MS Disease-Modifying Medications

Science.gov (United States)

... disease-modifying therapies Approval: 2014 US; 2014 CAN Pregnancy Category C (see footnote, page 11) Rash, headache, fever, nasal congestion, nausea, urinary tract infection, fatigue, insomnia, upper respiratory tract infection, herpes viral ...

Dyneins: structure, biology and disease

National Research Council Canada - National Science Library

King, Stephen M

2012-01-01

.... From bench to bedside, Dynein: Structure, Biology and Disease offers research on fundamental cellular processes to researchers and clinicians across developmental biology, cell biology, molecular biology, biophysics, biomedicine...

Biologic agents therapy for Saudi children with rheumatic diseases: indications and safety.

Science.gov (United States)

Al-Mayouf, Sulaiman M; Alenazi, Abdullatif; AlJasser, Hind

2016-06-01

To report the indications and safety of biologic agents in childhood rheumatic diseases at a tertiary hospital. Children with rheumatic diseases treated with biologic agents at King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia, from January 2001 to December 2011 were included. All patients were reviewed for: demographic characteristics, diagnosis, concomitant treatment and indications of using biologic agents, age at start of therapy and side effects during the treatment period. In all, 134 children (89 female) with various rheumatic diseases were treated with biologic agents. Mean age at starting biologic treatment was 9.3 (4.25-14) years and mean therapy duration was 14.7 (3-88) months. Juvenile idiopathic arthritis (JIA) was the most frequent diagnosis (70.1%) followed by systemic lupus erythematosus (12.7%) and vasculitis (4.5%). All patients received concomitant therapy (corticosteroids and disease-modifying antirheumatic drugs). In total, 273 treatments with biologic agents were used, (95 etanercept, 52 rituximab, 47 adalimumab, 37 infliximab, 23 anakinra, 10 tocilizumab and nine abatacept). Therapy was switched to another agent in 57 (42.5%) patients, mainly because of inefficacy (89.4%) or adverse event (10.6%). A total of 95 (34.8%) adverse events were notified; of these, the most frequent were infusion-related reactions (33.7%) followed by infections (24.2%) and autoantibody positivity (10.6%). One patient developed macrophage activation syndrome. Biologic agents were used in children with a range of rheumatic diseases. Of these, the most frequent was JIA. Off-label use of biologic agents in our cohort is common. These agents seem safe. However, they may associated with various adverse events. Sequential therapy seems well tolerated. However, this should be carefully balanced and considered on an individual basis. © 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

Quantifying the contributions of behavioral and biological risk factors to socioeconomic disparities in coronary heart disease incidence: the MORGEN study

NARCIS (Netherlands)

Kershaw, Kiarri N.; Droomers, Mariël; Robinson, Whitney R.; Carnethon, Mercedes R.; Daviglus, Martha L.; Verschuren, W. M. Monique

2013-01-01

Quantifying the impact of different modifiable behavioral and biological risk factors on socioeconomic disparities in coronary heart disease (CHD) may help inform targeted, population-specific strategies to reduce the unequal distribution of the disease. Previous studies have used analytic

Disease-modifying anti-rheumatic drug use in pregnant women with rheumatic diseases: a systematic review of the risk of congenital malformations.

Science.gov (United States)

Baldwin, Corisande; Avina-Zubieta, Antonio; Rai, Sharan K; Carruthers, Erin; De Vera, Mary A

2016-01-01

Despite the high incidence of rheumatic diseases during the reproductive years, little is known about the impact of disease-modifying anti-rheumatic drug (DMARD) use during pregnancy. Our objective was to systematically review and appraise evidence in women with rheumatic disease on the use of traditional and biologic DMARDs during pregnancy and the risk of congenital malformation outcomes. We conducted a systematic search of MEDLINE, EMBASE, and INTERNATIONAL PHARMACEUTICAL ABSTRACTS databases. Inclusion criteria were: 1) study sample including women with rheumatic disease; 2) use of traditional and/or biologic DMARDs during pregnancy; and 3) congenital malformation outcome(s) reported. We extracted information on study design, data source, number of exposed pregnancies, type of DMARD, number of live births, and number of congenital malformations. Altogether, we included 79 studies; the majority were based on designs that did not involve a comparison group, including 26 case reports, 17 case series, 20 cross-sectional studies, and 4 surveys. Studies that had a comparator group included 1 case control, 10 cohort studies, and 1 controlled trial. Hydroxychloroquine and azathioprine represent the most studied traditional DMARD exposures and, among biologics, most of the reports were on infliximab and etanercept. This is the first systematic review on the use of both traditional and biologic DMARDs during pregnancy among women with rheumatic diseases and congenital malformation outcomes, with a focus on study design and quality. Findings confirm the limited number of studies, as well as the need to improve study designs.

In silico search for modifier genes associated with pancreatic and liver disease in Cystic Fibrosis.

Directory of Open Access Journals (Sweden)

Pascal Trouvé

Full Text Available Cystic Fibrosis is the most common lethal autosomal recessive disorder in the white population, affecting among other organs, the lung, the pancreas and the liver. Whereas Cystic Fibrosis is a monogenic disease, many studies reveal a very complex relationship between genotype and clinical phenotype. Indeed, the broad phenotypic spectrum observed in Cystic Fibrosis is far from being explained by obvious genotype-phenotype correlations and it is admitted that Cystic Fibrosis disease is the result of multiple factors, including effects of the environment as well as modifier genes. Our objective was to highlight new modifier genes with potential implications in the lung, pancreatic and liver outcomes of the disease. For this purpose we performed a system biology approach which combined, database mining, literature mining, gene expression study and network analysis as well as pathway enrichment analysis and protein-protein interactions. We found that IFI16, CCNE2 and IGFBP2 are potential modifiers in the altered lung function in Cystic Fibrosis. We also found that EPHX1, HLA-DQA1, HLA-DQB1, DSP and SLC33A1, GPNMB, NCF2, RASGRP1, LGALS3 and PTPN13, are potential modifiers in pancreas and liver, respectively. Associated pathways indicate that immune system is likely involved and that Ubiquitin C is probably a central node, linking Cystic Fibrosis to liver and pancreatic disease. We highlight here new modifier genes with potential implications in Cystic Fibrosis. Nevertheless, our in silico analysis requires functional analysis to give our results a physiological relevance.

Delayed wound healing and postoperative surgical site infections in patients with rheumatoid arthritis treated with or without biological disease-modifying antirheumatic drugs.

Science.gov (United States)

Tada, Masahiro; Inui, Kentaro; Sugioka, Yuko; Mamoto, Kenji; Okano, Tadashi; Kinoshita, Takuya; Hidaka, Noriaki; Koike, Tatsuya

2016-06-01

Biological disease-modifying antirheumatic drugs (bDMARDs) have become more popular for treating rheumatoid arthritis (RA). Whether or not bDMARDs increase the postoperative risk of surgical site infection (SSI) has remained controversial. We aimed to clarify the effects of bDMARDs on the outcomes of elective orthopedic surgery. We used multivariate logistic regression analysis to analyze risk factors for SSI and delayed wound healing among 227 patients with RA (mean age, 65.0 years; disease duration, 16.9 years) after 332 elective orthopedic surgeries. We also attempted to evaluate the effects of individual medications on infection. Rates of bDMARD and conventional synthetic DMARD (csDMARD) administration were 30.4 and 91.0 %, respectively. Risk factors for SSI were advanced age (odds ratio [OR], 1.11; P = 0.045), prolonged surgery (OR, 1.02; P = 0.03), and preoperative white blood cell count >10,000/μL (OR, 3.66; P = 0.003). Those for delayed wound healing were advanced age (OR, 1.16; P = 0.001), prolonged surgery (OR, 1.02; P = 0.007), preoperative white blood cell count >10,000/μL (OR, 4.56; P = 0.02), and foot surgery (OR, 6.60; P = 0.001). Risk factors for SSI and medications did not significantly differ. No DMARDs were risk factors for any outcome examined. Biological DMARDs were not risk factors for postoperative SSI. Foot surgery was a risk factor for delayed wound healing.

Radiographic complications of biologic response modifiers

International Nuclear Information System (INIS)

Miketic, L.M.; Bahnson, R.R.; Ernstoff, M.S.; Kirkwood, J.M.; Nair, S.; Logan, T.; Downs, M.A.; Neuhart, J.A.

1989-01-01

Biologic response modifiers, such as the interferons, are increasingly used in the treatment of cancer as an adjunct to conventional chemotherapy. In certain malignancies, particularly renal cell carcinoma, they are becoming agents of choice due to higher tumor response rate. The authors have reviewed 202 patients. Protocols include interferon, interleukin, tumor necrosis factor, and monoclonal antibodies. The radiology of significant clinical complications is discussed, especially the vascular leak syndrome often seen with interleukin administration and the cardiac toxicity of interferon. Less common abnormalities include progressive splenomegaly in one interferon study and a hemorrhagic episode caused by tumor necrosis factor

Genetic Modifiers of Sickle Cell Disease

Science.gov (United States)

Steinberg, Martin H.; Sebastiani, Paola

2015-01-01

Sickle cell anemia is associated with unusual clinical heterogeneity for a Mendelian disorder. Fetal hemoglobin concentration and coincident ∝ thalassemia, both which directly affect the sickle erythrocyte, are the major modulators of the phenotype of disease. Understanding the genetics underlying the heritable subphenotypes of sickle cell anemia would be prognostically useful, could inform personalized therapeutics, and might help the discovery of new “druggable” pathophysiologic targets. Genotype-phenotype association studies have been used to identify novel genetic modifiers. In the future, whole genome sequencing with its promise of discovering hitherto unsuspected variants could add to our understanding of the genetic modifiers of this disease. PMID:22641398

Biologics for rheumatoid arthritis: an overview of Cochrane reviews

DEFF Research Database (Denmark)

Singh, Jasvinder A; Christensen, Robin; Wells, George A

2010-01-01

the biologic disease-modifying anti-rheumatic drugs (DMARDs) are very effective in treating rheumatoid arthritis (RA), however there is a lack of head-to-head comparison studies.......the biologic disease-modifying anti-rheumatic drugs (DMARDs) are very effective in treating rheumatoid arthritis (RA), however there is a lack of head-to-head comparison studies....

ChemProt: a disease chemical biology database

DEFF Research Database (Denmark)

Taboureau, Olivier; Nielsen, Sonny Kim; Audouze, Karine Marie Laure

2011-01-01

Systems pharmacology is an emergent area that studies drug action across multiple scales of complexity, from molecular and cellular to tissue and organism levels. There is a critical need to develop network-based approaches to integrate the growing body of chemical biology knowledge with network...... biology. Here, we report ChemProt, a disease chemical biology database, which is based on a compilation of multiple chemical-protein annotation resources, as well as disease-associated protein-protein interactions (PPIs). We assembled more than 700 000 unique chemicals with biological annotation for 30...... evaluation of environmental chemicals, natural products and approved drugs, as well as the selection of new compounds based on their activity profile against most known biological targets, including those related to adverse drug events. Results from the disease chemical biology database associate citalopram...

Distribution of Podoplanin in Synovial Tissues in Rheumatoid Arthritis Patients Using Biologic or Conventional Disease-Modifying Anti-Rheumatic Drugs.

Science.gov (United States)

Takakubo, Yuya; Oki, Hiroharu; Naganuma, Yasushi; Saski, Kan; Sasaki, Akiko; Tamaki, Yasunobu; Suran, Yang; Konta, Tsuneo; Takagi, Michiaki

2017-01-01

Podoplanin (PDPN) mediates tumor cell migration and invasion, which phenomena might also play a role in severe rheumatoid arthritis (RA). Therefore, the precise cellular distribution of PDPN and it's relationships with inflammation was studied in RA treated with biologic disease-modifying anti-rheumatic drugs (DMARD) or conventional DMARDs (cDMARD). PDPN+ cells were immunostained by NZ-1 mAb, and scored (3+; >50%/ area, 2+; 20%- 50%, 1+; 5%-20%, 0: <5%) in synovial tissues from RA treated with biologic DMARDs (BIO, n=20) or cDMARD (n=20) for comparison with osteoarthritis (OA, n=5), followed by cell grading of inflammation and cell-typing. Inflammatory synovitis score was 1.4 in both BIO and cDMARD, compared to only 0.2 in OA. PDPN+ cells were found in the lining layer (BIO 1.6, cDMARD 1.3, OA 0.2) and lymphoid aggregates (BIO 0.6, cDMRD 0.7, OA 0.2), and correlated with RA-inflammation in BIO- and cDMARD-groups in both area (r=0.7/0.9, r=0.6/0.7, respectively p<0.05). PDPN was expressed in CD68+ type A macrophage-like and 5B5+ type B fibroblast-like cells in the lining layer, and in IL- 17+ cells in lymphoid aggregates in RA. PDPN was markedly increased in the immunologically inflamed RA synovitis, which was surgically treated due to BIO- and cDMARD-resistant RA. PDPN may have potential of a new marker of residual arthritis in local joints for inflammation-associated severe RA. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Biological resistance of polyethylene composites made with chemically modified fiber or flour

Science.gov (United States)

Rebecca E. Ibach; Craig M. Clemons

2002-01-01

The role of moisture in the biological decay of wood-plastic composites was investigated. Southern pine wood fiber and ponderosa pine wood flour were chemically modified using either acetic anhydride (AA), butylene oxide (BO), or propylene oxide (PO). A 50:50 mixture of high density polyethylene and either chemically modified fiber or flour, or untreated fiber or flour...

Tumour necrosis factor inhibitors versus combination intensive therapy with conventional disease modifying anti-rheumatic drugs in established rheumatoid arthritis: TACIT non-inferiority randomised controlled trial.

Science.gov (United States)

Scott, David L; Ibrahim, Fowzia; Farewell, Vern; O'Keeffe, Aidan G; Walker, David; Kelly, Clive; Birrell, Fraser; Chakravarty, Kuntal; Maddison, Peter; Heslin, Margaret; Patel, Anita; Kingsley, Gabrielle H

2015-03-13

To determine whether intensive combinations of synthetic disease modifying drugs can achieve similar clinical benefits at lower costs to high cost biologics such as tumour necrosis factor inhibitors in patients with active rheumatoid arthritis resistant to initial methotrexate and other synthetic disease modifying drugs. Open label pragmatic randomised multicentre two arm non-inferiority trial over 12 months. 24 rheumatology clinics in England. Patients with rheumatoid arthritis who were eligible for treatment with tumour necrosis factor inhibitors according to current English guidance were randomised to either the tumour necrosis factor inhibitor strategy or the combined disease modifying drug strategy. Biologic strategy: start tumour necrosis factor inhibitor; second biologic in six month for non-responders. Alternative strategy: start combination of disease modifying drugs; start tumour necrosis factor inhibitors after six months in non-responders. reduction in disability at 12 months measured with patient recorded heath assessment questionnaire (range 0.00-3.00) with a 0.22 non-inferiority margin for combination treatment versus the biologic strategy. quality of life, joint damage, disease activity, adverse events, and costs. Intention to treat analysis used multiple imputation methods for missing data. 432 patients were screened: 107 were randomised to tumour necrosis factor inhibitors and 101 started taking; 107 were randomised to the combined drug strategy and 104 started taking the drugs. Initial assessments were similar; 16 patients were lost to follow-up (seven with the tumour necrosis factor inhibitor strategy, nine with the combined drug strategy); 42 discontinued the intervention but were followed-up (19 and 23, respectively). The primary outcome showed mean falls in scores on the health assessment questionnaire of -0.30 with the tumour necrosis factor inhibitor strategy and -0.45 with the alternative combined drug strategy. The difference between

Optimizing biological therapy in Crohn's disease.

Science.gov (United States)

Gecse, Krisztina Barbara; Végh, Zsuzsanna; Lakatos, Péter László

2016-01-01

Anti-TNF therapy has revolutionized the treatment of inflammatory bowel diseases, including both Crohn's disease and ulcerative colitis. However, a significant proportion of patients does not respond to anti-TNF agents or lose response over time. Recently, therapeutic drug monitoring has gained a major role in identifying the mechanism and management of loss of response. The aim of this review article is to summarize the predictors of efficacy and outcomes, the different mechanisms of anti-TNF/biological failure in Crohn's disease and identify strategies to optimize biological treatment.

Efficacy and safety of tofacitinib following inadequate response to conventional synthetic or biological disease-modifying antirheumatic drugs.

Science.gov (United States)

Charles-Schoeman, Christina; Burmester, Gerd; Nash, Peter; Zerbini, Cristiano A F; Soma, Koshika; Kwok, Kenneth; Hendrikx, Thijs; Bananis, Eustratios; Fleischmann, Roy

2016-07-01

Biological disease-modifying antirheumatic drugs (bDMARDs) have shown diminished clinical response following an inadequate response (IR) to ≥1 previous bDMARD. Here, tofacitinib was compared with placebo in patients with an IR to conventional synthetic DMARDs (csDMARDs; bDMARD-naive) and in patients with an IR to bDMARDs (bDMARD-IR). Data were taken from phase II and phase III studies of tofacitinib in patients with rheumatoid arthritis (RA). Patients received tofacitinib 5 or 10 mg twice daily, or placebo, as monotherapy or with background methotrexate or other csDMARDs. Efficacy endpoints and incidence rates of adverse events (AEs) of special interest were assessed. 2812 bDMARD-naive and 705 bDMARD-IR patients were analysed. Baseline demographics and disease characteristics were generally similar between treatment groups within subpopulations. Across subpopulations, improvements in efficacy parameters at month 3 were generally significantly greater for both tofacitinib doses versus placebo. Clinical response was numerically greater with bDMARD-naive versus bDMARD-IR patients (overlapping 95% CIs). Rates of safety events of special interest were generally similar between tofacitinib doses and subpopulations; however, patients receiving glucocorticoids had more serious AEs, discontinuations due to AEs, serious infection events and herpes zoster. Numerically greater clinical responses and incidence rates of AEs of special interest were generally reported for tofacitinib 10 mg twice daily versus tofacitinib 5 mg twice daily (overlapping 95% CIs). Tofacitinib demonstrated efficacy in both bDMARD-naive and bDMARD-IR patients with RA. Clinical response to tofacitinib was generally numerically greater in bDMARD-naive than bDMARD-IR patients. The safety profile appeared similar between subpopulations. (NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385). Published by the BMJ Publishing Group Limited

Progress in the understanding and utilization of biologic response modifiers in the treatment of uveitis.

Science.gov (United States)

Maleki, Arash; Meese, Halea; Sahawneh, Haitham; Foster, C Stephen

2016-07-01

Uveitis is the third most common cause of blindness in developed countries. Considering the systemic and local complications of long-term corticosteroid therapy and the intolerance due to side effects and ineffectiveness of conventional chemotherapy, use of biologic response modifiers is a reasonable alternative in the treatment of non-infectious uveitis and persistent uveitic macular edema. The majority of the evidence presented here comes from open uncontrolled analyses. Based on these studies, tumor necrosis factor alpha inhibitors, especially infliximab and adalimumab, have been shown to be effective in the treatment of non-infectious uveitis in numerous studies. More research is necessary, particularly multi-center randomized clinical trials, to address the choice of biologic response modifier agent and the length of treatment as we employ biologic response modifiers in different types of uveitis and persistent uveitic macular edema.

ChemProt: A disease chemical biology database

DEFF Research Database (Denmark)

Taboureau, Olivier; Oprea, Tudor I.

2013-01-01

The integration of chemistry, biology, and informatics to study drug actions across multiple biological targets, pathways, and biological systems is an emerging paradigm in drug discovery. Rather than reducing a complex system to simplistic models, fields such as chemogenomics and translational...... informatics are seeking to build a holistic model for a better understanding of the drug pharmacology and clinical effects. Here we will present a webserver called ChemProt that can assist, in silico, the drug actions in the context of cellular and disease networks and contribute in the field of disease...... chemical biology, drug repurposing, and off-target effects prediction....

Evolutionary perspectives into placental biology and disease

Directory of Open Access Journals (Sweden)

Edward B. Chuong

2013-12-01

Full Text Available In all mammals including humans, development takes place within the protective environment of the maternal womb. Throughout gestation, nutrients and waste products are continuously exchanged between mother and fetus through the placenta. Despite the clear importance of the placenta to successful pregnancy and the health of both mother and offspring, relatively little is understood about the biology of the placenta and its role in pregnancy-related diseases. Given that pre- and peri-natal diseases involving the placenta affect millions of women and their newborns worldwide, there is an urgent need to understand placenta biology and development. Here, we suggest that the placenta is an organ under unique selective pressures that have driven its rapid diversification throughout mammalian evolution. The high divergence of the placenta complicates the use of non-human animal models and necessitates an evolutionary perspective when studying its biology and role in disease. We suggest that diversifying evolution of the placenta is primarily driven by intraspecies evolutionary conflict between mother and fetus, and that many pregnancy diseases are a consequence of this evolutionary force. Understanding how maternal–fetal conflict shapes both basic placental and reproductive biology – in all species – will provide key insights into diseases of pregnancy.

New FDA-Approved Disease-Modifying Therapies for Multiple Sclerosis.

Science.gov (United States)

English, Clayton; Aloi, Joseph J

2015-04-01

Interferon injectables and glatiramer acetate have served as the primary disease-modifying treatments for multiple sclerosis (MS) since their introduction in the 1990s and are first-line treatments for relapsing-remitting forms of MS (RRMS). Many new drug therapies were launched since early 2010, expanding the drug treatment options considerably in a disease state that once had a limited treatment portfolio. The purpose of this review is to critically evaluate the safety profile and efficacy data of disease-modifying agents for MS approved by the US Food and Drug Administration (FDA) from 2010 to the present and provide cost and available pharmacoeconomic data about each new treatment. Peer-reviewed clinical trials, pharmacoeconomic studies, and relevant pharmacokinetic/pharmacologic studies were identified from MEDLINE (January 2000-December 2014) by using the search terms multiple sclerosis, fingolimod, teriflunomide, alemtuzumab, dimethyl fumarate, pegylated interferon, peginterferon beta-1a, glatiramer 3 times weekly, and pharmacoeconomics. Citations from available articles were also reviewed for additional references. The databases publically available at www.clinicaltrials.gov and www.fda.gov were searched for unpublished studies or studies currently in progress. A total of 5 new agents and 1 new dosage formulation were approved by the FDA for the treatment of RRMS since 2010. Peginterferon beta-1a and high-dose glatiramer acetate represent 2 new effective injectable options for MS that reduce burden of administration seen with traditional interferon and low-dose glatiramer acetate. Fingolimod, teriflunomide, and dimethyl fumarate represent new oral agents available for MS, and their efficacy in reducing annualized relapse rates is 48% to 55%, 22% to 36.3%, and 44% to 53%, respectively, compared with placebo. Alemtuzumab is a biologic given over a 2-year span that reduced annualized relapse rates by 55% in treatment-naive patients and by 49% in patients

Biologics in Paediatric Crohn's Disease

Directory of Open Access Journals (Sweden)

Oliver Gouldthorpe

2011-01-01

Full Text Available Crohn's disease affects increasing numbers of children worldwide. Generally, childhood-onset disease runs a more severe course than in adults and has a greater impact on quality of life. Therapy in children must take account of a different set of risks for toxicity compared to adults, but also to their longevity. Biologic drugs present remarkable advantages in terms of disease control for children, especially in those whose disease cannot be controlled with conventional therapies, but their long-term risks are still being assessed. Data regarding biologic use in children is limited and mostly amounts to case series, but results have been promising, both in terms of controlling disease activity and improving growth parameters. Adverse reactions are infrequent in the short term, but loss of response is a long-term problem, particularly in children. More information is needed about very long term risks. Infliximab and adalimumab are the most studied agents in children, while there is relatively limited data on certolizumab and natalizumab. Further collection of data on these agents is still needed, but this should not restrict access to these agents for children in whom no other agent is effective.

Biological treatment of Crohn's disease

DEFF Research Database (Denmark)

Nielsen, Ole Haagen; Bjerrum, Jacob Tveiten; Seidelin, Jakob Benedict

2012-01-01

Introduction of biological agents for the treatment of Crohn's disease (CD) has led to a transformation of the treatment paradigm. Several biological compounds have been approved for patients with CD refractory to conventional treatment: infliximab, adalimumab and certolizumab pegol (and...... natalizumab in several countries outside the European Union). However, despite the use of biologics for more than a decade, questions still remain about the true efficacy and the best treatment regimens - especially about when to discontinue treatment. Furthermore, a need for optimizing treatment...... with biologics still exists, as 20-40% of patients with CD (depending on selection criteria) do not have any relevant response to the current biological agents (i.e. primary failures). A better patient selection might maximize the clinical outcome while minimizing the complications associated with this type...

77 FR 59930 - Clinical Development Programs for Disease-Modifying Agents for Peripheral Neuropathy; Public...

Science.gov (United States)

2012-10-01

...] Clinical Development Programs for Disease-Modifying Agents for Peripheral Neuropathy; Public Workshop... to the clinical development of disease-modifying agents for the treatment of peripheral neuropathy... disease-modifying products for the management of peripheral neuropathy. Date and Time: The public workshop...

Leukotrienes and leukotriene modifiers in pediatric allergic diseases

African Journals Online (AJOL)

Ehab

... 12(1):3-12. 3. Leukotrienes and leukotriene modifiers in pediatric allergic diseases ... childhood allergic diseases. This review ... produce cysteinyl-LTs and LTB4 spontaneously in vitro.8. Although nonleukocyte cells generally do not have sufficient 5-LO and FLAP to synthesize .... uninterrupted sleep in these patients.55.

Modified laminar flow biological safety cabinet.

Science.gov (United States)

McGarrity, G J; Coriell, L L

1974-10-01

Tests are reported on a modified laminar flow biological safety cabinet in which the return air plenum that conducts air from the work area to the high efficiency particulate air filters is under negative pressure. Freon gas released inside the cabinet could not be detected outside by a freon gas detection method capable of detecting 10(-6) cc/s. When T3 bacteriophage was aerosolized 5 cm outside the front opening in 11 tests, no phage could be detected inside the cabinet with the motor-filter unit in operation. An average of 2.8 x 10(5) plaque-forming units (PFU)/ft(3) (ca. 0.028 m(3)) were detected with the motor-filter unit not in operation, a penetration of 0.0%. Aerosolization 5 cm inside the cabinet yielded an average of 10 PFU/ft(3) outside the cabinet with the motor-filter unit in operation and an average of 4.1 x 10(5) PFU/ft(3) with the motor-filter unit not in operation, a penetration of 0.002%. These values are the same order of effectiveness as the positive-pressure laminar flow biological safety cabinets previously tested. The advantages of the negative-pressure return plenum design include: (i) assurance that if cracks or leaks develop in the plenum it will not lead to discharge of contaminated air into the laboratory; and (ii) the price is lower due to reduced manufacturing costs.

Modified rotating biological contactor for removal of dichloromethane vapours.

Science.gov (United States)

Ravi, R; Philip, Ligy; Swaminathan, T

2015-01-01

Bioreactors are used for the treatment of waste gas and odour that has gained much acceptance in the recent years to treat volatile organic compounds (VOCs). The different types of bioreactors (biofilter, biotrickling filter and bioscrubber) have been used for waste gas treatment. Each of these reactors has some advantages and some limitations. Though biodegradation is the main process for the removal of the pollutants, the mechanisms of removal and the microbial communities may differ among these bioreactors. Consequently, their performance or removal efficiency may also be different. Clogging of reactor and pressure drop are the main problems. In this study attempts are made to use the principle of rotating biological contactor (RBC) used for wastewater treatment for the removal of VOC. To overcome the above problem the RBC is modified which is suitable for the treatment of VOC (dichloromethane, DCM). DCM is harmful to human health and hazardous to the atmospheric environment. Modified RBC had no clogging problems and no pressure drop. So, it can handle the pollutant load for a longer period of time. A maximum elimination capacity of 25.7 g/m3 h has been achieved in this study for the DCM inlet load of 58 g/m3 h. The average biofilm thickness is 1 mm. The transient behaviour of the modified RBC treating DCM was investigated. The modified RBC is able to handle shutdown, restart and shock loading operations.

Older Americans' risk-benefit preferences for modifying the course of Alzheimer disease.

Science.gov (United States)

Hauber, A Brett; Johnson, F Reed; Fillit, Howard; Mohamed, Ateesha F; Leibman, Christopher; Arrighi, H Michael; Grundman, Michael; Townsend, Raymond J

2009-01-01

Alzheimer disease (AD) is a progressive, ultimately fatal neurodegenerative illness affecting millions of patients, families, and caregivers. Effective disease-modifying therapies for AD are desperately needed, but none currently exist on the market. Thus, accelerating the discovery, development, and approval of new disease-modifying drugs for AD is a high priority for individuals, physicians, and medical decision makers. Potentially disease-modifying drugs likely will have significant therapeutic benefits but also may have treatment-related risks. We quantified older Americans' treatment-related risk tolerance by eliciting their willingness to accept the risk of treatment-related death or permanent severe disability in exchange for modifying the course of AD. A stated-choice survey instrument was administered to 2146 American residents 60 years of age and older. On average, subjects were willing to accept a 1-year risk of treatment-related death or permanent severe disability from stroke of over 30% for a treatment that prevents AD from progressing beyond the mild stage. Thus, most people in this age cohort are willing to accept considerable risks in return for disease-modifying benefits of new AD drugs. These results are consistent with other studies indicating that individuals view AD as a serious, life threatening illness that imposes heavy burdens on both patients and caregivers.

Nutritional Systems Biology

DEFF Research Database (Denmark)

Jensen, Kasper

and network biology has the potential to increase our understanding of how small molecules affect metabolic pathways and homeostasis, how this perturbation changes at the disease state, and to what extent individual genotypes contribute to this. A fruitful strategy in approaching and exploring the field...... biology research. The paper also shows as a proof-of-concept that a systems biology approach to diet is meaningful and demonstrates some basic principles on how to work with diet systematic. The second chapter of this thesis we developed the resource NutriChem v1.0. A foodchemical database linking...... sites of diet on the disease pathway. We propose a framework for interrogating the critical targets in colon cancer process and identifying plant-based dietary interventions as important modifiers using a systems chemical biology approach. The fifth chapter of the thesis is on discovering of novel anti...

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

LENUS (Irish Health Repository)

Lonergan, Roisin

2012-02-01

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

Fungal endophytes: modifiers of plant disease.

Science.gov (United States)

Busby, Posy E; Ridout, Mary; Newcombe, George

2016-04-01

Many recent studies have demonstrated that non-pathogenic fungi within plant microbiomes, i.e., endophytes ("endo" = within, "phyte" = plant), can significantly modify the expression of host plant disease. The rapid pace of advancement in endophyte ecology warrants a pause to synthesize our understanding of endophyte disease modification and to discuss future research directions. We reviewed recent literature on fungal endophyte disease modification, and here report on several emergent themes: (1) Fungal endophyte effects on plant disease span the full spectrum from pathogen antagonism to pathogen facilitation, with pathogen antagonism most commonly reported. (2) Agricultural plant pathosystems are the focus of research on endophyte disease modification. (3) A taxonomically diverse group of fungal endophytes can influence plant disease severity. And (4) Fungal endophyte effects on plant disease severity are context-dependent. Our review highlights the importance of fungal endophytes for plant disease across a broad range of plant pathosystems, yet simultaneously reveals that complexity within plant microbiomes presents a significant challenge to disentangling the biotic environmental factors affecting plant disease severity. Manipulative studies integrating eco-evolutionary approaches with emerging molecular tools will be poised to elucidate the functional importance of endophytes in natural plant pathosystems that are fundamental to biodiversity and conservation.

The marked and rapid therapeutic effect of tofacitinib in combination with subcutaneous methotrexate in a rheumatoid arthritis patient with poor prognostic factors who is resistant to standard disease-modifying antirheumatic drugs and biologicals: A clinical case

Directory of Open Access Journals (Sweden)

N. V. Demidova

2016-01-01

Full Text Available Today, it is generally accepted that it is necessary to achieve clinical remission in rheumatoid arthritis (RA or as minimum a low disease activity. The paper describes a clinical case of a female patient diagnosed with RA who was observed to have inefficiency of standard disease-modifying antirheumatic therapy with methotrexate 25 mg/week, secondary inefficiency of tumor necrosis factor-α inhibitors (adalimumab, and inefficiency/poor tolerance of the interlukin-6 receptor antagonist tocilizumab. This determined the need to use fofacitinib (TOFA, a drug with another mechanism of action. TOFA is the first agent from a new group of immunomodulatory and anti-inflammatory drugs, intracellular kinase inhibitors. Disease remission could be achieved during therapy with TOFA, which enables one to consider this synthetic drug as a therapy option that potentially competes with therapy with biologicals.

Biological Control of Plant Disease Caused by Bacteria

Directory of Open Access Journals (Sweden)

Triwidodo Arwiyanto

2014-07-01

Full Text Available Bacterial diseases in plants are difficult to control. The emphasis is on preventing the spread of the bacteria rather than curing the diseased plant. Integrated management measures for bacterial plant pathogens should be applied for successfull control. Biological control is one of the control measures viz. through the use of microorganisms to suppress the growth and development of bacterial plant pathogen and ultimately reduce the possibility of disease onset. The study of biological control of bacterial plant pathogen was just began compared with of fungal plant pathogen. The ecological nature of diverse bacterial plant pathogens has led scientists to apply different approach in the investigation of its biological control. The complex process of entrance to its host plant for certain soil-borne bacterial plant pathogens need special techniques and combination of more than one biological control agent. Problem and progress in controlling bacterial plant pathogens biologically will be discussed in more detail in the paper and some commercial products of biological control agents (biopesticides will be introduced.     Penyakit tumbuhan karena bakteri sulit dikendalikan. Penekanan pengendalian adalah pada pencegahan penyebaran bakteri patogen dan bukan pada penyembuhan tanaman yang sudah sakit. Untuk suksesnya pengendalian bakteri patogen tumbuhan diperlukan cara pengelolaan yang terpadu. Pengendalian secara biologi merupakan salah satu cara pengendalian dengan menggunakan mikroorganisme untuk menekan pertumbuhan dan perkembangan bakteri patogen tumbuhan dengan tujuan akhir menurunkan kemungkinan timbulnya penyakit. Sifat ekologi bakteri patogen tumbuhan yang berbeda-beda mengharuskan pendekatan yang berbeda pula dalam pengendaliannya secara biologi. Masalah dan perkembangan dalam pengendalian bakteri patogen tumbuhan secara biologi didiskusikan secara detail dalam makalah ini.

Modified Primers for the Identification of Nonpathogenic Fusarium oxysporum Isolates That Have Biological Control Potential against Fusarium Wilt of Cucumber in Taiwan

Science.gov (United States)

Wang, Chaojen; Lin, Yisheng; Lin, Yinghong; Chung, Wenhsin

2013-01-01

Previous investigations demonstrated that Fusarium oxysporum (Fo), which is not pathogenic to cucumbers, could serve as a biological control agent for managing Fusarium wilt of cucumber caused by Fo f. sp. cucumerinum (Foc) in Taiwan. However, thus far it has not been possible to separate the populations of pathogenic Fo from the nonpathogenic isolates that have biological control potential through their morphological characteristics. Although these two populations can be distinguished from one another using a bioassay, the work is laborious and time-consuming. In this study, a fragment of the intergenic spacer (IGS) region of ribosomal DNA from an Fo biological control agent, Fo366, was PCR-amplified with published general primers, FIGS11/FIGS12 and sequenced. A new primer, NPIGS-R, which was designed based on the IGS sequence, was paired with the FIGS11 primer. These primers were then evaluated for their specificity to amplify DNA from nonpathogenic Fo isolates that have biological control potential. The results showed that the modified primer pair, FIGS11/NPIGS-R, amplified a 500-bp DNA fragment from five of seven nonpathogenic Fo isolates. These five Fo isolates delayed symptom development of cucumber Fusarium wilt in greenhouse bioassay tests. Seventy-seven Fo isolates were obtained from the soil and plant tissues and then subjected to amplification using the modified primer pair; six samples showed positive amplification. These six isolates did not cause symptoms on cucumber seedlings when grown in peat moss infested with the isolates and delayed disease development when the same plants were subsequently inoculated with a virulent isolate of Foc. Therefore, the modified primer pair may prove useful for the identification of Fo isolates that are nonpathogenic to cucumber which can potentially act as biocontrol agents for Fusarium wilt of cucumber. PMID:23762289

Allosteric regulation of epigenetic modifying enzymes.

Science.gov (United States)

Zucconi, Beth E; Cole, Philip A

2017-08-01

Epigenetic enzymes including histone modifying enzymes are key regulators of gene expression in normal and disease processes. Many drug development strategies to target histone modifying enzymes have focused on ligands that bind to enzyme active sites, but allosteric pockets offer potentially attractive opportunities for therapeutic development. Recent biochemical studies have revealed roles for small molecule and peptide ligands binding outside of the active sites in modulating the catalytic activities of histone modifying enzymes. Here we highlight several examples of allosteric regulation of epigenetic enzymes and discuss the biological significance of these findings. Copyright © 2017 Elsevier Ltd. All rights reserved.

Healthy aging and disease : role for telomere biology?

NARCIS (Netherlands)

Zhu, Haidong; Belcher, Matthew; van der Harst, Pim

Aging is a biological process that affects most cells, organisms and species. Human aging is associated with increased susceptibility to a variety of chronic diseases, including cardiovascular disease, Type 2 diabetes, neurological diseases and cancer. Despite the remarkable progress made during the

Biologics or tofacitinib for rheumatoid arthritis in incomplete responders to methotrexate or other traditional disease-modifying anti-rheumatic drugs

DEFF Research Database (Denmark)

Singh, Jasvinder A; Hossain, Alomgir; Tanjong Ghogomu, Elizabeth

2016-01-01

, tocilizumab) and small molecule tofacitinib, versus comparator (MTX, DMARD, placebo (PL), or a combination) in adults with rheumatoid arthritis who have failed to respond to methotrexate (MTX) or other disease-modifying anti-rheumatic drugs (DMARDs), i.e., MTX/DMARD incomplete responders (MTX.......78)) were similarly inconclusive and downgraded to low quality for both imprecision and indirectness.Main results text shows the results for tofacitinib and differences between medications. AUTHORS' CONCLUSIONS: Based primarily on RCTs of 6 months' to 12 months' duration, there is moderate quality evidence...

Ultrasound-detected bone erosion is a relapse risk factor after discontinuation of biologic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis whose ultrasound power Doppler synovitis activity and clinical disease activity are well controlled.

Science.gov (United States)

Kawashiri, Shin-Ya; Fujikawa, Keita; Nishino, Ayako; Okada, Akitomo; Aramaki, Toshiyuki; Shimizu, Toshimasa; Umeda, Masataka; Fukui, Shoichi; Suzuki, Takahisa; Koga, Tomohiro; Iwamoto, Naoki; Ichinose, Kunihiro; Tamai, Mami; Mizokami, Akinari; Nakamura, Hideki; Origuchi, Tomoki; Ueki, Yukitaka; Aoyagi, Kiyoshi; Maeda, Takahiro; Kawakami, Atsushi

2017-05-25

In the present study, we explored the risk factors for relapse after discontinuation of biologic disease-modifying antirheumatic drug (bDMARD) therapy in patients with rheumatoid arthritis (RA) whose ultrasound power Doppler (PD) synovitis activity and clinical disease activity were well controlled. In this observational study in clinical practice, the inclusion criteria were based on ultrasound disease activity and clinical disease activity, set as low or remission (Disease Activity Score in 28 joints based on erythrocyte sedimentation rate Ultrasound was performed in 22 joints of bilateral hands at discontinuation for evaluating synovitis severity and presence of bone erosion. Patients with a maximum PD score ≤1 in each joint were enrolled. Forty patients with RA were consecutively recruited (November 2010-March 2015) and discontinued bDMARD therapy. Variables at the initiation and discontinuation of bDMARD therapy that were predictive of relapse during the 12 months after discontinuation were assessed. The median patient age was 54.5 years, and the median disease duration was 3.5 years. Nineteen (47.5%) patients relapsed during the 12 months after the discontinuation of bDMARD therapy. Logistic regression analysis revealed that only the presence of bone erosion detected by ultrasound at discontinuation was predictive of relapse (OR 8.35, 95% CI 1.78-53.2, p = 0.006). No clinical characteristics or serologic biomarkers were significantly different between the relapse and nonrelapse patients. The ultrasound synovitis scores did not differ significantly between the groups. Our findings are the first evidence that ultrasound bone erosion may be a relapse risk factor after the discontinuation of bDMARD therapy in patients with RA whose PD synovitis activity and clinical disease activity are well controlled.

A modifier of Huntington's disease onset at the MLH1 locus.

Science.gov (United States)

Lee, Jong-Min; Chao, Michael J; Harold, Denise; Abu Elneel, Kawther; Gillis, Tammy; Holmans, Peter; Jones, Lesley; Orth, Michael; Myers, Richard H; Kwak, Seung; Wheeler, Vanessa C; MacDonald, Marcy E; Gusella, James F

2017-10-01

Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by an expanded CAG repeat in HTT. Many clinical characteristics of HD such as age at motor onset are determined largely by the size of HTT CAG repeat. However, emerging evidence strongly supports a role for other genetic factors in modifying the disease pathogenesis driven by mutant huntingtin. A recent genome-wide association analysis to discover genetic modifiers of HD onset age provided initial evidence for modifier loci on chromosomes 8 and 15 and suggestive evidence for a locus on chromosome 3. Here, genotyping of candidate single nucleotide polymorphisms in a cohort of 3,314 additional HD subjects yields independent confirmation of the former two loci and moves the third to genome-wide significance at MLH1, a locus whose mouse orthologue modifies CAG length-dependent phenotypes in a Htt-knock-in mouse model of HD. Both quantitative and dichotomous association analyses implicate a functional variant on ∼32% of chromosomes with the beneficial modifier effect that delays HD motor onset by 0.7 years/allele. Genomic DNA capture and sequencing of a modifier haplotype localize the functional variation to a 78 kb region spanning the 3'end of MLH1 and the 5'end of the neighboring LRRFIP2, and marked by an isoleucine-valine missense variant in MLH1. Analysis of expression Quantitative Trait Loci (eQTLs) provides modest support for altered regulation of MLH1 and LRRFIP2, raising the possibility that the modifier affects regulation of both genes. Finally, polygenic modification score and heritability analyses suggest the existence of additional genetic modifiers, supporting expanded, comprehensive genetic analysis of larger HD datasets. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Age by Disease Biological Interactions: Implications for Late-Life Depression

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Brandon eMcKinney

2012-11-01

Full Text Available Onset of depressive symptoms after the age of 65, or late-life depression (LLD, is common and poses a significant burden on affected individuals, caretakers and society. Evidence suggests a unique biological basis for LLD, but current hypotheses do not account for its pathophysiological complexity. Here we propose a novel etiological framework for LLD, the age-by-disease biological interaction hypothesis, based on the observations that the subset of genes that undergoes lifelong progressive changes in expression is restricted to a specific set of biological processes, and that a disproportionate number of these age-dependent genes have been previously and similarly implicated in neurodegenerative and neuropsychiatric disorders, including depression. The age-by-disease biological interaction hypothesis posits that age-dependent biological processes (i are pushed in LLD-promoting directions by changes in gene expression naturally occurring during brain aging, which (ii directly contribute to pathophysiological mechanisms of LLD, and (iii that individual variability in rates of age-dependent changes determines risk or resiliency to develop age-related disorders, including LLD. We review observations supporting this hypothesis, including consistent and specific age-dependent changes in brain gene expression, and their overlap with neuropsychiatric and neurodegenerative disease pathways. We then review preliminary reports supporting the genetic component of this hypothesis. Other potential biological mediators of age-dependent gene changes are proposed. We speculate that studies examining the relative contribution of these mechanisms to age-dependent changes and related disease mechanisms will not only provide critical information on the biology of normal aging of the human brain, but will inform our understanding our age-dependent diseases, in time fostering the development of new interventions for prevention and treatment of age-dependent diseases

Perianal disease, small bowel disease, smoking, prior steroid or early azathioprine/biological therapy are predictors of disease behavior change in patients with Crohn's disease.

Science.gov (United States)

Lakatos, Peter Laszlo; Czegledi, Zsofia; Szamosi, Tamas; Banai, Janos; David, Gyula; Zsigmond, Ferenc; Pandur, Tunde; Erdelyi, Zsuzsanna; Gemela, Orsolya; Papp, Janos; Lakatos, Laszlo

2009-07-28

To assess the combined effect of disease phenotype, smoking and medical therapy [steroid, azathioprine (AZA), AZA/biological therapy] on the probability of disease behavior change in a Caucasian cohort of patients with Crohn's disease (CD). Three hundred and forty well-characterized, unrelated, consecutive CD patients were analyzed (M/F: 155/185, duration: 9.4 +/- 7.5 years) with a complete clinical follow-up. Medical records including disease phenotype according to the Montreal classification, extraintestinal manifestations, use of medications and surgical events were analyzed retrospectively. Patients were interviewed on their smoking habits at the time of diagnosis and during the regular follow-up visits. A change in disease behavior was observed in 30.8% of patients with an initially non-stricturing, non-penetrating disease behavior after a mean disease duration of 9.0 +/- 7.2 years. In a logistic regression analysis corrected for disease duration, perianal disease, smoking, steroid use, early AZA or AZA/biological therapy use were independent predictors of disease behavior change. In a subsequent Kaplan-Meier survival analysis and a proportional Cox regression analysis, disease location (P = 0.001), presence of perianal disease (P < 0.001), prior steroid use (P = 0.006), early AZA (P = 0.005) or AZA/biological therapy (P = 0.002), or smoking (P = 0.032) were independent predictors of disease behavior change. Our data suggest that perianal disease, small bowel disease, smoking, prior steroid use, early AZA or AZA/biological therapy are all predictors of disease behavior change in CD patients.

Top-down approach to biological therapy of Crohn's disease.

Science.gov (United States)

Hirschmann, Simon; Neurath, Markus F

2017-03-01

Crohn's disease (CD) is a chronic, immune-mediated condition with a potentially disabling and destructive course. Despite growing data on when to use a therapeutic 'top-down' strategy, clinical management of this complex disorder is still challenging. Currently, the discussion of 'top-down' strategy in CD mostly includes biological therapy alone or in combination. Areas covered: This article is based on a review of existing literature regarding the use of biological therapy in a 'top-down' approach for the treatment of Crohn's disease. The authors reviewed all the major databases including MEDLINE as well as DDW and ECCO abstracts, respectively. Expert opinion: A 'top-down' therapeutic approach in Crohn's disease is strongly supported by existing data in patients with several risk factors for a severe course of disease. Moreover, there is an increasing amount of published data recommending a more individualised therapeutic strategy to identify candidates for 'top-down' treatment, based on enhanced diagnostics using biomarkers. Emerging therapeutic approaches besides existing therapy concepts using biologicals may possibly redefine the 'top-down' therapeutic strategy for Crohn's disease in the future.

Total and phosphorylated tau protein as biological markers of Alzheimer's disease.

LENUS (Irish Health Repository)

Hampel, Harald

2012-02-01

Advances in our understanding of tau-mediated neurodegeneration in Alzheimer\\'s disease (AD) are moving this disease pathway to center stage for the development of biomarkers and disease modifying drug discovery efforts. Immunoassays were developed detecting total (t-tau) and tau phosphorylated at specific epitopes (p-tauX) in cerebrospinal fluid (CSF), methods to analyse tau in blood are at the experimental beginning. Clinical research consistently demonstrated CSF t- and p-tau increased in AD compared to controls. Measuring these tau species proved informative for classifying AD from relevant differential diagnoses. Tau phosphorylated at threonine 231 (p-tau231) differentiated between AD and frontotemporal dementia, tau phosphorylated at serine 181 (p-tau181) enhanced classification between AD and dementia with Lewy bodies. T- and p-tau are considered "core" AD biomarkers that have been successfully validated by controlled large-scale multi-center studies. Tau biomarkers are implemented in clinical trials to reflect biological activity, mechanisms of action of compounds, support enrichment of target populations, provide endpoints for proof-of-concept and confirmatory trials on disease modification. World-wide quality control initiatives are underway to set required methodological and protocol standards. Discussions with regulatory authorities gain momentum defining the role of tau biomarkers for trial designs and how they may be further qualified for surrogate marker status.

Network biology concepts in complex disease comorbidities

DEFF Research Database (Denmark)

Hu, Jessica Xin; Thomas, Cecilia Engel; Brunak, Søren

2016-01-01

collected electronically, disease co-occurrences are starting to be quantitatively characterized. Linking network dynamics to the real-life, non-ideal patient in whom diseases co-occur and interact provides a valuable basis for generating hypotheses on molecular disease mechanisms, and provides knowledge......The co-occurrence of diseases can inform the underlying network biology of shared and multifunctional genes and pathways. In addition, comorbidities help to elucidate the effects of external exposures, such as diet, lifestyle and patient care. With worldwide health transaction data now often being...

Research on the Hydrophilic Modified of LDPE for the New Biological Suspended Filler

Directory of Open Access Journals (Sweden)

Kang Weijia

2016-01-01

Full Text Available Urban sewage is one of the main pollution sources of the city, which pollute soil, deteriorate the water quality and increase the water shortages and urban load. LDPE is low cost and widely used as the basic material of wastewater treatment, but LDPE’s hydrophilic is not good enough to meet the need of suspended filler in wastewater treatment. In this paper the hydrophilic modified of LDPE for the new biological suspended filler was studied and the preparation and processing technique based on LDPE was researched. The hydrophilic and mechanic performance of the hydrophilic modified materials was tested. Results shown that the new type of hydrophilic modified materials has good hydrophilic and meets the demand of urban sewage treatment. The research on the new suspended filler materials has great meaning in solving the problem of urban sewage and recycling.

Variations in criteria regulating treatment with reimbursed biologic DMARDs across European countries. Are differences related to country's wealth?

DEFF Research Database (Denmark)

Putrik, Polina; Ramiro, Sofia; Kvien, Tore K

2014-01-01

To explore criteria regulating treatment with reimbursed biologic disease-modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) across Europe and to relate criteria to indicators of national socioeconomic welfare.......To explore criteria regulating treatment with reimbursed biologic disease-modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) across Europe and to relate criteria to indicators of national socioeconomic welfare....

Needle-free and microneedle drug delivery in children: a case for disease-modifying antirheumatic drugs (DMARDs).

Science.gov (United States)

Shah, Utpal U; Roberts, Matthew; Orlu Gul, Mine; Tuleu, Catherine; Beresford, Michael W

2011-09-15

Parenteral routes of drug administration have poor acceptability and tolerability in children. Advances in transdermal drug delivery provide a potential alternative for improving drug administration in this patient group. Issues with parenteral delivery in children are highlighted and thus illustrate the scope for the application of needle-free and microneedle technologies. This mini-review discusses the opportunities and challenges for providing disease-modifying antirheumatic drugs (DMARDs) currently prescribed to paediatric rheumatology patients using such technologies. The aim is to raise further awareness of the need for age-appropriate formulations and drug delivery systems and stimulate exploration of these options for DMARDs, and in particular, rapidly emerging biologics on the market. The ability of needle-free and microneedle technologies to deliver monoclonal antibodies and fusion proteins still remains largely untested. Such an understanding is crucial for future drug design opportunities. The bioavailability, safety and tolerance of delivering biologics into the viable epidermis also need to be studied. Copyright © 2011 Elsevier B.V. All rights reserved.

Design, Synthesis, and Biological Evaluation of 2-(Benzylamino-2-HydroxyalkylIsoindoline-1,3-Diones Derivatives as Potential Disease-Modifying Multifunctional Anti-Alzheimer Agents

Directory of Open Access Journals (Sweden)

Dawid Panek

2018-02-01

Full Text Available The complex nature of Alzheimer’s disease calls for multidirectional treatment. Consequently, the search for multi-target-directed ligands may lead to potential drug candidates. The aim of the present study is to seek multifunctional compounds with expected activity against disease-modifying and symptomatic targets. A series of 15 drug-like various substituted derivatives of 2-(benzylamino-2-hydroxyalkylisoindoline-1,3-diones was designed by modification of cholinesterase inhibitors toward β-secretase inhibition. All target compounds have been synthesized and tested against eel acetylcholinesterase (eeAChE, equine serum butyrylcholinesterase (eqBuChE, human β-secretase (hBACE-1, and β-amyloid (Aβ-aggregation. The most promising compound, 12 (2-(5-(benzylamino-4-hydroxypentylisoindoline-1,3-dione, displayed inhibitory potency against eeAChE (IC50 = 3.33 μM, hBACE-1 (43.7% at 50 μM, and Aβ-aggregation (24.9% at 10 μM. Molecular modeling studies have revealed possible interaction of compound 12 with the active sites of both enzymes—acetylcholinesterase and β-secretase. In conclusion: modifications of acetylcholinesterase inhibitors led to the discovery of a multipotent anti-Alzheimer’s agent, with moderate and balanced potency, capable of inhibiting acetylcholinesterase, a symptomatic target, and disease-modifying targets: β-secretase and Aβ-aggregation.

Rheumatoid Arthritis Patients after Initiation of a New Biologic Agent

DEFF Research Database (Denmark)

Courvoisier, D. S.; Alpizar-Rodriguez, D.; Gottenberg, Jacques-Eric

2016-01-01

BACKGROUND: Response to disease modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA) is often heterogeneous. We aimed to identify types of disease activity trajectories following the initiation of a new biologic DMARD (bDMARD). METHODS: Pooled analysis of nine national registries...

Systematic review and meta-analysis of serious infections with tofacitinib and biologic disease-modifying antirheumatic drug treatment in rheumatoid arthritis clinical trials.

Science.gov (United States)

Strand, Vibeke; Ahadieh, Sima; French, Jonathan; Geier, Jamie; Krishnaswami, Sriram; Menon, Sujatha; Checchio, Tina; Tensfeldt, Thomas G; Hoffman, Elaine; Riese, Richard; Boy, Mary; Gómez-Reino, Juan J

2015-12-15

were 2.21 (0.60, 8.14) and 2.02 (0.56, 7.28), respectively. Risk differences (95% CIs) versus placebo for tofacitinib 5 and 10 mg BID were 0.38% (-0.24%, 0.99%) and 0.40% (-0.22%, 1.02%), respectively. In interventional studies, the risk of serious infections with tofacitinib is comparable to published rates for biologic disease-modifying antirheumatic drugs in patients with moderate to severely active RA.

Perianal disease, small bowel disease, smoking, prior steroid or early azathioprine/biological therapy are predictors of disease behavior change in patients with Crohn’s disease

Science.gov (United States)

Lakatos, Peter Laszlo; Czegledi, Zsofia; Szamosi, Tamas; Banai, Janos; David, Gyula; Zsigmond, Ferenc; Pandur, Tunde; Erdelyi, Zsuzsanna; Gemela, Orsolya; Papp, Janos; Lakatos, Laszlo

2009-01-01

AIM: To assess the combined effect of disease phenotype, smoking and medical therapy [steroid, azathioprine (AZA), AZA/biological therapy] on the probability of disease behavior change in a Caucasian cohort of patients with Crohn’s disease (CD). METHODS: Three hundred and forty well-characterized, unrelated, consecutive CD patients were analyzed (M/F: 155/185, duration: 9.4 ± 7.5 years) with a complete clinical follow-up. Medical records including disease phenotype according to the Montreal classification, extraintestinal manifestations, use of medications and surgical events were analyzed retrospectively. Patients were interviewed on their smoking habits at the time of diagnosis and during the regular follow-up visits. RESULTS: A change in disease behavior was observed in 30.8% of patients with an initially non-stricturing, non-penetrating disease behavior after a mean disease duration of 9.0 ± 7.2 years. In a logistic regression analysis corrected for disease duration, perianal disease, smoking, steroid use, early AZA or AZA/biological therapy use were independent predictors of disease behavior change. In a subsequent Kaplan-Meier survival analysis and a proportional Cox regression analysis, disease location (P = 0.001), presence of perianal disease (P < 0.001), prior steroid use (P = 0.006), early AZA (P = 0.005) or AZA/biological therapy (P = 0.002), or smoking (P = 0.032) were independent predictors of disease behavior change. CONCLUSION: Our data suggest that perianal disease, small bowel disease, smoking, prior steroid use, early AZA or AZA/biological therapy are all predictors of disease behavior change in CD patients. PMID:19630105

Beyond disease susceptibility-Leveraging genome-wide association studies for new insights into complex disease biology.

Science.gov (United States)

Lee, J C

2017-12-01

Genetic studies in complex diseases have been highly successful, but have also been largely one-dimensional: predominantly focusing on the genetic contribution to disease susceptibility. While this is undoubtedly important-indeed it is a pre-requisite for understanding the mechanisms underlying disease development-there are many other important aspects of disease biology that have received comparatively little attention. In this review, I will discuss how existing genetic data can be leveraged to provide new insights into other aspects of disease biology, why such insights could change the way we think about complex disease, and how this could provide opportunities for better therapies and/or facilitate personalised medicine. To do this, I will use the example of Crohn's disease-a chronic form of inflammatory bowel disease that has been one of the main success stories in complex disease genetics. Indeed, thanks to genetic studies, we now have a much more detailed understanding of the processes involved in Crohn's disease development, but still know relatively little about what determines the subsequent disease course (prognosis) and why this differs so considerably between individuals. I will discuss how we came to realise that genetic variation plays an important role in determining disease prognosis and how this has changed the way we think about Crohn's disease genetics. This will illustrate how phenotypic data can be used to leverage new insights from genetic data and will provide a broadly applicable framework that could yield new insights into the biology of multiple diseases. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Potential of chromatin modifying compounds for the treatment of Alzheimer's disease.

Science.gov (United States)

Karagiannis, Tom C; Ververis, Katherine

2012-01-01

Alzheimer's disease is a very common progressive neurodegenerative disorder affecting the learning and memory centers in the brain. The hallmarks of disease are the accumulation of β-amyloid neuritic plaques and neurofibrillary tangles formed by abnormally phosphorylated tau protein. Alzheimer's disease is currently incurable and there is an intense interest in the development of new potential therapies. Chromatin modifying compounds such as sirtuin modulators and histone deacetylase inhibitors have been evaluated in models of Alzheimer's disease with some promising results. For example, the natural antioxidant and sirtuin 1 activator resveratrol has been shown to have beneficial effects in animal models of disease. Similarly, numerous histone deacetylase inhibitors including Trichostatin A, suberoylanilide hydroxamic acid, valproic acid and phenylbutyrate reduction have shown promising results in models of Alzheimer's disease. These beneficial effects include a reduction of β-amyloid production and stabilization of tau protein. In this review we provide an overview of the histone deacetylase enzymes, with a focus on enzymes that have been identified to have an important role in the pathobiology of Alzheimer's disease. Further, we discuss the potential for pharmacological intervention with chromatin modifying compounds that modulate histone deacetylase enzymes.

Potential of chromatin modifying compounds for the treatment of Alzheimer's disease

Directory of Open Access Journals (Sweden)

Tom C. Karagiannis

2012-02-01

Full Text Available Alzheimer's disease is a very common progressive neurodegenerative disorder affecting the learning and memory centers in the brain. The hallmarks of disease are the accumulation of β-amyloid neuritic plaques and neurofibrillary tangles formed by abnormally phosphorylated tau protein. Alzheimer's disease is currently incurable and there is an intense interest in the development of new potential therapies. Chromatin modifying compounds such as sirtuin modulators and histone deacetylase inhibitors have been evaluated in models of Alzheimer's disease with some promising results. For example, the natural antioxidant and sirtuin 1 activator resveratrol has been shown to have beneficial effects in animal models of disease. Similarly, numerous histone deacetylase inhibitors including Trichostatin A, suberoylanilide hydroxamic acid, valproic acid and phenylbutyrate reduction have shown promising results in models of Alzheimer's disease. These beneficial effects include a reduction of β-amyloid production and stabilization of tau protein. In this review we provide an overview of the histone deacetylase enzymes, with a focus on enzymes that have been identified to have an important role in the pathobiology of Alzheimer's disease. Further, we discuss the potential for pharmacological intervention with chromatin modifying compounds that modulate histone deacetylase enzymes.

Demographic, genetic, and environmental factors that modify disease course.

Science.gov (United States)

Marrie, Ruth Ann

2011-05-01

As with susceptibility to disease, it is likely that multiple factors interact to influence the phenotype of multiple sclerosis and long-term disease outcomes. Such factors may include genetic factors, socioeconomic status, comorbid diseases, and health behaviors, as well as environmental exposures. An improved understanding of the influence of these factors on disease course may reap several benefits, such as improved prognostication, allowing us to tailor disease management with respect to intensity of disease-modifying therapies and changes in specific health behaviors, in the broad context of coexisting health issues. Such information can facilitate appropriately adjusted comparisons within and between populations. Elucidation of these factors will require careful study of well-characterized populations in which the roles of multiple factors are considered simultaneously. Copyright © 2011 Elsevier Inc. All rights reserved.

Development and validation of modified disease activity scores in rheumatoid arthritis

DEFF Research Database (Denmark)

Baker, Joshua F; Conaghan, Philip G; Smolen, Josef S

2014-01-01

-CDAI) were generated for each subject in the validation cohort. The M-DAS28, M-SDAI, and M-CDAI scores were compared to conventional scores of disease activity with regard to associations with MRI measures of synovitis and radiographic progression, assessed using Pearson's and Spearman's correlations, linear......OBJECTIVE: To develop and validate composite disease activity scores, based on widely available clinical measures, that would demonstrate improved correlation with detection of synovitis on magnetic resonance imaging (MRI) and radiographic progression, in comparison with conventional measures.......15 × SJC28 + 0.22 × EvGA + 1 and M-SDAI = CRP + SJC28 + EvGA. Both modified and conventional disease activity scores correlated significantly with MRI measures of synovitis. Modified scores showed superior correlation with synovitis, as compared to conventional scores, at all time points (P

Benefits and costs of biologically contained genetically modified tomatoes and eggplants in Italy and Spain

NARCIS (Netherlands)

Groeneveld, R.A.; Ansink, E.; Wiel, van de C.C.M.; Wesseler, J.H.H.

2011-01-01

In this paper we assess the benefits and costs of introducing biologically contained genetically modified (GM) crops, with an application to the potential introduction of GM tomatoes and eggplants in Italy and Spain. Such crops possess both the standard beneficial GM traits, and they prevent

Potentials of single-cell biology in identification and validation of disease biomarkers.

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Niu, Furong; Wang, Diane C; Lu, Jiapei; Wu, Wei; Wang, Xiangdong

2016-09-01

Single-cell biology is considered a new approach to identify and validate disease-specific biomarkers. However, the concern raised by clinicians is how to apply single-cell measurements for clinical practice, translate the message of single-cell systems biology into clinical phenotype or explain alterations of single-cell gene sequencing and function in patient response to therapies. This study is to address the importance and necessity of single-cell gene sequencing in the identification and development of disease-specific biomarkers, the definition and significance of single-cell biology and single-cell systems biology in the understanding of single-cell full picture, the development and establishment of whole-cell models in the validation of targeted biological function and the figure and meaning of single-molecule imaging in single cell to trace intra-single-cell molecule expression, signal, interaction and location. We headline the important role of single-cell biology in the discovery and development of disease-specific biomarkers with a special emphasis on understanding single-cell biological functions, e.g. mechanical phenotypes, single-cell biology, heterogeneity and organization of genome function. We have reason to believe that such multi-dimensional, multi-layer, multi-crossing and stereoscopic single-cell biology definitely benefits the discovery and development of disease-specific biomarkers. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Modified clay minerals efficiency against chemical and biological warfare agents for civil human protection.

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Plachá, Daniela; Rosenbergová, Kateřina; Slabotínský, Jiří; Kutláková, Kateřina Mamulová; Studentová, Soňa; Martynková, Gražyna Simha

2014-04-30

Sorption efficiencies of modified montmorillonite and vermiculite of their mono ionic Na and organic HDTMA and HDP forms were studied against chemical and biological warfare agents such as yperite and selected bacterial strains. Yperite interactions with modified clay minerals were observed through its capture in low-density polyethylene foil-modified clay composites by measuring yperite gas permeation with using chemical indication and gas chromatography methods. The antibacterial activities of synthetized organoclays were tested against selected Gram-positive and Gram-negative bacterial species in minimum inhibitory concentration tests. The obtained results showed a positive influence of modified clay minerals on the significant yperite breakthrough-time increase. The most effective material was the polyethylene-Na form montmorillonite, while the polyethylene-Na form vermiculite showed the lowest efficiency. With increasing organic cations loading in the interlayer space the montmorillonite efficiency decreased, and in the case of vermiculite an opposite effect was observed. Generally the modified montmorillonites were more effective than modified vermiculites. The HDP cations seem to be more effective compare to the HDTMA. The antibacterial activity tests confirmed efficiency of all organically modified clay minerals against Gram-positive bacteria. The confirmation of antibacterial activity against Y. pestis, plague bacteria, is the most interesting result of this part of the study. Copyright © 2014 Elsevier B.V. All rights reserved.

Modulation at Age of Onset in Tunisian Huntington Disease Patients: Implication of New Modifier Genes

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Dorra Hmida-Ben Brahim

2014-01-01

Full Text Available Huntington’s disease (HD is an autosomal dominant neurodegenerative disorder. The causative mutation is an expansion of more than 36 CAG repeats in the first exon of IT15 gene. Many studies have shown that the IT15 interacts with several modifier genes to regulate the age at onset (AO of HD. Our study aims to investigate the implication of CAG expansion and 9 modifiers in the age at onset variance of 15 HD Tunisian patients and to establish the correlation between these modifiers genes and the AO of this disease. Despite the small number of studied patients, this report consists of the first North African study in Huntington disease patients. Our results approve a specific effect of modifiers genes in each population.

Benefits and Costs of Biologically Contained Genetically Modified Tomatoes and Eggplants in Italy and Spain

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Rolf A. Groeneveld

2011-08-01

Full Text Available In this paper we assess the benefits and costs of introducing biologically contained genetically modified (GM crops, with an application to the potential introduction of GM tomatoes and eggplants in Italy and Spain. Such crops possess both the standard beneficial GM traits, and they prevent introgression of transgenes from GM crops to their conventional or wild relatives, thereby adding to the safety of their cultivation. As a result, coexistence regulations for these crops are less stringent than for crops without biological containment. The potential adoption of biologically contained GM tomatoes and eggplants is assessed in a cost-benefit framework for Italy and Spain. We conclude that biological containment has considerable potential benefits if policy makers are willing to loosen the restrictions on the introduction of these varieties.

Vitamin D deficiency in patients with either rheumatic diseases or inflammatory bowel diseases on biologic therapy.

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Bruzzese, Vincenzo; Zullo, Angelo; Picchianti Diamanti, Andrea; Ridola, Lorenzo; Lorenzetti, Roberto; Marrese, Cinzia; Scolieri, Palma; De Francesco, Vincenzo; Hassan, Cesare; Migliore, Alberto; Laganà, Bruno

2016-09-01

Vitamin D deficiency has been reported in patients with chronic inflammatory conditions, such as rheumatic and inflammatory bowel diseases (IBD). We evaluated the role of biologic therapy on vitamin D, calcium and parathormone (PTH) levels. This cross-sectional study enrolled consecutive patients with either rheumatic diseases or IBD who underwent an ambulatory visit. Patients receiving vitamin D/calcium supplementation were excluded. Vitamin D deficiency or insufficiency was diagnosed when values were rheumatic disease (M/F 37/99; mean age 60.7 ± 12.9 years) and 64 with IBD (M/F 41/23; Mean age 49.6 ± 13.1 years) were enrolled. Vitamin D deficiency/insufficiency was detected in as many as 63.5 % patients, being 61.8 and 67.2 % in patients with either rheumatic diseases or IBD, respectively. The prevalence of vitamin D deficiency/insufficiency was higher in those receiving biologics than other therapies (78.3 vs 43.2 %; p rheumatic diseases (78.7 vs 41 %; p rheumatic diseases or IBD receiving a biologic therapy.

Guidance for Modifying the Definition of Diseases: A Checklist.

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Doust, Jenny; Vandvik, Per O; Qaseem, Amir; Mustafa, Reem A; Horvath, Andrea R; Frances, Allen; Al-Ansary, Lubna; Bossuyt, Patrick; Ward, Robyn L; Kopp, Ina; Gollogly, Laragh; Schunemann, Holger; Glasziou, Paul

2017-07-01

No guidelines exist currently for guideline panels and others considering changes to disease definitions. Panels frequently widen disease definitions, increasing the proportion of the population labeled as unwell and potentially causing harm to patients. We set out to develop a checklist of issues, with guidance, for panels to consider prior to modifying a disease definition. We assembled a multidisciplinary, multicontinent working group of 13 members, including members from the Guidelines International Network, Grading of Recommendations Assessment, Development and Evaluation working group, and the World Health Organisation. We used a 5-step process to develop the checklist: (1) a literature review of issues, (2) a draft outline document, (3) a Delphi process of feedback on the list of issues, (4) a 1-day face-to-face meeting, and (5) further refinement of the checklist. The literature review identified 12 potential issues. From these, the group developed an 8-item checklist that consisted of definition changes, number of people affected, trigger, prognostic ability, disease definition precision and accuracy, potential benefits, potential harms, and the balance between potential harms and benefits. The checklist is accompanied by an explanation of each item and the types of evidence to assess each one. We used a panel's recent consideration of a proposed change in the definition of gestational diabetes mellitus (GDM) to illustrate use of the checklist. We propose that the checklist be piloted and validated by groups developing new guidelines. We anticipate that the use of the checklist will be a first step to guidance and better documentation of definition changes prior to introducing modified disease definitions.

Relationships Between Essential Manganese Biology and Manganese Toxicity in Neurological Disease.

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Pfalzer, Anna C; Bowman, Aaron B

2017-06-01

Manganese (Mn) is critical for neurodevelopment but also has been implicated in the pathophysiology of several neurological diseases. We discuss how Mn requirements intersect with Mn biology and toxicity, and how these requirements may be altered in neurological disease. Furthermore, we discuss the emerging evidence that the level of Mn associated with optimal overall efficiency for Mn biology does not necessarily coincide with optimal cognitive outcomes. Studies have linked Mn exposures with urea cycle metabolism and autophagy, with evidence that exposures typically neurotoxic may be able to correct deficiencies in these processes at least short term. The line between Mn-dependent biology and toxicity is thus blurred. Further, new work suggests that Mn exposures correlating to optimal cognitive scores in children are associated with cognitive decline in adults. This review explores relationships between Mn-dependent neurobiology and Mn-dependent neurotoxicity. We propose the hypothesis that Mn levels/exposures that are toxic to some biological processes are beneficial for other biological processes and influenced by developmental stage and disease state.

The DNA-damage response in human biology and disease

DEFF Research Database (Denmark)

Jackson, Stephen P; Bartek, Jiri

2009-01-01

, signal its presence and mediate its repair. Such responses, which have an impact on a wide range of cellular events, are biologically significant because they prevent diverse human diseases. Our improving understanding of DNA-damage responses is providing new avenues for disease management....

Modelling biological control with wild-type and genetically modified baculoviruses in the Helicoverpa armigera-cotton system

NARCIS (Netherlands)

Sun, X.; Werf, van der W.; Bianchi, F.J.J.A.; Hu, Z.; Vlak, J.M.

2006-01-01

A comprehensive model was developed to simulate virus epizootics in a stage structured insect population and analyse scenarios for the biological control of cotton bollworm (CBW), Helicoverpa armigera, in cotton, using wild-type or genetically modified baculoviruses. In simulations on dosage and

Developing Disease-Modifying Treatments in Alzheimer's Disease - A Perspective from Roche and Genentech.

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Doody, R

2017-01-01

Alzheimer's disease (AD) is a chronic neurodegenerative disease for which no preventative or disease-modifying treatments currently exist. Pathological hallmarks include amyloid plaques and neurofibrillary tangles composed of hyper-phosphorylated tau protein. Evidence suggests that both pathologies are self-propagating once established. However, the lag time between neuropathological changes in the brain and the onset of even subtle clinical symptomatology means that patients are often diagnosed late when pathology, and neurodegeneration secondary to these changes, may have been established for several years. Complex pathological pathways associated with susceptibility to AD and changes that occur downstream of the neuropathologic process further contribute to the challenging endeavour of developing novel disease-modifying therapy. Recognising this complexity, effective management of AD must include reliable screening and early diagnosis in combination with effective therapeutic management of the pathological processes. Roche and Genentech are committed to addressing these unmet needs through developing a comprehensive portfolio of diagnostics and novel therapies. Beginning with the most scientifically supported targets, this approach includes two targeted amyloid-β monoclonal antibody therapies, crenezumab and gantenerumab, and an anti-tau monoclonal antibody, RO7105705, as well as a robust biomarker platform to aid in the early identification of people at risk or in the early stages of AD. Identification and implementation of diagnostic tools will support the enrolment of patients into clinical trials; furthermore, these tools should also support evaluation of the clinical efficacy and safety profile of the novel therapeutic agents tested in these trials. This review discusses the therapeutic agents currently under clinical development.

CLC-2 single nucleotide polymorphisms (SNPs) as potential modifiers of cystic fibrosis disease severity

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Blaisdell, Carol J; Howard, Timothy D; Stern, Augustus; Bamford, Penelope; Bleecker, Eugene R; Stine, O Colin

2004-01-01

Background Cystic fibrosis (CF) lung disease manifest by impaired chloride secretion leads to eventual respiratory failure. Candidate genes that may modify CF lung disease severity include alternative chloride channels. The objectives of this study are to identify single nucleotide polymorphisms (SNPs) in the airway epithelial chloride channel, CLC-2, and correlate these polymorphisms with CF lung disease. Methods The CLC-2 promoter, intron 1 and exon 20 were examined for SNPs in adult CF dF508/dF508 homozygotes with mild and severe lung disease (forced expiratory volume at one second (FEV1) > 70% and < 40%). Results PCR amplification of genomic CLC-2 and sequence analysis revealed 1 polymorphism in the hClC -2 promoter, 4 in intron 1, and none in exon 20. Fisher's analysis within this data set, did not demonstrate a significant relationship between the severity of lung disease and SNPs in the CLC-2 gene. Conclusions CLC-2 is not a key modifier gene of CF lung phenotype. Further studies evaluating other phenotypes associated with CF may be useful in the future to assess the ability of CLC-2 to modify CF disease severity. PMID:15507145

CLC-2 single nucleotide polymorphisms (SNPs as potential modifiers of cystic fibrosis disease severity

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Bleecker Eugene R

2004-10-01

Full Text Available Abstract Background Cystic fibrosis (CF lung disease manifest by impaired chloride secretion leads to eventual respiratory failure. Candidate genes that may modify CF lung disease severity include alternative chloride channels. The objectives of this study are to identify single nucleotide polymorphisms (SNPs in the airway epithelial chloride channel, CLC-2, and correlate these polymorphisms with CF lung disease. Methods The CLC-2 promoter, intron 1 and exon 20 were examined for SNPs in adult CF dF508/dF508 homozygotes with mild and severe lung disease (forced expiratory volume at one second (FEV1 > 70% and Results PCR amplification of genomic CLC-2 and sequence analysis revealed 1 polymorphism in the hClC -2 promoter, 4 in intron 1, and none in exon 20. Fisher's analysis within this data set, did not demonstrate a significant relationship between the severity of lung disease and SNPs in the CLC-2 gene. Conclusions CLC-2 is not a key modifier gene of CF lung phenotype. Further studies evaluating other phenotypes associated with CF may be useful in the future to assess the ability of CLC-2 to modify CF disease severity.

An Integrative Systems Biology Approach to Understanding Pulmonary Diseases

NARCIS (Netherlands)

Auffray, Charles; Adcock, Ian M.; Chung, Kian Fan; Djukanovic, Ratko; Pison, Christophe; Sterk, Peter J.

2010-01-01

Chronic inflammatory pulmonary diseases such as COPD and asthma are highly prevalent and associated with a major health burden worldwide. Despite a wealth of biologic and clinical information on normal and pathologic airway structure and function, the primary causes and mechanisms of disease remain

Social-Biological Interactions in Oral Disease: A 'Cells to Society' View.

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Noha Gomaa

Full Text Available Oral diseases constitute a major worldwide public health problem, with their burden concentrating in socially disadvantaged and less affluent groups of the population, resulting in significant oral health inequalities. Biomedical and behavioural approaches have proven relatively ineffective in reducing these inequalities, and have potentially increased the health gap between social groups. Some suggest this stems from a lack of understanding of how the social and psychosocial contexts in which behavioural and biological changes occur influence oral disease. To unravel the pathways through which social factors affect oral health outcomes, a better understanding is thus needed of how the social 'gets under the skin,' or becomes embodied, to alter the biological. In this paper, we present the current knowledge on the interplay between social and biological factors in oral disease. We first provide an overview of the process of embodiment in chronic disease and then evaluate the evidence on embodiment in oral disease by reviewing published studies in this area. Results show that, in periodontal disease, income, education and perceived stress are correlated with elevated levels of stress hormones, disrupted immune biomarkers and increased allostatic load. Similarly, socioeconomic position and increased financial stress are related to increased stress hormones and cariogenic bacterial counts in dental caries. Based on these results, we propose a dynamic model depicting social-biological interactions that illustrates potential interdependencies between social and biological factors that lead to poor oral health. This work and the proposed model may aid in developing a better understanding of the causes of oral health inequalities and implicate the importance of addressing the social determinants of oral health in innovating public health interventions.

Using biological networks to improve our understanding of infectious diseases

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Nicola J. Mulder

2014-08-01

Full Text Available Infectious diseases are the leading cause of death, particularly in developing countries. Although many drugs are available for treating the most common infectious diseases, in many cases the mechanism of action of these drugs or even their targets in the pathogen remain unknown. In addition, the key factors or processes in pathogens that facilitate infection and disease progression are often not well understood. Since proteins do not work in isolation, understanding biological systems requires a better understanding of the interconnectivity between proteins in different pathways and processes, which includes both physical and other functional interactions. Such biological networks can be generated within organisms or between organisms sharing a common environment using experimental data and computational predictions. Though different data sources provide different levels of accuracy, confidence in interactions can be measured using interaction scores. Connections between interacting proteins in biological networks can be represented as graphs and edges, and thus studied using existing algorithms and tools from graph theory. There are many different applications of biological networks, and here we discuss three such applications, specifically applied to the infectious disease tuberculosis, with its causative agent Mycobacterium tuberculosis and host, Homo sapiens. The applications include the use of the networks for function prediction, comparison of networks for evolutionary studies, and the generation and use of host–pathogen interaction networks.

Measures of Rheumatoid Arthritis Disease Activity in Australian Clinical Practice

OpenAIRE

Taylor, Andrew; Bagga, Hanish

2011-01-01

Objectives. To investigate which rheumatoid arthritis (RA) disease activity measures are being collected in patients receiving glucocorticoids, non-biologic or biologic disease-modifying antirheumatic drugs (DMARDs) in Australian rheumatology practice. Methods. A retrospective audit of medical records was conducted from eight rheumatology practices around Australia. Each rheumatologist recruited 30 consecutive eligible patients into the review, 10 of whom must have been receiving a biological...

Impaired Perception of Biological Motion in Parkinson’s Disease

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Jaywant, Abhishek; Shiffrar, Maggie; Roy, Serge; Cronin-Golomb, Alice

2016-01-01

Objective We examined biological motion perception in Parkinson’s disease (PD). Biological motion perception is related to one’s own motor function and depends on the integrity of brain areas affected in PD, including posterior superior temporal sulcus. If deficits in biological motion perception exist, they may be specific to perceiving natural/fast walking patterns that individuals with PD can no longer perform, and may correlate with disease-related motor dysfunction. Method 26 non-demented individuals with PD and 24 control participants viewed videos of point-light walkers and scrambled versions that served as foils, and indicated whether each video depicted a human walking. Point-light walkers varied by gait type (natural, parkinsonian) and speed (0.5, 1.0, 1.5 m/s). Participants also completed control tasks (object motion, coherent motion perception), a contrast sensitivity assessment, and a walking assessment. Results The PD group demonstrated significantly less sensitivity to biological motion than the control group (pperception (p=.02, Cohen’s d=.68). There was no group difference in coherent motion perception. Although individuals with PD had slower walking speed and shorter stride length than control participants, gait parameters did not correlate with biological motion perception. Contrast sensitivity and coherent motion perception also did not correlate with biological motion perception. Conclusion PD leads to a deficit in perceiving biological motion, which is independent of gait dysfunction and low-level vision changes, and may therefore arise from difficulty perceptually integrating form and motion cues in posterior superior temporal sulcus. PMID:26949927

Proteome-wide Structural Analysis of PTM Hotspots Reveals Regulatory Elements Predicted to Impact Biological Function and Disease.

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Torres, Matthew P; Dewhurst, Henry; Sundararaman, Niveda

2016-11-01

Post-translational modifications (PTMs) regulate protein behavior through modulation of protein-protein interactions, enzymatic activity, and protein stability essential in the translation of genotype to phenotype in eukaryotes. Currently, less than 4% of all eukaryotic PTMs are reported to have biological function - a statistic that continues to decrease with an increasing rate of PTM detection. Previously, we developed SAPH-ire (Structural Analysis of PTM Hotspots) - a method for the prioritization of PTM function potential that has been used effectively to reveal novel PTM regulatory elements in discrete protein families (Dewhurst et al., 2015). Here, we apply SAPH-ire to the set of eukaryotic protein families containing experimental PTM and 3D structure data - capturing 1,325 protein families with 50,839 unique PTM sites organized into 31,747 modified alignment positions (MAPs), of which 2010 (∼6%) possess known biological function. Here, we show that using an artificial neural network model (SAPH-ire NN) trained to identify MAP hotspots with biological function results in prediction outcomes that far surpass the use of single hotspot features, including nearest neighbor PTM clustering methods. We find the greatest enhancement in prediction for positions with PTM counts of five or less, which represent 98% of all MAPs in the eukaryotic proteome and 90% of all MAPs found to have biological function. Analysis of the top 1092 MAP hotspots revealed 267 of truly unknown function (containing 5443 distinct PTMs). Of these, 165 hotspots could be mapped to human KEGG pathways for normal and/or disease physiology. Many high-ranking hotspots were also found to be disease-associated pathogenic sites of amino acid substitution despite the lack of observable PTM in the human protein family member. Taken together, these experiments demonstrate that the functional relevance of a PTM can be predicted very effectively by neural network models, revealing a large but testable

MSD-MAP: A Network-Based Systems Biology Platform for Predicting Disease-Metabolite Links.

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Wathieu, Henri; Issa, Naiem T; Mohandoss, Manisha; Byers, Stephen W; Dakshanamurthy, Sivanesan

2017-01-01

Cancer-associated metabolites result from cell-wide mechanisms of dysregulation. The field of metabolomics has sought to identify these aberrant metabolites as disease biomarkers, clues to understanding disease mechanisms, or even as therapeutic agents. This study was undertaken to reliably predict metabolites associated with colorectal, esophageal, and prostate cancers. Metabolite and disease biological action networks were compared in a computational platform called MSD-MAP (Multi Scale Disease-Metabolite Association Platform). Using differential gene expression analysis with patient-based RNAseq data from The Cancer Genome Atlas, genes up- or down-regulated in cancer compared to normal tissue were identified. Relational databases were used to map biological entities including pathways, functions, and interacting proteins, to those differential disease genes. Similar relational maps were built for metabolites, stemming from known and in silico predicted metabolite-protein associations. The hypergeometric test was used to find statistically significant relationships between disease and metabolite biological signatures at each tier, and metabolites were assessed for multi-scale association with each cancer. Metabolite networks were also directly associated with various other diseases using a disease functional perturbation database. Our platform recapitulated metabolite-disease links that have been empirically verified in the scientific literature, with network-based mapping of jointly-associated biological activity also matching known disease mechanisms. This was true for colorectal, esophageal, and prostate cancers, using metabolite action networks stemming from both predicted and known functional protein associations. By employing systems biology concepts, MSD-MAP reliably predicted known cancermetabolite links, and may serve as a predictive tool to streamline conventional metabolomic profiling methodologies. Copyright© Bentham Science Publishers; For any

Biological Control Strategies for Mosquito Vectors of Arboviruses.

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Huang, Yan-Jang S; Higgs, Stephen; Vanlandingham, Dana L

2017-02-10

Historically, biological control utilizes predatory species and pathogenic microorganisms to reduce the population of mosquitoes as disease vectors. This is particularly important for the control of mosquito-borne arboviruses, which normally do not have specific antiviral therapies available. Although development of resistance is likely, the advantages of biological control are that the resources used are typically biodegradable and ecologically friendly. Over the past decade, the advancement of molecular biology has enabled optimization by the manipulation of genetic materials associated with biological control agents. Two significant advancements are the discovery of cytoplasmic incompatibility induced by Wolbachia bacteria, which has enhanced replacement programs, and the introduction of dominant lethal genes into local mosquito populations through the release of genetically modified mosquitoes. As various arboviruses continue to be significant public health threats, biological control strategies have evolved to be more diverse and become critical tools to reduce the disease burden of arboviruses.

Improved ability of biological and previous caries multimarkers to predict caries disease as revealed by multivariate PLS modelling

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Ericson Thorild

2009-11-01

Full Text Available Abstract Background Dental caries is a chronic disease with plaque bacteria, diet and saliva modifying disease activity. Here we have used the PLS method to evaluate a multiplicity of such biological variables (n = 88 for ability to predict caries in a cross-sectional (baseline caries and prospective (2-year caries development setting. Methods Multivariate PLS modelling was used to associate the many biological variables with caries recorded in thirty 14-year-old children by measuring the numbers of incipient and manifest caries lesions at all surfaces. Results A wide but shallow gliding scale of one fifth caries promoting or protecting, and four fifths non-influential, variables occurred. The influential markers behaved in the order of plaque bacteria > diet > saliva, with previously known plaque bacteria/diet markers and a set of new protective diet markers. A differential variable patterning appeared for new versus progressing lesions. The influential biological multimarkers (n = 18 predicted baseline caries better (ROC area 0.96 than five markers (0.92 and a single lactobacilli marker (0.7 with sensitivity/specificity of 1.87, 1.78 and 1.13 at 1/3 of the subjects diagnosed sick, respectively. Moreover, biological multimarkers (n = 18 explained 2-year caries increment slightly better than reported before but predicted it poorly (ROC area 0.76. By contrast, multimarkers based on previous caries predicted alone (ROC area 0.88, or together with biological multimarkers (0.94, increment well with a sensitivity/specificity of 1.74 at 1/3 of the subjects diagnosed sick. Conclusion Multimarkers behave better than single-to-five markers but future multimarker strategies will require systematic searches for improved saliva and plaque bacteria markers.

Disease-threat model explains acceptance of genetically modified products

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Prokop Pavol

2013-01-01

Full Text Available Natural selection favoured survival of individuals who were able to avoid disease. The behavioural immune system is activated especially when our sensory system comes into contact with disease-connoting cues and/or when these cues resemble disease threat. We investigated whether or not perception of modern risky technologies, risky behaviour, expected reproductive goals and food neophobia are associated with the behavioural immune system related to specific attitudes toward genetically modified (GM products. We found that respondents who felt themselves more vulnerable to infectious diseases had significantly more negative attitudes toward GM products. Females had less positive attitudes toward GM products, but engaging in risky behaviours, the expected reproductive goals of females and food neophobia did not predict attitudes toward GM products. Our results suggest that evolved psychological mechanisms primarily designed to protect us against pathogen threat are activated by modern technologies possessing potential health risks.

[The trend of developing new disease-modifying drugs in Alzheimer's disease].

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Arai, Hiroyuki; Furukawa, Katsutoshi; Tomita, Naoki; Ishiki, Aiko; Okamura, Nobuyuki; Kudo, Yukitsuka

2016-03-01

Development of symptomatic treatment of Alzheimer s disease by cholinesterase inhibitors like donepezil was successful. However, it is a disappointment that development of disease-modifying drugs such as anti-amyloid drug based on amyloid-cascade theory has been interrupted or unsuccessful. Therefore, we have to be more cautious regarding inclusion criteria for clinical trials of new drugs. We agree that potentially curative drugs should be started before symptoms begin as a preemptive therapy or prevention trial. The concept of personalized medicine also is important when ApoE4-related amyloid reducing therapy is considered. Unfortunately, Japanese-ADNI has suffered a setback since 2014. However, Ministry of Health, Labour and Welfare gave a final remark that there was nothing wrong in the data managing process in the J-ADNI data center. We should pay more attention to worldwide challenges of speeding up new drug development.

Analysis of the Threat of Genetically Modified Organisms for Biological Warfare

Science.gov (United States)

2011-05-01

biological warfare. The primary focus of the framework are those aspects of the technology directly affecting humans by inducing virulent infectious disease...applications. Simple organisms such as fruit flies have been used to study the effects of genetic changes across generations. Transgenic mice are...Analysis * Multi-cell pathogens * Toxins (Chemical products of living cells.) * Fungi (Robust organism; no genetic manipulation needed

Systems Biology of Meridians, Acupoints, and Chinese Herbs in Disease

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Li-Ling Lin

2012-01-01

Full Text Available Meridians, acupoints, and Chinese herbs are important components of traditional Chinese medicine (TCM. They have been used for disease treatment and prevention and as alternative and complementary therapies. Systems biology integrates omics data, such as transcriptional, proteomic, and metabolomics data, in order to obtain a more global and complete picture of biological activity. To further understand the existence and functions of the three components above, we reviewed relevant research in the systems biology literature and found many recent studies that indicate the value of acupuncture and Chinese herbs. Acupuncture is useful in pain moderation and relieves various symptoms arising from acute spinal cord injury and acute ischemic stroke. Moreover, Chinese herbal extracts have been linked to wound repair, the alleviation of postmenopausal osteoporosis severity, and anti-tumor effects, among others. Different acupoints, variations in treatment duration, and herbal extracts can be used to alleviate various symptoms and conditions and to regulate biological pathways by altering gene and protein expression. Our paper demonstrates how systems biology has helped to establish a platform for investigating the efficacy of TCM in treating different diseases and improving treatment strategies.

Modifier genes: Moving from pathogenesis to therapy.

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McCabe, Edward R B

2017-09-01

This commentary will focus on how we can use our knowledge about the complexity of human disease and its pathogenesis to identify novel approaches to therapy. We know that even for single gene Mendelian disorders, patients with identical mutations often have different presentations and outcomes. This lack of genotype-phenotype correlation led us and others to examine the roles of modifier genes in the context of biological networks. These investigations have utilized vertebrate and invertebrate model organisms. Since one of the goals of research on modifier genes and networks is to identify novel therapeutic targets, the challenges to patient access and compliance because of the high costs of medications for rare genetic diseases must be recognized. A recent article explored protective modifiers, including plastin 3 (PLS3) and coronin 1C (CORO1C), in spinal muscular atrophy (SMA). SMA is an autosomal recessive deficit of survival motor neuron protein (SMN) caused by mutations in SMN1. However, the severity of SMA is determined primarily by the number of SMN2 copies, and this results in significant phenotypic variability. PLS3 was upregulated in siblings who were asymptomatic compared with those who had SMA2 or SMA3, but identical homozygous SMN1 deletions and equal numbers of SMN2 copies. CORO1C was identified by interrogation of the PLS3 interactome. Overexpression of these proteins rescued endocytosis in SMA models. In addition, antisense RNA for upregulation of SMN2 protein expression is being developed as another way of modifying the SMA phenotype. These investigations suggest the practical application of protective modifiers to rescue SMA phenotypes. Other examples of the potential therapeutic value of novel protective modifiers will be discussed, including in Duchenne muscular dystrophy and glycerol kinase deficiency. This work shows that while we live in an exciting era of genomic sequencing, a functional understanding of biology, the impact of its

Mining tissue specificity, gene connectivity and disease association to reveal a set of genes that modify the action of disease causing genes

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Reverter Antonio

2008-09-01

genes. Our guilt-by-association algorithm should be useful for the discovery of additional modifiers of genetic diseases, and more generally, for the ability to associate genes of unknown function to clusters of genes with defined functions allowing for novel biological inference that can be subsequently validated.

Modifiable Cardiovascular Disease Risk Factors among Indigenous Populations

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Adam A. Lucero

2014-01-01

Full Text Available Objective. To identify modifiable cardio-metabolic and lifestyle risk factors among indigenous populations from Australia (Aboriginal Australians/Torres Strait Islanders, New Zealand (Māori, and the United States (American Indians and Alaska Natives that contribute to cardiovascular disease (CVD. Methods. National health surveys were identified where available. Electronic databases identified sources for filling missing data. The most relevant data were identified, organized, and synthesized. Results. Compared to their non-indigenous counterparts, indigenous populations exhibit lower life expectancies and a greater prevalence of CVD. All indigenous populations have higher rates of obesity and diabetes, hypertension is greater for Māori and Aboriginal Australians, and high cholesterol is greater only among American Indians/Alaska Natives. In turn, all indigenous groups exhibit higher rates of smoking and dangerous alcohol behaviour as well as consuming less fruits and vegetables. Aboriginal Australians and American Indians/Alaska Natives also exhibit greater rates of sedentary behaviour. Conclusion. Indigenous groups from Australia, New Zealand, and the United States have a lower life expectancy then their respective non-indigenous counterparts. A higher prevalence of CVD is a major driving force behind this discrepancy. A cluster of modifiable cardio-metabolic risk factors precede CVD, which, in turn, is linked to modifiable lifestyle risk factors.

Biological therapy in inflammatory bowel diseases: Access in Central and Eastern Europe

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Rencz, Fanni; Péntek, Márta; Bortlik, Martin; Zagorowicz, Edyta; Hlavaty, Tibor; Śliwczyński, Andrzej; Diculescu, Mihai M; Kupcinskas, Limas; Gecse, Krisztina B; Gulácsi, László; Lakatos, Peter L

2015-01-01

Biological drugs opened up new horizons in the management of inflammatory bowel diseases (IBD). This study focuses on access to biological therapy in IBD patients across 9 selected Central and Eastern European (CEE) countries, namely Bulgaria, the Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Romania and Slovakia. Literature data on the epidemiology and disease burden of IBD in CEE countries was systematically reviewed. Moreover, we provide an estimation on prevalence of IBD as well as biological treatment rates. In all countries with the exception of Romania, lower biological treatment rates were observed in ulcerative colitis (UC) compared to Crohn’s disease despite the higher prevalence of UC. Great heterogeneity (up to 96-fold) was found in access to biologicals across the CEE countries. Poland, Bulgaria, Romania and the Baltic States are lagging behind Hungary, Slovakia and the Czech Republic in their access to biologicals. Variations of reimbursement policy may be one of the factors explaining the differences to a certain extent in Bulgaria, Latvia, Lithuania, and Poland, but association with other possible determinants (differences in prevalence and incidence, price of biologicals, total expenditure on health, geographical access, and cost-effectiveness results) was not proven. We assume, nevertheless, that health deterioration linked to IBD might be valued differently against other systemic inflammatory conditions in distinct countries and which may contribute to the immense diversity in the utilization of biological drugs for IBD. In conclusion, access to biologicals varies widely among CEE countries and this difference cannot be explained by epidemiological factors, drug prices or total health expenditure. Changes in reimbursement policy could contribute to better access to biologicals in some countries. PMID:25684937

Biological Control Strategies for Mosquito Vectors of Arboviruses

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Yan-Jang S. Huang

2017-02-01

Full Text Available Historically, biological control utilizes predatory species and pathogenic microorganisms to reduce the population of mosquitoes as disease vectors. This is particularly important for the control of mosquito-borne arboviruses, which normally do not have specific antiviral therapies available. Although development of resistance is likely, the advantages of biological control are that the resources used are typically biodegradable and ecologically friendly. Over the past decade, the advancement of molecular biology has enabled optimization by the manipulation of genetic materials associated with biological control agents. Two significant advancements are the discovery of cytoplasmic incompatibility induced by Wolbachia bacteria, which has enhanced replacement programs, and the introduction of dominant lethal genes into local mosquito populations through the release of genetically modified mosquitoes. As various arboviruses continue to be significant public health threats, biological control strategies have evolved to be more diverse and become critical tools to reduce the disease burden of arboviruses.

ECOLOGY OF PANTOEA AGGLOMERANS 2066-7 STRAIN: A BIOLOGICAL CONTROL OF BACTERIA ONION DISEASES

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Soumia Sadik

2016-06-01

Full Text Available The growth response of the biocontrol agent Pantoea agglomerans 2066-7 to change in water activity (aw, temperature, and pH was determined in vitro in basic medium. The minimum temperature at which 2066-7 was able to grow was 7°C, and the growth of 2066-7 did not change at varying pH levels (4–10.34. The best growth was obtained at a water activity of 0.98 in all media modified with the four solutes (glucose, glycerol, NaCl and polyethylene glycol. The solute used to reduce water activity had a great influence on bacterial growth, especially at unfavorable conditions (low temperature. This study has defined the range of environmental conditions (aw, pH, and temperature over which the bacteria may be developed for biological control of plant diseases.

Disease-modifying antirheumatic drugs in pregnancy - Current status and implications for the future

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Vroom, Fokaline; de Walle, Hermien E. K.; van de Laar, Mart A. J. F.; Brouwers, Jacobus R. B. J.; de Jong-van den Berg, Lolkje T. W.

2006-01-01

Drug use during pregnancy is sometimes unavoidable, especially in chronic inflammatory diseases such as rheumatoid arthritis (RA). The use of disease-modifying antirheumatic drugs (DMARDs) often starts in the early stage of RA; therefore, women of reproductive age are at risk for exposure to a DMARD

Proteome-wide Structural Analysis of PTM Hotspots Reveals Regulatory Elements Predicted to Impact Biological Function and Disease*

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Dewhurst, Henry; Sundararaman, Niveda

2016-01-01

Post-translational modifications (PTMs) regulate protein behavior through modulation of protein-protein interactions, enzymatic activity, and protein stability essential in the translation of genotype to phenotype in eukaryotes. Currently, less than 4% of all eukaryotic PTMs are reported to have biological function - a statistic that continues to decrease with an increasing rate of PTM detection. Previously, we developed SAPH-ire (Structural Analysis of PTM Hotspots) - a method for the prioritization of PTM function potential that has been used effectively to reveal novel PTM regulatory elements in discrete protein families (Dewhurst et al., 2015). Here, we apply SAPH-ire to the set of eukaryotic protein families containing experimental PTM and 3D structure data - capturing 1,325 protein families with 50,839 unique PTM sites organized into 31,747 modified alignment positions (MAPs), of which 2010 (∼6%) possess known biological function. Here, we show that using an artificial neural network model (SAPH-ire NN) trained to identify MAP hotspots with biological function results in prediction outcomes that far surpass the use of single hotspot features, including nearest neighbor PTM clustering methods. We find the greatest enhancement in prediction for positions with PTM counts of five or less, which represent 98% of all MAPs in the eukaryotic proteome and 90% of all MAPs found to have biological function. Analysis of the top 1092 MAP hotspots revealed 267 of truly unknown function (containing 5443 distinct PTMs). Of these, 165 hotspots could be mapped to human KEGG pathways for normal and/or disease physiology. Many high-ranking hotspots were also found to be disease-associated pathogenic sites of amino acid substitution despite the lack of observable PTM in the human protein family member. Taken together, these experiments demonstrate that the functional relevance of a PTM can be predicted very effectively by neural network models, revealing a large but testable

Multi-agent systems in epidemiology: a first step for computational biology in the study of vector-borne disease transmission

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Guégan Jean-François

2008-10-01

Full Text Available Abstract Background Computational biology is often associated with genetic or genomic studies only. However, thanks to the increase of computational resources, computational models are appreciated as useful tools in many other scientific fields. Such modeling systems are particularly relevant for the study of complex systems, like the epidemiology of emerging infectious diseases. So far, mathematical models remain the main tool for the epidemiological and ecological analysis of infectious diseases, with SIR models could be seen as an implicit standard in epidemiology. Unfortunately, these models are based on differential equations and, therefore, can become very rapidly unmanageable due to the too many parameters which need to be taken into consideration. For instance, in the case of zoonotic and vector-borne diseases in wildlife many different potential host species could be involved in the life-cycle of disease transmission, and SIR models might not be the most suitable tool to truly capture the overall disease circulation within that environment. This limitation underlines the necessity to develop a standard spatial model that can cope with the transmission of disease in realistic ecosystems. Results Computational biology may prove to be flexible enough to take into account the natural complexity observed in both natural and man-made ecosystems. In this paper, we propose a new computational model to study the transmission of infectious diseases in a spatially explicit context. We developed a multi-agent system model for vector-borne disease transmission in a realistic spatial environment. Conclusion Here we describe in detail the general behavior of this model that we hope will become a standard reference for the study of vector-borne disease transmission in wildlife. To conclude, we show how this simple model could be easily adapted and modified to be used as a common framework for further research developments in this field.

“Gestaltomics”: Systems Biology Schemes for the Study of Neuropsychiatric Diseases

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Nora A. Gutierrez Najera

2017-05-01

Full Text Available The integration of different sources of biological information about what defines a behavioral phenotype is difficult to unify in an entity that reflects the arithmetic sum of its individual parts. In this sense, the challenge of Systems Biology for understanding the “psychiatric phenotype” is to provide an improved vision of the shape of the phenotype as it is visualized by “Gestalt” psychology, whose fundamental axiom is that the observed phenotype (behavior or mental disorder will be the result of the integrative composition of every part. Therefore, we propose the term “Gestaltomics” as a term from Systems Biology to integrate data coming from different sources of information (such as the genome, transcriptome, proteome, epigenome, metabolome, phenome, and microbiome. In addition to this biological complexity, the mind is integrated through multiple brain functions that receive and process complex information through channels and perception networks (i.e., sight, ear, smell, memory, and attention that in turn are programmed by genes and influenced by environmental processes (epigenetic. Today, the approach of medical research in human diseases is to isolate one disease for study; however, the presence of an additional disease (co-morbidity or more than one disease (multimorbidity adds complexity to the study of these conditions. This review will present the challenge of integrating psychiatric disorders at different levels of information (Gestaltomics. The implications of increasing the level of complexity, for example, studying the co-morbidity with another disease such as cancer, will also be discussed.

Dissecting the Molecular Mechanisms of Neurodegenerative Diseases through Network Biology

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Jose A. Santiago

2017-05-01

Full Text Available Neurodegenerative diseases are rarely caused by a mutation in a single gene but rather influenced by a combination of genetic, epigenetic and environmental factors. Emerging high-throughput technologies such as RNA sequencing have been instrumental in deciphering the molecular landscape of neurodegenerative diseases, however, the interpretation of such large amounts of data remains a challenge. Network biology has become a powerful platform to integrate multiple omics data to comprehensively explore the molecular networks in the context of health and disease. In this review article, we highlight recent advances in network biology approaches with an emphasis in brain-networks that have provided insights into the molecular mechanisms leading to the most prevalent neurodegenerative diseases including Alzheimer’s (AD, Parkinson’s (PD and Huntington’s diseases (HD. We discuss how integrative approaches using multi-omics data from different tissues have been valuable for identifying biomarkers and therapeutic targets. In addition, we discuss the challenges the field of network medicine faces toward the translation of network-based findings into clinically actionable tools for personalized medicine applications.

Enhancing biological control of basal stem rot disease (Ganoderma boninense) in oil palm plantations.

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Susanto, A; Sudharto, P S; Purba, R Y

2005-01-01

Basal Stem Rot (BSR) disease caused by Ganoderma boninense is the most destructive disease in oil palm, especially in Indonesia and Malaysia. The available control measures for BSR disease such as cultural practices and mechanical and chemical treatment have not proved satisfactory due to the fact that Ganoderma has various resting stages such as melanised mycelium, basidiospores and pseudosclerotia. Alternative control measures to overcome the Ganoderma problem are focused on the use of biological control agents and planting resistant material. Present studies conducted at Indonesian Oil Palm Research Institute (IOPRI) are focused on enhancing the use of biological control agents for Ganoderma. These activities include screening biological agents from the oil palm rhizosphere in order to evaluate their effectiveness as biological agents in glasshouse and field trials, testing their antagonistic activities in large scale experiments and eradicating potential disease inoculum with biological agents. Several promising biological agents have been isolated, mainly Trichoderma harzianum, T. viride, Gliocladium viride, Pseudomonas fluorescens, and Bacillus sp. A glasshouse and field trial for Ganoderma control indicated that treatment with T. harzianum and G. viride was superior to Bacillus sp. A large scale trial showed that the disease incidence was lower in a field treated with biological agents than in untreated fields. In a short term programme, research activities at IOPRI are currently focusing on selecting fungi that can completely degrade plant material in order to eradicate inoculum. Digging holes around the palm bole and adding empty fruit bunches have been investigated as ways to stimulate biological agents.

Biologic therapies for chronic inflammatory bowel disease

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M. P. Martínez-Montiel

Full Text Available Crohn's disease (CD and ulcerative colitis (UC make up the so-called chronic inflammatory bowel disease (IBD. Advances in the understanding of IBD pathophysiologic mechanisms in the last few years have allowed the development of novel therapies such as biologic therapies, which at least theoretically represent a more specific management of this disease with fewer side effects. Currently, the only effective and widely accepted biologic therapy for the treatment of intraluminal, fistulizing CD, both for remission induction and maintenance, is infliximab. The role of other monoclonal antibodies such as adalimumab is not clearly established. It could be deemed an alternative for patients with allergic reactions to infliximab, and for those with lost response because of anti-infliximab antibody development. However, relevant issues such as dosage and administration regimen remain to be established. Anti-integrin α4 therapies, despite encouraging results in phase-3 studies, are still unavailable, as their marketing authorization was held back in view of a number of reports regarding progressive multifocal leukoencephalopathy cases. Immunostimulating therapy may be highly relevant in the near future, as it represents a novel strategy against disease with the inclusion of granulocyte-monocyte colony-stimulating factors. Regarding ulcerative colitis, results from the ACT-1 and ACT-2 studies showed that infliximab is also useful for the management of serious UC flare-ups not responding to standard treatment, which will lead to a revision of therapeutic algorithms, where this drug should be given preference before intravenous cyclosporine. In the next few years, the role of anti-CD3 drugs (vilisilizumab, T-cell inhibiting therapies, and epithelial repair and healing stimulating factors will be established.

Biological therapy and development of neoplastic disease in patients with juvenile rheumatic disease: a systematic review

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Vanessa Patricia L. Pereira

Full Text Available Abstract Juvenile rheumatic diseases affect the musculoskeletal system and begin before the age of 18. These conditions have varied, identifiable or unknown etiologies, but those of an autoimmune inflammatory nature have been associated with an increased risk of development of cancer, regardless of treatment. This study aims to assess, through a systematic review of the literature according to Prisma (Preferred Reporting Items for Systematic Reviews and Meta-Analyses quality criteria, the risk of cancer in patients with juvenile rheumatic disease, and its association with biological agents. The criteria described by the Strengthening the Reporting of Observational Studies in Epidemiology initiative were used in order to assess the methodological quality of those individual items selected in this study. We analyzed nine publications, from a total of 251 papers initially selected. There was an increase in cancer risk in the population with juvenile rheumatic disease versus the general population. Most specified cancers were of a lymphoproliferative nature. Seven studies did not specify the treatment or not defined an association between treatment and cancer risk. Only one study has suggested this association; in it, their authors observed high risk in patients diagnosed in the last 20 years, a period of the advent of new therapies. One study found an increased risk in a population not treated with biological agents, suggesting a disease in its natural course, and not an adverse effect of therapy. Studies have shown an increased risk of malignancy associated with juvenile rheumatic disease, and this may be related to disease activity and not specifically to the treatment with biological agents.

The Neuroprotective Disease-Modifying Potential of Psychotropics in Parkinson's Disease

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Edward C. Lauterbach

2012-01-01

Full Text Available Neuroprotective treatments in Parkinson's disease (PD have remained elusive. Psychotropics are commonly prescribed in PD without regard to their pathobiological effects. The authors investigated the effects of psychotropics on pathobiological proteins, proteasomal activity, mitochondrial functions, apoptosis, neuroinflammation, trophic factors, stem cells, and neurogenesis. Only findings replicated in at least 2 studies were considered for these actions. Additionally, PD-related gene transcription, animal model, and human neuroprotective clinical trial data were reviewed. Results indicate that, from a PD pathobiology perspective, the safest drugs (i.e., drugs least likely to promote cellular neurodegenerative mechanisms balanced against their likelihood of promoting neuroprotective mechanisms include pramipexole, valproate, lithium, desipramine, escitalopram, and dextromethorphan. Fluoxetine favorably affects transcription of multiple genes (e.g., MAPT, GBA, CCDC62, HIP1R, although it and desipramine reduced MPTP mouse survival. Haloperidol is best avoided. The most promising neuroprotective investigative priorities will involve disease-modifying trials of the safest agents alone or in combination to capture salutary effects on H3 histone deacetylase, gene transcription, glycogen synthase kinase-3, α-synuclein, reactive oxygen species (ROS, reactive nitrogen species (RNS, apoptosis, inflammation, and trophic factors including GDNF and BDNF.

Regulation of drug-metabolizing enzymes in infectious and inflammatory disease: implications for biologics-small molecule drug interactions.

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Mallick, Pankajini; Taneja, Guncha; Moorthy, Bhagavatula; Ghose, Romi

2017-06-01

Drug-metabolizing enzymes (DMEs) are primarily down-regulated during infectious and inflammatory diseases, leading to disruption in the metabolism of small molecule drugs (smds), which are increasingly being prescribed therapeutically in combination with biologics for a number of chronic diseases. The biologics may exert pro- or anti-inflammatory effect, which may in turn affect the expression/activity of DMEs. Thus, patients with infectious/inflammatory diseases undergoing biologic/smd treatment can have complex changes in DMEs due to combined effects of the disease and treatment. Areas covered: We will discuss clinical biologics-SMD interaction and regulation of DMEs during infection and inflammatory diseases. Mechanistic studies will be discussed and consequences on biologic-small molecule combination therapy on disease outcome due to changes in drug metabolism will be highlighted. Expert opinion: The involvement of immunomodulatory mediators in biologic-SMDs is well known. Regulatory guidelines recommend appropriate in vitro or in vivo assessments for possible interactions. The role of cytokines in biologic-SMDs has been documented. However, the mechanisms of drug-drug interactions is much more complex, and is probably multi-factorial. Studies aimed at understanding the mechanism by which biologics effect the DMEs during inflammation/infection are clinically important.

ANALISIS ARGUMENTASI MAHASISWA PENDIDIKAN BIOLOGI PADA ISU SOSIOSAINFIK KONSUMSI GENETICALLY MODIFIED ORGANISM (GMO

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Y. Herlanti

2014-04-01

Full Text Available Penelitian ini bertujuan untuk menganalisis argumentasi yang dikemukakan oleh mahasiswa pendidikan biologi terkait isu sosiosaintifik yaitu konsumsi pangan Genetically Modified Organism (GMO.  Penelitian menggunakan metode survei secara online.  Partisipan yang berasal dari semester III-VII Universitas Islam Negeri Jakarta yang secara sukarela mengisi kuisioner online yang diunggah pada weblog. Hasil penelitian menunjukkan isu sosiosaintifik GMO lebih banyak ditanggapi secara saintifik oleh partisipan.  Argumentasi sebagian besar berada pada level II, yaitu telah mampu mengungkapkan sebuah klaim disertai dengan alasan. Hanya sedikit yang sudah mampu memberikan argumen secara holistik (level IV, yaitu mampu mengungkapkan argumen dengan alasan yang kuat yang tidak mudah dibantah.  Umumnya argumentasi yang dikemukan partisipan berjenis argumentasi sederhana dan argumentasi tipe rantai.  Berdasarkan temuan ini, perlu dikembangkan sebuah model perkuliahan yang dapat meningkatkan keterampilan berargumentasi. This research aimed to analyze the argument for socioscientifik issue “Genetically Modified Organism (GMO Food Consumtion”.  This reseach used online survey.  Participant filled online questionaire that uploaded in weblog.  Participants are student of biology education in Jakarta Islamic State University. The result showed most participants gave scientific view in their argument.  Most of argumentations were in level II; participants gave a klaim within a warrant.  Only a few argument were in level IV, it’s a holistic argument that contained a klaim, a warrant, a backing, and a rebuttal.  Most of argument had simple type or chain type.  From this result, university must develop strategies of lecturing to improve argumentation skill.

Integrating phosphoproteomics in systems biology

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Yu Liu

2014-07-01

Full Text Available Phosphorylation of serine, threonine and tyrosine plays significant roles in cellular signal transduction and in modifying multiple protein functions. Phosphoproteins are coordinated and regulated by a network of kinases, phosphatases and phospho-binding proteins, which modify the phosphorylation states, recognize unique phosphopeptides, or target proteins for degradation. Detailed and complete information on the structure and dynamics of these networks is required to better understand fundamental mechanisms of cellular processes and diseases. High-throughput technologies have been developed to investigate phosphoproteomes in model organisms and human diseases. Among them, mass spectrometry (MS-based technologies are the major platforms and have been widely applied, which has led to explosive growth of phosphoproteomic data in recent years. New bioinformatics tools are needed to analyze and make sense of these data. Moreover, most research has focused on individual phosphoproteins and kinases. To gain a more complete knowledge of cellular processes, systems biology approaches, including pathways and networks modeling, have to be applied to integrate all components of the phosphorylation machinery, including kinases, phosphatases, their substrates, and phospho-binding proteins. This review presents the latest developments of bioinformatics methods and attempts to apply systems biology to analyze phosphoproteomics data generated by MS-based technologies. Challenges and future directions in this field will be also discussed.

Use of tofacitinib in real clinical practice to treat patients with rheumatoid arthritis resistant to synthetic and biological disease-modifying antirheumatic drugs: Results of a multicenter observational study

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D. E. Karateev

2016-01-01

Full Text Available Tofacitinib (TOFA, a member of a new class of targeted synthetic disease-modifying antirheumatic drugs (DMARDs, is a promising medication for the treatment of rheumatoid arthritis (RA and other immunoinflammatory diseases. The paper describes the Russian experi-ence with TOFA used to treat severe RA.Patients and methods. 101 RA patients (18 men and 83 women; mean age, 51.03±11.28 years; mean disease duration, 105.4±81.43 months who were positive for rheumatoid factor (89.1% and anti-cyclic citrullinated peptide antibodies (74.7% and resistant to therapy with synthetic DMARDs (sDMARDs (80.2% and biological agents (19.8% were given TOFA at a dose of 5 mg twice daily, which could be doubled if necessary. TOFA was used alone (n=9 or in combination with methotrexate (MT (n=75 or other sDMARDs (n=17. The achievement of low disease activity (LDA and clinical remission at 3 and 6 months of treatment by DAS28-ESR SDAI, and CDAI scores, and the indices of safety and tolerability were assessed.Results. A total of 93 (92.1% of the 101 patients completed a 24-week period of the investigation. 8 (7.9% patients prematurely discontinued TOFA after an average of 2.75±0.71 months. At the end of the study, the patients achieved the primary endpoint (LDA including remission in terms of DAS28-ESR ≤3.2 (34.7%, SDAI ≤11 (47.5%, and CDAI ≤10 (48.5% and the secondary endpoints (clinical remission in terms of DAS28-ESR ≤2.6 (17.8%, SDAI ≤3.3 (8.9%, and CDAI ≤2.8 (6.9%. When TOFA was combined with MT, the discontinuation rate for the former was significantly lower (2.7% than when TOFA was used in combination with other sDMARDs (29.4% or alone (11.1%; p<0.01. At 3 and 6 months of follow-up, LDA was achieved more frequently when TOFA was combined with MT than when other treatment regimens were used. Fatal outcomes and serious adverse events (AEs, as AEs previously undescribed in the literature, were not seen during a follow-up within

The role of EMMPRIN in T cell biology and immunological diseases.

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Hahn, Jennifer Nancy; Kaushik, Deepak Kumar; Yong, V Wee

2015-07-01

EMMPRIN (CD147), originally described as an inducer of the expression of MMPs, has gained attention in its involvement in various immunologic diseases, such that anti-EMMPRIN antibodies are considered as potential therapeutic medications. Given that MMPs are involved in the pathogenesis of various disease states, it is relevant that targeting an upstream inducer would make for an effective therapeutic strategy. Additionally, EMMPRIN is now appreciated to have multiple roles apart from MMP induction, including in cellular functions, such as migration, adhesion, invasion, energy metabolism, as well as T cell activation and proliferation. Here, we review what is known about EMMPRIN in numerous immunologic/inflammatory disease conditions with a particular focus on its complex roles in T cell biology. © Society for Leukocyte Biology.

Modified Harrington Procedure for Acetabular Insuficiency Due to Metastatic Malignant Disease

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WI Faisham

2009-05-01

Full Text Available Extensive peri-acetabular osteolysis caused by malignant disease process is a major surgical challenge as conventional hip arthroplasty is not adequate. We describe a modified use of the Harrington procedure for acetabular insufficiency secondary to metastatic disease in twelve patients. The procedures include application of multiple threaded pins to bridge the acetabular columns, anti-protrusio cage and cemented acetabular cup. Eleven patients were able to walk pain free and achieved a mean Musculoskeletal Tumour Society Functional Score of 80 (range, 68 to 86.

Modifying Eating Behavior: Novel Approaches for Reducing Body Weight, Preventing Weight Regain, and Reducing Chronic Disease Risk123

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Gletsu-Miller, Nana; McCrory, Megan A

2014-01-01

This article is a summary of the symposium “Modifying Eating Behavior: Novel Approaches for Reducing Body Weight, Preventing Weight Regain, and Reducing Chronic Disease Risk” held 29 April 2014 at the ASN Scientific Sessions and Annual Meeting at Experimental Biology 2014 in San Diego, CA. In this symposium, novel approaches to modifying eating behavior were highlighted, including 1) alteration of meal timing and macronutrient composition and 2) retraining and provision of feedback about eating behavior. Dr. Ciampolini discussed a method for teaching individuals to recognize a decrease in blood glucose concentration, and therefore the need for energy, by learning the associated physical sensations (signifying hunger). Dr. Madar and Sigal Sofer presented their work on reducing hunger during energy reduction by feeding carbohydrate only in the evening. Dr. Hamilton-Shield reviewed studies on the Mandometer (Mikrodidakt), a device for training individuals to slow eating rate. Finally, Dr. Sazonov presented information on a wearable device, the Automatic Ingestion Monitor, which senses jaw motion and/or hand-to-mouth gestures to detect and characterize food intake. His goal is to use the instrument to prevent overeating by providing feedback to the user to stop ingestion at a predetermined limit. PMID:25398742

Quantity and economic value of unused oral anti-cancer and biological disease-modifying anti-rheumatic drugs among outpatient pharmacy patients who discontinue therapy.

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Bekker, C L; Melis, E J; Egberts, A C G; Bouvy, M L; Gardarsdottir, H; van den Bemt, B J F

2018-03-24

Patients sometimes discontinue the use of expensive oral anti-cancer drug (OACD) or biological disease-modifying anti-rheumatic drug (bDMARD) therapies early, leading to medication waste if the patient has not used all dispensed medication. To determine the proportion of patients who have unused OACDs or bDMARDs after therapy discontinuation, and the quantity and economic value of these unused medications. Furthermore, patients' reasons for therapy discontinuation and their disposal method for unused medications were determined. In a retrospective follow-up study using a Dutch outpatient pharmacy database, patients (≥18 years) who did not refill an OACD or bDMARD prescription, dispensed between November 2015 and February 2016, within two weeks of the prescription end date were contacted by phone and asked about their unused medication and reasons thereof. The economic value was calculated using Dutch medication prices. Data were descriptively analyzed in STATA13. The database included 1173 patients, of whom 159 likely had discontinued therapy and were contacted. Of these, 88 patients were excluded (39 refilled, 47 missing, and 2 other). Of the 71 patients who had discontinued therapy, 39 (54.9%) had unused medications, comprising 22 OACD users (mean age 63.0 (SD ± 15.9) years, 50.0% female) and 17 bDMARD users (mean age 50.7 (SD ± 13.5) years, 47.1% female). A total of 59 packages were unused, with a total value of €60,341. Unused OACD packages and bDMARD packages had median values of €179 (IQR €24-2487) and €992 (IQR €681-1093), respectively. Patients primarily discontinued therapy due to adverse or insufficient effects. This study illustrates that more than half of patients discontinuing OACD or bDMARD therapies have unused medication. This emphasizes the need for waste-reducing interventions. Copyright © 2018 Elsevier Inc. All rights reserved.

The Cost-effectiveness of Sequences of Biological Disease-modifying Antirheumatic Drug Treatment in England for Patients with Rheumatoid Arthritis Who Can Tolerate Methotrexate.

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Stevenson, Matt D; Wailoo, Allan J; Tosh, Jonathan C; Hernandez-Alava, Monica; Gibson, Laura A; Stevens, John W; Archer, Rachel J; Simpson, Emma L; Hock, Emma S; Young, Adam; Scott, David L

2017-07-01

To ascertain whether strategies of treatment with a biological disease-modifying antirheumatic drug (bDMARD) are cost-effective in an English setting. Results are presented for those patients with moderate to severe rheumatoid arthritis (RA) and those with severe RA. An economic model to assess the cost-effectiveness of 7 bDMARD was developed. A systematic literature review and network metaanalysis was undertaken to establish relative clinical effectiveness. The results were used to populate the model, together with estimates of Health Assessment Questionnaire (HAQ) score following European League Against Rheumatism response; annual costs, and utility, per HAQ band; trajectory of HAQ for patients taking bDMARD; and trajectory of HAQ for patients using nonbiologic therapy (NBT). Results were presented as those associated with the strategy with the median cost-effectiveness. Supplementary analyses were undertaken assessing the change in cost-effectiveness when only patients with the most severe prognoses taking NBT were provided with bDMARD treatment. The costs per quality-adjusted life-year (QALY) values were compared with reported thresholds from the UK National Institute for Health and Care Excellence of £20,000 to £30,000 (US$24,700 to US$37,000). In the primary analyses, the cost per QALY of a bDMARD strategy was £41,600 for patients with severe RA and £51,100 for those with moderate to severe RA. Under the supplementary analyses, the cost per QALY fell to £25,300 for those with severe RA and to £28,500 for those with moderate to severe RA. The cost-effectiveness of bDMARD in RA in England is questionable and only meets current accepted levels in subsets of patients with the worst prognoses.

Towards the concept of disease-modifier in post-stroke or vascular cognitive impairment: a consensus report.

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Bordet, Régis; Ihl, Ralf; Korczyn, Amos D; Lanza, Giuseppe; Jansa, Jelka; Hoerr, Robert; Guekht, Alla

2017-05-24

Vascular cognitive impairment (VCI) is a complex spectrum encompassing post-stroke cognitive impairment (PSCI) and small vessel disease-related cognitive impairment. Despite the growing health, social, and economic burden of VCI, to date, no specific treatment is available, prompting the introduction of the concept of a disease modifier. Within this clinical spectrum, VCI and PSCI remain advancing conditions as neurodegenerative diseases with progression of both vascular and degenerative lesions accounting for cognitive decline. Disease-modifying strategies should integrate both pharmacological and non-pharmacological multimodal approaches, with pleiotropic effects targeting (1) endothelial and brain-blood barrier dysfunction; (2) neuronal death and axonal loss; (3) cerebral plasticity and compensatory mechanisms; and (4) degenerative-related protein misfolding. Moreover, pharmacological and non-pharmacological treatment in PSCI or VCI requires valid study designs clearly stating the definition of basic methodological issues, such as the instruments that should be used to measure eventual changes, the biomarker-based stratification of participants to be investigated, and statistical tests, as well as the inclusion and exclusion criteria that should be applied. A consensus emerged to propose the development of a disease-modifying strategy in VCI and PSCI based on pleiotropic pharmacological and non-pharmacological approaches.

Biological Control of Diseases of Vegetables Grown Hydroponically in Thailand: Challenge and Opportunity.

Science.gov (United States)

Kanjanamaneesathian, Mana

2015-01-01

In Thailand, yield loss due to plant diseases in vegetables grown hydroponically is very high as a result of the growers` lack of knowledge for controlling diseases and their un- willingness to invest in setting-up the proper hydroponic system from the beginning. Severe root rot disease caused by Pythium spp. is frequent and can be anticipated in the hot climate in Thailand. This review focuses on the diseases in temperate lettuces which have been produced hydroponically and have been attacked by plant pathogens, particularly Pythium spp. Biological control of vegetable diseases grown hydroponically has been investigated in Thailand. Research is being carried out to identify effective strains of the antagonists, formulating the applicable products and delivering them appropriately to control the disease. Products of Bacillus subtilis, Chaetomium globosom and Trichoderma harzianum have been recommended for use to control diseases in vegetables grown hydroponically. Control efficacy of these products is varied as the biological products have been used by the growers in the paradigm of using chemical fungicide for disease control in hydroponic production system, overlooking the intrinsic characteristics of the biological control products. The recent patent, which minimizes the effects of sunlight and heat on the nutrient solution without the use of an external energy for cooling the nutrient, should be applied in producing hydroponic vegetables to mitigate poor plant growth and root rot disease outbreak in Thailand.

Chemical composition of silica-based biocidal modifier

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Grishina Anna Nikolaevna

2016-11-01

Full Text Available Increase of the amount of fungi spores and micotixines causes the increase in the number of different diseases. Because of this, ensuring the biological safety in buildings is becoming more and more important today. The preferred way to guarantee the biological safety of a building is to employ modern building materials that prevent the settlement of the fungi colonies on the inner surfaces of walls. Such building materials can be produced using novel biocidal modifiers that allow controlling the number of microorganisms on the surface and in the bulk of a composite construction. The precipitation product of zinc hydrosilicates and sodium sulfate is one of the mentioned modifiers. Till now, the exact chemical composition of such precipitation product is controversial; it is obvious, though, that the efficacy of the biocidal modifier is mostly determined by the type of the copper compounds. In the present work an integrated approach is used for the investigation of the chemical composition of the biocidal modifier. Such an approach consists in the examination of the modifier’s composition by means of different, yet complementary, research methods: X-ray diffraction, infrared spectroscopy and DTA. It is shown that the chemical composition of the modifier mainly depends on the amount of precipitant. X-ray diffraction reveals that the major part of the modifier is represented by amorphous phase. Along with the increase of the precipitant’s amount the crystalline phase Zn4SO4(OH6•xH2O formation takes place. Such a crystalline phase is not appropriate as a component of the biocidal modifier. Another two methods - DTA and IR spectroscopy - reveal that the amorphous phase consists essentially of zinc hydrosilicates.

Bacteriophage-based synthetic biology for the study of infectious diseases

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Lu, Timothy K.

2014-01-01

Since their discovery, bacteriophages have contributed enormously to our understanding of molecular biology as model systems. Furthermore, bacteriophages have provided many tools that have advanced the fields of genetic engineering and synthetic biology. Here, we discuss bacteriophage-based technologies and their application to the study of infectious diseases. New strategies for engineering genomes have the potential to accelerate the design of novel phages as therapies, diagnostics, and tools. Though almost a century has elapsed since their discovery, bacteriophages continue to have a major impact on modern biological sciences, especially with the growth of multidrug-resistant bacteria and interest in the microbiome. PMID:24997401

A Systematic Review of the Cost-Effectiveness of Biologics for the Treatment of Inflammatory Bowel Diseases.

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Saara Huoponen

Full Text Available Biologics are used for the treatment of inflammatory bowel diseases, Crohn´s disease and ulcerative colitis refractory to conventional treatment. In order to allocate healthcare spending efficiently, costly biologics for inflammatory bowel diseases are an important target for cost-effectiveness analyses. The aim of this study was to systemically review all published literature on the cost-effectiveness of biologics for inflammatory bowel diseases and to evaluate the methodological quality of cost-effectiveness analyses.A literature search was performed using Medline (Ovid, Cochrane Library, and SCOPUS. All cost-utility analyses comparing biologics with conventional medical treatment, another biologic treatment, placebo, or surgery for the treatment of inflammatory bowel diseases in adults were included in this review. All costs were converted to the 2014 euro. The methodological quality of the included studies was assessed by Drummond's, Philips', and the Consolidated Health Economic Evaluation Reporting Standards checklist.Altogether, 25 studies were included in the review. Among the patients refractory to conventional medical treatment, the incremental cost-effectiveness ratio ranged from dominance to 549,335 €/Quality-Adjusted Life Year compared to the incremental cost-effectiveness ratio associated with conventional medical treatment. When comparing biologics with another biologic treatment, the incremental cost-effectiveness ratio ranged from dominance to 24,012,483 €/Quality-Adjusted Life Year. A study including both direct and indirect costs produced more favorable incremental cost-effectiveness ratios than those produced by studies including only direct costs.With a threshold of 35,000 €/Quality-Adjusted Life Year, biologics seem to be cost-effective for the induction treatment of active and severe inflammatory bowel disease. Between biologics, the cost-effectiveness remains unclear.

[Biological treatment of rare inflammatory rheumatic diseases

DEFF Research Database (Denmark)

Baslund, B.

2008-01-01

The current status of the use of biological medicine in the treatment of adult onset morbus still, Wegeners granulomatosis and systemic lupus erythematosus (SLE) is reviewed. The need for controlled trials is emphasized. Anti-CD20 treatment for SLE patients with kidney involvement and patients wi...... with Wegeners granulomatosis seems promising. Anti-TNF and IL1 receptor antagonist can control disease activity in most patients with adult morbus still Udgivelsesdato: 2008/6/9...

Established and emerging biological activity markers of inflammatory bowel disease

DEFF Research Database (Denmark)

Nielsen, O H; Vainer, B; Madsen, S M

2000-01-01

Assessment of disease activity in inflammatory bowel disease (IBD), i.e., ulcerative colitis (UC) and Crohn's disease (CD), is done using clinical parameters and various biological disease markers. Ideally, a disease marker must: be able to identify individuals at risk of a given disorder......, be disease specific, mirror the disease activity and, finally, be easily applicable for routine clinical purposes. However, no such disease markers have yet been identified for IBD. In this article, classical disease markers including erythrocyte sedimentation rate, acute phase proteins (especially...... orosomucoid and CRP), leukocyte and platelet counts, albumin, neopterin, and beta2-microglobulin will be reviewed together with emerging disease markers such as antibodies of the ANCA/ASCA type, cytokines (e.g., IL-1, IL-2Ralpha, IL-6, IL-8, TNF-alpha, and TNF-alpha receptors) and with various adhesion...

Established and emerging biological activity markers of inflammatory bowel disease

DEFF Research Database (Denmark)

Nielsen, O H; Vainer, B; Madsen, S M

2000-01-01

orosomucoid and CRP), leukocyte and platelet counts, albumin, neopterin, and beta2-microglobulin will be reviewed together with emerging disease markers such as antibodies of the ANCA/ASCA type, cytokines (e.g., IL-1, IL-2Ralpha, IL-6, IL-8, TNF-alpha, and TNF-alpha receptors) and with various adhesion......Assessment of disease activity in inflammatory bowel disease (IBD), i.e., ulcerative colitis (UC) and Crohn's disease (CD), is done using clinical parameters and various biological disease markers. Ideally, a disease marker must: be able to identify individuals at risk of a given disorder......, be disease specific, mirror the disease activity and, finally, be easily applicable for routine clinical purposes. However, no such disease markers have yet been identified for IBD. In this article, classical disease markers including erythrocyte sedimentation rate, acute phase proteins (especially...

A novel approach to delayed-start analyses for demonstrating disease-modifying effects in Alzheimer's disease.

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Hong Liu-Seifert

Full Text Available One method for demonstrating disease modification is a delayed-start design, consisting of a placebo-controlled period followed by a delayed-start period wherein all patients receive active treatment. To address methodological issues in previous delayed-start approaches, we propose a new method that is robust across conditions of drug effect, discontinuation rates, and missing data mechanisms. We propose a modeling approach and test procedure to test the hypothesis of noninferiority, comparing the treatment difference at the end of the delayed-start period with that at the end of the placebo-controlled period. We conducted simulations to identify the optimal noninferiority testing procedure to ensure the method was robust across scenarios and assumptions, and to evaluate the appropriate modeling approach for analyzing the delayed-start period. We then applied this methodology to Phase 3 solanezumab clinical trial data for mild Alzheimer's disease patients. Simulation results showed a testing procedure using a proportional noninferiority margin was robust for detecting disease-modifying effects; conditions of high and moderate discontinuations; and with various missing data mechanisms. Using all data from all randomized patients in a single model over both the placebo-controlled and delayed-start study periods demonstrated good statistical performance. In analysis of solanezumab data using this methodology, the noninferiority criterion was met, indicating the treatment difference at the end of the placebo-controlled studies was preserved at the end of the delayed-start period within a pre-defined margin. The proposed noninferiority method for delayed-start analysis controls Type I error rate well and addresses many challenges posed by previous approaches. Delayed-start studies employing the proposed analysis approach could be used to provide evidence of a disease-modifying effect. This method has been communicated with FDA and has been

CINRG: Systems Biology of Glucocorticoids in Muscle Disease

Science.gov (United States)

2013-10-01

Contract W81XWH-09-1-0726 SYSTEMS BIOLOGY OF GLUCOCORTICOIDS IN MUSCLE DISEASE Introduction Duchenne muscular dystrophy (DMD) is the most... muscle and enable the development of better targeted and more effective therapies for Duchenne muscular dystrophy dynamically. This MDA grant...common and incurable muscular dystrophy of childhood. Muscle regeneration fails with advancing age, leading to considerable fibrosis. Corticosteroid

Modified vegetation indices for Ganoderma disease detection in oil palm from field spectroradiometer data

Science.gov (United States)

Shafri, Helmi Z. M.; Anuar, M. Izzuddin; Saripan, M. Iqbal

2009-10-01

High resolution field spectroradiometers are important for spectral analysis and mobile inspection of vegetation disease. The biggest challenges in using this technology for automated vegetation disease detection are in spectral signatures pre-processing, band selection and generating reflectance indices to improve the ability of hyperspectral data for early detection of disease. In this paper, new indices for oil palm Ganoderma disease detection were generated using band ratio and different band combination techniques. Unsupervised clustering method was used to cluster the values of each class resultant from each index. The wellness of band combinations was assessed by using Optimum Index Factor (OIF) while cluster validation was executed using Average Silhouette Width (ASW). 11 modified reflectance indices were generated in this study and the indices were ranked according to the values of their ASW. These modified indices were also compared to several existing and new indices. The results showed that the combination of spectral values at 610.5nm and 738nm was the best for clustering the three classes of infection levels in the determination of the best spectral index for early detection of Ganoderma disease.

Applications of Genetically Modified Immunobiotics with High Immunoregulatory Capacity for Treatment of Inflammatory Bowel Diseases.

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Shigemori, Suguru; Shimosato, Takeshi

2017-01-01

Inflammatory bowel diseases (IBDs), including ulcerative colitis and Crohn's disease, are chronic inflammatory diseases characterized by dysregulated immune responses of the gastrointestinal tract. In recent years, the incidence of IBDs has increased in developed nations, but their prophylaxis/treatment is not yet established. Site-directed delivery of molecules showing anti-inflammatory properties using genetically modified (gm)-probiotics shows promise as a new strategy for the prevention and treatment of IBD. Advantages of gm-probiotics include (1) the ability to use bacteria as a delivery vehicle, enabling safe and long-term use by humans, (2) decreased risks of side effects, and (3) reduced costs. The intestinal delivery of anti-inflammatory proteins such as cytokines and enzymes using Lactococcus lactis has been shown to regulate host intestinal homeostasis depending on the delivered protein-specific machinery. Additionally, clinical experience using interleukin 10-secreting Lc. lactis has been shown to be safe and to facilitate biological containment in IBD therapy. On the other hand, some preclinical studies have demonstrated that gm-strains of immunobiotics (probiotic strains able to beneficially regulate the mucosal immunity) provide beneficial effects on intestinal inflammation as a result of the synergy between the immunoregulatory effects of the bacterium itself and the anti-inflammatory effects of the delivered recombinant proteins. In this review, we discuss the rapid progression in the development of strategies for the prophylaxis and treatment of IBD using gm-probiotics that exhibit immune regulation effects (gm-immunobiotics). In particular, we discuss the type of strains used as delivery agents.

How safe are the biologicals in treating asthma and rhinitis?

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Cox Linda S

2009-10-01

Full Text Available Abstract A number of biological agents are available or being investigated for the treatment of asthma and rhinitis. The safety profiles of these biologic agents, which may modify allergic and immunological diseases, are still being elucidated. Subcutaneous allergen immunotherapy, the oldest biologic agent in current use, has the highest of frequency of the most serious and life-threatening reaction, anaphylaxis. It is also one of the only disease modifying interventions for allergic rhinitis and asthma. Efforts to seek safer and more effective allergen immunotherapy treatment have led to investigations of alternate routes of delivery and modified immunotherapy formulations. Sublingual immunotherapy appears to be associated with a lower, but not zero, risk of anaphylaxis. No fatalities have been reported to date with sublingual immunotherapy. Immunotherapy with modified formulations containing Th1 adjuvants, DNA sequences containing a CpG motif (CpG and 3-deacylated monophospholipid A, appears to provide the benefits of subcutaneous immunotherapy with a single course of 4 to 6 preseasonal injections. There were no serious treatment-related adverse events or anaphylaxis in the clinical trials of these two immunotherapy adjuvants. Omalizumab, a monoclonal antibody against IgE, has been associated with a small risk of anaphylaxis, affecting 0.09% to 0.2% of patients. It may also be associated with a higher risk of geohelminth infection in patients at high risk for parasitic infections but it does not appear to affect the response to treatment or severity of the infection. Clinical trials with other biologic agents that have targeted IL-4/IL-13, or IL-5, have not demonstrated any definite serious treatment-related adverse events. However, these clinical trials were generally done in small populations of asthma patients, which may be too small for uncommon side effects to be identified. There is conflicting information about the safety TNF

Huperzine A: Is it an Effective Disease-Modifying Drug for Alzheimer's Disease?

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Qian, Zhong Ming; Ke, Ya

2014-01-01

Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there is no cure. Huperzine A (HupA) is a natural inhibitor of acetylcholinesterase (AChE) derived from the Chinese folk medicine Huperzia serrata (Qian Ceng Ta). It is a licensed anti-AD drug in China and is available as a nutraceutical in the US. A growing body of evidence has demonstrated that HupA has multifaceted pharmacological effects. In addition to the symptomatic, cognitive-enhancing effect via inhibition of AChE, a number of recent studies have reported that this drug has "non-cholinergic" effects on AD. Most important among these is the protective effect of HupA on neurons against amyloid beta-induced oxidative injury and mitochondrial dysfunction as well as via the up-regulation of nerve growth factor and antagonizing N-methyl-d-aspartate receptors. The most recent discovery that HupA may reduce brain iron accumulation lends further support to the argument that HupA could serve as a potential disease-modifying agent for AD and also other neurodegenerative disorders by significantly slowing down the course of neuronal death.

Measures of rheumatoid arthritis disease activity in Australian clinical practice.

Science.gov (United States)

Taylor, Andrew; Bagga, Hanish

2011-01-01

Objectives. To investigate which rheumatoid arthritis (RA) disease activity measures are being collected in patients receiving glucocorticoids, non-biologic or biologic disease-modifying antirheumatic drugs (DMARDs) in Australian rheumatology practice. Methods. A retrospective audit of medical records was conducted from eight rheumatology practices around Australia. Each rheumatologist recruited 30 consecutive eligible patients into the review, 10 of whom must have been receiving a biological agent for rheumatoid arthritis. Disease activity measures and radiographic assessments were collected from each patient's last consultation. For biologic patients, disease activity measures were also collected from when the patient was first initiated on the biological agent. Results. At last consultation, the disease measures that were recorded most often were ESR (89.2%), haemoglobin (87.5%), and CRP (84.2%). DAS28 was infrequently recorded (16.3%). The rate of recording disease activity measures for patients receiving biologic DMARDs decreased over time (mean 27 months). Conclusion. This review has shown inconsistency of RA activity measures being recorded in Australian rheumatology clinical practice. An accurate assessment of the disease process is necessary to effectively target rheumatoid arthritis patients to treat in order to achieve optimal outcomes.

A new proposal for randomized start design to investigate disease-modifying therapies for Alzheimer disease.

Science.gov (United States)

Zhang, Richard Y; Leon, Andrew C; Chuang-Stein, Christy; Romano, Steven J

2011-02-01

The increasing prevalence of Alzheimer disease (AD) and lack of effective agents to attenuate progression have accelerated research and development of disease modifying (DM) therapies. The traditional parallel group design and single time point analysis used in the support of past AD drug approvals address symptomatic benefit over relatively short treatment durations. More recent trials investigating disease modification are by necessity longer in duration and require larger sample sizes. Nevertheless, trial design and analysis remain mostly unchanged and may not be adequate to meet the objective of demonstrating disease modification. Randomized start design (RSD) has been proposed as an option to study DM effects, but its application in AD trials may have been hampered by certain methodological challenges. To address the methodological issues that have impeded more extensive use of RSD in AD trial and to encourage other researchers to develop novel design and analysis methodologies to better ascertain DM effects for the next generation of AD therapies, we propose a stepwise testing procedure to evaluate potential DM effects of novel AD therapies. Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-cog) is used for illustration. We propose to test three hypotheses in a stepwise sequence. The three tests pertain to treatment difference at two separate time points and a difference in the rate of change. Estimation is facilitated by the Mixed-effects Model for Repeated Measures approach. The required sample size is estimated using Monte Carlo simulations and by modeling ADAS-cog data from prior longitudinal AD studies. The greatest advantage of the RSD proposed in this article is its ability to critically address the question on a DM effect. The AD trial using the new approach would be longer (12-month placebo period plus 12-month delay-start period; total 24-month duration) and require more subjects (about 1000 subjects per arm for the non-inferiority margin

Associations between Potentially Modifiable Risk Factors and Alzheimer Disease : A Mendelian Randomization Study

NARCIS (Netherlands)

Ostergaard, Soren D.; Mukherjee, Shubhabrata; Sharp, Stephen J.; Proitsi, Petroula; Lotta, Luca A.; Day, Felix; Perry, John R. B.; Boehme, Kevin L.; Walter, Stefan; Kauwe, John S.; Gibbons, Laura E.; Larson, Eric B.; Powell, John F.; Langenberg, Claudia; Crane, Paul K.; Wareham, Nicholas J.; Scott, Robert A.; van der Schouw, YT

Background Potentially modifiable risk factors including obesity, diabetes, hypertension, and smoking are associated with Alzheimer disease (AD) and represent promising targets for intervention. However, the causality of these associations is unclear. We sought to assess the causal nature of these

A SNP in the HTT promoter alters NF-κB binding and is a bidirectional genetic modifier of Huntington disease

DEFF Research Database (Denmark)

Bečanović, Kristina; Nørremølle, Anne; Neal, Scott J

2015-01-01

Cis-regulatory variants that alter gene expression can modify disease expressivity, but none have previously been identified in Huntington disease (HD). Here we provide in vivo evidence in HD patients that cis-regulatory variants in the HTT promoter are bidirectional modifiers of HD age of onset....

Geography, ecology and emerging infectious diseases.

Science.gov (United States)

Mayer, J D

2000-04-01

Emerging infectious diseases are the focus of increased attention and even alarm in the scholarly and popular literature. The emergence of new diseases and the resurgence of older and previously recognized infectious diseases both in developing and developed country poses challenges for understanding the ecological web of causation, including social, economic, environmental and biological components. This paper is a synthesis of the major characteristics of emerging diseases, in an interdisciplinary context. Political ecology is one framework for analysis that is promising in developing a modified ecology of disease.

TaBoo SeArch Algorithm with a Modified Inverse Histogram for Reproducing Biologically Relevant Rare Events of Proteins.

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Harada, Ryuhei; Takano, Yu; Shigeta, Yasuteru

2016-05-10

The TaBoo SeArch (TBSA) algorithm [ Harada et al. J. Comput. Chem. 2015 , 36 , 763 - 772 and Harada et al. Chem. Phys. Lett. 2015 , 630 , 68 - 75 ] was recently proposed as an enhanced conformational sampling method for reproducing biologically relevant rare events of a given protein. In TBSA, an inverse histogram of the original distribution, mapped onto a set of reaction coordinates, is constructed from trajectories obtained by multiple short-time molecular dynamics (MD) simulations. Rarely occurring states of a given protein are statistically selected as new initial states based on the inverse histogram, and resampling is performed by restarting the MD simulations from the new initial states to promote the conformational transition. In this process, the definition of the inverse histogram, which characterizes the rarely occurring states, is crucial for the efficiency of TBSA. In this study, we propose a simple modification of the inverse histogram to further accelerate the convergence of TBSA. As demonstrations of the modified TBSA, we applied it to (a) hydrogen bonding rearrangements of Met-enkephalin, (b) large-amplitude domain motions of Glutamine-Binding Protein, and (c) folding processes of the B domain of Staphylococcus aureus Protein A. All demonstrations numerically proved that the modified TBSA reproduced these biologically relevant rare events with nanosecond-order simulation times, although a set of microsecond-order, canonical MD simulations failed to reproduce the rare events, indicating the high efficiency of the modified TBSA.

Early cost-utility analysis of general and cerebrospinal fluid-specific Alzheimer's disease biomarkers for hypothetical disease-modifying treatment decision in mild cognitive impairment

NARCIS (Netherlands)

Handels, Ron L. H.; Joore, Manuela A.; Tran-Duy, An; Wimo, Anders; Wolfs, Claire A. G.; Verhey, Frans R. J.; Severens, Johan L.

Introduction: The study aimed to determine the room for improvement of a perfect cerebrospinal fluid (CSF) biomarker and the societal incremental net monetary benefit of CSF in subjects with mild cognitive impairment (MCI) assuming a hypothetical disease-modifying Alzheimer's disease (AD) treatment.

Genetic Diseases and Genetic Determinism Models in French Secondary School Biology Textbooks

Science.gov (United States)

Castera, Jeremy; Bruguiere, Catherine; Clement, Pierre

2008-01-01

The presentation of genetic diseases in French secondary school biology textbooks is analysed to determine the major conceptions taught in the field of human genetics. References to genetic diseases, and the processes by which they are explained (monogeny, polygeny, chromosomal anomaly and environmental influence) are studied in recent French…

Molecular biological aspects of acquired bullous diseases

DEFF Research Database (Denmark)

Dabelsteen, Erik

1998-01-01

Bullous diseases of the oral mucosa and skin were originally classified on the basis of clinical and histological criteria. The discovery of autoantibodies in some of these patients and the introduction of molecular biology have resulted in a new understanding of the pathological mechanisms of many...... of the bullous lesions. In this article, updated topics of the immune-mediated bullous lesions which involve oral mucosa and skin are reviewed. Pemphigus antigens, which are desmosomal-associated proteins and belong to the cadherin superfamily of cell adhesion proteins, have been isolated, and their genes have...

Clinical course and therapeutic approach to varicella zoster virus infection in children with rheumatic autoimmune diseases under immunosuppression

OpenAIRE

Leuvenink, Raphael; Aeschlimann, Florence; Baer, Walter; Berthet, Gerald; Cannizzaro, Elvira; Hofer, Michael; Kaiser, Daniela; Schroeder, Silke; Heininger, Ulrich; Woerner, Andreas

2016-01-01

Background To analyze the clinical presentation and complications of varicella zoster virus (VZV) infection in children with rheumatic diseases treated with immunosuppressive medication such as biological disease-modifying antirheumatic drugs (bDMARDs) and/or conventional disease-modifying antirheumatic drugs (cDMARDs), and to analyze the therapeutic approach to VZV infections with respect to the concomitant immunosuppressive treatment. Methods Retrospective multicenter study using the Swiss ...

Established and novel disease-modifying treatments in multiple sclerosis.

Science.gov (United States)

Cross, A H; Naismith, R T

2014-04-01

Multiple sclerosis (MS) is a presumed autoimmune disorder of the central nervous system, resulting in inflammatory demyelination and axonal and neuronal injury. New diagnostic criteria that incorporate magnetic resonance imaging have resulted in earlier and more accurate diagnosis of MS. Several immunomodulatory and immunosuppressive therapeutic agents are available for relapsing forms of MS, which allow individualized treatment based upon the benefits and risks. Disease-modifying therapies introduced in the 1990s, the beta-interferons and glatiramer acetate, have an established track record of efficacy and safety, although they require administration via injection. More recently, monoclonal antibodies have been engineered to act through specific mechanisms such as blocking alpha-4 integrin interactions (natalizumab) or lysing cells bearing specific markers, for example CD52 (alemtuzumab) or CD20 (ocrelizumab and ofatumumab). These agents can be highly efficacious, but sometimes have serious potential complications (natalizumab is associated with progressive multifocal leukoencephalopathy; alemtuzumab is associated with the development of new autoimmune disorders). Three new oral therapies (fingolimod, teriflunomide and dimethyl fumarate, approved for MS treatment from 2010 onwards) provide efficacy, tolerability and convenience; however, as yet, there are no long-term postmarketing efficacy and safety data in a general MS population. Because of this lack of long-term data, in some cases, therapy is currently initiated with the older, safer injectable medications, but patients are monitored closely with the plan to switch therapies if there is any indication of a suboptimal response or intolerance or lack of adherence to the initial therapy. For patients with MS who present with highly inflammatory and potentially aggressive disease, the benefit-to-risk ratio may support initiating therapy using a drug with greater potential efficacy despite greater risks (e

Huntingtin interacting proteins are genetic modifiers of neurodegeneration.

Directory of Open Access Journals (Sweden)

Linda S Kaltenbach

2007-05-01

Full Text Available Huntington's disease (HD is a fatal neurodegenerative condition caused by expansion of the polyglutamine tract in the huntingtin (Htt protein. Neuronal toxicity in HD is thought to be, at least in part, a consequence of protein interactions involving mutant Htt. We therefore hypothesized that genetic modifiers of HD neurodegeneration should be enriched among Htt protein interactors. To test this idea, we identified a comprehensive set of Htt interactors using two complementary approaches: high-throughput yeast two-hybrid screening and affinity pull down followed by mass spectrometry. This effort led to the identification of 234 high-confidence Htt-associated proteins, 104 of which were found with the yeast method and 130 with the pull downs. We then tested an arbitrary set of 60 genes encoding interacting proteins for their ability to behave as genetic modifiers of neurodegeneration in a Drosophila model of HD. This high-content validation assay showed that 27 of 60 orthologs tested were high-confidence genetic modifiers, as modification was observed with more than one allele. The 45% hit rate for genetic modifiers seen among the interactors is an order of magnitude higher than the 1%-4% typically observed in unbiased genetic screens. Genetic modifiers were similarly represented among proteins discovered using yeast two-hybrid and pull-down/mass spectrometry methods, supporting the notion that these complementary technologies are equally useful in identifying biologically relevant proteins. Interacting proteins confirmed as modifiers of the neurodegeneration phenotype represent a diverse array of biological functions, including synaptic transmission, cytoskeletal organization, signal transduction, and transcription. Among the modifiers were 17 loss-of-function suppressors of neurodegeneration, which can be considered potential targets for therapeutic intervention. Finally, we show that seven interacting proteins from among 11 tested were able to

Prospects for biological soil-borne disease control: application of indigenous versus synthetic microbiomes

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Biological disease control of soil-borne plant diseases has traditionally employed the biopesticide approach whereby single strains or strain mixtures are introduced into production systems through inundative/inoculative release. The approach has significant barriers that have long been recognized,...

Possibility of biological control of primocane fruiting raspberry disease caused by Fusarium sambucinum.

Science.gov (United States)

Shternshis, Margarita V; Belyaev, Anatoly A; Matchenko, Nina S; Shpatova, Tatyana V; Lelyak, Anastasya A

2015-10-01

Biological control agents are a promising alternative to chemical pesticides for plant disease suppression. The main advantage of the natural biocontrol agents, such as antagonistic bacteria compared with chemicals, includes environmental pollution prevention and a decrease of chemical residues in fruits. This study is aimed to evaluate the impact of three Bacillus strains on disease of primocane fruiting raspberry canes caused by Fusarium sambucinum under controlled infection load and uncontrolled environmental factors. Bacillus subtilis, Bacillus licheniformis, and Bacillus amyloliquefaciens were used for biocontrol of plant disease in 2013 and 2014 which differed by environmental conditions. The test suspensions were 10(5) CFU/ml for each bacterial strain. To estimate the effect of biological agents on Fusarium disease, canes were cut at the end of vegetation, and the area of outer and internal lesions was measured. In addition to antagonistic effect, the strains revealed the ability to induce plant resistance comparable with chitosan-based formulation. Under variable ways of cane treatment by bacterial strains, the more effective were B. subtilis and B. licheniformis demonstrating dual biocontrol effect. However, environmental factors were shown to impact the strain biocontrol ability; changes in air temperature and humidity led to the enhanced activity of B. amyloliquefaciens. For the first time, the possibility of replacing chemicals with environmentally benign biological agents for ecologically safe control of the raspberry primocane fruiting disease was shown.

Systems biology elucidates common pathogenic mechanisms between nonalcoholic and alcoholic-fatty liver disease.

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Silvia Sookoian

Full Text Available The abnormal accumulation of fat in the liver is often related either to metabolic risk factors associated with metabolic syndrome in the absence of alcohol consumption (nonalcoholic fatty liver disease, NAFLD or to chronic alcohol consumption (alcoholic fatty liver disease, AFLD. Clinical and histological studies suggest that NAFLD and AFLD share pathogenic mechanisms. Nevertheless, current data are still inconclusive as to whether the underlying biological process and disease pathways of NAFLD and AFLD are alike. Our primary aim was to integrate omics and physiological data to answer the question of whether NAFLD and AFLD share molecular processes that lead to disease development. We also explored the extent to which insulin resistance (IR is a distinctive feature of NAFLD. To answer these questions, we used systems biology approaches, such as gene enrichment analysis, protein-protein interaction networks, and gene prioritization, based on multi-level data extracted by computational data mining. We observed that the leading disease pathways associated with NAFLD did not significantly differ from those of AFLD. However, systems biology revealed the importance of each molecular process behind each of the two diseases, and dissected distinctive molecular NAFLD and AFLD-signatures. Comparative co-analysis of NAFLD and AFLD clarified the participation of NAFLD, but not AFLD, in cardiovascular disease, and showed that insulin signaling is impaired in fatty liver regardless of the noxa, but the putative regulatory mechanisms associated with NAFLD seem to encompass a complex network of genes and proteins, plausible of epigenetic modifications. Gene prioritization showed a cancer-related functional map that suggests that the fatty transformation of the liver tissue is regardless of the cause, an emerging mechanism of ubiquitous oncogenic activation. In conclusion, similar underlying disease mechanisms lead to NAFLD and AFLD, but specific ones depict a

Long-Term Outcomes in Puerto Ricans with Rheumatoid Arthritis (RA) Receiving Early Treatment with Disease-Modifying Anti-Rheumatic Drugs using the American College of Rheumatology Definition of Early RA.

Science.gov (United States)

Varela-Rosario, Noemí; Arroyo-Ávila, Mariangelí; Fred-Jiménez, Ruth M; Díaz-Correa, Leyda M; Pérez-Ríos, Naydi; Rodríguez, Noelia; Ríos, Grissel; Vilá, Luis M

2017-01-01

Early treatment of rheumatoid arthritis (RA) results in better long-term outcomes. However, the optimal therapeutic window has not been clearly established. To determine the clinical outcome of Puerto Ricans with RA receiving early treatment with conventional and/or biologic disease-modifying anti-rheumatic drugs (DMARDs) based on the American College of Rheumatology (ACR) definition of early RA. A cross-sectional study was performed in a cohort of Puerto Ricans with RA. Demographic features, clinical manifestations, disease activity, functional status, and pharmacotherapy were determined. Early treatment was defined as the initiation of DMARDs (conventional and/or biologic) in less than 6 months from the onset of symptoms attributable to RA. Patients who received early (disease duration was 14.9 years and 337 (87.0%) patients were women. One hundred and twenty one (31.3%) patients received early treatment. In the multivariate analysis adjusted for age and sex, early treatment was associated with better functional status, lower probability of joint deformities, intra-articular injections and joint replacement surgeries, and lower scores in the physician's assessments of global health, functional impairment and physical damage of patients. Using the ACR definition of early RA, this group of patients treated with DMARDs within 6 months of disease had better long-term outcomes with less physical damage and functional impairment.

Disease-modifying treatments for early and advanced multiple sclerosis: a new treatment paradigm.

Science.gov (United States)

Giovannoni, Gavin

2018-06-01

The treatment of multiple sclerosis is evolving rapidly with 11 classes of disease-modifying therapies (DMTs). This article provides an overview of a new classification system for DMTs and treatment paradigm for using these DMTs effectively and safely. A summary of research into the use of more active approaches to early and effective treatment of multiple sclerosis with defined treatment targets of no evident disease activity (NEDA). New insights are discussed that is allowing the field to begin to tackle more advanced multiple sclerosis, including people with multiple sclerosis using wheelchairs. However, the need to modify expectations of what can be achieved in more advanced multiple sclerosis are discussed; in particular, the focus on neuronal systems with reserve capacity, for example, upper limb, bulbar and visual function. The review describes a new more active way of managing multiple sclerosis and concludes with a call to action in solving the problem of slow adoption of innovations and the global problem of untreated, or undertreated, multiple sclerosis.

Re-evaluating concepts of biological function in clinical medicine: towards a new naturalistic theory of disease.

Science.gov (United States)

Chin-Yee, Benjamin; Upshur, Ross E G

2017-08-01

Naturalistic theories of disease appeal to concepts of biological function, and use the notion of dysfunction as the basis of their definitions. Debates in the philosophy of biology demonstrate how attributing functions in organisms and establishing the function-dysfunction distinction is by no means straightforward. This problematization of functional ascription has undermined naturalistic theories and led some authors to abandon the concept of dysfunction, favoring instead definitions based in normative criteria or phenomenological approaches. Although this work has enhanced our understanding of disease and illness, we need not necessarily abandon naturalistic concepts of function and dysfunction in the disease debate. This article attempts to move towards a new naturalistic theory of disease that overcomes the limitations of previous definitions and offers advantages in the clinical setting. Our approach involves a re-evaluation of concepts of biological function employed by naturalistic theories. Drawing on recent insights from the philosophy of biology, we develop a contextual and evaluative account of function that is better suited to clinical medicine and remains consistent with contemporary naturalism. We also show how an updated naturalistic view shares important affinities with normativist and phenomenological positions, suggesting a possibility for consilience in the disease debate.

Effect of biologic therapy on radiological progression in rheumatoid arthritis: what does it add to methotrexate?

Directory of Open Access Journals (Sweden)

Jones G

2012-07-01

Full Text Available Graeme Jones, Erica Darian-Smith, Michael Kwok, Tania WinzenbergMenzies Research Institute, University of Tasmania, Tasmania, AustraliaAbstract: There have been substantial advances in the treatment of rheumatoid arthritis in recent years. Traditional disease-modifying antirheumatic drugs (DMARDs have been shown to have small effects on the progression of radiographic damage. This quantitative overview summarizes the evidence for biologic DMARDS and radiographic damage either alone or in combination with methotrexate. Two outcomes were used (standardized mean difference and odds of progression. A total of 21 trials were identified of which 18 had useable data. For biologic monotherapy, tocilizumab, adalimumab, and etanercept were significantly better than methotrexate, with tocilizumab ranking first in both outcomes while golimumab was ineffective in both outcomes. For a biologic in combination with methotrexate compared with methotrexate alone, most therapies studied (etanercept, adalimumab, infliximab, certolizumab, tocilizumab, and rituximab were effective at slowing X-ray progression using either outcome, with infliximab ranking first in both outcomes. The exceptions to this were golimumab (no effect on standardized mean difference and abatacept (no effect on odds of progression. This effect was additional to methotrexate; thus, the overall benefit is moderate to large in magnitude, which is clearly of major clinical significance for sufferers of rheumatoid arthritis and supports the use of biologic DMARDs in those with a poor disease prognosis.Keywords: rheumatoid, trials, meta-analysis, radiographs, biologic, disease-modifying antirheumatic drugs, DMARDs

Systems Biology-Based Platforms to Accelerate Research of Emerging Infectious Diseases.

Science.gov (United States)

Oh, Soo Jin; Choi, Young Ki; Shin, Ok Sarah

2018-03-01

Emerging infectious diseases (EIDs) pose a major threat to public health and security. Given the dynamic nature and significant impact of EIDs, the most effective way to prevent and protect against them is to develop vaccines in advance. Systems biology approaches provide an integrative way to understand the complex immune response to pathogens. They can lead to a greater understanding of EID pathogenesis and facilitate the evaluation of newly developed vaccine-induced immunity in a timely manner. In recent years, advances in high throughput technologies have enabled researchers to successfully apply systems biology methods to analyze immune responses to a variety of pathogens and vaccines. Despite recent advances, computational and biological challenges impede wider application of systems biology approaches. This review highlights recent advances in the fields of systems immunology and vaccinology, and presents ways that systems biology-based platforms can be applied to accelerate a deeper understanding of the molecular mechanisms of immunity against EIDs. © Copyright: Yonsei University College of Medicine 2018.

Plague in Egypt: Disease biology, history and contemporary analysis: A minireview

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Wael M. Lotfy

2015-07-01

Full Text Available Plague is a zoonotic disease with a high mortality rate in humans. Unfortunately, it is still endemic in some parts of the world. Also, natural foci of the disease are still found in some countries. Thus, there may be a risk of global plague re-emergence. This work reviews plague biology, history of major outbreaks, and threats of disease re-emergence in Egypt. Based on the suspected presence of potential natural foci in the country, the global climate change, and the threat posed by some neighbouring countries disease re-emergence in Egypt should not be excluded. The country is in need for implementation of some preventive measures.

Patients' considerations in the decision-making process of initiating disease-modifying anti-rheumatic drugs

NARCIS (Netherlands)

Nota, Ingrid; Drossaert, Constance H.C.; Taal, Erik; van de Laar, Mart A F J

2015-01-01

Objectives To explore what considerations patients have when deciding about disease-modifying anti-rheumatic drugs (DMARDs) and what information patients need to participate in the decision-making process. Methods In-depth face-to-face interviews were conducted with 32 inflammatory arthritis

A Systems Biology Approach to Infectious Disease Research: Innovating the Pathogen-Host Research Paradigm

Energy Technology Data Exchange (ETDEWEB)

Aderem, Alan; Adkins, Joshua N.; Ansong, Charles; Galagan, James; Kaiser, Shari; Korth, Marcus J.; Law, G. L.; McDermott, Jason E.; Proll, Sean; Rosenberger, Carrie; Schoolnik, Gary; Katze, Michael G.

2011-02-01

The 20th century was marked by extraordinary advances in our understanding of microbes and infectious disease, but pandemics remain, food and water borne illnesses are frequent, multi-drug resistant microbes are on the rise, and the needed drugs and vaccines have not been developed. The scientific approaches of the past—including the intense focus on individual genes and proteins typical of molecular biology—have not been sufficient to address these challenges. The first decade of the 21st century has seen remarkable innovations in technology and computational methods. These new tools provide nearly comprehensive views of complex biological systems and can provide a correspondingly deeper understanding of pathogen-host interactions. To take full advantage of these innovations, the National Institute of Allergy and Infectious Diseases recently initiated the Systems Biology Program for Infectious Disease Research. As participants of the Systems Biology Program we think that the time is at hand to redefine the pathogen-host research paradigm.

Modifiable Coronary Heart Disease Risk Factors in the Population Aged 20-49 Years

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Francisco Carlos Valladares Mas

2014-04-01

Full Text Available Background: evidence provided by the Framingham Heart Study established the critical role of risk factors in the development of coronary heart disease. Over half a century later, current detection and control are still inadequate. Objective: to identify modifiable risk factors of coronary heart disease in individuals aged 20 to 49 years. Methods: a descriptive, cross-sectional study was conducted in 276 individuals from the doctor’s office No. 1 of the Fabio di Celmo Community Teaching Polyclinic in Cienfuegos. Patients were examined in the clinic visit and/or whole family visit. The studied variables included age, sex, skin color, risk factors (excess weight/obesity, physical inactivity, smoking, hypertension, diabetes, dyslipidemia and psychosocial factors, which were obtained from the medical interview, physical examination, laboratory tests (total cholesterol and triglycerides and review of individual medical records and family history. Results: risk factors most frequently identified were excess weight/obesity (42.4 %, physical inactivity (34.4 % and smoking (20.3 %. Presence of these risk factors increased with age, showing differences in the distribution by sex and was associated with psychosocial factors. Their coexistence and progress with age was significant. Conclusion: prevalence of modifiable risk factors for coronary heart disease in a young population was high, with frequent association, predominating factors related to unhealthy lifestyles.

Leprosy Mimicking Common Rheumatologic Entities: A Trial for the Clinician in the Era of Biologics

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Deepak Rath

2014-01-01

Full Text Available Rheumatoid arthritis and seronegative spondyloarthritis, which make up the lion’s share of cases attending a rheumatology clinic, are relatively easy to diagnose. However, when an entity of infective aetiology like leprosy known to be a great mimic of different autoimmune conditions presents with features similar to these, the possibility of it being diagnosed at the outset is very slim indeed. The ease with which the diagnosis of leprosy can be missed assumes sinister proportions as the use of disease modifying agents can have deleterious effects in these patients. In the era of increasing availability and use of biologic disease modifying agents, it is imperative not only to actively rule out the presence of leprosy but also to make it a part of the prebiologic screening of patients in whom biologics are being planned to be administered, especially in leprosy endemic areas.

Endothelin 1 gene is not a major modifier of chronic kidney disease advancement among the autosomal dominant polycystic kidney disease patients

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Annapareddy Shiva Nagendra Reddy

2016-01-01

Full Text Available Introduction: Autosomal dominant polycystic kidney disease (ADPKD is characterized by the presence of numerous cysts in the kidney and manifest with various renal and extra-renal complications leading to ESRD. Endothelin may contribute to various renal and extra-renal manifestations pointing to genetic and environmental modifying factors that alter the risk of developing chronic kidney disease (CKD in ADPKD. In the present study we investigated six genes coding for endothelin 1 (EDN1 tagging-single nucleotide polymorphisms (tag-SNPs to unravel the EDN1 gene modifier effect for renal disease progression in ADPKD. Materials and Methods: The tag-SNPs were genotyped using FRET-based KASPar method in 108 ADPKD patients and 119 healthy subjects. Cochran-Armitage trend test was used to determine the association between ADPKD and EDN1 tag-SNPs. Multivariate logistic regression analysis was performed to assess the effect of tag-SNPs on CKD progression. The relationship between different CKD stages and hypertension and their interaction Mantel-Haenszel stratified analysis was performed. Results: All loci are polymorphic and followed Hardy-Weinberg equilibrium. Distribution of EDN1 genotypes and haplotypes in control and ADPKD is not statistically significant. Five SNPs covering 3.4 kb forming single LD block, but the LD was not strong between SNPs. The EDN1 genotypes are not contributing to the CKD advancement among the ADPKD patients. Conclusion: These results suggest that the EDN1 gene is not a major modifier of CKD advancement among ADPKD patients.

Behavioural biology of Chagas disease vectors.

Science.gov (United States)

Lazzari, Claudio Ricardo; Pereira, Marcos Horácio; Lorenzo, Marcelo Gustavo

2013-01-01

Many arthropod species have adopted vertebrate blood as their main food source. Blood is rich in nutrients and, except for the presence of parasites, sterile. However, this food source is not freely available, nor is obtaining it devoid of risk. It circulates inside vessels hidden underneath the skin of mobile hosts that are able to defend themselves and even predate the insects that try to feed on them. Thus, the haematophagous lifestyle is associated with major morphological, physiological and behavioural adaptations that have accumulated throughout the evolutionary history of the various lineages of blood-sucking arthropods. These adaptations have significant consequences for the evolution of parasites as well as for the epidemiology of vector-transmitted diseases. In this review article, we analyse various aspects of the behaviour of triatomine bugs to illustrate how each behavioural trait represents a particular adaptation to their close association with their hosts, which may easily turn into predators. Our aim is to offer to the reader an up-to-date integrative perspective on the behaviour of Chagas disease vectors and to propose new research avenues to encourage both young and experienced colleagues to explore this aspect of triatomine biology.

Behavioural biology of Chagas disease vectors

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Claudio Ricardo Lazzari

2013-01-01

Full Text Available Many arthropod species have adopted vertebrate blood as their main food source. Blood is rich in nutrients and, except for the presence of parasites, sterile. However, this food source is not freely available, nor is obtaining it devoid of risk. It circulates inside vessels hidden underneath the skin of mobile hosts that are able to defend themselves and even predate the insects that try to feed on them. Thus, the haematophagous lifestyle is associated with major morphological, physiological and behavioural adaptations that have accumulated throughout the evolutionary history of the various lineages of blood-sucking arthropods. These adaptations have significant consequences for the evolution of parasites as well as for the epidemiology of vector-transmitted diseases. In this review article, we analyse various aspects of the behaviour of triatomine bugs to illustrate how each behavioural trait represents a particular adaptation to their close association with their hosts, which may easily turn into predators. Our aim is to offer to the reader an up-to-date integrative perspective on the behaviour of Chagas disease vectors and to propose new research avenues to encourage both young and experienced colleagues to explore this aspect of triatomine biology.

Original paper Influence of biologic therapy on growth in children with chronic inflammatory connective tissue diseases

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Joanna Świdrowska

2015-04-01

Full Text Available Objectives: Connective tissue diseases (CTD are a heterogeneous group of chronic inflammatory conditions. One of their complications in children is the inhibition of growth velocity. Due to direct inflammation within the musculoskeletal system as well as glucocorticoid therapy, this feature is the most essential and is mainly expressed in the course of juvenile spondyloarthropathies and juvenile idiopathic arthritis (JIA. Duration of the disease, but predominantly the activity of the inflammatory process, seems to have a significant impact on the abnormal growth profile in children. Effective biological therapy leads to improvement of the patient’s clinical condition and also, through the extinction of disease activity and reduction of daily doses of glucocorticosteroids (GCS, it gradually accelerates and normalizes the growth rate in children with CTD. Our objective was to evaluate the impact of biological therapy on growth in children with chronic inflammatory CTD. Material and methods: Data from 24 patients with CTD treated with tumor necrosis factor--blockers (etanercept, adalimumab, golimumab and an interleukin-6 receptor blocker (tocilizumab were reviewed at the time of disease onset, biological treatment initiation and at least 12 up to 24 months onwards. The rate of growth was correlated with the daily doses of GCS, and the type and duration of biological therapy. Results : Patient median height, measured as the change in height standard deviation score, was 0.36 ±1.07 at disease onset and –0.13 ±1.02 at biologic therapy initiation. The growth velocity accelerated in 17 patients (70.1% during the biological treatment. Mean height-SDS improvement between biological treatment initiation up to two years was 0.51 ±0.58. In 47% of patients daily doses of GCS were reduced to 0 mg/kg/day. Conclusions : In the treatment of CTD, biological agents restore growth velocity not only by inflammation inhibition, but also through limiting GCS

Diabetes and modifiable risk factors for cardiovascular disease: the prospective Million Women Study

International Nuclear Information System (INIS)

Spencer, Elizabeth A.; Pirie, Kirstin L.; Stevens, Richard J.; Beral, Valerie; Brown, Anna; Liu, Bette; Green, Jane; Reeves, Gillian K.

2008-01-01

To compare the effect of potentially modifiable lifestyle factors on the incidence of vascular disease in women with and without diabetes. In 1996-2001 over one million middle-aged women in the UK joined a prospective study, providing medical history, lifestyle and socio-demographic information. All participants were followed for hospital admissions and deaths using electronic record-linkage. Adjusted relative risks (RRs) and incidence rates were calculated to compare the incidence of coronary heart disease and stroke in women with and without diabetes and by lifestyle factors. At recruitment 25,915 women (2.1% of 1,242,338) reported current treatment for diabetes. During a mean follow-up of 6.1 years per woman, 21,928 had a first hospital admission or death from coronary heart disease (RR for women with versus without diabetes = 3.30, 95% CI 3.14-3.47) and 7,087 had a first stroke (RR = 2.47, 95% CI 2.24-2.74). Adjusted incidence rates of these conditions in women with diabetes increased with duration of diabetes, obesity, inactivity and smoking. The 5-year adjusted incidence rates for cardiovascular disease were 4.6 (95% CI 4.4-4.9) per 100 women aged 50-69 in non-smokers with diabetes, 5.9 (95% CI 4.6-7.6) in smokers with diabetes not using insulin and 11.0 (95% CI 8.3-14.7) in smokers with diabetes using insulin. Non-smoking women with diabetes who were not overweight or inactive still had threefold increased rate for coronary disease or stroke compared with women without diabetes. Of the modifiable factors examined in middle aged women with diabetes, smoking causes the greatest increase in cardiovascular disease, especially in those with insulin treated diabetes

The Method of Coating Fe₃O₄ with Carbon Nanoparticles to Modify Biological Properties of Oxide Measured in Vitro.

Science.gov (United States)

Niemiec, Tomasz; Dudek, Mariusz; Dziekan, Natalia; Jaworski, Sławomir; Przewozik, Aleksandra; Soszka, Emilia; Koperkiewicz, Anna; Koczoń, Piotr

2017-07-01

The coating of nanoparticles on materials for medical application [e.g., the coating of Fe3O4 nanopowder (IONP) with a carbon nanolayer] serves to protect and modify the selected biological, physical, and chemical properties of the coated material. Increases in chemical stability, changes in biocompatibility, and a modified surface structure are examples of the effects caused by the formation of carbon coatings. In the current study, Fe3O4 nanoparticles were coated with a carbon nanolayer (IONP@C) in a plasmochemical reactor (using radio-frequency plasma-enhanced chemical vapor deposition methods) under various experimental conditions. Based on data from X-ray diffraction, Raman, and IR spectroscopy, the best processing parameters were determined in order to produce a carbon coating that would not change the structure of the IONP. The materials with the best cover, i.e., a uniform carbon nanolayer, were used in cytotoxic tests to investigate their biological properties using the human HepG2 hepatocarcinoma cell line and chicken embryo red blood cells as an in vitro model. The obtained results proved the low cytotoxicity of Fe3O4 micropowder and IONP in contrast to IONP@C, which reduced cell viability, increased hemolysis, and generally was more toxic than bare Fe3O4.

Banking of biological fluids for studies of disease-associated protein biomarkers

DEFF Research Database (Denmark)

Rasmussen, Anne-Sofie Schrohl; Würtz, Sidse Ørnbjerg; Kohn, Elise

2008-01-01

With the increasing demand of providing personalized medicine the need for biobanking of biological material from individual patients has increased. Such samples are essential for molecular research aimed at characterizing diseases at several levels ranging from epidemiology and diagnostic and pr...

Biological effects of proton radiation: an update

International Nuclear Information System (INIS)

Girdhani, S.; Hlatky, L.; Sachs, R.

2015-01-01

Proton radiation provides significant dosimetric advantages when compared with gamma radiation due to its superior energy deposition characteristics. Although the physical aspects of proton radiobiology are well understood, biological and clinical endpoints are understudied. The current practice to assume the relative biological effectiveness of low linear energy transfer (LET) protons to be a generic value of about 1.1 relative to photons likely obscures important unrecognised differentials in biological response between these radiation qualities. A deeper understanding of the biological properties induced by proton radiation would have both radiobiological and clinical impact. This article briefly points to some of the literature pertinent to the effects of protons on tissue-level processes that modify disease progression, such as angiogenesis, cell invasion and cancer metastasis. Recent findings hint that proton radiation may, in addition to offering improved radio-therapeutic targeting, be a means to provide a new dimension for increasing therapeutic benefits for patients by manipulating these tissue-level processes. (authors)

Role of biologics and biosimilars in inflammatory bowel disease: current trends and future perspectives

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Rawla P

2018-05-01

Full Text Available Prashanth Rawla,1 Tagore Sunkara,2 Jeffrey Pradeep Raj3 1Department of Internal Medicine, Memorial Hospital of Martinsville and Henry County, Martinsville, VA, 2Division of Gastroenterology and Hepatology, The Brooklyn Hospital Center, Clinical Affiliate of The Mount Sinai Hospital, New York, NY, USA; 3Department of Pharmacology, St John’s Medical College, Bangalore, India Abstract: Inflammatory bowel disease (IBD is an idiopathic chronic inflammatory disease of the gastrointestinal system. The spectrum is of predominantly two types, namely, ulcerative colitis and Crohn’s disease. The incidence of IBD has been increasing steadily since 1990, and so the number of agents used in their treatment. Biologics that are derived partly or completely from living biological sources such as animals and humans have become widely available, which provide therapeutic benefits to the IBD patients. Currently, monoclonal antibodies against tumor necrosis factor-alpha (infliximab, adalimumab, certolizumab, and golimumab, integrins (vedolizumab and natalizumab, and interleukin (IL-12 and IL-23 antagonists (ustekinumab are approved for use in IBD. Biosimilars of infliximab and adalimumab are also available for the treatment of IBD. This review summarizes the clinical pharmacology, studies leading to their approval, overall indications and their use in IBD, usage in pregnancy and lactation, and the adverse effects of these agents. This review also summarizes the recent advances and future perspectives specific to biologics and biosimilars in IBD. Keywords: inflammatory bowel disease, Crohn’s disease, ulcerative colitis, biologics, biosimilars, tumor necrosis factor, integrin, interleukin, adalimumab, Humira®, certolizumab, Cimzia®, golimumab, Simponi®, infliximab, Remicade®, vedolizumab, Entyvio, natalizumab, Tysabri®, ustekinumab, Stelara® 

An improved ashing procedure for biologic sample

Energy Technology Data Exchange (ETDEWEB)

Zongmei, Wu [Zhejiang Province Enviromental Radiation Monitoring Centre (China)

1992-07-01

The classical ashing procedure in muffle was modified for biologic samples. In the modified procedure the door of muffle was open in the duration of ashing process, the ashing was accelerated and the ashing product quality was comparable to that the classical procedure. The modified procedure is suitable for ashing biologic samples in large batches.

An improved ashing procedure for biologic sample

International Nuclear Information System (INIS)

Wu Zongmei

1992-01-01

The classical ashing procedure in muffle was modified for biologic samples. In the modified procedure the door of muffle was open in the duration of ashing process, the ashing was accelerated and the ashing product quality was comparable to that the classical procedure. The modified procedure is suitable for ashing biologic samples in large batches

Discovery of innovative therapies for rare immune-mediated inflammatory diseases via off-label prescription of biologics: the case of IL-6 receptor blockade in Castleman’s disease

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Anne eMusters

2015-12-01

Full Text Available Biologics have revolutionized the field of clinical immunology and proven to be both effective and safe in common immune-mediated inflammatory diseases (IMIDs such as rheumatoid arthritis, inflammatory bowel diseases, and various haematological disorders. However, in patients with rare, severe IMIDs failing on standard therapies it is virtually impossible to conduct randomized controlled trials. Therefore, biologics are usually prescribed off-label in these often severely ill patients. Unfortunately, off-label prescription is sometimes hampered in these diseases due to a lack of reimbursement that is often based on a presumed lack of evidence for effectiveness. In the present article will discuss that off-label prescription of biologics can be a good way to discover new treatments for rare diseases. This will be ilustrated using a case of multicentric Castleman’s disease, an immune-mediated lymphoproliferative disorder, in which off-label tocilizumab (humanized anti-IL-6 receptor blocking antibody treatment resulted in remarkable clinical improvement. Furthermore, we will give recommendations for monitoring efficacy and safety of biologic treatment in rare IMIDs, including the use of registries. In conclusion, we put forward that innovative treatments for rare IMIDs can be discovered via off-label prescription of biologicals, provided that this is based on rational arguments including knowledge of the pathophysiology of the disease.

PSK, a biological response modifier, modifies p53 expression, mitosis and apoptosis in X-ray irradiated mouse embryos. Possible cellular mechanism of the anti-teratogenic effect

International Nuclear Information System (INIS)

Kagohashi, Yukiko; Naora, Hiroyuki; Otani, Hiroki

2002-01-01

We previously showed that PSK, a biological response modifier, suppressed X-ray irradiation induced ocular anomalies in mouse embryos. In the present study, in mouse embryos irradiated at E7.5, PSK, when administered immediately after irradiation, suppressed mitosis and increased apoptosis as compared with embryos not treated with PSK at 12 hrs after irradiation. In the irradiated embryos, p53, which is normally expressed at a high level in early embryos, increased at 6 hrs and decreased at 12 hrs after irradiation. In the irradiated and PSK-treated embryos, the p53 level did not change at 6 hrs, increased at 12 hrs and decreased at 24 hrs after irradiation. This timing of PSK-induced delayed increase of p53 coincided with that of the PSK-induced decrease in mitosis and increase in apoptosis. These results suggested that PSK modified the p53 level and affected cell proliferation and apoptosis, which might contribute to the suppression of teratogenesis. (author)

Discovery of novel propargylamine-modified 4-aminoalkyl imidazole substituted pyrimidinylthiourea derivatives as multifunctional agents for the treatment of Alzheimer's disease.

Science.gov (United States)

Xu, Yi-Xiang; Wang, Huan; Li, Xiao-Kang; Dong, Sheng-Nan; Liu, Wen-Wen; Gong, Qi; Wang, Tian-Duan-Yi; Tang, Yun; Zhu, Jin; Li, Jian; Zhang, Hai-Yan; Mao, Fei

2018-01-01

A series of novel propargylamine-modified pyrimidinylthiourea derivatives (1-3) were designed and synthesized as multifunctional agents for Alzheimer's disease (AD) therapy, and their potential was evaluated through various biological experiments. Among these derivatives, compound 1b displayed good selective inhibitory activity against AChE (vs BuChE, IC 50  = 0.324 μM, SI > 123) and MAO-B (vs MAO-A, IC 50  = 1.427 μM, SI > 35). Molecular docking study showed that the pyrimidinylthiourea moiety of 1b could bind to the catalytic active site (CAS) of AChE, and the propargylamine moiety interacted directly with the flavin adenine dinucleotide (FAD) of MAO-B. Moreover, 1b demonstrated mild antioxidant ability, good copper chelating property, effective inhibitory activity against Cu 2+ -induced Aβ 1-42 aggregation, moderate neuroprotection, low cytotoxicity, and appropriate blood-brain barrier (BBB) permeability in vitro and was capable of ameliorating scopolamine-induced cognitive impairment in mice. These results indicated that 1b has the potential to be a multifunctional candidate for the treatment of Alzheimer's disease. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Huperzine A: Is it an Effective Disease-Modifying Drug for Alzheimer’s Disease?

Science.gov (United States)

Qian, Zhong Ming; Ke, Ya

2014-01-01

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder for which there is no cure. Huperzine A (HupA) is a natural inhibitor of acetylcholinesterase (AChE) derived from the Chinese folk medicine Huperzia serrata (Qian Ceng Ta). It is a licensed anti-AD drug in China and is available as a nutraceutical in the US. A growing body of evidence has demonstrated that HupA has multifaceted pharmacological effects. In addition to the symptomatic, cognitive-enhancing effect via inhibition of AChE, a number of recent studies have reported that this drug has “non-cholinergic” effects on AD. Most important among these is the protective effect of HupA on neurons against amyloid beta-induced oxidative injury and mitochondrial dysfunction as well as via the up-regulation of nerve growth factor and antagonizing N-methyl-d-aspartate receptors. The most recent discovery that HupA may reduce brain iron accumulation lends further support to the argument that HupA could serve as a potential disease-modifying agent for AD and also other neurodegenerative disorders by significantly slowing down the course of neuronal death. PMID:25191267

Huperzine A: is it an effective disease-modifying drug for Alzheimer’s disease?

Directory of Open Access Journals (Sweden)

Zhong Ming eQian

2014-08-01

Full Text Available Alzheimer's disease (AD is a progressive neurodegenerative disorder for which there is no cure. Huperzine A (HupA is a natural inhibitor of acetylcholinesterase (AChE derived from the Chinese folk medicine Huperzia serrata (Qian Ceng Ta. It is a licensed anti-AD drug in China and is available as a nutraceutical in the US. A growing body of evidence has demonstrated that HupA has multifaceted pharmacological effects. In addition to the symptomatic, cognitive-enhancing effect via inhibition of AChE, a number of recent studies have reported that this drug has non-cholinergic effects on AD. Most important among these is the protective effect of HupA on neurons against amyloid beta-induced oxidative injury and mitochondrial dysfunction as well as via the up-regulation of nerve growth factor and antagonizing N-methyl-D-aspartate receptors. The most recent discovery that HupA may reduce brain iron accumulation lends further support to the argument that HupA could serve as a potential disease-modifying agent for AD and also other neurodegenerative disorders by significantly slowing down the course of neuronal death.

Gastric cancer: a primer on the epidemiology and biology of the disease and an overview of the medical management of advanced disease.

Science.gov (United States)

Shah, Manish A; Kelsen, David P

2010-04-01

Gastric cancer is a cause of significant morbidity and cancer-related mortality worldwide. Despite recent advances in targeted therapy and understanding of the biology and development of the malignancy, progress in the treatment of gastric cancer has been limited. Most newly diagnosed patients will present with incurable disease, and have a median survival of less than 1 year. Although the disease has widespread ethnic and epidemiologic differences, medical management of gastric cancer does not distinguish among the various disease subtypes. The recent report of the ToGA phase III study has validated Her2 as a molecular target in this disease, supporting the concept that a greater understanding of the biology of gastric cancer subsets may improve treatment selection and overall outcome of individual patients. This article summarizes the epidemiology and ethnic variation of this disease to crystalize subtypes of gastric cancer in the context of current and future medical management of advanced disease.

Potentials of biological control of plant diseases in the tropics | Ofor ...

African Journals Online (AJOL)

This paper highlights the various categories of biological control, which are employed in an Integrated Disease Management (IDM) scheme. These include conservation, classical biocontrol and augmentation. Also, the various types of biocontrol agents/agencies which are currently in use in various parts of the world like, ...

Biologic treatment or immunomodulation is not associated with postoperative anastomotic complications in abdominal surgery for Crohn's disease

DEFF Research Database (Denmark)

El-Hussuna, Alaa Abdul-Hussein H; Andersen, Jens; Bisgaard, Thue

2012-01-01

There are concerns that biologic treatments or immunomodulation may negatively influence anastomotic healing. This study investigates the relationship between these treatments and anastomotic complications after surgery for Crohn's disease.......There are concerns that biologic treatments or immunomodulation may negatively influence anastomotic healing. This study investigates the relationship between these treatments and anastomotic complications after surgery for Crohn's disease....

Risk of invasive melanoma in patients with rheumatoid arthritis treated with biologics

DEFF Research Database (Denmark)

Mercer, Louise K; Askling, Johan; Raaschou, Pauline

2017-01-01

-specific general population of each register as reference, age, sex and calendar year standardised incidence ratios (SIRs) of invasive histology-confirmed cutaneous melanoma were calculated within each register. Pooled SIR and incidence rate ratios (IRRs) comparing biologic cohorts to biologic-naïve were...... calculated across countries by taking the size of the register into account. RESULTS: Overall 130 315 RA patients with a mean age of 58 years contributing 579 983 person-years were available for the analysis and 287 developed a first melanoma. Pooled SIRs for biologic-naïve, TNFi and rituximab...... with TNF inhibitors (TNFi), other biologic disease modifying drugs and non-biologic therapy. METHODS: Eleven biologic registers from nine European countries participated in this collaborative project. According to predefined exposure definitions, cohorts of patients with RA were selected. Using the country...

Polysaccharides from Traditional Chinese Medicines: Extraction, Purification, Modification, and Biological Activity.

Science.gov (United States)

Chen, Yun; Yao, Fangke; Ming, Ke; Wang, Deyun; Hu, Yuanliang; Liu, Jiaguo

2016-12-13

Traditional Chinese Medicine (TCM) has been used to treat diseases in China for thousands of years. TCM compositions are complex, using as their various sources plants, animals, fungi, and minerals. Polysaccharides are one of the active and important ingredients of TCMs. Polysaccharides from TCMs exhibit a wide range of biological activities in terms of immunity- modifying, antiviral, anti-inflammatory, anti-oxidative, and anti-tumor properties. With their widespread biological activities, polysaccharides consistently attract scientist's interests, and the studies often concentrate on the extraction, purification, and biological activity of TCM polysaccharides. Currently, numerous studies have shown that the modification of polysaccharides can heighten or change the biological activities, which is a new angle of polysaccharide research. This review highlights the current knowledge of TCM polysaccharides, including their extraction, purification, modification, and biological activity, which will hopefully provide profound insights facilitating further research and development.

Differentially expressed genes distributed over chromosomes and implicated in certain biological processes for site insertion genetically modified rice Kemingdao.

Science.gov (United States)

Liu, Zhi; Li, Yunhe; Zhao, Jie; Chen, Xiuping; Jian, Guiliang; Peng, Yufa; Qi, Fangjun

2012-01-01

Release of genetically modified (GM) plants has sparked off intensive debates worldwide partly because of concerns about potential adverse unintended effects of GM plants to the agro system and the safety of foods. In this study, with the aim of revealing the molecular basis for unintended effects of a single site insertion GM Kemingdao (KMD) rice transformed with a synthetic cry1Ab gene, and bridging unintended effects of KMD rice through clues of differentially expressed genes, comparative transcriptome analyses were performed for GM KMD rice and its parent rice of Xiushui11 (XS11). The results showed that 680 differentially expressed transcripts were identified from 30-day old seedlings of GM KMD rice. The absolute majority of these changed expression transcripts dispersed and located over all rice chromosomes, and existed physical distance on chromosome from the insertion site, while only two transcripts were found to be differentially expressed within the 21 genes located within 100 kb up and down-stream of the insertion site. Pathway and biology function analyses further revealed that differentially expressed transcripts of KMD rice were involved in certain biological processes, and mainly implicated in two types of pathways. One type was pathways implicated in plant stress/defense responses, which were considerably in coordination with the reported unintended effects of KMD rice, which were more susceptible to rice diseases compared to its parent rice XS11; the other type was pathways associated with amino acids metabolism. With this clue, new unintended effects for changes in amino acids synthesis of KMD rice leaves were successfully revealed. Such that an actual case was firstly provided for identification of unintended effects in GM plants by comparative transciptome analysis.

Validation of modified World Health Organization classification for pregnant women with heart disease in a tertiary care center in southern Thailand

Directory of Open Access Journals (Sweden)

Suwanrath C

2018-01-01

Full Text Available Chitkasaem Suwanrath,1 Putthaporn Thongphanang,1 Sutham Pinjaroen,1 Saranyou Suwanugsorn2 1Department of Obstetrics and Gynecology, 2Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand Purpose: To validate the modified World Health Organization (WHO classification in pregnant women with congenital and acquired heart diseases. Patients and methods: The database of pregnant women with heart disease, who delivered at Songklanagarind Hospital between January 1995 and December 2016, was retrieved from the Statistical Unit, Department of Obstetrics and Gynecology, along with the Hospital Information System of Songklanagarind Hospital, Faculty of Medicine, Prince of Songkla University. Each patient was retrospectively classified according to the modified WHO classification of maternal cardiovascular risk. Comparison of maternal and fetal outcomes among the modified WHO classes were analyzed using the chi-square test or Fisher’s exact test and one-way ANOVA test. A p-value of <0.05 was considered statistically significant. Results: A total of 331 cases were studied: 157 cases with congenital heart disease and 174 cases with acquired heart disease. There were 48, 173, 32 and 78 cases in the modified WHO class I, II, III and IV, respectively. Congestive heart failure was the most common complication. The overall maternal mortality rate was 3.6%, all of which were in the modified WHO class IV. Maternal cardiovascular events occurred in 24.2% of cases, increasing rates with higher modified WHO class: 4.2%, 15.0%, 25.0% and 56.4% in class I, II, III and IV, respectively (p<0.001. Adverse fetal outcomes including preterm delivery, low birth weight, small for gestational age and neonatal intensive care unit admission were also significantly increased in class III and IV (p<0.05. Conclusion: The modified WHO classification is useful not only for obtaining a cardiovascular risk assessment in pregnant

New-onset vitiligo and progression of pre-existing vitiligo during treatment with biological agents in chronic inflammatory diseases.

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Méry-Bossard, L; Bagny, K; Chaby, G; Khemis, A; Maccari, F; Marotte, H; Perrot, J L; Reguiai, Z; Sigal, M L; Avenel-Audran, M; Boyé, T; Grasland, A; Gillard, J; Jullien, D; Toussirot, E

2017-01-01

The development of vitiligo during treatment with biological agents is an unusual event and only a few isolated cases have been reported. To describe the clinical characteristics and evolution of patients developing new-onset vitiligo following initiation of a biological agent for chronic inflammatory disease; and also to report the clinical course of pre-existing vitiligo under biological therapy. This nationwide multicentre, retrospective study, carried out between July 2013 and January 2015, describes the characteristics of a large series of 18 patients (psoriasis N = 8, inflammatory rheumatic diseases N = 8, ulcerative colitis N = 1, uveitis N = 1) who developed new-onset vitiligo while receiving a biological agent. TNFα inhibitors were the most common biological agent involved (13/18) while anti-IL-12/23 and anti-IL-17 agents or abatacept were less common (4/18 and 1/18 respectively). Mean duration of biological agent exposure before vitiligo onset was 13.9 ± 16.5 months. Outcome was favourable for most patients (15/17) while maintaining the biological agent. Data were also collected for 18 patients (psoriasis N = 5, inflammatory rheumatic diseases N = 10, inflammatory bowel diseases N = 2, SAPHO N = 1) who had pre-existing vitiligo when treatment with a biological agent started (TNFα inhibitors N = 15, ustekinumab N = 1, rituximab N = 1, tocilizumab N = 1). Vitiligo progressed in seven patients and was stable or improved in eight cases. Vitiligo may thus emerge and/or progress during treatment with various biological agents, mainly TNFα inhibitors and could be a new paradoxical skin reaction. De novo vitiligo displays a favourable outcome when maintaining the biological agent, whereas the prognosis seems worse in cases of pre-existing vitiligo. © 2016 European Academy of Dermatology and Venereology.

Work-Family Conflict Modifies the Association of Smoking and Periodontal Disease.

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Brennan, David S; Spencer, A John; Roberts-Thomson, Kaye F

2017-02-01

The aims of the study were to assess the association of periodontal loss of attachment with smoking and work-family conflict and assess whether work-family conflict modifies the association of smoking and periodontal disease. A random sample of 45-54 year olds from metropolitan Adelaide, South Australia, was surveyed by mailed self-complete questionnaire during 2004-2005. Oral examinations were performed on persons who responded to the questionnaire, providing an assessment of periodontal status. A total of 879 responded (participation rate = 43.8 %), with n = 709 oral examinations (completion rate = 80.7 %). Prevalence of periodontal loss of attachment (LOA) of 6+ mm was higher (p periodontal disease. Higher levels of work interfering with family were associated with higher levels of periodontal LOA for smokers compared with non-smokers.

Biologiske lægemidler til behandling af ikke-cancerrelaterede sygdommeTumor necrosis factor-alpha binding capacity and anti-infliximab antibodies measured by fluid-phase radioimmunoassays as predictors of clinical efficacy of infliximab in Crohn's disease

DEFF Research Database (Denmark)

Skov, L.; Bendtzen, K.

2008-01-01

Biological response modifiers are modified (poly) peptides from living organisms designed to modulate a specific biologic process. Biotechnology has led to the rapid development of recombinant drugs for treatment of many immunoinflammatory diseases. In this article, we briefly describe the main t...

Gaseous VOCs rapidly modify particulate matter and its biological effects - Part 1: Simple VOCs and model PM

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Ebersviller, S.; Lichtveld, K.; Sexton, K. G.; Zavala, J.; Lin, Y.-H.; Jaspers, I.; Jeffries, H. E.

2012-12-01

This is the first of a three-part study designed to demonstrate dynamic entanglements among gaseous organic compounds (VOC), particulate matter (PM), and their subsequent potential biological effects. We study these entanglements in increasingly complex VOC and PM mixtures in urban-like conditions in a large outdoor chamber. To the traditional chemical and physical characterizations of gas and PM, we added new measurements of biological effects, using cultured human lung cells as model indicators. These biological effects are assessed here as increases in cellular damage or expressed irritation (i.e., cellular toxic effects) from cells exposed to chamber air relative to cells exposed to clean air. The exposure systems permit virtually gas-only- or PM-only-exposures from the same air stream containing both gases and PM in equilibria, i.e., there are no extractive operations prior to cell exposure. Our simple experiments in this part of the study were designed to eliminate many competing atmospheric processes to reduce ambiguity in our results. Simple volatile and semi-volatile organic gases that have inherent cellular toxic properties were tested individually for biological effect in the dark (at constant humidity). Airborne mixtures were then created with each compound to which we added PM that has no inherent cellular toxic properties for another cellular exposure. Acrolein and p-tolualdehyde were used as model VOCs and mineral oil aerosol (MOA) was selected as a surrogate for organic-containing PM. MOA is appropriately complex in composition to represent ambient PM, and exhibits no inherent cellular toxic effects and thus did not contribute any biological detrimental effects on its own. Chemical measurements, combined with the responses of our biological exposures, clearly demonstrate that gas-phase pollutants can modify the composition of PM (and its resulting detrimental effects on lung cells). We observed that, even if the gas-phase pollutants are not

Adenosine A2B receptor: from cell biology to human diseases

Science.gov (United States)

Sun, Ying; Huang, Pingbo

2016-08-01

Extracellular adenosine is a ubiquitous signaling molecule that modulates a wide array of biological processes. Recently, significant advances have been made in our understanding of A2B adenosine receptor (A2BAR). In this review, we first summarize some of the general characteristics of A2BAR, and then we describe the multiple binding partners of the receptor, such as newly identified α-actinin-1 and p105, and discuss how these associated proteins could modulate A2BAR’s functions, including certain seemingly paradoxical functions of the receptor. Growing evidence indicates a critical role of A2BAR in cancer, renal disease, and diabetes, in addition to its importance in the regulation of vascular diseases and lung disease. Here, we also discuss the role of A2BAR in cancer, renal disease, and diabetes and the potential of the receptor as a target for treating these three diseases.

Health-Related Quality of Life in Patients with Multiple Sclerosis : Impact of Disease-Modifying Drugs

NARCIS (Netherlands)

Jongen, Peter Joseph

Multiple sclerosis (MS) has a profound impact on health-related quality of life (HRQoL), a comprehensive subjective measure of the patient's health status. Assessment of HRQoL informs on the potential advantages and disadvantages of disease-modifying drugs (DMDs) beyond their effects on

Reduced or modified dietary fat for preventing cardiovascular disease

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Lee Hooper

Full Text Available ABSTRACT: BACKGROUND: Reduction and modification of dietary fats have differing effects on cardiovascular risk factors (such as serum cholesterol, but their effects on important health outcomes are less clear. OBJECTIVE: To assess the effect of reduction and/or modification of dietary fats on mortality, cardiovascular mortality, cardiovascular morbidity and individual outcomes including myocardial infarction, stroke and cancer diagnoses in randomised clinical trials of at least 6 months duration. METHODS: Search methods: For this review update, the Cochrane Central Register of Controlled Trials (CENTRAL, Medline and Embase, were searched through to June 2010. References of Included studies and reviews were also checked. Selection criteria: Trials fulfilled the following criteria: 1 randomized with appropriate control group, 2 intention to reduce or modify fat or cholesterol intake (excluding exclusively omega-3 fat interventions, 3 not multi factorial, 4 adult humans with or without cardiovascular disease, 5 intervention at least six months, 6 mortality or cardiovascular morbidity data available. Data collection and analysis: Participant numbers experiencing health outcomes in each arm were extracted independently in duplicate and random effects meta-analyses, meta-regression, sub-grouping, sensitivity analyses and funnel plots were performed. MAIN RESULTS: This updated review suggested that reducing saturated fat by reducing and/or modifying dietary fat reduced the risk of cardiovascular events by 14% (RR 0.86, 95% CI 0.77 to 0.96, 24 comparisons, 65,508 participants of whom 7% had a cardiovascular event, I2 50%. Subgrouping suggested that this reduction in cardiovascular events was seen in studies of fat modification (not reduction - which related directly to the degree of effect on serum total and LDL cholesterol and triglycerides, of at least two years duration and in studies of men (not of women. There were no clear effects of dietary fat

Reduced or modified dietary fat for preventing cardiovascular disease

Science.gov (United States)

Hooper, Lee; Summerbell, Carolyn D; Thompson, Rachel; Sills, Deirdre; Roberts, Felicia G; Moore, Helen; Smith, George Davey

2014-01-01

Background Reduction and modification of dietary fats have differing effects on cardiovascular risk factors (such as serum cholesterol), but their effects on important health outcomes are less clear. Objectives To assess the effect of reduction and/or modification of dietary fats on mortality, cardiovascular mortality, cardiovascular morbidity and individual outcomes including myocardial infarction, stroke and cancer diagnoses in randomised clinical trials of at least 6 months duration. Search methods For this review update, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE, were searched through to June 2010. References of Included studies and reviews were also checked. Selection criteria Trials fulfilled the following criteria: 1) randomised with appropriate control group, 2) intention to reduce or modify fat or cholesterol intake (excluding exclusively omega-3 fat interventions), 3) not multi factorial, 4) adult humans with or without cardiovascular disease, 5) intervention at least six months, 6) mortality or cardiovascular morbidity data available. Data collection and analysis Participant numbers experiencing health outcomes in each arm were extracted independently in duplicate and random effects meta-analyses, meta-regression, sub-grouping, sensitivity analyses and funnel plots were performed. Main results This updated review suggested that reducing saturated fat by reducing and/or modifying dietary fat reduced the risk of cardiovascular events by 14% (RR 0.86, 95% CI 0.77 to 0.96, 24 comparisons, 65,508 participants of whom 7% had a cardiovascular event, I2 50%). Subgrouping suggested that this reduction in cardiovascular events was seen in studies of fat modification (not reduction - which related directly to the degree of effect on serum total and LDL cholesterol and triglycerides), of at least two years duration and in studies of men (not of women). There were no clear effects of dietary fat changes on total mortality (RR 0

Role of epigenetics in developmental biology and transgenerational inheritance.

Science.gov (United States)

Skinner, Michael K

2011-03-01

The molecular mechanisms involved in developmental biology and cellular differentiation have traditionally been considered to be primarily genetic. Environmental factors that influence early life critical windows of development generally do not have the capacity to modify genome sequence, nor promote permanent genetic modifications. Epigenetics provides a molecular mechanism for environment to influence development, program cellular differentiation, and alter the genetic regulation of development. The current review discusses how epigenetics can cooperate with genetics to regulate development and allow for greater plasticity in response to environmental influences. This impacts area such as cellular differentiation, tissue development, environmental induced disease etiology, epigenetic transgenerational inheritance, and the general systems biology of organisms and evolution. Copyright © 2011 Wiley-Liss, Inc.

Polysaccharides from Traditional Chinese Medicines: Extraction, Purification, Modification, and Biological Activity

Directory of Open Access Journals (Sweden)

Yun Chen

2016-12-01

Full Text Available Traditional Chinese Medicine (TCM has been used to treat diseases in China for thousands of years. TCM compositions are complex, using as their various sources plants, animals, fungi, and minerals. Polysaccharides are one of the active and important ingredients of TCMs. Polysaccharides from TCMs exhibit a wide range of biological activities in terms of immunity- modifying, antiviral, anti-inflammatory, anti-oxidative, and anti-tumor properties. With their widespread biological activities, polysaccharides consistently attract scientist's interests, and the studies often concentrate on the extraction, purification, and biological activity of TCM polysaccharides. Currently, numerous studies have shown that the modification of polysaccharides can heighten or change the biological activities, which is a new angle of polysaccharide research. This review highlights the current knowledge of TCM polysaccharides, including their extraction, purification, modification, and biological activity, which will hopefully provide profound insights facilitating further research and development.

Risk of serious infection in biological treatment of patients with rheumatoid arthritis

DEFF Research Database (Denmark)

Singh, Jasvinder A; Cameron, Chris; Noorbaloochi, Shahrzad

2015-01-01

). We did a systematic review and meta-analysis of serious infections in patients treated with biological drugs compared with those treated with traditional DMARDs. METHODS: We did a systematic literature search with Medline, Embase, Cochrane Central Register of Controlled Trials, and Clinical......Trials.gov from their inception to Feb 11, 2014. Search terms included "biologics", "rheumatoid arthritis" and their synonyms. Trials were eligible for inclusion if they included any of the approved biological drugs and reported serious infections. We assessed the risk of bias with the Cochrane Risk of Bias Tool......BACKGROUND: Serious infections are a major concern for patients considering treatments for rheumatoid arthritis. Evidence is inconsistent as to whether biological drugs are associated with an increased risk of serious infection compared with traditional disease-modifying antirheumatic drugs (DMARDs...

Comparison of independent screens on differentially vulnerable motor neurons reveals alpha-synuclein as a common modifier in motor neuron diseases.

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Kline, Rachel A; Kaifer, Kevin A; Osman, Erkan Y; Carella, Francesco; Tiberi, Ariana; Ross, Jolill; Pennetta, Giuseppa; Lorson, Christian L; Murray, Lyndsay M

2017-03-01

The term "motor neuron disease" encompasses a spectrum of disorders in which motor neurons are the primary pathological target. However, in both patients and animal models of these diseases, not all motor neurons are equally vulnerable, in that while some motor neurons are lost very early in disease, others remain comparatively intact, even at late stages. This creates a valuable system to investigate the factors that regulate motor neuron vulnerability. In this study, we aim to use this experimental paradigm to identify potential transcriptional modifiers. We have compared the transcriptome of motor neurons from healthy wild-type mice, which are differentially vulnerable in the childhood motor neuron disease Spinal Muscular Atrophy (SMA), and have identified 910 transcriptional changes. We have compared this data set with published microarray data sets on other differentially vulnerable motor neurons. These neurons were differentially vulnerable in the adult onset motor neuron disease Amyotrophic Lateral Sclerosis (ALS), but the screen was performed on the equivalent population of neurons from neurologically normal human, rat and mouse. This cross species comparison has generated a refined list of differentially expressed genes, including CELF5, Col5a2, PGEMN1, SNCA, Stmn1 and HOXa5, alongside a further enrichment for synaptic and axonal transcripts. As an in vivo validation, we demonstrate that the manipulation of a significant number of these transcripts can modify the neurodegenerative phenotype observed in a Drosophila line carrying an ALS causing mutation. Finally, we demonstrate that vector-mediated expression of alpha-synuclein (SNCA), a transcript decreased in selectively vulnerable motor neurons in all four screens, can extend life span, increase weight and decrease neuromuscular junction pathology in a mouse model of SMA. In summary, we have combined multiple data sets to identify transcripts, which are strong candidates for being phenotypic modifiers

Role of biologics in intractable urticaria

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Cooke A

2015-04-01

Full Text Available Andrew Cooke,1 Adeeb Bulkhi,1,2 Thomas B Casale1 1Department of Internal Medicine, Division of Allergy and Immunology, University of South Florida, Tampa, FL, USA; 2Department of Internal Medicine, College of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia Abstract: Chronic urticaria (CU is a common condition faced by many clinicians. CU has been estimated to affect approximately 0.5%–1% of the population, with nearly 20% of sufferers remaining symptomatic 20 years after onset. Antihistamines are the first-line therapy for CU. Unfortunately, nearly half of these patients will fail this first-line therapy and require other medication, including immune response modifiers or biologics. Recent advances in our understanding of urticarial disorders have led to more targeted therapeutic options for CU and other urticarial diseases. The specific biologic agents most investigated for antihistamine-refractory CU are omalizumab, rituximab, and intravenous immunoglobulin (IVIG. Of these, the anti-IgE monoclonal antibody omalizumab is the best studied, and has recently been approved for the management of CU. Other agents, such as interleukin-1 inhibitors, have proved beneficial for Schnitzler syndrome and cryopyrin-associated periodic syndromes (CAPS, diseases associated with urticaria. This review summarizes the relevant data regarding the efficacy of biologics in antihistamine-refractory CU. Keywords: chronic urticaria, omalizumab, intravenous immunoglobulin, anakinra, canakinumab

Validation of Alzheimer's disease CSF and plasma biological markers: the multicentre reliability study of the pilot European Alzheimer's Disease Neuroimaging Initiative (E-ADNI)

DEFF Research Database (Denmark)

Buerger, Katharina; Frisoni, Giovanni; Uspenskaya, Olga

2009-01-01

BACKGROUND: Alzheimer's Disease Neuroimaging Initiatives ("ADNI") aim to validate neuroimaging and biochemical markers of Alzheimer's disease (AD). Data of the pilot European-ADNI (E-ADNI) biological marker programme of cerebrospinal fluid (CSF) and plasma candidate biomarkers are reported. METHO...

Epstein-Barr Virus Sequence Variation—Biology and Disease

Science.gov (United States)

Tzellos, Stelios; Farrell, Paul J.

2012-01-01

Some key questions in Epstein-Barr virus (EBV) biology center on whether naturally occurring sequence differences in the virus affect infection or EBV associated diseases. Understanding the pattern of EBV sequence variation is also important for possible development of EBV vaccines. At present EBV isolates worldwide can be grouped into Type 1 and Type 2, a classification based on the EBNA2 gene sequence. Type 1 EBV is the most prevalent worldwide but Type 2 is common in parts of Africa. Type 1 transforms human B cells into lymphoblastoid cell lines much more efficiently than Type 2 EBV. Molecular mechanisms that may account for this difference in cell transformation are now becoming clearer. Advances in sequencing technology will greatly increase the amount of whole EBV genome data for EBV isolated from different parts of the world. Study of regional variation of EBV strains independent of the Type 1/Type 2 classification and systematic investigation of the relationship between viral strains, infection and disease will become possible. The recent discovery that specific mutation of the EBV EBNA3B gene may be linked to development of diffuse large B cell lymphoma illustrates the importance that mutations in the virus genome may have in infection and human disease. PMID:25436768

Denosumab for bone diseases: translating bone biology into targeted therapy.

Science.gov (United States)

Tsourdi, Elena; Rachner, Tilman D; Rauner, Martina; Hamann, Christine; Hofbauer, Lorenz C

2011-12-01

Signalling of receptor activator of nuclear factor-κB (RANK) ligand (RANKL) through RANK is a critical pathway to regulate the differentiation and activity of osteoclasts and, hence, a master regulator of bone resorption. Increased RANKL activity has been demonstrated in diseases characterised by excessive bone loss such as osteoporosis, rheumatoid arthritis and osteolytic bone metastases. The development and approval of denosumab, a fully MAB against RANKL, has heralded a new era in the treatment of bone diseases by providing a potent, targeted and reversible inhibitor of bone resorption. This article summarises the molecular and cellular biology of the RANKL/RANK system and critically reviews preclinical and clinical studies that have established denosumab as a promising novel therapy for metabolic and malignant bone diseases. We will discuss the potential indications for denosumab along with a critical review of safety and analyse its potential within the concert of established therapies.

A Systems Biology Approach Reveals Converging Molecular Mechanisms that Link Different POPs to Common Metabolic Diseases.

Science.gov (United States)

Ruiz, Patricia; Perlina, Ally; Mumtaz, Moiz; Fowler, Bruce A

2016-07-01

A number of epidemiological studies have identified statistical associations between persistent organic pollutants (POPs) and metabolic diseases, but testable hypotheses regarding underlying molecular mechanisms to explain these linkages have not been published. We assessed the underlying mechanisms of POPs that have been associated with metabolic diseases; three well-known POPs [2,3,7,8-tetrachlorodibenzodioxin (TCDD), 2,2´,4,4´,5,5´-hexachlorobiphenyl (PCB 153), and 4,4´-dichlorodiphenyldichloroethylene (p,p´-DDE)] were studied. We used advanced database search tools to delineate testable hypotheses and to guide laboratory-based research studies into underlying mechanisms by which this POP mixture could produce or exacerbate metabolic diseases. For our searches, we used proprietary systems biology software (MetaCore™/MetaDrug™) to conduct advanced search queries for the underlying interactions database, followed by directional network construction to identify common mechanisms for these POPs within two or fewer interaction steps downstream of their primary targets. These common downstream pathways belong to various cytokine and chemokine families with experimentally well-documented causal associations with type 2 diabetes. Our systems biology approach allowed identification of converging pathways leading to activation of common downstream targets. To our knowledge, this is the first study to propose an integrated global set of step-by-step molecular mechanisms for a combination of three common POPs using a systems biology approach, which may link POP exposure to diseases. Experimental evaluation of the proposed pathways may lead to development of predictive biomarkers of the effects of POPs, which could translate into disease prevention and effective clinical treatment strategies. Ruiz P, Perlina A, Mumtaz M, Fowler BA. 2016. A systems biology approach reveals converging molecular mechanisms that link different POPs to common metabolic diseases. Environ

Evaluation of a Modified Italian European Prospective Investigation into Cancer and Nutrition Food Frequency Questionnaire for Individuals with Celiac Disease.

Science.gov (United States)

Mazzeo, Teresa; Roncoroni, Leda; Lombardo, Vincenza; Tomba, Carolina; Elli, Luca; Sieri, Sabina; Grioni, Sara; Bardella, Maria T; Agostoni, Carlo; Doneda, Luisa; Brighenti, Furio; Pellegrini, Nicoletta

2016-11-01

To date, it is unclear whether individuals with celiac disease following a gluten-free (GF) diet for several years have adequate intake of all recommended nutrients. Lack of a food frequency questionnaire (FFQ) for individuals with celiac disease could be partly responsible for this still-debated issue. The aim of the study is to evaluate the performance of a modified European Prospective Investigation into Cancer and Nutrition (EPIC) FFQ in estimating nutrient and food intake in a celiac population. In a cross-sectional study, the dietary habits of individuals with celiac disease were reported using a modified Italian EPIC FFQ and were compared to a 7-day weighed food record as a reference method. A total of 200 individuals with histologically confirmed celiac disease were enrolled in the study between October 2012 and August 2014 at the Center for Prevention and Diagnosis of Celiac Disease (Milan, Italy). Nutrient and food category intake were calculated by 7-day weighed food record using an Italian food database integrated with the nutrient composition of 60 GF foods and the modified EPIC FFQ, in which 24 foods were substituted with GF foods comparable for energy and carbohydrate content. An evaluation of the modified FFQ compared to 7-day weighed food record in assessing the reported intake of nutrient and food groups was conducted using Spearman's correlation coefficients and weighted κ. One hundred individuals completed the study. The Spearman's correlation coefficients of FFQ and 7-day weighed food record ranged from .13 to .73 for nutrients and from .23 to .75 for food groups. A moderate agreement, which was defined as a weighted κ value of .40 to .60, was obtained for 30% of the analyzed nutrients, and 40% of the nutrients showed values between .30 and .40. The weighted κ exceeded .40 for 60% of the 15 analyzed food groups. The modified EPIC FFQ demonstrated moderate congruence with a weighed food record in ranking individuals by dietary intakes

Minimal Disease Activity as a Treatment Target in Psoriatic Arthritis

DEFF Research Database (Denmark)

Gossec, Laure; McGonagle, Dennis; Korotaeva, Tatiana

2018-01-01

As in other inflammatory rheumatic diseases, the objective of psoriatic arthritis (PsA) treatment is the achievement of a defined target. Recent recommendations propose aiming for remission or low disease activity; however, a consensual definition of remission is lacking. A state of minimal disease....... Since its development, MDA has been used increasingly in studies and clinical trials. In this article, the potential use of MDA as a treatment target in PsA is reviewed. The frequencies of MDA achievement with biologic disease-modifying antirheumatic drugs are summarized based on data from registries...

Inhibition effect of B7-H1 gene-modified regulatory dendritic cells on thyroid-associated ophthalmopathy in mice

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Hua-Xin Chen

2014-10-01

Full Text Available AIM:To construct adenovirus vector expressing mice B7-H1 gene, transfect dendritic cells(DCs, and to study the therapeutic effect of modified DC on thyroid-associated ophthalmopathy(TAOin mice.METHODS: We designed and constructed B7-H1 gene adenovirus expression vector, and transfected DCs from mouse bone marrow, tested the phenotype and function of modified DCs, identificated its negative regulation to immune responses. The modified DCs were infected the sicked mice. And then the immunotherapeutic effect of modified DCs to TAO were tested. RESULTS: B7-H1 gene adenovirus vector was constructed and transfected DCs from bone marrow. The titer of the recombinant adenovirus was 1.8×109PFU/mL. B7-H1 gene modified DCs characteristics of regulatory DCs, could inhibit positive immune responses. The inhibition proceeding of TAO into mice infected modified DCs, was obviously prior to the control mice. The gene modified DCs, maybe become the new immunotherapy biological agent to thy TAO.CONCLUSION: We constructed the expression of mouse B7-H1 gene adenovirus expressed vector successfully, transfected DCs,by vector have properties of regulatory DCs, inhibiting positive immune response and the occurrence and development of thyroid eye disease. Gene modified DCs, reveal potent to the treatment of thyroid eye disease.

Analysis of recent failures of disease modifying therapies in Alzheimer's disease suggesting a new methodology for future studies.

Science.gov (United States)

Amanatkar, Hamid Reza; Papagiannopoulos, Bill; Grossberg, George Thomas

2017-01-01

Pharmaceutical companies and the NIH have invested heavily in a variety of potential disease-modifying therapies for Alzheimer's disease (AD) but unfortunately all double-blind placebo-controlled Phase III studies of these drugs have failed to show statistically significant results supporting their clinical efficacy on cognitive measures. These negative results are surprising as most of these medications have the capability to impact the biomarkers which are associated with progression of Alzheimer's disease. Areas covered: This contradiction prompted us to review all study phases of Intravenous Immunoglobulin (IVIG), Bapineuzumab, Solanezumab, Avagacestat and Dimebolin to shed more light on these recent failures. We critically analyzed these studies, recommending seven lessons from these failures which should not be overlooked. Expert commentary: We suggest a new methodology for future treatment research in Alzheimer's disease considering early intervention with more focus on cognitive decline as a screening tool, more sophisticated exclusion criteria with more reliance on biomarkers, stratification of subjects based on the rate of cognitive decline aiming less heterogeneity, and a longer study duration with periodic assessment of cognition and activities of daily living during the study and also after a washout period.

Recovery of Renibacterium salmoninarum from naturally infected salmonine stocks in Michigan using a modified culture protocol

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Mohamed Faisal

2010-01-01

Full Text Available Renibacterium salmoninarum, the causative agent of bacterial kidney disease (BKD, is a fastidious and slow-growing bacterium that is extremely difficult to grow in vitro. Herein, we describe a modified primary culture protocol that encompasses a modified bacteriological culture medium and a tissue processing procedure. In order to facilitate the release of R. salmoninarum from granulomatous tissues, kidneys of infected fish were homogenized in a high speed stomacher. The kidney disease medium (KDM2, routinely used for primary culture of R. salmoninarum was modified by the addition of antibiotics and metabolites. When a relatively large inoculum of diluted kidney homogenate was streak-plate inoculated onto the modified KDM2, colonial growth of R. salmoninarum was achieved within 5–7 days, compared to the standard of two weeks or more. The modified procedure was then used to determine the prevalence of R. salmoninarum among representative captive and feral salmonid stocks in Michigan. Prevalence and clinical manifestations varied among species, strains of fish, and locations; however, R. salmoninarum isolates were biochemically homogenous. The improved primary culture procedure described in this study enabled selective and quick isolation of R. salmoninarum. Also, the isolates retrieved in this study constitute a unique biological resource for future studies of R. salmoninarum in the Laurentian Great Lakes.

Knowledge of modifiable risk factors of Coronary Atherosclerotic Heart Disease (CASHD among a sample in India

Directory of Open Access Journals (Sweden)

Ku Melvin

2009-02-01

Full Text Available Abstract Background The prevalence of Coronary Atherosclerotic Heart Disease (CASHD is increasing in India. Several modifiable risk factors contribute directly to this disease burden. Public knowledge of such risk factors among the urban Indian population is largely unknown. This investigation attempts to quantify knowledge of modifiable risk factors of CASHD as sampled among an Indian population at a large metropolitan hospital. Methods A hospital-based, cross sectional study was conducted at All India Institute of Medical Sciences (AIIMS, a major tertiary care hospital in New Delhi, India. Participants (n = 217 recruited from patient waiting areas in the emergency room were provided with standardized questionnaires to assess their knowledge of modifiable risk factors of CASHD. The risk factors specifically included smoking, hypertension, elevated cholesterol levels, diabetes mellitus and obesity. Identifying 3 or less risk factors was regarded as a poor knowledge level, whereas identifying 4 or more risk factors was regarded as a good knowledge level. A multiple logistic regression model was used to isolate independent demographic markers predictive of a participant's level of knowledge. Results 41% of the sample surveyed had a good level of knowledge. 68%, 72%, 73% and 57% of the population identified smoking, obesity, hypertension, and high cholesterol correctly, respectively. 30% identified diabetes mellitus as a modifiable risk factor of CASHD. In multiple logistic regression analysis independent demographic predictors of a good knowledge level with a statistically significant (p Conclusion An Indian population in a hospital setting shows a lack of knowledge pertaining to modifiable risk factors of CASHD. By isolating demographic predictors of poor knowledge, such as current smokers and persons who do not exercise regularly, educational interventions can be effectively targeted and implemented as primary and secondary prevention strategies

Optical force on diseased blood cells: Towards the optical sorting of biological matter

KAUST Repository

Gongora, J. S. Totero; Fratalocchi, Andrea

2015-01-01

By employing a series of massively parallel ab-initio simulations, we study how optical forces act on biological matter subject to morphological disease. As a representative case study, we here consider the case of Plasmodium falciparum on red blood

Microbiome and metabolome modifying effects of several cardiovascular disease interventions in apo-E-/- mice.

Science.gov (United States)

Ryan, Paul M; London, Lis E E; Bjorndahl, Trent C; Mandal, Rupasri; Murphy, Kiera; Fitzgerald, Gerald F; Shanahan, Fergus; Ross, R Paul; Wishart, David S; Caplice, Noel M; Stanton, Catherine

2017-03-13

There is strong evidence indicating that gut microbiota have the potential to modify, or be modified by the drugs and nutritional interventions that we rely upon. This study aims to characterize the compositional and functional effects of several nutritional, neutraceutical, and pharmaceutical cardiovascular disease interventions on the gut microbiome, through metagenomic and metabolomic approaches. Apolipoprotein-E-deficient mice were fed for 24 weeks either high-fat/cholesterol diet alone (control, HFC) or high-fat/cholesterol in conjunction with one of three dietary interventions, as follows: plant sterol ester (PSE), oat β-glucan (OBG) and bile salt hydrolase-active Lactobacillus reuteri APC 2587 (BSH), or the drug atorvastatin (STAT). The gut microbiome composition was then investigated, in addition to the host fecal and serum metabolome. We observed major shifts in the composition of the gut microbiome of PSE mice, while OBG and BSH mice displayed more modest fluctuations, and STAT showed relatively few alterations. Interestingly, these compositional effects imparted by PSE were coupled with an increase in acetate and reduction in isovalerate (p metabolome, including alterations in several acylcarnitines previously associated with a state of metabolic dysfunction (p < 0.05). We observed functional alterations in microbial and host-derived metabolites, which may have important implications for systemic metabolic health, suggesting that cardiovascular disease interventions may have a significant impact on the microbiome composition and functionality. This study indicates that the gut microbiome-modifying effects of novel therapeutics should be considered, in addition to the direct host effects.

Biology and therapy of inherited retinal degenerative disease: insights from mouse models

Science.gov (United States)

Veleri, Shobi; Lazar, Csilla H.; Chang, Bo; Sieving, Paul A.; Banin, Eyal; Swaroop, Anand

2015-01-01

Retinal neurodegeneration associated with the dysfunction or death of photoreceptors is a major cause of incurable vision loss. Tremendous progress has been made over the last two decades in discovering genes and genetic defects that lead to retinal diseases. The primary focus has now shifted to uncovering disease mechanisms and designing treatment strategies, especially inspired by the successful application of gene therapy in some forms of congenital blindness in humans. Both spontaneous and laboratory-generated mouse mutants have been valuable for providing fundamental insights into normal retinal development and for deciphering disease pathology. Here, we provide a review of mouse models of human retinal degeneration, with a primary focus on diseases affecting photoreceptor function. We also describe models associated with retinal pigment epithelium dysfunction or synaptic abnormalities. Furthermore, we highlight the crucial role of mouse models in elucidating retinal and photoreceptor biology in health and disease, and in the assessment of novel therapeutic modalities, including gene- and stem-cell-based therapies, for retinal degenerative diseases. PMID:25650393

The effect of tofacitinib on function and quality of life indicators in patients with rheumatoid arthritis resistant to synthetic and biological disease-modifying antirheumatic drugs in real clinical practice: Results of a multicenter observational study

Directory of Open Access Journals (Sweden)

D. E. Karateev

2017-01-01

Full Text Available Tofacitinib (TOFA, a representative of a new class of targeted synthetic disease-modifying antirheumatic drugs (s-DMARD, is a promising drug for treating rheumatoid arthritis (RA and other immune inflammatory diseases.Objective: to evaluate the efficiency and safety of therapy with TOFA in combination with methotrexate (MTX and other s-DMARDs in real clinical practice in patients with active RA and previous ineffective therapy.Patients and methods. A 6-month Russian multicenter study of function and quality of life enrolled 101 patients with resistant RA: 18 men and 83 women; mean age, 51.03±11.28 years; mean disease duration, 105.4±81.43 months; rheumatoid factor-positive individuals (89.1%; and anticyclic citrullinated peptide antibody-positive ones (74.7%. 93 (92,1% of these patients completed a 24-week study. TOFA was used as both second-line drug (after failure of therapy with s-DMARD (n=74 and as a third-line drug (after failure of therapy with s-DMARDs and biological agents (BAs (n=74. The tools RAPID3, HAQ, and EQ-5D were used to determine disease outcomes from a patient's assessment.Results. All the three tools demonstrated significant positive changes at 3–6 months following therapy initiation. RAPID3 scores for the status of a patient achieving a low disease activity or remission coincided with the mean DAS28-ESR and SDAI scores in 60% and 68% of cases, respectively. The achievement rates of the minimally clinically significant improvement (ΔHAQ≥0.22 and functional remission (HAQ≤0.5 at 6 months of TOFA therapy were 79.6 and 30.1%, respectively. The mean change value in EQ-5D scores over 6 months was -0.162±0.21. There were no significant between the groups of patients who used TOFA as a second- or third-line agent in the majority of indicators, except EQ-5D scores at 6 months.Conclusions. The results of our multicenter study using considerable Russian material confirmed the pronounced positive effect of TOFA used

Biological control agents for suppression of post-harvest diseases of potatoes: strategies on discovery and development

Science.gov (United States)

As used in plant pathology, the term "biological control" or its short form “biocontrol” commonly refers to the decrease in the inoculum or the disease-producing activity of a pathogen accomplished through one or more organisms, including the host plant but excluding man. Biological control of plant...

Proteins Encoded in Genomic Regions Associated with Immune-Mediated Disease Physically Interact and Suggest Underlying Biology

DEFF Research Database (Denmark)

Rossin, Elizabeth J.; Hansen, Kasper Lage; Raychaudhuri, Soumya

2011-01-01

Genome-wide association studies (GWAS) have defined over 150 genomic regions unequivocally containing variation predisposing to immune-mediated disease. Inferring disease biology from these observations, however, hinges on our ability to discover the molecular processes being perturbed by these r......Genome-wide association studies (GWAS) have defined over 150 genomic regions unequivocally containing variation predisposing to immune-mediated disease. Inferring disease biology from these observations, however, hinges on our ability to discover the molecular processes being perturbed...... in rheumatoid arthritis (RA) and Crohn's disease (CD) GWAS, we build protein-protein interaction (PPI) networks for genes within associated loci and find abundant physical interactions between protein products of associated genes. We apply multiple permutation approaches to show that these networks are more...... that the RA and CD networks have predictive power by demonstrating that proteins in these networks, not encoded in the confirmed list of disease associated loci, are significantly enriched for association to the phenotypes in question in extended GWAS analysis. Finally, we test our method in 3 non...

Concise review: current status of stem cells and regenerative medicine in lung biology and diseases.

Science.gov (United States)

Weiss, Daniel J

2014-01-01

Lung diseases remain a significant and devastating cause of morbidity and mortality worldwide. In contrast to many other major diseases, lung diseases notably chronic obstructive pulmonary diseases (COPDs), including both asthma and emphysema, are increasing in prevalence and COPD is expected to become the third leading cause of disease mortality worldwide by 2020. New therapeutic options are desperately needed. A rapidly growing number of investigations of stem cells and cell therapies in lung biology and diseases as well as in ex vivo lung bioengineering have offered exciting new avenues for advancing knowledge of lung biology as well as providing novel potential therapeutic approaches for lung diseases. These initial observations have led to a growing exploration of endothelial progenitor cells and mesenchymal stem (stromal) cells in clinical trials of pulmonary hypertension and COPD with other clinical investigations planned. Ex vivo bioengineering of the trachea, larynx, diaphragm, and the lung itself with both biosynthetic constructs as well as decellularized tissues have been used to explore engineering both airway and vascular systems of the lung. Lung is thus a ripe organ for a variety of cell therapy and regenerative medicine approaches. Current state-of-the-art progress for each of the above areas will be presented as will discussion of current considerations for cell therapy-based clinical trials in lung diseases. © AlphaMed Press.

Infectious diseases, parasites, and biological toxins in sea ducks: Chapter 4

Science.gov (United States)

Hollmén, Tuula E.; Franson, J. Christian

2015-01-01

This chapter addresses disease agents in the broad sense, including viruses, bacteria, fungi, protozoan and helminth parasites, and biological toxins. Some of these agents are known to cause mortality in sea ducks, some are thought to be incidental findings, and the significance of others is yet poorly understood. Although the focus of the chapter is on free-living sea ducks, the study of disease in this taxonomic group has been relatively limited and examples from captive sea ducks and other wild waterfowl are used to illustrate the pathogenicity of certain diseases. Much of the early work in sea ducks consisted of anecdotal and descriptive reports of parasites, but it was soon recognized that diseases such as avian cholera, renal coccidiosis, and intestinal infections with acanthocephalans were causes of mortality in wild populations. More recently, adenoviruses, reoviruses, and the newly emergent Wellfleet Bay virus, for example, also have been linked to die-offs of sea ducks. Declining populations of animals are particularly vulnerable to the threats posed by disease and it is important that we improve our understanding of the significance of disease in sea ducks. To conclude, we offer our recommendations for future directions in this field.

Single-stage Modified Duhamel procedure for Hirschsprung′s disease : Our experience

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Paras R Kothari

2012-01-01

Full Text Available Introduction: Primary single-stage pull-through for Hirschsprung′s disease (HD has been reported to give comparable surgical outcomes to staged operations with less morbidity. Herein, we present our experience with single-stage Modified Duhamel procedure for management of HD. Patients and Methods: This was a review of 48 cases of HD who underwent single-stage Modified Duhamel procedure without a protective colostomy. Results: The age at surgery ranged from 6 months to 10 years (median - 9 months, mean - 2.3 years. The average weight of the child was 7.2 kg (range, 4.9-22 kg. 38 (79.2% patients had classical rectosigmoid HD, the rest being long segment HD (the proximal most level being the splenic flexure. The average duration of surgery was 175 minutes (range, 130-245 minutes. The average blood loss was 45 ml. The average hospital stay was 7.2 days (range: 6-10 days. The major postoperative complications (n=3 included postoperative adhesive intestinal obstruction, anastomotic leak and persistent constipation due to residual aganglionosis. Each required a re-exploration. Minor complications included surgical site infection (n=3 and post-operative enterocolitis (n=3, which were managed conservatively. Six patients had constipation for a limited period post-operatively. All patients have a satisfactory functional outcome and normal development and growth. Conclusions: For HD, we recommend that single-stage Modified Duhamel procedure should be the preferred approach in view of its low morbidity, satisfactory functional outcome and avoidance of stoma, multiple surgeries and economic benefit in view of decreased hospital stay.

Genetic Factors Interact With Tobacco Smoke to Modify Risk for Inflammatory Bowel Disease in Humans and Mice

DEFF Research Database (Denmark)

Yadav, Pankaj; Ellinghaus, David; Rémy, Gaëlle

2017-01-01

BACKGROUND & AIMS: The role of tobacco smoke in the etiology of inflammatory bowel disease (IBD) is unclear. We investigated interactions between genes and smoking (gene-smoking interactions) that affect risk for Crohn's disease (CD) and ulcerative colitis (UC) in a case-only study of patients...... chamber, or ambient air (controls). Intestines were collected and analyzed histologically and by reverse transcription polymerase chain reaction. RESULTS: We identified 64 single nucleotide polymorphisms (SNPs) for which the association between the SNP and IBD were modified by smoking behavior (meta...... to smoke. CONCLUSIONS: In an analysis of 55 Immunochip-wide datasets, we identified 64 SNPs whose association with risk for IBD is modified by tobacco smoking. Gene-smoking interactions were confirmed in mice with disruption of Il10 and Nod2-variants of these genes have been associated with risk for IBD...

Screening prior to biological therapy in Crohn's disease: adherence to guidelines and prevalence of infections. Results from a multicentre retrospective study

NARCIS (Netherlands)

van der Have, Mike; Belderbos, Tim D. G.; Fidder, Herma H.; Leenders, Max; Dijkstra, Gerard; Peters, Charlotte P.; Eshuis, Emma J.; Ponsioen, Cyriel Y.; Siersema, Peter D.; van Oijen, Martijn G. H.; Oldenburg, Bas

2014-01-01

Screening for opportunistic infections prior to starting biological therapy in patients with inflammatory bowel disease is recommended. To assess adherence to screening for opportunistic infections prior to starting biological therapy in Crohn's disease patients and its yield. A multicentre

Screening prior to biological therapy in Crohn's disease : Adherence to guidelines and prevalence of infections. Results from a multicentre retrospective study

NARCIS (Netherlands)

van der Have, Mike; Belderbos, Tim D. G.; Fidder, Herma H.; Leenders, Max; Dijkstra, Gerard; Peters, Charlotte P.; Eshuis, Emma J.; Ponsioen, Cyriel Y.; Siersema, Peter D.; van Oijen, Martijn G. H.; Oldenburg, Bas

2014-01-01

Background: Screening for opportunistic infections prior to starting biological therapy in patients with inflammatory bowel disease is recommended. Aims: To assess adherence to screening for opportunistic infections prior to starting biological therapy in Crohn's disease patients and its yield.

Factors that modify risks of radiation-induced cancer

International Nuclear Information System (INIS)

Fabrikant, J.I.

1988-11-01

The collective influence of biologic and physical factors that modify risks of radiation-induced cancer introduces uncertainties sufficient to deny precision of estimates of human cancer risk that can be calculated for low-dose radiation in exposed populations. The important biologic characteristics include the tissue sites and cell types, baseline cancer incidence, minimum latent period, time-to-tumor recognition, and the influence of individual host (age and sex) and competing etiologic influences. Physical factors include radiation dose, dose rate, and radiation quality. Statistical factors include time-response projection models, risk coefficients, and dose-response relationships. Other modifying factors include other carcinogens, and other biological sources (hormonal status, immune status, hereditary factors)

Magnetically modified biocells in constant magnetic field

Energy Technology Data Exchange (ETDEWEB)

Abramov, E.G.; Panina, L.K. [Saint Petersburg State University, St. Petersburg (Russian Federation); Kolikov, V.A., E-mail: kolikov1@yandex.ru [Institute for Electrophysics and Electric Power of the RAS, St. Petersburg (Russian Federation); Bogomolova, E.V. [Botanical Institute of the RAS after V.L.Komarov, St. Petersburg (Russian Federation); Snetov, V.N. [Institute for Electrophysics and Electric Power of the RAS, St. Petersburg (Russian Federation); Cherepkova, I.A. [Saint Petersburg State Institute of Technology, St. Petersburg (Russian Federation); Kiselev, A.A. [Institute for Electrophysics and Electric Power of the RAS, St. Petersburg (Russian Federation)

2017-02-01

Paper addresses the inverse problem in determining the area, where the external constant magnetic field captures the biological cells modified by the magnetic nanoparticles. Zero velocity isolines, in area where the modified cells are captured by the magnetic field were determined by numerical method for two locations of the magnet. The problem was solved taking into account the gravitational field, magnetic induction, density of medium, concentration and size of cells, and size and magnetization of nanoparticles attached to the cell. Increase in the number of the nanoparticles attached to the cell and decrease in the cell’ size, enlarges the area, where the modified cells are captured and concentrated by the magnet. Solution is confirmed by the visible pattern formation of the modified cells Saccharomyces cerevisiae. - Highlights: • The inverse problem was solved for finding zero velocity isolines of magnetically modified biological cells. • Solution of the inverse problem depends on the size of cells and the number of nanoparticles attached to the single cell. • The experimental data are in agreement with theoretical solution.

Regulatory and biosafety issues in relation to transgenic animals in food and agriculture, feeds containing genetically modified organisms (GMO) and veterinary biologics

International Nuclear Information System (INIS)

Kochhar, H.P.S.; Gifford, G.A.; Kahn, S.

2005-01-01

biotechnology must be shown to be pure, potent, safe and effective when used according to label recommendations. The Canadian regulatory system relies on the 'precautionary principle' in its approach to regulate the 'product' instead of the 'process'. The regulatory framework captures transgenic animals under the Canadian Environmental Protection Act (CEPA). Food from transgenic animals is assessed for safety by Health Canada under its Novel Foods Regulations of the Food and Drugs Act. Feed containing any genetically modified organism is considered Novel Feed under the Feeds Act and Regulations. The regulation of veterinary biologics, in an effort to prevent and diagnose infectious diseases of animals, relies on effective science-based regulatory controls under the Health of Animals Act and Regulations. The Canadian system of regulation for feeds, veterinary biologics and transgenic animals could be useful to developing countries in the process of establishing an effective framework for new regulations. (author)

Use of modified cornstarch therapy to extend fasting in glycogen storage disease types Ia and Ib

NARCIS (Netherlands)

Correia, Catherine E.; Bhattacharya, Kaustuv; Lee, Philip J.; Shuster, Jonathan J.; Theriaque, Douglas W.; Shankar, Meena N.; Smit, G. Peter A.; Weinstein, David A.

2008-01-01

Background: Type I glycogen storage disease (GSD) is caused by a deficiency of glucose-6-phosphatase resulting in severe fasting hypoglycemia. Objective: We compared the efficacy of a new modified starch with the currently used cornstarch therapy in patients with type Ia and Ib GSD. Design: This was

Piezosurgery in Modified Pterional Orbital Decompression Surgery in Graves Disease.

Science.gov (United States)

Grauvogel, Juergen; Scheiwe, Christian; Masalha, Waseem; Jarc, Nadja; Grauvogel, Tanja; Beringer, Andreas

2017-10-01

Piezosurgery uses microvibrations to selectively cut bone, preserving the adjacent soft tissue. The present study evaluated the use of piezosurgery for bone removal in orbital decompression surgery in Graves disease via a modified pterional approach. A piezosurgical device (Piezosurgery medical) was used in 14 patients (20 orbits) with Graves disease who underwent orbital decompression surgery in additional to drills and rongeurs for bone removal of the lateral orbital wall and orbital roof. The practicability, benefits, and drawbacks of this technique in orbital decompression surgery were recorded. Piezosurgery was evaluated with respect to safety, preciseness of bone cutting, and preservation of the adjacent dura and periorbita. Preoperative and postoperative clinical outcome data were assessed. The orbital decompression surgery was successful in all 20 orbits, with good clinical outcomes and no postoperative complications. Piezosurgery proved to be a safe tool, allowing selective bone cutting with no damage to the surrounding soft tissue structures. However, there were disadvantages concerning the intraoperative handling in the narrow space and the efficiency of bone removal was limited in the orbital decompression surgery compared with drills. Piezosurgery proved to be a useful tool in bone removal for orbital decompression in Graves disease. It is safe and easy to perform, without any danger of damage to adjacent tissue because of its selective bone-cutting properties. Nonetheless, further development of the device is necessary to overcome the disadvantages in intraoperative handling and the reduced bone removal rate. Copyright © 2017 Elsevier Inc. All rights reserved.

Knowlege of, attitudes toward, and acceptance of genetically modified organisms among prospective teachers of biology, home economics, and grade school in Slovenia.

Science.gov (United States)

Sorgo, Andrej; Ambrožič-Dolinšek, Jana

2010-05-01

The objective of this study was to investigate knowledge, opinions, and attitudes toward, as well as readiness to accept genetically modified organisms (GMOs) among prospective primary and secondary Slovene teachers. Our findings are that prospective teachers want to take an active role in rejecting or supporting individual GMOs and are aware of the importance of education about genetically modified organism (GMO) items and their potential significance for society. Through cluster analysis, we recognized four clusters of GMOs, separated by degree of genetically modified acceptability. GM plants and microorganisms which are recognized as useful are accepted. They are undecided about organisms used in research or medicine and reject organisms used for food consumption and for fun. There are only weak correlations between knowledge and attitudes and knowledge and acceptance of GMOs, and a strong correlation between attitudes and acceptance. The appropriate strategies and actions for improving university courses in biotechnology are discussed. Copyright © 2010 International Union of Biochemistry and Molecular Biology, Inc.

Relationship between Periodontal Diseases and Preterm Birth: Recent Epidemiological and Biological Data

Science.gov (United States)

Huck, O.; Tenenbaum, H.; Davideau, J.-L.

2011-01-01

For ten years, the incidence of preterm birth does not decrease in developed countries despite the promotion of public health programs. Many risk factors have been identified including ethnicity, age, tobacco, and infection. However, almost 50% of preterm birth causes remain unknown. The periodontal diseases are highly prevalent inflammatory and infectious diseases of tooth supporting tissues leading to an oral disability. They influence negatively general health worsening cardiovascular diseases and diabetes. Periodontal diseases have been also suspected to increase the rate of preterm birth, but data remain contradictory. The objective of this review is to present the principal results of epidemiological, biological, and interventional studies on the link between periodontal diseases and preterm birth. The conclusions of this work underline the importance for the physician/obstetrician to identify women at risk for preterm birth and to address these patients to dentist for periodontal examination and treatment in order to limit adverse pregnancy outcomes. PMID:22132334

Relationship between Periodontal Diseases and Preterm Birth: Recent Epidemiological and Biological Data

Directory of Open Access Journals (Sweden)

O. Huck

2011-01-01

Full Text Available For ten years, the incidence of preterm birth does not decrease in developed countries despite the promotion of public health programs. Many risk factors have been identified including ethnicity, age, tobacco, and infection. However, almost 50% of preterm birth causes remain unknown. The periodontal diseases are highly prevalent inflammatory and infectious diseases of tooth supporting tissues leading to an oral disability. They influence negatively general health worsening cardiovascular diseases and diabetes. Periodontal diseases have been also suspected to increase the rate of preterm birth, but data remain contradictory. The objective of this review is to present the principal results of epidemiological, biological, and interventional studies on the link between periodontal diseases and preterm birth. The conclusions of this work underline the importance for the physician/obstetrician to identify women at risk for preterm birth and to address these patients to dentist for periodontal examination and treatment in order to limit adverse pregnancy outcomes.

The Spanish biology/disease initiative within the human proteome project: Application to rheumatic diseases.

Science.gov (United States)

Ruiz-Romero, Cristina; Calamia, Valentina; Albar, Juan Pablo; Casal, José Ignacio; Corrales, Fernando J; Fernández-Puente, Patricia; Gil, Concha; Mateos, Jesús; Vivanco, Fernando; Blanco, Francisco J

2015-09-08

The Spanish Chromosome 16 consortium is integrated in the global initiative Human Proteome Project, which aims to develop an entire map of the proteins encoded following a gene-centric strategy (C-HPP) in order to make progress in the understanding of human biology in health and disease (B/D-HPP). Chromosome 16 contains many genes encoding proteins involved in the development of a broad range of diseases, which have a significant impact on the health care system. The Spanish HPP consortium has developed a B/D platform with five programs focused on selected medical areas: cancer, obesity, cardiovascular, infectious and rheumatic diseases. Each of these areas has a clinical leader associated to a proteomic investigator with the responsibility to get a comprehensive understanding of the proteins encoded by Chromosome 16 genes. Proteomics strategies have enabled great advances in the area of rheumatic diseases, particularly in osteoarthritis, with studies performed on joint cells, tissues and fluids. In this manuscript we describe how the Spanish HPP-16 consortium has developed a B/D platform with five programs focused on selected medical areas: cancer, obesity, cardiovascular, infectious and rheumatic diseases. Each of these areas has a clinical leader associated to a proteomic investigator with the responsibility to get a comprehensive understanding of the proteins encoded by Chromosome 16 genes. We show how the Proteomic strategy has enabled great advances in the area of rheumatic diseases, particularly in osteoarthritis, with studies performed on joint cells, tissues and fluids. This article is part of a Special Issue entitled: HUPO 2014. Copyright © 2015 Elsevier B.V. All rights reserved.

[In vitro early detection of amyloid plaques in Alzheimer's disease by Pittsburgh compound B-modified magnetic nanoparticles].

Science.gov (United States)

Zeng, J Q; Wu, J Q; Li, M H; Wang, P J

2017-11-07

Objective: To construct magnetic nanoparticles targeting β-amyloid (Aβ) plaques, the pathological biomarker of Alzheimer's disease (AD) and to study their binding capability in vitro . Methods: Superparamagnetic nanoparticles Mn(0.6)Zn(0.4)Fe(2)O(4) (MZF) were coated with amphiphilic star-block copolymeric micelles and modified with Aβ-specific probe Pittsburgh compound B (PiB) to construct a novel magnetic nanoparticle MZF-PiB, which specifically targeted amyloid plaques. Transmission electron microscope was used to study the morphological features of MZF-PiB. Superparamagnetism of MZF-PiB was assessed by its r(2) relaxation rate by using 3.0 T MRI scanner. Cytotoxic test was applied to determine biosafety of MZF-PiB nanoparticles in differentiated human neuroblastoma cells (SH-SY5Y) and Madin-Darby canine kidney (MDCK). In vitro binding tests were conducted via immunohistochemistry on 6-month old AD mice brain sections. Differences of cell viability between groups were compared with one-way analysis of variance. Results: MZF-PiB nanoparticles were successfully constructed. Transmission electron microscope images showed that the nanoparticles were about 100 nm in size. The r(2) relaxation rate was 163.11 mMS(-1). No differences were found in cell viability of SH-SY5Y and MDCK incubated with MZF-PiB suspension for 24 h or 48 h when compared with those of untreated cells ( F =2.336, 2.539, 0.293, 1.493, all P >0.05). In vitro binding tests indicated that the MZF-PiB were specifically bound to amyloid plaques. The smallest size of detected plaques was 27 μm. Conclusion: PiB-modified nanoparticles targeting Aβ are biologically safe and highly superparamagnetic, possessing the capability to detect amyloid plaques early in vitro and the potential for early diagnosis of AD.

Periodontal manifestations of inflammatory bowel disease: emerging epidemiologic and biologic evidence.

Science.gov (United States)

Agossa, K; Dendooven, A; Dubuquoy, L; Gower-Rousseau, C; Delcourt-Debruyne, E; Capron, M

2017-06-01

Inflammatory bowel disease and periodontitis are both described as a disproportionate mucosal inflammatory response to a microbial environment in susceptible patients. Moreover, these two conditions share major environmental and lifestyle-related risk factors. Despite this intriguing pathogenic parallel, large-scale studies and basic research have only recently considered periodontal outcomes as relevant data. There are mounting and consistent arguments, from recent epidemiologic studies and animal models, that these two conditions might be related. This article is a comprehensive and critical up-to-date review of the current evidence and future prospects in understanding the biologic and epidemiologic relationships between periodontal status and inflammatory bowel disease. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

78 FR 47319 - Fee Schedule for Reference Biological Standards and Biological Preparations

Science.gov (United States)

2013-08-05

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention Fee Schedule for Reference Biological Standards and Biological Preparations AGENCY: Centers for Disease Control and... for Disease Control and Prevention (CDC), located within the Department of Health and Human Services...

Biological markers of amyloid beta-related mechanisms in Alzheimer's disease.

LENUS (Irish Health Repository)

Hampel, Harald

2010-06-01

Recent research progress has given detailed knowledge on the molecular pathogenesis of Alzheimer\\'s disease (AD), which has been translated into an intense, ongoing development of disease-modifying treatments. Most new drug candidates are targeted on inhibiting amyloid beta (Abeta) production and aggregation. In drug development, it is important to co-develop biomarkers for Abeta-related mechanisms to enable early diagnosis and patient stratification in clinical trials, and to serve as tools to identify and monitor the biochemical effect of the drug directly in patients. Biomarkers are also requested by regulatory authorities to serve as safety measurements. Molecular aberrations in the AD brain are reflected in the cerebrospinal fluid (CSF). Core CSF biomarkers include Abeta isoforms (Abeta40\\/Abeta42), soluble APP isoforms, Abeta oligomers and beta-site APP-cleaving enzyme 1 (BACE1). This article reviews recent research advances on core candidate CSF and plasma Abeta-related biomarkers, and gives a conceptual review on how to implement biomarkers in clinical trials in AD.

Biological markers of amyloid beta-related mechanisms in Alzheimer's disease.

LENUS (Irish Health Repository)

Hampel, Harald

2012-02-01

Recent research progress has given detailed knowledge on the molecular pathogenesis of Alzheimer\\'s disease (AD), which has been translated into an intense, ongoing development of disease-modifying treatments. Most new drug candidates are targeted on inhibiting amyloid beta (Abeta) production and aggregation. In drug development, it is important to co-develop biomarkers for Abeta-related mechanisms to enable early diagnosis and patient stratification in clinical trials, and to serve as tools to identify and monitor the biochemical effect of the drug directly in patients. Biomarkers are also requested by regulatory authorities to serve as safety measurements. Molecular aberrations in the AD brain are reflected in the cerebrospinal fluid (CSF). Core CSF biomarkers include Abeta isoforms (Abeta40\\/Abeta42), soluble APP isoforms, Abeta oligomers and beta-site APP-cleaving enzyme 1 (BACE1). This article reviews recent research advances on core candidate CSF and plasma Abeta-related biomarkers, and gives a conceptual review on how to implement biomarkers in clinical trials in AD.

Comparison of renal dynamic imaging and modified MDRD equation in determining the stage of chronic kidney disease patients

International Nuclear Information System (INIS)

Xie Peng; Liu Xiaomei; Huang Jianmin; Zhang Fang; Pan Liping; Wu Weijie; Gao Jianqing

2013-01-01

Objective: To compare the accuracy of 99 Tc m -diethylene triamine pentaacetic acid ( 99 Tc m -DTPA) renal dynamic imaging and modified modification of diet in renal disease trail (MDRD) equation in determining the stage of the chronic kidney disease (CKD) patients in clinical practice. Methods: A total of 169 patients were enrolled whose glomerular filtration rate (GFR) were determined simultaneously by 3 methods: dual plasma sample clearance method, renal dynamic imaging and modified MDRD equation. The dual plasma sample clearance method was employed as the reference method. The accuracy of the other methods in determining the stage of CKD patients was compared and the comparison was repeated based on the different stages. Results: The accuracy of renal dynamic imaging and modified MDRD equation was 56.80% and 68.64%, respectively (P=0.019<0.05). And only in the stage of uremia, the difference of the above-mentioned two method reached statistical significance (P=0.012<0.05), while in other stages they showed similar performance (P=0.180, 0.424, 0.629 and 0.754, all P>0.05). Conclusion: Modified MDRD equation showed better performance than renal dynamic imaging or as good as the second one in determining the stage of CKD patients and the former one should be the first choice in clinical practice because of its simplicity and economy. (authors)

Optical force on diseased blood cells: Towards the optical sorting of biological matter

KAUST Repository

Gongora, J. S. Totero

2015-05-01

By employing a series of massively parallel ab-initio simulations, we study how optical forces act on biological matter subject to morphological disease. As a representative case study, we here consider the case of Plasmodium falciparum on red blood cells (RBC) illuminated by a monochromatic plane wave. Realistic parameters for the geometry and the refractive index are then taken from published experiments. In our theoretical campaign, we study the dependence of the optical force on the disease stage for different incident wavelengths. We show that optical forces change significantly with the disease, with amplitude variation in the hundreds of pN range. Our results open up new avenues for the design of new optical systems for the treatment of human disease. © 2015 Elsevier Ltd.

Biology and therapy of inherited retinal degenerative disease: insights from mouse models

Directory of Open Access Journals (Sweden)

Shobi Veleri

2015-02-01

Full Text Available Retinal neurodegeneration associated with the dysfunction or death of photoreceptors is a major cause of incurable vision loss. Tremendous progress has been made over the last two decades in discovering genes and genetic defects that lead to retinal diseases. The primary focus has now shifted to uncovering disease mechanisms and designing treatment strategies, especially inspired by the successful application of gene therapy in some forms of congenital blindness in humans. Both spontaneous and laboratory-generated mouse mutants have been valuable for providing fundamental insights into normal retinal development and for deciphering disease pathology. Here, we provide a review of mouse models of human retinal degeneration, with a primary focus on diseases affecting photoreceptor function. We also describe models associated with retinal pigment epithelium dysfunction or synaptic abnormalities. Furthermore, we highlight the crucial role of mouse models in elucidating retinal and photoreceptor biology in health and disease, and in the assessment of novel therapeutic modalities, including gene- and stem-cell-based therapies, for retinal degenerative diseases.

The use of simultaneous chemical precipitation in modified activated ...

African Journals Online (AJOL)

The use of simultaneous chemical precipitation in modified activated sludge systems exhibiting biological excess phosphate removal: Part 6: Modelling of simultaneous chemical-biological P removal - review of existing models.

Aberrant Free Radical Biology Is a Unifying Theme in the Etiology and Pathogenesis of Major Human Diseases

Directory of Open Access Journals (Sweden)

Frederick E. Domann

2013-04-01

Full Text Available The seemingly disparate areas of oxygen toxicity, radiation exposure, and aging are now recognized to share a common feature—the aberrant production and/or removal of biologically derived free radicals and other reactive oxygen and nitrogen species (ROS/RNS. Advances in our understanding of the effects of free radicals in biology and medicine have been, and continue to be, actively translated into clinically tractable diagnostic and therapeutic applications. This issue is dedicated to recent advances, both basic discoveries and clinical applications, in the field of free radicals in biology and medicine. As more is understood about the proximal biological targets of aberrantly produced or removed reactive species, their sensors, and effectors of compensatory response, a great deal more will be learned about the commonalities in mechanisms underlying seemingly disparate disease states. Together with this deeper understanding, opportunities will arise to devise rational therapeutic interventions to decrease the incidence and severity of these diseases and positively impact the human healthspan.

Minireview: Clinical severity in sickle cell disease: the challenges of definition and prognostication.

Science.gov (United States)

Quinn, Charles T

2016-04-01

Sickle cell disease (SCD) is a monogenic, yet highly phenotypically variable disease with multisystem pathology. This manuscript provides an overview of many of the known determinants, modifiers, and correlates of disease severity in SCD. Despite this wealth of data, modeling the variable and multisystem pathology of SCD continues to be difficult. The current status of prediction of specific adverse outcomes and global disease severity in SCD is also reviewed, highlighting recent successes and ongoing challenges. © 2016 by the Society for Experimental Biology and Medicine.

Chimeric antigen receptor (CAR)-modified natural killer cell-based immunotherapy and immunological synapse formation in cancer and HIV.

Science.gov (United States)

Liu, Dongfang; Tian, Shuo; Zhang, Kai; Xiong, Wei; Lubaki, Ndongala Michel; Chen, Zhiying; Han, Weidong

2017-12-01

Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells contribute to the body's immune defenses. Current chimeric antigen receptor (CAR)-modified T cell immunotherapy shows strong promise for treating various cancers and infectious diseases. Although CAR-modified NK cell immunotherapy is rapidly gaining attention, its clinical applications are mainly focused on preclinical investigations using the NK92 cell line. Despite recent advances in CAR-modified T cell immunotherapy, cost and severe toxicity have hindered its widespread use. To alleviate these disadvantages of CAR-modified T cell immunotherapy, additional cytotoxic cell-mediated immunotherapies are urgently needed. The unique biology of NK cells allows them to serve as a safe, effective, alternative immunotherapeutic strategy to CAR-modified T cells in the clinic. While the fundamental mechanisms underlying the cytotoxicity and side effects of CAR-modified T and NK cell immunotherapies remain poorly understood, the formation of the immunological synapse (IS) between CAR-modified T or NK cells and their susceptible target cells is known to be essential. The role of the IS in CAR T and NK cell immunotherapies will allow scientists to harness the power of CAR-modified T and NK cells to treat cancer and infectious diseases. In this review, we highlight the potential applications of CAR-modified NK cells to treat cancer and human immunodeficiency virus (HIV), and discuss the challenges and possible future directions of CAR-modified NK cell immunotherapy, as well as the importance of understanding the molecular mechanisms of CAR-modified T cell- or NK cell-mediated cytotoxicity and side effects, with a focus on the CAR-modified NK cell IS.

Plant synthetic biology.

Science.gov (United States)

Liu, Wusheng; Stewart, C Neal

2015-05-01

Plant synthetic biology is an emerging field that combines engineering principles with plant biology toward the design and production of new devices. This emerging field should play an important role in future agriculture for traditional crop improvement, but also in enabling novel bioproduction in plants. In this review we discuss the design cycles of synthetic biology as well as key engineering principles, genetic parts, and computational tools that can be utilized in plant synthetic biology. Some pioneering examples are offered as a demonstration of how synthetic biology can be used to modify plants for specific purposes. These include synthetic sensors, synthetic metabolic pathways, and synthetic genomes. We also speculate about the future of synthetic biology of plants. Copyright © 2015 Elsevier Ltd. All rights reserved.

S-Nitrosothiol measurements in biological systems⋄

Science.gov (United States)

Gow, Andrew; Doctor, Allan; Mannick, Joan; Gaston, Benjamin

2007-01-01

S-Nitrosothiol (SNO) cysteine modifications are regulated signaling reactions that dramatically affect, and are affected by, protein conformation. The lability of the S-NO bond can make SNO-modified proteins cumbersome to measure accurately. Here, we review methodologies for detecting SNO modifications in biology. There are three caveats. 1) Many assays for biological SNOs are used near the limit of detection: standard curves must be in the biologically relevant concentration range. 2) The assays that are most reliable are those that modify SNO protein or peptide chemistry the least. 3) Each result should be quantitatively validated using more than one assay. Improved assays are needed and are in development. PMID:17379583

Surface chemical and biological characterization of flax fabrics modified with silver nanoparticles for biomedical applications

International Nuclear Information System (INIS)

Paladini, F.; Picca, R.A.; Sportelli, M.C.; Cioffi, N.; Sannino, A.; Pollini, M.

2015-01-01

Silver nanophases are increasingly used as effective antibacterial agent for biomedical applications and wound healing. This work aims to investigate the surface chemical composition and biological properties of silver nanoparticle-modified flax substrates. Silver coatings were deposited on textiles through the in situ photo-reduction of a silver solution, by means of a large-scale apparatus. The silver-coated materials were characterized through X-ray Photoelectron Spectroscopy (XPS), to assess the surface elemental composition of the coatings, and the chemical speciation of both the substrate and the antibacterial nanophases. A detailed investigation of XPS high resolution regions outlined that silver is mainly present on nanophases' surface as Ag 2 O. Scanning electron microscopy and energy dispersive X-ray spectroscopy were also carried out, in order to visualize the distribution of silver particles on the fibers. The materials were also characterized from a biological point of view in terms of antibacterial capability and cytotoxicity. Agar diffusion tests and bacterial enumeration tests were performed on Gram positive and Gram negative bacteria, namely Staphylococcus aureus and Escherichia coli. In vitro cytotoxicity tests were performed through the extract method on murine fibroblasts in order to verify if the presence of the silver coating affected the cellular viability and proliferation. Durability of the coating was also assessed, thus confirming the successful scaling up of the process, which will be therefore available for large-scale production. - Highlights: • Silver nanophases are increasingly used as effective antibacterial agent for biomedical applications. • Silver coatings were deposited on textiles through the in situ photo-reduction of a silver solution. • Flax fabrics were characterized from a biological and surface chemical point of view. • Scaling up of the process was confirmed

Let Food Be Thy Medicine: Diet, Nutrition, and Biomarkers’ Risk of Alzheimer’s Disease

Science.gov (United States)

Mosconi, Lisa; McHugh, Pauline F.

2015-01-01

Epidemiological evidence linking diet—one of the most important modifiable lifestyle factors—and risk of Alzheimer’s disease (AD)—the most common cause of dementia—is rapidly increasing. However, the biological mechanisms underlying the relationship between dietary nutrients, brain aging, and risk of AD are largely unexplored. Recent studies using brain imaging and biological markers of AD have begun to clarify how diet and nutrition modulate risk of AD in cognitively normal individuals, especially those at increased genetic risk. Such knowledge is critical prior to implementing dietary recommendations for prevention and treatment of disease. PMID:26167396

Diagnostics Strategies with Electrochemical Affinity Biosensors Using Carbon Nanomaterials as Electrode Modifiers

Science.gov (United States)

Campuzano, Susana; Yáñez-Sedeño, Paloma; Pingarrón, José M.

2016-01-01

Early diagnosis is often the key to successful patient treatment and survival. The identification of various disease signaling biomarkers which reliably reflect normal and disease states in humans in biological fluids explain the burgeoning research field in developing new methodologies able to determine the target biomarkers in complex biological samples with the required sensitivity and selectivity and in a simple and rapid way. The unique advantages offered by electrochemical sensors together with the availability of high affinity and specific bioreceptors and their great capabilities in terms of sensitivity and stability imparted by nanostructuring the electrode surface with different carbon nanomaterials have led to the development of new electrochemical biosensing strategies that have flourished as interesting alternatives to conventional methodologies for clinical diagnostics. This paper briefly reviews the advantages of using carbon nanostructures and their hybrid nanocomposites as electrode modifiers to construct efficient electrochemical sensing platforms for diagnosis. The review provides an updated overview of some selected examples involving attractive amplification and biosensing approaches which have been applied to the determination of relevant genetic and protein diagnostics biomarkers. PMID:28035946

Patient perspectives on switching disease-modifying therapies in the NARCOMS registry.

Science.gov (United States)

Salter, Amber R; Marrie, Ruth Ann; Agashivala, Neetu; Belletti, Daniel A; Kim, Edward; Cutter, Gary R; Cofield, Stacey S; Tyry, Tuula

2014-01-01

The evolving landscape of disease-modifying therapies (DMTs) for multiple sclerosis raises important questions about why patients change DMTs. Physicians and patients could benefit from a better understanding of the reasons for switching therapy. To investigate the reasons patients switch DMTs and identify characteristics associated with the decision to switch. The North American Research Committee on Multiple Sclerosis (NARCOMS) Registry conducted a supplemental survey among registry participants responding to the 2011 update survey. The supplemental survey investigated reasons for switching DMT, origin of the discussion of DMT change, and which factors influenced the decision. Chi-square tests, Fisher's exact tests, and logistic regression were used for the analyses. Of the 691 eligible candidates, 308 responded and met the inclusion criteria (relapsing disease course, switched DMT after September 2010). The responders were 83.4% female, on average 52 years old, with a median (interquartile range) Patient-Determined Disease Steps score of 4 (2-5). The most recent prior therapy included first-line injectables (74.5%), infusions (18.1%), an oral DMT (3.4%), and other DMTs (4.0%). The discussion to switch DMT was initiated almost equally by physicians and participants. The primary reason for choosing the new DMT was based most frequently on physician's recommendation (24.5%) and patient perception of efficacy (13.7%). Participants frequently initiated the discussion regarding changing DMT, although physician recommendations regarding the specific therapy were still weighed highly. Long-term follow-up of these participants will provide valuable information on their disease trajectory, satisfaction with, and effectiveness of their new medication.

Cognitive enhancers (Nootropics). Part 3: drugs interacting with targets other than receptors or enzymes. Disease-modifying drugs. Update 2014.

Science.gov (United States)

Froestl, Wolfgang; Pfeifer, Andrea; Muhs, Andreas

2014-01-01

Scientists working in the field of Alzheimer's disease and, in particular, cognitive enhancers, are very productive. The review "Drugs interacting with Targets other than Receptors or Enzymes. Disease-modifying Drugs" was accepted in October 2012. In the last 20 months, new targets for the potential treatment of Alzheimer's disease were identified. Enormous progress was realized in the pharmacological characterization of natural products with cognitive enhancing properties. This review covers the evolution of research in this field through May 2014.

Biological Risks and Laboratory-Acquired Infections: A Reality That Cannot be Ignored in Health Biotechnology

Science.gov (United States)

Coelho, Ana Cláudia; García Díez, Juan

2015-01-01

Advances and research in biotechnology have applications over a wide range of areas, such as microbiology, medicine, the food industry, agriculture, genetically modified organisms, and nanotechnology, among others. However, research with pathogenic agents, such as virus, parasites, fungi, rickettsia, bacterial microorganisms, or genetic modified organisms, has generated concern because of their potential biological risk – not only for people, but also for the environment due to their unpredictable behavior. In addition, concern for biosafety is associated with the emergence of new diseases or re-emergence of diseases that were already under control. Biotechnology laboratories require biosafety measures designed to protect their staff, the population, and the environment, which may be exposed to hazardous organisms and materials. Laboratory staff training and education is essential, not only to acquire a good understanding about the direct handling of hazardous biological agents but also knowledge of the epidemiology, pathogenicity, and human susceptibility to the biological materials used in research. Biological risk can be reduced and controlled by the correct application of internationally recognized procedures such as proper microbiological techniques, proper containment apparatus, adequate facilities, protective barriers, and special training and education of laboratory workers. To avoid occupational infections, knowledge about standardized microbiological procedures and techniques and the use of containment devices, facilities, and protective barriers is necessary. Training and education about the epidemiology, pathogenicity, and biohazards of the microorganisms involved may prevent or decrease the risk. In this way, the scientific community may benefit from the lessons learned in the past to anticipate future problems. PMID:25973418

Biological risks and laboratory-acquired infections. A reality that cannot be ignored in health biotechnology

Directory of Open Access Journals (Sweden)

Ana Cláudia Coelho

2015-04-01

Full Text Available Advances and research in biotechnology have applications over a wide range of areas such as microbiology, medicine, the food industry, agriculture, genetically modified organisms and nanotechnology, among others. However, research with pathogenic agents such as virus, parasites, fungi, rickettsia, bacterial microorganisms or genetic modified organisms has generated concern because of their potential biological risk - not only for people, but also for the environment due to their unpredictable behavior. In addition, concern for biosafety is associated with the emergence of new diseases or re-emergence of diseases that were already under control. Biotechnology laboratories require biosafety measures designed to protect their staff, the population and the environment, which may be exposed to hazardous organisms and materials. Laboratory staff training and education is essential, not only to acquire a good understanding about the direct handling of hazardous biological agents but also knowledge of the epidemiology, pathogenicity and human susceptibility to the biological materials used in research. Biological risk can be reduced and controlled by the correct application of internationally recognized procedures such as proper microbiological techniques, proper containment apparatus, adequate facilities, protective barriers and special training and education of laboratory workers. To avoid occupational infections, knowledge about standardized microbiological procedures and techniques and the use of containment devices, facilities and protective barriers is necessary. Training and education about the epidemiology, pathogenicity and biohazards of the microorganisms involved may prevent or decrease the risk. In this way, the scientific community may benefit from the lessons learned in the past to anticipate future problems.

Identification of total reversible cysteine oxidation in an atherosclerosis model using a modified biotin switch assay.

Science.gov (United States)

Li, Ru; Huang, Jiqing; Kast, Juergen

2015-05-01

Oxidative stress due to the imbalance of reactive oxygen species (ROS) and the resulting reversible cysteine oxidation (CysOX) are involved in the early proatherogenic aspect of atherosclerosis. Given that the corresponding redox signaling pathways are still unclear, a modified biotin switch assay was developed to quantify the reversible CysOX in an atherosclerosis model established by using a monocytic cell line treated with platelet releasate. The accumulation of ROS was observed in the model system and validated in human primary monocytes. Through the application of the modified biotin switch assay, we obtained the first reversible CysOX proteome for this model. A total of 75 peptides, corresponding to 53 proteins, were quantified with oxidative modification. The bioinformatics analysis of these CysOX-containing proteins highlighted biological processes including glycolysis, cytoskeleton arrangement, and redox regulation. Moreover, the reversible oxidation of three glycolysis enzymes was observed using this method, and the regulation influence was verified by an enzyme activity assay. NADPH oxidase (NOX) inhibition treatment, in conjunction with the modified biotin switch method, was used to evaluate the global CysOX status. In conclusion, this versatile modified biotin switch assay provides an approach for the quantification of all reversible CysOX and for the study of redox signaling in atherosclerosis as well as in diseases in other biological systems.

Mining biological databases for candidate disease genes

Science.gov (United States)

Braun, Terry A.; Scheetz, Todd; Webster, Gregg L.; Casavant, Thomas L.

2001-07-01

The publicly-funded effort to sequence the complete nucleotide sequence of the human genome, the Human Genome Project (HGP), has currently produced more than 93% of the 3 billion nucleotides of the human genome into a preliminary `draft' format. In addition, several valuable sources of information have been developed as direct and indirect results of the HGP. These include the sequencing of model organisms (rat, mouse, fly, and others), gene discovery projects (ESTs and full-length), and new technologies such as expression analysis and resources (micro-arrays or gene chips). These resources are invaluable for the researchers identifying the functional genes of the genome that transcribe and translate into the transcriptome and proteome, both of which potentially contain orders of magnitude more complexity than the genome itself. Preliminary analyses of this data identified approximately 30,000 - 40,000 human `genes.' However, the bulk of the effort still remains -- to identify the functional and structural elements contained within the transcriptome and proteome, and to associate function in the transcriptome and proteome to genes. A fortuitous consequence of the HGP is the existence of hundreds of databases containing biological information that may contain relevant data pertaining to the identification of disease-causing genes. The task of mining these databases for information on candidate genes is a commercial application of enormous potential. We are developing a system to acquire and mine data from specific databases to aid our efforts to identify disease genes. A high speed cluster of Linux of workstations is used to analyze sequence and perform distributed sequence alignments as part of our data mining and processing. This system has been used to mine GeneMap99 sequences within specific genomic intervals to identify potential candidate disease genes associated with Bardet-Biedle Syndrome (BBS).

Employment of modified Fe3 O4 nanoparticles using thermo-sensitive polymer for extraction and pre-concentration of cefexime in biological samples.

Science.gov (United States)

Naghibi, Saman; Sahebi, Hamed

2018-02-01

Cefexime is a useful antibiotic that can be prescribed to treat bacterial infections. Nanoparticles have been widely marketed as a universal solution among scientists. Many studies have been performed to modify nanoparticles to make them functional as extraction and pre-concentration agents and drug carriers. Temperature-sensitive polymers belong to a group of substances that undergo a major change in their physical features in response to temperature. Recently developed polymers can be used in many different areas, including modification of nanoparticles. In order to modify this nanoparticle, grafting copolymerization of Fe 3 O 4 nanoparticles was performed using poly (N-vinylcaprolactam) and 3-allyloxy-1,2-propanediol. The optimum conditions for pre-concentration of cefexime were studied. Under these optimum conditions, extraction recovery of biological samples in the range of 71-89% was obtained. The limit of detection and precision of proposed method were 4.5 × 10 -4  μg mL -1 and analysis of cefexime, in biological samples using the proposed method, the ability of this method to extract and pre-concentrate cefexime was confirmed. Also, satisfactory results from an in vitro study on drug release in simulated intestine media were obtained. Copyright © 2017 John Wiley & Sons, Ltd.

Looking through the Lens: Adapting and Modifying Photovoice Projects for Active Learning and Engagement in Biology

OpenAIRE

Karobi Moitra

2016-01-01

Photovoice projects traditionally include original visual imagery and minimal text to tell a powerful story. Photovoice student projects have been utilized in the health and social sciences to involve students with the local community and also in community-based projects to help at-risk youth call attention to their community problems, such as disease and drug use. The tool of the photovoice can be used in the biology classroom to engage students in the active learning process through communi...

From biological anthropology to applied public health: epidemiological approaches to the study of infectious disease.

Science.gov (United States)

Albalak, Rachel

2009-01-01

This article describes two large, multisite infectious disease programs: the Tuberculosis Epidemiologic Studies Consortium (TBESC) and the Emerging Infections Programs (EIPs). The links between biological anthropology and applied public health are highlighted using these programs as examples. Funded by the Centers for Disease Control and Prevention (CDC), the TBESC and EIPs conduct applied public health research to strengthen infectious disease prevention and control efforts in the United States. They involve collaborations among CDC, public health departments, and academic and clinical institutions. Their unique role in national infectious disease work, including their links to anthropology, shared elements, key differences, strengths and challenges, is discussed.

Perspectives and experiences of Dutch multiple sclerosis patients and multiple sclerosis-specialized neurologists on injectable disease-modifying treatment

NARCIS (Netherlands)

Visser, Leo H.; Heerings, Marco A.; Jongen, Peter J.; van der Hiele, Karin

2016-01-01

Background: The adherence to treatment with injectable disease-modifying drugs (DMDs) in multiple sclerosis (MS) may benefit from adequate information provision and management of expectations. The communication between patients and physicians is very important in this respect. The current study

Carryover effect of postpartum inflammatory diseases on developmental biology and fertility in lactating dairy cows.

Science.gov (United States)

Ribeiro, E S; Gomes, G; Greco, L F; Cerri, R L A; Vieira-Neto, A; Monteiro, P L J; Lima, F S; Bisinotto, R S; Thatcher, W W; Santos, J E P

2016-03-01

The objective of this series of studies was to investigate the effects of inflammatory diseases occurring before breeding on the developmental biology and reproductive responses in dairy cows. Data from 5 studies were used to investigate different questions associating health status before breeding and reproductive responses. Health information for all studies was composed of the incidence of retained fetal membranes, metritis, mastitis, lameness, and respiratory and digestive problems from parturition until the day of breeding. Retained placenta and metritis were grouped as uterine disease (UTD). Mastitis, lameness, digestive and respiratory problems were grouped as nonuterine diseases (NUTD). Study 1 evaluated the effect of disease before artificial insemination (AI), anovulation before synchronization of the estrous cycle, and low body condition score at AI on pregnancy per AI, as well as their potential interactions or additive effects. Study 2 investigated the effect of site of inflammation (UTD vs. NUTD) and time of occurrence relative to preantral or antral stages of ovulatory follicle development, and the effect of UTD and NUTD on fertility responses of cows bred by AI or by embryo transfer. Study 3 evaluated the effect of disease on fertilization and embryonic development to the morula stage. Study 4 evaluated the effect of disease on preimplantation conceptus development as well as secretion of IFN-τ and transcriptome. Study 5 investigated the effect of diseases before AI on the transcript expression of interferon-stimulated genes in peripheral blood leukocytes during peri-implantation stages of conceptus development after first AI postpartum. Altogether, these studies demonstrated that inflammatory disease before breeding reduced fertilization of oocytes and development to morula, and impaired early conceptus development to elongation stages and secretion of IFN-τ in the uterine lumen. Diseases caused inflammation-like changes in transcriptome of

Type 1 Diabetes TrialNet: A Multifaceted Approach to Bringing Disease-Modifying Therapy to Clinical Use in Type 1 Diabetes.

Science.gov (United States)

Bingley, Polly J; Wherrett, Diane K; Shultz, Ann; Rafkin, Lisa E; Atkinson, Mark A; Greenbaum, Carla J

2018-04-01

What will it take to bring disease-modifying therapy to clinical use in type 1 diabetes? Coordinated efforts of investigators involved in discovery, translational, and clinical research operating in partnership with funders and industry and in sync with regulatory agencies are needed. This Perspective describes one such effort, Type 1 Diabetes TrialNet, a National Institutes of Health-funded and JDRF-supported international clinical trials network that emerged from the Diabetes Prevention Trial-Type 1 (DPT-1). Through longitudinal natural history studies, as well as trials before and after clinical onset of disease combined with mechanistic and ancillary investigations to enhance scientific understanding and translation to clinical use, TrialNet is working to bring disease-modifying therapies to individuals with type 1 diabetes. Moreover, TrialNet uses its expertise and experience in clinical studies to increase efficiencies in the conduct of trials and to reduce the burden of participation on individuals and families. Herein, we highlight key contributions made by TrialNet toward a revised understanding of the natural history of disease and approaches to alter disease course and outline the consortium's plans for the future. © 2018 by the American Diabetes Association.

Global Association of Air Pollution and Cardiorespiratory Diseases: A Systematic Review, Meta-Analysis, and Investigation of Modifier Variables

Science.gov (United States)

Adams, Matthew D.; Arain, Altaf; Papatheodorou, Stefania; Koutrakis, Petros; Mahmoud, Moataz

2018-01-01

Background. Little is known about the health risks of air pollution and cardiorespiratory diseases, globally, across regions and populations, which may differ because of external factors. Objectives. We systematically reviewed the evidence on the association between air pollution and cardiorespiratory diseases (hospital admissions and mortality), including variability by energy, transportation, socioeconomic status, and air quality. Search Methods. We conducted a literature search (PubMed and Web of Science) for studies published between 2006 and May 11, 2016. Selection Criteria. We included studies if they met all of the following criteria: (1) considered at least 1 of these air pollutants: carbon monoxide, sulfur dioxide, nitrogen dioxide, ozone, or particulate matter (PM2.5 or PM10); (2) reported risk for hospital admissions, mortality, or both; (3) presented individual results for respiratory diseases, cardiovascular diseases, or both; (4) considered the age groups younger than 5 years, older than 65 years, or all ages; and (5) did not segregate the analysis by gender. Data Collection and Analysis. We extracted data from each study, including location, health outcome, and risk estimates. We performed a meta-analysis to estimate the overall effect and to account for both within- and between-study heterogeneity. Then, we applied a model selection (least absolute shrinkage and selection operator) to assess the modifier variables, and, lastly, we performed meta-regression analyses to evaluate the modifier variables contributing to heterogeneity among studies. Main Results. We assessed 2183 studies, of which we selected 529 for in-depth review, and 70 articles fulfilled our study inclusion criteria. The 70 studies selected for meta-analysis encompass more than 30 million events across 28 countries. We found positive associations between cardiorespiratory diseases and different air pollutants. For example, when we considered only the association between PM2.5 and

The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

DEFF Research Database (Denmark)

Metzger, Silke; Walter, Carolin; Riess, Olaf

2013-01-01

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently......, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second...... independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the "REGISTRY" cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing...

Portuguese guidelines for the use of biological agents in rheumatoid arthritis - March 2010 update.

Science.gov (United States)

Fonseca, João Eurico; Canhão, Helena; Reis, Paulo; Santos, Maria José; Branco, Jaime; Quintal, Alberto; Malcata, Armando; Araújo, Domingos; Ventura, Francisco; Figueiredo, Guilherme; da Silva, José Canas; Patto, José Vaz; de Queiroz, Mário Viana; Santos, Rui André; Neto, Adriano José; de Matos, Alves de; Rodrigues, Ana; Mourão, Ana Filipa; Ribeiro, Ana Sofia; Cravo, Ana Rita; Barcelos, Anabela; Cardoso, Anabela; Vilar, António; Braña, Arecili; Faustino, Augusto; Silva, Candida; Godinho, Fátima; Cunha, Inês; Costa, José António; Gomes, José António Melo; Pinto, José António Araújo; da Silva, J A Pereira; Miranda, Luís Cunha; Inês, Luís; Santos, Luís Maurício; Cruz, Margarida; Salvador, Maria João; Ferreira, Maria Júlia; Rial, Maria; Bernardes, Miguel; Bogas, Mónica; Araújo, Paula; Machado, Pedro; Pinto, Patrícia; de Melo, Rui Gomes; Cortes, Sara; Alcino, Sérgio; Capela, Susana

2010-01-01

The authors present the revised version of the Portuguese Society of Rheumatology (SPR) guidelines for the treatment of rheumatoid arthritis (RA) with biological therapies. In these guidelines the criteria for introduction and maintenance of biological agents are discussed as well as the contraindications and procedures in the case of non-responders. Biological treatment should be considered in RA patients with a disease activity score 28 (DAS 28) superior to 3.2 despite treatment with 20mg/week of methotrexate (MTX) for at least 3 months or, if such treatment is not possible, after 6 months of other conventional disease modifying drug or combination therapy. A DAS 28 score between 2.6 and 3.2 with a significant functional or radiological deterioration under treatment with conventional regimens could also constitute an indication for biological treatment. The treatment goal should be remission or, if that is not achievable, at least a low disease activity, characterized by a DAS28 lower than 3.2, without significative functional or radiological worsening. The response criteria, at the end of the first 3 months of treatment, are a decrease of 0.6 in the DAS28 score. After 6 months of treatment response criteria is defined as a decrease of more than 1.2 in the DAS28 score. Non-responders, in accordance to the Rheumatologist's clinical opinion, should try a switch to another biological agent (tumour necrosis factor antagonist, abatacept, rituximab or tocilizumab).

Microarrays – new possibilities for detecting biological factors hazardous for humans and animals, and for use in environmental protection

Directory of Open Access Journals (Sweden)

Tomasz Mirski

2015-12-01

Full Text Available Both the known biological agents that cause infectious diseases, as well as modified (ABF-Advanced Biological Factors or new, emerging agents pose a significant diagnostic problem using previously applied methods, both classical, as well as based on molecular biology methods. The latter, such as PCR and real-time PCR, have significant limitations, both quantitative (low capacity, and qualitative (limited number of targets. The article discusses the results of studies on using the microarray method for the identification of viruses (e.g. Orthopoxvirus group, noroviruses, influenza A and B viruses, rhino- and enteroviruses responsible for the FRI (Febrile Respiratory Illness, European bunyaviruses, and SARS-causing viruses, and bacteria ([i]Mycobacterium spp., Yersinia spp., Campylobacter spp., Streptococcus pneumoniae, Salmonella typhi, Salmonella enterica, Staphylococcus aureus, Neisseria meningitidis, Clostridium difficile , Helicobacter pylori[/i], including multiple antibiotic-resistant strains. The method allows for the serotyping and genotyping of bacteria, and is useful in the diagnosis of genetically modified agents. It allows the testing of thousands of genes in one experiment. In addition to diagnosis, it is applicable for gene expression studies, analysis of the function of genes, microorganisms virulence, and allows the detection of even single mutations. The possibility of its operational application in epidemiological surveillance, and in the detection of disease outbreak agents is demonstrated.

Next generation of biologics for the treatment of Crohn’s disease: an evidence-based review on ustekinumab

Directory of Open Access Journals (Sweden)

Jauregui-Amezaga A

2017-11-01

Full Text Available Aranzazu Jauregui-Amezaga, Michael Somers, Heiko De Schepper, Elisabeth Macken Department of Gastroenterology, Universitair Ziekenhuis Antwerpen, University of Antwerp, Antwerp, Belgium Abstract: The limited efficacy of the currently available medical therapies in a proportion of patients with Crohn’s disease has led to the research and development of molecules that can block new inflammatory pathways. Ustekinumab is a fully human IgG1 monoclonal antibody which targets the common p40 subunit of the cytokines interleukin-12 as well as interleukin-23. Consequently, the Th1 and Th17 inflammatory responses are inhibited. Ustekinumab has been recently approved for its use in patients with Crohn’s disease. Its efficacy and safety was initially proved in patients with psoriasis and psoriatic arthritis. More recently, three Phase III trials have confirmed its efficacy in patients with Crohn’s disease refractory to anti-tumor necrosis factor therapy. This biologic agent appears safe, with no increased risk of infectious or malignant complications, and a low immunogenic profile. Keywords: ustekinumab, interleukin-12, interleukin-23, biologic therapy, inflammatory bowel disease, Crohn’s disease

In situ biomolecule production by bacteria; a synthetic biology approach to medicine.

Science.gov (United States)

Flores Bueso, Yensi; Lehouritis, Panos; Tangney, Mark

2018-04-10

The ability to modify existing microbiota at different sites presents enormous potential for local or indirect management of various diseases. Because bacteria can be maintained for lengthy periods in various regions of the body, they represent a platform with enormous potential for targeted production of biomolecules, which offer tremendous promise for therapeutic and diagnostic approaches for various diseases. While biological medicines are currently limited in the clinic to patient administration of exogenously produced biomolecules from engineered cells, in situ production of biomolecules presents enormous scope in medicine and beyond. The slow pace and high expense of traditional research approaches has particularly hampered the development of biological medicines. It may be argued that bacterial-based medicine has been "waiting" for the advent of enabling technology. We propose that this technology is Synthetic Biology, and that the wait is over. Synthetic Biology facilitates a systematic approach to programming living entities and/or their products, using an approach to Research and Development (R&D) that facilitates rapid, cheap, accessible, yet sophisticated product development. Full engagement with the Synthetic Biology approach to R&D can unlock the potential for bacteria as medicines for cancer and other indications. In this review, we describe how by employing Synthetic Biology, designer bugs can be used as drugs, drug-production factories or diagnostic devices, using oncology as an exemplar for the concept of in situ biomolecule production in medicine. Copyright © 2018 Elsevier B.V. All rights reserved.

Validation of a model to investigate the effects of modifying cardiovascular disease (CVD) risk factors on the burden of CVD: the rotterdam ischemic heart disease and stroke computer simulation (RISC) model

NARCIS (Netherlands)

van Kempen, Bob J. H.; Ferket, Bart S.; Hofman, Albert; Steyerberg, Ewout W.; Colkesen, Ersen B.; Boekholdt, S. Matthijs; Wareham, Nicholas J.; Khaw, Kay-Tee; Hunink, M. G. Myriam

2012-01-01

Background: We developed a Monte Carlo Markov model designed to investigate the effects of modifying cardiovascular disease (CVD) risk factors on the burden of CVD. Internal, predictive, and external validity of the model have not yet been established. Methods: The Rotterdam Ischemic Heart Disease

Biological treatments in Behçet's disease: beyond anti-TNF therapy.

Science.gov (United States)

Caso, Francesco; Costa, Luisa; Rigante, Donato; Lucherini, Orso Maria; Caso, Paolo; Bascherini, Vittoria; Frediani, Bruno; Cimaz, Rolando; Marrani, Edoardo; Nieves-Martín, Laura; Atteno, Mariangela; Raffaele, Carmela G L; Tarantino, Giusyda; Galeazzi, Mauro; Punzi, Leonardo; Cantarini, Luca

2014-01-01

Behçet's disease (BD) is universally recognized as a multisystemic inflammatory disease of unknown etiology with chronic course and unpredictable exacerbations: its clinical spectrum varies from pure vasculitic manifestations with thrombotic complications to protean inflammatory involvement of multiple organs and tissues. Treatment has been revolutionized by the progressed knowledge in the pathogenetic mechanisms of BD, involving dysfunction and oversecretion of multiple proinflammatory molecules, chiefly tumor necrosis factor- (TNF-) α, interleukin- (IL-) 1β, and IL-6. However, although biological treatment with anti-TNF-α agents has been largely demonstrated to be effective in BD, not all patients are definite responders, and this beneficial response might drop off over time. Therefore, additional therapies for a subset of refractory patients with BD are inevitably needed. Different agents targeting various cytokines and their receptors or cell surface molecules have been studied: the IL-1 receptor has been targeted by anakinra, the IL-1 by canakinumab and gevokizumab, the IL-6 receptor by tocilizumab, the IL12/23 receptor by ustekinumab, and the B-lymphocyte antigen CD-20 by rituximab. The aim of this review is to summarize all current experiences and the most recent evidence regarding these novel approaches with biological drugs other than TNF-α blockers in BD, providing a valuable addition to the actually available therapeutic armamentarium.

Systems Biology and Ratio-Based, Real-Time Disease Surveillance.

Science.gov (United States)

Fair, J M; Rivas, A L

2015-08-01

Most infectious disease surveillance methods are not well fit for early detection. To address such limitation, here we evaluated a ratio- and Systems Biology-based method that does not require prior knowledge on the identity of an infective agent. Using a reference group of birds experimentally infected with West Nile virus (WNV) and a problem group of unknown health status (except that they were WNV-negative and displayed inflammation), both groups were followed over 22 days and tested with a system that analyses blood leucocyte ratios. To test the ability of the method to discriminate small data sets, both the reference group (n = 5) and the problem group (n = 4) were small. The questions of interest were as follows: (i) whether individuals presenting inflammation (disease-positive or D+) can be distinguished from non-inflamed (disease-negative or D-) birds, (ii) whether two or more D+ stages can be detected and (iii) whether sample size influences detection. Within the problem group, the ratio-based method distinguished the following: (i) three (one D- and two D+) data classes; (ii) two (early and late) inflammatory stages; (iii) fast versus regular or slow responders; and (iv) individuals that recovered from those that remained inflamed. Because ratios differed in larger magnitudes (up to 48 times larger) than percentages, it is suggested that data patterns are likely to be recognized when disease surveillance methods are designed to measure inflammation and utilize ratios. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.

The role of bacillus-based biological control agents in integrated pest management systems: plant diseases.

Science.gov (United States)

Jacobsen, B J; Zidack, N K; Larson, B J

2004-11-01

ABSTRACT Bacillus-based biological control agents (BCAs) have great potential in integrated pest management (IPM) systems; however, relatively little work has been published on integration with other IPM management tools. Unfortunately, most research has focused on BCAs as alternatives to synthetic chemical fungicides or bactericides and not as part of an integrated management system. IPM has had many definitions and this review will use the national coalition for IPM definition: "A sustainable approach to managing pests by combining biological, cultural, physical and chemical tools in a way that minimizes economic, health and environmental risks." This review will examine the integrated use of Bacillus-based BCAs with disease management tools, including resistant cultivars, fungicides or bactericides, or other BCAs. This integration is important because the consistency and degree of disease control by Bacillus-based BCAs is rarely equal to the control afforded by the best fungicides or bactericides. In theory, integration of several tools brings stability to disease management programs. Integration of BCAs with other disease management tools often provides broader crop adaptation and both more efficacious and consistent levels of disease control. This review will also discuss the use of Bacillus-based BCAs in fungicide resistance management. Work with Bacillus thuringiensis and insect pest management is the exception to the relative paucity of reports but will not be the focus of this review.

Selective biologics for ulcerative colitis and Crohn's disease – clinical utility of vedolizumab

Directory of Open Access Journals (Sweden)

Petkau JM

2016-03-01

Full Text Available Jill MV Petkau, Bertus Eksteen Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada Abstract: Inflammatory bowel disease (IBD encompasses a cluster of different disease phenotypes which are broadly classified into ulcerative colitis and Crohn's disease. Disease pathogenesis is driven by abnormal host immune responses to their resident gut microbiome in genetically susceptible individuals. Clinical disease features and outcomes are heterogenous and not unexpected as over 163 genetic loci are associated with disease susceptibility, and there are great variability in environmental exposures. Despite this variability, there has been relatively few efficacious therapies for particularly moderate-to-severe IBD. Treatment has been dominated by antitumor necrosis alpha agents with significant success but equally potentially serious adverse events. Therapeutic targeting of leucocyte trafficking has emerged as a viable alternative therapy, with vedolizumab being the lead compound. This review focuses primarily on its biological function as a selective gut immunotherapy, its safety and efficacy, and its emerging role as a mainstream therapy in managing IBD. Keywords: adhesion molecule antagonist, anti-α4β7 integrin, inflammatory bowel disease, leukocyte trafficking, monoclonal antibody, selective gut immunotherapy, tumor necrosis factor alpha

International biological engagement programs facilitate Newcastle disease epidemiological studies

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Patti J. Miller

2015-10-01

Full Text Available Infections of poultry species with virulent strains of Newcastle disease virus (NDV cause Newcastle disease (ND, one of the most economically significant and devastating diseases for poultry producers worldwide. Biological engagement programs (BEP between the Southeast Poultry Research Laboratory (SEPRL of the United States Department of Agriculture and laboratories from Russia, Pakistan, Ukraine, Kazakhstan and Indonesia collectively have produced a better understanding of the genetic diversity and evolution of the viruses responsible for ND, which is crucial for the control of the disease. The data from Kazakhstan, Russia and Ukraine identified possible migratory routes for birds that may carry both virulent NDV (vNDV and NDV of low virulence into Europe. In addition, related NDV strains were isolated from wild birds in Ukraine and Nigeria, and from birds in continental USA, Alaska, Russia, and Japan, identifying wild birds as a possible mechanism of intercontinental spread of NDV of low virulence. More recently, the detection of new sub-genotypes of vNDV suggests that a new, fifth, panzootic of ND has already originated in Southeast Asia, extended to the Middle East, and is now entering into Eastern Europe. Despite expected challenges when multiple independent laboratories interact, many scientists from the collaborating countries have successfully been trained by SEPRL on molecular diagnostics, best laboratory practices, and critical biosecurity protocols, providing our partners the capacity to further train other employees and to identify locally the viruses that cause this OIE listed disease. These and other collaborations with partners in Mexico, Bulgaria, Israel, and Tanzania have allowed SEPRL scientists to engage in field studies, to elucidate more aspects of ND epidemiology in endemic countries, and to understand the challenges that the scientists and field veterinarians in these countries face on a daily basis. Finally, new viral

International Biological Engagement Programs Facilitate Newcastle Disease Epidemiological Studies

Science.gov (United States)

Miller, Patti J.; Dimitrov, Kiril M.; Williams-Coplin, Dawn; Peterson, Melanie P.; Pantin-Jackwood, Mary J.; Swayne, David E.; Suarez, David L.; Afonso, Claudio L.

2015-01-01

Infections of poultry species with virulent strains of Newcastle disease virus (NDV) cause Newcastle disease (ND), one of the most economically significant and devastating diseases for poultry producers worldwide. Biological engagement programs between the Southeast Poultry Research Laboratory (SEPRL) of the United States Department of Agriculture and laboratories from Russia, Pakistan, Ukraine, Kazakhstan, and Indonesia collectively have produced a better understanding of the genetic diversity and evolution of the viruses responsible for ND, which is crucial for the control of the disease. The data from Kazakhstan, Russia, and Ukraine identified possible migratory routes for birds that may carry both virulent NDV (vNDV) and NDV of low virulence into Europe. In addition, related NDV strains were isolated from wild birds in Ukraine and Nigeria, and from birds in continental USA, Alaska, Russia, and Japan, identifying wild birds as a possible mechanism of intercontinental spread of NDV of low virulence. More recently, the detection of new sub-genotypes of vNDV suggests that a new, fifth, panzootic of ND has already originated in Southeast Asia, extended to the Middle East, and is now entering into Eastern Europe. Despite expected challenges when multiple independent laboratories interact, many scientists from the collaborating countries have successfully been trained by SEPRL on molecular diagnostics, best laboratory practices, and critical biosecurity protocols, providing our partners the capacity to further train other employes and to identify locally the viruses that cause this OIE listed disease. These and other collaborations with partners in Mexico, Bulgaria, Israel, and Tanzania have allowed SEPRL scientists to engage in field studies, to elucidate more aspects of ND epidemiology in endemic countries, and to understand the challenges that the scientists and field veterinarians in these countries face on a daily basis. Finally, new viral characterization tools

International Biological Engagement Programs Facilitate Newcastle Disease Epidemiological Studies.

Science.gov (United States)

Miller, Patti J; Dimitrov, Kiril M; Williams-Coplin, Dawn; Peterson, Melanie P; Pantin-Jackwood, Mary J; Swayne, David E; Suarez, David L; Afonso, Claudio L

2015-01-01

Infections of poultry species with virulent strains of Newcastle disease virus (NDV) cause Newcastle disease (ND), one of the most economically significant and devastating diseases for poultry producers worldwide. Biological engagement programs between the Southeast Poultry Research Laboratory (SEPRL) of the United States Department of Agriculture and laboratories from Russia, Pakistan, Ukraine, Kazakhstan, and Indonesia collectively have produced a better understanding of the genetic diversity and evolution of the viruses responsible for ND, which is crucial for the control of the disease. The data from Kazakhstan, Russia, and Ukraine identified possible migratory routes for birds that may carry both virulent NDV (vNDV) and NDV of low virulence into Europe. In addition, related NDV strains were isolated from wild birds in Ukraine and Nigeria, and from birds in continental USA, Alaska, Russia, and Japan, identifying wild birds as a possible mechanism of intercontinental spread of NDV of low virulence. More recently, the detection of new sub-genotypes of vNDV suggests that a new, fifth, panzootic of ND has already originated in Southeast Asia, extended to the Middle East, and is now entering into Eastern Europe. Despite expected challenges when multiple independent laboratories interact, many scientists from the collaborating countries have successfully been trained by SEPRL on molecular diagnostics, best laboratory practices, and critical biosecurity protocols, providing our partners the capacity to further train other employes and to identify locally the viruses that cause this OIE listed disease. These and other collaborations with partners in Mexico, Bulgaria, Israel, and Tanzania have allowed SEPRL scientists to engage in field studies, to elucidate more aspects of ND epidemiology in endemic countries, and to understand the challenges that the scientists and field veterinarians in these countries face on a daily basis. Finally, new viral characterization tools

Evaluation of a genetically modified foot-and-mouth disease virus vaccine candidate generated by reverse genetics

Science.gov (United States)

2012-01-01

Background Foot-and-mouth disease (FMD) is the most economically important and highly contagious disease of cloven-hoofed animals worldwide. Control of the disease has been mainly based on large-scale vaccinations with whole-virus inactivated vaccines. In recent years, a series of outbreaks of type O FMD occurred in China (including Chinese Taipei, Chinese Hong Kong) posed a tremendous threat to Chinese animal husbandry. Its causative agent, type O FMDV, has evolved into three topotypes (East–South Asia (ME-SA), Southeast Asia (SEA), Cathay (CHY)) in these regions, which represents an important obstacle to disease control. The available FMD vaccine in China shows generally good protection against ME-SA and SEA topotype viruses infection, but affords insufficient protection against some variants of the CHY topotype. Therefore, the choice of a new vaccine strain is of fundamental importance. Results The present study describes the generation of a full-length infectious cDNA clone of FMDV vaccine strain and a genetically modified virus with some amino acid substitutions in antigenic sites 1, 3, and 4, based on the established infectious clone. The recombinant viruses had similar growth properties to the wild O/HN/CHA/93 virus. All swine immunized with inactivated vaccine prepared from the O/HN/CHA/93 were fully protected from challenge with the viruses of ME-SA and SEA topotypes and partially protected against challenge with the virus of CHY topotype at 28 days post-immunization. In contrast, the swine inoculated with the genetically modified vaccine were completely protected from the infection of viruses of the three topotypes. Conclusions Some amino acid substitutions in the FMDV vaccine strain genome did not have an effect on the ability of viral replication in vitro. The vaccine prepared from genetically modified FMDV by reverse genetics significantly improved the protective efficacy to the variant of the CHY topotype, compared with the wild O/HN/CHA/93 virus

Evaluation of a genetically modified foot-and-mouth disease virus vaccine candidate generated by reverse genetics

Directory of Open Access Journals (Sweden)

Li Pinghua

2012-05-01

Full Text Available Abstract Background Foot-and-mouth disease (FMD is the most economically important and highly contagious disease of cloven-hoofed animals worldwide. Control of the disease has been mainly based on large-scale vaccinations with whole-virus inactivated vaccines. In recent years, a series of outbreaks of type O FMD occurred in China (including Chinese Taipei, Chinese Hong Kong posed a tremendous threat to Chinese animal husbandry. Its causative agent, type O FMDV, has evolved into three topotypes (East–South Asia (ME-SA, Southeast Asia (SEA, Cathay (CHY in these regions, which represents an important obstacle to disease control. The available FMD vaccine in China shows generally good protection against ME-SA and SEA topotype viruses infection, but affords insufficient protection against some variants of the CHY topotype. Therefore, the choice of a new vaccine strain is of fundamental importance. Results The present study describes the generation of a full-length infectious cDNA clone of FMDV vaccine strain and a genetically modified virus with some amino acid substitutions in antigenic sites 1, 3, and 4, based on the established infectious clone. The recombinant viruses had similar growth properties to the wild O/HN/CHA/93 virus. All swine immunized with inactivated vaccine prepared from the O/HN/CHA/93 were fully protected from challenge with the viruses of ME-SA and SEA topotypes and partially protected against challenge with the virus of CHY topotype at 28 days post-immunization. In contrast, the swine inoculated with the genetically modified vaccine were completely protected from the infection of viruses of the three topotypes. Conclusions Some amino acid substitutions in the FMDV vaccine strain genome did not have an effect on the ability of viral replication in vitro. The vaccine prepared from genetically modified FMDV by reverse genetics significantly improved the protective efficacy to the variant of the CHY topotype, compared with the

The role of the sociotype in managing chronic disease: integrating bio-psycho-sociology with systems biology.

Science.gov (United States)

Berry, Elliot M

2011-10-01

Attempts have been made to replace the bio-medical approach with that of systems biology, which considers dynamic human behavior (internal factors) for chronic (rather than acute) disease management. They have not yet incorporated the Bio-psycho-social (BPS) model of Engel which adds patients' background and cultural beliefs (external factors) contributing to their susceptibility to, and coping strategies for, non-communicable diseases (NCDs) the increasing domain of global Public Health. The problem is how to include the social determinants of disease in a comprehensive model of care, especially in the management of chronic disease. The concept of "sociotype" is proposed as a framework for understanding the interactions between the social, cultural and environmental inputs that influence the growth, development and life-long behavior of a person, including relationships, lifestyle and coping strategies. Pre-/peri-natal influences on development and subsequent susceptibility to chronic disease are examples of interactions between the sociotype, genotype and phenotype. Disorders of the sociotype, encompassing social determinants (e.g. poverty, education, networking), of disease are major contributors to the increase in NCDs, as well as for mental illness and absenteeism. Thus, people are the product of a threefold cord--genotype, phenotype and sociotype. WHAT NEXT?: Holistic management of patients through the BPS model have to be aligned with the relevant elements of systems biology--context, space, time and robustness--that pertain to the sociotype. Medical curricula should balance basic sciences with disciplines such as psychology, sociology, anthropology and public health that attempt to explain human behavior and the social determinants of disease. This requires methodologies combining qualitative and quantitative research to study simultaneous interactions (and their possible mechanisms) between systems biology and the BPS model. The neologism "sociotype

Classifying PML risk with disease modifying therapies.

Science.gov (United States)

Berger, Joseph R

2017-02-01

To catalogue the risk of PML with the currently available disease modifying therapies (DMTs) for multiple sclerosis (MS). All DMTs perturb the immune system in some fashion. Natalizumab, a highly effective DMT, has been associated with a significant risk of PML. Fingolimod and dimethyl fumarate have also been unquestionably associated with a risk of PML in the MS population. Concerns about PML risk with other DMTs have arisen due to their mechanism of action and pharmacological parallel to other agents with known PML risk. A method of contextualizing PML risk for DMTs is warranted. Classification of PML risk was predicated on three criteria:: 1) whether the underlying condition being treated predisposes to PML in the absence of the drug; 2) the latency from initiation of the drug to the development of PML; and 3) the frequency with which PML is observed. Among the DMTs, natalizumab occupies a place of its own with respect to PML risk. Significantly lesser degrees of risk exist for fingolimod and dimethyl fumarate. Whether PML will be observed with other DMTs in use for MS, such as, rituximab, teriflunomide, and alemtuzumab, remains uncertain. A logical classification for stratifying DMT PML risk is important for both the physician and patient in contextualizing risk/benefit ratios. As additional experience accumulates regarding PML and the DMTs, this early effort will undoubtedly require revisiting. Copyright © 2016 Elsevier B.V. All rights reserved.

Catfish Biology and Farming.

Science.gov (United States)

Dunham, Rex A; Elaswad, Ahmed

2018-02-15

This article summarizes the biology and culture of ictalurid catfish, an important commercial, aquaculture, and sport fish family in the United States. The history of the propagation as well as spawning of common catfish species in this family is reviewed, with special emphasis on channel catfish and its hybridization with blue catfish. The importance of the channel catfish female×blue catfish male hybrid, including current and future methods of hybrid catfish production, and the potential role it plays in the recovery of the US catfish industry are discussed. Recent advances in catfish culture elements, including environment, management, nutrition, feeding, disease control, culture systems, genetic improvement programs, transgenics, and the application of genome-based approaches in catfish production and welfare, are reviewed. The current status, needs, and future projections are discussed, as well as genetically modified organism developments that are changing the future.

Safety and effectiveness of collagenase clostridium histolyticum in the treatment of Peyronie's disease using a new modified shortened protocol.

Science.gov (United States)

Abdel Raheem, Amr; Capece, Marco; Kalejaiye, Odunayo; Abdel-Raheem, Tarek; Falcone, Marco; Johnson, Mark; Ralph, Oliver G; Garaffa, Giulio; Christopher, Andrew N; Ralph, David J

2017-11-01

To evaluate the efficacy and safety of collagenase clostridium histolyticum (CCH; Xiapex ® , Xiaflex ® ) in the treatment of Peyronie's disease (PD) using a new modified treatment protocol that aims at reducing the number of injections needed and reducing patient visits, thus reducing the duration and cost of treatment. A prospective study of 53 patients with PD who had treatment with CCH at a single centre using a new modified protocol. The angle of curvature assessment after an intracavernosal injection of prostaglandin E1, the International Index of Erectile Function (IIEF) and Peyronie's Disease Questionnaire (PDQ) were completed at baseline and at week 12 (4 weeks after the last injection). The Global Assessment of Peyronie's disease (GAPD) questionnaire was completed at week 12. Under a penile block of 10 mL plain lignocaine 1%, a total of three intralesional injections of CCH (0.9 mg) were given at 4-weekly intervals using a new modified injection technique. In between injections patients used a combination of home modelling, stretching and a vacuum device on a daily basis to mechanically stretch the plaque. Investigator modelling was not performed. The mean (range) penile curvature at baseline was 54 (30-90)°. Of the 53 patients in the study, 51 patients (96.2%) had an improvement in the angel of curvature by a mean (range) of 17.36 (0-40)° or 31.4 (0-57)% from baseline after three CCH injections. The final mean (range) curvature was 36.9 (12-75)° (P effective, and cost efficient. The results of using only three CCH injections according to this modified protocol are comparable to those of the clinical trials that used eight CCH injections. © 2017 The Authors BJU International © 2017 BJU International Published by John Wiley & Sons Ltd.

Infections in patients with multiple sclerosis: Implications for disease-modifying therapy.

Science.gov (United States)

Celius, E G

2017-11-01

Patients with multiple sclerosis have an increased risk of infections compared to the general population. The increased risk has been described for decades and is not alone attributed to the use of disease-modifying drugs, but secondary to the disability. The introduction of more potent immunomodulatory drugs may cause an additional challenge, and depending on the mechanism of action, a treatment-induced increased risk of bacterial, viral, fungal or parasitic infections is observed. The choice of treatment in the individual patient with infections and multiple sclerosis must be guided by the drugs' specific mechanism of action, the drug-specific risk of infection and comorbidities. Increased monitoring and follow-up through treatment registries is warranted to increase our understanding and thereby improve management. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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

Directory of Open Access Journals (Sweden)

Anna Bobrowska

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

Synthetic Biology: Advancing Biological Frontiers by Building Synthetic Systems

OpenAIRE

Chen, Yvonne Yu-Hsuan; Galloway, Kate E; Smolke, Christina D

2012-01-01

Advances in synthetic biology are contributing to diverse research areas, from basic biology to biomanufacturing and disease therapy. We discuss the theoretical foundation, applications, and potential of this emerging field.

SQ grass sublingual allergy immunotherapy tablet for disease-modifying treatment of grass pollen allergic rhinoconjunctivitis

DEFF Research Database (Denmark)

Dahl, Ronald; Roberts, Graham; de Blic, Jacques

2016-01-01

BACKGROUND: Allergy immunotherapy is a treatment option for allergic rhinoconjunctivitis (ARC). It is unique compared with pharmacotherapy in that it modifies the immunologic pathways that elicit an allergic response. The SQ Timothy grass sublingual immunotherapy (SLIT) tablet is approved in North...... America and throughout Europe for the treatment of adults and children (≥5 years old) with grass pollen-induced ARC. OBJECTIVE: The clinical evidence for the use of SQ grass SLIT-tablet as a disease-modifying treatment for grass pollen ARC is discussed in this review. METHODS: The review included...... the suitability of SQ grass SLIT-tablet for patients with clinically relevant symptoms to multiple Pooideae grass species, single-season efficacy, safety, adherence, coseasonal initiation, and cost-effectiveness. The data from the long-term SQ grass SLIT-tablet clinical trial that evaluated a clinical effect 2...

Physical Activity and Telomere Biology: Exploring the Link with Aging-Related Disease Prevention

Directory of Open Access Journals (Sweden)

Andrew T. Ludlow

2011-01-01

Full Text Available Physical activity is associated with reduced risk of several age-related diseases as well as with increased longevity in both rodents and humans. Though these associations are well established, evidence of the molecular and cellular factors associated with reduced disease risk and increased longevity resulting from physical activity is sparse. A long-standing hypothesis of aging is the telomere hypothesis: as a cell divides, telomeres shorten resulting eventually in replicative senescence and an aged phenotype. Several reports have recently associated telomeres and telomere-related proteins to diseases associated with physical inactivity and aging including cardiovascular disease, insulin resistance, and hypertension. Interestingly several reports have also shown that longer telomeres are associated with higher physical activity levels, indicating a potential mechanistic link between physical activity, reduced age-related disease risk, and longevity. The primary purpose of this review is to discuss the potential importance of physical activity in telomere biology in the context of inactivity- and age-related diseases. A secondary purpose is to explore potential mechanisms and important avenues for future research in the field of telomeres and diseases associated with physical inactivity and aging.

Biologics in pediatric psoriasis - efficacy and safety.

Science.gov (United States)

Dogra, Sunil; Mahajan, Rahul

2018-01-01

Childhood psoriasis is a special situation that is a management challenge for the treating dermatologist. As is the situation with traditional systemic agents, which are commonly used in managing severe psoriasis in children, the biologics are being increasingly used in the recalcitrant disease despite limited data on long term safety. Areas covered: We performed an extensive literature search to collect evidence-based data on the use of biologics in pediatric psoriasis. The relevant literature published from 2000 to September 2017 was obtained from PubMed, using the MeSH words 'biologics', 'biologic response modifiers' and 'treatment of pediatric/childhood psoriasis'. All clinical trials, randomized double-blind or single-blind controlled trials, open-label studies, retrospective studies, reviews, case reports and letters concerning the use of biologics in pediatric psoriasis were screened. Articles covering the use of biologics in pediatric psoriasis were screened and reference lists in the selected articles were scrutinized to identify other relevant articles that had not been found in the initial search. Articles without relevant information about biologics in general (e.g. its mechanism of action, pharmacokinetics and adverse effects) and its use in psoriasis in particular were excluded. We screened 427 articles and finally selected 41 relevant articles. Expert opinion: The available literature on the use of biologics such as anti-tumor necrosis factor (TNF)-α agents, and anti-IL-12/23 agents like ustekinumab suggests that these are effective and safe in managing severe pediatric psoriasis although there is an urgent need to generate more safety data. Dermatologists must be careful about the potential adverse effects of the biologics before administering them to children with psoriasis. It is likely that with rapidly evolving scenario of biologics in psoriasis, these will prove to be very useful molecules particularly in managing severe and recalcitrant

Genetic susceptibility to infectious disease: lessons from mouse models of leishmaniasis

Czech Academy of Sciences Publication Activity Database

Lipoldová, Marie; Demant, P.

2006-01-01

Roč. 7, č. 4 (2006), s. 294-305 ISSN 1471-0056 R&D Projects: GA ČR(CZ) GA310/03/1381 Grant - others:Howard Hughes Medical Institute(US) HHMI55000323 Institutional research plan: CEZ:AV0Z50520514 Keywords : leishmaniasis * susceptibility to infectious disease * modifying genes Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 22.947, year: 2006

Biological Behavior of Osteoblast Cell and Apatite Forming Ability of the Surface Modified Ti Alloys.

Science.gov (United States)

Zhao, Jingming; Hwang, K H; Choi, W S; Shin, S J; Lee, J K

2016-02-01

Titanium as one kind of biomaterials comes in direct contact with the body, making evaluation of biocompatibility an important aspect to biomaterials development. Surface chemistry of titanium plays an important role in osseointegration. Different surface modification alters the surface chemistry and result in different biological response. In this study, three kinds of mixed acid solutions were used to treat Ti specimens to induce Ca-P formation. Following a strong mixed acid activation process, Ca-P coating successfully formed on the Ti surfaces in simulated body fluid. Strong mixed acid increased the roughness of the metal surface, because the porous and rough surface allows better adhesion between Ca-P coatings and substrates. After modification of titanium surface by mixed acidic solution and subsequently H2O2/HCL treatment evaluation of biocompatibility was conducted from hydroxyapatite formation by biomimetic process and cell viability on modified titanium surface. Nano-scale modification of titanium surfaces can alter cellular and tissue responses, which may benefit osseointegration and dental implant therapy. Results from this study indicated that surface treatment methods affect the surface morphology, type of TiO2 layer formed and subsequent apatite deposition and biological responses. The thermo scientific alamarblue cell viability assay reagent is used to quantitatively measure the viability of mammalian cell lines, bacteria and fungi by incorporating a rapid, sensitive and reliable fluorometric/colorimetric growth indicator, without any toxic and side effect to cell line. In addition, mixed acid treatment uses a lower temperature and shorter time period than widely used alkali treatment.

Human procollagen type I surface-modified PHB-based non-woven textile scaffolds for cell growth: preparation and short-term biological tests

International Nuclear Information System (INIS)

Kawalec, Michał; Sobota, Michał; Kurcok, Piotr; Sitkowska, Anna; Sieroń, Aleksander L; Komar, Patrycja

2014-01-01

3D fine porous structures obtained by electrospinning a poly[(R,S)-3-hydroxybutyrate] (aPHB)/ poly[(R)-3-hydroxybutyrate] (PHB) (85/15 w/w) blend were successfully modified with human procollagen type I by simple immersion of the polyester scaffold in an aqueous solution of the protein. Effective modification of the scaffold with human procollagen I was confirmed by an immunodetection test, which revealed the presence of the procollagen type I as an outer layer even on inner structures of the porous matrixes. Biological tests of 3D fabrics made of the PHB blend provide support for the adhesion and proliferation of human fibroblasts, while their modification with procollagen type I increased the biocompatibility of the final scaffolds significantly, as shown by the notable increase in the number of attached cells during the early hours of their incubation. Based on these findings, human procollagen type I surface-modified aPHB/PHB scaffolds should be considered a promising material in regenerative medicine. (paper)

EOSINOPHILS: MULTIFACETED BIOLOGIC PROPERTIES AND ROLES IN HEALTH AND DISEASE

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Kita, Hirohito

2011-01-01

Summary Eosinophils are leukocytes resident in mucosal tissues. During Th2-type inflammation, eosinophils are recruited from bone marrow and blood to the sites of immune response. While eosinophils have been considered end-stage cells involved in host protection against parasite infection and immunopathology in hypersensitivity disease, recent studies changed this perspective. Eosinophils are now considered multifunctional leukocytes involved in tissue homeostasis, modulation of adaptive immune responses, and innate immunity to certain microbes. Eosinophils are capable of producing immunoregulatory cytokines and are actively involved in regulation of Th2-type immune responses. However, such new information does not preclude earlier observations showing that eosinophils, in particular human eosinophils, are also effector cells with pro-inflammatory and destructive capabilities. Eosinophils with activation phenotypes are observed in biological specimens from patients with disease, and deposition of eosinophil products is readily seen in the affected tissues from these patients. Therefore, it would be reasonable to consider the eosinophil a multifaceted leukocyte that contributes to various physiological and pathological processes depending on their location and activation status. This review summarizes the emerging concept of the multifaceted immunobiology of eosinophils and discusses the roles of eosinophils in health and disease and the challenges and perspectives in the field. PMID:21682744

Electrochemical Cathodic Polarization, a Simplified Method That Can Modified and Increase the Biological Activity of Titanium Surfaces: A Systematic Review.

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Jose Carlos Bernedo Alcazar

Full Text Available The cathodic polarization seems to be an electrochemical method capable of modifying and coat biomolecules on titanium surfaces, improving the surface activity and promoting better biological responses.The aim of the systematic review is to assess the scientific literature to evaluate the cellular response produced by treatment of titanium surfaces by applying the cathodic polarization technique.The literature search was performed in several databases including PubMed, Web of Science, Scopus, Science Direct, Scielo and EBSCO Host, until June 2016, with no limits used. Eligibility criteria were used and quality assessment was performed following slightly modified ARRIVE and SYRCLE guidelines for cellular studies and animal research.Thirteen studies accomplished the inclusion criteria and were considered in the review. The quality of reporting studies in animal models was low and for the in vitro studies it was high. The in vitro and in vivo results reported that the use of cathodic polarization promoted hydride surfaces, effective deposition, and adhesion of the coated biomolecules. In the experimental groups that used the electrochemical method, cellular viability, proliferation, adhesion, differentiation, or bone growth were better or comparable with the control groups.The use of the cathodic polarization method to modify titanium surfaces seems to be an interesting method that could produce active layers and consequently enhance cellular response, in vitro and in vivo animal model studies.

Portuguese guidelines for the use of biological agents in rheumatoid arthritis - October 2011 update.

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Fonseca, João Eurico; Bernardes, Miguel; Canhão, Helena; Santos, Maria José; Quintal, Alberto; Malcata, Armando; Neto, Adriano; Cordeiro, Ana; Rodrigues, Ana; Mourão, Ana Filipa; Ribeiro, Ana Sofia; Cravo, Ana Rita; Barcelos, Anabela; Cardoso, Anabela; Vilar, António; Braña, Arecili; Faustino, Augusto; Silva, Candida; Duarte, Cátia; Araújo, Domingos; Nour, Dolores; Sousa, Elsa; Simões, Eugénia; Godinho, Fátima; Brandão, Filipe; Ventura, Francisco; Sequeira, Graça; Figueiredo, Guilherme; Cunha, Inês; Matos, J Alves; Branco, Jaime; Ramos, João; Costa, José António; Gomes, José António; Pinto, José; Silva, José Canas; Silva, J A; Patto, José Vaz; Costa, Lúcia; Miranda, Luís Cunha; Inês, Luís; Santos, Luís Maurício; Cruz, Margarida; Salvador, Maria João; Ferreira, Maria Júlia; Rial, Maria; Queiroz, Mário Viana; Bogas, Mónica; Araújo, Paula; Reis, Paulo; Abreu, Pedro; Machado, Pedro; Pinto, Patrícia; André, Rui; Melo, Rui; Garcês, Sandra; Cortes, Sara; Alcino, Sérgio; Ramiro, Sofia; Capela, Susana

2011-01-01

The authors present the revised version of the Portuguese Society of Rheumatology (SPR) guidelines for the treatment of Rheumatoid Arthritis (RA) with biological therapies. In these guidelines the criteria for introduction and maintenance of biological agents are discussed as well as the contraindications and procedures in the case of nonresponders. Biological treatment (with a tumour necrosis factor antagonist, abatacept or tocilizumab) should be considered in RA patients with a disease activity score 28 (DAS 28) equal to or greater than 3.2 despite treatment with at least 20mg-weekly-dose of methotrexate (MTX) for at least 3 months or, if such treatment is not possible, after 3 months of other conventional disease modifying drug or combination therapy. A DAS 28 score between 2.6 and 3.2 with a significant functional or radiological deterioration under treatment with conventional regimens could also constitute an indication for biological treatment. The treatment goal should be remission or, if that is not achievable, at least a low disease activity, defined by a DAS28 lower than 3.2, without significative functional or radiological worsening. The response criteria, at the end of the first 3 months of treatment, are a decrease of at least 0.6 in the DAS28 score. After 6 months of treatment res­ponse criteria is defined as a decrease greater than 1.2 in the DAS28 score. Non-responders, in accordance to the Rheumatologist’s clinical opinion, should try a switch to another biological agent (tumour necrosis factor antagonist, abatacept, rituximab or tocilizumab).

Comparing Effects of Biologic Agents in Treating Patients with Rheumatoid Arthritis: A Multiple Treatment Comparison Regression Analysis.

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Ingunn Fride Tvete

Full Text Available Rheumatoid arthritis patients have been treated with disease modifying anti-rheumatic drugs (DMARDs and the newer biologic drugs. We sought to compare and rank the biologics with respect to efficacy. We performed a literature search identifying 54 publications encompassing 9 biologics. We conducted a multiple treatment comparison regression analysis letting the number experiencing a 50% improvement on the ACR score be dependent upon dose level and disease duration for assessing the comparable relative effect between biologics and placebo or DMARD. The analysis embraced all treatment and comparator arms over all publications. Hence, all measured effects of any biologic agent contributed to the comparison of all biologic agents relative to each other either given alone or combined with DMARD. We found the drug effect to be dependent on dose level, but not on disease duration, and the impact of a high versus low dose level was the same for all drugs (higher doses indicated a higher frequency of ACR50 scores. The ranking of the drugs when given without DMARD was certolizumab (ranked highest, etanercept, tocilizumab/ abatacept and adalimumab. The ranking of the drugs when given with DMARD was certolizumab (ranked highest, tocilizumab, anakinra/rituximab, golimumab/ infliximab/ abatacept, adalimumab/ etanercept [corrected]. Still, all drugs were effective. All biologic agents were effective compared to placebo, with certolizumab the most effective and adalimumab (without DMARD treatment and adalimumab/ etanercept (combined with DMARD treatment the least effective. The drugs were in general more effective, except for etanercept, when given together with DMARDs.

Exemplary Programs in Secondary School Biology.

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McComas, William F.; Penick, John E.

1989-01-01

Summarizes 10 exemplary programs which address topics on individualized biology, a modified team approach, limnology, physical anthropology, the relevance of biology to society, ecology, and health. Provides names and addresses of contact persons for further information. Units cover a broad range of abilities and activities. (RT)

Glycogen storage disease type III: modified Atkins diet improves myopathy.

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Mayorandan, Sebene; Meyer, Uta; Hartmann, Hans; Das, Anibh Martin

2014-11-28

Frequent feeds with carbohydrate-rich meals or continuous enteral feeding has been the therapy of choice in glycogen storage disease (Glycogenosis) type III. Recent guidelines on diagnosis and management recommend frequent feedings with high complex carbohydrates or cornstarch avoiding fasting in children, while in adults a low-carb-high-protein-diet is recommended. While this regimen can prevent hypoglycaemia in children it does not improve skeletal and heart muscle function, which are compromised in patients with glycogenosis IIIa. Administration of carbohydrates may elicit reactive hyperinsulinism, resulting in suppression of lipolysis, ketogenesis, gluconeogenesis, and activation of glycogen synthesis. Thus, heart and skeletal muscle are depleted of energy substrates. Modified Atkins diet leads to increased blood levels of ketone bodies and fatty acids. We hypothesize that this health care intervention improves the energetic balance of muscles. We treated 2 boys with glycogenosis IIIa aged 9 and 11 years with a modified Atkins diet (10 g carbohydrate per day, protein and fatty acids ad libitum) over a period of 32 and 26 months, respectively. In both patients, creatine kinase levels in blood dropped in response to Atkins diet. When diet was withdrawn in one of the patients he complained of chest pain, reduced physical strength and creatine kinase levels rapidly increased. This was reversed when Atkins diet was reintroduced. One patient suffered from severe cardiomyopathy which significantly improved under diet. Patients with glycogenosis IIIa benefit from an improved energetic state of heart and skeletal muscle by introduction of Atkins diet both on a biochemical and clinical level. Apart from transient hypoglycaemia no serious adverse effects were observed.

Identification of Novel Fibrosis Modifiers by In Vivo siRNA Silencing

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Elisabeth H. Vollmann

2017-06-01

Full Text Available Fibrotic diseases contribute to 45% of deaths in the industrialized world, and therefore a better understanding of the pathophysiological mechanisms underlying tissue fibrosis is sorely needed. We aimed to identify novel modifiers of tissue fibrosis expressed by myofibroblasts and their progenitors in their disease microenvironment through RNA silencing in vivo. We leveraged novel biology, targeting genes upregulated during liver and kidney fibrosis in this cell lineage, and employed small interfering RNA (siRNA-formulated lipid nanoparticles technology to silence these genes in carbon-tetrachloride-induced liver fibrosis in mice. We identified five genes, Egr2, Atp1a2, Fkbp10, Fstl1, and Has2, which modified fibrogenesis based on their silencing, resulting in reduced Col1a1 mRNA levels and collagen accumulation in the liver. These genes fell into different groups based on the effects of their silencing on a transcriptional mini-array and histological outcomes. Silencing of Egr2 had the broadest effects in vivo and also reduced fibrogenic gene expression in a human fibroblast cell line. Prior to our study, Egr2, Atp1a2, and Fkbp10 had not been functionally validated in fibrosis in vivo. Thus, our results provide a major advance over the existing knowledge of fibrogenic pathways. Our study is the first example of a targeted siRNA assay to identify novel fibrosis modifiers in vivo.

Enhancing the role of veterinary vaccines reducing zoonotic diseases of humans: Linking systems biology with vaccine development

Energy Technology Data Exchange (ETDEWEB)

Adams, Leslie G.; Khare, Sangeeta; Lawhon, Sara D.; Rossetti, Carlos A.; Lewin, Harris A.; Lipton, Mary S.; Turse, Joshua E.; Wylie, Dennis C.; Bai, Yu; Drake, Kenneth L.

2011-09-22

The aim of research on infectious diseases is their prevention, and brucellosis and salmonellosis as such are classic examples of worldwide zoonoses for application of a systems biology approach for enhanced rational vaccine development. When used optimally, vaccines prevent disease manifestations, reduce transmission of disease, decrease the need for pharmaceutical intervention, and improve the health and welfare of animals, as well as indirectly protecting against zoonotic diseases of people. Advances in the last decade or so using comprehensive systems biology approaches linking genomics, proteomics, bioinformatics, and biotechnology with immunology, pathogenesis and vaccine formulation and delivery are expected to enable enhanced approaches to vaccine development. The goal of this paper is to evaluate the role of computational systems biology analysis of host:pathogen interactions (the interactome) as a tool for enhanced rational design of vaccines. Systems biology is bringing a new, more robust approach to veterinary vaccine design based upon a deeper understanding of the host pathogen interactions and its impact on the host's molecular network of the immune system. A computational systems biology method was utilized to create interactome models of the host responses to Brucella melitensis (BMEL), Mycobacterium avium paratuberculosis (MAP), Salmonella enterica Typhimurium (STM), and a Salmonella mutant (isogenic *sipA, sopABDE2) and linked to the basis for rational development of vaccines for brucellosis and salmonellosis as reviewed by Adams et al. and Ficht et al. [1,2]. A bovine ligated ileal loop biological model was established to capture the host gene expression response at multiple time points post infection. New methods based on Dynamic Bayesian Network (DBN) machine learning were employed to conduct a comparative pathogenicity analysis of 219 signaling and metabolic pathways and 1620 gene ontology (GO) categories that defined the host

The Role of Histone Protein Modifications and Mutations in Histone Modifiers in Pediatric B-Cell Progenitor Acute Lymphoblastic Leukemia

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Janczar, Szymon; Janczar, Karolina; Pastorczak, Agata; Harb, Hani; Paige, Adam J. W.; Zalewska-Szewczyk, Beata; Danilewicz, Marian; Mlynarski, Wojciech

2017-01-01

While cancer has been long recognized as a disease of the genome, the importance of epigenetic mechanisms in neoplasia was acknowledged more recently. The most active epigenetic marks are DNA methylation and histone protein modifications and they are involved in basic biological phenomena in every cell. Their role in tumorigenesis is stressed by recent unbiased large-scale studies providing evidence that several epigenetic modifiers are recurrently mutated or frequently dysregulated in multiple cancers. The interest in epigenetic marks is especially due to the fact that they are potentially reversible and thus druggable. In B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) there is a relative paucity of reports on the role of histone protein modifications (acetylation, methylation, phosphorylation) as compared to acute myeloid leukemia, T-cell ALL, or other hematologic cancers, and in this setting chromatin modifications are relatively less well studied and reviewed than DNA methylation. In this paper, we discuss the biomarker associations and evidence for a driver role of dysregulated global and loci-specific histone marks, as well as mutations in epigenetic modifiers in BCP-ALL. Examples of chromatin modifiers recurrently mutated/disrupted in BCP-ALL and associated with disease outcomes include MLL1, CREBBP, NSD2, and SETD2. Altered histone marks and histone modifiers and readers may play a particular role in disease chemoresistance and relapse. We also suggest that epigenetic regulation of B-cell differentiation may have parallel roles in leukemogenesis. PMID:28054944

A SNP in the HTT promoter alters NF-κB binding and is a bidirectional genetic modifier of Huntington disease.

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Bečanović, Kristina; Nørremølle, Anne; Neal, Scott J; Kay, Chris; Collins, Jennifer A; Arenillas, David; Lilja, Tobias; Gaudenzi, Giulia; Manoharan, Shiana; Doty, Crystal N; Beck, Jessalyn; Lahiri, Nayana; Portales-Casamar, Elodie; Warby, Simon C; Connolly, Colúm; De Souza, Rebecca A G; Tabrizi, Sarah J; Hermanson, Ola; Langbehn, Douglas R; Hayden, Michael R; Wasserman, Wyeth W; Leavitt, Blair R

2015-06-01

Cis-regulatory variants that alter gene expression can modify disease expressivity, but none have previously been identified in Huntington disease (HD). Here we provide in vivo evidence in HD patients that cis-regulatory variants in the HTT promoter are bidirectional modifiers of HD age of onset. HTT promoter analysis identified a NF-κB binding site that regulates HTT promoter transcriptional activity. A non-coding SNP, rs13102260:G > A, in this binding site impaired NF-κB binding and reduced HTT transcriptional activity and HTT protein expression. The presence of the rs13102260 minor (A) variant on the HD disease allele was associated with delayed age of onset in familial cases, whereas the presence of the rs13102260 (A) variant on the wild-type HTT allele was associated with earlier age of onset in HD patients in an extreme case-based cohort. Our findings suggest a previously unknown mechanism linking allele-specific effects of rs13102260 on HTT expression to HD age of onset and have implications for HTT silencing treatments that are currently in development.

Effects of Immunomodulators and Biologic Agents on Sexual Health in Patients With Inflammatory Bowel Disease.

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Kanar, Ozdemir; Berry, Andrew C; Nakshabendi, Rahman; Lee, Ann Joo; Aldridge, Petra; Myers, Travis; Eid, Emely

2017-01-01

Although much knowledge has been gained regarding the medical and surgical management of inflammatory bowel disease (IBD), a paucity of information is available on the psychosexual issues related to IBD. The aim of this study was to evaluate the sexual health of patients with IBD who were taking immunomodulators and/or biologic agents vs patients with IBD who were not on that medication regimen. All study participants completed a validated sexual health questionnaire, the Female Sexual Function Index or the International Index of Erectile Function, to assess their subjective perception of the effect of IBD on the different domains of sexual function during the prior 1-month time period. No statistically significant differences in any baseline demographic variables were found for either sex between the group taking immunomodulators/biologic agents and the nontreatment group. Among females and males, individual question responses, domain scores, and total scores showed no statistically significant differences between the 2 treatment groups. Our data suggest that the use of immunomodulators or biologic agents does not affect female or male sexual health. However, treatment of patients with IBD must be individualized based on the aggressive nature of the disease, treatment goals, and the tolerability of various medications.

Frequency of the use of biological treatment of patients with rheumatoid arthritis and ankylosing spondylitis in Lower Silesia

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Wojciech Tański

2016-09-01

Full Text Available Background: Rheumatoid arthritis (RA and ankylosing spondylitis (AS are chronic connective tissue diseases. Inadequate treatment of RA and AS results in health failure, disability and premature death. In recent years, development of immunology and genetic engineering techniques has started a new generation of drugs in the treatment of RA and AS, called biologic response modifiers or biologics. It is a very effective therapy of serious RA and AS. In many cases, they represent the only way to improve the quality of life, slowing or even arresting the development of these diseases. According to national statistics, the percentage of patients with rheumatic diseases treated with biologic treatment in Poland is less than 1.5%, and it is much lower than in Western European countries (20%.Purpose: The aim of the study was to evaluate the use of biological treatment in Lower Silesia in patients with RA and AS in the years 2006-2015, based on data obtained from the Lower Silesian Branch of the Polish National Health Fund.Results and conclusions: In the last 10 years the frequency of biological treatment of RA or AS in Lower Silesia was estimated as 2.06% of patients (in 2011 to 6.03% of patients (during the first 8 months of 2015. Biological treatment is more often used in Lower Silesia in comparison to national statistics and ranks at a similar level as in other countries of Central and Eastern Europe.

Introduction to radiation biology

International Nuclear Information System (INIS)

Uma Devi, P.; Satish Rao, B.S.; Nagarathnam, A.

2000-01-01

This book is arranged in a logical sequence, starting from radiation physics and radiation chemistry, followed by molecular, subcellular and cellular effects and going on to the level of organism. Topics covered include applied radiobiology like modifiers of radiosensitivity, predictive assay, health physics, human genetics and radiopharmaceuticals. The topics covered are : 1. Radiation Physics, 2. Detection and Measurement of Radiation, 3. Radiation Chemistry, 4. DNA Damage and Repair, 5. Chromosomal Aberrations and Gene Mutations, 6. Cellular Radiobiology 7. Acute Radiation Effects, 8. Delayed Effects of Radiation, 9. Biological Basis of Radiotherapy, 10. Chemical Modifiers of Radiosensitivity, 11. Hyperthermia, 12. High LET Radiations in Cancer, Therapy, 13. Predictive Assays, 14. Radiation Effects on Embryos, 15. Human Radiation Genetics, 16. Radiolabelled Compounds in Biology and Medicine and 17. Radiological Health

Biological Treatments in Behçet’s Disease: Beyond Anti-TNF Therapy

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Francesco Caso

2014-01-01

Full Text Available Behçet’s disease (BD is universally recognized as a multisystemic inflammatory disease of unknown etiology with chronic course and unpredictable exacerbations: its clinical spectrum varies from pure vasculitic manifestations with thrombotic complications to protean inflammatory involvement of multiple organs and tissues. Treatment has been revolutionized by the progressed knowledge in the pathogenetic mechanisms of BD, involving dysfunction and oversecretion of multiple proinflammatory molecules, chiefly tumor necrosis factor- (TNF- α, interleukin- (IL- 1β, and IL-6. However, although biological treatment with anti-TNF-α agents has been largely demonstrated to be effective in BD, not all patients are definite responders, and this beneficial response might drop off over time. Therefore, additional therapies for a subset of refractory patients with BD are inevitably needed. Different agents targeting various cytokines and their receptors or cell surface molecules have been studied: the IL-1 receptor has been targeted by anakinra, the IL-1 by canakinumab and gevokizumab, the IL-6 receptor by tocilizumab, the IL12/23 receptor by ustekinumab, and the B-lymphocyte antigen CD-20 by rituximab. The aim of this review is to summarize all current experiences and the most recent evidence regarding these novel approaches with biological drugs other than TNF-α blockers in BD, providing a valuable addition to the actually available therapeutic armamentarium.

[Application of Ischemia Modified Albumin for Acute Ischemic Heart Disease in Forensic Science].

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Wang, P; Zhu, Z L; Zhu, N; Yu, H; Yue, Q; Wang, X L; Feng, C M; Wang, C L; Zhang, G H

2017-10-01

To explore the application value and forensic significance of ischemia modified albumin （IMA） in pericardial fluid to diagnose sudden cardiac death. IMA level in pericardial fluid was detected in acute ischemic heart disease group （ n =36）, acute myocardial infarction group （ n =6）, cardiomyopathy group （ n =4） and control group （ n =15） by albumin cobalt binding method. The levels of IMA were compared among these groups. The best cut-off IMA value was estimated and the sensitivity and specificity of acute myocardial ischemia group was distinguished from control group by receiver operating characteristics （ROC） curve. The IMA level in acute ischemic heart disease group was significantly higher than that of control group （ P 0.05）. The cut-off value for the identification of acute myocardial ischemia which obtained by ROC analysis was 40.65 U/mL. And the sensitivity and specificity for distinguishing acute ischemia cardiac disease was 60.0% and 80.5%, respectively. The IMA value in pericardial fluid can be a reference marker for the diagnosis of acute myocardial ischemia, which also can provide objective basis for the forensic identification of sudden cardiac death. Copyright© by the Editorial Department of Journal of Forensic Medicine

Correlation between the Modified Systemic Lupus Erythematosus Disease Activity Index 2000 and the European Consensus Lupus Activity Measurement in juvenile systemic lupus erythematosus.

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Sato, J O; Corrente, J E; Saad-Magalhães, C

2016-11-01

Objective The objective of this study was to assess Modified Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and European Consensus Lupus Activity Measurement (ECLAM) disease activity correlation in addition to their respective correlation to Pediatric Systemic Lupus International Collaborative Clinics/American College of Rheumatology (SLICC/ACR) Damage Index (Ped-SDI), in juvenile systemic lupus erythematosus (JSLE). Methods The activity indices were scored retrospectively and summarized by adjusted means during follow-up. The Ped-SDI was scored during the last visit for those with more than six months follow-up. Pearson correlation between the Modified SLEDAI-2K and ECLAM, as well as Spearman correlations between the Modified SLEDAI-2K, ECLAM, and Ped-SDI were calculated. The receiver operating characteristic (ROC) curve was calculated for both activity indices discriminating damage measured by Ped-SDI. Results Thirty-seven patients with mean age at diagnosis 11 ± 2.9 years and mean follow-up time 3.2 ± 2.4 years were studied. The Modified SLEDAI-2K and ECLAM adjusted means were highly correlated ( r = 0.78, p  0.7, p < 0.001), but Modified SLEDAI-2K and ECLAM correlation with Ped-SDI was only moderate. ROC analysis discriminant performance for both activity indices resulted in area under curve (AUC) of 0.74 and 0.73 for Modified SLEDAI-2K and ECLAM, respectively. Conclusion The high correlation found between the Modified SLEDAI-2K and ECLAM adjusted means indicated that both tools can be equally useful for longitudinal estimates of JSLE activity.

New perspectives on Mars and Venus: unravelling the role of androgens in gender differences in cardiovascular biology and disease.

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Ng, Martin K C

2007-06-01

There are substantial gender differences in the pattern, severity and clinical outcomes of coronary heart disease independent of environmental risk factor exposure. As a consequence, there has been considerable interest in the potential role of sex hormones in atherogenesis, particularly the potential protective effects of oestrogen. However, the failure of the recent clinical randomised trials to show a cardioprotective effect for oestrogen coupled with a growing interest in androgen replacement therapy in elderly men has refocused interest on the role of androgens in cardiovascular biology and disease. Over the last decade, compelling evidence has emerged that sex differences in vascular biology are not only determined by gender-related differences in sex steroid levels but also by gender-specific tissue and cellular characteristics which mediate sex-specific responses to a variety of stimuli. In the vasculature, androgens often act in a gender-specific manner, with differential effects in male and female cells. This gender-dependent regulation may have important implications for understanding the basis of the gender gap in atherosclerosis and may eventually lead to the development of sex-specific treatments for cardiovascular disease. This review will summarise the current data for the role of androgens in gender differences in coronary heart disease and cardiovascular biology.

Pathway reconstruction of airway remodeling in chronic lung diseases: a systems biology approach.

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Ali Najafi

Full Text Available Airway remodeling is a pathophysiologic process at the clinical, cellular, and molecular level relating to chronic obstructive airway diseases such as chronic obstructive pulmonary disease (COPD, asthma and mustard lung. These diseases are associated with the dysregulation of multiple molecular pathways in the airway cells. Little progress has so far been made in discovering the molecular causes of complex disease in a holistic systems manner. Therefore, pathway and network reconstruction is an essential part of a systems biology approach to solve this challenging problem. In this paper, multiple data sources were used to construct the molecular process of airway remodeling pathway in mustard lung as a model of airway disease. We first compiled a master list of genes that change with airway remodeling in the mustard lung disease and then reconstructed the pathway by generating and merging the protein-protein interaction and the gene regulatory networks. Experimental observations and literature mining were used to identify and validate the master list. The outcome of this paper can provide valuable information about closely related chronic obstructive airway diseases which are of great importance for biologists and their future research. Reconstructing the airway remodeling interactome provides a starting point and reference for the future experimental study of mustard lung, and further analysis and development of these maps will be critical to understanding airway diseases in patients.

Phenotypic charactheristics of fluorescent pseudomonss, biological control agent of lincat disease of temanggung tobacco

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NINING NURUL AZIZAH

2007-04-01

Full Text Available Fluorescent pseudomonass isolated from local plants-rishosphere in temanggung controlled lincat disease of tobacco. This report describe phenotypic charactheristics of the bacteria in order to be used as a base for the development of the bacteria as a biological control agent of lincat disease. Phenotypic charactheristics of six isolates of fluorescent Pseudomonass which controlled lincat disease in the field were determined in the laboratory of Plant Bacteriology, Faculty of Agriculture, Gadjah Mada University. Plant pathogenicity tests were conducted by hypersensitive reaction into tobacco leaf and inoculation to tobacco plants. Antagonism test between fluorescent Pseudomonass and other candidate of biological control agents were also conducted. The results indicated that the bacteria were rod shape, Gram negative, positive reaction in catalase and oxidase tests. Nitrate reduce to nitrite, arginine was hydrolysed, fluorescent pigment were produced on King’s B medium, levan formation positive and all bacteria denitrifiy. The bacteria used urea, tween 80 and amylum were not hydrolised, poly--hydroxybutyrate was not accumulated in the cells. Negative reactions were observed for lysine decarboxylation, indol production, VP/MR reaction, and gelatn liquefation. Some compounds could be used as solely carbon sources. All isolates grew on the medium containing 2% NaCl. The best pH for growth was 6-7 and all isolates grew at 20-41C. Negative result were obtained for hypersensitive reaction and pathogenicity tests.

Interstitial Lung Disease in Rheumatoid Arthritis in the Era of Biologics

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A. Picchianti Diamanti

2011-01-01

Full Text Available Interstitial lung disease (ILD represents a severe manifestation in connective tissue diseases (CTD, with an overall incidence of 15%, and it is still a challenge for clinicians evaluation and management. ILD is the most common manifestation of lung involvement in Rheumatoid Arthritis (RA, observed in up to 80% of biopsies, 50% of chest Computed Tomography (CT and only 5% of chest radiographs. Histopatological patterns of ILD in RA may present with different patterns, such as: usual interstitial pneumonia, non specific interstitial pneumonia, desquamative interstitial pneumonia, organizing pneumonia, and eosinophilic infiltration. The incidence of ILD in RA patients is not only related to the disease itself, many drugs may be in fact associated with the development of pulmonary damage. Some reports suggest a causative role for TNFα inhibitors in RA-ILD development/worsening, anyway, no definitive statement can be drawn thus data are incomplete and affected by several variables. A tight control (pulmonary function tests and/or HRCT is mandatory in patients with preexisting ILD, but it should be also performed in those presenting risk factors for ILD and mild respiratory symptoms. Biologic therapy should be interrupted, and, after excluding triggering infections, corticosteroids should be administered.

A modified Wright-Fisher model that incorporates Ne: A variant of the standard model with increased biological realism and reduced computational complexity.

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Zhao, Lei; Gossmann, Toni I; Waxman, David

2016-03-21

The Wright-Fisher model is an important model in evolutionary biology and population genetics. It has been applied in numerous analyses of finite populations with discrete generations. It is recognised that real populations can behave, in some key aspects, as though their size that is not the census size, N, but rather a smaller size, namely the effective population size, Ne. However, in the Wright-Fisher model, there is no distinction between the effective and census population sizes. Equivalently, we can say that in this model, Ne coincides with N. The Wright-Fisher model therefore lacks an important aspect of biological realism. Here, we present a method that allows Ne to be directly incorporated into the Wright-Fisher model. The modified model involves matrices whose size is determined by Ne. Thus apart from increased biological realism, the modified model also has reduced computational complexity, particularly so when Ne⪡N. For complex problems, it may be hard or impossible to numerically analyse the most commonly-used approximation of the Wright-Fisher model that incorporates Ne, namely the diffusion approximation. An alternative approach is simulation. However, the simulations need to be sufficiently detailed that they yield an effective size that is different to the census size. Simulations may also be time consuming and have attendant statistical errors. The method presented in this work may then be the only alternative to simulations, when Ne differs from N. We illustrate the straightforward application of the method to some problems involving allele fixation and the determination of the equilibrium site frequency spectrum. We then apply the method to the problem of fixation when three alleles are segregating in a population. This latter problem is significantly more complex than a two allele problem and since the diffusion equation cannot be numerically solved, the only other way Ne can be incorporated into the analysis is by simulation. We have

Variations in the Biological Functions of HIV-1 Clade C Envelope in a SHIV-Infected Rhesus Macaque during Disease Progression.

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For Yue Tso

Full Text Available A better understanding of how the biological functions of the HIV-1 envelope (Env changes during disease progression may aid the design of an efficacious anti-HIV-1 vaccine. Although studies from patient had provided some insights on this issue, the differences in the study cohorts and methodology had make it difficult to reach a consensus of the variations in the HIV-1 Env functions during disease progression. To this end, an animal model that can be infected under controlled environment and reflect the disease course of HIV-1 infection in human will be beneficial. Such an animal model was previously demonstrated by the infection of macaque with SHIV, expressing HIV-1 clade C Env V1-V5 region. By using this model, we examined the changes in biological functions of Env in the infected animal over the entire disease course. Our data showed an increase in the neutralization resistance phenotype over time and coincided with the decrease in the net charges of the V1-V5 region. Infection of PBMC with provirus expressing various Env clones, isolated from the infected animal over time, showed a surprisingly better replicative fitness for viruses expressing the Env from early time point. Biotinylation and ELISA data also indicated a decrease of cell-surface-associated Env and virion-associated gp120 content with disease progression. This decrease did not affect the CD4-binding capability of Env, but were positively correlated with the decrease of Env fusion ability. Interestingly, some of these changes in biological functions reverted to the pre-AIDS level during advance AIDS. These data suggested a dynamic relationship between the Env V1-V5 region with the host immune pressure. The observed changes of biological functions in this setting might reflect and predict those occurring during natural disease progression in human.

Trends in Modifiable Risk Factors Are Associated With Declining Incidence of Hospitalized and Nonhospitalized Acute Coronary Heart Disease in a Population.

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Mannsverk, Jan; Wilsgaard, Tom; Mathiesen, Ellisiv B; Løchen, Maja-Lisa; Rasmussen, Knut; Thelle, Dag S; Njølstad, Inger; Hopstock, Laila Arnesdatter; Bønaa, Kaare Harald

2016-01-05

Few studies have used individual person data to study whether contemporary trends in the incidence of coronary heart disease are associated with changes in modifiable coronary risk factors. We identified 29 582 healthy men and women ≥25 years of age who participated in 3 population surveys conducted between 1994 and 2008 in Tromsø, Norway. Age- and sex-adjusted incidence rates were calculated for coronary heart disease overall, out-of-hospital sudden death, and hospitalized ST-segment-elevation and non-ST-segment-elevation myocardial infarction. We measured coronary risk factors at each survey and estimated the relationship between changes in risk factors and changes in incidence trends. A total of 1845 participants had an incident acute coronary heart disease event during 375 064 person-years of follow-up from 1994 to 2010. The age- and sex-adjusted incidence of total coronary heart disease decreased by 3% (95% confidence interval, 2.0-4.0; Pcoronary risk factors accounted for 66% (95% confidence interval, 48-97; Pcoronary heart disease. Favorable changes in cholesterol contributed 32% to the decline, whereas blood pressure, smoking, and physical activity each contributed 14%, 13%, and 9%, respectively. We observed a substantial decline in the incidence of coronary heart disease that was driven by reductions in out-of-hospital sudden death and hospitalized ST-segment-elevation myocardial infarction. Changes in modifiable coronary risk factors accounted for 66% of the decline in coronary heart disease events. © 2015 American Heart Association, Inc.

Paving the way of systems biology and precision medicine in allergic diseases

DEFF Research Database (Denmark)

Bousquet, J; Anto, J M; Akdis, M

2016-01-01

or severity of allergic diseases. Environmental exposures are relevant for the development of allergy-related diseases. To complement the population-based studies in children, MeDALL included mechanistic experimental animal studies and in vitro studies in humans. The integration of multimorbidities......MeDALL (Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015) has proposed an innovative approach to develop early indicators for the prediction, diagnosis, prevention and targets for therapy. MeDALL has linked epidemiological, clinical and basic research using...... a stepwise, large-scale and integrative approach: MeDALL data of precisely phenotyped children followed in 14 birth cohorts spread across Europe were combined with systems biology (omics, IgE measurement using microarrays) and environmental data. Multimorbidity in the same child is more common than expected...

Biological and phylogenetic characterization of a genotype VII Newcastle disease virus from Venezuela: Efficacy of vaccination

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Here we describe the characterization a virulent genotype VII Newcastle disease virus (NDV) from Venezuela and evaluate the efficacy of heterologous genotype commercial vaccination under field and controlled rearing conditions. Biological pathotyping and molecular analysis were applied. Results sh...

Efficacy and safety of biological and targeted-synthetic DMARDs: a systematic literature review informing the 2016 update of the ASAS/EULAR recommendations for the management of axial spondyloarthritis

NARCIS (Netherlands)

Sepriano, Alexandre; Regel, Andrea; van der Heijde, Désirée; Braun, Jürgen; Baraliakos, Xenofon; Landewé, Robert; van den Bosch, Filip; Falzon, Louise; Ramiro, Sofia

2017-01-01

To update the evidence for the efficacy and safety of (b)biological and (ts)targeted-synthetic disease-modifying anti-rheumatic drugs (DMARDs) in patients with axial spondyloarthritis (axSpA) to inform the 2016 update of the Assessment of SpondyloArthritis international Society/European League

Most Trial Eligibility Criteria and Patient Baseline Characteristics Do Not Modify Treatment Effect in Trials Using Targeted Therapies for Rheumatoid Arthritis

DEFF Research Database (Denmark)

Christensen, Anton Wulf; Tarp, Simon; Furst, Daniel E

2015-01-01

OBJECTIVE: To determine if variations in trial eligibility criteria and patient baseline characteristics could be considered effect modifiers of the treatment response when testing targeted therapies (biological agents and targeted synthetic disease modifying antirheumatic drugs (DMARDs....... Odds ratios (ORs) were calculated from the response rates and compared among the trial eligibility criteria/patient baseline characteristics of interest. Comparisons are presented as the Ratio of Odds Ratios (ROR). RESULTS: Sixty-two trials (19,923 RA patients) were included in the primary analyses...... using ACR20 response. Overall, targeted therapies constituted an effective treatment (OR 3.96 95% confidence interval (CI) 3.41 to 4.60). The majority of the trial eligibility criteria and patient baseline characteristics did not modify treatment effect. The added benefit of targeted therapies was lower...

Reuma.pt - the rheumatic diseases portuguese register.

Science.gov (United States)

Canhão, H; Faustino, A; Martins, F; Fonseca, J E

2011-01-01

Since June 2008, Portuguese rheumatologists have been collecting on a routine basis, data into the nationwide Reuma.pt, the Rheumatic Diseases Portuguese Register from the Portuguese Society of Rheumatology (SPR), which includes rheumatic patients (rheumatoid arthritis - RA, ankylosing spondylitis - AS, psoriatic arthritis - PsA and juvenile idiopathic arthritis - JIA) receiving biological therapies or patients receiving synthetic disease modifying anti-rheumatic drugs (DMARDs). The aim of this publication is to describe the structure of Reuma.pt and the population registered since June 2008. Demographic and anthropometric data, life style habits, work status, co-morbidities, disease activity and functional assessment scores, previous and current therapies, adverse events codified by the Medical Dictionary for Regulatory Activities (MedDRA), reasons for discontinuation and laboratory measurements are registered at each visit. The platform is based on a structured electronic medical record linked to a SQL Server database. All Rheumatology Departments assigned to the Portuguese National Health Service (n=21), 2 Military Hospitals (Lisboa and Porto), 1 public-private Institution and 6 private centers adhered to the Register. Until now, 18 centers have entered data into Reuma.pt. By January 2011, 3438 patients and 16130 visits had been registered. 2162 (63%) were RA patients, 700 of them treated with biological agents and 1462 with synthetic DMARDs. From the 515 (15%) AS patients, 297 were medicated with biological and 218 with non-biological therapies. 293 (8%) were PsA patients, 151 treated with biological drugs and 142 with other treatment strategies. 368 (11%) had the diagnosis of JIA, 68 were under biological treatment and 300 were managed with other treatment options. The register also includes 100 (3%) patients with other rheumatic diseases, submitted to treatments that required hospital day care infusions including 18 exposed to biological therapies. Registers

Modified Hemocorrection in the Complex Treatment of Patients with Pyoinflammatory Lung Diseases

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V. V. Gavrikov

2007-01-01

Full Text Available Objective: To evaluate the efficiency of extracorporeal hemocorrection used in the complex therapy in patients with a pyoinflammatory process in the lung.Materials and methods: 62 patients, including 22 patients with lung abscess who underwent routine plasmapheresis and 40 patients with varying pyoinflammatory lung diseases who received modified hemocorrection — plasma exchange combined with laser extracorporeally washed-off cytomass irradiation, were examined and treated. The severity of their general condition was assessed by the SAPS scale and the severity of intoxication was evaluated by the content of low and medium-molecular weight substances (LMMWSs. The hemostatic system was studied by standardized studies.Results. Routine plasmapheresis was established to produce no impact on platelet functional activity within the first 24 hours and, three days later, promoted the progression of disseminated intravascular coagulation. A combination of plasma exchange and laser extracorporeally washed-off cytomass irradiation in patients with pyoinflam-matory lung diseases was attended by a lower blood coagulative activity and plasmin stabilization with attenuated throm-binemia. The plasma and erythrocytic levels of LMMWSs decreased and their urinary concentrations increased, which is indicative of the body’s detoxification block disorders irrespective of the severity of the disease.Conclusion. It is expedient to apply the plasma-exchanging technique in combination with laser extracorporeally washed-off cytomass irradiation to patients with the uncomplicated and complicated course of pulmonary pyoinflammatory processes without the signs of multiple organ dysfunction on admission to a specialized hospital. 

Translational environmental biology: cell biology informing conservation.

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Traylor-Knowles, Nikki; Palumbi, Stephen R

2014-05-01

Typically, findings from cell biology have been beneficial for preventing human disease. However, translational applications from cell biology can also be applied to conservation efforts, such as protecting coral reefs. Recent efforts to understand the cell biological mechanisms maintaining coral health such as innate immunity and acclimatization have prompted new developments in conservation. Similar to biomedicine, we urge that future efforts should focus on better frameworks for biomarker development to protect coral reefs. Copyright © 2014 Elsevier Ltd. All rights reserved.

Critical appraisal of the guidelines for the management of ankylosing spondylitis: disease-modifying antirheumatic drugs.

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Soriano, Enrique R; Clegg, Daniel O; Lisse, Jeffrey R

2012-05-01

Surprisingly, little data are available for the use of disease-modifying antirheumatic drugs in ankylosing spondylitis. Sulfasalazine has been the best studied. Efficacy data for individual agents (including pamidronate) and combinations of agents are detailed in this review. Intriguingly, these agents continue to be used with some frequency, even in the absence of efficacy data. To answer these questions, additional systematic studies of these agents in ankylosing spondylitis are needed and will likely need to be done by interested collaborative groups such as SPARTAN.

Biological Characteristics of Caspase-14 and Its Expression in Neoplastic Diseases in the View of Translational Medicine

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Kang-sheng LIU

2016-06-01

Full Text Available Caspase-14, a member of caspase family, only exists in mammals. As the most divergent member in the family of mammalian caspases, caspase-14 displays a variety of unique characteristics. It is expressed in a limited number of tissues and has the shortest amino acid sequence within the caspase protein family. At present, it has been found that caspase-14 is functionally different from the inflammatory reaction group of typical caspase family members. It exerts a certain effect in the promotion of final differentiation of epidermal cells and hydration of stratum corneum so as to maintain the steady state of skin barrier. In recent years, caspase-14 expression has been discovered in neoplastic diseases. Translational medicine integrates experimental research results and clinical guidance into the optimal implementation criteria for promoting the prediction, prevention and treatment of diseases. Via human genomics and molecular biology, translational medicine offers a possibility of screening molecular markers so that it can be used to diagnose the neoplastic diseases. In this article, the biological characteristics and substrates of caspase-14 as well as its expression in embryonic period and neoplastic diseases were reviewed.

Hydrophobically Modified siRNAs Silence Huntingtin mRNA in Primary Neurons and Mouse Brain

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Julia F Alterman

2015-01-01

Full Text Available Applications of RNA interference for neuroscience research have been limited by a lack of simple and efficient methods to deliver oligonucleotides to primary neurons in culture and to the brain. Here, we show that primary neurons rapidly internalize hydrophobically modified siRNAs (hsiRNAs added directly to the culture medium without lipid formulation. We identify functional hsiRNAs targeting the mRNA of huntingtin, the mutation of which is responsible for Huntington's disease, and show that direct uptake in neurons induces potent and specific silencing in vitro. Moreover, a single injection of unformulated hsiRNA into mouse brain silences Htt mRNA with minimal neuronal toxicity. Thus, hsiRNAs embody a class of therapeutic oligonucleotides that enable simple and straightforward functional studies of genes involved in neuronal biology and neurodegenerative disorders in a native biological context.

Proteins Encoded in Genomic Regions Associated with Immune-Mediated Disease Physically Interact and Suggest Underlying Biology

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Rossin, Elizabeth J.; Lage, Kasper; Raychaudhuri, Soumya; Xavier, Ramnik J.; Tatar, Diana; Benita, Yair

2011-01-01

Genome-wide association studies (GWAS) have defined over 150 genomic regions unequivocally containing variation predisposing to immune-mediated disease. Inferring disease biology from these observations, however, hinges on our ability to discover the molecular processes being perturbed by these risk variants. It has previously been observed that different genes harboring causal mutations for the same Mendelian disease often physically interact. We sought to evaluate the degree to which this is true of genes within strongly associated loci in complex disease. Using sets of loci defined in rheumatoid arthritis (RA) and Crohn's disease (CD) GWAS, we build protein–protein interaction (PPI) networks for genes within associated loci and find abundant physical interactions between protein products of associated genes. We apply multiple permutation approaches to show that these networks are more densely connected than chance expectation. To confirm biological relevance, we show that the components of the networks tend to be expressed in similar tissues relevant to the phenotypes in question, suggesting the network indicates common underlying processes perturbed by risk loci. Furthermore, we show that the RA and CD networks have predictive power by demonstrating that proteins in these networks, not encoded in the confirmed list of disease associated loci, are significantly enriched for association to the phenotypes in question in extended GWAS analysis. Finally, we test our method in 3 non-immune traits to assess its applicability to complex traits in general. We find that genes in loci associated to height and lipid levels assemble into significantly connected networks but did not detect excess connectivity among Type 2 Diabetes (T2D) loci beyond chance. Taken together, our results constitute evidence that, for many of the complex diseases studied here, common genetic associations implicate regions encoding proteins that physically interact in a preferential manner, in

The biological age linked to oxidative stress modifies breast cancer aggressiveness.

Science.gov (United States)

Sáez-Freire, María Del Mar; Blanco-Gómez, Adrián; Castillo-Lluva, Sonia; Gómez-Vecino, Aurora; Galvis-Jiménez, Julie Milena; Martín-Seisdedos, Carmen; Isidoro-García, María; Hontecillas-Prieto, Lourdes; García-Cenador, María Begoña; García-Criado, Francisco Javier; Patino-Alonso, María Carmen; Galindo-Villardón, Purificación; Mao, Jian-Hua; Prieto, Carlos; Castellanos-Martín, Andrés; Kaderali, Lars; Pérez-Losada, Jesús

2018-03-14

The incidence of breast cancer increases with age until menopause, and breast cancer is more aggressive in younger women. The existence of epidemiological links between breast cancer and aging indicates that both processes share some common mechanisms of development. Oxidative stress is associated with both cancer susceptibility and aging. Here we observed that ERBB2-positive breast cancer, which developed in genetically heterogeneous ERBB2-positive transgenic mice generated by a backcross, is more aggressive in chronologically younger than in older mice (differentiated by the median survival of the cohort that was 79 weeks), similar to what occurs in humans. In this cohort, we estimated the oxidative biological age using a mathematical model that integrated several subphenotypes directly or indirectly related to oxidative stress. The model selected the serum levels of HDL-cholesterol and magnesium and total AKT1 and glutathione concentrations in the liver. The grade of aging was calculated as the difference between the predicted biological age and the chronological age. This comparison permitted the identification of biologically younger and older mice compared with their chronological age. Interestingly, biologically older mice developed more aggressive breast cancer than the biologically younger mice. Genomic regions on chromosomes 2 and 15 linked to the grade of oxidative aging were identified. The levels of expression of Zbp1 located on chromosome 2, a gene related to necroptosis and inflammation, positively correlated with the grade of aging and tumour aggressiveness. Moreover, the pattern of gene expression of genes linked to the inflammation and the response to infection pathways was enriched in the livers of biologically old mice. This study shows part of the complex interactions between breast cancer and aging. Copyright © 2018 Elsevier Inc. All rights reserved.

Design of fuzzy classifier for diabetes disease using Modified Artificial Bee Colony algorithm.

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Beloufa, Fayssal; Chikh, M A

2013-10-01

In this study, diagnosis of diabetes disease, which is one of the most important diseases, is conducted with artificial intelligence techniques. We have proposed a novel Artificial Bee Colony (ABC) algorithm in which a mutation operator is added to an Artificial Bee Colony for improving its performance. When the current best solution cannot be updated, a blended crossover operator (BLX-α) of genetic algorithm is applied, in order to enhance the diversity of ABC, without compromising with the solution quality. This modified version of ABC is used as a new tool to create and optimize automatically the membership functions and rules base directly from data. We take the diabetes dataset used in our work from the UCI machine learning repository. The performances of the proposed method are evaluated through classification rate, sensitivity and specificity values using 10-fold cross-validation method. The obtained classification rate of our method is 84.21% and it is very promising when compared with the previous research in the literature for the same problem. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Coronary artery disease reporting and data system (CAD-RADSTM): Inter-observer agreement for assessment categories and modifiers.

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Maroules, Christopher D; Hamilton-Craig, Christian; Branch, Kelley; Lee, James; Cury, Roberto C; Maurovich-Horvat, Pál; Rubinshtein, Ronen; Thomas, Dustin; Williams, Michelle; Guo, Yanshu; Cury, Ricardo C

The Coronary Artery Disease Reporting and Data System (CAD-RADS) provides a lexicon and standardized reporting system for coronary CT angiography. To evaluate inter-observer agreement of the CAD-RADS among an panel of early career and expert readers. Four early career and four expert cardiac imaging readers prospectively and independently evaluated 50 coronary CT angiography cases using the CAD-RADS lexicon. All readers assessed image quality using a five-point Likert scale, with mean Likert score ≥4 designating high image quality, and CAD-RADS assessment categories and modifiers were assessed using intra-class correlation (ICC) and Fleiss' Kappa (κ).The impact of reader experience and image quality on inter-observer agreement was also examined. Inter-observer agreement for CAD-RADS assessment categories was excellent (ICC 0.958, 95% CI 0.938-0.974, p CAD-RADS assessment categories and modifiers is excellent, except for high-risk plaque (modifier V) which demonstrates fair agreement. These results suggest CAD-RADS is feasible for clinical implementation. Copyright © 2017. Published by Elsevier Inc.

The disease modifying osteoarthritis drug (DMOAD)

DEFF Research Database (Denmark)

Qvist, Per; Bay-Jensen, Anne-Christine; Christiansen, Claus

2008-01-01

and with DMOADs in particular, and we advance the need for a new development paradigm for DMOADs. Two central elements in this paradigm are a stronger focus on the biology of the joint and the application of new and more sensitive biomarkers allowing redesign of clinical trials in osteoarthritis....

Nature and Consequences of Biological Reductionism for the Immunological Study of Infectious Diseases

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Ariel L. Rivas

2017-05-01

Full Text Available Evolution has conserved “economic” systems that perform many functions, faster or better, with less. For example, three to five leukocyte types protect from thousands of pathogens. To achieve so much with so little, biological systems combine their limited elements, creating complex structures. Yet, the prevalent research paradigm is reductionist. Focusing on infectious diseases, reductionist and non-reductionist views are here described. The literature indicates that reductionism is associated with information loss and errors, while non-reductionist operations can extract more information from the same data. When designed to capture one-to-many/many-to-one interactions—including the use of arrows that connect pairs of consecutive observations—non-reductionist (spatial–temporal constructs eliminate data variability from all dimensions, except along one line, while arrows describe the directionality of temporal changes that occur along the line. To validate the patterns detected by non-reductionist operations, reductionist procedures are needed. Integrated (non-reductionist and reductionist methods can (i distinguish data subsets that differ immunologically and statistically; (ii differentiate false-negative from -positive errors; (iii discriminate disease stages; (iv capture in vivo, multilevel interactions that consider the patient, the microbe, and antibiotic-mediated responses; and (v assess dynamics. Integrated methods provide repeatable and biologically interpretable information.

Protecting Bone Health in Pediatric Rheumatic Diseases: Pharmacological Considerations.

Science.gov (United States)

Zhang, Yujuan; Milojevic, Diana

2017-06-01

Bone health in children with rheumatic conditions may be compromised due to several factors related to the inflammatory disease state, delayed puberty, altered life style, including decreased physical activities, sun avoidance, suboptimal calcium and vitamin D intake, and medical treatments, mainly glucocorticoids and possibly some disease-modifying anti-rheumatic drugs. Low bone density or even fragility fractures could be asymptomatic; therefore, children with diseases of high inflammatory load, such as systemic onset juvenile idiopathic arthritis, juvenile dermatomyositis, systemic lupus erythematosus, and those requiring chronic glucocorticoids may benefit from routine screening of bone health. Most commonly used assessment tools are laboratory testing including serum 25-OH-vitamin D measurement and bone mineral density measurement by a variety of methods, dual-energy X-ray absorptiometry as the most widely used. Early disease control, use of steroid-sparing medications such as disease-modifying anti-rheumatic drugs and biologics, supplemental vitamin D and calcium, and promotion of weight-bearing physical activities can help optimize bone health. Additional treatment options for osteoporosis such as bisphosphonates are still controversial in children with chronic rheumatic diseases, especially those with decreased bone density without fragility fractures. This article reviews common risk factors leading to compromised bone health in children with chronic rheumatic diseases and discusses the general approach to prevention and treatment of bone fragility.

Update on the use of systemic biologic agents in the treatment of noninfectious uveitis

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Pasadhika S

2014-02-01

Full Text Available Sirichai Pasadhika,1 James T Rosenbaum2 1Department of Ophthalmology, Southern Arizona Veterans Administration Health Care System, Tucson, AZ, USA; 2Legacy Devers Eye Institute, Portland, OR, USA Abstract: Uveitis is one of the leading causes of blindness worldwide. Noninfectious uveitis may be associated with other systemic conditions, such as human leukocyte antigen B27-related spondyloarthropathies, inflammatory bowel disease, juvenile idiopathic arthritis, Behçet's disease, and sarcoidosis. Conventional therapy with corticosteroids and immunosuppressive agents (such as methotrexate, azathioprine, mycophenolate mofetil, and cyclosporine may not be sufficient to control ocular inflammation or prevent non-ophthalmic complications in refractory patients. Off-label use of biologic response modifiers has been studied as primary and secondary therapeutic agents. They are very useful when conventional immunosuppressive therapy has failed or has been poorly tolerated, or to treat concomitant ophthalmic and systemic inflammation that might benefit from these medications. Biologic therapy, primarily infliximab, and adalimumab, have been shown to be rapidly effective for the treatment of various subtypes of refractory uveitis and retinal vasculitis, especially Behçet's disease-related eye conditions and the uveitis associated with juvenile idiopathic arthritis. Other agents such as golimumab, abatacept, canakinumab, gevokizumab, tocilizumab, and alemtuzumab may have great future promise for the treatment of uveitis. It has been shown that with proper monitoring, biologic therapy can significantly improve quality of life in patients with uveitis, particularly those with concurrent systemic symptoms. However, given high cost as well as the limited long-term safety data, we do not routinely recommend biologics as first-line therapy for noninfectious uveitis in most patients. These agents should be used with caution by experienced clinicians. The present

Identification and Prioritization of Important Attributes of Disease-Modifying Drugs in Decision Making among Patients with Multiple Sclerosis: A Nominal Group Technique and Best-Worst Scaling.

Science.gov (United States)

Kremer, Ingrid E H; Evers, Silvia M A A; Jongen, Peter J; van der Weijden, Trudy; van de Kolk, Ilona; Hiligsmann, Mickaël

2016-01-01

Understanding the preferences of patients with multiple sclerosis (MS) for disease-modifying drugs and involving these patients in clinical decision making can improve the concordance between medical decisions and patient values and may, subsequently, improve adherence to disease-modifying drugs. This study aims first to identify which characteristics-or attributes-of disease-modifying drugs influence patients´ decisions about these treatments and second to quantify the attributes' relative importance among patients. First, three focus groups of relapsing-remitting MS patients were formed to compile a preliminary list of attributes using a nominal group technique. Based on this qualitative research, a survey with several choice tasks (best-worst scaling) was developed to prioritize attributes, asking a larger patient group to choose the most and least important attributes. The attributes' mean relative importance scores (RIS) were calculated. Nineteen patients reported 34 attributes during the focus groups and 185 patients evaluated the importance of the attributes in the survey. The effect on disease progression received the highest RIS (RIS = 9.64, 95% confidence interval: [9.48-9.81]), followed by quality of life (RIS = 9.21 [9.00-9.42]), relapse rate (RIS = 7.76 [7.39-8.13]), severity of side effects (RIS = 7.63 [7.33-7.94]) and relapse severity (RIS = 7.39 [7.06-7.73]). Subgroup analyses showed heterogeneity in preference of patients. For example, side effect-related attributes were statistically more important for patients who had no experience in using disease-modifying drugs compared to experienced patients (p decision making would be needed and requires eliciting individual preferences.

Update on the use of systemic biologic agents in the treatment of noninfectious uveitis

Science.gov (United States)

Pasadhika, Sirichai; Rosenbaum, James T

2014-01-01

Uveitis is one of the leading causes of blindness worldwide. Noninfectious uveitis may be associated with other systemic conditions, such as human leukocyte antigen B27-related spondyloarthropathies, inflammatory bowel disease, juvenile idiopathic arthritis, Behçet’s disease, and sarcoidosis. Conventional therapy with corticosteroids and immunosuppressive agents (such as methotrexate, azathioprine, mycophenolate mofetil, and cyclosporine) may not be sufficient to control ocular inflammation or prevent non-ophthalmic complications in refractory patients. Off-label use of biologic response modifiers has been studied as primary and secondary therapeutic agents. They are very useful when conventional immunosuppressive therapy has failed or has been poorly tolerated, or to treat concomitant ophthalmic and systemic inflammation that might benefit from these medications. Biologic therapy, primarily infliximab, and adalimumab, have been shown to be rapidly effective for the treatment of various subtypes of refractory uveitis and retinal vasculitis, especially Behçet’s disease-related eye conditions and the uveitis associated with juvenile idiopathic arthritis. Other agents such as golimumab, abatacept, canakinumab, gevokizumab, tocilizumab, and alemtuzumab may have great future promise for the treatment of uveitis. It has been shown that with proper monitoring, biologic therapy can significantly improve quality of life in patients with uveitis, particularly those with concurrent systemic symptoms. However, given high cost as well as the limited long-term safety data, we do not routinely recommend biologics as first-line therapy for noninfectious uveitis in most patients. These agents should be used with caution by experienced clinicians. The present work aims to provide a broad and updated review of the current and in-development systemic biologic agents for the treatment of noninfectious uveitis. PMID:24600203

CRISPR/Cas9 for Human Genome Engineering and Disease Research.

Science.gov (United States)

Xiong, Xin; Chen, Meng; Lim, Wendell A; Zhao, Dehua; Qi, Lei S

2016-08-31

The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system, a versatile RNA-guided DNA targeting platform, has been revolutionizing our ability to modify, manipulate, and visualize the human genome, which greatly advances both biological research and therapeutics development. Here, we review the current development of CRISPR/Cas9 technologies for gene editing, transcription regulation, genome imaging, and epigenetic modification. We discuss the broad application of this system to the study of functional genomics, especially genome-wide genetic screening, and to therapeutics development, including establishing disease models, correcting defective genetic mutations, and treating diseases.

Modifiable Risk Factors for Common Ragweed (Ambrosia artemisiifolia Allergy and Disease in Children: A Case-Control Study

Directory of Open Access Journals (Sweden)

Maureen Agnew

2018-06-01

Full Text Available Ragweed allergy is a major public health concern. Within Europe, ragweed is an introduced species and research has indicated that the amounts of ragweed pollen are likely to increase over Europe due to climate change, with corresponding increases in ragweed allergy. To address this threat, improving our understanding of predisposing factors for allergic sensitisation to ragweed and disease is necessary, specifically focusing upon factors that are potentially modifiable (i.e., environmental. In this study, a total of 4013 children aged 2–13 years were recruited across Croatia to undergo skin prick tests to determine sensitisation to ragweed and other aeroallergens. A parental questionnaire collected home environment, lifestyle, family and personal medical history, and socioeconomic information. Environmental variables were obtained using Geographical Information Systems and data from nearby pollen, weather, and air pollution stations. Logistic regression was performed (clustered on school focusing on risk factors for allergic sensitisation and disease. Ragweed sensitisation was strongly associated with ragweed pollen at levels over 5000 grains m–3 year−1 and, above these levels, the risk of sensitisation was 12–16 times greater than in low pollen areas with about 400 grains m–3 year−1. Genetic factors were strongly associated with sensitisation but nearly all potentially modifiable factors were insignificant. This included measures of local land use and proximity to potential sources of ragweed pollen. Rural residence was protective (odds ratio (OR 0.73, 95% confidence interval (CI 0.55–0.98, but the factors underlying this association were unclear. Being sensitised to ragweed doubled (OR 2.17, 95% CI 1.59–2.96 the risk of rhinoconjunctivitis. No other potentially modifiable risk factors were associated with rhinoconjunctivitis. Ragweed sensitisation was strongly associated with ragweed pollen, and sensitisation was significantly

Telomere biology in healthy aging and disease

NARCIS (Netherlands)

Oeseburg, Hisko; de Boer, Rudolf A.; van Gilst, Wiek H.; van der Harst, Pim

Aging is a biological process that affects most cells, organisms and species. Telomeres have been postulated as a universal biological clock that shortens in parallel with aging in cells. Telomeres are located at the end of the chromosomes and consist of an evolutionary conserved repetitive

Modifiable life style associated risk factors for non communicable diseases among students of pre-university college of Udupi taluk

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Shradha S Parsekar

2015-01-01

Full Text Available Background Non-communicable diseases are diseases of longer period and are increasing. This study was intended to find out the proportion of adolescents having modifiable life style associated risk factors. Materials and methods A cross sectional study was carried out in 15 pre-university colleges (PUC of Udupi taluk, which were randomly selected, a class from each PUC was randomly chosen. WHO stepwise approach was used to collect data. A total of 838 adolescents in the age group 15 to 19 years were included. Data was analysed using SPSS software version 15. Chi square test was used to find the association. Results Current smoking was found in 1.67% of the participants. Nearly 16.94% participants were exposed to second hand smoke. About 2.15% of the participants were current alcohol drinkers. Junk food consumption was found in 64.08% of the participants. About 89.86% of the participants were physically inactive. Nearly 31.98% of the participants reported adding extra salt to the diet. Conclusion The behavioural risk factors investigated in the present study are potentially modifiable; identifying subgroups having one or multiple risk factors at an early age is of extreme importance for preventing risk of acquiring chronic diseases in adult life.

Development of biologically modified anodes for energy harvesting using microbial fuel cells

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Sumner, James J.; Ganguli, Rahul; Chmelka, Brad

2012-06-01

Biological fuel cells hold promise as an alternative energy source to batteries for unattended ground sensor applications due to the fact that they can be extremely long lived. This lifetime can be extended over batteries by scavenging fuel from the deployed environment. Microbial fuel cells (MFC) are one class of such sources that produce usable energy from small organic compounds (i.e. sugars, alcohols, organic acids, and biopolymers) which can be easily containerized or scavenged from the environment. The use of microorganisms as the anodic catalysts is what makes these systems unique from other biofuel cell designs. One of the main drawbacks of engineering a sensor system powered by an MFC is that power densities and current flux are extremely low in currently reported systems. The power density is limited by the mass transfer of the fuel source to the catalyst, the metabolism of the microbial catalysts and the electron transfer from the organism to the anode. This presentation will focus on the development of a new style of microbially-modified anodes which will increase power density to a level where a practical power source can be engineered. This is being achieved by developing a three dimensional matrix as an artificial, conductive biofilm. These artificial biofilms will allow the capture of a consortium of microbes designed for efficient metabolism of the available fuel source. Also it will keep the microbes close to the electrode allowing ready access by fuel and providing a low resistance passage of the liberated electrons from fuel oxidation.

Managing rheumatic and musculoskeletal diseases - past, present and future.

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Burmester, Gerd R; Bijlsma, Johannes W J; Cutolo, Maurizio; McInnes, Iain B

2017-07-01

Progress in rheumatology has been remarkable in the past 70 years, favourably affecting quality of life for people with rheumatic and musculoskeletal diseases. Therapeutics have advanced considerably in this period, from early developments such as the introduction of glucocorticoid therapy to the general use of methotrexate and other disease-modifying agents, followed by the advent of biologic DMARDs and, most recently, small-molecule signalling inhibitors. Novel strategies for the use of such agents have also transformed outcomes, as have multidisciplinary nonpharmacological approaches to the management of rheumatic musculoskeletal disease including surgery, physical therapy and occupational therapy. Breakthroughs in our understanding of disease pathogenesis, diagnostics and the use of 'big data' continue to drive the field forward. Critically, the patient is now at the centre of management strategies as well as the future research agenda.

Aryloxyalkanoic Acids as Non-Covalent Modifiers of the Allosteric Properties of Hemoglobin

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Abdelsattar M. Omar

2016-08-01

Full Text Available Hemoglobin (Hb modifiers that stereospecifically inhibit sickle hemoglobin polymer formation and/or allosterically increase Hb affinity for oxygen have been shown to prevent the primary pathophysiology of sickle cell disease (SCD, specifically, Hb polymerization and red blood cell sickling. Several such compounds are currently being clinically studied for the treatment of SCD. Based on the previously reported non-covalent Hb binding characteristics of substituted aryloxyalkanoic acids that exhibited antisickling properties, we designed, synthesized and evaluated 18 new compounds (KAUS II series for enhanced antisickling activities. Surprisingly, select test compounds showed no antisickling effects or promoted erythrocyte sickling. Additionally, the compounds showed no significant effect on Hb oxygen affinity (or in some cases, even decreased the affinity for oxygen. The X-ray structure of deoxygenated Hb in complex with a prototype compound, KAUS-23, revealed that the effector bound in the central water cavity of the protein, providing atomic level explanations for the observed functional and biological activities. Although the structural modification did not lead to the anticipated biological effects, the findings provide important direction for designing candidate antisickling agents, as well as a framework for novel Hb allosteric effectors that conversely, decrease the protein affinity for oxygen for potential therapeutic use for hypoxic- and/or ischemic-related diseases.

Biological warfare agents

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Duraipandian Thavaselvam

2010-01-01

Full Text Available The recent bioterrorist attacks using anthrax spores have emphasized the need to detect and decontaminate critical facilities in the shortest possible time. There has been a remarkable progress in the detection, protection and decontamination of biological warfare agents as many instrumentation platforms and detection methodologies are developed and commissioned. Even then the threat of biological warfare agents and their use in bioterrorist attacks still remain a leading cause of global concern. Furthermore in the past decade there have been threats due to the emerging new diseases and also the re-emergence of old diseases and development of antimicrobial resistance and spread to new geographical regions. The preparedness against these agents need complete knowledge about the disease, better research and training facilities, diagnostic facilities and improved public health system. This review on the biological warfare agents will provide information on the biological warfare agents, their mode of transmission and spread and also the detection systems available to detect them. In addition the current information on the availability of commercially available and developing technologies against biological warfare agents has also been discussed. The risk that arise due to the use of these agents in warfare or bioterrorism related scenario can be mitigated with the availability of improved detection technologies.

Biological warfare agents

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Thavaselvam, Duraipandian; Vijayaraghavan, Rajagopalan

2010-01-01

The recent bioterrorist attacks using anthrax spores have emphasized the need to detect and decontaminate critical facilities in the shortest possible time. There has been a remarkable progress in the detection, protection and decontamination of biological warfare agents as many instrumentation platforms and detection methodologies are developed and commissioned. Even then the threat of biological warfare agents and their use in bioterrorist attacks still remain a leading cause of global concern. Furthermore in the past decade there have been threats due to the emerging new diseases and also the re-emergence of old diseases and development of antimicrobial resistance and spread to new geographical regions. The preparedness against these agents need complete knowledge about the disease, better research and training facilities, diagnostic facilities and improved public health system. This review on the biological warfare agents will provide information on the biological warfare agents, their mode of transmission and spread and also the detection systems available to detect them. In addition the current information on the availability of commercially available and developing technologies against biological warfare agents has also been discussed. The risk that arise due to the use of these agents in warfare or bioterrorism related scenario can be mitigated with the availability of improved detection technologies. PMID:21829313

Harnessing the Power of Integrated Mitochondrial Biology and Physiology: A Special Report on the NHLBI Mitochondria in Heart Diseases Initiative.

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Ping, Peipei; Gustafsson, Åsa B; Bers, Don M; Blatter, Lothar A; Cai, Hua; Jahangir, Arshad; Kelly, Daniel; Muoio, Deborah; O'Rourke, Brian; Rabinovitch, Peter; Trayanova, Natalia; Van Eyk, Jennifer; Weiss, James N; Wong, Renee; Schwartz Longacre, Lisa

2015-07-17

Mitochondrial biology is the sum of diverse phenomena from molecular profiles to physiological functions. A mechanistic understanding of mitochondria in disease development, and hence the future prospect of clinical translations, relies on a systems-level integration of expertise from multiple fields of investigation. Upon the successful conclusion of a recent National Institutes of Health, National Heart, Lung, and Blood Institute initiative on integrative mitochondrial biology in cardiovascular diseases, we reflect on the accomplishments made possible by this unique interdisciplinary collaboration effort and exciting new fronts on the study of these remarkable organelles. © 2015 American Heart Association, Inc.

Do Genetic Markers of Inflammation Modify the Relationship between Periodontitis and Nonalcoholic Fatty Liver Disease? Findings from the SHIP Study.

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Akinkugbe, A A; Avery, C L; Barritt, A S; Cole, S R; Lerch, M; Mayerle, J; Offenbacher, S; Petersmann, A; Nauck, M; Völzke, H; Slade, G D; Heiss, G; Kocher, T; Holtfreter, B

2017-11-01

An association between periodontitis and nonalcoholic fatty liver disease (NAFLD) has been reported by experimental animal and epidemiologic studies. This study investigated whether circulating levels of serum C-reactive protein (CRP) and a weighted genetic CRP score representing markers of inflammatory burden modify the association between periodontitis and NAFLD. Data came from 2,481 participants of the Study of Health in Pomerania who attended baseline examination that occurred between 1997 and 2001. Periodontitis was defined as the percentage of sites (0%, 3 mg/L. Periodontitis was positively associated with higher prevalence odds of NAFLD, and this relationship was modified by serum CRP levels.

Modified Allergens for Immunotherapy.

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Satitsuksanoa, Pattraporn; Głobińska, Anna; Jansen, Kirstin; van de Veen, Willem; Akdis, Mübeccel

2018-02-16

During the past few decades, modified allergens have been developed for use in allergen-specific immunotherapy (AIT) with the aim to improve efficacy and reduce adverse effects. This review aims to provide an overview of the different types of modified allergens, their mechanism of action and their potential for improving AIT. In-depth research in the field of allergen modifications as well as the advance of recombinant DNA technology have paved the way for improved diagnosis and research on human allergic diseases. A wide range of structurally modified allergens has been generated including allergen peptides, chemically altered allergoids, adjuvant-coupled allergens, and nanoparticle-based allergy vaccines. These modified allergens show promise for the development of AIT regimens with improved safety and long-term efficacy. Certain modifications ensure reduced IgE reactivity and retained T cell reactivity, which facilities induction of immune tolerance to the allergen. To date, multiple clinical trials have been performed using modified allergens. Promising results were obtained for the modified cat, grass and birch pollen, and house dust mite allergens. The use of modified allergens holds promise for improving AIT efficacy and safety. There is however a need for larger clinical studies to reliably assess the added benefit for the patient of using modified allergens for AIT.

Sequencing of disease-modifying therapies for relapsing-remitting multiple sclerosis: a theoretical approach to optimizing treatment.

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Grand'Maison, Francois; Yeung, Michael; Morrow, Sarah A; Lee, Liesly; Emond, Francois; Ward, Brian J; Laneuville, Pierre; Schecter, Robyn

2018-04-18

Multiple sclerosis (MS) is a chronic disease which usually begins in young adulthood and is a lifelong condition. Individuals with MS experience physical and cognitive disability resulting from inflammation and demyelination in the central nervous system. Over the past decade, several disease-modifying therapies (DMTs) have been approved for the management of relapsing-remitting MS (RRMS), which is the most prevalent phenotype. The chronic nature of the disease and the multiple treatment options make benefit-risk-based sequencing of therapy essential to ensure optimal care. The efficacy and short- and long-term risks of treatment differ for each DMT due to their different mechanism of action on the immune system. While transitioning between DMTs, in addition to immune system effects, factors such as age, disease duration and severity, disability status, monitoring requirements, preference for the route of administration, and family planning play an important role. Determining a treatment strategy is therefore challenging as it requires careful consideration of the differences in efficacy, safety and tolerability, while at the same time minimizing risks of immune modulation. In this review, we discuss a sequencing approach for treating RRMS, with importance given to the long-term risks and individual preference when devising a treatment plan. Evidence-based strategies to counter breakthrough disease are also addressed.

Modifiable risk factors for Alzheimer disease and subjective memory impairment across age groups.

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Chen, Stephen T; Siddarth, Prabha; Ercoli, Linda M; Merrill, David A; Torres-Gil, Fernando; Small, Gary W

2014-01-01

Previous research has identified modifiable risk factors for Alzheimer's disease (AD) in older adults. Research is limited on the potential link between these risk factors and subjective memory impairment (SMI), which may precede AD and other dementias. Examination of these potential relationships may help identify those at risk for AD at a stage when interventions may delay or prevent further memory problems. The objective of this study was to determine whether risk factors for AD are associated with SMI among different age groups. Trained interviewers conducted daily telephone surveys (Gallup-Healthways) of a representative community sample of 18,614 U.S. respondents, including 4,425 younger (age 18 to 39 years), 6,365 middle-aged (40 to 59 years), and 7,824 older (60 to 99 years) adults. The surveyors collected data on demographics, lifestyles, and medical information. Less education, smoking, hypertension, diabetes, less exercise, obesity and depression, and interactions among them, were examined for associations with SMI. Weighted logistic regressions and chi-square tests were used to calculate odds ratios and confidence intervals for SMI with each risk factor and pairwise interactions across age groups. Depression, less education, less exercise, and hypertension were significantly associated with SMI in all three age groups. Several interactions between risk factors were significant in younger and middle-aged adults and influenced their associations with SMI. Frequency of SMI increased with age and number of risk factors. Odds of having SMI increased significantly with just having one risk factor. These results indicate that modifiable risk factors for AD are also associated with SMI, suggesting that these relationships occur in a broad range of ages and may be targeted to mitigate further memory problems. Whether modifying these risk factors reduces SMI and the eventual incidence of AD and other dementias later in life remains to be determined.

Modifiable risk factors for Alzheimer disease and subjective memory impairment across age groups.

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Stephen T Chen

Full Text Available INTRODUCTION: Previous research has identified modifiable risk factors for Alzheimer's disease (AD in older adults. Research is limited on the potential link between these risk factors and subjective memory impairment (SMI, which may precede AD and other dementias. Examination of these potential relationships may help identify those at risk for AD at a stage when interventions may delay or prevent further memory problems. The objective of this study was to determine whether risk factors for AD are associated with SMI among different age groups. METHOD: Trained interviewers conducted daily telephone surveys (Gallup-Healthways of a representative community sample of 18,614 U.S. respondents, including 4,425 younger (age 18 to 39 years, 6,365 middle-aged (40 to 59 years, and 7,824 older (60 to 99 years adults. The surveyors collected data on demographics, lifestyles, and medical information. Less education, smoking, hypertension, diabetes, less exercise, obesity and depression, and interactions among them, were examined for associations with SMI. Weighted logistic regressions and chi-square tests were used to calculate odds ratios and confidence intervals for SMI with each risk factor and pairwise interactions across age groups. RESULTS: Depression, less education, less exercise, and hypertension were significantly associated with SMI in all three age groups. Several interactions between risk factors were significant in younger and middle-aged adults and influenced their associations with SMI. Frequency of SMI increased with age and number of risk factors. Odds of having SMI increased significantly with just having one risk factor. CONCLUSIONS: These results indicate that modifiable risk factors for AD are also associated with SMI, suggesting that these relationships occur in a broad range of ages and may be targeted to mitigate further memory problems. Whether modifying these risk factors reduces SMI and the eventual incidence of AD and other

Cognitive biology dealing with information from bacteria to minds

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Auletta, Gennaro

2011-01-01

Providing a new conceptual scaffold for further research in biology and cognition, this text introduces the new field of cognitive biology, treating developing organisms as information processors which use cognition to control and modify their environments.

Synthetic Biology and Personalized Medicine

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Jain, K.K.

2013-01-01

Synthetic biology, application of synthetic chemistry to biology, is a broad term that covers the engineering of biological systems with structures and functions not found in nature to process information, manipulate chemicals, produce energy, maintain cell environment and enhance human health. Synthetic biology devices contribute not only to improve our understanding of disease mechanisms, but also provide novel diagnostic tools. Methods based on synthetic biology enable the design of novel strategies for the treatment of cancer, immune diseases metabolic disorders and infectious diseases as well as the production of cheap drugs. The potential of synthetic genome, using an expanded genetic code that is designed for specific drug synthesis as well as delivery and activation of the drug in vivo by a pathological signal, was already pointed out during a lecture delivered at Kuwait University in 2005. Of two approaches to synthetic biology, top-down and bottom-up, the latter is more relevant to the development of personalized medicines as it provides more flexibility in constructing a partially synthetic cell from basic building blocks for a desired task. PMID:22907209

Biological Activities of 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-Glucoside in Antiaging and Antiaging-Related Disease Treatments

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Shuang Ling

2016-01-01

Full Text Available 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside (THSG is active component of the Chinese medicinal plant Polygonum multiflorum Thunb. (THSG. Pharmacological studies have demonstrated that THSG exhibits numerous biological functions in treating atherosclerosis, lipid metabolism, vascular and cardiac remodeling, vascular fibrosis, cardiac-cerebral ischemia, learning and memory disorders, neuroinflammation, Alzheimer and Parkinson diseases, diabetic complications, hair growth problems, and numerous other conditions. This review focuses on the biological effects of THSG in antiaging and antiaging-related disease treatments and discusses its molecular mechanisms.

From biological neural networks to thinking machines: Transitioning biological organizational principles to computer technology

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Ross, Muriel D.

1991-01-01

The three-dimensional organization of the vestibular macula is under study by computer assisted reconstruction and simulation methods as a model for more complex neural systems. One goal of this research is to transition knowledge of biological neural network architecture and functioning to computer technology, to contribute to the development of thinking computers. Maculas are organized as weighted neural networks for parallel distributed processing of information. The network is characterized by non-linearity of its terminal/receptive fields. Wiring appears to develop through constrained randomness. A further property is the presence of two main circuits, highly channeled and distributed modifying, that are connected through feedforward-feedback collaterals and biasing subcircuit. Computer simulations demonstrate that differences in geometry of the feedback (afferent) collaterals affects the timing and the magnitude of voltage changes delivered to the spike initiation zone. Feedforward (efferent) collaterals act as voltage followers and likely inhibit neurons of the distributed modifying circuit. These results illustrate the importance of feedforward-feedback loops, of timing, and of inhibition in refining neural network output. They also suggest that it is the distributed modifying network that is most involved in adaptation, memory, and learning. Tests of macular adaptation, through hyper- and microgravitational studies, support this hypothesis since synapses in the distributed modifying circuit, but not the channeled circuit, are altered. Transitioning knowledge of biological systems to computer technology, however, remains problematical.

Constraints on Biological Mechanism from Disease Comorbidity Using Electronic Medical Records and Database of Genetic Variants.

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Steven C Bagley

2016-04-01

Full Text Available Patterns of disease co-occurrence that deviate from statistical independence may represent important constraints on biological mechanism, which sometimes can be explained by shared genetics. In this work we study the relationship between disease co-occurrence and commonly shared genetic architecture of disease. Records of pairs of diseases were combined from two different electronic medical systems (Columbia, Stanford, and compared to a large database of published disease-associated genetic variants (VARIMED; data on 35 disorders were available across all three sources, which include medical records for over 1.2 million patients and variants from over 17,000 publications. Based on the sources in which they appeared, disease pairs were categorized as having predominant clinical, genetic, or both kinds of manifestations. Confounding effects of age on disease incidence were controlled for by only comparing diseases when they fall in the same cluster of similarly shaped incidence patterns. We find that disease pairs that are overrepresented in both electronic medical record systems and in VARIMED come from two main disease classes, autoimmune and neuropsychiatric. We furthermore identify specific genes that are shared within these disease groups.

Organic chemistry and biology: chemical biology through the eyes of collaboration.

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Hruby, Victor J

2009-12-18

From a scientific perspective, efforts to understand biology including what constitutes health and disease has become a chemical problem. However, chemists and biologists "see" the problems of understanding biology from different perspectives, and this has retarded progress in solving the problems especially as they relate to health and disease. This suggests that close collaboration between chemists and biologists is not only necessary but essential for progress in both the biology and chemistry that will provide solutions to the global questions of biology. This perspective has directed my scientific efforts for the past 45 years, and in this overview I provide my perspective of how the applications of synthetic chemistry, structural design, and numerous other chemical principles have intersected in my collaborations with biologists to provide new tools, new science, and new insights that were only made possible and fruitful by these collaborations.

Clinical Trials for Disease-Modifying Therapies in Alzheimer's Disease: A Primer, Lessons Learned, and a Blueprint for the Future.

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Cummings, Jeffrey; Ritter, Aaron; Zhong, Kate

2018-03-16

Alzheimer's disease (AD) has no currently approved disease-modifying therapies (DMTs), and treatments to prevent, delay the onset, or slow the progression are urgently needed. A delay of 5 years if available by 2025 would decrease the total number of patients with AD by 50% in 2050. To meet the definition of DMT, an agent must produce an enduring change in the course of AD; clinical trials of DMTs have the goal of demonstrating this effect. AD drug discovery entails target identification followed by high throughput screening and lead optimization of drug-like compounds. Once an optimized agent is available and has been assessed for efficacy and toxicity in animals, it progresses through Phase I testing with healthy volunteers, Phase II learning trials to establish proof-of-mechanism and dose, and Phase III confirmatory trials to demonstrate efficacy and safety in larger populations. Phase III is followed by Food and Drug Administration review and, if appropriate, market access. Trial populations include cognitively normal at-risk participants in prevention trials, mildly impaired participants with biomarker evidence of AD in prodromal AD trials, and subjects with cognitive and functional impairment in AD dementia trials. Biomarkers are critical in trials of DMTs, assisting in participant characterization and diagnosis, target engagement and proof-of-pharmacology, demonstration of disease-modification, and monitoring side effects. Clinical trial designs include randomized, parallel group; delayed start; staggered withdrawal; and adaptive. Lessons learned from completed trials inform future trials and increase the likelihood of success.

LGscore: A method to identify disease-related genes using biological literature and Google data.

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Kim, Jeongwoo; Kim, Hyunjin; Yoon, Youngmi; Park, Sanghyun

2015-04-01

Since the genome project in 1990s, a number of studies associated with genes have been conducted and researchers have confirmed that genes are involved in disease. For this reason, the identification of the relationships between diseases and genes is important in biology. We propose a method called LGscore, which identifies disease-related genes using Google data and literature data. To implement this method, first, we construct a disease-related gene network using text-mining results. We then extract gene-gene interactions based on co-occurrences in abstract data obtained from PubMed, and calculate the weights of edges in the gene network by means of Z-scoring. The weights contain two values: the frequency and the Google search results. The frequency value is extracted from literature data, and the Google search result is obtained using Google. We assign a score to each gene through a network analysis. We assume that genes with a large number of links and numerous Google search results and frequency values are more likely to be involved in disease. For validation, we investigated the top 20 inferred genes for five different diseases using answer sets. The answer sets comprised six databases that contain information on disease-gene relationships. We identified a significant number of disease-related genes as well as candidate genes for Alzheimer's disease, diabetes, colon cancer, lung cancer, and prostate cancer. Our method was up to 40% more accurate than existing methods. Copyright © 2015 Elsevier Inc. All rights reserved.

A conceptual framework for managing modifiable risk factors for cardiovascular diseases in Fiji.

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Witter, Trevor; Poudevigne, Melanie; Lambrick, Danielle M; Faulkner, James; Lucero, Adam A; Page, Rachel; Perry, Lane G; Tarrant, Michael A; Stoner, Lee

2015-03-01

The current review will look at modifiable lifestyle (physical inactivity, poor nutrition, risky alcohol behavior and cigarette smoking) and cardio-metabolic (obesity, diabetes mellitus, high cholesterol and high blood pressure) cardiovascular disease (CVD) risk factors among Indigenous-Fijian and Indo-Fijian subgroups. A framework for monitoring and managing these risk factors will be presented. National health surveys were identified where available. Electronic databases identified sources for filling missing data. The most relevant data were identified, organized and synthesized. Compared to Indo-Fijians, Indigenous-Fijians have higher rates of obesity (17% vs 11%) and hypertension (21% vs 16%), but lower rates of diabetes mellitus (12% vs 21%) and high cholesterol (33% vs 39%). Indigenous-Fijians report higher rates of prescribed physical activity (25% vs 21%), but poorer recommended vegetable intake (48% vs 56%), greater risky alcohol behavior (17% vs 15%) and a much greater prevalence of cigarette smoking (45% vs 24%). Both Indigenous-Fijians and Indo-Fijians report a low prevalence of recommended fruit intake (17% vs 15%). Fiji is progressing through demographic and epidemiological transitions, including a decline in infectious diseases and improved life expectancy. However, in concert with other developing nations, 'modernization' is accompanied by increased mortality from non-communicable diseases, with CVD being the most prevalent. This transition has been associated with changes to socio-cultural aspects of Fiji, including poor lifestyle choices that may contribute to a cluster of cardio-metabolic conditions which precede CVD. © Royal Society for Public Health 2013.

Fertility, pregnancy and childbirth in patients with multiple sclerosis: impact of disease-modifying drugs.

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Amato, Maria Pia; Portaccio, Emilio

2015-03-01

In recent decades, pregnancy-related issues in multiple sclerosis (MS) have received growing interest. MS is more frequent in women than in men and typically starts during child-bearing age. An increasing number of disease-modifying drugs (DMDs) for the treatment of MS are becoming available. Gathering information on their influences on pregnancy-related issues is of crucial importance for the counselling of MS patients. As for the immunomodulatory drugs (interferons and glatiramer acetate), accumulating evidence points to the relative safety of pregnancy exposure in terms of maternal and foetal outcomes. In case of higher clinical disease activity before pregnancy, these drugs could be continued until conception. As for the 'newer' drugs (fingolimod, natalizumab, teriflunomide, dimethyl fumarate and alemtuzumab), the information is more limited. Whereas fingolimod and teriflunomide are likely associated with an increased risk of foetal malformations, the effects of natalizumab, dimethyl fumarate and alemtuzumab still need to be ascertained. This article provides a review of the available information on the use of DMDs during pregnancy, with a specific focus on fertility, foetal development, delivery and breast-feeding.

Patient perspectives on switching disease-modifying therapies in the NARCOMS registry

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Salter AR

2014-07-01

Full Text Available Amber R Salter,1 Ruth Ann Marrie,2,3 Neetu Agashivala,4 Daniel A Belletti,4 Edward Kim,4 Gary R Cutter,1 Stacey S Cofield,1 Tuula Tyry51Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA; 2Department of Internal Medicine, 3Department of Community Health Sciences, University of Manitoba, Winnipeg, MB, Canada; 4Novartis Pharmaceutical Corporation, East Hanover, NJ, USA; 5Division of Neurology, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, USAIntroduction: The evolving landscape of disease-modifying therapies (DMTs for multiple sclerosis raises important questions about why patients change DMTs. Physicians and patients could benefit from a better understanding of the reasons for switching therapy. Purpose: To investigate the reasons patients switch DMTs and identify characteristics associated with the decision to switch.Method: The North American Research Committee on Multiple Sclerosis (NARCOMS Registry conducted a supplemental survey among registry participants responding to the 2011 update survey. The supplemental survey investigated reasons for switching DMT, origin of the discussion of DMT change, and which factors influenced the decision. Chi-square tests, Fisher’s exact tests, and logistic regression were used for the analyses. Results: Of the 691 eligible candidates, 308 responded and met the inclusion criteria (relapsing disease course, switched DMT after September 2010. The responders were 83.4% female, on average 52 years old, with a median (interquartile range Patient-Determined Disease Steps score of 4 (2–5. The most recent prior therapy included first-line injectables (74.5%, infusions (18.1%, an oral DMT (3.4%, and other DMTs (4.0%. The discussion to switch DMT was initiated almost equally by physicians and participants. The primary reason for choosing the new DMT was based most frequently on physician’s recommendation (24.5% and patient perception of efficacy (13.7%. Conclusion

Frequency and prognostic role of mucosal healing in patients with Crohn’s disease and ulcerative colitis after one-year of biological therapy

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Farkas, Klaudia; Lakatos, Péter László; Szűcs, Mónika; Pallagi-Kunstár, Éva; Bálint, Anita; Nagy, Ferenc; Szepes, Zoltán; Vass, Noémi; Kiss, Lajos S; Wittmann, Tibor; Molnár, Tamás

2014-01-01

AIM: To assess the endoscopic activity before and after a one-year period of biological therapy and to evaluate the frequency of relapses and need for retreatment after stopping the biologicals in patients with Crohn’s disease (CD) and ulcerative colitis (UC). METHODS: The data from 41 patients with CD and 22 patients with UC were assessed. Twenty-four CD patients received infliximab, and 17 received adalimumab. The endoscopic severity of CD was quantified with the simplified endoscopic activity score for Crohn’s disease in CD and with the Mayo endoscopic subscore in UC. RESULTS: Mucosal healing was achieved in 23 CD and 7 UC patients. Biological therapy had to be restarted in 78% of patients achieving complete mucosal healing with CD and in 100% of patients with UC. Neither clinical remission nor mucosal healing was associated with the time to restarting the biological therapy in either CD or UC. CONCLUSION: Mucosal healing did not predict sustained clinical remission in patients in whom the biological therapies had been stopped. PMID:24659890

Tofacitinib suppresses disease activity and febrile attacks in a patient with coexisting rheumatoid arthritis and familial Mediterranean fever.

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Gök, Kevser; Cengiz, Gizem; Erol, Kemal; Ozgocmen, Salih

2017-01-01

Familial Mediterranean fever (FMF) is the most common hereditary auto-inflammatory (periodic fever) syndrome, and usually successfully treated with colchicine. However, nearly 5-10% of FMF cases are resistant or intolerant to colchicine and treatment options are highly restricted in these cases. Biologics including anakinra, canakinumab, rilonacept, etanercept, infliximab, interferon-alpha, and tocilizumab are shown to have efficacy to control FMF attacks. Tofacitinib, a Janus kinase (JAK) inhibitor, is an orally administered non-biologic disease modifying anti-rheumatic drug for the treatment of rheumatoid arthritis (RA). Herein we report a female patient with coexisting RA and colchicine resistant FMF whose FMF attacks and disease activity were completely controlled after treatment with tofacitinib, a small-molecule JAK3 inhibitor.

The emerging problem of biological treatment in migrant and travelling populations: it is time to extend guidelines for the screening of infectious diseases.

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Bartalesi, F; Bartoloni, A; Bisoffi, Z; Spinicci, M; Giménez Sánchez, F; Muñoz, J; Richi, P; Minisola, G; Muñoz-Fernandez, S; Matucci-Cerinic, M

2014-05-01

The use of biological agents in the treatment of rheumatic diseases has been widely associated with an increased risk of reactivation of several latent infections. National and international guidelines recommend screening for infectious diseases before starting these drugs. In Western countries screening is limited to latent tuberculosis infection, HIV and viral hepatitis. However, the increasing globalisation and the remarkable number of migrating and travelling people worldwide make this approach no longer adequate. The Italian and Spanish Societies of Rheumatology and Tropical Medicine wish to issue a warning about the need to improve awareness of doctors about the risk of reactivation of infectious tropical diseases in migrant or travelling patients who undergo biological therapy. Thus, the Italian and Spanish Societies are now planning to issue specific recommendations, based on a multidisciplinary contribution and a systematic review of the literature, for screening and follow-up of active and latent chronic infections in candidate patients for biological agents, taking into account the patient's area of origin and risk of infectious diseases.

A computational systems biology software platform for multiscale modeling and simulation: Integrating whole-body physiology, disease biology, and molecular reaction networks

Directory of Open Access Journals (Sweden)

Thomas eEissing

2011-02-01

Full Text Available Today, in silico studies and trial simulations already complement experimental approaches in pharmaceutical R&D and have become indispensable tools for decision making and communication with regulatory agencies. While biology is multi-scale by nature, project work and software tools usually focus on isolated aspects of drug action, such as pharmacokinetics at the organism scale or pharmacodynamic interaction on the molecular level. We present a modeling and simulation software platform consisting of PK-Sim® and MoBi® capable of building and simulating models that integrate across biological scales. A prototypical multiscale model for the progression of a pancreatic tumor and its response to pharmacotherapy is constructed and virtual patients are treated with a prodrug activated by hepatic metabolization. Tumor growth is driven by signal transduction leading to cell cycle transition and proliferation. Free tumor concentrations of the active metabolite inhibit Raf kinase in the signaling cascade and thereby cell cycle progression. In a virtual clinical study, the individual therapeutic outcome of the chemotherapeutic intervention is simulated for a large population with heterogeneous genomic background. Thereby, the platform allows efficient model building and integration of biological knowledge and prior data from all biological scales. Experimental in vitro model systems can be linked with observations in animal experiments and clinical trials. The interplay between patients, diseases, and drugs and topics with high clinical relevance such as the role of pharmacogenomics, drug-drug or drug-metabolite interactions can be addressed using this mechanistic, insight driven multiscale modeling approach.

Biological and mechanical properties of an experimental glass-ionomer cement modified by partial replacement of CaO with MgO or ZnO

Directory of Open Access Journals (Sweden)

Dong-Ae KIM

2015-08-01

Full Text Available AbstractSome weaknesses of conventional glass ionomer cement (GIC as dental materials, for instance the lack of bioactive potential and poor mechanical properties, remain unsolved.Objective The purpose of this study was to investigate the effects of the partial replacement of CaO with MgO or ZnO on the mechanical and biological properties of the experimental glass ionomer cements.Material and Methods Calcium fluoro-alumino-silicate glass was prepared for an experimental glass ionomer cement by melt quenching technique. The glass composition was modified by partial replacement (10 mol% of CaO with MgO or ZnO. Net setting time, compressive and flexural properties, and in vitrorat dental pulp stem cells (rDPSCs viability were examined for the prepared GICs and compared to a commercial GIC.Results The experimental GICs set more slowly than the commercial product, but their extended setting times are still within the maximum limit (8 min specified in ISO 9917-1. Compressive strength of the experimental GIC was not increased by the partial substitution of CaO with either MgO or ZnO, but was comparable to the commercial control. For flexural properties, although there was no significance between the base and the modified glass, all prepared GICs marked a statistically higher flexural strength (p<0.05 and comparable modulus to control. The modified cements showed increased cell viability for rDPSCs.Conclusions The experimental GICs modified with MgO or ZnO can be considered bioactive dental materials.

Biological and mechanical properties of an experimental glass-ionomer cement modified by partial replacement of CaO with MgO or ZnO

Science.gov (United States)

Dong-Ae, KIM; Hany, ABO-MOSALLAM; Hye-Young, LEE; Jung-Hwan, LEE; Hae-Won, KIM; Hae-Hyoung, LEE

2015-01-01

Some weaknesses of conventional glass ionomer cement (GIC) as dental materials, for instance the lack of bioactive potential and poor mechanical properties, remain unsolved. Objective The purpose of this study was to investigate the effects of the partial replacement of CaO with MgO or ZnO on the mechanical and biological properties of the experimental glass ionomer cements. Material and Methods Calcium fluoro-alumino-silicate glass was prepared for an experimental glass ionomer cement by melt quenching technique. The glass composition was modified by partial replacement (10 mol%) of CaO with MgO or ZnO. Net setting time, compressive and flexural properties, and in vitro rat dental pulp stem cells (rDPSCs) viability were examined for the prepared GICs and compared to a commercial GIC. Results The experimental GICs set more slowly than the commercial product, but their extended setting times are still within the maximum limit (8 min) specified in ISO 9917-1. Compressive strength of the experimental GIC was not increased by the partial substitution of CaO with either MgO or ZnO, but was comparable to the commercial control. For flexural properties, although there was no significance between the base and the modified glass, all prepared GICs marked a statistically higher flexural strength (p<0.05) and comparable modulus to control. The modified cements showed increased cell viability for rDPSCs. Conclusions The experimental GICs modified with MgO or ZnO can be considered bioactive dental materials. PMID:26398508

Validation of a model to investigate the effects of modifying cardiovascular disease (CVD) risk factors on the burden of CVD: The rotterdam ischemic heart disease and stroke computer simulation (RISC) model

NARCIS (Netherlands)

B.J.H. van Kempen (Bob); B.S. Ferket (Bart); A. Hofman (Albert); E.W. Steyerberg (Ewout); E.B. Colkesen (Ersen); S.M. Boekholdt (Matthijs); N.J. Wareham (Nick); K-T. Khaw (Kay-Tee); M.G.M. Hunink (Myriam)

2012-01-01

textabstractBackground: We developed a Monte Carlo Markov model designed to investigate the effects of modifying cardiovascular disease (CVD) risk factors on the burden of CVD. Internal, predictive, and external validity of the model have not yet been established.Methods: The Rotterdam Ischemic

Development of criteria for evaluating clinical response in thyroid eye disease using a modified Delphi technique

DEFF Research Database (Denmark)

Douglas, Raymond S; Tsirbas, Angelo; Gordon, Mark

2009-01-01

OBJECTIVE: To identify components of a provisional clinical response index for thyroid eye disease using a modified Delphi technique. METHODS: The International Thyroid Eye Disease Society conducted a structured, 3-round Delphi exercise establishing consensus for a core set of measures for clinical...... parsed into 11 domains for the Delphi surveys. Eighty-four respondents participated in the Delphi 1 survey, providing 220 unique items. Ninety-two members (100% of the respondents from Delphi 1 plus 8 new participants) responded in Delphi 2 and rated the same 220 items. Sixty-four members (76......% of participants) rated 153 criteria in Delphi 3 (67 criteria were excluded because of redundancy). Criteria with a mean greater than 6 (1 = least appropriate to 9 = most appropriate) were further evaluated by the nominal group technique and provisional core measures were chosen. CONCLUSIONS: Using a Delphi...

Adherence to Disease Modifying Drugs among Patients with Multiple Sclerosis in Germany: A Retrospective Cohort Study.

Directory of Open Access Journals (Sweden)

Kerstin Hansen

Full Text Available Long-term therapies such as disease modifying therapy for Multiple Sclerosis (MS demand high levels of medication adherence in order to reach acceptable outcomes. The objective of this study was to describe adherence to four disease modifying drugs (DMDs among statutorily insured patients within two years following treatment initiation. These drugs were interferon beta-1a i.m. (Avonex, interferon beta-1a s.c. (Rebif, interferon beta-1b s.c. (Betaferon and glatiramer acetate s.c. (Copaxone.This retrospective cohort study used pharmacy claims data from the data warehouse of the German Institute for Drug Use Evaluation (DAPI from 2001 through 2009. New or renewed DMD prescriptions in the years 2002 to 2006 were identified and adherence was estimated during 730 days of follow-up by analyzing the medication possession ratio (MPR as proxy for compliance and persistence defined as number of days from initiation of DMD therapy until discontinuation or interruption.A total of 52,516 medication profiles or therapy cycles (11,891 Avonex, 14,060 Betaferon, 12,353 Copaxone and 14,212 Rebif from 50,057 patients were included into the analysis. Among the 4 cohorts, no clinically relevant differences were found in available covariates. The Medication Possession Ratio (MPR measured overall compliance, which was 39.9% with a threshold MPR≥0.8. There were small differences in the proportion of therapy cycles during which a patient was compliant for the following medications: Avonex (42.8%, Betaferon (40.6%, Rebif (39.2%, and Copaxone (37%. Overall persistence was 32.3% at the end of the 24 months observation period, i.e. during only one third of all included therapy cycles patients did not discontinue or interrupt DMD therapy. There were also small differences in the proportion of therapy cycles during which a patient was persistent as follows: Avonex (34.2%, Betaferon (33.4%, Rebif (31.7% and Copaxone (29.8%.Two years after initiating MS-modifying therapy, only

Psychiatric and cognitive symptoms in Huntington's disease are modified by polymorphisms in catecholamine regulating enzyme genes

DEFF Research Database (Denmark)

Vinther-Jensen, T; Nielsen, Troels Tolstrup; Budtz-Jørgensen, E

2016-01-01

Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder characterized by motor, psychiatric, and cognitive manifestations. HD is caused by a CAG repeat expansion in the Huntingtin (HTT) gene but the exact pathogenesis remains unknown. Dopamine imbalance has......-described cohort of Danish HD gene-expansion carriers. We show that cognitive impairment and psychiatric symptoms in HD are modified by polymorphisms in the monoamine oxidase A (MAOA) and catechol-O-methyltransferase (COMT) genes and by the 4p16.3 B haplotype. These results support the theory of dopamine imbalance...

Learning Cell Biology as a Team: A Project-Based Approach to Upper-Division Cell Biology

Science.gov (United States)

Wright, Robin; Boggs, James

2002-01-01

To help students develop successful strategies for learning how to learn and communicate complex information in cell biology, we developed a quarter-long cell biology class based on team projects. Each team researches a particular human disease and presents information about the cellular structure or process affected by the disease, the cellular…

Organic Chemistry and Biology: Chemical Biology Through the Eyes of Collaboration

Science.gov (United States)

Hruby, Victor J.

2011-01-01

From a scientific perspective, efforts to understand biology including what constitutes health and disease has become a chemical problem. However, chemists and biologists “see” the problems of understanding biology from different perspectives, and this has retarded progress in solving the problems especially as they relate to health and disease. This suggests that close collaboration between chemists and biologists is not only necessary but essential for progress in both the biology and chemistry that will provide solutions to the global questions of biology. This perspective has directed my scientific efforts for the past 45 years, and in this overview I provide my perspective of how the applications of synthetic chemistry, structural design, and numerous other chemical principles have intersected in my collaborations with biologists to provide new tools, new science, and new insights that were only made possible and fruitful by these collaborations. PMID:20000552

Determination of drug lipophilicity by phosphatidylcholine-modified microemulsion high-performance liquid chromatography.

Science.gov (United States)

Xuan, Xueyi; Xu, Liyuan; Li, Liangxing; Gao, Chongkai; Li, Ning

2015-07-25

A new biomembrane-mimetic liquid chromatographic method using a C8 stationary phase and phosphatidylcholine-modified (PC-modified) microemulsion mobile phase was used to estimate unionized and ionized drugs lipophilicity expressed as an n-octanol/water partition coefficient (logP and logD). The introduction of PC into sodium dodecyl sulfate (SDS) microemulsion yielded a good correlation between logk and logD (R(2)=0.8). The optimal composition of the PC-modified microemulsion liquid chromatography (PC-modified MELC) mobile phase was 0.2% PC-3.0% SDS-6.0% n-butanol-0.8% ethyl acetate-90.0% water (pH 7.0) for neutral and ionized molecules. The interactions between the analytes and system described by this chromatographic method is more similar to biological membrane than the n-octanol/water partition system. The result in this paper suggests that PC-modified MELC can serve as a possible alternative to the shake-flask method for high-throughput unionized and ionized drugs lipophilicity determination and simulation of biological processes. Copyright © 2015 Elsevier B.V. All rights reserved.

Systems-based biological concordance and predictive reproducibility of gene set discovery methods in cardiovascular disease.

Science.gov (United States)

Azuaje, Francisco; Zheng, Huiru; Camargo, Anyela; Wang, Haiying

2011-08-01

The discovery of novel disease biomarkers is a crucial challenge for translational bioinformatics. Demonstration of both their classification power and reproducibility across independent datasets are essential requirements to assess their potential clinical relevance. Small datasets and multiplicity of putative biomarker sets may explain lack of predictive reproducibility. Studies based on pathway-driven discovery approaches have suggested that, despite such discrepancies, the resulting putative biomarkers tend to be implicated in common biological processes. Investigations of this problem have been mainly focused on datasets derived from cancer research. We investigated the predictive and functional concordance of five methods for discovering putative biomarkers in four independently-generated datasets from the cardiovascular disease domain. A diversity of biosignatures was identified by the different methods. However, we found strong biological process concordance between them, especially in the case of methods based on gene set analysis. With a few exceptions, we observed lack of classification reproducibility using independent datasets. Partial overlaps between our putative sets of biomarkers and the primary studies exist. Despite the observed limitations, pathway-driven or gene set analysis can predict potentially novel biomarkers and can jointly point to biomedically-relevant underlying molecular mechanisms. Copyright © 2011 Elsevier Inc. All rights reserved.

Protective glove use and hygiene habits modify the associations of specific pesticides with Parkinson’s disease

Science.gov (United States)

Furlong, Melissa; Tanner, Caroline M; Goldman, Samuel M; Bhudhikanok, Grace S.; Blair, Aaron; Chade, Anabel; Comyns, Kathleen; Hoppin, Jane A.; Kasten, Meike; Korell, Monica; Langston, J William; Marras, Connie; Meng, Cheryl; Richards, Marie; Ross, G Webster; Umbach, David M; Sandler, Dale P; Kamel, Freya

2014-01-01

Pesticides have been associated with Parkinson’s disease (PD), and protective gloves and workplace hygiene can reduce pesticide exposure. We assessed whether use of gloves and workplace hygiene modified associations between pesticides and PD. The Farming and Movement Evaluation (FAME) Study is a nested case-control study within the Agricultural Health Study. Use of protective gloves, other PPE, and hygiene practices were determined by questionnaire (69 cases and 237 controls were included). We considered interactions of gloves and hygiene with ever-use of pesticides for all pesticides with ≥ 5 exposed and unexposed cases and controls in each glove-use stratum (paraquat, permethrin, rotenone, and trifluralin). 61% of respondents consistently used protective gloves and 87% consistently used ≥ 2 hygiene practices. Protective glove use modified the associations of paraquat and permethrin with PD: neither pesticide was associated with PD among protective glove users, while both pesticides were associated with PD among non-users (paraquat OR 3.9 [95% CI 1.3, 11.7], interaction p=0.15; permethrin OR 4.3 [95% CI 1.2, 15.6] interaction p=0.05). Rotenone was associated with PD regardless of glove use. Trifluralin was associated with PD among people who used glove use and hygiene practices appeared to be important modifiers of the association between pesticides and PD and may reduce risk of PD associated with certain pesticides. PMID:25461423

Artificial Specific Binders Directly Recovered from Chemically Modified Nucleic Acid Libraries

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Yuuya Kasahara

2012-01-01

Full Text Available Specific binders comprised of nucleic acids, that is, RNA/DNA aptamers, are attractive functional biopolymers owing to their potential broad application in medicine, food hygiene, environmental analysis, and biological research. Despite the large number of reports on selection of natural DNA/RNA aptamers, there are not many examples of direct screening of chemically modified nucleic acid aptamers. This is because of (i the inferior efficiency and accuracy of polymerase reactions involving transcription/reverse-transcription of modified nucleotides compared with those of natural nucleotides, (ii technical difficulties and additional time and effort required when using modified nucleic acid libraries, and (iii ambiguous efficacies of chemical modifications in binding properties until recently; in contrast, the effects of chemical modifications on biostability are well studied using various nucleotide analogs. Although reports on the direct screening of a modified nucleic acid library remain in the minority, chemical modifications would be essential when further functional expansion of nucleic acid aptamers, in particular for medical and biological uses, is considered. This paper focuses on enzymatic production of chemically modified nucleic acids and their application to random screenings. In addition, recent advances and possible future research are also described.

Artificial specific binders directly recovered from chemically modified nucleic acid libraries.

Science.gov (United States)

Kasahara, Yuuya; Kuwahara, Masayasu

2012-01-01

Specific binders comprised of nucleic acids, that is, RNA/DNA aptamers, are attractive functional biopolymers owing to their potential broad application in medicine, food hygiene, environmental analysis, and biological research. Despite the large number of reports on selection of natural DNA/RNA aptamers, there are not many examples of direct screening of chemically modified nucleic acid aptamers. This is because of (i) the inferior efficiency and accuracy of polymerase reactions involving transcription/reverse-transcription of modified nucleotides compared with those of natural nucleotides, (ii) technical difficulties and additional time and effort required when using modified nucleic acid libraries, and (iii) ambiguous efficacies of chemical modifications in binding properties until recently; in contrast, the effects of chemical modifications on biostability are well studied using various nucleotide analogs. Although reports on the direct screening of a modified nucleic acid library remain in the minority, chemical modifications would be essential when further functional expansion of nucleic acid aptamers, in particular for medical and biological uses, is considered. This paper focuses on enzymatic production of chemically modified nucleic acids and their application to random screenings. In addition, recent advances and possible future research are also described.

Emotional management and biological markers of dietetic regimen in chronic kidney disease patients.

Science.gov (United States)

Lai, Carlo; Aceto, Paola; Luciani, Massimiliano; Fazzari, Erika; Cesari, Valerio; Luciano, Stella; Fortini, Antonio; Berloco, Desiderata; Canulla, Francesco; Bruzzese, Vincenzo; Lai, Silvia

2017-11-01

The aim of the study was to investigate the association between psychological characteristics and biological markers of adherence in chronic kidney disease patients receiving conservative therapy, hemodialysis, peritoneal dialysis (PD), or kidney transplantation. Seventy-nine adult patients were asked to complete the following questionnaires: Toronto Alexithymia scale, Snaith-Hamilton Pleasure Scale, and Short Form Health Survey. Biological markers of adherence to treatment were measured. Peritoneal dialysis patients showed a lower capacity to feel pleasure from sensorial experience (p = .011) and a higher values of phosphorus compared to the other patients' groups (p = .0001). The inability to communicate emotions was negatively correlated with hemoglobin levels (r = -(0).69; p = .001) and positively correlated with phosphorus values in the PD patients (r = .45; p = .050). Findings showed higher psychological impairments and a lower adherence to the treatment in PD patients and suggest the implication of emotional competence in adherence to treatment.

Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series

NARCIS (Netherlands)

Nigrovic, Peter A.; Mannion, Melissa; Prince, Femke H. M.; Zeft, Andrew; Rabinovich, C. Egla; van Rossum, Marion A. J.; Cortis, Elisabetta; Pardeo, Manuela; Miettunen, Paivi M.; Janow, Ginger; Birmingham, James; Eggebeen, Aaron; Janssen, Erin; Shulman, Andrew I.; Son, Mary Beth; Hong, Sandy; Jones, Karla; Ilowite, Norman T.; Cron, Randy Q.; Higgins, Gloria C.

2011-01-01

To examine the safety and efficacy of the interleukin-1 (IL-1) receptor antagonist anakinra as first-line therapy for systemic juvenile idiopathic arthritis (JIA). Patients with systemic JIA receiving anakinra as part of initial disease-modifying antirheumatic drug (DMARD) therapy were identified

Biological therapeutics

National Research Council Canada - National Science Library

Greenstein, Ben; Brook, Daniel A

2011-01-01

This introductory textbook covers all the main categories of biological medicines, including vaccines, hormonal preparations, drugs for rheumatoid arthritis and other connective tissue diseases, drugs...

78 FR 57293 - Distribution of Reference Biological Standards and Biological Preparations

Science.gov (United States)

2013-09-18

... DEPARTMENT OF HEALTH AND HUMAN SERVICES 42 CFR Part 7 [Docket No. CDC-2013-0013] RIN 0920-AA52 Distribution of Reference Biological Standards and Biological Preparations AGENCY: Centers for Disease Control and Prevention (HHS/CDC), Department of Health and Human Services (HHS). ACTION: Confirmation of...

Preoperative biological therapy and short-term outcomes of abdominal surgery in patients with inflammatory bowel disease.

Science.gov (United States)

Waterman, Matti; Xu, Wei; Dinani, Amreen; Steinhart, A Hillary; Croitoru, Kenneth; Nguyen, Geoffrey C; McLeod, Robin S; Greenberg, Gordon R; Cohen, Zane; Silverberg, Mark S

2013-03-01

Previous investigations of short-term outcomes after preoperative exposure to biological therapy in inflammatory bowel disease (IBD) were conflicting. The authors aimed to assess postoperative outcomes in patients who underwent abdominal surgery with recent exposure to anti-tumour necrosis factor therapy. A retrospective case-control study with detailed matching was performed for subjects with IBD with and without exposure to biologics within 180 days of abdominal surgery. Postoperative outcomes were compared between the groups. 473 procedures were reviewed consisting of 195 patients with exposure to biologics and 278 matched controls. There were no significant differences in most postoperative outcomes such as: length of stay, fever (≥ 38.5°C), urinary tract infection, pneumonia, bacteraemia, readmission, reoperations and mortality. On univariate analysis, procedures on biologics had more wound infections compared with controls (19% vs 11%; p=0.008), but this was not significant in multivariate analysis. Concomitant therapy with biologics and thiopurines was associated with increased frequencies of urinary tract infections (p=0.0007) and wound infections (p=0.0045). Operations performed ≤ 14 days from last biologic dose had similar rates of infections and other outcomes when compared with those performed within 15-30 days or 31-180 days. Patients with detectable preoperative infliximab levels had similar rates of wound infection compared with those with undetectable levels (3/10 vs 0/9; p=0.21). Preoperative treatment with TNF-α antagonists in patients with IBD is not associated with most early postoperative complications. A shorter time interval from last biological dose is not associated with increased postoperative complications. In most cases, surgery should not be delayed, and appropriate biological therapy may be continued perioperatively.

Comparison of an Agent-based Model of Disease Propagation with the Generalised SIR Epidemic Model

Science.gov (United States)

2009-08-01

utilising 10 metre square buildings with the outcome of in-building combat resolved using a modified Lanchester equation. This limited the usefulness of...observations and the Australian Army’s “Future Land Warfighting Concept – Complex Warfare ” [9] document that highlighted three inter-related complex...by military commanders wishing to assess the impact of disease (naturally occurring or through deliberate biological warfare attack) on their

Biological warfare, bioterrorism, and biocrime

NARCIS (Netherlands)

Jansen, H. J.; Breeveld, F. J.; Stijnis, C.; Grobusch, M. P.

2014-01-01

Biological weapons achieve their intended target effects through the infectivity of disease-causing infectious agents. The ability to use biological agents in warfare is prohibited by the Biological and Toxin Weapon Convention. Bioterrorism is defined as the deliberate release of viruses, bacteria

Patients’ satisfaction with and views about treatment with disease-modifying drugs in multiple sclerosis

Directory of Open Access Journals (Sweden)

Caroline Vieira Spessotto

2016-08-01

Full Text Available ABSTRACT Objective The treatment of multiple sclerosis (MS with disease-modifying-drugs (DMDs is evolving and new drugs are reaching the market. Efficacy and safety aspects of the drugs are crucial, but the patients’ satisfaction with the treatment must be taken into consideration. Methods Individual interview with patients with MS regarding their satisfaction and points of view on the treatment with DMDs. Results One hundred and twenty eight patients attending specialized MS Units in five different cities were interviewed. Over 80% of patients were very satisfied with the drugs in use regarding convenience and perceived benefits. The only aspect scoring lesser values was tolerability. Conclusion Parameters for improving treatment in MS must include efficacy, safety, and patient satisfaction with the given DMD.

Chitosan scaffold modified with D-(+) raffinose and enriched with thiol-modified gelatin for improved osteoblast adhesion

International Nuclear Information System (INIS)

Galli, C; Parisi, L; Smerieri, A; Lumetti, S; Manfredi, E; Macaluso, G M; Elviri, L; Bianchera, A; Bettini, R; Lagonegro, P

2016-01-01

The aim of the present study was to investigate whether chitosan-based scaffolds modified with D-(+) raffinose and enriched with thiol-modified gelatin could selectively improve osteoblast adhesion and proliferation. 2, 3 and 4.5% chitosan films were prepared. Chitosan suitability for tissue engineering was confirmed by protein adsorption assay. Scaffolds were incubated with a 2.5 mg ml −1 BSA solution and the decrease of protein content in the supernatants was measured by spectrophotometry. Chitosan films were then enriched with thiol-modified gelatin and their ability to bind BSA was also measured. Then, 2% chitosan discs with or without thiol-modified gelatin were used as culture substrates for MC3T3-E1 cells. After 72 h cells were stained with trypan blue or with calcein AM and propidium iodide for morphology, viability and proliferation assays. Moreover, cell viability was measured at 48, 72, 96 and 168 h to obtain a growth curve. Chitosan films efficiently bound and retained BSA proportionally to the concentration of chitosan discs. The amount of protein retained was higher on chitosan enriched with thiol-modified gelatin. Moreover, chitosan discs allowed the adhesion and the viability of cells, but inhibited their proliferation. The functionalization of chitosan with thiol-modified gelatin enhanced cell spreading and proliferation. Our data confirm that chitosan is a suitable material for tissue engineering. Moreover, our data show that the enrichment of chitosan with thiol-modified gelatin enhances its biological properties. (paper)

Recombinant Newcastle disease virus-vectored vaccines against human and animal infectious diseases.

Science.gov (United States)

Duan, Zhiqiang; Xu, Houqiang; Ji, Xinqin; Zhao, Jiafu

2015-01-01

Recent advances in recombinant genetic engineering techniques have brought forward a leap in designing new vaccines in modern medicine. One attractive strategy is the application of reverse genetics technology to make recombinant Newcastle disease virus (rNDV) deliver protective antigens of pathogens. In recent years, numerous studies have demonstrated that rNDV-vectored vaccines can induce quicker and better humoral and mucosal immune responses than conventional vaccines and are protective against pathogen challenges. With deeper understanding of NDV molecular biology, it is feasible to develop gene-modified rNDV vaccines accompanied by good safety, high efficacy, low toxicity and better immunogenicity. This review summarizes the development of reverse genetics technology in using NDV as a promising vaccine vector to design new vaccines for human and animal use.

[Incidence of biological accidents at work and immune status for vaccine-preventable diseases among resident physicians in specialist training at Ferrara University Hospital].

Science.gov (United States)

Stefanati, Armando; Brosio, Federica; Kuhdari, Parvanè; Baccello, Valeria; De Paris, Paola; Nardini, Marco; Boschetto, Piera; Lupi, Silvia; Gabutti, Giovanni

2017-01-01

The hospital as a work environment is particularly characterized by various risks for healthcare workers (HCWs). The main risk is represented by biological accidents, associated with the parenteral transmission of pathogens. Biological injuries can occur during the care service and the manipulation of biological fluids. Hepatitis B (and hepatitis D), hepatitis C and HIV are the most common infections transmitted by biological injuries. Physicians should acquire awareness of the risks associated with their professional activity during their training as medical residents (MRs). Some infectious diseases are preventable by vaccination and the "National Immunization Plan 2017-2019" (PNPV) recommends HCWs vaccination against hepatitis B, influenza, measles -mumps -rubella, chicken pox, and pertussis. Besides, not only HCWs' vaccination can prevent the disease in healthcare professionals, but it also may reduce the transmission to patients. Therefore, active immunization of HCWs by recommended vaccinations plays an important role to prevent disease cases, complications and death in patients. An increased awareness of risk behaviors is the first important point to address in order to reduce biological accidents and infectious diseases transmission, so as to reduce their frequency. Besides, HCWs' vaccination is useful to reinforce protection and to prevent the transmission of some infectious diseases in case of exposure. The aim of this five-year incidence study is to investigate the MRs' biological accidents characteristics and to analyze the MRs' immune status at the University of Ferrara in the period 2011-2015. Data on MRs' biological accidents and immune status at Azienda Ospedaliero-Universitaria of Ferrara in 2011-2015 were analyzed by Microsoft Excel 2007 Software. In this study, the percentage of MRs' biological injuries compared to the total number of MRs showed an annual variability, with a peak in 2011 (11.9%). During the analyzed period, there were 190

Climate change and occupational allergies: an overview on biological pollution, exposure and prevention.

Science.gov (United States)

D'Ovidio, Maria Concetta; Annesi-Maesano, Isabella; D'Amato, Gennaro; Cecchi, Lorenzo

2016-01-01

Climate change, air pollution, temperature increase and other environmental variables are modifying air quality, contributing to the increase of prevalence of allergic respiratory diseases. Allergies are complex diseases characterized by multilevel interactions between individual susceptibility, response to immune modulation and environmental exposures to physical, chemical and biological agents. Occupational allergies introduce a further complexity to these relationships by adding occupational exposure to both the indoor and outdoor ones in the living environment. The aim of this paper is to overview climate-related allergy affecting environmental and occupational health, as literature data are scanty in this regard, and to suggest a management model of this risk based on a multidisciplinary approach, taking the case of biological pollution, with details on exposure and prevention. The management of climate-related occupational allergy should take into account preventive health strategies, environmental, public and occupational interventions, as well as to develop, implement, evaluate, and improve guidelines and standards protecting workers health under changing climatic conditions; new tools and strategies based on local conditions will have to be developed. Experimental studies and acquisition of environmental and personal data have to be matched to derive useful information for the scope of occupational health and safety.

Natural biological variation of white matter microstructure is accentuated in Huntington's disease.

Science.gov (United States)

Gregory, Sarah; Crawford, Helen; Seunarine, Kiran; Leavitt, Blair; Durr, Alexandra; Roos, Raymund A C; Scahill, Rachael I; Tabrizi, Sarah J; Rees, Geraint; Langbehn, Douglas; Orth, Michael

2018-04-22

Huntington's disease (HD) is a monogenic neurodegenerative disorder caused by a CAG-repeat expansion in the Huntingtin gene. Presence of this expansion signifies certainty of disease onset, but only partly explains age at which onset occurs. Genome-wide association studies have shown that naturally occurring genetic variability influences HD pathogenesis and disease onset. Investigating the influence of biological traits in the normal population, such as variability in white matter properties, on HD pathogenesis could provide a complementary approach to understanding disease modification. We have previously shown that while white matter diffusivity patterns in the left sensorimotor network were similar in controls and HD gene-carriers, they were more extreme in the HD group. We hypothesized that the influence of natural variation in diffusivity on effects of HD pathogenesis on white matter is not limited to the sensorimotor network but extends to cognitive, limbic, and visual networks. Using tractography, we investigated 32 bilateral pathways within HD-related networks, including motor, cognitive, and limbic, and examined diffusivity metrics using principal components analysis. We identified three independent patterns of diffusivity common to controls and HD gene-carriers that predicted HD status. The first pattern involved almost all tracts, the second was limited to sensorimotor tracts, and the third encompassed cognitive network tracts. Each diffusivity pattern was associated with network specific performance. The consistency in diffusivity patterns across both groups coupled with their association with disease status and task performance indicates that naturally-occurring patterns of diffusivity can become accentuated in the presence of the HD gene mutation to influence clinical brain function. © 2018 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Ethics for the "New Biology"

Science.gov (United States)

Kieffer, George H.

1977-01-01

Discusses biological contributions to the changes occurring in today's society, stressing the need for modifying traditional ethics. Issues include contraception and abortion, fetal research, population control and food supply, individual freedom versus common welfare, and euthanasia. Suggests that study in personal and group ethics be…

Subclinical chronic kidney disease modifies the diagnosis of experimental acute kidney injury.

Science.gov (United States)

Succar, Lena; Pianta, Timothy J; Davidson, Trent; Pickering, John W; Endre, Zoltán H

2017-09-01

Extensive structural damage within the kidney must be present before serum creatinine increases. However, a subclinical phase of chronic kidney disease (CKD) usually goes undetected. Here we tested whether experimental subclinical CKD would modify functional and damage biomarker profiles of acute kidney injury (AKI). Subclinical CKD was induced in rats by adenine or aristolochic acid models but without increasing serum creatinine. After prolonged recovery (three to six weeks), AKI was induced with a subnephrotoxic dose of cisplatin. Urinary levels of kidney injury molecule-1 (KIM-1), cytochrome C, monocyte chemotactic protein-1 (MCP-1), clusterin, and interleukin-18 increased during CKD induction, without an increase in serum creatinine. After AKI in adenine-induced CKD, serum creatinine increased more rapidly, while increased urinary KIM-1, clusterin, and MCP-1 were delayed and reduced. Increased serum creatinine and biomarker excretion were associated with diffuse tubulointerstitial injury in the outer stripe of outer medulla coupled with over 50% cortical damage. Following AKI in aristolochic acid-induced CKD, increased serum creatinine, urinary KIM-1, clusterin, MCP-1, cytochrome C, and interleukin-18 concentrations and excretion were greater at day 21 than day 42 and inversely correlated with cortical injury. Subclinical CKD modified functional and damage biomarker profiles in diametrically opposite ways. Functional biomarker profiles were more sensitive, while damage biomarker diagnostic thresholds and increases were diminished and delayed. Damage biomarker concentrations and excretion were inversely linked to the extent of prior cortical damage. Thus, thresholds for AKI biomarkers may need to be lower or sampling delayed in the known presence of CKD. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

Tofacitinib suppresses disease activity and febrile attacks in a patient with coexisting rheumatoid arthritis and familial Mediterranean fever

Directory of Open Access Journals (Sweden)

Kevser Gök

2017-01-01

Full Text Available Familial Mediterranean fever (FMF is the most common hereditary auto-inflammatory (periodic fever syndrome, and usually successfully treated with colchicine. However, nearly 5-10% of FMF cases are resistant or intolerant to colchicine and treatment options are highly restricted in these cases. Biologics including anakinra, canakinumab, rilonacept, etanercept, infliximab, interferon-alpha, and tocilizumab are shown to have efficacy to control FMF attacks. Tofacitinib, a Janus kinase (JAK inhibitor, is an orally administered non-biologic disease modifying anti-rheumatic drug for the treatment of rheumatoid arthritis (RA. Herein we report a female patient with coexisting RA and colchicine resistant FMF whose FMF attacks and disease activity were completely controlled after treatment with tofacitinib, a small-molecule JAK3 inhibitor.

SCLC extensive disease – treatment guidance by extent or/and biology of response?

International Nuclear Information System (INIS)

Eckert, Franziska; Müller, Arndt-Christian

2008-01-01

In extensive disease of small cell lung cancer a doubling of the one-year-survival rate was reported in August 2007 by prophylactic cranial irradiation applied to patients who experienced any response to initial chemotherapy. We discuss the treatment concept of extensive disease in the face of the latest results and older studies with additional thoracic irradiation in this subgroup. A randomized trial with prophylactic cranial irradiation published in 1999 demonstrated an improvement of 5-year-overall-survival for complete responders (at least at distant levels) receiving additional thoracic radiochemotherapy compared to chemotherapy alone (9.1% vs. 3.7%). But, these results were almost neglected and thoracic radiotherapy was not further investigated for good responders of extensive disease. However, in the light of current advances by prophylactic cranial irradiation these findings are noteworthy on all accounts. Considering both, a possible interpretation of these data could be a survival benefit of local control by simultaneous thoracic radiochemotherapy in the case of improved distant control due to chemotherapy and prophylactic cranial irradiation. Furthermore the question arises whether the tumor biology indicated by the response to chemotherapy should be integrated in the present classification

Perspectives of a systems biology of the brain: the big data conundrum understanding psychiatric diseases.

Science.gov (United States)

Mewes, H W

2013-05-01

Psychiatric diseases provoke human tragedies. Asocial behaviour, mood imbalance, uncontrolled affect, and cognitive malfunction are the price for the biological and social complexity of neurobiology. To understand the etiology and to influence the onset and progress of mental diseases remains of upmost importance, but despite the much improved care for the patients, more then 100 years of research have not succeeded to understand the basic disease mechanisms and enabling rationale treatment. With the advent of the genome based technologies, much hope has been created to join the various dimension of -omics data to uncover the secrets of mental illness. Big Data as generated by -omics do not come with explanations. In this essay, I will discuss the inherent, not well understood methodological foundations and problems that seriously obstacle in striving for a quick success and may render lucky strikes impossible. © Georg Thieme Verlag KG Stuttgart · New York.

Smoking modifies the associated increased risk of future cardiovascular disease by genetic variation on chromosome 9p21.

Directory of Open Access Journals (Sweden)

Viktor Hamrefors

Full Text Available AIMS: Genetic predisposition for cardiovascular disease (CVD is likely to be modified by environmental exposures. We tested if the associated risk of CVD and CVD-mortality by the single nucleotide polymorphism rs4977574 on chromosome 9p21 is modified by life-style factors. METHODS AND RESULTS: A total of 24,944 middle-aged subjects (62% females from the population-based Malmö-Diet-and-Cancer-Cohort were genotyped. Smoking, education and physical activity-levels were recorded. Subjects were followed for 15 years for incidence of coronary artery disease (CAD; N = 2309, ischemic stroke (N = 1253 and CVD-mortality (N = 1156. Multiplicative interactions between rs4977574 and life-style factors on endpoints were tested in Cox-regression-models. We observed an interaction between rs4977574 and smoking on incident CAD (P = 0.035 and CVD-mortality (P = 0.012. The hazard ratios (HR per risk allele of rs4977574 were highest in never smokers (N = 9642 for CAD (HR = 1.26; 95% CI 1.13-1.40; P<0.001 and for CVD-mortality (HR = 1.40; 95% CI 1.20-1.63; P<0.001, whereas the risk increase by rs4977574 was attenuated in current smokers (N = 7000 for both CAD (HR = 1.05; 95%CI 0.95-1.16; P = 0.326 and CVD-mortality (HR = 1.08; 95%CI 0.94-1.23; P = 0.270. A meta-analysis supported the finding that the associated increased risk of CAD by the risk-allele was attenuated in smokers. Neither education nor physical activity-levels modified the associated risk of CAD, ischemic stroke and CVD mortality conferred by rs4977574. CONCLUSION: Smoking may modify the associated risk of CAD and CVD-mortality conferred by genetic variation on chromosome 9p21. Whether the observed attenuation of the genetic risk reflects a pathophysiological mechanism or is a result of smoking being such a strong risk-factor that it may eliminate the associated genetic effect, requires further investigation.

Oleanolic Acid and Its Derivatives: Biological Activities and Therapeutic Potential in Chronic Diseases

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Taiwo Betty Ayeleso

2017-11-01

Full Text Available The increasing demand for natural products as an alternative therapy for chronic diseases has encouraged research into the pharmacological importance of bioactive compounds from plants. Recently, there has been a surge of interest in the therapeutic potential of oleanolic acid (OA in the prevention and management of chronic diseases. Oleanolic acid is a pentacyclic triterpenoid widely found in plants, including fruits and vegetables with different techniques and chromatography platforms being employed in its extraction and isolation. Several studies have demonstrated the potential therapeutic effects of OA on different diseases and their symptoms. Furthermore, oleanolic acid also serves as a framework for the development of novel semi-synthetic triterpenoids that could prove vital in finding therapeutic modalities for various ailments. There are recent advances in the design and synthesis of chemical derivatives of OA to enhance its solubility, bioavailability and potency. Some of these derivatives have also been therapeutic candidates in a number of clinical trials. This review consolidates and expands on recent reports on the biological effects of oleanolic acid from different plant sources and its synthetic derivatives as well as their mechanisms of action in in vitro and in vivo study models. This review suggests that oleanolic acid and its derivatives are important candidates in the search for alternative therapy in the treatment and management of chronic diseases.

Ten questions about systems biology

DEFF Research Database (Denmark)

Joyner, Michael J; Pedersen, Bente K

2011-01-01

to understand how whole animals adapt to the real world. We argue that a lack of fluency in these concepts is a major stumbling block for what has been narrowly defined as 'systems biology' by some of its leading advocates. We also point out that it is a failure of regulation at multiple levels that causes many......In this paper we raise 'ten questions' broadly related to 'omics', the term systems biology, and why the new biology has failed to deliver major therapeutic advances for many common diseases, especially diabetes and cardiovascular disease. We argue that a fundamentally narrow and reductionist...

Ten questions about systems biology

DEFF Research Database (Denmark)

Joyner, Michael J; Pedersen, Bente K

2011-01-01

In this paper we raise 'ten questions' broadly related to 'omics', the term systems biology, and why the new biology has failed to deliver major therapeutic advances for many common diseases, especially diabetes and cardiovascular disease. We argue that a fundamentally narrow and reductionist...... to understand how whole animals adapt to the real world. We argue that a lack of fluency in these concepts is a major stumbling block for what has been narrowly defined as 'systems biology' by some of its leading advocates. We also point out that it is a failure of regulation at multiple levels that causes many...

[Validation of the Russian version of the modified Addenbrooke's cognitive examination for Alzheimer's disease diagnosis].

Science.gov (United States)

Levin, O S; Lavrov, A Yu; Lyashenko, Е А; Vasenina, E E; Trusova, N A; Datieva, V K; Makotrova, T A; Pilipenko, A Yu

2015-01-01

To evaluate the validity of the Russian version of the modified Addenbrooke's cognitive examination (ACE-m) for Alzheimer's disease (AD) diagnosis. ACE-m and MMSE, as a comparison scale, were administered to 78 patients including 49 patients with AD and 29 healthy people. ACE-m demonstrated the high validity in the diagnosis of dementia in AD. Cronbach's alpha was 0.89. ACE-m is a brief and simple in use test that measures a wide spectrum of cognitive functions, gives a general impression about cognitive deficit and diagnoses dementia in AD with the greater validity compared to MMSE. This scale is useful not only in diagnosis of AD but also in differentiation with other causes of dementia.

Mapping of courses on vector biology and vector-borne diseases systems: time for a worldwide effort

Science.gov (United States)

Casas, Jérôme; Lazzari, Claudio; Insausti, Teresita; Launois, Pascal; Fouque, Florence

2016-01-01

Major emergency efforts are being mounted for each vector-borne disease epidemiological crisis anew, while knowledge about the biology of arthropods vectors is dwindling slowly but continuously, as is the number of field entomologists. The discrepancy between the rates of production of knowledge and its use and need for solving crises is widening, in particular due to the highly differing time spans of the two concurrent processes. A worldwide web based search using multiple key words and search engines of onsite and online courses in English, Spanish, Portuguese, French, Italian and German concerned with the biology of vectors identified over 140 courses. They are geographically and thematically scattered, the vast majority of them are on-site, with very few courses using the latest massive open online course (MOOC) powerfulness. Over two third of them is given in English and Western Africa is particularity poorly represented. The taxonomic groups covered are highly unbalanced towards mosquitoes. A worldwide unique portal to guide students of all grades and levels of expertise, in particular those in remote locations, is badly needed. This is the objective a new activity supported by the Special Programme for Research and Training in Tropical Diseases (TDR). PMID:27759770

Biological and biomedical aspects of genetically modified food.

Science.gov (United States)

Celec, Peter; Kukucková, Martina; Renczésová, Veronika; Natarajan, Satheesh; Pálffy, Roland; Gardlík, Roman; Hodosy, Július; Behuliak, Michal; Vlková, Barbora; Minárik, Gabriel; Szemes, Tomás; Stuchlík, Stanislav; Turna, Ján

2005-12-01

Genetically modified (GM) foods are the product of one of the most progressive fields of science-biotechnology. There are major concerns about GM foods in the public; some of them are reasonable, some of them are not. Biomedical risks of GM foods include problems regarding the potential allergenicity, horizontal gene transfer, but environmental side effects on biodiversity must also be recognized. Numerous methods have been developed to assess the potential risk of every GM food type. Benefits of the first generation of GM foods were oriented towards the production process and companies, the second generation of GM foods offers, on contrary, various advantages and added value for the consumer. This includes improved nutritional composition or even therapeutic effects. Recombinant probiotics and the principle of alternative gene therapy represent the latest approach of using GM organisms for biomedical applications. This article tries to summarize and to explain the problematic topic of GM food.

A systematic review of cost-effectiveness studies comparing conventional, biological and surgical interventions for inflammatory bowel disease.

Science.gov (United States)

Pillai, Nadia; Dusheiko, Mark; Burnand, Bernard; Pittet, Valérie

2017-01-01

Inflammatory bowel disease (IBD) is a chronic disease placing a large health and economic burden on health systems worldwide. The treatment landscape is complex with multiple strategies to induce and maintain remission while avoiding long-term complications. The extent to which rising treatment costs, due to expensive biologic agents, are offset by improved outcomes and fewer hospitalisations and surgeries needs to be evaluated. This systematic review aimed to assess the cost-effectiveness of treatment strategies for IBD. A systematic literature search was performed in March 2017 to identify economic evaluations of pharmacological and surgical interventions, for adults diagnosed with Crohn's disease (CD) or ulcerative colitis (UC). Costs and incremental cost-effectiveness ratios (ICERs) were adjusted to reflect 2015 purchasing power parity (PPP). Risk of bias assessments and a narrative synthesis of individual study findings are presented. Forty-nine articles were included; 24 on CD and 25 on UC. Infliximab and adalimumab induction and maintenance treatments were cost-effective compared to standard care in patients with moderate or severe CD; however, in patients with conventional-drug refractory CD, fistulising CD and for maintenance of surgically-induced remission ICERs were above acceptable cost-effectiveness thresholds. In mild UC, induction of remission using high dose mesalazine was dominant compared to standard dose. In UC refractory to conventional treatments, infliximab and adalimumab induction and maintenance treatment were not cost-effective compared to standard care; however, ICERs for treatment with vedolizumab and surgery were favourable. We found that, in general, while biologic agents helped improve outcomes, they incurred high costs and therefore were not cost-effective, particularly for use as maintenance therapy. The cost-effectiveness of biologic agents may improve as market prices fall and with the introduction of biosimilars. Future research

Resorbable electrospun polydioxanone fibres modify the behaviour of cells from both healthy and diseased human tendons

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A Kendal

2017-02-01

Full Text Available Chronic tendinopathy in an active and ageing population represents an increasing burden to healthcare systems. Rotator cuff tendinopathy alone accounts for approximately 70 % of all shoulder pain. Tendinopathic tissue has a disorganised extracellular matrix, altered vasculature, and infiltration of fibroblasts and inflammatory cells. This altered biology may contribute to the limited success of surgical repair strategies. Electrospun resorbable scaffolds can potentially enhance endogenous repair mechanisms by influencing the tissue microenvironment. Polydioxanone (PDO has an established safety profile in patients. We compared the response of healthy and diseased human tendon cells to electrospun PDO fibres using live cell imaging, proliferation, flow cytometry, and gene expression studies. Within 4 h of initial contact with electrospun PDO, healthy tendon cells underwent a marked transformation; elongating along the fibres in a fibre density dependent manner. Diseased tendon cells initially responded at a slower rate, but ultimately underwent a similar morphological change. Electrospun fibres increased the proliferation rate of diseased tendon cells and increased the ratio of type I:IIIcollagenmRNA expression. Flow cytometry revealed decreased expression of CD106, a marker of mesenchymal stem cells, and increased expression of CD10 on healthy versus diseased tendon cells. PDO electrospun scaffolds further promoted CD106negCD10pos expression of healthy tendon cells. Despite their behavioural differences, both healthy and diseased human tendon cells responded to electrospun PDO fibres. This encourages further work establishing their efficacy in augmenting surgical repair of diseased tendons.

Systems biology in critical-care nursing.

Science.gov (United States)

Schallom, Lynn; Thimmesch, Amanda R; Pierce, Janet D

2011-01-01

Systems biology applies advances in technology and new fields of study including genomics, transcriptomics, proteomics, and metabolomics to the development of new treatments and approaches of care for the critically ill and injured patient. An understanding of systems biology enhances a nurse's ability to implement evidence-based practice and to educate patients and families on novel testing and therapies. Systems biology is an integrated and holistic view of humans in relationship with the environment. Biomarkers are used to measure the presence and severity of disease and are rapidly expanding in systems biology endeavors. A systems biology approach using predictive, preventive, and participatory involvement is being utilized in a plethora of conditions of critical illness and injury including sepsis, cancer, pulmonary disease, and traumatic injuries.

Molecular Elucidation of Disease Biomarkers at the Interface of Chemistry and Biology.

Science.gov (United States)

Zhang, Liqin; Wan, Shuo; Jiang, Ying; Wang, Yanyue; Fu, Ting; Liu, Qiaoling; Cao, Zhijuan; Qiu, Liping; Tan, Weihong

2017-02-22

Disease-related biomarkers are objectively measurable molecular signatures of physiological status that can serve as disease indicators or drug targets in clinical diagnosis and therapy, thus acting as a tool in support of personalized medicine. For example, the prostate-specific antigen (PSA) biomarker is now widely used to screen patients for prostate cancer. However, few such biomarkers are currently available, and the process of biomarker identification and validation is prolonged and complicated by inefficient methods of discovery and few reliable analytical platforms. Therefore, in this Perspective, we look at the advanced chemistry of aptamer molecules and their significant role as molecular probes in biomarker studies. As a special class of functional nucleic acids evolved from an iterative technology termed Systematic Evolution of Ligands by Exponential Enrichment (SELEX), these single-stranded oligonucleotides can recognize their respective targets with selectivity and affinity comparable to those of protein antibodies. Because of their fast turnaround time and exceptional chemical properties, aptamer probes can serve as novel molecular tools for biomarker investigations, particularly in assisting identification of new disease-related biomarkers. More importantly, aptamers are able to recognize biomarkers from complex biological environments such as blood serum and cell surfaces, which can provide direct evidence for further clinical applications. This Perspective highlights several major advancements of aptamer-based biomarker discovery strategies and their potential contribution to the practice of precision medicine.

Learning Biology with Plant Pathology.

Science.gov (United States)

Carroll, Juliet E.

This monograph contains 10 plant pathology experiments that were written to correspond to portions of a biology curriculum. Each experiment is suitable to a biology topic and designed to encourage exploration of those biological concepts being taught. Experiments include: (1) The Symptoms and Signs of Disease; (2) Koch's Postulates; (3)…

An overview of the biological disease modifying drugs available for ...

African Journals Online (AJOL)

transcription factors AP-1 and NF-κB to the cell nucleus, as shown in Figure ... of naïve T cells requires the CD80/86 costimulatory molecules on .... arthritis: abridged Cochrane systematic review and network meta-analysis. Br ... N. Engl J Med.

Biomedicines—Moving Biologic Agents into Approved Treatment Options

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Kenneth Cornetta

2013-03-01

Full Text Available The development of biologic agents for therapeutic purposes, or biomedicines, has seen an active area of research both at the bench and in clinical trials. There is mounting evidence that biologic products can provide effective therapy for diseases that have been unresponsive to traditional pharmacologic approaches. Monoclonal antibody therapy for cancer and rheumatologic diseases has become a well accepted part of disease treatment plans. Gene therapy products have been approved in China and Europe. Bioengineering of new agents capitalizing on microRNA biology, nanoparticle technology, stem cell biology, and an increasing understanding of immunology predict a rich future for product development. [...

Development of Voltammetric Double-Polymer-Modified Electrodes for Nanomolar Ion Detection for Environmental and Biological Applications

Science.gov (United States)

Kim, Yushin

Qualitative and quantitative electrochemical methods for trace ion analysis of organic and inorganic species with environmental and biological attention have been developed and reported during past decades. The development of fast and accurate electrochemical methods is critical for field applications with various blocking contaminants. Voltammetric method is attractive not only to analyze selective ion species due to its characteristic based on ion lipophilicity, but also to lower the limit of detection by combining with stripping analysis. In my PhD work, I have developed and studied a highly selective and sensitive electrochemical method that can be used to characterize fundamental transport dynamics and to develop electrochemical sensors at liquid/liquid interfaces based on electrochemically-controlled ion transfer and recognition. The understanding of the kinetic and thermodynamic properties of the voltammetric ion transfer through polymer-modified ion-selective electrodes leads to realize the highly selective and sensitive analytical method. The ultrathin polymer membrane is used to maximize a current response by complete exhaustion of preconcentrated ions. Therefore, nanomolar detection is achieved and confirmed by a thermodynamic mechanism that controls the detection limit. It was also demonstrated experimentally and theoretically that more lipophilic ionic species gives a significantly lower detection limit. The voltammetric method was expanded into inexpensive and disposable applications based on pencil lead modified with the thin polymer membrane. In the other hand, micropipet/nanopipet voltammetry as an artificial cell membrane was used to study the interface between two immiscible solutions for environmental and biomedical applications. It is very useful to get quantitative kinetic and thermodynamic information by studying numerical simulations of ion transfer and diffusion. Molecular recognition and transport of heparin and low

Inflammatory bowel disease: immunodiagnostics, immunotherapeutics, and ecotherapeutics.

LENUS (Irish Health Repository)

Shanahan, F

2012-02-03

Treatment options for inflammatory bowel disease (IBD) reflect a continuing shift from empiricism to strategies based on improved understanding of the pathophysiology of disease. In susceptible individuals, IBD appears to be the result of defective regulation of mucosal immune interactions with the enteric microflora. This has prompted research directed at the interface of the traditional disciplines of immunology, microbiology, and epithelial cell biology. Whereas immunodiagnostics have been of limited clinical value in IBD, assessments of mucosal rather than systemic immune function are promising. Therapeutically, there is an increasing trend toward more aggressive and earlier use of immunomodulatory agents, particularly for prevention of relapse, with cytokine manipulation as a bridge therapy to achieve remission in patients with acute severe disease. Although most drug treatments are directed toward altering the host response, the rationale for manipulating the enteric flora appears sound and will be the basis of additional future therapeutic strategies. Notwithstanding the widening range of options for drug therapy in IBD, other outcome modifiers and well-established principles of managing chronic disease are as important as ever.

Evaluation of V, Ir, Ru, V-Ir, V-Ru, and W-V as permanent chemical modifiers for the determination of cadmium, lead, and zinc in botanic and biological slurries by electrothermal atomic absorption spectrometry

International Nuclear Information System (INIS)

Acar, Orhan

2005-01-01

Permanent modifiers (V, Ir, Ru, V-Ir, V-Ru, and W-V) thermally coated on to platforms of pyrolytic graphite tubes were employed for the determination of Cd, Pb, and Zn in botanic and biological slurries by electrothermal atomic absorption spectrometry (ETAAS). Conventional Pd + Mg(NO 3 ) 2 modifier mixture was also used for the determination of analytes in slurries and digested samples. Optimum masses and mass ratios of permanent modifiers for Cd, Pb, and Zn in slurry sample solutions were investigated. The 280 μg of V, 280 μg of V + 200 μg of Ir, 280 μg of V + 200 μg of Ru or 240 μg of W + 280 μg of V in 0.2% (v/v) Triton X-100 plus 0.5% (v/v) HNO 3 mixture was found as efficient as 5 μg of Pd + 3 μg of Mg(NO 3 ) 2 modifier mixture for obtaining thermal stabilization, and for obtaining best recoveries. Optimization conditions of analytes, such as pyrolysis and atomization temperature, characteristic masses and detection limits, and atomization and background peak profiles were studied with permanent and 5 μg of Pd + 3 μg of Mg(NO 3 ) 2 conventional modifiers and compared with each other. The permanent V-Ir, V-Ru, and W-V modifiers remained stable for approximately 250-300 firings when 20 μl of slurries and digested samples were delivered into the atomizer. In addition, the mixed permanent modifiers increase the tube lifetime by 50-95% when compared with untreated platforms. The characteristic masses and detection limits of analytes (dilution factor of 125 ml g -1 ) obtained with V-Ir based on integrated absorbance as example for 0.8% (m/v) slurries were 1.0 pg and 3 ng g -1 for Cd, 18 pg and 17 ng g -1 for Pb, and 0.7 pg and 4 ng g -1 for Zn, respectively. The results of analytes obtained by employing V-Ir, V-Ru, and W-V permanent modifier mixtures in botanic and biological certified and standard reference materials were in agreement with the certified values of reference materials

Precision pharmacology for Alzheimer's disease.

Science.gov (United States)

Hampel, Harald; Vergallo, Andrea; Aguilar, Lisi Flores; Benda, Norbert; Broich, Karl; Cuello, A Claudio; Cummings, Jeffrey; Dubois, Bruno; Federoff, Howard J; Fiandaca, Massimo; Genthon, Remy; Haberkamp, Marion; Karran, Eric; Mapstone, Mark; Perry, George; Schneider, Lon S; Welikovitch, Lindsay A; Woodcock, Janet; Baldacci, Filippo; Lista, Simone

2018-04-01

The complex multifactorial nature of polygenic Alzheimer's disease (AD) presents significant challenges for drug development. AD pathophysiology is progressing in a non-linear dynamic fashion across multiple systems levels - from molecules to organ systems - and through adaptation, to compensation, and decompensation to systems failure. Adaptation and compensation maintain homeostasis: a dynamic equilibrium resulting from the dynamic non-linear interaction between genome, epigenome, and environment. An individual vulnerability to stressors exists on the basis of individual triggers, drivers, and thresholds accounting for the initiation and failure of adaptive and compensatory responses. Consequently, the distinct pattern of AD pathophysiology in space and time must be investigated on the basis of the individual biological makeup. This requires the implementation of systems biology and neurophysiology to facilitate Precision Medicine (PM) and Precision Pharmacology (PP). The regulation of several processes at multiple levels of complexity from gene expression to cellular cycle to tissue repair and system-wide network activation has different time delays (temporal scale) according to the affected systems (spatial scale). The initial failure might originate and occur at every level potentially affecting the whole dynamic interrelated systems within an organism. Unraveling the spatial and temporal dynamics of non-linear pathophysiological mechanisms across the continuum of hierarchical self-organized systems levels and from systems homeostasis to systems failure is key to understand AD. Measuring and, possibly, controlling space- and time-scaled adaptive and compensatory responses occurring during AD will represent a crucial step to achieve the capacity to substantially modify the disease course and progression at the best suitable timepoints, thus counteracting disrupting critical pathophysiological inputs. This approach will provide the conceptual basis for effective

Systems biology from micro-organisms to human metabolic diseases: the role of detailed kinetic models.

Science.gov (United States)

Bakker, Barbara M; van Eunen, Karen; Jeneson, Jeroen A L; van Riel, Natal A W; Bruggeman, Frank J; Teusink, Bas

2010-10-01

Human metabolic diseases are typically network diseases. This holds not only for multifactorial diseases, such as metabolic syndrome or Type 2 diabetes, but even when a single gene defect is the primary cause, where the adaptive response of the entire network determines the severity of disease. The latter may differ between individuals carrying the same mutation. Understanding the adaptive responses of human metabolism naturally requires a systems biology approach. Modelling of metabolic pathways in micro-organisms and some mammalian tissues has yielded many insights, qualitative as well as quantitative, into their control and regulation. Yet, even for a well-known pathway such as glycolysis, precise predictions of metabolite dynamics from experimentally determined enzyme kinetics have been only moderately successful. In the present review, we compare kinetic models of glycolysis in three cell types (African trypanosomes, yeast and skeletal muscle), evaluate their predictive power and identify limitations in our understanding. Although each of these models has its own merits and shortcomings, they also share common features. For example, in each case independently measured enzyme kinetic parameters were used as input. Based on these 'lessons from glycolysis', we will discuss how to make best use of kinetic computer models to advance our understanding of human metabolic diseases.

Genetically modified soybean plants and their ecosystem

Directory of Open Access Journals (Sweden)

Milošević Mirjana B.

2004-01-01

Full Text Available Transgenic plants are developed by introgressing new genes using methods of molecular genetics and genetic engineering. The presence of these genes in plant genome is identified on the basis of specific oligonucleotides primers, and the use of PCR (Polymerase Chain Reaction and DNA fragments multiplication. Genetically modified plants such as soybean constitute a newly created bioenergetic potential whose gene expression can cause disturbance of the biological balance ecosystem, soil structure and soil microbiological activity. Genetically modified plants may acquire monogenic or polygenic traits causing genetic and physiological changes in these plants, which may elicit a certain reaction of the environment including changes of microbiological composition of soil rhizosphere. The aim of introgressing genes for certain traits into a cultivated plant is to enhance its yield and intensify food production. There are more and more genetically modified plant species such as soybean, corn, potato, rice and others and there is a pressure to use them as human food and animal feed. Genetically modified soybean plants with introgressed gene for resistance to total herbicides, such as Round-up, are more productive than non-modified herbicide-sensitive soybeans.

Field testing genetically modified organisms: framework for decisions

National Research Council Canada - National Science Library

National Research Council Staff

1989-01-01

... on Scientific Evaluation of the Introduction of Genetically Modified Microoganisms and Plants into the Environment Board on Biology Commission on Life Sciences National Research Council NATIONAL ACADEMY PRESS Washington, D.C. 1989 i Copyrightthe cannot be not from book, paper however, version for formatting, original authoritative the typesetting-s...

Human Environmental Disease Network

DEFF Research Database (Denmark)

Taboureau, Olivier; Audouze, Karine

2017-01-01

During the past decades, many epidemiological, toxicological and biological studies have been performed to assess the role of environmental chemicals as potential toxicants for diverse human disorders. However, the relationships between diseases based on chemical exposure have been rarely studied...... by computational biology. We developed a human environmental disease network (EDN) to explore and suggest novel disease-disease and chemical-disease relationships. The presented scored EDN model is built upon the integration on systems biology and chemical toxicology using chemical contaminants information...... and their disease relationships from the reported TDDB database. The resulting human EDN takes into consideration the level of evidence of the toxicant-disease relationships allowing including some degrees of significance in the disease-disease associations. Such network can be used to identify uncharacterized...

Ocular Behçet disease: current therapeutic approaches.

Science.gov (United States)

Evereklioglu, Cem

2011-11-01

To alert physician to timely recognition and current treatment of recurrent hypopyon iridocyclitis or panuveitis in ocular Behçet disease (OBD). Interferon-α, rituximab, intravitreal triamcinolone, and biological response modifiers by tumor necrosis factor inhibitors such as infliximab and adalimumab are being used increasingly for the treatment of severe sight-threatening ocular inflammation including retinal vasculitis and cystoid macular edema (CME). Biological agents offer tremendous potential in the treatment of OBD. Given that OBD predominantly afflicts the younger adults in their most productive years, dermatologist, rheumatologist, internist, or general practitioners supervising patients with oculo-articulo-oromucocutaneous syndromes should be aware of systemic Behçet disease. Early recognition of ocular involvement is important and such patients should strongly be instructed to visit immediately an ophthalmologist, as uveitis management differs from extraocular involvements with high ocular morbidity from sight-threatening complications due to relapsing inflammatory attacks in the posterior segment of the eye. A single infliximab infusion should be considered for the control of acute panuveitis, whereas repeated long-term infliximab infusions were proved to be more effective in reducing the number of episodes in refractory uveoretinitis with faster regression and complete remission of CME.

Patterns of Care for Biologic-Dosing Outliers and Nonoutliers in Biologic-Naive Patients with Rheumatoid Arthritis.

Science.gov (United States)

Delate, Thomas; Meyer, Roxanne; Jenkins, Daniel

2017-08-01

Although most biologic medications for patients with rheumatoid arthritis (RA) have recommended fixed dosing, actual biologic dosing may vary among real-world patients, since some patients can receive higher (high-dose outliers) or lower (low-dose outliers) doses than what is recommended in medication package inserts. To describe the patterns of care for biologic-dosing outliers and nonoutliers in biologic-naive patients with RA. This was a retrospective, longitudinal cohort study of patients with RA who were not pregnant and were aged ≥ 18 and 110% of the approved dose in the package insert at any time during the study period. Baseline patient profiles, treatment exposures, and outcomes were collected during the 180 days before and up to 2 years after biologic initiation and compared across index biologic outlier groups. Patients were followed for at least 1 year, with a subanalysis of those patients who remained as members for 2 years. This study included 434 RA patients with 1 year of follow-up and 372 RA patients with 2 years of follow-up. Overall, the vast majority of patients were female (≈75%) and had similar baseline characteristics. Approximately 10% of patients were outliers in both follow-up cohorts. ETN patients were least likely to become outliers, and ADA patients were most likely to become outliers. Of all outliers during the 1-year follow-up, patients were more likely to be a high-dose outlier (55%) than a low-dose outlier (45%). Median 1- and 2-year adjusted total biologic costs (based on wholesale acquisition costs) were higher for ADA and ETA nonoutliers than for IFX nonoutliers. Biologic persistence was highest for IFX patients. Charlson Comorbidity Index score, ETN and IFX index biologic, and treatment with a nonbiologic disease-modifying antirheumatic drug (DMARD) before biologic initiation were associated with becoming high- or low-dose outliers (c-statistic = 0.79). Approximately 1 in 10 study patients with RA was identified as a

Synthesis of base-modified 2'-deoxyribonucleoside triphosphates and their use in enzymatic synthesis of modified DNA for applications in bioanalysis and chemical biology.

Science.gov (United States)

Hocek, Michal

2014-11-07

The synthesis of 2'-deoxyribonucleoside triphosphates (dNTPs) either by classical triphosphorylation of nucleosides or by aqueous cross-coupling reactions of halogenated dNTPs is discussed. Different enzymatic methods for synthesis of modified oligonucleotides and DNA by polymerase incorporation of modified nucleotides are summarized, and the applications in redox or fluorescent labeling, as well as in bioconjugations and modulation of interactions of DNA with proteins, are outlined.

The Human Proteome Organization Chromosome 6 Consortium: integrating chromosome-centric and biology/disease driven strategies.

Science.gov (United States)

Borchers, C H; Kast, J; Foster, L J; Siu, K W M; Overall, C M; Binkowski, T A; Hildebrand, W H; Scherer, A; Mansoor, M; Keown, P A

2014-04-04

The Human Proteome Project (HPP) is designed to generate a comprehensive map of the protein-based molecular architecture of the human body, to provide a resource to help elucidate biological and molecular function, and to advance diagnosis and treatment of diseases. Within this framework, the chromosome-based HPP (C-HPP) has allocated responsibility for mapping individual chromosomes by country or region, while the biology/disease HPP (B/D-HPP) coordinates these teams in cross-functional disease-based groups. Chromosome 6 (Ch6) provides an excellent model for integration of these two tasks. This metacentric chromosome has a complement of 1002-1034 genes that code for known, novel or putative proteins. Ch6 is functionally associated with more than 120 major human diseases, many with high population prevalence, devastating clinical impact and profound societal consequences. The unique combination of genomic, proteomic, metabolomic, phenomic and health services data being drawn together within the Ch6 program has enormous potential to advance personalized medicine by promoting robust biomarkers, subunit vaccines and new drug targets. The strong liaison between the clinical and laboratory teams, and the structured framework for technology transfer and health policy decisions within Canada will increase the speed and efficacy of this transition, and the value of this translational research. Canada has been selected to play a leading role in the international Human Proteome Project, the global counterpart of the Human Genome Project designed to understand the structure and function of the human proteome in health and disease. Canada will lead an international team focusing on chromosome 6, which is functionally associated with more than 120 major human diseases, including immune and inflammatory disorders affecting the brain, skeletal system, heart and blood vessels, lungs, kidney, liver, gastrointestinal tract and endocrine system. Many of these chronic and persistent

Radiation biology and radiation protection

International Nuclear Information System (INIS)

Hendry, J.H.

2012-01-01

For protection purposes, the biological effects of radiation are separated into stochastic effects (cancer, hereditary effects) presumed to be unicellular in origin, and tissue reactions due to injury in populations of cells. The latter are deterministic effects, renamed ‘tissue reactions’ in the 2007 Recommendations of the International Commission on Radiological Protection because of the increasing evidence of the ability to modify responses after irradiation. Tissue reactions become manifest either early or late after doses above a threshold dose, which is the basis for recommended dose limits for avoiding such effects. Latency time before manifestation is related to cell turnover rates, and tissue proliferative and structural organisation. Threshold doses have been defined for practical purposes at 1% incidence of an effect. In general, threshold doses are lower for longer follow-up times because of the slow progression of injury before manifestation. Radiosensitive individuals in the population may contribute to low threshold doses, and in the future, threshold doses may be increased by the use of various biological response modifiers post irradiation for reducing injury. Threshold doses would be expected to be higher for fractionated or protracted doses, unless doses below the threshold dose only cause single-hit-type events that are not modified by repair/recovery phenomena, or if different mechanisms of injury are involved at low and high doses.

NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease.

Science.gov (United States)

Jack, Clifford R; Bennett, David A; Blennow, Kaj; Carrillo, Maria C; Dunn, Billy; Haeberlein, Samantha Budd; Holtzman, David M; Jagust, William; Jessen, Frank; Karlawish, Jason; Liu, Enchi; Molinuevo, Jose Luis; Montine, Thomas; Phelps, Creighton; Rankin, Katherine P; Rowe, Christopher C; Scheltens, Philip; Siemers, Eric; Snyder, Heather M; Sperling, Reisa

2018-04-01

In 2011, the National Institute on Aging and Alzheimer's Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer's disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer's Association to update and unify the 2011 guidelines. This unifying update is labeled a "research framework" because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer's Association Research Framework, Alzheimer's disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers

Endemic infectious diseases and biological warfare during the Gulf War: a decade of analysis and final concerns.

Science.gov (United States)

Hyams, K C; Riddle, J; Trump, D H; Graham, J T

2001-11-01

Infectious diseases were one of the first health threats confronted by Coalition troops deployed to the Arabian desert in August 1990. On the basis of experiences in World War II, the major endemic infectious disease risks were thought to be sandfly fever, cutaneous leishmaniasis, diarrheal disease, and malaria. Although there was active surveillance, no case of sandfly fever and few other endemic infectious diseases were identified among over 500,000 U.S., British, and Canadian ground troops. In addition, there was no diagnosis of biological warfare (BW) exposure, and BW agents were not detected in clinical, environmental, or veterinary samples. The most common infectious disease problems were those associated with crowding (acute upper respiratory infections) and reduced levels of sanitation (travelers-type diarrhea). Only one endemic infectious disease has been confirmed as causing chronic health problems: visceral Leishmania tropica infection (viscerotropic leishmaniasis). However, this protozoan infection was diagnosed in only 12 U.S. veterans, and no new cases have been identified during the last 8 years. Infectious diseases were not a serious problem for Gulf War troops because of extensive preventive medicine efforts and favorable weather and geographic factors. Moreover, it is unlikely that an endemic infectious disease or a BW agent could cause chronic health problems and remain undetected over a 10-year period.

Cigarette use and cardiovascular risk in chronic kidney disease: an unappreciated modifiable lifestyle risk factor.

LENUS (Irish Health Repository)

Stack, Austin G

2012-01-31

Tobacco use is a major modifiable cardiovascular risk factor in the general population and contributes to excess cardiovascular risk. Emerging evidence from large-scale observational studies suggests that continued tobacco use is also an independent cardiovascular risk factor among patients with chronic kidney disease (CKD). The benefits of smoking cessation programs on improving the heath status of patients and reducing mortality are unequivocal in the general population. Despite this, there has been little effort in pursuing tobacco cessation programs in dialysis cohorts or those with lesser degrees of kidney impairment. Most of our attention to date has focused on the development of "kidney-specific" interventions that reduce rates of renal disease progression and improve dialysis outcomes. The purpose of this current review is to describe the epidemiology of tobacco use among patients with CKD, draw attention to its negative impact on cardiovascular morbidity and mortality, and finally highlight potential strategies for successful intervention. We hope that this study heightens the importance of tobacco use in CKD, stimulates renewed interest in the barriers and challenges that exist in achieving smoking cessation, and endorses the efficacy of intervention strategies and the immeasurable benefits of quitting on cardiovascular and noncardiovascular outcomes.

Copper hexacyanoferrate formation on the modified silica surface with DAB-Am-16 dendrimer

International Nuclear Information System (INIS)

Carmo, Devaney R. do; Gabriel Junior, Suelino; Bicalho, Urquisa O.; Paim, Leonardo L.

2009-01-01

The dendrimer hexadecamine poly(propylene)imine (DAB-Am-16) of third generation (G-3) was anchored on the silica gel surface. The modified silica interact easily with Cu 2+ and then with hexacyanoferrate to form copper hexacyanoferrate. The modified silica was characterized by following techniques: nuclear magnetic resonance (NMR), infrared (FTIR), energy dispersive X-ray (EDX) and cyclic voltammetry. As application of the composite obtained, the modified silica containing copper hexacyanoferrate (CuHCFSD) was tested for a voltammetric determination of nitrite using a graphite paste modified electrode. The modified graphite paste electrode can be applied also to the determination of others biological substances with success. (author)

Screening prior to biological therapy in Crohn's disease: adherence to guidelines and prevalence of infections. Results from a multicentre retrospective study.

Science.gov (United States)

van der Have, Mike; Belderbos, Tim D G; Fidder, Herma H; Leenders, Max; Dijkstra, Gerard; Peters, Charlotte P; Eshuis, Emma J; Ponsioen, Cyriel Y; Siersema, Peter D; van Oijen, Martijn G H; Oldenburg, Bas

2014-10-01

Screening for opportunistic infections prior to starting biological therapy in patients with inflammatory bowel disease is recommended. To assess adherence to screening for opportunistic infections prior to starting biological therapy in Crohn's disease patients and its yield. A multicentre retrospective study was conducted in Crohn's disease patients in whom infliximab or adalimumab was started between 2000 and 2010. Screening included tuberculin skin test, interferon-gamma release assay or chest X-ray for tuberculosis. Extended screening included screening for tuberculosis and viral infections. Patients were followed until three months after ending treatment. Primary endpoints were opportunistic and serious infections. 611 patients were included, 91% on infliximab. 463 (76%) patients were screened for tuberculosis, of whom 113 (24%) underwent extended screening. Screening for tuberculosis and hepatitis B increased to, respectively, 90-97% and 36-49% in the last two years. During a median follow-up of two years, 64/611 (9%, 3.4/100 patient-years) opportunistic infections and 26/611 (4%, 1.6/100 patient-years) serious infections were detected. Comorbidity was significantly associated with serious infections (hazard ratio 3.94). Although screening rates for tuberculosis and hepatitis B increased, screening for hepatitis B was still suboptimal. More caution is required when prescribing biologicals in patients with comorbid conditions. Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

EFFECTS OF SYNTHETIC DISEASE-MODIFYING ANTIRHEUMATIC DRUGS, BIOLOGICAL AGENTS, AND PSYCHOPHARMACOTHERAPY ON THE MENTAL DISORDERS IN PATIENTS WITH RHEUMATOID ARTHRITIS

Directory of Open Access Journals (Sweden)

A. A. Abramkin

2017-01-01

Full Text Available Mental disorders (MDs of the anxiety-depressive spectrum (ADS and cognitive impairment (CI are characteristic of the majority of patients with rheumatoid arthritis (RA; however, the effects of disease-modifying antirheumatic drugs (DMARDs, biological agents (BAs, and their combinations with psychopharmacological drugs (PPDs on these abnormalities have been insufficiently studied. Objective: to investigate trends in the incidence of MDs in RA patients receiving different treatment regimens.Subjects and methods. The investigation included 128 RA patients (13% men and 87% women who fulfilled the 1987 American College of Rheumatology criteria; their mean age was 47.4±0.9 years; the median duration of RA was 96 [48; 228] months. RA activity was found to be high, moderate, and low in 48, 56, and 24 patients, respectively. DAS28 averaged 5.34±0.17. 80% of the patients received DMARDs. MDs were diagnosed based on ICD-10 coding, by using a semi-structured interview and scales, such as the Hospital Anxiety and Depression Scale, the Hamilton Anxiety Scale, and the Montgomery-Asberg Depression Rating Scale. Clinical and psychological procedures were used to diagnose CI. At the study inclusion stage, ADS disorders were detected in 123 (96.1% patients; CI was found in 88 (68.7%. Forty-one (32.1% patients were diagnosed with major depression (an obvious or moderate depressive episode, 53 (41.4% patients had minor depression (a mild depressive episode and dysthymia, and 29 (22.6% had anxiety disorders (ADs (adjustment disorders with anxiety symptoms, as well as generalized anxiety disorder. The dynamics of MDs was estimated in 112 (87.5% of the 128 patients and in 83 (64.8% at one- and five-year follow-ups, respectively. The following groups were identified according to the performed therapy: 1 synthetic DMARDs (n = 39; 2 synthetic DMARDs + PPDs (n = 43; 3 BAs + DMARDs (n = 32; 4 BAs + DMARDs + PPDs (n = 9.Results and discussion. In Group 1, the

What does systems biology mean for drug development?

Science.gov (United States)

Schrattenholz, André; Soskić, Vukić

2008-01-01

The complexity and flexibility of cellular architectures is increasingly recognized by impressive progress on the side of molecular analytics, i.e. proteomics, genomics and metabolomics. One of the messages from systems biology is that the number of molecular species in cellular networks is orders of magnitude bigger than anticipated by genomic analysis, in particular by fast posttranslational modifications of proteins. The requirements to manage external signals, integrate spatiotemporal signal transduction inside an organism and at the same time optimizing networks of biochemical and chemical reactions result in chemically extremely fine tuned molecular entities. Chemical side reactions of enzymatic activity, like e.g. random oxidative damage of proteins by free radicals during aging constantly introduce epigenetic alterations of protein targets. These events gradually and on an individual stochastic scale, keep modifying activities of these targets, and their affinities and selectivities towards biological and pharmacological ligands. One further message is that many of the key reactions in living systems are essentially based on interactions of low affinities and even low selectivities. This principle is responsible for the enormous flexibility and redundancy of cellular circuitries. So, in complex disorders like cancer or neurodegenerative diseases, which are rooted in relatively subtle and multimodal dysfunction of important physiologic pathways, drug discovery programs based on the concept of high affinity/high specificity compounds ("one-target, one-disease"), which still dominate the pharmaceutical industry increasingly turn out to be unsuccessful. Despite improvements in rational drug design and high throughput screening methods, the number of novel, single-target drugs fell much behind expectations during the past decade and the treatment of "complex diseases" remains a most pressing medical need. Currently a change of paradigm can be observed with

PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome

Science.gov (United States)

Ebermann, Inga; Phillips, Jennifer B.; Liebau, Max C.; Koenekoop, Robert K.; Schermer, Bernhard; Lopez, Irma; Schäfer, Ellen; Roux, Anne-Francoise; Dafinger, Claudia; Bernd, Antje; Zrenner, Eberhart; Claustres, Mireille; Blanco, Bernardo; Nürnberg, Gudrun; Nürnberg, Peter; Ruland, Rebecca; Westerfield, Monte; Benzing, Thomas; Bolz, Hanno J.

2010-01-01

Usher syndrome is a genetically heterogeneous recessive disease characterized by hearing loss and retinitis pigmentosa (RP). It frequently presents with unexplained, often intrafamilial, variability of the visual phenotype. Although 9 genes have been linked with Usher syndrome, many patients do not have mutations in any of these genes, suggesting that there are still unidentified genes involved in the syndrome. Here, we have determined that mutations in PDZ domain–containing 7 (PDZD7), which encodes a homolog of proteins mutated in Usher syndrome subtype 1C (USH1C) and USH2D, contribute to Usher syndrome. Mutations in PDZD7 were identified only in patients with mutations in other known Usher genes. In a set of sisters, each with a homozygous mutation in USH2A, a frame-shift mutation in PDZD7 was present in the sister with more severe RP and earlier disease onset. Further, heterozygous PDZD7 mutations were present in patients with truncating mutations in USH2A, G protein–coupled receptor 98 (GPR98; also known as USH2C), and an unidentified locus. We validated the human genotypes using zebrafish, and our findings were consistent with digenic inheritance of PDZD7 and GPR98, and with PDZD7 as a retinal disease modifier in patients with USH2A. Pdzd7 knockdown produced an Usher-like phenotype in zebrafish, exacerbated retinal cell death in combination with ush2a or gpr98, and reduced Gpr98 localization in the region of the photoreceptor connecting cilium. Our data challenge the view of Usher syndrome as a traditional Mendelian disorder and support the reclassification of Usher syndrome as an oligogenic disease. PMID:20440071

PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome.

Science.gov (United States)

Ebermann, Inga; Phillips, Jennifer B; Liebau, Max C; Koenekoop, Robert K; Schermer, Bernhard; Lopez, Irma; Schäfer, Ellen; Roux, Anne-Francoise; Dafinger, Claudia; Bernd, Antje; Zrenner, Eberhart; Claustres, Mireille; Blanco, Bernardo; Nürnberg, Gudrun; Nürnberg, Peter; Ruland, Rebecca; Westerfield, Monte; Benzing, Thomas; Bolz, Hanno J

2010-06-01

Usher syndrome is a genetically heterogeneous recessive disease characterized by hearing loss and retinitis pigmentosa (RP). It frequently presents with unexplained, often intrafamilial, variability of the visual phenotype. Although 9 genes have been linked with Usher syndrome, many patients do not have mutations in any of these genes, suggesting that there are still unidentified genes involved in the syndrome. Here, we have determined that mutations in PDZ domain-containing 7 (PDZD7), which encodes a homolog of proteins mutated in Usher syndrome subtype 1C (USH1C) and USH2D, contribute to Usher syndrome. Mutations in PDZD7 were identified only in patients with mutations in other known Usher genes. In a set of sisters, each with a homozygous mutation in USH2A, a frame-shift mutation in PDZD7 was present in the sister with more severe RP and earlier disease onset. Further, heterozygous PDZD7 mutations were present in patients with truncating mutations in USH2A, G protein-coupled receptor 98 (GPR98; also known as USH2C), and an unidentified locus. We validated the human genotypes using zebrafish, and our findings were consistent with digenic inheritance of PDZD7 and GPR98, and with PDZD7 as a retinal disease modifier in patients with USH2A. Pdzd7 knockdown produced an Usher-like phenotype in zebrafish, exacerbated retinal cell death in combination with ush2a or gpr98, and reduced Gpr98 localization in the region of the photoreceptor connecting cilium. Our data challenge the view of Usher syndrome as a traditional Mendelian disorder and support the reclassification of Usher syndrome as an oligogenic disease.

Alternative Splicing and Tissue-specific Elastin Misassembly Act as Biological Modifiers of Human Elastin Gene Frameshift Mutations Associated with Dominant Cutis Laxa*

Science.gov (United States)

Sugitani, Hideki; Hirano, Eiichi; Knutsen, Russell H.; Shifren, Adrian; Wagenseil, Jessica E.; Ciliberto, Christopher; Kozel, Beth A.; Urban, Zsolt; Davis, Elaine C.; Broekelmann, Thomas J.; Mecham, Robert P.

2012-01-01

Elastin is the extracellular matrix protein in vertebrates that provides elastic recoil to blood vessels, the lung, and skin. Because the elastin gene has undergone significant changes in the primate lineage, modeling elastin diseases in non-human animals can be problematic. To investigate the pathophysiology underlying a class of elastin gene mutations leading to autosomal dominant cutis laxa, we engineered a cutis laxa mutation (single base deletion) into the human elastin gene contained in a bacterial artificial chromosome. When expressed as a transgene in mice, mutant elastin was incorporated into elastic fibers in the skin and lung with adverse effects on tissue function. In contrast, only low levels of mutant protein incorporated into aortic elastin, which explains why the vasculature is relatively unaffected in this disease. RNA stability studies found that alternative exon splicing acts as a modifier of disease severity by influencing the spectrum of mutant transcripts that survive nonsense-mediated decay. Our results confirm the critical role of the C-terminal region of tropoelastin in elastic fiber assembly and suggest tissue-specific differences in the elastin assembly pathway. PMID:22573328

Recent Trends in Control Methods for Bacterial Wilt Diseases Caused by Ralstonia solanacearum

Science.gov (United States)

Yuliar; Nion, Yanetri Asi; Toyota, Koki

2015-01-01

Previous studies have described the development of control methods against bacterial wilt diseases caused by Ralstonia solanacearum. This review focused on recent advances in control measures, such as biological, physical, chemical, cultural, and integral measures, as well as biocontrol efficacy and suppression mechanisms. Biological control agents (BCAs) have been dominated by bacteria (90%) and fungi (10%). Avirulent strains of R. solanacearum, Pseudomonas spp., Bacillus spp., and Streptomyces spp. are well-known BCAs. New or uncommon BCAs have also been identified such as Acinetobacter sp., Burkholderia sp., and Paenibacillus sp. Inoculation methods for BCAs affect biocontrol efficacy, such as pouring or drenching soil, dipping of roots, and seed coatings. The amendment of different organic matter, such as plant residue, animal waste, and simple organic compounds, have frequently been reported to suppress bacterial wilt diseases. The combined application of BCAs and their substrates was shown to more effectively suppress bacterial wilt in the tomato. Suppression mechanisms are typically attributed to the antibacterial metabolites produced by BCAs or those present in natural products; however, the number of studies related to host resistance to the pathogen is increasing. Enhanced/modified soil microbial communities are also indirectly involved in disease suppression. New promising types of control measures include biological soil disinfection using substrates that release volatile compounds. This review described recent advances in different control measures. We focused on the importance of integrated pest management (IPM) for bacterial wilt diseases. PMID:25762345