01-01

Since hepatitis C virus therapy is typically prioritized for patients with more advanced disease, predicting which patients will progress could help direct scarce resources to those likely to benefit most. This study aims to identify demographics and clinical characteristics associated with high healthcare resource utilization (HRU) and liver disease progression among CHC patients. Using health insurance claims (January 2001-March 2013), adult patients with ≥2 CHC claims (ICD-9-CM: 070.44 or 070.54), and ≥6 months of continuous insurance coverage before and ≥36 months after the first CHC diagnosis were included. Patients with human immunodeficiency virus were excluded. Generalized estimating equations were used to identify the demographic and clinical characteristics of being in the 20% of patients with the highest HRU. Factors predicting liver disease progression were also identified. In the study population (n = 4898), liver disease severity and both CHC- and non-CHC-related comorbidities and conditions were strong predictors of high healthcare costs, with odds ratios (ORs; 95% confidence interval [CI]) for ≥2 CHC-related and ≥2 non-CHC-related comorbidities/conditions of 2.78 (2.48-3.12) and 2.19 (1.76-2.72), respectively. CHC- and non-CHC-related comorbidities and conditions were also strong predictors of liver disease progression with ORs (95% CI) for ≥2 CHC-related and ≥2 non-CHC-related comorbidities and conditions of 2.18 (1.83-2.60) and 1.50 (1.14-1.97), respectively. Potential inaccuracies in claims data, information or classification bias, and findings based on a privately insured population. This study suggests that CHC patients with high healthcare resource utilization have a high level of comorbidity at baseline and also that non-CHC comorbidities and conditions are strong predictors of high HRU. Non-cirrhotic CHC patients with one or more comorbidities are at high risk of progressing to cirrhosis or end-stage liver disease.

Brain stem and cerebellar atrophy in chronic progressive neuro-Behçet's disease

International Nuclear Information System (INIS)

Kanoto, Masafumi; Hosoya, Takaaki; Toyoguchi, Yuuki; Oda, Atsuko

2013-01-01

Purpose: Chronic progressive neuro-Behçet's disease (CPNBD) resembles multiple sclerosis (MS) on patient background and image findings, and therefore is difficult to diagnose. The purpose is to identify the characteristic magnetic resonance imaging (MRI) findings of CPNBD and to clarify the differences between the MRI findings of CPNBD and those of MS. Materials and methods: The subjects consist of a CPNBD group (n = 4; 1 male and 3 females; mean age, 51 y.o.), a MS group (n = 19; 3 males and 16 females; mean age, 45 y.o.) and a normal control group (n = 23; 10 males and 13 females; mean age, 45 y.o.). Brain stem atrophy, cerebellar atrophy, and leukoencephalopathy were retrospectively evaluated in each subjects. In middle sagittal brain MR images, the prepontine distance was measured as an indirect index of brain stem and cerebellar atrophy and the pontine and mesencephalic distance was measured as a direct index of brain stem atrophy. These indexes were statistically analyzed. Results: Brain stem atrophy, cerebellar atrophy, and leukoencephalopathy were seen in all CPNBD cases. Prepontine distance was significantly different between the CPNBD group and the MS group (p < 0.05), and between the CPNBD group and the normal control group (p < 0.001). Pontine and mesencephalic distance were significantly different between the CPNBD group and the MS group (p < 0.001, p < 0.01 respectively), and between the CPNBD group and the normal control group (p < 0.001). Conclusions: Chronic progressive neuro-Behçet's disease should be considered in patients with brain stem and cerebellar atrophy in addition to leukoencephalopathy similar to that seen in multiple sclerosis

Pretreatment F-18 FDG PET/CT Parameters to Evaluate Progression-Free Survival in Gastric Cancer

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Kim, Jeonghun; Lim, Seok Tae; Na, Chang Ju; Han, Yeonhee; Kim, Chanyoung; Jeong, Hwanjeong; Sohn, Myunghee [Chonbuk National Univ., Jeonju (Korea, Republic of)

2014-03-15

We performed this study to evaluate the predictive value of pretreatment F-18 FDG PET/CT for progression-free survival (PFS) in patients with gastric cancer. Of 321 patients with a diagnosis of gastric cancer, we retrospectively enrolled 97 patients (men:women = 61:36, age 59.8±13.2 years), who underwent pretreatment F-18 fluoro-2-deoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) from January 2009 to December 2009. Maximum standardized uptake value (SUVmax) was measured for each case with detectable primary lesions. In the remaining non-detectable cases, SUVmax was measured from the corresponding site seen on gastroduodenoscopy for analysis. In subgroup analysis, metabolic tumor volume (MTV) was measured in 50 patients with clearly distinguishable primary lesions. SUVmax, stage, depth of tumor invasion and presence of lymph node metastasis were analyzed in terms of PFS. Receiver operating characteristic (ROC) curves were used to find optimal cutoff values of SUVmax and MTV for disease progression. The relationship between SUVmax, MTV and PFS was analyzed using the Kaplan-Meier with log-rank test and Cox's proportional hazard regression methods. Of 97 patients, 15 (15.5 %) had disease progression. The mean follow-up duration was 29.6±10.2 months. The mean PFS of low SUVmax group (≤5.74) was significantly longer than that of the high SUVmax group (>5.74) (30.9±8.0 vs 24.3±13.6 months, p =0.008). In univariate analysis, stage (I vs II, III, IV), depth of tumor invasion (T1 vs T2, T3, T4), presence of lymph node metastasis and SUVmax (>5.74 vs ≤5.74) were significantly associated with recurrence. In multivariate analysis, high SUVmax (>5.74) was the only poor prognostic factor for PFS (p =0.002, HR 11.03, 95% CI 2.48.49.05). Subgroup multivariate analysis revealed that high MTV (>16.42) was the only poor prognostic factor for PFS (p =0.034, HR 3.59, 95 % CI 1.10.11.71). In gastric cancer, SUVmax measured by pretreatment F-18

Disease impact in chronic progressive external ophthalmoplegia: more than meets the eye

NARCIS (Netherlands)

Smits, B.W.; Fermont, J.; Delnooz, C.C.S.; Kalkman, J.S.; Bleijenberg, G.; Engelen, B.G.M. van

2011-01-01

We determined the extent of disease impact in 28 patients with genetically confirmed chronic progressive external ophthalmoplegia (CPEO) and compared the outcomes to those of matched myotonic dystrophy type I patients. CPEO patients reported a high frequency of severe fatigue (67.9%), pain (96.2%),

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

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Meliana Riwanto

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

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

Science.gov (United States)

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

2016-04-01

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

Mass Spectrometric Methodologies for Investigating the Metabolic Signatures of Parkinson's Disease: Current Progress and Future Perspectives.

Science.gov (United States)

Gill, Emily L; Koelmel, Jeremy P; Yost, Richard A; Okun, Michael S; Vedam-Mai, Vinata; Garrett, Timothy J

2018-03-06

Parkinson's disease (PD) is a neurodegenerative disorder resulting from the loss of dopaminergic neurons of the substantia nigra as well as degeneration of motor and nonmotor basal ganglia circuitries. Typically known for classical motor deficits (tremor, rigidity, bradykinesia), early stages of the disease are associated with a large nonmotor component (depression, anxiety, apathy, etc.). Currently, there are no definitive biomarkers of PD, and the measurement of dopamine metabolites does not allow for detection of prodromal PD nor does it aid in long-term monitoring of disease progression. Given that PD is increasingly recognized as complex and heterogeneous, involving several neurotransmitters and proteins, it is of importance that we advance interdisciplinary studies to further our knowledge of the molecular and cellular pathways that are affected in PD. This approach will possibly yield useful biomarkers for early diagnosis and may assist in the development of disease-modifying therapies. Here, we discuss preanalytical factors associated with metabolomics studies, summarize current mass spectrometric methodologies used to evaluate the metabolic signature of PD, and provide future perspectives of the rapidly developing field of MS in the context of PD.

Muscle-Derived Proteins as Serum Biomarkers for Monitoring Disease Progression in Three Forms of Muscular Dystrophy

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Burch, Peter M.; Pogoryelova, Oksana; Goldstein, Richard; Bennett, Donald; Guglieri, Michela; Straub, Volker; Bushby, Kate; Lochmüller, Hanns; Morris, Carl

2015-01-01

Abstract Background: Identifying translatable, non-invasive biomarkers of muscular dystrophy that better reflect the disease pathology than those currently available would aid the development of new therapies, the monitoring of disease progression and the response to therapy. Objective: The goal of this study was to evaluate a panel of serum protein biomarkers with the potential to specifically detect skeletal muscle injury. Method: Serum concentrations of skeletal troponin I (sTnI), myosin light chain 3 (Myl3), fatty acid binding protein 3 (FABP3) and muscle-type creatine kinase (CKM) proteins were measured in 74 Duchenne muscular dystrophy (DMD), 38 Becker muscular dystrophy (BMD) and 49 Limb-girdle muscular dystrophy type 2B (LGMD2B) patients and 32 healthy controls. Results: All four proteins were significantly elevated in the serum of these three muscular dystrophy patient populations when compared to healthy controls, but, interestingly, displayed different profiles depending on the type of muscular dystrophy. Additionally, the effects of patient age, ambulatory status, cardiac function and treatment status on the serum concentrations of the proteins were investigated. Statistical analysis revealed correlations between the serum concentrations and certain clinical endpoints including forced vital capacity in DMD patients and the time to walk ten meters in LGMD2B patients. Serum concentrations of these proteins were also elevated in two preclinical models of muscular dystrophy, the mdx mouse and the golden-retriever muscular dystrophy dog. Conclusions: These proteins, therefore, are potential muscular dystrophy biomarkers for monitoring disease progression and therapeutic response in both preclinical and clinical studies. PMID:26870665

The effect of progressive resistance training on aerobic fitness and strength in adults with coronary heart disease: A systematic review and meta-analysis of randomised controlled trials.

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Hollings, Matthew; Mavros, Yorgi; Freeston, Jonathan; Fiatarone Singh, Maria

2017-08-01

Design We aimed to evaluate the effect of progressive resistance training on cardiorespiratory fitness and muscular strength in coronary heart disease, when compared to control or aerobic training, and when combined with aerobic training. Secondary aims were to evaluate the safety and efficacy of progressive resistance training on other physiological and clinical outcomes. Methods and results Electronic databases were searched from inception until July 2016. Designs included progressive resistance training vs control, progressive resistance training vs aerobic training, and combined training vs aerobic training. From 268,778 titles, 34 studies were included (1940 participants; 71.9% male; age 60 ± 7 years). Progressive resistance training was more effective than control for lower (standardized mean difference 0.57, 95% confidence interval (0.17-0.96)) and upper (1.43 (0.73-2.13)) body strength. Aerobic fitness improved similarly after progressive resistance training (16.9%) or aerobic training (21.0%); (standardized mean difference -0.13, 95% confidence interval (-0.35-0.08)). Combined training was more effective than aerobic training for aerobic fitness (0.21 (0.09-0.34), lower (0.62 (0.32-0.92)) and upper (0.51 (0.27-0.74)) body strength. Twenty studies reported adverse event information, with five reporting 64 cardiovascular complications, 63 during aerobic training. Conclusion Isolated progressive resistance training resulted in an increase in lower and upper body strength, and improved aerobic fitness to a similar degree as aerobic training in coronary heart disease cohorts. Importantly, when progressive resistance training was added to aerobic training, effects on both fitness and strength were enhanced compared to aerobic training alone. Reporting of adverse events was poor, and clinical gaps were identified for women, older adults, high intensity progressive resistance training and long-term outcomes, warranting future trials to confirm safety and

Dietary Energy Density, Renal Function, and Progression of Chronic Kidney Disease

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Mohammad Hossein Rouhani

2016-01-01

Full Text Available Background. There is evidence of the association between dietary energy density and chronic diseases. However, no report exists regarding the relation between DED and chronic kidney disease (CKD. Objective. To examine the association between dietary energy density (DED, renal function, and progression of chronic kidney disease (CKD. Design. Cross-sectional. Setting. Three nephrology clinics. Subjects. Two hundred twenty-one subjects with diagnosed CKD. Main Outcome Measure. Dietary intake of patients was assessed by a validated food frequency questionnaire. DED (in kcal/g was calculated with the use of energy content and weight of solid foods and energy yielding beverages. Renal function was measured by blood urea nitrogen (BUN, serum creatinine (Cr, and estimated glomerular filtration rate (eGFR. Results. Patients in the first tertile of DED consumed more amounts of carbohydrate, dietary fiber, potassium, phosphorus, zinc, magnesium, calcium, folate, vitamin C, and vitamin B2. After adjusting for confounders, we could not find any significant trend for BUN and Cr across tertiles of DED. In multivariate model, an increased risk of being in the higher stage of CKD was found among those in the last tertile of DED (OR: 3.15; 95% CI: 1.30, 7.63; P=0.01. Conclusion. We observed that lower DED was associated with better nutrient intake and lower risk of CKD progression.

Retinopathy of prematurity: mutations in the Norrie disease gene and the risk of progression to advanced stages.

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Haider, M Z; Devarajan, L V; Al-Essa, M; Srivastva, B S; Kumar, H; Azad, R; Rashwan, N

2001-04-01

Retinopathy of prematurity (ROP) is a retinal vascular disease that occurs in infants with short gestational age and low birth weight and may lead to retinal detachment and blindness. Missense mutations in the Norrie disease (ND) gene have been associated with the risk of progression to advanced stages in cases of ROP from the US and also in clinically similar ND and familial exudative vitreoretinopathy. We have screened two ND gene mutations, namely A105T and Val60Glu, by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and allele-specific PCR methods, respectively, in 210 Kuwaiti premature newborns to replicate these findings in a different ethnic group. In the Kuwaiti premature newborn cohort, 115 of 210 babies had no eye problems and served as controls, while 95 were cases of ROP. In 71 of 95 ROP cases, the disease regressed spontaneously on or before stage 3, while in 24 of 95 ROP cases the disease progressed to advanced stages 4 and 5. In case of missense mutation (A105T), the AA genotype was detected in 96% of controls compared with 87% of ROP cases (NS); similarly no significant difference was found between spontaneously regressed ROP cases and those who progressed to advanced stages. For the Val60Glu mutation, no significant association was detected between the genotype and progression of ROP to advanced stages. Unlike data from the US, our findings from a Kuwaiti cohort of ROP cases and controls suggest a lack of association between the two ND gene mutations (A105T and Val60Glu) and ROP and the risk of progression of the disease to advanced stages.

Accuracy of MR markers for differentiating Progressive Supranuclear Palsy from Parkinson's disease

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Stefano Zanigni

2016-01-01

Conclusion: Although several quantitative brain MR markers provided high diagnostic accuracy in differentiating Progressive Supranuclear Palsy-Richardson's Syndrome from Parkinson's disease, the morphometric assessment of midbrain area is the best single diagnostic marker and should be routinely included in the neuroradiological work-up of parkinsonian patients.

Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis.

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Ditsworth, Dara; Maldonado, Marcus; McAlonis-Downes, Melissa; Sun, Shuying; Seelman, Amanda; Drenner, Kevin; Arnold, Eveline; Ling, Shuo-Chien; Pizzo, Donald; Ravits, John; Cleveland, Don W; Da Cruz, Sandrine

2017-06-01

Mutations in TDP-43 cause amyotrophic lateral sclerosis (ALS), a fatal paralytic disease characterized by degeneration and premature death of motor neurons. The contribution of mutant TDP-43-mediated damage within motor neurons was evaluated using mice expressing a conditional allele of an ALS-causing TDP-43 mutant (Q331K) whose broad expression throughout the central nervous system mimics endogenous TDP-43. TDP-43 Q331K mice develop age- and mutant-dependent motor deficits from degeneration and death of motor neurons. Cre-recombinase-mediated excision of the TDP-43 Q331K gene from motor neurons is shown to delay onset of motor symptoms and appearance of TDP-43-mediated aberrant nuclear morphology, and abrogate subsequent death of motor neurons. However, reduction of mutant TDP-43 selectively in motor neurons did not prevent age-dependent degeneration of axons and neuromuscular junction loss, nor did it attenuate astrogliosis or microgliosis. Thus, disease mechanism is non-cell autonomous with mutant TDP-43 expressed in motor neurons determining disease onset but progression defined by mutant acting within other cell types.

Oscillation of Angiogenesis and Vascular Dropout in Progressive Human Vascular Disease. [Vascular Pattern as Useful Read-Out of Complex Molecular Signaling

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Parsons-Wingerter, Patricia

2010-01-01

When analyzed by VESsel GENeration Analysis (VESGEN) software, vascular patterns provide useful integrative read-outs of complex, interacting molecular signaling pathways. Using VESGEN, we recently discovered and published our innovative, surprising findings that angiogenesis oscillated with vascular dropout throughout progression of diabetic retinopathy, a blinding vascular disease. Our findings provide a potential paradigm shift in the current prevailing view on progression and treatment of this disease, and a new early-stage window of regenerative therapeutic opportunities. The findings also suggest that angiogenesis may oscillate with vascular disease in a homeostatic-like manner during early stages of other inflammatory progressive diseases such as cancer and coronary vascular disease.

Weight preserving image registration for monitoring disease progression in lung CT

DEFF Research Database (Denmark)

Gorbunova, Vladlena; Lo, Pechin Chien Pau; Haseem, Ashraf

2008-01-01

We present a new image registration based method for monitoring regional disease progression in longitudinal image studies of lung disease. A free-form image registration technique is used to match a baseline 3D CT lung scan onto a following scan. Areas with lower intensity in the following scan...... the density of lung tissue with respect to local expansion or compression such that the total weight of the lungs is preserved during deformation. Our method provides a good estimation of regional destruction of lung tissue for subjects with a significant difference in inspiration level between CT scans...

Immune Evasion Mechanisms of Entamoeba histolytica: Progression to Disease.

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Begum, Sharmin; Quach, Jeanie; Chadee, Kris

2015-01-01

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

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

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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

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. Clinical trial registration: ISRCTN76742797 and EudraCT2004-000446-20 DOI: http://dx.doi.org/10.7554/eLife.03821.001 PMID:25217531

Association Between Breast Cancer Disease Progression and Workplace Productivity in the United States.

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Yin, Wesley; Horblyuk, Ruslan; Perkins, Julia Jane; Sison, Steve; Smith, Greg; Snider, Julia Thornton; Wu, Yanyu; Philipson, Tomas J

2017-02-01

Determine workplace productivity losses attributable to breast cancer progression. Longitudinal analysis linking 2005 to 2012 medical and pharmacy claims and workplace absence data in the US patients were commercially insured women aged 18 to 64 diagnosed with breast cancer. Productivity was measured as employment status and total quarterly workplace hours missed, and valued using average US wages. Six thousand four hundred and nine women were included. Breast cancer progression was associated with a lower probability of employment (hazard ratio [HR] = 0.65, P work was $24,166 for non-metastatic and $30,666 for metastatic patients. Thus, progression to metastatic disease is associated with an additional $6500 in lost work time (P < 0.05), or 14% of average US wages. Breast cancer progression leads to diminished likelihood of employment, increased workplace hours missed, and increased cost burden.

Progress and challenges in the prevention and control of nonalcoholic fatty liver disease.

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Cai, Jingjing; Zhang, Xiao-Jing; Li, Hongliang

2018-05-30

Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the most common liver disease worldwide. Individuals with NAFLD have a high frequency of developing progressive liver disease and metabolism-related comorbidities, which result from of a lack of awareness and poor surveillance of the disease and a paucity of approved and effective therapies. Managing the complications of NAFLD has already begun to place a tremendous burden on health-care systems. Although efforts to identify effective therapies are underway, the lack of validated preclinical NAFLD models that represent the biology and outcomes of human disease remains a major barrier. This review summarizes the characteristics and prevalence of the disease and the status of our understanding of its mechanisms and potential therapeutic targets. © 2018 Wiley Periodicals, Inc.

Renin-Angiotensin System Inhibitors, Type 2 Diabetes and Fibrosis Progression: An Observational Study in Patients with Nonalcoholic Fatty Liver Disease.

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Serena Pelusi

Full Text Available The clinical determinants of fibrosis progression in nonalcoholic fatty liver disease (NAFLD are still under definition.To assess the clinical determinants of fibrosis progression rate (FPR in NAFLD patients with baseline and follow-up histological evaluation, with a special focus on the impact of pharmacological therapy.In an observational cohort of 118 Italian patients from tertiary referral centers, liver histology was evaluated according to Kleiner. Independent predictors of FPR were selected by a stepwise regression approach.Median follow-up was 36 months (IQR 24-77. Twenty-five patients (18% showed some amelioration, 63 (53% had stability, 30 (25% had progression of fibrosis. Patients with nonalcoholic steatohepatitis (NASH had similar demographic and anthropometric features, but a higher prevalence of type 2 diabetes (T2D; p = 0.010, and use of renin-angiotensin axis system (RAS inhibitors (p = 0.005. Fibrosis progression was dependent of the length of follow-up, and was associated with, but did not require, the presence of NASH (p<0.05. Both fibrosis progression and faster FPR were independently associated with higher APRI score at follow-up, absence of treatment with RAS inhibitors, and T2D diagnosis at baseline (p<0.05. There was a significant interaction between use of RAS inhibitors and T2D on FPR (p = 0.002. RAS inhibitors were associated with slower FPR in patients with (p = 0.011, but not in those without (p = NS T2D.NASH is not required for fibrosis progression in NAFLD, whereas T2D seems to drive fibrogenesis independently of hepatic inflammation. Use of RAS inhibitors may contrast fibrosis progression especially in high-risk patients affected by T2D.

Progress on Chinese evaluated nuclear parameters library (CENPL). Pt. 3

International Nuclear Information System (INIS)

Su Zongdi; Ge Zhigang; Zhou Chunmei

1994-01-01

The progress on Chinese evaluated nuclear parameters library (CENPL) is introduced. The setting up work of each sub-library of CENPL has got some new progresses at the past period. These sub-libraries are atomic mass and characteristic constant for nuclear ground state sub-library, discrete level scheme and batch ratio of γ decay sub-library, level density parameter sub-library, giant dipole resonance parameter for γ-ray strength function sub-library and optical model parameter sub-library

Osteoarthritis in the XXIst Century: Risk Factors and Behaviours that Influence Disease Onset and Progression

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Musumeci, Giuseppe; Aiello, Flavia Concetta; Szychlinska, Marta Anna; Di Rosa, Michelino; Castrogiovanni, Paola; Mobasheri, Ali

2015-01-01

Osteoarthritis (OA) is a growing public health problem across the globe, affecting more than half of the over 65 population. In the past, OA was considered a wear and tear disease, leading to the loss of articular cartilage and joint disability. Nowadays, thanks to advancements in molecular biology, OA is believed to be a very complex multifactorial disease. OA is a degenerative disease characterized by “low-grade inflammation” in cartilage and synovium, resulting in the loss of joint structure and progressive deterioration of cartilage. Although the disease can be dependent on genetic and epigenetic factors, sex, ethnicity, and age (cellular senescence, apoptosis and lubricin), it is also associated with obesity and overweight, dietary factors, sedentary lifestyle and sport injuries. The aim of this review is to highlight how certain behaviors, habits and lifestyles may be involved in the onset and progression of OA and to summarize the principal risk factors involved in the development of this complicated joint disorder. PMID:25785564

High affinity radiopharmaceuticals based upon lansoprazole for PET imaging of aggregated tau in Alzheimer's disease and progressive supranuclear palsy: synthesis, preclinical evaluation, and lead selection.

Science.gov (United States)

Fawaz, Maria V; Brooks, Allen F; Rodnick, Melissa E; Carpenter, Garrett M; Shao, Xia; Desmond, Timothy J; Sherman, Phillip; Quesada, Carole A; Hockley, Brian G; Kilbourn, Michael R; Albin, Roger L; Frey, Kirk A; Scott, Peter J H

2014-08-20

Abnormally aggregated tau is the hallmark pathology of tauopathy neurodegenerative disorders and is a target for development of both diagnostic tools and therapeutic strategies across the tauopathy disease spectrum. Development of carbon-11- or fluorine-18-labeled radiotracers with appropriate affinity and specificity for tau would allow noninvasive quantification of tau burden using positron emission tomography (PET) imaging. We have synthesized [(18)F]lansoprazole, [(11)C]N-methyl lansoprazole, and [(18)F]N-methyl lansoprazole and identified them as high affinity radiotracers for tau with low to subnanomolar binding affinities. Herein, we report radiosyntheses and extensive preclinical evaluation with the aim of selecting a lead radiotracer for translation into human PET imaging trials. We demonstrate that [(18)F]N-methyl lansoprazole, on account of the favorable half-life of fluorine-18 and its rapid brain entry in nonhuman primates, favorable kinetics, low white matter binding, and selectivity for binding to tau over amyloid, is the lead compound for progression into clinical trials.

Effect of disease stage on progression of hydroxychloroquine retinopathy.

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Marmor, Michael F; Hu, Julia

2014-09-01

Hydroxychloroquine sulfate retinopathy can progress after the drug is stopped. It is not clear how this relates to the stage of retinopathy or whether early screening with modern imaging technology can prevent progression and visual loss. To determine the relationship between progression of retinopathy and the severity of disease using objective data from optical coherence tomography and assess the value of early screening for the toxic effects of hydroxychloroquine. Clinical findings in patients with hydroxychloroquine retinopathy were monitored with repeated anatomical and functional examinations for 13 to 40 months after the drug was stopped in a referral practice in a university medical center. Eleven patients participated, with the severity of toxic effects categorized as early (patchy parafoveal damage shown on field or objective testing), moderate (a 50%-100% parafoveal ring of optical coherence tomography thinning but intact retinal pigment epithelium), and severe (visible bull's-eye damage). Visual acuity, white 10-2 visual field pattern density plots, fundus autofluorescence, spectral-density optical coherence tomography cross sections, thickness (from cube diagrams), and ellipsoid zone length. Visual acuity and visual fields showed no consistent change. Fundus autofluorescence showed little or no change except in severe cases in which the bull's-eye damage expanded progressively. Optical coherence tomography cross sections showed little visible change in early and moderate cases but progressive foveal thinning (approximately 7 μm/y) and loss of ellipsoid zone (in the range of 100 μm/y) in severe cases, which was confirmed by quantitative measurements. The measurements also showed some foveal thinning (approximately 4 μm/y) and deepening of parafoveal loss in moderate cases, but the breadth of the ellipsoid zone remained constant in both early and moderate cases. A few cases showed a suggestion of ellipsoid zone improvement. Patients with

Correction to: Progressive multifocal leukoencephalopathy in rituximab-treated rheumatic diseases: a rare event.

Science.gov (United States)

Berger, Joseph R; Malik, Vineeta; Lacey, Stuart; Brunetta, Paul; Lehane, Patricia B

2018-04-10

The article "Progressive multifocal leukoencephalopathy in rituximab-treated rheumatic diseases: a rare event," written by Joseph R. Berger, Vineeta Malik, Stuart Lacey, Paul Brunetta, and Patricia B. Lehane 3 , was originally published electronically on the publisher's internet portal (currently SpringerLink).

Subjective cognitive concerns and neuropsychiatric predictors of progression to the early clinical stages of Alzheimer disease.

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Donovan, Nancy J; Amariglio, Rebecca E; Zoller, Amy S; Rudel, Rebecca K; Gomez-Isla, Teresa; Blacker, Deborah; Hyman, Bradley T; Locascio, Joseph J; Johnson, Keith A; Sperling, Reisa A; Marshall, Gad A; Rentz, Dorene M

2014-12-01

To examine neuropsychiatric and neuropsychological predictors of progression from normal to early clinical stages of Alzheimer disease (AD). From a total sample of 559 older adults from the Massachusetts Alzheimer's Disease Research Center longitudinal cohort, 454 were included in the primary analysis: 283 with clinically normal cognition (CN), 115 with mild cognitive impairment (MCI), and 56 with subjective cognitive concerns (SCC) but no objective impairment, a proposed transitional group between CN and MCI. Two latent cognitive factors (memory-semantic, attention-executive) and two neuropsychiatric factors (affective, psychotic) were derived from the Alzheimer's Disease Centers' Uniform Data Set neuropsychological battery and Neuropsychiatric Inventory brief questionnaire. Factors were analyzed as predictors of time to progression to a worse diagnosis using a Cox proportional hazards regression model with backward elimination. Covariates included baseline diagnosis, gender, age, education, prior depression, antidepressant medication, symptom duration, and interaction terms. Higher/better memory-semantic factor score predicted lower hazard of progression (hazard ratio [HR] = 0.4 for 1 standard deviation [SD] increase, p factor score predicted higher hazard (HR = 1.3 for one SD increase, p = 0.01). No other predictors were significant in adjusted analyses. Using diagnosis as a sole predictor of transition to MCI, the SCC diagnosis carried a fourfold risk of progression compared with CN (HR = 4.1, p factors as significant predictors of more rapid progression from normal to early stages of cognitive decline and highlight the subgroup of cognitively normal elderly with SCC as those with elevated risk of progression to MCI. Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

Validating a proxy for disease progression in metastatic cancer patients using prescribing and dispensing data.

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Joshi, Vikram; Adelstein, Barbara-Ann; Schaffer, Andrea; Srasuebkul, Preeyaporn; Dobbins, Timothy; Pearson, Sallie-Anne

2017-10-01

Routine data collections are used increasingly to examine outcomes of real-world cancer drug use. These datasets lack clinical details about important endpoints such as disease progression. To validate a proxy for disease progression in metastatic cancer patients using prescribing and dispensing claims. We used data from a cohort study of patients undergoing chemotherapy who provided informed consent to the collection of cancer-treatment data from medical records and linkage to pharmaceutical claims. We derived proxy decision rules based on changes to drug treatment in prescription histories (n = 36 patients) and validated the proxy in prescribing data (n = 62 patients). We adapted the decision rules and validated the proxy in dispensing data (n = 109). Our gold standard was disease progression ascertained in patient medical records. Individual progression episodes were the unit of analysis for sensitivity and Positive Predictive Value (PPV) calculations and specificity and Negative Predictive Value (NPV) were calculated at the patient level. The sensitivity of our proxy in prescribing data was 74.3% (95% Confidence Interval (CI), 55.6-86.6%) and PPV 61.2% (95% CI, 45.0-75.3%); specificity and NPV were 87.8% (95% CI, 73.8-95.9%) and 100% (95% CI, 90.3-100%), respectively. In dispensing data, the sensitivity of our proxy was 64% (95% CI, 55.0-77.0%) and PPV 56.0% (95% CI, 43.0-69.0%); specificity and NPV were 81% (95% CI, 70.05-89.0%) and 91.0% (95% CI, 82.0-97.0%), respectively. Our proxy overestimated episodes of disease progression. The proxy's performance is likely to improve if the date of prescribing is used instead of date of dispensing in claims data and by incorporating medical service claims (such as imaging prior to drug changes) in the algorithm. Our proxy is not sufficiently robust for use in real world comparative effectiveness research for cancer medicines. © 2016 John Wiley & Sons Australia, Ltd.

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

International Nuclear Information System (INIS)

Lake, April D.; Novak, Petr; Shipkova, Petia; Aranibar, Nelly; Robertson, Donald; Reily, Michael D.; Lu, Zhenqiang; Lehman-McKeeman, Lois D.; Cherrington, Nathan J.

2013-01-01

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

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

Energy Technology Data Exchange (ETDEWEB)

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

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

Salivary DJ-1 could be an indicator of Parkinson’s disease progression

Directory of Open Access Journals (Sweden)

Wen-yan eKang

2014-06-01

Full Text Available 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.

Research progress of rehabilitation therapy in Parkinson's disease and its mechanism

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Jin LIU

2017-07-01

Full Text Available Parkinson's disease (PD is characterized by the progressive degeneration of dopaminergic neurons in substantia nigra pars compacta. Rehabilitation therapy can delay the development of disease, improve motor symptoms and non - motor symptoms (NMS, and consequently improve the activities of daily living (ADL in patients with PD. The mechanism of rehabilitation improving the symptoms of PD is very complex, involving a variety of molecular mechanisms. Thus, this review will focus on the effect of rehabilitation therapy on PD and the underlying molecular mechanism including neurotransmitters, trophic factors, synaptic plasticity and immune system. DOI: 10.3969/j.issn.1672-6731.2017.06.003

International vision requirements for driver licensing and disability pensions: using a milestone approach in characterization of progressive eye disease

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Alain M Bron

2010-11-01

Full Text Available Alain M Bron1, Ananth C Viswanathan2, Ulrich Thelen3, Renato de Natale4, Antonio Ferreras5, Jens Gundgaard6, Gail Schwartz7, Patricia Buchholz81Department of Ophthalmology, University Hospital, Dijon, France; 2Glaucoma Research Unit, Moorfields Eye Hospital NHS Foundation Trust and Department of Genetics, University College of London Institute of Ophthalmology, London, UK; 3Private Practice, Munster, Germany; 4Ospedale Civile di Monselice, Monselice, Italy; 5Ophthalmology, Miguel Servet University Hospital, Zaragoza, Spain; 6COWI, Kolding, Denmark; 7Wilmer Eye Institute, Johns Hopkins University, Glaucoma Consultants, Baltimore, MD, USA; 8Patricia Buchholz Consulting, Karlsruhe, GermanyObjective: Low vision that causes forfeiture of driver’s licenses and collection of disability pension benefits can lead to negative psychosocial and economic consequences. The purpose of this study was to review the requirements for holding a driver’s license and rules for obtaining a disability pension due to low vision. Results highlight the possibility of using a milestone approach to describe progressive eye disease.Methods: Government and research reports, websites, and journal articles were evaluated to review rules and requirements in Germany, Spain, Italy, France, the UK, and the US.Results: Visual acuity limits are present in all driver’s license regulations. In most countries, the visual acuity limit is 0.5. Visual field limits are included in some driver’s license regulations. In Europe, binocular visual field requirements typically follow the European Union standard of ≥120°. In the US, the visual field requirements are typically between 110° and 140°. Some countries distinguish between being partially sighted and blind in the definition of legal blindness, and in others there is only one limit.Conclusions: Loss of driving privileges could be used as a milestone to monitor progressive eye disease. Forfeiture could be standardized as a

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

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Masataka Kikuchi

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

An Unrecognized Rash Progressing to Lyme Carditis: Important Features and Recommendations Regarding Lyme Disease.

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Lee, Shawn; Singla, Montish

2016-01-01

We present a case report of 46-year-old man with no medical history, who complained of extreme fatigue, near-syncope, and palpitations. He initially presented in complete heart block. A transvenous pacemaker was placed in the emergency department, and he was started empirically on Ceftriaxone for Lyme disease. He was admitted and over the course of the next few days, his rhythm regressed to Mobitz type I first-degree atrioventricular block and then to normal sinus rhythm. This case report highlights some important features regarding Lyme carditis, a rare presentation of early disseminated Lyme disease (seen in a few weeks to months after the initial tick bite). In 25%-30% of patients, the characteristic targetoid rash may not be seen, a likely culprit of the disease not being detected early and progressing to disseminated disease. The most common cardiac complaint of Lyme disease is palpitations, occurring in 6.6% of patients, which may not accurately reflect progression into disseminated Lyme disease because it is a nonspecific finding. Conduction abnormality, occurring in 1.8% of patients, is a more specific finding of Borrelia invading cardiac tissue. Finally, this case report highlights a recommendation that patients with confirmed Lyme disease or those presenting with cardiac abnormalities or symptoms who have an atypical profile for a cardiac event should be screened with a 12-lead electrocardiogram, Lyme serology, and be considered for antibiotic therapy with the possibility of temporary pacing.

Immune evasion mechanisms of Entamoeba histolytica: progression to disease

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Sharmin eBegum

2015-12-01

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

Latest progress of BIGH3 gene in corneal diseases and diabetic retinopathy

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Fan-Qian Song

2017-03-01

Full Text Available BIGH3 gene plays an important role in ocular diseases. On the one hand, it is closely related to the occurrence of corneal diseases. BIGH3 gene can inhibit corneal neovascularization, lead to corneal dystrophy, participate in keratoconus formation. On the other hand, it can lead to the formation of neovascularization in diabetic retinopathy. The latest experiments show that TGF beta secreted by macrophages can promote the expression of BIGH3 mRNA and BIGH3 protein, and promote apoptosis of retinal endothelial cells and pericytes, which leads to the formation of neovascularization in diabetic retinopathy. This article will describe the new progress of BIGH3 gene in ocular diseases from several aspects as mentioned above.

Maximum standard uptake value on pre-chemotherapeutic FDG-PET is a significant parameter for disease progression of newly diagnosed lymphoma

International Nuclear Information System (INIS)

Eo, Jae Seon; Lee, Won Woo; Chung, June Key; Lee, Myung Chul; Kim, Sang Eun

2005-01-01

F-18 FDG-PET is useful for detection and staging of lymphoma. We investigated the prognostic significance of maximum standard uptake (maxSUV) value of FDG-PET for newly diagnosed lymphoma patients before chemotherapy. Twenty-seven patients (male: female = 17: 10: age: 49±19 years) with newly diagnosed lymphoma were enrolled. Nine-teen patients suffered from B cell lymphoma, 6 Hodgkins disease and 2 T cell lymphoma. One patient was stage I, 9 stage II, 3 stage III, 1 stage IV and 13 others. All patients underwent FDG-PET before initiation of chemotherapy. MaxSUV values using lean body weight were obtained for main and largest lesion to represent maxSUV of the patients. The disease progression was defined as total change of the chemotherapeutic regimen or addition of new chemotherapeutic agent during follow up period. The observed period was 389±224 days. The value of maxSUV ranged from 3 to 18 (mean±SD = 10.6±4.4). The disease progressions occurred in 6 patients. Using Cox proportional-hazard regression analysis, maxSUV was identified as a significant parameter for the disease progression free survival (p=0.044). Kaplan-Meier survival curve analysis revealed that the group with higher maxSUV (=10.6, n=5) suffered from shorter disease progression free survival (median 299 days) than the group with lower maxSUV (<10.6, n = 22) (median 378 days, p=0.0146). We found that maxSUV on pre-chemotherapeutic F-18 FDG-PET for newly diagnosed lymphoma patients is a significant parameter for disease progression. Lymphoma patients can be stratified before initiation of chemotherapy in terms of disease progression by the value of maxSUV 10.6

[Evaluation and treatment of dysphagia in amyotrophic lateral sclerosis and Parkinson's disease].

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Yamamoto, Toshiyuki

2011-11-01

As both amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) exhibit a variety of patterns of dysphagia, appropriate symptomatic treatment is provided after evaluation of swallowing function through videofluoroscopic examination of swallowing. In ALS, disease progression is rapid, therefore, respiratory function, swallowing function and nutritional status should be evaluated regularly. When the oral or pharyngeal stage of swallowing are affected early in dysphagia, adjusting swallowing volume and varying consistency can be beneficial in ALS. When all stages of swallowing are impaired in ALS, such complications as pneumonia, dehydration and malnutrition, are observed. In such patients, it is necessary to consider an alternative to oral dietary intake. In PD, dysphagia is not necessarily associated with severity of parkinsonism and can appear at any time during the course of the disease. Dysphagia in PD can occur at any stage of swallowing and frequently accompanies multiple abnormalities. In particular, aspiration is an important risk factor for pneumonia in PD. The effect of L-dopa treatment for dysphagia is often insufficient; however, this treatment remains the first choice because dysphagia is exacerbated during off state. Rehabilitation for dysphagia in PD has also some effect.

Clinical reactivations of herpes simplex virus type 2 infection and human immunodeficiency virus disease progression markers.

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Bulbulgul Aumakhan

Full Text Available BACKGROUND: The natural history of HSV-2 infection and role of HSV-2 reactivations in HIV disease progression are unclear. METHODS: Clinical symptoms of active HSV-2 infection were used to classify 1,938 HIV/HSV-2 co-infected participants of the Women's Interagency HIV Study (WIHS into groups of varying degree of HSV-2 clinical activity. Differences in plasma HIV RNA and CD4+ T cell counts between groups were explored longitudinally across three study visits and cross-sectionally at the last study visit. RESULTS: A dose dependent association between markers of HIV disease progression and degree of HSV-2 clinical activity was observed. In multivariate analyses after adjusting for baseline CD4+ T cell levels, active HSV-2 infection with frequent symptomatic reactivations was associated with 21% to 32% increase in the probability of detectable plasma HIV RNA (trend p = 0.004, an average of 0.27 to 0.29 log10 copies/ml higher plasma HIV RNA on a continuous scale (trend p<0.001 and 51 to 101 reduced CD4+ T cells/mm(3 over time compared to asymptomatic HSV-2 infection (trend p<0.001. CONCLUSIONS: HIV induced CD4+ T cell loss was associated with frequent symptomatic HSV-2 reactivations. However, effect of HSV-2 reactivations on HIV disease progression markers in this population was modest and appears to be dependent on the frequency and severity of reactivations. Further studies will be necessary to determine whether HSV-2 reactivations contribute to acceleration of HIV disease progression.

Progression of Liver Disease

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... Legacy Society Make Gifts of Stock Donate Your Car Personal Fundraising Partnership & Support Share Your Story Spread the Word Give While You Shop Contact Us Donate Now The Progression of Liver ...

Early intranasal insulin therapy halts progression of neurodegeneration: progress in Alzheimer’s disease therapeutics

OpenAIRE

de la Monte, Suzanne M.

2012-01-01

Evaluation of Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, et al. Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment: A Pilot Clinical Trial. Arch Neurol. 2011 Sep 12. Alzheimer’s disease is associated with brain insulin deficiency and insulin resistance, similar to the problems in diabetes. If insulin could be supplied to the brain in the early stages of Alzheimer’s, subsequent neurodegeneration might be prevented. ...

Renal expression of FGF23 in progressive renal disease of diabetes and the effect of ACE inhibitor.

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Cristina Zanchi

Full Text Available Fibroblast growth factor 23 (FGF23 is a phosphaturic hormone mainly produced by bone that acts in the kidney through FGF receptors and Klotho. Here we investigated whether the kidney was an additional source of FGF23 during renal disease using a model of type 2 diabetic nephropathy. Renal expression of FGF23 and Klotho was assessed in Zucker diabetic fatty (ZDF and control lean rats at 2, 4, 6, 8 months of age. To evaluate whether the renoprotective effect of angiotensin converting enzyme (ACE inhibitor in this model was associated with changes in FGF23 and Klotho, ZDF rats received ramipril from 4, when proteinuric, to 8 months of age. FGF23 mRNA was not detectable in the kidney of lean rats, nor of ZDF rats at 2 months of age. FGF23 became measurable in the kidney of diabetic rats at 4 months and significantly increased thereafter. FGF23 protein localized in proximal and distal tubules. Renal Klotho mRNA and protein decreased during time in ZDF rats. As renal disease progressed, serum phosphate levels increased in parallel with decline of fractional phosphorus excretion. Ramipril limited proteinuria and renal injury, attenuated renal FGF23 upregulation and ameliorated Klotho expression. Ramipril normalized serum phosphate levels and tended to increase fractional phosphorus excretion. These data indicate that during progressive renal disease the kidney is a site of FGF23 production which is limited by ACE inhibition. Interfering pharmacologically with the delicate balance of FGF23 and phosphorus in diabetes may have implications in clinics.

Risk factors associated with disease progression and mortality in chronic kidney disease of uncertain etiology: a cohort study in Medawachchiya, Sri Lanka.

Science.gov (United States)

Senevirathna, Lalantha; Abeysekera, Tilak; Nanayakkara, Shanika; Chandrajith, Rohana; Ratnatunga, Neelakanthi; Harada, Kouji H; Hitomi, Toshiaki; Komiya, Toshiyuki; Muso, Eri; Koizumi, Akio

2012-05-01

The alarming rise in the prevalence of chronic kidney disease of uncertain etiology (CKDu) among the low socioeconomic farming community in the North Central Province of Sri Lanka has been recognized as an emerging public health issue in the country. This study sought to determine the possible factors associated with the progression and mortality of CKDu. The study utilized a single-center cohort registered in 2003 and followed up until 2009 in a regional clinic in the endemic region, and used a Cox proportional hazards model. We repeatedly found an association between disease progression and hypertension. Men were at higher risk of CKDu than women. A significant proportion of the patients in this cohort were underweight, which emphasized the need for future studies on the nutritional status of these patients. Compared with findings in western countries and other regions of Asia, we identified hypertension as a major risk factor for progression of CKDu in this cohort.

The urine albumin-to-creatinine ratio is a reliable indicator for evaluating complications of chronic kidney disease and progression in IgA nephropathy in China

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Lu Huan

2016-05-01

Full Text Available OBJECTIVE: This study investigated the correlation between the albumin-to-creatinine ratio in the urine and 24-hour urine proteinuria and whether the ratio can predict chronic kidney disease progression even more reliably than 24-hour proteinuria can, particularly in primary IgA nephropathy. METHODS: A total of 182 patients with primary IgA nephropathy were evaluated. Their mean urine albumin-to-creatinine ratio and 24-hour proteinuria were determined during hospitalization. Blood samples were also analyzed. Follow-up data were recorded for 44 patients. A cross-sectional study was then conducted to test the correlation between these parameters and their associations with chronic kidney disease complications. Subsequently, a canonical correlation analysis was employed to assess the correlation between baseline proteinuria and parameters of the Oxford classification. Finally, a prospective observational study was performed to evaluate the association between proteinuria and clinical outcomes. Our study is registered in the Chinese Clinical Trial Registry, and the registration number is ChiCTR-OCH-14005137. RESULTS: A strong correlation (r=0.81, p<0.001 was found between the ratio and 24-hour proteinuria except in chronic kidney disease stage 5. First-morning urine albumin-to-creatinine ratios of ≥125.15, 154.44 and 760.31 mg/g reliably predicted equivalent 24-hour proteinuria ‘thresholds’ of ≥0.15, 0.3 and 1.0 g/24 h, respectively. In continuous analyses, the albumin-to-creatinine ratio was significantly associated with anemia, acidosis, hypoalbuminemia, hyperphosphatemia, hyperkalemia, hypercholesterolemia and higher serum cystatin C. However, higher 24-hour proteinuria was only associated with hypoalbuminemia and hypercholesterolemia. Higher tubular atrophy and interstitial fibrosis scores were also associated with a greater albumin-to-creatinine ratio, as observed in the canonical correlation analysis. Finally, the albumin

Research progress on animal models of Alzheimer's disease

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Wen DONG

2015-08-01

Full Text Available Alzheimer's disease (AD is a degenerative disease of the central nervous system, and its pathogenesis is complex. Animal models play an important role in study on pathogenesis and treatment of AD. This paper summarized methods of building models, observation on animal models and evaluation index in recent years, so as to provide related evidence for basic and clinical research in future. DOI: 10.3969/j.issn.1672-6731.2015.08.003

Minimal Residual Disease in Acute Myeloid Leukemia: Still a Work in Progress?

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Federico Mosna

2017-06-01

Full Text Available Minimal residual disease evaluation refers to a series of molecular and immunophenotypical techniques aimed at detecting submicroscopic disease after therapy. As such, its application in acute myeloid leukemia has greatly increased our ability to quantify treatment response, and to determine the chemosensitivity of the disease, as the final product of the drug schedule, dose intensity, biodistribution, and the pharmakogenetic profile of the patient. There is now consistent evidence for the prognostic power of minimal residual disease evaluation in acute myeloid leukemia, which is complementary to the baseline prognostic assessment of the disease. The focus for its use is therefore shifting to individualize treatment based on a deeper evaluation of chemosensitivity and residual tumor burden. In this review, we will summarize the results of the major clinical studies evaluating minimal residual disease in acute myeloid leukemia in adults in recent years and address the technical and practical issues still hampering the spread of these techniques outside controlled clinical trials. We will also briefly speculate on future developments and offer our point of view, and a word of caution, on the present use of minimal residual disease measurements in “real-life” practice. Still, as final standardization and diffusion of the methods are sorted out, we believe that minimal residual disease will soon become the new standard for evaluating response in the treatment of acute myeloid leukemia.

The effect of angiotensin-converting-enzyme inhibitors on progression of advanced polycystic kidney disease

DEFF Research Database (Denmark)

Jafar, Tazeen H; Stark, Paul C; Schmid, Christopher H

2005-01-01

BACKGROUND: It is not known whether angiotensin-converting-enzyme (ACE) inhibitors slow the progression of polycystic kidney disease (PKD). We performed a patient-level meta-analysis to compare the effect of antihypertensive regimens, including ACE inhibitors, to those without ACE inhibitors...... of doubling of baseline serum creatinine or onset of kidney failure). We also performed multivariable linear regression and Cox proportional hazards analyses. Based on previous findings, we searched for interactions between the treatment effect (effect of ACE inhibitors vs. controls) and baseline urine......%) in the ACE inhibitor group and 30 patients (41%) in the control group (P= 0.17). ACE inhibitors had a greater effect on lowering urine protein excretion and slowing kidney disease progression in patients with higher levels of baseline urine protein excretion (interaction P

Research progress in role of iron overload in non-alcoholic fatty liver disease

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LI Guangming

2013-12-01

Full Text Available Iron overload is an important research focus in non-alcoholic fatty liver disease (NAFLD. The relationship between iron overload and NAFLD is summarized from the assessment method for iron overload, relationship between iron load and hemochromatosis gene mutations, incidence of iron load in NAFLD, and relationship between iron load and progression of NAFLD; the action mechanism of iron overload in the progression of NAFLD is reviewed from the causes of iron overload, relationship between iron overload and lipid metabolism, and relationship between type of iron deposition and liver damage; the significance of iron overload in the diagnosis and treatment of NAFLD is discussed from iron overload as a new marker of risk stratification and potential therapeutic target in NAFLD. It is currently considered that iron overload, whether the cause or result of NAFLD progression, will promote the progression of NAFLD once it occurs; as a new marker of risk stratification and potential therapeutic target in NAFLD, iron load is worthy of further study.

Evaluation of Absolute and Relative Reinforcer Value Using Progressive-Ratio Schedules

Science.gov (United States)

Francisco, Monica T.; Borrero, John C.; Sy, Jolene R.

2008-01-01

We evaluated behavior exhibited by individuals with developmental disabilities using progressive-ratio (PR) schedules. High- and low-preference stimuli were determined based on the results of a paired-stimulus preference assessment and were evaluated in subsequent reinforcer and PR assessments using concurrent and single schedules of presentation.…

The Role of Dendritic Cells in Fibrosis Progression in Nonalcoholic Fatty Liver Disease

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Paloma Almeda-Valdes

2015-01-01

Full Text Available Nonalcoholic fatty liver disease (NAFLD is the most frequent cause of chronic liver disease. NAFLD encompasses a wide range of pathologies, from simple steatosis to steatosis with inflammation to fibrosis. The pathogenesis of NAFLD progression has not been completely elucidated, and different liver cells could be implicated. This review focuses on the current evidence of the role of liver dendritic cells (DCs in the progression from NAFLD to fibrosis. Liver DCs are a heterogeneous population of hepatic antigen-presenting cells; their main function is to induce T-cell mediated immunity by antigen processing and presentation to T cells. During the steady state liver DCs are immature and tolerogenic. However, in an environment of chronic inflammation, DCs are transformed to potent inducers of immune responses. There is evidence about the role of DC in liver fibrosis, but it is not clearly understood. Interestingly, there might be a link between lipid metabolism and DC function, suggesting that immunogenic DCs are associated with liver lipid storage, representing a possible pathophysiological mechanism in NAFLD development. A better understanding of the interaction between inflammatory pathways and the different cell types and the effect on the progression of NAFLD is of great relevance.

Geoscientific evaluation factors and criteria for siting and site evaluation. Progress report

International Nuclear Information System (INIS)

Stroem, A.; Ericsson, Lars O.; Svemar, C.; Almen, K.E.; Andersson, Johan

1999-03-01

The purposes of the present report are to: present the work that has been done to identify the parameters that need to be determined in a geoscientific site investigation and that serve as the basis for the work with geoscientific evaluation factors; give a progress report from the project that was initiated in 1997 named Siting Factors and Criteria for Site Evaluation, with an emphasis on definitions, outline and structure for the execution of the work; present geoscientific requirements on function both general and in detail in the form of an example for the discipline rock mechanics; present geoscientific evaluation factors associated with different stages in the siting work in the form of an example for the discipline hydrogeochemical composition; present plans for further work as regards criteria for site evaluation in different siting stages. The project is under way, and this is to be regarded as a progress report since e.g. criteria for site evaluation will be presented at a later date. The long-term performance and safety of the deep repository must always be evaluated by means of an integrated safety assessment. The work with factors and criteria can never take the place of such an assessment, but can provide guidance regarding its outcome. Requirements and preferences regarding the function of the rock in the deep repository have been clarified in this progress report. What is new here is the structuring that has been carried out, with a classification into different geoscientific disciplines, and the formalism that has been given to the terms requirement, preference and function. Based on fundamental safety and construction functions, requirements on function have been specified for the disciplines geology, thermal properties, hydro-geology, rock mechanics, chemistry and transport properties. Furthermore, function analyses have been identified by means of which it is possible to concretize requirements on function and which geoscientific parameters are

Geoscientific evaluation factors and criteria for siting and site evaluation. Progress report

Energy Technology Data Exchange (ETDEWEB)

Stroem, A.; Ericsson, Lars O.; Svemar, C. [Swedish Nuclear Fuel and Waste Management Co., Stockholm (Sweden); Almen, K.E. [KEA GEO-konsult AB (Sweden); Andersson, Johan [Golder Grundteknik KB (Sweden)

1999-03-01

The purposes of the present report are to: present the work that has been done to identify the parameters that need to be determined in a geoscientific site investigation and that serve as the basis for the work with geoscientific evaluation factors; give a progress report from the project that was initiated in 1997 named Siting Factors and Criteria for Site Evaluation, with an emphasis on definitions, outline and structure for the execution of the work; present geoscientific requirements on function both general and in detail in the form of an example for the discipline rock mechanics; present geoscientific evaluation factors associated with different stages in the siting work in the form of an example for the discipline hydrogeochemical composition; present plans for further work as regards criteria for site evaluation in different siting stages. The project is under way, and this is to be regarded as a progress report since e.g. criteria for site evaluation will be presented at a later date. The long-term performance and safety of the deep repository must always be evaluated by means of an integrated safety assessment. The work with factors and criteria can never take the place of such an assessment, but can provide guidance regarding its outcome. Requirements and preferences regarding the function of the rock in the deep repository have been clarified in this progress report. What is new here is the structuring that has been carried out, with a classification into different geoscientific disciplines, and the formalism that has been given to the terms requirement, preference and function. Based on fundamental safety and construction functions, requirements on function have been specified for the disciplines geology, thermal properties, hydro-geology, rock mechanics, chemistry and transport properties. Furthermore, function analyses have been identified by means of which it is possible to concretize requirements on function and which geoscientific parameters are

Lipidomic Signature of Progression of Chronic Kidney Disease in the Chronic Renal Insufficiency Cohort

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Farsad Afshinnia

2016-11-01

Discussion: We conclude that a distinct panel of lipids may improve prediction of progression of chronic kidney disease beyond estimated glomerular filtration rate and urine protein-to-creatinine ratio when added to the base model.

Evidence for chronic inflammation as a component of the interstitial lung disease associated with progressive systemic sclerosis

International Nuclear Information System (INIS)

Rossi, G.A.; Bitterman, P.B.; Rennard, S.I.; Ferrans, V.J.; Crystal, R.G.

1985-01-01

Progressive systemic sclerosis (PSS) is a generalized disorder characterized by fibrosis of many organs including the lung parenchyma. Unlike most other interstitial disorders, traditional concepts of the interstitial lung disease associated with PSS have held it to be a ''pure'' fibrotic disorder without a significant inflammatory component. To directly evaluate whether an active alveolitis is associated with this disorder, patients with chronic interstitial lung disease and PSS were studied by open lung biopsy, gallium-67 scanning, and bronchoalveolar lavage. Histologic evaluation of the biopsies demonstrated that the interstitial fibrosis of PSS is clearly associated with the presence of macrophages, lymphocytes, and polymorphonuclear leukocytes, both in the interstitium and on the alveolar epithelial surface. Gallium-67 scans were positive in 77% of the patients, showing diffuse, primarily lower zone uptake, suggestive of active inflammation. Consistent with the histologic findings, bronchoalveolar lavage studies demonstrated a mild increase in the proportions of neutrophils and eosinophils with occasional increased numbers of lymphocytes. Importantly, alveolar macrophages from patients with PSS showed increased release of fibronectin and alveolar-macrophage-derived growth factor, mediators that together stimulate lung fibroblasts to proliferate, thus suggesting at least one mechanism modulating the lung fibrosis of these patients

Accelerating regional atrophy rates in the progression from normal aging to Alzheimer's disease

NARCIS (Netherlands)

Sluimer, J.D.; van der Flier, W.M.; Karas, G.B.; van Schijndel, R.; Barnes, J.; Boyes, R.G.; Cover, K.S.; Olabarriaga, S.D.; Fox, N.C.; Scheltens, P.; Vrenken, H.; Barkhof, F.

2009-01-01

We investigated progression of atrophy in vivo, in Alzheimer's disease (AD), and mild cognitive impairment (MCI). We included 64 patients with AD, 44 with MCI and 34 controls with serial MRI examinations (interval 1.8 +/- 0.7 years). A nonlinear registration algorithm (fluid) was used to calculate

High Affinity Radiopharmaceuticals Based Upon Lansoprazole for PET Imaging of Aggregated Tau in Alzheimer’s Disease and Progressive Supranuclear Palsy: Synthesis, Preclinical Evaluation, and Lead Selection

Science.gov (United States)

2014-01-01

Abnormally aggregated tau is the hallmark pathology of tauopathy neurodegenerative disorders and is a target for development of both diagnostic tools and therapeutic strategies across the tauopathy disease spectrum. Development of carbon-11- or fluorine-18-labeled radiotracers with appropriate affinity and specificity for tau would allow noninvasive quantification of tau burden using positron emission tomography (PET) imaging. We have synthesized [18F]lansoprazole, [11C]N-methyl lansoprazole, and [18F]N-methyl lansoprazole and identified them as high affinity radiotracers for tau with low to subnanomolar binding affinities. Herein, we report radiosyntheses and extensive preclinical evaluation with the aim of selecting a lead radiotracer for translation into human PET imaging trials. We demonstrate that [18F]N-methyl lansoprazole, on account of the favorable half-life of fluorine-18 and its rapid brain entry in nonhuman primates, favorable kinetics, low white matter binding, and selectivity for binding to tau over amyloid, is the lead compound for progression into clinical trials. PMID:24896980

Klinefelter′s syndrome associated with progressive muscular atrophy simulating Kennedy′s disease

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Pedro Enrique Jiménez Caballero

2012-01-01

Full Text Available 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.

Quantitative Evaluation of Heavy Duty Machine Tools Remanufacturing Based on Modified Catastrophe Progression Method

Science.gov (United States)

shunhe, Li; jianhua, Rao; lin, Gui; weimin, Zhang; degang, Liu

2017-11-01

The result of remanufacturing evaluation is the basis for judging whether the heavy duty machine tool can remanufacture in the EOL stage of the machine tool lifecycle management.The objectivity and accuracy of evaluation is the key to the evaluation method.In this paper, the catastrophe progression method is introduced into the quantitative evaluation of heavy duty machine tools’ remanufacturing,and the results are modified by the comprehensive adjustment method,which makes the evaluation results accord with the standard of human conventional thinking.Using the catastrophe progression method to establish the heavy duty machine tools’ quantitative evaluation model,to evaluate the retired TK6916 type CNC floor milling-boring machine’s remanufacturing.The evaluation process is simple,high quantification,the result is objective.

Defining natural history: assessment of the ability of college students to aid in characterizing clinical progression of Niemann-Pick disease, type C.

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Jenny Shin

Full Text Available Niemann-Pick Disease, type C (NPC is a fatal, neurodegenerative, lysosomal storage disorder. It is a rare disease with broad phenotypic spectrum and variable age of onset. These issues make it difficult to develop a universally accepted clinical outcome measure to assess urgently needed therapies. To this end, clinical investigators have defined emerging, disease severity scales. The average time from initial symptom to diagnosis is approximately 4 years. Further, some patients may not travel to specialized clinical centers even after diagnosis. We were therefore interested in investigating whether appropriately trained, community-based assessment of patient records could assist in defining disease progression using clinical severity scores. In this study we evolved a secure, step wise process to show that pre-existing medical records may be correctly assessed by non-clinical practitioners trained to quantify disease progression. Sixty-four undergraduate students at the University of Notre Dame were expertly trained in clinical disease assessment and recognition of major and minor symptoms of NPC. Seven clinical records, randomly selected from a total of thirty seven used to establish a leading clinical severity scale, were correctly assessed to show expected characteristics of linear disease progression. Student assessment of two new records donated by NPC families to our study also revealed linear progression of disease, but both showed accelerated disease progression, relative to the current severity scale, especially at the later stages. Together, these data suggest that college students may be trained in assessment of patient records, and thus provide insight into the natural history of a disease.

S100-A9 protein in exosomes from chronic lymphocytic leukemia cells promotes NF-κB activity during disease progression.

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Prieto, Daniel; Sotelo, Natalia; Seija, Noé; Sernbo, Sandra; Abreu, Cecilia; Durán, Rosario; Gil, Magdalena; Sicco, Estefanía; Irigoin, Victoria; Oliver, Carolina; Landoni, Ana Inés; Gabus, Raúl; Dighiero, Guillermo; Oppezzo, Pablo

2017-08-10

Chronic lymphocytic leukemia (CLL) is an incurable disease characterized by accumulation of clonal B lymphocytes, resulting from a complex balance between cell proliferation and apoptotic death. Continuous crosstalk between cancer cells and local/distant host environment is required for effective tumor growth. Among the main actors of this dynamic interplay between tumoral cells and their microenvironment are the nano-sized vesicles called exosomes. Emerging evidence indicates that secretion, composition, and functional capacity of exosomes are altered as tumors progress to an aggressive phenotype. In CLL, no data exist exploring the specific changes in the proteomic profile of plasma-derived exosomes from patients during disease evolution. We hereby report for the first time different proteomic profiles of plasma exosomes, both between indolent and progressive CLLs as well as within the individual patients at the onset of disease and during its progression. Next, we focus on the changes of the exosome protein cargoes, which are found exclusively in patients with progressive CLL after disease progression. The alterations in the proteomic cargoes underline different networks specific for leukemia progression related to inflammation, oxidative stress, and NF-κB and phosphatidylinositol 3-kinase/AKT pathway activation. Finally, our results suggest a preponderant role for the protein S100-A9 as an activator of the NFκB pathway during CLL progression and suggest that the leukemic clone can generate an autoactivation loop through S100-A9 expression, NF-κB activation, and exosome secretion. Collectively, our data propose a new pathway for NF-κB activation in CLL and highlight the importance of exosomes as extracellular mediators promoting tumor progression in CLL. © 2017 by The American Society of Hematology.

Celiac disease: progress towards diagnosis and definition of pathogenic mechanisms.

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Rossi, Mauro; Bot, Adrian

2011-08-01

The current issue of the International Reviews of Immunology is dedicated entirely to Celiac Disease (CD). Recent development of additional biomarkers and diagnostics resulted in a sharp revision of the prevalence of this condition, with a previously unrecognized subclinical occurrence in the adult population. This was paralleled by groundbreaking progress in understanding its molecular pathogenesis: while gluten-derived peptides activate the innate immunity, post-translationally modified gluten elicits an adaptive immunity. These arms amplify each other, resulting in a self- perpetuating autoimmune condition, influenced by disturbances of the gut flora and mucus chemistry. The process evolves dramatically in a subset of patients with vulnerable immune homeostasis (eg. Treg cells) explaining the progressive, aggravating syndrome in the clinically overt version of CD. In depth understanding of the pathogenesis of CD thus creates the premises of developing novel, more accurate animal models that should support a rationale development of new prophylactic and therapeutic interventions.

Adult polyglucosan body disease presenting as a unilateral progressive plexopathy.

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Naddaf, Elie; Kassardjian, Charles D; Kurt, Yasemin Gulcan; Akman, Hasan Orhan; Windebank, Anthony J

2016-06-01

Adult polyglucosan body disease (APBD) usually presents with progressive spastic paraparesis, neurogenic bladder, and distal lower limb sensory abnormalities. It is caused by mutations in the glycogen branching enzyme gene (GBE1). We describe a woman with an unusual phenotype manifesting as progressive left brachial more than lumbosacral plexopathies, with central sensory and corticospinal tract involvement. Magnetic resonance imaging of the brain and cervical spine showed abnormal T2 signal within the ventral pons and medulla bilaterally, involving the pyramidal tracts and the medial leminisci. There was also medullary and cervical spine atrophy. On nerve biopsy, large polyglucosan bodies were noted in the endoneurium. The patient was found to be compound heterozygous for 2 novel mutations in GBE1. Peripheral blood leukocyte GBE activity was markedly reduced to 7% of normal, confirming the diagnosis of APBD. In this report we describe a new phenotype of APBD associated with 2 novel mutations. Muscle Nerve 53: 976-981, 2016. © 2016 Wiley Periodicals, Inc.

Semantic Memory in the Clinical Progression of Alzheimer Disease.

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Tchakoute, Christophe T; Sainani, Kristin L; Henderson, Victor W

2017-09-01

Semantic memory measures may be useful in tracking and predicting progression of Alzheimer disease. We investigated relationships among semantic memory tasks and their 1-year predictive value in women with Alzheimer disease. We conducted secondary analyses of a randomized clinical trial of raloxifene in 42 women with late-onset mild-to-moderate Alzheimer disease. We assessed semantic memory with tests of oral confrontation naming, category fluency, semantic recognition and semantic naming, and semantic density in written narrative discourse. We measured global cognition (Alzheimer Disease Assessment Scale, cognitive subscale), dementia severity (Clinical Dementia Rating sum of boxes), and daily function (Activities of Daily Living Inventory) at baseline and 1 year. At baseline and 1 year, most semantic memory scores correlated highly or moderately with each other and with global cognition, dementia severity, and daily function. Semantic memory task performance at 1 year had worsened one-third to one-half standard deviation. Factor analysis of baseline test scores distinguished processes in semantic and lexical retrieval (semantic recognition, semantic naming, confrontation naming) from processes in lexical search (semantic density, category fluency). The semantic-lexical retrieval factor predicted global cognition at 1 year. Considered separately, baseline confrontation naming and category fluency predicted dementia severity, while semantic recognition and a composite of semantic recognition and semantic naming predicted global cognition. No individual semantic memory test predicted daily function. Semantic-lexical retrieval and lexical search may represent distinct aspects of semantic memory. Semantic memory processes are sensitive to cognitive decline and dementia severity in Alzheimer disease.

[Specificities of the logopenic variant of primary progressive aphasia].

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Magnin, E; Teichmann, M; Martinaud, O; Moreaud, O; Ryff, I; Belliard, S; Pariente, J; Moulin, T; Vandel, P; Démonet, J-F

2015-01-01

The logopenic variant of primary progressive aphasia is a syndrome with neuropsychological and linguistic specificities, including phonological loop impairment for which diagnosis is currently mainly based on the exclusion of the two other variants, semantic and nonfluent/agrammatic primary progressive aphasia. The syndrome may be underdiagnosed due (1) to mild language difficulties during the early stages of the disease or (2) to being mistaken for mild cognitive impairment or Alzheimer's disease when the evaluation of episodic memory is based on verbal material and (3) finally, it is not uncommon that the disorders are attributed to psychiatric co-morbidities such as, for example, anxiety. Moreover, compared to other variants of primary progressive aphasia, brain abnormalities are different. The left temporoparietal junction is initially affected. Neuropathology and biomarkers (cerebrospinal fluid, molecular amyloid nuclear imaging) frequently reveal Alzheimer's disease. Consequently this variant of primary progressive aphasia does not fall under the traditional concept of frontotemporal lobar degeneration. These distinctive features highlight the utility of correct diagnosis, classification, and use of biomarkers to show the neuropathological processes underlying logopenic primary progressive aphasia. The logopenic variant of primary progressive aphasia is a specific form of Alzheimer's disease frequently presenting a rapid decline; specific linguistic therapies are needed. Further investigation of this syndrome is needed to refine screening, improve diagnostic criteria and better understand the epidemiology and the biological mechanisms involved. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Quantitative and qualitative evaluation of dermal elastin of draught horses with chronic progressive lymphoedema.

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De Cock, H E V; Van Brantegem, L; Affolter, V K; Oosterlinck, M; Ferraro, G L; Ducatelle, R

2009-01-01

Chronic progressive lymphoedema (CPL) in horses, a disease of certain draught breeds, is associated with altered elastin metabolism. The characteristic lesions are seen in the skin of the lower (distal) limbs. This study was based on horses of susceptible breeds, with and without CPL, and on horses of a non-susceptible breed. Skin samples were obtained for examination from the neck (considered a non-affected region) and from the distal limb. The skin lesions were characterized histologically and the dermal elastic fibres were evaluated morphologically and quantitatively. In all horses the mean elastin concentrations were highest in the superficial dermis, gradually decreasing in the mid-dermis and deep dermis. As compared with horses of a non-susceptible breed, affected horses had increased amounts of dermal elastin in both the distal limb and neck, while non-affected horses of a susceptible breed had decreased amounts. The findings support an earlier hypothesis that CPL of horses is a generalized disease. Reduced efficiency of the elastic network in supporting the dermal lymphatics may explain the development of CPL.

Increased diacylglycerols characterize hepatic lipid changes in progression of human nonalcoholic fatty liver disease; comparison to a murine model.

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Gorden, D Lee; Ivanova, Pavlina T; Myers, David S; McIntyre, J Oliver; VanSaun, Michael N; Wright, J Kelly; Matrisian, Lynn M; Brown, H Alex

2011-01-01

The spectrum of nonalcoholic fatty liver disease (NAFLD) includes steatosis, nonalcoholic steatohepatitis (NASH), and progression to cirrhosis. While differences in liver lipids between disease states have been reported, precise composition of phospholipids and diacylglycerols (DAG) at a lipid species level has not been previously described. The goal of this study was to characterize changes in lipid species through progression of human NAFLD using advanced lipidomic technology and compare this with a murine model of early and advanced NAFLD. Utilizing mass spectrometry lipidomics, over 250 phospholipid and diacylglycerol species (DAGs) were identified in normal and diseased human and murine liver extracts. Significant differences between phospholipid composition of normal and diseased livers were demonstrated, notably among DAG species, consistent with previous reports that DAG transferases are involved in the progression of NAFLD and liver fibrosis. In addition, a novel phospholipid species (ether linked phosphatidylinositol) was identified in human cirrhotic liver extracts. Using parallel lipidomics analysis of murine and human liver tissues it was determined that mice maintained on a high-fat diet provide a reproducible model of NAFLD in regards to specificity of lipid species in the liver. These studies demonstrated that novel lipid species may serve as markers of advanced liver disease and importantly, marked increases in DAG species are a hallmark of NAFLD. Elevated DAGs may contribute to altered triglyceride, phosphatidylcholine (PC), and phosphatidylethanolamine (PE) levels characteristic of the disease and specific DAG species might be important lipid signaling molecules in the progression of NAFLD.

Gender, apolipoprotein E genotype, and mesial temporal atrophy: 2-year follow-up in patients with stable mild cognitive impairment and with progression from mild cognitive impairment to Alzheimer's disease

International Nuclear Information System (INIS)

Spampinato, M.V.; Patrick, K.E.; Collins, H.; Langdon, B.R.; Parker, R.O.; Pravata', E.

2016-01-01

This study aimed to examine the relationship between gender, apolipoprotein E (APOE) genotype, and mesial temporal atrophy in mild cognitive impairment (MCI) with and without progression to Alzheimer's disease (AD). We evaluated 236 MCI patients with (n = 121) and without (n = 115) AD progression. Longitudinal MRI-based hippocampal volumes (HV) and entorhinal cortex (ERC) thickness were obtained. The Clinical Dementia Rating Sum of Boxes (CDR-SB) score was used to assess disease severity. We found a significant effect of APOE, gender, and clinical course (stable MCI versus MCI-AD progression) on HV. There was a significant effect of clinical course and APOE, but not gender, on ERC. Baseline HV and APOE4 status predicted MCI-AD progression in women. Baseline ERC and APOE4 status predicted MCI-AD progression in men. There were significant differences in CDR-SB scores between patients with and without MCI-AD progression, but not between males and females, or APOE4 carriers and non-carriers. HV, but not ERC, is strongly influenced by gender in MCI. The effects of gender and APOE4 on neuroimaging biomarkers have potentially important implications in the prediction of MCI-AD progression and should be taken into account in clinical trials. (orig.)

Progress toward an integrated understanding of Parkinson's disease [version 1; referees: 2 approved

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Maxime W.C. Rousseaux

2017-07-01

Full Text Available Parkinson's disease (PD is the second most common neurodegenerative disorder after Alzheimer's disease, affecting over 10 million individuals worldwide. While numerous effective symptomatic treatments are currently available, no curative or disease-modifying therapies exist. An integrated, comprehensive understanding of PD pathogenic mechanisms will likely address this unmet clinical need. Here, we highlight recent progress in PD research with an emphasis on promising translational findings, including (i advances in our understanding of disease susceptibility, (ii improved knowledge of cellular dysfunction, and (iii insights into mechanisms of spread and propagation of PD pathology. We emphasize connections between these previously disparate strands of PD research and the development of an emerging systems-level understanding that will enable the next generation of PD therapeutics.

Primary progressive multiple sclerosis in the Polish population

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Waldemar Brola

2017-03-01

Full Text Available Objectives: The aim of the study was the epidemiological analysis and evaluation of selected clinical and sociodemographic factors in Polish patients with primary progressive multiple sclerosis. Methods: The study included patients from 7 provinces in central and eastern Poland registered in the Registry of Patients with Multiple Sclerosis on 31 December 2016. The incidence of various forms of the disease was compared, and clinical, demographic and social disparities between relapsing-remitting and primary progressive multiple sclerosis were analysed. Results: Of 3,199 registered patients, 2,188 persons (66.2% had the relapsing-remitting form of multiple sclerosis, 774 (24.2% had the secondary progressive type and 307 (9.6% suffered from primary progressive disease. The first symptoms of primary progressive multiple sclerosis appeared almost 10 years later than in patients with the relapsing-remitting type (39.2 ± 11.4 vs. 29.8 ± 9.8. The period from the first symptoms to diagnosis was more than twice as long in patients with primary progressive multiple sclerosis (5.8 ± 3.4 as in those with relapsing-remitting disease (2.4 ± 1.6. The average degree of disability in the Expanded Disability Status Scale was similar and amounted to 3.2 ± 2.1 for relapsing-remitting and 3.6 ± 2.4 for primary progressive multiple sclerosis. The relapsing-remitting form was observed more often in women (2.4:1, and the primary progressive form appeared with equal frequency in both sexes (1:1. Disease-modifying treatment was received by 34% of patients with relapsing-remitting and in only 1.9% of patients with primary progressive multiple sclerosis. Conclusions: The primary progressive form affects approximately 10% of Polish patients with multiple sclerosis. The first symptoms appear at about 40 years of age with equal frequency in both sexes, and its diagnosis takes more than twice as much time as in the case of relapsing-remitting multiple

A single-arm phase II trial of pazopanib in patients with advanced non-small cell lung cancer with non-squamous histology with disease progression on bevacizumab containing therapy.

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Weiss, Jared M; Villaruz, Liza C; Socinski, Mark A; Ivanova, Anastasia; Grilley-Olson, Juneko; Dhruva, Nirav; Stinchcombe, Thomas E

2014-11-01

Platinum-based chemotherapy with bevacizumab is a standard therapy for patients with stage IIIB/IV non-small cell lung cancer (NSCLC) with non-squamous (NS) histology. Mechanisms of resistance to bevacizumab include increased VEGF signaling or activation of VEGF receptors. Pazopanib is a multi-targeted VEGF receptor tyrosine kinase with single agent activity in NSCLC. Stage IIIB/IV patients with adequate organ function, who progressed on a bevacizumab containing therapy were eligible if it had been ≤8 weeks since the last bevacizumab treatment. The primary end-point was disease control rate (DCR), defined as partial or complete response, or stable disease for ≥12 weeks. Patients were assessed radiographically every 2 cycles (6 weeks). A Simon 2-stage design was used, and if in the first stage ≤4 of 17 patients experienced disease control the trial was to have been stopped for futility. An unplanned analysis was performed after 15 patients were evaluable secondary to slow accrual. Between December 2010 and November 2013, 15 patients were treated on trial. The median age was 61 years (range 39-74), and all patients had stage IV disease. Of the 15 patients, 4 discontinued therapy prior to cycle 2 evaluation due to adverse events (n=3) and medical illness (n=1), 5 patients had progressive disease, 4 patients had stable disease for <12 weeks, and 2 patients had stable disease for ≥12 weeks. No responses were observed. The DCR observed was 13% (2/15), and the trial did not meet the criteria to proceed to the second stage. Episodes of grade 3 treatment related toxicities observed included: increased ALT (n=2), increased AST (n=1), anorexia (n=3), fatigue (n=3), hypertension (n=1), infection (n=1), mucositis (n=2), nausea (n=3), pericardial effusion (n=1), and vomiting (n=1). Pazopanib has limited activity in NSCLC-NS in patients who have experienced disease progression on bevacizumab. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Phenotypic Progression of Stargardt Disease in a Large Consanguineous Tunisian Family Harboring New ABCA4 Mutations

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Yousra Falfoul

2018-01-01

Full Text Available To assess the progression of Stargardt (STGD disease over nine years in two branches of a large consanguineous Tunisian family. Initially, different phenotypes were observed with clinical intra- and interfamilial variations. At presentation, four different retinal phenotypes were observed. In phenotype 1, bull’s eye maculopathy and slight alteration of photopic responses in full-field electroretinography were observed in the youngest child. In phenotype 2, macular atrophy and yellow white were observed in two brothers. In phenotype 3, diffuse macular, peripapillary, and peripheral RPE atrophy and hyperfluorescent dots were observed in two sisters. In phenotype 4, Stargardt disease-fundus flavimaculatus phenotype was observed in two cousins with later age of onset. After a progression of 9 years, all seven patients displayed the same phenotype 3 with advanced stage STGD and diffuse atrophy. WES and MLPA identified two ABCA4 mutations M1: c.[(?_4635_(5714+?dup; (?_6148_(6479_+? del] and M2: c.[2041C>T], p.[R681∗]. In one branch, the three affected patients had M1/M1 causal mutations and in the other branch the two affected patients had M1/M2 causal mutations. After 9-year follow-up, all patients showed the same phenotypic evolution, confirming the progressive nature of the disease. Genetic variations in the two branches made no difference to similar end-stage disease.

ALS patients' regulatory T lymphocytes are dysfunctional, and correlate with disease progression rate and severity.

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Beers, David R; Zhao, Weihua; Wang, Jinghong; Zhang, Xiujun; Wen, Shixiang; Neal, Dan; Thonhoff, Jason R; Alsuliman, Abdullah S; Shpall, Elizabeth J; Rezvani, Katy; Appel, Stanley H

2017-03-09

Neuroinflammation is a pathological hallmark of ALS in both transgenic rodent models and patients, and is characterized by proinflammatory T lymphocytes and activated macrophages/microglia. In ALS mouse models, decreased regulatory T lymphocytes (Tregs) exacerbate the neuroinflammatory process, leading to accelerated motoneuron death and shortened survival; passive transfer of Tregs suppresses the neuroinflammation and prolongs survival. Treg numbers and FOXP3 expression are also decreased in rapidly progressing ALS patients. A key question is whether the marked neuroinflammation in ALS can be attributed to the impaired suppressive function of ALS Tregs in addition to their decreased numbers. To address this question, T lymphocyte proliferation assays were performed. Compared with control Tregs, ALS Tregs were less effective in suppressing responder T lymphocyte proliferation. Although both slowly and rapidly progressing ALS patients had dysfunctional Tregs, the greater the clinically assessed disease burden or the more rapidly progressing the patient, the greater the Treg dysfunction. Epigenetically, the percentage methylation of the Treg-specific demethylated region was greater in ALS Tregs. After in vitro expansion, ALS Tregs regained suppressive abilities to the levels of control Tregs, suggesting that autologous passive transfer of expanded Tregs might offer a novel cellular therapy to slow disease progression.

ALS patients’ regulatory T lymphocytes are dysfunctional, and correlate with disease progression rate and severity

Science.gov (United States)

Beers, David R.; Zhao, Weihua; Wang, Jinghong; Zhang, Xiujun; Wen, Shixiang; Neal, Dan; Thonhoff, Jason R.; Alsuliman, Abdullah S.; Shpall, Elizabeth J.; Rezvani, Katy

2017-01-01

Neuroinflammation is a pathological hallmark of ALS in both transgenic rodent models and patients, and is characterized by proinflammatory T lymphocytes and activated macrophages/microglia. In ALS mouse models, decreased regulatory T lymphocytes (Tregs) exacerbate the neuroinflammatory process, leading to accelerated motoneuron death and shortened survival; passive transfer of Tregs suppresses the neuroinflammation and prolongs survival. Treg numbers and FOXP3 expression are also decreased in rapidly progressing ALS patients. A key question is whether the marked neuroinflammation in ALS can be attributed to the impaired suppressive function of ALS Tregs in addition to their decreased numbers. To address this question, T lymphocyte proliferation assays were performed. Compared with control Tregs, ALS Tregs were less effective in suppressing responder T lymphocyte proliferation. Although both slowly and rapidly progressing ALS patients had dysfunctional Tregs, the greater the clinically assessed disease burden or the more rapidly progressing the patient, the greater the Treg dysfunction. Epigenetically, the percentage methylation of the Treg-specific demethylated region was greater in ALS Tregs. After in vitro expansion, ALS Tregs regained suppressive abilities to the levels of control Tregs, suggesting that autologous passive transfer of expanded Tregs might offer a novel cellular therapy to slow disease progression. PMID:28289705

Neurophysiological evaluation of patients with degenerative diseases of the cervical spine

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Ilić Tihomir V.

2011-01-01

Full Text Available Bacground/Aim. Diagnostic protocol for patients with degenerative diseases of the cervical spine demands, in parallel with neuroimaging methods, functional evaluation through neurophysiological methods (somatosensitive and motor evoked potentials and electromyoneurography aiming to evaluate possible subclinical affection of spinal medula resulting in neurological signs of long tract abnormalities. Considering diversities of clinical outcomes for these patients, complex diagnostic evaluation provides a prognosis of the disease progression. Methods. The study included 21 patients (48.24 ± 11.01 years of age with clinical presentation of cervical spondylarthropathy, without neuroradiological signs of myelopathy. For each patient, in addition to conventional neurophysiological tests (somatisensory evoked potentials - SSEP, motor evoked potentials - MEP, electromyoneurography - EMG, nerve conduction studies, we calculated central motor conduction time (CMCTF, as well the same parameter in relation to a different position of the head (maximal anteflexion and retroflexion, so-called dynamic tests. Results. Abnormalities of the peripheral motor neurone by conventional EMNeG was established in 2/3 of the patients, correponding to the findings of root condution time. Prolonged conventional CVMPF were found in 29% of the patients, comparing to 43% CVMPF abnormalities found with the dynamic tests. In addition, the SSEP findings were abnormal in 38% of the patients with degenerative diseases of the cervical spine. Conclusion. An extended neurophysiological protocol of testing corticospinal functions, including dynamic tests of central and periheral motor neurons are relevant for detection of subclinical forms of cervical spondylothic myelopathy, even at early stages. In addition to the conventional neurophysiological tests, we found usefull to include the dynamic motor tests and root conduction time measurement in diagnostic evaluation.

Plasma Metabolomics Biosignature According to HIV Stage of Infection, Pace of Disease Progression, Viremia Level and Immunological Response to Treatment.

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Bruno Scarpellini

Full Text Available We evaluated plasma samples HIV-infected individuals with different phenotypic profile among five HIV-infected elite controllers and five rapid progressors after recent HIV infection and one year later and from 10 individuals subjected to antiretroviral therapy, five of whom were immunological non-responders (INR, before and after one year of antiretroviral treatment compared to 175 samples from HIV-negative patients. A targeted quantitative tandem mass spectrometry metabolomics approach was used in order to determine plasma metabolomics biosignature that may relate to HIV infection, pace of HIV disease progression, and immunological response to treatment.Twenty-five unique metabolites were identified, including five metabolites that could distinguish rapid progressors and INRs at baseline. Severe deregulation in acylcarnitine and sphingomyelin metabolism compatible with mitochondrial deficiencies was observed. β-oxidation and sphingosine-1-phosphate-phosphatase-1 activity were down-regulated, whereas acyl-alkyl-containing phosphatidylcholines and alkylglyceronephosphate synthase levels were elevated in INRs. Evidence that elite controllers harbor an inborn error of metabolism (late-onset multiple acyl-coenzyme A dehydrogenase deficiency [MADD] was detected.Blood-based markers from metabolomics show a very high accuracy of discriminating HIV infection between varieties of controls and have the ability to predict rapid disease progression or poor antiretroviral immunological response. These metabolites can be used as biomarkers of HIV natural evolution or treatment response and provide insight into the mechanisms of the disease.

Plasma Metabolomics Biosignature According to HIV Stage of Infection, Pace of Disease Progression, Viremia Level and Immunological Response to Treatment.

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Scarpellini, Bruno; Zanoni, Michelle; Sucupira, Maria Cecilia Araripe; Truong, Hong-Ha M; Janini, Luiz Mario Ramos; Segurado, Ismael Dale Cotrin; Diaz, Ricardo Sobhie

2016-01-01

We evaluated plasma samples HIV-infected individuals with different phenotypic profile among five HIV-infected elite controllers and five rapid progressors after recent HIV infection and one year later and from 10 individuals subjected to antiretroviral therapy, five of whom were immunological non-responders (INR), before and after one year of antiretroviral treatment compared to 175 samples from HIV-negative patients. A targeted quantitative tandem mass spectrometry metabolomics approach was used in order to determine plasma metabolomics biosignature that may relate to HIV infection, pace of HIV disease progression, and immunological response to treatment. Twenty-five unique metabolites were identified, including five metabolites that could distinguish rapid progressors and INRs at baseline. Severe deregulation in acylcarnitine and sphingomyelin metabolism compatible with mitochondrial deficiencies was observed. β-oxidation and sphingosine-1-phosphate-phosphatase-1 activity were down-regulated, whereas acyl-alkyl-containing phosphatidylcholines and alkylglyceronephosphate synthase levels were elevated in INRs. Evidence that elite controllers harbor an inborn error of metabolism (late-onset multiple acyl-coenzyme A dehydrogenase deficiency [MADD]) was detected. Blood-based markers from metabolomics show a very high accuracy of discriminating HIV infection between varieties of controls and have the ability to predict rapid disease progression or poor antiretroviral immunological response. These metabolites can be used as biomarkers of HIV natural evolution or treatment response and provide insight into the mechanisms of the disease.

Fear of progression in chronic diseases: psychometric properties of the Fear of Progression Questionnaire.

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Herschbach, Peter; Berg, Petra; Dankert, Andrea; Duran, Gabriele; Engst-Hastreiter, Ursula; Waadt, Sabine; Keller, Monika; Ukat, Robert; Henrich, Gerhard

2005-06-01

The aim of this study was the development and psychometric testing of a new psychological questionnaire to measure the fear of progression (FoP) in chronically ill patients (cancer, diabetes mellitus and rheumatic diseases). The Fear of Progression Questionnaire (FoP-Q) was developed in four phases: (1) generation of items (65 interviews); (2) reduction of items--the initial version of the questionnaire (87 items) was presented to 411 patients, to construct subscales and test the reliability; (3) testing the convergent and discriminative validity of the reduced test version (43 items) within a new sample (n=439); (4) translation--German to English. The scale comprised five factors (Cronbach's alpha >.70): affective reactions (13 items), partnership/family (7), occupation (7), loss of autonomy (7) and coping with anxiety (9). The test-retest reliability coefficients varied between .77 and .94. There was only a medium relationship to traditional anxiety scales. This is an indication of the independence of the FoP. Significant relationships between the FoP-Q and the patient's illness behaviour indicate discriminative validity. The FoP-Q is a new and unique questionnaire developed for the chronically ill. A major problem and source of stress for this patient group has been measuring both specifically and economically the FoP of an illness. The FoP-Q was designed to resolve this problem, fulfill this need and reduce this stress.

Demyelination versus remyelination in progressive multiple sclerosis

DEFF Research Database (Denmark)

Bramow, Stephan; Frischer, Josa M; Lassmann, Hans

2010-01-01

The causes of incomplete remyelination in progressive multiple sclerosis are unknown, as are the pathological correlates of the different clinical characteristics of patients with primary and secondary progressive disease. We analysed brains and spinal cords from 51 patients with progressive...... multiple sclerosis by planimetry. Thirteen patients with primary progressive disease were compared with 34 with secondary progressive disease. In patients with secondary progressive multiple sclerosis, we found larger brain plaques, more demyelination in total and higher brain loads of active demyelination...... compared with patients with primary progressive disease. In addition, the brain density of plaques with high-grade inflammation and active demyelination was highest in secondary progressive multiple sclerosis and remained ~18% higher than in primary progressive multiple sclerosis after adjustments...

Artificial neural network for prediction of the area under the disease progress curve of tomato late blight

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Daniel Pedrosa Alves

Full Text Available ABSTRACT: Artificial neural networks (ANN are computational models inspired by the neural systems of living beings capable of learning from examples and using them to solve problems such as non-linear prediction, and pattern recognition, in addition to several other applications. In this study, ANN were used to predict the value of the area under the disease progress curve (AUDPC for the tomato late blight pathosystem. The AUDPC is widely used by epidemiologic studies of polycyclic diseases, especially those regarding quantitative resistance of genotypes. However, a series of six evaluations over time is necessary to obtain the final area value for this pathosystem. This study aimed to investigate the utilization of ANN to construct an AUDPC in the tomato late blight pathosystem, using a reduced number of severity evaluations. For this, four independent experiments were performed giving a total of 1836 plants infected with Phytophthora infestans pathogen. They were assessed every three days, comprised six opportunities and AUDPC calculations were performed by the conventional method. After the ANN were created it was possible to predict the AUDPC with correlations of 0.97 and 0.84 when compared to conventional methods, using 50 % and 67 % of the genotype evaluations, respectively. When using the ANN created in an experiment to predict the AUDPC of the other experiments the average correlation was 0.94, with two evaluations, 0.96, with three evaluations, between the predicted values of the ANN and they were observed in six evaluations. We present in this study a new paradigm for the use of AUDPC information in tomato experiments faced with P. infestans. This new proposed paradigm might be adapted to different pathosystems.

Expression profiling of cervical cancers in Indian women at different stages to identify gene signatures during progression of the disease

International Nuclear Information System (INIS)

Thomas, Asha; Mahantshetty, Umesh; Kannan, Sadhana; Deodhar, Kedar; Shrivastava, Shyam K; Kumar-Sinha, Chandan; Mulherkar, Rita

2013-01-01

Cervical cancer is the second most common cancer among women worldwide, with developing countries accounting for >80% of the disease burden. Although in the West, active screening has been instrumental in reducing the incidence of cervical cancer, disease management is hampered due to lack of biomarkers for disease progression and defined therapeutic targets. Here we carried out gene expression profiling of 29 cervical cancer tissues from Indian women, spanning International Federation of Gynaecology and Obstetrics (FIGO) stages of the disease from early lesion (IA and IIA) to progressive stages (IIB and IIIA–B), and identified distinct gene expression signatures. Overall, metabolic pathways, pathways in cancer and signaling pathways were found to be significantly upregulated, while focal adhesion, cytokine–cytokine receptor interaction and WNT signaling were downregulated. Additionally, we identified candidate biomarkers of disease progression such as SPP1, proliferating cell nuclear antigen (PCNA), STK17A, and DUSP1 among others that were validated by quantitative real-time polymerase chain reaction (qRT-PCR) in the samples used for microarray studies as well in an independent set of 34 additional samples. Integrative analysis of our results with other cervical cancer profiling studies could facilitate the development of multiplex diagnostic markers of cervical cancer progression

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

International Nuclear Information System (INIS)

Mierke, Claudia Tanja

2014-01-01

The role of mechanical properties in cancer disease and inflammation is still underinvestigated and even ignored in many oncological and immunological reviews. In particular, eight classical hallmarks of cancer have been proposed, but they still ignore the mechanics behind the processes that facilitate cancer progression. To define the malignant transformation of neoplasms and finally reveal the functional pathway that enables cancer cells to promote cancer progression, these classical hallmarks of cancer require the inclusion of specific mechanical properties of cancer cells and their microenvironment such as the extracellular matrix as well as embedded cells such as fibroblasts, macrophages or endothelial cells. Thus, this review will present current cancer research from a biophysical point of view and will therefore focus on novel physical aspects and biophysical methods to investigate the aggressiveness of cancer cells and the process of inflammation. As cancer or immune cells are embedded in a certain microenvironment such as the extracellular matrix, the mechanical properties of this microenvironment cannot be neglected, and alterations of the microenvironment may have an impact on the mechanical properties of the cancer or immune cells. Here, it is highlighted how biophysical approaches, both experimental and theoretical, have an impact on the classical hallmarks of cancer and inflammation. It is even pointed out how these biophysical approaches contribute to the understanding of the regulation of cancer disease and inflammatory responses after tissue injury through physical microenvironmental property sensing mechanisms. The recognized physical signals are transduced into biochemical signaling events that guide cellular responses, such as malignant tumor progression, after the transition of cancer cells from an epithelial to a mesenchymal phenotype or an inflammatory response due to tissue injury. Moreover, cell adaptation to mechanical alterations, in

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

Science.gov (United States)

Mierke, Claudia Tanja

2014-07-01

The role of mechanical properties in cancer disease and inflammation is still underinvestigated and even ignored in many oncological and immunological reviews. In particular, eight classical hallmarks of cancer have been proposed, but they still ignore the mechanics behind the processes that facilitate cancer progression. To define the malignant transformation of neoplasms and finally reveal the functional pathway that enables cancer cells to promote cancer progression, these classical hallmarks of cancer require the inclusion of specific mechanical properties of cancer cells and their microenvironment such as the extracellular matrix as well as embedded cells such as fibroblasts, macrophages or endothelial cells. Thus, this review will present current cancer research from a biophysical point of view and will therefore focus on novel physical aspects and biophysical methods to investigate the aggressiveness of cancer cells and the process of inflammation. As cancer or immune cells are embedded in a certain microenvironment such as the extracellular matrix, the mechanical properties of this microenvironment cannot be neglected, and alterations of the microenvironment may have an impact on the mechanical properties of the cancer or immune cells. Here, it is highlighted how biophysical approaches, both experimental and theoretical, have an impact on the classical hallmarks of cancer and inflammation. It is even pointed out how these biophysical approaches contribute to the understanding of the regulation of cancer disease and inflammatory responses after tissue injury through physical microenvironmental property sensing mechanisms. The recognized physical signals are transduced into biochemical signaling events that guide cellular responses, such as malignant tumor progression, after the transition of cancer cells from an epithelial to a mesenchymal phenotype or an inflammatory response due to tissue injury. Moreover, cell adaptation to mechanical alterations, in

Assessment of Local Control after Laser-Induced Thermotherapy of Liver Metastases from Colorectal Cancer: Contribution of FDG-PET in Patients with Clinical Suspicion of Progressive Disease

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Denecke, T.; Steffen, I.; Hildebrandt, B.; Ruehl, R.; Streitparth, F.; Lehmk uhl, L.; Langrehr, J.; Ricke, J.; Amthauer, H.; Lopez Haenninen, E.

2007-01-01

Background: Management of patients after locally ablative treatment of liver metastases requires exact information about local control and systemic disease status. To fulfill these requirements, whole-body imaging using positron emission tomography with 18 F-fluorodeoxyglucose (FDG-PET) is a promising alternative to morphologic imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI). Purpose: To evaluate FDG-PET for the assessment of local control and systemic disease in patients with clinical suspicion of tumor progression after laser-induced thermotherapy (LITT) of colorectal liver metastases. Material and Methods: In 21 patients with suspicion of progressive disease after LITT, whole-body FDG-PET was performed. The presence of viable tumor within treated lesions, new liver metastases, and extrahepatic disease was evaluated visually and semi quantitatively (maximal standard uptake value [SUVmax], tumor-to-normal ratio [T/N]). The standard of reference was histopathology (n = 25 lesions) and/or clinical follow-up (>12 months) including contrast-enhanced MRI of the liver. Results: Among 54 metastases treated with LITT, 29 had residual tumor. Receiver operating characteristic (ROC) analysis of SUVmax (area under the curve (AUC) 0.990) and T/N (AUC 0.968) showed a significant discrimination level of negative or positive lesion status with an equal accuracy of 94% (51/54). The overall accuracy of visual FDG-PET was 96% (52/54), with one false-negative lesion among six examined within 3 days after LITT, and one false-positive lesion examined 54 days after LITT. In the detection of new intra- and extrahepatic lesions, FDG-PET resulted in correct alteration of treatment strategy in 43% of patients (P = 0.007). Conclusion: FDG-PET is a promising tool for the assessment of local control and whole-body restaging in patients with clinical suspicion of tumor progression after locally ablative treatment of colorectal liver metastases with LITT

Sex and gender differences in chronic kidney disease: progression to end-stage renal disease and haemodialysis.

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Cobo, Gabriela; Hecking, Manfred; Port, Friedrich K; Exner, Isabella; Lindholm, Bengt; Stenvinkel, Peter; Carrero, Juan Jesús

2016-07-01

Sex and gender differences are of fundamental importance in most diseases, including chronic kidney disease (CKD). Men and women with CKD differ with regard to the underlying pathophysiology of the disease and its complications, present different symptoms and signs, respond differently to therapy and tolerate/cope with the disease differently. Yet an approach using gender in the prevention and treatment of CKD, implementation of clinical practice guidelines and in research has been largely neglected. The present review highlights some sex- and gender-specific evidence in the field of CKD, starting with a critical appraisal of the lack of inclusion of women in randomized clinical trials in nephrology, and thereafter revisits sex/gender differences in kidney pathophysiology, kidney disease progression, outcomes and management of haemodialysis care. In each case we critically consider whether apparent discrepancies are likely to be explained by biological or psycho-socioeconomic factors. In some cases (a few), these findings have resulted in the discovery of disease pathways and/or therapeutic opportunities for improvement. In most cases, they have been reported as merely anecdotal findings. The aim of the present review is to expose some of the stimulating hypotheses arising from these observations as a preamble for stricter approaches using gender for the prevention and treatment of CKD and its complications. © 2016 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Disruption of spatial organization and interjoint coordination in Parkinson's disease, progressive supranuclear palsy, and multiple system atrophy.

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Leiguarda, R; Merello, M; Balej, J; Starkstein, S; Nogues, M; Marsden, C D

2000-07-01

Patients with basal ganglia diseases may exhibit ideomotor apraxia. To define the nature of the impairment of the action production system, we studied a repetitive gesture of slicing bread by three-dimensional computergraphic analysis in eight nondemented patients with Parkinson's disease in the "on" state, five with progressive supranuclear palsy and four with multiple system atrophy. Two patients with Parkinson's disease and two with progressive supranuclear palsy showed ideomotor apraxia for transitive movements on standard testing. A Selspott II system was used for kinematic analysis of wrist trajectories and angular motions of the shoulder and elbow joints. Patients with Parkinson's disease, progressive supranuclear palsy, and even some with multiple system atrophy exhibited kinematic deficits in the spatial precision of movement and velocity-curvature relationships; in addition, they failed to maintain proper angle/angle relationships and to apportion their relative joint amplitudes normally. Spatial disruption of wrist trajectories was more severe in patients with ideomotor apraxia. We posit that the basal ganglia are part of the parallel parieto-frontal circuits devoted to sensorimotor integration for object-oriented behavior. The severity and characteristics of spatial abnormalities of a transitive movement would therefore depend on the location and distribution of the pathologic process within these circuits.

Radiographic evaluation of degenerative joint disease in horses: interpretive principles

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Widmer, W.R.; Blevins, W.E.

1994-01-01

Degenerative joint disease in horses is characterized by the progressive deterioration of articular cartilage of synovial joints. The morbidity associated with degenerative joint disease, particularly the loss of function in pleasure and performance horses, costs horse owners millions of dollars each year. Although new drugs, such as polysulfated glycosaminoglycans and hyaluronic acid, are available for the treatment of patients with degenerative joint disease, the success of therapy depends on early diagnosis. Diagnostic imaging strategies, therefore, should focus on accurate and timely diagnosis of degenerative joint disease to provide prompt therapy. Early identification of degenerative joint disease is also beneficial because the use and/or training methods of affected patients may be altered, possibly limiting the progression of the disease. The pathogenesis of degenerative joint disease is complex and multifactorial. Current evidence suggests that initiating factors lead to a final common pathway-breakdown of articular cartilage. There are many diagnostic tests that aid practitioners in detecting degenerative joint disease; however, the most important imaging technique is radiography. During the early stages of the disease, radiographic changes may be slight; therefore, it is essential that practitioners have adequate equipment to obtain high-quality radiographs. Thinning of the joint space, osteophytosis, enthesopathy, changes in subchondral bone, and increased synovium and synovia provide radiographic evidence of degenerative joint disease. By understanding the pathophysiology of the disease and how technical alterations affect the subtle radiographic changes, practitioners can more accurately diagnose degenerative joint disease during its early stages and institute proper therapy

A longitudinal study of Stargardt disease: quantitative assessment of fundus autofluorescence, progression, and genotype correlations.

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Fujinami, Kaoru; Lois, Noemi; Mukherjee, Rajarshi; McBain, Vikki A; Tsunoda, Kazushige; Tsubota, Kazuo; Stone, Edwin M; Fitzke, Fred W; Bunce, Catey; Moore, Anthony T; Webster, Andrew R; Michaelides, Michel

2013-12-17

We characterized subtypes of fundus autofluorescence (AF) and the progression of retinal atrophy, and correlated these findings with genotype in Stargardt disease. Full clinical examination and AF imaging was undertaken in 68 patients with Stargardt disease. The baseline data were compared to those at follow-up. Patients were classified into three AF subtypes: type 1 had a localized low signal at the fovea surrounded by a homogeneous background, type 2 had a localized low signal at the macula surrounded by a heterogeneous background with numerous foci of abnormal signal, and type 3 had multiple low signal areas at the posterior pole with a heterogeneous background. At baseline, there were 19 patients with type 1, 41 with type 2, and 8 with type 3 disease. The areas of reduced AF signal were measured and rate of atrophy enlargement (RAE) was calculated as the difference of the atrophy size over time (mm²) divided by the follow-up interval (years). Molecular screening of ABCA4 was undertaken. The mean follow-up interval was 9.1 years. A total of 42% cases with type 1 disease progressed to type 2, and 12% with type 2 progressed to type 3. The RAE (mm²/y) based upon baseline AF subtypes was significantly different; 0.06 in type 1, 0.67 in type 2, and 4.37 in type 3. ABCA4 variants were identified in 57 patients. There was a significant association between AF subtype and genotype. The AF pattern at baseline influences the enlargement of atrophy over time and has genetic correlates. These data are likely to assist in the provision of counseling on prognosis in Stargardt disease and be valuable for future clinical trials.

Dietary manipulation and social isolation alter disease progression in a murine model of coronary heart disease.

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Yumiko Nakagawa-Toyama

Full Text Available BACKGROUND: Mice with a deficiency in the HDL receptor SR-BI and low expression of a modified apolipoprotein E gene (SR-BI KO/ApoeR61(h/h called 'HypoE' when fed an atherogenic, 'Paigen' diet develop occlusive, atherosclerotic coronary arterial disease (CHD, myocardial infarctions (MI, and heart dysfunction and die prematurely (50% mortality ~40 days after initiation of this diet. Because few murine models share with HypoE mice these cardinal, human-like, features of CHD, HypoE mice represent a novel, small animal, diet-inducible and genetically tractable model for CHD. To better describe the properties of this model, we have explored the effects of varying the composition and timing of administration of atherogenic diets, as well as social isolation vs. group housing, on these animals. METHODOLOGY/PRINCIPAL FINDINGS: HypoE mice were maintained on a standard lab chow diet (control until two months of age. Subsequently they received one of three atherogenic diets (Paigen, Paigen without cholate, Western or control diet for varying times and were housed in groups or singly, and we determined the plasma cholesterol levels, extent of cardiomegaly and/or survival. The rate of disease progression could be reduced by lowering the severity of the atherogenic diet and accelerated by social isolation. Disease could be induced by Paigen diets either containing or free of cholate. We also established conditions under which CHD could be initiated by an atherogenic diet and then subsequently, by replacing this diet with standard lab chow, hypercholesterolemia could be reduced and progression to early death prevented. CONCLUSIONS/SIGNIFICANCE: HypoE mice provide a powerful, surgery-free, diet-'titratable' small animal model that can be used to study the onset of recovery from occlusive, atherosclerotic CHD and heart failure due to MI. HypoE mice can be used for the analysis of the effects of environment (diet, social isolation on a variety of features of

Disease progression in usual interstitial pneumonia compared with desquamative interstitial pneumonia. Assessment with serial CT

International Nuclear Information System (INIS)

Hartman, T.E.; Primack, S.L.; Kang, E.Y.

1997-01-01

Objective. To determine the outcome of areas of ground-glass attenuation and assess disease progression on serial high-resolution CT (HRCT) scans of patients with biopsy specimen-proved usual interstitial pneumonia (UIP) and desquamative interstitial pneumonia (DIP). Materials and methods. Twelve patients with biopsy specimen-proved UIP and 11 patients with biopsy specimen-proved DIP who had initial and follow-up HRCT scans (median interval, 10 months) were reviewed. Eleven patients with UIP and 11 with DIP received treatment between the initial and follow-up CT scans. The scans were evaluated for the presence and extent of ground-glass attenuation, irregular linear opacities and honeycombing, and overall extent of parenchymal involvement. Results. On initial CT scans, all 12 patients with UIP had areas of ground-glass attenuation (mean±SD extent, 30±16%) and irregular lines (mean±SD extent, 17±7%) and 10 patients had honeycombing (mean±SD extent, 10±6%). All 11 patients with DIP had areas of ground-glass attenuation on initial HRCT scans (mean±SD extent, 51±26%), 5 patients had irregular linear opacities (mean±SD extent, 5±5%), and 1 patient had honeycombing. Nine of the 12 patients with UIP showed increase in the extent of ground-glass attenuation (n=6) or progression to irregular lines (n=2) or honeycombing (n=4) on follow-up as compared with only 2 patients with DIP who showed progression to irregular lines (n=1) or honeycombing (n=1) (p 2 test). Conclusion. In patients with UIP, areas of ground-glass attenuation usually increase in extent or progress to fibrosis despite treatment. Areas of ground-glass attenuation in most patients with DIP remain stable or improve with treatment. (authors)

Risk of progression from mild memory impairment to clinically diagnosable Alzheimer's disease in a Japanese community (from the Nakayama Study).

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Sonobe, Naomi; Hata, Ryuji; Ishikawa, Tomohisa; Sonobe, Kantaro; Matsumoto, Teruhisa; Toyota, Yasutaka; Mori, Takaaki; Fukuhara, Ryuji; Komori, Kenjiro; Ueno, Shu-Ichi; Tanimukai, Satoshi; Ikeda, Manabu

2011-06-01

Memory impairment has been proposed as the most common early sign of Alzheimer's disease (AD). The aims of this work were to evaluate the risk of progression from mild memory impairment/no dementia (MMI/ND) to clinically diagnosable AD in a community-based prospective cohort and to establish the risk factors for progression from MMI/ND to AD in the elderly. Elderly subjects aged over 65 years were selected from the participants in the first Nakayama study. MMI/ND was defined as memory deficit on objective memory assessment, without dementia, impairment of general cognitive function, or disability in activities of daily living. A total of 104 MMI/ND subjects selected from 1242 community-dwellers were followed longitudinally for five years. During the five-year follow-up, 11 (10.6%) subjects were diagnosed with AD, five (4.8%) with vascular dementia (VaD), and six (5.8%) with dementia of other etiology. Logistic regression analysis revealed that diabetes mellitus (DM) and a family history of dementia (within third-degree relatives) were positively associated with progression to AD, while no factor was significantly associated with progression to VaD or all types of dementia. DM and a family history of dementia were significant risk factors for progression from MMI/ND to clinically diagnosable AD in the elderly in a Japanese community.

Risk Matrix for Prediction of Disease Progression in a Referral Cohort of Patients with Crohn's Disease.

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Lakatos, Peter L; Sipeki, Nora; Kovacs, Gyorgy; Palyu, Eszter; Norman, Gary L; Shums, Zakera; Golovics, Petra A; Lovasz, Barbara D; Antal-Szalmas, Peter; Papp, Maria

2015-10-01

Early identification of patients with Crohn's disease (CD) at risk of subsequent complications is essential for adapting the treatment strategy. We aimed to develop a prediction model including clinical and serological markers for assessing the probability of developing advanced disease in a prospective referral CD cohort. Two hundred and seventy-one consecutive CD patients (42.4% males, median follow-up 108 months) were included and followed up prospectively. Anti-Saccharomyces cerevisiae antibodies (ASCA IgA/IgG) were determined by enzyme-linked immunosorbent assay. The final analysis was limited to patients with inflammatory disease behaviour at diagnosis. The final definition of advanced disease outcome was having intestinal resection or disease behaviour progression. Antibody (ASCA IgA and/or IgG) status, disease location and need for early azathioprine were included in a 3-, 5- and 7-year prediction matrix. The probability of advanced disease after 5 years varied from 6.2 to 55% depending on the combination of predictors. Similar findings were obtained in Kaplan-Meier analysis; the combination of ASCA, location and early use of azathioprine was associated with the probability of developing advanced disease (p < 0.001, log rank test). Our prediction models identified substantial differences in the probability of developing advanced disease in the early disease course of CD. Markers identified in this referral cohort were different from those previously published in a population-based cohort, suggesting that different prediction models should be used in the referral setting. Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Progressive Hemifacial Atrophy and Linear Scleroderma En Coup de Sabre: A Spectrum of the Same Disease?

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Irina Khamaganova

2018-01-01

Full Text Available Similar clinical and histhopathological features in progressive hemifacial atrophy and linear scleroderma en coup de sabre are well known. Trauma may predispose to the development of both diseases. The lack of association with anti-Borrelia antibodies was shown in both cases as well. The otolaryngological and endocrine disorders may be associated findings in both diseases. However, there are certain differences in neurological and ophthalmological changes in the diseases.

MicroRNA-124 slows down the progression of Huntington′s disease by promoting neurogenesis in the striatum

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Tian Liu

2015-01-01

Full Text Available MicroRNA-124 contributes to neurogenesis through regulating its targets, but its expression both in the brain of Huntington′s disease mouse models and patients is decreased. However, the effects of microRNA-124 on the progression of Huntington′s disease have not been reported. Results from this study showed that microRNA-124 increased the latency to fall for each R6/2 Huntington′s disease transgenic mouse in the rotarod test. 5-Bromo-2′-deoxyuridine (BrdU staining of the striatum shows an increase in neurogenesis. In addition, brain-derived neurotrophic factor and peroxisome proliferator-activated receptor gamma coactivator 1-alpha protein levels in the striatum were increased and SRY-related HMG box transcription factor 9 protein level was decreased. These findings suggest that microRNA-124 slows down the progression of Huntington′s disease possibly through its important role in neuronal differentiation and survival.

[Progress in research on pathogenic genes and gene therapy for inherited retinal diseases].

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Zhu, Ling; Cao, Cong; Sun, Jiji; Gao, Tao; Liang, Xiaoyang; Nie, Zhipeng; Ji, Yanchun; Jiang, Pingping; Guan, Minxin

2017-02-10

Inherited retinal diseases (IRDs), including retinitis pigmentosa, Usher syndrome, Cone-Rod degenerations, inherited macular dystrophy, Leber's congenital amaurosis, Leber's hereditary optic neuropathy are the most common and severe types of hereditary ocular diseases. So far more than 200 pathogenic genes have been identified. With the growing knowledge of the genetics and mechanisms of IRDs, a number of gene therapeutic strategies have been developed in the laboratory or even entered clinical trials. Here the progress of IRD research on the pathogenic genes and therapeutic strategies, particularly gene therapy, are reviewed.

[Progressive visual agnosia].

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Sugimoto, Azusa; Futamura, Akinori; Kawamura, Mitsuru

2011-10-01

Progressive visual agnosia was discovered in the 20th century following the discovery of classical non-progressive visual agnosia. In contrast to the classical type, which is caused by cerebral vascular disease or traumatic injury, progressive visual agnosia is a symptom of neurological degeneration. The condition of progressive visual loss, including visual agnosia, and posterior cerebral atrophy was named posterior cortical atrophy (PCA) by Benson et al. (1988). Progressive visual agnosia is also observed in semantic dementia (SD) and other degenerative diseases, but there is a difference in the subtype of visual agnosia associated with these diseases. Lissauer (1890) classified visual agnosia into apperceptive and associative types, and it in most cases, PCA is associated with the apperceptive type. However, SD patients exhibit symptoms of associative visual agnosia before changing to those of semantic memory disorder. Insights into progressive visual agnosia have helped us understand the visual system and discover how we "perceive" the outer world neuronally, with regard to consciousness. Although PCA is a type of atypical dementia, its diagnosis is important to enable patients to live better lives with appropriate functional support.

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

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

2015-05-28

We present a case of rapidly progressing Addison's disease in adrenal crisis with severe hyponatraemia and absence of hyperkalaemia in a 10-year-old girl. She presented with 2 weeks of vomiting, fatigue and weight loss. Her serum electrolytes obtained 1 week prior to presentation were normal, except for mild hyponatraemia at 131 mmol/L, which dropped to 112 mmol/L on admission. She had normal serum potassium, low-serum osmolality, with elevated urine sodium and osmolality, indistinguishable from syndrome of inappropriate antidiuretic hormone (SIADH). Subsequently, Addison's disease was diagnosed on the basis of gingival hyperpigmentation and undetectable cortisol on adrenocorticotropic hormone stimulation test. She rapidly responded to stress dose hydrocortisone, followed by hydrocortisone and fludrocortisone replacement therapy. The absence of hyperkalaemia in the presence of severe hyponatraemia cannot rule out Addison's disease in children. The mechanism of hypo-osmolar hyponatraemia in primary adrenal insufficiency and clinical clues to differentiate it from SIADH are discussed. 2015 BMJ Publishing Group Ltd.

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

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Mora, Ana L.; Rojas, Mauricio; Pardo, Annie; Selman, Moises

2018-01-01

Idiopathic pulmonary fibrosis (IPF) is a fatal age-associated disease that is characterized by progressive and irreversible scarring of the lung. The pathogenesis of IPF is not completely understood and current therapies are limited to those that reduce the rate of functional decline in patients with mild-to-moderate disease. In this context, new therapeutic approaches that substantially improve the survival time and quality of life of these patients are urgently needed. Our incomplete understanding of the pathogenic mechanisms of IPF and the lack of appropriate experimental models that reproduce the key characteristics of the human disease are major challenges. As ageing is a major risk factor for IPF, age-related cell perturbations such as telomere attrition, senescence, epigenetic drift, stem cell exhaustion, loss of proteostasis and mitochondrial dysfunction are becoming targets of interest for IPF therapy. In this Review, we discuss current and emerging therapies for IPF, particularly those targeting age-related mechanisms, and discuss future therapeutic approaches. PMID:29081515

Progress in the last decade in our understanding of primary progressive aphasia

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Ratnavalli Ellajosyula

2010-10-01

Full Text Available Primary progressive aphasia (PPA is a focal neurodegeneration of the brain affecting the language network. Patients can have isolated language impairment for years without impairment in other areas. PPA is classified as primary progressive nonfluent aphasia (PNFA, semantic dementia (SD, and logopenic aphasia, which have distinct patterns of atrophy on neuroimaging. PNFA and SD are included under frontotemporal lobar degenerations. PNFA patients have effortful speech with agrammatism, which is frequently associated with apraxia of speech and demonstrate atrophy in the left Broca′s area and surrounding region on neuroimaging. Patients with SD have dysnomia with loss of word and object (or face meaning with asymmetric anterior temporal lobe atrophy. Logopenic aphasics have word finding difficulties with frequent pauses in conversation, intact grammar, and word comprehension but impaired repetition for sentences. The atrophy is predominantly in the left posterior temporal and inferior parietal regions. Recent studies have described several progranulin mutations on chromosome 17 in PNFA. The three clinical syndromes have a less robust relationship to the underlying pathology, which is heterogeneous and includes tauopathy, ubiquitinopathy, Pick′s disease, corticobasal degeneration, progressive supranuclear palsy, and Alzheimer′s disease. Recent studies, however, seem to indicate that a better characterization of the clinical phenotype (apraxic, agrammatic, semantic, logopenic, jargon increases the predictive value of the underlying pathology. Substantial advances have been made in our understanding of PPAs but developing new biomarkers is essential in making accurate causative diagnoses in individual patients. This is critically important in the development and evaluation of disease-modifying drugs.

Brain stem and cerebellar atrophy in chronic progressive neuro-Behçet's disease

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Kanoto, Masafumi, E-mail: mkanoto@med.id.yamagata-u.ac.jp [Department of Diagnostic Radiology, Faculty of Medicine, Yamagata University, Iida-Nishi 2-2-2, 990-9585 Yamagata (Japan); Hosoya, Takaaki, E-mail: thosoya@med.id.yamagata-u.ac.jp [Department of Diagnostic Radiology, Faculty of Medicine, Yamagata University, Iida-Nishi 2-2-2, 990-9585 Yamagata (Japan); Toyoguchi, Yuuki, E-mail: c-elegans_0201g@mail.goo.ne.jp [Department of Diagnostic Radiology, Faculty of Medicine, Yamagata University, Iida-Nishi 2-2-2, 990-9585 Yamagata (Japan); Oda, Atsuko, E-mail: a.oda@med.id.yamagata-u.ac.jp [Department of Diagnostic Radiology, Faculty of Medicine, Yamagata University, Iida-Nishi 2-2-2, 990-9585 Yamagata (Japan)

2013-01-15

Purpose: Chronic progressive neuro-Behçet's disease (CPNBD) resembles multiple sclerosis (MS) on patient background and image findings, and therefore is difficult to diagnose. The purpose is to identify the characteristic magnetic resonance imaging (MRI) findings of CPNBD and to clarify the differences between the MRI findings of CPNBD and those of MS. Materials and methods: The subjects consist of a CPNBD group (n = 4; 1 male and 3 females; mean age, 51 y.o.), a MS group (n = 19; 3 males and 16 females; mean age, 45 y.o.) and a normal control group (n = 23; 10 males and 13 females; mean age, 45 y.o.). Brain stem atrophy, cerebellar atrophy, and leukoencephalopathy were retrospectively evaluated in each subjects. In middle sagittal brain MR images, the prepontine distance was measured as an indirect index of brain stem and cerebellar atrophy and the pontine and mesencephalic distance was measured as a direct index of brain stem atrophy. These indexes were statistically analyzed. Results: Brain stem atrophy, cerebellar atrophy, and leukoencephalopathy were seen in all CPNBD cases. Prepontine distance was significantly different between the CPNBD group and the MS group (p < 0.05), and between the CPNBD group and the normal control group (p < 0.001). Pontine and mesencephalic distance were significantly different between the CPNBD group and the MS group (p < 0.001, p < 0.01 respectively), and between the CPNBD group and the normal control group (p < 0.001). Conclusions: Chronic progressive neuro-Behçet's disease should be considered in patients with brain stem and cerebellar atrophy in addition to leukoencephalopathy similar to that seen in multiple sclerosis.

PLOS Neglected Tropical Diseases: Ten years of progress in neglected tropical disease control and elimination … More or less.

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Peter Hotez

2017-04-01

Full Text Available This year PLOS Neglected Tropical Diseases (PLOS NTDs celebrates its tenth anniversary following the publication of the first issue in 2007 [1]. When PLOS NTDs was founded, the framework of the neglected tropical diseases (NTDs as an alternative to "other diseases" (as they were then referred to in the Millennium Development Goals was just getting started-especially for Africa [2, 3]. In the decade since, PLOS NTDs has overseen enormous successes in NTD control and elimination. Here, we want to briefly review the ten year progress made towards the control or elimination of the diseases now identified by the WHO as NTDs. Many of the details are highlighted in PLOS NTDs papers cited here, but the summary information is based on the recently released Global Burden of Disease (GBD Study 2015 (also launched with Gates Foundation support that summarized past-decade changes in disease prevalence, mortality, or disability rates (from the years 2005 to 2015 [4-6], as well as the GBD Study 2013 that summarizes disease prevalence changes over a longer time horizon from 1990 to 2013 [7].

Application of PET in Alzheimer's disease

International Nuclear Information System (INIS)

Zhang Chun

2003-01-01

Alzheimer's disease (AD) is a neurodegenerative disease of central nervous system that causes progressive cognitive and memory deterioration in the elderly people. Affected brains of AD patients are characterized by the presence of senile plaques (SP) and neurofilbrillary tangles (NFT). The review will focus on the application of positron emission tomography (PET) in the diagnosis, progression prediction, treatment and evaluation of neurotransmission activity of AD

Biomarkers of evasive resistance predict disease progression in cancer patients treated with antiangiogenic therapies

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Pircher, Andreas; Jöhrer, Karin; Kocher, Florian; Steiner, Normann; Graziadei, Ivo; Heidegger, Isabel; Pichler, Renate; Leonhartsberger, Nicolai; Kremser, Christian; Kern, Johann; Untergasser, Gerold; Gunsilius, Eberhard; Hilbe, Wolfgang

2016-01-01

Numerous antiangiogenic agents are approved for the treatment of oncological diseases. However, almost all patients develop evasive resistance mechanisms against antiangiogenic therapies. Currently no predictive biomarker for therapy resistance or response has been established. Therefore, the aim of our study was to identify biomarkers predicting the development of therapy resistance in patients with hepatocellular cancer (n = 11), renal cell cancer (n = 7) and non-small cell lung cancer (n = 2). Thereby we measured levels of angiogenic growth factors, tumor perfusion, circulating endothelial cells (CEC), circulating endothelial progenitor cells (CEP) and tumor endothelial markers (TEM) in patients during the course of therapy with antiangiogenic agents, and correlated them with the time to antiangiogenic progression (aTTP). Importantly, at disease progression, we observed an increase of proangiogenic factors, upregulation of CEC/CEP levels and downregulation of TEMs, such as Robo4 and endothelial cell-specific chemotaxis regulator (ECSCR), reflecting the formation of torturous tumor vessels. Increased TEM expression levels tended to correlate with prolonged aTTP (ECSCR high = 275 days vs. ECSCR low = 92.5 days; p = 0.07 and for Robo4 high = 387 days vs. Robo4 low = 90.0 days; p = 0.08). This indicates that loss of vascular stabilization factors aggravates the development of antiangiogenic resistance. Thus, our observations confirm that CEP/CEC populations, proangiogenic cytokines and TEMs contribute to evasive resistance in antiangiogenic treated patients. Higher TEM expression during disease progression may have clinical and pathophysiological implications, however, validation of our results is warranted for further biomarker development. PMID:26956051

Autosomal dominant polycystic kidney disease and pain - a review of the disease from aetiology, evaluation, past surgical treatment options to current practice.

Science.gov (United States)

Badani, K K; Hemal, A K; Menon, M

2004-01-01

Autosomal Dominant Polycystic Kidney Disease (ADPKD), often referred to as "adult" polycystic kidney disease, is one of the commonest hereditary disorders. It affects approximately 4 to 6 million individuals worldwide. The disease progresses to end-stage renal disease and it accounts for 10-15% of patients requiring dialysis in the United States. A comprehensive Medline search for aetiology, evaluation, screening, cellular biology, and treatment was utilized to locate, extract, and synthesize relevant data with respect to this topic. Special attention was focused on urologic literature and surgical textbooks regarding operative treatment of pain associated with ADPKD. Now, patients with ADPKD have more treatment options. More specifically, several therapeutic alternatives are now available for the management of pain in these patients. A recent review of literature supports the performance of open or laparoscopic cyst decortication procedures for control of pain and infection without the worry of causing further renal impairment in those with preserved renal function.

Regional Cerebral Disease Progression in Friedreich's Ataxia: A Longitudinal Diffusion Tensor Imaging Study.

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Mascalchi, Mario; Toschi, Nicola; Giannelli, Marco; Ginestroni, Andrea; Della Nave, Riccardo; Tessa, Carlo; Piacentini, Silvia; Dotti, Maria Teresa; Aiello, Marco; Nicolai, Emanuele; Soricelli, Andrea; Salvi, Fabrizio; Diciotti, Stefano

2016-01-01

Imaging biomarkers of disease progression are desirable in inherited ataxias. MRI has demonstrated brain damage in Friedreich ataxia (FRDA) in form of regional atrophy of the medulla, peridentate cerebellar white matter (WM) and superior cerebellar peduncles (visible in T1-weighted images) and of change of microstructural characteristics of WM tracts of the brainstem, cerebellar peduncles, cerebellum, and supratentorial structures (visible through diffusion-weighted imaging). We explored the potential of brain MR morphometry and diffusion tensor imaging (DTI) to track the progression of neurodegeneration in FRDA. Eight patients (5F, 3M; age 13.4-41.2 years) and 8 healthy controls (2F, 6M; age 26.2-48.3 years) underwent 2 MRI examinations (mean 3.9 and 4.1 years apart, respectively) on the same 1.5T scanner. The protocol included 3D T1-weighted images and axial diffusion-weighted images (b-value 1,000 s/mm(2)) for calculating maps of fractional anisotropy, mean, axial and radial diffusivity, and mode of anisotropy. Tensor-based morphometry was used to investigate regional volume changes and tract-based spatial statistics was used to investigate microstructural changes in WM tracts. Longitudinal analyses showed no differences in regional volume changes but a significant difference in axial diffusivity changes in cerebral and corpus callosum WM of patients as compared to controls (mean longitudinal rate of change for axial diffusivity: -.02 × 10(-3) mm(2)/s/year in patients vs. .01 × 10(-3) mm(2)/s/year in controls). No correlation with number of triplets, disease duration, and worsening of the clinical deficit was observed. DTI can track brain microstructural changes in FRDA and can be considered a potential biomarker of disease progression. Copyright © 2015 by the American Society of Neuroimaging.

Post-ischemic azotemia as a partial 'brake', slowing progressive kidney disease.

Science.gov (United States)

Zager, Richard A; Johnson, Ali C; Becker, Kirsten

2013-06-01

Recent experimental work suggests a paradox: although uremia evokes systemic toxicities, in the setting of AKI, it can induce intrarenal cytoprotective and anti-inflammatory effects. Whether these influences can attenuate post-ischemic kidney disease progression remains unknown. To explore this possibility, male CD-1 mice were subjected to a 30-min unilateral (left) kidney ischemia model, previously shown to reduce renal mass by ∼50% over 2-3 weeks. Stepwise azotemia/acute uremia was superimposed by inducing different lengths of contralateral (right) kidney ischemia (0, 15, 18, 20 min). Subsequent loss of left renal mass (kidney weight) was assessed 2 weeks later and contrasted with the degree of initial azotemia 24-h BUN. A striking correlation between 24-h BUNs and 2-week left renal mass was observed (r, 0.77; P < 0.001). With 20 min of right kidney ischemia, left kidney size was completely preserved. This preservation did not result from increased tubular cell proliferation or decreased microvascular loss, as gauged by KI-67 and CD-34 immunohistochemistry, respectively. Rather, an early reduction in proximal tubule cell dropout (as judged by renal cortical N-acetyl-glucosaminidase content), with a subsequent preservation of tubule mass, was observed. In summary, these findings advance a novel concept: acute uremia can confer early post-ischemic cytoprotection resulting in a slowed progression of post-ischemic kidney disease.

Timely Referral to Outpatient Nephrology Care Slows Progression and Reduces Treatment Costs of Chronic Kidney Diseases

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Gerhard Lonnemann

2017-03-01

Discussion: Timely referral to outpatient nephrology care is associated with slowed disease progression, less hospital admissions, reduced total treatment costs, and improved survival in patients with CKD.

Longitudinal evaluation of bronchopulmonary disease in children with cystic fibrosis.

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Farrell, Philip M; Li, Zhanhai; Kosorok, Michael R; Laxova, Anita; Green, Christopher G; Collins, Jannette; Lai, Hui-Chuan; Makholm, Linda M; Rock, Michael J; Splaingard, Mark L

2003-09-01

Children with cystic fibrosis (CF) develop bronchopulmonary disease at variable ages. Determining the epidemiology of chronic lung disease and quantifying its severity, however, have been difficult in infants and young children. As part of the Wisconsin CF Neonatal Screening Project, we were presented with an ideal opportunity to assess longitudinally the evolution of symptoms, signs, and quantitative measures of CF respiratory disease. After newborn screening test results led to early recognition, 64 patients diagnosed at a median age of 6.71 weeks were enrolled and studied systematically at a median age of 11.3 years to obtain clinical information, chest radiographs, and pulmonary function tests. Our observations revealed that a frequent cough by history is evident by 10.5 months of age in half the patients. Quantitative chest radiology (CXR scoring) demonstrated that potentially irreversible abnormalities are present in half the children by 2 years. The severity of Wisconsin and Brasfield CXR scores increased in association with respiratory infections. Longitudinal progression of Wisconsin CXR scores was related to age (P < 0.001), pancreatic insufficiency (P = 0.005), and respiratory secretion cultures positive for Staphylococus aureas (P = 0.039). In contrast, serial spirometry showed limited sensitivity, as did lung volume determinations; neither was satisfactory as repeated measures with acceptable quality control until after 7 years of age. Time to event analyses revealed that half the patients had % predicted FEF(25-75) and FEV(1)/FVC values greater than 80% until 10.7 and 9.9 years, respectively. We conclude that of the methods evaluated, quantitative chest radiology is currently the best procedure for frequent assessment of bronchopulmonary disease in CF, and that radiographic progression is evident in approximately 85% of patients by 5 years of age. Our results also suggest that bronchiectasis and other radiographic evidence of chronic infection are

Blood platelets in the progression of Alzheimer's disease.

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Nina S Gowert

Full Text Available 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.

Frosted branch angiitis associated with rapidly progressive glomerulonephritis.

Directory of Open Access Journals (Sweden)

Gupta Amod

2002-01-01

Full Text Available Simultaneous occurrence of frosted branch angiitis and immune-mediated rapidly progressive glomerulonephritis is reported. The two diseases possibly share a common immune mechanism. Patients of frosted branch angiitis should undergo complete systemic evaluation including renal function tests even if the patient is systemically asymptomatic.

A new semiquantitative method for evaluation of metastasis progression.

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Volarevic, A; Ljujic, B; Volarevic, V; Milovanovic, M; Kanjevac, T; Lukic, A; Arsenijevic, N

2012-01-01

Although recent technical advancements are directed toward developing novel assays and methods for detection of micro and macro metastasis, there are still no reports of reliable, simple to use imaging software that could be used for the detection and quantification of metastasis in tissue sections. We herein report a new semiquantitative method for evaluation of metastasis progression in a well established 4T1 orthotopic mouse model of breast cancer metastasis. The new semiquantitative method presented here was implemented by using the Autodesk AutoCAD 2012 program, a computer-aided design program used primarily for preparing technical drawings in 2 dimensions. By using the Autodesk AutoCAD 2012 software- aided graphical evaluation we managed to detect each metastatic lesion and we precisely calculated the average percentage of lung and liver tissue parenchyma with metastasis in 4T1 tumor-bearing mice. The data were highly specific and relevant to descriptive histological analysis, confirming reliability and accuracy of the AutoCAD 2012 software as new method for quantification of metastatic lesions. The new semiquantitative method using AutoCAD 2012 software provides a novel approach for the estimation of metastatic progression in histological tissue sections.

Bone marrow morphology and disease progression in congenital thrombocytopenia: a detailed clinicopathologic and genetic study of eight cases.

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Tsang, Hamilton C; Bussel, James B; Mathew, Susan; Liu, Yen-Chun; Imahiyerobo, Allison A; Orazi, Attilio; Geyer, Julia T

2017-04-01

Patients with congenital thrombocytopenia have an increased risk of developing myeloid neoplasms. In these cases, the morphologic distinction between disease at baseline and at progression is challenging. This report analyzes clinicopathologic features of congenital thrombocytopenia with long-term follow-up at one referral center. Records from the last 20 years were searched for cases of congenital thrombocytopenia with bone marrow biopsies and peripheral blood smears. The clinical, morphologic, immunophenotypic, and molecular features were analyzed. Six adult and two pediatric patients were identified (six male, two female). Age range at first biopsy was 1-47 (median, 31) years. Underlying diseases included thrombocytopenia-absent radius syndrome, congenital thrombocytopenia with radial-ulnar synostosis, MYH9-related disorder, shortened telomere syndrome, congenital thrombocytopenia with ANKRD26 mutation, and familial platelet disorder with predisposition to acute myeloid leukemia. Four patients had myelodysplastic/myeloproliferative neoplasm-like marrow changes such as hypercellularity, increased myeloid to erythroid ratio, numerous micromegakaryocytes (highlighted by CD42b), and marrow fibrosis. Two patients had marrow hypoplasia and two had unremarkable marrow morphology. Three patients-all in the myelodysplastic/myeloproliferative neoplasm-like group-developed disease progression characterized by erythroid and myeloid dysplasia, elevated bone marrow blasts, and new cytogenetic abnormalities. Unlike non-familial myeloid neoplasms, congenital thrombocytopenia patients in the myelodysplastic/myeloproliferative neoplasm-like group had a long and indolent clinical course (average age at disease progression, 47 years). In summary, three distinct morphologic types of congenital thrombocytopenia were identified: a hyperplastic myelodysplastic/myeloproliferative neoplasm-like group, a hypoplastic bone marrow failure-like group, and a group with relatively normal marrow

Computed tomographic findings of progressive supranuclear palsy compared with Parkinson's disease

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Yuki, Nobuhiro; Sato, Shuzo; Yuasa, Tatsuhiko; Ito, Jusuke; Miyatake, Tadashi [Niigata Univ. (Japan). School of Dentistry

1990-10-01

We investigated computed tomographic (CT) films of 4 pathologically documented cases of progressive supranuclear palsy (PSP) in which the clinical presentations were atypical and compared the findings with those of 15 patients with Parkinson's disease (PD). Dilatation of the third ventricle, atrophy of the midbrain tegmentum, and enlargement of the interpeduncular cistern toward the aqueduct were found to be the characteristic findings in PSP. Thus, radiological findings can be useful when the differential diagnosis between PSP and PD is clinically difficult. (author).

Parkinson disease and progressive supranuclear palsy: protein expression in skin.

Science.gov (United States)

Rodríguez-Leyva, Ildefonso; Chi-Ahumada, Erika G; Carrizales, Juan; Rodríguez-Violante, Mayela; Velázquez-Osuna, Salvador; Medina-Mier, Verónica; Martel-Gallegos, María G; Zarazúa, Sergio; Enríquez-Macías, Lourdes; Castro, Adriana; Calderón-Garcidueñas, Ana Laura; Jiménez-Capdeville, María E

2016-03-01

This study characterizes the expression of tau (p-tau) and α-synuclein (α-syn) by immunohistochemistry in the skin of three different populations: healthy control (HC), Parkinson disease (PD), and progressive supranuclear paralysis (PSP) subjects, with the purpose of finding a biomarker that could differentiate between subjects with PD and PSP. We evaluated the presence of p-tau and α-syn in a pilot study in the skin of three distinct groups of patients: 17 healthy subjects, 17 patients with PD, and 10 patients with PSP. Four millimeters punch biopsies were obtained from the occipital area and analyzed by immunohistochemistry using antibodies against α-syn and phosphorylated species of tau. PHF (paired helical filaments) antibody identifies p-tau in both normal and pathological conditions and AT8 recognizes p-tau characteristic of pathological conditions. Differences between the three groups were assessed by quantification of immunopositive areas in the epidermis. The immunopositivity pattern of p-tau and α-syn was significantly different among the three groups. Healthy subjects showed minimal staining using AT8 and α-syn. The PD group showed significantly higher α-syn and AT8 immunopositivity, while the PSP group only expressed higher AT8 immunopositivity than HCs. These data suggest that the skin reflects brain pathology. Therefore, immunohistochemical analysis of p-tau and α-syn in the skin can be useful for further characterization of PD and PSP.

'Alzheimer's Progression Score': Development of a Biomarker Summary Outcome for AD Prevention Trials.

Science.gov (United States)

Leoutsakos, J-M; Gross, A L; Jones, R N; Albert, M S; Breitner, J C S

2016-01-01

Alzheimer's disease (AD) prevention research requires methods for measurement of disease progression not yet revealed by symptoms. Preferably, such measurement should encompass multiple disease markers. Evaluate an item response theory (IRT) model-based latent variable Alzheimer Progression Score (APS) that uses multi-modal disease markers to estimate pre-clinical disease progression. Estimate APS scores in the BIOCARD observational study, and in the parallel PREVENT-AD Cohort and its sister INTREPAD placebo-controlled prevention trial. Use BIOCARD data to evaluate whether baseline and early APS trajectory predict later progression to MCI/dementia. Similarly, use longitudinal PREVENT-AD data to assess test measurement invariance over time. Further, assess portability of the PREVENT-AD IRT model to baseline INTREPAD data, and explore model changes when CSF markers are added or withdrawn. BIOCARD was established in 1995 and participants were followed up to 20 years in Baltimore, USA. The PREVENT-AD and INTREPAD trial cohorts were established between 2011-2015 in Montreal, Canada, using nearly identical entry criteria to enroll high-risk cognitively normal persons aged 60+ then followed for several years. 349 cognitively normal, primarily middle-aged participants in BIOCARD, 125 high-risk participants aged 60+ in PREVENT-AD, and 217 similar subjects in INTREPAD. 106 INTREPAD participants donated up to four serial CSF samples. Global cognitive assessment and multiple structural, functional, and diffusion MRI metrics, sensori-neural tests, and CSF concentrations of tau, Aβ42 and their ratio. Both baseline values and early slope of APS scores in BIOCARD predicted later progression to MCI or AD. Presence of CSF variables strongly improved such prediction. A similarly derived APS in PREVENT-AD showed measurement invariance over time and portability to the parallel INTREPAD sample. An IRT-based APS can summarize multimodal information to provide a longitudinal measure of

The DIAN-TU Next Generation Alzheimer’s prevention trial: adaptive design and disease progression model

Science.gov (United States)

Bateman, Randall J.; Benzinger, Tammie L.; Berry, Scott; Clifford, David B.; Duggan, Cynthia; Fagan, Anne M.; Fanning, Kathleen; Farlow, Martin R.; Hassenstab, Jason; McDade, Eric M.; Mills, Susan; Paumier, Katrina; Quintana, Melanie; Salloway, Stephen P.; Santacruz, Anna; Schneider, Lon S.; Wang, Guoqiao; Xiong, Chengjie

2016-01-01

INTRODUCTION The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) trial is an adaptive platform trial testing multiple drugs to slow or prevent the progression of Alzheimer’s disease in autosomal dominant Alzheimer’s disease (ADAD) families. With completion of enrollment of the first two drug arms, the DIAN-TU now plans to add new drugs to the platform, designated as the Next Generation Prevention Trial (NexGen). METHODS In collaboration with ADAD families, philanthropic organizations, academic leaders, the DIAN-TU Pharma Consortium, the NIH, and regulatory colleagues, the DIAN-TU developed innovative clinical study designs for the DIAN-TU NexGen trial. RESULTS Our expanded trials toolbox consists of a Disease Progression Model for ADAD, primary endpoint DIAN-TU cognitive performance composite, biomarker development, self-administered cognitive assessments, adaptive dose adjustments, and blinded data collection through the last participant completion. CONCLUSION These steps represent elements to improve efficacy of the adaptive platform trial and a continued effort to optimize prevention and treatment trials in ADAD. PMID:27583651

Does significant renal ablation truly and invariably lead to hyperfiltration and progressive chronic kidney disease?

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Wang, Andrew; Sam, Ramin

2017-06-01

It is generally believed that significant renal ablation leads to hyperfiltration and eventually progressively worsening chronic kidney disease. The data behind this belief have not been scrutinized intensively. More importantly, the above belief leads many physicians to manage patients differently than they otherwise would manage. Here, we examine the data behind whether hyperfiltration occurs when patients lose kidney mass (by excision or by disease) and whether the hyperfiltration is uniformly injurious.

Gender, apolipoprotein E genotype, and mesial temporal atrophy: 2-year follow-up in patients with stable mild cognitive impairment and with progression from mild cognitive impairment to Alzheimer's disease

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Spampinato, M.V.; Patrick, K.E.; Collins, H. [Medical University of South Carolina, Department of Radiology and Radiological Science, Charleston, SC (United States); Langdon, B.R. [Medical University of South Carolina, Department of Internal Medicine, Charleston, SC (United States); Parker, R.O. [Vanderbilt University, Department of Anesthesiology, Nashville, TN (United States); Pravata' , E. [Medical University of South Carolina, Department of Radiology and Radiological Science, Charleston, SC (United States); Ospedale Regionale di Lugano, Department of Neuroradiology, Neurocenter of Southern Switzerland, Lugano (Switzerland); Collaboration: For the Alzheimer' s Disease Neuroimaging Initiative

2016-11-15

This study aimed to examine the relationship between gender, apolipoprotein E (APOE) genotype, and mesial temporal atrophy in mild cognitive impairment (MCI) with and without progression to Alzheimer's disease (AD). We evaluated 236 MCI patients with (n = 121) and without (n = 115) AD progression. Longitudinal MRI-based hippocampal volumes (HV) and entorhinal cortex (ERC) thickness were obtained. The Clinical Dementia Rating Sum of Boxes (CDR-SB) score was used to assess disease severity. We found a significant effect of APOE, gender, and clinical course (stable MCI versus MCI-AD progression) on HV. There was a significant effect of clinical course and APOE, but not gender, on ERC. Baseline HV and APOE4 status predicted MCI-AD progression in women. Baseline ERC and APOE4 status predicted MCI-AD progression in men. There were significant differences in CDR-SB scores between patients with and without MCI-AD progression, but not between males and females, or APOE4 carriers and non-carriers. HV, but not ERC, is strongly influenced by gender in MCI. The effects of gender and APOE4 on neuroimaging biomarkers have potentially important implications in the prediction of MCI-AD progression and should be taken into account in clinical trials. (orig.)

Progress on Chinese evaluated nuclear parameter library (CENPL) (II)

International Nuclear Information System (INIS)

Su Zhongdi; Ge Zhigang; Zhou Chunmei

1993-01-01

CENPL collected, evaluated and compiled nuclear basic constants and model parameters. CENPL-1 contain six sub-libraries, they are: (1) Atomic masses and characteristic constants for nuclear ground states; (2) discrete level schemes and branch ratios of γ decay; (3) level density parameters; (4) giant dipole resonance parameters for γ-ray strength function (5) fission barrier parameter; (6) optical model parameters. Their progresses are introduced

Cystic lung disease: Achieving a radiologic diagnosis

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Trotman-Dickenson, Beatrice, E-mail: btrotmandickenson@partners.org

2014-01-15

Diffuse cystic lung disease represents a diverse group of uncommon disorders with characteristic appearance on high resolution CT imaging. The combination of imaging appearance with clinical features and genetic testing where appropriate permits a confident and accurate diagnosis in the majority of the diseases without recourse for open lung biopsy. The mechanism of cyst development disease is unclear but in some disorders appears to be related to small airways obstruction. These diseases are incurable, with the exception of Langerhans cell histiocytosis which may spontaneously remit or resolve on smoking cessation. Disease progression is unpredictable; in general older patients have a more benign disease, while young patients may progress rapidly to respiratory failure. An understanding of the complications of cystic lung disease and the appearance of disease progression is essential for the management of these patients. A number of these disorders are associated with malignancy, recognition of the potential tumors permits appropriate imaging surveillance. Due to the widespread use of CT, pulmonary cysts are increasingly discovered incidentally in an asymptomatic individual. The diagnostic challenge is to determine whether these cysts represent an early feature of a progressive disease or have no clinical significance. In the elderly population the cysts are unlikely to represent a progressive disease. In individuals <50 years further evaluation is recommended.

Cystic lung disease: Achieving a radiologic diagnosis

International Nuclear Information System (INIS)

Trotman-Dickenson, Beatrice

2014-01-01

Diffuse cystic lung disease represents a diverse group of uncommon disorders with characteristic appearance on high resolution CT imaging. The combination of imaging appearance with clinical features and genetic testing where appropriate permits a confident and accurate diagnosis in the majority of the diseases without recourse for open lung biopsy. The mechanism of cyst development disease is unclear but in some disorders appears to be related to small airways obstruction. These diseases are incurable, with the exception of Langerhans cell histiocytosis which may spontaneously remit or resolve on smoking cessation. Disease progression is unpredictable; in general older patients have a more benign disease, while young patients may progress rapidly to respiratory failure. An understanding of the complications of cystic lung disease and the appearance of disease progression is essential for the management of these patients. A number of these disorders are associated with malignancy, recognition of the potential tumors permits appropriate imaging surveillance. Due to the widespread use of CT, pulmonary cysts are increasingly discovered incidentally in an asymptomatic individual. The diagnostic challenge is to determine whether these cysts represent an early feature of a progressive disease or have no clinical significance. In the elderly population the cysts are unlikely to represent a progressive disease. In individuals <50 years further evaluation is recommended

Plasma microRNAs serve as biomarkers of therapeutic efficacy and disease progression in hypertension-induced heart failure

NARCIS (Netherlands)

Dickinson, Brent A; Semus, Hillary M; Montgomery, Rusty L; Stack, Christianna; Latimer, Paul A; Lewton, Steven M; Lynch, Joshua M; Hullinger, Thomas G; Seto, Anita G; van Rooij, Eva

AIMS: Recent studies have shown that microRNAs (miRNAs), besides being potent regulators of gene expression, can additionally serve as circulating biomarkers of disease. The aim of this study is to determine if plasma miRNAs can be used as indicators of disease progression or therapeutic efficacy in

The Progressive BSSG Rat Model of Parkinson's: Recapitulating Multiple Key Features of the Human Disease.

Directory of Open Access Journals (Sweden)

Jackalina M Van Kampen

Full Text Available The development of effective neuroprotective therapies for Parkinson's disease (PD has been severely hindered by the notable lack of an appropriate animal model for preclinical screening. Indeed, most models currently available are either acute in nature or fail to recapitulate all characteristic features of the disease. Here, we present a novel progressive model of PD, with behavioural and cellular features that closely approximate those observed in patients. Chronic exposure to dietary phytosterol glucosides has been found to be neurotoxic. When fed to rats, β-sitosterol β-d-glucoside (BSSG triggers the progressive development of parkinsonism, with clinical signs and histopathology beginning to appear following cessation of exposure to the neurotoxic insult and continuing to develop over several months. Here, we characterize the progressive nature of this model, its non-motor features, the anatomical spread of synucleinopathy, and response to levodopa administration. In Sprague Dawley rats, chronic BSSG feeding for 4 months triggered the progressive development of a parkinsonian phenotype and pathological events that evolved slowly over time, with neuronal loss beginning only after toxin exposure was terminated. At approximately 3 months following initiation of BSSG exposure, animals displayed the early emergence of an olfactory deficit, in the absence of significant dopaminergic nigral cell loss or locomotor deficits. Locomotor deficits developed gradually over time, initially appearing as locomotor asymmetry and developing into akinesia/bradykinesia, which was reversed by levodopa treatment. Late-stage cognitive impairment was observed in the form of spatial working memory deficits, as assessed by the radial arm maze. In addition to the progressive loss of TH+ cells in the substantia nigra, the appearance of proteinase K-resistant intracellular α-synuclein aggregates was also observed to develop progressively, appearing first in the

Intracerebroventricular gene therapy that delays neurological disease progression is associated with selective preservation of retinal ganglion cells in a canine model of CLN2 disease.

Science.gov (United States)

Whiting, Rebecca E H; Jensen, Cheryl A; Pearce, Jacqueline W; Gillespie, Lauren E; Bristow, Daniel E; Katz, Martin L

2016-05-01

CLN2 disease is one of a group of lysosomal storage disorders called the neuronal ceroid lipofuscinoses (NCLs). The disease results from mutations in the TPP1 gene that cause an insufficiency or complete lack of the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1). TPP1 is involved in lysosomal protein degradation, and lack of this enzyme results in the accumulation of protein-rich autofluorescent lysosomal storage bodies in numerous cell types including neurons throughout the central nervous system and the retina. CLN2 disease is characterized primarily by progressive loss of neurological functions and vision as well as generalized neurodegeneration and retinal degeneration. In children the progressive loss of neurological functions typically results in death by the early teenage years. A Dachshund model of CLN2 disease with a null mutation in TPP1 closely recapitulates the human disorder with a progression from disease onset at approximately 4 months of age to end-stage at 10-11 months. Delivery of functional TPP1 to the cerebrospinal fluid (CSF), either by periodic infusion of the recombinant protein or by a single administration of a TPP1 gene therapy vector to the CSF, significantly delays the onset and progression of neurological signs and prolongs life span but does not prevent the loss of vision or modest retinal degeneration that occurs by 11 months of age. In this study we found that in dogs that received the CSF gene therapy treatment, the degeneration of the retina and loss of retinal function continued to progress during the prolonged life spans of the treated dogs. Eventually the normal cell layers of the retina almost completely disappeared. An exception was the ganglion cell layer. In affected dogs that received TPP1 gene therapy to the CSF and survived an average of 80 weeks, ganglion cell axons were present in numbers comparable to those of normal Dachshunds of similar age. The selective preservation of the retinal ganglion cells suggests

Metabolomics insights into activated redox signaling and lipid metabolism dysfunction in chronic kidney disease progression

Directory of Open Access Journals (Sweden)

Hua Chen

2016-12-01

Full Text Available Early detection is critical in prevention and treatment of kidney disease. However currently clinical laboratory and histopathological tests do not provide region-specific and accurate biomarkers for early detection of kidney disease. The present study was conducted to identify sensitive biomarkers for early detection and progression of tubulo-interstitial nephropathy in aristolochic acid I-induced rats at weeks 4, 8 and 12. Biomarkers were validated using aristolochic acid nephropathy (AAN rats at week 24, adenine-induced chronic kidney disease (CKD rats and CKD patients. Compared with control rats, AAN rats showed anemia, increased serum urea and creatinine, progressive renal interstitial fibrosis, activation of nuclear factor-kappa B, and up-regulation of pro-inflammatory, pro-oxidant, and pro-fibrotic proteins at weeks 8 and 12. However, no significant difference was found at week 4. Metabolomics identified 12-ketodeoxycholic acid, taurochenodesoxycholic acid, LPC(15:0 and docosahexaenoic acid as biomarkers for early detection of tubulo-interstitial nephropathy. With prolonging aristolochic acid I exposure, LPE(20:2, cholic acid, chenodeoxycholic acid and LPC(17:0 were identified as biomarkers for progression from early to advanced AAN and lysoPE(22:5, indoxyl sulfate, uric acid and creatinine as biomarkers of advanced AAN. These biomarkers were reversed by treatment of irbesartan and ergone in AAN rats at week 24 and adenine-induced CKD rats. In addition, these biomarkers were also reversed by irbesartan treatment in CKD patients.

[Research progress in root rot diseases of Chinese herbal medicine and control strategy by antagonistic microorganisms].

Science.gov (United States)

Gao, Fen; Ren, Xiao-xia; Wang, Meng-liang; Qin, Xue-mei

2015-11-01

In recent years, root rot diseases of Chinese herbal medicine have been posing grave threat to the development of the traditional Chinese medicine industry. This article presents a review on the occurring situation of the root rot disease, including the occurrence of the disease, the diversity of the pathogens, the regional difference in dominant pathogens,and the complexity of symptoms and a survey of the progress in bio-control of the disease using antagonistic microorganisms. The paper also discusses the existing problems and future prospects in the research.

Diminished disease progression rate in a chronic kidney disease population following the replacement of dietary water source with quality drinking water: A pilot study.

Science.gov (United States)

Siriwardhana, Edirisinghe Arachchige Ranga Iroshanie Edirisinghe; Perera, Ponnamperuma Aratchige Jayasumana; Sivakanesan, Ramiah; Abeysekara, Tilak; Nugegoda, Danaseela Bandara; Weerakoon, Kosala; Siriwardhana, Dunusingha Asitha Surandika

2018-05-01

Environmental toxin/s is alleged to be the contributory factor for the chronic kidney disease of unknown aetiology (CKDu) in Sri Lanka. The potential of drinking water as a medium for the nephrotoxic agents in the affected subjects has been comprehensively discoursed in the recent past. The present study was aimed to assess the effect of replacing the habitual drinking water on the kidney function of CKDu patients residing in the North Central Province of Sri Lanka: METHODS: An interventional study was carried out to assess the disease progression rate of a CKDu population whose habitual drinking water was replaced by bottled spring water certified by Sri Lanka Standard (SLS) for a period of 18 month along with a population of CKDu patients who continued with their usual drinking water. Kidney function of subjects in both groups were monitored in terms of blood pressure, serum creatinine, serum calcium, serum phosphorus, hemoglobin, estimated glomerular filtration rate and urinary protein at 6 months intervals during the intervention and follow up periods. Diminished disease progression rate was observed in CKDu patients in the intervention group when compared with the non- intervention group based on serum creatinine, Hb, estimated glomerular filtration rate and urinary protein levels. Extensive interventional studies are required to generalize effect of drinking water on CKDu population. The habitual drinking water is likely to be a contributory factor towards the progression of the disease. © 2017 Asian Pacific Society of Nephrology.

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

Science.gov (United States)

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

2014-01-01

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

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

Science.gov (United States)

Marzi, Andrea; Feldmann, Friederike; Hanley, Patrick W; Scott, Dana P; Günther, Stephan; Feldmann, Heinz

2015-10-01

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

Hypoxemia in patients with COPD: cause, effects, and disease progression.

LENUS (Irish Health Repository)

Kent, Brian D

2012-02-01

Chronic obstructive pulmonary disease (COPD) is a leading cause of death and disability internationally. Alveolar hypoxia and consequent hypoxemia increase in prevalence as disease severity increases. Ventilation\\/perfusion mismatch resulting from progressive airflow limitation and emphysema is the key driver of this hypoxia, which may be exacerbated by sleep and exercise. Uncorrected chronic hypoxemia is associated with the development of adverse sequelae of COPD, including pulmonary hypertension, secondary polycythemia, systemic inflammation, and skeletal muscle dysfunction. A combination of these factors leads to diminished quality of life, reduced exercise tolerance, increased risk of cardiovascular morbidity, and greater risk of death. Concomitant sleep-disordered breathing may place a small but significant subset of COPD patients at increased risk of these complications. Long-term oxygen therapy has been shown to improve pulmonary hemodynamics, reduce erythrocytosis, and improve survival in selected patients with severe hypoxemic respiratory failure. However, the optimal treatment for patients with exertional oxyhemoglobin desaturation, isolated nocturnal hypoxemia, or mild-to-moderate resting daytime hypoxemia remains uncertain.

Aldosterone synthase gene is not a major susceptibility gene for progression of chronic kidney disease in patients with autosomal dominant polycystic kidney disease

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Gnanasambandan Ramanathan

2017-01-01

Full Text Available Autosomal dominant polycystic kidney disease (ADPKD is the most common heritable kidney disease and is characterized by bilateral renal cysts. Hypertension is a frequent cause of chronic kidney disease (CKD and mortality in patients with ADPKD. The aldosterone synthase gene polymorphisms of the renin-angiotensin-aldosterone system have been extensively studied as hypertension candidate genes. The present study is aimed to investigate the potential modifier effect of CYP11B2 gene on the progression of CKD in ADPKD. One hundred and two ADPKD patients and 106 healthy controls were recruited based on Ravine inclusion and exclusion criteria. The three tag-SNPs within CYP11B2 gene (rs3802230, rs4543, and rs4544 were genotyped using FRET-based KASPar method. Cochran-Armitage trend test was used to assess the potential associations between these polymorphisms and CKD stages. Mantel- Haenszel stratified analysis was used to explore confounding and interaction effects of these polymorphisms. Of the three tag-SNPs genotyped, rs4544 polymorphism was monomorphic and rs3802230 deviated Hardy-Weinberg equilibrium. The CYP11B2 tag-SNPs did not show significant association with ADPKD or CKD. Further, these polymorphisms did not exhibit confounding effect on the relationship between CKD progression and hypertension. Our results suggest that aldosterone synthase gene is not a major susceptibility gene for progression of CKD in South Indian ADPKD patients.

The treatment of juvenile/adult GM1-gangliosidosis with Miglustat may reverse disease progression.

Science.gov (United States)

Deodato, Federica; Procopio, Elena; Rampazzo, Angelica; Taurisano, Roberta; Donati, Maria Alice; Dionisi-Vici, Carlo; Caciotti, Anna; Morrone, Amelia; Scarpa, Maurizio

2017-10-01

Juvenile and adult GM1-gangliosidosis are invariably characterized by progressive neurological deterioration. To date only symptomatic therapies are available. We report for the first time the positive results of Miglustat (OGT 918, N-butyl-deoxynojirimycin) treatment on three Italian GM1-gangliosidosis patients. The first two patients had a juvenile form (enzyme activity ≤5%, GLB1 genotype p.R201H/c.1068 + 1G > T; p.R201H/p.I51N), while the third patient had an adult form (enzyme activity about 7%, p.T329A/p.R442Q). Treatment with Miglustat at the dose of 600 mg/day was started at the age of 10, 17 and 28 years; age at last evaluation was 21, 20 and 38 respectively. Response to treatment was evaluated using neurological examinations in all three patients every 4-6 months, the assessment of Movement Disorder-Childhood Rating Scale (MD-CRS) in the second patient, and the 6-Minute Walking Test (6-MWT) in the third patient. The baseline neurological status was severely impaired, with loss of autonomous ambulation and speech in the first two patients, and gait and language difficulties in the third patient. All three patients showed gradual improvement while being treated; both juvenile patients regained the ability to walk without assistance for few meters, and increased alertness and vocalization. The MD-CRS class score in the second patient decreased from 4 to 2. The third patient improved in movement and speech control, the distance covered during the 6-MWT increased from 338 to 475 m. These results suggest that Miglustat may help slow down or reverse the disease progression in juvenile/adult GM1-gangliosidosis.

Role of Lipids in the Onset, Progression and Treatment of Periodontal Disease. A Systematic Review of Studies in Humans

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Alfonso Varela-López

2016-07-01

Full Text Available The risk of different oral problems (root caries, tooth mobility, and tooth loss can be increased by the presence of periodontal disease, which has also been associated with a growing list of systemic diseases. The presence of some bacteria is the primary etiology of this disease; a susceptible host is also necessary for disease initiation. In this respect, the progression of periodontal disease and healing of the periodontal tissues can be modulated by nutritional status. To clarify the role of lipids in the establishment, progression, and/or treatment of this pathology, a systematic review was conducted of English-written literature in PubMed until May 2016, which included research on the relationship of these dietary components with the onset and progression of periodontal disease. According to publication type, randomized-controlled trials, cohort, case-control and cross-sectional studies were included. Among all the analyzed components, those that have any effect on oxidative stress and/or inflammation seem to be the most interesting according to current evidence. On one hand, there is quite a lot of information in favor of a positive role of n-3 fatty acids, due to their antioxidant and immunomodulatory effects. On the other hand, saturated fat-rich diets increase oxidative stress as well the as intensity and duration of inflammatory processes, so they must be avoided.

Blood Transcriptional Signatures for Disease Progression in a Rat Model of Osteoarthritis

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Michał Korostyński

2017-01-01

Full Text Available Biomarkers of osteoarthritis (OA that can accurately diagnose the disease at the earliest stage would significantly support efforts to develop treatments for prevention and early intervention. We have sought to determine the time course of alterations in peripheral blood gene expression profile associated with the development of OA. Blood samples were collected from a tail vein of individual rats with monosodium iodoacetate- (MIA- induced OA (2, 14, 21, and 28 days after the treatment. We used whole-genome microarrays to reveal OA-related transcriptional alterations of 72 transcripts. Three main groups of coexpressed genes revealed diverse time-dependent profiles of up- and downregulation. Functional links that connect expression of the gradually downregulated genes to the G13 signaling pathway were indicated. The mRNA abundance levels of the identified transcripts were further analyzed in publicly available gene expression dataset obtained from a GARP study cohort of OA patients. We revealed three-gene signature differentially expressed in both rat and human blood (TNK2, KCTD2, and WDR37. The alterations in expression of the selected transcripts in peripheral blood samples of the patients indicate heterogeneity of the OA profiles potentially related to disease progress and severity of clinical symptoms. Our study identifies several potential stage-specific biomarkers of OA progression.

Instrumentation and quantitative methods of evaluation. Progress report, January 15-September 14, 1986

International Nuclear Information System (INIS)

Beck, R.N.

1986-09-01

This document reports progress under grant entitled ''Instrumentation and Quantitative Methods of Evaluation.'' Individual reports are presented on projects entitled the physical aspects of radionuclide imaging, image reconstruction and quantitative evaluation, PET-related instrumentation for improved quantitation, improvements in the FMI cyclotron for increased utilization, and methodology for quantitative evaluation of diagnostic performance

Recommendations for cerebrospinal fluid Alzheimer's disease biomarkers in the diagnostic evaluation of mild cognitive impairment

DEFF Research Database (Denmark)

Herukka, Sanna-Kaisa; Simonsen, Anja Hviid; Andreasen, Niels

2017-01-01

) patient counseling. The working group recommended using CSF AD biomarkers in the diagnostic workup of MCI patients, after prebiomarker counseling, as an add-on to clinical evaluation to predict functional decline or conversion to AD dementia and to guide disease management. Because of insufficient...... evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers. Furthermore, the working group provided recommendations for interpretation of ambiguous CSF biomarker results and for pre- and post-biomarker counseling....... impairment (MCI). The recommendations were developed by a multidisciplinary working group and based on the available evidence and consensus from focused group discussions for 1) prediction of clinical progression to Alzheimer's disease (AD) dementia, 2) cost-effectiveness, 3) interpretation of results, and 4...

Environmental factors affecting inflammatory bowel disease: have we made progress?

Science.gov (United States)

Lakatos, Peter Laszlo

2009-01-01

The pathogenesis of inflammatory bowel disease (IBD) is only partially understood; various environmental and host (e.g. genetic, epithelial, immune, and nonimmune) factors are involved. The critical role for environmental factors is strongly supported by recent worldwide trends in IBD epidemiology. One important environmental factor is smoking. A meta-analysis partially confirms previous findings that smoking was found to be protective against ulcerative colitis and, after the onset of the disease, might improve its course, decreasing the need for colectomy. In contrast, smoking increases the risk of developing Crohn's disease and aggravates its course. The history of IBD is dotted by cyclic reports on the isolation of specific infectious agents responsible for Crohn's disease or ulcerative colitis. The more recently published cold chain hypothesis is providing an even broader platform by linking dietary factors and microbial agents. An additional, recent theory has suggested a breakdown in the balance between putative species of 'protective' versus 'harmful' intestinal bacteria - this concept has been termed dysbiosis resulting in decreased bacterial diversity. Other factors such as oral contraceptive use, appendectomy, dietary factors (e.g. refined sugar, fat, and fast food), perinatal events, and childhood infections have also been associated with both diseases, but their role is more controversial. Nonetheless, there is no doubt that economic development, leading to improved hygiene and other changes in lifestyle ('westernized lifestyle') may play a role in the increase in IBD. This review article focuses on the role of environmental factors in the pathogenesis and progression of IBDs. Copyright 2009 S. Karger AG, Basel.

Performance Evaluation of Moment Connections of Moment Resisting Frames Against Progressive Collapse

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M. Mahmoudi

2017-02-01

Full Text Available When a primary structural element fails due to sudden load such as explosion, the building undergoes progressive collapse. The method for design of moment connections during progressive collapse is different to seismic design of moment connections. Because in this case, the axial force on the connections makes it behave differently. The purpose of this paper is to evaluate the performance of a variety of moment connections in preventing progressive collapse in steel moment frames. To achieve this goal, three prequalified moment connections (BSEEP, BFP and WUP-W were designed according seismic codes. These moment connections were analyzed numerically using ABAQUS software for progressive collapse. The results show that the BFP connection (bolted flange plate has capacity much more than other connections because of the use of plates at the junction of beam-column.

Klinefelter′s syndrome associated with progressive muscular atrophy simulating Kennedy′s disease

OpenAIRE

Pedro Enrique Jiménez Caballero

2012-01-01

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 Klin...

Impairment of vowel articulation as a possible marker of disease progression in Parkinson's disease.

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Sabine Skodda

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

PROGRESSIVE MUSCLE RELAXATION INCREASE PEAK EXPIRATORY FLOW RATE ON CHRONIC OBSTRUCTIVE PULMONARY DISEASE PATIENTS

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Tintin Sukartini

2017-07-01

Full Text Available Introduction: Limited progressive air flow in Chronic Obstructive Pulmonary Disease (COPD can caused by small airway disease (bronchiolitis obstructive and loss of elasticity of the lung (emphysema. Further it can be decreasing the quality of life in COPD patients because dyspnea and uncomfortable in activity. Progressive muscle relaxation (PMR is one of the relaxation technique that can repair pulmonary ventilation by decreasing chronic constriction of the respiratory muscles. The objective of this study was to analyze the effect of progressive muscle relaxation on raised peak expiratory flow rate (PEFR. Method: A pre-experimental one group pre-post test design was used in this study. Population was all of the COPD patients at Pulmonary Specialist Polyclinic Dr Mohamad Soewandhie Surabaya. There were 8 respondents taken by using purposive sampling. PEFR was counted by using peak flow meter every six day. Data were analyzed by using Paired t-Test with significance level  p≤0.05. Result: The result showed that PMR had significance level on increasing of PEFR (p=0.012. Discussion: It can be concluded that PMR has an effect on raise PEFR. Further studies are recommended to measure the effect of PMR on respiratory rate (RR, heart rate (HR subjective dyspnoe symptoms, forced expiration volume on the first minute (FEV1 and mid maximum flow rate (MMFR in COPD patients.

Progress Evaluation for the Restaurant Industry Assessed by a Voluntary Marketing-Mix and Choice-Architecture Framework That Offers Strategies to Nudge American Customers toward Healthy Food Environments, 2006-2017.

Science.gov (United States)

Kraak, Vivica; Englund, Tessa; Misyak, Sarah; Serrano, Elena

2017-07-12

Consumption of restaurant food and beverage products high in fat, sugar and sodium contribute to obesity and non-communicable diseases. We evaluated restaurant-sector progress to promote healthy food environments for Americans. We conducted a desk review of seven electronic databases (January 2006-January 2017) to examine restaurant strategies used to promote healthful options in the United States (U.S.). Evidence selection ( n = 84) was guided by the LEAD principles (i.e., locate, evaluate, and assemble evidence to inform decisions) and verified by data and investigator triangulation. A marketing-mix and choice-architecture framework was used to examine eight voluntary strategies (i.e., place, profile, portion, pricing, promotion, healthy default picks, priming or prompting and proximity) to evaluate progress (i.e., no, limited, some or extensive) toward 12 performance metrics based on available published evidence. The U.S. restaurant sector has made limited progress to use pricing, profile (reformulation), healthy default picks (choices), promotion (responsible marketing) and priming and prompting (information and labeling); and some progress to reduce portions. No evidence was available to assess progress for place (ambience) and proximity (positioning) to promote healthy choices during the 10-year review period. Chain and non-chain restaurants can apply comprehensive marketing-mix and nudge strategies to promote healthy food environments for customers.

Plasma Vascular Endothelial Growth Factor Concentration and Alveolar Nitric Oxide as Potential Predictors of Disease Progression and Mortality in Idiopathic Pulmonary Fibrosis

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Jalpa Kotecha

2016-09-01

Full Text Available Background: Declining lung function signifies disease progression in idiopathic pulmonary fibrosis (IPF. Vascular endothelial growth factor (VEGF concentration is associated with declining lung function in 6 and 12-month studies. Alveolar nitric oxide concentration (CANO is increased in patients with IPF, however its significance is unclear. This study investigated whether baseline plasma VEGF concentration and CANO are associated with disease progression or mortality in IPF. Methods: 27 IPF patients were studied (maximum follow-up 65 months. Baseline plasma VEGF concentration, CANO and pulmonary function tests (PFTs were measured. PFTs were performed the preceding year and subsequent PFTs and data regarding mortality were collected. Disease progression was defined as one of: death, relative decrease of ≥10% in baseline forced vital capacity (FVC % predicted, or relative decrease of ≥15% in baseline single breath diffusion capacity of carbon monoxide (TLCO-SB % predicted. Results: Plasma VEGF concentration was not associated with progression-free survival or mortality. There was a trend towards shorter time to disease progression and death with higher CANO. CANO was significantly higher in patients with previous declining versus stable lung function. Conclusion: The role of VEGF in IPF remains uncertain. It may be of value to further investigate CANO in IPF.

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

DEFF Research Database (Denmark)

Fløyel, Tina; Brorsson, Caroline; Nielsen, Lotte B

2014-01-01

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...

Orphan drugs in development for Huntington's disease: challenges and progress

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Burgunder JM

2015-02-01

Full Text Available Jean-Marc Burgunder1–4 1Swiss Huntington’s Disease Centre, Department of Neurology, University of Bern, Bern, Switzerland; 2Department of Neurology, West China Hospital, Sichuan University, Chengdu, 3Department of Neurology, Xiangya Hospital, Central South University, Changsha, 4Department of Neurology, Sun Yat-sen University, Guangzhou, People’s Republic of China Abstract: Huntington’s disease is a monogenic disorder encompassing a variable phenotype with progressive cognitive, psychiatric, and movement disorders. Knowledge of the mechanisms involved in this disorder has made substantial advances since the discovery of the gene mutation. The dynamic mutation is the expansion of a CAG (cytosine-adenine-guanine repeat in the huntingtin (HTT gene, which is transcribed into an abnormal protein with an elongated polyglutamine tract. Polyglutamine HTT accumulates and is changed in its function in multifaceted ways related to the numerous roles of the normal protein. The protein is expressed in numerous areas of the brain and also in other organs. The major brain region involved in the disease process is the striatum, but it is clear that other systems are involved as well. This accumulated knowledge has now led to the development of treatment strategies based on specific molecular pathways for symptomatic and disease course-modifying treatment. The most proximal way to handle the disturbed protein is to hinder the gene transcription, translation, and/or to increase protein clearance. Other mechanisms now being approached include modulation of energy and intracellular signaling, induction of factors potentially leading to neuroprotection, as well as modulation of glial function. Several clinical trials based on these approaches are now under way, and it is becoming clear that a future disease-modifying therapy will be a combination of several approaches harmonized with symptomatic treatments. In this review, some of the most promising and

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

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Patel Uptal D

2011-06-01

Full Text Available Abstract Background Chronic kidney disease (CKD is the focus of recent national policy efforts; however, decision makers must account for multiple therapeutic options, comorbidities and complications. The objective of the Chronic Kidney Disease model is to provide guidance to decision makers. We describe this model and give an example of how it can inform clinical and policy decisions. Methods Monte Carlo simulation of CKD natural history and treatment. Health states include myocardial infarction, stroke with and without disability, congestive heart failure, CKD stages 1-5, bone disease, dialysis, transplant and death. Each cycle is 1 month. Projections account for race, age, gender, diabetes, proteinuria, hypertension, cardiac disease, and CKD stage. Treatment strategies include hypertension control, diabetes control, use of HMG-CoA reductase inhibitors, use of angiotensin converting enzyme inhibitors, nephrology specialty care, CKD screening, and a combination of these. The model architecture is flexible permitting updates as new data become available. The primary outcome is quality adjusted life years (QALYs. Secondary outcomes include health state events and CKD progression rate. Results The model was validated for GFR change/year -3.0 ± 1.9 vs. -1.7 ± 3.4 (in the AASK trial, and annual myocardial infarction and mortality rates 3.6 ± 0.9% and 1.6 ± 0.5% vs. 4.4% and 1.6% in the Go study. To illustrate the model's utility we estimated lifetime impact of a hypothetical treatment for primary prevention of vascular disease. As vascular risk declined, QALY improved but risk of dialysis increased. At baseline, 20% and 60% reduction: QALYs = 17.6, 18.2, and 19.0 and dialysis = 7.7%, 8.1%, and 10.4%, respectively. Conclusions The CKD Model is a valid, general purpose model intended as a resource to inform clinical and policy decisions improving CKD care. Its value as a tool is illustrated in our example which projects a relationship between

Serum creatinine is associated with the prevalence but not disease progression of multiple system atrophy in Chinese population.

Science.gov (United States)

Cao, Bei; Guo, XiaoYan; Chen, Ke; Song, Wei; Huang, Rui; Wei, QianQian; Zhao, Bi; Shang, Hui-Fang

2016-03-01

Oxidative stress is involved in the pathogenesis of multiple system atrophy (MSA). Creatine, which is converted to creatinine, has an anti-oxidative effect. Our aim is to clarify the correlations between creatinine and the occurrence as well as the progression of MSA. A total of 115 patients with probable MSA and 115 age- and gender-matched healthy controls were included in the study. The serum creatinine level of all patients and controls were evaluated and compared. The mean age of MSA patients was 58.18 ± 8.67 years and the mean disease duration was 2.85 ± 1.71 years. The creatinine level of MSA patients was significantly lower than that of healthy controls (P creatinine quartiles compared with the lowest creatinine quartiles. In a gender-specific analysis, patients with the highest quartiles and second quartiles of creatinine level had decreased occurrence than patients with the lowest quartile in females, but not in males. The serum level of creatinine was not found correlated with the mean rate of annualised changes, neither with other independent factors, such as age, body mass index (BMI), sex, Unified MSA Rating Scale (UMSARS) scores and disease duration at the initial visit in patients with MSA. High level of serum creatinine may be associated with a low occurrence of MSA in Chinese population, especially in female. However, serum creatinine does not deteriorate or ameliorate the progression of MSA.

Association of serum microRNAs with islet autoimmunity, disease progression and metabolic impairment in relatives at risk of type 1 diabetes.

Science.gov (United States)

Snowhite, Isaac V; Allende, Gloria; Sosenko, Jay; Pastori, Ricardo L; Messinger Cayetano, Shari; Pugliese, Alberto

2017-08-01

MicroRNAs (miRNAs) are key regulators of gene expression and novel biomarkers for many diseases. We investigated the hypothesis that serum levels of some miRNAs would be associated with islet autoimmunity and/or progression to type 1 diabetes. We measured levels of 93 miRNAs most commonly detected in serum. This retrospective cohort study included 150 autoantibody-positive and 150 autoantibody-negative family-matched siblings enrolled in the TrialNet Pathway to Prevention Study. This was a young cohort (mean age = 11 years), and most autoantibody-positive relatives were at high risk because they had multiple autoantibodies, with 39/150 (26%, progressors) developing type 1 diabetes within an average 8.7 months of follow-up. We analysed miRNA levels in relation to autoantibody status, future development of diabetes and OGTT C-peptide and glucose indices of disease progression. Fifteen miRNAs were differentially expressed when comparing autoantibody-positive/negative siblings (range -2.5 to 1.3-fold). But receiver operating characteristic (ROC) analysis indicated low specificity and sensitivity. Seven additional miRNAs were differentially expressed among autoantibody-positive relatives according to disease progression; ROC returned significant AUC values and identified miRNA cut-off levels associated with an increased risk of disease in both cross-sectional and survival analyses. Levels of several miRNAs showed significant correlations (r values range 0.22-0.55) with OGTT outcomes. miR-21-3p, miR-29a-3p and miR-424-5p had the most robust associations. Serum levels of selected miRNAs are associated with disease progression and confer additional risk of the development of type 1 diabetes in young autoantibody-positive relatives. Further studies, including longitudinal assessments, are warranted to further define miRNA biomarkers for prediction of disease risk and progression.

Risk factors for the progression of periodontal disease in a Greek adult population.

Science.gov (United States)

Chrysanthakopoulos, Nikolaos A

2017-05-01

The purpose of the present study was to investigate the progression risk factors of periodontal disease by individual characteristics at baseline in a Greek adult population. The study sample consisted of 854 individuals. All participants were clinically examined and answered questions regarding sex, smoking status, socioeconomic status, low educational level, frequency of dental follow up, and oral hygiene habits. Serum levels of disease markers were investigated, and attachment levels were clinically recorded. For the assessment of periodontal disease progression, additional clinical attachment loss (CAL) was used if one or more sites showed a 3 mm or more increase in probing attachment level over a 2-year period. Statistical analysis was performed by using a modified multiple Poisson's analysis model. A total of 74% of the participants exhibited additional CAL over a 2-year period. Significant associations were observed between additional CAL and smoking (relative risk [RR] = 0.78, 95% confidence level [CI] = 0.65-0.92), attachment level of 5 mm or more at baseline (RR = 0.89, 95% CI = 0.75-1.05), educational level (RR = 0.90, 95% CI = 0.76-1.07), socioeconomic status (RR = 0.86, 95% CI = 0.59-1.14), and irregular dental follow up (RR = 1.23, 95% CI = 1.04-1.45). Smoking, baseline attachment level of 5 mm or more, low educational level, low socioeconomic status, and irregular dental follow up could be considered risk factors for further CAL. © 2015 Wiley Publishing Asia Pty Ltd.

Hepatitis B and C co-infection are independent predictors of progressive kidney disease in HIV-positive, antiretroviral-treated adults

DEFF Research Database (Denmark)

Mocroft, Amanda; Neuhaus, Jacqueline; Peters, Lars

2012-01-01

B (HBV) co-infection and progressive CKD among 3,441 antiretroviral-treated clinical trial participants. Progressive CKD was defined as the composite of end-stage renal disease, renal death, or significant glomerular filtration rate (eGFR) decline (25% decline to eGFR 800,000 IU/ml had increased...

Progression of regional neuropathology in Alzheimer disease and normal elderly: findings from the Nun study.

Science.gov (United States)

Wolf, D S; Gearing, M; Snowdon, D A; Mori, H; Markesbery, W R; Mirra, S S

1999-01-01

Although diffuse plaques in the neocortex may represent an early stage in the evolution of neuritic plaques, plaques in the striatum and cerebellum retain their predominantly diffuse nature in Alzheimer disease (AD), regardless of disease duration. We had the opportunity to explore the progression of these regional features by using autopsy brain specimens from 15 cognitively normal and five AD subjects, all Catholic sisters enrolled in the Nun Study, a longitudinal study on aging and AD. Neuropathologic changes were assessed in the temporal cortex, striatum, and cerebellum without knowledge of clinical status. We found diffuse plaques in the striatum in six (40%) and cerebellar plaques in none of the brains from the non-demented subjects. Striatal plaques were present in all five and cerebellar plaques in four of the five AD cases. In the 20 cases overall, the presence of striatal plaques generally paralleled the occurrence of neuritic plaques in neocortex and correlated with lower scores on several neuropsychologic tests assessing memory. Our findings suggest that striatal diffuse plaques occur relatively early in the progression of AD pathology and coincide with neocortical pathology and cognitive changes. Thus, it is unlikely that temporal factors alone account for regional differences in progression of AD neuropathology.

Gene Expression Differences in Peripheral Blood of Parkinson's Disease Patients with Distinct Progression Profiles.

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Raquel Pinho

Full Text Available The prognosis of neurodegenerative disorders is clinically challenging due to the inexistence of established biomarkers for predicting disease progression. Here, we performed an exploratory cross-sectional, case-control study aimed at determining whether gene expression differences in peripheral blood may be used as a signature of Parkinson's disease (PD progression, thereby shedding light into potential molecular mechanisms underlying disease development. We compared transcriptional profiles in the blood from 34 PD patients who developed postural instability within ten years with those of 33 patients who did not develop postural instability within this time frame. Our study identified >200 differentially expressed genes between the two groups. The expression of several of the genes identified was previously found deregulated in animal models of PD and in PD patients. Relevant genes were selected for validation by real-time PCR in a subset of patients. The genes validated were linked to nucleic acid metabolism, mitochondria, immune response and intracellular-transport. Interestingly, we also found deregulation of these genes in a dopaminergic cell model of PD, a simple paradigm that can now be used to further dissect the role of these molecular players on dopaminergic cell loss. Altogether, our study provides preliminary evidence that expression changes in specific groups of genes and pathways, detected in peripheral blood samples, may be correlated with differential PD progression. Our exploratory study suggests that peripheral gene expression profiling may prove valuable for assisting in prediction of PD prognosis, and identifies novel culprits possibly involved in dopaminergic cell death. Given the exploratory nature of our study, further investigations using independent, well-characterized cohorts will be essential in order to validate our candidates as predictors of PD prognosis and to definitively confirm the value of gene expression

The Significance of α-Synuclein, Amyloid-β and Tau Pathologies in Parkinson’s Disease Progression and Related Dementia

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Compta, Y.; Parkkinen, L.; Kempster, P.; Selikhova, M.; Lashley, T.; Holton, J.L.; Lees, A.J.; Revesz, T.

2014-01-01

Background Dementia is one of the milestones of advanced Parkinson’s disease (PD), with its neuropathological substrate still being a matter of debate, particularly regarding its potential mechanistic implications. Objective The aim of this study was to review the relative importance of Lewy-related α-synuclein and Alzheimer’s tau and amyloid-β (Aβ) pathologies in disease progression and dementia in PD. Methods We reviewed studies conducted at the Queen Square Brain Bank, Institute of Neurology, University College London, using large PD cohorts. Results Cortical Lewy- and Alzheimer-type pathologies are associated with milestones of poorer prognosis and with non-tremor predominance, which have been, in turn, linked to dementia. The combination of these pathologies is the most robust neuropathological substrate of PD-related dementia, with cortical Aβ burden determining a faster progression to dementia. Conclusion The shared relevance of these pathologies in PD progression and dementia is in line with experimental data suggesting synergism between α-synuclein, tau and Aβ and with studies testing these proteins as disease biomarkers, hence favouring the eventual testing of therapeutic strategies targeting these proteins in PD. PMID:24028925

HBV genome analysis in the progression of HBV related chronic liver disease

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Ruksana Raihan

2017-12-01

Full Text Available Although HBV is a non-cytopathic virus, alteration of viral genome may also alter host immunity and may play a part in the pathogenesis LC and HCC. During the last decade, various studies have shown that mutations in the HBV genome may play a role in HCC pathogenesis. Here, we have analyzed HBV genome from patients with asymptomatic HBV carrier [ASC], chronic hepatitis B (CHB, cirrhosis of liver (LC, and hepatocellular carcinoma (HCC of Bangladeshi origin. A total of 225 patients tested positive for HBV with different stages of chronic HBV infection were enrolled in this study. The extent of liver damages were assayed by estimating serum levels of alanine aminotransferase (ALT, serum bilirubin and finally by abdominal ultrasonography and/or fine needle aspiration cytology. Wherever required, cancer marker like alpha fetoprotein (AFP was assessed. HBV genotype was evaluated by immunoassays and sequenced. A total of 25 patients were ASC, 135 were CHB and 65 were LC and HCC. Among ASC patients, 5, 7 and 13 belonged to HBV genotype A, C, and D, respectively. On the other hand, HBV genotype C was most prevalent in CHB patients (about 42%, followed by HBV genotype D (36%. About 69% patients with LC and HCC also had genotype C. Full genomic analysis of sera of patients with progressive liver damages (LC and HCC revealed mutations at HBeAg promoter regions in more than 80% patients. However, mutations in this region were mostly unseen in ASC and patients with less progressive liver diseases. HBV genotype was found quite different in Bangladeshi HBV patients which seem a mixture of Indian and Asia-Pacific region. This study also reveals that HBeAg promoter region mutation may have role in development of HBV related LC and HCC.

Progressive microstructural changes of the occipital cortex in Huntington's disease.

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Odish, Omar F F; Reijntjes, Robert H A M; van den Bogaard, Simon J A; Roos, Raymund A C; Leemans, Alexander

2018-02-28

In this study we longitudinally investigated the rate of microstructural alterations in the occipital cortex in different stages of Huntington's disease (HD) by applying an automated atlas-based approach to diffusion MRI data. Twenty-two premanifest (preHD), 10 early manifest HD (early HD) and 24 healthy control subjects completed baseline and two year follow-up scans. The preHD group was stratified based on the predicted years to disease onset into a far (preHD-A) and near (preHD-B) to disease onset group. Clinical and behavioral measures were collected per assessment time point. An automated atlas-based DTI analysis approach was used to obtain the mean, axial and radial diffusivities of the occipital cortex. We found that the longitudinal rate of diffusivity change in the superior occipital gyrus (SOG), middle occipital gyrus (MOG), and inferior occipital gyrus (IOG) was significantly higher in early HD compared to both preHD and controls (all p's ≤ 0.005), which can be interpreted as an increased rate of microstructural degeneration. Furthermore, the change rate in the diffusivity of the MOG could significantly discriminate between preHD-B compared to preHD-A and the other groups (all p's ≤ 0.04). Finally, we found an inverse correlation between the Stroop Word Reading task and diffusivities in the SOG and MOG (all p's ≤ 0.01). These findings suggest that measures obtained from the occipital cortex can serve as sensitive longitudinal biomarkers for disease progression in preHD-B and early HD. These could in turn be used to assess potential effects of proposed disease modifying therapies.

Autologous neural progenitor cell transplantation into newborn mice modeling for E200K genetic prion disease delays disease progression.

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Frid, Kati; Binyamin, Orli; Fainstein, Nina; Keller, Guy; Ben-Hur, Tamir; Gabizon, Ruth

2018-05-01

TgMHu2ME199K mice, a transgenic line mimicking genetic prion disease, are born healthy and gradually deteriorate to a terminal neurological condition concomitant with the accumulation of disease-related PrP. To investigate whether transplantation of neural progenitor cells (NPCs) to these mice can delay disease aggravation, we first tested the properties of mutant PrP in homogenates and enriched NPCs from TgMHu2ME199K embryos, as compared to PrP in sick TgMHu2ME199K brains. Next, we tested the clinical effect of NPCs transplantation into newborn TgMHu2ME199K mice. We show that mutant PrP does not convert into a disease-related isoform while in progenitor cells. Most important, transplantation of both wild type and transgenic NPCs significantly delayed the progression of spontaneous prion disease in TgMHu2ME199K mice. While the strong clinical effect was not accompanied by a reduced accumulation of disease-related PrP, treated mouse brains presented a significant reduction in amyloid glycosaminoglycans and preservation of neurogenesis levels, indicating a strong neuroprotective effect. These results may encourage the investigation of new pathways for treatment in these terrible diseases. Copyright © 2018 Elsevier Inc. All rights reserved.

Value of HBsAg level in dynamic monitoring of disease progression in patients with chronic HBV infection

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BAO Teng

2017-08-01

/ml, and ＞20 000 IU/ml (F=?, P=?. In the HBeAg-positive CHB group, HBeAg-negative CHB group, LC-C group, and LC-D group, serum HBsAg level was positively correlated with HBV DNA level (r=0.554, 0.501, 0.320, and 0.432, all P＜0.001. ConclusionHBsAg level gradually decreases with disease progression and is closely associated with HBV DNA level. Dynamic monitoring of HBsAg level helps to evaluate disease progression after HBV infection.

Untreated periodontal disease in Indonesian adolescents : Subgingival microbiota in relation to experienced progression of periodontitis

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Timmerman, MF; Van der Weijden, GA; Arief, EM; Armand, S; Abbas, F; Winkel, EG; Van Winkelhoff, AJ; Van der Velden, U

Background/aims: In an Indonesian population deprived of regular dental care, the experienced progression of disease between baseline (1987) and follow-up (1994) was investigated in relation to the composition of the subgingival microbiota at follow-up. At baseline the age ranged from 15 to 25

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

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Claire E Le Pichon

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

Progress in etiology, diagnosis, and therapy of idiopathic orbital inflammatory disease

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Bijlsma, W.R.

2011-01-01

Idiopathic orbital inflammation (IOI) is a disease with signs and symptoms of an orbital inflammatory lesion with after local and systemic evaluation no apparent cause. Little is known about the etiology of the disease. This study aimed to answer three questions: a) what etiologic factors are

Progress Evaluation for the Restaurant Industry Assessed by a Voluntary Marketing-Mix and Choice-Architecture Framework That Offers Strategies to Nudge American Customers toward Healthy Food Environments, 2006–2017

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Misyak, Sarah; Serrano, Elena

2017-01-01

Consumption of restaurant food and beverage products high in fat, sugar and sodium contribute to obesity and non-communicable diseases. We evaluated restaurant-sector progress to promote healthy food environments for Americans. We conducted a desk review of seven electronic databases (January 2006–January 2017) to examine restaurant strategies used to promote healthful options in the United States (U.S.). Evidence selection (n = 84) was guided by the LEAD principles (i.e., locate, evaluate, and assemble evidence to inform decisions) and verified by data and investigator triangulation. A marketing-mix and choice-architecture framework was used to examine eight voluntary strategies (i.e., place, profile, portion, pricing, promotion, healthy default picks, priming or prompting and proximity) to evaluate progress (i.e., no, limited, some or extensive) toward 12 performance metrics based on available published evidence. The U.S. restaurant sector has made limited progress to use pricing, profile (reformulation), healthy default picks (choices), promotion (responsible marketing) and priming and prompting (information and labeling); and some progress to reduce portions. No evidence was available to assess progress for place (ambience) and proximity (positioning) to promote healthy choices during the 10-year review period. Chain and non-chain restaurants can apply comprehensive marketing-mix and nudge strategies to promote healthy food environments for customers. PMID:28704965

Health-Related Quality of Life Impacts Mortality but Not Progression to End-Stage Renal Disease in Pre-Dialysis Chronic Kidney Disease: A Prospective Observational Study.

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Jesky, Mark D; Dutton, Mary; Dasgupta, Indranil; Yadav, Punit; Ng, Khai Ping; Fenton, Anthony; Kyte, Derek; Ferro, Charles J; Calvert, Melanie; Cockwell, Paul; Stringer, Stephanie J

2016-01-01

Chronic kidney disease (CKD) is associated with reduced health-related quality of life (HRQL). However, the relationship between pre-dialysis CKD, HRQL and clinical outcomes, including mortality and progression to end-stage renal disease (ESRD) is unclear. All 745 participants recruited into the Renal Impairment In Secondary Care study to end March 2014 were included. Demographic, clinical and laboratory data were collected at baseline including an assessment of HRQL using the Euroqol EQ-5D-3L. Health states were converted into an EQ-5Dindex score using a set of weighted preferences specific to the UK population. Multivariable Cox proportional hazards regression and competing risk analyses were undertaken to evaluate the association of HRQL with progression to ESRD or all-cause mortality. Regression analyses were then performed to identify variables associated with the significant HRQL components. Median eGFR was 25.8 ml/min/1.73 m2 (IQR 19.6-33.7ml/min) and median ACR was 33 mg/mmol (IQR 6.6-130.3 mg/mmol). Five hundred and fifty five participants (75.7%) reported problems with one or more EQ-5D domains. When adjusted for age, gender, comorbidity, eGFR and ACR, both reported problems with self-care [hazard ratio 2.542, 95% confidence interval 1.222-5.286, p = 0.013] and reduced EQ-5Dindex score [hazard ratio 0.283, 95% confidence interval 0.099-0.810, p = 0.019] were significantly associated with an increase in all-cause mortality. Similar findings were observed for competing risk analyses. Reduced HRQL was not a risk factor for progression to ESRD in multivariable analyses. Impaired HRQL is common in the pre-dialysis CKD population. Reduced HRQL, as demonstrated by problems with self-care or a lower EQ-5Dindex score, is associated with a higher risk for death but not ESRD. Multiple factors influence these aspects of HRQL but renal function, as measured by eGFR and ACR, are not among them.

Chronic obstructive pulmonary disease: getting it right. Does optimal management of chronic obstructive pulmonary disease alter disease progression and improve survival?

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Russell, Richard E

2014-03-01

We live in a world where people live longer lives. The standardized mortality rate for many diseases is decreasing. Chronic obstructive pulmonary disease (COPD) is not following this trend. Over the last 10 years, interventions for COPD have been developed, but have any changed the prognosis or trajectory of this modern epidemic? We review the most recent and classical literature in order to answer this question. Recent analyses of data have clarified which interventions are effective in COPD and which are not. New studies have defined what is achievable with the current therapies. Only two interventions have been demonstrated to improve survival: smoking cessation and long-term oxygen therapy. Other treatments do reduce exacerbations, improve lung function and improve the patient's quality of life, but do not affect physiological disease progression or mortality. There is much work to do, not only to improve the treatments we have for this disease, but also to diagnose it early, intervene at the right time, reduce the treatment side-effects and most importantly understand the pathophysiology better. Moreover, we are duty bound to look at each patient and review what we are trying to achieve for each one through appropriate phenotyping as well as sometimes taking a more palliative approach.

Von Hippel-Lindau disease: an evaluation of natural history and functional disability.

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Feletti, Alberto; Anglani, Mariagiulia; Scarpa, Bruno; Schiavi, Francesca; Boaretto, Francesca; Zovato, Stefania; Taschin, Elisa; Gardi, Mario; Zanoletti, Elisabetta; Piermarocchi, Stefano; Murgia, Alessandra; Pavesi, Giacomo; Opocher, Giuseppe

2016-07-01

Although many studies have been published about specific lesions characterizing von Hippel-Lindau(VHL) disease, none have dealt with the natural history of the whole disease and the consequent disabilities. We aim to define the comprehensive natural history of VHL disease and to describe the functional disabilities and their impact upon patients' quality of life, thereby tailoring the follow-up schedule accordingly. We performed a prospective analysis on 128 VHL-affected patients beginning in 1996. For each affected organ, we defined intervals between the first and subsequent VHL-related manifestations and compared them with current VHL surveillance protocols. We looked for any association of the number of involved organs with age, sex, type of VHL gene mutation, and functional domain mutation. Ultimately, we assessed the organ-specific disabilities caused by VHL disease. Hemangioblastomas show different patterns of progression depending on their location, whereas both renal cysts and carcinomas have similar progression rates. Surgery for pheochromocytoma and CNS hemangioblastoma is performed earlier than for pancreatic or renal cancer. The number of involved organs is associated with age but not with sex, type of VHL gene mutation, or functional domain mutation. A thorough analysis of functional disabilities showed that age is related to the first-appearing functional impairment, but it is not predictive of the final number of disabilities. Our study defines the disease progression and provides a comprehensive view of the syndrome over time. We analyzed for the first time the functional disability of VHL patients, assessing the progression for each function. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Progressive Pigmentary Purpura

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... Category: Share: Yes No, Keep Private Progressive Pigmentary Purpura Share | Progressive pigmentary purpura (we will call it PPP) is a group ... conditions ( Schamberg's disease , Lichenoid dermatitis of Gourgerot-Blum, purpura annularis telangiectodes of Majocchi and Lichen aureus). Schamberg's ...

Vitamin D and clinical disease progression in HIV infection: results from the EuroSIDA study

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Viard, Jean-Paul; Souberbielle, Jean-Claude; Kirk, Ole

2011-01-01

BACKGROUND:: We examined the association between vitamin D [25(OH)D] level and disease progression in HIV infection. METHODS:: Within the EuroSIDA study, 2000 persons were randomly selected for 25(OH)D measurement in stored plasma samples closest to study entry. 25(OH)D results were stratified...

Markers, Cofactors and Staging Systems in the Study of HIV Disease Progression: A Review

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MC Portela

1997-07-01

Full Text Available This paper is aimed at providing a comprehensive review of markers, cofactors and staging systems used for HIV disease, focusing on some aspects that nowadays could even be considered historical, and advancing in current issues such as the prognostic value of viral load measurements, viral genotypic and phenotypic characterization, and new HIV disease treatment protocols. CD4+ cell values, combined with the new viral markers mentioned are promising as a parsimonious predictor set for defining both severity and progression. An adequate predictor of patient resource use for planning purposes still needs to be defined

Urine liver fatty acid binding protein and chronic kidney disease progression

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Khatir, Dinah S; Bendtsen, Mette D; Birn, Henrik

2017-01-01

, regarding progression of chronic kidney disease (CKD). In a prospective study design a cohort of 74 stage 3-4 CKD patients (age 61 ± 13 years) were included. Glomerular filtration ratio (GFR, 51Cr-EDTA-clearance), 24-hour ambulatory BP, 24-hour urinary albumin/creatinine ratio (UAC) and urinary L......Excretion of the tubular protein liver fatty acid binding protein (L-FABP) is a potential novel biomarker of renal dysfunction. We examined whether urine L-FABP excretion adds prognostic information to the well-established risk markers, blood pressure (BP), albumin excretion and baseline GFR...

Variations in the Biological Functions of HIV-1 Clade C Envelope in a SHIV-Infected Rhesus Macaque during Disease Progression.

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For Yue Tso

Full Text Available A better understanding of how the biological functions of the HIV-1 envelope (Env changes during disease progression may aid the design of an efficacious anti-HIV-1 vaccine. Although studies from patient had provided some insights on this issue, the differences in the study cohorts and methodology had make it difficult to reach a consensus of the variations in the HIV-1 Env functions during disease progression. To this end, an animal model that can be infected under controlled environment and reflect the disease course of HIV-1 infection in human will be beneficial. Such an animal model was previously demonstrated by the infection of macaque with SHIV, expressing HIV-1 clade C Env V1-V5 region. By using this model, we examined the changes in biological functions of Env in the infected animal over the entire disease course. Our data showed an increase in the neutralization resistance phenotype over time and coincided with the decrease in the net charges of the V1-V5 region. Infection of PBMC with provirus expressing various Env clones, isolated from the infected animal over time, showed a surprisingly better replicative fitness for viruses expressing the Env from early time point. Biotinylation and ELISA data also indicated a decrease of cell-surface-associated Env and virion-associated gp120 content with disease progression. This decrease did not affect the CD4-binding capability of Env, but were positively correlated with the decrease of Env fusion ability. Interestingly, some of these changes in biological functions reverted to the pre-AIDS level during advance AIDS. These data suggested a dynamic relationship between the Env V1-V5 region with the host immune pressure. The observed changes of biological functions in this setting might reflect and predict those occurring during natural disease progression in human.