Cancer Stem-like Cells Act via Distinct Signaling Pathways in Promoting Late Stages of Malignant Progression.

PubMed

da Silva-Diz, Victoria; Simón-Extremera, Pilar; Bernat-Peguera, Adrià; de Sostoa, Jana; Urpí, Maria; Penín, Rosa M; Sidelnikova, Diana Pérez; Bermejo, Oriol; Viñals, Joan Maria; Rodolosse, Annie; González-Suárez, Eva; Moruno, Antonio Gómez; Pujana, Miguel Ángel; Esteller, Manel; Villanueva, Alberto; Viñals, Francesc; Muñoz, Purificación

2016-03-01

Cancer stem-like cells (CSC) play key roles in long-term tumor propagation and metastasis, but their dynamics during disease progression are not understood. Tumor relapse in patients with initially excised skin squamous cell carcinomas (SCC) is characterized by increased metastatic potential, and SCC progression is associated with an expansion of CSC. Here, we used genetically and chemically-induced mouse models of skin SCC to investigate the signaling pathways contributing to CSC function during disease progression. We found that CSC regulatory mechanisms change in advanced SCC, correlating with aggressive tumor growth and enhanced metastasis. β-Catenin and EGFR signaling, induced in early SCC CSC, were downregulated in advanced SCC. Instead, autocrine FGFR1 and PDGFRα signaling, which have not been previously associated with skin SCC CSC, were upregulated in late CSC and promoted tumor growth and metastasis, respectively. Finally, high-grade and recurrent human skin SCC recapitulated the signaling changes observed in advanced mouse SCC. Collectively, our findings suggest a stage-specific switch in CSC regulation during disease progression that could be therapeutically exploited by targeting the PDGFR and FGFR1 pathways to block relapse and metastasis of advanced human skin SCC. ©2015 American Association for Cancer Research.

DO URBAN ENVIRONMENTAL POLLUTANTS EXACERBATE CHILDHOOD LUNG DISEASES? (R827442)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

Tumor Microenvironment and Progression to Invasion after a Diagnosis of Ductal Carcinoma In Situ

DTIC Science & Technology

2013-11-01

disease, in which the disease of interest is treated as a single outcome. However, many human diseases, including colon cancer, type II diabetes mellitus ...Wisconsin Madison, WI 53715-1218 REPORT DATE: November 2013 TYPE OF REPORT: Final PREPARED FOR: U.S. Army Medical Research and Materiel...not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. 1. REPORT DATE November 2013 2 . REPORT

Progression of Inflammatory Bowel Disease to Cancer: Is the Patient Better Off without Lymphatic Vessels or Nodes (or Angiopoietin 2)?

DTIC Science & Technology

2013-12-01

carcinoma (CRC) in IBD patients and experimental models. Nonetheless, the pathogenic link, interrelationship, and practical clinical application of these...and are continuing final data analysis and latest imaging studies. This project has potentially high impact because of the substantial incidence of...pathogenic link, interrelationship, and practical clinical application of these various theories of progression have remained elusive. We proposed that

Slow Progress In Finalizing Measles And Rubella Elimination In The European Region.

PubMed

Biellik, Robin; Davidkin, Iria; Esposito, Susanna; Lobanov, Andrey; Kojouharova, Mira; Pfaff, Günter; Santos, José Ignacio; Simpson, John; Mamou, Myriam Ben; Butler, Robb; Deshevoi, Sergei; Huseynov, Shahin; Jankovic, Dragan; Shefer, Abigail

2016-02-01

All countries in the World Health Organization European Region committed to eliminating endemic transmission of measles and rubella by 2015, and disease incidence has decreased dramatically. However, there was little progress between 2012 and 2013, and the goal will likely not be achieved on time. Genuine political commitment, increased technical capacity, and greater public awareness are urgently needed, especially in Western Europe. Project HOPE—The People-to-People Health Foundation, Inc.

Abiraterone acetate for patients with metastatic castration-resistant prostate cancer progressing after chemotherapy: final analysis of a multicentre, open-label, early-access protocol trial.

PubMed

Sternberg, Cora N; Castellano, Daniel; Daugaard, Gedske; Géczi, Lajos; Hotte, Sebastien J; Mainwaring, Paul N; Saad, Fred; Souza, Ciro; Tay, Miah H; Garrido, José M Tello; Galli, Luca; Londhe, Anil; De Porre, Peter; Goon, Betty; Lee, Emma; McGowan, Tracy; Naini, Vahid; Todd, Mary B; Molina, Arturo; George, Daniel J

2014-10-01

In the final analysis of the phase 3 COU-AA-301 study, abiraterone acetate plus prednisone significantly prolonged overall survival compared with prednisone alone in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy. Here, we present the final analysis of an early-access protocol trial that was initiated after completion of COU-AA-301 to enable worldwide preapproval access to abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy. We did a multicentre, open-label, early-access protocol trial in 23 countries. We enrolled patients who had metastatic castration-resistant prostate cancer progressing after taxane chemotherapy. Participants received oral doses of abiraterone acetate (1000 mg daily) and prednisone (5 mg twice a day) in 28-day cycles until disease progression, development of sustained side-effects, or abiraterone acetate becoming available in the respective country. The primary outcome was the number of adverse events arising during study treatment and within 30 days of discontinuation. Efficacy measures (time to prostate-specific antigen [PSA] progression and time to clinical progression) were gathered to guide treatment decisions. We included in our analysis all patients who received at least one dose of abiraterone acetate. This study is registered with ClinicalTrials.gov, number NCT01217697. Between Nov 17, 2010, and Sept 30, 2013, 2314 patients were enrolled into the early-access protocol trial. Median follow-up was 5·7 months (IQR 3·5-10·6). 952 (41%) patients had a grade 3 or 4 treatment-related adverse event, and grade 3 or 4 serious adverse events were recorded in 585 (25%) people. The most common grade 3 and 4 adverse events were hepatotoxicity (188 [8%]), hypertension (99 [4%]), cardiac disorders (52 [2%]), osteoporosis (31 [1%]), hypokalaemia (28 [1%]), and fluid retention or oedema (23 [1%]). 172 (7%) patients discontinued the study because of adverse events (64 [3%] were drug-related), as assessed by the investigator, and 171 (7%) people died. The funder assessed causes of death, which were due to disease progression (85 [4%]), an unrelated adverse experience (72 [3%]), and unknown reasons (14 [1%]). Of the 86 deaths not attributable to disease progression, 18 (<1%) were caused by a drug-related adverse event, as assessed by the investigator. Median time to PSA progression was 8·5 months (95% CI 8·3-9·7) and median time to clinical progression was 12·7 months (11·8-13·8). No new safety signals or unexpected adverse events were found in this early-access protocol trial to assess abiraterone acetate for patients with metastatic castration-resistant prostate cancer who progressed after chemotherapy. Future work is needed to ascertain the most effective regimen of abiraterone acetate to optimise patients' outcomes. Janssen Research & Development. Copyright © 2014 Elsevier Ltd. All rights reserved.

A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer.

PubMed

Carducci, Michael A; Saad, Fred; Abrahamsson, Per-Anders; Dearnaley, David P; Schulman, Claude C; North, Scott A; Sleep, Darryl J; Isaacson, Jeffrey D; Nelson, Joel B

2007-11-01

The objective of this study was to evaluate the efficacy and safety of atrasentan (Xinlay), a selective endothelin-A receptor antagonist, in patients with metastatic hormone-refractory prostate cancer (HRPC). This multinational, double-blind, placebo-controlled trial enrolled 809 men with metastatic HRPC. Patients were randomized 1:1 to receive either atrasentan 10 mg per day or placebo. The primary endpoint was time to disease progression (TTP), which was determined according to radiographic and clinical measures. Analyses of overall survival and changes in biomarkers also were performed. Atrasentan did not reduce the risk of disease progression relative to placebo (hazards ratio, 0.89; 95% confidence interval, 0.76-1.04; P = .136). Most patients progressed radiographically at the first 12-week bone scan without concomitant clinical progression. In exploratory analyses, increases from baseline to final bone alkaline phosphatase (BAP) and prostate-specific antigen (PSA) levels were significantly lower with atrasentan treatment (P < .05 for each). The median time to BAP progression (>/=50% increase from nadir) was twice as long with atrasentan treatment (505 days vs 254 days; P < .01). The delay in time to PSA progression did not reach statistical significance. Atrasentan generally was tolerated well, and the most common adverse events associated with treatment were headache, rhinitis, and peripheral edema, reflecting the vasodilatory and fluid-retention properties of endothelin-A receptor antagonism. Atrasentan did not delay disease progression in men with metastatic HRPC despite evidence of biologic effects on PSA and BAP as markers of disease burden.

Natural history, treatment and prevention of hepatitis C recurrence after liver transplantation: past, present and future.

PubMed

Dumortier, Jérôme; Boillot, Olivier; Scoazec, Jean-Yves

2014-08-28

Hepatitis C virus (HCV)-related liver disease, including cirrhosis and hepatocellular carcinoma is the main indication for liver transplantation (LT) worldwide. Post-transplant HCV re-infection is almost universal and results in accelerated progression from acute hepatitis to chronic hepatitis, and liver cirrhosis. Comprehension and treatment of recurrent HCV infection after LT have been major issues for all transplant hepatologists and transplant surgeons for the last decades. The aim of this paper is to review the evolution of our knowledge on the natural history of HCV recurrence after LT, including risk factors for disease progression, and antiviral therapy. We will focus our attention on possible ways (present and future) to improve the final long-term results of LT for HCV-related liver disease.

Glutamate system, amyloid β peptides and tau protein: functional interrelationships and relevance to Alzheimer disease pathology

PubMed Central

Revett, Timothy J.; Baker, Glen B.; Jhamandas, Jack; Kar, Satyabrata

2013-01-01

Alzheimer disease is the most prevalent form of dementia globally and is characterized premortem by a gradual memory loss and deterioration of higher cognitive functions and postmortem by neuritic plaques containing amyloid β peptide and neurofibrillary tangles containing phospho-tau protein. Glutamate is the most abundant neurotransmitter in the brain and is essential to memory formation through processes such as long-term potentiation and so might be pivotal to Alzheimer disease progression. This review discusses how the glutamatergic system is impaired in Alzheimer disease and how interactions of amyloid β and glutamate influence synaptic function, tau phosphorylation and neurodegeneration. Interestingly, glutamate not only influences amyloid β production, but also amyloid β can alter the levels of glutamate at the synapse, indicating that small changes in the concentrations of both molecules could influence Alzheimer disease progression. Finally, we describe how the glutamate receptor antagonist, memantine, has been used in the treatment of individuals with Alzheimer disease and discuss its effectiveness. PMID:22894822

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

PubMed

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

2015-07-01

Notch3 expression is found in the glomerular podocytes of patients with lupus nephritis or focal segmental GN but not in normal kidneys. Here, we show that activation of the Notch3 receptor in the glomeruli is a turning point inducing phenotypic changes in podocytes promoting renal inflammation and fibrosis and leading to disease progression. In a model of rapidly progressive GN, Notch3 expression was induced by several-fold in podocytes concurrently with disease progression. By contrast, mice lacking Notch3 expression were protected because they exhibited less proteinuria, uremia, and inflammatory infiltration. Podocyte outgrowth from glomeruli isolated from wild-type mice during the early phase of the disease was higher than outgrowth from glomeruli of mice lacking Notch3. In vitro studies confirmed that podocytes expressing active Notch3 reorganize their cytoskeleton toward a proliferative/migratory and inflammatory phenotype. We then administered antisense oligodeoxynucleotides targeting Notch3 or scramble control oligodeoxynucleotides in wild-type mice concomitant to disease induction. Both groups developed chronic renal disease, but mice injected with Notch3 antisense had lower values of plasma urea and proteinuria and inflammatory infiltration. The improvement of renal function was accompanied by fewer deposits of fibrin within the glomeruli and by decreased peritubular inflammation. Finally, abnormal Notch3 staining was observed in biopsy samples of patients with crescentic GN. These results demonstrate that abnormal activation of Notch3 may be involved in the progression of renal disease by promoting migratory and proinflammatory pathways. Inhibiting Notch3 activation could be a novel, promising approach to treat GN. Copyright © 2015 by the American Society of Nephrology.

Identifying driving gene clusters in complex diseases through critical transition theory

NASA Astrophysics Data System (ADS)

Wolanyk, Nathaniel; Wang, Xujing; Hessner, Martin; Gao, Shouguo; Chen, Ye; Jia, Shuang

A novel approach of looking at the human body using critical transition theory has yielded positive results: clusters of genes that act in tandem to drive complex disease progression. This cluster of genes can be thought of as the first part of a large genetic force that pushes the body from a curable, but sick, point to an incurable diseased point through a catastrophic bifurcation. The data analyzed is time course microarray blood assay data of 7 high risk individuals for Type 1 Diabetes who progressed into a clinical onset, with an additional larger study requested to be presented at the conference. The normalized data is 25,000 genes strong, which were narrowed down based on statistical metrics, and finally a machine learning algorithm using critical transition metrics found the driving network. This approach was created to be repeatable across multiple complex diseases with only progression time course data needed so that it would be applicable to identifying when an individual is at risk of developing a complex disease. Thusly, preventative measures can be enacted, and in the longer term, offers a possible solution to prevent all Type 1 Diabetes.

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

PubMed

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.

CONTRIBUTION OF RESPIRATORY DISEASE TO NON-RESPIRATORY MORTALITY ASSOCIATIONS WITH AIR POLLUTION. (R827351)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

Gout: A Disease of Kings.

PubMed

Tang, Sydney C W

2018-01-01

As a disease of kings, and the king of diseases, gout is one of the oldest joint diseases known to humans. First described as far back as 2640 B.C., gout is still the most common form of inflammatory arthritis haunting humans in the 21st century. The disease is caused by the chronic elevation of serum uric acid levels above the saturation point for monosodium urate crystal formation. Its incidence is progressively rising even today, but there are also regional and ethnic variations. Finally, the role of genetics is only beginning to be unraveled. © 2018 S. Karger AG, Basel.

Non-alcoholic fatty liver disease and dyslipidemia: An update.

PubMed

Katsiki, Niki; Mikhailidis, Dimitri P; Mantzoros, Christos S

2016-08-01

Non-alcoholic fatty liver (NAFLD) is the most common liver disease worldwide, progressing from simple steatosis to necroinflammation and fibrosis (leading to non-alcoholic steatohepatitis, NASH), and in some cases to cirrhosis and hepatocellular carcinoma. Inflammation, oxidative stress and insulin resistance are involved in NAFLD development and progression. NAFLD has been associated with several cardiovascular (CV) risk factors including obesity, dyslipidemia, hyperglycemia, hypertension and smoking. NAFLD is also characterized by atherogenic dyslipidemia, postprandial lipemia and high-density lipoprotein (HDL) dysfunction. Most importantly, NAFLD patients have an increased risk for both liver and CV disease (CVD) morbidity and mortality. In this narrative review, the associations between NAFLD, dyslipidemia and vascular disease in NAFLD patients are discussed. NAFLD treatment is also reviewed with a focus on lipid-lowering drugs. Finally, future perspectives in terms of both NAFLD diagnostic biomarkers and therapeutic targets are considered. Copyright © 2016 Elsevier Inc. All rights reserved.

Nanotechnology, a new paradigm in atherosclerosis treatment.

PubMed

Martín Giménez, Virna M; Ruiz-Roso, María Belén; Camargo, Alejandra Beatriz; Kassuha, Diego; Manucha, Walter

Atherosclerosis, a known and prevalent disease, causes progressive deterioration of affected vessels, inducing a blood flow reduction with different complications, and its symptoms usually manifest in advanced stages of the disease. Therefore, the classic therapeutic alternatives are insufficient because the damages are many times irreversible. For this reason, there is a need to implement intelligent forms of drug administration and develop new therapeutic targets that reduce the progression of atherosclerotic lesion. The implementation of new tools for prevention, diagnosis and treatment of this cardiovascular disease is of special interest, focusing our attention on achieving a more effective control of the immune system. Finally, this review highlights the latest knowledge about nanotechnology as a powerful, modern, and promising therapeutic alternative applied to atherosclerotic disease, as well as warning of the potential complications with their use. Copyright © 2016 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.

[Research progress of mammalian synthetic biology in biomedical field].

PubMed

Yang, Linfeng; Yin, Jianli; Wang, Meiyan; Ye, Haifeng

2017-03-25

Although still in its infant stage, synthetic biology has achieved remarkable development and progress during the past decade. Synthetic biology applies engineering principles to design and construct gene circuits uploaded into living cells or organisms to perform novel or improved functions, and it has been widely used in many fields. In this review, we describe the recent advances of mammalian synthetic biology for the treatment of diseases. We introduce common tools and design principles of synthetic gene circuits, and then we demonstrate open-loop gene circuits induced by different trigger molecules used in disease diagnosis and close-loop gene circuits used for biomedical applications. Finally, we discuss the perspectives and potential challenges of synthetic biology for clinical applications.

CONTRIBUTION OF RESPIRATORY DISEASE TO NONRESPIRATORY MORTALITY ASSOCIATIONS WITH AIR POLLUTION. (R827351C001)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

THE CONTRIBUTION OF RESPIRATORY DISEASE TO NON-RESPIRATORY MORTALITY ASSOCIATIONS WITH AMBIENT AIR POLLUTION. (R827351)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

RESPIRATORY DISEASE AS A CONTRIBUTING CAUSE OF NON-RESPIRATORY MORTALITY ASSOCIATIONS WITH PARTICLE MASS. (R825271)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

AIR POLLUTION, POLLENS AND RESPIRATORY ADMISSIONS FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE IN KING COUNTY. (R827355)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

AIR POLLUTION, POLLENS, AND ADMISSIONS FOR CHRONIC RESPIRATORY DISEASE IN KING COUNTY, WASHINGTON. (R825266)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

Fibulin-1 Predicts Disease Progression in Patients With Idiopathic Pulmonary Fibrosis

PubMed Central

Unger, Sofia; Corte, Tamera J.; Keller, Michael; Wolters, Paul J.; Richeldi, Luca; Cerri, Stefania; Prêle, Cecilia M.; Hansbro, Philip M.; Argraves, William Scott; Oliver, Rema A.; Oliver, Brian G.; Black, Judith L.; Burgess, Janette K.

2014-01-01

BACKGROUND: The underlying mechanisms of idiopathic pulmonary fibrosis (IPF) are unknown. This progressive disease has high mortality rates, and current models for prediction of mortality have limited value in identifying which patients will progress. We previously showed that the glycoprotein fibulin-1 is involved in enhanced proliferation and wound repair by mesenchymal cells and, thus, may contribute to lung fibrosis in IPF. METHODS: Serum, lung tissue, and lung function values were obtained from four independent locations (Sydney, NSW, and Perth, WA, Australia; San Francisco, CA; and Modena, Italy). Patients with IPF were followed for a minimum of 1 year and progression was defined as a significant decline in lung function or death. Primary parenchymal lung fibroblasts of 15 patients with and without IPF were cultured under nonstimulatory conditions. Fibulin-1 levels in serum, and secreted or deposited by fibroblasts, were measured by western blot and in lung tissue by immunohistochemistry. RESULTS: Serum fibulin-1 levels were increased in patients with IPF compared with subjects without lung disease (P = .006). Furthermore, tissue fibulin-1 levels were increased in patients with IPF (P = .02) and correlated negatively with lung function (r = −0.9, P < .05). Primary parenchymal fibroblasts from patients with IPF produced more fibulin-1 than those from subjects without IPF (P < .05). Finally, serum fibulin-1 levels at first blood draw predicted disease progression in IPF within 1 year (area under the curve , 0.71; 95% CI, 0.57-0.86; P = .012). CONCLUSIONS: Fibulin-1 is a novel potential biomarker for disease progression in IPF and raises the possibility that it could be used as a target for the development of new treatments. PMID:24832167

Effect of vaccination against leptospirosis on the frequency, days to recurrence and progression of disease in horses with equine recurrent uveitis.

PubMed

Rohrbach, Barton W; Ward, Daniel A; Hendrix, Diane V H; Cawrse-Foss, Margaret; Moyers, Tammy D

2005-01-01

To evaluate the effect of vaccination against leptospirosis on frequency and days to recurrence of uveitis and progression of disease in horses with equine recurrent uveitis (ERU). Forty-one horses with ERU. Horses were randomly assigned to experimental (vaccinated) or control groups. Vaccine containing six serovars of Leptospira or placebo was administered, an ophthalmic examination performed and blood samples drawn on days 0, 28, 180 and 365. Antibody titers were measured against each serovar. Recurrence of uveitis was verified by ophthalmic examination. Results of the initial and final ophthalmic examinations were compared and progression of disease defined as an increase in extent of synechiae, or development of new or progression of an existing cataract. Vaccination increased the average geometric mean serum antibody titer from 225 on day 0, to 4077 and 593 on days 28 and 180, respectively. After the second vaccination, days to first recurrence was significantly longer (median 126 days; range 24-231 days) when compared with controls (median 86 days; range 14-192 days, P=0.04). Recurrence of ERU was observed among 7/20 (35%) vaccinated horses and 12/21 (57%) controls; however, this difference was not statistically significant (P=0.061, OR 0.25, 95% CI 0.06, 1.07). More horses in the experimental group 13/20 (65%) experienced progression of disease when compared with controls 12/21(57%); however, this difference was statistically nonsignificant (P=0.35). Vaccine significantly increased days to recurrence, but failed to slow the progression of disease. These data do not support the use of vaccination against leptospirosis as adjunct therapy for the routine treatment of horses with ERU.

Fibulin-1 predicts disease progression in patients with idiopathic pulmonary fibrosis.

PubMed

Jaffar, Jade; Unger, Sofia; Corte, Tamera J; Keller, Michael; Wolters, Paul J; Richeldi, Luca; Cerri, Stefania; Prêle, Cecilia M; Hansbro, Philip M; Argraves, William Scott; Oliver, Rema A; Oliver, Brian G; Black, Judith L; Burgess, Janette K

2014-10-01

The underlying mechanisms of idiopathic pulmonary fibrosis (IPF) are unknown. This progressive disease has high mortality rates, and current models for prediction of mortality have limited value in identifying which patients will progress. We previously showed that the glycoprotein fibulin-1 is involved in enhanced proliferation and wound repair by mesenchymal cells and, thus, may contribute to lung fibrosis in IPF. Serum, lung tissue, and lung function values were obtained from four independent locations (Sydney, NSW, and Perth, WA, Australia; San Francisco, CA; and Modena, Italy). Patients with IPF were followed for a minimum of 1 year and progression was defined as a significant decline in lung function or death. Primary parenchymal lung fibroblasts of 15 patients with and without IPF were cultured under nonstimulatory conditions. Fibulin-1 levels in serum, and secreted or deposited by fibroblasts, were measured by western blot and in lung tissue by immunohistochemistry. Serum fibulin-1 levels were increased in patients with IPF compared with subjects without lung disease (P = .006). Furthermore, tissue fibulin-1 levels were increased in patients with IPF (P = .02) and correlated negatively with lung function (r = -0.9, P < .05). Primary parenchymal fibroblasts from patients with IPF produced more fibulin-1 than those from subjects without IPF (P < .05). Finally, serum fibulin-1 levels at first blood draw predicted disease progression in IPF within 1 year (area under the curve , 0.71; 95% CI, 0.57-0.86; P = .012). Fibulin-1 is a novel potential biomarker for disease progression in IPF and raises the possibility that it could be used as a target for the development of new treatments.

EXPOSURE-DISEASE CONTINUUM FOR 2-CHLORO-2'-DEOXYADENOSINE, A PROTOTYPE OCULAR TERATOGEN. 3. INTERVENTION WITH PK11195. (R827445)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

EFFECTS OF THE EL NINO AND AMBIENT TEMPERATURE ON HOSPITAL ADMISSIONS FOR DIARRHOEAL DISEASES IN PERUVIAN CHILDREN. (R824995)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

HOSPITAL ADMISSIONS FOR ASTHMA AND CHRONIC OBSTRUCTIVE AIRWAYS DISEASE IN EAST LONDON HOSPITALS AND PROXIMITY TO MAJOR ROADS. (R825173)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

RESPIRATORY DISEASE AS A CONTRIBUTING CAUSE OF NON-RESPIRATORY MORTALITY ASSOCIATIONS WITH PARTICLE MASS IN NEW YORK CITY. (R825271)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

RESPIRATORY DISEASE AS A CAUSE OF NON-RESPIRATORY MORTALITY ASSOCIATIONS WITH AMBIENT AIR POLLUTION. (R827351C001)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

SIMULATION MODEL RESULTS OF LYME DISEASE INFECTIVITY RATES IN VERTEBRATE HOSTS UNDER CLIMATE CHANGE SCENARIOS. (R824995)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

THE TEMPORAL PATTERN OF RESPIRATORY AND HEART DISEASE MORTALITY IN RESPONSE TO AIR POLLUTION. (R827353C004)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

ENDOTOXIN RESPONSIVENESS AND SUBCHRONIC GRAIN DUST-INDUCED AIRWAY DISEASE. (R826711C001,R826711C002)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

DNA methylation and the potential role of demethylating agents in prevention of progressive chronic kidney disease.

PubMed

Larkin, Benjamin P; Glastras, Sarah J; Chen, Hui; Pollock, Carol A; Saad, Sonia

2018-04-24

Chronic kidney disease (CKD) is a global epidemic, and its major risk factors include obesity and type 2 diabetes. Obesity not only promotes metabolic dysregulation and the development of diabetic kidney disease but also may independently lead to CKD by a variety of mechanisms, including endocrine and metabolic dysfunction, inflammation, oxidative stress, altered renal hemodynamics, and lipotoxicity. Deleterious renal effects of obesity can also be transmitted from one generation to the next, and it is increasingly recognized that offspring of obese mothers are predisposed to CKD. Epigenetic modifications are changes that regulate gene expression without altering the DNA sequence. Of these, DNA methylation is the most studied. Epigenetic imprints, particularly DNA methylation, are laid down during critical periods of fetal development, and they may provide a mechanism by which maternal-fetal transmission of chronic disease occurs. Our current review explores the evidence for the role of DNA methylation in the development of CKD, diabetic kidney disease, diabetes, and obesity. DNA methylation has been implicated in renal fibrosis-the final pathophysiologic pathway in the development of end-stage kidney disease-which supports the notion that demethylating agents may play a potential therapeutic role in preventing development and progression of CKD.-Larkin, B. P., Glastras, S. J., Chen, H., Pollock, C. A., Saad, S. DNA methylation and the potential role of demethylating agents in prevention of progressive chronic kidney disease.

Chronic lymphocytic leukemia.

PubMed

Kay, Neil E; Hamblin, Terry J; Jelinek, Diane F; Dewald, Gordon W; Byrd, John C; Farag, Sherif; Lucas, Margaret; Lin, Thomas

2002-01-01

This update of early stage B-cell chronic lymphocytic leukemia (B-CLL) embraces current information on the diagnosis, biology, and intervention required to more fully develop algorithms for management of this disease. Emphasis on early stage is based on the rapid advancement in our understanding of the disease parameters and our increasing ability to predict for a given early stage patient whether there is a need for more aggressive management. In Section I, Dr. Terry Hamblin addresses the nature of the disease, accurate diagnostic procedures, evidence for an early "preclinical" phase, the use of newer prognostic features to distinguish who will be likely to progress or not, and whether it is best to watch or treat early stage disease. In Section II, Dr. Neil Kay and colleagues address the biologic aspects of the disease and how they may relate to disease progression. Review of the newer insights into gene expression, recurring genetic defects, role of cytokines/autocrine pathways, and the interaction of the CLL B cell with the microenvironment are emphasized. The relationship of these events to both trigger disease progression and as opportunities for future therapeutic intervention even in early stage disease is also considered. In Section III, Dr. John Byrd and colleagues review the historical and now current approaches to management of the previously untreated progressive B-CLL patient. They discuss what decision tree could be used in the initial decision to treat a given patient. The use of single agents versus newer combination approaches such as chemoimmunotherapy are discussed here. In addition, the place of marrow transplant and some of the newer antibodies available for treatment of B-CLL are considered. Finally, a challenge to utilize our growing knowledge of the biology of B-CLL in the early stage B-CLL is proffered.

Initiation and inhibitory control of saccades with the progression of Parkinson's disease - changes in three major drives converging on the superior colliculus.

PubMed

Terao, Yasuo; Fukuda, Hideki; Yugeta, Akihiro; Hikosaka, Okihide; Nomura, Yoshiko; Segawa, Masaya; Hanajima, Ritsuko; Tsuji, Shoji; Ugawa, Yoshikazu

2011-06-01

The cardinal pathophysiology of Parkinson's disease (PD) is considered to be the increase in the activities of basal ganglia (BG) output nuclei, which excessively inhibits the thalamus and superior colliculus (SC) and causes preferential impairment of internal over external movements. Here we recorded saccade performance in 66 patients with PD and 87 age-matched controls, and studied how the abnormality changed with disease progression. PD patients were impaired not only in memory guided saccades, but also in visually guided saccades, beginning in the relatively early stages of the disease. On the other hand, they were impaired in suppressing reflexive saccades (saccades to cue). All these changes deteriorated with disease progression. The frequency of reflexive saccades showed a negative correlation with the latency of visually guided saccades and Unified Parkinson's Disease Rating Scale motor subscores reflecting dopaminergic function. We suggest that three major drives converging on SC determine the saccade abnormalities in PD. The impairment in visually and memory guided saccades may be caused by the excessive inhibition of the SC due to the increased BG output and the decreased activity of the frontal cortex-BG circuit. The impaired suppression of reflexive saccades may be explained if the excessive inhibition of SC is "leaky." Changes in saccade parameters suggest that frontal cortex-BG circuit activity decreases with disease progression, whereas SC inhibition stays relatively mild in comparison throughout the course of the disease. Finally, SC disinhibition due to leaky suppression may represent functional compensation from neural structures outside BG, leading to hyper-reflexivity of saccades and milder clinical symptoms. Copyright © 2011 Elsevier Ltd. All rights reserved.

The polio endgame.

PubMed

Minor, Philip

2014-01-01

Paralytic poliomyelitis is a disease that became a public health issue at the beginning of the twentieth century and was more or less eliminated in developed countries by the early 1970s. The Global Polio Eradication Initiative of WHO has now eradicated endemic polio from all but three countries although re-introductions occur. The progress in polio eradication is striking and has accelerated over the last few years. It is likely that it will be finally eradicated from the world soon, the looming issue will then be how to stop vaccinating or modify immunization programs safely so that poliomyelitis does not re-emerge. This review article discusses the history and pathogenesis of poliomyelitis. The progress made, and challenges in sustaining the eradication of this debilitating infectious disease are considered.

The polio endgame

PubMed Central

Minor, Philip

2014-01-01

Paralytic poliomyelitis is a disease that became a public health issue at the beginning of the twentieth century and was more or less eliminated in developed countries by the early 1970s. The Global Polio Eradication Initiative of WHO has now eradicated endemic polio from all but three countries although re-introductions occur. The progress in polio eradication is striking and has accelerated over the last few years. It is likely that it will be finally eradicated from the world soon, the looming issue will then be how to stop vaccinating or modify immunization programs safely so that poliomyelitis does not re-emerge. This review article discusses the history and pathogenesis of poliomyelitis. The progress made, and challenges in sustaining the eradication of this debilitating infectious disease are considered. PMID:25608050

Favorable outcome of early treatment of new onset child and adolescent migraine-implications for disease modification.

PubMed

Charles, James A; Peterlin, B L; Rapoport, Alan M; Linder, Steven L; Kabbouche, Marielle A; Sheftell, Fred D

2009-08-01

There is evidence that the prevalence of migraine in children and adolescents may be increasing. Current theories of migraine pathophysiology in adults suggest activation of central cortical and brainstem pathways in conjunction with the peripheral trigeminovascular system, which ultimately results in release of neuropeptides, facilitation of central pain pathways, neurogenic inflammation surrounding peripheral vessels, and vasodilatation. Although several risk factors for frequent episodic, chronic, and refractory migraine have been identified, the causes of migraine progression are not known. Migraine pathophysiology has not been fully evaluated in children. In this review, we will first discuss the evidence that early therapeutic interventions in the child or adolescent new onset migraineur, may halt or limit progression and disability. We will then review the evidence suggesting that many adults with chronic or refractory migraine developed their migraine as children or adolescents and may not have been treated adequately with migraine-specific therapy. Finally, we will show that early, appropriate and optimal treatment of migraine during childhood and adolescence may result in disease modification and prevent progression of this disease.

[The pathogenesis and regulation of autoimmunity].

PubMed

Miyake, Sachiko

2008-06-01

The pathogenesis of autoimmunity has been studied extensively using animal models and genome-wide genetic analysis. Moreover, recent advance in the therapy for the autoimmune diseases using molecular-targeted drugs has provided us a lot of information in the pathogenesis of human autoimmune diseases. In this review, we overviewed the recent progress in the study of autoimmunity including central tolerance, regulatory cells and cytokines. Finally, we discuss the relationship of innate immunity and adoptive immunity in the context of autoimmunity.

Nonlinear Dynamics, Noise and Cooperative Behavior in Affective Disorders

NASA Astrophysics Data System (ADS)

Huber, Martin

2001-03-01

Mood disorders tend to be recurrent and progressive and illness patterns typically evolve from isolated episodes at the beginning to more rapid, rhythmic and finally irregular "chaotic" mood patterns. This chararacteristic timecourse prompted the consideration of nonlinear dynamics as a way to describe and analyze course and disease states of mood disorders. Indeed, some evidences now exist indicating that low-dimensional dynamics underly the illness progression. To gain an understanding of prinicple mechanisms that might underly the course and disease patterns of mood disorders, we developed a phenomenological mathematical model for the disease course. In doing so, we made use of a neuronal analogy that exists between disease patterns and neuronal spike patterns and which is commonly referred to as the kindling model of mood disorders (Post, Am J of Psychiatry 1992,149:999-1010; Huber, Braun, Krieg, Biol Psychiatry 1999,46:256-262; Huber, Braun, Krieg, Biol Psychiatry 2000,47:634-642). Using a computational implementation of this approach we investigated the possible relevance of nonlinear dynamics for the disease course, the role of cooperative interactions between nonlinear and noisy dynamics as well as the effect of sensitization mechanisms between disease episodes and disease system. Our simulations show that a low-dimensional model can phenomenologically map the timecourse of mood disorders. From a functional perspective, the model indicates an important role for stochastic fluctuations which can amplify subthreshold states into disease states and can induce transitions to irregular rapidly changing disease patterns. Interesting dynamics are observed with respect to deterministically defined disease states and their dependence on noise intensity. Finally, our simulations show how sensitization effects quite naturally lead to a disease course which ends in irregular fluctuating disease patterns as observed in clinical data. Our findings indicate the usefulness of a computational approach as a way to understand and explain the complexity of temporal disease dynamics of mood disorders but also to procede to new experimental approaches for disease characterisation with the aim of better treatment options.

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

PubMed

Lee, Shawn; Singla, Montish

2016-01-01

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

RESPIRATORY DISEASE AS A CONTRIBUTING CAUSE OF NON-RESPIRATORY MORTALITY ASSOCIATIONS WITH PARTICLE MASS IN 5 U.S. CITIES. (R825271)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

RESPIRATORY DISEASE AS A RISK FACTOR FOR CIRCULATORY MORTALITY ASSOCIATIONS WITH AIR POLLUTION IN NYC. (R825271,R827351,R827351C001)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

Healthy People 2000 Final Review: National Health Promotion and Disease Prevention Objectives.

ERIC Educational Resources Information Center

National Center for Health Statistics (DHHS/PHS), Hyattsville, MD.

This report completes the series of "Healthy People 2000 Reviews" published to monitor and evaluate U.S. progress toward year 2000 targets. It examines Healthy People 2000 goals (to increase the span of healthy life, reduce health disparities, and achieve access to preventive services); discusses health indicators and priority data…

EXPOSURES OF ELDERLY VOLUNTEERS WITH AND WITHOUT CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) TO CONCENTRATED AMBIENT FINE PARTICULATE POLLUTION. (R827352C018)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

EXPOSURE TO AMBIENT FINE PARTICULATE MATTER AND PRIMARY CARDIAC ARREST AMONG PERSONS WITH AND WITHOUT CLINICALLY RECOGNIZED HEART DISEASE. (R827355C001)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

Diffuse Alveolar Damage: A Common Phenomenon in Progressive Interstitial Lung Disorders

PubMed Central

Kaarteenaho, Riitta; Kinnula, Vuokko L.

2011-01-01

It has become obvious that several interstitial lung diseases, and even viral lung infections, can progress rapidly, and exhibit similar features in their lung morphology. The final histopathological feature, common in these lung disorders, is diffuse alveolar damage (DAD). The histopathology of DAD is considered to represent end stage phenomenon in acutely behaving interstitial pneumonias, such as acute interstitial pneumonia (AIP) and acute exacerbations of idiopathic pulmonary fibrosis (IPF). Acute worsening and DAD may occur also in patients with nonspecific interstitial pneumonias (NSIPs), and even in severe viral lung infections where there is DAD histopathology in the lung. A better understanding of the mechanisms underlying the DAD reaction is needed to clarify the treatment for these serious lung diseases. There is an urgent need for international efforts for studying DAD-associated lung diseases, since the prognosis of these patients has been and is still dismal. PMID:21637367

Immunologic Endocrine Disorders

PubMed Central

Michels, Aaron W.; Eisenbarth, George S.

2010-01-01

Autoimmunity affects multiple glands in the endocrine system. Animal models and human studies highlight the importance of alleles in HLA (human leukocyte antigen)-like molecules determining tissue specific targeting that with the loss of tolerance leads to organ specific autoimmunity. Disorders such as type 1A diabetes, Grave's disease, Hashimoto's thyroiditis, Addison's disease, and many others result from autoimmune mediated tissue destruction. Each of these disorders can be divided into stages beginning with genetic susceptibility, environmental triggers, active autoimmunity, and finally metabolic derangements with overt symptoms of disease. With an increased understanding of the immunogenetics and immunopathogenesis of endocrine autoimmune disorders, immunotherapies are becoming prevalent, especially in type 1A diabetes. Immunotherapies are being used more in multiple subspecialty fields to halt disease progression. While therapies for autoimmune disorders stop the progress of an immune response, immunomodulatory therapies for cancer and chronic infections can also provoke an unwanted immune response. As a result, there are now iatrogenic autoimmune disorders arising from the treatment of chronic viral infections and malignancies. PMID:20176260

Second-Line Intraperitoneal Chemotherapy for Recurrent Epithelial Ovarian, Tubal and Peritoneal Cancer: A Propensity Score-Matching Study.

PubMed

Lu, Chien-Hsing; Chang, Yen-Hou; Lee, Wai-Hou; Chang, Yi; Peng, Chia-Wen; Chuang, Chi-Mu

2016-01-01

The superiority of frontline intraperitoneal (IP) over intravenous (IV) chemotherapy is well established in the treatment of epithelial ovarian cancer. However, the role of IP chemotherapy in the second-line setting has rarely been investigated. Consecutive patients diagnosed with recurrent epithelial, tubal and peritoneal cancers between January 2000 and December 2012 were recruited using a propensity score-matching technique to adjust relevant risk factors. In total, 310 patients were included in the final analysis (94 for platinum-refractory/resistant disease and 216 for platinum-sensitive disease). IP chemotherapy demonstrated significantly longer median progression-free survival than IV chemotherapy (4.9 vs. 2.4 months, p < 0.001, for platinum-refractory/resistant disease, and 9.8 vs. 6.9 months, p < 0.001, for platinum-sensitive disease). Second-line IP chemotherapy confers longer progression-free survival than IV chemotherapy. Large-scale clinical trials should be conducted to validate the true efficacy. © 2016 S. Karger AG, Basel.

Novel promising therapeutics against chronic neuroinflammation and neurodegeneration in Alzheimer's disease.

PubMed

Venigalla, Madhuri; Sonego, Sandra; Gyengesi, Erika; Sharman, Matthew J; Münch, Gerald

2016-05-01

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, characterized by deposition of amyloid plaques and neurofibrillary tangles, as well as microglial and astroglial activation, and, finally, leading to neuronal dysfunction and death. Current treatments for AD primarily focus on enhancement of cholinergic transmission. However, these treatments are only symptomatic, and no disease-modifying drug is available for the treatment of AD patients. This review will provide an overview of the antioxidant, anti-inflammatory, anti-amyloidogenic, neuroprotective, and cognition-enhancing effects of a variety of nutraceuticals including curcumin, apigenin, docosahexaenoic acid, epigallocatechin gallate, α-lipoic acid and resveratrol and their potential for AD prevention and treatment. We suggest that therapeutic use of these compounds might lead to a safe strategy to delay the onset of AD or slow down its progression. The continuing investigation of the potential of these substances is necessary as they are promising compounds to yield a possible remedy for this pervasive disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

NASA Astrophysics Data System (ADS)

Mierke, Claudia Tanja

2014-07-01

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

Evaluation of Liver Function After Proton Beam Therapy for Hepatocellular Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mizumoto, Masashi; Okumura, Toshiyuki; Hashimoto, Takayuki

Purpose: Our previous results for treatment of hepatocellular carcinoma with proton beam therapy (PBT) revealed excellent local control. In this study, we focused on the impact of PBT on normal liver function. Methods and Materials: The subjects were 259 patients treated with PBT at University of Tsukuba between January 2001 and December 2007. We evaluated the Child-Pugh score pretreatment, on the final day of PBT, and 6, 12, and 24 months after treatment with PBT. Patients who had disease progression or who died with tumor progression at each evaluation point were excluded from the analysis to rule out an effectmore » of tumor progression. An increase in the Child-Pugh score of 1 or more was defined as an adverse event. Results: Of the 259 patients, 241 had no disease progression on the final day of PBT, and 91 had no progression within 12 months after PBT. In univariate analysis, the percentage volumes of normal liver receiving at least 0, 10, 20, and 30 GyE in PBT (V0, 10, 20, and 30) were significantly associated with an increase of Child-Pugh score at 12 months after PBT. Of the 91 patients evaluated at 12 months, 66 had no increase of Child-Pugh score, 15 had a 1-point increase, and 10 had an increase of {>=}2 points. For the Youden index, the optimal cut-offs for V0, V10, V20, and V30 were 30%, 20%, 26%, and 18%, respectively. Conclusion: Our findings indicate that liver function after PBT is significantly related to the percentage volume of normal liver that is not irradiated. This suggests that further study of the relationship between liver function and PBT is required.« less

Motor neurone disease presenting as polycythaemia.

PubMed

Santana-Vaz, Natasha; Bwika, Jumaa; Morley, Kirstie; Mukherjee, Rahul

2014-04-28

Motor neurone disease (MND) is a chronic, progressive and currently incurable neurodegenerative disorder. This case report discusses an instance of MND presenting initially as polycythaemia, caused via insidious respiratory failure through ventilatory insufficiency. This case aims to improve clinicians' awareness of this atypical presentation and highlights the need for a high index of suspicion of respiratory failure in any patient with polycythaemia. Finally it demonstrates an improvement in quality of life associated with the use of non-invasive ventilation (NIV) in a patient with MND.

[The changing spectrum of fever of unknown origin: trends and comparison with previous series at the Salvador Zubirán National Institute of Nutrition].

PubMed

Molina-Gamboa, J; Rivera-Morales, I; Camacho-Mezquita, E; Ponce-de-León, S

1994-01-01

We reviewed 400 medical records of patients admitted because of fever at the National Institute of Nutrition Salvador Zubirán between January 1, 1988 to December 31, 1992. Patient characteristics, diagnostic methods, final diagnosis and patient progress were analyzed, comparing these data with the previous series of the institute. We found 77 cases of fever of unknown origin (FUO), 47 males and 30 females, between 14 to 87 years of age. The final diagnosis encountered were: infections (40%), neoplasias (23%), collagen diseases (13%), and other diagnosis (8%). Sixteen percent of the cases remained without a final diagnosis. The most frequent infections were HIV infection (19%), tuberculosis (19%) and endocarditis (13%). The most common neoplasia was lymphoma (55.6%), with 90% of Hodgkin's disease. SLE was the most common autoimmune disease found. The methods to establish a final diagnosis were: biopsies (52%), serology (17%), cultures (12%), image (11%), and clinical (8%). Final diagnosis by serology tests increased from 2 to 17% in comparison with previous reports. Eight laparotomies were done, which is a less frequent practice than previously (10 vs 35%). We saw only one case of amebic hepatic abscess and had no cases of malaria and salmonellosis as final diagnosis of FUO; HIV infection was found to be a new major cause of FUO.

Hitler's parkinsonism.

PubMed

Boettcher, Lillian B; Bonney, Phillip A; Smitherman, Adam D; Sughrue, Michael E

2015-07-01

Of the multitude of medical and psychiatric conditions ascribed to Hitler both in his lifetime and since his suicide in April 1945, few are more substantiated than parkinsonism. While the timeline of the development of this condition, as well as its etiology, are debated, there is clear evidence for classic manifestations of the disease, most prominently a resting tremor but also stooped posture, bradykinesia, micrographia, and masked facial expressions, with progression steadily seen over his final years. Though ultimately speculation, some have suggested that Hitler suffered from progressive cognitive and mood disturbances, possibly due to parkinsonism, that affected the course of events in the war. Here, the authors discuss Hitler's parkinsonism in the context of the Third Reich and its eventual destruction, maintaining that ultimately his disease had little effect on the end result.

Which Dengue Vaccine Approach Is the Most Promising, and Should We Be Concerned about Enhanced Disease after Vaccination? The Challenges of a Dengue Vaccine.

PubMed

Screaton, Gavin; Mongkolsapaya, Juthathip

2017-07-17

A dengue vaccine has been pursued for more than 50 years and, unlike other flaviviral vaccines such as that against yellow fever, progress has been slow. In this review, we describe progress toward the first licensed dengue vaccine Dengvaxia, which does not give complete protection against disease. The antibody response to the dengue virion is reviewed, highlighting immunodominant yet poorly neutralizing responses in the context of a highly dynamic structurally flexible dengue virus particle. Finally, we review recent evidence for cross-reactivity between antibody responses to Zika and dengue viruses, which may further complicate the development of broadly protective dengue virus vaccines. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.

PARTICULATE AIR POLLUTION AND RISK OF ST-SEGMENT DEPRESSION DURING REPEATED SUB-MAXIMAL EXERCISE TESTS AMONG SUBJECTS WITH CORONARY HEART DISEASE. THE ULTRA STUDY. (R827354C002)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

A CASE-CROSSOVER STUDY OF THE RELATIONSHIP OF FINE PM LEVELS TO SUDDEN CARDIAC ARREST IN INDIVIDUALS WITH AND WITHOUT CARDIAC DISEASE. (R827355C001)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

ASSOCIATION BETWEEN SHORT-TERM EXPOSURE TO FINE PARTICULATE MATTER AND HEART RATE VARIABILITY IN OLDER SUBJECTS WITH AND WITHOUT HEART DISEASE. (R827355C002)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

ASSOCIATION BETWEEN SHORT-TEAM EXPOSURE TO FINE PARTICULATE MATTER AND HEART RATE VARIABILITY IN OLDER SUBJECTS WITH AND WITHOUT HEART DISEASE. (R827355C007)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

Modeling Dynamic Fluctuations in Type 1 Diabetes Progression: Quantifying β-cell variation after the appearance of islet-specific autoimmune responses

PubMed Central

Nelson, Patrick; Smith, Noah; Ciupe, Stanca; Zou, Weiping; Omenn, Gilbert S.; Pietropaolo, Massimo

2015-01-01

Type 1 diabetes (T1DM) is a chronic autoimmune disease with a long prodrome, which is characterized by dysfunction and ultimately destruction of pancreatic β-cells. Because of the limited access to pancreatic tissue and pancreatic lymph nodes during the normoglycemic phase of the disease, little is known about the dynamics involved in the chain of events leading to the clinical onset of the disease in humans. In particular, during T1DM progression there is limited information about temporal fluctuations of immunologic abnormalities and their effect on pancreatic β-cell function and mass. Therefore, our understanding of the pathoetiology of T1DM relies almost entirely on studies in animal models of this disease. In an effort to elucidate important mechanisms that may play a critical role in the progression to overt disease, we propose a mathematical model that takes into account the dynamics of functional and dysfunctional β-cells, regulatory T cells, and pathogenic T cells. The model assumes that all individuals carrying susceptible HLA haplotypes will develop variable degrees of T1DM-related immunologic abnormalities. The results provide information about the concentrations and ratios of pathogenic T cells and regulatory T cells, the timing in which β-cells become dysfunctional, and how certain kinetic parameters affect the progression to T1DM. Our model is able to describe changes in the ratio of pathogenic T cells and regulatory T cells after the appearance islet antibodies in the pancreas. Finally, we discuss the robustness of the model and its ability to assist experimentalists in designing studies to test complicated theories about the disease. PMID:19835428

Female Sexual Dysfunction in Presymptomatic Mutation Carriers and Patients with Huntington's Disease.

PubMed

Kolenc, Matej; Kobal, Jan; Podnar, Simon

2017-01-01

Although in Huntington's disease (HD) movement, cognition, and personality are most significantly affected, autonomic dysfunction should not be neglected. In women with HD sexual dysfunction has not been adequately studied yet. To report sexual dysfunction in a systematically studied cohort of female HD patients and compare it with controls of a similar age. In female HD patients and presymptomatic HD mutation carriers, we compared the Female Sexual Function Index (FSFI) questionnaire, neurologic assessment using the Unified Huntington's Disease Rating Scale (UHDRS) and the Total Functional Capacity (TFC). Of 44 female HD patients and 9 presymptomatic HD mutation carriers, 30 HD patients and 8 HD mutation carriers responded our invitation to complete FFSI questionnaire. Finally, 23 HD women with a partner were compared to 47 controls with a partner. HD patients had more problems with sexual arousal, lubrication, orgasm and sexual satisfaction. By contrast, we found no difference in sexual desire and pain. Sexual dysfunction progressed in parallel with the decline in the TFC; severe sexual dysfunction occurred with TFC <7/13. Our study demonstrated a significant impact of HD on female sexual function that progressed with patients' functional decline and impaired patients' quality of life. Sexual dysfunction may be caused by progression of the disease itself, side effects of medication, and comorbidities like depression or dementia.

Host susceptibility hypothesis for shell disease in American lobsters.

PubMed

Tlusty, Michael F; Smolowitz, Roxanna M; Halvorson, Harlyn O; DeVito, Simone E

2007-12-01

Epizootic shell disease (ESD) in American lobsters Homarus americanus is the bacterial degradation of the carapace resulting in extensive irregular, deep erosions. The disease is having a major impact on the health and mortality of some American lobster populations, and its effects are being transferred to the economics of the fishery. While the onset and progression of ESD in American lobsters is undoubtedly multifactorial, there is little understanding of the direct causality of this disease. The host susceptibility hypothesis developed here states that although numerous environmental and pathological factors may vary around a lobster, it is eventually the lobster's internal state that is permissive to or shields it from the final onset of the diseased state. To support the host susceptibility hypothesis, we conceptualized a model of shell disease onset and severity to allow further research on shell disease to progress from a structured model. The model states that shell disease onset will occur when the net cuticle degradation (bacterial degradation, decrease of host immune response to bacteria, natural wear, and resorption) is greater than the net deposition (growth, maintenance, and inflammatory response) of the shell. Furthermore, lesion severity depends on the extent to which cuticle degradation exceeds deposition. This model is consistent with natural observations of shell disease in American lobster.

A53T-α-synuclein overexpression in murine locus coeruleus induces Parkinson's disease-like pathology in neurons and glia.

PubMed

Henrich, Martin Timo; Geibl, Fanni Fruzsina; Lee, Bolam; Chiu, Wei-Hua; Koprich, James Benjamin; Brotchie, Jonathan Michael; Timmermann, Lars; Decher, Niels; Matschke, Lina Anita; Oertel, Wolfgang Hermann

2018-05-10

Degeneration of noradrenergic locus coeruleus neurons occurs during the prodromal phase of Parkinson's disease and contributes to a variety of non-motor symptoms, e.g. depression, anxiety and REM sleep behavior disorder. This study was designed to establish the first locus coeruleus α-synucleinopathy mouse model, which should provide sufficient information about the time-course of noradrenergic neurodegeneration, replicate cardinal histopathological features of the human Parkinson's disease neuropathology and finally lead to robust histological markers, which are sufficient to assess the pathological changes in a quantitative and qualitative way. We show that targeted viral vector-mediated overexpression of human mutant A53T-α-synuclein in vivo in locus coeruleus neurons of wild-type mice resulted in progressive noradrenergic neurodegeneration over a time frame of 9 weeks. Observed neuronal cell loss was accompanied by progressive α-synuclein phosphorylation, formation of proteinase K-resistant α-synuclein-aggregates, accumulation of Ubi-1- and p62-positive inclusions in microglia and induction of progressive micro- and astrogliosis. Apart from this local pathology, abundant α-synuclein-positive axons were found in locus coeruleus output regions, indicating rapid anterograde axonal transport of A53T-α-synuclein. Taken together, we present the first model of α-synucleinopathy in the murine locus coeruleus, replicating essential morphological features of human Parkinson's disease pathology. This new model may contribute to the research on prodromal Parkinson's disease, in respect to pathophysiology and the development of disease-modifying therapy.

Joseph Haydn's encephalopathy: new aspects.

PubMed

Blahak, Christian; Bäzner, Hansjörg; Hennerici, Michael G

2015-01-01

With increasing age, Joseph Haydn complained of progressive forgetfulness preventing him from composing for about the last 8 years of his life. He spent his days more and more inactive and immobilized, suffering from a disabling gait disturbance. Still, most biographers consider diffuse atherosclerosis and congestive heart failure to be reasons for Haydn's medical condition and physical decline during the last years of his life. A more sophisticated and detailed inspection of documents and sources, however, leads to the diagnosis of subcortical vascular encephalopathy (SVE), caused by progressive cerebral small vessel disease. Important features of the disease are mood changes, urinary symptoms, and in particular a characteristic gait disturbance, while dementia is only mild and occurs later in the course. Haydn was severely disabled by the symptoms of SVE for several years and often reported difficulties in the completion of his last oratorio "Die Jahreszeiten" (The Seasons). Subsequently, the disease prevented him from composing another large oratorio, "Das jüngste Gericht" (The last judgement), which had been already drafted. Finally, the progress of SVE stopped his long career as a composer and conductor at the age of 73 years. © 2015 Elsevier B.V. All rights reserved.

Androgen Receptor (AR) in Cardiovascular Diseases

PubMed Central

Huang, Chiung-Kuei; Lee, Soo Ok; Chang, Eugene; Pang, Haiyan; Chang, Chawnshang

2016-01-01

Cardiovascular diseases (CVDs) are still the highest leading cause of death worldwide. Several risk factors have been linked to CVDs, including smoking, diabetes, hyperlipidemia, and gender among others. Sex hormones, especially the androgen and its receptor, androgen receptor (AR), have been linked to many diseases with a clear gender difference. Here, we summarize androgen/AR effects on CVDs, including hypertension, stroke, atherosclerosis, abdominal aortic aneurysm (AAA), myocardial hypertrophy, and heart failure, as well as metabolic syndrome/diabetes and their impacts on CVDs. Androgen/AR signaling exacerbates hypertension and anti-androgens may suppress hypertension. Androgen/AR signaling plays dual roles in strokes, depending on different kinds of factors, but generally males have a higher incidence of strokes than females. Androgen and AR differentially modulate atherosclerosis. Androgen deficiency causes elevated lipid accumulation to enhance atherosclerosis, but targeting AR in selective cells without altering serum androgen levels would suppress atherosclerosis progression. Androgen/AR signaling is crucial in AAA development and progression, and targeting androgen/AR profoundly restricts AAA progression. Men have increased cardiac hypertrophy as compared to age-matched women that may be due to androgens. Finally, androgen/AR plays important roles in contributing to obesity and insulin/leptin resistance to increase the metabolic syndrome. PMID:26769913

Toxoplasmosis presented as a submental mass: a common disease, uncommon presentation

PubMed Central

Li, Bo; Zou, Jian; Wang, Wei-Ya; Liu, Shi-Xi

2015-01-01

Submental mass secondary to toxoplasmosis is not common in clinical work. A diagnosis of toxoplasmosis is rarely considered by physicians. Here we describe a 50-year-old woman presented with a progressive, painful, submental and left neck swelling for 1 month. After having obtained an insufficient evidence from the fine-needle biopsy, the patient finally received an excisional biopsy which highly indicated the possibility of lymphadenopathy consistent with toxoplasmosis. Diagnosis of toxoplasmosis was finally established by a combination of the pathological criteria, together with the positive serological finding. According to review the clinical presentations, pathological characteristics, diagnostic standard and treatment of this disease, the article aims to remind otolaryngologists who are evaluating a neck mass should be aware of the infectious cause of lymphadenopathy and the possibility of toxoplasmosis. PMID:26045858

Toxoplasmosis presented as a submental mass: a common disease, uncommon presentation.

PubMed

Li, Bo; Zou, Jian; Wang, Wei-Ya; Liu, Shi-Xi

2015-01-01

Submental mass secondary to toxoplasmosis is not common in clinical work. A diagnosis of toxoplasmosis is rarely considered by physicians. Here we describe a 50-year-old woman presented with a progressive, painful, submental and left neck swelling for 1 month. After having obtained an insufficient evidence from the fine-needle biopsy, the patient finally received an excisional biopsy which highly indicated the possibility of lymphadenopathy consistent with toxoplasmosis. Diagnosis of toxoplasmosis was finally established by a combination of the pathological criteria, together with the positive serological finding. According to review the clinical presentations, pathological characteristics, diagnostic standard and treatment of this disease, the article aims to remind otolaryngologists who are evaluating a neck mass should be aware of the infectious cause of lymphadenopathy and the possibility of toxoplasmosis.

Role of Circulating miRNAs as Biomarkers in Idiopathic Pulmonary Arterial Hypertension: Possible Relevance of miR-23a

PubMed Central

Sarrion, Irene; Milian, Lara; Juan, G.; Ramon, Mercedes; Furest, Idelfonso; Carda, Carmen; Cortijo Gimeno, Julio; Mata Roig, Manuel

2015-01-01

Idiopathic pulmonary hypertension (IPAH) is a rare disease characterized by a progressive increase in pulmonary vascular resistance leading to heart failure. MicroRNAs (miRNAs) are small noncoding RNAs that control the expression of genes, including some involved in the progression of IPAH, as studied in animals and lung tissue. These molecules circulate freely in the blood and their expression is associated with the progression of different vascular pathologies. Here, we studied the expression profile of circulating miRNAs in 12 well-characterized IPAH patients using microarrays. We found significant changes in 61 miRNAs, of which the expression of miR23a was correlated with the patients' pulmonary function. We also studied the expression profile of circulating messenger RNA (mRNAs) and found that miR23a controlled 17% of the significantly changed mRNA, including PGC1α, which was recently associated with the progression of IPAH. Finally we found that silencing of miR23a resulted in an increase of the expression of PGC1α, as well as in its well-known regulated genes CYC, SOD, NRF2, and HO1. The results point to the utility of circulating miRNA expression as a biomarker of disease progression. PMID:25815108

FcgammaRIIa genotype predicts progression of HIV infection.

PubMed

Forthal, Donald N; Landucci, Gary; Bream, Jay; Jacobson, Lisa P; Phan, Tran B; Montoya, Benjamin

2007-12-01

Polymorphisms in FcgammaR genes are associated with susceptibility to or severity of a number of autoimmune and infectious diseases. We found that HIV-infected men in the Multicenter AIDS Cohort Study with the FcgammaRIIa RR genotype progressed to a CD4(+) cell count of <200/mm(3) at a faster rate than individuals with the RH or HH genotypes (relative hazard = 1.6; p = 0.0001). However, progression to AIDS (using the broad definition of either a CD4(+) cell count <200/mm(3) or development of an AIDS-defining illness) was less impacted by FcgammaRIIa genotype, largely because HH homozygotes had an increased risk of Pneumocystis jiroveci pneumonia as an AIDS-defining illness. We also showed that chronically infected subjects develop a substantial anti-gp120-specific IgG2 response. Moreover, HIV-1 immune complexes are more efficiently internalized by monocytes from HH subjects compared with RR subjects, likely because of the presence of IgG2 in the complexes. Finally, the FcgammaRIIIa F/V gene polymorphism was not associated with progression of HIV infection, but, as demonstrated previously, did predict the risk of Kaposi's sarcoma. These results demonstrate the importance of FcgammaRs in AIDS pathogenesis and point toward a critical role for interactions between FcgammaRs and immune complexes in disease progression.

Reducing the Child Death Rate. KIDS COUNT Indicator Brief

ERIC Educational Resources Information Center

Shore, Rima; Shore, Barbara

2009-01-01

In the 20th century's final decades, advances in the prevention and treatment of infectious diseases sharply reduced the child death rate. Despite this progress, the child death rate in the U.S. remains higher than in many other wealthy nations. The under-five mortality rate in the U.S. is almost three times higher than that of Iceland and Sweden…

Eliminating minimal residual disease as a therapeutic end point: working toward cure for patients with CLL.

PubMed

Thompson, Philip A; Wierda, William G

2016-01-21

Deep remission and prolonged disease-free survival can be achieved with first-line chemoimmunotherapy (CIT), such as combined fludarabine, cyclophosphamide, and rituximab, in the majority of patients with chronic lymphocytic leukemia (CLL). More modest results are reported with less intense regimens like obinutuzumab plus chlorambucil. Clinical assessment has limited sensitivity in detecting residual disease responsible for subsequent relapse, even including morphologic bone marrow (BM) evaluation. Multicolor flow cytometry and polymerase chain reaction (PCR)-based methods can detect minimal residual disease (MRD) to a sensitivity of ≥1:10,000 (10(-4)). Achieving BM MRD-negative complete remission (CR) is associated with superior progression-free survival (PFS) and overall survival; MRD status is the single best posttreatment predictor of long-term outcomes after CIT. Newer oral B-cell receptor signaling pathway inhibitors are highly effective at controlling disease, but best monotherapy responses are typically partial remission, and patients must remain on treatment to maintain disease control. Therapeutic progress is still needed for CLL. We propose that targeting MRD provides opportunity to realize this progress. Achieving BM MRD-negative CR is a prerequisite for long-term unmaintained disease-free survival and potential for cure. We review available methodologies for detecting MRD and correlations with posttreatment outcomes. We discuss the potential utility of MRD to direct individualized therapy. Finally, we discuss the importance of MRD-negative status as a surrogate marker for longer PFS in clinical studies to allow more rapid determination of clinical benefit. © 2016 by The American Society of Hematology.

Cocoon formation in patients with midgut neuroendocrine tumors: a rare and unrecognized final pathway.

PubMed

Wang, Yi-Zarn; King, Heather; Diebold, Anne

2013-08-01

Neuroendocrine tumors (NETs) are relatively rare with an indolent nature. As a result, treatment is often delayed and passive. The most commonly recognized disease progression leading to death is from the sequelae of bowel obstruction, ischemia, or liver failure secondary to liver metastasis. We recently recognized a rare cocoon-like formation in patients with metastatic gastroenteropancreatic NETs and hypothesize that this may be a distinct, final pathway for these patients. Ten patients with stage IV gastroenteropancreatic NETs, seen at our center between October 2008 and November 2011, who developed a cocoon were identified. Patient's charts, operative reports, pathology, and tumor markers were reviewed. No discernable predictors were identified as precursors to this condition. One patient survived 13 months after cocoon diagnosis, and the remaining 9 patients were all deceased within 5 months. Surgical treatment was attempted in 6 patients and was only partially successful in 1 patient who had the earliest stage of cocoon formation (type 1). Cocoon-like formations in patients with stage IV gastroenteropancreatic NETs is rare and may be a terminal disease progression that has not been previously recognized. The best treatment option remains unknown. Surgical treatment is not advisable, with the exception of type 1 abdominal cocoons.

Genomics, transcriptomics and proteomics: enabling insights into social evolution and disease challenges for managed and wild bees.

PubMed

Trapp, Judith; McAfee, Alison; Foster, Leonard J

2017-02-01

Globally, there are over 20 000 bee species (Hymenoptera: Apoidea: Anthophila) with a host of biologically fascinating characteristics. Although they have long been studied as models for social evolution, recent challenges to bee health (mainly diseases and pesticides) have gathered the attention of both public and research communities. Genome sequences of twelve bee species are now complete or under progress, facilitating the application of additional 'omic technologies. Here, we review recent developments in honey bee and native bee research in the genomic era. We discuss the progress in genome sequencing and functional annotation, followed by the enabled comparative genomics, proteomics and transcriptomics applications regarding social evolution and health. Finally, we end with comments on future challenges in the postgenomic era. © 2016 John Wiley & Sons Ltd.

MicroRNAs in right ventricular remodelling.

PubMed

Batkai, Sandor; Bär, Christian; Thum, Thomas

2017-10-01

Right ventricular (RV) remodelling is a lesser understood process of the chronic, progressive transformation of the RV structure leading to reduced functional capacity and subsequent failure. Besides conditions concerning whole hearts, some pathology selectively affects the RV, leading to a distinct RV-specific clinical phenotype. MicroRNAs have been identified as key regulators of biological processes that drive the progression of chronic diseases. The role of microRNAs in diseases affecting the left ventricle has been studied for many years, however there is still limited information on microRNAs specific to diseases in the right ventricle. Here, we review recently described details on the expression, regulation, and function of microRNAs in the pathological remodelling of the right heart. Recently identified strategies using microRNAs as pharmacological targets or biomarkers will be highlighted. Increasing knowledge of pathogenic microRNAs will finally help improve our understanding of underlying distinct mechanisms and help utilize novel targets or biomarkers to develop treatments for patients suffering from right heart diseases. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.

Cognitive impairment and cardiovascular diseases in the elderly. A heart-brain continuum hypothesis.

PubMed

Abete, Pasquale; Della-Morte, David; Gargiulo, Gaetano; Basile, Claudia; Langellotto, Assunta; Galizia, Gianluigi; Testa, Gianluca; Canonico, Vincenzo; Bonaduce, Domenico; Cacciatore, Francesco

2014-11-01

The aging population is increasing and, therefore, a higher prevalence of cardiac disease is emerging; including hypertension, coronary artery disease, atrial fibrillation and chronic heart failure. Large cohort studies have revealed a relationship among increased risk for cognitive impairment and dementia in cardiovascular diseases probably due to embolic stroke or chronic cerebral hypoperfusion. Thus, the aim of the present review is to overview the studies that investigate the presence and/or the development of cognitive impairments and dementia in patients with varied types of cardiovascular disease. Finally, a continuum among hypertension, coronary artery disease, atrial fibrillation and chronic heart failure with to the development of cognitive impairment and progression to dementia has been hypothesized. Copyright © 2014 Elsevier B.V. All rights reserved.

Simulation-based planning of surgical interventions in pediatric cardiology

NASA Astrophysics Data System (ADS)

Marsden, Alison

2012-11-01

Hemodynamics plays an essential role in the progression and treatment of cardiovascular disease. This is particularly true in pediatric cardiology, due to the wide variation in anatomy observed in congenital heart disease patients. While medical imaging provides increasingly detailed anatomical information, clinicians currently have limited knowledge of important fluid mechanical parameters. Treatment decisions are therefore often made using anatomical information alone, despite the known links between fluid mechanics and disease progression. Patient-specific simulations now offer the means to provide this missing information, and, more importantly, to perform in-silico testing of new surgical designs at no risk to the patient. In this talk, we will outline the current state of the art in methods for cardiovascular blood flow simulation and virtual surgery. We will then present new methodology for coupling optimization with simulation and uncertainty quantification to customize treatments for individual patients. Finally, we will present examples in pediatric cardiology that illustrate the potential impact of these tools in the clinical setting.

Epigenetic pathway targets for the treatment of disease: accelerating progress in the development of pharmacological tools: IUPHAR Review 11

PubMed Central

Tough, David F; Lewis, Huw D; Rioja, Inmaculada; Lindon, Matthew J; Prinjha, Rab K

2014-01-01

The properties of a cell are determined both genetically by the DNA sequence of its genes and epigenetically through processes that regulate the pattern, timing and magnitude of expression of its genes. While the genetic basis of disease has been a topic of intense study for decades, recent years have seen a dramatic increase in the understanding of epigenetic regulatory mechanisms and a growing appreciation that epigenetic misregulation makes a significant contribution to human disease. Several large protein families have been identified that act in different ways to control the expression of genes through epigenetic mechanisms. Many of these protein families are finally proving tractable for the development of small molecules that modulate their function and represent new target classes for drug discovery. Here, we provide an overview of some of the key epigenetic regulatory proteins and discuss progress towards the development of pharmacological tools for use in research and therapy. PMID:25060293

Global Breast Cancer: The Lessons to Bring Home

PubMed Central

Formenti, Silvia C.; Arslan, Alan A.; Love, Susan M.

2012-01-01

Breast cancer is the most common cancer affecting women globally. This paper discusses the current progress in breast cancer in Western countries and focuses on important differences of this disease in low- and middle-income countries (LMCs). It introduces several arguments for applying caution before globalizing some of the US-adopted practices in the screening and management of the disease. Finally, it suggests that studies of breast cancer in LMCs might offer important insights for a more effective management of the problem both in developing as well as developed countries. PMID:22295243

Therapeutic RNA interference for neurodegenerative diseases: From promise to progress.

PubMed

Gonzalez-Alegre, Pedro

2007-04-01

RNA interference (RNAi) has emerged as a powerful tool to manipulate gene expression in the laboratory. Due to its remarkable discriminating properties, individual genes, or even alleles can be targeted with exquisite specificity in cultured cells or living animals. Among its many potential biomedical applications, silencing of disease-linked genes stands out as a promising therapeutic strategy for many incurable disorders. Neurodegenerative diseases represent one of the more attractive targets for the development of therapeutic RNAi. In this group of diseases, the progressive loss of neurons leads to the gradual appearance of disabling neurological symptoms and premature death. Currently available therapies aim to improve the symptoms but not to halt the process of neurodegeneration. The increasing prevalence and economic burden of some of these diseases, such as Alzheimer's disease (AD) or Parkinson's disease (PD), has boosted the efforts invested in the development of interventions, such as RNAi, aimed at altering their natural course. This review will summarize where we stand in the therapeutic application of RNAi for neurodegenerative diseases. The basic principles of RNAi will be reviewed, focusing on features important for its therapeutic manipulation. Subsequently, a stepwise strategy for the development of therapeutic RNAi will be presented. Finally, the different preclinical trials of therapeutic RNAi completed in disease models will be summarized, stressing the experimental questions that need to be addressed before planning application in human disease.

Early clinics of the cardiac forms of Chagas' disease: Discovery and study of original medical files (1909-1915).

PubMed

Gachelin, Gabriel; Bestetti, Reinaldo B

2017-10-01

We have uncovered 80 medical files corresponding to original cases of Chagas' disease used for the classical description of the acute and cardiac forms of the disease. Sixty of them were diagnosed cardiac forms of the disease. The detailed clinical description of these 60 files is in excellent agreement with the nosography of progressive heart disease given by Chagas in his original 1922 paper. The reports we had access to, characterize a novel form of cardiac disease, dominated by progressive AV block, enlargement and displacement of the heart and sudden death, in relatively young adults including juveniles. In contrast to that remarkable clinical description, the assertion made by Chagas that this set of clinical signs was the consequence of an earlier infection by Trypanosoma cruzi rests on weak evidence, due to the difficulty to identify the parasite in most patients. Moreover, the association of thyroid dysfunction with cardiac disease emphasized by Chagas cannot be deduced from the files we have examined. Finally, the main reason why the disease had not been recognized for long as a defined clinical entity, is likely the absence of markedly distinctive clinical signs compared to most other parasitic diseases, poor sanitary conditions and the probable lack of clinical skills of the rare doctors working in the area where the disease was described. Copyright © 2017 Elsevier B.V. All rights reserved.

Confronting "hereditary" disease: eugenic attempts to eliminate tuberculosis in progressive era America.

PubMed

Wilson, Philip K

2006-01-01

Tuberculosis was clearly one of the most predominant diseases of the early twentieth century. At this time, Americans involved in the eugenics movement grew increasingly interested in methods to prevent this disease's potential hereditary spread. To do so, as this essay examines, eugenicists' attempted to shift the accepted view that tuberculosis arose from infection and contagion to a view of its heritable nature. The methods that they employed to better understand the propagation and control of tuberculosis are also discussed. Finally, the essay explores the interpretative analyses of data that the Eugenics Record Office used in an attempt to convince contemporaries of the hereditary transmission of tuberculosis.

23 CFR 140.609 - Progress and final vouchers.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 23 Highways 1 2011-04-01 2011-04-01 false Progress and final vouchers. 140.609 Section 140.609 Highways FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION PAYMENT PROCEDURES REIMBURSEMENT Reimbursement for Bond Issue Projects § 140.609 Progress and final vouchers. (a) Progress vouchers may be...

23 CFR 140.609 - Progress and final vouchers.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 23 Highways 1 2013-04-01 2013-04-01 false Progress and final vouchers. 140.609 Section 140.609 Highways FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION PAYMENT PROCEDURES REIMBURSEMENT Reimbursement for Bond Issue Projects § 140.609 Progress and final vouchers. (a) Progress vouchers may be...

23 CFR 140.609 - Progress and final vouchers.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 23 Highways 1 2014-04-01 2014-04-01 false Progress and final vouchers. 140.609 Section 140.609 Highways FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION PAYMENT PROCEDURES REIMBURSEMENT Reimbursement for Bond Issue Projects § 140.609 Progress and final vouchers. (a) Progress vouchers may be...

23 CFR 140.609 - Progress and final vouchers.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 23 Highways 1 2010-04-01 2010-04-01 false Progress and final vouchers. 140.609 Section 140.609 Highways FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION PAYMENT PROCEDURES REIMBURSEMENT Reimbursement for Bond Issue Projects § 140.609 Progress and final vouchers. (a) Progress vouchers may be...

Antibodies to the HIV-1 Tat protein correlated with nonprogression to AIDS: a rationale for the use of Tat toxoid as an HIV-1 vaccine.

PubMed

Zagury, J F; Sill, A; Blattner, W; Lachgar, A; Le Buanec, H; Richardson, M; Rappaport, J; Hendel, H; Bizzini, B; Gringeri, A; Carcagno, M; Criscuolo, M; Burny, A; Gallo, R C; Zagury, D

1998-01-01

To investigate which immune parameters, such as antibodies against HIV-1 specificities, or viral parameters, such as p24 antigenemia, are predictive of disease progression. We performed studies on serum collected from individuals exhibiting two extremes of disease evolution--67 fast progressors (FP) and 182 nonprogressors (NP)--at their enrollment. After a 1- to 2-year clinical follow-up of 104 nonprogressors after their enrollment, we could determine the best serologic predictors for disease progression. We investigated levels of antibodies to tetanus toxoid and to HIV antigens including Env, Gag, Nef, and Tat proteins, as well as p24 antigenemia, viremia, CD4 cell count, and interferon-alpha (IFN-alpha) titers in FPs and NPs, and we correlated these data with clinical and biologic signs of progression. p24 Antigenemia, a marker of viral replication, and anti-Tat antibodies were highly and inversely correlated in both groups (P < .001). Furthermore, anti-p24 antibodies and low serum IFN-alpha levels were correlated to the NP versus the FP cohort. Finally, among NPs, only antibodies to Tat and not to the other HIV specificities (Env, Nef, Gag) were significantly predictive of clinical stability during their follow-up. Antibodies toward HIV-1 Tat, which are inversely correlated to p24 antigenemia, appear as a critical marker for a lack of disease progression. This study strongly suggests that rising anti-Tat antibodies through active immunization may be beneficial in AIDS vaccine development to control viral replication.

Lysosomal acid lipase deficiency--an under-recognized cause of dyslipidaemia and liver dysfunction.

PubMed

Reiner, Željko; Guardamagna, Ornella; Nair, Devaki; Soran, Handrean; Hovingh, Kees; Bertolini, Stefano; Jones, Simon; Ćorić, Marijana; Calandra, Sebastiano; Hamilton, John; Eagleton, Terence; Ros, Emilio

2014-07-01

Lysosomal acid lipase deficiency (LAL-D) is a rare autosomal recessive lysosomal storage disease caused by deleterious mutations in the LIPA gene. The age at onset and rate of progression vary greatly and this may relate to the nature of the underlying mutations. Patients presenting in infancy have the most rapidly progressive disease, developing signs and symptoms in the first weeks of life and rarely surviving beyond 6 months of age. Children and adults typically present with some combination of dyslipidaemia, hepatomegaly, elevated transaminases, and microvesicular hepatosteatosis on biopsy. Liver damage with progression to fibrosis, cirrhosis and liver failure occurs in a large proportion of patients. Elevated low-density lipoprotein cholesterol levels and decreased high-density lipoprotein cholesterol levels are common features, and cardiovascular disease may manifest as early as childhood. Given that these clinical manifestations are shared with other cardiovascular, liver and metabolic diseases, it is not surprising that LAL-D is under-recognized in clinical practice. This article provides practical guidance to lipidologists, endocrinologists, cardiologists and hepatologists on how to recognize individuals with this life-limiting disease. A diagnostic algorithm is proposed with a view to achieving definitive diagnosis using a recently developed blood test for lysosomal acid lipase. Finally, current management options are reviewed in light of the ongoing development of enzyme replacement therapy with sebelipase alfa (Synageva BioPharma Corp., Lexington, MA, USA), a recombinant human lysosomal acid lipase enzyme. Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Molecular chaperones and protein folding as therapeutic targets in Parkinson's disease and other synucleinopathies.

PubMed

Ebrahimi-Fakhari, Darius; Saidi, Laiq-Jan; Wahlster, Lara

2013-12-05

Changes in protein metabolism are key to disease onset and progression in many neurodegenerative diseases. As a prime example, in Parkinson's disease, folding, post-translational modification and recycling of the synaptic protein α-synuclein are clearly altered, leading to a progressive accumulation of pathogenic protein species and the formation of intracellular inclusion bodies. Altered protein folding is one of the first steps of an increasingly understood cascade in which α-synuclein forms complex oligomers and finally distinct protein aggregates, termed Lewy bodies and Lewy neurites. In neurons, an elaborated network of chaperone and co-chaperone proteins is instrumental in mediating protein folding and re-folding. In addition to their direct influence on client proteins, chaperones interact with protein degradation pathways such as the ubiquitin-proteasome-system or autophagy in order to ensure the effective removal of irreversibly misfolded and potentially pathogenic proteins. Because of the vital role of proper protein folding for protein homeostasis, a growing number of studies have evaluated the contribution of chaperone proteins to neurodegeneration. We herein review our current understanding of the involvement of chaperones, co-chaperones and chaperone-mediated autophagy in synucleinopathies with a focus on the Hsp90 and Hsp70 chaperone system. We discuss genetic and pathological studies in Parkinson's disease as well as experimental studies in models of synucleinopathies that explore molecular chaperones and protein degradation pathways as a novel therapeutic target. To this end, we examine the capacity of chaperones to prevent or modulate neurodegeneration and summarize the current progress in models of Parkinson's disease and related neurodegenerative disorders.

The eGFR-C study: accuracy of glomerular filtration rate (GFR) estimation using creatinine and cystatin C and albuminuria for monitoring disease progression in patients with stage 3 chronic kidney disease--prospective longitudinal study in a multiethnic population.

PubMed

Lamb, Edmund J; Brettell, Elizabeth A; Cockwell, Paul; Dalton, Neil; Deeks, Jon J; Harris, Kevin; Higgins, Tracy; Kalra, Philip A; Khunti, Kamlesh; Loud, Fiona; Ottridge, Ryan S; Sharpe, Claire C; Sitch, Alice J; Stevens, Paul E; Sutton, Andrew J; Taal, Maarten W

2014-01-14

Uncertainty exists regarding the optimal method to estimate glomerular filtration rate (GFR) for disease detection and monitoring. Widely used GFR estimates have not been validated in British ethnic minority populations. Iohexol measured GFR will be the reference against which each estimating equation will be compared. The estimating equations will be based upon serum creatinine and/or cystatin C. The eGFR-C study has 5 components: 1) A prospective longitudinal cohort study of 1300 adults with stage 3 chronic kidney disease followed for 3 years with reference (measured) GFR and test (estimated GFR [eGFR] and urinary albumin-to-creatinine ratio) measurements at baseline and 3 years. Test measurements will also be undertaken every 6 months. The study population will include a representative sample of South-Asians and African-Caribbeans. People with diabetes and proteinuria (ACR ≥30 mg/mmol) will comprise 20-30% of the study cohort.2) A sub-study of patterns of disease progression of 375 people (125 each of Caucasian, Asian and African-Caribbean origin; in each case containing subjects at high and low risk of renal progression). Additional reference GFR measurements will be undertaken after 1 and 2 years to enable a model of disease progression and error to be built.3) A biological variability study to establish reference change values for reference and test measures.4) A modelling study of the performance of monitoring strategies on detecting progression, utilising estimates of accuracy, patterns of disease progression and estimates of measurement error from studies 1), 2) and 3).5) A comprehensive cost database for each diagnostic approach will be developed to enable cost-effectiveness modelling of the optimal strategy.The performance of the estimating equations will be evaluated by assessing bias, precision and accuracy. Data will be modelled as a linear function of time utilising all available (maximum 7) time points compared with the difference between baseline and final reference values. The percentage of participants demonstrating large error with the respective estimating equations will be compared. Predictive value of GFR estimates and albumin-to-creatinine ratio will be compared amongst subjects that do or do not show progressive kidney function decline. The eGFR-C study will provide evidence to inform the optimal GFR estimate to be used in clinical practice. ISRCTN42955626.

Present and Future in the Treatment of Diabetic Kidney Disease

PubMed Central

de Arriba, Gabriel

2015-01-01

Diabetic kidney disease is the leading cause of end-stage renal disease. Albuminuria is recognized as the most important prognostic factor for chronic kidney disease progression. For this reason, blockade of renin-angiotensin system remains the main recommended strategy, with either angiotensin converting enzyme inhibitors or angiotensin II receptor blockers. However, other antiproteinuric treatments have begun to be studied, such as direct renin inhibitors or aldosterone blockers. Beyond antiproteinuric treatments, other drugs such as pentoxifylline or bardoxolone have yielded conflicting results. Finally, alternative pathogenic pathways are being explored, and emerging therapies including antifibrotic agents, endothelin receptor antagonists, or transcription factors show promising results. The aim of this review is to explain the advances in newer agents to treat diabetic kidney disease, along with the background of the renin-angiotensin system blockade. PMID:25945357

Plasma α-synuclein and cognitive impairment in the Parkinson's Associated Risk Syndrome: A pilot study.

PubMed

Wang, Hua; Atik, Anzari; Stewart, Tessandra; Ginghina, Carmen; Aro, Patrick; Kerr, Kathleen F; Seibyl, John; Jennings, Danna; Jensen, Poul Henning; Marek, Kenneth; Shi, Min; Zhang, Jing

2018-04-27

Plasma total and nervous system derived exosomal (NDE) α-synuclein have been determined as potential biomarkers of Parkinson's disease (PD). To explore the utility of plasma α-synuclein in the prodromal phase of PD, plasma total and NDE α-synuclein were evaluated in baseline and 2-year follow-up samples from 256 individuals recruited as part of the Parkinson's Associated Risk Syndrome (PARS) study. The results demonstrated that baseline and longitudinal increases in total α-synuclein predicted progression of cognitive decline in hyposmic individuals with dopamine transporter (DAT) binding reduction. On the other hand, a longitudinal decrease in NDE α-synuclein predicted worsening cognitive scores in hyposmic individuals with DAT binding reduction. Finally, in individuals with faster DAT progression, decreasing NDE/total α-synuclein ratio was associated with a larger reduction in DAT from baseline to follow-up. These results suggest that, though underlying mechanisms remain to be defined, alterations in plasma total and NDE α-synuclein concentrations are likely associated with PD progression, especially in the aspect of cognitive impairment, at early stages of the disease. Copyright © 2018. Published by Elsevier Inc.

How to Deal with Interval-Censored Data Practically while Assessing the Progression-Free Survival: A Step-by-Step Guide Using SAS and R Software.

PubMed

Dugué, Audrey Emmanuelle; Pulido, Marina; Chabaud, Sylvie; Belin, Lisa; Gal, Jocelyn

2016-12-01

We describe how to estimate progression-free survival while dealing with interval-censored data in the setting of clinical trials in oncology. Three procedures with SAS and R statistical software are described: one allowing for a nonparametric maximum likelihood estimation of the survival curve using the EM-ICM (Expectation and Maximization-Iterative Convex Minorant) algorithm as described by Wellner and Zhan in 1997; a sensitivity analysis procedure in which the progression time is assigned (i) at the midpoint, (ii) at the upper limit (reflecting the standard analysis when the progression time is assigned at the first radiologic exam showing progressive disease), or (iii) at the lower limit of the censoring interval; and finally, two multiple imputations are described considering a uniform or the nonparametric maximum likelihood estimation (NPMLE) distribution. Clin Cancer Res; 22(23); 5629-35. ©2016 AACR. ©2016 American Association for Cancer Research.

Populations, not clones, are the unit of vibrio pathogenesis in naturally infected oysters.

PubMed

Lemire, Astrid; Goudenège, David; Versigny, Typhaine; Petton, Bruno; Calteau, Alexandra; Labreuche, Yannick; Le Roux, Frédérique

2015-07-01

Disease in oysters has been steadily rising over the past decade, threatening the long-term survival of commercial and natural stocks. Our understanding and management of such diseases are of critical importance as aquaculture is an important aspect of dealing with the approaching worldwide food shortage. Although some bacteria of the Vibrio genus isolated from diseased oysters have been demonstrated to be pathogenic by experimental infection, direct causality has not been established. Little is known about the dynamics of how the bacterial population hosted by oysters changes during disease progression. Combining experimental ecology, a high-throughput infection assay and genome sequencing, we show that the onset of disease in oysters is associated with progressive replacement of diverse benign colonizers by members of a phylogenetically coherent virulent population. Although the virulent population is genetically diverse, all members of that population can cause disease. Comparative genomics across virulent and nonvirulent populations identified candidate virulence factors that were clustered in population-specific genomic regions. Genetic analyses revealed that one gene for a candidate virulent factor, a putative outer membrane protein, is necessary for infection of oysters. Finally, analyses of oyster mortality following experimental infection suggest that disease onset can be facilitated by the presence of nonvirulent strains. This is a new form of polymicrobial disease, in which nonpathogenic strains contribute to increase mortality.

Populations, not clones, are the unit of vibrio pathogenesis in naturally infected oysters

PubMed Central

Lemire, Astrid; Goudenège, David; Versigny, Typhaine; Petton, Bruno; Calteau, Alexandra; Labreuche, Yannick; Le Roux, Frédérique

2015-01-01

Disease in oysters has been steadily rising over the past decade, threatening the long-term survival of commercial and natural stocks. Our understanding and management of such diseases are of critical importance as aquaculture is an important aspect of dealing with the approaching worldwide food shortage. Although some bacteria of the Vibrio genus isolated from diseased oysters have been demonstrated to be pathogenic by experimental infection, direct causality has not been established. Little is known about the dynamics of how the bacterial population hosted by oysters changes during disease progression. Combining experimental ecology, a high-throughput infection assay and genome sequencing, we show that the onset of disease in oysters is associated with progressive replacement of diverse benign colonizers by members of a phylogenetically coherent virulent population. Although the virulent population is genetically diverse, all members of that population can cause disease. Comparative genomics across virulent and nonvirulent populations identified candidate virulence factors that were clustered in population-specific genomic regions. Genetic analyses revealed that one gene for a candidate virulent factor, a putative outer membrane protein, is necessary for infection of oysters. Finally, analyses of oyster mortality following experimental infection suggest that disease onset can be facilitated by the presence of nonvirulent strains. This is a new form of polymicrobial disease, in which nonpathogenic strains contribute to increase mortality. PMID:25489729

Chronic inflammatory demyelinating polyneuropathy in Waldenström's macroglobulinemia.

PubMed

Cassereau, J; Letournel, F; François, S; Dubas, F; Nicolas, G

2011-04-01

Waldenström's disease (WD) is frequently associated with a predominantly sensory neuropathy with a progressive course due to the monoclonal IgM activity against Myelin Associated Glycoprotein (MAG). However, neurolymphomatosis or chronic demyelinating inflammatory polyneuropathy (CDIP) may occur in some patients with WD. We report a case of Waldenström's macroglobulinemia in an adult male presenting with cranial nerve palsy and rapidly progressive asymmetric polyneuropathy. Intravenous IgM treatment that provided transient amelioration was followed by a relapse involving tetraparesis. Cerebrospinal fluid analysis, medullar magnetic resonance imaging, and electrophysiological studies led to equivocal findings suggesting the presence of either neurolymphomatosis or CIDP. Finally, sural nerve biopsy results supported the diagnosis of CIDP, which then received appropriate treatment. In patients with WD, the possible occurrence of CIDP should be investigated with a neuromuscular biopsy when other investigations are equivocal since the disease calls for a specific treatment. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Molecular biology of anal squamous cell carcinoma: implications for future research and clinical intervention.

PubMed

Bernardi, Maria-Pia; Ngan, Samuel Y; Michael, Michael; Lynch, A Craig; Heriot, Alexander G; Ramsay, Robert G; Phillips, Wayne A

2015-12-01

Anal squamous cell carcinoma is a human papillomavirus-related disease, in which no substantial advances in treatment have been made in over 40 years, especially for those patients who develop disease relapse and for whom no surgical options exist. HPV can evade the immune system and its role in disease progression can be exploited in novel immunotherapy platforms. Although several studies have investigated the expression and inactivation (through loss of heterozygosity) of tumour suppressor genes in the pathways to cancer, no clinically valuable biomarkers have emerged. Regulators of apoptosis, including survivin, and agents targeting the PI3K/AKT pathway, offer opportunities for targeted therapy, although robust data are scarce. Additionally, antibody therapy targeting EGFR may prove effective, although its safety profile in combination with standard chemoradiotherapy has proven to be suboptimal. Finally, progress in the treatment of anal cancer has remained stagnant due to a lack of preclinical models, including cell lines and mouse models. In this Review, we discuss the molecular biology of anal squamous cell carcinoma, clinical trials in progress, and implications for novel therapeutic targets. Future work should focus on preclinical models to provide a resource for investigation of new molecular pathways and for testing novel targets. Copyright © 2015 Elsevier Ltd. All rights reserved.

How to Constrain and Maintain a Lexicon for the Treatment of Progressive Semantic Naming Deficits: Principles of Item Selection for Formal Semantic Therapy

PubMed Central

Reilly, Jamie

2015-01-01

The progressive degradation of semantic memory is a common feature of many forms of dementia, including Alzheimer’s Disease and the semantic variant of Primary Progressive Aphasia (svPPA). One of the most functionally debilitating effects of this semantic impairment is the inability to name common people and objects (i.e., anomia). Clinical management of a progressive, semantically-based anomia presents extraordinary challenge for neurorehabilitation. Techniques such as errorless learning and spaced-retrieval training show promise for retraining forgotten words. However, we lack complementary detail about what to train (i.e., item selection) and how to flexibly adapt the training to a declining cognitive system. In this position paper, I weigh the relative merits of several treatment rationales (e.g., restore vs. compensate) and advocate for maintenance of known words over reacquisition of forgotten knowledge in the context of semantic treatment paradigms. I propose a system for generating an item pool and outline a set of core principles for training and sustaining a micro-lexicon consisting of approximately 100 words. These principles are informed by lessons learned over the course of a Phase I treatment study targeting language maintenance over a 5-year span in Alzheimer’s Disease and Frontotemporal Degeneration. Finally, I propose a semantic training approach that capitalizes on lexical frequency and repeated training on conceptual structure to offset the loss of key vocabulary as disease severity worsens. PMID:25609229

Progressive Ischemic Stroke due to Thyroid Storm-Associated Cerebral Venous Thrombosis

PubMed Central

Tanabe, Natsumi; Hiraoka, Eiji; Hoshino, Masataka; Deshpande, Gautam A.; Sawada, Kana; Norisue, Yasuhiro; Tsukuda, Jumpei; Suzuki, Toshihiko

2017-01-01

Patient: Female, 49 Final Diagnosis: Cerebral venous thrombosis Symptoms: Altered mental state • weakness in limbs Medication: — Clinical Procedure: — Specialty: Endocrinology and Metabolic Objective: Rare co-existance of disease or pathology Background: Cerebral venous thrombosis (CVT) is a rare but fatal complication of hyperthyroidism that is induced by the hypercoagulable state of thyrotoxicosis. Although it is frequently difficult to diagnose CVT promptly, it is important to consider it in the differential diagnosis when a hyperthyroid patient presents with atypical neurologic symptoms. Care Report: A 49-year-old Japanese female with unremarkable medical history came in with thyroid storm and multiple progressive ischemic stroke identified at another hospital. Treatment for thyroid storm with beta-blocker, glucocorticoid, and potassium iodide-iodine was started and MR venography was performed on hospital day 3 for further evaluation of her progressive ischemic stroke. The MRI showed CVT, and anticoagulation therapy, in addition to the anti-thyroid agents, was initiated. The patient’s thyroid function was successfully stabilized by hospital day 10 and further progression of CVT was prevented. Conclusions: Physicians should consider CVT when a patient presents with atypical course of stroke or with atypical MRI findings such as high intensity area in apparent diffusion coefficient (ADC) mapping. Not only is an early diagnosis and initiation of anticoagulation important, but identifying and treating the underlying disease is essential to avoid the progression of CVT. PMID:28228636

Predicting Outcomes to Optimize Disease Management in Inflammatory Bowel Diseases.

PubMed

Torres, Joana; Caprioli, Flavio; Katsanos, Konstantinos H; Lobatón, Triana; Micic, Dejan; Zerôncio, Marco; Van Assche, Gert; Lee, James C; Lindsay, James O; Rubin, David T; Panaccione, Remo; Colombel, Jean-Frédéric

2016-12-01

Efforts to slow or prevent the progressive course of inflammatory bowel diseases [IBD] include early and intensive monitoring and treatment of patients at higher risk for complications. It is therefore essential to identify high-risk patients - both at diagnosis and throughout disease course. As a part of an IBD Ahead initiative, we conducted a comprehensive literature review to identify predictors of long-term IBD prognosis and generate draft expert summary statements. Statements were refined at national meetings of IBD experts in 32 countries and were finalized at an international meeting in November 2014. Patients with Crohn's disease presenting at a young age or with extensive anatomical involvement, deep ulcerations, ileal/ileocolonic involvement, perianal and/or severe rectal disease or penetrating/stenosing behaviour should be regarded as high risk for complications. Patients with ulcerative colitis presenting at young age, with extensive colitis and frequent flare-ups needing steroids or hospitalization present increased risk for colectomy or future hospitalization. Smoking status, concurrent primary sclerosing cholangitis and concurrent infections may impact the course of disease. Current genetic and serological markers lack accuracy for clinical use. Simple demographic and clinical features can guide the clinician in identifying patients at higher risk for disease complications at diagnosis and throughout disease course. However, many of these risk factors have been identified retrospectively and lack validation. Appropriately powered prospective studies are required to inform algorithms that can truly predict the risk for disease progression in the individual patient. © European Crohn’s and Colitis Organisation 2016.

Omic studies reveal the pathogenic lipid droplet proteins in non-alcoholic fatty liver disease.

PubMed

Zhang, Xuelin; Wang, Yang; Liu, Pingsheng

2017-01-01

Non-alcoholic fatty liver disease (NAFLD) is an epidemic metabolic condition driven by an underlying lipid homeostasis disorder. The lipid droplet (LD), the main organelle involved in neutral lipid storage and hydrolysis, is a potential target for NAFLD therapeutic treatment. In this review, we summarize recent progress elucidating the connections between LD-associated proteins and NAFLD found by genome-wide association studies (GWAS), genomic and proteomic studies. Finally, we discuss a possible mechanism by which the protein 17β-hydroxysteroid dehydrogenase 13 (17β-HSD13) may promote the development of NAFLD.

Cardiovascular risk in women with polycystic ovary syndrome.

PubMed

Cho, L W; Atkin, S L

2007-12-01

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women that has received an immense amount of attention in the recent years due to the possible associated risk of cardiovascular disease. Women with PCOS demonstrate an adverse cardiovascular profile characteristic of the cardiometabolic syndrome and an established risk of progression to type 2 diabetes. Despite the presence of cardiovascular risk factors and increased surrogate markers of cardiovascular disease, it is unclear if they develop accelerated atherosclerosis. This article summarized the recent development and findings of cardiovascular risk in women with PCOS, and finally the therapeutic options will be discussed.

Review of the GAS3 Family of Proteins and their Relevance to Cancer

PubMed Central

Ashki, Negin; Gordon, Lynn; Wadehra, Madhuri

2017-01-01

The GAS3 family of tetraspan proteins has recently been implicated in the progression of cancer. Currently, six members of the GAS3 family have been identified in humans and mice, and while their expressions in disease vary, data suggest that they play a role in epithelial cell structure and function. In this review, we highlight the studies implicating four of the members in disease pathogenesis as well as probe the structural similarities between the family members. Finally, the impact of targeting select members of the family such as PMP22 and EMP2 is discussed. PMID:27279240

Review of the GAS3 Family of Proteins and their Relevance to Cancer.

PubMed

Ashki, Negin; Gordon, Lynn; Wadehra, Madhuri

2015-01-01

The GAS3 family of tetraspan proteins has recently been implicated in the progression of cancer. Currently, six members of the GAS3 family have been identified in humans and mice, and while their expressions in disease vary, data suggest that they play a role in epithelial cell structure and function. In this review, we highlight the studies implicating four of the members in disease pathogenesis as well as probe the structural similarities between the family members. Finally, the impact of targeting select members of the family such as PMP22 and EMP2 is discussed.

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

PubMed Central

Mosna, Federico; Capelli, Debora; Gottardi, Michele

2017-01-01

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. PMID:28587190

New Advances in Molecular Therapy for Muscle Repair after Diseases and Injuries

DTIC Science & Technology

2009-04-01

broader scientific community . Investigator: Johnny Huard - 9 - Project # 1 Progress Report The use of suramin to improve muscle healing after...black arrow ) in grey matter indicated small neuron and axon communication . Project # 5 Final Report Inhibiting cell death and promoting muscle...potential to treat muscle wasting induced by cancer. We anticipate that these results can be generalized to the treatment of other genetic and acquired

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

PubMed

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

2013-05-01

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

Expression of autophagy-related protein LC3B, p62, and cytoplasmic p53 in human retinoblastoma tissues.

PubMed

Zhang, M; Zhou, Y-F; Gong, J-Y; Gao, C-B; Li, S-L

2016-07-01

Dysfunction of autophagy has been implicated in development and progression of diverse human cancers. However, the exact role and mechanism of autophagy have not been fully understood in human cancers, especially in retinoblastoma (Rb). We determined the autophagy activity in human Rb tissues by assessing the autophagy markers microtubule-associated protein light chain 3B (LC3) and p62 (SQSTM1) in formalin fixed and paraffin embedded human tissue by immunohistochemistry and then associated their expression with patient clinicopathological features. We further explored the correlation between the expression of LC3B and p62 and the expression of cytoplasmic p53, a newly identified autophagy suppressor, in Rb tissues. Our data revealed that the expression of LC3B and p62, was significantly associated with disease progression and tumor invasion of Rb. Furthermore, we also revealed that cytoplasmic expression of p53 was inversely associated with the behavior of tumor invasion. Finally, Spearman correlation analysis demonstrated that cytoplasmic expression of p53 was significantly and inversely correlated to the expression of both LC3B and p62. Autophagy might play an important role in human Rb progression, and LC3B and p62 may be useful predictors of disease progression in patients with Rb.

Protein Oxidation in Aging: Does It Play a Role in Aging Progression?

PubMed Central

Reeg, Sandra

2015-01-01

Abstract Significance: A constant accumulation of oxidized proteins takes place during aging. Oxidation of proteins leads to a partial unfolding and, therefore, to aggregation. Protein aggregates impair the activity of cellular proteolytic systems (proteasomes, lysosomes), resulting in further accumulation of oxidized proteins. In addition, the accumulation of highly crosslinked protein aggregates leads to further oxidant formation, damage to macromolecules, and, finally, to apoptotic cell death. Furthermore, protein oxidation seems to play a role in the development of various age-related diseases, for example, neurodegenerative diseases. Recent Advances: The highly oxidized lipofuscin accumulates during aging. Lipofuscin formation might cause impaired lysosomal and proteasomal degradation, metal ion accumulation, increased reactive oxygen species formation, and apoptosis. Critical Issues: It is still unclear to which extent protein oxidation is involved in the progression of aging and in the development of some age-related diseases. Future Directions: An extensive knowledge of the effects of protein oxidation on the aging process and its contribution to the development of age-related diseases could enable further strategies to reduce age-related impairments. Strategies aimed at lowering aggregate formation might be a straightforward intervention to reduce age-related malfunctions of organs. Antioxid. Redox Signal. 23, 239–255. PMID:25178482

Current Experimental Studies of Gene Therapy in Parkinson's Disease

PubMed Central

Lin, Jing-ya; Xie, Cheng-long; Zhang, Su-fang; Yuan, Weien; Liu, Zhen-Guo

2017-01-01

Parkinson's disease (PD) was characterized by late-onset, progressive dopamine neuron loss and movement disorders. The progresses of PD affected the neural function and integrity. To date, most researches had largely addressed the dopamine replacement therapies, but the appearance of L-dopa-induced dyskinesia hampered the use of the drug. And the mechanism of PD is so complicated that it's hard to solve the problem by just add drugs. Researchers began to focus on the genetic underpinnings of Parkinson's disease, searching for new method that may affect the neurodegeneration processes in it. In this paper, we reviewed current delivery methods used in gene therapies for PD, we also summarized the primary target of the gene therapy in the treatment of PD, such like neurotrophic factor (for regeneration), the synthesis of neurotransmitter (for prolong the duration of L-dopa), and the potential proteins that might be a target to modulate via gene therapy. Finally, we discussed RNA interference therapies used in Parkinson's disease, it might act as a new class of drug. We mainly focus on the efficiency and tooling features of different gene therapies in the treatment of PD. PMID:28515689

Is It Time to Change the Definition of Acute Exacerbation of Chronic Obstructive Pulmornary Disease? What Do We Need to Add?

PubMed

Montes de Oca, Maria; Laucho-Contreras, Maria Eugenia

2018-06-14

Acute exacerbations in chronic obstructive pulmonary disease (AECOPD) are associated with increased mortality, rate of hospitalization, use of healthcare resources, and have a negative impact on disease progression, quality of life and lung function of patients with chronic obstructive pulmonary disease (COPD). There is an imperative need to homogenize the definition of AECOPD because the incidence of exacerbations has a significant influence or implication on treatment decision making, particularly in pharmacotherapy and could impact the outcome or change the statistical significance of a therapeutic intervention in clinical trials. In this review, using PubMed searches, we have analyzed the weaknesses and strengths of the different used AECOPD definitions (symptom-based, healthcare-based definition or the combinations of both), as well as the findings of the studies that have assessed the relationship of different biomarkers with the diagnosis, etiology and differential diagnosis of AECOPD and the progress towards the development of a more precise definition of COPD exacerbation. Finally, we have proposed a simple definition of AECOPD, which must be validated in future clinical trials to define its accuracy and usefulness in daily practice.

Subacute sclerosing panencephalitis: an update.

PubMed

Gutierrez, Jose; Issacson, Richard S; Koppel, Barbara S

2010-10-01

Subacute sclerosing panencephalitis (SSPE) is a chronic encephalitis occurring after infection with measles virus. The prevalence of the disease varies depending on uptake of measles vaccination, with the virus disproportionally affecting regions with low vaccination rates. The physiopathology of the disease is not fully understood; however, there is evidence that it involves factors that favour humoral over cellular immune response against the virus. As a result, the virus is able to infect the neurons and to survive in a latent form for years. The clinical manifestations occur, on average, 6 years after measles virus infection. The onset of SSPE is insidious, and psychiatric manifestations are prominent. Subsequently, myoclonic seizures usually lead to a final stage of akinetic mutism. The diagnosis is clinical, supported by periodic complexes on electroencephalography, brain imaging suggestive of demyelination, and immunological evidence of measles infection. Management of the disease includes seizure control and avoidance of secondary complications associated with the progressive disability. Trials of treatment with interferon, ribavirin, and isoprinosine using different methodologies have reported beneficial results. However, the disease shows relentless progression; only 5% of individuals with SSPE undergo spontaneous remission, with the remaining 95% dying within 5 years of diagnosis.

Revisiting the NIH Taskforce on the Research needs of Eosinophil-Associated Diseases (RE-TREAD).

PubMed

Khoury, Paneez; Akuthota, Praveen; Ackerman, Steven J; Arron, Joseph R; Bochner, Bruce S; Collins, Margaret H; Kahn, Jean-Emmanuel; Fulkerson, Patricia C; Gleich, Gerald J; Gopal-Srivastava, Rashmi; Jacobsen, Elizabeth A; Leiferman, Kristen M; Francesca, Levi-Schaffer; Mathur, Sameer K; Minnicozzi, Michael; Prussin, Calman; Rothenberg, Marc E; Roufosse, Florence; Sable, Kathleen; Simon, Dagmar; Simon, Hans-Uwe; Spencer, Lisa A; Steinfeld, Jonathan; Wardlaw, Andrew J; Wechsler, Michael E; Weller, Peter F; Klion, Amy D

2018-04-19

Eosinophil-associated diseases (EADs) are rare, heterogeneous disorders characterized by the presence of eosinophils in tissues and/or peripheral blood resulting in immunopathology. The heterogeneity of tissue involvement, lack of sufficient animal models, technical challenges in working with eosinophils, and lack of standardized histopathologic approaches have hampered progress in basic research. Additionally, clinical trials and drug development for rare EADs are limited by the lack of primary and surrogate endpoints, biomarkers, and validated patient-reported outcomes. Researchers with expertise in eosinophil biology and eosinophil-related diseases reviewed the state of current eosinophil research, resources, progress, and unmet needs in the field since the 2012 meeting of the NIH Taskforce on the Research of Eosinophil-Associated Diseases (TREAD). RE-TREAD focused on gaps in basic science, translational, and clinical research on eosinophils and eosinophil-related pathogenesis. Improved recapitulation of human eosinophil biology and pathogenesis in murine models was felt to be of importance. Characterization of eosinophil phenotypes, the role of eosinophil subsets in tissues, identification of biomarkers of eosinophil activation and tissue load, and a better understanding of the role of eosinophils in human disease were prioritized. Finally, an unmet need for tools for use in clinical trials was emphasized. Histopathologic scoring, patient- and clinician-reported outcomes, and appropriate coding were deemed of paramount importance for research collaborations, drug development, and approval by regulatory agencies. Further exploration of the eosinophil genome, epigenome, and proteome was also encouraged. Although progress has been made since 2012, unmet needs in eosinophil research remain a priority. ©2018 Society for Leukocyte Biology.

Heat Shock Proteins and Autophagy Pathways in Neuroprotection: From Molecular Bases to Pharmacological Interventions

PubMed Central

Penke, Botond; Bogár, Ferenc; Sántha, Miklós; Tóth, Melinda E.; Vígh, László

2018-01-01

Neurodegenerative diseases (NDDs) such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease (HD), amyotrophic lateral sclerosis, and prion diseases are all characterized by the accumulation of protein aggregates (amyloids) into inclusions and/or plaques. The ubiquitous presence of amyloids in NDDs suggests the involvement of disturbed protein homeostasis (proteostasis) in the underlying pathomechanisms. This review summarizes specific mechanisms that maintain proteostasis, including molecular chaperons, the ubiquitin-proteasome system (UPS), endoplasmic reticulum associated degradation (ERAD), and different autophagic pathways (chaperon mediated-, micro-, and macro-autophagy). The role of heat shock proteins (Hsps) in cellular quality control and degradation of pathogenic proteins is reviewed. Finally, putative therapeutic strategies for efficient removal of cytotoxic proteins from neurons and design of new therapeutic targets against the progression of NDDs are discussed. PMID:29361800

Antineutrophil cytoplasm autoantibodies: usefulness in rheumatology.

PubMed

Flores-Suárez, Luis Felipe

2012-01-01

The primary vasculitidies are complex diseases with varied clinical manifestations, which may be common to those present in multiple diseases. The antineutrophil cytoplasm autoantibodies (ANCA) led to a revolution in the diagnosis and research of these diseases, being the first and so far, the only biomarkers for three of these diseases, which affect small caliber vessels. From their description, much progress has been made, but there are still gray or misunderstood areas regarding their best use in the clinic. This can lead to errors as making a positive test synonym for vasculitis, or to overestimation of its importance. This review will address aspects such as nomenclature, employment in the diagnosis and monitoring of vasculitis, their presence in other diseases, their methods of detection, and finally, some comments on other potential biomarkers in vasculitis. Copyright © 2012 Elsevier España, S.L. All rights reserved.

Disease course and management strategy of pouch neoplasia in patients with underlying inflammatory bowel diseases.

PubMed

Wu, Xian-Rui; Remzi, Feza H; Liu, Xiu-Li; Lian, Lei; Stocchi, Luca; Ashburn, Jean; Shen, Bo

2014-11-01

To evaluate the disease course and management strategy for pouch neoplasia. Patients undergoing ileal pouch surgery for underlying ulcerative colitis who developed low-grade dysplasia (LGD), high-grade dysplasia, or adenocarcinoma in the pouch were identified. All eligible 44 patients were evaluated. Of the 22 patients with initial diagnosis of pouch LGD, 6 (27.3%) had persistence or progression after a median follow-up of 9.5 (4.1-17.6) years. Family history of colorectal cancer was shown to be a risk factor associated with persistence or progression of LGD (P = 0.03). Of the 12 patients with pouch high-grade dysplasia, 5 (41.7%) had a history of (n = 2, 16.7%) or synchronous (n = 4, 33.3%) pouch LGD. Pouch high-grade dysplasia either persisted or progressed in 3 patients (25.0%) after the initial management, during a median time interval of 5.4 (2.2-9.2) years. Of the 14 patients with pouch adenocarcinoma, 12 (85.7%) had a history of (n = 2, 14.3%) or synchronous dysplasia (n = 12, 85.7%). After a median follow-up of 2.1 (0.6-5.2) years, 6 patients with pouch cancer (42.9%) died. Comparison of patients with a final diagnosis of pouch adenocarcinoma (14, 32.6%), and those with dysplasia (29, 67.4%) showed that patients with adenocarcinoma were older (P = 0.04) and had a longer duration from IBD diagnosis or pouch construction to the detection of pouch neoplasia (P = 0.007 and P = 0.0013). The risk for progression of pouch dysplasia can be stratified. The presence of family history of colorectal cancer seemed to increase the risk for persistence or progression for patients with pouch LGD. The prognosis for pouch adenocarcinoma was poor.

[Neurological evaluation of the leper king Baldwin IV of Jerusalem].

PubMed

Guerrero-Peral, A L

In the medieval period, physicians became more aware of leprosy symptoms and differentiated it from other similar diseases. Baldwin, the leper king of Jerusalem (1161-1185), probably contributed to an increasing interest and tolerance to this disease in medieval Christian states. We review historical descriptions of the neurological manifestations he developed. William of Tyre gives us a description of first symptoms experienced by the prince when aged nine. He notices that half of his right arm and hand were partially numb. No skin or nervous lesions are described. By his early twenties, muscle weakness makes him unable to walk. He gets blinded, probably due to keratopathy related to facial nerves involvement. Repeated attacks of fever lead to progressive worsening of his disease. He finally dies in Jerusalem, aged twenty-five, probably due to a septicaemia from infected sores. The earliest sign of Baldwin's disease is anaesthesia. Though skin lesions are not described, it is likely that at this point he had a tuberculoid form of leprosy. As his disease finally takes a lepromatous form, we suspect that it began as a borderline, immunologically unstable form. Leper king Baldwin biography gives us interesting descriptions of neurological clinical features of leprosy. Besides, it helps us to discover twelfth century medicine knowledge about this disease.

Neural stimulation for Parkinson's disease: current therapies and future directions.

PubMed

Neimat, Joseph S; Hamani, Clement; Lozano, Andres M

2006-01-01

Neural stimulation has rapidly become an integral tool in the treatment of Parkinson's disease and other movement disorders. Today it serves as an important adjunct to medical therapy that continues to gain applicability to patients in whom the disease has progressed significantly. Studies have demonstrated efficacy in several deep-brain targets, with prolonged benefit exceeding 5-year follow-up times. Continuing study is teaching us more about the mechanism of deep-brain stimulation effect. New targets, which may treat the disease more successfully, are being examined. In this review, the history of deep-brain stimulation, the rationale for the known targets of stimulation; the clinical evidence demonstrating their benefit and, finally, future perspectives on new treatments that are being investigated and may have an impact on the field are discussed.

Epoetin beta pegol alleviates oxidative stress and exacerbation of renal damage from iron deposition, thereby delaying CKD progression in progressive glomerulonephritis rats.

PubMed

Hirata, Michinori; Tashiro, Yoshihito; Aizawa, Ken; Kawasaki, Ryohei; Shimonaka, Yasushi; Endo, Koichi

2015-12-01

The increased deposition of iron in the kidneys that occurs with glomerulopathy hinders the functional and structural recovery of the tubules and promotes progression of chronic kidney disease (CKD). Here, we evaluated whether epoetin beta pegol (continuous erythropoietin receptor activator: CERA), which has a long half-life in blood and strongly suppresses hepcidin-25, exerts renoprotection in a rat model of chronic progressive glomerulonephritis (cGN). cGN rats showed elevated urinary total protein excretion (uTP) and plasma urea nitrogen (UN) from day 14 after the induction of kidney disease (day 0) and finally declined into end-stage kidney disease (ESKD), showing reduced creatinine clearance with glomerulosclerosis, tubular dilation, and tubulointerstitial fibrosis. A single dose of CERA given on day 1, but not on day 16, alleviated increasing uTP and UN, thereby delaying ESKD. In the initial disease phase, CERA significantly suppressed urinary 8-OHdG and liver-type fatty acid-binding protein (L-FABP), a tubular damage marker. CERA also inhibited elevated plasma hepcidin-25 levels and alleviated subsequent iron accumulation in kidneys in association with elevated urinary iron excretion and resulted in alleviation of growth of Ki67-positive tubular and glomerular cells. In addition, at day 28 when the exacerbation of uTP occurs, a significant correlation was observed between iron deposition in the kidney and urinary L-FABP. In our study, CERA mitigated increasing kidney damage, thereby delaying CKD progression in this glomerulonephritis rat model. Alleviation by CERA of the exacerbation of kidney damage could be attributable to mitigation of tubular damage that might occur with lowered iron deposition in tubules. © 2015 Chugai Pharmaceutical Co., Ltd. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Health-related quality-of-life parameters as independent prognostic factors in advanced or metastatic bladder cancer.

PubMed

Roychowdhury, D F; Hayden, A; Liepa, A M

2003-02-15

This retrospective analysis examined prognostic significance of health-related quality-of-life (HRQoL) parameters combined with baseline clinical factors on outcomes (overall survival, time to progressive disease, and time to treatment failure) in bladder cancer. Outcome and HRQoL (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30) data were collected prospectively in a phase III study assessing gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in locally advanced or metastatic bladder cancer. Prespecified baseline clinical factors (performance status, tumor-node-metastasis staging, visceral metastases [VM], alkaline phosphatase [AP] level, number of metastatic sites, prior radiotherapy, disease measurability, sex, time from diagnosis, and sites of disease) and selected HRQoL parameters (global QoL; all functional scales; symptoms: pain, fatigue, insomnia, dyspnea, anorexia) were evaluated using Cox's proportional hazards model. Factors with individual prognostic value (P <.05) on outcomes in univariate models were assessed for joint prognostic value in a multivariate model. A final model was developed using a backward selection strategy. Patients with baseline HRQoL were included (364 of 405, 90%). The final model predicted longer survival with low/normal AP levels, no VM, high physical functioning, low role functioning, and no anorexia. Positive prognostic factors for time to progressive disease were good performance status, low/normal AP levels, no VM, and minimal fatigue; for time to treatment failure, they were low/normal AP levels, minimal fatigue, and no anorexia. Global QoL was a significant predictor of outcome in univariate analyses but was not retained in the multivariate model. HRQoL parameters are independent prognostic factors for outcome in advanced bladder cancer; their prognostic importance needs further evaluation.

Predicting analysis time in events-driven clinical trials using accumulating time-to-event surrogate information.

PubMed

Wang, Jianming; Ke, Chunlei; Yu, Zhinuan; Fu, Lei; Dornseif, Bruce

2016-05-01

For clinical trials with time-to-event endpoints, predicting the accrual of the events of interest with precision is critical in determining the timing of interim and final analyses. For example, overall survival (OS) is often chosen as the primary efficacy endpoint in oncology studies, with planned interim and final analyses at a pre-specified number of deaths. Often, correlated surrogate information, such as time-to-progression (TTP) and progression-free survival, are also collected as secondary efficacy endpoints. It would be appealing to borrow strength from the surrogate information to improve the precision of the analysis time prediction. Currently available methods in the literature for predicting analysis timings do not consider utilizing the surrogate information. In this article, using OS and TTP as an example, a general parametric model for OS and TTP is proposed, with the assumption that disease progression could change the course of the overall survival. Progression-free survival, related both to OS and TTP, will be handled separately, as it can be derived from OS and TTP. The authors seek to develop a prediction procedure using a Bayesian method and provide detailed implementation strategies under certain assumptions. Simulations are performed to evaluate the performance of the proposed method. An application to a real study is also provided. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Subacute sclerosing panencephalitis presenting as neuromyelitis optica.

PubMed

Raut, Tushar Premraj; Singh, Maneesh Kumar; Garg, Ravindra Kumar; Naphade, Pravin Umakant

2012-12-14

Subacute sclerosing panencephalitis (SSPE) is a slowly progressing inflammatory and degenerative disorder of the brain caused by a mutant measles virus. The diagnosis of SSPE is based on characteristic clinical and EEG findings (periodic complexes) and demonstration of elevated antibody titres against measles in cerebrospinal fluid. SSPE can have atypical clinical features at the onset. The authors here report a case of a 3-year-old child who presented with vision loss followed 15 months later by quadriparesis with bladder involvement. These clinical features resembled that of neuromyelitis optica. However, as the disease progressed, appearance of myoclonic jerks, periodic discharges on EEG and positive cerebrospinal fluid serology for measles led to the final diagnosis of SSPE.

Subacute sclerosing panencephalitis presenting as neuromyelitis optica

PubMed Central

Raut, Tushar Premraj; Singh, Maneesh Kumar; Garg, Ravindra Kumar; Naphade, Pravin Umakant

2012-01-01

Subacute sclerosing panencephalitis (SSPE) is a slowly progressing inflammatory and degenerative disorder of the brain caused by a mutant measles virus. The diagnosis of SSPE is based on characteristic clinical and EEG findings (periodic complexes) and demonstration of elevated antibody titres against measles in cerebrospinal fluid. SSPE can have atypical clinical features at the onset. The authors here report a case of a 3-year-old child who presented with vision loss followed 15 months later by quadriparesis with bladder involvement. These clinical features resembled that of neuromyelitis optica. However, as the disease progressed, appearance of myoclonic jerks, periodic discharges on EEG and positive cerebrospinal fluid serology for measles led to the final diagnosis of SSPE. PMID:23242079

Molecular chaperones in Parkinson's disease--present and future.

PubMed

Ebrahimi-Fakhari, Darius; Wahlster, Lara; McLean, Pamela J

2011-01-01

Parkinson's disease, like many other neurodegenerative disorders, is characterized by the progressive accumulation of pathogenic protein species and the formation of intracellular inclusion bodies. The cascade by which the small synaptic protein α-synuclein misfolds to form distinctive protein aggregates, termed Lewy bodies and Lewy neurites, has been the subject of intensive research for more than a decade. Genetic and pathological studies in Parkinson's disease patients as well as experimental studies in disease models have clearly established altered protein metabolism as a key element in the pathogenesis of Parkinson's disease. Alterations in protein metabolism include misfolding and aggregation, post-translational modification and dysfunctional degradation of cytotoxic protein species. Protein folding and re-folding are both mediated by a highly conserved network of molecules, called molecular chaperones and co-chaperones. In addition to the regulatory role in protein folding, molecular chaperone function is intimately associated with pathways of protein degradation, such as the ubiquitin-proteasome system and the autophagy-lysosomal pathway, to effectively remove irreversibly misfolded proteins. Because of the central role of molecular chaperones in maintaining protein homeostasis, we herein review our current knowledge on the involvement of molecular chaperones and co-chaperones in Parkinson's disease. We further discuss the capacity of molecular chaperones to prevent or modulate neurodegeneration, an important concept for future neuroprotective strategies and summarize the current progress in preclinical studies in models of Parkinson's disease and other neurodegenerative disorders. Finally we include a discussion on the future potential of using molecular chaperones as a disease modifying therapy.

Diabetic kidney disease.

PubMed

Thomas, Merlin C; Brownlee, Michael; Susztak, Katalin; Sharma, Kumar; Jandeleit-Dahm, Karin A M; Zoungas, Sophia; Rossing, Peter; Groop, Per-Henrik; Cooper, Mark E

2015-07-30

The kidney is arguably the most important target of microvascular damage in diabetes. A substantial proportion of individuals with diabetes will develop kidney disease owing to their disease and/or other co-morbidity, including hypertension and ageing-related nephron loss. The presence and severity of chronic kidney disease (CKD) identify individuals who are at increased risk of adverse health outcomes and premature mortality. Consequently, preventing and managing CKD in patients with diabetes is now a key aim of their overall management. Intensive management of patients with diabetes includes controlling blood glucose levels and blood pressure as well as blockade of the renin-angiotensin-aldosterone system; these approaches will reduce the incidence of diabetic kidney disease and slow its progression. Indeed, the major decline in the incidence of diabetic kidney disease (DKD) over the past 30 years and improved patient prognosis are largely attributable to improved diabetes care. However, there remains an unmet need for innovative treatment strategies to prevent, arrest, treat and reverse DKD. In this Primer, we summarize what is now known about the molecular pathogenesis of CKD in patients with diabetes and the key pathways and targets implicated in its progression. In addition, we discuss the current evidence for the prevention and management of DKD as well as the many controversies. Finally, we explore the opportunities to develop new interventions through urgently needed investment in dedicated and focused research. For an illustrated summary of this Primer, visit: http://go.nature.com/NKHDzg.

Integrated metagenomic data analysis demonstrates that a loss of diversity in oral microbiota is associated with periodontitis.

PubMed

Ai, Dongmei; Huang, Ruocheng; Wen, Jin; Li, Chao; Zhu, Jiangping; Xia, Li Charlie

2017-01-25

Periodontitis is an inflammatory disease affecting the tissues supporting teeth (periodontium). Integrative analysis of metagenomic samples from multiple periodontitis studies is a powerful way to examine microbiota diversity and interactions within host oral cavity. A total of 43 subjects were recruited to participate in two previous studies profiling the microbial community of human subgingival plaque samples using shotgun metagenomic sequencing. We integrated metagenomic sequence data from those two studies, including six healthy controls, 14 sites representative of stable periodontitis, 16 sites representative of progressing periodontitis, and seven periodontal sites of unknown status. We applied phylogenetic diversity, differential abundance, and network analyses, as well as clustering, to the integrated dataset to compare microbiological community profiles among the different disease states. We found alpha-diversity, i.e., mean species diversity in sites or habitats at a local scale, to be the single strongest predictor of subjects' periodontitis status (P < 0.011). More specifically, healthy subjects had the highest alpha-diversity, while subjects with stable sites had the lowest alpha-diversity. From these results, we developed an alpha-diversity logistic model-based naive classifier able to perfectly predict the disease status of the seven subjects with unknown periodontal status (not used in training). Phylogenetic profiling resulted in the discovery of nine marker microbes, and these species are able to differentiate between stable and progressing periodontitis, achieving an accuracy of 94.4%. Finally, we found that the reduction of negatively correlated species is a notable signature of disease progression. Our results consistently show a strong association between the loss of oral microbiota diversity and the progression of periodontitis, suggesting that metagenomics sequencing and phylogenetic profiling are predictive of early periodontitis, leading to potential therapeutic intervention. Our results also support a keystone pathogen-mediated polymicrobial synergy and dysbiosis (PSD) model to explain the etiology of periodontitis. Apart from P. gingivalis, we identified three additional keystone species potentially mediating the progression of periodontitis progression based on pathogenic characteristics similar to those of known keystone pathogens.

Hair diseases: a big problem on a small surface

PubMed Central

Wcisło-Dziadecka, Dominika

2016-01-01

Civilizational progress initially contributes to the problem of hair loss and then to alopecia as regards both frequency and therapeutic dilemmas. The work presents trichological problems which occur more rarely, i.e. drug-induced, anagen and telogen alopecia, congenital and acquired structural hair disorders, psychic disturbances concerning the hair as well as the hair during menopause. Then, the article briefly describes contagious (infectious) diseases as well as diseases with inflammatory etiology which are accompanied by exfoliation and (frequently) pruritus. Finally, alopecia cicatricans is discussed. Alopecia areata and androgenetic alopecia are omitted herein because they occur more often and will be described in another work. Any disproportions and upset balance concerning correct functioning of mechanisms within the scalp hair system are the evidence of pathologies. PMID:27881935

Hair diseases: a big problem on a small surface.

PubMed

Brzezińska-Wcisło, Ligia A; Wcisło-Dziadecka, Dominika

2016-10-01

Civilizational progress initially contributes to the problem of hair loss and then to alopecia as regards both frequency and therapeutic dilemmas. The work presents trichological problems which occur more rarely, i.e. drug-induced, anagen and telogen alopecia, congenital and acquired structural hair disorders, psychic disturbances concerning the hair as well as the hair during menopause. Then, the article briefly describes contagious (infectious) diseases as well as diseases with inflammatory etiology which are accompanied by exfoliation and (frequently) pruritus. Finally, alopecia cicatricans is discussed. Alopecia areata and androgenetic alopecia are omitted herein because they occur more often and will be described in another work. Any disproportions and upset balance concerning correct functioning of mechanisms within the scalp hair system are the evidence of pathologies.

Mechanisms of fibrosis: therapeutic translation for fibrotic disease

PubMed Central

Wynn, Thomas A; Ramalingam, Thirumalai R

2012-01-01

Fibrosis is a pathological feature of most chronic inflammatory diseases. Fibrosis, or scarring, is defined by the accumulation of excess extracellular matrix components. If highly progressive, the fibrotic process eventually leads to organ malfunction and death. Fibrosis affects nearly every tissue in the body. Here we discuss how key components of the innate and adaptive immune response contribute to the pathogenesis of fibrosis. We also describe how cell-intrinsic changes in important structural cells can perpetuate the fibrotic response by regulating the differentiation, recruitment, proliferation and activation of extracellular matrix–producing myofibroblasts. Finally, we highlight some of the key mechanisms and pathways of fibrosis that are being targeted as potential therapies for a variety of important human diseases. PMID:22772564

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

PubMed Central

Van Kampen, Jackalina M.; Baranowski, David C.; Robertson, Harold A.; Shaw, Christopher A.; Kay, Denis G.

2015-01-01

The development of effective neuroprotective therapies for Parkinson's disease (PD) has been severely hindered by the notable lack of an appropriate animal model for preclinical screening. Indeed, most models currently available are either acute in nature or fail to recapitulate all characteristic features of the disease. Here, we present a novel progressive model of PD, with behavioural and cellular features that closely approximate those observed in patients. Chronic exposure to dietary phytosterol glucosides has been found to be neurotoxic. When fed to rats, β-sitosterol β-d-glucoside (BSSG) triggers the progressive development of parkinsonism, with clinical signs and histopathology beginning to appear following cessation of exposure to the neurotoxic insult and continuing to develop over several months. Here, we characterize the progressive nature of this model, its non-motor features, the anatomical spread of synucleinopathy, and response to levodopa administration. In Sprague Dawley rats, chronic BSSG feeding for 4 months triggered the progressive development of a parkinsonian phenotype and pathological events that evolved slowly over time, with neuronal loss beginning only after toxin exposure was terminated. At approximately 3 months following initiation of BSSG exposure, animals displayed the early emergence of an olfactory deficit, in the absence of significant dopaminergic nigral cell loss or locomotor deficits. Locomotor deficits developed gradually over time, initially appearing as locomotor asymmetry and developing into akinesia/bradykinesia, which was reversed by levodopa treatment. Late-stage cognitive impairment was observed in the form of spatial working memory deficits, as assessed by the radial arm maze. In addition to the progressive loss of TH+ cells in the substantia nigra, the appearance of proteinase K-resistant intracellular α-synuclein aggregates was also observed to develop progressively, appearing first in the olfactory bulb, then the striatum, the substantia nigra and, finally, hippocampal and cortical regions. The slowly progressive nature of this model, together with its construct, face and predictive validity, make it ideal for the screening of potential neuroprotective therapies for the treatment of PD. PMID:26439489

Clinical, cognitive and anatomical evolution from nonfluent progressive aphasia to corticobasal syndrome: a case report.

PubMed

Gorno-Tempini, Maria Luisa; Murray, Ryan C; Rankin, Katherine P; Weiner, Michael W; Miller, Bruce L

2004-12-01

Recent clinical and pathological studies have suggested that frontotemporal lobar degeneration (FTLD) and corticobasal syndrome (CBS) show clinical and pathological overlap. We present four years of longitudinal clinical, cognitive and anatomical data in the case of a 56-year-old woman, AS, whose clinical picture evolved from FTLD to CBS. For the first three years, AS showed a progressive speech and language disorder compatible with a diagnosis of the nonfluent aphasia variant of FTLD. At year four, 10 years after her first symptom, AS developed the classical clinical signs of CBS, including alien limb phenomenon and dystonia. Voxel-based morphometry (VBM) applied to AS's four annual scans showed progression of atrophy from the inferior posterior frontal gyrus, to the left insula and finally to the medial frontal lobe. This case demonstrates the clinical overlap between FTLD and CBS and shows that the two can appear in the same patient at different stages of the disease in relation to the progression of anatomical damage.

Emergence of MET hyper-amplification at progression to MET and BRAF inhibition in colorectal cancer.

PubMed

Oddo, Daniele; Siravegna, Giulia; Gloghini, Annunziata; Vernieri, Claudio; Mussolin, Benedetta; Morano, Federica; Crisafulli, Giovanni; Berenato, Rosa; Corti, Giorgio; Volpi, Chiara Costanza; Buscarino, Michela; Niger, Monica; Dunne, Philip D; Rospo, Giuseppe; Valtorta, Emanuele; Bartolini, Alice; Fucà, Giovanni; Lamba, Simona; Martinetti, Antonia; Di Bartolomeo, Maria; de Braud, Filippo; Bardelli, Alberto; Pietrantonio, Filippo; Di Nicolantonio, Federica

2017-07-25

Combined MET and BRAF inhibition showed clinical benefit in a patient with rectal cancer carrying BRAF V600E and MET amplification. However after 4 months, acquired resistance emerged and the patient deceased shortly after disease progression. The mechanism of resistance to this drug combination is unknown. We analysed plasma circulating tumour DNA obtained at progression by exome sequencing and digital PCR. MET gene and mRNA in situ hybridisation analyses in two bioptic specimens obtained at progression were used to confirm the plasma data. We identified in plasma MET gene hyper-amplification as a potential mechanism underlying therapy resistance. Increased MET gene copy and transcript levels were detected in liver and lymph node metastatic biopsies. Finally, transduction of MET in BRAF mutant colorectal cancer cells conferred refractoriness to BRAF and MET inhibition. We identified in a rectal cancer patient MET gene hyper-amplification as mechanism of resistance to dual BRAF and MET inhibition.

Microvascular disease precedes the decline in renal function in the streptozotocin-induced diabetic rat

PubMed Central

Maric-Bilkan, Christine; Flynn, Elizabeth R.

2012-01-01

Diabetic nephropathy is a progressive and generalized vasculopathic condition associated with abnormal angiogenesis. We aim to determine whether changes in renal microvascular (MV) density correlate with and play a role in the progressive deterioration of renal function in diabetes. We hypothesize that MV changes represent the early steps of renal injury that worsen as diabetes progresses, initiating a vicious circle that leads to irreversible renal injury. Male nondiabetic (ND) or streptozotocin-induced diabetic (D) Sprague-Dawley rats were followed for 4 or 12 wk. Renal blood flow and glomerular filtration rate (GFR) were measured by PAH and 125I-[iothalamate], respectively. Renal MV density was quantified ex vivo using three-dimensional micro computed tomography and JG-12 immunoreactivity. Vascular endothelial growth factor (VEGF) levels (ELISA) and expression of VEGF receptors and factors involved in MV remodeling were quantified in renal tissue by Western blotting. Finally, renal morphology was investigated by histology. Four weeks of diabetes was associated with increased GFR, accompanied by a 34% reduction in renal MV density and augmented renal VEGF levels. However, at 12 wk, while GFR remained similarly elevated, reduction of MV density was more pronounced (75%) and associated with increased MV remodeling, renal fibrosis, but unchanged renal VEGF compared with ND at 12 wk. The damage, loss, and subsequent remodeling of the renal MV architecture in the diabetic kidney may represent the initiating events of progressive renal injury. This study suggests a novel concept of MV disease as an early instigator of diabetic kidney disease that may precede and likely promote the decline in renal function. PMID:22031855

The Complex Interplay between Chronic Inflammation, the Microbiome, and Cancer: Understanding Disease Progression and What We Can Do to Prevent It

PubMed Central

Bording-Jorgensen, Michael; Dijk, Stephanie

2018-01-01

Cancer is a multifaceted condition, in which a senescent cell begins dividing in an irregular manner due to various factors such as DNA damage, growth factors and inflammation. Inflammation is not typically discussed as carcinogenic; however, a significant percentage of cancers arise from chronic microbial infections and damage brought on by chronic inflammation. A hallmark cancer-inducing microbe is Helicobacter pylori and its causation of peptic ulcers and potentially gastric cancer. This review discusses the recent developments in understanding microbes in health and disease and their potential role in the progression of cancer. To date, microbes can be linked to almost every cancer, including colon, pancreatic, gastric, and even prostate. We discuss the known mechanisms by which these microbes can induce cancer growth and development and how inflammatory cells may contribute to cancer progression. We also discuss new treatments that target the chronic inflammatory conditions and their associated cancers, and the impact microbes have on treatment success. Finally, we examine common dietary misconceptions in relation to microbes and cancer and how to avoid getting caught up in the misinterpretation and over inflation of the results. PMID:29558443

Crohn's Disease Candidate Gene Alleles Predict Time to Progression from Inflammatory B1 to Stricturing B2, or Penetrating B3 Phenotype.

PubMed

Pernat Drobež, Cvetka; Ferkolj, Ivan; Potočnik, Uroš; Repnik, Katja

2018-03-01

Crohn's disease (CD) patients are mostly diagnosed with the uncomplicated inflammatory form of disease; however, the majority will progress to complicated stricturing or penetrating disease over time. It is important to identify patients at risk for disease progression at an early stage. The aim of our study was to examine the role of 33 candidate CD genes as possible predictors of disease progression and their influence on time to progression from an inflammatory to a stricturing or penetrating phenotype. Patients with an inflammatory phenotype at diagnosis were followed for 10 years and 33 CD-associated polymorphisms were genotyped. To test for association with CD, 449 healthy individuals were analyzed as the control group. Ten years after diagnosis, 39.1% of patients had not progressed beyond an inflammatory phenotype, but 60.9% had progressed to complicated disease, with average time to progression being 5.91 years. Association analyses of selected single nucleotide polymorphisms (SNPs) confirmed associations with CD for 12 SNPs. Furthermore, seven loci were associated with disease progression, out of which SNP rs4263839 in the gene TNFSF15 showed the strongest association with disease progression and the frameshift mutation rs2066847 in the gene NOD2 showed the strongest association with time to progression. The results of our study identified specific genetic biomarkers as useful predictors of both disease progression and speed of disease progression in patients with CD.

Subacute sclerosing panencephalitis in a child with recurrent febrile seizures.

PubMed

Kartal, Ayşe; Çıtak Kurt, Ayşegül Neşe; Hirfanoğlu, Tuğba; Aydın, Kürşad; Serdaroğlu, Ayşe

2015-01-01

Subacute sclerosing panencephalitis (SSPE) is a devastating disease of the central nervous system (CNS) caused by persistent mutant measles virus infection. The diagnosis of SSPE is based on characteristic clinical and EEG findings and demonstration of elevated antibody titres against measles in cerebrospinal fluid. Subacute sclerosing panencephalitis can have atypical clinical features at the onset. Herein, we report an unusual case of subacute sclerosing panencephalitis in a child with recurrent febrile seizures. The disease progressed with an appearance of myoclonic jerks, periodic high amplitude generalized complexes on EEG, and elevated titers of measles antibodies in cerebrospinal fluid leading to the final diagnosis of subacute sclerosing panencephalitis.

Subacute Sclerosing Panencephalitis in a Child with Recurrent Febrile Seizures

PubMed Central

Kartal, Ayşe; Çıtak Kurt, Ayşegül Neşe; Hirfanoğlu, Tuğba; Aydın, Kürşad; Serdaroğlu, Ayşe

2015-01-01

Subacute sclerosing panencephalitis (SSPE) is a devastating disease of the central nervous system (CNS) caused by persistent mutant measles virus infection. The diagnosis of SSPE is based on characteristic clinical and EEG findings and demonstration of elevated antibody titres against measles in cerebrospinal fluid. Subacute sclerosing panencephalitis can have atypical clinical features at the onset. Herein, we report an unusual case of subacute sclerosing panencephalitis in a child with recurrent febrile seizures. The disease progressed with an appearance of myoclonic jerks, periodic high amplitude generalized complexes on EEG, and elevated titers of measles antibodies in cerebrospinal fluid leading to the final diagnosis of subacute sclerosing panencephalitis. PMID:25802788

Grant Closeout Requirements and Reports

Cancer.gov

Requirements and reports to comply with grant closeout, including Final Federal Financial Report (FFR, SF425); Final Research Performance Progress Report (FRPPR); Interim Research Performance Progress Report (IRPPR); Final Invention Statement (FIS, HHS

Physical break-down of the classical view on cancer cell invasion and metastasis.

PubMed

Mierke, Claudia T

2013-03-01

Eight classical hallmarks of cancer have been proposed and are well-defined by using biochemical or molecular genetic methods, but are not yet precisely defined by cellular biophysical processes. To define the malignant transformation of neoplasms and finally reveal the functional pathway, which enables cancer cells to promote cancer progression, these classical hallmarks of cancer require the inclusion of specific biomechanical properties of cancer cells and their microenvironment such as the extracellular matrix and embedded cells such as fibroblasts, macrophages or endothelial cells. Nonetheless a main novel ninth hallmark of cancer is still elusive in classical tumor biological reviews, which is the aspect of physics in cancer disease by the natural selection of an aggressive (highly invasive) subtype of cancer cells. The physical aspects can be analyzed by using state-of-the-art biophysical methods. Thus, this review will present current cancer research in a different light and will focus on novel physical methods to investigate the aggressiveness of cancer cells from a biophysicist's point of view. This may lead to novel insights into cancer disease and will overcome classical views on cancer. In addition, this review will discuss how physics of cancer can help to reveal whether cancer cells will invade connective tissue and metastasize. In particular, this review will point out how physics can improve, break-down or support classical approaches to examine tumor growth even across primary tumor boundaries, the invasion of single or collective cancer cells, transendothelial migration of cancer cells and metastasis in targeted organs. Finally, this review will show how physical measurements can be integrated into classical tumor biological analysis approaches. The insights into physical interactions between cancer cells, the primary tumor and the microenvironment may help to solve some "old" questions in cancer disease progression and may finally lead to novel approaches for development and improvement of cancer diagnostics and therapies. Copyright © 2013 Elsevier GmbH. All rights reserved.

Long-term consequences of developmental vascular defects on retinal vessel homeostasis and function in a mouse model of Norrie disease.

PubMed

Beck, Susanne C; Feng, Yuxi; Sothilingam, Vithiyanjali; Garcia Garrido, Marina; Tanimoto, Naoyuki; Acar, Niyazi; Shan, Shenliang; Seebauer, Britta; Berger, Wolfgang; Hammes, Hans-Peter; Seeliger, Mathias W

2017-01-01

Loss of Norrin signalling due to mutations in the Norrie disease pseudoglioma gene causes severe vascular defects in the retina, leading to visual impairment and ultimately blindness. While the emphasis of experimental work so far was on the developmental period, we focus here on disease mechanisms that induce progression into severe adult disease. The goal of this study was the comprehensive analysis of the long-term effects of the absence of Norrin on vascular homeostasis and retinal function. In a mouse model of Norrie disease retinal vascular morphology and integrity were studied by means of in vivo angiography; the vascular constituents were assessed in detailed histological analyses using quantitative retinal morphometry. Finally, electroretinographic analyses were performed to assess the retinal function in adult Norrin deficient animals. We could show that the primary developmental defects not only persisted but developed into further vascular abnormalities and microangiopathies. In particular, the overall vessel homeostasis, the vascular integrity, and also the cellular constituents of the vascular wall were affected in the adult Norrin deficient retina. Moreover, functional analyses indicated to persistent hypoxia in the neural retina which was suggested as one of the major driving forces of disease progression. In summary, our data provide evidence that the key to adult Norrie disease are ongoing vascular modifications, driven by the persistent hypoxic conditions, which are ineffective to compensate for the primary Norrin-dependent defects.

Review article: moving towards common therapeutic goals in Crohn's disease and rheumatoid arthritis.

PubMed

Allen, P B; Olivera, P; Emery, P; Moulin, D; Jouzeau, J-Y; Netter, P; Danese, S; Feagan, B; Sandborn, W J; Peyrin-Biroulet, L

2017-04-01

Crohn's disease (CD) and rheumatoid arthritis are chronic, progressive and disabling conditions that frequently lead to structural tissue damage. Based on strategies originally developed for rheumatoid arthritis, the treatment goal for CD has recently moved from exclusively controlling symptoms to both clinical remission and complete mucosal healing (deep remission), with the final aim of preventing bowel damage and disability. To review the similarities and differences in treatment goals between CD and rheumatoid arthritis. This review examined manuscripts from 1982 to 2016 that discussed and/or proposed therapeutic goals with their supportive evidence in CD and rheumatoid arthritis. Proposed therapeutic strategies to improve outcomes in both rheumatoid arthritis and CD include: (i) evaluation of musculoskeletal or organ damage and disability, (ii) tight control, (iii) treat-to-target, (iv) early intervention and (v) disease modification. In contrast to rheumatoid arthritis, there is a paucity of disease-modification trials in CD. Novel therapeutic strategies in CD based on tight control of objective signs of inflammation are expected to change disease course and patients' lives by halting progression or, ideally, preventing the occurrence of bowel damage. Most of these strategies require validation in prospective studies, whereas several disease-modification trials have addressed these issues in rheumatoid arthritis over the last decade. The recent approval of new drugs in CD such as vedolizumab and ustekinumab should facilitate initiation of disease-modification trials in CD in the near future. © 2017 John Wiley & Sons Ltd.

Long-term consequences of developmental vascular defects on retinal vessel homeostasis and function in a mouse model of Norrie disease

PubMed Central

Sothilingam, Vithiyanjali; Garcia Garrido, Marina; Tanimoto, Naoyuki; Acar, Niyazi; Shan, Shenliang; Seebauer, Britta; Berger, Wolfgang; Hammes, Hans-Peter; Seeliger, Mathias W.

2017-01-01

Loss of Norrin signalling due to mutations in the Norrie disease pseudoglioma gene causes severe vascular defects in the retina, leading to visual impairment and ultimately blindness. While the emphasis of experimental work so far was on the developmental period, we focus here on disease mechanisms that induce progression into severe adult disease. The goal of this study was the comprehensive analysis of the long-term effects of the absence of Norrin on vascular homeostasis and retinal function. In a mouse model of Norrie disease retinal vascular morphology and integrity were studied by means of in vivo angiography; the vascular constituents were assessed in detailed histological analyses using quantitative retinal morphometry. Finally, electroretinographic analyses were performed to assess the retinal function in adult Norrin deficient animals. We could show that the primary developmental defects not only persisted but developed into further vascular abnormalities and microangiopathies. In particular, the overall vessel homeostasis, the vascular integrity, and also the cellular constituents of the vascular wall were affected in the adult Norrin deficient retina. Moreover, functional analyses indicated to persistent hypoxia in the neural retina which was suggested as one of the major driving forces of disease progression. In summary, our data provide evidence that the key to adult Norrie disease are ongoing vascular modifications, driven by the persistent hypoxic conditions, which are ineffective to compensate for the primary Norrin-dependent defects. PMID:28575130

Longitudinal patterns of leukoaraiosis and brain atrophy in symptomatic small vessel disease

PubMed Central

Benjamin, Philip; Zeestraten, Eva; Lawrence, Andrew J.; Barrick, Thomas R.; Markus, Hugh S.

2016-01-01

Abstract Cerebral small vessel disease is a common condition associated with lacunar stroke, cognitive impairment and significant functional morbidity. White matter hyperintensities and brain atrophy, seen on magnetic resonance imaging, are correlated with increasing disease severity. However, how the two are related remains an open question. To better define the relationship between white matter hyperintensity growth and brain atrophy, we applied a semi-automated magnetic resonance imaging segmentation analysis pipeline to a 3-year longitudinal cohort of 99 subjects with symptomatic small vessel disease, who were followed-up for ≥1 years. Using a novel two-stage warping pipeline with tissue repair step, voxel-by-voxel rate of change maps were calculated for each tissue class (grey matter, white matter, white matter hyperintensities and lacunes) for each individual. These maps capture both the distribution of disease and spatial information showing local rates of growth and atrophy. These were analysed to answer three primary questions: first, is there a relationship between whole brain atrophy and magnetic resonance imaging markers of small vessel disease (white matter hyperintensities or lacune volume)? Second, is there regional variation within the cerebral white matter in the rate of white matter hyperintensity progression? Finally, are there regionally specific relationships between the rates of white matter hyperintensity progression and cortical grey matter atrophy? We demonstrate that the rates of white matter hyperintensity expansion and grey matter atrophy are strongly correlated (Pearson’s R = −0.69, P < 1 × 10 −7 ), and significant grey matter loss and whole brain atrophy occurs annually ( P < 0.05). Additionally, the rate of white matter hyperintensity growth was heterogeneous, occurring more rapidly within long association fasciculi. Using voxel-based quantification (family-wise error corrected P < 0.05), we show the rate of white matter hyperintensity progression is associated with increases in cortical grey matter atrophy rates, in the medial-frontal, orbito-frontal, parietal and occipital regions. Conversely, increased rates of global grey matter atrophy are significantly associated with faster white matter hyperintensity growth in the frontal and parietal regions. Together, these results link the progression of white matter hyperintensities with increasing rates of regional grey matter atrophy, and demonstrate that grey matter atrophy is the major contributor to whole brain atrophy in symptomatic cerebral small vessel disease. These measures provide novel insights into the longitudinal pathogenesis of small vessel disease, and imply that therapies aimed at reducing progression of white matter hyperintensities via end-arteriole damage may protect against secondary brain atrophy and consequent functional morbidity. PMID:26936939

Longitudinal patterns of leukoaraiosis and brain atrophy in symptomatic small vessel disease.

PubMed

Lambert, Christian; Benjamin, Philip; Zeestraten, Eva; Lawrence, Andrew J; Barrick, Thomas R; Markus, Hugh S

2016-04-01

Cerebral small vessel disease is a common condition associated with lacunar stroke, cognitive impairment and significant functional morbidity. White matter hyperintensities and brain atrophy, seen on magnetic resonance imaging, are correlated with increasing disease severity. However, how the two are related remains an open question. To better define the relationship between white matter hyperintensity growth and brain atrophy, we applied a semi-automated magnetic resonance imaging segmentation analysis pipeline to a 3-year longitudinal cohort of 99 subjects with symptomatic small vessel disease, who were followed-up for ≥1 years. Using a novel two-stage warping pipeline with tissue repair step, voxel-by-voxel rate of change maps were calculated for each tissue class (grey matter, white matter, white matter hyperintensities and lacunes) for each individual. These maps capture both the distribution of disease and spatial information showing local rates of growth and atrophy. These were analysed to answer three primary questions: first, is there a relationship between whole brain atrophy and magnetic resonance imaging markers of small vessel disease (white matter hyperintensities or lacune volume)? Second, is there regional variation within the cerebral white matter in the rate of white matter hyperintensity progression? Finally, are there regionally specific relationships between the rates of white matter hyperintensity progression and cortical grey matter atrophy? We demonstrate that the rates of white matter hyperintensity expansion and grey matter atrophy are strongly correlated (Pearson's R = -0.69, P < 1 × 10(-7)), and significant grey matter loss and whole brain atrophy occurs annually (P < 0.05). Additionally, the rate of white matter hyperintensity growth was heterogeneous, occurring more rapidly within long association fasciculi. Using voxel-based quantification (family-wise error corrected P < 0.05), we show the rate of white matter hyperintensity progression is associated with increases in cortical grey matter atrophy rates, in the medial-frontal, orbito-frontal, parietal and occipital regions. Conversely, increased rates of global grey matter atrophy are significantly associated with faster white matter hyperintensity growth in the frontal and parietal regions. Together, these results link the progression of white matter hyperintensities with increasing rates of regional grey matter atrophy, and demonstrate that grey matter atrophy is the major contributor to whole brain atrophy in symptomatic cerebral small vessel disease. These measures provide novel insights into the longitudinal pathogenesis of small vessel disease, and imply that therapies aimed at reducing progression of white matter hyperintensities via end-arteriole damage may protect against secondary brain atrophy and consequent functional morbidity. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.

Mesenchymal cell differentiation and diseases: involvement of translin/TRAX complexes and associated proteins.

PubMed

Kasai, Masataka; Ishida, Reiko; Nakahara, Kazuhiko; Okumura, Ko; Aoki, Katsunori

2018-05-08

Translin and translin-associated factor X (translin/TRAX) proteins have been implicated in a variety of cellular activities central to nucleic acid metabolism. Accumulating evidence indicates that translin/TRAX complexes participate in processes ensuring the replication of DNA, as well as cell division. Significant progress has been made in understanding the roles of translin/TRAX complexes in RNA metabolism, such as through RNA-induced silencing complex activation or the microRNA depletion that occurs in Dicer deficiency. At the cellular level, translin-deficient (Tsn -/- ) mice display delayed endochondral ossification or progressive bone marrow failure with ectopic osteogenesis and adipogenesis, suggesting involvement in mesenchymal cell differentiation. In this review, we summarize the molecular and cellular functions of translin homo-octamer and translin/TRAX hetero-octamer. Finally, we discuss the multifaceted roles of translin, TRAX, and associated proteins in the healthy and disease states. © 2018 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals, Inc. on behalf of The New York Academy of Sciences.

Cerebrospinal Fluid HIV Escape from Antiretroviral Therapy.

PubMed

Ferretti, Francesca; Gisslen, Magnus; Cinque, Paola; Price, Richard W

2015-06-01

CNS infection is a nearly constant facet of systemic CNS infection and is generally well controlled by suppressive systemic antiretroviral therapy (ART). However, there are instances when HIV can be detected in the cerebrospinal fluid (CSF) despite suppression of plasma viruses below the clinical limits of measurement. We review three types of CSF viral escape: asymptomatic, neuro-symptomatic, and secondary. The first, asymptomatic CSF escape, is seemingly benign and characterized by lack of discernable neurological deterioration or subsequent CNS disease progression. Neuro-symptomatic CSF escape is an uncommon, but important, entity characterized by new or progressive CNS disease that is critical to recognize clinically because of its management implications. Finally, secondary CSF escape, which may be even more uncommon, is defined by an increase of CSF HIV replication in association with a concomitant non-HIV infection, as a consequence of the local inflammatory response. Understanding these CSF escape settings not only is important for clinical diagnosis and management but also may provide insight into the CNS HIV reservoir.

Mass mortality of eastern box turtles with upper respiratory disease following atypical cold weather.

PubMed

Agha, Mickey; Price, Steven J; Nowakowski, A Justin; Augustine, Ben; Todd, Brian D

2017-04-20

Emerging infectious diseases cause population declines in many ectotherms, with outbreaks frequently punctuated by periods of mass mortality. It remains unclear, however, whether thermoregulation by ectotherms and variation in environmental temperature is associated with mortality risk and disease progression, especially in wild populations. Here, we examined environmental and body temperatures of free-ranging eastern box turtles Terrapene carolina during a mass die-off coincident with upper respiratory disease. We recorded deaths of 17 turtles that showed clinical signs of upper respiratory disease among 76 adult turtles encountered in Berea, Kentucky (USA), in 2014. Of the 17 mortalities, 11 occurred approximately 14 d after mean environmental temperature dropped 2.5 SD below the 3 mo mean. Partial genomic sequencing of the major capsid protein from 1 sick turtle identified a ranavirus isolate similar to frog virus 3. Turtles that lacked clinical signs of disease had significantly higher body temperatures (23°C) than sick turtles (21°C) during the mass mortality, but sick turtles that survived and recovered eventually warmed (measured by temperature loggers). Finally, there was a significant negative effect of daily environmental temperature deviation from the 3 mo mean on survival, suggesting that rapid decreases in environmental temperature were correlated with mortality. Our results point to a potential role for environmental temperature variation and body temperature in disease progression and mortality risk of eastern box turtles affected by upper respiratory disease. Given our findings, it is possible that colder or more variable environmental temperatures and an inability to effectively thermoregulate are associated with poorer disease outcomes in eastern box turtles.

Microbiota Promotes Chronic Pulmonary Inflammation by Enhancing IL-17A and Autoantibodies.

PubMed

Yadava, Koshika; Pattaroni, Céline; Sichelstiel, Anke K; Trompette, Aurélien; Gollwitzer, Eva S; Salami, Olawale; von Garnier, Christophe; Nicod, Laurent P; Marsland, Benjamin J

2016-05-01

Changes in the pulmonary microbiota are associated with progressive respiratory diseases including chronic obstructive pulmonary disease (COPD). Whether there is a causal relationship between these changes and disease progression remains unknown. To investigate the link between an altered microbiota and disease, we used a murine model of chronic lung inflammation that is characterized by key pathological features found in COPD and compared responses in specific pathogen-free (SPF) mice and mice depleted of microbiota by antibiotic treatment or devoid of a microbiota (axenic). Mice were challenged with LPS/elastase intranasally over 4 weeks, resulting in a chronically inflamed and damaged lung. The ensuing cellular infiltration, histological damage, and decline in lung function were quantified. Similar to human disease, the composition of the pulmonary microbiota was altered in diseased animals. We found that the microbiota richness and diversity were decreased in LPS/elastase-treated mice, with an increased representation of the genera Pseudomonas and Lactobacillus and a reduction in Prevotella. Moreover, the microbiota was implicated in disease development as mice depleted, or devoid, of microbiota exhibited an improvement in lung function, reduced inflammation, and lymphoid neogenesis. The absence of microbial cues markedly decreased the production of IL-17A, whereas intranasal transfer of fluid enriched with the pulmonary microbiota isolated from diseased mice enhanced IL-17A production in the lungs of antibiotic-treated or axenic recipients. Finally, in mice harboring a microbiota, neutralizing IL-17A dampened inflammation and restored lung function. Collectively, our data indicate that host-microbial cross-talk promotes inflammation and could underlie the chronicity of inflammatory lung diseases.

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

PubMed Central

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

2013-01-01

Background/purpose Light-chain deposition disease (LCDD) is a rare condition characterised by deposition of monoclonal immunoglobulin light chains (LCs) in tissues, resulting in varying degrees of organ dysfunction. This study reports the characteristic clinical ocular findings seen in advanced LCDD upon development of ocular fundus changes. This is the first report to describe this entity in vivo in a series of patients. Methods A case series of ocular fundus changes in three patients with kidney biopsy-proven LCDD. All patients underwent best corrected visual acuity (BCVA) exam, perimetry, colour fundus photography and fluorescein angiography; two patients underwent indocyanine green angiography, optical coherence tomography, ultrasound and electroretinography; and one patient underwent fundus autofluorescence. Results Three patients, 53–60 years old at initial presentation, were studied. All three presented with night blindness, poor dark adaptation, metamorphopsia and visual loss. Examination revealed serous and serohaemorrhagic detachments, multiple retinal pigment epithelial (RPE) tears, diffuse RPE degeneration and progressive fibrotic changes. Neither choroidal neovascularisation nor other vascular abnormalities were present. Final best corrected visual acuity (BCVA) ranged from 20/40 to 20/300. Conclusions Progressive LC deposition in the fundus seems to damage RPE pump function with flow disturbance between choroid and retina. This pathogenesis can explain the evolution to RPE detachments and subsequent rips and progressive retinal malfunction. PMID:23385633

Comprehensive SDG goal and targets for non-communicable diseases and mental health.

PubMed

Minas, Harry; Tsutsumi, Atsuro; Izutsu, Takashi; Goetzke, Kathryn; Thornicroft, Graham

2015-01-01

The negotiations on the SDG goals and targets, leading to the sustainable development Declaration in September 2015, are now in the final stages. Ensuring that people with mental disorders are not left behind in the global development program from 2015 to 2030 will require specific and explicit commitments and targets against which progress in mental health can be measured and reported. The arguments for inclusion of explicit mental health targets in the SDGs are compelling. The final negotiations on the SDG goals and targets will now determine whether people with mental illness and psychosocial disabilities will continue to be neglected or will benefit equitably from inclusion in the post-2015 development program.

Predicting Progression from Mild Cognitive Impairment to Alzheimer's Dementia Using Clinical, MRI, and Plasma Biomarkers via Probabilistic Pattern Classification

PubMed Central

Korolev, Igor O.; Symonds, Laura L.; Bozoki, Andrea C.

2016-01-01

Background Individuals with mild cognitive impairment (MCI) have a substantially increased risk of developing dementia due to Alzheimer's disease (AD). In this study, we developed a multivariate prognostic model for predicting MCI-to-dementia progression at the individual patient level. Methods Using baseline data from 259 MCI patients and a probabilistic, kernel-based pattern classification approach, we trained a classifier to distinguish between patients who progressed to AD-type dementia (n = 139) and those who did not (n = 120) during a three-year follow-up period. More than 750 variables across four data sources were considered as potential predictors of progression. These data sources included risk factors, cognitive and functional assessments, structural magnetic resonance imaging (MRI) data, and plasma proteomic data. Predictive utility was assessed using a rigorous cross-validation framework. Results Cognitive and functional markers were most predictive of progression, while plasma proteomic markers had limited predictive utility. The best performing model incorporated a combination of cognitive/functional markers and morphometric MRI measures and predicted progression with 80% accuracy (83% sensitivity, 76% specificity, AUC = 0.87). Predictors of progression included scores on the Alzheimer's Disease Assessment Scale, Rey Auditory Verbal Learning Test, and Functional Activities Questionnaire, as well as volume/cortical thickness of three brain regions (left hippocampus, middle temporal gyrus, and inferior parietal cortex). Calibration analysis revealed that the model is capable of generating probabilistic predictions that reliably reflect the actual risk of progression. Finally, we found that the predictive accuracy of the model varied with patient demographic, genetic, and clinical characteristics and could be further improved by taking into account the confidence of the predictions. Conclusions We developed an accurate prognostic model for predicting MCI-to-dementia progression over a three-year period. The model utilizes widely available, cost-effective, non-invasive markers and can be used to improve patient selection in clinical trials and identify high-risk MCI patients for early treatment. PMID:26901338

Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: an Australian and New Zealand perspective: part 2 new and emerging therapies and their efficacy. MS Neurology Group of the Australian and New Zealand Association of Neurologists.

PubMed

Broadley, Simon A; Barnett, Michael H; Boggild, Mike; Brew, Bruce J; Butzkueven, Helmut; Heard, Robert; Hodgkinson, Suzanne; Kermode, Allan G; Lechner-Scott, Jeannette; Macdonell, Richard A L; Marriott, Mark; Mason, Deborah F; Parratt, John; Reddel, Stephen W; Shaw, Cameron P; Slee, Mark; Spies, Judith; Taylor, Bruce V; Carroll, William M; Kilpatrick, Trevor J; King, John; McCombe, Pamela A; Pollard, John D; Willoughby, Ernest

2014-11-01

In Part 2 of this three part review of multiple sclerosis (MS) treatment with a particular focus on the Australian and New Zealand perspective, we review the newer therapies that have recently become available and emerging therapies that have now completed phase III clinical trial programs. We go on to compare the relative efficacies of these newer and emerging therapies alongside the existing therapies. The effectiveness of β-interferon in the treatment of different stages and the different disease courses of MS is critically reviewed with the conclusion that the absolute level of response in term of annualised relapse rates (where relapses occur) and MRI activity are similar, but are disappointing in terms of sustained disability progression for progressive forms of the disease. Finally we review the controversial area of combination therapy for MS. Whilst it remains the case that we have no cure or means of preventing MS, we do have a range of effective therapies that when used appropriately and early in the disease course can have a significant impact on short term and longer term outcomes. Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

Forest type influences transmission of Phytophthora ramorum in California oak woodlands.

PubMed

Davidson, Jennifer M; Patterson, Heather A; Wickland, Allison C; Fichtner, Elizabeth J; Rizzo, David M

2011-04-01

The transmission ecology of Phytophthora ramorum from bay laurel (Umbellularia californica) leaves was compared between mixed-evergreen and redwood forest types throughout winter and summer disease cycles in central, coastal California. In a preliminary multisite study, we found that abscission rates of infected leaves were higher at mixed-evergreen sites. In addition, final infection counts were slightly higher at mixed-evergreen sites or not significantly different than at redwood sites, in part due to competition from other foliar pathogens at redwood sites. In a subsequent, detailed study of paired sites where P. ramorum was the main foliar pathogen, summer survival of P. ramorum in bay laurel leaves was lower in mixed-evergreen forest due to lower recovery from infected attached leaves and higher abscission rates of infected leaves. Onset of inoculum production and new infections of bay laurel leaves occurred later in mixed-evergreen forest. Mean inoculum levels in rainwater and final infection counts on leaves were higher in redwood forest. Based on these two studies, lower summer survival of reservoir inoculum in bay laurel leaves in mixed-evergreen forest may result in delayed onset of both inoculum production and new infections, leading to slower disease progress in the early rainy season compared with redwood forest. Although final infection counts also will depend on other foliar pathogens and disease history, in sites where P. ramorum is the main foliar pathogen, these transmission patterns suggest higher rates of disease spread in redwood forests during rainy seasons of short or average length.

COMPLEXITY AND HETEROGENEITY: WHAT DRIVES THE EVER-CHANGING BRAIN IN HUNTINGTONS DISEASE?

PubMed Central

Rosas, H. Diana; Salat, David H; Lee, Stephanie Y; Zaleta, Alexandra K; Hevelone, Nathanael; Hersch, Steven M.

2008-01-01

Significant advances are being made in our understanding of basic pathophyiological and biochemical mechanisms that cause HuntingtonÕs disease (HD). There is increasing reason to believe that pathologic alterations occur in the brain for years before symptoms manifest. The “classic” hallmark of neuropathology in HD is selective neurodegeneration in which vulnerable populations of neurons degenerate while less vulnerable populations are spared. While, the earliest and most striking neuropathologic changes have been found in the neostriatum, neuronal loss has been identified in many other regions of the brain. We report topologically selective, early, and progressive changes in the cortex, striatum, extra-striatal brain structures and white matter throughout the spectrum of disease. Our growing understanding of HD underscores the reality that points to the complexity of HD. A single, well-defined genetic mutation causes a cascade of events whose final result is an aggregate insult of the homeostatic process. We explore possible explanations for the selective vulnerability of the brain in HD. The ultimate goal in HD is to develop disease-modifying therapies that will prevent the onset of clinical symptoms in those individuals who are at risk and slow the progression of symptoms in those individuals already affected with symptoms. Understanding changes in brain morphometry and their relationship to clinical symptoms may provide important new and important insights into basic pathophysiological mechanisms at play in the disease. PMID:19076442

Etiopathology of chronic tubular, glomerular and renovascular nephropathies: Clinical implications

PubMed Central

2011-01-01

Chronic kidney disease (CKD) comprises a group of pathologies in which the renal excretory function is chronically compromised. Most, but not all, forms of CKD are progressive and irreversible, pathological syndromes that start silently (i.e. no functional alterations are evident), continue through renal dysfunction and ends up in renal failure. At this point, kidney transplant or dialysis (renal replacement therapy, RRT) becomes necessary to prevent death derived from the inability of the kidneys to cleanse the blood and achieve hydroelectrolytic balance. Worldwide, nearly 1.5 million people need RRT, and the incidence of CKD has increased significantly over the last decades. Diabetes and hypertension are among the leading causes of end stage renal disease, although autoimmunity, renal atherosclerosis, certain infections, drugs and toxins, obstruction of the urinary tract, genetic alterations, and other insults may initiate the disease by damaging the glomerular, tubular, vascular or interstitial compartments of the kidneys. In all cases, CKD eventually compromises all these structures and gives rise to a similar phenotype regardless of etiology. This review describes with an integrative approach the pathophysiological process of tubulointerstitial, glomerular and renovascular diseases, and makes emphasis on the key cellular and molecular events involved. It further analyses the key mechanisms leading to a merging phenotype and pathophysiological scenario as etiologically distinct diseases progress. Finally clinical implications and future experimental and therapeutic perspectives are discussed. PMID:21251296

Estrogen related receptor alpha in castration-resistant prostate cancer cells promotes tumor progression in bone

PubMed Central

Delliaux, Carine; Gervais, Manon; Kan, Casina; Benetollo, Claire; Pantano, Francesco; Vargas, Geoffrey; Bouazza, Lamia; Croset, Martine; Bala, Yohann; Leroy, Xavier; Rosol, Thomas J; Rieusset, Jennifer; Bellahcène, Akeila; Castronovo, Vincent; Aubin, Jane E; Clézardin, Philippe; Duterque-Coquillaud, Martine; Bonnelye, Edith

2016-01-01

Bone metastases are one of the main complications of prostate cancer and they are incurable. We investigated whether and how estrogen receptor-related receptor alpha (ERRα) is involved in bone tumor progression associated with advanced prostate cancer. By meta-analysis, we first found that ERRα expression is correlated with castration-resistant prostate cancer (CRPC), the hallmark of progressive disease. We then analyzed tumor cell progression and the associated signaling pathways in gain-of-function/loss-of-function CRPC models in vivo and in vitro. Increased levels of ERRα in tumor cells led to rapid tumor progression, with both bone destruction and formation, and direct impacts on osteoclasts and osteoblasts. VEGF-A, WNT5A and TGFβ1 were upregulated by ERRα in tumor cells and all of these factors also significantly and positively correlated with ERRα expression in CRPC patient specimens. Finally, high levels of ERRα in tumor cells stimulated the pro-metastatic factor periostin expression in the stroma, suggesting that ERRα regulates the tumor stromal cell microenvironment to enhance tumor progression. Taken together, our data demonstrate that ERRα is a regulator of CRPC cell progression in bone. Therefore, inhibiting ERRα may constitute a new therapeutic strategy for prostate cancer skeletal-related events. PMID:27776343

Late-onset dysferlinopathy presented as "liver enzyme" abnormalities: a technical note.

PubMed

Li, Fang; Yin, Geng; Xie, Qibing; Shi, Guixiu

2014-08-01

Limb-girdle muscular dystrophy type 2B,a type of dysferlinopathy, is caused by mutations in the dysferlin gene (DYSE). It is characterized by predominant weakness and atrophy of muscles of the pelvic and shoulder girdles, massive elevation of serum CK concentration, slow progression, and onset usually within the second or third decade of life. We present a Chinese patient whose disease onset was at the age of 50 years with persistent elevation of transaminases for 3 years before weakness appeared. She had been considered as having liver disease for a long time and then polymyositis. Finally, biceps brachii biopsy revealed dystrophic morphology and depletion of dysferlin in immunohistochemistry. This case should remind readers that late-age onset of dysferlinopathy can be misdiagnosed as liver disease or polymyositis.

[The case of Wegener's granulomatosis of the nose, larynx and ear].

PubMed

Wojciechowski, I; Piotrowski, S; Zaniewska-Kulesza, I; Komorowska, E

2001-01-01

We have described a rare case of Wegener's granulomatosis in our 41-year old patient, located in the nose, larynx and ear. The disease usually presents as a triad of respiratory, vascular and kidney location. It may occur as a rapid or indolent progress. We have shown in our paper diagnostic difficulties connected with this disease. The biopsies of involved organs and blood tests are the best steps of establish proper diagnosis. Antineutrophil cytoplasmic antibodies (ANCA) are typical markers of Wegeners's granulomatosis. The conservative therapy including immunosuppression and surgical treatment (laserotherapy) are main methods of management. Our patient was given antibiotic therapy, and immunosuppressive therapy. Her condition improved during the first hospitalisation. Remission lasted very short, and she was admitted to the hospital again and underwent intensive investigations and therapy. We observed dyspnea caused by subglottic stenosis. The histologic examination of the tracheal mucosa showed granulomatous inflammation. After intensive therapy our patient felt better. She has been in our records till now, we observe no progress of disease. Finally, we would like to pay attention to the fact, that early diagnosis is important to prevent complications such subglottic stenosis which can lead to death.

Novel Positional Devices for the Treatment of Positional Obstructive Sleep Apnea, and How This Relates to Sleep Surgery.

PubMed

Ravesloot, Madeline J L; Benoist, Linda; van Maanen, Peter; de Vries, Nico

2017-01-01

If untreated, obstructive sleep apnea (OSA) develops as a gradual progressive disease. In the early stage of the disease most patients with OSA are positional. The archetypical patient might progress from simple positional snoring via positional early-stage mild disease to less positional moderate and finally nonpositional severe OSA. At first, the apnea-hypopnea index (AHI) is high only in the supine position, and later is high in all sleeping positions. The phenomenon is reversible. After partial effective treatment, patients with severe OSA can reverse to less severe positional OSA or, in other words, the AHI drops more in the lateral position than in supine position. This has been shown for palatal surgery, multilevel surgery, bimaxillary osteotomies, and bariatric surgery. The absence or presence of positional dependency has a great influence on sleep surgery. First, the results of sleep surgery might be worse in positional patients. Second, the addition of positional therapy to sleep surgery might improve the overall outcome and, as such, enhance the indication of sleep surgery as an alternative to continuous positive airway pressure and mandibular advancement device treatment. © 2017 S. Karger AG, Basel.

Intramuscular transplantation of bone marrow cells prolongs the lifespan of SOD1G93A mice and modulates expression of prognosis biomarkers of the disease.

PubMed

Rando, Amaya; Pastor, Diego; Viso-León, Mari Carmen; Martínez, Anna; Manzano, Raquel; Navarro, Xavier; Osta, Rosario; Martínez, Salvador

2018-04-06

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive muscle weakness, paralysis and death. There is no effective treatment for ALS and stem cell therapy has arisen as a potential therapeutic approach. SOD1 mutant mice were used to study the potential neurotrophic effect of bone marrow cells grafted into quadriceps femoris muscle. Bone marrow intramuscular transplants resulted in increased longevity with improved motor function and decreased motoneuron degeneration in the spinal cord. Moreover, the increment of the glial-derived neurotrophic factor and neurotrophin 4 observed in the grafted muscles suggests that this partial neuroprotective effect is mediated by neurotrophic factor release at the neuromuscular junction level. Finally, certain neurodegeneration and muscle disease-specific markers, which are altered in the SOD1 G93A mutant mouse and may serve as molecular biomarkers for the early detection of ALS in patients, have been studied with encouraging results. This work demonstrates that stem cell transplantation in the muscle prolonged the lifespan, increased motoneuron survival and slowed disease progression, which was also assessed by genetic expression analysis.

Staphylococcus aureus-dependent septic arthritis in murine knee joints: local immune response and beneficial effects of vaccination

PubMed Central

Corrado, Alessia; Donato, Paolo; Maccari, Silvia; Cecchi, Raffaella; Spadafina, Tiziana; Arcidiacono, Letizia; Tavarini, Simona; Sammicheli, Chiara; Laera, Donatello; Manetti, Andrea Guido Oreste; Ruggiero, Paolo; Galletti, Bruno; Nuti, Sandra; De Gregorio, Ennio; Bertholet, Sylvie; Seubert, Anja; Bagnoli, Fabio; Bensi, Giuliano; Chiarot, Emiliano

2016-01-01

Staphylococcus aureus is the major cause of human septic arthritis and osteomyelitis, which deserve special attention due to their rapid evolution and resistance to treatment. The progression of the disease depends on both bacterial presence in situ and uncontrolled disruptive immune response, which is responsible for chronic disease. Articular and bone infections are often the result of blood bacteremia, with the knees and hips being the most frequently infected joints showing the worst clinical outcome. We report the development of a hematogenous model of septic arthritis in murine knees, which progresses from an acute to a chronic phase, similarly to what occurs in humans. Characterization of the local and systemic inflammatory and immune responses following bacterial infection brought to light specific signatures of disease. Immunization of mice with the vaccine formulation we have recently described (4C-Staph), induced a strong antibody response and specific CD4+ effector memory T cells, and resulted in reduced bacterial load in the knee joints, a milder general inflammatory state and protection against bacterial-mediated cellular toxicity. Possible correlates of protection are finally proposed, which might contribute to the development of an effective vaccine for human use. PMID:27901071

Concise Review: Mending a Broken Heart: The Evolution of Biological Therapeutics.

PubMed

Chen, Caressa; Termglinchan, Vittavat; Karakikes, Ioannis

2017-05-01

Heart failure (HF), a common sequela of cardiovascular diseases, remains a staggering clinical problem, associated with high rates of morbidity and mortality worldwide. Advances in pharmacological, interventional, and operative management have improved patient care, but these interventions are insufficient to halt the progression of HF, particularly the end-stage irreversible loss of functional cardiomyocytes. Innovative therapies that could prevent HF progression and improve the function of the failing heart are urgently needed. Following successful preclinical studies, two main strategies have emerged as potential solutions: cardiac gene therapy and cardiac regeneration through stem and precursor cell transplantation. Many potential gene- and cell-based therapies have entered into clinical studies, intending to ameliorate cardiac dysfunction in patients with advanced HF. In this review, we focus on the recent advances in cell- and gene-based therapies in the context of cardiovascular disease, emphasizing the most advanced therapies. The principles and mechanisms of action of gene and cell therapies for HF are discussed along with the limitations of current approaches. Finally, we highlight the emerging technologies that hold promise to revolutionize the biological therapies for cardiovascular diseases. Stem Cells 2017;35:1131-1140. © 2017 AlphaMed Press.

How I treat smoldering multiple myeloma

PubMed Central

Landgren, Ola

2014-01-01

Smoldering myeloma is a heterogeneous clinical entity where a subset of patients has an indolent course of disease that mimics monoclonal gammopathy of undermined significance, whereas others have a more aggressive course that has been described as “early myeloma.” It is defined as either serum M-protein ≥3 g/L or ≥10% monoclonal plasma cells in the bone marrow. There are currently no molecular factors to differentiate risks of progression for these patients. Current recommendations of therapy continue to be patient observation or patient enrollment in clinical trials. However, new definitions of active multiple myeloma recently agreed upon by the International Myeloma Working Group may alter the timing of therapy. On the basis of emerging data of therapy in these patients, it seems reasonable to believe that future recommendations for therapy of patients with smoldering myeloma will become an increasingly important topic. In this article, we review the current knowledge of this disease and risk factors associated with progression. We also examine biological insights and alterations that occur in the tumor clone and the surrounding bone marrow niche. Finally, we review clinical trials that have been performed in these patients and provide recommendations for follow-up of patients with this unique disease entity. PMID:25298034

Is Dysregulation of the HPA-Axis a Core Pathophysiology Mediating Co-Morbid Depression in Neurodegenerative Diseases?

PubMed Central

Du, Xin; Pang, Terence Y.

2015-01-01

There is increasing evidence of prodromal manifestation of neuropsychiatric symptoms in a variety of neurodegenerative diseases such as Parkinson’s disease (PD) and Huntington’s disease (HD). These affective symptoms may be observed many years before the core diagnostic symptoms of the neurological condition. It is becoming more apparent that depression is a significant modifying factor of the trajectory of disease progression and even treatment outcomes. It is therefore crucial that we understand the potential pathophysiologies related to the primary condition, which could contribute to the development of depression. The hypothalamic–pituitary–adrenal (HPA)-axis is a key neuroendocrine signaling system involved in physiological homeostasis and stress response. Disturbances of this system lead to severe hormonal imbalances, and the majority of such patients also present with behavioral deficits and/or mood disorders. Dysregulation of the HPA-axis is also strongly implicated in the pathology of major depressive disorder. Consistent with this, antidepressant drugs, such as the selective serotonin reuptake inhibitors have been shown to alter HPA-axis activity. In this review, we will summarize the current state of knowledge regarding HPA-axis pathology in Alzheimer’s, PD and HD, differentiating between prodromal and later stages of disease progression when evidence is available. Both clinical and preclinical evidence will be examined, but we highlight animal model studies as being particularly useful for uncovering novel mechanisms of pathology related to co-morbid mood disorders. Finally, we purpose utilizing the preclinical evidence to better inform prospective, intervention studies. PMID:25806005

Natural history of Niemann-Pick disease type C in a multicentre observational retrospective cohort study.

PubMed

Wraith, J E; Guffon, N; Rohrbach, M; Hwu, W L; Korenke, G C; Bembi, B; Luzy, C; Giorgino, R; Sedel, F

2009-11-01

Niemann-Pick disease type C (NP-C) is a devastating genetic disorder characterised by progressive neurological deterioration. However, data on the progression of neurological manifestations, particularly across different patient age-of-disease onsets, are limited. This is an observational retrospective cohort study designed to assess the progression of neurological disease in patients with NP-C. Physicians were asked to retrospectively complete a web-based questionnaire for each patient, at diagnosis and at up to three follow-up visits. An NP-C-specific disability scale was used to measure disease progression. The scale comprised four key parameters of neurological disease progression; ambulation, manipulation, language and swallowing. Disease progression was evaluated based on the annual rate of change in each parameter and the composite score using a linear mixed model analysis, and by classifying patients according to the number of worsened parameters during the observation period. Data were collected from 57 patients. The rate of deterioration was similar across the four individual parameters of the disability scale. The mean (95% CI) annual disease progression was +0.12 (0.09, 0.15) units. Among patients with a time interval of at least 1 year between diagnosis and last visit (n=49), 42 (86%) patients had progressed disease and 7 (14%) patients had stable disease. Disease progression was consistently more rapid in patients diagnosed in early childhood, compared with those diagnosed in late childhood, or with juvenile or adult presentation. In conclusion, our findings showed a progression in all four parameters of the disability scale, representing a continuous, unbroken progression of neurological manifestations.

Mycophenolate mofetil combined with systemic corticosteroids prevents progression to chronic recurrent inflammation and development of 'sunset glow fundus' in initial-onset acute uveitis associated with Vogt-Koyanagi-Harada disease.

PubMed

Abu El-Asrar, Ahmed M; Dosari, Mona; Hemachandran, Suhail; Gikandi, Priscilla W; Al-Muammar, Abdulrahman

2017-02-01

To evaluate the effectiveness and safety of mycophenolate mofetil (MMF) as first-line therapy combined with systemic corticosteroids in initial-onset acute uveitis associated with Vogt-Koyanagi-Harada (VKH) disease. This prospective study included 38 patients (76 eyes). The main outcome measures were final visual acuity, corticosteroid-sparing effect, progression to chronic recurrent granulomatous uveitis and development of complications, particularly 'sunset glow fundus'. The mean follow-up period was 37.0 ± 29.3 (range 9-120 months). Visual acuity of 20/20 was achieved by 93.4% of the eyes. Corticosteroid-sparing effect was achieved in all patients. The mean interval between starting treatment and tapering to 10 mg or less daily was 3.8 ± 1.3 months (range 3-7 months). Twenty-two patients (57.9%) discontinued treatment without relapse of inflammation. The mean time observed off of treatment was 28.1 ± 19.6 months (range 1-60 months). None of the eyes progressed to chronic recurrent granulomatous uveitis. The ocular complications encountered were glaucoma in two eyes (2.6%) and cataract in five eyes (6.6%). None of the eyes developed 'sunset glow fundus', and none of the patients developed any systemic adverse events associated with the treatment. Use of MMF as first-line therapy combined with systemic corticosteroids in patients with initial-onset acute VKH disease prevents progression to chronic recurrent granulomatous inflammation and development of 'sunset glow fundus'. © 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Regulation of pulmonary inflammation by mesenchymal cells.

PubMed

Alkhouri, Hatem; Poppinga, Wilfred Jelco; Tania, Navessa Padma; Ammit, Alaina; Schuliga, Michael

2014-12-01

Pulmonary inflammation and tissue remodelling are common elements of chronic respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and pulmonary hypertension (PH). In disease, pulmonary mesenchymal cells not only contribute to tissue remodelling, but also have an important role in pulmonary inflammation. This review will describe the immunomodulatory functions of pulmonary mesenchymal cells, such as airway smooth muscle (ASM) cells and lung fibroblasts, in chronic respiratory disease. An important theme of the review is that pulmonary mesenchymal cells not only respond to inflammatory mediators, but also produce their own mediators, whether pro-inflammatory or pro-resolving, which influence the quantity and quality of the lung immune response. The notion that defective pro-inflammatory or pro-resolving signalling in these cells potentially contributes to disease progression is also discussed. Finally, the concept of specifically targeting pulmonary mesenchymal cell immunomodulatory function to improve therapeutic control of chronic respiratory disease is considered. Copyright © 2014 Elsevier Ltd. All rights reserved.

Panhypopituitarism due to Absence of the Pituitary Stalk: A Rare Aetiology of Liver Cirrhosis.

PubMed

Gonzalez Rozas, Marta; Hernanz Roman, Lidia; Gonzalez, Diego Gonzalez; Pérez-Castrillón, José Luis

2016-01-01

Studies have established a relationship between hypothalamic-pituitary dysfunction and the onset of liver damage, which may occasionally progress to cirrhosis. Patients with hypopituitarism can develop a metabolic syndrome-like phenotype. Insulin resistance is the main pathophysiological axis of metabolic syndrome and is the causal factor in the development of nonalcoholic fatty liver disease (NAFLD). We present the case of a young patient with liver cirrhosis of unknown aetiology that was finally attributed to panhypopituitarism.

Panhypopituitarism due to Absence of the Pituitary Stalk: A Rare Aetiology of Liver Cirrhosis

PubMed Central

Gonzalez Rozas, Marta; Hernanz Roman, Lidia; Gonzalez, Diego Gonzalez; Pérez-Castrillón, José Luis

2016-01-01

Studies have established a relationship between hypothalamic-pituitary dysfunction and the onset of liver damage, which may occasionally progress to cirrhosis. Patients with hypopituitarism can develop a metabolic syndrome-like phenotype. Insulin resistance is the main pathophysiological axis of metabolic syndrome and is the causal factor in the development of nonalcoholic fatty liver disease (NAFLD). We present the case of a young patient with liver cirrhosis of unknown aetiology that was finally attributed to panhypopituitarism. PMID:27213061

In Vivo Clotting Breast Cancer Stem Cells and Platelets: A New Endogenous Precursor of Metastasis Progression

DTIC Science & Technology

2013-05-01

different magnifications (objective lenses of ×10, ×20, ×40 and ×100). To verify metastatic disease, multiple organs were also used for histological...indicate the influence of metastasis in the distant organs or cancer recurrence in the pri- mary tumor site. Although the animal model was used in... ORGANIZATION : University of Arkansas Little Rock AR 72205-7101 REPORT DATE: 2013 TYPE OF REPORT: Final PREPARED FOR: U.S. Army Medical

Can Intestinal Phosphate Binding or Inhibition of Hydroxyapatite Growth in the Vascular Wall Halt the Progression of Established Aortic Calcification in Chronic Kidney Disease?

PubMed

Neven, Ellen; Opdebeeck, Britt; De Maré, Annelies; Bashir-Dar, Rida; Dams, Geert; Marynissen, Rita; Behets, Geert J; Verhulst, Anja; Riser, Bruce L; D'Haese, Patrick C

2016-11-01

Vascular calcification significantly contributes to mortality in chronic kidney disease (CKD) patients. Sevelamer and pyrophosphate (PPi) have proven to be effective in preventing vascular calcification, the former by controlling intestinal phosphate absorption, the latter by directly interfering with the hydroxyapatite crystal formation. Since most patients present with established vascular calcification, it is important to evaluate whether these compounds may also halt or reverse the progression of preexisting vascular calcification. CKD and vascular calcification were induced in male Wistar rats by a 0.75 % adenine low protein diet for 4 weeks. Treatment with PPi (30 or 120 µmol/kg/day), sevelamer carbonate (1500 mg/kg/day) or vehicle was started at the time point at which vascular calcification was present and continued for 3 weeks. Hyperphosphatemia and vascular calcification developed prior to treatment. A significant progression of aortic calcification in vehicle-treated rats with CKD was observed over the final 3-week period. Sevelamer treatment significantly reduced further progression of aortic calcification as compared to the vehicle control. No such an effect was seen for either PPi dose. Sevelamer but not PPi treatment resulted in an increase in both osteoblast and osteoid perimeter. Our study shows that sevelamer was able to reduce the progression of moderate to severe preexisting aortic calcification in a CKD rat model. Higher doses of PPi may be required to induce a similar reduction of severe established arterial calcification in this CKD model.

Chronic traumatic encephalopathy: The unknown disease.

PubMed

Martínez-Pérez, R; Paredes, I; Munarriz, P M; Paredes, B; Alén, J F

2017-04-01

Chronic traumatic encephalopathy is a neurodegenerative disease produced by accumulated minor traumatic brain injuries; no definitive premortem diagnosis and no treatments are available for chronic traumatic encephalopathy. Risk factors associated with chronic traumatic encephalopathy include playing contact sports, presence of the apolipoprotein E4, and old age. Although it shares certain histopathological findings with Alzheimer disease, chronic traumatic encephalopathy has a more specific presentation (hyperphosphorylated tau protein deposited as neurofibrillary tangles, associated with neuropil threads and sometimes with beta-amyloid plaques). Its clinical presentation is insidious; patients show mild cognitive and emotional symptoms before progressing to parkinsonian motor signs and finally dementia. Results from new experimental diagnostic tools are promising, but these tools are not yet available. The mainstay of managing this disease is prevention and early detection of its first symptoms. Copyright © 2014 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Genetics of Human and Canine Dilated Cardiomyopathy

PubMed Central

Simpson, Siobhan; Edwards, Jennifer; Ferguson-Mignan, Thomas F. N.; Cobb, Malcolm; Mongan, Nigel P.; Rutland, Catrin S.

2015-01-01

Cardiovascular disease is a leading cause of death in both humans and dogs. Dilated cardiomyopathy (DCM) accounts for a large number of these cases, reported to be the third most common form of cardiac disease in humans and the second most common in dogs. In human studies of DCM there are more than 50 genetic loci associated with the disease. Despite canine DCM having similar disease progression to human DCM studies into the genetic basis of canine DCM lag far behind those of human DCM. In this review the aetiology, epidemiology, and clinical characteristics of canine DCM are examined, along with highlighting possible different subtypes of canine DCM and their potential relevance to human DCM. Finally the current position of genetic research into canine and human DCM, including the genetic loci, is identified and the reasons many studies may have failed to find a genetic association with canine DCM are reviewed. PMID:26266250

Genetics of Human and Canine Dilated Cardiomyopathy.

PubMed

Simpson, Siobhan; Edwards, Jennifer; Ferguson-Mignan, Thomas F N; Cobb, Malcolm; Mongan, Nigel P; Rutland, Catrin S

2015-01-01

Cardiovascular disease is a leading cause of death in both humans and dogs. Dilated cardiomyopathy (DCM) accounts for a large number of these cases, reported to be the third most common form of cardiac disease in humans and the second most common in dogs. In human studies of DCM there are more than 50 genetic loci associated with the disease. Despite canine DCM having similar disease progression to human DCM studies into the genetic basis of canine DCM lag far behind those of human DCM. In this review the aetiology, epidemiology, and clinical characteristics of canine DCM are examined, along with highlighting possible different subtypes of canine DCM and their potential relevance to human DCM. Finally the current position of genetic research into canine and human DCM, including the genetic loci, is identified and the reasons many studies may have failed to find a genetic association with canine DCM are reviewed.

The impact of obesity on risk factors and prevalence and prognosis of coronary heart disease-the obesity paradox.

PubMed

De Schutter, Alban; Lavie, Carl J; Milani, Richard V

2014-01-01

Obesity is associated with a host of cardiovascular risk factors and its prevalence is rising rapidly. Despite strong evidence that obesity predisposes to the development and progression of coronary heart disease (CHD), numerous studies have shown an inverse relationship between various measures of obesity (most commonly body mass index) and outcomes in established CHD. In this article we review the evidence surrounding the ≪obesity paradox≫ in the secondary care of CHD patients and the CHD presentations where a paradox has been found. Finally we discuss the impact of cardiorespiratory fitness and a number of mechanisms which may offer potential explanations for this puzzling phenomenon. © 2014.

Progress with new malaria vaccines.

PubMed Central

Webster, Daniel; Hill, Adrian V. S.

2003-01-01

Malaria is a parasitic disease of major global health significance that causes an estimated 2.7 million deaths each year. In this review we describe the burden of malaria and discuss the complicated life cycle of Plasmodium falciparum, the parasite responsible for most of the deaths from the disease, before reviewing the evidence that suggests that a malaria vaccine is an attainable goal. Significant advances have recently been made in vaccine science, and we review new vaccine technologies and the evaluation of candidate malaria vaccines in human and animal studies worldwide. Finally, we discuss the prospects for a malaria vaccine and the need for iterative vaccine development as well as potential hurdles to be overcome. PMID:14997243

Long-term lamivudine treatment achieves regression of advanced liver fibrosis/cirrhosis in patients with chronic hepatitis B.

PubMed

Xu, Bei; Lin, Lanyi; Xu, Guoguang; Zhuang, Yan; Guo, Qing; Liu, Yunye; Wang, Hui; Zhou, Xiaqiu; Wu, Shanming; Bao, Shisan; Cai, Wei; Xie, Qing

2015-02-01

Antiviral therapy is important in advanced liver fibrosis/cirrhosis with chronic hepatitis B (AdLF-CHB) patients, but complete regression of cirrhosis remains to be the challenge. We aimed to investigate whether up to 10 years lamivudine treatment achieves liver fibrosis/cirrhosis regression in AdLF-CHB patients. Improvement of hepatic fibrosis/cirrhosis, virological response and disease progression were evaluated in 28 AdLF-CHB patients with up to 10 years lamivudine treatment. Liver biopsy was performed in all of the 28 patients at baseline, but only 19 patients had second biopsy at year 10. There were 24 hepatitis B e antigen (HBeAg)-positive and 4 HBeAg-negative patients within the original 28 AdLF-CHB patients. At the end of 10 years lamivudine treatment, 20 of the 24 HBeAg-positive patients had HBeAg loss. HBeAg seroconversion was detected in 10 of these 20 HBeAg loss patients. HBsAg loss was observed in 4 of the original 28 patients. Among these four HBsAg loss patients, three had HBsAg seroconversion. All patients achieved hepatitis B virus DNA (HBV DNA) undetectable. Histopathology was evaluated between paired original and final liver biopsies among 19 patients as follows: 4/19 achieved complete liver fibrosis/cirrhosis regression; 9/19 improved in Ishak fibrosis score; whereas 6/19 showed no fibrosis improvement. About 75% patients achieved inflammatory/fibrotic improvement. No significant disease progression was observed in 24/28 patients. Furthermore, no significant difference in histopathology improvement, cirrhosis regression, disease progression between non-resistance and rescue for resistance was observed. Long-term lamivudine therapy achieves regression of fibrosis/cirrhosis and improvement of histological and disease progression in AdLF-CHB patients. © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

Alzheimer's disease Braak Stage progressions: reexamined and redefined as Borrelia infection transmission through neural circuits.

PubMed

MacDonald, Alan B

2007-01-01

Brain structure in health is a dynamic energized equation incorporating chemistry, neuronal structure, and circuitry components. The chemistry "piece" is represented by multiple neurotransmitters such as Acetylcholine, Serotonin, and Dopamine. The neuronal structure "piece" incorporates synapses and their connections. And finally circuits of neurons establish "architectural blueprints" of anatomic wiring diagrams of the higher order of brain neuron organizations. In Alzheimer's disease, there are progressive losses in all of these components. Brain structure crumbles. The deterioration in Alzheimer's is ordered, reproducible, and stepwise. Drs. Braak and Braak have described stages in the Alzheimer disease continuum. "Progressions" through Braak Stages benchmark "Regressions" in Cognitive function. Under the microscope, the Stages of Braak commence in brain regions near to the hippocampus, and over time, like a tsunami wave of destruction, overturn healthy brain regions, with neurofibrillary tangle damaged neurons "marching" through the temporal lobe, neocortex and occipital cortex. In effect the destruction ascends from the limbic regions to progressively destroy the higher brain centers. Rabies infection also "begins low and finishes high" in its wave of destruction of brain tissue. Herpes Zoster infections offer the paradigm of clinical latency of infection inside of nerves before the "marching commences". Varicella Zoster virus enters neurons in the pediatric years. Dormant virus remains inside the neurons for 50-80 years, tissue damage late in life (shingles) demonstrates the "march of the infection" down neural pathways (dermatomes) as linear areas of painful blisters loaded with virus from a childhood infection. Amalgamation of Zoster with Rabies models produces a hybrid model to explain all of the Braak Stages of Alzheimer's disease under a new paradigm, namely "Alzheimer's neuroborreliosis" in which latent Borrelia infections ascend neural circuits through the hippocampus to the higher brain centers, creating a trail of neurofibrillary tangle injured neurons in neural circuits of cholinergic neurons by transsynaptic transmission of infection from nerve to nerve.

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

PubMed Central

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

2013-01-01

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

Whole Blood Gene Expression Profiling in Preclinical and Clinical Cattle Infected with Atypical Bovine Spongiform Encephalopathy

PubMed Central

Xerxa, Elena; Barbisin, Maura; Chieppa, Maria Novella; Krmac, Helena; Vallino Costassa, Elena; Vatta, Paolo; Simmons, Marion; Caramelli, Maria; Casalone, Cristina; Corona, Cristiano

2016-01-01

Prion diseases, such as bovine spongiform encephalopathies (BSE), are transmissible neurodegenerative disorders affecting humans and a wide variety of mammals. Variant Creutzfeldt-Jakob disease (vCJD), a prion disease in humans, has been linked to exposure to BSE prions. This classical BSE (cBSE) is now rapidly disappearing as a result of appropriate measures to control animal feeding. Besides cBSE, two atypical forms (named H- and L-type BSE) have recently been described in Europe, Japan, and North America. Here we describe the first wide-spectrum microarray analysis in whole blood of atypical BSE-infected cattle. Transcriptome changes in infected animals were analyzed prior to and after the onset of clinical signs. The microarray analysis revealed gene expression changes in blood prior to the appearance of the clinical signs and during the progression of the disease. A set of 32 differentially expressed genes was found to be in common between clinical and preclinical stages and showed a very similar expression pattern in the two phases. A 22-gene signature showed an oscillating pattern of expression, being differentially expressed in the preclinical stage and then going back to control levels in the symptomatic phase. One gene, SEL1L3, was downregulated during the progression of the disease. Most of the studies performed up to date utilized various tissues, which are not suitable for a rapid analysis of infected animals and patients. Our findings suggest the intriguing possibility to take advantage of whole blood RNA transcriptional profiling for the preclinical identification of prion infection. Further, this study highlighted several pathways, such as immune response and metabolism that may play an important role in peripheral prion pathogenesis. Finally, the gene expression changes identified in the present study may be further investigated as a fingerprint for monitoring the progression of disease and for developing targeted therapeutic interventions. PMID:27073865

Atypical moyamoya syndrome with brain calcification and stenosis of abdominal aorta and renal arteries.

PubMed

Uchikawa, Hideki; Fujii, Katsunori; Fujita, Mayuko; Okunushi, Tomoko; Shimojo, Naoki

2017-09-01

Moyamoya syndrome is a progressive cerebrovascular disease that is characterized by stenosis of the terminal portion of the internal carotid artery and its main branches, in combination with an accompanying disease. We herein describe an 8-year-old boy exhibiting transient loss of consciousness, who had recurrent seizures in infancy with progressive brain calcification. On admission, he was alert but magnetic resonance angiography showed bilateral stenosis of the whole internal carotid artery and proliferation of vascular collaterals, and brain CT revealed calcification on bilateral putamen. Given that this fulfilled diagnostic criteria, we finally diagnosed him as having moyamoya syndrome, though the etiology was unclear. Interestingly, a whole vessel survey revealed vascular stenosis of abdominal aorta and renal arteries, in which the former has not been reported in moyamoya syndrome. We considered that brain calcification was gradually formed by decreased cerebral vascular flow from infancy, and stenosis of abdominal aorta was possibly extended from renal arteries. This is, moyamoya syndrome with brain calcification and stenosis of abdominal aorta, suggesting that morphological screening of whole vessels containing cerebral and abdominal arteries should be considered in cases of slowly progressive brain calcification. Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Glial degeneration with oxidative damage drives neuronal demise in MPSII disease

PubMed Central

Zalfa, Cristina; Verpelli, Chiara; D'Avanzo, Francesca; Tomanin, Rosella; Vicidomini, Cinzia; Cajola, Laura; Manara, Renzo; Sala, Carlo; Scarpa, Maurizio; Vescovi, Angelo Luigi; De Filippis, Lidia

2016-01-01

Mucopolysaccharidosis type II (MPSII) is a lysosomal storage disorder due to the deficit of the iduronate 2-sulfatase (IDS) enzyme, causing progressive neurodegeneration in patients. Neural stem cells (NSCs) derived from the IDS-ko mouse can recapitulate MPSII pathogenesis in vitro. In differentiating IDS-ko NSCs and in the aging IDS-ko mouse brain, glial degeneration precedes neuronal degeneration. Here we show that pure IDS-ko NSC-derived astrocytes are selectively able to drive neuronal degeneration when cocultured with healthy neurons. This phenotype suggests concurrent oxidative damage with metabolic dysfunction. Similar patterns were observed in murine IDS-ko animals and in human MPSII brains. Most importantly, the mutant phenotype of IDS-ko astrocytes was reversed by low oxygen conditions and treatment with vitamin E, which also reversed the toxic effect on cocultured neurons. Moreover, at very early stages of disease we detected in vivo the development of a neuroinflammatory background that precedes astroglial degeneration, thus suggesting a novel model of MPSII pathogenesis, with neuroinflammation preceding glial degeneration, which is finally followed by neuronal death. This hypothesis is also consistent with the progression of white matter abnormalities in MPSII patients. Our study represents a novel breakthrough in the elucidation of MPSII brain pathogenesis and suggests the antioxidant molecules as potential therapeutic tools to delay MPSII onset and progression. PMID:27512952

Glial degeneration with oxidative damage drives neuronal demise in MPSII disease.

PubMed

Zalfa, Cristina; Verpelli, Chiara; D'Avanzo, Francesca; Tomanin, Rosella; Vicidomini, Cinzia; Cajola, Laura; Manara, Renzo; Sala, Carlo; Scarpa, Maurizio; Vescovi, Angelo Luigi; De Filippis, Lidia

2016-08-11

Mucopolysaccharidosis type II (MPSII) is a lysosomal storage disorder due to the deficit of the iduronate 2-sulfatase (IDS) enzyme, causing progressive neurodegeneration in patients. Neural stem cells (NSCs) derived from the IDS-ko mouse can recapitulate MPSII pathogenesis in vitro. In differentiating IDS-ko NSCs and in the aging IDS-ko mouse brain, glial degeneration precedes neuronal degeneration. Here we show that pure IDS-ko NSC-derived astrocytes are selectively able to drive neuronal degeneration when cocultured with healthy neurons. This phenotype suggests concurrent oxidative damage with metabolic dysfunction. Similar patterns were observed in murine IDS-ko animals and in human MPSII brains. Most importantly, the mutant phenotype of IDS-ko astrocytes was reversed by low oxygen conditions and treatment with vitamin E, which also reversed the toxic effect on cocultured neurons. Moreover, at very early stages of disease we detected in vivo the development of a neuroinflammatory background that precedes astroglial degeneration, thus suggesting a novel model of MPSII pathogenesis, with neuroinflammation preceding glial degeneration, which is finally followed by neuronal death. This hypothesis is also consistent with the progression of white matter abnormalities in MPSII patients. Our study represents a novel breakthrough in the elucidation of MPSII brain pathogenesis and suggests the antioxidant molecules as potential therapeutic tools to delay MPSII onset and progression.

Longitudinal follow-up study of smoking-induced emphysema progression in low-dose CT screening of lung cancer

NASA Astrophysics Data System (ADS)

Suzuki, H.; Matsuhiro, M.; Kawata, Y.; Niki, N.; Nakano, Y.; Ohmatsu, H.; Kusumoto, M.; Tsuchida, T.; Eguchi, K.; Kaneko, Masahiro; Moriyama, N.

2014-03-01

Chronic obstructive pulmonary disease is a major public health problem that is predicted to be third leading cause of death in 2030. Although spirometry is traditionally used to quantify emphysema progression, it is difficult to detect the loss of pulmonary function by emphysema in early stage, and to assess the susceptibility to smoking. This study presents quantification method of smoking-induced emphysema progression based on annual changes of low attenuation volume (LAV) by each lung lobe acquired from low-dose CT images in lung cancer screening. The method consists of three steps. First, lung lobes are segmented using extracted interlobar fissures by enhancement filter based on fourdimensional curvature. Second, LAV of each lung lobe is segmented. Finally, smoking-induced emphysema progression is assessed by statistical analysis of the annual changes represented by linear regression of LAV percentage in each lung lobe. This method was applied to 140 participants in lung cancer CT screening for six years. The results showed that LAV progressions of nonsmokers, past smokers, and current smokers are different in terms of pack-year and smoking cessation duration. This study demonstrates effectiveness in diagnosis and prognosis of early emphysema in lung cancer CT screening.

Final Report - DOE Center for Laser Imaging and Cancer Diagnostics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Alfano, Robert R.; Koutcher, Jason A.

2002-10-31

This Final Report summarizes the significant progress made by the researchers, students and staff of the Center for Laser Imaging and Cancer Diagnostics (CLICD) from January 1998 through May 2002. During this period, the Center supported several projects. Most projects were proposed initially, some were added subsequently as their relevance and importance to the DOE mission became evident. DOE support has been leveraged to obtain continuing funding for some projects. Leveraged funds come from various sources, including NIH, Army, NSF and the Air Force. The goal of the Center was to develop laser-based instruments for use in the detection andmore » diagnosis of major diseases, with an emphasis on detection and diagnosis of various cancers. Each of the supported projects is a collaborative effort between physicists and laser scientists and the City College of New York and noted physicians, surgeons, pathologists, and biologists located at medical centers in the Metropolitan area. The participating institutions were: City College of New York Institute for Ultrafast Lasers and Spectroscopy, Hackensack University Medical Center, Lawrence Livermore National Laboratory, Memorial Sloan Kettering Cancer Center, and New York Eye and Ear Institute. Each of the projects funded by the Center is grouped into one of four research categories: a) Disease Detection, b) Non-Disease Applications, c) New Diagnostic Tools, and, d) Education, Training, Outreach and Dissemination. The progress achieved by the multidisciplinary teams was reported in 51 publications and 32 presentations at major national conferences. Also, one U.S. patent was obtained and six U.S. patent applications have been filed for innovations resulting from the projects sponsored by the Center.« less

Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis.

PubMed

Yardley, Denise A; Noguchi, Shinzaburo; Pritchard, Kathleen I; Burris, Howard A; Baselga, José; Gnant, Michael; Hortobagyi, Gabriel N; Campone, Mario; Pistilli, Barbara; Piccart, Martine; Melichar, Bohuslav; Petrakova, Katarina; Arena, Francis P; Erdkamp, Frans; Harb, Wael A; Feng, Wentao; Cahana, Ayelet; Taran, Tetiana; Lebwohl, David; Rugo, Hope S

2013-10-01

Effective treatments for hormone-receptor-positive (HR(+)) breast cancer (BC) following relapse/progression on nonsteroidal aromatase inhibitor (NSAI) therapy are needed. Initial Breast Cancer Trials of OraL EveROlimus-2 (BOLERO-2) trial data demonstrated that everolimus and exemestane significantly prolonged progression-free survival (PFS) versus placebo plus exemestane alone in this patient population. BOLERO-2 is a phase 3, double-blind, randomized, international trial comparing everolimus (10 mg/day) plus exemestane (25 mg/day) versus placebo plus exemestane in postmenopausal women with HR(+) advanced BC with recurrence/progression during or after NSAIs. The primary endpoint was PFS by local investigator review, and was confirmed by independent central radiology review. Overall survival, response rate, and clinical benefit rate were secondary endpoints. Final study results with median 18-month follow-up show that median PFS remained significantly longer with everolimus plus exemestane versus placebo plus exemestane [investigator review: 7.8 versus 3.2 months, respectively; hazard ratio = 0.45 (95% confidence interval 0.38-0.54); log-rank P < 0.0001; central review: 11.0 versus 4.1 months, respectively; hazard ratio = 0.38 (95% confidence interval 0.31-0.48); log-rank P < 0.0001] in the overall population and in all prospectively defined subgroups, including patients with visceral metastases, [corrected] and irrespective of age. The incidence and severity of adverse events were consistent with those reported at the interim analysis and in other everolimus trials. The addition of everolimus to exemestane markedly prolonged PFS in patients with HR(+) advanced BC with disease recurrence/progression following prior NSAIs. These results further support the use of everolimus plus exemestane in this patient population. ClinicalTrials.gov #NCT00863655.

Comparison between innominate osteotomy and arthrodistraction as a primary treatment for Legg-Calvé-Perthes disease: a prospective controlled trial.

PubMed

Volpon, José Batista

2012-09-01

Legg-Calvé-Perthes (LCP) disease is currently managed by mechanical containment of the femoral head in the hip socket. As evidence suggests that hip distraction may offer a new treatment strategy, we used arthrodistraction as a primary treatment for active forms of LCP disease and prospectively compared the results with the Salter innominate osteotomy. A total of 54 children, six years or older of both genders with severe forms of LCP disease in the stages of necrosis or revascularisation, were enrolled. Patients were submitted to either Salter innominate osteotomy (n = 28) or hip arthrodistraction (n = 26). Final radiographs were used to evaluate the Mose index, Wiberg angle, extrusion index and the Stulberg et al. classification. There were no significant differences in gender, age, lateral pillar classification and average follow-up time between the two groups. The osteotomy group progressed without major complications, but children in the joint distraction group experienced episodes of pin tract pain and infection, leading to the early removal of the external device in one case. Two patients developed joint stiffness, treated by physiotherapy or manipulation, and one child developed subluxation of the femoral head. The average time in distraction was 4.44 months (2.53-7.23 months). In the final evaluation the osteotomy group showed better containment of the femoral head. The Mose index and the Stulberg et al. classification were statistically similar between the two groups. Despite similar final radiological results, arthrodistraction was associated with a higher morbidity. Consequently, we do not recommend hip distraction as a primary treatment for the early stages of LCP disease.

Loss of HCN1 enhances disease progression in mouse models of CNG channel-linked retinitis pigmentosa and achromatopsia.

PubMed

Schön, Christian; Asteriti, Sabrina; Koch, Susanne; Sothilingam, Vithiyanjali; Garcia Garrido, Marina; Tanimoto, Naoyuki; Herms, Jochen; Seeliger, Mathias W; Cangiano, Lorenzo; Biel, Martin; Michalakis, Stylianos

2016-03-15

Most inherited blinding diseases are characterized by compromised retinal function and progressive degeneration of photoreceptors. However, the factors that affect the life span of photoreceptors in such degenerative retinal diseases are rather poorly understood. Here, we explore the role of hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) in this context. HCN1 is known to adjust retinal function under mesopic conditions, and although it is expressed at high levels in rod and cone photoreceptor inner segments, no association with any retinal disorder has yet been found. We investigated the effects of an additional genetic deletion of HCN1 on the function and survival of photoreceptors in a mouse model of CNGB1-linked retinitis pigmentosa (RP). We found that the absence of HCN1 in Cngb1 knockout (KO) mice exacerbated photoreceptor degeneration. The deleterious effect was reduced by expression of HCN1 using a viral vector. Moreover, pharmacological inhibition of HCN1 also enhanced rod degeneration in Cngb1 KO mice. Patch-clamp recordings revealed that the membrane potentials of Cngb1 KO and Cngb1/Hcn1 double-KO rods were both significantly depolarized. We also found evidence for altered calcium homeostasis and increased activation of the protease calpain in Cngb1/Hcn1 double-KO mice. Finally, the deletion of HCN1 also exacerbated degeneration of cone photoreceptors in a mouse model of CNGA3-linked achromatopsia. Our results identify HCN1 as a major modifier of photoreceptor degeneration and suggest that pharmacological inhibition of HCN channels may enhance disease progression in RP and achromatopsia patients. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Cardiovascular calcifications in chronic kidney disease: Potential therapeutic implications.

PubMed

Bover, Jordi; Ureña-Torres, Pablo; Górriz, José Luis; Lloret, María Jesús; da Silva, Iara; Ruiz-García, César; Chang, Pamela; Rodríguez, Mariano; Ballarín, José

Cardiovascular (CV) calcification is a highly prevalent condition at all stages of chronic kidney disease (CKD) and is directly associated with increased CV and global morbidity and mortality. In the first part of this review, we have shown that CV calcifications represent an important part of the CKD-MBD complex and are a superior predictor of clinical outcomes in our patients. However, it is also necessary to demonstrate that CV calcification is a modifiable risk factor including the possibility of decreasing (or at least not aggravating) its progression with iatrogenic manoeuvres. Although, strictly speaking, only circumstantial evidence is available, it is known that certain drugs may modify the progression of CV calcifications, even though a direct causal link with improved survival has not been demonstrated. For example, non-calcium-based phosphate binders demonstrated the ability to attenuate the progression of CV calcification compared with the liberal use of calcium-based phosphate binders in several randomised clinical trials. Moreover, although only in experimental conditions, selective activators of the vitamin D receptor seem to have a wider therapeutic margin against CV calcification. Finally, calcimimetics seem to attenuate the progression of CV calcification in dialysis patients. While new therapeutic strategies are being developed (i.e. vitamin K, SNF472, etc.), we suggest that the evaluation of CV calcifications could be a diagnostic tool used by nephrologists to personalise their therapeutic decisions. Copyright © 2016 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

Peptide inhibitor of CXCL4-CCL5 heterodimer formation, MKEY, inhibits experimental aortic aneurysm initiation and progression.

PubMed

Iida, Yasunori; Xu, Baohui; Xuan, Haojun; Glover, Keith J; Tanaka, Hiroki; Hu, Xiaolei; Fujimura, Naoki; Wang, Wei; Schultz, Joshua R; Turner, Court R; Dalman, Ronald L

2013-04-01

Macrophages are critical contributors to abdominal aortic aneurysm (AAA) disease. We examined the ability of MKEY, a peptide inhibitor of CXCL4-CCL5 interaction, to influence AAA progression in murine models. AAAs were created in 10-week-old male C57BL/6J mice by transient infrarenal aortic porcine pancreatic elastase infusion. Mice were treated with MKEY via intravenous injection either (1) before porcine pancreatic elastase infusion or (2) after aneurysm initiation. Immunostaining demonstrated CCL5 and CCR5 expression on aneurysmal aortae and mural monocytes/macrophages, respectively. MKEY treatment partially inhibited migration of adaptively transferred leukocytes into aneurysmal aortae in recipient mice. Although all vehicle-pretreated mice developed AAAs, aneurysms formed in only 60% (3/5) and 14% (1/7) of mice pretreated with MKEY at 10 and 20 mg/kg, respectively. MKEY pretreatment reduced aortic diameter enlargement, preserved medial elastin fibers and smooth muscle cells, and attenuated mural macrophage infiltration, angiogenesis, and aortic metalloproteinase 2 and 9 expression after porcine pancreatic elastase infusion. MKEY initiated after porcine pancreatic elastase infusion also stabilized or reduced enlargement of existing AAAs. Finally, MKEY treatment was effective in limiting AAA formation after angiotensin II infusion in apolipoprotein E-deficient mice. MKEY suppresses AAA formation and progression in 2 complementary experimental models. Peptide inhibition of CXCL4-CCL5 interactions may represent a viable translational strategy to limit progression of human AAA disease.

Epigenetics of kidney disease.

PubMed

Wanner, Nicola; Bechtel-Walz, Wibke

2017-07-01

DNA methylation and histone modifications determine renal programming and the development and progression of renal disease. The identification of the way in which the renal cell epigenome is altered by environmental modifiers driving the onset and progression of renal diseases has extended our understanding of the pathophysiology of kidney disease progression. In this review, we focus on current knowledge concerning the implications of epigenetic modifications during renal disease from early development to chronic kidney disease progression including renal fibrosis, diabetic nephropathy and the translational potential of identifying new biomarkers and treatments for the prevention and therapy of chronic kidney disease and end-stage kidney disease.

The gut-kidney axis in chronic renal failure: A new potential target for therapy.

PubMed

Khoury, Tawfik; Tzukert, Keren; Abel, Roy; Abu Rmeileh, Ayman; Levi, Ronen; Ilan, Yaron

2017-07-01

Evidence is accumulating to consider the gut microbiome as a central player in the gut-kidney axis. Microbiome products, such as advanced glycation end products, phenols, and indoles, are absorbed into the circulation but are cleared by normal-functioning kidneys. These products then become toxic and contribute to the uremic load and to the progression of chronic kidney failure. In this review, we discuss the gut-kidney interaction under the state of chronic kidney failure as well as the potential mechanisms by which a change in the gut flora (termed gut dysbiosis) in chronic kidney disease (CKD) exacerbates uremia and leads to further progression of CKD and inflammation. Finally, the potential therapeutic interventions to target the gut microbiome in CKD are discussed. © 2016 International Society for Hemodialysis.

The Biology of Cancer Exosomes: Insights and New Perspectives.

PubMed

Ruivo, Carolina F; Adem, Bárbara; Silva, Miguel; Melo, Sónia A

2017-12-01

Exosomes are a subclass of extracellular vesicles involved in intercellular communication that are released by all cell types, including cancer cells. Cancer exosomes carry malignant information in the form of proteins, lipids, and nucleic acids that can reprogram recipient cells. Exosomes have emerged as putative biological mediators in cancer contributing to major steps of disease progression. A leading role exists for cancer exosomes in specific aspects of tumor progression: modulation of immune response, tumor microenvironment reprogramming, and metastasis. This review will address the functions attributed to cancer exosomes in these three aspects of cancer biology, highlighting recent advances and potential limitations. Finally, we explore alternative strategies to develop better models to study cancer exosomes biology. Cancer Res; 77(23); 6480-8. ©2017 AACR . ©2017 American Association for Cancer Research.

Advances in the medical treatment of juvenile rheumatoid arthritis.

PubMed

Onel, K B

2000-02-01

Juvenile rheumatoid arthritis (JRA) remains a challenge for clinicians. Nonsteroidal anti-inflammatory drugs and corticosteroids remain the mainstays of therapy, but concerns persist about side effects and the ability of these agents to prevent progression of bony disease. In recent years, novel treatments have been developed and quickly discarded because of unexpected toxicities or lack of efficacy. However, recent studies have shown that methotrexate and sulfasalazine are relatively safe and effective for JRA. Newly developed drugs, such as selective cyclooxygenase-2 inhibitors and soluble tumor necrosis factor receptor, whose development has stemmed from a more basic understanding of pathophysiology, may provide better disease control with fewer side effects. Finally, novel therapies, such as stem cell transplantation, may offer hope for children with JRA, especially systemic-onset JRA, whose disease has been refractory to conventional therapy.

Progression of motor and nonmotor features of Parkinson's disease and their response to treatment

PubMed Central

Vu, Thuy C.; Nutt, John G.; Holford, Nicholas H. G.

2012-01-01

AIMS (i) To describe the progression of the cardinal features of Parkinson's disease (PD); (ii) to investigate whether baseline PD subtypes explain disease progression; and (iii) to quantify the symptomatic and disease-modifying effects of anti-parkinsonian treatments. METHODS Data were available for 795 PD subjects, initially untreated, followed for up to 8 years. Cardinal features [tremor, rigidity, bradykinesia, and postural instability and gait disorder (PIGD)] were derived from the total unified Parkinson's disease rating scale (total UPDRS), cognitive status from the mini-mental status exam score (MMSE) and depression status from the Hamilton depression scale (HAM-D). Analysis was performed using a nonlinear mixed effects approach with an asymptotic model for natural disease progression. Treatment effects (i.e. symptomatic and disease modifying) were evaluated by describing changes in the natural history model parameters. RESULTS Tremor progressed more slowly (half-time of 3.9 years) than all other motor features (half-time 2–3 years). The MMSE progression was negligible, while HAM-D progressed with a half-time of 5 years. Levodopa had marked symptomatic effects on all features, but low potency for effect on PIGD (ED50 of 1237 mg day−1 compared with 7–24 mg day−1 for other motor and nonmotor features). Other anti-parkinsonian treatments had much smaller symptomatic effects. All treatments had disease-modifying effects on the cardinal features of PD. Baseline PD subtypes only explained small differences in disease progression. CONCLUSIONS This analysis indicates that tremor progresses more slowly than other cardinal features and that PIGD is less treatment responsive in early PD patients. There was no evidence of baseline PD subtypes as a clinically useful predictor of disease progression rate. Anti-parkinsonian treatments have symptomatic and disease-modifying effects on all major features of PD. PMID:22283961

Pro-inflammatory cytokines and structural biomarkers are effective to categorize osteoarthritis phenotype and progression in Standardbred racehorses over five years of racing career.

PubMed

Bertuglia, Andrea; Pagliara, Eleonora; Grego, Elena; Ricci, Alessandro; Brkljaca-Bottegaro, Nika

2016-11-08

Joint impact injuries initiate a progressive articular damage finally leading to post-traumatic osteoarthritis (PTOA). Racehorses represent an ideal, naturally available, animal model of the disease. Standardbred racehorses developing traumatic osteoarthritis of the fetlock joint during the first year of their career were enrolled in our study. Age-matched controls were contemporarily included. Biomarker levels of equine osteoarthritis were measured in serum and synovial fluid (SF) at baseline, and repeated yearly over the next 4 years of training (from T1 to T4). The effect of time and disease on the biomarker concentrations were analysed, and their relationship with clinical and radiographic parameters were assessed. We hypothesized that the kinetics of pro-inflammatory cytokines and structural biomarkers of joint disease would demonstrate progression of degenerative joint status during post-traumatic osteoarthritis and clarify the effect of early joint trauma. The concentrations of IL1-ß, IL-6, TNF-α in the SF of PTOA group peaked at T0, decreased at T1, and then progressively increased with time, reaching levels higher than those observed at baseline starting from T3. CTXII and COMP levels were similar in PTOA and control horses at baseline, and increased in serum and synovial fluid of PTOA horses starting from T2 (serum and synovial CTXII, and serum COMP) or T3 (synovial COMP). The percentual change of TNF-α in the SF of the affected joints independently contributed to explaining the radiological changes at T3 vs T2 and T4 vs T3. Temporal changes of selected biomarkers in STBRs with an acute episode of traumatic fetlock OA demonstrated that long-term increased concentrations of inflammatory cytokines, type II collagen fragments and COMP, in the SF and serum, are related to PTOA. Based on the observed decrease in inflammatory merkers at T1, we hypothesize that the progression of PTOA could be effectively modulated by proper treatment strategies. Annual variations of synovial concentration of TNF-α can reliably predict radiographic progression of PTOA.

The Alzheimer's Disease Neuroimaging Initiative 3: Continued innovation for clinical trial improvement

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weiner, Michael W.; Veitch, Dallas P.; Aisen, Paul S.

Overall, the goal of the Alzheimer's Disease Neuroimaging Initiative (ADNI) is to validate biomarkers for Alzheimer's disease (AD) clinical trials. ADNI-3, which began on August 1, 2016, is a 5-year renewal of the current ADNI-2 study. ADNI-3 will follow current and additional subjects with normal cognition, mild cognitive impairment, and AD using innovative technologies such as tau imaging, magnetic resonance imaging sequences for connectivity analyses, and a highly automated immunoassay platform and mass spectroscopy approach for cerebrospinal fluid biomarker analysis. A Systems Biology/pathway approach will be used to identify genetic factors for subject selection/enrichment. Amyloid positron emission tomography scanning willmore » be standardized using the Centiloid method. The Brain Health Registry will help recruit subjects and monitor subject cognition. Multimodal analyses will provide insight into AD pathophysiology and disease progression. Finally, ADNI-3 will aim to inform AD treatment trials and facilitate development of AD disease-modifying treatments.« less

Network structure of brain atrophy in de novo Parkinson's disease

PubMed Central

Zeighami, Yashar; Ulla, Miguel; Iturria-Medina, Yasser; Dadar, Mahsa; Zhang, Yu; Larcher, Kevin Michel-Herve; Fonov, Vladimir; Evans, Alan C; Collins, D Louis; Dagher, Alain

2015-01-01

We mapped the distribution of atrophy in Parkinson's disease (PD) using magnetic resonance imaging (MRI) and clinical data from 232 PD patients and 117 controls from the Parkinson's Progression Markers Initiative. Deformation-based morphometry and independent component analysis identified PD-specific atrophy in the midbrain, basal ganglia, basal forebrain, medial temporal lobe, and discrete cortical regions. The degree of atrophy reflected clinical measures of disease severity. The spatial pattern of atrophy demonstrated overlap with intrinsic networks present in healthy brain, as derived from functional MRI. Moreover, the degree of atrophy in each brain region reflected its functional and anatomical proximity to a presumed disease epicenter in the substantia nigra, compatible with a trans-neuronal spread of the disease. These results support a network-spread mechanism in PD. Finally, the atrophy pattern in PD was also seen in healthy aging, where it also correlated with the loss of striatal dopaminergic innervation. DOI: http://dx.doi.org/10.7554/eLife.08440.001 PMID:26344547

Why sleep is important for health: a psychoneuroimmunology perspective.

PubMed

Irwin, Michael R

2015-01-03

Sleep has a critical role in promoting health. Research over the past decade has documented that sleep disturbance has a powerful influence on the risk of infectious disease, the occurrence and progression of several major medical illnesses including cardiovascular disease and cancer, and the incidence of depression. Increasingly, the field has focused on identifying the biological mechanisms underlying these effects. This review highlights the impact of sleep on adaptive and innate immunity, with consideration of the dynamics of sleep disturbance, sleep restriction, and insomnia on (a) antiviral immune responses with consequences for vaccine responses and infectious disease risk and (b) proinflammatory immune responses with implications for cardiovascular disease, cancer, and depression. This review also discusses the neuroendocrine and autonomic neural underpinnings linking sleep disturbance and immunity and the reciprocal links between sleep and inflammatory biology. Finally, interventions are discussed as effective strategies to improve sleep, and potential opportunities are identified to promote sleep health for therapeutic control of chronic infectious, inflammatory, and neuropsychiatric diseases.

Progressive restoration of spinal sagittal balance after surgical correction of lumbosacral spondylolisthesis before skeletal maturity.

PubMed

Thomas, Diala; Bachy, Manon; Courvoisier, Aurélien; Dubory, Arnaud; Bouloussa, Houssam; Vialle, Raphaël

2015-03-01

Spinopelvic alignment is crucial in assessing an energy-efficient posture in both normal and disease states, such as high-displacement developmental spondylolisthesis (HDDS). The overall effect in patients with HDDS who have undergone local surgical correction of lumbosacral imbalance for the global correction of spinal balance remains unclear. This paper reports the progressive spontaneous improvement of global sagittal balance following surgical correction of lumbosacral imbalance in patients with HDDS. The records of 15 patients with HDDS who underwent surgery between 2005 and 2010 were reviewed. The treatment consisted of L4-sacrum reduction and fusion via a posterior approach, resulting in complete correction of lumbosacral kyphosis. Preoperative, 6-month postoperative, and final follow-up postoperative angular measurements were taken from full-spine lateral radiographs obtained with the patient in a standard standing position. Radiographic measurements included pelvic incidence, sacral slope, lumbar lordosis, and thoracic kyphosis. The degree of lumbosacral kyphosis was evaluated by the lumbosacral angle. Because of the small number of patients, nonparametric tests were considered for data analysis. Preoperative lumbosacral kyphosis and L-5 anterior slip were corrected by instrumentation. Transient neurological complications were noted in 5 patients. Statistical analysis showed a significant increase of thoracic kyphosis on 6-month postoperative and final follow-up radiographs (p < 0.001). A statistically significant decrease of lumbar lordosis was noted between preoperative and 6-month control radiographs (p < 0.001) and between preoperative and final follow-up radiographs (p < 0.001). Based on the authors' observations, this technique resulted in an effective reduction of L-5 anterior slip and significant reduction of lumbosacral kyphosis (from 69.8° to 105.13°). Due to complete reduction of lumbosacral kyphosis and anterior trunk displacement associated with L-5 anterior slipping, lumbar lordosis progressively decreased and thoracic kyphosis progressively increased postoperatively. Adjusting the sagittal trunk balance produced not only pelvic anteversion, but also reciprocal adjustment of lumbar lordosis and thoracic kyphosis, creating a satisfactory level of compensated global sagittal balance.

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

PubMed Central

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

2014-01-01

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

Using a multidimensional unfolding approach to assess multiple sclerosis patient preferences for disease-modifying therapy: a pilot study

PubMed Central

Sempere, Angel Perez; Vera-Lopez, Vanesa; Gimenez-Martinez, Juana; Ruiz-Beato, Elena; Cuervo, Jesús; Maurino, Jorge

2017-01-01

Purpose Multidimensional unfolding is a multivariate method to assess preferences using a small sample size, a geometric model locating individuals and alternatives as points in a joint space. The objective was to evaluate relapsing–remitting multiple sclerosis (RRMS) patient preferences toward key disease-modifying therapy (DMT) attributes using multidimensional unfolding. Patients and methods A cross-sectional pilot study in RRMS patients was conducted. Drug attributes included relapse prevention, disease progression prevention, side-effect risk and route and schedule of administration. Assessment of preferences was performed through a five-card game. Patients were asked to value attributes from 1 (most preferred) to 5 (least preferred). Results A total of 37 patients were included; the mean age was 38.6 years, and 78.4% were female. Disease progression prevention was the most important factor (51.4%), followed by relapse prevention (40.5%). The frequency of administration had the lowest preference rating for 56.8% of patients. Finally, 19.6% valued the side-effect risk attribute as having low/very low importance. Conclusion Patients’ perspective for DMT attributes may provide valuable information to facilitate shared decision-making. Efficacy attributes were the most important drug characteristics for RRMS patients. Multidimensional unfolding seems to be a feasible approach to assess preferences in multiple sclerosis patients. Further elicitation studies using multidimensional unfolding with other stated choice methods are necessary to confirm these findings. PMID:28615928

Prostate embryonal rhabdomyosarcoma in adults: Case report and review of literature

PubMed Central

Ciammella, Patrizia; Galeandro, Maria; D’Abbiero, Nunziata; Palmieri, Tamara; Donini, Elisa; Iotti, Cinzia

2013-01-01

Introduction Prostate embryonal rhabdomyosarcoma (ERMS) is a common tumour in infants and children, with a median occurrence age of 5 years, but it is rare in adults. It is characterized by a high degree of malignancy, both local rapid growth with formation of large pelvic masses, often leading to renal failure due to urethral obstruction, and systemic spread, commonly to the lungs, liver and bone. Several therapeutic approaches have been employed in the effort to treat prostate ERMS, but all of them have failed to gain a significant survival benefit in adult patients. Case report We report on a case of a stage IV prostate ERMS, approached with combined-modality treatment, with the administration of 5 courses of doxorubicin, ifosfamide and 2-mercaptoethane sulfonate sodium (mesna), and, subsequent radiotherapy to the prostatic bed (60 Gy/30 fxs). The patient remained free of progression of disease for about 1 year to finally experience a systemic relapse with multiple lung metastases and pleural effusion. The patient died for metastatic disease 27 months following the initial diagnosis. Conclusion While it remains questionable which therapeutic approach for prostate ERMS in adults is the most appropriate, our report demonstrates that a chemo-radiation combined treatment can control the prostate disease, reducing the symptoms and improving the quality of life of these patients, for the most part destined to die for systemic progression of disease. PMID:24416569

Roles of O-GlcNAc in chronic diseases of aging.

PubMed

Banerjee, Partha S; Lagerlöf, Olof; Hart, Gerald W

2016-10-01

O-GlcNAcylation, a dynamic nutrient and stress sensitive post-translational modification, occurs on myriad proteins in the cell nucleus, cytoplasm and mitochondria. O-GlcNAcylation serves as a nutrient sensor to regulate signaling, transcription, translation, cell division, metabolism, and stress sensitivity in all cells. Aberrant protein O-GlcNAcylation plays a critical role both in the development, as well as in the progression of a variety of age related diseases. O-GlcNAcylation underlies the etiology of diabetes, and changes in specific protein O-GlcNAc levels and sites are responsible for insulin expression and sensitivity and glucose toxicity. Abnormal O-GlcNAcylation contributes directly to diabetes related dysfunction of the heart, kidney and eyes and affects progression of cardiomyopathy, nephropathy and retinopathy. O-GlcNAcylation is a critical modification in the brain and plays a role in both plaque and tangle formation, thus making its study important in neurodegenerative disorders. O-GlcNAcylation also affects cellular growth and metabolism during the development and metastasis of cancer. Finally, alterations in O-GlcNAcylation of transcription factors in macrophages and lymphocytes affect inflammation and cytokine production. Thus, O-GlcNAcylation plays key roles in many of the major diseases associated with aging. Elucidation of its specific functions in both normal and diseased tissues is likely to uncover totally novel avenues for therapeutic intervention. Copyright © 2016 Elsevier Ltd. All rights reserved.

Treatment strategies for multiple sclerosis: When to start, when to change, when to stop?

PubMed Central

Gajofatto, Alberto; Benedetti, Maria Donata

2015-01-01

Multiple sclerosis (MS) is a chronic inflammatory condition of the central nervous system determined by a presumed autoimmune process mainly directed against myelin components but also involving axons and neurons. Acute demyelination shows as clinical relapses that may fully or partially resolve, while chronic demyelination and neuroaxonal injury lead to persistent and irreversible neurological symptoms, often progressing over time. Currently approved disease-modifying therapies are immunomodulatory or immunosuppressive drugs that significantly although variably reduce the frequency of attacks of the relapsing forms of the disease. However, they have limited efficacy in preventing the transition to the progressive phase of MS and are of no benefit after it has started. It is therefore likely that the potential advantage of a given treatment is condensed in a relatively limited window of opportunity for each patient, depending on individual characteristics and disease stage, most frequently but not necessarily in the early phase of the disease. In addition, a sizable proportion of patients with MS may have a very mild clinical course not requiring a disease-modifying therapy. Finally, individual response to existing therapies for MS varies significantly across subjects and the risk of serious adverse events remains an issue, particularly for the newest agents. The present review is aimed at critically describing current treatment strategies for MS with a particular focus on the decision of starting, switching and stopping commercially available immunomodulatory and immunosuppressive therapies. PMID:26244148

Effectiveness of Chêneau brace treatment for idiopathic scoliosis: prospective study in 79 patients followed to skeletal maturity

PubMed Central

2011-01-01

Background Progressive idiopathic scoliosis can negatively influence the development and functioning of 2-3% of adolescents, with health consequences and economic costs, placing the disease in the centre of interest of the developmental medicine. The aim of this study was to evaluate the effectiveness of Chêneau brace in the management of idiopathic scoliosis. Methods A prospective observational study according to SOSORT and SRS recommendations comprised 79 patients (58 girls and 21 boys) with progressive idiopathic scoliosis, treated with Chêneau brace and physiotherapy, with initial Cobb angle between 20 and 45 degrees, no previous brace treatment, Risser 4 or more at the final evaluation and minimum one year follow-up after weaning the brace. Achieving 50° of Cobb angle was considered surgical recommendation. Results At follow-up 20 patients (25.3%) improved, 18 patients (22.8%) were stable, 31 patients (39.2%) progressed below 50 degrees and 10 patients (12.7%) progressed beyond 50 degrees (2 of these 10 patients progressed beyond 60 degrees). Progression concerned the younger and less skeletally mature patients. Conclusion Conservative treatment with Chêneau orthosis and physiotherapy was effective in halting scoliosis progression in 48.1% of patients. The results of this study suggest that bracing is effective in reducing the incidence of surgery in comparison with natural history. PMID:21266084

Modelling human disease with pluripotent stem cells.

PubMed

Siller, Richard; Greenhough, Sebastian; Park, In-Hyun; Sullivan, Gareth J

2013-04-01

Recent progress in the field of cellular reprogramming has opened up the doors to a new era of disease modelling, as pluripotent stem cells representing a myriad of genetic diseases can now be produced from patient tissue. These cells can be expanded and differentiated to produce a potentially limitless supply of the affected cell type, which can then be used as a tool to improve understanding of disease mechanisms and test therapeutic interventions. This process requires high levels of scrutiny and validation at every stage, but international standards for the characterisation of pluripotent cells and their progeny have yet to be established. Here we discuss the current state of the art with regard to modelling diseases affecting the ectodermal, mesodermal and endodermal lineages, focussing on studies which have demonstrated a disease phenotype in the tissue of interest. We also discuss the utility of pluripotent cell technology for the modelling of cancer and infectious disease. Finally, we spell out the technical and scientific challenges which must be addressed if the field is to deliver on its potential and produce improved patient outcomes in the clinic.

Genetic risk variants as therapeutic targets for Crohn's disease.

PubMed

Gabbani, Tommaso; Deiana, Simona; Marocchi, Margherita; Annese, Vito

2017-04-01

The pathogenesis of Inflammatory bowel diseases (IBD) is multifactorial, with interactions between genetic and environmental factors. Despite the existence of genetic factors being largely demonstrated by epidemiological data and several genetic studies, only a few findings have been useful in term of disease prediction, disease progression and targeting therapy. Areas covered: This review summarizes the results of genome-wide association studies in Crohn's disease, the role of epigenetics and the recent discovery by genetic studies of new pathogenetic pathways. Furthermore, it focuses on the importance of applying genetic data to clinical practice, and more specifically how to better target therapy and predict potential drug-related toxicity. Expert opinion: Some genetic markers identified in Crohn`s disease have allowed investigators to hypothesize about, and in some cases, prove the usefulness of new specific therapeutic agents. However, the heterogeneity and complexity of this disease has so far limited the daily clinical use of genetic information. Finally, the study of the implications of genetics on therapy, either to predict efficacy or avoid toxicity, is considered still to be in its infancy.

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

PubMed

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.

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

PubMed Central

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

Paraneoplastic subacute lower motor neuron syndrome associated with solid cancer.

PubMed

Verschueren, Annie; Gallard, Julien; Boucraut, José; Honnorat, Jerome; Pouget, Jean; Attarian, Shahram

2015-11-15

We retrospectively analyzed three patients with pure motor neuronopathy followed for more than four years in our center. The patients presented a rapidly progressive lower motor neuron syndrome (LMNS) over the course of a few weeks leading to a severe functional impairment. The neurological symptoms preceded the diagnosis of a breast adenocarcinoma and a thymoma in the first two patients, one of them with anti-CV2/CRMP5 antibodies. Cancer was not detected in the third patient who had circulating anti-Hu antibodies. A final diagnosis of paraneoplastic syndrome was made after investigations for alternative causes of lower motor neuron syndrome. Early diagnosis, combined treatment of the underlying cancer, and immunomodulatory treatment led to neurological improvement of the disease in two out of the three cases in which the cancer was diagnosed. Cases of subacute LMNS with rapid progression may occur as an expression of a paraneoplastic neurological syndrome. Identification of these syndromes is important, as the treatment of underlying malignancy along with immunomodulatory treatment may result in a favorable long-term outcome of these potentially fatal diseases. Copyright © 2015 Elsevier B.V. All rights reserved.

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

PubMed Central

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 (<7 percentage points (pp)) in HIV infections averted over 10 years was seen between progression assumptions for the same increases in 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 CD4<200 cells/μl, assumption C predicted substantially larger fractions of HIV infections and deaths averted than other assumptions (up to 20pp and 37pp larger, respectively). Conclusion Different disease progression assumptions on and post-ART 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

Bug Smash, Bug Splash: A Case Report of an Unusual Transmission of American Trypanosomiasis with a Brief Review of the Literature

PubMed Central

Navarrete-Sandoval, Rafael Hernán; Servín-Rojas, Maximiliano

2016-01-01

Patient: Male, 44 Final Diagnosis: Acute phase Chagas disease Symptoms: Fever • headache • periorbital oedema Medication: — Clinical Procedure: — Specialty: Infectious Diseases Objective: Rare disease Background: Chagas disease is a chronic parasitosis transmitted by the inoculation of infected triatomine feces into wounds or conjunctival sac, transfusion, congenitally, organ transplantation, and ingestion of contaminated food. The disease is classified into an acute and chronic phase; the latter is a life-long infection that can be asymptomatic or progress to cardiac or digestive complications. Case Report: We report a case of acute-phase Chagas disease, transmitted by the splash of gut content from an infected triatomine into the conjunctival mucosa. Conclusions: The diagnosis of Chagas disease is made by the direct visualization of the parasite in blood smears during the acute phase of the disease; during the chronic phase of the disease the diagnosis is made by the detection of IgG antibodies. Parasitological cure can be achieved in up to 80% of the cases in acute phase of the disease, in contrast with less than 30% during the chronic phase. PMID:28031550

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

PubMed Central

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

2012-01-01

Repetitive finger tapping is commonly used to assess bradykinesia in Parkinson's disease. The Queen Square Brain Bank diagnostic criterion of Parkinson's disease defines bradykinesia as ‘slowness of initiation with progressive reduction in speed and amplitude of repetitive action’. Although progressive supranuclear palsy is considered an atypical parkinsonian syndrome, it is not known whether patients with progressive supranuclear palsy have criteria-defined bradykinesia. This study objectively assessed repetitive finger tap performance and handwriting in patients with Parkinson's disease (n = 15), progressive supranuclear palsy (n = 9) and healthy age- and gender-matched controls (n = 16). The motion of the hand and digits was recorded in 3D during 15-s repetitive index finger-to-thumb tapping trials. The main finding was hypokinesia without decrement in patients with progressive supranuclear palsy, which differed from the finger tap pattern in Parkinson's disease. Average finger separation amplitude in progressive supranuclear palsy was less than half of that in controls and Parkinson's disease (P < 0.001 in both cases). Change in tap amplitude over consecutive taps was computed by linear regression. The average amplitude slope in progressive supranuclear palsy was nearly zero (0.01°/cycle) indicating a lack of decrement, which differed from the negative slope in patients with Parkinson's disease OFF levodopa (−0.20°/cycle, P = 0.002). ‘Hypokinesia’, defined as <50% of control group's mean amplitude, combined with ‘absence of decrement’, defined as mean positive amplitude slope, were identified in 87% of finger tap trials in the progressive supranuclear palsy group and only 12% in the Parkinson's disease OFF levodopa group. In progressive supranuclear palsy, the mean amplitude was not correlated with disease duration or other clinimetric scores. In Parkinson's disease, finger tap pattern was compatible with criteria-defined bradykinesia, characterized by slowness with progressive reduction in amplitude and speed and increased variability in speed throughout the tap trial. In Parkinson's disease, smaller amplitude, slower speed and greater speed variability were all associated with a more severe Unified Parkinson's Disease Rating Scale motor score. Analyses of handwriting showed that micrographia, defined as smaller than 50% of the control group's mean script size, was present in 75% of patients with progressive supranuclear palsy and 15% of patients with Parkinson's disease (P = 0.022). Most scripts performed by patients with progressive supranuclear palsy did not exhibit decrements in script size. In conclusion, patients with progressive supranuclear palsy have a specific finger tap pattern of ‘hypokinesia without decrement’ and they do not have criteria-defined limb bradykinesia. Similarly, ‘micrographia’ and ‘lack of decrement in script size’ are also more common in progressive supranuclear palsy than in Parkinson's disease. PMID:22396397

Progress towards eliminating canine rabies: policies and perspectives from Latin America and the Caribbean.

PubMed

Vigilato, Marco Antonio Natal; Clavijo, Alfonso; Knobl, Terezinha; Silva, Hugo Marcelo Tamayo; Cosivi, Ottorino; Schneider, Maria Cristina; Leanes, Luis Fernando; Belotto, Albino José; Espinal, Marcos Antonio

2013-08-05

Human rabies transmitted by dogs is considered a neglected disease that can be eliminated in Latin America and the Caribbean (LAC) by 2015. The aim of this paper is to discuss canine rabies policies and projections for LAC regarding current strategies for achieving this target and to critically review the political, economic and geographical factors related to the successful elimination of this deadly disease in the context of the difficulties and challenges of the region. The strong political and technical commitment to control rabies in LAC in the 1980s, started with the regional programme coordinated by the Pan American Health Organization. National and subnational programmes involve a range of strategies including mass canine vaccination with more than 51 million doses of canine vaccine produced annually, pre- and post-exposure prophylaxis, improvements in disease diagnosis and intensive surveillance. Rabies incidence in LAC has dramatically declined over the last few decades, with laboratory confirmed dog rabies cases decreasing from approximately 25 000 in 1980 to less than 300 in 2010. Dog-transmitted human rabies cases also decreased from 350 to less than 10 during the same period. Several countries have been declared free of human cases of dog-transmitted rabies, and from the 35 countries in the Americas, there is now only notification of human rabies transmitted by dogs in seven countries (Bolivia, Peru, Honduras, Haiti, Dominican Republic, Guatemala and some states in north and northeast Brazil). Here, we emphasize the importance of the political commitment in the final progression towards disease elimination. The availability of strategies for rabies control, the experience of most countries in the region and the historical ties of solidarity between countries with the support of the scientific community are evidence to affirm that the elimination of dog-transmitted rabies can be achieved in the short term. The final efforts to confront the remaining obstacles, like achieving and sustaining high vaccination coverage in communities that are most impoverished or in remote locations, are faced by countries that struggle to allocate sufficient financial and human resources for rabies control. Continent-wide cooperation is therefore required in the final efforts to secure the free status of remaining countries in the Americas, which is key to the regional elimination of human rabies transmitted by dogs.

Progress towards eliminating canine rabies: policies and perspectives from Latin America and the Caribbean

PubMed Central

Vigilato, Marco Antonio Natal; Clavijo, Alfonso; Knobl, Terezinha; Silva, Hugo Marcelo Tamayo; Cosivi, Ottorino; Schneider, Maria Cristina; Leanes, Luis Fernando; Belotto, Albino José; Espinal, Marcos Antonio

2013-01-01

Human rabies transmitted by dogs is considered a neglected disease that can be eliminated in Latin America and the Caribbean (LAC) by 2015. The aim of this paper is to discuss canine rabies policies and projections for LAC regarding current strategies for achieving this target and to critically review the political, economic and geographical factors related to the successful elimination of this deadly disease in the context of the difficulties and challenges of the region. The strong political and technical commitment to control rabies in LAC in the 1980s, started with the regional programme coordinated by the Pan American Health Organization. National and subnational programmes involve a range of strategies including mass canine vaccination with more than 51 million doses of canine vaccine produced annually, pre- and post-exposure prophylaxis, improvements in disease diagnosis and intensive surveillance. Rabies incidence in LAC has dramatically declined over the last few decades, with laboratory confirmed dog rabies cases decreasing from approximately 25 000 in 1980 to less than 300 in 2010. Dog-transmitted human rabies cases also decreased from 350 to less than 10 during the same period. Several countries have been declared free of human cases of dog-transmitted rabies, and from the 35 countries in the Americas, there is now only notification of human rabies transmitted by dogs in seven countries (Bolivia, Peru, Honduras, Haiti, Dominican Republic, Guatemala and some states in north and northeast Brazil). Here, we emphasize the importance of the political commitment in the final progression towards disease elimination. The availability of strategies for rabies control, the experience of most countries in the region and the historical ties of solidarity between countries with the support of the scientific community are evidence to affirm that the elimination of dog-transmitted rabies can be achieved in the short term. The final efforts to confront the remaining obstacles, like achieving and sustaining high vaccination coverage in communities that are most impoverished or in remote locations, are faced by countries that struggle to allocate sufficient financial and human resources for rabies control. Continent-wide cooperation is therefore required in the final efforts to secure the free status of remaining countries in the Americas, which is key to the regional elimination of human rabies transmitted by dogs. PMID:23798691

Improvements in stage of change correlate to changes in dietary intake and clinical outcomes in a 5-year lifestyle intervention in young high-risk Sri Lankans.

PubMed

Guess, N; Vasantharajah, L; Gulliford, M; Viberti, G; Gnudi, L; Karalliedde, J; Wijesuriya, M

2016-09-01

The objectives of a stage-matched approach to lifestyle change are that individuals progress forward through the stages of change. It also posits that progression through the stages of change is associated with positive changes in lifestyle behaviours. Measuring the relationship between stage of change and food intake is challenging due to the plurality of dietary behaviours. Furthermore, it is not clear whether changes in behaviour are sustained long-term. In this study we assess the movement through stages of change in the intensive (visits every 3months) and control groups (visits annually) of a large-scale primary prevention study in cardiovascular disease, carried out in 2637 children and young adults in Sri Lanka between 2007 and 2012. We also examine their relationship to dietary behaviours and clinical outcomes. We demonstrate that individuals in both groups continue to progress through stages of change over the course of the study and that measures of dietary behaviours improved from baseline to final follow-up. We also demonstrate that stage of change positively correlates to dietary behaviours including the ratio of recommended:not-recommended items, unpolished:polished starches and low-fat:high-fat food items throughout each year of the study. Finally, participants in the later stages of change at Y2, Y3 and Y4, had a significantly attenuated increase in weight and waist circumference at the final visit in both groups. We therefore demonstrate the usefulness of stage-matched approach in modifying complex dietary behaviours, and that stage of change is a valid measure of dietary behaviours across a large population over time. Copyright © 2016 Elsevier Inc. All rights reserved.

Progression of chronic periodontitis can be predicted by the levels of Porphyromonas gingivalis and Treponema denticola in subgingival plaque.

PubMed

Byrne, S J; Dashper, S G; Darby, I B; Adams, G G; Hoffmann, B; Reynolds, E C

2009-12-01

Chronic periodontitis is an inflammatory disease of the supporting tissues of the teeth associated with bacteria. Diagnosis is achieved retrospectively by clinical observation of attachment loss. Predicting disease progression would allow for targeted preventive therapy. The aim of this study was to monitor disease progression in patients on a maintenance program and determine the levels of specific bacteria in subgingival plaque samples and then examine the ability of the clinical parameters of disease and levels of specific bacteria in the plaque samples to predict disease progression. During a 12-month longitudinal study of 41 subjects, 25 sites in 21 subjects experienced disease progression indicated by at least 2 mm of clinical attachment loss. Real-time polymerase chain reaction was used to determine the levels of Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, Fusobacterium nucleatum, and Prevotella intermedia in subgingival plaque samples. No clinical parameters were able to predict periodontal disease progression. In sites undergoing imminent periodontal disease progression within the next 3 months, significant partial correlations were found between P. gingivalis and T. forsythia (r = 0.55, P < 0.001) and T. denticola and T. forsythia (r = 0.43, P = 0.04). The odds of a site undergoing imminent periodontal disease progression increased with increasing levels of P. gingivalis and T. denticola. Monitoring the proportions of P. gingivalis and T. denticola in subgingival plaque has the potential to help identify sites at significant risk for progression of periodontitis, which would assist in the targeted treatment of disease.

Physiology of Hyperuricemia and Urate-Lowering Treatments.

PubMed

Benn, Caroline L; Dua, Pinky; Gurrell, Rachel; Loudon, Peter; Pike, Andrew; Storer, R Ian; Vangjeli, Ciara

2018-01-01

Gout is the most common form of inflammatory arthritis and is a multifactorial disease typically characterized by hyperuricemia and monosodium urate crystal deposition predominantly in, but not limited to, the joints and the urinary tract. The prevalence of gout and hyperuricemia has increased in developed countries over the past two decades and research into the area has become progressively more active. We review the current field of knowledge with emphasis on active areas of hyperuricemia research including the underlying physiology, genetics and epidemiology, with a focus on studies which suggest association of hyperuricemia with common comorbidities including cardiovascular disease, renal insufficiency, metabolic syndrome and diabetes. Finally, we discuss current therapies and emerging drug discovery efforts aimed at delivering an optimized clinical treatment strategy.

[Evolution of the diet from the paleolithic to today: progress or regress?].

PubMed

Chauveau, Philippe; Fouque, Denis; Combe, Christian; Aparicio, Michel

2013-07-01

The changes in eating habits and decreased physical activity have been responsible for part of the high prevalence of chronic diseases such as hypertension or diabetes, currently observed in the so-called civilized societies. These diseases are less prevalent in previous civilizations and several decades of nutrition research have enabled better understanding of the eating habits of our ancestors, and have demonstrated the value of diet called "Mediterranean or Paleolithic". This review provides an update on the latest research. What dietary changes since the Paleolithic period, and finally how can we adapt our current diet? Several animal studies or human clinical demonstrate the value of historical research and nutrition. Copyright © 2013. Published by Elsevier SAS.

Neuroendocrine–immune disequilibrium and endometriosis: an interdisciplinary approach

PubMed Central

Tariverdian, Nadja; Theoharides, Theoharis C.; Siedentopf, Friederike; Gutiérrez, Gabriela; Jeschke, Udo; Rabinovich, Gabriel A.; Blois, Sandra M.

2007-01-01

Endometriosis, a chronic disease characterized by endometrial tissue located outside the uterine cavity, affects one fourth of young women and is associated with chronic pelvic pain and infertility. However, an in-depth understanding of the pathophysiology and effective treatment strategies of endometriosis is still largely elusive. Inadequate immune and neuroendocrine responses are significantly involved in the pathophysiology of endometriosis, and key findings are summarized in the present review. We discuss here the role of different immune mechanisms particularly adhesion molecules, protein–glycan interactions, and pro-angiogenic mediators in the development and progression of the disease. Finally, we introduce the concept of endometrial dissemination as result of a neuroendocrine-immune disequilibrium in response to high levels of perceived stress caused by cardinal clinical symptoms of endometriosis. PMID:17621704

Advances in pediatric asthma and atopic dermatitis.

PubMed

Foroughi, Shabnam; Thyagarajan, Ananth; Stone, Kelly D

2005-10-01

Allergic diseases, including asthma, allergic rhinitis, atopic dermatitis, food allergy, and urticaria are common in general pediatric practice. This review highlights several significant advances in pediatric allergy over the past year, focusing on asthma and atopic dermatitis. With increasing options for the treatment of allergic diseases, much work is now focused on methods for individualizing treatments to a patient's phenotype and genotype. Progress over the past year includes the characterization of effects of regular albuterol use in patients with genetic variations in the beta-adrenergic receptor. Maintenance asthma regimens for children in the first years of life are also an ongoing focus. The relation between upper airway allergic inflammation and asthma has continued to accumulate support and now extends to the middle ear. Environmental influences on asthma and interventions have been described, including environmental controls for asthma and the role of air pollution on lung development in children. Finally, concerns have been raised regarding the use of topical immunomodulators in young children with atopic dermatitis. Progress continues in the care of children with atopic diseases. Attention to treatment with appropriate medications, patient-individualized environmental controls, and extensive education are the keys to successfully treating atopic children. This review highlights several recent advances but is not intended to be a comprehensive review.

Perspective on CFD studies of coronary artery disease lesions and hemodynamics: a review.

PubMed

Zhang, Jun-Mei; Zhong, Liang; Su, Boyang; Wan, Min; Yap, Jinq Shya; Tham, Jasmine P L; Chua, Leok Poh; Ghista, Dhanjoo N; Tan, Ru San

2014-06-01

Coronary artery disease (CAD) is the most common cardiovascular disease. Early diagnosis of CAD's physiological significance is of utmost importance for guiding individualized risk-tailored treatment strategies. In this paper, we first review the state-of-the-art clinical diagnostic indices to quantify the severity of CAD and the associated invasive and noninvasive imaging technologies in order to quantify the anatomical parameters of diameter stenosis, area stenosis, and hemodynamic indices of coronary flow reserve and fractional flow reserve. With the development of computational technologies and CFD methods, tremendous progress has been made in applying image-based CFD simulation techniques to elucidate the effects of hemodynamics in vascular pathophysiology toward the initialization and progression of CAD. So then, we review the advancements of CFD technologies in patient-specific modeling, involving the development of geometry reconstruction, boundary conditions, and fluid-structure interaction. Next, we review the applications of CFD to stenotic sites, in order to compute their hemodynamic parameters and study the relationship between the hemodynamic conditions and the clinical indices, to thereby assess the amount of viable myocardium and candidacy for percutaneous coronary intervention. Finally, we review the strengths and limitations of current researches of applying CFD to CAD studies. Copyright © 2014 John Wiley & Sons, Ltd.

Dimethyl fumarate modulation of immune and antioxidant responses: application to HIV therapy

PubMed Central

Gill, Alexander J.; Kolson, Dennis L.

2013-01-01

The persistence of chronic immune activation and oxidative stress in human immunodeficiency virus (HIV)-infected, antiretroviral drug-treated individuals are major obstacles to fully preventing HIV disease progression. The immune modulator and antioxidant dimethyl fumarate (DMF) is effective in treating immune-mediated diseases and it also has potential applications to limiting HIV disease progression. Among the relevant effects of DMF and its active metabolite monomethyl fumarate (MMF) are induction of a Th1 → Th2 lymphocyte shift, inhibition of pro-inflammatory cytokine signaling, inhibition of NF-κB nuclear translocation, inhibition of dendritic cell maturation, suppression of lymphocyte and endothelial cell adhesion molecule expression, and induction of the Nrf2-dependent antioxidant response element (ARE) and effector genes. Associated with these effects are reduced lymphocyte and monocyte infiltration into psoriatic skin lesions in humans and immune-mediated demyelinating brain lesions in rodents, which confirms potent systemic and central nervous system (CNS) effects. In addition, DMF and MMF limit HIV infection in macrophages in vitro, albeit by unknown mechanisms. Finally, DMF and MMF also suppress neurotoxin production from HIV-infected macrophages, which drives CNS neurodegeneration. Thus, DMF might protect against systemic and CNS complications in HIV infection through its effective suppression of immune activation, oxidative stress, HIV replication, and macrophage-associated neuronal injury. PMID:23971529

Early Cerebellar Network Shifting in Spinocerebellar Ataxia Type 6

PubMed Central

Falcon, M.I.; Gomez, C.M.; Chen, E.E.; Shereen, A.; Solodkin, A.

2016-01-01

Spinocerebellar ataxia 6 (SCA6), an autosomal dominant degenerative disease, is characterized by diplopia, gait ataxia, and incoordination due to severe progressive degeneration of Purkinje cells in the vestibulo- and spinocerebellum. Ocular motor deficits are common, including difficulty fixating on moving objects, nystagmus and disruption of smooth pursuit movements. In presymptomatic SCA6, there are alterations in saccades and smooth-pursuit movements. We sought to assess functional and structural changes in cerebellar connectivity associated with a visual task, hypothesizing that gradual changes would parallel disease progression. We acquired functional magnetic resonance imaging and diffusion tensor imaging data during a passive smooth-pursuit task in 14 SCA6 patients, representing a range of disease duration and severity, and performed a cross-sectional comparison of cerebellar networks compared with healthy controls. We identified a shift in activation from vermis in presymptomatic individuals to lateral cerebellum in moderate-to-severe cases. Concomitantly, effective connectivity between regions of cerebral cortex and cerebellum was at its highest in moderate cases, and disappeared in severe cases. Finally, we noted structural differences in the cerebral and cerebellar peduncles. These unique results, spanning both functional and structural domains, highlight widespread changes in SCA6 and compensatory mechanisms associated with cerebellar physiology that could be utilized in developing new therapies. PMID:26209844

Late-onset Alzheimer's risk variants in memory decline, incident mild cognitive impairment, and Alzheimer's disease.

PubMed

Carrasquillo, Minerva M; Crook, Julia E; Pedraza, Otto; Thomas, Colleen S; Pankratz, V Shane; Allen, Mariet; Nguyen, Thuy; Malphrus, Kimberly G; Ma, Li; Bisceglio, Gina D; Roberts, Rosebud O; Lucas, John A; Smith, Glenn E; Ivnik, Robert J; Machulda, Mary M; Graff-Radford, Neill R; Petersen, Ronald C; Younkin, Steven G; Ertekin-Taner, Nilüfer

2015-01-01

We tested association of nine late-onset Alzheimer's disease (LOAD) risk variants from genome-wide association studies (GWAS) with memory and progression to mild cognitive impairment (MCI) or LOAD (MCI/LOAD) in older Caucasians, cognitively normal at baseline and longitudinally evaluated at Mayo Clinic Rochester and Jacksonville (n>2000). Each variant was tested both individually and collectively using a weighted risk score. APOE-e4 associated with worse baseline memory and increased decline with highly significant overall effect on memory. CLU-rs11136000-G associated with worse baseline memory and incident MCI/LOAD. MS4A6A-rs610932-C associated with increased incident MCI/LOAD and suggestively with lower baseline memory. ABCA7-rs3764650-C and EPHA1-rs11767557-A associated with increased rates of memory decline in subjects with a final diagnosis of MCI/LOAD. PICALM-rs3851179-G had an unexpected protective effect on incident MCI/LOAD. Only APOE-inclusive risk scores associated with worse memory and incident MCI/LOAD. The collective influence of the nine top LOAD GWAS variants on memory decline and progression to MCI/LOAD appears limited. Discovery of biologically functional variants at these loci may uncover stronger effects on memory and incident disease. Copyright © 2015 Elsevier Inc. All rights reserved.

Expression patterns of STAT3, ERK and estrogen-receptor α are associated with development and histologic severity of hepatic steatosis: a retrospective study.

PubMed

Choi, Euno; Kim, Won; Joo, Sae Kyung; Park, Sunyoung; Park, Jeong Hwan; Kang, Yun Kyung; Jin, So-Young; Chang, Mee Soo

2018-04-03

Hepatic steatosis renders hepatocytes vulnerable to injury, resulting in the progression of preexisting liver disease. Previous animal and cell culture studies implicated mammalian target of rapamycin (mTOR), signal transducer and activator of transcription-3 (STAT3), extracellular signal-regulated kinase (ERK) and estrogen-receptor α in the pathogenesis of hepatic steatosis and disease progression. However, to date there have been few studies performed using human liver tissue to study hepatic steatosis. We examined the expression patterns of mTOR, STAT3, ERK and estrogen-receptor α in liver tissues from patients diagnosed with hepatic steatosis. We reviewed the clinical and histomorphological features of 29 patients diagnosed with hepatic steatosis: 18 with non-alcoholic fatty liver disease (NAFLD), 11 with alcoholic fatty acid disease (AFLD), and a control group (16 biliary cysts and 22 hepatolithiasis). Immunohistochemistry was performed on liver tissue using an automated immunostainer. The histologic severity of hepatic steatosis was evaluated by assessing four key histomorphologic parameters common to NAFLD and AFLD: steatosis, lobular inflammation, ballooning degeneration and fibrosis. mTOR, phosphorylated STAT3, phosphorylated pERK, estrogen-receptor α were found to be more frequently expressed in the hepatic steatosis group than in the control group. Specifically, mTOR was expressed in 78% of hepatocytes, and ERK in 100% of hepatic stellate cells, respectively, in patients with NAFLD. Interestingly, estrogen-receptor α was diffusely expressed in hepatocytes in all NALFD cases. Phosphorylated (active) STAT3 was expressed in 73% of hepatocytes and 45% of hepatic stellate cells in patients with AFLD, and phosphorylated (active) ERK was expressed in hepatic stellate cells in all AFLD cases. Estrogen-receptor α was expressed in all AFLD cases (focally in 64% of AFLD cases, and diffusely in 36%). Phosphorylated STAT3 expression in hepatocytes and hepatic stellate cells correlated with severe lobular inflammation, severe ballooning degeneration and advanced fibrosis, whereas diffusely expressed estrogen-receptor α correlated with a mild stage of fibrosis. Our data indicate ERK activation and estrogen-receptor α may be relevant in the development of hepatic steatosis. However, diffuse expression of estrogen-receptor α would appear to impede disease progression, including hepatic fibrosis. Finally, phosphorylated STAT3 may also contribute to disease progression.

Quantitative assessment of multiple sclerosis lesion load using CAD and expert input

NASA Astrophysics Data System (ADS)

Gertych, Arkadiusz; Wong, Alexis; Sangnil, Alan; Liu, Brent J.

2008-03-01

Multiple sclerosis (MS) is a frequently encountered neurological disease with a progressive but variable course affecting the central nervous system. Outline-based lesion quantification in the assessment of lesion load (LL) performed on magnetic resonance (MR) images is clinically useful and provides information about the development and change reflecting overall disease burden. Methods of LL assessment that rely on human input are tedious, have higher intra- and inter-observer variability and are more time-consuming than computerized automatic (CAD) techniques. At present it seems that methods based on human lesion identification preceded by non-interactive outlining by CAD are the best LL quantification strategies. We have developed a CAD that automatically quantifies MS lesions, displays 3-D lesion map and appends radiological findings to original images according to current DICOM standard. CAD is also capable to display and track changes and make comparison between patient's separate MRI studies to determine disease progression. The findings are exported to a separate imaging tool for review and final approval by expert. Capturing and standardized archiving of manual contours is also implemented. Similarity coefficients calculated from quantities of LL in collected exams show a good correlation of CAD-derived results vs. those incorporated as expert's reading. Combining the CAD approach with an expert interaction may impact to the diagnostic work-up of MS patients because of improved reproducibility in LL assessment and reduced time for single MR or comparative exams reading. Inclusion of CAD-generated outlines as DICOM-compliant overlays into the image data can serve as a better reference in MS progression tracking.

Oncogenic Properties of Apoptotic Tumor Cells in Aggressive B Cell Lymphoma

PubMed Central

Ford, Catriona A.; Petrova, Sofia; Pound, John D.; Voss, Jorine J.L.P.; Melville, Lynsey; Paterson, Margaret; Farnworth, Sarah L.; Gallimore, Awen M.; Cuff, Simone; Wheadon, Helen; Dobbin, Edwina; Ogden, Carol Anne; Dumitriu, Ingrid E.; Dunbar, Donald R.; Murray, Paul G.; Ruckerl, Dominik; Allen, Judith E.; Hume, David A.; van Rooijen, Nico; Goodlad, John R.; Freeman, Tom C.; Gregory, Christopher D.

2015-01-01

Summary Background Cells undergoing apoptosis are known to modulate their tissue microenvironments. By acting on phagocytes, notably macrophages, apoptotic cells inhibit immunological and inflammatory responses and promote trophic signaling pathways. Paradoxically, because of their potential to cause death of tumor cells and thereby militate against malignant disease progression, both apoptosis and tumor-associated macrophages (TAMs) are often associated with poor prognosis in cancer. We hypothesized that, in progression of malignant disease, constitutive loss of a fraction of the tumor cell population through apoptosis could yield tumor-promoting effects. Results Here, we demonstrate that apoptotic tumor cells promote coordinated tumor growth, angiogenesis, and accumulation of TAMs in aggressive B cell lymphomas. Through unbiased “in situ transcriptomics” analysis—gene expression profiling of laser-captured TAMs to establish their activation signature in situ—we show that these cells are activated to signal via multiple tumor-promoting reparatory, trophic, angiogenic, tissue remodeling, and anti-inflammatory pathways. Our results also suggest that apoptotic lymphoma cells help drive this signature. Furthermore, we demonstrate that, upon induction of apoptosis, lymphoma cells not only activate expression of the tumor-promoting matrix metalloproteinases MMP2 and MMP12 in macrophages but also express and process these MMPs directly. Finally, using a model of malignant melanoma, we show that the oncogenic potential of apoptotic tumor cells extends beyond lymphoma. Conclusions In addition to its profound tumor-suppressive role, apoptosis can potentiate cancer progression. These results have important implications for understanding the fundamental biology of cell death, its roles in malignant disease, and the broader consequences of apoptosis-inducing anti-cancer therapy. PMID:25702581

Effect of solar radiation on severity of soybean rust.

PubMed

Young, Heather M; George, Sheeja; Narváez, Dario F; Srivastava, Pratibha; Schuerger, Andrew C; Wright, David L; Marois, James J

2012-08-01

Soybean rust (SBR), caused by Phakopsora pachyrhizi, is a damaging fungal disease of soybean (Glycine max). Although solar radiation can reduce SBR urediniospore survival, limited information is available on how solar radiation affects SBR progress within soybean canopies. Such information can aid in developing accurate SBR prediction models. To manipulate light penetration into soybean canopies, structures of shade cloth attenuating 30, 40, and 60% sunlight were constructed over soybean plots. In each plot, weekly evaluations of severity in lower, middle, and upper canopies, and daily temperature and relative humidity were recorded. Final plant height and leaf area index were also recorded for each plot. The correlation between amount of epicuticular wax and susceptibility of leaves in the lower, middle, and upper canopies was assessed with a detached leaf assay. Final disease severity was 46 to 150% greater in the lower canopy of all plots and in the middle canopy of 40 and 60% shaded plots. While daytime temperature within the canopy of nonshaded soybean was greater than shaded soybean by 2 to 3°C, temperatures recorded throughout typical evenings and mornings of the growing season in all treatments were within the range (10 to 28.5°C) for SBR development as was relative humidity. This indicates temperature and relative humidity were not limiting factors in this experiment. Epicuticular wax and disease severity in detached leaf assays from the upper canopy had significant negative correlation (P = 0.009, R = -0.84) regardless of shade treatment. In laboratory experiments, increasing simulated total solar radiation (UVA, UVB, and PAR) from 0.15 to 11.66 MJ m(-2) increased mortality of urediniospores from 2 to 91%. Variability in disease development across canopy heights in early planted soybean may be attributed to the effects of solar radiation not only on urediniospore viability, but also on plant height, leaf area index, and epicuticular wax, which influence disease development of SBR. These results provide an understanding of the effect solar radiation has on the progression of SBR within the soybean canopy.

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

PubMed

Pytka, Karolina; Zygmunt, Małgorzata; Filipek, Barbara

2013-07-24

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

Physical View on the Interactions Between Cancer Cells and the Endothelial Cell Lining During Cancer Cell Transmigration and Invasion

NASA Astrophysics Data System (ADS)

Mierke, Claudia T.

There exist many reviews on the biological and biochemical interactions of cancer cells and endothelial cells during the transmigration and tissue invasion of cancer cells. For the malignant progression of cancer, the ability to metastasize is a prerequisite. In particular, this means that certain cancer cells possess the property to migrate through the endothelial lining into blood or lymph vessels, and are possibly able to transmigrate through the endothelial lining into the connective tissue and follow up their invasion path in the targeted tissue. On the molecular and biochemical level the transmigration and invasion steps are well-defined, but these signal transduction pathways are not yet clear and less understood in regards to the biophysical aspects of these processes. To functionally characterize the malignant transformation of neoplasms and subsequently reveal the underlying pathway(s) and cellular properties, which help cancer cells to facilitate cancer progression, the biomechanical properties of cancer cells and their microenvironment come into focus in the physics-of-cancer driven view on the metastasis process of cancers. Hallmarks for cancer progression have been proposed, but they still lack the inclusion of specific biomechanical properties of cancer cells and interacting surrounding endothelial cells of blood or lymph vessels. As a cancer cell is embedded in a special environment, the mechanical properties of the extracellular matrix also cannot be neglected. Therefore, in this review it is proposed that a novel hallmark of cancer that is still elusive in classical tumor biological reviews should be included, dealing with the aspect of physics in cancer disease such as the natural selection of an aggressive (highly invasive) subtype of cancer cells displaying a certain adhesion or chemokine receptor on their cell surface. Today, the physical aspects can be analyzed by using state-of-the-art biophysical methods. Thus, this review will present current cancer research in a different light from a physical point of view with respect to cancer cell mechanics and the special and unique role of the endothelium on cancer cell invasion. The physical view on cancer disease may lead to novel insights into cancer disease and will help to overcome the classical views on cancer. In addition, in this review it will be discussed how physics of cancer can help to reveal and propose the functional mechanism which cancer cells use to invade connective tissue and transmigrate through the endothelium to finally metastasize. Finally, in this review it will be demonstrated how biophysical measurements can be combined with classical analysis approaches of tumor biology. The insights into physical interactions between cancer cells, the endothelium and the microenvironment may help to answer some "old," but still important questions in cancer disease progression.

Physical View on the Interactions Between Cancer Cells and the Endothelial Cell Lining During Cancer Cell Transmigration and Invasion

NASA Astrophysics Data System (ADS)

Mierke, Claudia T.

2015-10-01

There exist many reviews on the biological and biochemical interactions of cancer cells and endothelial cells during the transmigration and tissue invasion of cancer cells. For the malignant progression of cancer, the ability to metastasize is a prerequisite. In particular, this means that certain cancer cells possess the property to migrate through the endothelial lining into blood or lymph vessels, and are possibly able to transmigrate through the endothelial lining into the connective tissue and follow up their invasion path in the targeted tissue. On the molecular and biochemical level the transmigration and invasion steps are well-defined, but these signal transduction pathways are not yet clear and less understood in regards to the biophysical aspects of these processes. To functionally characterize the malignant transformation of neoplasms and subsequently reveal the underlying pathway(s) and cellular properties, which help cancer cells to facilitate cancer progression, the biomechanical properties of cancer cells and their microenvironment come into focus in the physics-of-cancer driven view on the metastasis process of cancers. Hallmarks for cancer progression have been proposed, but they still lack the inclusion of specific biomechanical properties of cancer cells and interacting surrounding endothelial cells of blood or lymph vessels. As a cancer cell is embedded in a special environment, the mechanical properties of the extracellular matrix also cannot be neglected. Therefore, in this review it is proposed that a novel hallmark of cancer that is still elusive in classical tumor biological reviews should be included, dealing with the aspect of physics in cancer disease such as the natural selection of an aggressive (highly invasive) subtype of cancer cells displaying a certain adhesion or chemokine receptor on their cell surface. Today, the physical aspects can be analyzed by using state-of-the-art biophysical methods. Thus, this review will present current cancer research in a different light from a physical point of view with respect to cancer cell mechanics and the special and unique role of the endothelium on cancer cell invasion. The physical view on cancer disease may lead to novel insights into cancer disease and will help to overcome the classical views on cancer. In addition, in this review it will be discussed how physics of cancer can help to reveal and propose the functional mechanism which cancer cells use to invade connective tissue and transmigrate through the endothelium to finally metastasize. Finally, in this review it will be demonstrated how biophysical measurements can be combined with classical analysis approaches of tumor biology. The insights into physical interactions between cancer cells, the endothelium and the microenvironment may help to answer some "old," but still important questions in cancer disease progression.

Identification of the lipid biomarkers from plasma in idiopathic pulmonary fibrosis by Lipidomics.

PubMed

Yan, Feng; Wen, Zhensong; Wang, Rui; Luo, Wenling; Du, Yufeng; Wang, Wenjun; Chen, Xianyang

2017-12-06

Idiopathic pulmonary fibrosis (IPF) is an irreversible interstitial pulmonary disease featured by high mortality, chronic and progressive course, and poor prognosis with unclear etiology. Currently, more studies have been focusing on identifying biomarkers to predict the progression of IPF, such as genes, proteins, and lipids. Lipids comprise diverse classes of molecules and play a critical role in cellular energy storage, structure, and signaling. The role of lipids in respiratory diseases, including cystic fibrosis, asthma and chronic obstructive pulmonary disease (COPD) has been investigated intensely in the recent years. The human serum lipid profiles in IPF patients however, have not been thoroughly understood and it will be very helpful if there are available molecular biomarkers, which can be used to monitor the disease progression or provide prognostic information for IPF disease. In this study, we performed the ultraperformance liquid chromatography coupled with quadrupole time of flight mass spectrometry (UPLC-QTOF/MS) to detect the lipid variation and identify biomarker in plasma of IPF patients. The plasma were from 22 IPF patients before received treatment and 18 controls. A total of 507 individual blood lipid species were determined with lipidomics from the 40 plasma samples including 20 types of fatty acid, 159 types of glycerolipids, 221 types of glycerophospholipids, 47 types of sphingolipids, 46 types of sterol lipids, 7 types of prenol lipids, 3 types of saccharolipids, and 4 types of polyketides. By comparing the variations in the lipid metabolite levels in IPF patients, a total of 62 unique lipids were identified by statistical analysis including 24 kinds of glycerophoslipids, 30 kinds of glycerolipids, 3 kinds of sterol lipids, 4 kinds of sphingolipids and 1 kind of fatty acids. Finally, 6 out of 62 discriminating lipids were selected as the potential biomarkers, which are able to differentiate between IPF disease and controls with ROC analysis. Our results provided vital information regarding lipid metabolism in IPF patients and more importantly, a few potentially promising biomarkers were firstly identified which may have a predictive role in monitoring and diagnosing IPF disease.

IgG4-related disease: description of a case with pulmonary lesions, mediastinal lymphadenopathies and rapidly progressive renal failure.

PubMed

Fernández Lorente, Loreto; Álvarez, Dolores López; López, Virginia García; Kollros, Vesna Abujder; Ariza, Aurelio; Gálvez, Alejandro; Bonet, Josep

2015-01-01

This is a case report of a 73-year-old man with new-onset acute renal failure while being investigated for pulmonary infiltrates and mediastinal lymphadenopathies. Urine tests showed tubular range proteinuria with no microhaematuria. Immunology tests showed elevated serum IgG and hypocomplementaemia (classical pathway activation). Renal biopsy and clinical-pathological correlation were crucial in this case, reinforcing their important role in the final diagnosis of acute kidney injury. Copyright © 2015. Published by Elsevier España, S.L.U.

Endocytic vesicle rupture is a conserved mechanism of cellular invasion by amyloid proteins.

PubMed

Flavin, William P; Bousset, Luc; Green, Zachary C; Chu, Yaping; Skarpathiotis, Stratos; Chaney, Michael J; Kordower, Jeffrey H; Melki, Ronald; Campbell, Edward M

2017-10-01

Numerous pathological amyloid proteins spread from cell to cell during neurodegenerative disease, facilitating the propagation of cellular pathology and disease progression. Understanding the mechanism by which disease-associated amyloid protein assemblies enter target cells and induce cellular dysfunction is, therefore, key to understanding the progressive nature of such neurodegenerative diseases. In this study, we utilized an imaging-based assay to monitor the ability of disease-associated amyloid assemblies to rupture intracellular vesicles following endocytosis. We observe that the ability to induce vesicle rupture is a common feature of α-synuclein (α-syn) assemblies, as assemblies derived from WT or familial disease-associated mutant α-syn all exhibited the ability to induce vesicle rupture. Similarly, different conformational strains of WT α-syn assemblies, but not monomeric or oligomeric forms, efficiently induced vesicle rupture following endocytosis. The ability to induce vesicle rupture was not specific to α-syn, as amyloid assemblies of tau and huntingtin Exon1 with pathologic polyglutamine repeats also exhibited the ability to induce vesicle rupture. We also observe that vesicles ruptured by α-syn are positive for the autophagic marker LC3 and can accumulate and fuse into large, intracellular structures resembling Lewy bodies in vitro. Finally, we show that the same markers of vesicle rupture surround Lewy bodies in brain sections from PD patients. These data underscore the importance of this conserved endocytic vesicle rupture event as a damaging mechanism of cellular invasion by amyloid assemblies of multiple neurodegenerative disease-associated proteins, and suggest that proteinaceous inclusions such as Lewy bodies form as a consequence of continued fusion of autophagic vesicles in cells unable to degrade ruptured vesicles and their amyloid contents.

The de-ubiquitinating enzyme ataxin-3 does not modulate disease progression in a knock-in mouse model of Huntington disease.

PubMed

Zeng, Li; Tallaksen-Greene, Sara J; Wang, Bo; Albin, Roger L; Paulson, Henry L

2013-01-01

Ataxin-3 is a deubiquitinating enzyme (DUB) that participates in ubiquitin-dependent protein quality control pathways and, based on studies in model systems, may be neuroprotective against toxic polyglutamine proteins such as the Huntington's disease (HD) protein, huntingtin (htt). HD is one of at least nine polyglutamine neurodegenerative diseases in which disease-causing proteins accumulate in ubiquitin-positive inclusions within neurons. In studies crossing mice null for ataxin-3 to an established HD knock-in mouse model (HdhQ200), we tested whether loss of ataxin-3 alters disease progression, perhaps by impairing the clearance of mutant htt or the ubiquitination of inclusions. While loss of ataxin-3 mildly exacerbated age-dependent motor deficits, it did not alter inclusion formation, ubiquitination of inclusions or levels of mutant or normal htt. Ataxin-3, itself a polyglutamine-containing protein with multiple ubiquitin binding domains, was not observed to localize to htt inclusions. Changes in neurotransmitter receptor binding known to occur in HD knock-in mice also were not altered by the loss of ataxin-3, although we unexpectedly observed increased GABAA receptor binding in the striatum of HdhQ200 mice, which has not previously been noted. Finally, we confirmed that CNS levels of hsp70 are decreased in HD mice as has been reported in other HD mouse models, regardless of the presence or absence of ataxin-3. We conclude that while ataxin-3 may participate in protein quality control pathways, it does not critically regulate the handling of mutant htt or contribute to major features of disease pathogenesis in HD.

Dracunculiasis (Guinea Worm Disease) and the Eradication Initiative

PubMed Central

Cairncross, Sandy; Muller, Ralph; Zagaria, Nevio

2002-01-01

Dracunculiasis, also known as guinea worm disease, is caused by the large female of the nematode Dracunculus medinensis, which emerges painfully and slowly from the skin, usually on the lower limbs. The disease can infect animals, and sustainable animal cycles occur in North America and Central Asia but do not act as reservoirs of human infection. The disease is endemic across the Sahel belt of Africa from Mauritania to Ethiopia, having been eliminated from Asia and some African countries. It has a significant socioeconomic impact because of the temporary disability that it causes. Dracunculiasis is exclusively caught from drinking water, usually from ponds. A campaign to eradicate the disease was launched in the 1980s and has made significant progress. The strategy of the campaign is discussed, including water supply, health education, case management, and vector control. Current issues including the integration of the campaign into primary health care and the mapping of cases by using geographic information systems are also considered. Finally, some lessons for other disease control and eradication programs are outlined. PMID:11932231

Circular RNA ZNF609 functions as a competitive endogenous RNA to regulate AKT3 expression by sponging miR-150-5p in Hirschsprung's disease.

PubMed

Peng, Lei; Chen, Guanglin; Zhu, Zhongxian; Shen, Ziyang; Du, Chunxia; Zang, Rujin; Su, Yang; Xie, Hua; Li, Hongxing; Xu, Xiaoqun; Xia, Yankai; Tang, Weibing

2017-01-03

Research over the past decade suggested critical roles for circular RNAs in the natural growth and disease progression. However, it remains poorly defined whether the circular RNAs participate in Hirschsprung disease (HSCR). Here, we reported that the cir-ZNF609 was down-regulated in HSCR compared with normal bowel tissues. Furthermore, suppression of cir-ZNF609 inhibited the proliferation and migration of cells. We screened out several putative cir-ZNF609 ceRNAs of which the AKT3 transcript was selected. Finally, RNA immunoprecipitation and luciferase reporter assays demonstrated that cir-ZNF609 may act as a sponge for miR-150-5p to modulate the expression of AKT3. In conclusion, these findings illustrated that cir-ZNF609 took part in the onset of HSCR through the crosstalk with AKT3 by competing for shared miR-150-5p.

Dioxygen and Metabolism; Dangerous Liaisons in Cardiac Function and Disease

PubMed Central

Angelini, Aude; Pi, Xinchun; Xie, Liang

2017-01-01

The heart must consume a significant amount of energy to sustain its contractile activity. Although the fuel demands are huge, the stock remains very low. Thus, in order to supply its daily needs, the heart must have amazing adaptive abilities, which are dependent on dioxygen availability. However, in myriad cardiovascular diseases, “fuel” depletion and hypoxia are common features, leading cardiomyocytes to favor low-dioxygen-consuming glycolysis rather than oxidation of fatty acids. This metabolic switch makes it challenging to distinguish causes from consequences in cardiac pathologies. Finally, despite the progress achieved in the past few decades, medical treatments have not improved substantially, either. In such a situation, it seems clear that much remains to be learned about cardiac diseases. Therefore, in this review, we will discuss how reconciling dioxygen availability and cardiac metabolic adaptations may contribute to develop full and innovative strategies from bench to bedside. PMID:29311974

A brief history of vaccines: smallpox to the present.

PubMed

Hsu, Jennifer L

2013-01-01

Modern vaccine history began in the late 18th century with the discovery of smallpox immunization by Edward Jenner. This pivotal step led to substantial progress in prevention of infectious diseases with inactivated vaccines for multiple infectious diseases, including typhoid, plague and cholera. Each advance produced significant decreases in infection-associated morbidity and mortality, thus shaping our modem cultures. As knowledge of microbiology and immunology grew through the 20th century, techniques were developed for cell culture of viruses. This allowed for rapid advances in prevention of polio, varicella, influenza and others. Finally, recent research has led to development of alternative vaccine strategies through use of vectored antigens, pathogen subunits (purified proteins or polysaccharides) or genetically engineered antigens. As the science of vaccinology continues to rapidly evolve, knowledge of the past creates added emphasis on the importance of developing safe and effective strategies for infectious disease prevention in the 21st century.

Myocardial lipid content in Fabry disease: a combined 1H-MR spectroscopy and MR imaging study at 3 Tesla.

PubMed

Petritsch, B; Köstler, H; Weng, A M; Horn, M; Gassenmaier, T; Kunz, A S; Weidemann, F; Wanner, C; Bley, T A; Beer, M

2016-10-28

Fabry disease is characterized by a progressive deposition of sphingolipids in different organ systems, whereby cardiac involvement leads to death. We hypothesize that lysosomal storage of sphingolipids in the heart as occurring in Fabry disease does not reflect in higher cardiac lipid concentrations detectable by 1 H magnetic resonance spectroscopy (MRS) at 3 Tesla. Myocardial lipid content was quantified in vivo by 1 H-MRS in 30 patients (12 male, 18 female; 18 patients treated with enzyme replacement therapy) with genetically proven Fabry disease and in 30 healthy controls. The study protocol combined 1 H-MRS with cardiac cine imaging and LGE MRI in a single examination. Myocardial lipid content was not significantly elevated in Fabry disease (p = 0.225). Left ventricular (LV) mass was significantly higher in patients suffering from Fabry disease compared to controls (p = 0.019). Comparison of patients without signs of myocardial fibrosis in MRI (LGE negative; n = 12) to patients with signs of fibrosis (LGE positive; n = 18) revealed similar myocardial lipid content in both groups (p > 0.05), while the latter showed a trend towards elevated LV mass (p = 0.076). This study demonstrates the potential of lipid metabolic investigation embedded in a comprehensive examination of cardiac morphology and function in Fabry disease. There was no evidence that lysosomal storage of sphingolipids influences cardiac lipid content as measured by 1 H-MRS. Finally, the authors share the opinion that a comprehensive cardiac examination including three subsections (LGE; 1 H-MRS; T 1 mapping), could hold the highest potential for the final assessment of early and late myocardial changes in Fabry disease.

Mucosal immunology of HIV infection.

PubMed

Xu, Huanbin; Wang, Xiaolei; Veazey, Ronald S

2013-07-01

Recent advances in the immunology, pathogenesis, and prevention of human immunodeficiency virus (HIV) infection continue to reveal clues to the mechanisms involved in the progressive immunodeficiency attributed to infection, but more importantly have shed light on the correlates of immunity to infection and disease progression. HIV selectively infects, eliminates, and/or dysregulates several key cells of the human immune system, thwarting multiple arms of the host immune response, and inflicting severe damage to mucosal barriers, resulting in tissue infiltration of 'symbiotic' intestinal bacteria and viruses that essentially become opportunistic infections promoting systemic immune activation. This leads to activation and recruitment or more target cells for perpetuating HIV infection, resulting in persistent, high-level viral replication in lymphoid tissues, rapid evolution of resistant strains, and continued evasion of immune responses. However, vaccine studies and studies of spontaneous controllers are finally providing correlates of immunity from protection and disease progression, including virus-specific CD4(+) T-cell responses, binding anti-bodies, innate immune responses, and generation of antibodies with potent antibody-dependent cell-mediated cytotoxicity activity. Emerging correlates of immunity indicate that prevention of HIV infection may be possible through effective vaccine strategies that protect and stimulate key regulatory cells and immune responses in susceptible hosts. Furthermore, immune therapies specifically directed toward boosting specific aspects of the immune system may eventually lead to a cure for HIV-infected patients. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Mucosal Immunology of HIV Infection

PubMed Central

Xu, Huanbin; Wang, Xiaolei; Veazey, Ronald S.

2013-01-01

Summary Recent advances in the immunology, pathogenesis, and prevention of human immunodeficiency virus (HIV) infection continue to reveal clues to the mechanisms involved in the progressive immunodeficiency attributed to infection but more importantly have shed light on the correlates of immunity to infection and disease progression. HIV selectively infects, eliminates, and/or dysregulates several key cells of the human immune system, thwarting multiple arms of the host immune response, and inflicting severe damage to mucosal barriers, resulting in tissue infiltration of ‘symbiotic’ intestinal bacteria and viruses that essentially become opportunistic infections promoting systemic immune activation. This leads to activation and recruitment or more target cells for perpetuating HIV infection, resulting in persistent, high level viral replication in lymphoid tissues, rapid evolution of resistant strains, and continued evasion of immune responses. However, vaccine studies and studies of spontaneous controllers are finally providing correlates of immunity from protection and disease progression, including virus-specific CD4+ T-cell responses, binding antibodies, innate immune responses, and generation of antibodies with potent antibody-dependent cell-mediated cytotoxicity activity. Emerging correlates of immunity indicate that prevention of HIV infection may be possible through effective vaccine strategies that protect and stimulate key regulatory cells and immune responses in susceptible hosts. Further, immune therapies specifically directed towards boosting specific aspects of the immune system may eventually lead to a cure for HIV-infected patients. PMID:23772612

Disease progression and neuroscience.

PubMed

Holford, Nick

2013-06-01

The concepts of disease progression are discussed in the context of neurological disorders. The importance of understanding the time course of the response to inactive (placebo) treatment is discussed. Disease progression and response to placebo treatment both need to be considered before drug effects can be reliably identified. Criteria for distinguishing between symptomatic and disease modifying drug effects are proposed and used to interpret the results of clinical trials in pain, depression, schizophrenia, stroke, Alzheimer's disease and Parkinson's disease.

Model-based economic evaluation in Alzheimer's disease: a review of the methods available to model Alzheimer's disease progression.

PubMed

Green, Colin; Shearer, James; Ritchie, Craig W; Zajicek, John P

2011-01-01

To consider the methods available to model Alzheimer's disease (AD) progression over time to inform on the structure and development of model-based evaluations, and the future direction of modelling methods in AD. A systematic search of the health care literature was undertaken to identify methods to model disease progression in AD. Modelling methods are presented in a descriptive review. The literature search identified 42 studies presenting methods or applications of methods to model AD progression over time. The review identified 10 general modelling frameworks available to empirically model the progression of AD as part of a model-based evaluation. Seven of these general models are statistical models predicting progression of AD using a measure of cognitive function. The main concerns with models are on model structure, around the limited characterization of disease progression, and on the use of a limited number of health states to capture events related to disease progression over time. None of the available models have been able to present a comprehensive model of the natural history of AD. Although helpful, there are serious limitations in the methods available to model progression of AD over time. Advances are needed to better model the progression of AD and the effects of the disease on peoples' lives. Recent evidence supports the need for a multivariable approach to the modelling of AD progression, and indicates that a latent variable analytic approach to characterising AD progression is a promising avenue for advances in the statistical development of modelling methods. Copyright © 2011 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

The progression rate of spinocerebellar ataxia type 2 changes with stage of disease.

PubMed

Monte, Thais Lampert; Reckziegel, Estela da Rosa; Augustin, Marina Coutinho; Locks-Coelho, Lucas D; Santos, Amanda Senna P; Furtado, Gabriel Vasata; de Mattos, Eduardo Preusser; Pedroso, José Luiz; Barsottini, Orlando Póvoas; Vargas, Fernando Regla; Saraiva-Pereira, Maria-Luiza; Camey, Suzi Alves; Leotti, Vanessa Bielefeldt; Jardim, Laura Bannach

2018-01-25

Spinocerebellar ataxia type 2 (SCA2) affects several neurological structures, giving rise to multiple symptoms. However, only the natural history of ataxia is well known, as measured during the study duration. We aimed to describe the progression rate of ataxia, by the Scale for the Assessment and Rating of Ataxia (SARA), as well as the progression rate of the overall neurological picture, by the Neurological Examination Score for Spinocerebellar Ataxias (NESSCA), and not only during the study duration but also in a disease duration model. Comparisons between these models might allow us to explore whether progression is linear during the disease duration in SCA2; and to look for potential modifiers. Eighty-eight evaluations were prospectively done on 49 symptomatic subjects; on average (SD), study duration and disease duration models covered 13 (2.16) months and 14 (6.66) years of individuals' life, respectively. SARA progressed 1.75 (CI 95%: 0.92-2.57) versus 0.79 (95% CI 0.45 to 1.14) points/year in the study duration and disease duration models. NESSCA progressed 1.45 (CI 95%: 0.74-2.16) versus 0.41 (95% CI 0.24 to 0.59) points/year in the same models. In order to explain these discrepancies, the progression rates of the study duration model were plotted against disease duration. Then an acceleration was detected after 10 years of disease duration: SARA scores progressed 0.35 before and 2.45 points/year after this deadline (p = 0.013). Age at onset, mutation severity, and presence of amyotrophy, parkinsonism, dystonic manifestations and cognitive decline at baseline did not influence the rate of disease progression. NESSCA and SARA progression rates were not constant during disease duration in SCA2: early phases of disease were associated with slower progressions. Modelling of future clinical trials on SCA2 should take this phenomenon into account, since disease duration might impact on inclusion criteria, sample size, and study duration. Our database is available online and accessible to future studies aimed to compare the present data with other cohorts.

Radiographic Progression-Free Survival as a Clinically Meaningful End Point in Metastatic Castration-Resistant Prostate Cancer: The PREVAIL Randomized Clinical Trial.

PubMed

Rathkopf, Dana E; Beer, Tomasz M; Loriot, Yohann; Higano, Celestia S; Armstrong, Andrew J; Sternberg, Cora N; de Bono, Johann S; Tombal, Bertrand; Parli, Teresa; Bhattacharya, Suman; Phung, De; Krivoshik, Andrew; Scher, Howard I; Morris, Michael J

2018-05-01

Drug development for metastatic castration-resistant prostate cancer has been limited by a lack of clinically relevant trial end points short of overall survival (OS). Radiographic progression-free survival (rPFS) as defined by the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) is a candidate end point that represents a clinically meaningful benefit to patients. To demonstrate the robustness of the PCWG2 definition and to examine the relationship between rPFS and OS. PREVAIL was a phase 3, randomized, double-blind, placebo-controlled multinational study that enrolled 1717 chemotherapy-naive men with metastatic castration-resistant prostate cancer from September 2010 through September 2012. The data were analyzed in November 2016. Patients were randomized 1:1 to enzalutamide 160 mg or placebo until confirmed radiographic disease progression or a skeletal-related event and initiation of either cytotoxic chemotherapy or an investigational agent for prostate cancer treatment. Sensitivity analyses (SAs) of investigator-assessed rPFS were performed using the final rPFS data cutoff (May 6, 2012; 439 events; SA1) and the interim OS data cutoff (September 16, 2013; 540 events; SA2). Additional SAs using investigator-assessed rPFS from the final rPFS data cutoff assessed the impact of skeletal-related events (SA3), clinical progression (SA4), a confirmatory scan for soft-tissue disease progression (SA5), and all deaths regardless of time after study drug discontinuation (SA6). Correlations between investigator-assessed rPFS (SA2) and OS were calculated using Spearman ρ and Kendall τ via Clayton copula. In the 1717 men (mean age, 72.0 [range, 43.0-93.0] years in enzalutamide arm and 71.0 [range, 42.0-93.0] years in placebo arm), enzalutamide significantly reduced risk of radiographic progression or death in all SAs, with hazard ratios of 0.22 (SA1; 95% CI, 0.18-0.27), 0.31 (SA2; 95% CI, 0.27-0.35), 0.21 (SA3; 95% CI, 0.18-0.26), 0.21 (SA4; 95% CI, 0.17-0.26), 0.23 (SA5; 95% CI, 0.19-0.30), and 0.23 (SA6; 95% CI, 0.19-0.30) (P < .001 for all). Correlations of rPFS and OS in enzalutamide-treated patients were 0.89 (95% CI, 0.86-0.92) by Spearman ρ and 0.72 (95% CI, 0.68-0.77) by Kendall τ. Sensitivity analyses in PREVAIL demonstrated the robustness of the PCWG2 rPFS definition using additional measures of progression. There was concordance between central and investigator review and a positive correlation between rPFS and OS among enzalutamide-treated patients. clinicaltrials.gov Identifier: NCT01212991.

PATHOPHYSIOLOGY AND THE CARDIORENAL CONNECTION IN HEART FAILURE. CIRCULATING HORMONES: BIOMARKERS OR MEDIATORS

PubMed Central

BUGLIONI, ALESSIA; BURNETT, JOHN C.

2014-01-01

Heart failure (HF) is a syndrome characterized by a complex pathophysiology which involves multiple organ systems, with the kidney playing a major role. HF can present with reduced ejection fraction (EF), HFrEF, or with preserved EF (HFpEF). The interplay between diverse organ systems contributing to HF is mediated by the activation of counteracting neurohormonal pathways focused to re-establishing hemodynamic homeostasis. During early stages of HF, these biochemical signals, consisting mostly of hormones and neurotransmitters secreted by a variety of cell types, are compensatory and the patient is asymptomatic. However, with disease progression, the attempt to reverse or delay cardiac dysfunction is deleterious, leading to multi-organ congestion, fibrosis and decompensation and finally symptomatic HF. In conclusion, these neurohormonal pathways mediate the evolution of HF and have become a way to monitor HF. Specifically, these mediators have become important in the diagnosis and prognosis of this highly fatal cardiovascular disease. Finally, while these multiple neurohumoral factors serve as important HF biomarkers, they can also be targeted for more effective and curative HF treatments. PMID:25445413

Effects of dietary salt restriction on renal progression and interstitial fibrosis in adriamycin nephrosis.

PubMed

Park, Joon-Sung; Kim, Sua; Jo, Chor Ho; Oh, Il Hwan; Kim, Gheun-Ho

2014-01-01

Although high salt intake is thought to accelerate renal progression in proteinuric kidney disease, it is not known whether strict dietary salt restriction could delay renal inflammation and interstitial fibrosis. Here, we sought to answer this question in a rat model of adriamycin-induced nephrotic syndrome. Adriamycin was administered via the femoral vein in a single bolus (7.5 mg/kg), and the rats were put on a sodium-deficient rodent diet. Rats with intact kidneys were studied for 5 weeks (experiment 1), and uninephrectomized rats were studied for 6 weeks (experiment 2). In experiment 1, restricting salt intake improved renal tubulointerstitial histopathology in adriamycin-treated rats. Immunohistochemical and immunoblot results additionally showed that restricting dietary salt lowered adriamycin-induced expression of osteopontin, collagen III, and fibronectin. In experiment 2, salt restriction improved adriamycin-induced azotemia, although it did not affect proteinuria or blood pressure. Dietary salt restriction also reduced adriamycin-induced infiltration of ED1-positive cells and the upregulated expression of osteopontin and α-SMA. Masson's trichrome and Sirius red staining revealed that salt restriction slowed Adriamycin-induced progression of renal interstitial fibrosis. Finally, qPCR revealed that adriamycin-induced expression of TNF-α, IκB-α, gp91(phox), p47(phox), and p67(phox) mRNA was blocked by salt restriction. Our findings demonstrate that strict dietary salt restriction delays the progress of renal inflammation and fibrosis in proteinuric kidney disease, most likely via relieving the reactive oxygen species-mediated NF-κB activation. © 2014 S. Karger AG, Basel.

Caprylic Triglyceride as a Novel Therapeutic Approach to Effectively Improve the Performance and Attenuate the Symptoms Due to the Motor Neuron Loss in ALS Disease

PubMed Central

Zhao, Wei; Varghese, Merina; Vempati, Prashant; Dzhun, Anastasiya; Cheng, Alice; Wang, Jun; Lange, Dale; Bilski, Amanda; Faravelli, Irene; Pasinetti, Giulio Maria

2012-01-01

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of motor neurons causing progressive muscle weakness, paralysis, and finally death. ALS patients suffer from asthenia and their progressive weakness negatively impacts quality of life, limiting their daily activities. They have impaired energy balance linked to lower activity of mitochondrial electron transport chain enzymes in ALS spinal cord, suggesting that improving mitochondrial function may present a therapeutic approach for ALS. When fed a ketogenic diet, the G93A ALS mouse shows a significant increase in serum ketones as well as a significantly slower progression of weakness and lower mortality rate. In this study, we treated SOD1-G93A mice with caprylic triglyceride, a medium chain triglyceride that is metabolized into ketone bodies and can serve as an alternate energy substrate for neuronal metabolism. Treatment with caprylic triglyceride attenuated progression of weakness and protected spinal cord motor neuron loss in SOD1-G93A transgenic animals, significantly improving their performance even though there was no significant benefit regarding the survival of the ALS transgenic animals. We found that caprylic triglyceride significantly promoted the mitochondrial oxygen consumption rate in vivo. Our results demonstrated that caprylic triglyceride alleviates ALS-type motor impairment through restoration of energy metabolism in SOD1-G93A ALS mice, especially during the overt stage of the disease. These data indicate the feasibility of using caprylic acid as an easily administered treatment with a high impact on the quality of life of ALS patients. PMID:23145119

Caprylic triglyceride as a novel therapeutic approach to effectively improve the performance and attenuate the symptoms due to the motor neuron loss in ALS disease.

PubMed

Zhao, Wei; Varghese, Merina; Vempati, Prashant; Dzhun, Anastasiya; Cheng, Alice; Wang, Jun; Lange, Dale; Bilski, Amanda; Faravelli, Irene; Pasinetti, Giulio Maria

2012-01-01

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of motor neurons causing progressive muscle weakness, paralysis, and finally death. ALS patients suffer from asthenia and their progressive weakness negatively impacts quality of life, limiting their daily activities. They have impaired energy balance linked to lower activity of mitochondrial electron transport chain enzymes in ALS spinal cord, suggesting that improving mitochondrial function may present a therapeutic approach for ALS. When fed a ketogenic diet, the G93A ALS mouse shows a significant increase in serum ketones as well as a significantly slower progression of weakness and lower mortality rate. In this study, we treated SOD1-G93A mice with caprylic triglyceride, a medium chain triglyceride that is metabolized into ketone bodies and can serve as an alternate energy substrate for neuronal metabolism. Treatment with caprylic triglyceride attenuated progression of weakness and protected spinal cord motor neuron loss in SOD1-G93A transgenic animals, significantly improving their performance even though there was no significant benefit regarding the survival of the ALS transgenic animals. We found that caprylic triglyceride significantly promoted the mitochondrial oxygen consumption rate in vivo. Our results demonstrated that caprylic triglyceride alleviates ALS-type motor impairment through restoration of energy metabolism in SOD1-G93A ALS mice, especially during the overt stage of the disease. These data indicate the feasibility of using caprylic acid as an easily administered treatment with a high impact on the quality of life of ALS patients.

Molecular Phenotypes Distinguish Patients with Relatively Stable from Progressive Idiopathic Pulmonary Fibrosis (IPF)

PubMed Central

Boon, Kathy; Bailey, Nathaniel W.; Yang, Jun; Steel, Mark P.; Groshong, Steve; Kervitsky, Dolly; Brown, Kevin K.; Schwarz, Marvin I.; Schwartz, David A.

2009-01-01

Background Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic interstitial lung disease that is unresponsive to current therapy and often leads to death. However, the rate of disease progression differs among patients. We hypothesized that comparing the gene expression profiles between patients with stable disease and those in which the disease progressed rapidly will lead to biomarker discovery and contribute to the understanding of disease pathogenesis. Methodology and Principal Findings To begin to address this hypothesis, we applied Serial Analysis of Gene Expression (SAGE) to generate lung expression profiles from diagnostic surgical lung biopsies in 6 individuals with relatively stable (or slowly progressive) IPF and 6 individuals with progressive IPF (based on changes in DLCO and FVC over 12 months). Our results indicate that this comprehensive lung IPF SAGE transcriptome is distinct from normal lung tissue and other chronic lung diseases. To identify candidate markers of disease progression, we compared the IPF SAGE profiles in stable and progressive disease, and identified a set of 102 transcripts that were at least 5-fold up regulated and a set of 89 transcripts that were at least 5-fold down regulated in the progressive group (P-value≤0.05). The over expressed genes included surfactant protein A1, two members of the MAPK-EGR-1-HSP70 pathway that regulate cigarette-smoke induced inflammation, and Plunc (palate, lung and nasal epithelium associated), a gene not previously implicated in IPF. Interestingly, 26 of the up regulated genes are also increased in lung adenocarcinomas and have low or no expression in normal lung tissue. More importantly, we defined a SAGE molecular expression signature of 134 transcripts that sufficiently distinguished relatively stable from progressive IPF. Conclusions These findings indicate that molecular signatures from lung parenchyma at the time of diagnosis could prove helpful in predicting the likelihood of disease progression or possibly understanding the biological activity of IPF. PMID:19347046

Cerebral causes and consequences of parkinsonian resting tremor: a tale of two circuits?

PubMed Central

Hallett, Mark; Deuschl, Günther; Toni, Ivan; Bloem, Bastiaan R.

2012-01-01

Tremor in Parkinson's disease has several mysterious features. Clinically, tremor is seen in only three out of four patients with Parkinson's disease, and tremor-dominant patients generally follow a more benign disease course than non-tremor patients. Pathophysiologically, tremor is linked to altered activity in not one, but two distinct circuits: the basal ganglia, which are primarily affected by dopamine depletion in Parkinson's disease, and the cerebello-thalamo-cortical circuit, which is also involved in many other tremors. The purpose of this review is to integrate these clinical and pathophysiological features of tremor in Parkinson's disease. We first describe clinical and pathological differences between tremor-dominant and non-tremor Parkinson's disease subtypes, and then summarize recent studies on the pathophysiology of tremor. We also discuss a newly proposed ‘dimmer-switch model’ that explains tremor as resulting from the combined actions of two circuits: the basal ganglia that trigger tremor episodes and the cerebello-thalamo-cortical circuit that produces the tremor. Finally, we address several important open questions: why resting tremor stops during voluntary movements, why it has a variable response to dopaminergic treatment, why it indicates a benign Parkinson's disease subtype and why its expression decreases with disease progression. PMID:22382359

Sporadic Jakob-Creutzfeldt Disease Presenting as Primary Progressive Aphasia

PubMed Central

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

2015-01-01

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

The Impact of the Nitric Oxide (NO)/Soluble Guanylyl Cyclase (sGC) Signaling Cascade on Kidney Health and Disease: A Preclinical Perspective.

PubMed

Krishnan, Shalini M; Kraehling, Jan R; Eitner, Frank; Bénardeau, Agnès; Sandner, Peter

2018-06-09

Chronic Kidney Disease (CKD) is a highly prevalent disease with a substantial medical need for new and more efficacious treatments. The Nitric Oxide (NO), soluble guanylyl cyclase (sGC), cyclic guanosine monophosphate (cGMP) signaling cascade regulates various kidney functions. cGMP directly influences renal blood flow, renin secretion, glomerular function, and tubular exchange processes. Downregulation of NO/sGC/cGMP signaling results in severe kidney pathologies such as CKD. Therefore, treatment strategies aiming to maintain or increase cGMP might have beneficial effects for the treatment of progressive kidney diseases. Within this article, we review the NO/sGC/cGMP signaling cascade and its major pharmacological intervention sites. We specifically focus on the currently known effects of cGMP on kidney function parameters. Finally, we summarize the preclinical evidence for kidney protective effects of NO-donors, PDE inhibitors, sGC stimulators, and sGC activators.

The promise of human embryonic stem cells in aging-associated diseases

PubMed Central

Yabut, Odessa; Bernstein, Harold S.

2011-01-01

Aging-associated diseases are often caused by progressive loss or dysfunction of cells that ultimately affect the overall function of tissues and organs. Successful treatment of these diseases could benefit from cell-based therapy that would regenerate lost cells or otherwise restore tissue function. Human embryonic stem cells (hESCs) promise to be an important therapeutic candidate in treating aging-associated diseases due to their unique capacity for self-renewal and pluripotency. To date, there are numerous hESC lines that have been developed and characterized. We will discuss how hESC lines are derived, their molecular and cellular properties, and how their ability to differentiate into all three embryonic germ layers is determined. We will also outline the methods currently employed to direct their differentiation into populations of tissue-specific, functional cells. Finally, we will highlight the general challenges that must be overcome and the strategies being developed to generate highly-purified hESC-derived cell populations that can safely be used for clinical applications. PMID:21566262

Therapeutic progress in amyotrophic lateral sclerosis-beginning to learning.

PubMed

Kumar, Vijay; Islam, Asimul; Hassan, Md Imtaiyaz; Ahmad, Faizan

2016-10-04

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with motor neuron degeneration, muscle weakness, paralysis and finally death. The proposed mechanisms of ALS include glutamate excitotoxicity, oxidative stress, inflammation, mitochondrial dysfunction, apoptosis and proteasomal dysfunction. Although numerous pathological mechanisms have been explained, ALS remains incurable disease because of failure of clinical trials and lack of any effective therapy. The rapid advancement in genetic discoveries in ALS emphasizes the point that ALS is a multi-subtype syndrome rather than a single disease. This can be argued as one of the single reason why many previous therapeutic drug trials have failed. Efforts to develop novel ALS treatments which target specific pathomechanisms are currently being pursued. Herein, we review the recent discovery and preclinical characterization of neuroprotective compounds and compare their effects on disease onset, duration and survival. Furthermore, the structure-activity relationships of these agents are analyzed with the overall goal of developing a screening strategy for future clinical applications. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

[Management of coronary artery disease in diabetic patients with lower limb critical ischaemia: assessment of operational risk, drug therapy and indications for interventions].

PubMed

Dedov, I I; Kalashnikov, V Iu; Terekhin, S A; Melkozerov, K V

2012-01-01

Despite obvious progress in management of diabetes mellitus, the DM-related complications rate remains inadmissibly high. Macroangiopathy is known to rank first amongst complications of diabetes mellitus, and coronary artery disease remains to be the major cause of death. Analysed herein are peculiarities of the clinical course in diabetic patients presenting with coronary artery disease and lower limb critical ischaemia, followed by discussing the issues concerning drug therapy, preoperative examination, and methods of diagnosis in this cohort of patients prior to vascular operations, assessment of the preoperative risk, indications for coronarography and myocardial revascularization. Also presented are the results of the main clinical trials dedicated to preoperative myocardial revascularization, including those in diabetic patients with limb critical ischaemia, and finally highlighting current importance of optimizing approaches to managing and working out algorithms of treatment policy for diabetic patients with a combination of coronary artery disease, diabetes mellitus, and critical limb ischaemia.

Synergistic interaction of fatty acids and oxysterols impairs mitochondrial function and limits liver adaptation during nafld progression.

PubMed

Bellanti, Francesco; Villani, Rosanna; Tamborra, Rosanna; Blonda, Maria; Iannelli, Giuseppina; di Bello, Giorgia; Facciorusso, Antonio; Poli, Giuseppe; Iuliano, Luigi; Avolio, Carlo; Vendemiale, Gianluigi; Serviddio, Gaetano

2018-05-01

The complete mechanism accounting for the progression from simple steatosis to steatohepatitis in nonalcoholic fatty liver disease (NAFLD) has not been elucidated. Lipotoxicity refers to cellular injury caused by hepatic free fatty acids (FFAs) and cholesterol accumulation. Excess cholesterol autoxidizes to oxysterols during oxidative stress conditions. We hypothesize that interaction of FAs and cholesterol derivatives may primarily impair mitochondrial function and affect biogenesis adaptation during NAFLD progression. We demonstrated that the accumulation of specific non-enzymatic oxysterols in the liver of animals fed high-fat+high-cholesterol diet induces mitochondrial damage and depletion of proteins of the respiratory chain complexes. When tested in vitro, 5α-cholestane-3β,5,6β-triol (triol) combined to FFAs was able to reduce respiration in isolated liver mitochondria, induced apoptosis in primary hepatocytes, and down-regulated transcription factors involved in mitochondrial biogenesis. Finally, a lower protein content in the mitochondrial respiratory chain complexes was observed in human non-alcoholic steatohepatitis. In conclusion, hepatic accumulation of FFAs and non-enzymatic oxysterols synergistically facilitates development and progression of NAFLD by impairing mitochondrial function, energy balance and biogenesis adaptation to chronic injury. Copyright © 2017. Published by Elsevier B.V.

Heparanase promotes myeloma progression by inducing mesenchymal features and motility of myeloma cells.

PubMed

Li, Juan; Pan, Qianying; Rowan, Patrick D; Trotter, Timothy N; Peker, Deniz; Regal, Kellie M; Javed, Amjad; Suva, Larry J; Yang, Yang

2016-03-08

Bone dissemination and bone disease occur in approximately 80% of patients with multiple myeloma (MM) and are a major cause of patient mortality. We previously demonstrated that MM cell-derived heparanase (HPSE) is a major driver of MM dissemination to and progression in new bone sites. However the mechanism(s) by which HPSE promotes MM progression remains unclear. In the present study, we investigated the involvement of mesenchymal features in HPSE-promoted MM progression in bone. Using a combination of molecular, biochemical, cellular, and in vivo approaches, we demonstrated that (1) HPSE enhanced the expression of mesenchymal markers in both MM and vascular endothelial cells; (2) HPSE expression in patient myeloma cells positively correlated with the expression of the mesenchymal markers vimentin and fibronectin. Additional mechanistic studies revealed that the enhanced mesenchymal-like phenotype induced by HPSE in MM cells is due, at least in part, to the stimulation of the ERK signaling pathway. Finally, knockdown of vimentin in HPSE expressing MM cells resulted in significantly attenuated MM cell dissemination and tumor growth in vivo. Collectively, these data demonstrate that the mesenchymal features induced by HPSE in MM cells contribute to enhanced tumor cell motility and bone-dissemination.

Brain pathology of spinocerebellar ataxias.

PubMed

Seidel, Kay; Siswanto, Sonny; Brunt, Ewout R P; den Dunnen, Wilfred; Korf, Horst-Werner; Rüb, Udo

2012-07-01

The autosomal dominant cerebellar ataxias (ADCAs) represent a heterogeneous group of neurodegenerative diseases with progressive ataxia and cerebellar degeneration. The current classification of this disease group is based on the underlying genetic defects and their typical disease courses. According to this categorization, ADCAs are divided into the spinocerebellar ataxias (SCAs) with a progressive disease course, and the episodic ataxias (EA) with episodic occurrences of ataxia. The prominent disease symptoms of the currently known and genetically defined 31 SCA types result from damage to the cerebellum and interconnected brain grays and are often accompanied by more specific extra-cerebellar symptoms. In the present review, we report the genetic and clinical background of the known SCAs and present the state of neuropathological investigations of brain tissue from SCA patients in the final disease stages. Recent findings show that the brain is commonly seriously affected in the polyglutamine SCAs (i.e. SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17) and that the patterns of brain damage in these diseases overlap considerably in patients suffering from advanced disease stages. In the more rarely occurring non-polyglutamine SCAs, post-mortem neuropathological data currently are scanty and investigations have been primarily performed in vivo by means of MRI brain imaging. Only a minority of SCAs exhibit symptoms and degenerative patterns allowing for a clear and unambiguous diagnosis of the disease, e.g. retinal degeneration in SCA7, tau aggregation in SCA11, dentate calcification in SCA20, protein depositions in the Purkinje cell layer in SCA31, azoospermia in SCA32, and neurocutaneous phenotype in SCA34. The disease proteins of polyglutamine ataxias and some non-polyglutamine ataxias aggregate as cytoplasmic or intranuclear inclusions and serve as morphological markers. Although inclusions may impair axonal transport, bind transcription factors, and block protein quality control, detailed molecular and pathogenetic consequences remain to be determined.

Expanding the spectrum of neuronal pathology in multiple system atrophy

PubMed Central

Cykowski, Matthew D.; Coon, Elizabeth A.; Powell, Suzanne Z.; Jenkins, Sarah M.; Benarroch, Eduardo E.; Low, Phillip A.; Schmeichel, Ann M.

2015-01-01

Multiple system atrophy is a sporadic alpha-synucleinopathy that typically affects patients in their sixth decade of life and beyond. The defining clinical features of the disease include progressive autonomic failure, parkinsonism, and cerebellar ataxia leading to significant disability. Pathologically, multiple system atrophy is characterized by glial cytoplasmic inclusions containing filamentous alpha-synuclein. Neuronal inclusions also have been reported but remain less well defined. This study aimed to further define the spectrum of neuronal pathology in 35 patients with multiple system atrophy (20 male, 15 female; mean age at death 64.7 years; median disease duration 6.5 years, range 2.2 to 15.6 years). The morphologic type, topography, and frequencies of neuronal inclusions, including globular cytoplasmic (Lewy body-like) neuronal inclusions, were determined across a wide spectrum of brain regions. A correlation matrix of pathologic severity also was calculated between distinct anatomic regions of involvement (striatum, substantia nigra, olivary and pontine nuclei, hippocampus, forebrain and thalamus, anterior cingulate and neocortex, and white matter of cerebrum, cerebellum, and corpus callosum). The major finding was the identification of widespread neuronal inclusions in the majority of patients, not only in typical disease-associated regions (striatum, substantia nigra), but also within anterior cingulate cortex, amygdala, entorhinal cortex, basal forebrain and hypothalamus. Neuronal inclusion pathology appeared to follow a hierarchy of region-specific susceptibility, independent of the clinical phenotype, and the severity of pathology was duration-dependent. Neuronal inclusions also were identified in regions not previously implicated in the disease, such as within cerebellar roof nuclei. Lewy body-like inclusions in multiple system atrophy followed the stepwise anatomic progression of Lewy body-spectrum disease inclusion pathology in 25.7% of patients with multiple system atrophy, including a patient with visual hallucinations. Further, the presence of Lewy body-like inclusions in neocortex, but not hippocampal alpha-synuclein pathology, was associated with cognitive impairment (P = 0.002). However, several cases had the presence of isolated Lewy body-like inclusions at atypical sites (e.g. thalamus, deep cerebellar nuclei) that are not typical for Lewy body-spectrum disease. Finally, interregional correlations (rho ≥ 0.6) in pathologic glial and neuronal lesion burden suggest shared mechanisms of disease progression between both discrete anatomic regions (e.g. basal forebrain and hippocampus) and cell types (neuronal and glial inclusions in frontal cortex and white matter, respectively). These findings suggest that in addition to glial inclusions, neuronal pathology plays an important role in the developmental and progression of multiple system atrophy. See Halliday (doi:10.1093/brain/awv151) for a scientific commentary on this article. PMID:25981961

Cytokine Profile in Patients with Progressive Multiple Sclerosis and Its Association with Disease Progression and Disability.

PubMed

Kallaur, Ana Paula; Oliveira, Sayonara Rangel; Simão, Andréa Name Colado; Alfieri, Daniela Frizon; Flauzino, Tamires; Lopes, Josiane; de Carvalho Jennings Pereira, Wildea Lice; de Meleck Proença, Caio; Borelli, Sueli Donizete; Kaimen-Maciel, Damacio Ramón; Maes, Michael; Reiche, Edna Maria Vissoci

2017-05-01

Inflammation is the driving force for brain injury in patients with multiple sclerosis (MS). The objective of the present study is to delineate the serum cytokine profile in patients with progressive MS in a Southern Brazilian population compared with healthy controls and patients with relapsing-remitting MS (RRMS) and its associations with disease progression and disability. We included 32 patients with progressive MS, 126 with RRMS, and 40 healthy controls. The patients were evaluated using the Expanded Disability Status Scale (EDSS) and magnetic resonance imaging (MRI) with gadolinium. Serum interleukin (IL)-1β, IL-6, IL-12, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-10, IL-4, and IL-17 levels were assessed using an enzyme-linked immunosorbent assay. IL-1β, IL-6, TNF-α, IFN-γ, IL-17, IL-4, and IL-10 levels were higher in progressive MS than in controls. Increased IL-1β and IFN-γ and decreased IL-12 and IL-4 levels were found in progressive MS compared with RRMS. Patients with progressive MS with disease progression presented higher TNF-α, IFN-γ, and IL-10 levels than those without disease progression. Patients with progressive MS with disease progression showed a higher frequency of positive gadolinium-enhanced lesions in MRI; higher TNF-α, IFN-γ, and IL-17 levels; and decreased IL-12 levels compared with RRMS patients with progression. There was a significant inverse correlation between IL-10 levels and EDSS score in patients with progressive MS. The results underscore the complex cytokine network imbalance exhibited by progressive MS patients and show the important involvement of TNF-α, IFN-γ, and IL-17 in the pathophysiology and progression of the disease. Moreover, serum IL-10 levels were inversely associated with disability in patients with progressive MS.

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

PubMed Central

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

2014-01-01

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

Predicting Disease Progression in Scleroderma with Skin and Blood Biomarkers

DTIC Science & Technology

2015-10-01

AWARD NUMBER: W81XWH-13-1-0452 TITLE: Predicting Disease Progression in Scleroderma with Skin and Blood Biomarkers PRINCIPAL INVESTIGATOR: Dr...Predicting Disease Progression in Scleroderma with Skin and Blood 5a. CONTRACT NUMBER Biomarkers 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR...autoimmune disease associated with high morbidity and mortality primarily due to lung disease . There is a large variability in individual patients’ courses

Quantifying Disease Progression in Amyotrophic Lateral Sclerosis

PubMed Central

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

2014-01-01

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

Florbetaben PET in the Early Diagnosis of Alzheimer's Disease: A Discrete Event Simulation to Explore Its Potential Value and Key Data Gaps

PubMed Central

Guo, Shien; Getsios, Denis; Hernandez, Luis; Cho, Kelly; Lawler, Elizabeth; Altincatal, Arman; Lanes, Stephan; Blankenburg, Michael

2012-01-01

The growing understanding of the use of biomarkers in Alzheimer's disease (AD) may enable physicians to make more accurate and timely diagnoses. Florbetaben, a beta-amyloid tracer used with positron emission tomography (PET), is one of these diagnostic biomarkers. This analysis was undertaken to explore the potential value of florbetaben PET in the diagnosis of AD among patients with suspected dementia and to identify key data that are needed to further substantiate its value. A discrete event simulation was developed to conduct exploratory analyses from both US payer and societal perspectives. The model simulates the lifetime course of disease progression for individuals, evaluating the impact of their patient management from initial diagnostic work-up to final diagnosis. Model inputs were obtained from specific analyses of a large longitudinal dataset from the New England Veterans Healthcare System and supplemented with data from public data sources and assumptions. The analyses indicate that florbetaben PET has the potential to improve patient outcomes and reduce costs under certain scenarios. Key data on the use of florbetaben PET, such as its influence on time to confirmation of final diagnosis, treatment uptake, and treatment persistency, are unavailable and would be required to confirm its value. PMID:23326754

Neuroendocrine evaluation of cardiac disease.

PubMed

Sisson, D David

2004-09-01

Current evidence favors the view that regardless of etiology, there is a predictable sequence of neuroendocrine activation that operates in most dogs and cats with progressive heart disease and that it is largely, but not entirely, independent of etiology. The natriuretic peptides and sympathetic nervous system seem to be early responders to developing cardiac and hemodynamic perturbations in both species. BNP plays a particularly prominent role in cats, possibly as a reflection of disease etiology. Shortly thereafter, plasma endothelin concentrations rise, reflecting the impact of the hemodynamic alterations on the vasculature. Endothelin and the natriuretic peptides directly suppress plasma renin release but have divergent effects on aldosterone. Activation of the tissue RAAS may operate early on to further the progression of heart failure, but evidence of plasma RAAS activation occurs comparatively late and near the time of development of overt CHF. Finally, in animals with severe CHF that are prone to hypotension,vasopressin levels may also rise, contributing to the retention of free water and congestion that is refractory to diuretics. Although oversimplified, this scenario seems to be consistent with data obtained in human, canine, and feline patients. These observations provide some impetus for evaluating ACE inhibitors in cats and beta-receptor-blocking drugs in dogs and cats. Perhaps we are also a little closer to identifying useful biochemical markers that can aid in the diagnosis of heart disease, guide therapy, and improve our understanding of the biologic processes occurring in our patients. Copyright 2004 Elsevier Inc.

Postischemic dementia with Alzheimer phenotype: selectively vulnerable versus resistant areas of the brain and neurodegeneration versus β-amyloid peptide.

PubMed

Pluta, Ryszard; Jabłoński, Mirosław; Czuczwar, Stanisław J

2012-01-01

The road to clarity for postischemic dementia mechanisms has been one fraught with a wide range of complications and numerous revisions with a lack of a final solution. Importantly, brain ischemia is a leading cause of death and cognitive impairment worldwide. However, the mechanisms of progressive cognitive decline following brain ischemia are not yet certain. Data from animal models and clinical pioneering studies of brain ischemia have demonstrated an increase in expression and processing of amyloid precursor protein to a neurotoxin oligomeric β-amyloid peptide. Functional and memory brain restoration after ischemic brain injury is delayed and incomplete due to a lesion related increase in the amount of the neurotoxin amyloid protein. Moreover, ischemic injury is strongly accelerated by aging, too. In this review, we will present our current thinking about biogenesis of amyloid from the amyloid precursor protein in ischemic brain injury, and how this factor presents etiological, therapeutic and diagnostic targets that are now under consideration. Progressive injury of the ischemic brain parenchyma may be caused not only by degeneration of selectively vulnerable neurons destroyed during ischemia but also by acute and chronic damage of resistant areas of the brain and progressive damage in the blood-brain barrier. We propose that in postischemic dementia an initial ischemic injury precedes the cerebrovascular and brain parenchyma accumulation of Alzheimer disease related neurotoxin β-amyloid peptide, which in turn amplifies the neurovascular dysfunction triggering focal ischemic episodes as a vicious cycle preceding final neurodegenerative pathology. Persistent ischemic blood-brain barrier insufficiency with accumulation of neurotoxin β-amyloid protein in the brain tissue, especially in extracellular perivascular space and blood-brain barrier microvessels, may gradually, over a lifetime, progress to brain atrophy and to full-blown ischemic dementia with Alzheimer phenotype.

RandomForest4Life: a Random Forest for predicting ALS disease progression.

PubMed

Hothorn, Torsten; Jung, Hans H

2014-09-01

We describe a method for predicting disease progression in amyotrophic lateral sclerosis (ALS) patients. The method was developed as a submission to the DREAM Phil Bowen ALS Prediction Prize4Life Challenge of summer 2012. Based on repeated patient examinations over a three- month period, we used a random forest algorithm to predict future disease progression. The procedure was set up and internally evaluated using data from 1197 ALS patients. External validation by an expert jury was based on undisclosed information of an additional 625 patients; all patient data were obtained from the PRO-ACT database. In terms of prediction accuracy, the approach described here ranked third best. Our interpretation of the prediction model confirmed previous reports suggesting that past disease progression is a strong predictor of future disease progression measured on the ALS functional rating scale (ALSFRS). We also found that larger variability in initial ALSFRS scores is linked to faster future disease progression. The results reported here furthermore suggested that approaches taking the multidimensionality of the ALSFRS into account promise some potential for improved ALS disease prediction.

Tooth-related risk factors for periodontal disease in community-dwelling elderly people.

PubMed

Hirotomi, Toshinobu; Yoshihara, Akihiro; Ogawa, Hiroshi; Miyazaki, Hideo

2010-06-01

While most previous epidemiological studies have focused on subject-level risk factors for periodontal destruction, tooth-related factors have not been fully explored. The purpose of this study was to evaluate both tooth-related and subject-related factors affecting periodontal disease progression using a two-level multilevel model. A longitudinal survey over a period of 10 years was carried out on 286 community-dwelling elderly subjects aged 70 years at baseline. Clinical attachment level (CAL) was measured at six sites per tooth on all teeth present and periodontal disease progression was defined as CAL> or =3 mm. Periodontal disease progression was found in 79% of the subjects and most frequently in maxillary molars. Multilevel logistic regressions revealed that subjects wearing removable dentures were significantly at risk for periodontal disease progression. Abutment teeth for removable/fixed dentures were also significantly more likely to suffer periodontal breakdown. Furthermore, the following tooth-related variables were found to be possible risk factors for periodontal disease progression: maxillary and multirooted teeth. Multirooted teeth and abutments for a fixed denture were possible risk factors for periodontal disease progression.

A GRP78-Directed Monoclonal Antibody Recaptures Response in Refractory Multiple Myeloma with Extramedullary Involvement.

PubMed

Rasche, Leo; Menoret, Emmanuelle; Dubljevic, Valentina; Menu, Eline; Vanderkerken, Karin; Lapa, Constantin; Steinbrunn, Torsten; Chatterjee, Manik; Knop, Stefan; Düll, Johannes; Greenwood, Deanne L; Hensel, Frank; Rosenwald, Andreas; Einsele, Hermann; Brändlein, Stephanie

2016-09-01

Glucose-regulated protein (GRP) 78 is overexpressed in multiple myeloma, and both its surface expression and its biologic significance as key sensor of the unfolded protein response make GRP78 an ideal candidate for immunotherapeutic intervention. The monoclonal antibody PAT-SM6 targets surface GRP78 and leads to disease stabilization when used as single agent in a clinical trial. In this article, we evaluated expression of GRP78 in relapsed-refractory disease and explored PAT-SM6 therapy in combination regimens. GRP78 expression was immunohistochemically analyzed during disease progression and development of drug resistance throughout different stages of multiple myeloma. Activity of PAT-SM6 was evaluated in combination with anti-multiple myeloma agents lenalidomide, bortezomib, and dexamethasone in vitro Finally, we report on a multiple myeloma patient with relapsed-refractory disease treated with PAT-SM6 in combination with bortezomib and lenalidomide. Although sGRP78 expression was present at all stages, it increased with disease progression and was even strongly elevated in patients with drug-resistant and extramedullary disease. Pretreatment with dexamethasone as well as dual combination of PAT-SM6/lenalidomide further increased sGRP78 expression and consecutively showed synergistic anti-multiple myeloma effects with PAT-SM6 in proliferation assays. As proof of concept, a 62-year-old male with triple resistant multiple myeloma treated with PAT-SM6, bortezomib, and lenalidomide experienced partial remission of both intra- and extramedullary lesions. PAT-SM6 therapy in combination regimens showed efficacy in relapsed-refractory multiple myeloma. Clin Cancer Res; 22(17); 4341-9. ©2016 AACR. ©2016 American Association for Cancer Research.

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

PubMed

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.

Predicting Disease Progression in Scleroderma with Skin and Blood Biomarkers

DTIC Science & Technology

2014-10-01

AWARD NUMBER: W81XWH-13-1-0452 TITLE: Predicting Disease Progression in Scleroderma with Skin...Annual 3. DATES COVERED 23Sep 2013 – 22 Sep 2014 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Predicting Disease Progression in...Scleroderma (Systemic Sclerosis, SSc) is a chronic, incurable autoimmune disease associated with high morbidity and mortality primarily due to SSc-lung

Disruption of zinc neuromodulation by Aß oligomers: therapeutic implications.

PubMed

Vogler, Emily C; Busciglio, Jorge

2014-01-01

So far, therapeutics focusing on reducing levels of amyloid beta for treatment of Alzheimer's disease have not been successful in completing clinical trials to come to market, suggesting the need of a wider perspective and the consideration of novel targets of intervention to slow or halt the progression of this disease. One such target is soluble amyloid beta in oligomeric forms, which have been demonstrated to bind with high affinity to zinc released during synaptic activity. This review considers the interaction of AβO and zinc and the role of zinc in neurotransmission along with possible neurotoxic effects of this interaction. Finally, it also discusses recent experimental data in animal models that have translated into potential treatments for AD based on the modulation of hyperexcitability and zinc homeostasis.

Recent Developments in Synthetic Carbohydrate-Based Diagnostics, Vaccines, and Therapeutics.

PubMed

Fernández-Tejada, Alberto; Cañada, F Javier; Jiménez-Barbero, Jesús

2015-07-20

Glycans are everywhere in biological systems, being involved in many cellular events with important implications for medical purposes. Building upon a detailed understanding of the functional roles of carbohydrates in molecular recognition processes and disease states, glycans are increasingly being considered as key players in pharmacological research. On the basis of the important progress recently made in glycochemistry, glycobiology, and glycomedicine, we provide a complete overview of successful applications and future perspectives of carbohydrates in the biopharmaceutical and medical fields. This review highlights the development of carbohydrate-based diagnostics, exemplified by glycan imaging techniques and microarray platforms, synthetic oligosaccharide vaccines against infectious diseases (e.g., HIV) and cancer, and finally carbohydrate-derived therapeutics, including glycomimetic drugs and glycoproteins. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

New insights of T cells in the pathogenesis of psoriasis

PubMed Central

Cai, Yihua; Fleming, Chris; Yan, Jun

2012-01-01

Psoriasis is one of the most common immune-mediated chronic, inflammatory skin diseases characterized by hyperproliferative keratinocytes and infiltration of T cells, dendritic cells, macrophages and neutrophils. Although the pathogenesis of psoriasis is not fully understood, there is ample evidence suggesting that the dysregulation of immune cells in the skin, particularly T cells, plays a critical role in psoriasis development. In this review, we mainly focus on the pathogenic T cells and discuss how these T cells are activated and involved in the disease pathogenesis. Newly identified ‘professional' IL-17-producing dermal γδ T cells and their potential role in psoriasis will also be included. Finally, we will briefly summarize the recent progress on the T cell and its related cytokine-targeted therapy for psoriasis treatment. PMID:22705915

[An outbreak of Legionnaire's disease associated with a Japanese spa].

PubMed

Nakadate, T; Yamauchi, K; Inoue, H

1999-08-01

From June 24 to July 5, 1996, 3 patients were admitted to the same hospital with atypical pneumonia. One of the patients, a 52-year-old man, demonstrated progressive pulmonary infiltrates and severe hypoxemia, and finally required mechanical ventilation. All 3 patients had elevated antibody titers for Legionella pneumophila serogroup 1, and had visited the same spa prior to the onset of their symptoms. On September 25, 1996 the district health department inspected the spa, and isolated Legionella pneumophila serogroup 1 from the facility's hot water tanks and outlets. Although it has been reported that many spas in Japan are contaminated with Legionellaceae, the outbreak we encountered suggests that Japanese spas, like whirlpool spas in Europe and North America, can be a source of Legionnaire's disease.

Does hypervascularity of liver metastases as detected on MRI predict disease progression in breast cancer patients?

PubMed

Braga, Larissa; Semelka, Richard C; Pietrobon, Ricardo; Martin, Diego; de Barros, Nestor; Guller, Ulrich

2004-05-01

The aim of our study was to evaluate the association of the vascularity of liver metastases, as characterized by MRI, and disease progression in breast cancer patients. Sixteen breast cancer patients with liver metastases who underwent MRI before and after systemic therapy were retrospectively identified. On the basis of comparison of each MRI examination with the previous examination, disease status of the patients was classified as complete response, partial response, stable disease, or progressive disease. Liver metastases were characterized as hyper- or hypovascular on the basis of the degree of enhancement in the arterial, portal, and interstitial phases of imaging after administration of a contrast agent. Fisher's exact test and ordinal logistic regression models, including the type of systemic therapy, presence of multiple metastases, and hormone receptor status, were used to estimate the unadjusted and risk-adjusted association between the presence of hypervascular liver metastases and disease progression. All patients in our sample (n = 16) were women and most (12/16, 75%) were white. Their median age was 51.5 years. In unadjusted analyses, the association between the presence of hypervascular liver metastases and disease progression was statistically significant (p < 0.0001). In multiple logistic regression analyses, hypervascular liver metastases were found to be an independent predictor of disease progression. Patients with hypervascular liver lesions were 20.5 times more likely to experience disease progression than patients without hypervascular metastases (odds ratio, 20.5; 95% confidence interval, 5.1-83.5; p < 0.0001). Our analysis provides suggestive evidence that disease progression can be predicted through MRI assessment of the vascularity of liver metastases in patients with breast cancer.

What can we learn about lipoprotein metabolism and coronary heart disease from studying rare variants?

PubMed

Jeff, Janina M; Peloso, Gina M; Do, Ron

2016-04-01

Rare variant association studies (RVAS) target the class of genetic variation with frequencies less than 1%. Recently, investigators have used exome sequencing in RVAS to identify rare alleles responsible for Mendelian diseases but have experienced greater difficulty discovering such alleles for complex diseases. In this review, we describe what we have learned about lipoprotein metabolism and coronary heart disease through the conduct of RVAS. Rare protein-altering genetic variation can provide important insights that are not as easily attainable from common variant association studies. First, RVAS can facilitate gene discovery by identifying novel rare protein-altering variants in specific genes that are associated with disease. Second, rare variant associations can provide supportive evidence for putative drug targets for novel therapies. Finally, rare variants can uncover new pathways and reveal new biologic mechanisms. The field of human genetics has already made tremendous progress in understanding lipoprotein metabolism and the causes of coronary heart disease in the context of rare variants. As next generation sequencing becomes more cost-effective, RVAS with larger sample sizes will be conducted. This will lead to more novel rare variant discoveries and the translation of genomic data into biological knowledge and clinical insights for cardiovascular disease.

Differential Network Analyses of Alzheimer’s Disease Identify Early Events in Alzheimer’s Disease Pathology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xia, Jing; Rocke, David M.; Perry, George

In late-onset Alzheimer’s disease (AD), multiple brain regions are not affected simultaneously. Comparing the gene expression of the affected regions to identify the differences in the biological processes perturbed can lead to greater insight into AD pathogenesis and early characteristics. We identified differentially expressed (DE) genes from single cell microarray data of four AD affected brain regions: entorhinal cortex (EC), hippocampus (HIP), posterior cingulate cortex (PCC), and middle temporal gyrus (MTG). We organized the DE genes in the four brain regions into region-specific gene coexpression networks. Differential neighborhood analyses in the coexpression networks were performed to identify genes with lowmore » topological overlap (TO) of their direct neighbors. The low TO genes were used to characterize the biological differences between two regions. Our analyses show that increased oxidative stress, along with alterations in lipid metabolism in neurons, may be some of the very early events occurring in AD pathology. Cellular defense mechanisms try to intervene but fail, finally resulting in AD pathology as the disease progresses. Furthermore, disease annotation of the low TO genes in two independent protein interaction networks has resulted in association between cancer, diabetes, renal diseases, and cardiovascular diseases.« less

Persisting eicosanoid pathways in rheumatic diseases.

PubMed

Korotkova, Marina; Jakobsson, Per-Johan

2014-04-01

An unmet clinical need exists for early treatment of rheumatic diseases and improved treatment strategies that can better maintain remission with reduced ongoing subclinical inflammation and bone destruction. Eicosanoids form one of the most complex networks in the body controlling many physiological and pathophysiological processes, including inflammation, autoimmunity and cancer. Persisting eicosanoid pathways are thought to be involved in the development of rheumatic diseases, and targeting this pathway might enable improved treatment strategies. Several enzymes of the arachidonic acid cascade as well as eicosanoid receptors (all part of the eicosanoid pathway) are today well-recognized targets for anti-inflammatory drugs that can reduce symptoms of inflammation in rheumatic diseases. In this Review, we outline the evidence supporting pivotal roles of eicosanoid signalling in the pathogenesis of rheumatic diseases and discuss findings from studies in animals and humans. We focus first on rheumatoid arthritis and discuss the upregulation of the cyclooxygenase and lipoxygenase pathways as most data are available in this condition. Research into the roles of eicosanoids in other rheumatic diseases (osteoarthritis, idiopathic inflammatory myopathies, systemic lupus erythematosus and gout) is also progressing rapidly and is discussed. Finally, we summarize the prospects of targeting eicosanoid pathways as anti-inflammatory treatment strategies for patients with rheumatic diseases.

Best's vitelliform dystrophy (VMD2) maps between D11S903 and PYGM: No evidence for locus heterogeneity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weber, B.H.F.; Walker, D.; Mar, L.

1994-03-15

Vitelliform macular dystrophy, also known as Best's disease (BD), is an autosomal dominant disorder typically characterized by an accumulation of yellowish material in the macular area. The disease is slowly progressive and eventually results in atrophy of the retinal pigment epithelium and photoreceptor cells, thus severely impairing central vision. The biochemical defect underlying this condition is unknown. More recently, the BD locus (VMD2) was mapped to chromosome 11 by genetic analysis in three multigeneration Best's disease families using eight microsatellite markers spanning approximately 26 cM around the putative BD locus. The authors demonstrate linkage between Best's disease and the markersmore » used. Furthermore, haplotype analysis in unrelated Best's disease families identified three distinct haplotypes associated with the disease, strongly suggesting independent origins of the BD mutation. Finally, they characterized two recombinant BD chromosomes that significantly refine the location of the disease gene to a 3.7-cM interval between markers at D11S903 and PYGM. PCR-hybrid mapping sublocalized this interval to the pericentromeric region of chromosome 11. 47 refs., 4 figs., 1 tab.« less

Differential Network Analyses of Alzheimer’s Disease Identify Early Events in Alzheimer’s Disease Pathology

DOE PAGES

Xia, Jing; Rocke, David M.; Perry, George; ...

2014-01-01

In late-onset Alzheimer’s disease (AD), multiple brain regions are not affected simultaneously. Comparing the gene expression of the affected regions to identify the differences in the biological processes perturbed can lead to greater insight into AD pathogenesis and early characteristics. We identified differentially expressed (DE) genes from single cell microarray data of four AD affected brain regions: entorhinal cortex (EC), hippocampus (HIP), posterior cingulate cortex (PCC), and middle temporal gyrus (MTG). We organized the DE genes in the four brain regions into region-specific gene coexpression networks. Differential neighborhood analyses in the coexpression networks were performed to identify genes with lowmore » topological overlap (TO) of their direct neighbors. The low TO genes were used to characterize the biological differences between two regions. Our analyses show that increased oxidative stress, along with alterations in lipid metabolism in neurons, may be some of the very early events occurring in AD pathology. Cellular defense mechanisms try to intervene but fail, finally resulting in AD pathology as the disease progresses. Furthermore, disease annotation of the low TO genes in two independent protein interaction networks has resulted in association between cancer, diabetes, renal diseases, and cardiovascular diseases.« less

Probiotics as oral health biotherapeutics.

PubMed

Saha, Shyamali; Tomaro-Duchesneau, Catherine; Tabrizian, Maryam; Prakash, Satya

2012-09-01

Oral health is affected by its resident microorganisms. Three prominent oral disorders are dental caries, gingivitis and periodontitis, with the oral microbiota playing a key role in the initiation/progression of all three. Understanding the microbiota and the diseases they may cause is critical to the development of new therapeutics. This review is focused on probiotics for the prevention and/or treatment of oral diseases. This review describes the oral ecosystem and its correlation with oral health/disease. The pathogenesis and current prevention/treatment strategies of periodontal diseases (PD) and dental caries (DC) are depicted. An introduction of probiotics is followed by an analysis of their role in PD and DC, and their potential role(s) in oral health. Finally, a discussion ensues on the future research directions and limitations of probiotics for oral health. An effective oral probiotic formulation should contribute to the prevention/treatment of microbial diseases of the oral cavity. Understanding the oral microbiota's role in oral disease is important for the development of a therapeutic to prevent/treat dental diseases. However, investigations into clinical efficacy, delivery/dose optimization, mechanism(s) of action and other related parameters are yet to be fully explored. Keeping this in mind, investigations into oral probiotic therapies are proving promising.

Progress in Defining Disease: Improved Approaches and Increased Impact.

PubMed

Schwartz, Peter H

2017-08-01

In a series of recent papers, I have made three arguments about how to define "disease" and evaluate and apply possible definitions. First, I have argued that definitions should not be seen as traditional conceptual analyses, but instead as proposals about how to define and use the term "disease" in the future. Second, I have pointed out and attempted to address a challenge for dysfunction-requiring accounts of disease that I call the "line-drawing" problem: distinguishing between low-normal functioning and dysfunctioning. Finally, I have used a dysfunction-requiring approach to argue that some extremely prevalent conditions, such as high blood pressure, high cholesterol, and ductal carcinoma in situ, are not diseases, but instead are risk factors. Four of the papers in this issue directly engage my previous work. In this commentary, I applaud the advances these authors make, address points of disagreement, and make suggestions about where the discussion should go next. © The Author 2017. 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.

[Cell therapy for Parkinson's disease: IV. Risks and future trends].

PubMed

Anisimov, S V

2009-01-01

Motor dysfunctions in Parkinson's disease are believed to be primarily due to the degeneration of dopaminergic neurons located in the substantia nigra pars compacta. Numerous cell replacement therapy approaches have been developed and tested, including these based on donor cell transplantation (embryonic and adult tissue-derived), adult mesenchymal stem cells (hMSCs)-, neural stem cells (hNSCs)- and finally human embryonic stem cells (hESCs)-based. Despite the progress achieved, numerous difficulties prevent wider practical application of stem cell-based therapy approaches for the treatment of Parkinson's disease. Among the latter, ethical, safety and technical issues stand out. Current series of reviews (Cell therapy for Parkinson's disease: I. Embryonic and adult donor tissue-based applications; II. Adult stem cell-based applications; III. Neonatal, fetal and embryonic stem cell-based applications; IV. Risks and future trends) aims providing a balanced and updated view on various issues associated with cell types (including stem cells) in regards to their potential in the treatment of Parkinson's disease. Essential features of the individual cell subtypes, principles of available cell handling protocols, transplantation, and safety issues are discussed extensively.

[Cell therapy for Parkinson's disease: III. Neonatal, fetal and embryonic stem cell-based applications].

PubMed

Anisimov, S V

2009-01-01

Motor dysfunctions in Parkinson's disease are believed to be primarily due to the degeneration of dopaminergic neurons located in the substantia nigra pars compacta. Numerous cell replacement therapy approaches have been developed and tested, including these based on donor cell transplantation (embryonic and adult tissue-derived), adult mesenchymal stem cells (hMSCs)-, neural stem cells (hNSCs)- and finally human embryonic stem cells (hESCs)-based. Despite the progress achieved, numerous difficulties prevent wider practical application of stem cell-based therapy approaches for the treatment of Parkinson's disease. Among the latter, ethical, safety and technical issues stand out. Current series of reviews (Cell therapy for Parkinson's disease: I. Embryonic and adult donor tissue-based applications; II. Adult stem cell-based applications; III. Neonatal, fetal and embryonic stem cell-based applications; IV. Risks and future trends) aims providing a balanced and updated view on various issues associated with cell types (including stem cells) in regards to their potential in the treatment of Parkinson's disease. Essential features of the individual cell subtypes, principles of available cell handling protocols, transplantation, and safety issues are discussed extensively.

Recreational scuba diving in patients with congenital heart disease: Time for new guidelines.

PubMed

Schleich, Jean-Marc; Schnell, Frédéric; Brouant, Benoît; Phan, Gerald; Lafay, Vincent; Bonnemains, Laurent; Bédossa, Marc

2016-01-01

The number of recreational scuba divers is steadily increasing. In its latest recommendations, the French Federation of Undersea Studies and Sports listed congenital heart disease as a formal and final contraindication to scuba diving. On the other hand, with the progress made in their management, the prognosis and quality of life of patients with congenital heart diseases have improved considerably, enabling them to engage in physical and sports endeavours, which are known to confer general health and psychological benefits. As a consequence, the ability of these patients to dive has become a regular and recurrent issue. We review the various types of scuba diving, the physical performance required for its practice, its effects on cardiovascular function and the elements that need to be considered before recommending whether it can be practiced safely at various levels of difficulty. Because of the diversity and broad heterogeneity of congenital heart diseases, a detailed evaluation of each patient's performance based on clinical criteria common to all congenital heart diseases is recommended. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Perception of emotion on faces in frontotemporal dementia and Alzheimer's disease: a longitudinal study.

PubMed

Lavenu, I; Pasquier, F

2005-01-01

Frontotemporal dementia (FTD) is a neurodegenerative disease characterised by behavioural disorders that suggest abnormalities of emotional processing. In a previous study, we showed that patients with Alzheimer's disease (AD) and with FTD were equally able to distinguish a face displaying affect from one not displaying affect. However, recognition of emotion was worse in patients with FTD than in patients with AD who did not differ significantly from controls. The aim of this study was to follow up the perception of emotions on faces in these patients. The poor perception of emotion could worsen differently in AD and in FTD, with the progression of atrophy of the amygdala, the anterior temporal cortex and the orbital frontal cortex, structures that are components of the brain's emotional processing systems. Patients with AD or with FTD had to recognise and point out the name of one of seven basic emotions (anger, disgust, happiness, fear, sadness, surprise and contempt) on a set of 28 faces presented on slides at the first visit and 3 years later. Thirty-seven patients (AD = 19, FTD = 18) performed the tests initially. The two patient groups did not differ for age, sex and duration of the disease. During the follow-up, 12 patients died, 4 patients refused to perform the tests and 8 could not be tested because of the severity of the disease. Finally, 7 patients with AD and 6 patients with FTD performed the two tests at a mean delay of 40 months. All patients with AD had worse results at follow-up on the perception of emotion despite the prescription of inhibitors of cholinesterase in all patients and of selective serotonin reuptake inhibitors (SSRIs) in 4 patients. As a whole, patients with FTD had better results in the second than in the first assessment (however, 3 of them had worse results) independently of the prescription of trazodone (n = 2), other SSRIs (n = 2), or the absence of treatment (n = 2), and of possible cognitive change. Recognition of emotion on faces in AD decreases with the progression of dementia and could be related to the progression of the degeneration of the structures implicated in emotional processing systems. Inconsistency of the results in FTD may be related to impulsiveness, lack of consistency of the patients and to heterogeneity of the progression of the lesions. Copyright 2005 S. Karger AG, Basel.

Final Progress Report for Ionospheric Dusty Plasma In the Laboratory [Smokey Plasma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Robertson, Scott

2010-07-31

“Ionospheric Dusty Plasma in the Laboratory” is a research project with the purpose of finding and reproducing the characteristics of plasma in the polar mesosphere that is unusually cold (down to 140 K) and contains nanometer-sized dust particles. This final progress report summarizes results from four years of effort that include a final year with a no-cost extension.

Quantitative magnetic resonance imaging assessments of autosomal recessive polycystic kidney disease progression and response to therapy in an animal model.

PubMed

Erokwu, Bernadette O; Anderson, Christian E; Flask, Chris A; Dell, Katherine M

2018-05-01

BackgroundAutosomal recessive polycystic kidney disease (ARPKD) is associated with significant mortality and morbidity, and currently, there are no disease-specific treatments available for ARPKD patients. One major limitation in establishing new therapies for ARPKD is a lack of sensitive measures of kidney disease progression. Magnetic resonance imaging (MRI) can provide multiple quantitative assessments of the disease.MethodsWe applied quantitative image analysis of high-resolution (noncontrast) T2-weighted MRI techniques to study cystic kidney disease progression and response to therapy in the PCK rat model of ARPKD.ResultsSerial imaging over a 2-month period demonstrated that renal cystic burden (RCB, %)=[total cyst volume (TCV)/total kidney volume (TKV) × 100], TCV, and, to a lesser extent, TKV detected cystic kidney disease progression, as well as the therapeutic effect of octreotide, a clinically available medication shown previously to slow both kidney and liver disease progression in this model. All three MRI measures correlated significantly with histologic measures of renal cystic area, although the correlation of RCB and TCV was stronger than that of TKV.ConclusionThese preclinical MRI results provide a basis for applying these quantitative MRI techniques in clinical studies, to stage and measure progression in human ARPKD kidney disease.

Imaging plus X: multimodal models of neurodegenerative disease.

PubMed

Oxtoby, Neil P; Alexander, Daniel C

2017-08-01

This article argues that the time is approaching for data-driven disease modelling to take centre stage in the study and management of neurodegenerative disease. The snowstorm of data now available to the clinician defies qualitative evaluation; the heterogeneity of data types complicates integration through traditional statistical methods; and the large datasets becoming available remain far from the big-data sizes necessary for fully data-driven machine-learning approaches. The recent emergence of data-driven disease progression models provides a balance between imposed knowledge of disease features and patterns learned from data. The resulting models are both predictive of disease progression in individual patients and informative in terms of revealing underlying biological patterns. Largely inspired by observational models, data-driven disease progression models have emerged in the last few years as a feasible means for understanding the development of neurodegenerative diseases. These models have revealed insights into frontotemporal dementia, Huntington's disease, multiple sclerosis, Parkinson's disease and other conditions. For example, event-based models have revealed finer graded understanding of progression patterns; self-modelling regression and differential equation models have provided data-driven biomarker trajectories; spatiotemporal models have shown that brain shape changes, for example of the hippocampus, can occur before detectable neurodegeneration; and network models have provided some support for prion-like mechanistic hypotheses of disease propagation. The most mature results are in sporadic Alzheimer's disease, in large part because of the availability of the Alzheimer's disease neuroimaging initiative dataset. Results generally support the prevailing amyloid-led hypothetical model of Alzheimer's disease, while revealing finer detail and insight into disease progression. The emerging field of disease progression modelling provides a natural mechanism to integrate different kinds of information, for example from imaging, serum and cerebrospinal fluid markers and cognitive tests, to obtain new insights into progressive diseases. Such insights include fine-grained longitudinal patterns of neurodegeneration, from early stages, and the heterogeneity of these trajectories over the population. More pragmatically, such models enable finer precision in patient staging and stratification, prediction of progression rates and earlier and better identification of at-risk individuals. We argue that this will make disease progression modelling invaluable for recruitment and end-points in future clinical trials, potentially ameliorating the high failure rate in trials of, e.g., Alzheimer's disease therapies. We review the state of the art in these techniques and discuss the future steps required to translate the ideas to front-line application.

Maintenance therapy with vinflunine plus best supportive care versus best supportive care alone in patients with advanced urothelial carcinoma with a response after first-line chemotherapy (MAJA; SOGUG 2011/02): a multicentre, randomised, controlled, open-label, phase 2 trial.

PubMed

García-Donas, Jesus; Font, Albert; Pérez-Valderrama, Begoña; Virizuela, José Antonio; Climent, Miquel Ángel; Hernando-Polo, Susana; Arranz, José Ángel; Del Mar Llorente, Maria; Lainez, Nuria; Villa-Guzmán, José Carlos; Mellado, Begoña; Del Alba, Aránzazu González; Castellano, Daniel; Gallardo, Enrique; Anido, Urbano; Del Muro, Xavier García; Domènech, Montserrat; Puente, Javier; Morales-Barrera, Rafael; Pérez-Gracia, Jose Luis; Bellmunt, Joaquim

2017-05-01

Maintenance therapy improves outcomes in various tumour types, but cumulative toxic effects limit the choice of drugs. We investigated whether maintenance therapy with vinflunine would delay disease progression in patients with advanced urothelial carcinoma who had achieved disease control with first-line chemotherapy. We did a randomised, controlled, open-label, phase 2 trial in 21 Spanish hospitals. Eligible patients had locally advanced, surgically unresectable, or metastatic transitional-cell carcinoma of the urothelial tract, adequate organ function, and disease control after four to six cycles of cisplatin and gemcitabine (carboplatin allowed after cycle four). Patients were randomly assigned (1:1) to receive vinflunine or best supportive care until disease progression. We initially used block randomisation with a block size of six. Four lists were created for the two stratification factors of starting dose of vinflunine and presence of liver metastases. After a protocol amendment, number of cisplatin and gemcitabine cycles was added as a stratification factor, and eight lists were created, still with a block size of six. Finally, we changed to a minimisation procedure to reduce the risk of imbalance between groups. Vinflunine was given every 21 days as a 20 min intravenous infusion at 320 mg/m 2 or at 280 mg/m 2 in patients with an Eastern Cooperative Oncology Group performance status score of 1, age 75 years or older, previous pelvic radiotherapy, or creatinine clearance lower than 60 mL/min. The primary endpoint was median progression-free survival longer than 5·3 months in the vinflunine group, assessed by modified intention to treat. Comparison of progression-free survival between treatment groups was a secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01529411. Between April 12, 2012, and Jan 29, 2015, we enrolled 88 patients, of whom 45 were assigned to receive vinflunine and 43 to receive best supportive care. One patient from the vinflunine group was lost to follow-up immediately after randomisation and was excluded from the analyses. One patient in the best supportive care group became ineligible for the study and did not receive treatment due to a delay in enrolment, but was included in the intention-to-treat efficacy analysis. After a median follow-up of 15·6 months (IQR 8·5-26·0), 29 (66%) of 44 patients in the vinflunine group had disease progression and 24 (55%) had died, compared with 36 (84%) of 43 patients with disease progression and 32 (74%) deaths in the best supportive care group. Median progression-free survival was 6·5 months (95% CI 2·0-11·1) in the vinflunine group and 4·2 months (2·1-6·3) in the best supportive care group (hazard ratio 0·59, 95% CI 0·37-0·96, p=0·031). The most common grade 3 or 4 adverse events were neutropenia (eight [18%] of 44 in the vinflunine group vs none of 42 in the best supportive care group), asthenia or fatigue (seven [16%] vs one [2%]), and constipation (six [14%] vs none). 18 serious adverse events were reported in the vinflunine group and 14 in the best supportive care group. One patient in the vinflunine group died from pneumonia that was deemed to be treatment related. In patients with disease control after first-line chemotherapy, progression-free survival exceeded the acceptable threshold with vinflunine maintenance therapy. Moreover, progression-free survival was longer with vinflunine maintenance therapy than with best supportive care. Vinflunine maintenance had an acceptable safety profile. Further studies of the role of vinflunine are warranted. Pierre-Fabre Médicament. Copyright © 2017 Elsevier Ltd. All rights reserved.

Everolimus for the Treatment of Advanced Pancreatic Neuroendocrine Tumors: Overall Survival and Circulating Biomarkers From the Randomized, Phase III RADIANT-3 Study.

PubMed

Yao, James C; Pavel, Marianne; Lombard-Bohas, Catherine; Van Cutsem, Eric; Voi, Maurizio; Brandt, Ulrike; He, Wei; Chen, David; Capdevila, Jaume; de Vries, Elisabeth G E; Tomassetti, Paola; Hobday, Timothy; Pommier, Rodney; Öberg, Kjell

2016-11-10

Purpose Everolimus improved median progression-free survival by 6.4 months in patients with advanced pancreatic neuroendocrine tumors (NET) compared with placebo in the RADIANT-3 study. Here, we present the final overall survival (OS) data and data on the impact of biomarkers on OS from the RADIANT-3 study. Methods Patients with advanced, progressive, low- or intermediate-grade pancreatic NET were randomly assigned to everolimus 10 mg/day (n = 207) or placebo (n = 203). Crossover from placebo to open-label everolimus was allowed on disease progression. Ongoing patients were unblinded after final progression-free survival analysis and could transition to open-label everolimus at the investigator's discretion (extension phase). OS analysis was performed using a stratified log-rank test in the intent-to-treat population. The baseline levels of chromogranin A, neuron-specific enolase, and multiple soluble angiogenic biomarkers were determined and their impact on OS was explored. Results Of 410 patients who were enrolled between July 2007 and March 2014, 225 received open-label everolimus, including 172 patients (85%) randomly assigned initially to the placebo arm. Median OS was 44.0 months (95% CI, 35.6 to 51.8 months) for those randomly assigned to everolimus and 37.7 months (95% CI, 29.1 to 45.8 months) for those randomly assigned to placebo (hazard ratio, 0.94; 95% CI, 0.73 to 1.20; P = .30). Elevated baseline chromogranin A, neuron-specific enolase, placental growth factor, and soluble vascular endothelial growth factor receptor 1 levels were poor prognostic factors for OS. The most common adverse events included stomatitis, rash, and diarrhea. Conclusion Everolimus was associated with a median OS of 44 months in patients with advanced, progressive pancreatic NET, the longest OS reported in a phase III study for this population. Everolimus was associated with a survival benefit of 6.3 months, although this finding was not statistically significant. Crossover of patients likely confounded the OS results.

Early-onset Alzheimer's Disease Phenotypes: Neuropsychology and Neural Networks

ClinicalTrials.gov

2017-05-11

Alzheimer Disease, Early Onset; Alzheimer Disease; Alzheimer Disease, Late Onset; Dementia, Alzheimer Type; Logopenic Progressive Aphasia; Primary Progressive Aphasia; Visuospatial/Perceptual Abilities; Posterior Cortical Atrophy; Executive Dysfunction; Corticobasal Degeneration; Ideomotor Apraxia

The role of tau in the pathological process and clinical expression of Huntington’s disease

PubMed Central

Vuono, Romina; Winder-Rhodes, Sophie; de Silva, Rohan; Cisbani, Giulia; Drouin-Ouellet, Janelle; Spillantini, Maria G.; Cicchetti, Francesca

2015-01-01

Huntington’s disease is a neurodegenerative disorder caused by an abnormal CAG repeat expansion within exon 1 of the huntingtin gene HTT. While several genetic modifiers, distinct from the Huntington’s disease locus itself, have been identified as being linked to the clinical expression and progression of Huntington’s disease, the exact molecular mechanisms driving its pathogenic cascade and clinical features, especially the dementia, are not fully understood. Recently the microtubule associated protein tau, MAPT, which is associated with several neurodegenerative disorders, has been implicated in Huntington’s disease. We explored this association in more detail at the neuropathological, genetic and clinical level. We first investigated tau pathology by looking for the presence of hyperphosphorylated tau aggregates, co-localization of tau with mutant HTT and its oligomeric intermediates in post-mortem brain samples from patients with Huntington’s disease (n = 16) compared to cases with a known tauopathy and healthy controls. Next, we undertook a genotype–phenotype analysis of a large cohort of patients with Huntington’s disease (n = 960) with a particular focus on cognitive decline. We report not only on the tau pathology in the Huntington’s disease brain but also the association between genetic variation in tau gene and the clinical expression and progression of the disease. We found extensive pathological inclusions containing abnormally phosphorylated tau protein that co-localized in some instances with mutant HTT. We confirmed this related to the disease process rather than age, by showing it is also present in two patients with young-onset Huntington’s disease (26 and 40 years old at death). In addition we demonstrate that tau oligomers (suggested to be the most likely neurotoxic tau entity) are present in the Huntington’s disease brains. Finally we highlight the clinical significance of this pathology by demonstrating that the MAPT haplotypes affect the rate of cognitive decline in a large cohort of patients with Huntington’s disease. Our findings therefore highlight a novel important role of tau in the pathogenic process and clinical expression of Huntington’s disease, which in turn opens up new therapeutic avenues for this incurable condition. PMID:25953777

Effect of urate-lowering therapies on renal disease progression in patients with hyperuricemia.

PubMed

Levy, Gerald D; Rashid, Nazia; Niu, Fang; Cheetham, T Craig

2014-05-01

To evaluate the association between hyperuricemia and renal disease progression in a real-world, large observational database study. We conducted a population-based retrospective cohort study identifying 111,992 patients with hyperuricemia (> 7 mg/dl) from a large medical group. The final cohort were ≥ 18 years old, urate-lowering therapy (ULT)-naïve, and had the following laboratory results available: at least 1 glomerular filtration rate (GFR) level before the index date and at least 1 serum uric acid (sUA) level and GFR in the followup 36-month period. The cohort was categorized into 3 groups: never treated (NoTx), ULT time receiving therapy of < 80% (< 80%), and ULT time receiving therapy of ≥ 80% (≥ 80%). Outcomes were defined as a ≥ 30% reduction in GFR from baseline, dialysis, or GFR of ≤ 15 ml/min. A subanalysis of patients with sUA < 6 mg/dl at study conclusion was performed. Cox proportional hazards regression model determined factors associated with renal function decline. A total of 16,186 patients met inclusion criteria. There were 11,192 NoTx patients, 3902 with < 80% time receiving ULT, and 1092 with ≥ 80% time receiving ULT. Factors associated with renal disease progression were age, sex, hypertension, diabetes, congestive heart failure, hospitalizations, rheumatoid arthritis, and higher sUA at baseline. Time receiving therapy was not associated with renal outcomes. Patients who achieved sUA < 6 mg/dl had a 37% reduction in outcome events (p < 0.0001; HR 0.63, 95% CI: 0.5-0.78). Hyperuricemia is an independent risk factor for renal function decline. Patients treated with ULT who achieved sUA < 6 mg/dl on ULT showed a 37% reduction in outcome events.

Prenatal maternal immune activation increases anxiety- and depressive-like behaviors in offspring with experimental autoimmune encephalomyelitis.

PubMed

Majidi-Zolbanin, J; Doosti, M-H; Kosari-Nasab, M; Salari, A-A

2015-05-21

Multiple sclerosis (MS) is thought to result from a combination of genetics and environmental factors. Several lines of evidence indicate that significant prevalence of anxiety and depression-related disorders in MS patients can influence the progression of the disease. Although we and others have already reported the consequences of prenatal maternal immune activation on anxiety and depression, less is known about the interplay between maternal inflammation, MS and gender. We here investigated the effects of maternal immune activation with Poly I:C during mid-gestation on the progression of clinical symptoms of experimental autoimmune encephalomyelitis (EAE; a mouse model of MS), and then anxiety- and depressive-like behaviors in non-EAE and EAE-induced offspring were evaluated. Stress-induced corticosterone and tumor necrosis factor-alpha (TNF-α) levels in EAE-induced offspring were also measured. Maternal immune activation increased anxiety and depression in male offspring, but not in females. This immune challenge also resulted in an earlier onset of the EAE clinical signs in male offspring and enhanced the severity of the disease in both male and female offspring. Interestingly, the severity of the disease was associated with increased anxiety/depressive-like behaviors and elevated corticosterone or TNF-α levels in both sexes. Overall, these data suggest that maternal immune activation with Poly I:C during mid-pregnancy increases anxiety- and depressive-like behaviors, and the clinical symptoms of EAE in a sex-dependent manner in non-EAE or EAE-induced offspring. Finally, the progression of EAE in offspring seems to be linked to maternal immune activation-induced dysregulation in neuro-immune-endocrine system. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Oncogenic properties of apoptotic tumor cells in aggressive B cell lymphoma.

PubMed

Ford, Catriona A; Petrova, Sofia; Pound, John D; Voss, Jorine J L P; Melville, Lynsey; Paterson, Margaret; Farnworth, Sarah L; Gallimore, Awen M; Cuff, Simone; Wheadon, Helen; Dobbin, Edwina; Ogden, Carol Anne; Dumitriu, Ingrid E; Dunbar, Donald R; Murray, Paul G; Ruckerl, Dominik; Allen, Judith E; Hume, David A; van Rooijen, Nico; Goodlad, John R; Freeman, Tom C; Gregory, Christopher D

2015-03-02

Cells undergoing apoptosis are known to modulate their tissue microenvironments. By acting on phagocytes, notably macrophages, apoptotic cells inhibit immunological and inflammatory responses and promote trophic signaling pathways. Paradoxically, because of their potential to cause death of tumor cells and thereby militate against malignant disease progression, both apoptosis and tumor-associated macrophages (TAMs) are often associated with poor prognosis in cancer. We hypothesized that, in progression of malignant disease, constitutive loss of a fraction of the tumor cell population through apoptosis could yield tumor-promoting effects. Here, we demonstrate that apoptotic tumor cells promote coordinated tumor growth, angiogenesis, and accumulation of TAMs in aggressive B cell lymphomas. Through unbiased "in situ transcriptomics" analysis-gene expression profiling of laser-captured TAMs to establish their activation signature in situ-we show that these cells are activated to signal via multiple tumor-promoting reparatory, trophic, angiogenic, tissue remodeling, and anti-inflammatory pathways. Our results also suggest that apoptotic lymphoma cells help drive this signature. Furthermore, we demonstrate that, upon induction of apoptosis, lymphoma cells not only activate expression of the tumor-promoting matrix metalloproteinases MMP2 and MMP12 in macrophages but also express and process these MMPs directly. Finally, using a model of malignant melanoma, we show that the oncogenic potential of apoptotic tumor cells extends beyond lymphoma. In addition to its profound tumor-suppressive role, apoptosis can potentiate cancer progression. These results have important implications for understanding the fundamental biology of cell death, its roles in malignant disease, and the broader consequences of apoptosis-inducing anti-cancer therapy. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

A mathematical approach to HIV infection dynamics

NASA Astrophysics Data System (ADS)

Ida, A.; Oharu, S.; Oharu, Y.

2007-07-01

In order to obtain a comprehensive form of mathematical models describing nonlinear phenomena such as HIV infection process and AIDS disease progression, it is efficient to introduce a general class of time-dependent evolution equations in such a way that the associated nonlinear operator is decomposed into the sum of a differential operator and a perturbation which is nonlinear in general and also satisfies no global continuity condition. An attempt is then made to combine the implicit approach (usually adapted for convective diffusion operators) and explicit approach (more suited to treat continuous-type operators representing various physiological interactions), resulting in a semi-implicit product formula. Decomposing the operators in this way and considering their individual properties, it is seen that approximation-solvability of the original model is verified under suitable conditions. Once appropriate terms are formulated to describe treatment by antiretroviral therapy, the time-dependence of the reaction terms appears, and such product formula is useful for generating approximate numerical solutions to the governing equations. With this knowledge, a continuous model for HIV disease progression is formulated and physiological interpretations are provided. The abstract theory is then applied to show existence of unique solutions to the continuous model describing the behavior of the HIV virus in the human body and its reaction to treatment by antiretroviral therapy. The product formula suggests appropriate discrete models describing the dynamics of host pathogen interactions with HIV1 and is applied to perform numerical simulations based on the model of the HIV infection process and disease progression. Finally, the results of our numerical simulations are visualized and it is observed that our results agree with medical and physiological aspects.

Lenalidomide maintenance after first-line therapy for high-risk chronic lymphocytic leukaemia (CLLM1): final results from a randomised, double-blind, phase 3 study.

PubMed

Fink, Anna Maria; Bahlo, Jasmin; Robrecht, Sandra; Al-Sawaf, Othman; Aldaoud, Ali; Hebart, Holger; Jentsch-Ullrich, Kathleen; Dörfel, Steffen; Fischer, Kirsten; Wendtner, Clemens-Martin; Nösslinger, Thomas; Ghia, Paolo; Bosch, Francesc; Kater, Arnon P; Döhner, Hartmut; Kneba, Michael; Kreuzer, Karl-Anton; Tausch, Eugen; Stilgenbauer, Stephan; Ritgen, Matthias; Böttcher, Sebastian; Eichhorst, Barbara; Hallek, Michael

2017-10-01

The combined use of genetic markers and detectable minimal residual disease identifies patients with chronic lymphocytic leukaemia with poor outcome after first-line chemoimmunotherapy. We aimed to assess lenalidomide maintenance therapy in these high-risk patients. In this randomised, double-blind, phase 3 study (CLLM1; CLL Maintenance 1 of the German CLL Study Group), patients older than 18 years and diagnosed with immunophenotypically confirmed chronic lymphocytic leukaemia with active disease, who responded to chemoimmunotherapy 2-5 months after completion of first-line therapy and who were assessed as having a high risk for an early progression with at least a partial response after four or more cycles of first-line chemoimmunotherapy, were eligible if they had high minimal residual disease levels or intermediate levels combined with an unmutated IGHV gene status or TP53 alterations. Patients were randomly assigned (2:1) to receive either lenalidomide (5 mg) or placebo. Randomisation was done with a fixed block size of three, and was stratified according to the minimal residual disease level achieved after first-line therapy. Maintenance was started with 5 mg daily, and was escalated to the target dose of 15 mg. If tolerated, medication was administered until disease progression. The primary endpoint was progression-free survival according to an independent review. The pre-planned interim analysis done by intention to treat was done after 20% of the calculated progression-free survival events. This study is registered with ClinicalTrials.gov, number NCT01556776; treatment in the lenalidomide group is still ongoing. Between July 5, 2012, and March 15, 2016, 468 previously untreated patients with chronic lymphocytic leukaemia were screened for the study; 379 (81%) were not eligible. Recruitment was closed prematurely due to poor accrual after 89 of 200 planned patients were randomly assigned: 60 (67%) enrolled patients were assigned to the lenalidomide group and 29 (33%) to the placebo group, of whom 56 (63%) received lenalidomide and 29 (33%) placebo, with a median of 11·0 (IQR 4·5-20·5) treatment cycles at data cutoff. After a median observation time of 17·9 months (IQR 9·1-28·1), the hazard ratio for progression-free survival assessed by an independent review was 0·168 (95% CI 0·074-0·379). Median progression-free survival was 13·3 months (95% CI 9·9-19·7) in the placebo group and not reached (95% CI 32·3-not evaluable) in the lenalidomide group. The most frequent adverse events were skin disorders (35 patients [63%] in the lenalidomide group vs eight patients [28%] in the placebo group), gastrointestinal disorders (34 [61%] vs eight [28%]), infections (30 [54%] vs 19 [66%]), haematological toxicity (28 [50%] vs five [17%]), and general disorders (28 [50%] vs nine [31%]). One fatal adverse event was reported in each of the treatment groups (one [2%] patient with fatal acute lymphocytic leukaemia in the lenalidomide group and one patient (3%) with fatal multifocal leukoencephalopathy in the placebo group). Lenalidomide is an efficacious maintenance therapy reducing the relative risk of progression in first-line patients with chronic lymphocytic leukaemia who do not achieve minimal residual disease negative disease state following chemoimmunotherapy approaches. The toxicity seems to be acceptable considering the poor prognosis of the eligible patients. The trial independently confirms the clinical significance of a novel, minimal residual disease-based algorithm to predict short progression-free survival, which might be incorporated in future clinical trials to identify candidates for additional maintenance treatment. Celgene Corporation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Estimate of the cost of multiple sclerosis in Spain by literature review.

PubMed

Fernández, Oscar; Calleja-Hernández, Miguel Angel; Meca-Lallana, José; Oreja-Guevara, Celia; Polanco, Ana; Pérez-Alcántara, Ferran

2017-08-01

Multiple Sclerosis (MS) is a progressive disease leading to increasing disability and costs. A literature review was carried out to identify MS costs and to estimate its economic burden in Spain. Areas Covered: The public electronic databases PubMed, ScienceDirect and IBECS were consulted and a manual review of communications presented at related congresses was carried out. A total of 225 references were obtained, of which 43 were finally included in the study. Expert Commentary: Three major cost groups were identified: direct healthcare costs, direct non-healthcare costs and indirect costs. There is a direct relationship between disease progression and increased costs, mainly direct non-healthcare costs (greater need for informal care) and indirect costs (greater loss of productivity). The total cost associated with MS in Spain is €1,395 million per year, and that the mean annual cost per patient is €30,050. Beyond costs, a large impact on the quality of life of patients, with an annual loss of up to 13,000 quality-adjusted life years was also estimated. MS has a large economic impact on Spanish society and a significant impact on the quality of life of patients.

A successful treatment of necrotizing fasciitis following the surgery of distal radius plate removal: A case report and literature review.

PubMed

Cai, Yuchen; Gan, Yaokai; Yu, Chao; Tang, Jian; Sun, Yuehua

2018-04-01

Necrotizing fasciitis (NF) is defined as a rare, rapidly progressive, and highly lethal skin infection characterized by necrosis of the fascia and subcutaneous tissue. The present study aims to discuss the case of a 35-year-old man who developed NF following a routine sterile right distal radius bone plate removal surgery. The patient was suspected of NF based on his clinical manifestations, laboratory tests, and imaging results. The diagnosis of NF was confirmed by histological examinations. Serial prompt and extensive debridement was performed during the rapid and aggressive extension of the skin infection, together with antibiotics and supportive treatments. The condition of the patient finally improved on the sixth day of disease progression. Skin grafting of his right forearm wound was performed successfully 2 months after the admission. NF can occur during the perioperative period for routine clean radius plate removal operation in patients with no risk factor for NF. The objective is to remind the physicians to stay aware of this disease, especially its early clinical signs and symptoms. Urgent subsequent treatment, including surgical debridement, antibiotic therapy, and supporting management, is the key to ensure the survival and better prognosis of patients.

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

PubMed

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.

[Technical guideline for human rabies prevention and control (2016)].

PubMed

Zhou, H; Li, Y; Chen, R F; Tao, X Y; Yu, P C; Cao, S C; Li, L; Chen, Z H; Zhu, W Y; Yin, W W; Li, Y H; Wang, C L; Yu, H J

2016-02-01

In order to promote the prevention and control programs on rabies in our country, to regulate the prevention and disposition of rabies and to reduce the deaths caused by rabies, the Chinese Center for Disease Control and Prevention has organized a panel of experts, in the reference with Guidelines issued by WHO, American Advisory Committee on Immunization Practices, and the latest research progress from home and abroad, and compiled this document-"Technical Guidelines for Human Rabies Prevention and Control (2016)". The Guidelines conducted a systematic review on the etiology, clinical characteristics, laboratory diagnosis, epidemiology of rabies and provided evidence on varieties, mechanisms, effects, side-effects and security of rabies vaccine, as well as on other preparations on passive immunity of its kind, on methods related to prevention and disposition of exposure etc, finally to have come up with the recommendation on the above mentioned various techniques. The guidelines will be used by staff working on prevention and control of rabies from the Center for Disease Control and Prevention at all levels, from the departments of outpatient and divisions of infection and emergency control in all the medical institutions. The guideline will be updated and revised, following the research progress from home and abroad.

A comprehensive review of recent studies on pharmacokinetics of traditional Chinese medicines (2014-2017) and perspectives.

PubMed

Shi, Peiying; Lin, Xinhua; Yao, Hong

2018-05-01

Traditional Chinese medicines (TCMs) have a long history for safely treating human diseases. Unlike western medicine, TCMs usually contain multiple components synergistically and holistically acting on the diseases. It remains a big challenge to represent rationally the in vivo process of multiple components of TCMs for understanding the relationship between administration and therapeutic effects. For years, efforts were always made to face the challenge, and the achievements were obvious. Here, we give an comprehensive overview of the recent investigation progress (from 2015 to 2017, except the part of 'integrated pharmacokinetics of TCMs' from 2014 to 2017 and the part of 'reverse pharmacokinetics in drug discovery from natural medicines' in 2014) on pharmacokinetics of TCMs, mainly referring to the following six aspects: (1) classical pharmacokinetic studies on TCMs; (2) absorbed components and metabolites identification of TCMs; (3) pharmacokinetic herb-drug interactions and herb-herb interactions with TCMs; (4) integrated pharmacokinetics of TCMs; (5) pharmacokinetic and pharmacodynamic combination studies to dissect the action mechanisms of TCMs; and (6) reverse pharmacokinetics in drug discovery from natural medicines. Finally, based on the insights from the recent progress and our latest efforts, we propose new perspectives on the integrated pharmacokinetics of TCMs.

Further Validation of the SIGMAR1 c.151+1G>T Mutation as Cause of Distal Hereditary Motor Neuropathy

PubMed Central

Lee, Jessica J. Y.; Drögemoller, Britt; Shyr, Casper; Tarailo-Graovac, Maja; Eydoux, Patrice; Ross, Colin J.; Wasserman, Wyeth W.; Björnson, Bruce; Wu, John K.

2016-01-01

Distal hereditary motor neuropathies represent a group of rare genetic disorders characterized by progressive distal motor weakness without sensory loss. Their genetic heterogeneity is high and thus eligible for diagnostic whole exome sequencing. The authors report successful application of whole exome sequencing in diagnosing a second consanguineous family with distal hereditary motor neuropathy due to a homozygous c.151+1G>T variant in SIGMAR1. This variant was recently proposed as causal for the same condition in a consanguineous Chinese family. Compared to this family, the Afghan ethnic origin of our patient is distinct, yet the features are identical, validating the SIGMAR1 deficiency phenotype: progressive muscle wasting/weakness in lower and upper limbs without sensory loss. Rapid disease progression during adolescent growth is similar and may be due to SIGMAR1’s role in regulating axon elongation and tau phosphorylation. Finally, the authors conclude that SIGMAR1 deficiency should be added to the differential diagnosis of distal hereditary motor neuropathies. PMID:28503617

CD147/EMMPRIN overexpression and prognosis in cancer: A systematic review and meta-analysis

PubMed Central

Xin, Xiaoyan; Zeng, Xianqin; Gu, Huajian; Li, Min; Tan, Huaming; Jin, Zhishan; Hua, Teng; Shi, Rui; Wang, Hongbo

2016-01-01

CD147/EMMPRIN (extracellular matrix metalloproteinase inducer) plays an important role in tumor progression and a number of studies have suggested that it is an indicator of tumor prognosis. This current meta-analysis systematically reevaluated the predictive potential of CD147/EMMPRIN in various cancers. We searched PubMed and Embase databases to screen the literature. Fixed-effect and random-effect meta-analytical techniques were used to correlate CD147 expression with outcome measures. A total of 53 studies that included 68 datasets were eligible for inclusion in the final analysis. We found a significant association between CD147/EMMPRIN overexpression and adverse tumor outcomes, such as overall survival, disease-specific survival, progression-free survival, metastasis-free survival or recurrence-free survival, irrespective of the model analysis. In addition, CD147/EMMPRIN overexpression predicted a high risk for chemotherapy drugs resistance. CD147/EMMPRIN is a central player in tumor progression and predicts a poor prognosis, including in patients who have received chemo-radiotherapy. Our results provide the evidence that CD147/EMMPRIN could be a potential therapeutic target for cancers. PMID:27608940

Progress in the development and integration of fluid flow control tools in paper microfluidics.

PubMed

Fu, Elain; Downs, Corey

2017-02-14

Paper microfluidics is a rapidly growing subfield of microfluidics in which paper-like porous materials are used to create analytical devices. There is a need for higher performance field-use tests for many application domains including human disease diagnosis, environmental monitoring, and veterinary medicine. A key factor in creating high performance paper-based devices is the ability to manipulate fluid flow within the devices. This critical review is focused on the progress that has been made in (i) the development of fluid flow control tools and (ii) the integration of those tools into paper microfluidic devices. Further, we strive to be comprehensive in our presentation and provide historical context through discussion and performance comparisons, when possible, of both relevant earlier work and recent work. Finally, we discuss the major areas of focus for fluid flow methods development to advance the potential of paper microfluidics for high-performance field applications.

The Light and Shadow of Senescence and Inflammation in Cardiovascular Pathology and Regenerative Medicine

PubMed Central

Dal Sasso, Eleonora; Schirone, Leonardo; Forte, Maurizio; Palmerio, Silvia; Gerosa, Gino; Sciarretta, Sebastiano

2017-01-01

Recent epidemiologic studies evidence a dramatic increase of cardiovascular diseases, especially associated with the aging of the world population. During aging, the progressive impairment of the cardiovascular functions results from the compromised tissue abilities to protect the heart against stress. At the molecular level, in fact, a gradual weakening of the cellular processes regulating cardiovascular homeostasis occurs in aging cells. Atherosclerosis and heart failure are particularly correlated with aging-related cardiovascular senescence, that is, the inability of cells to progress in the mitotic program until completion of cytokinesis. In this review, we explore the intrinsic and extrinsic causes of cellular senescence and their role in the onset of these cardiovascular pathologies. Additionally, we dissect the effects of aging on the cardiac endogenous and exogenous reservoirs of stem cells. Finally, we offer an overview on the strategies of regenerative medicine that have been advanced in the quest for heart rejuvenation. PMID:29118467

Everolimus affects vasculogenic mimicry in renal carcinoma resistant to sunitinib

PubMed Central

Serova, Maria; Tijeras-Raballand, Annemilaï; Santos, Celia Dos; Martinet, Matthieu; Neuzillet, Cindy; Lopez, Alfred; Mitchell, Dianne C.; Bryan, Brad A.; Gapihan, Guillaume; Janin, Anne; Bousquet, Guilhem; Riveiro, Maria Eugenia; Bieche, Ivan; Faivre, Sandrine

2016-01-01

Angiogenesis is hallmark of clear cell renal cell carcinogenesis. Anti-angiogenic therapies have been successful in improving disease outcome; however, most patients treated with anti-angiogenic agents will eventually progress. In this study we report that clear cell renal cell carcinoma was associated with vasculogenic mimicry in both mice and human with tumor cells expressing endothelial markers in the vicinity of tumor vessels. We show that vasculogenic mimicry was efficiently targeted by sunitinib but eventually associated with tumor resistance and a more aggressive phenotype both in vitro and in vivo. Re-challenging these resistant tumors in mice, we showed that second-line treatment with everolimus particularly affected vasculogenic mimicry and tumor cell differentiation compared to sorafenib and axitinib. Finally, our results highlighted the phenotypic and genotypic changes at the tumor cell and microenvironment levels during sunitinib response and progression and the subsequent improvement second-line therapies bring to the current renal cell carcinoma treatment paradigm. PMID:27509260

Endometriosis and Ovarian Cancer: A Review of Clinical, Pathologic, and Molecular Aspects

PubMed Central

Wei, Jian-Jun; William, Josette; Bulun, Serdar

2014-01-01

Summary Endometriosis is a chronic disease that affects millions of reproductive-age women. Despite the destructive and invasive nature of endometrioses, most cases are perpetually benign or eventually regress; however, atypical endometriosis is a precursor lesion and can lead to certain types of ovarian cancer. Endometriosis induced inflammation and auto- and paracrine production of sex steroid hormones contribute to ovarian tumorigenesis. These changes provide microenvironment necessary to accumulate enough genetic alterations for endometriosis associated malignant transformation. It takes years for endometriosis to undergo the pathophysiological progression that begins with atypical epithelial proliferation (atypical endometriosis and metaplasia), and then is followed by the formation of well-defined borderline tumors, and finally culminates in fully malignant ovarian cancer. This study is a review of the natural history of endometriosis and the role of microenvironments that favor the accumulation of genetic alterations and endometriosis-associated ovarian cancer progression. PMID:21979592

Alzheimer's Caregiver Support Online: lessons learned, initial findings and future directions.

PubMed

Glueckauf, Robert L; Loomis, Jeffrey S

2003-01-01

Family caregivers of older adults with progressive dementia (e.g., Alzheimer's disease) are faced with a variety of emotional and behavioral difficulties, such as dealing with persistent, repetitive questions, managing agitation and depression, and monitoring hygiene and self-care activities. Although professional and governmental organizations have called for the creation of community-based education and support programs, most dementia caregivers continue to receive little or no formal instruction in responding effectively to these challenges. The current paper describes the development and implementation of Alzheimer's Caregiver Support Online, a Web- and telephone-based education and support network for caregivers of individuals with progressive dementia. Lessons learned from the first two years of this state-supported initiative are discussed, followed by the findings of a Robert Wood Johnson Foundation-funded strategic marketing initiative and an initial program evaluation of AlzOnline's Positive Caregiving classes. Finally, clinical implications and future directions for program development and evaluation research are proposed.

A review of plant-based compounds and medicinal plants effective on atherosclerosis

PubMed Central

Sedighi, Mehrnoosh; Bahmani, Mahmoud; Asgary, Sedigheh; Beyranvand, Fatemeh; Rafieian-Kopaei, Mahmoud

2017-01-01

Atherosclerosis is one of the most important cardiovascular diseases that involve vessels through the development of fatty streaks and plaques. Plant-based compounds can help treat or prevent atherosclerosis through affecting the involved factors. The main purpose of this review article is to investigate and introduce medicinal plants and their potential activities regarding antioxidant properties, effective on lipids level and development of plaque, atherosclerosis, and progression of atherosclerosis as well as the development of cardiovascular disease and ischemia. To search for the relevant articles indexed in Information Sciences Institute, PubMed, Scientific Information Database, IranMedex, and Scopus between 1980 and 2013, with further emphasis on those indexed from 2004 to 2015, we used these search terms: atherosclerosis, antioxidant, cholesterol, inflammation, and the medicinal plants below. Then, the articles with inclusion criteria were used in the final analysis of the findings. Plant-based active compounds, including phenols, flavonoids, and antioxidants, can be effective on atherosclerosis predisposing factors and hence in preventing this disease and associated harmful complications, especially through reducing cholesterol, preventing increase in free radicals, and ultimately decreasing vascular plaque and vascular resistance. Hence, medicinal plants can contribute to treating atherosclerosis and preventing its progression through reducing cholesterolemia, free radicals, inflammation, vascular resistance, and certain enzymes. They, alone or in combination with hypocholesterolemic drugs, can therefore be useful for patients with hyperlipidemia and its complications. PMID:28461816

Pros and cons of rituximab maintenance in follicular lymphoma.

PubMed

Zhang, Lu; Ghielmini, Michele; Cheson, Bruce D; Ujjani, Chaitra

2017-07-01

Follicular lymphoma (FL) is the most prevalent indolent non-Hodgkin lymphoma. Most patients present with advanced disease and are incurable with current therapy. The approval of rituximab has revolutionized the treatment of follicular lymphoma when administered in the induction setting for high-tumor burden disease, but the use of rituximab as a maintenance therapy (MR) continues to be a point of controversy. In this article, we review the main data and arguments in favor and against MR in FL. In summary, most studies have demonstrated a significant benefit in progression-free or event-free survival in this notoriously recurrent disease; however, long-term outcomes could not consistently demonstrate to be improved with this intervention. In a meta-analysis of randomized trials overall survival (OS) showed a tendency to improvement when given to patients in relapse, but no single study reached a significant OS advantage. The risk of high-grade transformation does not seem to be reduced in prospective trials. On the other hand, MR clearly increases toxicity without an improvement in quality of life. Finally, MR is expensive, and it is not proven that the delayed relapse time can compensate for these costs. In conclusion, despite the proven increase in progression-free survival, MR can't be recommended as a standard for the treatment of FL. Copyright © 2017 Elsevier Ltd. All rights reserved.

Coupled Harmonic Bases for Longitudinal Characterization of Brain Networks

PubMed Central

Hwang, Seong Jae; Adluru, Nagesh; Collins, Maxwell D.; Ravi, Sathya N.; Bendlin, Barbara B.; Johnson, Sterling C.; Singh, Vikas

2016-01-01

There is a great deal of interest in using large scale brain imaging studies to understand how brain connectivity evolves over time for an individual and how it varies over different levels/quantiles of cognitive function. To do so, one typically performs so-called tractography procedures on diffusion MR brain images and derives measures of brain connectivity expressed as graphs. The nodes correspond to distinct brain regions and the edges encode the strength of the connection. The scientific interest is in characterizing the evolution of these graphs over time or from healthy individuals to diseased. We pose this important question in terms of the Laplacian of the connectivity graphs derived from various longitudinal or disease time points — quantifying its progression is then expressed in terms of coupling the harmonic bases of a full set of Laplacians. We derive a coupled system of generalized eigenvalue problems (and corresponding numerical optimization schemes) whose solution helps characterize the full life cycle of brain connectivity evolution in a given dataset. Finally, we show a set of results on a diffusion MR imaging dataset of middle aged people at risk for Alzheimer’s disease (AD), who are cognitively healthy. In such asymptomatic adults, we find that a framework for characterizing brain connectivity evolution provides the ability to predict cognitive scores for individual subjects, and for estimating the progression of participant’s brain connectivity into the future. PMID:27812274

A review of plant-based compounds and medicinal plants effective on atherosclerosis.

PubMed

Sedighi, Mehrnoosh; Bahmani, Mahmoud; Asgary, Sedigheh; Beyranvand, Fatemeh; Rafieian-Kopaei, Mahmoud

2017-01-01

Atherosclerosis is one of the most important cardiovascular diseases that involve vessels through the development of fatty streaks and plaques. Plant-based compounds can help treat or prevent atherosclerosis through affecting the involved factors. The main purpose of this review article is to investigate and introduce medicinal plants and their potential activities regarding antioxidant properties, effective on lipids level and development of plaque, atherosclerosis, and progression of atherosclerosis as well as the development of cardiovascular disease and ischemia. To search for the relevant articles indexed in Information Sciences Institute, PubMed, Scientific Information Database, IranMedex, and Scopus between 1980 and 2013, with further emphasis on those indexed from 2004 to 2015, we used these search terms: atherosclerosis, antioxidant, cholesterol, inflammation, and the medicinal plants below. Then, the articles with inclusion criteria were used in the final analysis of the findings. Plant-based active compounds, including phenols, flavonoids, and antioxidants, can be effective on atherosclerosis predisposing factors and hence in preventing this disease and associated harmful complications, especially through reducing cholesterol, preventing increase in free radicals, and ultimately decreasing vascular plaque and vascular resistance. Hence, medicinal plants can contribute to treating atherosclerosis and preventing its progression through reducing cholesterolemia, free radicals, inflammation, vascular resistance, and certain enzymes. They, alone or in combination with hypocholesterolemic drugs, can therefore be useful for patients with hyperlipidemia and its complications.

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

NASA Technical Reports Server (NTRS)

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.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Neft, R.E.; Tierney, L.A.; Belinsky, S.A.

Molecular and immunological techniques may enhance the usefulness of sputum cytology as a screening tool for lung cancer. These techniques may also be useful in detecting and following the early progression of disease from metaplasia to dysplasia, carcinoma in situ, and finally to invasive carcinoma. Longitudinal information on the evolution of these malignant changes in the respiratory epithelium can be gained by prospective study of populations at high risk for lung cancer. This work is significant because double-labeling of cells in sputum with p53 and cytokeratin antibodies facilitates rapid screening of p53 positive neoplastic and preneoplastic lung cells by brightfieldmore » and fluorescence microscopy.« less

Chinese Herbal Medicine Meets Biological Networks of Complex Diseases: A Computational Perspective

PubMed Central

Gu, Shuo

2017-01-01

With the rapid development of cheminformatics, computational biology, and systems biology, great progress has been made recently in the computational research of Chinese herbal medicine with in-depth understanding towards pharmacognosy. This paper summarized these studies in the aspects of computational methods, traditional Chinese medicine (TCM) compound databases, and TCM network pharmacology. Furthermore, we chose arachidonic acid metabolic network as a case study to demonstrate the regulatory function of herbal medicine in the treatment of inflammation at network level. Finally, a computational workflow for the network-based TCM study, derived from our previous successful applications, was proposed. PMID:28690664

Chinese Herbal Medicine Meets Biological Networks of Complex Diseases: A Computational Perspective.

PubMed

Gu, Shuo; Pei, Jianfeng

2017-01-01

With the rapid development of cheminformatics, computational biology, and systems biology, great progress has been made recently in the computational research of Chinese herbal medicine with in-depth understanding towards pharmacognosy. This paper summarized these studies in the aspects of computational methods, traditional Chinese medicine (TCM) compound databases, and TCM network pharmacology. Furthermore, we chose arachidonic acid metabolic network as a case study to demonstrate the regulatory function of herbal medicine in the treatment of inflammation at network level. Finally, a computational workflow for the network-based TCM study, derived from our previous successful applications, was proposed.

Treatment of onychomycosis caused by dermatophytes--an opinion proposed by Committee for Standardization of the Japanese Society for Medical Mycology 2007.

PubMed

Mohri, Shinobu; Watanabe, Shinichi; Toshio, Kusunoki; Shibuya, Kazutoshi; Nishiyama, Yayoi; Abe, Michiko; Uno, Jun; Oguri, Toyoko; Maeasaki, Shigefumi; Ikeda, Reiko; Abe, Shigeru

2008-01-01

After the rapid progress in therapeutic pharmaceutics against onychomycosis caused by dermatophytes in the 1990s, an optimal therapeutic strategy for individual patients with the onychomycosis has become possible for clinical dermatologists. In this review, we discuss on clinical problems concerning this disease and propose recommendable treatments for each patient with topical and/or systemic use of antifungal agents. Finally, with consideration of already published therapeutic guidelines, we stress the necessity of "order-made" therapy for each patient with his/her medical status and wishes taking into account.

[Adrenoleukodystrophy: clinical and histopathological study of a case associated to the use of abortifacient agents in the second month of pregnancy].

PubMed

de Brito-Marques, P R; de Melo, R J; Barraquer i Bordas, L

1992-06-01

The authors report a case of adrenoleukodystrophy in a 8 years old male patient whose mother has taken several abortive drugs during the first three months of pregnancy. The disease was progressive starting with auditory, visual and mental disturbances, followed by neurovegetatives and motor changes with convulsion and fetal position. At the final stage the patient became blind, deaf, quadriplegic and dementiated. Death resulted from lung infection. The diagnosis was confirmed by the CSF, electrophysiological, radiological and necropsy findings. Necropsy changes in the brain and adrenal cortex are detailed.

Longitudinal Study of Gray Matter Changes in Parkinson Disease.

PubMed

Jia, X; Liang, P; Li, Y; Shi, L; Wang, D; Li, K

2015-12-01

The pathology of Parkinson disease leads to morphological brain volume changes. So far, the progressive gray matter volume change across time specific to patients with Parkinson disease compared controls remains unclear. Our aim was to investigate the pattern of gray matter changes in patients with Parkinson disease and to explore the progressive gray matter volume change specific to patients with Parkinson disease with disease progression by using voxel-based morphometry analysis. Longitudinal cognitive assessment and structural MR imaging of 89 patients with Parkinson disease (62 men) and 55 healthy controls (33 men) were from the Parkinson's Progression Markers Initiative data base, including the initial baseline and 12-month follow-up data. Two-way analysis of covariance was performed with covariates of age, sex, years of education, imaging data from multiple centers, and total intracranial volume by using Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra tool from SPM8 software. Gray matter volume changes for patients with Parkinson disease were detected with decreased gray matter volume in the frontotemporoparietal areas and the bilateral caudate, with increased gray matter volume in the bilateral limbic/paralimbic areas, medial globus pallidus/putamen, and the right occipital cortex compared with healthy controls. Progressive gray matter volume decrease in the bilateral caudate was found for both patients with Parkinson disease and healthy controls, and this caudate volume was positively associated with cognitive ability for both groups. The progressive gray matter volume increase specific to the patients with Parkinson disease was identified close to the left ventral lateral nucleus of thalamus, and a positive relationship was found between the thalamic volume and the tremor scores in a subgroup with tremor-dominant patients with Parkinson disease. The observed progressive changes in gray matter volume in Parkinson disease may provide new insights into the neurodegenerative process. The current findings suggest that the caudate volume loss may contribute to cognitive decline in patients with Parkinson disease and the progressive thalamus enlargement may have relevance to tremor severity in Parkinson disease. © 2015 by American Journal of Neuroradiology.

Efficacy and Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma or Leiomyosarcoma After Failure of Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clinical Trial.

PubMed

Demetri, George D; von Mehren, Margaret; Jones, Robin L; Hensley, Martee L; Schuetze, Scott M; Staddon, Arthur; Milhem, Mohammed; Elias, Anthony; Ganjoo, Kristen; Tawbi, Hussein; Van Tine, Brian A; Spira, Alexander; Dean, Andrew; Khokhar, Nushmia Z; Park, Youn Choi; Knoblauch, Roland E; Parekh, Trilok V; Maki, Robert G; Patel, Shreyaskumar R

2016-03-10

This multicenter study, to our knowledge, is the first phase III trial to compare trabectedin versus dacarbazine in patients with advanced liposarcoma or leiomyosarcoma after prior therapy with an anthracycline and at least one additional systemic regimen. Patients were randomly assigned in a 2:1 ratio to receive trabectedin or dacarbazine intravenously every 3 weeks. The primary end point was overall survival (OS), secondary end points were disease control-progression-free survival (PFS), time to progression, objective response rate, and duration of response-as well as safety and patient-reported symptom scoring. A total of 518 patients were enrolled and randomly assigned to either trabectedin (n = 345) or dacarbazine (n = 173). In the final analysis of PFS, trabectedin administration resulted in a 45% reduction in the risk of disease progression or death compared with dacarbazine (median PFS for trabectedin v dacarbazine, 4.2 v 1.5 months; hazard ratio, 0.55; P < .001); benefits were observed across all preplanned subgroup analyses. The interim analysis of OS (64% censored) demonstrated a 13% reduction in risk of death in the trabectedin arm compared with dacarbazine (median OS for trabectedin v dacarbazine, 12.4 v 12.9 months; hazard ratio, 0.87; P = .37). The safety profiles were consistent with the well-characterized toxicities of both agents, and the most common grade 3 to 4 adverse effects were myelosuppression and transient elevation of transaminases in the trabectedin arm. Trabectedin demonstrates superior disease control versus conventional dacarbazine in patients who have advanced liposarcoma and leiomyosarcoma after they experience failure of prior chemotherapy. Because disease control in advanced sarcomas is a clinically relevant end point, this study supports the activity of trabectedin for patients with these malignancies. © 2015 by American Society of Clinical Oncology.

The ubiquitin proteasomal system: a potential target for the management of Alzheimer's disease.

PubMed

Gadhave, Kundlik; Bolshette, Nityanand; Ahire, Ashutosh; Pardeshi, Rohit; Thakur, Krishan; Trandafir, Cristiana; Istrate, Alexandru; Ahmed, Sahabuddin; Lahkar, Mangala; Muresanu, Dafin F; Balea, Maria

2016-07-01

The cellular quality control system degrades abnormal or misfolded proteins and consists of three different mechanisms: the ubiquitin proteasomal system (UPS), autophagy and molecular chaperones. Any disturbance in this system causes proteins to accumulate, resulting in neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease (AD), Parkinson's disease, Huntington's disease and prion or polyglutamine diseases. Alzheimer's disease is currently one of the most common age-related neurodegenerative diseases. However, its exact cause and pathogenesis are unknown. Currently approved medications for AD provide symptomatic relief; however, they fail to influence disease progression. Moreover, the components of the cellular quality control system represent an important focus for the development of targeted and potent therapies for managing AD. This review aims to evaluate whether existing evidence supports the hypothesis that UPS impairment causes the early pathogenesis of neurodegenerative disorders. The first part presents basic information about the UPS and its molecular components. The next part explains how the UPS is involved in neurodegenerative disorders. Finally, we emphasize how the UPS influences the management of AD. This review may help in the design of future UPS-related therapies for AD. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

[Nutritional approaches to modulate oxidative stress that induce Alzheimer's disease. Nutritional approaches to prevent Alzheimer's disease].

PubMed

Lara, Humberto Herman; Alanís-Garza, Eduardo Javier; Estrada Puente, María Fernanda; Mureyko, Lucía Liliana; Alarcón Torres, David Alejandro; Ixtepan Turrent, Liliana

2015-01-01

Alzheimer's disease is the most common cause of dementia in the world; symptoms first appear after age 65 and have a progressive evolution. Expecting an increase on its incidence and knowing there is currently no cure for Alzheimer's disease, it is a necessity to prevent progression. The change in diet due to globalization may explain the growth of the incidence in places such as Japan and Mediterranean countries, which used to have fewer incidences. There is a direct correlation between disease progression and the increased intake of alcohol, saturated fats, and red meat. Therefore, we find obesity and higher serum levels in cholesterol due to saturated fat as a result. A way to decrease the progression of Alzheimer's is through a diet rich in polipheno/es (potent antioxidants), unsaturated fats (monounsaturated and polyunsaturated), fish, vegetable fa t, fruits with low glycemic index, and a moderate consumption of red wine. Through this potent antioxidant diet we accomplish the prevention of dementia and the progression of Alzheimer's disease. This article emphasizes the food and other components that have been demonstrated to decrease the oxidative stress related to these progressive diseases.

PSI-Center Final Progress Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jarboe, Thomas R.; Shumlak, Uri; Sovinec, Carl

This is the Final Progress Report of the Plasma Science and Innovation Center (PSI-Center) covering March 2014 through February 2017. The Center has accomplished a great deal during this period. The PSI-Center is organized into four groups: Edge and Dynamic Neutrals; Transport and Kinetic Effects; Equilibrium, Stability, and Kinetic Effects in 3D Topologies; and Interface for Validation. Each group has made good progress and the results from each group are given in detail.

Profibrogenic chemokines and viral evolution predict rapid progression of hepatitis C to cirrhosis

PubMed Central

Farci, Patrizia; Wollenberg, Kurt; Diaz, Giacomo; Engle, Ronald E.; Lai, Maria Eliana; Klenerman, Paul; Purcell, Robert H.; Pybus, Oliver G.; Alter, Harvey J.

2012-01-01

Chronic hepatitis C may follow a mild and stable disease course or progress rapidly to cirrhosis and liver-related death. The mechanisms underlying the different rates of disease progression are unknown. Using serial, prospectively collected samples from cases of transfusion-associated hepatitis C, we identified outcome-specific features that predict long-term disease severity. Slowly progressing disease correlated with an early alanine aminotransferase peak and antibody seroconversion, transient control of viremia, and significant induction of IFN-γ and MIP-1β, all indicative of an effective, albeit insufficient, adaptive immune response. By contrast, rapidly progressive disease correlated with persistent and significant elevations of alanine aminotransferase and the profibrogenic chemokine MCP-1 (CCL-2), greater viral diversity and divergence, and a higher rate of synonymous substitution. This study suggests that the long-term course of chronic hepatitis C is determined early in infection and that disease severity is predicted by the evolutionary dynamics of hepatitis C virus and the level of MCP-1, a chemokine that appears critical to the induction of progressive fibrogenesis and, ultimately, the ominous complications of cirrhosis. PMID:22829669

Calculating stage duration statistics in multistage diseases.

PubMed

Komarova, Natalia L; Thalhauser, Craig J

2011-01-01

Many human diseases are characterized by multiple stages of progression. While the typical sequence of disease progression can be identified, there may be large individual variations among patients. Identifying mean stage durations and their variations is critical for statistical hypothesis testing needed to determine if treatment is having a significant effect on the progression, or if a new therapy is showing a delay of progression through a multistage disease. In this paper we focus on two methods for extracting stage duration statistics from longitudinal datasets: an extension of the linear regression technique, and a counting algorithm. Both are non-iterative, non-parametric and computationally cheap methods, which makes them invaluable tools for studying the epidemiology of diseases, with a goal of identifying different patterns of progression by using bioinformatics methodologies. Here we show that the regression method performs well for calculating the mean stage durations under a wide variety of assumptions, however, its generalization to variance calculations fails under realistic assumptions about the data collection procedure. On the other hand, the counting method yields reliable estimations for both means and variances of stage durations. Applications to Alzheimer disease progression are discussed.

Profibrogenic chemokines and viral evolution predict rapid progression of hepatitis C to cirrhosis.

PubMed

Farci, Patrizia; Wollenberg, Kurt; Diaz, Giacomo; Engle, Ronald E; Lai, Maria Eliana; Klenerman, Paul; Purcell, Robert H; Pybus, Oliver G; Alter, Harvey J

2012-09-04

Chronic hepatitis C may follow a mild and stable disease course or progress rapidly to cirrhosis and liver-related death. The mechanisms underlying the different rates of disease progression are unknown. Using serial, prospectively collected samples from cases of transfusion-associated hepatitis C, we identified outcome-specific features that predict long-term disease severity. Slowly progressing disease correlated with an early alanine aminotransferase peak and antibody seroconversion, transient control of viremia, and significant induction of IFN-γ and MIP-1β, all indicative of an effective, albeit insufficient, adaptive immune response. By contrast, rapidly progressive disease correlated with persistent and significant elevations of alanine aminotransferase and the profibrogenic chemokine MCP-1 (CCL-2), greater viral diversity and divergence, and a higher rate of synonymous substitution. This study suggests that the long-term course of chronic hepatitis C is determined early in infection and that disease severity is predicted by the evolutionary dynamics of hepatitis C virus and the level of MCP-1, a chemokine that appears critical to the induction of progressive fibrogenesis and, ultimately, the ominous complications of cirrhosis.

Predicting kidney disease progression in patients with acute kidney injury after cardiac surgery.

PubMed

Mizuguchi, K Annette; Huang, Chuan-Chin; Shempp, Ian; Wang, Justin; Shekar, Prem; Frendl, Gyorgy

2018-06-01

The study objective was to identify patients who are likely to develop progressive kidney dysfunction (acute kidney disease) before their hospital discharge after cardiac surgery, allowing targeted monitoring of kidney function in this at-risk group with periodic serum creatinine measurements. Risks of progression to acute kidney disease (a state in between acute kidney injury and chronic kidney disease) were modeled from acute kidney injury stages (Kidney Disease: Improving Global Outcomes) in patients undergoing cardiac surgery. A modified Poisson regression with robust error variance was used to evaluate the association between acute kidney injury stages and the development of acute kidney disease (defined as doubling of creatinine 2-4 weeks after surgery) in this observational study. Acute kidney disease occurred in 4.4% of patients with no preexisting kidney disease and 4.8% of patients with preexisting chronic kidney disease. Acute kidney injury predicted development of acute kidney disease in a graded manner in which higher stages of acute kidney injury predicted higher relative risk of progressive kidney disease (area under the receiver operator characteristic curve = 0.82). This correlation persisted regardless of baseline kidney function (P < .001). Of note, development of acute kidney disease was associated with higher mortality and need for renal replacement therapy. The degree of acute kidney injury can identify patients who will have a higher risk of progression to acute kidney disease. These patients may benefit from close follow-up of renal function because they are at risk of progressing to chronic kidney disease or end-stage renal disease. Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

HIV Type 1 Disease Progression to AIDS and Death in a Rural Ugandan Cohort Is Primarily Dependent on Viral Load Despite Variable Subtype and T-Cell Immune Activation Levels

PubMed Central

Eller, Michael A.; Opollo, Marc S.; Liu, Michelle; Redd, Andrew D.; Eller, Leigh Anne; Kityo, Cissy; Kayiwa, Joshua; Laeyendecker, Oliver; Wawer, Maria J.; Milazzo, Mark; Kiwanuka, Noah; Gray, Ronald H.; Serwadda, David; Sewankambo, Nelson K.; Quinn, Thomas C.; Michael, Nelson L.; Wabwire-Mangen, Fred; Sandberg, Johan K.; Robb, Merlin L.

2015-01-01

Background. Untreated human immunodeficiency virus type 1 (HIV) infection is associated with persistent immune activation, which is an independent driver of disease progression in European and United States cohorts. In Uganda, HIV-1 subtypes A and D and recombinant AD viruses predominate and exhibit differential rates of disease progression. Methods. HIV-1 seroconverters (n = 156) from rural Uganda were evaluated to assess the effects of T-cell activation, viral load, and viral subtype on disease progression during clinical follow-up. Results. The frequency of activated T cells was increased in HIV-1–infected Ugandans, compared with community matched uninfected individuals, but did not differ significantly between viral subtypes. Higher HIV-1 load, subtype D, older age, and high T-cell activation levels were associated with faster disease progression to AIDS or death. In a multivariate Cox regression analysis, HIV-1 load was the strongest predictor of progression, with subtype also contributing. T-cell activation did not emerge an independent predictor of disease progression from this particular cohort. Conclusions. These findings suggest that the independent contribution of T-cell activation on morbidity and mortality observed in European and North American cohorts may not be directly translated to the HIV epidemic in East Africa. In this setting, HIV-1 load appears to be the primary determinant of disease progression. PMID:25404522

MNDR v2.0: an updated resource of ncRNA–disease associations in mammals

PubMed Central

Cui, Tianyu; Zhang, Lin; Huang, Yan; Yi, Ying; Tan, Puwen; Zhao, Yue; Hu, Yongfei

2018-01-01

Abstract Accumulating evidence suggests that diverse non-coding RNAs (ncRNAs) are involved in the progression of a wide variety of diseases. In recent years, abundant ncRNA–disease associations have been found and predicted according to experiments and prediction algorithms. Diverse ncRNA–disease associations are scattered over many resources and mammals, whereas a global view of diverse ncRNA–disease associations is not available for any mammals. Hence, we have updated the MNDR v2.0 database (www.rna-society.org/mndr/) by integrating experimental and prediction associations from manual literature curation and other resources under one common framework. The new developments in MNDR v2.0 include (i) an over 220-fold increase in ncRNA–disease associations enhancement compared with the previous version (including lncRNA, miRNA, piRNA, snoRNA and more than 1400 diseases); (ii) integrating experimental and prediction evidence from 14 resources and prediction algorithms for each ncRNA–disease association; (iii) mapping disease names to the Disease Ontology and Medical Subject Headings (MeSH); (iv) providing a confidence score for each ncRNA–disease association and (v) an increase of species coverage to six mammals. Finally, MNDR v2.0 intends to provide the scientific community with a resource for efficient browsing and extraction of the associations between diverse ncRNAs and diseases, including >260 000 ncRNA–disease associations. PMID:29106639

Combined Diffusion Tensor Imaging and Apparent Transverse Relaxation Rate Differentiate Parkinson Disease and Atypical Parkinsonism.

PubMed

Du, G; Lewis, M M; Kanekar, S; Sterling, N W; He, L; Kong, L; Li, R; Huang, X

2017-05-01

Both diffusion tensor imaging and the apparent transverse relaxation rate have shown promise in differentiating Parkinson disease from atypical parkinsonism (particularly multiple system atrophy and progressive supranuclear palsy). The objective of the study was to assess the ability of DTI, the apparent transverse relaxation rate, and their combination for differentiating Parkinson disease, multiple system atrophy, progressive supranuclear palsy, and controls. A total of 106 subjects (36 controls, 35 patients with Parkinson disease, 16 with multiple system atrophy, and 19 with progressive supranuclear palsy) were included. DTI and the apparent transverse relaxation rate measures from the striatal, midbrain, limbic, and cerebellar regions were obtained and compared among groups. The discrimination performance of DTI and the apparent transverse relaxation rate among groups was assessed by using Elastic-Net machine learning and receiver operating characteristic curve analysis. Compared with controls, patients with Parkinson disease showed significant apparent transverse relaxation rate differences in the red nucleus. Compared to those with Parkinson disease, patients with both multiple system atrophy and progressive supranuclear palsy showed more widespread changes, extending from the midbrain to striatal and cerebellar structures. The pattern of changes, however, was different between the 2 groups. For instance, patients with multiple system atrophy showed decreased fractional anisotropy and an increased apparent transverse relaxation rate in the subthalamic nucleus, whereas patients with progressive supranuclear palsy showed an increased mean diffusivity in the hippocampus. Combined, DTI and the apparent transverse relaxation rate were significantly better than DTI or the apparent transverse relaxation rate alone in separating controls from those with Parkinson disease/multiple system atrophy/progressive supranuclear palsy; controls from those with Parkinson disease; those with Parkinson disease from those with multiple system atrophy/progressive supranuclear palsy; and those with Parkinson disease from those with multiple system atrophy; but not those with Parkinson disease from those with progressive supranuclear palsy, or those with multiple system atrophy from those with progressive supranuclear palsy. DTI and the apparent transverse relaxation rate provide different but complementary information for different parkinsonisms. Combined DTI and apparent transverse relaxation rate may be a superior marker for the differential diagnosis of parkinsonisms. © 2017 by American Journal of Neuroradiology.

Re-Evaluating Progression in an Era of Progress: A Review of First- and Second-Line Treatment Options in Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer.

PubMed

Castellanos, Emily H; Horn, Leora

2016-06-01

: The advent of crizotinib, the first small molecule inhibitor against anaplastic lymphoma kinase (ALK), has led to impressive advances in the care of patients with advanced ALK-rearranged non-small cell lung cancer. The development of second-generation ALK inhibitors, starting with the recent U.S. Food and Drug Administration approval of ceritinib, promises to expand the therapeutic landscape for this cohort of patients. With increasing use of molecularly targeted therapy options, it has been observed that disease progression in patients receiving targeted agents has a heterogeneous biology, manifesting as either oligoprogressive or widely progressive disease, which may require development of innovative treatment strategies. This review discusses the first- and second-generation ALK inhibitors approved or in clinical development, as well as the novel challenges and approaches to disease progression in patients on targeted agents. The identification of driver mutations in non-small cell lung cancer (NSCLC), most prominently epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), has expanded treatment options for a significant cohort of patients. However, the success of targeted agents has brought new challenges, particularly regarding management of progression. Progression manifests heterogeneously, and management of oligoprogression may differ from diffusely progressive disease. Multiple options for treatment at progression exist, and it is becoming evident that selecting the best avenue of care requires understanding the biology and potential drivers of disease progression. This review discusses the array of treatment options available for patients with ALK-positive NSCLC, as well as evaluation and treatment of progressive disease. ©AlphaMed Press.

Re-Evaluating Progression in an Era of Progress: A Review of First- and Second-Line Treatment Options in Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer

PubMed Central

Castellanos, Emily H.

2016-01-01

The advent of crizotinib, the first small molecule inhibitor against anaplastic lymphoma kinase (ALK), has led to impressive advances in the care of patients with advanced ALK-rearranged non-small cell lung cancer. The development of second-generation ALK inhibitors, starting with the recent U.S. Food and Drug Administration approval of ceritinib, promises to expand the therapeutic landscape for this cohort of patients. With increasing use of molecularly targeted therapy options, it has been observed that disease progression in patients receiving targeted agents has a heterogeneous biology, manifesting as either oligoprogressive or widely progressive disease, which may require development of innovative treatment strategies. This review discusses the first- and second-generation ALK inhibitors approved or in clinical development, as well as the novel challenges and approaches to disease progression in patients on targeted agents. Implications for Practice: The identification of driver mutations in non-small cell lung cancer (NSCLC), most prominently epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), has expanded treatment options for a significant cohort of patients. However, the success of targeted agents has brought new challenges, particularly regarding management of progression. Progression manifests heterogeneously, and management of oligoprogression may differ from diffusely progressive disease. Multiple options for treatment at progression exist, and it is becoming evident that selecting the best avenue of care requires understanding the biology and potential drivers of disease progression. This review discusses the array of treatment options available for patients with ALK-positive NSCLC, as well as evaluation and treatment of progressive disease. PMID:27053502

Clinical trials in progressive multiple sclerosis: lessons learned and future perspectives

PubMed Central

Ontaneda, Daniel; Fox, Robert J.; Chataway, Jeremy

2015-01-01

Progressive multiple sclerosis is characterized by the gradual accrual of disability independent of relapses and can occur with disease onset (primary progressive) or preceded by a relapsing disease course (secondary progressive). An effective disease modifying treatment for progressive multiple sclerosis has not been identified, and the results of clinical trials to date have been generally disappointing. Ongoing advances in our understanding of pathogenesis, identification of novel targets for neuro-protection, and improved outcome measures have the potential to lead to effective treatments for progressive multiple sclerosis. In this review lessons learned from previous clinical trials and perspectives from current trials in progressive multiple sclerosis are summarized. Promising clinical, imaging, and biological markers will also be reviewed, along with novel clinical trial designs. PMID:25772899

The Swedish BioFINDER 2 Study

ClinicalTrials.gov

2018-04-16

Dementia; Alzheimer Disease; Parkinson Disease; Lewy Body Disease; Parkinson-Dementia Syndrome; Frontotemporal Degeneration; Semantic Dementia; Progressive Nonfluent Aphasia; Progressive Supranuclear Palsy; Corticobasal Degeneration; Multiple System Atrophy; Mild Cognitive Impairment

HATT: a phase IV, single-arm, open-label study of sorafenib in Taiwanese patients with advanced hepatocellular carcinoma.

PubMed

Lin, Shi-Ming; Lu, Sheng-Nan; Chen, Ping-Tsung; Jeng, Long-Bin; Chen, Shinn-Cherng; Hu, Chi-Tan; Yang, Sien-Sing; Le Berre, Marie-Aude; Liu, Xuan; Mitchell, David Y; Prins, Klaas; Grevel, Joachim; Peña, Carol A E; Meinhardt, Gerold

2017-03-01

Sorafenib significantly improves survival in patients with advanced hepatocellular carcinoma (HCC). This phase IV study assessed sorafenib efficacy/safety in Taiwanese patients with advanced HCC and Child-Pugh A status. All patients received 400 mg sorafenib BID. Safety, efficacy, sorafenib pharmacokinetics, and Child-Pugh progression were evaluated. A hand-foot skin reaction (HFSR) prevention substudy assessed HFSR incidence and grade/severity and time to HFSR in 29 and 34 patients randomized to corticosteroid and noncorticosteroid ointments, respectively, and in 88 nonrandomized patients. The 151 patients included 120 (80%) male patients and 81 (54%) with stage IV disease. Mean sorafenib dose was 626 mg/day, and median treatment duration was 4.2 months. Median overall survival (OS), progression-free survival, and time to progression (TTP) were 8.6, 2.7, and 3.8 months, respectively. Disease control and response rates (partial responses only) were 48 and 6.6%, respectively. Median TTP from Child-Pugh A to B/C was 88 days. Drug-related adverse events (AEs) occurred in 89.4% of patients; none were new or unexpected. The most frequent grade ≥3 drug-related, treatment-emergent AEs were HFSR (13.2%), diarrhea (11.9%), and hypertension (6.6%). Corticosteroid ointment tended to reduce the severity and incidence of all HFSR-associated parameters. Pharmacokinetic exposure was unaltered by Child-Pugh progression. The final pharmacokinetic model predicted 13.1 and 33.8% reductions in sorafenib exposure over 6 and 12 months, respectively. There was a trend of longer OS and TTP in Taiwanese patients with advanced HCC compared with patients with advanced HCC in the Asia-Pacific trial. Sorafenib exposure did not correlate with liver function. Reduced pharmacokinetic exposure over time was unrelated to reduced or interrupted dosing.

Structural and functional hallmarks of amyotrophic lateral sclerosis progression in motor- and memory-related brain regions

PubMed Central

Stoppel, Christian Michael; Vielhaber, Stefan; Eckart, Cindy; Machts, Judith; Kaufmann, Jörn; Heinze, Hans-Jochen; Kollewe, Katja; Petri, Susanne; Dengler, Reinhard; Hopf, Jens-Max; Schoenfeld, Mircea Ariel

2014-01-01

Previous studies have shown that in amyotrophic lateral sclerosis (ALS) multiple motor and extra-motor regions display structural and functional alterations. However, their temporal dynamics during disease-progression are unknown. To address this question we employed a longitudinal design assessing motor- and novelty-related brain activity in two fMRI sessions separated by a 3-month interval. In each session, patients and controls executed a Go/NoGo-task, in which additional presentation of novel stimuli served to elicit hippocampal activity. We observed a decline in the patients' movement-related activity during the 3-month interval. Importantly, in comparison to controls, the patients' motor activations were higher during the initial measurement. Thus, the relative decrease seems to reflect a breakdown of compensatory mechanisms due to progressive neural loss within the motor-system. In contrast, the patients' novelty-evoked hippocampal activity increased across 3 months, most likely reflecting the build-up of compensatory processes typically observed at the beginning of lesions. Consistent with a stage-dependent emergence of hippocampal and motor-system lesions, we observed a positive correlation between the ALSFRS-R or MRC-Megascores and the decline in motor activity, but a negative one with the hippocampal activation-increase. Finally, to determine whether the observed functional changes co-occur with structural alterations, we performed voxel-based volumetric analyses on magnetization transfer images in a separate patient cohort studied cross-sectionally at another scanning site. Therein, we observed a close overlap between the structural changes in this cohort, and the functional alterations in the other. Thus, our results provide important insights into the temporal dynamics of functional alterations during disease-progression, and provide support for an anatomical relationship between functional and structural cerebral changes in ALS. PMID:25161894

HIV-associated progressive multifocal leukoencephalopathy: longitudinal study of JC virus non-coding control region rearrangements and host immunity.

PubMed

Iannetta, Marco; Bellizzi, Anna; Lo Menzo, Sara; Anzivino, Elena; D'Abramo, Alessandra; Oliva, Alessandra; D'Agostino, Claudia; d'Ettorre, Gabriella; Pietropaolo, Valeria; Vullo, Vincenzo; Ciardi, Maria Rosa

2013-06-01

John Cunningham virus (JCV), the etiological agent of progressive multifocal leukoencephalopathy (PML), contains a hyper-variable non-coding control region usually detected in urine of healthy individuals as archetype form and in the brain and cerebrospinal fluid (CSF) of PML patients as rearranged form. We report a case of HIV-related PML with clinical, immunological and virological data longitudinally collected. On admission (t0), after 8-week treatment with a rescue highly active antiretroviral therapy (HAART), the patient showed a CSF-JCV load of 16,732 gEq/ml, undetectable HIV-RNA and an increase of CD4+ cell count. Brain magnetic resonance imaging (MRI) showed PML-compatible lesions without contrast enhancement. We considered PML-immune reconstitution inflammatory syndrome as plausible because of the sudden onset of neurological symptoms after the effective HAART. An experimental JCV treatment with mefloquine and mirtazapine was added to steroid boli. Two weeks later (t1), motor function worsened and MRI showed expanded lesions with cytotoxic oedema. CSF JCV-DNA increased (26,263 gEq/ml) and JCV viremia was detected. After 4 weeks (t2), JCV was detected only in CSF (37,719 gEq/ml), and 8 weeks after admission (t3), JC viral load decreased in CSF and JCV viremia reappeared. The patient showed high level of immune activation both in peripheral blood and CSF. He died 4 weeks later. Considering disease progression, combined therapy failure and immune hyper-activation, we finally classified the case as classical PML. The archetype variant found in CSF at t0/t3 and a rearranged sequence detected at t1/t2 suggest that PML can develop from an archetype virus and that the appearance of rearranged genotypes contribute to faster disease progression.

Prevalence of obesity in paediatric psoriasis and its impact on disease severity and progression.

PubMed

Ergun, Tulin; Seckin Gencosmanoglu, Dilek; Karakoc-Aydiner, Elif; Salman, Andac; Tekin, Burak; Bulbul-Baskan, Emel; Alpsoy, Erkan; Cakıroglu, Aylin; Onsun, Nahide

2017-11-01

The current literature suggests there is a possible connection between paediatric psoriasis and obesity. However, there is a paucity of research on the influence of increased adiposity on the severity of paediatric psoriasis and disease progression. We aimed to compare the prevalence of being overweight or obese in paediatric psoriasis patients and controls and assess the potential impact of being overweight/obese on disease severity and progression of disease. This multicentre prospective case-control study included 289 psoriasis patients (aged < 18 years) treated and followed up by one of the four university hospitals in Turkey. The control group consisted of 151 consecutive age-matched and sex-matched children who lacked a personal or family history of psoriasis. The participants' characteristics, psoriasis-related parametres (e.g., initial subtype, psoriasis area and severity index, presence of psoriatic arthritis) and body mass index were determined. The difference between the prevalence of being overweight/obese among psoriatics (28%) and the control group (19%) was significant (P = 0.024). Being overweight/obese had no significant impact on disease severity and unresponsiveness to topical treatment. Within a median follow-up time of 12 months, 23% of our patients with localised disease at disease onset progressed to generalised disease. The impact of being overweight/obese on disease progression was found to be non-significant; however, disease duration was found to have a significant impact on disease progression (P = 0.026). Although it is not associated with disease severity and course, increased bodyweight may be a health problem for psoriatic children. © 2016 The Australasian College of Dermatologists.

Risk factors for progression to invasive carcinoma in patients with borderline ovarian tumors.

PubMed

Song, Taejong; Lee, Yoo-Young; Choi, Chel Hun; Kim, Tae-Joong; Lee, Jeong-Won; Bae, Duk-Soo; Kim, Byoung-Gie

2014-09-01

The aim of this study was to identify risk factors for progression to invasive carcinoma in patients with borderline ovarian tumors (BOTs). We performed a retrospective review of all patients treated and followed for BOTs between 1996 and 2011. Multivariate Cox proportional hazards model analysis was performed to identify independent risk factors for progression to invasive carcinoma. A total of 364 patients were identified. During the median follow-up of 53.8 months, 31 patients (8.5%) developed recurrent disease: 12 (3.3%) had recurrent disease with progression to invasive carcinoma, and 19 (5.2%) had recurrent disease with borderline histology. Disease-related deaths (7/364; 1.7%) were observed only in patients with progression to invasive carcinoma. The multivariate analysis showed that independent risk factors for progression to invasive carcinoma were advanced disease stage (hazard ratio [HR], 5.59; P = 0.005), age 65 years or older (HR, 5.13; P = 0.037), and the presence of microinvasion (HR, 3.71; P = 0.047). These 3 factors were also independently related to overall survival. Although patients with BOTs have an excellent prognosis, the risk of progression to invasive carcinoma and thereby death remains. Therefore, physicians should pay closer attention to BOT patients with these risk factors (ie, advanced disease stage, old age, and microinvasion), and more careful surveillance for progression to invasive carcinoma is needed.

Advances of Molecular Imaging for Monitoring the Anatomical and Functional Architecture of the Olfactory System.

PubMed

Zhang, Xintong; Bi, Anyao; Gao, Quansheng; Zhang, Shuai; Huang, Kunzhu; Liu, Zhiguo; Gao, Tang; Zeng, Wenbin

2016-01-20

The olfactory system of organisms serves as a genetically and anatomically model for studying how sensory input can be translated into behavior output. Some neurologic diseases are considered to be related to olfactory disturbance, especially Alzheimer's disease, Parkinson's disease, multiple sclerosis, and so forth. However, it is still unclear how the olfactory system affects disease generation processes and olfaction delivery processes. Molecular imaging, a modern multidisciplinary technology, can provide valid tools for the early detection and characterization of diseases, evaluation of treatment, and study of biological processes in living subjects, since molecular imaging applies specific molecular probes as a novel approach to produce special data to study biological processes in cellular and subcellular levels. Recently, molecular imaging plays a key role in studying the activation of olfactory system, thus it could help to prevent or delay some diseases. Herein, we present a comprehensive review on the research progress of the imaging probes for visualizing olfactory system, which is classified on different imaging modalities, including PET, MRI, and optical imaging. Additionally, the probes' design, sensing mechanism, and biological application are discussed. Finally, we provide an outlook for future studies in this field.

Infection processes of xylem-colonizing pathogenic bacteria: possible explanations for the scarcity of qualitative disease resistance genes against them in crops.

PubMed

Bae, Chungyun; Han, Sang Wook; Song, Yu-Rim; Kim, Bo-Young; Lee, Hyung-Jin; Lee, Je-Min; Yeam, Inhwa; Heu, Sunggi; Oh, Chang-Sik

2015-07-01

Disease resistance against xylem-colonizing pathogenic bacteria in crops. Plant pathogenic bacteria cause destructive diseases in many commercially important crops. Among these bacteria, eight pathogens, Ralstonia solanacearum, Xanthomonas oryzae pv. oryzae, X. campestris pv. campestris, Erwinia amylovora, Pantoea stewartii subsp. stewartii, Clavibacter michiganensis subsp. michiganensis, Pseudomonas syringae pv. actinidiae, and Xylella fastidiosa, infect their host plants through different infection sites and paths and eventually colonize the xylem tissues of their host plants, resulting in wilting symptoms by blocking water flow or necrosis of xylem tissues. Noticeably, only a relatively small number of resistant cultivars in major crops against these vascular bacterial pathogens except X. oryzae pv. oryzae have been found or generated so far, although these pathogens threaten productivity of major crops. In this review, we summarize the lifestyles of major xylem-colonizing bacterial pathogens and then discuss the progress of current research on disease resistance controlled by qualitative disease resistance genes or quantitative trait loci against them. Finally, we propose infection processes of xylem-colonizing bacterial pathogens as one of possible reasons for why so few qualitative disease resistance genes against these pathogens have been developed or identified so far in crops.

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

PubMed Central

2010-01-01

Changes to the glycosylation profile on HIV gp120 can influence viral pathogenesis and alter AIDS disease progression. The characterization of glycosylation differences at the sequence level is inadequate as the placement of carbohydrates is structurally complex. However, no structural framework is available to date for the study of HIV disease progression. In this study, we propose a novel machine-learning based framework for the prediction of AIDS disease progression in three stages (RP, SP, and LTNP) using the HIV structural gp120 profile. This new intelligent framework proves to be accurate and provides an important benchmark for predicting AIDS disease progression computationally. The model is trained using a novel HIV gp120 glycosylation structural profile to detect possible stages of AIDS disease progression for the target sequences of HIV+ individuals. The performance of the proposed model was compared to seven existing different machine-learning models on newly proposed gp120-Benchmark_1 dataset in terms of error-rate (MSE), accuracy (CCI), stability (STD), and complexity (TBM). The novel framework showed better predictive performance with 67.82% CCI, 30.21 MSE, 0.8 STD, and 2.62 TBM on the three stages of AIDS disease progression of 50 HIV+ individuals. This framework is an invaluable bioinformatics tool that will be useful to the clinical assessment of viral pathogenesis. PMID:21143806

Translating airway biomarker information into practice: from theoretical science to applied medicine.

PubMed

Ameredes, Bill T

2011-04-01

Biomarkers ranging from simple to sophisticated have been used by man for many years of his existence. The main use for biomarkers over that time has been to assess relative states health and well-being, including the presence of functional limitations that presage debilitation and even death. In recent years, there has been intense interest in the development of non-invasive biomarkers to accurately predict disease state and progression, as well as potential drug therapy to assist in early mitigation of morbidity and possibly, forestall premature mortality. The development of biomarkers of airway status has followed a similar pattern, and in recent years, several biomarkers have followed the progression from basic and pre-clinical development, to clinical/translational application, and finally to potential clinical therapeutic application. Inherent in this progression is the refinement of technology that has allowed measurement of these biomarkers in a fast, convenient, and reliable fashion, such that they can be obtainable within a clinical practice setting, to allow the physician to make treatment decisions for diseases such as asthma and COPD. While the clinical therapeutic application of airway biomarkers such as exhaled nitric oxide and β(2)-adrenoreceptor Arg-16 polymorphism are still in their infancy, they have followed this common pathway of development, and now will require some years of application to demonstrate their true utility as predictive biomarkers of airway status and treatment response. Copyright © 2010 Elsevier Ltd. All rights reserved.

Intervening to reduce the risk of future disability from multiple sclerosis: are we there yet?

PubMed

Dahdaleh, Maurice; Alroughani, Raed; Aljumah, Mohammed; AlTahan, Abdulrahman; Alsharoqi, Issa; Bohlega, Saeed A; Daif, Abdulkader; Deleu, Dirk; Inshasi, Jihad; Karabudak, Rana; Sahraian, Mohammed A; Taha, Karim; Yammout, Bassem I; Zakaria, Magd

2017-10-01

Disease-modifying therapies (DMTs) delay or may prevent the progression of patients with high-risk clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (MS), and from relapsing-remitting MS to secondary progressive MS. Current evidence on the effects of DMT on disability in MS is supported by the use of the Expanded Disability Status Scale (EDSS), which is dominated by ambulation, and usually used as a secondary outcome measure. Less is known about the long-term effects of DMTs on other aspects of functional status, particularly cognition, which is a key determinant of ability to work. The time scale for measurements of disability is at most a few years, with scant data from more than 10 years of observation. Longer prospective follow-up of large numbers of patients with CIS is needed to determine whether early intervention with a DMT influences long-term disease progression. Finally, the emergence of the radiologically isolated syndrome (RIS) as a clinical entity has shifted the debate about when to intervene to an even earlier time frame. Balancing the significant side-effects associated with DMT in general and the expected outcome of pharmacologic intervention is increasingly problematic for managing patients with uncertain prognosis, as many patients may have low-risk CIS, benign MS or patients with RIS only. Preventing long-term disability in MS should be recognised more clearly as an important outcome in its own right, with disability measured more consistently with more sensitive instruments beyond the use of the EDSS.

46 CFR 172.195 - Survival conditions.

Code of Federal Regulations, 2014 CFR

2014-10-01

... assumed damage if it meets the following conditions in the final stage of flooding: (a) Final waterline... of an opening through which progressive flooding may take place, such as an air pipe, or an opening... least 3.94 inches (10 cm). (3) Each submerged opening must be weathertight. (d) Progressive flooding. If...

46 CFR 172.195 - Survival conditions.

Code of Federal Regulations, 2013 CFR

2013-10-01

... assumed damage if it meets the following conditions in the final stage of flooding: (a) Final waterline... of an opening through which progressive flooding may take place, such as an air pipe, or an opening... least 3.94 inches (10 cm). (3) Each submerged opening must be weathertight. (d) Progressive flooding. If...

46 CFR 172.195 - Survival conditions.

Code of Federal Regulations, 2012 CFR

2012-10-01

... assumed damage if it meets the following conditions in the final stage of flooding: (a) Final waterline... of an opening through which progressive flooding may take place, such as an air pipe, or an opening... least 3.94 inches (10 cm). (3) Each submerged opening must be weathertight. (d) Progressive flooding. If...

Early Cerebral Blood Volume Changes Predict Progression After Convection-Enhanced Delivery of Topotecan for Recurrent Malignant Glioma.

PubMed

Surapaneni, Krishna; Kennedy, Benjamin C; Yanagihara, Ted K; DeLaPaz, Robert; Bruce, Jeffrey N

2015-07-01

To assess whether early changes in enhancing tumor volume (eTV) and relative cerebral blood volume (rCBV) 1 month after convection-enhanced delivery of topotecan in patients with recurrent malignant glioma correlated with 6-month disease progression status. Sixteen patients were enrolled in a Phase Ib trial of convection-enhanced delivery of topotecan for recurrent malignant glioma. Each patient was evaluated with serial follow-up magnetic resonance imaging at baseline and at 4- to 8-week intervals. Changes at 1 month compared with baseline in eTV and rCBV were evaluated as potential predictors of 6-month progression status, classified as either progressive disease or nonprogressive disease. Relationships between percent changes in eTV and rCBV at 1 month with the probability of progressive disease at 6 months were estimated by the use of logistic regression analysis. Receiver operating characteristic curves for varying percent change thresholds in eTV and rCBV were evaluated by the use of 6-month progressive disease as the reference. There was a significant difference in the percent change in rCBV at 1 month in patients with progressive disease compared with those with nonprogressive disease at 6 months (+12% vs. -29%, P = 0.02). Logistic regression analysis demonstrated on average that a 10% increase in rCBV at 1 month after convection-enhanced delivery of topotecan was associated with 1.7 times the odds of developing progressive disease at 6 months (95% confidence interval [CI] 1.0-2.9 P = 0.05). Receiver operating characteristic analysis for determining progressive disease at 6 months showed a greater area under the curve with rCBV (0.867; 95% CI 0.66-1.00) than with change in enhancing tumor volume (0.767; 95% CI 0.51-1.00). In this selected population of patients with recurrent malignant glioma treated with convection-enhanced delivery of topotecan, early changes in rCBV at 4 weeks after therapy may help predict progression status at 6 months. Copyright © 2015 Elsevier Inc. All rights reserved.

Osteo-articular manifestations of amyloidosis.

PubMed

M'bappé, Pauline; Grateau, Gilles

2012-08-01

Whether it is overload disease or mispleated proteins, amyloid is a great pretender. This is especially true for all of the osteo-articular manifestations of amyloid light chain (AL) amyloidosis, which may mimic rheumatoid arthritis, polymyalgia rheumatica, a myeloma or a bone tumour. To improve the prognosis, AL amyloidosis must be considered in front of atypical osteo-articular manifestations. Amyloidosis Ab2M of chronic haemodialysis (members' arthropathy and destructive spondylitis) is a specific entity that needs to be differentiated from other osteoarthropathies of chronic renal failure. It has become exceptional since the progress of haemodialysis. Finally transthyretin amyloidosis(ATTR) can be responsible for carpal tunnel syndrome(CTS) in its genetic and senile form. Although amyloidosis is rare, it represents one of the aetiologies of CSC, regardless of its type. In the specific context of haemodialysis, this poses no difficulty for the clinician. Yet AL amyloidosis must be considered more often, as must senile amyloidosis ATTR in the elderly. It seems obvious that the anatomo-pathologic analysis with specific staining with Congo red - see typing - should be systematically performed in the case of surgical neurolysis. Amyloidosis is defined by the extracellular deposit of proteins which share common tinctorial affinities, a fibril aspect under electron microscopy and spatial conformation called beta pleated. Once regarded as a mere overload disease, it is currently considered as a disease of misfolded proteins. Indeed, it is certain that abnormalities of spatial pattern play an essential role in the responsibility for the pathology of many proteins whose amyloid fibre is the final common way. They involve both changes in the conformation of proteins and other major in vivo interactions between amyloid protein and the extracellular matrix. In most cases, amyloidosis represents the bulk of histopathological lesions and its pathogenic role is certain. In other cases, it is only one elementary lesion of the disease and its role is controversial. The amyloidosis responsible for osteo-articular manifestations are the AL immunoglobulin amyloidosis, the beta2-microglobulin amyloidosis in patients under haemodialysis and finally the amyloidosis of transthyretin (genetic and senile). Rheumatological manifestations of immunoglobulin amyloidosis are numerous and often indicative of the disease. Deposits affect joint and periarticular structures. The most common presentation is a progressively developing bilateral symmetric polyarthritis with negative immunology and absent specific structural abnormalities. Carpal tunnel syndrome (CTS) is very common and should suggest the aetiology. Other clinical representations are rarer as an isolated bone tumour (amyloidoma) or integrating systemic AL amyloidosis. β 2-Microglobulin amyloidosis occurs in patients under chronic haemodialysis. It is responsible for CTS, arthralgia and above all a specific destructive spondyloarthropathy. The transthyretin amyloidosis also causes CTS. Copyright © 2012 Elsevier Ltd. All rights reserved.

On the Spatial Spread of Rabies among Foxes

NASA Astrophysics Data System (ADS)

Murray, J. D.; Stanley, E. A.; Brown, D. L.

1986-11-01

We present a simple model for the spatial spread of rabies among foxes and use it to quantify its progress in England if rabies were introduced. The model is based on the known ecology of fox behaviour and on the assumption that the main vector for the spread of the disease is the rabid fox. Known data and facts are used to determine real parameter values involved in the model. We calculate the speed of propagation of the epizootic front, the threshold for the existence of an epidemic, the period and distance apart of the subsequent cyclical epidemics which follow the main front, and finally we quantify a means for control of the spatial spread of the disease. By way of illustration we use the model to determine the progress of rabies up through the southern part of England if it were introduced near Southampton. Estimates for the current fox density in England were used in the simulations. These suggest that the disease would reach Manchester within about 3.5 years, moving at speeds as high as 100 km per year in the central region. The model further indicates that although it might seem that the disease had disappeared after the wave had passed it would reappear in the south of England after just over 6 years and at periodic times after that. We consider the possibility of stopping the spread of the disease by creating a rabies `break' ahead of the front through vaccination to reduce the population to a level below the threshold for an epidemic to exist. Based on parameter values relevant to England, we estimate its minimum width to be about 15 km. The model suggests that vaccination has considerable advantages over severe culling.

Search and retrieval of medical images for improved diagnosis of neurodegenerative diseases

NASA Astrophysics Data System (ADS)

Ekin, Ahmet; Jasinschi, Radu; Turan, Erman; Engbers, Rene; van der Grond, Jeroen; van Buchem, Mark A.

2007-01-01

In the medical world, the accuracy of diagnosis is mainly affected by either lack of sufficient understanding of some diseases or the inter-, and/or intra-observer variability of the diagnoses. The former requires understanding the progress of diseases at much earlier stages, extraction of important information from ever growing amounts of data, and finally finding correlations with certain features and complications that will illuminate the disease progression. The latter (inter-, and intra- observer variability) is caused by the differences in the experience levels of different medical experts (inter-observer variability) or by mental and physical tiredness of one expert (intra-observer variability). We believe that the use of large databases can help improve the current status of disease understanding and decision making. By comparing large number of patients, some of the otherwise hidden relations can be revealed that results in better understanding, patients with similar complications can be found, the diagnosis and treatment can be compared so that the medical expert can make a better diagnosis. To this effect, this paper introduces a search and retrieval system for brain MR databases and shows that brain iron accumulation shape provides additional information to the shape-insensitive features, such as the total brain iron load, that are commonly used in the clinics. We propose to use Kendall's correlation value to automatically compare various returns to a query. We also describe a fully automated and fast brain MR image analysis system to detect degenerative iron accumulation in brain, as it is the case in Alzheimer's and Parkinson's. The system is composed of several novel image processing algorithms and has been extensively tested in Leiden University Medical Center over so far more than 600 patients.

CVD-associated non-coding RNA, ANRIL, modulates expression of atherogenic pathways in VSMC

DOE Office of Scientific and Technical Information (OSTI.GOV)

Congrains, Ada; Kamide, Kei; Katsuya, Tomohiro

Highlights: Black-Right-Pointing-Pointer ANRIL maps in the strongest susceptibility locus for cardiovascular disease. Black-Right-Pointing-Pointer Silencing of ANRIL leads to altered expression of tissue remodeling-related genes. Black-Right-Pointing-Pointer The effects of ANRIL on gene expression are splicing variant specific. Black-Right-Pointing-Pointer ANRIL affects progression of cardiovascular disease by regulating proliferation and apoptosis pathways. -- Abstract: ANRIL is a newly discovered non-coding RNA lying on the strongest genetic susceptibility locus for cardiovascular disease (CVD) in the chromosome 9p21 region. Genome-wide association studies have been linking polymorphisms in this locus with CVD and several other major diseases such as diabetes and cancer. The role of thismore » non-coding RNA in atherosclerosis progression is still poorly understood. In this study, we investigated the implication of ANRIL in the modulation of gene sets directly involved in atherosclerosis. We designed and tested siRNA sequences to selectively target two exons (exon 1 and exon 19) of the transcript and successfully knocked down expression of ANRIL in human aortic vascular smooth muscle cells (HuAoVSMC). We used a pathway-focused RT-PCR array to profile gene expression changes caused by ANRIL knock down. Notably, the genes affected by each of the siRNAs were different, suggesting that different splicing variants of ANRIL might have distinct roles in cell physiology. Our results suggest that ANRIL splicing variants play a role in coordinating tissue remodeling, by modulating the expression of genes involved in cell proliferation, apoptosis, extra-cellular matrix remodeling and inflammatory response to finally impact in the risk of cardiovascular disease and other pathologies.« less

Time-Restricted Feeding Improves Circadian Dysfunction as well as Motor Symptoms in the Q175 Mouse Model of Huntington's Disease.

PubMed

Wang, Huei-Bin; Loh, Dawn H; Whittaker, Daniel S; Cutler, Tamara; Howland, David; Colwell, Christopher S

2018-01-01

Huntington's disease (HD) patients suffer from a progressive neurodegeneration that results in cognitive, psychiatric, cardiovascular, and motor dysfunction. Disturbances in sleep/wake cycles are common among HD patients with reports of delayed sleep onset, frequent bedtime awakenings, and fatigue during the day. The heterozygous Q175 mouse model of HD has been shown to phenocopy many HD core symptoms including circadian dysfunctions. Because circadian dysfunction manifests early in the disease in both patients and mouse models, we sought to determine if early intervention that improve circadian rhythmicity can benefit HD and delay disease progression. We determined the effects of time-restricted feeding (TRF) on the Q175 mouse model. At six months of age, the animals were divided into two groups: ad libitum (ad lib) and TRF. The TRF-treated Q175 mice were exposed to a 6-h feeding/18-h fasting regimen that was designed to be aligned with the middle of the time when mice are normally active. After three months of treatment (when mice reached the early disease stage), the TRF-treated Q175 mice showed improvements in their locomotor activity rhythm and sleep awakening time. Furthermore, we found improved heart rate variability (HRV), suggesting that their autonomic nervous system dysfunction was improved. Importantly, treated Q175 mice exhibited improved motor performance compared to untreated Q175 controls, and the motor improvements were correlated with improved circadian output. Finally, we found that the expression of several HD-relevant markers was restored to WT levels in the striatum of the treated mice using NanoString gene expression assays.

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

PubMed

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.

Periodontal profile classes predict periodontal disease progression and tooth loss.

PubMed

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 personalized propensity scores provide clinical periodontal definitions that reflect disease patterns in the population and offer a useful system for patient stratification that is predictive for disease progression and tooth loss. © 2018 American Academy of Periodontology.

Radiographic Progression-Free Survival as a Clinically Meaningful End Point in Metastatic Castration-Resistant Prostate Cancer

PubMed Central

Rathkopf, Dana E.; Beer, Tomasz M.; Loriot, Yohann; Higano, Celestia S.; Armstrong, Andrew J.; Sternberg, Cora N.; de Bono, Johann S.; Tombal, Bertrand; Parli, Teresa; Bhattacharya, Suman; Phung, De; Krivoshik, Andrew; Scher, Howard I.

2018-01-01

Importance Drug development for metastatic castration-resistant prostate cancer has been limited by a lack of clinically relevant trial end points short of overall survival (OS). Radiographic progression-free survival (rPFS) as defined by the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) is a candidate end point that represents a clinically meaningful benefit to patients. Objective To demonstrate the robustness of the PCWG2 definition and to examine the relationship between rPFS and OS. Design, Setting, and Participants PREVAIL was a phase 3, randomized, double-blind, placebo-controlled multinational study that enrolled 1717 chemotherapy-naive men with metastatic castration-resistant prostate cancer from September 2010 through September 2012. The data were analyzed in November 2016. Interventions Patients were randomized 1:1 to enzalutamide 160 mg or placebo until confirmed radiographic disease progression or a skeletal-related event and initiation of either cytotoxic chemotherapy or an investigational agent for prostate cancer treatment. Main Outcomes and Measures Sensitivity analyses (SAs) of investigator-assessed rPFS were performed using the final rPFS data cutoff (May 6, 2012; 439 events; SA1) and the interim OS data cutoff (September 16, 2013; 540 events; SA2). Additional SAs using investigator-assessed rPFS from the final rPFS data cutoff assessed the impact of skeletal-related events (SA3), clinical progression (SA4), a confirmatory scan for soft-tissue disease progression (SA5), and all deaths regardless of time after study drug discontinuation (SA6). Correlations between investigator-assessed rPFS (SA2) and OS were calculated using Spearman ρ and Kendall τ via Clayton copula. Results In the 1717 men (mean age, 72.0 [range, 43.0-93.0] years in enzalutamide arm and 71.0 [range, 42.0-93.0] years in placebo arm), enzalutamide significantly reduced risk of radiographic progression or death in all SAs, with hazard ratios of 0.22 (SA1; 95% CI, 0.18-0.27), 0.31 (SA2; 95% CI, 0.27-0.35), 0.21 (SA3; 95% CI, 0.18-0.26), 0.21 (SA4; 95% CI, 0.17-0.26), 0.23 (SA5; 95% CI, 0.19-0.30), and 0.23 (SA6; 95% CI, 0.19-0.30) (P < .001 for all). Correlations of rPFS and OS in enzalutamide-treated patients were 0.89 (95% CI, 0.86-0.92) by Spearman ρ and 0.72 (95% CI, 0.68-0.77) by Kendall τ. Conclusions and Relevance Sensitivity analyses in PREVAIL demonstrated the robustness of the PCWG2 rPFS definition using additional measures of progression. There was concordance between central and investigator review and a positive correlation between rPFS and OS among enzalutamide-treated patients. Trial Registration clinicaltrials.gov Identifier: NCT01212991 PMID:29522174

Monitoring clinical progression with mitochondrial disease biomarkers

PubMed Central

Steele, Hannah E; Horvath, Rita; Lyon, Jon J; Chinnery, Patrick F

2017-01-01

Abstract Mitochondrial disorders are genetically determined metabolic diseases due to a biochemical deficiency of the respiratory chain. Given that multi-system involvement and disease progression are common features of mitochondrial disorders they carry substantial morbidity and mortality. Despite this, no disease-modifying treatments exist with clear clinical benefits, and the current best management of mitochondrial disease is supportive. Several therapeutic strategies for mitochondrial disorders are now at a mature preclinical stage. Some are making the transition into early-phase patient trials, but the lack of validated biomarkers of disease progression presents a challenge when developing new therapies for patients. This update discusses current biomarkers of mitochondrial disease progression including metabolomics, circulating serum markers, exercise physiology, and both structural and functional imaging. We discuss the advantages and disadvantages of each approach, and consider emerging techniques with a potential role in trials of new therapies. PMID:28969370

Advances in mechanisms of asthma, allergy, and immunology in 2011.

PubMed

Boyce, Joshua A; Bochner, Bruce; Finkelman, Fred D; Rothenberg, Marc E

2012-02-01

2011 was marked by rapid progress in the identification of basic mechanisms of allergic disease and the translation of these mechanisms into human cell systems. Studies published in the Journal of Allergy and Clinical Immunology this year provided new insights into the molecular determinants of allergenicity, as well as the environmental, cellular, and genetic factors involved in sensitization to allergens. Several articles focused on mechanisms of allergen immunotherapy and the development of novel strategies to achieve tolerance to allergens. Additional studies identified substantial contributions from T(H)17-type cells and cytokines to human disease pathogenesis. Finally, new therapeutic applications of anti-IgE were identified. The highlights of these studies and their potential clinical implications are summarized in this review. Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

An in vivo model of functional and vascularized human brain organoids.

PubMed

Mansour, Abed AlFatah; Gonçalves, J Tiago; Bloyd, Cooper W; Li, Hao; Fernandes, Sarah; Quang, Daphne; Johnston, Stephen; Parylak, Sarah L; Jin, Xin; Gage, Fred H

2018-06-01

Differentiation of human pluripotent stem cells to small brain-like structures known as brain organoids offers an unprecedented opportunity to model human brain development and disease. To provide a vascularized and functional in vivo model of brain organoids, we established a method for transplanting human brain organoids into the adult mouse brain. Organoid grafts showed progressive neuronal differentiation and maturation, gliogenesis, integration of microglia, and growth of axons to multiple regions of the host brain. In vivo two-photon imaging demonstrated functional neuronal networks and blood vessels in the grafts. Finally, in vivo extracellular recording combined with optogenetics revealed intragraft neuronal activity and suggested graft-to-host functional synaptic connectivity. This combination of human neural organoids and an in vivo physiological environment in the animal brain may facilitate disease modeling under physiological conditions.

The Role of Biomarkers in Detection of Cardio-toxicity.

PubMed

Shah, Kevin S; Yang, Eric H; Maisel, Alan S; Fonarow, Gregg C

2017-06-01

The goal of this paper is to review the current literature on the role of biomarkers in the detection and management of patients with cardio-oncologic disease. The role of biomarker surveillance in patients with known cardiac disease, as a result of chemotherapy or with the potential to develop cardio-toxicity, will be discussed. In addition, the studies surrounding sub-clinical cardiac toxicity monitoring during therapy, identification of high-risk patients prior to therapy, and tailoring oncologic therapies to potential biomarker risk profiles are reviewed. Based on evidence, to date, troponin and natriuretic peptides have the greatest potential to detect sub-clinical cardiac dysfunction and even tailor therapy to prevent progression based on biomarker profiles. Finally, future directions for potential utilization of novel biomarkers for the improvement of care of patients in the field of cardio-oncology are discussed.

Scoliosis in Patients with Severe Cerebral Palsy: Three Different Courses in Adolescents.

PubMed

Oda, Yoshiaki; Takigawa, Tomoyuki; Sugimoto, Yoshihisa; Tanaka, Masato; Akazawa, Hirofumi; Ozaki, Toshifumi

2017-04-01

Patients with cerebral palsy (CP) frequently present with scoliosis; however, the pattern of curve progression is difficult to predict. We aimed to clarify the natural course of the progression of scoliosis and to identify scoliosis predictors. This was a retrospective, single-center, observational study. Total of 92 CP patients from Asahikawasou Ryouiku Iryou Center in Okayama, Japan were retrospectively analyzed. Cobb angle, presence of hip dislocation and pelvic obliquity, and Gross Motor Function Classification System (GMFCS) were investigated. Severe CP was defined as GMFCS level IV or V. The mean observation period was 10.7 years. Thirtyfour severe CP patients presented with scoliosis and were divided into 3 groups based on their clinical courses: severe, moderate and mild. The mean Cobb angles at the final follow-up were 129°, 53°, and 13° in the severe, moderate, and mild groups, respectively. The average progressions from 18 to 25 years were 2.7°/year, 0.7°/year, and 0.1°/year in the severe, moderate, and mild curve groups, respectively. We observed the natural course of scoliosis and identified 3 courses based on the Cobb angle at 15 and 18 years of age. This method of classification may help clinicians predict the patients' disease progression.

Expression of disease resistance in genetically modified grapevines correlates with the contents of viral sequences in the T-DNA and global genome methylation.

PubMed

Dal Bosco, Daniela; Sinski, Iraci; Ritschel, Patrícia S; Camargo, Umberto A; Fajardo, Thor V M; Harakava, Ricardo; Quecini, Vera

2018-06-06

Increased tolerance to pathogens is an important goal in conventional and biotechnology-assisted grapevine breeding programs worldwide. Fungal and viral pathogens cause direct losses in berry production, but also affect the quality of the final products. Precision breeding strategies allow the introduction of resistance characters in elite cultivars, although the factors determining the plant's overall performance are not fully characterized. Grapevine plants expressing defense proteins, from fungal or plant origins, or of the coat protein gene of grapevine leafroll-associated virus 3 (GLRaV-3) were generated by Agrobacterium-mediated transformation of somatic embryos and shoot apical meristems. The responses of the transformed lines to pathogen challenges were investigated by biochemical, phytopathological and molecular methods. The expression of a Metarhizium anisopliae chitinase gene delayed pathogenesis and disease progression against the necrotrophic pathogen Botrytis cinerea. Modified lines expressing a Solanum nigrum osmotin-like protein also exhibited slower disease progression, but to a smaller extent. Grapevine lines carrying two hairpin-inducing constructs had lower GLRaV-3 titers when challenged by grafting, although disease symptoms and viral multiplication were detected. The levels of global genome methylation were determined for the genetically engineered lines, and correlation analyses demonstrated the association between higher levels of methylated DNA and larger portions of virus-derived sequences. Resistance expression was also negatively correlated with the contents of introduced viral sequences and genome methylation, indicating that the effectiveness of resistance strategies employing sequences of viral origin is subject to epigenetic regulation in grapevine.

JAK2V617F expression in mice amplifies early hematopoietic cells and gives them a competitive advantage that is hampered by IFNα.

PubMed

Hasan, Salma; Lacout, Catherine; Marty, Caroline; Cuingnet, Marie; Solary, Eric; Vainchenker, William; Villeval, Jean-Luc

2013-08-22

The acquired gain-of-function V617F mutation in the Janus Kinase 2 (JAK2(V617F)) is the main mutation involved in BCR/ABL-negative myeloproliferative neoplasms (MPNs), but its effect on hematopoietic stem cells as a driver of disease emergence has been questioned. Therefore, we reinvestigated the role of endogenous expression of JAK2(V617F) on early steps of hematopoiesis as well as the effect of interferon-α (IFNα), which may target the JAK2(V617F) clone in humans by using knock-in mice with conditional expression of JAK2(V617F) in hematopoietic cells. These mice develop a MPN mimicking polycythemia vera with large amplification of myeloid mature and precursor cells, displaying erythroid endogenous growth and progressing to myelofibrosis. Interestingly, early hematopoietic compartments [Lin-, LSK, and SLAM (LSK/CD48-/CD150+)] increased with the age. Competitive repopulation assays demonstrated disease appearance and progressive overgrowth of myeloid, Lin-, LSK, and SLAM cells, but not lymphocytes, from a low number of engrafted JAK2(V617F) SLAM cells. Finally, IFNα treatment prevented disease development by specifically inhibiting JAK2(V617F) cells at an early stage of differentiation and eradicating disease-initiating cells. This study shows that JAK2(V617F) in mice amplifies not only late but also early hematopoietic cells, giving them a proliferative advantage through high cell cycling and low apoptosis that may sustain MPN emergence but is lost upon IFNα treatment.

Iron Accumulates in Huntington’s Disease Neurons: Protection by Deferoxamine

PubMed Central

Chen, Jianfang; Lai, Barry; Zhang, Zhaojie; Duce, James A.; Lam, Linh Q.; Volitakis, Irene; Bush, Ashley I.; Hersch, Steven

2013-01-01

Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by a polyglutamine-encoding CAG expansion in the huntingtin gene. Iron accumulates in the brains of HD patients and mouse disease models. However, the cellular and subcellular sites of iron accumulation, as well as significance to disease progression are not well understood. We used independent approaches to investigate the location of brain iron accumulation. In R6/2 HD mouse brain, synchotron x-ray fluorescence analysis revealed iron accumulation as discrete puncta in the perinuclear cytoplasm of striatal neurons. Further, perfusion Turnbull’s staining for ferrous iron (II) combined with transmission electron microscope ultra-structural analysis revealed increased staining in membrane bound peri-nuclear vesicles in R6/2 HD striatal neurons. Analysis of iron homeostatic proteins in R6/2 HD mice revealed decreased levels of the iron response proteins (IRPs 1 and 2) and accordingly decreased expression of iron uptake transferrin receptor (TfR) and increased levels of neuronal iron export protein ferroportin (FPN). Finally, we show that intra-ventricular delivery of the iron chelator deferoxamine results in an improvement of the motor phenotype in R6/2 HD mice. Our data supports accumulation of redox-active ferrous iron in the endocytic / lysosomal compartment in mouse HD neurons. Expression changes of IRPs, TfR and FPN are consistent with a compensatory response to an increased intra-neuronal labile iron pool leading to increased susceptibility to iron-associated oxidative stress. These findings, together with protection by deferoxamine, support a potentiating role of neuronal iron accumulation in HD. PMID:24146952

Giant cell tumor of the spine.

PubMed

Ozaki, Toshifumi; Liljenqvist, Ulf; Halm, Henry; Hillmann, Axel; Gosheger, Georg; Winkelmann, Winfried

2002-08-01

Six patients with giant cell tumor of the spine had surgery between 1981 and 1995. Three lesions were located in the scrum, two lesions were in the thoracic spine, and one lesion was in the lumbar spine. Preoperatively, all patients had local pain and neurologic symptoms. Two patients had cement implanted after curettage or intralesional excision of the sacral tumor; one patient had a local relapse. After the second curettage and cement implantation, the tumor was controlled. One patient with a sacral lesion had marginal excision and spondylodesis; no relapse developed. Two patients with thoracic lesions had planned marginal excision and spondylodesis; the margins finally became intralesional, but no relapse developed. One patient with a lumbar lesion had incomplete removal of the tumor and received postoperative irradiation. At the final followup (median, 69 months), five of six patients were disease-free and one patient died of disease progression. Two of the five surviving patients had pain after standing or neurologic problems. Although some contamination occurred, planning a marginal excision of the lesion seems beneficial for vertebral lesions above the sacrum. Total sacrectomy of a sacral lesion seems to be too invasive when cement implantation can control the lesion.

Guaranteed Time Observations Support for Goddard High Resolution Spectrograph (GHRS) on HST

NASA Technical Reports Server (NTRS)

Beaver, Edward

1998-01-01

We assemble this final grant report by combining our previously submitted progress reports with the last year's progress report. Section 2 is the progress report for the June 1, 1991 to Nov. 14, 1995 period. Section 4 is the progress report for the Nov. 14, 1996 to Dec. 31, 1996 period. Section 5 is the progress report for the Nov. 14 to Aug. 31, 1997 period. Section 6 is the new progress report for the Sept. 15, 1997 to Nov. 14, 1998 final period. Section 3 is a summary of our spare detector high voltage transient tests activity in 1992 in support of the renewed safe operation of the GHRS HST D1 detector. Note that we have left the format of each progress report the same as originally sent out. The slight differences in format presentation are thus intended.

Progression of Liver Disease

MedlinePlus

... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

Expanding the spectrum of neuronal pathology in multiple system atrophy.

PubMed

Cykowski, Matthew D; Coon, Elizabeth A; Powell, Suzanne Z; Jenkins, Sarah M; Benarroch, Eduardo E; Low, Phillip A; Schmeichel, Ann M; Parisi, Joseph E

2015-08-01

Multiple system atrophy is a sporadic alpha-synucleinopathy that typically affects patients in their sixth decade of life and beyond. The defining clinical features of the disease include progressive autonomic failure, parkinsonism, and cerebellar ataxia leading to significant disability. Pathologically, multiple system atrophy is characterized by glial cytoplasmic inclusions containing filamentous alpha-synuclein. Neuronal inclusions also have been reported but remain less well defined. This study aimed to further define the spectrum of neuronal pathology in 35 patients with multiple system atrophy (20 male, 15 female; mean age at death 64.7 years; median disease duration 6.5 years, range 2.2 to 15.6 years). The morphologic type, topography, and frequencies of neuronal inclusions, including globular cytoplasmic (Lewy body-like) neuronal inclusions, were determined across a wide spectrum of brain regions. A correlation matrix of pathologic severity also was calculated between distinct anatomic regions of involvement (striatum, substantia nigra, olivary and pontine nuclei, hippocampus, forebrain and thalamus, anterior cingulate and neocortex, and white matter of cerebrum, cerebellum, and corpus callosum). The major finding was the identification of widespread neuronal inclusions in the majority of patients, not only in typical disease-associated regions (striatum, substantia nigra), but also within anterior cingulate cortex, amygdala, entorhinal cortex, basal forebrain and hypothalamus. Neuronal inclusion pathology appeared to follow a hierarchy of region-specific susceptibility, independent of the clinical phenotype, and the severity of pathology was duration-dependent. Neuronal inclusions also were identified in regions not previously implicated in the disease, such as within cerebellar roof nuclei. Lewy body-like inclusions in multiple system atrophy followed the stepwise anatomic progression of Lewy body-spectrum disease inclusion pathology in 25.7% of patients with multiple system atrophy, including a patient with visual hallucinations. Further, the presence of Lewy body-like inclusions in neocortex, but not hippocampal alpha-synuclein pathology, was associated with cognitive impairment (P = 0.002). However, several cases had the presence of isolated Lewy body-like inclusions at atypical sites (e.g. thalamus, deep cerebellar nuclei) that are not typical for Lewy body-spectrum disease. Finally, interregional correlations (rho ≥ 0.6) in pathologic glial and neuronal lesion burden suggest shared mechanisms of disease progression between both discrete anatomic regions (e.g. basal forebrain and hippocampus) and cell types (neuronal and glial inclusions in frontal cortex and white matter, respectively). These findings suggest that in addition to glial inclusions, neuronal pathology plays an important role in the developmental and progression of multiple system atrophy. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Combined Population Dynamics and Entropy Modelling Supports Patient Stratification in Chronic Myeloid Leukemia

NASA Astrophysics Data System (ADS)

Brehme, Marc; Koschmieder, Steffen; Montazeri, Maryam; Copland, Mhairi; Oehler, Vivian G.; Radich, Jerald P.; Brümmendorf, Tim H.; Schuppert, Andreas

2016-04-01

Modelling the parameters of multistep carcinogenesis is key for a better understanding of cancer progression, biomarker identification and the design of individualized therapies. Using chronic myeloid leukemia (CML) as a paradigm for hierarchical disease evolution we show that combined population dynamic modelling and CML patient biopsy genomic analysis enables patient stratification at unprecedented resolution. Linking CD34+ similarity as a disease progression marker to patient-derived gene expression entropy separated established CML progression stages and uncovered additional heterogeneity within disease stages. Importantly, our patient data informed model enables quantitative approximation of individual patients’ disease history within chronic phase (CP) and significantly separates “early” from “late” CP. Our findings provide a novel rationale for personalized and genome-informed disease progression risk assessment that is independent and complementary to conventional measures of CML disease burden and prognosis.

Evaluation of the efficiency of the Chêneau brace on scoliosis deformity : A systematic review of the literature.

PubMed

Taghi Karimi, Mohammad; Rabczuk, Timon; Kavyani, Mahsa

2018-03-01

Scoliosis is a three-dimensional deformity of the spine and rib cage. Depending on the severity of this disease, various kinds of treatment methods have been used and bracing is among the most common. One of the braces which has been used for subjects with scoliosis is the Chêneau brace. The aim of this review was to evaluate the efficiency of the Chêneau brace on the scoliosis curve progression and control based on the available literature. We conducted a Medline search via PubMed, Google Scholar, ISI Web of Sciences, Ebsco and Scopus. Keywords such as Chêneau brace, Chêneau light and CAD/CAM spinal brace were used in combination with scoliosis. The quality of the studies was evaluated by the Down and Black tool. Based on the aforementioned keywords, 55 papers were found. Finally based on the mentioned criteria 14 papers were selected for final analysis. The quality of the studies varied between scores of 13 and 25 using the Down and Black tool. The results of the selected studies confirmed that a good scoliotic curve correction can be achieved with the Chêneau brace. The Chêneau brace provides a 3-dimensional correction of the spinal deformity which not only influences the progression of scoliotic curve but also influences its natural history. It cannot be concluded that the Chêneau brace is superior to other available braces; however, it has been shown that this brace is effective to control the scoliotic curve progression especially in the lumbar and thoracolumbar regions.

[Practical guidelines for genetic testing in cardiovascular diseases].

PubMed

Reinhard, W; Trenkwalder, T; Schunkert, H

2017-08-01

In the last decade, genetic testing for cardiovascular disorders has become more and more relevant. Progress in molecular genetics has led to new opportunities for diagnostics, improved risk prediction and could lead to novel therapeutic approaches. Genetic diagnostic testing is relevant for both confirming a diagnosis as well as deciding on therapeutic consequences, if applicable. Furthermore, predictive testing in family members for specific cardiovascular diseases is now a standard procedure in holistic patient management. The process of genetic testing as well as documentation requirements and discussion of test results with patients are subject to legal regulations. These regulations might be confusing for clinical practitioners/cardiologists. The aim of this article is to provide a clinical framework for genetic testing. First, we explain the legal and ethical background. Second, we illustrate the process of genetic testing step by step and present updates on remuneration. Finally, we discuss the significance of genetic testing and specific disease indications in cardiology.

Review on iron and its importance for human health

PubMed Central

Abbaspour, Nazanin; Hurrell, Richard; Kelishadi, Roya

2014-01-01

It is well-known that deficiency or over exposure to various elements has noticeable effects on human health. The effect of an element is determined by several characteristics, including absorption, metabolism, and degree of interaction with physiological processes. Iron is an essential element for almost all living organisms as it participates in a wide variety of metabolic processes, including oxygen transport, deoxyribonucleic acid (DNA) synthesis, and electron transport. However, as iron can form free radicals, its concentration in body tissues must be tightly regulated because in excessive amounts, it can lead to tissue damage. Disorders of iron metabolism are among the most common diseases of humans and encompass a broad spectrum of diseases with diverse clinical manifestations, ranging from anemia to iron overload, and possibly to neurodegenerative diseases. In this review, we discuss the latest progress in studies of iron metabolism and bioavailability, and our current understanding of human iron requirement and consequences and causes of iron deficiency. Finally, we discuss strategies for prevention of iron deficiency. PMID:24778671

The Altered Hepatic Tubulin Code in Alcoholic Liver Disease

PubMed Central

Groebner, Jennifer L.; Tuma, Pamela L.

2015-01-01

The molecular mechanisms that lead to the progression of alcoholic liver disease have been actively examined for decades. Because the hepatic microtubule cytoskeleton supports innumerable cellular processes, it has been the focus of many such mechanistic studies. It has long been appreciated that α-tubulin is a major target for modification by highly reactive ethanol metabolites and reactive oxygen species. It is also now apparent that alcohol exposure induces post-translational modifications that are part of the natural repertoire, mainly acetylation. In this review, the modifications of the “tubulin code” are described as well as those adducts by ethanol metabolites. The potential cellular consequences of microtubule modification are described with a focus on alcohol-induced defects in protein trafficking and enhanced steatosis. Possible mechanisms that can explain hepatic dysfunction are described and how this relates to the onset of liver injury is discussed. Finally, we propose that agents that alter the cellular acetylation state may represent a novel therapeutic strategy for treating liver disease. PMID:26393662

The Altered Hepatic Tubulin Code in Alcoholic Liver Disease.

PubMed

Groebner, Jennifer L; Tuma, Pamela L

2015-09-18

The molecular mechanisms that lead to the progression of alcoholic liver disease have been actively examined for decades. Because the hepatic microtubule cytoskeleton supports innumerable cellular processes, it has been the focus of many such mechanistic studies. It has long been appreciated that α-tubulin is a major target for modification by highly reactive ethanol metabolites and reactive oxygen species. It is also now apparent that alcohol exposure induces post-translational modifications that are part of the natural repertoire, mainly acetylation. In this review, the modifications of the "tubulin code" are described as well as those adducts by ethanol metabolites. The potential cellular consequences of microtubule modification are described with a focus on alcohol-induced defects in protein trafficking and enhanced steatosis. Possible mechanisms that can explain hepatic dysfunction are described and how this relates to the onset of liver injury is discussed. Finally, we propose that agents that alter the cellular acetylation state may represent a novel therapeutic strategy for treating liver disease.

Genetic epidemiology of hip and knee osteoarthritis.

PubMed

Valdes, Ana M; Spector, Tim D

2011-01-01

Osteoarthritis (OA) is the most common cause of arthritis and represents an enormous healthcare burden in industrialized societies. Current therapeutic approaches for OA are limited and are insufficient to prevent the initiation and progression of the disease. Genetic studies of patients with OA can help to unravel the molecular mechanisms responsible for specific disease manifestations, including joint damage, nociception and chronic pain. Indeed, these studies have identified molecules, such as growth/differentiation factor 5, involved in signaling cascades that are important for the pathology of joint components. Genome-wide association studies have uncovered a likely role in OA for the genes encoding structural extracellular matrix components (such as DVWA) and molecules involved in prostaglandin metabolism (such as DQB1 and BTNL2). A ∼300 kilobase region in chromosome 7q22 is also associated with OA susceptibility. Finally, the identification of individuals at a high risk of OA and of total joint arthroplasty failure might be facilitated by the use of combinations of genetic markers, allowing for the application of preventive and disease-management strategies.

Serum-free light-chain analysis in diagnosis and management of multiple myeloma and related conditions.

PubMed

Milani, Paolo; Palladini, Giovanni; Merlini, Giampaolo

2016-01-01

The introduction of the serum-free light-chain (S-FLC) assay has been a breakthrough in the diagnosis and management of plasma cell dyscrasias, particularly monoclonal light-chain diseases. The first method, proposed in 2001, quantifies serum-free light-chains using polyclonal antibodies. More recently, assays based on monoclonal antibodies have entered into clinical practice. S-FLC measurement plays a central role in the screening for multiple myeloma and related conditions, in association with electrophoretic techniques. Analysis of S-FLC is essential in assessing the risk of progression of precursor diseases to overt plasma cell dyscrasias. It is also useful for risk stratification in solitary plasmacytoma and AL amyloidosis. The S-FLC measurement is part of the new diagnostic criteria for multiple myeloma, and provides a marker to follow changes in clonal substructure over time. Finally, the evaluation of S-FLC is fundamental for assessing the response to treatment in monoclonal light chain diseases.

Diagnosis and management of an elderly patient with severe tracheomalacia: A case report and review of the literature

PubMed Central

JIANG, AI-GUI; GAO, XIAO-YAN; LU, HUI-YU

2013-01-01

Severe adult tracheomalacia is a dangerous disease that is difficult to manage, particularly at the time of airway infection, and has a high mortality rate. The present study reports the diagnosis and treatment of an elderly patient with severe adult tracheomalacia. In March 2012, the 59-year-old patient presented with progressive dyspnea to the Department of Respiratory Medicine, Taizhou People’s Hospital (Jiangsu, China). Following admission, chest radiography revealed symptoms consistent with chronic obstructive pulmonary disease (COPD) and chest computed tomography (CT) demonstrated an evident stenosis of the tracheal lumen at the end of expiration. Bronchoscopy revealed a 91% reduction in the cross-sectional area of the tracheal lumen at the end of expiration. Following the final diagnosis, the patient was successfully treated with nasal continuous positive airway pressure (CPAP) combined with implantation of a temporary Chinese Li’s metallic stent. These treatment methods appeared to be temporarily effective in alleviating the symptoms of the disease. PMID:24137262

Diagnosis and management of an elderly patient with severe tracheomalacia: A case report and review of the literature.

PubMed

Jiang, Ai-Gui; Gao, Xiao-Yan; Lu, Hui-Yu

2013-09-01

Severe adult tracheomalacia is a dangerous disease that is difficult to manage, particularly at the time of airway infection, and has a high mortality rate. The present study reports the diagnosis and treatment of an elderly patient with severe adult tracheomalacia. In March 2012, the 59-year-old patient presented with progressive dyspnea to the Department of Respiratory Medicine, Taizhou People's Hospital (Jiangsu, China). Following admission, chest radiography revealed symptoms consistent with chronic obstructive pulmonary disease (COPD) and chest computed tomography (CT) demonstrated an evident stenosis of the tracheal lumen at the end of expiration. Bronchoscopy revealed a 91% reduction in the cross-sectional area of the tracheal lumen at the end of expiration. Following the final diagnosis, the patient was successfully treated with nasal continuous positive airway pressure (CPAP) combined with implantation of a temporary Chinese Li's metallic stent. These treatment methods appeared to be temporarily effective in alleviating the symptoms of the disease.

A Biobehavioral Model of Cancer Stress and Disease Course

PubMed Central

Andersen, Barbara L.; Kiecolt-Glaser, Janice K.; Glaser, Ronald

2009-01-01

Approximately 1 million Americans are diagnosed with cancer each year and must cope with the disease and treatments. Many studies have documented the deteriorations in quality of life that occur. These data suggest that the adjustment process is burdensome and lengthy. There is ample evidence showing that adults experiencing other long-term stressors experience not only high rates of adjustment difficulties (e.g., syndromal depression) but important biologic effects, such as persistent downregulation of elements of the immune system, and adverse health outcomes, such as higher rates of respiratory tract infections. Thus, deteriorations in quality of life with cancer are underscored if they have implications for biological processes, such as the immune system, relating to disease progression and spread. Considering these and other data, a biobehavioral model of adjustment to the stresses of cancer is offered, and mechanisms by which psychological and behavioral responses may influence biological processes and, perhaps, health outcomes are proposed. Finally, strategies for testing the model via experiments testing psychological interventions are offered. PMID:8024167

USHERING IN THE STUDY AND TREATMENT OF PRECLINICAL ALZHEIMER DISEASE

PubMed Central

Langbaum, Jessica B.S.; Fleisher, Adam S.; Chen, Kewei; Ayutyanont, Napatkamon; Lopera, Francisco; Quiroz, Yakeel T.; Caselli, Richard J.; Tariot, Pierre N.; Reiman, Eric M.

2014-01-01

Researchers have begun to characterize the subtle biological and cognitive processes that precede the clinical onset of Alzheimer disease (AD), and to set the stage for accelerated evaluation of experimental treatments to delay the onset, reduce the risk of or completely prevent clinical decline. Here, we provide an overview of the experimental strategies, and brain imaging and cerebrospinal fluid biomarker measures that are used in early detection and tracking of AD, highlighting at-risk individuals who could be suitable for preclinical monitoring. We discuss how these advances have contributed to reconceptualization of AD as a sequence of biological changes that occur during progression from preclinical AD, to mild cognitive impairment and finally dementia, and we review recently proposed research criteria for preclinical AD. Advances in the study of preclinical AD have driven the recognition that efficacy of at least some AD therapies may depend on initiation of treatment before clinical manifestation of disease, leading to a new era of AD prevention research. PMID:23752908

Ushering in the study and treatment of preclinical Alzheimer disease.

PubMed

Langbaum, Jessica B; Fleisher, Adam S; Chen, Kewei; Ayutyanont, Napatkamon; Lopera, Francisco; Quiroz, Yakeel T; Caselli, Richard J; Tariot, Pierre N; Reiman, Eric M

2013-07-01

Researchers have begun to characterize the subtle biological and cognitive processes that precede the clinical onset of Alzheimer disease (AD), and to set the stage for accelerated evaluation of experimental treatments to delay the onset, reduce the risk of, or completely prevent clinical decline. In this Review, we provide an overview of the experimental strategies, and brain imaging and cerebrospinal fluid biomarker measures that are used in early detection and tracking of AD, highlighting at-risk individuals who could be suitable for preclinical monitoring. We discuss how advances in the field have contributed to reconceptualization of AD as a sequence of biological changes that occur during progression from preclinical AD, to mild cognitive impairment and finally dementia, and we review recently proposed research criteria for preclinical AD. Advances in the study of preclinical AD have driven the recognition that efficacy of at least some AD therapies may depend on initiation of treatment before clinical manifestation of disease, leading to a new era of AD prevention research.

Renal outcomes of agalsidase beta treatment for Fabry disease: role of proteinuria and timing of treatment initiation.

PubMed

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

2012-03-01

The purpose of this study was to identify determinants of renal disease progression in adults with Fabry disease during treatment with agalsidase beta. Renal function was evaluated in 151 men and 62 women from the Fabry Registry who received agalsidase beta at an average dose of 1 mg/kg/2 weeks for at least 2 years. Patients were categorized into quartiles based on slopes of estimated glomerular filtration rate (eGFR) during treatment. Multivariate logistic regression analyses were used to identify factors associated with renal disease progression. Men within the first quartile had a mean eGFR slope of -0.1 mL/min/1.73m(2)/year, whereas men with the most rapid renal disease progression (Quartile 4) had a mean eGFR slope of -6.7 mL/min/1.73m(2)/year. The risk factor most strongly associated with renal disease progression was averaged urinary protein:creatinine ratio (UP/Cr) ≥1 g/g (odds ratio 112, 95% confidence interval (95% CI) 4-3109, P = 0.0054). Longer time from symptom onset to treatment was also associated with renal disease progression (odds ratio 19, 95% CI 2-184, P = 0.0098). Women in Quartile 4 had the highest averaged UP/Cr (mean 1.8 g/g) and the most rapid renal disease progression: (mean slope -4.4 mL/min/1.73m(2)/year). Adults with Fabry disease are at risk for progressive loss of eGFR despite enzyme replacement therapy, particularly if proteinuria is ≥1 g/g. Men with little urinary protein excretion and those who began receiving agalsidase beta sooner after the onset of symptoms had stable renal function. These findings suggest that early intervention may lead to optimal renal outcomes.

Personality and HIV Disease Progression: Role of NEO-PI-R Openness, Extraversion, and Profiles of Engagement

PubMed Central

O'Cleirigh, Conall; Schneiderman, Neil; Weiss, Alexander; Costa, Paul T.

2008-01-01

Objective To examine the role of the big five personality domains (Neuroticism, Extraversion, Openness, Agreeableness, Conscientiousness) and their respective facets and profiles on change in CD4 and log HIV-RNA copies/ml (VL) over 4 years. The examination of psychosocial predictors of disease progression in human immunodeficiency virus (HIV) has focused primarily on depression, coping, and stress, with little attention paid to stable individual differences. Methods A diverse sample of HIV-seropositive patients (n = 104) completed personality assessment (NEO-PI-R), underwent comprehensive psychological assessment and blood samples every 6 months for 4 years. Linear rates of change for CD4 cells and VL were modeled using Hierarchical Linear Modeling controlling for antiretrovirals (time dependent covariate), initial disease status, age, gender, ethnicity, and education. Results Domains that were significantly associated with slower disease progression over 4 years included Openness (CD4, VL), Extraversion (CD4, VL), and Conscientiousness (VL). Facets of the above domains that were significantly related to slower disease progression were assertiveness, positive emotions, and gregariousness (Extraversion); ideas, esthetics (Openness); achievement striving and order (Conscientiousness). In addition, profile analyses suggested personality styles which seem to underscore the importance of remaining engaged (e.g., Creative Interactors (E+O+), Upbeat Optimists (N−E+), Welcomers (E+A+), Go Getters (C+E+), and Directed (N−C+)) had slower disease progression, whereas the “homebody” profile (Low Extraversion-Low Openness) was significantly associated with faster disease progression. Conclusions These results provide good initial evidence of the relationship between personality and disease progression in HIV and suggest protective aspects of profiles of engagement. These finding may help identify those individuals at risk for poorer disease course and specify targets for psychosocial interventions. PMID:18256349

Emerging therapies for Parkinson's disease.

PubMed

Poewe, Werner; Mahlknecht, Philipp; Jankovic, Joseph

2012-08-01

The experimental therapeutics of Parkinson's disease are reviewed, highlighting the current pipeline of emerging therapeutic approaches. This review includes novel approaches to dopaminergic drug delivery such as intraintestinal infusions or new extended-release formulations of levodopa and also intrapulmonary delivery of apomorphine as well as novel dopaminergic agents like the monoamine oxidase-B inhibitor safinamide or novel catechol-O-methyl transferase inhibitors. An even greater number of ongoing clinical trials assess the efficacy and safety of nondopaminergic approaches to enhance motor control or reduce motor complications like fluctuations and dyskinesias. These include adenosine A2A antagonists, α-adrenergic and serotonergic agonists as well as drugs acting on the glutamatergic system. Gene-based or cell-based intrastriatal delivery of therapeutic principles that enhance striatal dopaminergic transmission directly or via the stimulation of trophic activity has also reached phase II clinical development with encouraging results in some studies. Finally, a wide spectrum of agents with a potential for slowing disease progression is currently tested. A variety of medical and nonmedical interventions in different phases of clinical development provide an interesting and promising portfolio of emerging therapies for Parkinson's disease.

Immunology of Prion Protein and Prions.

PubMed

Mabbott, Neil A

2017-01-01

Many natural prion diseases are acquired peripherally, such as following the oral consumption of contaminated food or pasture. After peripheral exposure many prion isolates initially accumulate to high levels within the host's secondary lymphoid tissues. The replication of prions within these tissues is essential for their efficient spread to the brain where they ultimately cause neurodegeneration. This chapter describes our current understanding of the critical tissues, cells, and molecules which the prions exploit to mediate their efficient propagation from the site of exposure (such as the intestine) to the brain. Interactions between the immune system and prions are not only restricted to the secondary lymphoid tissues. Therefore, an account of how the activation status of the microglial in the brain can also influence progression of prion disease pathogenesis is provided. Prion disease susceptibility may also be influenced by additional factors such as chronic inflammation, coinfection with other pathogens, and aging. Finally, the potential for immunotherapy to provide a means of safe and effective prophylactic or therapeutic intervention in these currently untreatable diseases is considered. © 2017 Elsevier Inc. All rights reserved.

A Nutrigenomic Approach to Non-Alcoholic Fatty Liver Disease.

PubMed

Dongiovanni, Paola; Valenti, Luca

2017-07-16

Following the epidemics of obesity due to the consumption of high-calorie diet and sedentary lifestyle, nonalcoholic fatty liver disease (NAFLD) is now the leading cause of liver disease in Western countries. NAFLD is epidemiologically associated with metabolic syndrome and insulin resistance, and in susceptible individuals it may progress to cirrhosis and hepatocellular carcinoma. Genetic factors play a key role in NAFLD predisposition by interacting with nutritional and other environmental factors. To date, there is no drug therapy for the treatment of NAFLD, and the main clinical recommendation is lifestyle modification. In the last years, nutrigenomics is promoting an increased understanding of how nutrition affects the switch from health to disease by altering the expression of an individual's genetic makeup. The present review tries to summarize the most recent data evidencing how the interactions between nutrients and genetic factors can influence NAFLD development. The final goal should be to develop tools to quantify these complex interactions. The definition of a "nutrigenomic risk score" for each individual may represent a novel therapeutic approach for the management of NAFLD patients.

Translating Stem Cell Research to Cardiac Disease Therapies: Pitfalls and Prospects for Improvement

PubMed Central

Rosen, Michael R.; Myerburg, Robert J.; Francis, Darrel P.; Cole, Graham D.; Marbán, Eduardo

2014-01-01

Over the past 2 decades, there have been numerous stem cell studies focused on cardiac diseases, ranging from proof-of-concept to phase 2 trials. This series of articles focuses on the legacy of these studies and the outlook for future treatment of cardiac diseases with stem cell therapies. The first section by Rosen and Myerburg is an independent review that analyzes the basic science and translational strategies supporting the rapid advance of stem cell technology to the clinic, the philosophies behind them, trial designs, and means for going forward that may impact favorably on progress. The second and third sections were collected in response to the initial section of this review. The commentary by Francis and Cole discusses the Rosen and Myerburg review and details how trial outcomes can be affected by noise, poor trial design (particularly the absence of blinding), and normal human tendencies toward optimism and denial. The final, independent article by Marbán takes a different perspective concerning the potential for positive impact of stem cell research applied to heart disease and future prospects for its clinical application. PMID:25169179

Human Induced Pluripotent Stem Cell-Derived Macrophages for Unraveling Human Macrophage Biology.

PubMed

Zhang, Hanrui; Reilly, Muredach P

2017-11-01

Despite a substantial appreciation for the critical role of macrophages in cardiometabolic diseases, understanding of human macrophage biology has been hampered by the lack of reliable and scalable models for cellular and genetic studies. Human induced pluripotent stem cell (iPSC)-derived macrophages (IPSDM), as an unlimited source of subject genotype-specific cells, will undoubtedly play an important role in advancing our understanding of the role of macrophages in human diseases. In this review, we summarize current literature in the differentiation and characterization of IPSDM at phenotypic, functional, and transcriptomic levels. We emphasize the progress in differentiating iPSC to tissue resident macrophages, and in understanding the ontogeny of in vitro differentiated IPSDM that resembles primitive hematopoiesis, rather than adult definitive hematopoiesis. We review the application of IPSDM in modeling both Mendelian genetic disorders and host-pathogen interactions. Finally, we highlighted the potential areas of research using IPSDM in functional validation of coronary artery disease loci in genome-wide association studies, functional genomic analyses, drug testing, and cell therapeutics in cardiovascular diseases. © 2017 American Heart Association, Inc.

A Latin American perspective of periodontology.

PubMed

Caffesse, Raúl G

2015-02-01

Periodontal diseases occur worldwide, and Latin American populations are significantly affected by different manifestations of periodontal disease. The interest in periodontics and periodontal therapy first developed in the early 1930s in the southernmost countries of Latin America, and spread, as the years went by, throughout the region. Today, periodontal research is vibrant in Latin America. The aim of this volume of Periodontology 2000 was to present an overview of the periodontal research currently being performed in different countries of Latin America. The epidemiology of periodontal diseases in adults, children and adolescents, and the pathogenesis of such diseases (including microbiological characteristics and risk factors), are discussed. The role of systemic antibiotic therapy and the effect of smoking are discussed in relation to the progression and the treatment of periodontitis. In addition, the benefit of lasers in periodontal therapy is evaluated. Latin American research groups have been active in exploring new venues of regenerative periodontal treatment, addressing the role of cementum proteins, growth factors and oral mesenchymal stem cells in tissue engineering. Finally, basic research to study cancerization is reported.

Obesity and cardiovascular diseases: implications regarding fitness, fatness, and severity in the obesity paradox.

PubMed

Lavie, Carl J; McAuley, Paul A; Church, Timothy S; Milani, Richard V; Blair, Steven N

2014-04-15

Obesity has been increasing in epidemic proportions, with a disproportionately higher increase in morbid or class III obesity, and obesity adversely affects cardiovascular (CV) hemodynamics, structure, and function, as well as increases the prevalence of most CV diseases. Progressive declines in physical activity over 5 decades have occurred and have primarily caused the obesity epidemic. Despite the potential adverse impact of overweight and obesity, recent epidemiological data have demonstrated an association of mild obesity and, particularly, overweight on improved survival. We review in detail the obesity paradox in CV diseases where overweight and at least mildly obese patients with most CV diseases seem to have a better prognosis than do their leaner counterparts. The implications of cardiorespiratory fitness with prognosis are discussed, along with the joint impact of fitness and adiposity on the obesity paradox. Finally, in light of the obesity paradox, the potential value of purposeful weight loss and increased physical activity to affect levels of fitness is reviewed. Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

DEFENDER: Detecting and Forecasting Epidemics Using Novel Data-Analytics for Enhanced Response.

PubMed

Thapen, Nicholas; Simmie, Donal; Hankin, Chris; Gillard, Joseph

2016-01-01

In recent years social and news media have increasingly been used to explain patterns in disease activity and progression. Social media data, principally from the Twitter network, has been shown to correlate well with official disease case counts. This fact has been exploited to provide advance warning of outbreak detection, forecasting of disease levels and the ability to predict the likelihood of individuals developing symptoms. In this paper we introduce DEFENDER, a software system that integrates data from social and news media and incorporates algorithms for outbreak detection, situational awareness and forecasting. As part of this system we have developed a technique for creating a location network for any country or region based purely on Twitter data. We also present a disease nowcasting (forecasting the current but still unknown level) approach which leverages counts from multiple symptoms, which was found to improve the nowcasting accuracy by 37 percent over a model that used only previous case data. Finally we attempt to forecast future levels of symptom activity based on observed user movement on Twitter, finding a moderate gain of 5 percent over a time series forecasting model.

Predictors of Clinical Progression in HIV-1-Infected Adults Initiating Combination Antiretroviral Therapy with Advanced Disease in the Asia-Pacific Region: Results from the TREAT Asia HIV Observational Database

PubMed Central

Byakwaga, H.; Petoumenos, K.; Ananworanich, J.; Zhang, F.; Boyd, M. A.; Sirisanthana, T.; Li, P. C. K.; Lee, C.; Mean, C. V.; Saphonn, V.; Omar, S. F. S.; Pujari, S.; Phanuphak, P.; Lim, P. L.; Kumarasamy, N.; Chen, Y. M. A.; Merati, T. P.; Sungkanuparph, S.; Ditangco, R.; Oka, S.; Tau, G.; Zhou, J.; Law, M. G.; Emery, S.

2013-01-01

The majority of HIV-infected patients in developing countries commences combination antiretroviral therapy (cART) with advanced disease. We examined predictors of disease progression in patients initiating cART with CD4 count ≤200 cells/mm3 in the TREAT Asia HIV Observational Database. The main outcome measure was progression to either an AIDS-defining illness or death occurring 6 months after initiation of cART. We used survival analysis methods. A total of 1255 patients contributed 2696 person years of follow-up; 73 were diagnosed with AIDS and 9 died. The rate of progression to the combined end point was 3.0 per 100 person years. The factors significantly associated with a higher risk of disease progression were Indian ethnicity, infection through intravenous drug use, lower CD4 count, and hemoglobin ≤130 g/dL at 6 months. In conclusion, measurements of CD4 count and hemoglobin at month 6 may be useful for early identification of disease progression in resource-limited settings. PMID:23422741

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

PubMed

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 <.01). Patients with higher 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.

Protein aggregation and neurodegeneration in prototypical neurodegenerative diseases: Examples of amyloidopathies, tauopathies and synucleinopathies.

PubMed

Bourdenx, Mathieu; Koulakiotis, Nikolaos Stavros; Sanoudou, Despina; Bezard, Erwan; Dehay, Benjamin; Tsarbopoulos, Anthony

2017-08-01

Alzheimer's and Parkinson's diseases are the most prevalent neurodegenerative diseases that generate important health-related direct and indirect socio-economic costs. They are characterized by severe neuronal losses in several disease-specific brain regions associated with deposits of aggregated proteins. In Alzheimer's disease, β-amyloid peptide-containing plaques and intraneuronal neurofibrillary tangles composed of hyperphosphorylated microtubule-associated protein tau are the two main neuropathological lesions, while Parkinson's disease is defined by the presence of Lewy Bodies that are intraneuronal proteinaceous cytoplasmic inclusions. α-Synuclein has been identified as a major protein component of Lewy Bodies and heavily implicated in the pathogenesis of Parkinson's disease. In the past few years, evidence has emerged to explain how these aggregate-prone proteins can undergo spontaneous self-aggregation, propagate from cell to cell, and mediate neurotoxicity. Current research now indicates that oligomeric forms are probably the toxic species. This article discusses recent progress in the understanding of the pathogenesis of these diseases, with a focus on the underlying mechanisms of protein aggregation, and emphasizes the pathophysiological molecular mechanisms leading to cellular toxicity. Finally, we present the putative direct link between β-amyloid peptide and tau in causing toxicity in Alzheimer's disease as well as α-synuclein in Parkinson's disease, along with some of the most promising therapeutic strategies currently in development for those incurable neurodegenerative disorders. Copyright © 2015 Elsevier Ltd. All rights reserved.

LITTLE FISH, BIG DATA: ZEBRAFISH AS A MODEL FOR CARDIOVASCULAR AND METABOLIC DISEASE.

PubMed

Gut, Philipp; Reischauer, Sven; Stainier, Didier Y R; Arnaout, Rima

2017-07-01

The burden of cardiovascular and metabolic diseases worldwide is staggering. The emergence of systems approaches in biology promises new therapies, faster and cheaper diagnostics, and personalized medicine. However, a profound understanding of pathogenic mechanisms at the cellular and molecular levels remains a fundamental requirement for discovery and therapeutics. Animal models of human disease are cornerstones of drug discovery as they allow identification of novel pharmacological targets by linking gene function with pathogenesis. The zebrafish model has been used for decades to study development and pathophysiology. More than ever, the specific strengths of the zebrafish model make it a prime partner in an age of discovery transformed by big-data approaches to genomics and disease. Zebrafish share a largely conserved physiology and anatomy with mammals. They allow a wide range of genetic manipulations, including the latest genome engineering approaches. They can be bred and studied with remarkable speed, enabling a range of large-scale phenotypic screens. Finally, zebrafish demonstrate an impressive regenerative capacity scientists hope to unlock in humans. Here, we provide a comprehensive guide on applications of zebrafish to investigate cardiovascular and metabolic diseases. We delineate advantages and limitations of zebrafish models of human disease and summarize their most significant contributions to understanding disease progression to date. Copyright © 2017 the American Physiological Society.

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

PubMed Central

Adland, Emily; Paioni, Paolo; Thobakgale, Christina; Laker, Leana; Mori, Luisa; Muenchhoff, Maximilian; Csala, Anna; Clapson, Margaret; Flynn, Jacquie; Novelli, Vas; Hurst, Jacob; Naidoo, Vanessa; Shapiro, Roger; Huang, Kuan-Hsiang Gary; Frater, John; Prendergast, Andrew; Prado, Julia G.; Ndung’u, Thumbi; Walker, Bruce D.; Carrington, Mary; Jooste, Pieter; Goulder, Philip J. R.

2015-01-01

HLA class I polymorphism has a major influence on adult HIV disease progression. An important mechanism mediating this effect is the impact on viral replicative capacity (VRC) of the escape mutations selected in response to HLA-restricted CD8+ T-cell responses. Factors that contribute to slow progression in pediatric HIV infection are less well understood. We here investigate the relationship between VRC and disease progression in pediatric infection, and the effect of HLA on VRC and on disease outcome in adult and pediatric infection. Studying a South African cohort of >350 ART-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. PMID:26076345

Biomarkers for Cognitive Impairment in Parkinson Disease

PubMed Central

Shi, Min; Huber, Bertrand R.; Zhang, Jing

2010-01-01

Cognitive impairment, including dementia, is commonly seen in those afflicted with Parkinson disease (PD), particularly at advanced disease stages. Pathologically, PD with dementia (PD-D) is most often associated with the presence of cortical Lewy bodies, as is the closely related dementia with Lewy bodies (DLB). Both PD-D and DLB are also frequently complicated by the presence of neurofibrillary tangles and amyloid plaques, features most often attributed to Alzheimer disease. Biomarkers are urgently needed to differentiate among these disease processes and predict dementia in PD as well as monitor responses of patients to new therapies. A few clinical assessments, along with structural and functional neuroimaging, have been utilized in the last few years with some success in this area. Additionally, a number of other strategies have been employed to identify biochemical/molecular biomarkers associated with cognitive impairment and dementia in PD, e.g., targeted analysis of candidate proteins known to be important to PD pathogenesis and progression in cerebrospinal fluid or blood. Finally, interesting results are emerging from preliminary studies with unbiased and high throughput genomic, proteomic and metabolomic techniques. The current findings and perspectives of applying these strategies and techniques are reviewed in this article, together with potential areas of advancement. PMID:20522092

Alzheimer disease.

PubMed

Calderon-Garcidueñas, Ana Laura; Duyckaerts, Charles

2017-01-01

Alzheimer disease neuropathology is characterized by the extracellular accumulation of Aβ peptide and intracellular aggregation of hyperphosphorylated tau. With the progression of the disease, macroscopic atrophy affects the entorhinal area and hippocampus, amygdala, and associative regions of the neocortex. The locus coeruleus is depigmented. The deposition of Aβ is first made of diffuse deposits. Amyloid focal deposits constitute the core of the senile plaque which also comprises a corona of tau-positive neurites. Aβ deposits are found successively in the neocortex, the hippocampus, the striatum, the mesencephalon, and finally the cerebellum together with the pontine nuclei (Thal phases). Tau pathology affects in a stereotyped order some specific nuclei of the brainstem, the entorhinal area, the hippocampus, and the neocortex - first the associative areas and secondarily the primary cortices (Braak stages). Loss of synapses is observed in association with tau and Aβ pathology; neuronal loss occurs in the most affected areas. Granulovacuolar degeneration and perisomatic granules are also linked to Alzheimer disease pathology. The physiopathology of Alzheimer disease remains unknown. Familial cases suggest that Aβ deposition is the initial step, but tau pathology appears early in the course and seems to be better correlated with the symptoms. Copyright © 2017 Elsevier B.V. All rights reserved.

In Vitro Tissue-Engineered Skeletal Muscle Models for Studying Muscle Physiology and Disease.

PubMed

Khodabukus, Alastair; Prabhu, Neel; Wang, Jason; Bursac, Nenad

2018-04-25

Healthy skeletal muscle possesses the extraordinary ability to regenerate in response to small-scale injuries; however, this self-repair capacity becomes overwhelmed with aging, genetic myopathies, and large muscle loss. The failure of small animal models to accurately replicate human muscle disease, injury and to predict clinically-relevant drug responses has driven the development of high fidelity in vitro skeletal muscle models. Herein, the progress made and challenges ahead in engineering biomimetic human skeletal muscle tissues that can recapitulate muscle development, genetic diseases, regeneration, and drug response is discussed. Bioengineering approaches used to improve engineered muscle structure and function as well as the functionality of satellite cells to allow modeling muscle regeneration in vitro are also highlighted. Next, a historical overview on the generation of skeletal muscle cells and tissues from human pluripotent stem cells, and a discussion on the potential of these approaches to model and treat genetic diseases such as Duchenne muscular dystrophy, is provided. Finally, the need to integrate multiorgan microphysiological systems to generate improved drug discovery technologies with the potential to complement or supersede current preclinical animal models of muscle disease is described. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Combined Population Dynamics and Entropy Modelling Supports Patient Stratification in Chronic Myeloid Leukemia

PubMed Central

Brehme, Marc; Koschmieder, Steffen; Montazeri, Maryam; Copland, Mhairi; Oehler, Vivian G.; Radich, Jerald P.; Brümmendorf, Tim H.; Schuppert, Andreas

2016-01-01

Modelling the parameters of multistep carcinogenesis is key for a better understanding of cancer progression, biomarker identification and the design of individualized therapies. Using chronic myeloid leukemia (CML) as a paradigm for hierarchical disease evolution we show that combined population dynamic modelling and CML patient biopsy genomic analysis enables patient stratification at unprecedented resolution. Linking CD34+ similarity as a disease progression marker to patient-derived gene expression entropy separated established CML progression stages and uncovered additional heterogeneity within disease stages. Importantly, our patient data informed model enables quantitative approximation of individual patients’ disease history within chronic phase (CP) and significantly separates “early” from “late” CP. Our findings provide a novel rationale for personalized and genome-informed disease progression risk assessment that is independent and complementary to conventional measures of CML disease burden and prognosis. PMID:27048866

Activation of microglia induces symptoms of Parkinson’s disease in wild-type, but not in IL-1 knockout mice

PubMed Central

2013-01-01

Background Parkinson’s disease (PD) is an age-related progressive neurodegenerative disorder caused by selective loss of dopaminergic neurons from the substantia nigra (SN) to the striatum. The initial factor that triggers neurodegeneration is unknown; however, inflammation has been demonstrated to be significantly involved in the progression of PD. The present study was designed to investigate the role of the pro-inflammatory cytokine interleukin-1 (IL-1) in the activation of microglia and the decline of motor function using IL-1 knockout (KO) mice. Methods Lipopolysaccharide (LPS) was stereotaxically injected into the SN of mice brains as a single dose or a daily dose for 5 days (5 mg/2 ml/injection, bilaterally). Animal behavior was assessed with the rotarod test at 2 hr and 8, 15 and 22 days after the final LPS injection. Results LPS treatment induced the activation of microglia, as demonstrated by production of IL-1β and tumor necrosis factor (TNF) α as well as a change in microglial morphology. The number of cells immunoreactive for 4-hydroxynonenal (4HNE) and nitrotyrosine (NT), which are markers for oxidative insults, increased in the SN, and impairment of motor function was observed after the subacute LPS treatment. Cell death and aggregation of α-synuclein were observed 21 and 30 days after the final LPS injection, respectively. Behavioral deficits were observed in wild-type and TNFα KO mice, but IL-1 KO mice behaved normally. Tyrosine hydroxylase (TH) gene expression was attenuated by LPS treatment in wild-type and TNFα KO mice but not in IL-1 KO mice. Conclusions The subacute injection of LPS into the SN induces PD-like pathogenesis and symptoms in mice that mimic the progressive changes of PD including the aggregation of α-synuclein. LPS-induced dysfunction of motor performance was accompanied by the reduced gene expression of TH. These findings suggest that activation of microglia by LPS causes functional changes such as dopaminergic neuron attenuation in an IL-1-dependent manner, resulting in PD-like behavioral impairment. PMID:24289537

Lysosomes in cancer-living on the edge (of the cell).

PubMed

Hämälistö, Saara; Jäättelä, Marja

2016-04-01

The lysosomes have definitely polished their status inside the cell. Being discovered as the last resort of discarded cellular biomass, the steady rising of this versatile signaling organelle is currently ongoing. This review discusses the recent data on the unconventional functions of lysosomes, focusing mainly on the less studied lysosomes residing in the cellular periphery. We emphasize our discussion on the emerging paths the lysosomes have taken in promoting cancer progression to metastatic disease. Finally, we address how the altered cancerous lysosomes in metastatic cancers may be specifically targeted and what are the pending questions awaiting for elucidation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Bioengineering of Artificial Lymphoid Organs.

PubMed

Nosenko, M A; Drutskaya, M S; Moisenovich, M M; Nedospasov, S A

2016-01-01

This review addresses the issue of bioengineering of artificial lymphoid organs.Progress in this field may help to better understand the nature of the structure-function relations that exist in immune organs. Artifical lymphoid organs may also be advantageous in the therapy or correction of immunodefficiencies, autoimmune diseases, and cancer. The structural organization, development, and function of lymphoid tissue are analyzed with a focus on the role of intercellular contacts and on the cytokine signaling pathways regulating these processes. We describe various polymeric materials, as scaffolds, for artificial tissue engineering. Finally, published studies in which artificial lymphoid organs were generated are reviewed and possible future directions in the field are discussed.

Bioengineering of Artificial Lymphoid Organs

PubMed Central

Nosenko, M. A.; Drutskaya, M. S.; Moisenovich, M. M.; Nedospasov, S. A.

2016-01-01

This review addresses the issue of bioengineering of artificial lymphoid organs.Progress in this field may help to better understand the nature of the structure-function relations that exist in immune organs. Artifical lymphoid organs may also be advantageous in the therapy or correction of immunodefficiencies, autoimmune diseases, and cancer. The structural organization, development, and function of lymphoid tissue are analyzed with a focus on the role of intercellular contacts and on the cytokine signaling pathways regulating these processes. We describe various polymeric materials, as scaffolds, for artificial tissue engineering. Finally, published studies in which artificial lymphoid organs were generated are reviewed and possible future directions in the field are discussed. PMID:27437136

Environmental factors influencing the risk of autism

PubMed Central

Karimi, Padideh; Kamali, Elahe; Mousavi, Seyyed Mohammad; Karahmadi, Mojgan

2017-01-01

Autism is a developmental disability with age of onset in childhood (under 3 years old), which is characterized by definite impairments in social interactions, abnormalities in speech, and stereotyped pattern of behaviors. Due to the progress of autism in recent decades, a wide range of studies have been done to identify the etiological factors of autism. It has been found that genetic and environmental factors are both involved in autism pathogenesis. Hence, in this review article, a set of environmental factors involved in the occurrence of autism has been collected, and finally, some practical recommendations for reduction of the risk of this devastating disease in children are represented. PMID:28413424

Cytokines, IBD and colitis-associated cancer

PubMed Central

Francescone, Ralph; Hou, Vivianty; Grivennikov, Sergei I.

2015-01-01

Inflammatory bowel diseases (IBDs) are debilitating conditions that result in intestinal damage due to chronic inflammation. In addition, the perpetual state of inflammation predisposes individuals to the development of colitis associated cancer (CAC). Because of the immense immune cell infiltration into colon, cytokines produced by immune cells are major players in the initiation and progression of IBD and CAC. In this review, we will explore the functions of many key cytokines and their roles in IBD and CAC, as well as their influences on the immune system and stromal cells. Finally, we will briefly discuss current therapies and current clinical trials targeting cytokines in IBD. PMID:25563695

Beneficial and detrimental role of adenosine signaling in diseases and therapy

PubMed Central

Liu, Hong

2015-01-01

Adenosine is a major signaling nucleoside that orchestrates cellular and tissue adaptation under energy depletion and ischemic/hypoxic conditions by activation of four G protein-coupled receptors (GPCR). The regulation and generation of extracellular adenosine in response to stress are critical in tissue protection. Both mouse and human studies reported that extracellular adenosine signaling plays a beneficial role during acute states. However, prolonged excess extracellular adenosine is detrimental and contributes to the development and progression of various chronic diseases. In recent years, substantial progress has been made to understand the role of adenosine signaling in different conditions and to clarify its significance during the course of disease progression in various organs. These efforts have and will identify potential therapeutic possibilities for protection of tissue injury at acute stage by upregulation of adenosine signaling or attenuation of chronic disease progression by downregulation of adenosine signaling. This review is to summarize current progress and the importance of adenosine signaling in different disease stages and its potential therapeutic effects. PMID:26316513

Progressive Cl- channel defects reveal disrupted skeletal muscle maturation in R6/2 Huntington's mice.

PubMed

Miranda, Daniel R; Wong, Monica; Romer, Shannon H; McKee, Cynthia; Garza-Vasquez, Gabriela; Medina, Alyssa C; Bahn, Volker; Steele, Andrew D; Talmadge, Robert J; Voss, Andrew A

2017-01-01

Huntington's disease (HD) patients suffer from progressive and debilitating motor dysfunction. Previously, we discovered reduced skeletal muscle chloride channel (ClC-1) currents, inwardly rectifying potassium (Kir) channel currents, and membrane capacitance in R6/2 transgenic HD mice. The ClC-1 loss-of-function correlated with increased aberrant mRNA processing and decreased levels of full-length ClC-1 mRNA (Clcn1 gene). Physiologically, the resulting muscle hyperexcitability may help explain involuntary contractions of HD. In this study, the onset and progression of these defects are investigated in R6/2 mice, ranging from 3 wk old (presymptomatic) to 9-13 wk old (late-stage disease), and compared with age-matched wild-type (WT) siblings. The R6/2 ClC-1 current density and level of aberrantly spliced Clcn1 mRNA remain constant with age. In contrast, the ClC-1 current density increases, and the level of aberrantly spliced Clcn1 mRNA decreases with age in WT mice. The R6/2 ClC-1 properties diverge from WT before the onset of motor symptoms, which occurs at 5 wk of age. The relative decrease in R6/2 muscle capacitance also begins in 5-wk-old mice and is independent of fiber atrophy. Kir current density is consistently lower in R6/2 compared with WT muscle. The invariable R6/2 ClC-1 properties suggest a disruption in muscle maturation, which we confirm by measuring elevated levels of neonatal myosin heavy chain (MyHC) in late-stage R6/2 skeletal muscle. Similar changes in ClC-1 and MyHC isoforms in the more slowly developing Q175 HD mice suggest an altered maturational state is relevant to adult-onset HD. Finally, we find nuclear aggregates of muscleblind-like protein 1 without predominant CAG repeat colocalization in R6/2 muscle. This is unlike myotonic dystrophy, another trinucleotide repeat disorder with similar ClC-1 defects, and suggests a novel mechanism of aberrant mRNA splicing in HD. These early and progressive skeletal muscle defects reveal much needed peripheral biomarkers of disease progression and better elucidate the mechanism underlying HD myopathy. © 2017 Miranda et al.

Progressive Cl− channel defects reveal disrupted skeletal muscle maturation in R6/2 Huntington’s mice

PubMed Central

Miranda, Daniel R.; Wong, Monica; Romer, Shannon H.; McKee, Cynthia; Garza-Vasquez, Gabriela; Medina, Alyssa C.; Bahn, Volker; Steele, Andrew D.; Talmadge, Robert J.

2017-01-01

Huntington’s disease (HD) patients suffer from progressive and debilitating motor dysfunction. Previously, we discovered reduced skeletal muscle chloride channel (ClC-1) currents, inwardly rectifying potassium (Kir) channel currents, and membrane capacitance in R6/2 transgenic HD mice. The ClC-1 loss-of-function correlated with increased aberrant mRNA processing and decreased levels of full-length ClC-1 mRNA (Clcn1 gene). Physiologically, the resulting muscle hyperexcitability may help explain involuntary contractions of HD. In this study, the onset and progression of these defects are investigated in R6/2 mice, ranging from 3 wk old (presymptomatic) to 9–13 wk old (late-stage disease), and compared with age-matched wild-type (WT) siblings. The R6/2 ClC-1 current density and level of aberrantly spliced Clcn1 mRNA remain constant with age. In contrast, the ClC-1 current density increases, and the level of aberrantly spliced Clcn1 mRNA decreases with age in WT mice. The R6/2 ClC-1 properties diverge from WT before the onset of motor symptoms, which occurs at 5 wk of age. The relative decrease in R6/2 muscle capacitance also begins in 5-wk-old mice and is independent of fiber atrophy. Kir current density is consistently lower in R6/2 compared with WT muscle. The invariable R6/2 ClC-1 properties suggest a disruption in muscle maturation, which we confirm by measuring elevated levels of neonatal myosin heavy chain (MyHC) in late-stage R6/2 skeletal muscle. Similar changes in ClC-1 and MyHC isoforms in the more slowly developing Q175 HD mice suggest an altered maturational state is relevant to adult-onset HD. Finally, we find nuclear aggregates of muscleblind-like protein 1 without predominant CAG repeat colocalization in R6/2 muscle. This is unlike myotonic dystrophy, another trinucleotide repeat disorder with similar ClC-1 defects, and suggests a novel mechanism of aberrant mRNA splicing in HD. These early and progressive skeletal muscle defects reveal much needed peripheral biomarkers of disease progression and better elucidate the mechanism underlying HD myopathy. PMID:27899419

Altered Tnnt3 characterizes selective weakness of fast fibers in mice overexpressing FSHD region gene 1 (FRG1)

PubMed Central

Sancisi, Valentina; Germinario, Elena; Esposito, Alessandra; Morini, Elisabetta; Peron, Samantha; Moggio, Maurizio; Tomelleri, Giuliano; Danieli-Betto, Daniela

2013-01-01

Facioscapulohumeral muscular dystrophy (FSHD), a common hereditary myopathy, is characterized by atrophy and weakness of selective muscle groups. FSHD is considered an autosomal dominant disease with incomplete penetrance and unpredictable variability of clinical expression within families. Mice overexpressing FRG1 (FSHD region gene 1), a candidate gene for this disease, develop a progressive myopathy with features of the human disorder. Here, we show that in FRG1-overexpressing mice, fast muscles, which are the most affected by the dystrophic process, display anomalous fast skeletal troponin T (fTnT) isoform, resulting from the aberrant splicing of the Tnnt3 mRNA that precedes the appearance of dystrophic signs. We determine that muscles of FRG1 mice develop less strength due to impaired contractile properties of fast-twitch fibers associated with an anomalous MyHC-actin ratio and a reduced sensitivity to Ca2+. We demonstrate that the decrease of Ca2+ sensitivity of fast-twitch fibers depends on the anomalous troponin complex and can be rescued by the substitution with the wild-type proteins. Finally, we find that the presence of aberrant splicing isoforms of TNNT3 characterizes dystrophic muscles in FSHD patients. Collectively, our results suggest that anomalous TNNT3 profile correlates with the muscle impairment in both humans and mice. On the basis of these results, we propose that aberrant fTnT represents a biological marker of muscle phenotype severity and disease progression. PMID:24305066

Automatic classification of patients with idiopathic Parkinson's disease and progressive supranuclear palsy using diffusion MRI datasets

NASA Astrophysics Data System (ADS)

Talai, Sahand; Boelmans, Kai; Sedlacik, Jan; Forkert, Nils D.

2017-03-01

Parkinsonian syndromes encompass a spectrum of neurodegenerative diseases, which can be classified into various subtypes. The differentiation of these subtypes is typically conducted based on clinical criteria. Due to the overlap of intra-syndrome symptoms, the accurate differential diagnosis based on clinical guidelines remains a challenge with failure rates up to 25%. The aim of this study is to present an image-based classification method of patients with Parkinson's disease (PD) and patients with progressive supranuclear palsy (PSP), an atypical variant of PD. Therefore, apparent diffusion coefficient (ADC) parameter maps were calculated based on diffusion-tensor magnetic resonance imaging (MRI) datasets. Mean ADC values were determined in 82 brain regions using an atlas-based approach. The extracted mean ADC values for each patient were then used as features for classification using a linear kernel support vector machine classifier. To increase the classification accuracy, a feature selection was performed, which resulted in the top 17 attributes to be used as the final input features. A leave-one-out cross validation based on 56 PD and 21 PSP subjects revealed that the proposed method is capable of differentiating PD and PSP patients with an accuracy of 94.8%. In conclusion, the classification of PD and PSP patients based on ADC features obtained from diffusion MRI datasets is a promising new approach for the differentiation of Parkinsonian syndromes in the broader context of decision support systems.

Suppression of SIK1 by miR-141 in human ovarian cancer cell lines and tissues.

PubMed

Chen, Jin-Long; Chen, Fang; Zhang, Ting-Ting; Liu, Nai-Fu

2016-06-01

Epithelial ovarian cancer (EOC), the sixth most common cancer in women worldwide, is the most commonly fatal gynecologic malignancy in developed countries. One of the main reasons for this is that relatively little was known about the molecular events responsible for the development of this highly aggressive disease. In the present study, we demonstrated that salt‑inducible kinase 1 (SIK1; which is also known as MSK/SIK/SNF1LK) was downregulated in ovarian cancer tissue samples. Using HEY ovarian cancer cells, we noted that SIK1 overexpression inhibited proliferation as well as cancer stem cell-associated traits. Silencing SIK1 promoted the proliferation of the EG ovarian cancer cell line. We performed an analysis of potential microRNAs (miRNAs or miRs) target sites using three commonly used prediction algorithms: miRanda, TargetScan and PicTar. All three algorithms predicted that miR-141 targets the 3'UTR of SIK1. Subsequent experiments not only confirmed this prediction, but also showed that miR-141 was associated with the progression of this disease. Finally, we found that miR-141 promoted proliferation of EG cells, whereas silencing miR-141 restored SIK1 expression and inhibited the proliferation of the HEY cells. Elucidating the molecular mechanism of ovarian cancer not only enables us to further understand the pathogenesis and progression of the disease, but also provides new targets for effective therapies.

Economic impact of disease progression in follicular non-Hodgkin lymphoma

PubMed Central

Beveridge, Roy; Satram-Hoang, Sacha; Sail, Kavita; Darragh, Joseph; Chen, Clara; Forsyth, Michael; Reyes, Carolina

2011-01-01

Using a retrospective claims database, we estimated the economic costs of progression among patients with follicular non-Hodgkin lymphoma (f-NHL) treated in an outpatient community-based setting. Patients with f-NHL who received care between 1 July 2006 and 31 December 2009 were categorized into two cohorts based on whether they experienced progressive disease (PD) or not. Costs per patient per month (PPPM) were compared between patients with PD versus non-PD. Follow-up time was censored at the last entry for disease status or 6 months after the date of remission/stable disease or progression. Of the 1002 patients with f-NHL identified, 268 progressed and 734 did not. The mean overall costs PPPM over the 6-month follow-up period were significantly higher for patients with PD versus non-PD ($3527 vs. $860; difference = $2667; p < 0.001). This cost difference persisted within all resource categories evaluated. Results of this study indicate that therapies which delay progression for patients with f-NHL may result in potential cost savings. PMID:21745172

Twenty years of audiology in a patient with Norrie disease.

PubMed

Halpin, Chris; Sims, Katherine

2008-11-01

To describe disease progression and treatment outcomes over a 20-year period (ages 5-25) in a young man with Norrie disease (occuloacousticocerebral dysplasia), ND; OMIM #310600. Affected individuals are born blind and develop progressive sensory loss with onset in adolescence. This disease is X-linked and has been associated with mutations of the NDP gene (Xp11.4). The patient was followed using repeated audiograms, as well as reports of educational progress and hearing aid use. The specific mutation was found by molecular analysis. The patient demonstrated progressive sensory loss with good preservation of word recognition. The loss was initially high frequency and asymmetric in adolescence and became more severe, more symmetric and affected practically all frequencies by the end of childhood. Educational progress was affected by the cognitive effects of the syndrome, and hearing aid use was very effective. A bilateral progressive sensory loss with good preservation of word recognition was documented in detail. The residual word recognition supported good use of hearing aids in this case.

Modifications of the mouse bone marrow microenvironment favor angiogenesis and correlate with disease progression from asymptomatic to symptomatic multiple myeloma

PubMed Central

Calcinotto, Arianna; Ponzoni, Maurilio; Ria, Roberto; Grioni, Matteo; Cattaneo, Elena; Villa, Isabella; Sabrina Bertilaccio, Maria Teresa; Chesi, Marta; Rubinacci, Alessandro; Tonon, Giovanni; Bergsagel, P Leif; Vacca, Angelo; Bellone, Matteo

2015-01-01

While multiple myeloma (MM) is almost invariably preceded by asymptomatic monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering MM (SMM), the alterations of the bone marrow (BM) microenvironment that establish progression to symptomatic disease are circumstantial. Here we show that in Vk*MYC mice harboring oncogene-driven plasma cell proliferative disorder, disease appearance associated with substantial modifications of the BM microenvironment, including a progressive accumulation of both CD8+ and CD4+ T cells with a dominant T helper type 1 (Th1) response. Progression from asymptomatic to symptomatic MM was characterized by further BM accrual of T cells with reduced Th1 and persistently increased Th2 cytokine production, which associated with accumulation of CD206+Tie2+ macrophages, and increased pro-angiogenic cytokines and microvessel density (MVD). Notably, MVD was also increased at diagnosis in the BM of MGUS and SMM patients that subsequently progressed to MM when compared with MGUS and SMM that remained quiescent. These findings suggest a multistep pathogenic process in MM, in which the immune system may contribute to angiogenesis and disease progression. They also suggest initiating a large multicenter study to investigate MVD in asymptomatic patients as prognostic factor for the progression and outcome of this disease. PMID:26155424

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

PubMed

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.

Crack-cocaine use accelerates HIV disease progression in a cohort of HIV-positive drug users.

PubMed

Baum, Marianna K; Rafie, Carlin; Lai, Shenghan; Sales, Sabrina; Page, Bryan; Campa, Adriana

2009-01-01

HIV infection is prevalent among substance abusers. The effects of specific illicit drugs on HIV disease progression have not been established. We evaluated the relationship between substances of abuse and HIV disease progression in a cohort of HIV-1-positive active drug users. A prospective, 30-month, longitudinal study was conducted on 222 HIV-1 seropositive drug users in Miami, FL. History of illicit drug, alcohol, and medication use, CD4+ cell count, and viral load were performed every 6 months. Crack-cocaine users were 2.14 times [95% confidence interval (CI): 1.08 to 4.25, P = 0.029] more likely to present a decline of CD4 to

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

PubMed

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.

Establishing a cGMP pancreatic islet processing facility: the first experience in Iran.

PubMed

Larijani, Bagher; Arjmand, Babak; Amoli, Mahsa M; Ao, Ziliang; Jafarian, Ali; Mahdavi-Mazdah, Mitra; Ghanaati, Hossein; Baradar-Jalili, Reza; Sharghi, Sasan; Norouzi-Javidan, Abbas; Aghayan, Hamid Reza

2012-12-01

It has been predicted that one of the greatest increase in prevalence of diabetes will happen in the Middle East bear in the next decades. The aim of standard therapeutic strategies for diabetes is better control of complications. In contrast, some new strategies like cell and gene therapy have aimed to cure the disease. In recent years, significant progress has occurred in beta-cell replacement therapies with a progressive improvement of short-term and long term outcomes. In year 2005, considering the impact of the disease in Iran and the promising results of the Edmonton protocol, the funding for establishing a current Good Manufacturing Practice (cGMP) islet processing facility by Endocrinology and Metabolism Research Center was approved by Tehran University of Medical Sciences. Several islet isolations were performed following establishment of cGMP facility and recruitment of all required equipments for process validation and experimental purpose. Finally the first successful clinical islet isolation and transplantation was performed in September 2010. In spite of a high cost of the procedure it is considered beneficial and may prevent long term complications and the costs associated with secondary cares. In this article we will briefly describe our experience in setting up a cGMP islet processing facility which can provide valuable information for regional countries interested to establish similar facilities.

Vitamin D and Osteoporosis in HIV/HCV Coinfected Patients: A Literature Review.

PubMed

Di Carlo, Paola; Siracusa, Lucia; Mazzola, Giovanni; Colletti, Piero; Soresi, Maurizio; Giannitrapani, Lydia; Li Vecchi, Valentina; Montalto, Giuseppe

2015-01-01

Vitamin D deficiency further increases the risk of osteoporosis in HIV-positive patients coinfected with hepatitis C virus (HCV); however, it is still unclear whether HCV-related increased fracture risk is a function of the severity of liver disease. The aim of this review was to identify studies on associative vitamin D deficiency patterns in high-risk populations such as HIV/HCV coinfected patients. We did this by searching MEDLINE and EMBASE databases, from inception to August 2014, and included bibliographies. The final 12 articles selected are homogeneous in terms of age but heterogeneous in terms of sample size, participant recruitment, and data source. Most of the HIV/HCV coinfected patients have less than adequate levels of vitamin D. After reviewing the selected articles, we concluded that vitamin D deficiency should be regarded as a continuum and that the lower limit of the ideal range is debatable. We found that vitamin D deficiency might influence liver disease progression in HIV/HCV coinfected patients. Methodological issues in evaluating vitamin D supplementation as a relatively inexpensive therapeutic option are discussed, as well as the need for future research, above all on its role in reducing the risk of HCV-related fracture by modifying liver fibrosis progression.

Clinical value of nutritional status in neurodegenerative diseases: What is its impact and how it affects disease progression and management?

PubMed

Tsagalioti, Eftyhia; Trifonos, Christina; Morari, Aggeliki; Vadikolias, Konstantinos; Giaginis, Constantinos

2018-04-01

Neurodegenerative diseases constitute a major problem of public health that is associated with an increased risk of mortality and poor quality of life. Malnutrition is considered as a major problem that worsens the prognosis of patients suffering from neurodegenerative diseases. In this aspect, the present review is aimed to critically collect and summarize all the available existing clinical data regarding the clinical impact of nutritional assessment in neurodegenerative diseases, highlighting on the crucial role of nutritional status in disease progression and management. According to the currently available clinical data, the nutritional status of patients seems to play a very important role in the development and progression of neurodegenerative diseases. A correct nutritional evaluation of neurodegenerative disease patients and a right nutrition intervention is essential in monitoring their disease.

Sleep and Quality of Life in People With COPD: A Descriptive-Correlational Study.

PubMed

Dignani, Lucia; Toccaceli, Andrea; Lucertini, Carla; Petrucci, Cristina; Lancia, Loreto

2016-08-01

Sleep disorders are very common in patients with chronic obstructive pulmonary disease (COPD). However, it is not clear how sleep disorders and quality of life (QoL) affect each other in the different stages of disease progression. This descriptive-correlational study investigated the relationship between QoL, quality of sleep, and degree of disease progression in 102 outpatients with COPD. The results showed that the QoL in patients with COPD is compromised and worsens with disease progression, and the quality of sleep is significantly associated with QoL and worsened as the disease progressed. The early identification of a risk of alteration of the quality of sleep, especially in nursing care, could facilitate a preventive approach for COPD patients that could positively affect their QoL. © The Author(s) 2015.

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

PubMed

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 progression depended on the initial size of the lesion. In Stargardt disease with DDAF lesions, fundus autofluorescence may serve as a monitoring tool for interventional clinical trials that aim to slow disease progression. Rates of progression depended mainly on initial lesion size.

Copper/MYC/CTR1 interplay: a dangerous relationship in hepatocellular carcinoma.

PubMed

Porcu, Cristiana; Antonucci, Laura; Barbaro, Barbara; Illi, Barbara; Nasi, Sergio; Martini, Maurizio; Licata, Anna; Miele, Luca; Grieco, Antonio; Balsano, Clara

2018-02-06

Free serum copper correlates with tumor incidence and progression of human cancers, including hepatocellular carcinoma (HCC). Copper extracellular uptake is provided by the transporter CTR1, whose expression is regulated to avoid excessive intracellular copper entry. Inadequate copper serum concentration is involved in the pathogenesis of Non Alcoholic Fatty Liver Disease (NAFLD), which is becoming a major cause of liver damage progression and HCC incidence. Finally, MYC is over-expressed in most of HCCs and is a critical regulator of cellular growth, tumor invasion and metastasis. The purpose of our study was to understand if higher serum copper concentrations might be involved in the progression of NAFLD-cirrhosis toward-HCC. We investigated whether high exogenous copper levels sensitize liver cells to transformation and if it exists an interplay between copper-related proteins and MYC oncogene. NAFLD-cirrhotic patients were characterized by a statistical significant enhancement of serum copper levels, even more evident in HCC patients. We demonstrated that high extracellular copper concentrations increase cell growth, migration, and invasion of liver cancer cells by modulating MYC/CTR1 axis. We highlighted that MYC binds a specific region of the CTR1 promoter, regulating its transcription. Accordingly, CTR1 and MYC proteins expression were progressively up-regulated in liver tissues from NAFLD-cirrhotic to HCC patients. This work provides novel insights on the molecular mechanisms by which copper may favor the progression from cirrhosis to cancer. The Cu/MYC/CTR1 interplay opens a window to refine HCC diagnosis and design new combined therapies.

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

USDA-ARS?s Scientific Manuscript database

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

The impact of individual-level heterogeneity on estimated infectious disease burden: a simulation study.

PubMed

McDonald, Scott A; Devleesschauwer, Brecht; Wallinga, Jacco

2016-12-08

Disease burden is not evenly distributed within a population; this uneven distribution can be due to individual heterogeneity in progression rates between disease stages. Composite measures of disease burden that are based on disease progression models, such as the disability-adjusted life year (DALY), are widely used to quantify the current and future burden of infectious diseases. Our goal was to investigate to what extent ignoring the presence of heterogeneity could bias DALY computation. Simulations using individual-based models for hypothetical infectious diseases with short and long natural histories were run assuming either "population-averaged" progression probabilities between disease stages, or progression probabilities that were influenced by an a priori defined individual-level frailty (i.e., heterogeneity in disease risk) distribution, and DALYs were calculated. Under the assumption of heterogeneity in transition rates and increasing frailty with age, the short natural history disease model predicted 14% fewer DALYs compared with the homogenous population assumption. Simulations of a long natural history disease indicated that assuming homogeneity in transition rates when heterogeneity was present could overestimate total DALYs, in the present case by 4% (95% quantile interval: 1-8%). The consequences of ignoring population heterogeneity should be considered when defining transition parameters for natural history models and when interpreting the resulting disease burden estimates.

Porcine Reproductive and Respiratory Syndrome Virus (PRRSV): Pathogenesis and Interaction with the Immune System.

PubMed

Lunney, Joan K; Fang, Ying; Ladinig, Andrea; Chen, Nanhua; Li, Yanhua; Rowland, Bob; Renukaradhya, Gourapura J

2016-01-01

This review addresses important issues of porcine reproductive and respiratory syndrome virus (PRRSV) infection, immunity, pathogenesis, and control. Worldwide, PRRS is the most economically important infectious disease of pigs. We highlight the latest information on viral genome structure, pathogenic mechanisms, and host immunity, with a special focus on immune factors that modulate PRRSV infections during the acute and chronic/persistent disease phases. We address genetic control of host resistance and probe effects of PRRSV infection on reproductive traits. A major goal is to identify cellular/viral targets and pathways for designing more effective vaccines and therapeutics. Based on progress in viral reverse genetics, host transcriptomics and genomics, and vaccinology and adjuvant technologies, we have identified new areas for PRRS control and prevention. Finally, we highlight the gaps in our knowledge base and the need for advanced molecular and immune tools to stimulate PRRS research and field applications.

New light on an old friend: targeting PUMA in radioprotection and therapy of cardiovascular and neurodegenerative diseases.

PubMed

Tichy, Ales; Marek, Jan; Havelek, Radim; Pejchal, Jaroslav; Seifrtova, Martina; Zarybnicka, Lenka; Filipova, Alzbeta; Rezacova, Martina; Sinkorova, Zuzana

2018-04-05

This review summarizes recent progress in understanding the role of p53-upregulated mediator of apoptosis (PUMA) in molecular pathways with respect to its potential therapeutic applications. Particular emphasis is given to the PUMA´s role in ionizing radiation-induced signalling as radiotoxicity of normal tissue is mediated mostly via apoptosis. PUMA and its p53-dependent and p53-independent induction is described and potential use as a new target for the development of radioprotective agents is suggested. Further implications, including targeting PUMA to prevent and treat cardiovascular and neurodegenerative diseases, are also discussed together with overview of other therapeutic applications. Finally, basic chemical structures for development of novel PUMA modulators such as pifithrine derivativeses, kinase inhibitors or modulators of Bcl-2 protein family are described. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Systems healthcare: a holistic paradigm for tomorrow.

PubMed

Fiandaca, Massimo S; Mapstone, Mark; Connors, Elenora; Jacobson, Mireille; Monuki, Edwin S; Malik, Shaista; Macciardi, Fabio; Federoff, Howard J

2017-12-19

Systems healthcare is a holistic approach to health premised on systems biology and medicine. The approach integrates data from molecules, cells, organs, the individual, families, communities, and the natural and man-made environment. Both extrinsic and intrinsic influences constantly challenge the biological networks associated with wellness. Such influences may dysregulate networks and allow pathobiology to evolve, resulting in early clinical presentation that requires astute assessment and timely intervention for successful mitigation. Herein, we describe the components of relevant biological systems and the nature of progression from at-risk to manifest disease. We illustrate the systems approach by examining two relevant clinical examples: Alzheimer's and cardiovascular diseases. The implications of systems healthcare management are examined through the lens of economics, ethics, policy and the law. Finally, we propose the need to develop new educational paradigms to enhance the training of the health professional in an era of systems medicine.

Sustainable control of zoonotic pathogens in wildlife: how to be fair to wild animals?

PubMed

Artois, M; Blancou, J; Dupeyroux, O; Gilot-Fromont, E

2011-12-01

Wildlife may harbour infectious pathogens that are of zoonotic concern. However, culling such reservoir populations to mitigate or control the transmission of these pathogens to humans has proved disappointingly inefficient. Alternatives are still in an experimental stage of development. They include vaccination, medication, contraception and environmental manipulation, including fencing and biosecurity measures. This review examines the general concepts involved in the control of wildlife diseases and presents relevant case studies. Since wildlife disease control inevitably involves interfering with wildlife ecology, this is a complex goal whose attempts at realisation should be supervised by a scientific organisation. Most approaches within natural ecosystems should first be carefully tested in trials that are progressively extended to a larger scale. Finally, all measures that aim to prevent infection in humans (such as personal hygiene or vaccination) or that encourage us to avoid infectious contacts with wildlife should be recommended.

Hepatic encephalopathy

PubMed Central

2017-01-01

Abstract Hepatic encephalopathy (HE) is a reversible syndrome of impaired brain function occurring in patients with advanced liver diseases. The precise pathophysiology of HE is still under discussion; the leading hypothesis focus on the role of neurotoxins, impaired neurotransmission due to metabolic changes in liver failure, changes in brain energy metabolism, systemic inflammatory response and alterations of the blood brain barrier. HE produces a wide spectrum of nonspecific neurological and psychiatric manifestations. Minimal HE is diagnosed by abnormal psychometric tests. Clinically overt HE includes personality changes, alterations in consciousness progressive disorientation in time and space, somnolence, stupor and, finally, coma. Except for clinical studies, no specific tests are required for diagnosis. HE is classified according to the underlying disease, the severity of manifestations, its time course and the existence of precipitating factors. Treatment of overt HE includes supportive therapies, treatment of precipitating factors, lactulose and/or rifaximin. Routine treatment for minimal HE is only recommended for selected patients. PMID:28533911

Public data and open source tools for multi-assay genomic investigation of disease.

PubMed

Kannan, Lavanya; Ramos, Marcel; Re, Angela; El-Hachem, Nehme; Safikhani, Zhaleh; Gendoo, Deena M A; Davis, Sean; Gomez-Cabrero, David; Castelo, Robert; Hansen, Kasper D; Carey, Vincent J; Morgan, Martin; Culhane, Aedín C; Haibe-Kains, Benjamin; Waldron, Levi

2016-07-01

Molecular interrogation of a biological sample through DNA sequencing, RNA and microRNA profiling, proteomics and other assays, has the potential to provide a systems level approach to predicting treatment response and disease progression, and to developing precision therapies. Large publicly funded projects have generated extensive and freely available multi-assay data resources; however, bioinformatic and statistical methods for the analysis of such experiments are still nascent. We review multi-assay genomic data resources in the areas of clinical oncology, pharmacogenomics and other perturbation experiments, population genomics and regulatory genomics and other areas, and tools for data acquisition. Finally, we review bioinformatic tools that are explicitly geared toward integrative genomic data visualization and analysis. This review provides starting points for accessing publicly available data and tools to support development of needed integrative methods. © The Author 2015. Published by Oxford University Press.

[Effectiveness of occupational therapy and other non-pharmacological therapies in cognitive impairment and Alzheimer's disease].

PubMed

Matilla-Mora, Rosa; Martínez-Piédrola, Rosa María; Fernández Huete, Javier

A review is presented on the existing knowledge about the usefulness of the occupational therapy in the non-pharmacological treatment of Alzheimer's disease. After conducting a literature search of the period 2010-2015, 25 articles that met the inclusion criteria were selected. The evidence obtained showed the efficiency and effectiveness of OT in delaying the progression of various disorders, especially when structured home OT programs are used. These programs should include aerobic and strengthening, sensory stimulation, and cognitive and memory training exercises based on learning without mistakes. These have shown benefits in the performance of activities of daily living, cognitive and emotional functioning. The importance is stressed of the combined and individual household level intervention and caregiver education. Finally, the need for more studies on the effectiveness of long-term sensory stimulation is highlighted. Copyright © 2015 SEGG. Publicado por Elsevier España, S.L.U. All rights reserved.

Cutaneous Surgical Denervation: A Method for Testing the Requirement for Nerves in Mouse Models of Skin Disease.

PubMed

Peterson, Shelby C; Brownell, Isaac; Wong, Sunny Y

2016-06-26

Cutaneous somatosensory nerves function to detect diverse stimuli that act upon the skin. In addition to their established sensory roles, recent studies have suggested that nerves may also modulate skin disorders including atopic dermatitis, psoriasis and cancer. Here, we describe protocols for testing the requirement for nerves in maintaining a cutaneous mechanosensory organ, the touch dome (TD). Specifically, we discuss methods for genetically labeling, harvesting and visualizing TDs by whole-mount staining, and for performing unilateral surgical denervation on mouse dorsal back skin. Together, these approaches can be used to directly compare TD morphology and gene expression in denervated as well as sham-operated skin from the same animal. These methods can also be readily adapted to examine the requirement for nerves in mouse models of skin pathology. Finally, the ability to repeatedly sample the skin provides an opportunity to monitor disease progression at different stages and times after initiation.

DNA polymorphisms predict time to progression from uncomplicated to complicated Crohn's disease.

PubMed

Pernat Drobež, Cvetka; Repnik, Katja; Gorenjak, Mario; Ferkolj, Ivan; Weersma, Rinse K; Potočnik, Uroš

2018-04-01

Most patients with Crohn's disease (CD) are diagnosed with the uncomplicated inflammatory form of the disease (Montreal stage B1). However, the majority of them will progress to complicated stricturing (B2) and penetrating (B3) CD during their lifetimes. The aim of our study was to identify the genetic factors associated with time to progression from uncomplicated to complicated CD. Patients with an inflammatory phenotype at diagnosis were followed up for 10 years. Genotyping was carried out using Illumina ImmunoChip. After quality control, association analyses, Bonferroni's adjustments, linear and Cox's regression, and Kaplan-Meier analysis were carried out for 111 patients and Manhattan plots were constructed. Ten years after diagnosis, 39.1% of the patients still had the inflammatory form and 60.9% progressed to complicated disease, with an average time to progression of 5.91 years. Ileal and ileocolonic locations were associated with the complicated CD (P=1.08E-03). We found that patients with the AA genotype at single-nucleotide polymorphism rs16857259 near the gene CACNA1E progressed to the complicated form later (8.80 years) compared with patients with the AC (5.11 years) or CC (2.00 years) genotypes (P=3.82E-07). In addition, nine single-nucleotide polymorphisms (near the genes RASGRP1, SULF2, XPO1, ZBTB44, HLA DOA/BRD2, HLA DRB1/HLA DQA1, PPARA, PUDP, and KIAA1614) showed a suggestive association with disease progression (P<10). Multivariate Cox's regression analysis on the basis of clinical and genetic data confirmed the association of the selected model with disease progression (P=5.73E-16). Our study confirmed the association between the locus on chromosome 1 near the gene CACNA1E with time to progression from inflammatory to stricturing or penetrating CD. Predicting the time to progression is useful to the clinician in terms of individualizing patients' management.

FOXA1 promotes tumor progression in prostate cancer and represents a novel hallmark of castration-resistant prostate cancer.

PubMed

Gerhardt, Josefine; Montani, Matteo; Wild, Peter; Beer, Marc; Huber, Fabian; Hermanns, Thomas; Müntener, Michael; Kristiansen, Glen

2012-02-01

Forkhead box protein A1 (FOXA1) modulates the transactivation of steroid hormone receptors and thus may influence tumor growth and hormone responsiveness in prostate cancer. We therefore investigated the correlation of FOXA1 expression with clinical parameters, prostate-specific antigen (PSA) relapse-free survival, and hormone receptor expression in a large cohort of prostate cancer patients at different disease stages. FOXA1 expression did not differ significantly between benign glands from the peripheral zone and primary peripheral zone prostate carcinomas. However, FOXA1 was overexpressed in metastases and particularly in castration-resistant cases, but was expressed at lower levels in both normal and neoplastic transitional zone tissues. FOXA1 levels correlated with higher pT stages and Gleason scores, as well as with androgen (AR) and estrogen receptor expression. Moreover, FOXA1 overexpression was associated with faster biochemical disease progression, which was pronounced in patients with low AR levels. Finally, siRNA-based knockdown of FOXA1 induced decreased cell proliferation and migration. Moreover, in vitro tumorigenicity was inducible by ARs only in the presence of FOXA1, substantiating a functional cooperation between FOXA1 and AR. In conclusion, FOXA1 expression is associated with tumor progression, dedifferentiation of prostate cancer cells, and poorer prognosis, as well as with cellular proliferation and migration and with AR signaling. These findings suggest FOXA1 overexpression as a novel mechanism inducing castration resistance in prostate cancer. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Mathematical modelling as a proof of concept for MPNs as a human inflammation model for cancer development.

PubMed

Andersen, Morten; Sajid, Zamra; Pedersen, Rasmus K; Gudmand-Hoeyer, Johanne; Ellervik, Christina; Skov, Vibe; Kjær, Lasse; Pallisgaard, Niels; Kruse, Torben A; Thomassen, Mads; Troelsen, Jesper; Hasselbalch, Hans Carl; Ottesen, Johnny T

2017-01-01

The chronic Philadelphia-negative myeloproliferative neoplasms (MPNs) are acquired stem cell neoplasms which ultimately may transform to acute myelogenous leukemia. Most recently, chronic inflammation has been described as an important factor for the development and progression of MPNs in the biological continuum from early cancer stage to the advanced myelofibrosis stage, the MPNs being described as "A Human Inflammation Model for Cancer Development". This novel concept has been built upon clinical, experimental, genomic, immunological and not least epidemiological studies. Only a few studies have described the development of MPNs by mathematical models, and none have addressed the role of inflammation for clonal evolution and disease progression. Herein, we aim at using mathematical modelling to substantiate the concept of chronic inflammation as an important trigger and driver of MPNs.The basics of the model describe the proliferation from stem cells to mature cells including mutations of healthy stem cells to become malignant stem cells. We include a simple inflammatory coupling coping with cell death and affecting the basic model beneath. First, we describe the system without feedbacks or regulatory interactions. Next, we introduce inflammatory feedback into the system. Finally, we include other feedbacks and regulatory interactions forming the inflammatory-MPN model. Using mathematical modeling, we add further proof to the concept that chronic inflammation may be both a trigger of clonal evolution and an important driving force for MPN disease progression. Our findings support intervention at the earliest stage of cancer development to target the malignant clone and dampen concomitant inflammation.

Voice- and swallow-related quality of life in idiopathic Parkinson's disease.

PubMed

van Hooren, Michel R A; Baijens, Laura W J; Vos, Rein; Pilz, Walmari; Kuijpers, Laura M F; Kremer, Bernd; Michou, Emilia

2016-02-01

This study explores whether changes in voice- and swallow-related QoL are associated with progression of idiopathic Parkinson's disease (IPD). Furthermore, it examines the relationship between patients' perception of both voice and swallowing disorders in IPD. Prospective clinical study, quality of life (QoL). One-hundred mentally competent IPD patients with voice and swallowing complaints were asked to answer four QoL questionnaires (Voice Handicap Index, MD Anderson Dysphagia Inventory, Visual Analog Scale [VAS] voice, and Dysphagia Severity Scale [DSS]). Differences in means for the QoL questionnaires and their subscales within Hoehn and Yahr stage groups were calculated using one-way analysis of variance. The relationship between voice- and swallow-related QoL questionnaires was determined with the Spearman correlation coefficient. Scores on both voice and swallow questionnaires suggest an overall decrease in QoL with progression of IPD. A plateau in QoL for VAS voice and the DSS was seen in the early Hoehn and Yahr stages. Finally, scores on voice-related QoL questionnaires were significantly correlated with swallow-related QoL outcomes. Voice- and swallow-related QoL decreases with progression of IPD. A significant association was found between voice- and swallow-related QoL questionnaires. Healthcare professionals can benefit from voice- and swallow-related QoL questionnaires in a multidimensional voice- or swallow-assessment protocol. The patient's perception of his/her voice and swallowing disorders and its impact on QoL in IPD should not be disregarded. 2b. © 2015 The American Laryngological, Rhinological and Otological Society, Inc.

Gene expression profiling of anti-GBM glomerulonephritis model: the role of NF-kappaB in immune complex kidney disease.

PubMed

Kim, Ju Han; Ha, Il Soo; Hwang, Chang-Il; Lee, Young-Ju; Kim, Jihoon; Yang, Seung-Hee; Kim, Yon Su; Cao, Yun Anna; Choi, Sangdun; Park, Woong-Yang

2004-11-01

Immune complexes may cause an irreversible onset of chronic renal disease. Most patients with chronic renal disease undergo a final common pathway, marked by glomerulosclerosis and interstitial fibrosis. We attempted to draw a molecular map of anti-glomerular basement membrane (GBM) glomerulonephritis in mice using oligonucleotide microarray technology. Kidneys were harvested at days 1, 3, 7, 11, and 16 after inducing glomerulonephritis by using anti-GBM antibody. In parallel with examining the biochemical and histologic changes, gene expression profiles were acquired against five pooled control kidneys. Gene expression levels were cross-validated by either reverse transcription-polymerase chain reaction (RT-PCR), real-time PCR, or immunohistochemistry. Pathologic changes in anti-GBM glomerulonephritis were confirmed in both BALB/c and C57BL/6 strains. Among the 13,680 spotted 65mer oligonucleotides, 1112 genes showing significant temporal patterns by permutation analysis of variance (ANOVA) with multiple testing correction [false discovery ratio (FDR) < 0.05] were chosen for cluster analysis. From the expression profile, acute inflammatory reactions characterized by the elevation of various cytokines, including interleukin (IL)-1 and IL-6, were identified within 3 days of disease onset. After 7 days, tissue remodeling response was prominent with highly induced extracellular-matrix (ECM) genes. Although cytokines related to lymphocyte activation were not detected, monocyte or mesangial cell proliferation-related genes were increased. Tumor necrosis factor-alpha (TNF-alpha) and nuclear factor-kappaB (NF-kappaB) pathway were consistently activated along the entire disease progression, inducing various target genes like complement 3, IL-1b, IL-6, Traf1, and Saa1. We made a large-scale gene expression time table for mouse anti-GBM glomerulonephritis model, providing a comprehensive overview on the mechanism governing the initiation and the progression of inflammatory renal disease.

Epithelioid sarcoma of the penis: a case report.

PubMed

Colombo, Fulvio; Franceschelli, Alessandro; Schiavina, Riccardo; Gentile, Giorgio; Passaretti, Giovanni; Martorana, Giuseppe

2013-11-01

Epithelioid sarcoma of the penis is a slowly growing soft tissue neoplasm that rarely arises from the penis. The aim of this case is to describe this rare pathology and to underline the importance of differential diagnosis with benign diseases such as Peyronie's disease. We report the case of a 20-year-old man who referred the onset of a progressive left dorsolateral penile curvature (about 60°) started 3 years before. The patient was evaluated with two US examinations that revealed two sites of tunical thickening with normal hemodynamic evaluation. The physical examination demonstrated a dorsal fibrotic plaque of about 2.5 cm. A juvenile form of Peyronie's Disease was diagnosed, and the patient was scheduled for surgical treatment (plaque's incision/excision and grafting). Intraoperative appearance showed that the great part of the left cavernous body was substituted by a very tough tissue which deeply involved the erectile tissue; intraoperative frozen section was suspicious for mesenchymal epithelioid neoplasm. In order to obtain definitive histological analysis and collect proper informed consent, we preferred to proceed with our original project, applying a dual graft (buccal mucosa and allograft dermal matrix) to cover the wide excised area. The final histological report confirmed the diagnosis of epithelioid sarcoma. Postoperative CT and MRI, at 3 and 6 months from surgery, were negative for metastases. The patient underwent radical intervention after 6 months. Epithelioid sarcoma of the penis and Peyronie's Disease can present with similar clinical findings although they obviously entail a different clinical progress. Since the diagnosis of neoplasm can be established only by the pathologist on biopsy specimen, in cases of unusual clinical presentation of Peyronie's disease (especially in young men suffering from a fast-growing penile induration), an early histological assessment should be performed to avoid the possibility of misdiagnosis in case of this poor-prognosis disease and to assure the definitive diagnosis. © 2012 International Society for Sexual Medicine.

[The control of vectorial transmission].

PubMed

Silveira, Antônio Carlos; Dias, João Carlos Pinto

2011-01-01

Between 1950 and 1951, the first Prophylactic campaign against Chagas Diseases was carried on in Brazil by the so existing Serviço Nacional de Malária. The actions involving chemical vector control comprehended 74 municipalities along the Rio Grande Valley, between the States of São Paulo and Minas Gerais. Ever since, until 1975, the activities were performed according the availability of resources, being executed with more or less regularity and coverage. At that time, Chagas disease did no represent priority, in comparison with other endemic diseases prevalent in the Country. Even so, taking into account the accumulated data along those 25 years, the volume of work realized cannot be considered despicable. Nevertheless, it was few consistent, in terms of its impact on disease transmission. In 1975, with an additional injection of resources surpassed from the malaria program, plus the methodological systematization of the activities, and with the results of two extensive national inquiries (entomologic and serologic), the activities for vector control could be performed regularly, following two basic principles: interventions in always contiguous areas, progressively enlarged, and sustainability (continuity) of the activities, until being attained determined requirements and purpose previously established. Such actions and strategies lead into the exhaustion of the populations of the principal vector species, Triatoma infestans, no autochthonous and exclusively domiciliary, as well as the control of the domiciliary colonization of autochthonous species important to disease transmission. Vector transmission today is being considered residual, by means of some few native and peridomestic species, such as Triatoma brasiliensis and Triatoma pseudomaculata. There is, also, the risk of progressive domiciliation of some species before considered sylvatic, such as Panstrongylus lutzi and Triatoma rubrovaria. Finally, there is the possibility of the occurrence of cases of human infection directly related to the enzootic cycle of the parasite. By all these reasons, it is still indispensable the maintenance of a strict epidemiological surveillance against Chagas Disease in Brazil.

Improved survival with vemurafenib in melanoma with BRAF V600E mutation.

PubMed

Chapman, Paul B; Hauschild, Axel; Robert, Caroline; Haanen, John B; Ascierto, Paolo; Larkin, James; Dummer, Reinhard; Garbe, Claus; Testori, Alessandro; Maio, Michele; Hogg, David; Lorigan, Paul; Lebbe, Celeste; Jouary, Thomas; Schadendorf, Dirk; Ribas, Antoni; O'Day, Steven J; Sosman, Jeffrey A; Kirkwood, John M; Eggermont, Alexander M M; Dreno, Brigitte; Nolop, Keith; Li, Jiang; Nelson, Betty; Hou, Jeannie; Lee, Richard J; Flaherty, Keith T; McArthur, Grant A

2011-06-30

Phase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have shown response rates of more than 50% in patients with metastatic melanoma with the BRAF V600E mutation. We conducted a phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation. Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg per square meter of body-surface area intravenously every 3 weeks). Coprimary end points were rates of overall and progression-free survival. Secondary end points included the response rate, response duration, and safety. A final analysis was planned after 196 deaths and an interim analysis after 98 deaths. At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects. Vemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann-La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.).

Serial in-office laser treatment of vocal fold leukoplakia: Disease control and voice outcomes.

PubMed

Koss, Shira L; Baxter, Peter; Panossian, Haig; Woo, Peak; Pitman, Michael J

2017-07-01

Although vocal fold (VF) leukoplakia is commonly treated with in-office laser, there is no data on its long-term effectiveness. This study hypothesizes that VF leukoplakia treated by serial in-office laser results in long-term disease control with maintenance of voice and minimal morbidity. Retrospective review (2008-2015). Forty-six patients with VF leukoplakia treated by in-office KTP (potassium titanyl phosphate) or PDL (pulsed dye laser) were included. Median follow-up from final laser treatment was 19.6 months. Main outcomes included: 1) rate of disease control, 2) percentage of disease regression using ImageJ analysis. Secondary outcomes included vocal assessment using the Voice Handicap Index-10 (VHI-10). Patients underwent a median of 2 (range: 1-6) in-office laser treatments. Time between treatments was median 7.6 months. After final treatment, 19 patients (41.3%) had no disease; two patients (4.3%) progressed to invasive cancer; overall disease regression was median 77.1% (P < 0.001); and VHI-10 score decreased by median 5 (P = 0.037). Thirty-one patients (67.4%) were responders (controlled with in-office treatment only); failures were 13 patients (28.3%) who required operative intervention and two patients (4%) who underwent radiation. Compared to responders, failures demonstrated significantly shorter duration between treatments (median 2.3 vs. 8.9 months, P = 0.038) and significantly less regression (median 49.3% vs. 100%, P = 0.006). Serial outpatient KTP or PDL treatment of VF leukoplakia is effective for disease control with minimal morbidity and preservation of voice quality. We suggest that patients requiring repeated in-office treatment every 6 months may benefit from earlier operative intervention; other factors associated with in-office success remain unclear. 4. Laryngoscope, 127:1644-1651, 2017. © 2017 The American Laryngological, Rhinological and Otological Society, Inc.

Copper and Zinc Homeostasis: Lessons from Drosophila melanogaster

PubMed Central

Navarro, Juan A.; Schneuwly, Stephan

2017-01-01

Maintenance of metal homeostasis is crucial for many different enzymatic activities and in turn for cell function and survival. In addition, cells display detoxification and protective mechanisms against toxic accumulation of metals. Perturbation of any of these processes normally leads to cellular dysfunction and finally to cell death. In the last years, loss of metal regulation has been described as a common pathological feature in many human neurodegenerative diseases. However, in most cases, it is still a matter of debate whether such dyshomeostasis is a primary or a secondary downstream defect. In this review, we will summarize and critically evaluate the contribution of Drosophila to model human diseases that involve altered metabolism of metals or in which metal dyshomeostasis influence their pathobiology. As a prerequisite to use Drosophila as a model, we will recapitulate and describe the main features of core genes involved in copper and zinc metabolism that are conserved between mammals and flies. Drosophila presents some unique strengths to be at the forefront of neurobiological studies. The number of genetic tools, the possibility to easily test genetic interactions in vivo and the feasibility to perform unbiased genetic and pharmacological screens are some of the most prominent advantages of the fruitfly. In this work, we will pay special attention to the most important results reported in fly models to unveil the role of copper and zinc in cellular degeneration and their influence in the development and progression of human neurodegenerative pathologies such as Parkinson's disease, Alzheimer's disease, Huntington's disease, Friedreich's Ataxia or Menkes, and Wilson's diseases. Finally, we show how these studies performed in the fly have allowed to give further insight into the influence of copper and zinc in the molecular and cellular causes and consequences underlying these diseases as well as the discovery of new therapeutic strategies, which had not yet been described in other model systems. PMID:29312444

Toward Development of a Fibromyalgia Responder Index and Disease Activity Score: OMERACT Module Update

PubMed Central

Mease, PJ; Clauw, DJ; Christensen, R; Crofford, L; Gendreau, M; Martin, SA; Simon, L; Strand, V; Williams, DA; Arnold, LM

2012-01-01

Following development of the core domain set for fibromyalgia (FM) in OMERACT 7–9, the FM working group has progressed toward the development of an FM responder index and a disease activity score based on these domains, utilizing outcome indices of these domains from archived randomized clinical trials (RCTs) in FM. Possible clinical domains that could be included in a responder index and disease activity score include: pain, fatigue, sleep disturbance, cognitive dysfunction, mood disturbance, tenderness, stiffness, and functional impairment. Outcome measures for these domains demonstrate good to adequate psychometric properties, although measures of cognitive dysfunction need to be further developed. The approach used in the development of responder indices and disease activity scores for rheumatoid arthritis and ankylosing spondylitis represent heuristic models for our work, but FM is challenging in that there is no clear algorithm of treatment that defines disease activity based on treatment decisions, nor are there objective markers that define thresholds of severity or response to treatment. The process of developing candidate dichotomous responder definitions and continuous quantitative disease activity measures is described, as is participant discussion that transpired at OMERACT 10. Final results of this work will be published in a separate manuscript pending completion of analyses. PMID:21724721

Effect of environmental air pollution on cardiovascular diseases.

PubMed

Meo, S A; Suraya, F

2015-12-01

Environmental air pollution has become a leading health concern especially in the developing countries with more urbanization, industrialization and rapidly growing population. Prolonged exposure to air pollution is a risk factor for cardiovascular diseases. The present study aimed to investigate the effects of environmental air pollution on progression of cardiovascular problems. In this study, we identified 6880 published articles through a systematic database including ISI-Web of Science, PubMed and EMBASE. The allied literature was searched by using the key words such as environmental pollution, air pollution, particulate matter pollutants PM 2.5 μm-PM 10 μm. Literature in which environmental air pollution and cardiac diseases were discussed was included. Descriptive information was retrieved from the selected literature. Finally, we included 67 publications and remaining studies were excluded. Environmental pollution can cause high blood pressure, arrhythmias, enhanced coagulation, thrombosis, acute arterial vasoconstriction, atherosclerosis, ischemic heart diseases, myocardial infarction and even heart failure. Environmental air pollution is associated with increased risk of cardiovascular diseases. Environmental pollution exerts its detrimental effects on the heart by developing pulmonary inflammation, systemic inflammation, oxidative stress, endothelial dysfunction and prothrombotic changes. Environmental protection officials must take high priority steps to minimize the air pollution to decrease the prevalence of cardiovascular diseases.

Diabetes mellitus and tuberculosis: programmatic management issues

PubMed Central

Kumar, A. M. V.; Satyanarayana, S.; Lin, Y.; Zachariah, R.; Lönnroth, K.; Kapur, A.

2015-01-01

SUMMARY In August 2011, the World Health Organization and the International Union Against Tuberculosis and Lung Disease launched the Collaborative Framework for Care and Control of Tuberculosis (TB) and diabetes mellitus (DM) to guide policy makers and implementers in combatting the epidemics of both diseases. Progress has been made, and includes identifying how best to undertake bidirectional screening for both diseases, how to provide optimal treatment and care for patients with dual disease and the most suitable framework for monitoring and evaluation. Key programmatic challenges include the following: whether screening should be directed at all patients or targeted at those with high-risk characteristics; the most suitable technologies for diagnosing TB and diabetes in routine settings; the best time to screen TB patients for DM; how to provide an integrated, coordinated approach to case management; and finally, how to persuade non-communicable disease programmes to adopt a cohort analysis approach, preferably using electronic medical records, for monitoring and evaluation. The link between DM and TB and the implementation of the collaborative framework for care and control have the potential to stimulate and strengthen the scale-up of non-communicable disease care and prevention programmes, which may help in reducing not only the global burden of DM but also the global burden of TB. PMID:26162352

Sudden oak death disease progression in oaks and tanoaks

Treesearch

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...

Renal outcomes of agalsidase beta treatment for Fabry disease: role of proteinuria and timing of treatment initiation

PubMed Central

Ortiz, Alberto; Mauer, Michael; Linthorst, Gabor E.; Oliveira, João P.; Serra, Andreas L.; Maródi, László; Mignani, Renzo; Vujkovac, Bojan; Beitner-Johnson, Dana; Lemay, Roberta; Cole, J.Alexander; Svarstad, Einar; Waldek, Stephen; Germain, Dominique P.; Wanner, Christoph

2012-01-01

Background. The purpose of this study was to identify determinants of renal disease progression in adults with Fabry disease during treatment with agalsidase beta. Methods. Renal function was evaluated in 151 men and 62 women from the Fabry Registry who received agalsidase beta at an average dose of 1 mg/kg/2 weeks for at least 2 years. Patients were categorized into quartiles based on slopes of estimated glomerular filtration rate (eGFR) during treatment. Multivariate logistic regression analyses were used to identify factors associated with renal disease progression. Results. Men within the first quartile had a mean eGFR slope of –0.1 mL/min/1.73m2/year, whereas men with the most rapid renal disease progression (Quartile 4) had a mean eGFR slope of –6.7 mL/min/1.73m2/year. The risk factor most strongly associated with renal disease progression was averaged urinary protein:creatinine ratio (UP/Cr) ≥1 g/g (odds ratio 112, 95% confidence interval (95% CI) 4–3109, P = 0.0054). Longer time from symptom onset to treatment was also associated with renal disease progression (odds ratio 19, 95% CI 2–184, P = 0.0098). Women in Quartile 4 had the highest averaged UP/Cr (mean 1.8 g/g) and the most rapid renal disease progression: (mean slope –4.4 mL/min/1.73m2/year). Conclusions. Adults with Fabry disease are at risk for progressive loss of eGFR despite enzyme replacement therapy, particularly if proteinuria is ≥1 g/g. Men with little urinary protein excretion and those who began receiving agalsidase beta sooner after the onset of symptoms had stable renal function. These findings suggest that early intervention may lead to optimal renal outcomes. PMID:21804088

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

PubMed Central

2014-01-01

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

Differentially Coexpressed Disease Gene Identification Based on Gene Coexpression Network.

PubMed

Jiang, Xue; Zhang, Han; Quan, Xiongwen

2016-01-01

Screening disease-related genes by analyzing gene expression data has become a popular theme. Traditional disease-related gene selection methods always focus on identifying differentially expressed gene between case samples and a control group. These traditional methods may not fully consider the changes of interactions between genes at different cell states and the dynamic processes of gene expression levels during the disease progression. However, in order to understand the mechanism of disease, it is important to explore the dynamic changes of interactions between genes in biological networks at different cell states. In this study, we designed a novel framework to identify disease-related genes and developed a differentially coexpressed disease-related gene identification method based on gene coexpression network (DCGN) to screen differentially coexpressed genes. We firstly constructed phase-specific gene coexpression network using time-series gene expression data and defined the conception of differential coexpression of genes in coexpression network. Then, we designed two metrics to measure the value of gene differential coexpression according to the change of local topological structures between different phase-specific networks. Finally, we conducted meta-analysis of gene differential coexpression based on the rank-product method. Experimental results demonstrated the feasibility and effectiveness of DCGN and the superior performance of DCGN over other popular disease-related gene selection methods through real-world gene expression data sets.

Determining causal miRNAs and their signaling cascade in diseases using an influence diffusion model.

PubMed

Nalluri, Joseph J; Rana, Pratip; Barh, Debmalya; Azevedo, Vasco; Dinh, Thang N; Vladimirov, Vladimir; Ghosh, Preetam

2017-08-15

In recent studies, miRNAs have been found to be extremely influential in many of the essential biological processes. They exhibit a self-regulatory mechanism through which they act as positive/negative regulators of expression of genes and other miRNAs. This has direct implications in the regulation of various pathophysiological conditions, signaling pathways and different types of cancers. Studying miRNA-disease associations has been an extensive area of research; however deciphering miRNA-miRNA network regulatory patterns in several diseases remains a challenge. In this study, we use information diffusion theory to quantify the influence diffusion in a miRNA-miRNA regulation network across multiple disease categories. Our proposed methodology determines the critical disease specific miRNAs which play a causal role in their signaling cascade and hence may regulate disease progression. We extensively validate our framework using existing computational tools from the literature. Furthermore, we implement our framework on a comprehensive miRNA expression data set for alcohol dependence and identify the causal miRNAs for alcohol-dependency in patients which were validated by the phase-shift in their expression scores towards the early stages of the disease. Finally, our computational framework for identifying causal miRNAs implicated in diseases is available as a free online tool for the greater scientific community.

Allele-Specific Methylation Occurs at Genetic Variants Associated with Complex Disease

PubMed Central

Hutchinson, John N.; Raj, Towfique; Fagerness, Jes; Stahl, Eli; Viloria, Fernando T.; Gimelbrant, Alexander; Seddon, Johanna; Daly, Mark; Chess, Andrew; Plenge, Robert

2014-01-01

We hypothesize that the phenomenon of allele-specific methylation (ASM) may underlie the phenotypic effects of multiple variants identified by Genome-Wide Association studies (GWAS). We evaluate ASM in a human population and document its genome-wide patterns in an initial screen at up to 380,678 sites within the genome, or up to 5% of the total genomic CpGs. We show that while substantial inter-individual variation exists, 5% of assessed sites show evidence of ASM in at least six samples; the majority of these events (81%) are under genetic influence. Many of these cis-regulated ASM variants are also eQTLs in peripheral blood mononuclear cells and monocytes and/or in high linkage-disequilibrium with variants linked to complex disease. Finally, focusing on autoimmune phenotypes, we extend this initial screen to confirm the association of cis-regulated ASM with multiple complex disease-associated variants in an independent population using next-generation bisulfite sequencing. These four variants are implicated in complex phenotypes such as ulcerative colitis and AIDS progression disease (rs10491434), Celiac disease (rs2762051), Crohn's disease, IgA nephropathy and early-onset inflammatory bowel disease (rs713875) and height (rs6569648). Our results suggest cis-regulated ASM may provide a mechanistic link between the non-coding genetic changes and phenotypic variation observed in these diseases and further suggests a route to integrating DNA methylation status with GWAS results. PMID:24911414

Urine peptidome analysis predicts risk of end-stage renal disease and reveals proteolytic pathways involved in autosomal dominant polycystic kidney disease progression.

PubMed

Pejchinovski, Martin; Siwy, Justyna; Metzger, Jochen; Dakna, Mohammed; Mischak, Harald; Klein, Julie; Jankowski, Vera; Bae, Kyongtae T; Chapman, Arlene B; Kistler, Andreas D

2017-03-01

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by slowly progressive bilateral renal cyst growth ultimately resulting in loss of kidney function and end-stage renal disease (ESRD). Disease progression rate and age at ESRD are highly variable. Therapeutic interventions therefore require early risk stratification of patients and monitoring of disease progression in response to treatment. We used a urine peptidomic approach based on capillary electrophoresis-mass-spectrometry (CE-MS) to identify potential biomarkers reflecting the risk for early progression to ESRD in the Consortium of Radiologic Imaging in Polycystic Kidney Disease (CRISP) cohort. A biomarker-based classifier consisting of 20 urinary peptides allowed the prediction of ESRD within 10-13 years of follow-up in patients 24-46 years of age at baseline. The performance of the biomarker score approached that of height-adjusted total kidney volume (htTKV) and the combination of the biomarker panel with htTKV improved prediction over either one alone. In young patients (<24 years at baseline), the same biomarker model predicted a 30 mL/min/1.73 m 2 glomerular filtration rate decline over 8 years. Sequence analysis of the altered urinary peptides and the prediction of the involved proteases by in silico analysis revealed alterations in distinct proteolytic pathways, in particular matrix metalloproteinases and cathepsins. We developed a urinary test that accurately predicts relevant clinical outcomes in ADPKD patients and suggests altered proteolytic pathways involved in disease progression. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Growth, progression and chromosome instability of Neuroblastoma: a new scenario of tumorigenesis?

PubMed

Tonini, Gian Paolo

2017-01-05

Neuroblastoma is a pediatric cancer with a low survival rate of patients with metastatic stage 4 disease. Tumor aggressiveness and progression have been associated with structural copy number variations (CNVs) that are observed in malignant cells. In contrast, localized Neuroblastomas, which are associated with a low number of structural CNVs but frequent numerical CNVs, are less aggressive, and patients have good outcomes. Finally, whole-genome and whole-exome sequencing of Neuroblastoma tissues have shown few damaging mutations in these tumors. In the present report it is proposed that chromosome instability (CIN) plays a major role in Neuroblastoma tumorigenesis and that CIN is already present in the early phases of tumor development. High CIN can promote several types of chromosomal damage including chromothripsis, gene deletion, amplification and rearrangements, which deregulate gene expression. Indeed, gene rearrangements have been reported as a new scenario in the development of Neuroblastoma, which supports the hypothesis that CIN is an early step preliminary to the late catastrophic events leading to tumor development.

Targeting inflammation in pancreatic cancer: Clinical translation

PubMed Central

Steele, Colin William; Kaur Gill, Nina Angharad; Jamieson, Nigel Balfour; Carter, Christopher Ross

2016-01-01

Preclinical modelling studies are beginning to aid development of therapies targeted against key regulators of pancreatic cancer progression. Pancreatic cancer is an aggressive, stromally-rich tumor, from which few people survive. Within the tumor microenvironment cellular and extracellular components exist, shielding tumor cells from immune cell clearance, and chemotherapy, enhancing progression of the disease. The cellular component of this microenvironment consists mainly of stellate cells and inflammatory cells. New findings suggest that manipulation of the cellular component of the tumor microenvironment is possible to promote immune cell killing of tumor cells. Here we explore possible immunogenic therapeutic strategies. Additionally extracellular stromal elements play a key role in protecting tumor cells from chemotherapies targeted at the pancreas. We describe the experimental findings and the pitfalls associated with translation of stromally targeted therapies to clinical trial. Finally, we discuss the key inflammatory signal transducers activated subsequent to driver mutations in oncogenic Kras in pancreatic cancer. We present the preclinical findings that have led to successful early trials of STAT3 inhibitors in pancreatic adenocarcinoma. PMID:27096033

Does an NKT-cell-based immunotherapeutic approach have a future in multiple myeloma?

PubMed Central

Favreau, Mérédis; Vanderkerken, Karin

2016-01-01

Natural killer T (NKT) cells constitute a unique subset of innate-like T lymphocytes which differ from conventional T cells by recognizing lipid antigens presented by the non-polymorphic major histocompatibility complex (MHC) I-like molecule CD1d. Despite being a relatively infrequent population of lymphocytes, NKT cells can respond rapidly upon activation with glycosphingolipids by production of cytokines which aim to polarize different axes of the immune system. Due to their dual effector capacities, NKT cells can play a vital role in cancer immunity, infection, inflammation and autoimmune diseases. It is believed that modulation of their activity towards immune activation can be a useful tool in anti-tumor immunotherapeutic strategies. Here we summarize the characteristics of NKT cells and discuss their involvement in immunosurveillance. Furthermore, an update is given about their role and the progress that has been made in the field of multiple myeloma (MM). Finally, some challenges are discussed that are currently hampering further progress. PMID:26895468

Check-up and cardiovascular risk progression: is there a room for innovation?

PubMed Central

Conceição, Raquel Dilguerian de Oliveira; Laurinavicius, Antonio Gabriele; Kashiwagi, Nea Miwa; de Carvalho, José Antonio Maluf; Oliva, Carlos Alberto Garcia; Santos, Raul Dias

2015-01-01

ABSTRACT Objective: To evaluate the impact of traditional check-up appointment on the progression of the cardiovascular risk throughout time. Methods: This retrospective cohort study included 11,126 medical records of asymptomatic executives who were evaluated between January, 2005 and October, 2008. Variables included participants’ demographics characteristics, smoking habit, history of cardiovascular diseases, diabetes, dyslipidemia, total cholesterol, HDL, triglycerides, glucose, c-reactive protein, waist circumference, hepatic steatosis, Framingham score, metabolic syndrome, level of physical activity, stress, alcohol consumption, and body mass index. Results: A total of 3,150 patients was included in the final analysis. A worsening was observed in all risk factors, excepting in smoking habit, incidence of myocardial infarction or stroke and in the number of individuals classified as medium or high risk for cardiovascular events. In addition, a decrease in stress level and alcohol consumption was also seen. Conclusion: The adoption of consistent health policies by companies is imperative in order to reduce the risk factors and the future costs associated with illness and absenteeism. PMID:26154540

Online support and education for dementia caregivers: overview, utilization, and initial program evaluation.

PubMed

Glueckauf, Robert L; Ketterson, Timothy U; Loomis, Jeffrey S; Dages, Pat

2004-01-01

Family caregivers of older adults with progressive dementia (e.g., Alzheimer's disease) are confronted with a variety of challenges in providing assistance to their loved ones, such as dealing with persistent, repetitive questions, managing episodes of agitation and aggressive responding, as well as monitoring hygiene and self-care activities. Although professional and governmental organizations have called for the creation of community-based education and support programs, a significant proportion of dementia caregivers in the United States continue to receive little or no formal instruction in responding effectively to these anxiety-provoking situations. This paper describes the development and implementation of Alzheimer's Caregiver Support Online (also known as AlzOnline), an Internet- and telephone-based education and support network for caregivers of individuals with progressive dementia. An outcome analysis of a Robert Wood Johnson Foundation-funded strategic marketing initiative to promote the use of AlzOnline is reviewed, followed by a presentation of the findings of an initial program evaluation. Finally, future directions for online caregiver evaluation research are proposed.

Human Herpesviruses as Copathogens of HIV Infection, Their Role in HIV Transmission, and Disease Progression

PubMed Central

Munawwar, Arshi; Singh, Sarman

2016-01-01

Of eight human herpesviruses (HHVs), often, only herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) find mention in medical literature as both of these viruses are commonly associated with genital lesions and oral ulcers, commonly known as cold sores. However, role of human herpesviruses as copathogens and in aggravation and in the transmission of other human diseases, especially the Acquired immunodeficiency syndrome (HIV/AIDS) has only very recently been recognized. Therefore, screening and treating subclinical HHV infections may offer slowing of HIV infection, disease progression, and its transmission. Beside HSV-1 and HSV-2, HHV-3 a causative agent of herpes zoster remained one of the first manifestations of HIV disease before the era of highly active antiretroviral therapy (HAART). HHV-5 also known as human Cytomegalovirus infection remains a significant risk factor for HIV-associated mortality and morbidity even in HAART era. It is proposed that Cytomegalovirus viremia could be a better predictor of HIV disease progression than CD4+ T-lymphocyte count. The role of HHV-4 or Epstein–Burr virus and HHV-6, HHV-7, and HHV-8 is still being investigated in HIV disease progression. This review provides insight into the current understanding about these 8 HHVs, their co-pathogenesis, and role in HIV/AIDS disease progression. The review also covers recent literature in favor and against administering anti-HHV treatment along with HAART for slower AIDS progression and interrupted sexual transmission. PMID:27013807

PDON: Parkinson's disease ontology for representation and modeling of the Parkinson's disease knowledge domain.

PubMed

Younesi, Erfan; Malhotra, Ashutosh; Gündel, Michaela; Scordis, Phil; Kodamullil, Alpha Tom; Page, Matt; Müller, Bernd; Springstubbe, Stephan; Wüllner, Ullrich; Scheller, Dieter; Hofmann-Apitius, Martin

2015-09-22

Despite the unprecedented and increasing amount of data, relatively little progress has been made in molecular characterization of mechanisms underlying Parkinson's disease. In the area of Parkinson's research, there is a pressing need to integrate various pieces of information into a meaningful context of presumed disease mechanism(s). Disease ontologies provide a novel means for organizing, integrating, and standardizing the knowledge domains specific to disease in a compact, formalized and computer-readable form and serve as a reference for knowledge exchange or systems modeling of disease mechanism. The Parkinson's disease ontology was built according to the life cycle of ontology building. Structural, functional, and expert evaluation of the ontology was performed to ensure the quality and usability of the ontology. A novelty metric has been introduced to measure the gain of new knowledge using the ontology. Finally, a cause-and-effect model was built around PINK1 and two gene expression studies from the Gene Expression Omnibus database were re-annotated to demonstrate the usability of the ontology. The Parkinson's disease ontology with a subclass-based taxonomic hierarchy covers the broad spectrum of major biomedical concepts from molecular to clinical features of the disease, and also reflects different views on disease features held by molecular biologists, clinicians and drug developers. The current version of the ontology contains 632 concepts, which are organized under nine views. The structural evaluation showed the balanced dispersion of concept classes throughout the ontology. The functional evaluation demonstrated that the ontology-driven literature search could gain novel knowledge not present in the reference Parkinson's knowledge map. The ontology was able to answer specific questions related to Parkinson's when evaluated by experts. Finally, the added value of the Parkinson's disease ontology is demonstrated by ontology-driven modeling of PINK1 and re-annotation of gene expression datasets relevant to Parkinson's disease. Parkinson's disease ontology delivers the knowledge domain of Parkinson's disease in a compact, computer-readable form, which can be further edited and enriched by the scientific community and also to be used to construct, represent and automatically extend Parkinson's-related computable models. A practical version of the Parkinson's disease ontology for browsing and editing can be publicly accessed at http://bioportal.bioontology.org/ontologies/PDON .

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

PubMed

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.

Knowledge-driven computational modeling in Alzheimer's disease research: Current state and future trends.

PubMed

Geerts, Hugo; Hofmann-Apitius, Martin; Anastasio, Thomas J

2017-11-01

Neurodegenerative diseases such as Alzheimer's disease (AD) follow a slowly progressing dysfunctional trajectory, with a large presymptomatic component and many comorbidities. Using preclinical models and large-scale omics studies ranging from genetics to imaging, a large number of processes that might be involved in AD pathology at different stages and levels have been identified. The sheer number of putative hypotheses makes it almost impossible to estimate their contribution to the clinical outcome and to develop a comprehensive view on the pathological processes driving the clinical phenotype. Traditionally, bioinformatics approaches have provided correlations and associations between processes and phenotypes. Focusing on causality, a new breed of advanced and more quantitative modeling approaches that use formalized domain expertise offer new opportunities to integrate these different modalities and outline possible paths toward new therapeutic interventions. This article reviews three different computational approaches and their possible complementarities. Process algebras, implemented using declarative programming languages such as Maude, facilitate simulation and analysis of complicated biological processes on a comprehensive but coarse-grained level. A model-driven Integration of Data and Knowledge, based on the OpenBEL platform and using reverse causative reasoning and network jump analysis, can generate mechanistic knowledge and a new, mechanism-based taxonomy of disease. Finally, Quantitative Systems Pharmacology is based on formalized implementation of domain expertise in a more fine-grained, mechanism-driven, quantitative, and predictive humanized computer model. We propose a strategy to combine the strengths of these individual approaches for developing powerful modeling methodologies that can provide actionable knowledge for rational development of preventive and therapeutic interventions. Development of these computational approaches is likely to be required for further progress in understanding and treating AD. Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Dry age-related macular degeneration: mechanisms, therapeutic targets, and imaging.

PubMed

Bowes Rickman, Catherine; Farsiu, Sina; Toth, Cynthia A; Klingeborn, Mikael

2013-12-13

Age-related macular degeneration is the leading cause of irreversible visual dysfunction in individuals over 65 in Western Society. Patients with AMD are classified as having early stage disease (early AMD), in which visual function is affected, or late AMD (generally characterized as either "wet" neovascular AMD, "dry" atrophic AMD or both), in which central vision is severely compromised or lost. Until recently, there have been no therapies available to treat the disorder(s). Now, the most common wet form of late-stage AMD, choroidal neovascularization, generally responds to treatment with anti-vascular endothelial growth factor therapies. Nevertheless, there are no current therapies to restore lost vision in eyes with advanced atrophic AMD. Oral supplementation with the Age-Related Eye Disease Study (AREDS) or AREDS2 formulation (antioxidant vitamins C and E, lutein, zeaxanthin, and zinc) has been shown to reduce the risk of progression to advanced AMD, although the impact was in neovascular rather than atrophic AMD. Recent findings, however, have demonstrated several features of early AMD that are likely to be druggable targets for treatment. Studies have established that much of the genetic risk for AMD is associated with complement genes. Consequently, several complement-based therapeutic treatment approaches are being pursued. Potential treatment strategies against AMD deposit formation and protein and/or lipid deposition will be discussed, including anti-amyloid therapies. In addition, the role of autophagy in AMD and prevention of oxidative stress through modulation of the antioxidant system will be explored. Finally, the success of these new therapies in clinical trials and beyond relies on early detection, disease typing, and predicting disease progression, areas that are currently being rapidly transformed by improving imaging modalities and functional assays.

Excess Mortality in Patients with Multiple Sclerosis Starts at 20 Years from Clinical Onset: Data from a Large-Scale French Observational Study

PubMed Central

Leray, Emmanuelle; Vukusic, Sandra; Debouverie, Marc; Clanet, Michel; Brochet, Bruno; de Sèze, Jérôme; Zéphir, Hélène; Defer, Gilles; Lebrun-Frenay, Christine; Moreau, Thibault; Clavelou, Pierre; Pelletier, Jean; Berger, Eric; Cabre, Philippe; Camdessanché, Jean-Philippe; Kalson-Ray, Shoshannah; Confavreux, Christian; Edan, Gilles

2015-01-01

Background Recent studies in multiple sclerosis (MS) showed longer survival times from clinical onset than older hospital-based series. However estimated median time ranges widely, from 24 to 45 years, which makes huge difference for patients as this neurological disease mainly starts around age 20 to 40. Precise and up-to-date reference data about mortality in MS are crucial for patients and neurologists, but unavailable yet in France. Objectives Estimate survival in MS patients and compare mortality with that of the French general population. Methods We conducted a multicenter observational study involving clinical longitudinal data from 30,413 eligible patients, linked to the national deaths register. Inclusion criteria were definite MS diagnosis and clinical onset prior to January, 1st 2009 in order to get a minimum of 1-year disease duration. Results After removing between-center duplicates and applying inclusion criteria, the final population comprised 27,603 MS patients (F/M sex ratio 2.5, mean age at onset 33.0 years, 85.5% relapsing onset). During the follow-up period (mean 15.2 +/- 10.3 years), 1569 deaths (5.7%) were identified; half related to MS. Death rates were significantly higher in men, patients with later clinical onset, and in progressive MS. Overall excess mortality compared with the general population was moderate (Standardized Mortality Ratio 1.48, 95% confidence interval [1.41-1.55]), but increased considerably after 20 years of disease (2.20 [2.10-2.31]). Conclusions This study revealed a moderate decrease in life expectancy in MS patients, and showed that the risk of dying is strongly correlated to disease duration and disability, highlighting the need for early actions that can slow disability progression. PMID:26148099

It's about time--directing our attention toward modifying the course of COPD.

PubMed

Cazzola, Mario; Hanania, Nicola A; Jones, Paul W; Mahler, Donald A; Make, Barry; Ohar, Jill; Rennard, Stephen

2008-06-01

The course of COPD has traditionally been equated with an accelerated decline in the forced expiratory volume in one second (FEVi) over time in patients with COPD, compared to healthy individuals. However, other important clinical outcomes associated with COPD also worsen over time and should also be considered in conceptualizing the course of COPD. These include health status, breathlessness related to activities of daily living, exercise capacity, the frequency of exacerbations, and peripheral muscle weakness. These outcomes are often quite responsive to therapy of COPD. Presently there is no evidence that any treatment other than smoking cessation can normalise the rate of decline of FEVi, and therefore be considered as modifying the physiologic course of the disease. Thus, smoking cessation reigns as the primary disease modifying strategy in COPD. Even though there are a number of smoking cessation products on the market and smoking prevalence continues to decrease marginally each year, more needs to be done to provide comprehensive programmes to help people quit smoking. In the US in 2004, 37.5% of preventable deaths were found to be tobacco-related. The FEVi does not reflect the clinical manifestations or the total burden of this multidimensional illness. As novel therapeutic agents become available that may alter the underlying pathology of COPD, additional markers and outcomes of disease progression will be needed to provide a more comprehensive assessment. There has been increasing interest in predicting and assessing mortality as it is the final outcome of disease progression. In this review we have considered three approaches toward modifying the course of COPD: smoking cessation, reduction in lung hyperinflation through medical and surgical approaches, and long-term pharmacotherapy.

Dopamine, 6-hydroxydopamine, iron, and dioxygen--their mutual interactions and possible implication in the development of Parkinson's disease.

PubMed

Linert, W; Herlinger, E; Jameson, R F; Kienzl, E; Jellinger, K; Youdim, M B

1996-08-23

The reactions of dopamine (1-amino-2-(3,4-dihydroxyphenyl)-ethane, DA), 5-hydroxydopamine (5-OHDA), and 6-hydroxydopamine (6-OHDA), with molecular oxygen-with and without the addition of catalytic amounts of iron(III) and other metal ions-have been studied and the implication of these results with respect to the chemistry involved in the progress of Parkinson's disease is discussed. In the presence of O2 DA reacts spontaneously without the necessity of metal-ion catalysis under the production of stoichiometric amounts of H2O2, to form initially pink dopaminochrome, which is not stable and reacts further (without the consumption of dioxygen) to form the insoluble polymeric material known as 'melanine'. DA reacts with iron(III) yielding an intermediate 1:1 complex, which decomposes releasing Fe(II) and the semiquinone, which reacts further under involvement of both Fe(III) and dioxygen. 6-OHDA reacts without showing the necessity of such an intermediate, and it is shown to be able to release iron as Fe(II) from ferritine. On the other hand, it is shown (in vitro) that Fe(II) reacts in a Fenton type reaction with DA and the present H2O2 producing 5-OHDA and especially 6-OHDA. Based on these mutual interacting reactions a mechanism for the initiation and progress of Parkinson's disease is suggested. The catalytic effects of some other transition-metal ions are presented and an explanation for the peculiarly toxic effects of manganese(II) is put forward. Finally, a possible reason for the effect that nicotine has in the mitigation of Parkinson's disease is discussed.

Oxidative stress drivers and modulators in obesity and cardiovascular disease: from biomarkers to therapeutic approach.

PubMed

Santilli, F; Guagnano, M T; Vazzana, N; La Barba, S; Davi, G

2015-01-01

This review article is intended to describe how oxidative stress regulates cardiovascular disease development and progression. Epigenetic mechanisms related to oxidative stress, as well as more reliable biomarkers of oxidative stress, are emerging over the last years as potentially useful tools to design therapeutic approaches aimed at modulating enhanced oxidative stress "in vivo", thereby mitigating the consequent atherosclerotic burden. As a paradigm, we describe the case of obesity, in which the intertwining among oxidative stress, due to caloric overload, chronic low-grade inflammation induced by adipose tissue dysfunction, and platelet activation represents a vicious cycle favoring the progression of atherothrombosis. Oxidative stress is a major player in the pathobiology of cardiovascular disease (CVD). Reactive oxygen species (ROS)- dependent signaling pathways prompt transcriptional and epigenetic dysregulation, inducing chronic low-grade inflammation, platelet activation and endothelial dysfunction. In addition, several oxidative biomarkers have been proposed with the potential to improve current understanding of the mechanisms underlying CVD. These include ROS-generating and/or quenching molecules, and ROS-modified compounds, such as F2-isoprostanes. There is also increasing evidence that noncoding micro- RNA (mi-RNA) are critically involved in post- transcriptional regulation of cell functions, including ROS generation, inflammation, regulation of cell proliferation, adipocyte differentiation, angiogenesis and apoptosis. These molecules have promising translational potential as both markers of disease and site of targeted interventions. Finally, oxidative stress is a critical target of several cardioprotective drugs and nutraceuticals, including antidiabetic agents, statins, renin-angiotensin system blockers, polyphenols and other antioxidants. Further understanding of ROS-generating mechanisms, their biological role as well as potential therapeutic implications would translate into consistent benefits for effective CV prevention.

[Is the introduction of clinical management programs for patients with chronic obstructive pulmonary disease useful? Comparison of the effectiveness of two interventions on the clinical progress and care received].

PubMed

Solanes, Ingrid; Bolíbar, Ignasi; Llauger, Maria Antònia; Peiro, Meritxell; Valverde, Pepi; Fraga, Mar; Medrano, Casimira; Bigorra, Teresa; Freixas, Montserrat; Ligüerre, Iskra; Pou, Maria Antònia; Domínguez, Leandra; Valero, Carles; Solà, Judit; Giner, Jordi; Plaza, Vicente

2018-03-01

To evaluate the effectiveness of two management programs on patients with chronic obstructive pulmonary disease (COPD). A study with a quasi-experimental design was used to evaluate the effectiveness of two interventions (I1, I2) for the care of patients with COPD after a mean follow-up of 31.2months. Primary Care Centres in two Barcelona Health Areas and their referral hospitals. Patients with COPD selected by simple random sampling using any disease code corresponding to COPD. I1: Integrated management program that was optimised and coordinated the resources. Training was given, as well as quality control of spirometry. I2: Isolated interventions like a call-centre. Care circuits and computerised clinical notes were shared. Variables were recorded as regards lung function, severity, use of inhalers, lifestyles, quality of life, and exacerbations. Of the 393 patients evaluated at the beginning, 120 and 104 (I1 and I2, respectively) received the final evaluation. With I1, there was a reduction in patients who smoked (P=.034). Lung function and quality of life did not change significantly in either group, but shortness of breath was slightly worse. There was an increase in the correct use of inhalers, although it only reached 48% and 61% with interventions I1 and I2, respectively. The percentage of patients with exacerbations decreased with I1 compared to that of I2 (P<.001), and there were less hospital admissions due to exacerbations with I2 compared to I1 (P<.003]). Both interventions achieved significant improvements, and no overall worsening of a chronic and progressive disease as is COPD. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

Dry Age-Related Macular Degeneration: Mechanisms, Therapeutic Targets, and Imaging

PubMed Central

Bowes Rickman, Catherine; Farsiu, Sina; Toth, Cynthia A.; Klingeborn, Mikael

2013-01-01

Age-related macular degeneration is the leading cause of irreversible visual dysfunction in individuals over 65 in Western Society. Patients with AMD are classified as having early stage disease (early AMD), in which visual function is affected, or late AMD (generally characterized as either “wet” neovascular AMD, “dry” atrophic AMD or both), in which central vision is severely compromised or lost. Until recently, there have been no therapies available to treat the disorder(s). Now, the most common wet form of late-stage AMD, choroidal neovascularization, generally responds to treatment with anti–vascular endothelial growth factor therapies. Nevertheless, there are no current therapies to restore lost vision in eyes with advanced atrophic AMD. Oral supplementation with the Age-Related Eye Disease Study (AREDS) or AREDS2 formulation (antioxidant vitamins C and E, lutein, zeaxanthin, and zinc) has been shown to reduce the risk of progression to advanced AMD, although the impact was in neovascular rather than atrophic AMD. Recent findings, however, have demonstrated several features of early AMD that are likely to be druggable targets for treatment. Studies have established that much of the genetic risk for AMD is associated with complement genes. Consequently, several complement-based therapeutic treatment approaches are being pursued. Potential treatment strategies against AMD deposit formation and protein and/or lipid deposition will be discussed, including anti-amyloid therapies. In addition, the role of autophagy in AMD and prevention of oxidative stress through modulation of the antioxidant system will be explored. Finally, the success of these new therapies in clinical trials and beyond relies on early detection, disease typing, and predicting disease progression, areas that are currently being rapidly transformed by improving imaging modalities and functional assays. PMID:24335072

Treatment of malignant phaeochromocytoma with a combination of cyclophosphamide, vincristine and dacarbazine: own experience and overview of the contemporary literature.

PubMed

Deutschbein, Timo; Fassnacht, Martin; Weismann, Dirk; Reincke, Martin; Mann, Klaus; Petersenn, Stephan

2015-01-01

Malignant phaeochromocytomas are rare and highly aggressive tumours. This retrospective study evaluated the outcome of combined chemotherapy with cyclophosphamide, vincristine and dacarbazine (also known as CVD regimen). Patients with histologically and radiologically confirmed malignant phaeochromocytoma who were treated with the CVD regimen for progressive disease were retrospectively identified from chart review. Treatment cycles were usually repeated at 21-day intervals, with cyclophosphamide (750 mg/m(2) ), vincristine (1·4 mg/m(2) ) and dacarbazine (600 mg/m(2) ) on day 1, and dacarbazine only (600 mg/m(2) ) on day 2. The main outcome measures were best response during treatment and progression-free survival. Eight patients (4 males; median age 55·5 (range 31-77) years) with progressive disease underwent a median of 6 (range 3-11) cycles. Best treatment responses were as follows: partial response, n = 2 (25%); stable disease, n = 3 (38%); and progressive disease, n = 3 (38%). The median progression-free survival was 5·4 (range 2·5-26·8) months. After the initial administration of 6 cycles, two patients received a second course of chemotherapy with another 6 cycles after new progressive disease had been detected. Subsequently, these patients were progression-free for another 6·0 and 6·4 months. Mild gastrointestinal symptoms and fatigue were the most common adverse events. Although objective tumour response rates were lower than previously reported in small series, the CVD regimen allowed disease stabilization for a substantial period of time and may therefore be considered as a treatment option in advanced stages. To improve disease outcome, however, new therapeutic approaches and larger multicentre studies are needed. © 2014 John Wiley & Sons Ltd.

Radiographic progression with nonrising PSA in metastatic castration-resistant prostate cancer: post hoc analysis of PREVAIL

PubMed Central

Bryce, A H; Alumkal, J J; Armstrong, A; Higano, C S; Iversen, P; Sternberg, C N; Rathkopf, D; Loriot, Y; de Bono, J; Tombal, B; Abhyankar, S; Lin, P; Krivoshik, A; Phung, D; Beer, T M

2017-01-01

Background: Advanced prostate cancer is a phenotypically diverse disease that evolves through multiple clinical courses. PSA level is the most widely used parameter for disease monitoring, but it has well-recognized limitations. Unlike in clinical trials, in practice, clinicians may rely on PSA monitoring alone to determine disease status on therapy. This approach has not been adequately tested. Methods: Chemotherapy-naive asymptomatic or mildly symptomatic men (n=872) with metastatic castration-resistant prostate cancer (mCRPC) who were treated with the androgen receptor inhibitor enzalutamide in the PREVAIL study were analyzed post hoc for rising versus nonrising PSA (empirically defined as >1.05 vs ⩽1.05 times the PSA level from 3 months earlier) at the time of radiographic progression. Clinical characteristics and disease outcomes were compared between the rising and nonrising PSA groups. Results: Of 265 PREVAIL patients with radiographic progression and evaluable PSA levels on the enzalutamide arm, nearly one-quarter had a nonrising PSA. Median progression-free survival in this cohort was 8.3 months versus 11.1 months in the rising PSA cohort (hazard ratio 1.68; 95% confidence interval 1.26–2.23); overall survival was similar between the two groups, although less than half of patients in either group were still at risk at 24 months. Baseline clinical characteristics of the two groups were similar. Conclusions: Non-rising PSA at radiographic progression is a common phenomenon in mCRPC patients treated with enzalutamide. As restaging in advanced prostate cancer patients is often guided by increases in PSA levels, our results demonstrate that disease progression on enzalutamide can occur without rising PSA levels. Therefore, a disease monitoring strategy that includes imaging not entirely reliant on serial serum PSA measurement may more accurately identify disease progression. PMID:28117385