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

PubMed

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.

Current concepts regarding pharmacologic treatment of rheumatoid and osteoarthritis.

PubMed

Wildy, K S; Wasko, M C

2001-05-01

Treating patients with osteoarthritis (OA) and rheumatoid arthritis (RA) remains challenging; however, new agents offer the chance for an improved quality of life. As an alternative to traditional nonsteroidal anti-inflammatories, cyclooxygenase-2 inhibitors provide pain relief for OA and RA patients with possible fewer side effects. Otherwise, OA patients may opt for topical agents, injections, or supplements. Rheumatoid arthritis research has led to an improved understanding of the inflammatory cascade and an appreciation of the early tissue destruction. A new treatment philosophy has thus emerged along with the development of new biologic agents; the latter, along with combination therapy and a new disease modifying antirheumatic drug, leflunomide, have greatly expanded the chances for disease control in RA patients.

Peptides and peptidomimetics as immunomodulators

PubMed Central

Gokhale, Ameya S; Satyanarayanajois, Seetharama

2014-01-01

Peptides and peptidomimetics can function as immunomodulating agents by either blocking the immune response or stimulating the immune response to generate tolerance. Knowledge of B- or T-cell epitopes along with conformational constraints is important in the design of peptide-based immunomodulating agents. Work on the conformational aspects of peptides, synthesis and modified amino acid side chains have contributed to the development of a new generation of therapeutic agents for autoimmune diseases and cancer. The design of peptides/peptidomimetics for immunomodulation in autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, systemic lupus and HIV infection is reviewed. In cancer therapy, peptide epitopes are used in such a way that the body is trained to recognize and fight the cancer cells locally as well as systemically. PMID:25186605

Epigenetics: A novel therapeutic approach for the treatment of Alzheimer’s disease

PubMed Central

Adwan, Lina; Zawia, Nasser H.

2013-01-01

Alzheimer’s disease (AD) is the most common type of dementia in the elderly. It is characterized by the deposition of two forms of aggregates within the brain, the amyloid β plaques and tau neurofibrillary tangles. Currently, no disease-modifying agent is approved for the treatment of AD. Approved pharmacotherapies target the peripheral symptoms but they do not prevent or slow down the progression of the disease. Although several disease-modifying immunotherapeutic agents are in clinical development, many have failed due to lack of efficacy or serious adverse events. Epigenetic changes including DNA methylation and histone modifications are involved in learning and memory and have been recently highlighted for holding promise as potential targets for AD therapeutics. Dynamic and latent epigenetic alterations are incorporated in AD pathological pathways and present valuable reversible targets for AD and other neurological disorders. The approval of epigenetic drugs for cancer treatment has opened the door for the development of epigenetic drugs for other disorders including neurodegenerative diseases. In particular, methyl donors and histone deacetylase inhibitors are being investigated for possible therapeutic effects to rescue memory and cognitive decline found in such disorders. This review explores the area of epigenetics for potential AD interventions and presents the most recent findings in this field. PMID:23562602

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

PubMed

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.

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

PubMed

Mirski, Tomasz; Bartoszcze, Michał; Bielawska-Drózd, Agata; Gryko, Romuald; Kocik, Janusz; Niemcewicz, Marcin; Chomiczewski, Krzysztof

2016-01-01

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 (Mycobacterium spp., Yersinia spp., Campylobacter spp., Streptococcus pneumoniae, Salmonella typhi, Salmonella enterica, Staphylococcus aureus, Neisseria meningitidis, Clostridium difficile , Helicobacter pylori), 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.

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

PubMed

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 relapsing on prior disease-modifying agents. Treatment emergent adverse effects were common with all new drug treatments. The cost of treating MS remains high, because MS therapies accounted for the highest spending growth of any specialty drug class in 2013. Most therapies cost, on average, US $6000/mo based on wholesale acquisition cost, and few cost-benefit studies are available for new treatments. With expansion of new treatments, patients and providers now have multiple options and improved flexibility in managing MS. The relative place in therapy of new treatments is unknown, and treatment decisions are largely based on patient preference, efficacy, and risk potential. The cost of treating MS continues to be high, even with more treatment options available. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.

Incorporating individual health-protective decisions into disease transmission models: a mathematical framework.

PubMed

Durham, David P; Casman, Elizabeth A

2012-03-07

It is anticipated that the next generation of computational epidemic models will simulate both infectious disease transmission and dynamic human behaviour change. Individual agents within a simulation will not only infect one another, but will also have situational awareness and a decision algorithm that enables them to modify their behaviour. This paper develops such a model of behavioural response, presenting a mathematical interpretation of a well-known psychological model of individual decision making, the health belief model, suitable for incorporation within an agent-based disease-transmission model. We formalize the health belief model and demonstrate its application in modelling the prevalence of facemask use observed over the course of the 2003 Hong Kong SARS epidemic, a well-documented example of behaviour change in response to a disease outbreak.

Incorporating individual health-protective decisions into disease transmission models: a mathematical framework

PubMed Central

Durham, David P.; Casman, Elizabeth A.

2012-01-01

It is anticipated that the next generation of computational epidemic models will simulate both infectious disease transmission and dynamic human behaviour change. Individual agents within a simulation will not only infect one another, but will also have situational awareness and a decision algorithm that enables them to modify their behaviour. This paper develops such a model of behavioural response, presenting a mathematical interpretation of a well-known psychological model of individual decision making, the health belief model, suitable for incorporation within an agent-based disease-transmission model. We formalize the health belief model and demonstrate its application in modelling the prevalence of facemask use observed over the course of the 2003 Hong Kong SARS epidemic, a well-documented example of behaviour change in response to a disease outbreak. PMID:21775324

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

PubMed

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.

Horizon 2020 in Diabetic Kidney Disease: The Clinical Trial Pipeline for Add-On Therapies on Top of Renin Angiotensin System Blockade

PubMed Central

Perez-Gomez, Maria Vanessa; Sanchez-Niño, Maria Dolores; Sanz, Ana Belen; Martín-Cleary, Catalina; Ruiz-Ortega, Marta; Egido, Jesus; Navarro-González, Juan F.; Ortiz, Alberto; Fernandez-Fernandez, Beatriz

2015-01-01

Diabetic kidney disease is the most frequent cause of end-stage renal disease. This implies failure of current therapeutic approaches based on renin-angiotensin system (RAS) blockade. Recent phase 3 clinical trials of paricalcitol in early diabetic kidney disease and bardoxolone methyl in advanced diabetic kidney disease failed to meet the primary endpoint or terminated on safety concerns, respectively. However, various novel strategies are undergoing phase 2 and 3 randomized controlled trials targeting inflammation, fibrosis and signaling pathways. Among agents currently undergoing trials that may modify the clinical practice on top of RAS blockade in a 5-year horizon, anti-inflammatory agents currently hold the most promise while anti-fibrotic agents have so far disappointed. Pentoxifylline, an anti-inflammatory agent already in clinical use, was recently reported to delay estimated glomerular filtration rate (eGFR) loss in chronic kidney disease (CKD) stage 3–4 diabetic kidney disease when associated with RAS blockade and promising phase 2 data are available for the pentoxifylline derivative CTP-499. Among agents targeting chemokines or chemokine receptors, the oral small molecule C-C chemokine receptor type 2 (CCR2) inhibitor CCX140 decreased albuminuria and eGFR loss in phase 2 trials. A dose-finding trial of the anti-IL-1β antibody gevokizumab in diabetic kidney disease will start in 2015. However, clinical development is most advanced for the endothelin receptor A blocker atrasentan, which is undergoing a phase 3 trial with a primary outcome of preserving eGFR. The potential for success of these approaches and other pipeline agents is discussed in detail. PMID:26239562

ENHANCED CONCENTRATION AND ISOLATION OF CYCLOSPORA CAYETANENSIS OOCYSTS FROM HUMAN FECAL SAMPLES

EPA Science Inventory

Cyclospora cayetanensis is the causative agent of cyclosporiasis, an emerging infections disease. A new method for the purification of Cycloposra cayetanensis oocysts from fecal matter has been developed, using a modified detachment solution and a Renocal-sucrose gradient sedimen...

Novel arylalkenylpropargylamines as neuroprotective, potent, and selective monoamine oxidase B inhibitors for the treatment of Parkinson's disease.

PubMed

Huleatt, Paul B; Khoo, Mui Ling; Chua, Yi Yuan; Tan, Tiong Wei; Liew, Rou Shen; Balogh, Balázs; Deme, Ruth; Gölöncsér, Flóra; Magyar, Kalman; Sheela, David P; Ho, Han Kiat; Sperlágh, Beáta; Mátyus, Péter; Chai, Christina L L

2015-02-12

To develop novel neuroprotective agents, a library of novel arylalkenylpropargylamines was synthesized and tested for inhibitory activities against monoamine oxidases. From this, a number of highly potent and selective monoamine oxidase B inhibitors were identified. Selected compounds were also tested for neuroprotection in in vitro studies with PC-12 cells treated with 6-OHDA and rotenone, respectively. It was observed that some of the compounds tested yielded a marked increase in survival in PC-12 cells treated with the neurotoxins. This indicates that these propargylamines are able to confer protection against the effects of the toxins and may also be considered as novel disease-modifying anti-Parkinsonian agents, which are much needed for the therapy of Parkinson's disease.

Modifying Risk Factors in the Management of Erectile Dysfunction: A Review

PubMed Central

DeLay, Kenneth J; Haney, Nora

2016-01-01

Erectile dysfunction (ED) is prevalent among men and its presence is often an indicator of systemic disease. Risk factors for ED include cardiovascular disease, hypertension, diabetes mellitus (DM), tobacco use, hyperlipidemia, hypogonadism, lower urinary tract symptoms, metabolic syndrome, and depression. Addressing the modifiable risk factors frequently improves a patient's overall health and increases lifespan. The literature suggests that smoking cessation, treatment of hyperlipidemia, and increasing physical activity will improve erectile function in many patients. How the treatment of DM, depression, and hypogonadism impacts erectile function is less clear. Clinicians need to be aware that certain antihypertensive agents can adversely impact erectile function. The treatment of men with ED needs to address the underlying risk factors to ameliorate the disease process. PMID:27574592

Update on the use of steroids in rheumatoid arthritis.

PubMed

García-Magallón, Blanca; Silva-Fernández, Lucía; Andreu-Sánchez, José Luis

2013-01-01

Corticosteroids are a mainstay in the therapy of rheumatoid arthritis (RA). In recent years, a number of high-quality controlled clinical trials have shown their effect as a disease-modifying anti-rheumatic drug (DMARD) and a favourable safety profile in recent-onset RA. Despite this, they are more frequently used as bridge therapy while other DMARDs initiate their action than as true disease-modifying agents. Low-dose corticosteroid use during the first two years of disease slows radiologic damage and reduces the need of biologic therapy aimed at reaching a state of clinical remission in recent-onset RA. Thus, their systematic use in this clinical scenario should be considered. Copyright © 2013 Elsevier España, S.L. All rights reserved.

Lurking in the Shadows: Emerging Rodent Infectious Diseases

PubMed Central

Besselsen, David G.; Franklin, Craig L.; Livingston, Robert S.; Riley, Lela K.

2013-01-01

Rodent parvoviruses, Helicobacter spp., murine norovirus, and several other previously unknown infectious agents have “emerged” in laboratory rodents relatively recently. These agents have been discovered serendipitously or through active investigation of atypical serology results, cell culture contamination, unexpected histopathology, or previously unrecognized clinical disease syndromes. The potential research impact of these agents is not fully known. Infected rodents have demonstrated immunomodulation, tumor suppression, clinical disease (particularly in immunodeficient rodents), and histopathology. Perturbations of organismal and cellular physiology also likely occur. These agents posed unique challenges to laboratory animal resource programs once discovered; it was necessary to develop specific diagnostic assays and an understanding of their epidemiology and transmission routes before attempting eradication, and then evaluate eradication methods for efficacy. Even then management approaches varied significantly, from apathy to total exclusion, and such inconsistency has hindered the sharing and transfer of rodents among institutions, particularly for genetically modified rodent models that may not be readily available. As additional infectious agents are discovered in laboratory rodents in coming years, much of what researchers have learned from experiences with the recently identified pathogens will be applicable. This article provides an overview of the discovery, detection, and research impact of infectious agents recently identified in laboratory rodents. We also discuss emerging syndromes for which there is a suspected infectious etiology, and the unique challenges of managing newly emerging infectious agents. PMID:18506061

Varicella Zoster Virus (Chickenpox) Infection in Pregnancy

PubMed Central

Lamont, Ronald F.; Sobel, Jack D; Carrington, D; Mazaki-Tovi, Shali; Kusanovic, Juan Pedro; Vaisbuch, Edi; Romero, Roberto

2011-01-01

Congenital varicella syndrome, maternal varicella zoster virus pneumonia and neonatal varicella infection are associated with serious feto-maternal morbidity and not infrequently with mortality. Vaccination against Varicella zoster virus can prevent the disease and outbreak control limits the exposure of pregnant women to the infectious agent. Maternal varicella zoster immune globulin (VZIG) administration before rash development, with or without antivirals medications can modify progression of the disease. PMID:21585641

Aggressive treatment of early rheumatoid arthritis: recognizing the window of opportunity and treating to target goals.

PubMed

Resman-Targoff, Beth H; Cicero, Marco P

2010-11-01

Evidence supports the use of aggressive therapy for patients with early rheumatoid arthritis (RA). Clinical outcomes in patients with early RA can improve with a treat-to-target approach that sets the goal at disease remission. The current selection of antirheumatic therapies, including conventional and biologic disease-modifying antirheumatic drugs (DMARDs), has made disease remission a realistic target for patients with early RA. The challenge is selecting the optimal antirheumatic drug or combination of drugs for initial and subsequent therapy to balance the clinical benefits, risks, and economic considerations. In some cases, the use of biologic agents as part of the treatment regimen has shown superior results compared with conventional DMARDs alone in halting the progression of disease, especially in reducing radiographic damage. However, the use of biologic agents as initial therapy is challenged by cost-effectiveness analyses, which favor the use of conventional DMARDs. The use of biologic agents may be justified in certain patients with poor prognostic factors or those who experience an inadequate response to conventional DMARDs as a means to slow or halt disease progression and its associated disability. In these cases, the higher cost of treatment with biologic agents may be offset by decreased societal costs, such as lost work productivity, and increased health-related quality of life. Further research is needed to understand optimal strategies for balancing costs, benefits, and risks of antirheumatic drugs. Some key questions are (1) when biologic agents are appropriate for initial therapy, and (2) when to conclude that response to conventional DMARDs is inadequate and biologic agents should be initiated.

Impact of nutritional status on body functioning in chronic obstructive pulmonary disease and how to intervene.

PubMed

Aniwidyaningsih, Wahju; Varraso, Raphaëlle; Cano, Noel; Pison, Christophe

2008-07-01

Chronic obstructive pulmonary disease is the fifth leading cause of mortality in the world. This study reviews diet as a risk or protective factor for chronic obstructive pulmonary disease, mechanisms of malnutrition, undernutrition consequences on body functioning and how to modulate nutritional status of patients with chronic obstructive pulmonary disease. Different dietary factors (dietary pattern, foods, nutrients) have been associated with chronic obstructive pulmonary disease and the course of the disease. Mechanical disadvantage, energy imbalance, disuse muscle atrophy, hypoxemia, systemic inflammation and oxidative stress have been reported to cause systemic consequences such as cachexia and compromise whole body functioning. Nutritional intervention makes it possible to modify the natural course of the disease provided that it is included in respiratory rehabilitation combining bronchodilators optimization, infection control, exercise and, in some patients, correction of hypogonadism. Diet, as a modifiable risk factor, appears more as an option to prevent and modify the course of chronic obstructive pulmonary disease. Reduction of mechanical disadvantage, physical training and anabolic agents should be used conjointly with oral nutrition supplements to overcome undernutrition and might change the prognosis of the disease in some cases. Major research challenges address the role of systemic inflammation and the best interventions for controlling it besides smoking cessation.

The role of the sand in chemical warfare agent exposure among Persian Gulf War veterans: Al Eskan disease and "dirty dust".

PubMed

Korényi-Both, A L; Svéd, L; Korényi-Both, G E; Juncer, D J; Korényi-Both, A L; Székely, A

2000-05-01

The purpose of this paper is to inquire into the relationship between Al Eskan disease and the probable exposure to chemical warfare agents by Persian Gulf War veterans. Al Eskan disease, first reported in 1991, compromises the body's immunological defense and is a result of the pathogenic properties of the extremely fine, dusty sand located in the central and eastern region of the Arabian peninsula. The disease manifests with localized expression of multisystem disorder. Signs and symptoms of Al Eskan disease have been termed by the news media "Persian Gulf syndrome." The dust becomes a warfare agent when toxic chemicals are microimpregnated into inert particles. The "dirty dust" concept, that the toxicity of an agent could be enhanced by absorption into inactive particles, dates from World War I. A growing body of evidence shows that coalition forces have encountered Iraqi chemical warfare in the theater of operation/Persian Gulf War to a much greater extent than early U.S. Department of Defense information had indicated. Veterans of that war were exposed to chemical warfare agents in the form of direct (deliberate) attacks by chemical weapons, such as missiles and mines, and indirect (accidental) contamination from demolished munition production plants and storage areas, or otherwise. We conclude that the microimpregnated sand particles in the theater of operation/Persian Gulf War depleted the immune system and simultaneously acted as vehicles for low-intensity exposure to chemical warfare agents and had a modifying-intensifying effect on the toxicity of exposed individuals. We recommend recognition of a new term, "dirty sand," as a subcategory of dirty dust/dusty chemical warfare agents. Our ongoing research efforts to investigate the health impact of chemical warfare agent exposure among Persian Gulf War veterans suggest that Al Eskan disease is a plausible and preeminent explanation for the preponderance of Persian Gulf War illnesses.

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

PubMed

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.

Genetic Determinants of Epigenetic Patterns: Providing Insight into Disease.

PubMed

Cazaly, Emma; Charlesworth, Jac; Dickinson, Joanne L; Holloway, Adele F

2015-03-26

The field of epigenetics and our understanding of the mechanisms that regulate the establishment, maintenance and heritability of epigenetic patterns continue to grow at a remarkable rate. This information is providing increased understanding of the role of epigenetic changes in disease, insight into the underlying causes of these epigenetic changes and revealing new avenues for therapeutic intervention. Epigenetic modifiers are increasingly being pursued as therapeutic targets in a range of diseases, with a number of agents targeting epigenetic modifications already proving effective in diseases such as cancer. Although it is well established that DNA mutations and aberrant expression of epigenetic modifiers play a key role in disease, attention is now turning to the interplay between genetic and epigenetic factors in complex disease etiology. The role of genetic variability in determining epigenetic profiles, which can then be modified by environmental and stochastic factors, is becoming more apparent. Understanding the interplay between genetic and epigenetic factors is likely to aid in identifying individuals most likely to benefit from epigenetic therapies. This goal is coming closer to realization because of continual advances in laboratory and statistical tools enabling improvements in the integration of genomic, epigenomic and phenotypic data.

Alternative strategies for the control and elimination of PRRS

USDA-ARS?s Scientific Manuscript database

Porcine reproductive and respiratory syndrome (PRRS) is the most costly disease of modern global pig production systems. The etiological agent, PRRS virus (PRRSV), an RNA virus, was identified in Europe (PRRSV-1 isolates) in 1991, and later in the US (PRRSV-2 isolates). Modified live virus (MLV) vac...

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

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-01

... for comments. SUMMARY: The Food and Drug Administration (FDA), Center for Drug Evaluation and Research... Contacts: Randi Clark, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New..., Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver...

Modern Technologies for Creating Synthetic Antibodies for Clinical application

PubMed Central

Lebedenko, E. N.

2009-01-01

The modular structure and versatility of antibodies enables one to modify natural immunoglobulins in different ways for various clinical applications. Rational design and molecular engineering make it possible to directionally modify the molecular size, affinity, specificity, and immunogenicity and effector functions of an antibody, as well as to combine them with other functional agents. This review focuses on up-to-date methods of antibody engineering for diagnosing and treating various diseases, particularly on new technologies meant to refine the effector functions of therapeutic antibodies. PMID:22649585

Monoamine oxidase-B inhibition in the treatment of Parkinson's disease.

PubMed

Fernandez, Hubert H; Chen, Jack J

2007-12-01

Inhibitors of monoamine oxidase (MAO) with selectivity and specificity for MAO type B prolong the activity of both endogenously and exogenously derived dopamine, making them an option either as monotherapy in early Parkinson's disease or as adjunctive therapy in patients treated with levodopa who are experiencing motor complications. In addition to symptomatic benefits, experimental data suggest that MAO-B inhibitors may be neuroprotective through MAO-B inhibition and other mechanisms that have yet to be clearly defined. The two available MAO-B inhibitors approved for use in the United States, rasagiline and selegiline, each provide symptomatic relief as monotherapy and as adjunctive therapy, and have shown potential disease-modifying effects in experimental models and clinical studies. Selegiline in a conventional tablet formulation is less bioavailable than rasagiline, resulting in limited potency. It also has amphetamine metabolites that may produce adverse effects and interfere with any putative disease-modifying effects. The oral disintegrating tablet formulation of selegiline allows pregastric absorption, minimizing first-pass metabolism, thereby increasing selegiline bioavailability and reducing the concentration of amphetamine metabolites. Rasagiline, more potent than selegiline, exhibits disease-modifying effects in experimental models and lacks amphetamine metabolites. Both the symptomatic and potential disease-modifying effects of rasagiline are under investigation. A third agent with MAO-B inhibition properties, safinamide, is in phase III development. Although not yet approved, safinamide may offer the added advantage of combined MAO-B and dopamine reuptake inhibition.

The cell labeling efficacy, cytotoxicity and relaxivity of copper-activated MRI/PET imaging contrast agents.

PubMed

Patel, Daksha; Kell, Arnold; Simard, Benoit; Xiang, Bo; Lin, Hung Yu; Tian, Ganghong

2011-02-01

A new class of nanoparticle-based dual-modality positron emission tomography/magnetic resonance imaging (PET/MRI) contrast agents has been developed. The probe consists of a superparamagnetic iron oxide (SPIO) or manganese oxide core coated with 3,4-dihydroxy-D,L-phenylalanine (DL-DOPA). The chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was conjugated to DOPA termini. The DOTA modified nanoparticles allow chelation of copper for PET imaging. These surface functionalized nanoparticle-based probes have been characterized by various analytical techniques. The cell-labeling efficacy, cytotoxicity and relaxivity of these nanoparticles have been evaluated and compared with the same properties of one of the most commonly utilized MRI contrast agents, Feridex(®). Evidently, this new nanoparticle has a great potential for use in cell tracking with MRI and PET in the absence of transfecting agent. It is noteworthy that there is a sharp increase in r(2) relaxivity of these nanoparticles on coordination with Cu(2+) ions. Thus these iron oxide nanoparticles can also be explored as the smart magnetic resonance (MR) sensor for the detection of micromolar changes in copper concentration for neurodegenerative diseases such as Alzheimer's disease, Menkes and Wilson's diseases, amyotrophic lateral sclerosis and prion diseases. Crown Copyright © 2010. Published by Elsevier Ltd. All rights reserved.

Adenovirus 2, Bordetella bronchiseptica, and Parainfluenza Molecular Diagnostic Assay Results in Puppies After vaccination with Modified Live Vaccines.

PubMed

Ruch-Gallie, R; Moroff, S; Lappin, M R

2016-01-01

Canine adenovirus 2, parainfluenza, and Bordetella bronchiseptica cause respiratory disease in dogs, and each has a modified live intranasal vaccine available. Molecular diagnostic assays to amplify specific nucleic acids are available for each of these agents. If positive molecular diagnostic assay results are common after vaccination, the positive predictive value of the diagnostic assays for disease would be decreased. To determine the impact of administration of commercially available modified live topical adenovirus 2, B. bronchiseptica, and parainfluenza vaccine has on the results of a commercially available PCR panel. Eight puppies from a research breeding facility negative for these pathogens. Blinded prospective pilot study. Puppies were vaccinated with a single dose of modified live topical adenovirus 2, B. bronchiseptica, and parainfluenza and parenteral dose of adenovirus 2, canine distemper virus, and parvovirus. Nasal and pharyngeal swabs were collected on multiple days and submitted for PCR assay. Nucleic acids of all 3 organisms contained in the topical vaccine were detected from both samples multiple times through 28 days after vaccination with higher numbers of positive samples detected between days 3 and 10 after vaccination. Vaccine status should be considered when interpreting respiratory agent PCR results if modified live vaccines have been used. Development of quantitative PCR and wild-type sequencing are necessary to improve positive predictive value of these assays by distinguishing vaccinate from natural infection. Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

New therapeutic directions for advanced pancreatic cancer: cell cycle inhibitors, stromal modifiers and conjugated therapies.

PubMed

Matera, Robert; Saif, Muhammad Wasif

2017-09-01

Pancreatic adenocarcinoma is a devastating malignancy with an extremely poor prognosis. These tumors progress rapidly and somewhat silently with few specific symptoms and are relatively resistant to chemotherapeutic agents. Many agents, including cell cycle inhibitors, are under development for the treatment of this cancer for which there are disappointingly few treatment options. Areas covered: Here we outline the existing approved treatments for advanced pancreatic disease and discuss a range of novel therapies currently under development including cell cycle inhibitors, stromal modifiers and conjugated therapies. We also describe the current state of the pancreatic cancer therapeutics market both past and future. Expert opinion: Despite the recent explosion of novel therapies with an array of unique targets, the core treatment of pancreatic cancer still with traditional cytotoxic agents with a few exceptions. However, as these novel treatments move through the pipeline, we are hopeful that there will soon be a number of effective options for patients with advanced pancreatic cancer.

Theranostic gas-generating nanoparticles for targeted ultrasound imaging and treatment of neuroblastoma.

PubMed

Lee, Jangwook; Min, Hyun-Su; You, Dong Gil; Kim, Kwangmeyung; Kwon, Ick Chan; Rhim, Taiyoun; Lee, Kuen Yong

2016-02-10

The development of safe and efficient diagnostic/therapeutic agents for treating cancer in clinics remains challenging due to the potential toxicity of conventional agents. Although the annual incidence of neuroblastoma is not that high, the disease mainly occurs in children, a population vulnerable to toxic contrast agents and therapeutics. We demonstrate here that cancer-targeting, gas-generating polymeric nanoparticles are useful as a theranostic tool for ultrasound (US) imaging and treating neuroblastoma. We encapsulated calcium carbonate using poly(d,l-lactide-co-glycolide) and created gas-generating polymer nanoparticles (GNPs). These nanoparticles release carbon dioxide bubbles under acidic conditions and enhance US signals. When GNPs are modified using rabies virus glycoprotein (RVG) peptide, a targeting moiety to neuroblastoma, RVG-GNPs effectively accumulate at the tumor site and substantially enhance US signals in a tumor-bearing mouse model. Intravenous administration of RVG-GNPs also reduces tumor growth in the mouse model without the use of conventional therapeutic agents. This approach to developing theranostic agents with disease-targeting ability may provide useful strategy for the detection and treatment of cancers, allowing safe and efficient clinical applications with fewer side effects than may occur with conventional agents. Copyright © 2015 Elsevier B.V. All rights reserved.

T-614, a novel immunomodulator, attenuates joint inflammation and articular damage in collagen-induced arthritis

PubMed Central

Du, Fang; Lü, Liang-jing; Fu, Qiong; Dai, Min; Teng, Jia-lin; Fan, Wei; Chen, Shun-le; Ye, Ping; Shen, Nan; Huang, Xin-fang; Qian, Jie; Bao, Chun-de

2008-01-01

Introduction T-614 is a novel oral antirheumatic agent for the treatment of rheumatoid arthritis. Whether it has immunomodulatory or disease-modifying properties and its mechanism of action are largely undetermined. Methods Rats with collagen-induced arthritis (CIA) were treated with T-614 (5 and 20 mg/kg) daily. Animals receiving methotrexate (1 mg/kg every 3 days) and the nonsteroidal anti-inflammatory agent nimesulide (10 mg/kg per day) were used as controls. A combination therapy group was treated with both T-614(10 mg/kg per day) and methotrexate (1 mg/kg every 3 days). Hind paw swelling was evaluated and radiographic scores calculated. Serum cytokine levels were assessed by Bio-plex analysis. Quantitative PCR was used to evaluate expression of mRNA for interferon-γ, IL-4 and IL-17. Serum IL-17 and anti-type II collagen antibodies (total IgG, IgG1, IgG2a, IgG2b and IgM) were measured using ELISA. Results Oral T-614 inhibited paw swelling and offered significant protection against arthritis-induced cartilage and bone erosion, comparable to the effects of methotrexate. CIA rats treated with T-614 exhibited decreases in both mRNA expression of IL-17 in peripheral blood mononuclear cells and lymph node cells, and circulating IL-17 in a dose-dependent manner. T-614 also reduced serum levels of tumor necrosis factor-α, IL-1β and IL-6. A synergistic effect was observed for the combination of methotrexate and T-614. In addition, T-614 (20 mg/kg per day) depressed production of anti-type II collagen antibodies and differentially affected levels of IgG2a subclasses in vivo, whereas IgM level was decreased without any change in the IgG1 level. Together, the findings presented here indicate that the novel agent T-614 has disease-modifying effects against experimental arthritis, as opposed to nimesulide. Conclusions Our data suggested that T-614 is an effective disease-modifying agent that can prevent bone/cartilage destruction and inflammation in in CIA rats. Combination with methotrexate markedly enhances the therapeutic effect of T-614. PMID:19019215

A probiotic approach to caries management.

PubMed

Anderson, M H; Shi, W

2006-01-01

The surgical approach has been the predominate mode of caries management for the past 150 years. Dentistry has, however, in recent years moved toward an antibiotic/antimicrobial model of disease management. This approach, however, raises serious questions: (1) do the antibiotic/antimicrobial agents (chlorhexidine, povidone iodine, fluoride, etc) kill all offending organisms?; (2) if so, do the agents preclude the re-entry of the same organisms from external sources?; and (3) if the agents do kill all the offending organisms, do any remaining pathogenic organisms have selective advantage in repopulating the tooth surfaces? To overcome the problems inherent in an antibiotic/antimicrobial approach, probiotic methods are currently under study as means of caries management. This paper discusses probiotic approaches, such as genetically modified Streptococcus mutans and targeted antimicrobials in the management of dental caries. Implications for this approach in the management of other diseases are also presented.

Pharmacogenetics and pharmacogenomics in psoriasis treatment: current challenges and future prospects.

PubMed

Sutherland, Alison; Power, Rebecca J; Rahman, Proton; O'Rielly, Darren D

2016-08-01

Topical, systemic, oral disease modifying, and biologic agents are part of the armamentarium to manage psoriatic disease. The choice of therapy depends upon disease severity, relevant co-morbidities and patient preference. There is great variability in patient response with these agents, and there is still no clear method of selecting the preferred therapeutic agent for efficacy or lack of adverse events. This article will review the pharmacogenetic and pharmacogenomic targets that are currently known with respect to psoriasis vulgaris, and the most frequent co-morbidity of psoriasis, psoriatic arthritis. Presently, no clinically actionable biomarker exists for any therapeutic agent used to treat psoriasis or psoriatic arthritis. The lack of validated outcome measures and conflicting results of open-label studies conducted may be attributed to a multitude of issues that confound discovery. Consequently, studies have been underpowered to identify genes or genetic variants worth translating to clinical practice. In order to achieve a pharmacogenetic/pharmacogenomic signature, improvements in study design of future investigations are required, including carefully designed prospective studies. It is imperative to combine known clinical, serological, and molecular markers with consistent outcomes and an adequate health economic evaluation before they can be adopted widely in clinical practice.

Measures of rheumatoid arthritis disease activity in Australian clinical practice.

PubMed

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.

Management of dry eye disease.

PubMed

Lemp, Michael A

2008-04-01

The management of dry eye disease (DED) encompasses both pharmacologic and nonpharmacologic approaches, including avoidance of exacerbating factors, eyelid hygiene, tear supplementation, tear retention, tear stimulation, and anti-inflammatory agents. Artificial tears are the mainstay of DED therapy but, although they improve symptoms and objective findings, there is no evidence that they can resolve the underlying inflammation in DED. Topical corticosteroids are effective anti-inflammatory agents, but are not recommended for long-term use because of their adverse-effect profiles. Topical cyclosporine--currently the only pharmacologic treatment approved by the US Food and Drug Administration specifically for DED--is safe for long-term use and is disease-modifying rather than merely palliative. Treatment selection is guided primarily by DED severity. Recently published guidelines propose a severity classification based on clinical signs and symptoms, with treatment recommendations according to severity level.

Deletion of the thymidine kinase gene induces complete attenuation of the Georgia isolate of African swine fever virus

USDA-ARS?s Scientific Manuscript database

African swine fever virus (ASFV) is the etiological agent of a contagious and often lethal viral disease of domestic pigs. There are no vaccines to control Africa swine fever (ASF). Experimental vaccines have been developed using genetically modified live attenuated ASFVs obtained by specifically de...

Defining the Role of the Monoamine Oxidase-B Inhibitors for Parkinson's Disease.

PubMed

Robakis, Daphne; Fahn, Stanley

2015-06-01

Inhibitors of monoamine oxidase-B (MAO-B) occupy an important place in the treatment of Parkinson's disease. Selegiline was the first MAO-B to be used therapeutically, while rasagiline is a second-generation drug with higher potency and selectivity. Safinamide is an investigational MAO-B inhibitor with non-dopaminergic properties that may provide advantages over its predecessors. As a class, MAO-B inhibitors are safe and well tolerated and provide symptomatic benefit both as monotherapy and in combination with other antiparkinsonian medications from early to late stages of disease. In combination with levodopa, MAO-B inhibitors may improve motor fluctuations and allow for lower total doses of levodopa. Patient characteristics and preferences can be important factors in deciding between agents. As a class, MAO-B inhibitors have shown promise as disease-modifying agents, but the clinical trial evidence to date has not been strong enough to afford them such a label. Future research may help further elucidate their relative merits and clarify their role in altering disease progression.

Potential Use of γ-Secretase Modulators in the Treatment of Alzheimer Disease

PubMed Central

Wagner, Steven L.; Tanzi, Rudolph E.; Mobley, William C.; Galasko, Douglas

2013-01-01

Although significant progress has occurred in the past 20 years regarding our understanding of Alzheimer disease pathogenesis, we have yet to identify disease-modifying therapeutics capable of substantially altering the clinical course of this prevalent neurodegenerative disease. In this short review, we discuss 2 approaches that are currently being tested clinically (γ-secretase inhibition and γ-secretase modulation) and emphasize the significant differences between these 2 therapeutic approaches. We also discuss certain genetic- and biomarker-based translational and clinical trial paradigms that may assist in developing a useful therapeutic agent. PMID:22801784

Host modulation therapeutics in periodontics: role as an adjunctive periodontal therapy.

PubMed

Shinwari, Muhammad Saad; Tanwir, Farzeen; Hyder, Pakiza Raza; Bin Saeed, Muhammad Humza

2014-09-01

Host Modulation Therapy (HMT) is a treatment concept that reduces tissue destruction and stabilizes or even regenerates inflammatory tissue by modifying host response factors. It has been used for treating osteoporosis and arthritis for several decades. However, its use in dentistry has only been recently reported. The objective of this article is to present a review of the various literatures available on HMT and also its role as adjunct therapy in periodontics. For identifying studies for this review, a PUBMED search was carried out in 2013 for all articles published till December 2012. The search was restricted to English language publications only. Longitudinal prospective and retrospective studies were included in the search. The key words used were: Host Modulation Therapy; Sub antimicrobial dose doxycycline and Non-Surgical Periodontal Therapy. The main outcomes sought were host modulation therapeutics in periodontics. Exclusion criteria included cross sectional studies, short case series as well as studies with short follow-up periods. There is a paucity of literature on HMT in periodontics although the only drug approved by United States Food and Drug Administration (FDA) is a subantimicrobial dose of doxycycline (SDD) with highly predictable results as a host modulating agent in periodontal diseases and also an effective adjunctive therapy in various diseases of periodontium. However, more randomized controlled trials are needed to obtain clinical guidelines on the usage of other host modulating agents as adjunct as well as definite therapy for periodontal diseases. SDD is an effective adjunct therapy when used in dosage of 20mg twice daily for minimum 3 months duration in various periodontal diseases with predictable clinical outcomes. It is also recommended that future clinical research on anti cytokine drugs, chemically modified tetracycline and other HMT agents should be conducted so that new drugs are available with highly predictable results.

An Update on Treatment of Pediatric Chronic Non-Infectious Uveitis.

PubMed

Sood, Arjun B; Angeles-Han, Sheila T

2017-03-01

There are no standardized treatment protocols for pediatric non-infectious uveitis. Topical corticosteroids are the typical first-line agent, although systemic corticosteroids are used in intermediate, posterior and panuveitic uveitis. Corticosteroids are not considered to be long-term therapy due to potential ocular and systemic side effects. In children with severe and/or refractory uveitis, timely management with higher dose disease-modifying antirheumatic drugs (DMARDs) and biologic agents is important. Increased doses earlier in the disease course may lead to improved disease control and better visual outcomes. In general, methotrexate is the usual first-line steroid-sparing agent and given as a subcutaneous weekly injection at >0.5 mg/kg/dose or 10-15 mg/m2 due to better bioavailability. Other DMARDs, for instance mycophenolate, azathioprine, and cyclosporine are less common treatments for pediatric uveitis. Anti-tumor necrosis factor-alpha agents, primarily infliximab and adalimumab are used as second line agents in children refractory to methotrexate, or as first-line treatment in those with severe complicated disease at presentation. Infliximab may be given at a minimum of 7.5 mg/kg/dose every 4 weeks after loading doses, up to 20 mg/kg/dose. Adalimumab may be given up to 20 or 40 mg weekly. In children who fail anti-tumor necrosis factor-alpha agents, develop anti-tumor necrosis factor-alpha antibodies, experience adverse effects, or have difficulty with tolerance, there is less data available regarding subsequent treatment. Promising results have been noted with tocilizumab infusions every 2-4 weeks, abatacept monthly infusions and rituximab.

An Update on Treatment of Pediatric Chronic Non-Infectious Uveitis

PubMed Central

Sood, Arjun B.; Angeles-Han, Sheila T.

2017-01-01

Opinion Statement There are no standardized treatment protocols for pediatric non-infectious uveitis. Topical corticosteroids are the typical first-line agent, although systemic corticosteroids are used in intermediate, posterior and panuveitic uveitis. Corticosteroids are not considered to be long-term therapy due to potential ocular and systemic side effects. In children with severe and/or refractory uveitis, timely management with higher dose disease-modifying antirheumatic drugs (DMARDs) and biologic agents is important. Increased doses earlier in the disease course may lead to improved disease control and better visual outcomes. In general, methotrexate is the usual first-line steroid-sparing agent and given as a subcutaneous weekly injection at >0.5 mg/kg/dose or 10–15 mg/m2 due to better bioavailability. Other DMARDs, for instance mycophenolate, azathioprine, and cyclosporine are less common treatments for pediatric uveitis. Anti-tumor necrosis factor-alpha agents, primarily infliximab and adalimumab are used as second line agents in children refractory to methotrexate, or as first-line treatment in those with severe complicated disease at presentation. Infliximab may be given at a minimum of 7.5 mg/kg/dose every 4 weeks after loading doses, up to 20 mg/kg/dose. Adalimumab may be given up to 20 or 40 mg weekly. In children who fail anti-tumor necrosis factor-alpha agents, develop anti-tumor necrosis factor-alpha antibodies, experience adverse effects, or have difficulty with tolerance, there is less data available regarding subsequent treatment. Promising results have been noted with tocilizumab infusions every 2–4 weeks, abatacept monthly infusions and rituximab. PMID:28944162

Biosensor platform based on carbon nanotubes covalently modified with aptamers

NASA Astrophysics Data System (ADS)

Komarov, I. A.; Rubtsova, E. I.; Golovin, A. V.; Bobrinetskiy, I. I.

2016-12-01

We developed a new platform for biosensing applications. Aptamers as sensitive agents have a great potential and gives us possibility to have highest possible selectivity among other sensing agents like enzymes or antibodies. We covalently bound aptamers to the functional groups of c-CNTs and then put this system on the surface of polymer substrate. Thus we got high sensitive flexible transparent biological sensors. We also suggest that by varying aptamer type we can make set of biosensors for disease detection which can be integrated into self-healthcare systems and gadgets.

[Special characteristics of antibiotic therapy in the elderly].

PubMed

Stock, Ingo

2012-03-01

The ever-increasing proportion of elderly people in the general population represents physicians and pharmacists with new challenges. Older people suffer more frequently than younger persons from bacterial diseases, and they have a higher tendency to develop more severe or progressive forms of these illnesses. Bacterial diseases of the urinary tract, respiratory tract, skin and soft tissues are especially common in old age. In general, most antibacterial agents are also promising agents for the therapy of bacterial diseases in the elderly. Prior to initiating therapy, however, the modified organ functions of the elderly have to be considered carefully. Depending on the individual and the antibacterial agent, a dose adjustment may be necessary. To reduce the high mortality rate characteristic for many infectious diseases in the elderly, antibacterial therapy ought to be carefully calculated and initiated as quickly as possible. It has to be born in mind that some side effects of antibiotics are more common and more severe in old age. Since older people often take several drugs simultaneously, the probability for the occurrence of side effects and drug interactions in this population is greatly increased. Significant compliance problems may also arise.

Sex differences in Parkinson's disease.

PubMed

Gillies, Glenda E; Pienaar, Ilse S; Vohra, Shiv; Qamhawi, Zahi

2014-08-01

Parkinson's disease (PD) displays a greater prevalence and earlier age at onset in men. This review addresses the concept that sex differences in PD are determined, largely, by biological sex differences in the NSDA system which, in turn, arise from hormonal, genetic and environmental influences. Current therapies for PD rely on dopamine replacement strategies to treat symptoms, and there is an urgent, unmet need for disease modifying agents. As a significant degree of neuroprotection against the early stages of clinical or experimental PD is seen, respectively, in human and rodent females compared with males, a better understanding of brain sex dimorphisms in the intact and injured NSDA system will shed light on mechanisms which have the potential to delay, or even halt, the progression of PD. Available evidence suggests that sex-specific, hormone-based therapeutic agents hold particular promise for developing treatments with optimal efficacy in men and women. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Current trends in pharmacy benefit designs: a threat to disease management in chronic complex diseases.

PubMed

Owens, Gary; Emons, Matthew F; Christian-Herman, Jennifer; Lawless, Grant

2007-04-01

With a focus on those patients who are candidates for treatment with biologic agents, we review the impact that current pharmacy benefit trends have on patients with chronic complex diseases and how they affect opportunities for disease management in this unique patient population. Dramatic increases in health care costs have led to a variety of strategies to manage cost. Many of these strategies either limit access to care or increase the patient's responsibility for choosing and paying for care, especially for medications. These strategies have a disproportionate impact on patients with chronic complex diseases, particularly those who require the use of biologic medications. A fundamental prerequisite of disease management has been coverage of disease-modifying therapies. If current pharmacy benefit trends continue, unintended consequences will likely occur including lost opportunities for disease management. Current pharmacy benefit trends could adversely impact disease management, particularly for patients requiring the use of biologic agents. Health plans should consider innovative benefit designs that reflect an appropriate level of cost sharing across all key stake-holders, ensuring appropriate access to needed therapies. Additional research is needed to clarify the value of newer approaches to therapies or benefit design changes.

Cancer-associated bone disease.

PubMed

Rizzoli, R; Body, J-J; Brandi, M-L; Cannata-Andia, J; Chappard, D; El Maghraoui, A; Glüer, C C; Kendler, D; Napoli, N; Papaioannou, A; Pierroz, D D; Rahme, M; Van Poznak, C H; de Villiers, T J; El Hajj Fuleihan, G

2013-12-01

Bone is commonly affected in cancer. Cancer-induced bone disease results from the primary disease, or from therapies against the primary condition, causing bone fragility. Bone-modifying agents, such as bisphosphonates and denosumab, are efficacious in preventing and delaying cancer-related bone disease. With evidence-based care pathways, guidelines assist physicians in clinical decision-making. Of the 57 million deaths in 2008 worldwide, almost two thirds were due to non-communicable diseases, led by cardiovascular diseases and cancers. Bone is a commonly affected organ in cancer, and although the incidence of metastatic bone disease is not well defined, it is estimated that around half of patients who die from cancer in the USA each year have bone involvement. Furthermore, cancer-induced bone disease can result from the primary disease itself, either due to circulating bone resorbing substances or metastatic bone disease, such as commonly occurs with breast, lung and prostate cancer, or from therapies administered to treat the primary condition thus causing bone loss and fractures. Treatment-induced osteoporosis may occur in the setting of glucocorticoid therapy or oestrogen deprivation therapy, chemotherapy-induced ovarian failure and androgen deprivation therapy. Tumour skeletal-related events include pathologic fractures, spinal cord compression, surgery and radiotherapy to bone and may or may not include hypercalcaemia of malignancy while skeletal complication refers to pain and other symptoms. Some evidence demonstrates the efficacy of various interventions including bone-modifying agents, such as bisphosphonates and denosumab, in preventing or delaying cancer-related bone disease. The latter includes treatment of patients with metastatic skeletal lesions in general, adjuvant treatment of breast and prostate cancer in particular, and the prevention of cancer-associated bone disease. This has led to the development of guidelines by several societies and working groups to assist physicians in clinical decision making, providing them with evidence-based care pathways to prevent skeletal-related events and bone loss. The goal of this paper is to put forth an IOF position paper addressing bone diseases and cancer and summarizing the position papers of other organizations.

An agent-based approach for modeling dynamics of contagious disease spread

PubMed Central

Perez, Liliana; Dragicevic, Suzana

2009-01-01

Background The propagation of communicable diseases through a population is an inherent spatial and temporal process of great importance for modern society. For this reason a spatially explicit epidemiologic model of infectious disease is proposed for a greater understanding of the disease's spatial diffusion through a network of human contacts. Objective The objective of this study is to develop an agent-based modelling approach the integrates geographic information systems (GIS) to simulate the spread of a communicable disease in an urban environment, as a result of individuals' interactions in a geospatial context. Methods The methodology for simulating spatiotemporal dynamics of communicable disease propagation is presented and the model is implemented using measles outbreak in an urban environment as a case study. Individuals in a closed population are explicitly represented by agents associated to places where they interact with other agents. They are endowed with mobility, through a transportation network allowing them to move between places within the urban environment, in order to represent the spatial heterogeneity and the complexity involved in infectious diseases diffusion. The model is implemented on georeferenced land use dataset from Metro Vancouver and makes use of census data sets from Statistics Canada for the municipality of Burnaby, BC, Canada study site. Results The results provide insights into the application of the model to calculate ratios of susceptible/infected in specific time frames and urban environments, due to its ability to depict the disease progression based on individuals' interactions. It is demonstrated that the dynamic spatial interactions within the population lead to high numbers of exposed individuals who perform stationary activities in areas after they have finished commuting. As a result, the sick individuals are concentrated in geographical locations like schools and universities. Conclusion The GIS-agent based model designed for this study can be easily customized to study the disease spread dynamics of any other communicable disease by simply adjusting the modeled disease timeline and/or the infection model and modifying the transmission process. This type of simulations can help to improve comprehension of disease spread dynamics and to take better steps towards the prevention and control of an epidemic outbreak. PMID:19656403

Risks of herpes zoster in patients with rheumatoid arthritis according to biologic disease-modifying therapy.

PubMed

Yun, Huifeng; Xie, Fenglong; Delzell, Elizabeth; Chen, Lang; Levitan, Emily B; Lewis, James D; Saag, Kenneth G; Beukelman, Timothy; Winthrop, Kevin; Baddley, John W; Curtis, Jeffrey R

2015-05-01

To evaluate whether the risks of herpes zoster (HZ) differed by biologic agents with different mechanisms of action (MOAs) in older rheumatoid arthritis (RA) patients. Using Medicare data from 2006-2011, among RA patients with prior biologic agent use and no history of cancer or other autoimmune diseases, this retrospective cohort study identified new treatment episodes of abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, and tocilizumab. Followup started on initiation of the new biologic agent and ended at any of the following: first incidence of HZ, a 30-day gap in current exposure, death, a diagnosis of other autoimmune disease or cancer, loss of insurance coverage, or December 31, 2011. We calculated the proportion of RA patients vaccinated for HZ in each calendar year prior to biologic agent initiation and HZ incidence rate for each biologic agent. We compared HZ risks among therapies using Cox regression adjusted for potential confounders. Of 29,129 new biologic treatment episodes, 28.7% used abatacept, 15.9% adalimumab, 14.8% rituximab, 12.4% infliximab, 12.2% etanercept, 6.1% tocilizumab, 5.8% certolizumab, and 4.4% golimumab. The proportion of RA patients vaccinated for HZ prior to biologic agent initiation ranged from 0.4% in 2007 to 4.1% in 2011. We identified 423 HZ diagnoses with the highest HZ incidence rate for certolizumab (2.45 per 100 person-years) and the lowest for golimumab (1.61 per 100 person-years). Neither the crude incidence rate nor the adjusted hazard ratio differed significantly among biologic agents. Glucocorticoid use had a significant association with HZ. Among older patients with RA, the HZ risk was similar across biologic agents, including those with different MOAs. © 2015, American College of Rheumatology.

Bridging the Gap between Research and Clinical Practice in Asymptomatic Alzheimer's Disease.

PubMed

Downing, A M; Yaari, R; Ball, D E; Selzler, K J; Devous, M D

2016-01-01

Due to the growing global health impact of Alzheimer's disease (AD), there is a greater need for interventions that prevent or delay the onset of clinical symptoms of this debilitating disease. Clinical trials for disease-modifying compounds in AD have shifted towards earlier stages in the spectrum of illness, including the stage prior to cognitive symptoms. A population of specific interest for clinical research includes individuals with evidence of Alzheimer's disease pathology who are asymptomatic (ADPa). The challenges and barriers regarding medical treatment of ADPa must be identified and addressed prior to the completion of a positive clinical trial in order to accelerate the translation of research findings to clinical practice. This report applies an existing public health impact model from Spencer and colleagues (2013) to evaluate the readiness of the clinical practice environment to treat ADPa individuals if a disease-modifying agent achieves approval. We contrast the current clinical practice environment with a potential future state through investigating the effectiveness, reach, feasibility, sustainability, and transferability of the practice of treating ADPa individuals.

Impact of nutritional status on body functioning in chronic obstructive pulmonary disease and how to intervene

PubMed Central

Aniwidyaningsih, Wahju; Varraso, Raphaëlle; Cano, Noel; Pison, Christophe

2008-01-01

Purpose of review Chronic obstructive pulmonary disease (COPD) is the fifth cause of mortality in the world. This article reviews diet as a risk or protective factor for COPD, mechanisms of malnutrition, undernutrition consequences on body functioning and how to modulate nutritional status of COPD patients. Recent findings Different dietary factors (dietary pattern, foods, nutrients) have been associated with COPD and the course of the disease. Mechanical disadvantage, energy imbalance, disuse muscle atrophy, hypoxemia, systemic inflammation and oxidative stress have been reported to cause systemic consequences such as cachexia and compromise whole body functioning. Nutritional intervention makes it possible to modify the natural course of the disease provide that it is included in respiratory rehabilitation combining bronchodilators optimization, infection control, exercise and in some patients correction of hypogonadism. Summary Diet, as a modifiable risk factor, appears more as an option to prevent and modify the course of COPD. Reduction of mechanical disadvantage, physical training and anabolic agents should be used conjointly with oral nutrition supplements to overcome undernutrition and might change the prognosis of the disease in some cases. Major research challenges address the role of systemic inflammation and the best interventions for control it besides smoking cessation. PMID:18542004

Novel multitarget-directed ligands (MTDLs) with acetylcholinesterase (AChE) inhibitory and serotonergic subtype 4 receptor (5-HT4R) agonist activities as potential agents against Alzheimer's disease: the design of donecopride.

PubMed

Rochais, Christophe; Lecoutey, Cédric; Gaven, Florence; Giannoni, Patrizia; Hamidouche, Katia; Hedou, Damien; Dubost, Emmanuelle; Genest, David; Yahiaoui, Samir; Freret, Thomas; Bouet, Valentine; Dauphin, François; Sopkova de Oliveira Santos, Jana; Ballandonne, Céline; Corvaisier, Sophie; Malzert-Fréon, Aurélie; Legay, Remi; Boulouard, Michel; Claeysen, Sylvie; Dallemagne, Patrick

2015-04-09

In this work, we describe the synthesis and in vitro evaluation of a novel series of multitarget-directed ligands (MTDL) displaying both nanomolar dual-binding site (DBS) acetylcholinesterase inhibitory effects and partial 5-HT4R agonist activity, among which donecopride was selected for further in vivo evaluations in mice. The latter displayed procognitive and antiamnesic effects and enhanced sAPPα release, accounting for a potential symptomatic and disease-modifying therapeutic benefit in the treatment of Alzheimer's disease.

Update on Huntington's disease: advances in care and emerging therapeutic options.

PubMed

Zielonka, Daniel; Mielcarek, Michal; Landwehrmeyer, G Bernhard

2015-03-01

Huntington's disease (HD) is the most common hereditary neurodegenerative disorder. Despite the fact that both the gene and the mutation causing this monogenetic disorder were identified more than 20 years ago, disease-modifying therapies for HD have not yet been established. While intense preclinical research and large cohort studies in HD have laid foundations for tangible improvements in understanding HD and caring for HD patients, identifying targets for therapeutic interventions and developing novel therapeutic modalities (new chemical entities and advanced therapies using DNA and RNA molecules as therapeutic agents) continues to be an ongoing process. The authors review recent achievements in HD research and focus on approaches towards disease-modifying therapies, ranging from huntingtin-lowering strategies to improving huntingtin clearance that may be promoted by posttranslational HTT modifications. The nature and number of upcoming clinical studies/trials in HD is a reason for hope for HD patients and their families. Copyright © 2014 Elsevier Ltd. All rights reserved.

Handheld Delivery System for Modified Boron-Type Fire Extinguishment Agent

DTIC Science & Technology

1993-11-01

was to develop and test a handheld portable delivery system for use with the modified boron-type fire extinguishing agent for metal fires . B...BACKGROUND A need exists for an extinguishing agent and accompanying delivery system that are effective against complex geometry metal fires . A modified...agent and its delivery system have proven effective against complex geometry metal fires containing up to 200 pounds of magnesium metal. Further

Bifunctional Coupling Agents for Radiolabeling of Biomolecules and Target-Specific Delivery of Metallic Radionuclides

PubMed Central

Liu, Shuang

2008-01-01

Receptor-based radiopharmaceuticals are of great current interest in early molecular imaging and radiotherapy of cancers, and provide a unique tool for target-specific delivery of radionuclides to the diseased tissues. In general, a target-specific radiopharmaceutical can be divided into four parts: targeting biomolecule (BM), pharmacokinetic modifying (PKM) linker, bifunctional coupling or chelating agent (BFC), and radionuclide. The targeting biomolecule serves as a “carrier” for specific delivery of the radionuclide. PKM linkers are used to modify radiotracer excretion kinetics. BFC is needed for radiolabeling of biomolecules with a metallic radionuclide. Different radiometals have significant difference in their coordination chemistry, and require BFCs with different donor atoms and chelator frameworks. Since the radiometal chelate can have a significant impact on physical and biological properties of the target-specific radiopharmaceutical, its excretion kinetics can be altered by modifying the coordination environment with various chelators or coligand, if needed. This review will focus on the design of BFCs and their coordination chemistry with technetium, copper, gallium, indium, yttrium and lanthanide radiometals. PMID:18538888

The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy.

PubMed

McGeer, Patrick L; McGeer, Edith G

2013-10-01

The amyloid cascade hypothesis is widely accepted as the centerpiece of Alzheimer disease (AD) pathogenesis. It proposes that abnormal production of beta amyloid protein (Abeta) is the cause of AD and that the neurotoxicity is due to Abeta itself or its oligomeric forms. We suggest that this, in itself, cannot be the cause of AD because demonstrating such toxicity requires micromolar concentrations of these Abeta forms, while their levels in brain are a million times lower in the picomolar range. AD probably results from the inflammatory response induced by extracellular Abeta deposits, which later become enhanced by aggregates of tau. The inflammatory response, which is driven by activated microglia, increases over time as the disease progresses. Disease-modifying therapeutic attempts to date have failed and may continue to do so as long as the central role of inflammation is not taken into account. Multiple epidemiological and animal model studies show that NSAIDs, the most widely used antiinflammatory agents, have a substantial sparing effect on AD. These studies provide a proof of concept regarding the anti-inflammatory approach to disease modification. Biomarker studies have indicated that early intervention may be necessary. They have established that disease onset occurs more than a decade before it becomes clinically evident. By combining biomarker and pathological data, it is possible to define six phases of disease development, each separated by about 5 years. Phase one can be identified by decreases in Abeta in the CSF, phase 2 by increases of tau in the CSF plus clear evidence of Abeta brain deposits by PET scanning, phase 3 by slight decreases in brain metabolic rate by PET-FDG scanning, phase 4 by slight decreases in brain volume by MRI scanning plus minimal cognitive impairment, phase 5 by increased scanning abnormalities plus clinical diagnosis of AD, and phase 6 by advanced AD requiring institutional care. Utilization of antiinflammatory agents early in the disease process remains an overlooked therapeutic opportunity. Such agents, while not preventative, have the advantage of being able to inhibit the consequences of both Abeta and tau aggregation. Since there is more than a decade between disease onset and cognitive decline, a window of opportunity exists to introduce truly effective disease-modifying regimens. Taking advantage of this opportunity is the challenge for the future.

Bivalent compound 17MN exerts neuroprotection through interaction at multiple sites in a cellular model of Alzheimer’s disease

PubMed Central

Liu, Kai; Chojnacki, Jeremy E.; Wade, Emily E.; Saathoff, John M.; Lesnefsky, Edward J.; Chen, Qun; Zhang, Shijun

2016-01-01

Multiple pathogenic factors have been suggested in playing a role in the development of Alzheimer’s disease (AD). The multifactorial nature of AD also suggests the potential use of compounds with polypharmacology as effective disease-modifying agents. Recently, we have developed a bivalent strategy to include cell membrane anchorage into the molecular design. Our results demonstrated that the bivalent compounds exhibited multifunctional properties and potent neuroprotection in a cellular AD model. Herein, we report the mechanistic exploration of one of the representative bivalent compounds, 17MN, in MC65 cells. Our results established that MC65 cells die through a necroptotic mechanism upon the removal of tetracycline (TC). Furthermore, we have shown that mitochondrial membrane potential (MMP) and cytosolic Ca2+ levels are increased upon removal of TC. Our bivalent compound 17MN can reverse such changes and protect MC65 cells from TC removal induced cytotoxicity. The results also suggest that 17MN may function between the Aβ species and RIPK1 in producing its neuroprotection. Colocalization studies employing a fluorescent analog of 17MN and confocal microscopy demonstrated the interactions of 17MN with both mitochondria and endoplasmic reticulum (ER), thus suggesting that 17MN exerts its neuroprotection via a multiple-site mechanism in MC65 cells. Collectively, these results strongly support our original design rationale of bivalent compounds and encourage further optimization of this bivalent strategy to develop more potent analogs as novel disease-modifying agents for AD. PMID:26401780

Nonenzymatic Reactions above Phospholipid Surfaces of Biological Membranes: Reactivity of Phospholipids and Their Oxidation Derivatives

PubMed Central

Solís-Calero, Christian; Ortega-Castro, Joaquín; Frau, Juan; Muñoz, Francisco

2015-01-01

Phospholipids play multiple and essential roles in cells, as components of biological membranes. Although phospholipid bilayers provide the supporting matrix and surface for many enzymatic reactions, their inherent reactivity and possible catalytic role have not been highlighted. As other biomolecules, phospholipids are frequent targets of nonenzymatic modifications by reactive substances including oxidants and glycating agents which conduct to the formation of advanced lipoxidation end products (ALEs) and advanced glycation end products (AGEs). There are some theoretical studies about the mechanisms of reactions related to these processes on phosphatidylethanolamine surfaces, which hypothesize that cell membrane phospholipids surface environment could enhance some reactions through a catalyst effect. On the other hand, the phospholipid bilayers are susceptible to oxidative damage by oxidant agents as reactive oxygen species (ROS). Molecular dynamics simulations performed on phospholipid bilayers models, which include modified phospholipids by these reactions and subsequent reactions that conduct to formation of ALEs and AGEs, have revealed changes in the molecular interactions and biophysical properties of these bilayers as consequence of these reactions. Then, more studies are desirable which could correlate the biophysics of modified phospholipids with metabolism in processes such as aging and diseases such as diabetes, atherosclerosis, and Alzheimer's disease. PMID:25977746

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

USGS Publications Warehouse

Faisal, M.; Eissa, A.E.; Starliper, C.E.

2010-01-01

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. ?? 2009 University of Cairo.

Glucocorticoids in the management of systemic juvenile idiopathic arthritis.

PubMed

Vannucci, Gaia; Cantarini, Luca; Giani, Teresa; Marrani, Edoardo; Moretti, Davide; Pagnini, Ilaria; Simonini, Gabriele; Cimaz, Rolando

2013-10-01

Glucocorticoids have been the mainstay of treatment for many years in systemic-onset juvenile idiopathic arthritis (sJIA), causing important side effects and some difficulties in the management of this disease. Until the introduction of biologic agents, oral glucocorticoids were used to control fever and other systemic features for several months or even years if systemic manifestations persisted. Nowadays, clinicians have valid alternatives that have revolutionized the natural history of sJIA. Biologic agents, such as the interleukin-1 inhibitors anakinra and the more recent canakinumab, or the interleukin-6 inhibitor tocilizumab, have improved the prognosis of this debilitating disease. Glucocorticoids still have to be considered at the onset of disease when a non-steroidal anti-inflammatory drug therapy fails or when there are life-threatening complications such as severe anemia or pericarditis, or macrophage activation syndrome. Local (intra-articular) triamcinolone hexacetonide is the treatment of choice for arthritis limited to one joint or a few joints in patients without systemic activity. To date, there is still great heterogeneity in the management of sJIA patients, but in recent years there have been attempts to design algorithms and treatment protocols for glucocorticoids, disease-modifying anti-rheumatic drugs, and biologic agents. This review provides an overview of the current knowledge of glucocorticoid therapy in sJIA, comments on recently published recommendations, and gives practical support to the clinician for management of this disease.

System configured for applying a modifying agent to a non-equidimensional substrate

DOEpatents

Janikowski,; Stuart K. , Argyle; Mark D. , Fox; Robert V. , Propp; W Alan, Toth [Idaho Falls, ID; William J. , Ginosar; Daniel M. , Allen; Charles A. , Miller; David, L [Idaho Falls, ID

2007-07-10

The present invention is related to systems and methods for modifying various non-equidimensional substrates with modifying agents. The system comprises a processing chamber configured for passing the non-equidimensional substrate therethrough, wherein the processing chamber is further configured to accept a treatment mixture into the chamber during movement of the non-equidimensional substrate through the processing chamber. The treatment mixture can comprise of the modifying agent in a carrier medium, wherein the carrier medium is selected from the group consisting of a supercritical fluid, a near-critical fluid, a superheated fluid, a superheated liquid, and a liquefied gas. Thus, the modifying agent can be applied to the non-equidimensional substrate upon contact between the treatment mixture and the non-equidimensional substrate.

System configured for applying a modifying agent to a non-equidimensional substrate

DOEpatents

Janikowski, Stuart K.; Toth, William J.; Ginosar, Daniel M.; Allen, Charles A.; Argyle, Mark D.; Fox, Robert V.; Propp, W. Alan; Miller, David L.

2003-09-23

The present invention is related to systems and methods for modifying various non-equidimensional substrates with modifying agents. The system comprises a processing chamber configured for passing the non-equidimensional substrate therethrough, wherein the processing chamber is further configured to accept a treatment mixture into the chamber during movement of the non-equidimensional substrate through the processing chamber. The treatment mixture can comprise of the modifying agent in a carrier medium, wherein the carrier medium is selected from the group consisting of a supercritical fluid, a near-critical fluid, a superheated fluid, a superheated liquid, and a liquefied gas. Thus, the modifying agent can be applied to the non-equidimensional substrate upon contact between the treatment mixture and the non-equidimensional substrate.

Hydroxyl radical-modified fibrinogen as a marker of thrombosis: the role of iron.

PubMed

Lipinski, B; Pretorius, E

2012-07-01

Excessive free iron in blood and in organ tissues (so called iron overload) has been observed in degenerative diseases such as atherosclerosis, cancer, neurological, and certain autoimmune diseases, in which fibrin-like deposits are also found. Although most of the body iron is bound to hemoglobin and myoglobin in a divalent ferrous form, a certain amount of iron exists in blood as a trivalent (ferric) ion. This particular chemical state of iron has been shown to be toxic to the human body when not controlled by endogenous and/or dietary chelating agents. Experiments described in this paper show for the first time that ferric ions (Fe(3+)) can generate hydroxyl radicals without participation of any redox agent, thus making it a special case of the Fenton reaction. Ferric chloride was also demonstrated to induce aggregation of purified fibrinogen at the same molar concentrations that were used for the generation of hydroxyl radicals. Iron-aggregated fibrinogen, by contrast to native molecule, could not be dissociated into polypeptide subunit chains as shown in a polyacrylamide gel electrophoresis. The mechanism of this phenomenon is very likely based on hydroxyl radical-induced modification of fibrinogen tertiary structure with the formation of insoluble aggregates resistant to enzymatic and chemical degradations. Soluble modified fibrinogen species can be determined in blood of thrombotic patients by the reaction with protamine sulfate and/or by scanning electron microscopy. In view of these findings, it is postulated that iron-induced alterations in fibrinogen structure is involved in pathogenesis of certain degenerative diseases associated with iron overload and persistent thrombosis. It is concluded that the detection of hydroxyl radical-modified fibrinogen may be utilized as a marker of a thrombotic condition in human subjects.

[Modifying action of oxytocin on the biological properties of the causative agents of anaerobic non-clostridial infection].

PubMed

Abramzon, O M; Kirillov, D A; Pan'kov, A S; Perunova, N B; Elagina, N N; Valyshev, A V; Bukharin, O V

2003-01-01

In a number of in vitro experiments the effect of oxytocin on the antilysozyme and anticomplemental activity of Propiobacterium propionicum, Bacteroides fragilis, Prevotella melaninogenica and Peptostreprtococcus anaerobius, isolated from patients with acute pyoinflammatory pleuropulmonary diseases, was studied. Antibiotic resistance dynamics of the infective agents under study to lincomycin, clindamycin, thienam, vancomycin was also detected. The inhibiting activity of oxytocin on the persistence properties of B. fragilis, P. melanogenica and P. anaerobius was noted. Under the influence of the preparations used changes in the sensitivity of the strains to a number of antibiotics of the lincosamide, carbapenem and glycopeptide groups were found to occur. The data thus obtained were indicative of the possible mechanisms of action of oxytocin in the treatment of acute pyoinflammatory pleuropulmonary diseases of anaerobic nonclostridial etiology.

Transferrin-modified liposome promotes α-mangostin to penetrate the blood-brain barrier.

PubMed

Chen, Zhi-Lan; Huang, Man; Wang, Xia-Rong; Fu, Jun; Han, Min; Shen, You-Qing; Xia, Zheng; Gao, Jian-Qing

2016-02-01

α-Mangostin (α-M) is a polyphenolic xanthone that protects and improves the survival of cerebral cortical neurons against Aβ oligomer-induced toxicity in rats. α-M is a potential candidate as a treatment for Alzheimer's disease (AD). However, the efficacy was limited by the poor penetration of the drug through the blood-brain barrier (BBB). In this study, we modified the α-M liposome with transferrin (Tf) and investigated the intracellular distribution of liposomes in bEnd3 cells. In addition, the transport of α-M across the BBB in the Tf(α-M) liposome group was examined. In vitro studies demonstrated that the Tf(α-M) liposome could cross the BBB in the form of an integrated liposome. Results of the in vivo studies on the α-M distribution in the brain demonstrated that the Tf(α-M) liposome improved the brain delivery of α-M. These results indicated that the Tf liposome is a potential carrier of α-M against AD. The use of α-Mangostin (α-M) as a potential agent to treat Alzheimer's disease (AD) has been reported. However, its use is limited by the poor penetration through the blood brain barrier. The delivery of this agent by transferrin-modified liposomes was investigated by the authors in this study. The positive results could point to a better drug delivery system for brain targeting. Copyright © 2015 Elsevier Inc. All rights reserved.

IL-6 inhibitors for treatment of rheumatoid arthritis: past, present, and future.

PubMed

Kim, Go Woon; Lee, Na Ra; Pi, Ryo Han; Lim, Yee Seul; Lee, Yu Mi; Lee, Jong Min; Jeong, Hye Seung; Chung, Sung Hyun

2015-01-01

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by polyarthritis. Numerous agents with varying mechanisms are used in the treatment of RA, including non-steroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs, and some biological agents. Studies to uncover the cause of RA have recently ended up scrutinizing the importance of pro-inflammatory cytokine such as tumor necrosis factor α (TNF-α) and interleukin (IL)-6 in the pathogenesis of RA. TNF-α inhibitors are increasingly used to treat RA patients who are non-responsive to conventional anti-arthritis drugs. Despite its effectiveness in a large patient population, up to two thirds of RA patients are found to be partially responsive to anti-TNF therapy. Therefore, agents targeting IL-6 such as tocilizumab (TCZ) attracted significant attention as a promising agent in RA treatment. In this article, we review the mechanism of anti-IL-6 in the treatment of RA, provide the key efficacy and safety data from clinical trials of approved anti-IL-6, TCZ, as well as six candidate IL-6 blockers including sarilumab, ALX-0061, sirukumab, MEDI5117, clazakizumab, and olokizumab, and their future perspectives in the treatment of RA.

Self-assembled dual-modality contrast agents for non-invasive stem cell tracking via near-infrared fluorescence and magnetic resonance imaging.

PubMed

Liu, Hong; Tan, Yan; Xie, Lisi; Yang, Lei; Zhao, Jing; Bai, Jingxuan; Huang, Ping; Zhan, Wugen; Wan, Qian; Zou, Chao; Han, Yali; Wang, Zhiyong

2016-09-15

Stem cells hold great promise for treating various diseases. However, one of the main drawbacks of stem cell therapy is the lack of non-invasive image-tracking technologies. Although magnetic resonance imaging (MRI) and near-infrared fluorescence (NIRF) imaging have been employed to analyse cellular and subcellular events via the assistance of contrast agents, the sensitivity and temporal resolution of MRI and the spatial resolution of NIRF are still shortcomings. In this study, superparamagnetic iron oxide nanocrystals and IR-780 dyes were co-encapsulated in stearic acid-modified polyethylenimine to form a dual-modality contrast agent with nano-size and positive charge. These resulting agents efficiently labelled stem cells and did not influence the cellular viability and differentiation. Moreover, the labelled cells showed the advantages of dual-modality imaging in vivo. Copyright © 2016 Elsevier Inc. All rights reserved.

Novel end points for clinical trials in young children with cystic fibrosis.

PubMed

Simpson, Shannon J; Mott, Lauren S; Esther, Charles R; Stick, Stephen M; Hall, Graham L

2013-06-01

Cystic fibrosis (CF) lung disease commences early in the disease progression and is the most common cause of mortality. While new CF disease-modifying agents are currently undergoing clinical trial evaluation, the implementation of such trials in young children is limited by the lack of age-appropriate clinical trial end points. Advances in infant and preschool lung function testing, imaging of the chest and the development of biochemical biomarkers have led to increased possibility of quantifying mild lung disease in young children with CF and objectively monitoring disease progression over the course of an intervention. Despite this, further standardization and development of these techniques is required to provide robust objective measures for clinical trials in this age group.

New developments in anti-sickling agents: can drugs directly prevent the polymerization of sickle haemoglobin in vivo?

PubMed

Oder, Esther; Safo, Martin K; Abdulmalik, Osheiza; Kato, Gregory J

2016-10-01

The hallmark of sickle cell disease is the polymerization of sickle haemoglobin due to a point mutation in the β-globin gene (HBB). Under low oxygen saturation, sickle haemoglobin assumes the tense (T-state) deoxygenated conformation that can form polymers, leading to rigid erythrocytes with impaired blood vessel transit, compounded or initiated by adhesion of erythrocytes to endothelium, neutrophils and platelets. This process results in vessel occlusion and ischaemia, with consequent acute pain, chronic organ damage, morbidity and mortality. Pharmacological agents that stabilize the higher oxygen affinity relaxed state (R-state) and/or destabilize the lower oxygen affinity T-state of haemoglobin have the potential to delay the sickling of circulating red cells by slowing polymerization kinetics. Relevant classes of agents include aromatic aldehydes, thiol derivatives, isothiocyanates and acyl salicylates derivatives. The aromatic aldehyde, 5-hydroxymethylfurfural (5-HMF) increases oxygen affinity of sickle haemoglobin and reduces hypoxia-induced sickling in vitro and protects sickle cell mice from effects of hypoxia. It has completed pre-clinical testing and has entered clinical trials as treatment for sickle cell disease. A related molecule, GBT440, has shown R-state stabilization and increased oxygen affinity in preclinical testing. Allosteric modifiers of haemoglobin as direct anti-sickling agents target the fundamental pathophysiological mechanism of sickle cell disease. © 2016 John Wiley & Sons Ltd.

The therapeutics of Alzheimer's disease: where we stand and where we are heading.

PubMed

Selkoe, Dennis J

2013-09-01

Few diagnoses in modern medicine evoke more apprehension in patients and their families than Alzheimer disease (AD). Defined as a clinical and pathological entity a century ago, the disorder only came under intense molecular scrutiny in the mid-1980s. Genetic, histopathological, biochemical, and animal modeling studies have combined to provide evidence that the disease may begin with an imbalance between the production and clearance of the self-aggregating amyloid β protein (Aβ) in brain regions serving memory and cognition. This concept has been furthered by recent analyses in humans of cerebrospinal fluid and neuroimaging biomarkers that suggest an approximate sequence of AD-type brain alterations beginning >2 decades before the onset of dementia. Although the Aβ hypothesis of Alzheimer causation does not explain all features of this multifactorial syndrome, experimental agents that lower or neutralize Aβ have become the major focus of therapeutic research. Several clinical trials in mild-to-moderate AD have not met standard cognitive and functional endpoints, but there were important shortcomings in the agent and/or the trial design in each case. Based on the lessons learned, the field has moved on to test potentially disease-modifying agents in mild AD patients or via secondary prevention in presymptomatic subjects bearing amyloid plaques. Immunotherapeutic agents are receiving the most study, but other antiamyloid strategies and, importantly, nonamyloid targets such as tau and neuroinflammation are of great interest. The pace of recent developments augurs well for 1 or more experimental agents being shown to slow cognitive decline without major side effects. However, research funding from all sources will need to increase dramatically and soon to stave off the approaching tsunami of AD. Copyright © 2013 American Neurological Association.

Endocannabinoids in Multiple Sclerosis and Amyotrophic Lateral Sclerosis.

PubMed

Pryce, Gareth; Baker, David

2015-01-01

There are numerous reports that people with multiple sclerosis (MS) have for many years been self-medicating with illegal street cannabis or more recently medicinal cannabis to alleviate the symptoms associated with MS and also amyotrophic lateral sclerosis (ALS). These anecdotal reports have been confirmed by data from animal models and more recently clinical trials on the ability of cannabinoids to alleviate limb spasticity, a common feature of progressive MS (and also ALS) and neurodegeneration. Experimental studies into the biology of the endocannabinoid system have revealed that cannabinoids have efficacy, not only in symptom relief but also as neuroprotective agents which may slow disease progression and thus delay the onset of symptoms. This review discusses what we now know about the endocannabinoid system as it relates to MS and ALS and also the therapeutic potential of cannabinoid therapeutics as disease-modifying or symptom control agents, as well as future therapeutic strategies including the potential for slowing disease progression in MS and ALS.

The efficacy of targeted Health Agents education to reduce the duration of untreated psychosis in a rural population

PubMed Central

Padilla, Eduardo; Molina, Juan; Kamis, Danielle; Calvo, Maria; Stratton, Lee; Strejilevich, Sergio; Aleman, Gabriela Gonzalez; Guerrero, Gonzalo; Bourdieu, Mercedes; Conesa, Horacio A.; Escobar, Javier I.; de Erausquin, Gabriel A.

2014-01-01

The duration of untreated psychosis (DUP) is a key determinant in the severity of symptoms in patients with schizophrenia. DUP is a modifiable factor that if reduced can improve patient outcome and treatment response. We sought to decrease DUP in rural Argentina by instituting annual training of local health agents to better identify signs of mental illness and offer earlier intervention. DUP was estimated using Schedules of Clinical Assessment in Neuropsychiatry (SCAN). Ongoing training was correlated with a reduction in DUP. Reducing DUP through better screening can decrease the psychosocial burden of disease and improve the trajectory of psychosis. PMID:25439394

Treatment options for rheumatoid arthritis: celecoxib, leflunomide, etanercept, and infliximab.

PubMed

Luong, B T; Chong, B S; Lowder, D M

2000-06-01

To review new pharmacologic agents approved for use in the management of rheumatoid arthritis (RA). A MEDLINE search (1966-January 2000) was conducted to identify English-language literature available on the pharmacotherapy of RA, focusing on celecoxib, leflunomide, etanercept, and infliximab. These articles, relevant abstracts, and data provided by the manufacturers were used to collect pertinent data. All controlled and uncontrolled trials were reviewed. Agents were reviewed with regard to mechanism of action, efficacy, drug interactions, pharmacokinetics, dosing, precautions/contraindications, adverse effects, and cost. Traditional pharmacologic treatments for RA have been limited by toxicity, loss of efficacy, or both. Increasing discoveries into the mechanisms of inflammation in RA have led to the development of new agents in hopes of addressing these limitations. With the development of celecoxib, a selective cyclooxygenase-2 inhibitor, the potential exists to minimize the gastrotoxicity associated with nonsteroidal antiinflammatory drugs. Leflunomide has been shown to be equal to or less efficacious than methotrexate, and may be beneficial as a second-line disease-modifying antirheumatic drug (DMARD). The biologic response modifiers, etanercept and infliximab, are alternatives that have shown benefit alone or in combination with methotrexate. However, they should be reserved for patients who fail to respond to DMARD therapy. Further studies should be conducted to evaluate the long-term safety and efficacy of these agents as well as their role in combination therapy. Celecoxib, leflunomide, etanercept, and infliximab are the newest agents approved for RA. Clinical trials have shown that these agents are beneficial in the treatment of RA; however, long-term safety and efficacy data are lacking.

In-Hospital Diuretic Agent Use and Post-Discharge Clinical Outcomes in Patients Hospitalized for Worsening Heart Failure: Insights From the EVEREST Trial.

PubMed

Mecklai, Alicia; Subačius, Haris; Konstam, Marvin A; Gheorghiade, Mihai; Butler, Javed; Ambrosy, Andrew P; Katz, Stuart D

2016-07-01

The aim of this study was to characterize the association between decongestion therapy and 30-day outcomes in patients hospitalized for heart failure (HF). Loop diuretic agents are commonly prescribed for the treatment of symptomatic congestion in patients hospitalized for HF, but the association between loop diuretic agent dose response and post-discharge outcomes has not been well characterized. Cox proportional hazards models were used to estimate the association among average loop diuretic agent dose, congestion status at discharge, and 30-day post-discharge all-cause mortality and HF rehospitalization in 3,037 subjects hospitalized with worsening HF enrolled in the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study With Tolvaptan) study. In univariate analysis, subjects exposed to high-dose diuretic agents (≥160 mg/day) had greater risk for the combined outcome than subjects exposed to low-dose diuretic agents (18.9% vs. 10.0%; hazard ratio: 2.00; 95% confidence interval: 1.64 to 2.46; p < 0.0001). After adjustment for pre-specified covariates of disease severity, the association between diuretic agent dose and outcomes was not significant (hazard ratio: 1.11; 95% confidence interval: 0.89 to 1.38; p = 0.35). Of the 3,011 subjects with clinical assessments of volume status, 2,063 (69%) had little or no congestion at hospital discharge. Congestion status at hospital discharge did not modify the association between diuretic agent exposure and the combined endpoint (p for interaction = 0.84). Short-term diuretic agent exposure during hospital treatment for worsening HF was not an independent predictor of 30-day all-cause mortality and HF rehospitalization in multivariate analysis. Congestion status at discharge did not modify the association between diuretic agent dose and clinical outcomes. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Power Calculations and Placebo Effect for Future Clinical Trials in Progressive Supranuclear Palsy

PubMed Central

Stamelou, Maria; Schöpe, Jakob; Wagenpfeil, Stefan; Ser, Teodoro Del; Bang, Jee; Lobach, Iryna Y.; Luong, Phi; Respondek, Gesine; Oertel, Wolfgang H.; Boxer, Adam L.; Höglinger, Günter U.

2016-01-01

Background Two recent randomized, placebo-controlled trials of putative disease-modifying agents (davunetide, tideglusib) in progressive supranuclear palsy (PSP) failed to show efficacy, but generated data relevant for future trials. Methods We provide sample size calculations based on data collected in 187 PSP patients assigned to placebo in these trials. A placebo effect was calculated. Results The total PSP-Rating Scale required the least number of patients per group (N = 51) to detect a 50% change in the 1-year progression and 39 when including patients with ≤ 5 years disease duration. The Schwab and England Activities of Daily Living required 70 patients per group and was highly correlated with the PSP-Rating Scale. A placebo effect was not detected in these scales. Conclusions We propose the 1-year PSP-Rating Scale score change as the single primary readout in clinical neuroprotective or disease-modifying trials. The Schwab and England Activities of Daily Living could be used as a secondary outcome. PMID:26948290

Achieving the best bowel preparation for colonoscopy

PubMed Central

Parra-Blanco, Adolfo; Ruiz, Alex; Alvarez-Lobos, Manuel; Amorós, Ana; Gana, Juan Cristóbal; Ibáñez, Patricio; Ono, Akiko; Fujii, Takahiro

2014-01-01

Bowel preparation is a core issue in colonoscopy, as it is closely related to the quality of the procedure. Patients often find that bowel preparation is the most unpleasant part of the examination. It is widely accepted that the quality of cleansing must be excellent to facilitate detecting neoplastic lesions. In spite of its importance and potential implications, until recently, bowel preparation has not been the subject of much study. The most commonly used agents are high-volume polyethylene glycol (PEG) electrolyte solution and sodium phosphate. There has been some confusion, even in published meta-analyses, regarding which of the two agents provides better cleansing. It is clear now that both PEG and sodium phosphate are effective when administered with proper timing. Consequently, the timing of administration is recognized as one of the central factors to the quality of cleansing. The bowel preparation agent should be administered, at least in part, a few hours in advance of the colonoscopy. Several low volume agents are available, and either new or modified schedules with PEG that usually improve tolerance. Certain adjuvants can also be used to reduce the volume of PEG, or to improve the efficacy of other agents. Other factors apart from the choice of agent can improve the quality of bowel cleansing. For instance, the effect of diet before colonoscopy has not been completely clarified, but an exclusively liquid diet is probably not required, and a low-fiber diet may be preferable because it improves patient satisfaction and the quality of the procedure. Some patients, such as diabetics and persons with heart or kidney disease, require modified procedures and certain precautions. Bowel preparation for pediatric patients is also reviewed here. In such cases, PEG remains the most commonly used agent. As detecting neoplasia is not the main objective with these patients, less intensive preparation may suffice. Special considerations must be made for patients with inflammatory bowel disease, including safety and diagnostic issues, so that the most adequate agent is chosen. Identifying neoplasia is one of the main objectives of colonoscopy with these patients, and the target lesions are often almost invisible with white light endoscopy. Therefore excellent quality preparation is required to find these lesions and to apply advanced methods such as chromoendoscopy. Bowel preparation for patients with lower gastrointestinal bleeding represents a challenge, and the strategies available are also reviewed here. PMID:25548470

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

PubMed Central

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

Cancer-associated bone disease

PubMed Central

Body, J.-J.; Brandi, M.-L.; Cannata-Andia, J.; Chappard, D.; El Maghraoui, A.; Glüer, C.C.; Kendler, D.; Napoli, N.; Papaioannou, A.; Pierroz, D.D.; Rahme, M.; Van Poznak, C.H.; de Villiers, T.J.; El Hajj Fuleihan, G.

2016-01-01

Bone is commonly affected in cancer. Cancer-induced bone disease results from the primary disease, or from therapies against the primary condition, causing bone fragility. Bone-modifying agents, such as bisphosphonates and denosumab, are efficacious in preventing and delaying cancer-related bone disease. With evidence-based care pathways, guidelines assist physicians in clinical decision-making. Of the 57 million deaths in 2008 worldwide, almost two thirds were due to non-communicable diseases, led by cardiovascular diseases and cancers. Bone is a commonly affected organ in cancer, and although the incidence of metastatic bone disease is not well defined, it is estimated that around half of patients who die from cancer in the USA each year have bone involvement. Furthermore, cancer-induced bone disease can result from the primary disease itself, either due to circulating bone resorbing substances or metastatic bone disease, such as commonly occurs with breast, lung and prostate cancer, or from therapies administered to treat the primary condition thus causing bone loss and fractures. Treatment-induced osteoporosis may occur in the setting of glucocorticoid therapy or oestrogen deprivation therapy, chemotherapy-induced ovarian failure and androgen deprivation therapy. Tumour skeletal-related events include pathologic fractures, spinal cord compression, surgery and radiotherapy to bone and may or may not include hypercalcaemia of malignancy while skeletal complication refers to pain and other symptoms. Some evidence demonstrates the efficacy of various interventions including bone-modifying agents, such as bisphosphonates and denosumab, in preventing or delaying cancer-related bone disease. The latter includes treatment of patients with metastatic skeletal lesions in general, adjuvant treatment of breast and prostate cancer in particular, and the prevention of cancer-associated bone disease. This has led to the development of guidelines by several societies and working groups to assist physicians in clinical decision making, providing them with evidence-based care pathways to prevent skeletal-related events and bone loss. The goal of this paper is to put forth an IOF position paper addressing bone diseases and cancer and summarizing the position papers of other organizations. PMID:24146095

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

PubMed

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.

Corticotropin-releasing factor receptor-1 antagonism mitigates beta amyloid pathology and cognitive and synaptic deficits in a mouse model of Alzheimer's disease.

PubMed

Zhang, Cheng; Kuo, Ching-Chang; Moghadam, Setareh H; Monte, Louise; Campbell, Shannon N; Rice, Kenner C; Sawchenko, Paul E; Masliah, Eliezer; Rissman, Robert A

2016-05-01

Stress and corticotropin-releasing factor (CRF) have been implicated as mechanistically involved in Alzheimer's disease (AD), but agents that impact CRF signaling have not been carefully tested for therapeutic efficacy or long-term safety in animal models. To test whether antagonism of the type-1 corticotropin-releasing factor receptor (CRFR1) could be used as a disease-modifying treatment for AD, we used a preclinical prevention paradigm and treated 30-day-old AD transgenic mice with the small-molecule, CRFR1-selective antagonist, R121919, for 5 months, and examined AD pathologic and behavioral end points. R121919 significantly prevented the onset of cognitive impairment in female mice and reduced cellular and synaptic deficits and beta amyloid and C-terminal fragment-β levels in both genders. We observed no tolerability or toxicity issues in mice treated with R121919. CRFR1 antagonism presents a viable disease-modifying therapy for AD, recommending its advancement to early-phase human safety trials. Copyright © 2015 Alzheimer's Association. All rights reserved.

Phosphorylation of psyllium seed polysaccharide and its characterization.

PubMed

Rao, Monica R P; Warrier, Deepa U; Gaikwad, Snehal R; Shevate, Prachi M

2016-04-01

Psyllium is widely used as a medicinally active natural polysaccharide for treating conditions like constipation, diarrhea, and irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis and colon cancer. Studies have been performed to characterize and modify the polysaccharide obtained from psyllium seed husk and to evaluate its use as a pharmaceutical excipient, but no studies have been performed to evaluate the properties of the polysaccharide present in psyllium seeds. The present study focuses on phosphorylation of psyllium seed polysaccharide (PPS) using sodium tri-meta phosphate as the cross-linking agent. The modified phosphorylated psyllium seed polysaccharide was then evaluated for physicochemical properties, rheological properties, spectral analysis, thermal analysis, crosslinking density and acute oral toxicity studies. The modified polysaccharide (PhPPS) has a high swelling index due to which it can be categorized as a hydrogel. The percent increase in swelling of PhPPS as compared to PPS was found to be 90.26%. The PPS & PhPPS mucilages of all strengths were found to have shear thinning properties. These findings are suggestive of the potential use of PhPPS as gelling & suspending agent. PhPPS was found to have a mucoadhesive property which was comparable with carbopol. Copyright © 2015 Elsevier B.V. All rights reserved.

Enteric Disease Surveillance Under the AFHSC-GEIS: Current Efforts, Landscape Analysis and Vision Forward

DTIC Science & Technology

2011-01-01

Severe diarrhea study at Cairo University • Case-control study of modifiable risk behaviors • Molecular biology and cholera/ rotavirus microbiology...capacity as WHO Rotavirus Reference Laboratory • Norovirus outbreak response support, Incirlik Air Base, Turkey NMRCD-Peru • Cohort study among basic...identified rotavirus as the leading causative agent • Advanced characterization of Campylobacter spp. and Shigella spp. USAMRU-K • Movement of Enteric

Drug-nutrient interactions.

PubMed

Thomas, J A

1995-10-01

Nutrition status plays a significant role in a drug's pharmacodynamics. Some disease states and other special conditions affect nutrient status and a drug's therapeutic efficacy. Many classes of drugs, including antimicrobials, hypoglycemics, and hypocholesterolemic agents, can be affected by the presence of food, with the geriatric patient particularly at risk. While a drug's pharmacokinetic profile can usually be predicted, it can be modified by nutrients and by certain pathophysiologic conditions, including aging, hepatic dysfunction, and micronutrients.

[Guidelines in RA treatment: concepts on safety and recommendations using anti-TNF-alpha inhibitors. Grupo de Estudio de Nuevas Terapias de Enfermedades reumáticas (GENTE)].

PubMed

Díaz-Jouanen, Efraín; Abud-Mendoza, Carlos; Garza-Elizondo, Mario Alberto; Medrano-Ramírez, Gabriel; Burgos-Vargas, Rubén; Orozco-Alcalá, José Javier; Pacheco-Tena, César Francisco; Pineda, Carlos; Pozos-Espíndola, Juan Carlos; Ramos-Niembro, Francisco; Robles-San-Román, Manuel; Santana-Sahagún, Jesús Ernesto

2009-01-01

Recommendations for the use of Disease-Modifying Antirheumatic Drugs (DMARD) with both conventional and biological agents in Rheumatoid Arthritis (RA) must be based on their safety profile, adverse effects, risks, and advantages. With the purpose of presenting the most updated information about the safety of tumor necrosis factor alpha (TNFalpha) antagonists, in this article we summarize the literature published during the last three years about this sort of biological agents in specific clinical situations, such as risk of developing infections, cancer, cardiovascular diseases, and autoimmunity; as well as their administration to patients who will undergo surgical procedures, pregnant and/or breast-feeding women, and patients who need immunizations. Likewise, in this analysis we offer specific recommendations, based on evidence, for the best anti-TNF-alfa management.

Cannabis and amyotrophic lateral sclerosis: hypothetical and practical applications, and a call for clinical trials.

PubMed

Carter, Gregory T; Abood, Mary E; Aggarwal, Sunil K; Weiss, Michael D

2010-08-01

Significant advances have increased our understanding of the molecular mechanisms of amyotrophic lateral sclerosis (ALS), yet this has not translated into any greatly effective therapies. It appears that a number of abnormal physiological processes occur simultaneously in this devastating disease. Ideally, a multidrug regimen, including glutamate antagonists, antioxidants, a centrally acting anti-inflammatory agent, microglial cell modulators (including tumor necrosis factor alpha [TNF-alpha] inhibitors), an antiapoptotic agent, 1 or more neurotrophic growth factors, and a mitochondrial function-enhancing agent would be required to comprehensively address the known pathophysiology of ALS. Remarkably, cannabis appears to have activity in all of those areas. Preclinical data indicate that cannabis has powerful antioxidative, anti-inflammatory, and neuroprotective effects. In the G93A-SOD1 ALS mouse, this has translated to prolonged neuronal cell survival, delayed onset, and slower progression of the disease. Cannabis also has properties applicable to symptom management of ALS, including analgesia, muscle relaxation, bronchodilation, saliva reduction, appetite stimulation, and sleep induction. With respect to the treatment of ALS, from both a disease modifying and symptom management viewpoint, clinical trials with cannabis are the next logical step. Based on the currently available scientific data, it is reasonable to think that cannabis might significantly slow the progression of ALS, potentially extending life expectancy and substantially reducing the overall burden of the disease.

Novel 3-phenylcoumarin-lipoic acid conjugates as multi-functional agents for potential treatment of Alzheimer's disease.

PubMed

Jalili-Baleh, Leili; Nadri, Hamid; Forootanfar, Hamid; Samzadeh-Kermani, Alireza; Küçükkılınç, Tuba Tüylü; Ayazgok, Beyza; Rahimifard, Mahban; Baeeri, Maryam; Doostmohammadi, Mohsen; Firoozpour, Loghman; Bukhari, Syed Nasir Abbas; Abdollahi, Mohammad; Ganjali, Mohammad Reza; Emami, Saeed; Khoobi, Mehdi; Foroumadi, Alireza

2018-05-02

New series of triazole-containing 3-phenylcoumarin-lipoic acid conjugates were designed as multi-functional agents for treatment of Alzheimer's disease. The target compounds 4a-o were synthesized via the azide-alkyne cycloaddition reaction and their biological activities were primarily evaluated in terms of neuroprotection against H 2 O 2 -induced cell death in PC12 cells and AChE/BuChE inhibition. The promising compounds 4j and 4i containing four carbons spacer were selected for further biological evaluations. Based on the obtained results, the benzocoumarin derivative 4j with IC 50 value of 7.3 µM was the most potent AChE inhibitor and displayed good inhibition toward intracellular reactive oxygen species (ROS). This compound with antioxidant and metal chelating ability showed also protective effect on cell injury induced by Aβ 1-42 in SH-SY5Y cells. Although the 8-methoxycoumarin analog 4i was slightly less active than 4j against AChE, but displayed higher protection ability against H 2 O 2 -induced cell death in PC12 and could significantly block Aβ-aggregation. The results suggested that the prototype compounds 4i and 4j might be promising multi-functional agents for the further development of the disease-modifying treatments of Alzheimer's disease. Copyright © 2018 Elsevier Inc. All rights reserved.

Methods for modifying monofilaments, bundles of monofilaments, and fibrous structural material

DOEpatents

Allen, Charles A.; Argyle, Mark D.; Fox, Robert V.; Ginosar, Daniel M.; Janikowski, Stuart K.; Miller, David L.; Propp, W. Alan; Toth, William J.

2002-12-17

The present invention is related to the modifying of substrates such as monofilaments, bundles of monofilaments, and fibrous structural material with a modifying agent. The modifying agent is suspended or dissolved in a supercritical fluid, near-critical fluid, superheated fluid, superheated liquid, or a liquified gas and is deposited by rapidly altering the pressure in a chamber to deposit the modifying material onto the substrate.

Mandating coverage of biologic therapies for rheumatic disease: where evidence and politics meet.

PubMed

Bair, Yali A; White, Richard H; Kravitz, Richard L

2006-06-15

In this issue of Arthritis Care & Research, we inaugurate an occasional series of commentaries entitled Policy Matters. In all of clinical research, our goal is to improve patient outcomes. Usually, that means focusing on the medical, demographic, and socioeconomic factors at the level of individuals with rheumatic diseases; sometimes, our scope of inquiry expands to encompass the impact of the communities in which they live. However, increasingly, the welfare of persons with rheumatic conditions is also affected by health policies through such diverse mechanisms as reimbursement decisions for specific treatments, insurance coverage, manpower, and NIH budgets (the foregoing list is hardly exhaustive).Recently, a piece of legislation was introduced in California (SB913) that has the potential to alter the availability of biologic response modifying agents (BRMs) by mandating that health plans that provide coverage for one such agent include all on their formularies (a revised version would preclude a trial of another disease-modifying antirheumatic drug before use of a BRM). In this state, the California Health Benefits Review Program (CHBRP) provides evidence reviews of the medical effectiveness, cost, and public health impact of proposed health insurance mandates for the legislature. The analysts from the University of California who conducted the medical effectiveness review of SB913 for CHBRP provide a legislative history of the proposed law in this article. We hope that the readership of Arthritis Care & Research find this article informative as an exemplar of the policies that could dramatically alter the welfare of our patients.

A Novel 1,4-Dihydropyridine Derivative Improves Spatial Learning and Memory and Modifies Brain Protein Expression in Wild Type and Transgenic APPSweDI Mice.

PubMed

Jansone, Baiba; Kadish, Inga; van Groen, Thomas; Beitnere, Ulrika; Moore, Doyle Ray; Plotniece, Aiva; Pajuste, Karlis; Klusa, Vija

2015-01-01

Ca2+ blockers, particularly those capable of crossing the blood-brain barrier (BBB), have been suggested as a possible treatment or disease modifying agents for neurodegenerative disorders, e.g., Alzheimer's disease. The present study investigated the effects of a novel 4-(N-dodecyl) pyridinium group-containing 1,4-dihydropyridine derivative (AP-12) on cognition and synaptic protein expression in the brain. Treatment of AP-12 was investigated in wild type C57BL/6J mice and transgenic Alzheimer's disease model mice (Tg APPSweDI) using behavioral tests and immunohistochemistry, as well as mass spectrometry to assess the blood-brain barrier (BBB) penetration. The data demonstrated the ability of AP-12 to cross the BBB, improve spatial learning and memory in both mice strains, induce anxiolytic action in transgenic mice, and increase expression of hippocampal and cortical proteins (GAD67, Homer-1) related to synaptic plasticity. The compound AP-12 can be seen as a prototype molecule for use in the design of novel drugs useful to halt progression of clinical symptoms (more specifically, anxiety and decline in memory) of neurodegenerative diseases, particularly Alzheimer's disease.

PCSK9 Inhibition With Monoclonal Antibodies: Modern Management of Hypercholesterolemia

PubMed Central

Santos, Raul D.

2016-01-01

Abstract Current guidelines for hypercholesterolemia treatment emphasize lifestyle modification and lipid‐modifying therapy to reduce the risk for cardiovascular disease. Statins are the primary class of agents used for the treatment of hypercholesterolemia. Although statins are effective for many patients, they fail to achieve optimal reduction in lipids for some patients, including those who have or are at high risk for cardiovascular disease. The PCSK9 gene was identified in the past decade as a potential therapeutic target for the management of patients with hypercholesterolemia. Pharmacologic interventions to decrease PCSK9 levels are in development, with the most promising approach using monoclonal antibodies that bind to PCSK9 in the plasma. Two monoclonal antibodies, alirocumab and evolocumab, have recently been approved for the treatment of hypercholesterolemia, and a third one, bococizumab, is in phase 3 clinical development. All 3 agents achieve significant reductions in levels of low‐density lipoprotein cholesterol, as well as reductions in non‐high‐density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a). Long‐term outcome trials are under way to determine the sustained efficacy, safety, and tolerability of PCSK9 inhibitors and whether this novel class of agents decreases the risk for major cardiovascular events in patients on lipid‐modifying therapy. Available data suggest that PCSK9 inhibitors provide a robust reduction in atherogenic cholesterol levels with a good safety profile, especially for patients who fail to obtain an optimal clinical response to statin therapy, those who are statin intolerant or have contraindications to statin therapy, and those with familial hypercholesterolemia. PMID:27195910

New drugs for the treatment of rheumatoid arthritis.

PubMed

Schuna, A A; Megeff, C

2000-02-01

New pharmacologic treatment options for rheumatoid arthritis (RA) are described. Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed for RA but are limited by the risk of adverse effects, especially gastrointestinal and renal toxicity. The therapeutic effects of these agents are mediated primarily through inhibition of cyclooxygenase (COX) and prevention of subsequent formation of prostaglandins and related inflammatory mediators. Nonspecific COX inhibition appears to be responsible for much of the toxicity of NSAIDs. Agents have been developed that can selectively inhibit the COX-2 isoform, while sparing COX-1. Celecoxib and other COX-2 inhibitors appear to be no more efficacious than conventional NSAIDs, but offer superior safety. COX-2 inhibitors should be considered for patients who are candidates for NSAID therapy but at risk for GI bleeding. Unlike disease-modifying antirheumatic drugs (DMARDs), these agents do not alter underlying disease progression. Leflunomide is a newer DMARD that reduces pyrimidine synthesis, thus decreasing rheumatoid inflammation. Leflunomide appears to be as effective as methotrexate but, unlike that drug, does not necessitate monitoring for bone marrow toxicity. Etanercept, the first biological agent with FDA-approved labeling for use in RA, has shown efficacy and minimal toxicity, except for injection-site reactions. Other biologicals that have been investigated for use in RA include infliximab and interleukin-1-receptor antagonist. COX-2 inhibitors, leflunomide, and etanercept are promising new drugs available for treating RA. Other agents are under development.

Latin American algorithm for treatment of relapsing-remitting multiple sclerosis using disease-modifying agents.

PubMed

Finkelsztejn, Alessandro; Gabbai, Alberto Alain; Fragoso, Yara Dadalti; Carrá, Adriana; Macías-Islas, Miguel Angel; Arcega-Revilla, Raul; García-Bonitto, Juan; Oehninger-Gatti, Carlos Luis; Orozco-Escobar, Geraldine; Tarulla, Adriana; Vergara, Fernando; Vizcarra, Darwin

2012-10-01

It is estimated that circa 50,000 individuals have relapsing-remitting multiple sclerosis in Latin America. European and North-American algorithms for the treatment of multiple sclerosis do not foresee our regional difficulties and the access of patients to treatment. The Latin American Multiple Sclerosis Forum is an independent and supra-institutional group of experts that has assessed the latest scientific evidence regarding efficacy and safety of disease-modifying treatments. Accesses to treatment and pharmacovigilance programs for each of the eight countries represented at the Forum were also analyzed. A specific set of guidelines based upon evidence-based recommendations was designed for Latin America. Future perspectives of multiple sclerosis treatment were also discussed. The present paper translated an effort from representatives of eight countries discussing a matter that cannot be adapted to our region directly from purely European and North-American guidelines for treatment.

The Antioxidant Additive Approach for Alzheimer's Disease Therapy: New Ferulic (Lipoic) Acid Plus Melatonin Modified Tacrines as Cholinesterases Inhibitors, Direct Antioxidants, and Nuclear Factor (Erythroid-Derived 2)-Like 2 Activators.

PubMed

Benchekroun, Mohamed; Romero, Alejandro; Egea, Javier; León, Rafael; Michalska, Patrycja; Buendía, Izaskun; Jimeno, María Luisa; Jun, Daniel; Janockova, Jana; Sepsova, Vendula; Soukup, Ondrej; Bautista-Aguilera, Oscar M; Refouvelet, Bernard; Ouari, Olivier; Marco-Contelles, José; Ismaili, Lhassane

2016-11-10

Novel multifunctional tacrines for Alzheimer's disease were obtained by Ugi-reaction between ferulic (or lipoic acid), a melatonin-like isocyanide, formaldehyde, and tacrine derivatives, according to the antioxidant additive approach in order to modulate the oxidative stress as therapeutic strategy. Compound 5c has been identified as a promising permeable agent showing excellent antioxidant properties, strong cholinesterase inhibitory activity, less hepatotoxicity than tacrine, and the best neuroprotective capacity, being able to significantly activate the Nrf2 transcriptional pathway.

Ginkgo biloba extract: from molecular mechanisms to the treatment of Alzhelmer's disease.

PubMed

Zimmermann, Martina; Colciaghi, Francesca; Cattabeni, Flaminio; Di Luca, Monica

2002-09-01

Ginkgo biloba is registered for the treatment of several diseases and disorders in Europe. In the United States, it is marketed as a dietary supplement; the French and the German agencies consider it to be effective for the treatment of several diseases, and the immense amount of clinical studies concerning Ginkgo biloba makes it worth revising the existing literature about this notable plant. A brief history of the common use of this drug will be followed by a short botanic characterization. The biochemical composition of the original drug, the leaf itself, will be described in detail together with a brief discussion of commercial extracts and the problem of studying Ginkgo biloba clinically to verify the safety and efficacy of its extracts in the treatment of disorders like Alzheimer's diseases. Aspects of molecular mechanisms modifying the efficacy of this drug will be outlined. Several agents like antioxidants, anti-inflammatory drugs, cholinergic agents, estrogens, or neurotrophic factors are in use for the treatment of this neurodegenerative disease, but none can prove fully convincing benefit. In this field, Ginkgo biloba appears as a useful and sensible supplementary medication to treat Alzheimer's disease, as it seems to be a synthesis of all the different profiles of action of the various, commonly used drugs but with less side effects.

What's in a name? That which we call IPF, by any other name would act the same.

PubMed

Wells, Athol U; Brown, Kevin K; Flaherty, Kevin R; Kolb, Martin; Thannickal, Victor J

2018-05-01

Idiopathic pulmonary fibrosis (IPF) remains a truly idiopathic fibrotic disease, with a modest genetic predilection and candidate triggers but no overall explanation for the development of disease in non-familial cases. Agreement on terminology has contributed to major clinical and translational advances since the millennium. It is likely that the entity currently captured by the term "IPF" will be radically reclassified over the next decade, either through "splitting" (into IPF subgroups responding selectively to individual disease-modifying agents) or through "lumping" of IPF with other forms of progressive fibrotic lung disease (with shared pathogenetic mechanisms and IPF-like disease behaviour). In this perspective, we summarise the clinical and pathogenetic justification for a focus on "the progressive fibrotic phenotype" in future clinical and translational research. By this means, we can hope to address the needs of non-IPF patients with inexorably progressive fibrotic disease, currently disenfranchised by lack of access to agents that are efficacious in IPF. In this regard, ongoing trials of anti-fibrotic therapies in non-IPF patients with progressive fibrosis may be highly influential. Future revision of IPF nomenclature may be warranted if there are major conceptual changes but without compelling justification, the benefits of renaming IPF are likely to be outweighed by the resulting confusion. Copyright ©ERS 2018.

A possible link between the Epstein-Barr virus infection and autoimmune thyroid disorders

PubMed Central

Gwizdek, Katarzyna; Michalski, Marek; Wojnicz, Romuald

2016-01-01

The Epstein-Barr virus (EBV), also known as human herpesvirus 4, is a member of the Herpesviridae virus family. EBV infection can cause infectious mononucleosis (IM) in the lytic phase of EBV’s life cycle. Past EBV infection is associated with lymphomas, and may also result in certain allergic and autoimmune diseases. Although potential mechanisms of autoimmune diseases have not been clearly elucidated, both genetic and environmental factors, such as infectious agents, are considered to be responsible for their development. In addition, EBV modifies the host immune response. The worldwide prevalence of autoimmune diseases shows how common this pathogen is. Normally, the virus stays in the body and remains dormant throughout life. However, this is not always the case, and a serious EBV-related illness may develop later in life. This explains the chronic course of autoimmune diseases that is often accompanied by exacerbations of symptoms. Based on the present studies, EBV infection can cause autoimmune diseases, such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), Sjögren’s syndrome, and autoimmune hepatitis. The EBV has also been reported in patients with autoimmune thyroid disorders. Although EBV is not the only agent responsible for the development of autoimmune thyroid diseases, it can be considered a contributory factor. PMID:27833448

A possible link between the Epstein-Barr virus infection and autoimmune thyroid disorders.

PubMed

Dittfeld, Anna; Gwizdek, Katarzyna; Michalski, Marek; Wojnicz, Romuald

2016-01-01

The Epstein-Barr virus (EBV), also known as human herpesvirus 4, is a member of the Herpesviridae virus family. EBV infection can cause infectious mononucleosis (IM) in the lytic phase of EBV's life cycle. Past EBV infection is associated with lymphomas, and may also result in certain allergic and autoimmune diseases. Although potential mechanisms of autoimmune diseases have not been clearly elucidated, both genetic and environmental factors, such as infectious agents, are considered to be responsible for their development. In addition, EBV modifies the host immune response. The worldwide prevalence of autoimmune diseases shows how common this pathogen is. Normally, the virus stays in the body and remains dormant throughout life. However, this is not always the case, and a serious EBV-related illness may develop later in life. This explains the chronic course of autoimmune diseases that is often accompanied by exacerbations of symptoms. Based on the present studies, EBV infection can cause autoimmune diseases, such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), Sjögren's syndrome, and autoimmune hepatitis. The EBV has also been reported in patients with autoimmune thyroid disorders. Although EBV is not the only agent responsible for the development of autoimmune thyroid diseases, it can be considered a contributory factor.

Environmental Exposures, Epigenetic Changes and the Risk of Lupus

PubMed Central

Somers, Emily C; Richardson, Bruce C

2013-01-01

A dose-dependent combination of environmental exposures, estrogenic hormones and genetic predisposition is thought to be required for lupus to develop and flare, but how the environment modifies the immune system in genetically predisposed people is unclear. Current evidence indicates that environmental agents that inhibit DNA methylation can convert normal antigen-specific CD4+ T lymphocytes into autoreactive, cytotoxic, pro-inflammatory cells that are sufficient to cause lupus-like autoimmunity in animal models, and that the same changes in DNA methylation characterize CD4+ T cells from patients with active lupus. Environmental agents implicated in inhibiting T cell DNA methylation include the lupus-inducing drugs procainamide and hydralazine, as well as diet, and agents causing oxidative stress, such as smoking, UV light exposure, and infections, which have been associated with lupus onset or disease activity. Other studies demonstrate that demethylated T cells cause only anti-DNA antibodies in mice lacking a genetic predisposition to lupus, but are sufficient to cause lupus-like autoimmunity in genetically predisposed mice and likely people, and that estrogens augment the disease. Collectively, these studies suggest that environmental agents that inhibit DNA methylation, together with lupus genes and estrogens or endocrine disruptors, combine in a dose-dependent fashion to cause lupus flares. PMID:24763540

The efficacy of targeted health agents education to reduce the duration of untreated psychosis in a rural population.

PubMed

Padilla, Eduardo; Molina, Juan; Kamis, Danielle; Calvo, Maria; Stratton, Lee; Strejilevich, Sergio; Aleman, Gabriela Gonzalez; Guerrero, Gonzalo; Bourdieu, Mercedes; Conesa, Horacio A; Escobar, Javier I; de Erausquin, Gabriel A

2015-02-01

The duration of untreated psychosis (DUP) is a key determinant in the severity of symptoms in patients with schizophrenia. DUP is a modifiable factor that if reduced can improve patient outcome and treatment response. We sought to decrease DUP in rural Argentina by instituting annual training of local health agents to better identify signs of mental illness and offer earlier intervention. DUP was estimated using Schedules of Clinical Assessment in Neuropsychiatry (SCAN). Ongoing training was correlated with a reduction in DUP. Reducing DUP through better screening can decrease the psychosocial burden of disease and improve the trajectory of psychosis. Copyright © 2014 Elsevier B.V. All rights reserved.

Bronchial asthma and COPD due to irritants in the workplace - an evidence-based approach

PubMed Central

2012-01-01

Background Respiratory irritants represent a major cause of occupational obstructive airway diseases. We provide an overview of the evidence related to irritative agents causing occupational asthma or occupational COPD. Methods We searched MEDLINE via PubMed. Reference lists of relevant reviews were also screened. The SIGN grading system was used to rate the quality of each study. The modified RCGP three-star system was used to grade the body of evidence for each irritant agent regarding its causative role in either occupational asthma or occupational COPD. Results A total of 474 relevant papers were identified, covering 188 individual agents, professions or work-sites. The focus of most of the studies and the predominant diagnosis was occupational asthma, whereas occupational COPD arose only incidentally. The highest level assigned using the SIGN grading was 2+ (well-conducted systematic review, cohort or case–control study with a low risk of confounding or bias). According to the modified RCGP three-star grading, the strongest evidence of association with an individual agent, profession or work-site (“**”) was found for 17 agents or work-sites, including benzene-1,2,4-tricarboxylicacid-1,2-anhydride, chlorine, platinum salt, isocyanates, cement dust, grain dust, animal farming, environmental tobacco smoke, welding fumes or construction work. Phthalic anhydride, glutaraldehyde, sulphur dioxide, cotton dust, cleaning agents, potrooms, farming (various), foundries were found to be moderately associated with occupational asthma or occupational COPD (“*[+]”). Conclusion This study let us assume that irritant-induced occupational asthma and especially occupational COPD are considerably underreported. Defining the evidence of the many additional occupational irritants for causing airway disorders will be the subject of continued studies with implications for diagnostics and preventive measures. PMID:23013890

Gene Therapy for Parkinson's Disease

PubMed Central

Denyer, Rachel; Douglas, Michael R.

2012-01-01

Current pharmacological and surgical treatments for Parkinson's disease offer symptomatic improvements to those suffering from this incurable degenerative neurological disorder, but none of these has convincingly shown effects on disease progression. Novel approaches based on gene therapy have several potential advantages over conventional treatment modalities. These could be used to provide more consistent dopamine supplementation, potentially providing superior symptomatic relief with fewer side effects. More radically, gene therapy could be used to correct the imbalances in basal ganglia circuitry associated with the symptoms of Parkinson's disease, or to preserve or restore dopaminergic neurons lost during the disease process itself. The latter neuroprotective approach is the most exciting, as it could theoretically be disease modifying rather than simply symptom alleviating. Gene therapy agents using these approaches are currently making the transition from the laboratory to the bedside. This paper summarises the theoretical approaches to gene therapy for Parkinson's disease and the findings of clinical trials in this rapidly changing field. PMID:22619738

Gene therapy for Parkinson's disease.

PubMed

Denyer, Rachel; Douglas, Michael R

2012-01-01

Current pharmacological and surgical treatments for Parkinson's disease offer symptomatic improvements to those suffering from this incurable degenerative neurological disorder, but none of these has convincingly shown effects on disease progression. Novel approaches based on gene therapy have several potential advantages over conventional treatment modalities. These could be used to provide more consistent dopamine supplementation, potentially providing superior symptomatic relief with fewer side effects. More radically, gene therapy could be used to correct the imbalances in basal ganglia circuitry associated with the symptoms of Parkinson's disease, or to preserve or restore dopaminergic neurons lost during the disease process itself. The latter neuroprotective approach is the most exciting, as it could theoretically be disease modifying rather than simply symptom alleviating. Gene therapy agents using these approaches are currently making the transition from the laboratory to the bedside. This paper summarises the theoretical approaches to gene therapy for Parkinson's disease and the findings of clinical trials in this rapidly changing field.

Old and new challenges in Parkinson's disease therapeutics.

PubMed

Pires, Ana O; Teixeira, F G; Mendes-Pinheiro, B; Serra, Sofia C; Sousa, Nuno; Salgado, António J

2017-09-01

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons and/or loss od neuronal projections, in several dopaminergic networks. Current treatments for idiopathic PD rely mainly on the use of pharmacologic agents to improve motor symptomatology of PD patients. Nevertheless, so far PD remains an incurable disease. Therefore, it is of utmost importance to establish new therapeutic strategies for PD treatment. Over the last 20 years, several molecular, gene and cell/stem-cell therapeutic approaches have been developed with the aim of counteracting or retarding PD progression. The scope of this review is to provide an overview of PD related therapies and major breakthroughs achieved within this field. In order to do so, this review will start by focusing on PD characterization and current treatment options covering thereafter molecular, gene and cell/stem cell-based therapies that are currently being studied in animal models of PD or have recently been tested in clinical trials. Among stem cell-based therapies, those using MSCs as possible disease modifying agents for PD therapy and, specifically, the MSCs secretome contribution to meet the clinical challenge of counteracting or retarding PD progression, will be more deeply explored. Copyright © 2017 Elsevier Ltd. All rights reserved.

Refractory pulmonary sarcoidosis - proposal of a definition and recommendations for the diagnostic and therapeutic approach.

PubMed

Korsten, Peter; Strohmayer, Katharina; Baughman, Robert P; Sweiss, Nadera J

2016-03-01

Patients with sarcoidosis undergo spontaneous remission or may be effectively controlled with glucocorticoids alone in many cases. Progressive and refractory pulmonary sarcoidoisis constitute more than 10% of patients seen at specialized centers. Pulmonary fibrosis and associated complications, such as infections and pulmonary hypertension are leading causes of mortality. No universal definition of refractoriness exists, we therefore propose classifying patients as having refractory disease when the following criteria are fulfilled: (1) progressive disease despite at least 10 mg of prednisolone or equivalent for at least three months and need for additional disease-modifying anti-sarcoid drugs due to lack of efficacy, drug toxicity or intolerability and (2) treatment started for significant impairment of life due to progressive pulmonary symptoms. Both criteria should be fulfilled. Treatment options in addition to or instead of glucocorticoids for these patients include second- (methotrexate, azathioprine, leflunomide) and third-line agents (infliximab, adalimumab). Other immunmodulating agents can be used, but the evidence is very limited. Newer agents with anti-fibrotic properties, such as pirfenidone or nintedanib, might hold promise also for the pulmonary fibrosis seen in sarcoidosis. Treating physicians have to actively look for potentially treatable complications, such as pulmonary hypertension, cardiac disease or infections before patients should be classified as treatment-refractory. Ultimately, lung transplantation has to be considered as treatment option for patients not responding to medical therapy. In this review, we aim to propose a new definition of refractoriness, describe the associated clinical features and suggest the therapeutic approach.

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

PubMed Central

Lauterbach, Edward C.; Fontenelle, Leonardo F.; Teixeira, Antonio L.

2012-01-01

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. PMID:22254151

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

PubMed Central

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

Distinguishing rational from irrational applications of pharmacogenetic synergies from the bench to clinical trials.

PubMed

Hucl, Tomas; Gallmeier, Eike; Kern, Scott E

2007-06-01

Single therapeutic agents very often fail in unselected patients. It is therefore commonplace to combine an agent specifically with a selected patient subgroup or with another agent. To support such efforts, it is useful to clarify the distinctions between the terms and the mathematical models used in analyzing combinations. To incorporate molecular disease classifications, the familiar concept of the therapeutic window is modified to define a pharmacogenetic window, which is an unambiguous numerical measure of the magnitude of interaction produced by a combination, and to define a test of pharmacogenetic synergy. In contrast, certain common comparative methods, such as vertical windows (comparing effects at a given dose) and animal models of mutational targets may be dominated by undesirable features. Although this discussion is oriented towards cancer therapy, an extension of these concepts to other comparative biologic assays is feasible and advisable.

Evaluation of Foaming Performance of Bitumen Modified with the Addition of Surface Active Agent

NASA Astrophysics Data System (ADS)

Chomicz-Kowalska, Anna; Mrugała, Justyna; Maciejewski, Krzysztof

2017-10-01

The article presents the analysis of the performance of foamed bitumen modified using surface active agents. Although, bitumen foaming permits production of asphalt concrete and other asphalt mix types without using chemical additives in significantly reduced temperatures, the decrease in processing temperatures still impacts the adhesion performance and bitumen coating of aggregates in final mixes. Therefore, in some cases it may be feasible to incorporate adhesion promoters and surface active agents into warm and half-warm mixes with foamed bitumen to increase their service life and resilience. Because of the various nature of the available surface active agents, varying bitumen compatibility and their possible impact on the rheological properties of bitumen, the introduction of surface active agents may significantly alter the bitumen foaming performance. The tests included basic performance tests of bitumen before and after foaming. The two tested bitumen were designated as 35/50 and 50/70 penetration grade binders, which were modified with a surface active agent widely used for improving mixture workability, compactibility and adhesion in a wide range of asphalt mixes and techniques, specifically Warm Mix Asphalt. Alongside to the reference unmodified bitumen, binders with 0.2%, 0.4% and 0.6% surface active agent concentration were tested. The analysis has shown a positive influence of the modifier on the foaming performance of both of the base bitumen increasing their maximum expansion ratio and bitumen foam halflife. In the investigations, it was found that the improvement was dependent on the bitumen type and modifier content. The improved expansion ratio and foam half-life has a positive impact on the aggregate coating and adhesion, which together with the adhesion promoting action of the modifier will have a combined positive effect on the quality of produced final asphalt mixes.

Isolation of a gene encoding a novel spectinomycin phosphotransferase from Legionella pneumophila.

PubMed

Suter, T M; Viswanathan, V K; Cianciotto, N P

1997-06-01

A gene capable of conferring spectinomycin resistance was isolated from Legionella pneumophila, the agent of Legionnaires' disease. The gene (aph) encoded a 36-kDa protein which has similarity to aminoglycoside phosphotransferases. Biochemical analysis confirmed that aph encodes a phosphotransferase which modifies spectinomycin but not hygromycin, kanamycin, or streptomycin. The strain that was the source of aph demonstrated resistance to spectinomycin, and Southern hybridizations determined that aph also exists in other legionellae.

Isolation of a gene encoding a novel spectinomycin phosphotransferase from Legionella pneumophila.

PubMed Central

Suter, T M; Viswanathan, V K; Cianciotto, N P

1997-01-01

A gene capable of conferring spectinomycin resistance was isolated from Legionella pneumophila, the agent of Legionnaires' disease. The gene (aph) encoded a 36-kDa protein which has similarity to aminoglycoside phosphotransferases. Biochemical analysis confirmed that aph encodes a phosphotransferase which modifies spectinomycin but not hygromycin, kanamycin, or streptomycin. The strain that was the source of aph demonstrated resistance to spectinomycin, and Southern hybridizations determined that aph also exists in other legionellae. PMID:9174205

Established and novel disease-modifying treatments in multiple sclerosis.

PubMed

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.g. fingolimod or natalizumab if JC virus antibody-negative). The aim of this review is to discuss the clinical benefits, mechanisms of action, safety profiles and monitoring strategies of current MS disease-modifying therapies in clinical practice and of those expected to enter the market in the near future. © 2014 The Association for the Publication of the Journal of Internal Medicine.

PCSK9 Inhibition With Monoclonal Antibodies: Modern Management of Hypercholesterolemia.

PubMed

Ito, Matthew K; Santos, Raul D

2017-01-01

Current guidelines for hypercholesterolemia treatment emphasize lifestyle modification and lipid-modifying therapy to reduce the risk for cardiovascular disease. Statins are the primary class of agents used for the treatment of hypercholesterolemia. Although statins are effective for many patients, they fail to achieve optimal reduction in lipids for some patients, including those who have or are at high risk for cardiovascular disease. The PCSK9 gene was identified in the past decade as a potential therapeutic target for the management of patients with hypercholesterolemia. Pharmacologic interventions to decrease PCSK9 levels are in development, with the most promising approach using monoclonal antibodies that bind to PCSK9 in the plasma. Two monoclonal antibodies, alirocumab and evolocumab, have recently been approved for the treatment of hypercholesterolemia, and a third one, bococizumab, is in phase 3 clinical development. All 3 agents achieve significant reductions in levels of low-density lipoprotein cholesterol, as well as reductions in non-high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a). Long-term outcome trials are under way to determine the sustained efficacy, safety, and tolerability of PCSK9 inhibitors and whether this novel class of agents decreases the risk for major cardiovascular events in patients on lipid-modifying therapy. Available data suggest that PCSK9 inhibitors provide a robust reduction in atherogenic cholesterol levels with a good safety profile, especially for patients who fail to obtain an optimal clinical response to statin therapy, those who are statin intolerant or have contraindications to statin therapy, and those with familial hypercholesterolemia. © 2016, The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Advanced Glycation End Products: Association with the Pathogenesis of Diseases and the Current Therapeutic Advances.

PubMed

Ajith, Thekkuttuparambil A; Vinodkumar, Puzhikunathu

2016-01-01

Advanced glycation end products (AGE) such as N-ε-carboxy-ethyl-lysine (CEL), N-ε-carboxy-methyl-lysine (CML), imidazolone, methyl-glyoxal-lysine dimer (MOLD), glyoxal-lysine dimer (GOLD), pyrraline and pentosidine have been imparted in the development and worsening of complications of diabetes. They are also involved in atherosclerosis, normal aging process, arthritis, cancer and progression of age-related neurodegenerative diseases like Alzheimer`s disease. Endogenously, they are formed by nonenzymatic glycation by aldoses/ketoses to form intermediate precursor that were slowly converted into AGE. A positive correlation was observed with the level of AGEs formation and progression of the diseases. Exogenously, they formed in foods when they were cooked at very high temperature. AGEs can interact with the cell surface receptors of AGE (RAGE) to release cytokines, free radicals as well as directly modify the extracellular matrix and action of hormones. Hence, the mechanism of AGE association with pathogenesis of diseases can be ascribed mainly to the generated cytokines and free radicals. Second type of receptors such as AGE receptor-1, 2 and 3 were more specific and involved in their detoxification and clearance. Therapeutic agents were used to inhibit AGEs formation, traps the reactive carbonyl intermediate precursors, interfering with Amadori`s products, cross-link breaker and low molecular weight inhibitors of RAGE had been described as well. Despite the several therapeutic agents described so far, none of them have proven to be recommended for clinical use. Furthermore, no methods or standard units were accepted universally to measure AGEs are existing. This review discusses AGEs formation, association with diseases and therapeutic agents to alleviate them.

It's about time--directing our attention toward modifying the course of COPD.

PubMed

Cazzola, Mario; Hanania, Nicola A; Jones, Paul W; Mahler, Donald A; Make, Barry; Ohar, Jill; Rennard, Stephen

2008-06-01

The course of COPD has traditionally been equated with an accelerated decline in the forced expiratory volume in one second (FEVi) over time in patients with COPD, compared to healthy individuals. However, other important clinical outcomes associated with COPD also worsen over time and should also be considered in conceptualizing the course of COPD. These include health status, breathlessness related to activities of daily living, exercise capacity, the frequency of exacerbations, and peripheral muscle weakness. These outcomes are often quite responsive to therapy of COPD. Presently there is no evidence that any treatment other than smoking cessation can normalise the rate of decline of FEVi, and therefore be considered as modifying the physiologic course of the disease. Thus, smoking cessation reigns as the primary disease modifying strategy in COPD. Even though there are a number of smoking cessation products on the market and smoking prevalence continues to decrease marginally each year, more needs to be done to provide comprehensive programmes to help people quit smoking. In the US in 2004, 37.5% of preventable deaths were found to be tobacco-related. The FEVi does not reflect the clinical manifestations or the total burden of this multidimensional illness. As novel therapeutic agents become available that may alter the underlying pathology of COPD, additional markers and outcomes of disease progression will be needed to provide a more comprehensive assessment. There has been increasing interest in predicting and assessing mortality as it is the final outcome of disease progression. In this review we have considered three approaches toward modifying the course of COPD: smoking cessation, reduction in lung hyperinflation through medical and surgical approaches, and long-term pharmacotherapy.

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

PubMed

Tvete, Ingunn Fride; Natvig, Bent; Gåsemyr, Jørund; Meland, Nils; Røine, Marianne; Klemp, Marianne

2015-01-01

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.

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

PubMed Central

Tvete, Ingunn Fride; Natvig, Bent; Gåsemyr, Jørund; Meland, Nils; Røine, Marianne; Klemp, Marianne

2015-01-01

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. 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. PMID:26356639

Pridopidine: Overview of Pharmacology and Rationale for its Use in Huntington's Disease.

PubMed

Waters, Susanna; Tedroff, Joakim; Ponten, Henrik; Klamer, Daniel; Sonesson, Clas; Waters, Nicholas

2018-01-01

Despite advances in understanding the pathophysiology of Huntington's disease (HD), there are currently no effective pharmacological agents available to treat core symptoms or to stop or prevent the progression of this hereditary neurodegenerative disorder. Pridopidine, a novel small molecule compound, has demonstrated potential for both symptomatic treatment and disease modifying effects in HD. While pridopidine failed to achieve its primary efficacy outcomes (Modified motor score) in two trials (MermaiHD and HART) there were consistent effects on secondary outcomes (TMS). In the most recent study (PrideHD) pridiopidine did not differ from placebo on TMS, possibly due to a large enduring placebo effect.This review describes the process, based on in vivo systems response profiling, by which pridopidine was discovered and discusses its pharmacological profile, aiming to provide a model for the system-level effects, and a rationale for the use of pridopidine in patients affected by HD. Considering the effects on brain neurochemistry, gene expression and behaviour in vivo, pridopidine displays a unique effect profile. A hallmark feature in the behavioural pharmacology of pridopidine is its state-dependent inhibition or activation of dopamine-dependent psychomotor functions. Such effects are paralleled by strengthening of synaptic connectivity in cortico-striatal pathways suggesting pridopidine has potential to modify phenotypic expression as well as progression of HD. The preclinical pharmacological profile is discussed with respect to the clinical results for pridopidine, and proposals are made for further investigation, including preclinical and clinical studies addressing disease progression and effects at different stages of HD.

Genetic modifiers of Huntington's disease.

PubMed

Gusella, James F; MacDonald, Marcy E; Lee, Jong-Min

2014-09-15

Huntington's disease (HD) is a devastating neurodegenerative disorder that directly affects more than 1 in 10,000 persons in Western societies but, as a family disorder with a long, costly, debilitating course, it has an indirect impact on a far greater proportion of the population. Although some palliative treatments are used, no effective treatment exists for preventing clinical onset of the disorder or for delaying its inevitable progression toward premature death, approximately 15 years after diagnosis. Huntington's disease involves a movement disorder characterized by chorea, as well as a variety of psychiatric disturbances and intellectual decline, with a gradual loss of independence. A dire need exists for effective HD therapies to alleviate the suffering and costs to the individual, family, and health care system. In past decades, genetics, the study of DNA sequence variation and its consequences, provided the tools to map the HD gene to chromosome 4 and ultimately to identify its mutation as an expanded CAG trinucleotide repeat in the coding sequence of a large protein, dubbed huntingtin. Now, advances in genetic technology offer an unbiased route to the identification of genetic factors that are disease-modifying agents in human patients. Such genetic modifiers are expected to highlight processes capable of altering the course of HD and therefore to provide new, human-validated targets for traditional drug development, with the goal of developing rational treatments to delay or prevent onset of HD clinical signs. © 2014 International Parkinson and Movement Disorder Society.

Modified titanium implant as a gateway to the human body: the implant mediated drug delivery system.

PubMed

Park, Young-Seok; Cho, Joo-Youn; Lee, Shin-Jae; Hwang, Chee Il

2014-01-01

The aim of this study was to investigate the efficacy of a proposed new implant mediated drug delivery system (IMDDS) in rabbits. The drug delivery system is applied through a modified titanium implant that is configured to be implanted into bone. The implant is hollow and has multiple microholes that can continuously deliver therapeutic agents into the systematic body. To examine the efficacy and feasibility of the IMDDS, we investigated the pharmacokinetic behavior of dexamethasone in plasma after a single dose was delivered via the modified implant placed in the rabbit tibia. After measuring the plasma concentration, the areas under the curve showed that the IMDDS provided a sustained release for a relatively long period. The result suggests that the IMDDS can deliver a sustained release of certain drug components with a high bioavailability. Accordingly, the IMDDS may provide the basis for a novel approach to treating patients with chronic diseases.

MicroRNAs as targets for dietary and pharmacological inhibitors of mutagenesis and carcinogenesis

PubMed Central

Izzotti, Alberto; Cartiglia, Cristina; Steele, Vernon E.; De Flora, Silvio

2012-01-01

MicroRNAs (miRNAs) have been implicated in many biological processes, cancer, and other diseases. In addition, miRNAs are dysregulated following exposure to toxic and genotoxic agents. Here we review studies evaluating modulation of miRNAs by dietary and pharmacological agents, which could potentially be exploited for inhibition of mutagenesis and carcinogenesis. This review covers natural agents, including vitamins, oligoelements, polyphenols, isoflavones, indoles, isothiocyanates, phospholipids, saponins, anthraquinones and polyunsaturated fatty acids, and synthetic agents, including thiols, nuclear receptor agonists, histone deacetylase inhibitors, antiinflammatory drugs, and selective estrogen receptor modulators. As many as 145 miRNAs, involved in the control of a variety of carcinogenesis mechanisms, were modulated by these agents, either individually or in combination. Most studies used cancer cells in vitro with the goal of modifying their phenotype by changing miRNA expression profiles. In vivo studies evaluated regulation of miRNAs by chemopreventive agents in organs of mice and rats, either untreated or exposed to carcinogens, with the objective of evaluating their safety and efficacy. The tissue specificity of miRNAs could be exploited for the chemoprevention of site-specific cancers, and the study of polymorphic miRNAs is expected to predict the individual response to chemopreventive agents as a tool for developing new prevention strategies. PMID:22683846

Therapies for peripheral joint disease in psoriatic arthritis. A systematic review.

PubMed

Soriano, Enrique R; McHugh, Neil J

2006-07-01

Traditional drug treatments for psoriatic arthritis (PsA) include nonsteroidal antiinflammatory agents (NSAID) and disease modifying antirheumatic drugs (DMARD), although the evidence base for their effectiveness is not well established. This review was compiled from a comprehensive literature search of electronic bibliographic databases for all English publications that were systematic reviews, metaanalyses, randomized controlled trials, controlled trials, and observational studies. The evidence supports NSAID for symptom relief, although data are lacking for COX-2-specific agents. No evidence exists to support systemic corticosteroids or corticosteroids by intraarticular injection, although the latter are commonly used in clinical practice. Among traditional DMARD, grade 1B evidence supports sulfasalazine, cyclosporine, and leflunomide for symptom relief, with lower-grade evidence for methotrexate. None of them slows radiographic progression. Grade 1B evidence supports improvement in symptoms, physical function, quality of life, and radiographic progression with anti-TNF antagonists (etanercept, infliximab, and adalimumab). The relative lack of evidence poses challenges in developing algorithms for treatment of peripheral arthritis in PsA.

VMAT2 Inhibitors for Tardive Dyskinesia-Practice Implications.

PubMed

Peckham, Alyssa M; Nicewonder, Jessica A

2018-01-01

Tardive dyskinesia is a potentially irreversible, debilitating, hyperkinetic movement disorder that can result from dopamine receptor antagonists. Prompt recognition and resolution of symptoms are instrumental in preventing disease irreversibility, though current treatment options have fallen short of robust, effective, and long-term symptom control. In April 2017, the Food and Drug Administration (FDA) approved 2 new vesicular monoamine transporter 2 (VMAT2) inhibitors, deutetrabenazine and valbenazine, for chorea related to Huntington's disease and tardive dyskinesia, respectively. These agents were pharmacologically modified from tetrabenazine, a VMAT2 inhibitor used off-label in the treatment of tardive dyskinesia. Despite FDA-labeled indications of deutetrabenazine and valbenazine, each agent was explored as a treatment option for those with tardive dyskinesia. In this study, the pharmacologic modifications of the 2 new VMAT2 inhibitors are described, with detailed explanation as to how these may impact clinical practice. The associated case series, observational studies, and clinical trials exploring their use in the treatment of tardive dyskinesia are reported with expert opinion on practice implication.

Drug Delivery Systems for Imaging and Therapy of Parkinson's Disease.

PubMed

Gunay, Mine Silindir; Ozer, A Yekta; Chalon, Sylvie

2016-01-01

Although a variety of therapeutic approaches are available for the treatment of Parkinson's disease, challenges limit effective therapy. Among these challenges are delivery of drugs through the blood brain barier to the target brain tissue and the side effects observed during long term administration of antiparkinsonian drugs. The use of drug delivery systems such as liposomes, niosomes, micelles, nanoparticles, nanocapsules, gold nanoparticles, microspheres, microcapsules, nanobubbles, microbubbles and dendrimers is being investigated for diagnosis and therapy. This review focuses on formulation, development and advantages of nanosized drug delivery systems which can penetrate the central nervous system for the therapy and/or diagnosis of PD, and highlights future nanotechnological approaches. It is esential to deliver a sufficient amount of either therapeutic or radiocontrast agents to the brain in order to provide the best possible efficacy or imaging without undesired degradation of the agent. Current treatments focus on motor symptoms, but these treatments generally do not deal with modifying the course of Parkinson's disease. Beyond pharmacological therapy, the identification of abnormal proteins such as α -synuclein, parkin or leucine-rich repeat serine/threonine protein kinase 2 could represent promising alternative targets for molecular imaging and therapy of Parkinson's disease. Nanotechnology and nanosized drug delivery systems are being investigated intensely and could have potential effect for Parkinson's disease. The improvement of drug delivery systems could dramatically enhance the effectiveness of Parkinson's Disease therapy and reduce its side effects.

Obesity and response to anti-tumor necrosis factor-α agents in patients with select immune-mediated inflammatory diseases: A systematic review and meta-analysis.

PubMed

Singh, Siddharth; Facciorusso, Antonio; Singh, Abha G; Casteele, Niels Vande; Zarrinpar, Amir; Prokop, Larry J; Grunvald, Eduardo L; Curtis, Jeffrey R; Sandborn, William J

2018-01-01

We sought to evaluate the association between obesity and response to anti-tumor necrosis factor-α (TNF) agents, through a systematic review and meta-analysis. Through a systematic search through January 24, 2017, we identified randomized controlled trials (RCTs) or observational studies in adults with select immune-mediated inflammatory diseases-inflammatory bowel diseases (IBD), rheumatoid arthritis (RA), spondyloarthropathies (SpA), psoriasis and psoriatic arthritis (PsA)-treated with anti-TNF agents, and reporting outcomes, stratified by body mass index (BMI) categories or weight. Primary outcome was failure to achieve clinical remission or response or treatment modification. We performed random effects meta-analysis and estimated odds ratios (OR) and 95% confidence interval (CI). Based on 54 cohorts including 19,372 patients (23% obese), patients with obesity had 60% higher odds of failing therapy (OR,1.60; 95% CI,1.39-1.83;I2 = 71%). Dose-response relationship was observed (obese vs. normal BMI: OR,1.87 [1.39-2.52]; overweight vs. normal BMI: OR,1.38 [1.11-1.74],p = 0.11); a 1kg/m2 increase in BMI was associated with 6.5% higher odds of failure (OR,1.065 [1.043-1.087]). These effects were observed across patients with rheumatic diseases, but not observed in patients with IBD. Effect was consistent based on dosing regimen/route, study design, exposure definition, and outcome measures. Less than 10% eligible RCTs reported outcomes stratified by BMI. Obesity is an under-reported predictor of inferior response to anti-TNF agents in patients with select immune-mediated inflammatory diseases. A thorough evaluation of obesity as an effect modifier in clinical trials is warranted, and intentional weight loss may serve as adjunctive treatment in patients with obesity failing anti-TNF therapy.

Allergen immunotherapy in allergic rhinitis: current use and future trends.

PubMed

Klimek, Ludger; Pfaar, Oliver; Bousquet, Jean; Senti, Gabriela; Kündig, Thomas

2017-09-01

Type-1 allergies are among the most chronic common diseases of humans. Allergen immunotherapy (AIT) is the only causative and disease-modifying treatment option besides allergen avoidance. Severe systemic adverse allergic reactions may be induced by every AIT treatment. Different approaches have been used to provide safer AIT preparations to lower or even totally overcome this risk. Areas covered: A structured literature recherche in Medline and Pubmed under inclusion of national and international guidelines and Cochrane meta-analyses has been performed aiming at reviewing clinical use of such approaches in AIT. New allergen preparations may include allergoids, recombinant allergens (recA) and modified recombinant allergens (recA) in subcutaneous as well as in mucosal immunotherapies (application e.g. using bronchial, nasal, oral and sublingual application) with sublingual being the established mucosal application route and new ways of application like intralymphatic and epicutaneous immunotherapy. Expert commentary: Immune-modifying agents like Virus-like particles and CpG-motifs, adjuvants like MPL and aluminum hydroxide are evaluated and found to increase and direct the immunological response toward immunological tolerance. New forms of allergen extracts can improve safety and efficacy of AIT and may change our way of performing allergen immunotherapy in the future.

Testing the Right Target and the Right Drug at the Right Stage

PubMed Central

Sperling, Reisa A.; Jack, Clifford R.; Aisen, Paul S.

2013-01-01

Alzheimer’s disease (AD) is the only leading cause of death for which no disease-modifying therapy is currently available. Recent disappointing trial results at the dementia stage of AD have raised multiple questions about our current approaches to the development of disease-modifying agents. Converging evidence suggests that the pathophysiological process of AD begins many years before the onset of dementia. So why do we keep testing drugs aimed at the initial stages of the disease process in patients at the end-stage of the illness? Alzheimer’s disease (AD) remains one of the most feared consequences of aging, affecting more than one out of every ten individuals over the age of 65. With more than 10,000 baby boomers turning 65 every day in the United States alone, we are truly facing an AD epidemic. Over the past decade, a string of disappointing clinical trial results have raised concerns about our current strategy for development of AD-modifying therapies. Three hypotheses can explain these recent AD trial failures: (i) We are targeting the wrong pathophysiological mechanisms; (ii) The drugs do not engage the intended targets in patients; and (iii) The drugs are hitting the right targets, but are doing so at the wrong stage of the disease. Here, we address the third supposition and suggest that specific amyloid-based therapies be directed at much earlier stages of ADperhaps even prior to the emergence of clinical symptoms. Furthermore, we argue that the field has sufficient tools to begin “secondary prevention” trials in asymptomatic individuals whoare at high risk for progression to cognitive impairment and AD dementia. PMID:22133718

Drug development in Parkinson's disease: from emerging molecules to innovative drug delivery systems.

PubMed

Garbayo, E; Ansorena, E; Blanco-Prieto, M J

2013-11-01

Current treatments for Parkinson's disease (PD) are aimed at addressing motor symptoms but there is no therapy focused on modifying the course of the disease. Successful treatment strategies have been so far limited and brain drug delivery remains a major challenge that restricts its treatment. This review provides an overview of the most promising emerging agents in the field of PD drug discovery, discussing improvements that have been made in brain drug delivery for PD. It will be shown that new approaches able to extend the length of the treatment, to release the drug in a continuous manner or to cross the blood-brain barrier and target a specific region are still needed. Overall, the results reviewed here show that there is an urgent need to develop both symptomatic and disease-modifying treatments, giving priority to neuroprotective treatments. Promising perspectives are being provided in this field by rasagiline and by neurotrophic factors like glial cell line-derived neurotrophic factor. The identification of disease-relevant genes has also encouraged the search for disease-modifying therapies that function by identifying molecularly targeted drugs. The advent of new molecular and cellular targets like α-synuclein, leucine-rich repeat serine/threonine protein kinase 2 or parkin, among others, will require innovative delivery therapies. In this regard, drug delivery systems (DDS) have shown great potential for improving the efficacy of conventional and new PD therapy and reducing its side effects. The new DDS discussed here, which include microparticles, nanoparticles and hydrogels among others, will probably open up possibilities that extend beyond symptomatic relief. However, further work needs to be done before DDS become a therapeutic option for PD patients. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

The druggable genome and support for target identification and validation in drug development.

PubMed

Finan, Chris; Gaulton, Anna; Kruger, Felix A; Lumbers, R Thomas; Shah, Tina; Engmann, Jorgen; Galver, Luana; Kelley, Ryan; Karlsson, Anneli; Santos, Rita; Overington, John P; Hingorani, Aroon D; Casas, Juan P

2017-03-29

Target identification (determining the correct drug targets for a disease) and target validation (demonstrating an effect of target perturbation on disease biomarkers and disease end points) are important steps in drug development. Clinically relevant associations of variants in genes encoding drug targets model the effect of modifying the same targets pharmacologically. To delineate drug development (including repurposing) opportunities arising from this paradigm, we connected complex disease- and biomarker-associated loci from genome-wide association studies to an updated set of genes encoding druggable human proteins, to agents with bioactivity against these targets, and, where there were licensed drugs, to clinical indications. We used this set of genes to inform the design of a new genotyping array, which will enable association studies of druggable genes for drug target selection and validation in human disease. Copyright © 2017, American Association for the Advancement of Science.

System Configured For Applying Multiple Modifying Agents To A Substrate.

DOEpatents

Propp, W. Alan; Argyle, Mark D.; Janikowski, Stuart K.; Fox, Robert V.; Toth, William J.; Ginosar, Daniel M.; Allen, Charles A.; Miller, David L.

2005-11-08

The present invention is related to the modifying of substrates with multiple modifying agents in a single continuous system. At least two processing chambers are configured for modifying the substrate in a continuous feed system. The processing chambers can be substantially isolated from one another by interstitial seals. Additionally, the two processing chambers can be substantially isolated from the surrounding atmosphere by end seals. Optionally, expansion chambers can be used to separate the seals from the processing chambers.

System configured for applying multiple modifying agents to a substrate

DOEpatents

Propp, W. Alan; Argyle, Mark D.; Janikowski, Stuart K.; Fox, Robert V.; Toth, William J.; Ginosar, Daniel M.; Allen, Charles A.; Miller, David L.

2003-11-25

The present invention is related to the modifying of substrates with multiple modifying agents in a single continuous system. At least two processing chambers are configured for modifying the substrate in a continuous feed system. The processing chambers can be substantially isolated from one another by interstitial seals. Additionally, the two processing chambers can be substantially isolated from the surrounding atmosphere by end seals. Optionally, expansion chambers can be used to separate the seals from the processing chambers.

Managing Chemotherapy-Related Cardiotoxicity in Survivors of Childhood Cancers

PubMed Central

Lipshultz, Steven E.; Diamond, Melissa B.; Franco, Vivian I.; Aggarwal, Sanjeev; Leger, Kasey; Santos, Maria Verônica; Sallan, Stephen E.; Chow, Eric J.

2015-01-01

In the US, children diagnosed with cancer are living longer, but not without consequences from the same drugs that cured their cancer. In these patients, cardiovascular disease is the leading cause of non-cancer-related morbidity and mortality. Although this review focuses on anthracycline-related cardiomyopathy in childhood cancer survivors, the global lifetime risk of other cardiovascular diseases such as atherosclerosis, arrhythmias and intracardiac conduction abnormalities, hypertension, and stroke also are increased. Besides anthracyclines, newer molecularly targeted agents, such as vascular endothelial growth factor receptor and tyrosine kinase inhibitors, also have been associated with acute hypertension, cardiomyopathy, increased risk of ischemic cardiac events and arrhythmias, and are summarized here. This review also covers other risk factors for chemotherapy-related cardiotoxicity (including both modifiable and non-modifiable factors), monitoring strategies (including both blood and imaging-based biomarkers) during and following cancer treatment, and discusses the management of cardiotoxicity (including prevention strategies such as cardioprotection by use of dexrazoxane). PMID:25134924

A modified R-type bacteriocin specifically targeting Clostridium difficile prevents colonization of mice without affecting gut microbiota diversity.

PubMed

Gebhart, Dana; Lok, Stephen; Clare, Simon; Tomas, Myreen; Stares, Mark; Scholl, Dean; Donskey, Curtis J; Lawley, Trevor D; Govoni, Gregory R

2015-03-24

Clostridium difficile is a leading cause of nosocomial infections worldwide and has become an urgent public health threat requiring immediate attention. Epidemic lineages of the BI/NAP1/027 strain type have emerged and spread through health care systems across the globe over the past decade. Limiting person-to-person transmission and eradicating C. difficile, especially the BI/NAP1/027 strain type, from health care facilities are difficult due to the abundant shedding of spores that are impervious to most interventions. Effective prophylaxis for C. difficile infection (CDI) is lacking. We have genetically modified a contractile R-type bacteriocin ("diffocin") from C. difficile strain CD4 to kill BI/NAP1/027-type strains for this purpose. The natural receptor binding protein (RBP) responsible for diffocin targeting was replaced with a newly discovered RBP identified within a prophage of a BI/NAP1/027-type target strain by genome mining. The resulting modified diffocins (a.k.a. Avidocin-CDs), Av-CD291.1 and Av-CD291.2, were stable and killed all 16 tested BI/NAP1/027-type strains. Av-CD291.2 administered in drinking water survived passage through the mouse gastrointestinal (GI) tract, did not detectably alter the mouse gut microbiota or disrupt natural colonization resistance to C. difficile or the vancomycin-resistant Enterococcus faecium (VREF), and prevented antibiotic-induced colonization of mice inoculated with BI/NAP1/027-type spores. Given the high incidence and virulence of the pathogen, preventing colonization by BI/NAP1/027-type strains and limiting their transmission could significantly reduce the occurrence of the most severe CDIs. This modified diffocin represents a prototype of an Avidocin-CD platform capable of producing targetable, precision anti-C. difficile agents that can prevent and potentially treat CDIs without disrupting protective indigenous microbiota. Treatment and prevention strategies for bacterial diseases rely heavily on traditional antibiotics, which impose strong selection for resistance and disrupt protective microbiota. One consequence has been an upsurge of opportunistic pathogens, such as Clostridium difficile, that exploit antibiotic-induced disruptions in gut microbiota to proliferate and cause life-threatening diseases. We have developed alternative agents that utilize contractile bactericidal protein complexes (R-type bacteriocins) to kill specific C. difficile pathogens. Efficacy in a preclinical animal study indicates these molecules warrant further development as potential prophylactic agents to prevent C. difficile infections in humans. Since these agents do not detectably alter the indigenous gut microbiota or colonization resistance in mice, we believe they will be safe to administer as a prophylactic to block transmission in high-risk environments without rendering patients susceptible to enteric infection after cessation of treatment. Copyright © 2015 Gebhart et al.

The Lens Capsule

PubMed Central

Danysh, Brian P.; Duncan, Melinda K.

2009-01-01

The lens capsule is a modified basement membrane that completely surrounds the ocular lens. It is known that this extracellular matrix is important for both the structure and biomechanics of the lens in addition to providing informational cues to maintain lens cell phenotype. This review covers the development and structure of the lens capsule, lens diseases associated with mutations in extracellular matrix genes and the role of the capsule in lens function including those proposed for visual accommodation, selective permeability to infectious agents, and cell signaling. PMID:18773892

Approach towards an integrative drug treatment of Alzheimer's disease.

PubMed

Windisch, M

2000-01-01

At present pharmacotherapy of Alzheimer's disease (AD) is limited to acetylcholinesterase inhibitors. These drugs produce small, but consistent improvements of memory and global function, some are also positively influencing activities of daily living. This therapeutic approach neglects the complexity of AD and the fact that most of the degenerating neurons are not cholinergic. Acetylcholinesterase inhibitors are symptomatic drugs, with no influence on disease progression. There is a need for disease modifying compounds, or preventive drugs. Data are indicating that vitamin E has some ability to influence the disease progression. The potency of non-steroidal anti-inflammatory drugs (NSAIDs) or estrogen as preventive agents has to be explored further in prospective clinical studies. The initial hope in the use of naturally occurring neurotrophic factors, like nerve growth factor, to rescue cholinergic neurons from degeneration and to restore cognitive function has been disappointed in first, small clinical studies. The peptidergic drug Cerebrolysin exhibiting neurotrophic stimulation, neuroimmunotrophic regulation and induction of BBB glucose transporter expression, might be able to address the pathological changes of AD at different levels simultaneously. In addition to an impressive preclinical database, results from 3 placebo-controlled, double-blind studies demonstrate significant improvements of cognitive performance, global function and activities of daily living in AD patients. In all studies persisting improvements, up to 6 months after drug withdrawal, indicate a powerful disease modifying activity.

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

PubMed Central

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

The effects of immunosuppressive and anti-inflammatory medications on fertility, pregnancy, and lactation.

PubMed

Janssen, N M; Genta, M S

2000-03-13

Many rheumatic diseases affect women of childbearing age, and the medications used to treat these diseases may affect conception, pregnancy, fetal development, and lactation. Physicians who care for these women need to be aware of the potential adverse effects of these medications, and which medications can be used safely prior to conception and during pregnancy and lactation. Although reviews of individual classes of medications are available, there is no practical and comprehensive review that summarizes all of this information, and includes anticoagulant drugs and 2 recently approved drugs for rheumatoid arthritis. Women who take cytotoxic drugs should be informed of the risks of impaired fertility and congenital malformations, and must use effective methods of contraception. During pregnancy, nonsteroidal anti-inflammatory agents may be used until the last 6 weeks, and low to moderate doses of corticosteroids are safe throughout pregnancy. Among the disease-modifying agents, sulfasalazine and hydroxychloroquine treatment may be maintained. Cytotoxic drugs may be used after the first trimester to treat life-threatening disease. During lactation, prednisone, sulfasalazine, and hydroxychloroquine may be used cautiously. Women using heparin for treatment of antiphospholipid antibody syndrome should take measures to prevent bone loss. Men taking methotrexate, sulfasalazine, cyclosporine, azathioprine, or leflunomide should be apprised of the possibilities of infertility and teratogenicity.

Recent developments in biomarkers in Parkinson disease

PubMed Central

Schapira, Anthony H.V.

2013-01-01

Purpose of review Parkinson disease is the second most common neurodegenerative disease after Alzheimer disease, and current demographic trends indicate a life-time risk approaching 4% and predict a doubling of prevalence by 2030. Strategies are being developed to apply recent advances in our understanding of the cause of Parkinson disease to the development of biomarkers that will enable the identification of at-risk individuals, enable early diagnosis and reflect the progression of disease. The latter will be particularly important for the testing of disease-modifying therapies. This review summarizes recent advances in Parkinson disease biomarker development. Recent findings Recent reports continue to reflect the application of a variety of clinical, imaging or biochemical measurements, alone or in combination, to general Parkinson disease populations. Probably the most promising is the assay of alpha-synuclein in the diagnosis and evolution of Parkinson disease. At present, detection techniques are still being refined, but once accurate and reproducible assays are available, it will be important to define the relationship of these to early diagnosis and progression. Alpha-synuclein concentrations may also be modulated by certain disease-modifying agents in development and so may represent a measure of their efficacy. It has to be accepted that no single measure currently fulfils all the necessary criteria for a biomarker in Parkinson disease, but combinations of measures are more likely to deliver benefit. Summary The Parkinson disease biomarker field is approaching a stage when certain combinations of clinical, imaging and biochemical measures may identify a proportion of individuals at risk for developing the disease. However, their general applicability may be limited. Attention is now turning to stratification of Parkinson disease into certain at-risk groups defined by genotype. The application of multimodal screening to these populations may be more rewarding in the short term. PMID:23823465

Toward precision medicine in primary biliary cholangitis.

PubMed

Carbone, Marco; Ronca, Vincenzo; Bruno, Savino; Invernizzi, Pietro; Mells, George F

2016-08-01

Primary biliary cholangitis is a chronic, cholestatic liver disease characterized by a heterogeneous presentation, symptomatology, disease progression and response to therapy. In contrast, clinical management and treatment of PBC is homogeneous with a 'one size fits all' approach. The evolving research landscape, with the emergence of the -omics field and the availability of large patient cohorts are creating a unique opportunity of translational epidemiology. Furthermore, several novel disease and symptom-modifying agents for PBC are currently in development. The time is therefore ripe for precision medicine in PBC. In this manuscript we describe the concept of precision medicine; review current approaches to risk-stratification in PBC, and speculate how precision medicine in PBC might develop in the near future. Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Genotoxic effect and antigen binding characteristics of SLE auto-antibodies to peroxynitrite-modified human DNA.

PubMed

Khan, Md Asad; Alam, Khursheed; Mehdi, Syed Hassan; Rizvi, M Moshahid A

2017-12-01

Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease characterized by auto-antibodies against native deoxyribonucleic acid after modification and is one of the reasons for the development of SLE. Here, we have evaluated the structural perturbations in human placental DNA by peroxynitrite using spectroscopy, thermal denaturation and high-performance liquid chromatography (HPLC). Peroxynitrite is a powerful potent bi-functional oxidative/nitrative agent that is produced both endogenously and exogenously. In experimental animals, the peroxynitrite-modified DNA was found to be highly immunogenic. The induced antibodies showed cross-reactions with different types of DNA and nitrogen bases that were modified with peroxynitrite by inhibition ELISA. The antibody activity was inhibited by approximately 89% with its immunogen as the inhibitor. The antigen-antibodies interaction between induced antibodies with peroxynitrite-modified DNA showed retarded mobility as compared to the native form. Furthermore, significantly increased binding was also observed in SLE autoantibodies with peroxynitrite-modified DNA than native form. Moreover, DNA isolated from lymphocyte of SLE patients revealed significant recognition of anti-peroxynitrite-modified DNA immunoglobulin G (IgG). Our data indicates that DNA modified with peroxynitrite presents unique antigenic determinants that may induce autoantibody response in SLE. Copyright © 2017 Elsevier Inc. All rights reserved.

Epidemiology of hypertensive kidney disease.

PubMed

Udani, Suneel; Lazich, Ivana; Bakris, George L

2011-01-01

The prevalence of hypertension, chronic kidney disease (CKD) and end-stage renal disease (ESRD) attributable to hypertension continues to rise worldwide. Identifying the precise prevalence of CKD attributable to hypertension is difficult owing to the absence of uniform criteria to establish a diagnosis of hypertensive nephropathy. Despite the increasing prevalence of CKD-associated hypertension, awareness of hypertension among individuals with CKD remains suboptimal and rates of blood-pressure control remain poor. Targeted subgroups involved in studies of CKD seem to reach better rates of blood-pressure control, suggesting that this therapeutic goal can be achieved in patients with CKD. Elevated blood-pressure levels are associated with CKD progression. However, the optimal blood-pressure level and pharmacological agent remains unclear. Physicians treating patients with CKD must recognize the importance of maintaining optimal salt and volume balance to achieve blood-pressure goals. Furthermore, agents that modify the renin-angiotensin-aldosterone axis can be an important adjunct to therapy and physicians must monitor expected changes in serum creatinine and electrolyte levels after their administration. Hypertension remains a common factor complicating CKD. Future investigations identifying early signs of hypertension-related CKD, increasing awareness of the effects of hypertension in CKD and determining optimal therapeutic interventions might help reduce the incidence of hypertensive nephropathy.

Review of the role of probiotics in gastrointestinal diseases in adults.

PubMed

Sebastián Domingo, Juan José

Probiotics may act as biological agents that modify the intestinal microbiota and certain cytokine profiles, which can lead to an improvement in certain gastrointestinal diseases. To conduct a review of the evidence of the role of probiotics in certain gastrointestinal diseases in adults. Review conducted using appropriate descriptors, filters and limits in the PubMed database (MEDLINE). The MeSH terms used were Probiotics [in the title] AND Gastrointestinal Diseases, with the following limits or filters: Types of study: Systematic Reviews, Meta-Analysis, Guideline, Practice Guideline, Consensus Development Conference (and Consensus Development Conference NIH), Randomized Controlled Trial, Controlled Clinical Trial and Clinical Trial; age: adults (19 or older); language: English and Spanish; in humans, and with at least one abstract. Full texts of all the Systematic Reviews and meta-analyses directly related to the review's objective were obtained, as well as the Randomised Controlled Trials of the studies that were considered relevant and of sufficient quality for this review. Certain probiotics, different for each process, have proven to be effective and beneficial in cases of acute infectious diarrhoea, antibiotic-associated diarrhoea, Clostridium difficile-associated diarrhoea, pouchitis and Helicobacter pylori infection eradication. Although some probiotics have not demonstrated any benefit, there are certain gastrointestinal diseases in which the use of probiotics, true biological agents, can be recommended. Copyright © 2017 Elsevier España, S.L.U., AEEH y AEG. All rights reserved.

Influence of Anti-TNF and Disease Modifying Antirheumatic Drugs Therapy on Pulmonary Forced Vital Capacity Associated to Ankylosing Spondylitis: A 2-Year Follow-Up Observational Study

PubMed Central

Rocha-Muñoz, Alberto Daniel; Brambila-Tapia, Aniel Jessica Leticia; Zavala-Cerna, María Guadalupe; Vásquez-Jiménez, José Clemente; De la Cerda-Trujillo, Liliana Faviola; Vázquez-Del Mercado, Mónica; Rodriguez-Jimenez, Norma Alejandra; Díaz-Rizo, Valeria; Díaz-González, Viviana; Cardona-Muñoz, Ernesto German; Dávalos-Rodríguez, Ingrid Patricia; Salazar-Paramo, Mario; Gamez-Nava, Jorge Ivan; Nava-Zavala, Arnulfo Hernan; Gonzalez-Lopez, Laura

2015-01-01

Objective. To evaluate the effect of anti-TNF agents plus synthetic disease modifying antirheumatic drugs (DMARDs) versus DMARDs alone for ankylosing spondylitis (AS) with reduced pulmonary function vital capacity (FVC%). Methods. In an observational study, we included AS who had FVC% <80% at baseline. Twenty patients were taking DMARDs and 16 received anti-TNF + DMARDs. Outcome measures: changes in FVC%, BASDAI, BASFI, 6-minute walk test (6MWT), Borg scale after 6MWT, and St. George's Respiratory Questionnaire at 24 months. Results. Both DMARDs and anti-TNF + DMARDs groups had similar baseline values in FVC%. Significant improvement was achieved with anti-TNF + DMARDs in FVC%, at 24 months, when compared to DMARDs alone (P = 0.04). Similarly, patients in anti-TNF + DMARDs group had greater improvement in BASDAI, BASFI, Borg scale, and 6MWT when compared to DMARDs alone. After 2 years of follow-up, 14/16 (87.5%) in the anti-TNF + DMARDs group achieved the primary outcome: FVC% ≥80%, compared with 11/20 (55%) in the DMARDs group (P = 0.04). Conclusions. Patients with anti-TNF + DMARDs had a greater improvement in FVC% and cardiopulmonary scales at 24 months compared with DMARDs. This preliminary study supports the fact that anti-TNF agents may offer additional benefits compared to DMARDs in patients with AS who have reduced FVC%. PMID:26078986

Underestimation of the efficacy, effectiveness, tolerability, and safety of weekly low-dose methotrexate in information presented to physicians and patients.

PubMed

Pincus, T; Furer, V; Sokka, T

2010-01-01

Ten specific examples of the underestimation of the efficacy, effectiveness and tolerability, and overestimation of adverse events of weekly, low-dose methotrexate, administered with folic acid, in treatment of rheumatic diseases are summarised. These examples include: 1) meta-analyses of clinical trials suggest that methotrexate has an efficacy similar to other disease-modifying anti-rheumatic drugs (DMARDs); 2) information in textbooks and websites may overstate adverse events and drug interactions associated with weekly low-dose methotrexate; 3) information presented to patients when filling a prescription for methotrexate understates 'side effects' of RA and overstates those of methotrexate; 4) an admonition to patients to refrain entirely from consumption of alcohol while taking methotrexate may be unnecessary; 5) frequent blood testing in patients who take methotrexate may be overused; 6) eligibility of only a small minority of patients for clinical trials to compare biologic agents and methotrexate; 7) Step-up design in most comparisons of biologic agents with methotrexate includes only patients who had experienced an incomplete response to methotrexate; 8) in parallel design trials, the efficacy of biologic agents is not substantially greater than that of methotrexate; 9) low, inflexible dosage schedules of methotrexate and requirement for withdrawal with minimal liver function abnormalities in many clinical trials may underestimate efficacy, effectiveness, tolerability and safety; 10) interpretation of clinical trial results may overstate the clinical significance of lower radiographic progression in patients treated with biologic agents versus patients treated with methotrexate. More accurate interpretation of information for physicians and other health professionals, as well as patients, concerning use of weekly low-dose methotrexate in contemporary care could improve care and outcomes for patients with RA and other rheumatic diseases.

Discovery of direct inhibitors of Keap1-Nrf2 protein-protein interaction as potential therapeutic and preventive agents.

PubMed

Abed, Dhulfiqar Ali; Goldstein, Melanie; Albanyan, Haifa; Jin, Huijuan; Hu, Longqin

2015-07-01

The Keap1-Nrf2-ARE pathway is an important antioxidant defense mechanism that protects cells from oxidative stress and the Keap1-Nrf2 protein-protein interaction (PPI) has become an important drug target to upregulate the expression of ARE-controlled cytoprotective oxidative stress response enzymes in the development of therapeutic and preventive agents for a number of diseases and conditions. However, most known Nrf2 activators/ARE inducers are indirect inhibitors of Keap1-Nrf2 PPI and they are electrophilic species that act by modifying the sulfhydryl groups of Keap1׳s cysteine residues. The electrophilicity of these indirect inhibitors may cause "off-target" side effects by reacting with cysteine residues of other important cellular proteins. Efforts have recently been focused on the development of direct inhibitors of Keap1-Nrf2 PPI. This article reviews these recent research efforts including the development of high throughput screening assays, the discovery of peptide and small molecule direct inhibitors, and the biophysical characterization of the binding of these inhibitors to the target Keap1 Kelch domain protein. These non-covalent direct inhibitors of Keap1-Nrf2 PPI could potentially be developed into effective therapeutic or preventive agents for a variety of diseases and conditions.

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

PubMed

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).

Transport of Zn(OH4)(2-) Ions Across a Polyolefin Microporous Membrane

DTIC Science & Technology

1992-12-22

studied using polarography and conductometry . Soluble Nafion as an ion exchange modifying agent was applied to the membrane by several techniques. The...polypropylene membranes was studied using polarography and conductometry . Soluble Nafion as an ion exchange modifying agent was applied to the membrane by

Predictive factors for structural remission using abatacept: results from the ABROAD study.

PubMed

Murakami, Kosaku; Sekiguchi, Masahiro; Hirata, Shintaro; Fujii, Takao; Matsui, Kiyoshi; Morita, Satoshi; Ohmura, Koichiro; Kawahito, Yutaka; Nishimoto, Norihiro; Mimori, Tsuneyo; Sano, Hajime

2018-05-29

To investigate the effect of abatacept (ABA) on preventing joint destruction in biological disease-modifying anti-rheumatic drug (bDMARD)-naïve rheumatoid arthritis (RA) patients in real-world clinical practice. RA patients were collected from the ABROAD (ABatacept Research Outcomes as a First-line Biological Agent in the Real WorlD) study cohort. They had moderate or high disease activity and were treated with ABA as a first-line bDMARD. Radiographic change between baseline and 1 year after ABA treatment was assessed with the van der Heijde's modified total Sharp score (mTSS). Predictive factors for structural remission (St-REM), defined as ΔmTSS ≤0.5/year, were determined. Among 118 patients, 81 (67.5%) achieved St-REM. Disease duration <3 years (odds ratio (OR) = 3.152, p = 0.007) and slower radiographic progression (shown as "baseline mTSS/year <3", OR = 3.727, p = 0.004) were independently significant baseline predictive factors for St-REM irrespective of age and sex. St-REM prevalence increased significantly if clinical remission based on the Simplified Disease Activity Index was achieved at least once until 24 weeks after ABA treatment. Shorter disease duration, smaller radiographic progression at baseline, and rapid clinical response were predictive factors for sustained St-REM after ABA therapy in bDMARD-naïve RA patients.

Drug Delivery Systems for Imaging and Therapy of Parkinson's Disease

PubMed Central

Gunay, Mine Silindir; Ozer, A. Yekta; Chalon, Sylvie

2016-01-01

Background: Although a variety of therapeutic approaches are available for the treatment of Parkinson’s disease, challenges limit effective therapy. Among these challenges are delivery of drugs through the blood brain barier to the target brain tissue and the side effects observed during long term administration of antiparkinsonian drugs. The use of drug delivery systems such as liposomes, niosomes, micelles, nanoparticles, nanocapsules, gold nanoparticles, microspheres, microcapsules, nanobubbles, microbubbles and dendrimers is being investigated for diagnosis and therapy. Methods: This review focuses on formulation, development and advantages of nanosized drug delivery systems which can penetrate the central nervous system for the therapy and/or diagnosis of PD, and highlights future nanotechnological approaches. Results: It is esential to deliver a sufficient amount of either therapeutic or radiocontrast agents to the brain in order to provide the best possible efficacy or imaging without undesired degradation of the agent. Current treatments focus on motor symptoms, but these treatments generally do not deal with modifying the course of Parkinson’s disease. Beyond pharmacological therapy, the identification of abnormal proteins such as α-synuclein, parkin or leucine-rich repeat serine/threonine protein kinase 2 could represent promising alternative targets for molecular imaging and therapy of Parkinson's disease. Conclusion: Nanotechnology and nanosized drug delivery systems are being investigated intensely and could have potential effect for Parkinson’s disease. The improvement of drug delivery systems could dramatically enhance the effectiveness of Parkinson’s Disease therapy and reduce its side effects. PMID:26714584

Current and experimental treatments of Parkinson disease: A guide for neuroscientists.

PubMed

Oertel, Wolfgang; Schulz, Jörg B

2016-10-01

Over a period of more than 50 years, the symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been optimized using pharmacotherapy, deep brain stimulation, and physiotherapy. The arsenal of pharmacotherapies includes L-Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase (COMT), and amantadine. In the later course of the disease, motor complications occur, at which stage different oral formulations of L-Dopa or dopamine agonists with long half-life, a transdermal application or parenteral pumps for continuous drug supply can be subscribed. Alternatively, the patient is offered deep brain stimulation of the subthalamic nucleus (STN) or the internal part of the globus pallidus (GPi). For a more efficacious treatment of motor complications, new formulations of L-Dopa, dopamine agonists, and amantadine as well as new MAO-B and COMT inhibitors are currently tested in clinical trials, and some of them already yielding positive results in phase 3 trials. In addition, non-dopaminergic agents have been tested in the early clinical phase for the treatment of motor fluctuations and dyskinesia, including adenosine A2A antagonists (istradefylline, preladenant, and tozadenant) and modulators of the metabolic glutamate receptor 5 (mGluR5 - mavoglurant) and serotonin (eltoprazine) receptors. Recent clinical trials testing coenzyme Q10, the dopamine agonist pramipexole, creatine monohydrate, pioglitazone, or AAV-mediated gene therapy aimed at increasing expression of neurturin, did not prove efficacious. Treatment with nicotine, caffeine, inosine (a precursor of urate), and isradipine (a dihydropyridine calcium channel blocker), as well as active and passive immunization against α-synuclein and inhibitors or modulators of α-synuclein-aggregation are currently studied in clinical trials. However, to date, no disease-modifying treatment is available. We here review the current status of treatment options for motor and non-motor symptoms, and discuss current investigative strategies for disease modification. This review provides basic insights, mainly addressing basic scientists and non-specialists. It stresses the need to intensify therapeutic PD research and points out reasons why the translation of basic research to disease-modifying therapies has been unsuccessful so far. The symptomatic treatment of the motor symptoms of Parkinson disease (PD) has been constantly optimized using pharmacotherapy (L-Dopa, several dopamine agonists, inhibitors of monoamine oxidase (MAO)-B and catechol-o-methyltransferase (COMT), and amantadine), deep brain stimulation, and physiotherapy. For a more efficacious treatment of motor complications, new formulations of L-Dopa, dopamine agonists, and amantadine as well as new MAO-B and COMT inhibitors are currently tested in clinical trials. Non-dopaminergic agents have been tested in the early clinical phase for the treatment of motor fluctuations and dyskinesia. Recent clinical trials testing coenzyme Q10, the dopamine agonist pramipexole, creatine monohydrate, pioglitazone, or AAV-mediated gene therapy aimed at increasing expression of neurturin, did not prove efficacious. Treatment with nicotine, caffeine, and isradipine - a dihydropyridine calcium channel blocker - as well as active and passive immunization against α-synuclein and inhibitors of α-synuclein-aggregation are currently studied in clinical trials. However, to date, no disease-modifying treatment is available for PD. We here review the current status of treatment options and investigative strategies for both motor and non-motor symptoms. This review stresses the need to intensify therapeutic PD research and points out reasons why the translation of basic research to disease-modifying therapies has been unsuccessful so far. This article is part of a special issue on Parkinson disease. © 2016 International Society for Neurochemistry.

A model for predicting Xanthomonas arboricola pv. pruni growth as a function of temperature

PubMed Central

Llorente, Isidre; Montesinos, Emilio; Moragrega, Concepció

2017-01-01

A two-step modeling approach was used for predicting the effect of temperature on the growth of Xanthomonas arboricola pv. pruni, causal agent of bacterial spot disease of stone fruit. The in vitro growth of seven strains was monitored at temperatures from 5 to 35°C with a Bioscreen C system, and a calibrating equation was generated for converting optical densities to viable counts. In primary modeling, Baranyi, Buchanan, and modified Gompertz equations were fitted to viable count growth curves over the entire temperature range. The modified Gompertz model showed the best fit to the data, and it was selected to estimate the bacterial growth parameters at each temperature. Secondary modeling of maximum specific growth rate as a function of temperature was performed by using the Ratkowsky model and its variations. The modified Ratkowsky model showed the best goodness of fit to maximum specific growth rate estimates, and it was validated successfully for the seven strains at four additional temperatures. The model generated in this work will be used for predicting temperature-based Xanthomonas arboricola pv. pruni growth rate and derived potential daily doublings, and included as the inoculum potential component of a bacterial spot of stone fruit disease forecaster. PMID:28493954

Interleukin 6 Inhibition and Coronary Artery Disease in a High-Risk Population: A Prospective Community-Based Clinical Study.

PubMed

Bacchiega, Bruno Cesar; Bacchiega, Ana Beatriz; Usnayo, Magali Justina Gomez; Bedirian, Ricardo; Singh, Gurkirpal; Pinheiro, Geraldo da Rocha Castelar

2017-03-13

Atherosclerosis is a chronic inflammatory disease, with interleukin 6 (IL-6) as a major player in inflammation cascade. IL-6 blockade may reduce cardiovascular risk, but current treatments to block IL-6 also induce dyslipidemia, a finding with an uncertain prognosis. We aimed to determine the endothelial function responses to the IL-6-blocking agent tocilizumab, anti-tumor necrosis factor α, and synthetic disease-modifying antirheumatic drug therapies in patients with rheumatoid arthritis in a 16-week prospective study. Sixty consecutive patients with rheumatoid arthritis were enrolled. Tocilizumab and anti-tumor necrosis factor α therapy were started in 18 patients each while 24 patients were treated with synthetic disease-modifying antirheumatic drugs. Forty patients completed the 16-week follow-up period. The main outcome was flow-mediated dilation percentage variation before and after therapy. In the tocilizumab group, flow-mediated dilation percentage variation increased statistically significantly from a pre-treatment mean of (3.43% [95% CI, 1.28-5.58] to 5.96% [95% CI, 3.95-7.97]; P =0.03). Corresponding changes were 4.78% (95% CI, 2.13-7.42) to 6.75% (95% CI, 4.10-9.39) ( P =0.09) and 2.87% (95% CI, -2.17 to 7.91) to 4.84% (95% CI, 2.61-7.07) ( P =0.21) in the anti-tumor necrosis factor α and the synthetic disease-modifying antirheumatic drug groups, respectively (both not statistically significant). Total cholesterol increased significantly in the tocilizumab group from 197.5 (95% CI, 177.59-217.36) to 232.3 (201.62-263.09) ( P =0.003) and in the synthetic disease-modifying antirheumatic drug group from 185.8 (95% CI, 169.76-201.81) to 202.8 (95% CI, 176.81-228.76) ( P =0.04), but not in the anti-tumor necrosis factor α group. High-density lipoprotein did not change significantly in any group. Endothelial function is improved by tocilizumab in a high-risk population, even as it increases total cholesterol and low-density lipoprotein levels. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Subregional neuroanatomical change as a biomarker for Alzheimer's disease

PubMed Central

Holland, Dominic; Brewer, James B.; Hagler, Donald J.; Fennema-Notestine, Christine; Dale, Anders M.; Weiner, Michael; Thal, Leon; Petersen, Ronald; Jack, Clifford R.; Jagust, William; Trojanowki, John; Toga, Arthur W.; Beckett, Laurel; Green, Robert C.; Gamst, Anthony; Potter, William Z.; Montine, Tom; Anders, Dale; Bernstein, Matthew; Felmlee, Joel; Fox, Nick; Thompson, Paul; Schuff, Norbert; Alexander, Gene; Bandy, Dan; Koeppe, Robert A.; Foster, Norm; Reiman, Eric M.; Chen, Kewei; Shaw, Les; Lee, Virginia M.-Y.; Korecka, Magdalena; Crawford, Karen; Neu, Scott; Harvey, Danielle; Kornak, John; Kachaturian, Zaven; Frank, Richard; Snyder, Peter J.; Molchan, Susan; Kaye, Jeffrey; Vorobik, Remi; Quinn, Joseph; Schneider, Lon; Pawluczyk, Sonia; Spann, Bryan; Fleisher, Adam S.; Vanderswag, Helen; Heidebrink, Judith L.; Lord, Joanne L.; Johnson, Kris; Doody, Rachelle S.; Villanueva-Meyer, Javier; Chowdhury, Munir; Stern, Yaakov; Honig, Lawrence S.; Bell, Karen L.; Morris, John C.; Mintun, Mark A.; Schneider, Stacy; Marson, Daniel; Griffith, Randall; Badger, Beverly; Grossman, Hillel; Tang, Cheuk; Stern, Jessica; deToledo-Morrell, Leyla; Shah, Raj C.; Bach, Julie; Duara, Ranjan; Isaacson, Richard; Strauman, Silvia; Albert, Marilyn S.; Pedroso, Julia; Toroney, Jaimie; Rusinek, Henry; de Leon, Mony J.; De Santi, Susan M.; Doraiswamy, P. Murali; Petrella, Jeffrey R.; Aiello, Marilyn; Clark, Christopher M.; Pham, Cassie; Nunez, Jessica; Smith, Charles D.; Given, Curtis A.; Hardy, Peter; DeKosky, Steven T.; Oakley, MaryAnn; Simpson, Donna M.; Ismail, M. Saleem; Porsteinsson, Anton; McCallum, Colleen; Cramer, Steven C.; Mulnard, Ruth A.; McAdams-Ortiz, Catherine; Diaz-Arrastia, Ramon; Martin-Cook, Kristen; DeVous, Michael; Levey, Allan I.; Lah, James J.; Cellar, Janet S.; Burns, Jeffrey M.; Anderson, Heather S.; Laubinger, Mary M.; Bartzokis, George; Silverman, Daniel H. S.; Lu, Po H.; Fletcher, Rita; Parfitt, Francine; Johnson, Heather; Farlow, Martin; Herring, Scott; Hake, Ann M.; van Dyck, Christopher H.; MacAvoy, Martha G.; Bifano, Laurel A.; Chertkow, Howard; Bergman, Howard; Hosein, Chris; Black, Sandra; Graham, Simon; Caldwell, Curtis; Feldman, Howard; Assaly, Michele; Hsiung, Ging-Yuek R.; Kertesz, Andrew; Rogers, John; Trost, Dick; Bernick, Charles; Gitelman, Darren; Johnson, Nancy; Mesulam, Marsel; Sadowsky, Carl; Villena, Teresa; Mesner, Scott; Aisen, Paul S.; Johnson, Kathleen B.; Behan, Kelly E.; Sperling, Reisa A.; Rentz, Dorene M.; Johnson, Keith A.; Rosen, Allyson; Tinklenberg, Jared; Ashford, Wes; Sabbagh, Marwan; Connor, Donald; Obradov, Sanja; Killiany, Ron; Norbash, Alex; Obisesan, Thomas O.; Jayam-Trouth, Annapurni; Wang, Paul; Auchus, Alexander P.; Huang, Juebin; Friedland, Robert P.; DeCarli, Charles; Fletcher, Evan; Carmichael, Owen; Kittur, Smita; Mirje, Seema; Johnson, Sterling C.; Borrie, Michael; Lee, T.-Y.; Asthana, Sanjay; Carlsson, Cynthia M.; Potkin, Steven G.; Highum, Diane; Preda, Adrian; Nguyen, Dana; Tariot, Pierre N.; Hendin, Barry A.; Scharre, Douglas W.; Kataki, Maria; Beversdorf, David Q.; Zimmerman, Earl A.; Celmins, Dzintra; Brown, Alice D.; Gandy, Sam; Marenberg, Marjorie E.; Rovner, Barry W.; Pearlson, Godfrey; Blank, Karen; Anderson, Karen; Saykin, Andrew J.; Santulli, Robert B.; Pare, Nadia; Williamson, Jeff D.; Sink, Kaycee M.; Potter, Huntington; Ashok Raj, B.; Giordano, Amy; Ott, Brian R.; Wu, Chuang-Kuo; Cohen, Ronald; Wilks, Kerri L.; Safirstein, Beth E.

2009-01-01

Regions of the temporal and parietal lobes are particularly damaged in Alzheimer's disease (AD), and this leads to a predictable pattern of brain atrophy. In vivo quantification of subregional atrophy, such as changes in cortical thickness or structure volume, could lead to improved diagnosis and better assessment of the neuroprotective effects of a therapy. Toward this end, we have developed a fast and robust method for accurately quantifying cerebral structural changes in several cortical and subcortical regions using serial MRI scans. In 169 healthy controls, 299 subjects with mild cognitive impairment (MCI), and 129 subjects with AD, we measured rates of subregional cerebral volume change for each cohort and performed power calculations to identify regions that would provide the most sensitive outcome measures in clinical trials of disease-modifying agents. Consistent with regional specificity of AD, temporal-lobe cortical regions showed the greatest disease-related changes and significantly outperformed any of the clinical or cognitive measures examined for both AD and MCI. Global measures of change in brain structure, including whole-brain and ventricular volumes, were also elevated in AD and MCI, but were less salient when compared to changes in normal subjects. Therefore, these biomarkers are less powerful for quantifying disease-modifying effects of compounds that target AD pathology. The findings indicate that regional temporal lobe cortical changes would have great utility as outcome measures in clinical trials and may also have utility in clinical practice for aiding early diagnosis of neurodegenerative disease. PMID:19996185

Subregional neuroanatomical change as a biomarker for Alzheimer's disease.

PubMed

Holland, Dominic; Brewer, James B; Hagler, Donald J; Fennema-Notestine, Christine; Fenema-Notestine, Christine; Dale, Anders M

2009-12-08

Regions of the temporal and parietal lobes are particularly damaged in Alzheimer's disease (AD), and this leads to a predictable pattern of brain atrophy. In vivo quantification of subregional atrophy, such as changes in cortical thickness or structure volume, could lead to improved diagnosis and better assessment of the neuroprotective effects of a therapy. Toward this end, we have developed a fast and robust method for accurately quantifying cerebral structural changes in several cortical and subcortical regions using serial MRI scans. In 169 healthy controls, 299 subjects with mild cognitive impairment (MCI), and 129 subjects with AD, we measured rates of subregional cerebral volume change for each cohort and performed power calculations to identify regions that would provide the most sensitive outcome measures in clinical trials of disease-modifying agents. Consistent with regional specificity of AD, temporal-lobe cortical regions showed the greatest disease-related changes and significantly outperformed any of the clinical or cognitive measures examined for both AD and MCI. Global measures of change in brain structure, including whole-brain and ventricular volumes, were also elevated in AD and MCI, but were less salient when compared to changes in normal subjects. Therefore, these biomarkers are less powerful for quantifying disease-modifying effects of compounds that target AD pathology. The findings indicate that regional temporal lobe cortical changes would have great utility as outcome measures in clinical trials and may also have utility in clinical practice for aiding early diagnosis of neurodegenerative disease.

Development and application of antibody microarray for lymphocystis disease virus detection in fish.

PubMed

Sheng, Xiuzhen; Xu, Xiaoli; Zhan, Wenbin

2013-05-01

Lymphocystis disease virus (LCDV) is the causative agent of lymphocystis disease affecting marine and freshwater fish worldwide. Here an antibody microarray was developed and employed to detect LCDV in fish. Rabbit anti-LCDV serum was arrayed on agarose gel-modified slides as capture antibody, and Cy3-conjugated anti-LCDV monoclonal antibody (MAbs) was added as detection antibody. The signals were imaged with a laser chip scanner and analyzed by corresponding software. To improve the sensitivity, different substrate binders (poly-L-lysine, MPTS, aldehyde, APES and agarose gel modified slides, and commercially available amino-modified slides), markers (fluorescein isothiocyanate, Cy3, horseradish peroxidase, biotin or colloidal gold) conjugated to anti-LCDV Mabs, and storage time of the antibody were assessed. The results showed that the antibody microarrays based on agarose gel-modified slides gave a lower detection limit of 0.55μg/ml of LCDV when Cy3 and HRP conjugated anti-LCDV MAbs were used as detection antibody; and the lowest detectable LCDV protein concentration was 0.0686 μg/ml when streptavidin-biotin conjugated to anti-LCDV MAbs served as detection antibody. The developed antibody microarray proved to have a high specificity for LCDV detection and a shelf-life of more than 8 months at -20°C. Furthermore, the LCDV detection results of the microarray in fish gills or fins (n=50) presented a concordance rate of 100% with enzyme-linked immunosorbent assay (ELISA) and 98% with immunofluorescence assay technique (IFAT). These results revealed that the developed antibody microarray could serve as an effective tool for diagnostic and epidemiological studies of LCDV in fish. Copyright © 2013 Elsevier B.V. All rights reserved.

Phosphoprotein binding agents and methods of their use

DOEpatents

Goshe, Michael B.; Conrads, Thomas P.; Veenstra, Timothy D.; Panisko, Ellen A.

2004-11-16

The invention provides reagents and methods for characterizing (i.e., identification and/or quantitation) the phosphorylation states of proteins. Proteins may be post-transcriptionally modified such that they contain phosphate groups at either some or all of their serine, threonine, tyrosine, histidine, and/or lysine amino acid residues. In many cases the extent to which a protein is phosphorylated determines it bioactivity, i.e., its ability to effect cell functions such as differentiation, division, and metabolism. Hence, a powerful tool for diagnosing various diseases and for furthering the understanding of protein--protein interactions is provided.

Complementary and Alternative Therapies in ALS

PubMed Central

Bedlack, Richard S.; Joyce, Nanette; Carter, Gregory T.; Pagononi, Sabrina; Karam, Chafic

2015-01-01

Synopsis Given the severity of their illness and lack of effective disease modifying agents, it is not surprising that most patients with ALS consider trying complementary and alternative therapies. Some of the most commonly considered alternative therapies include special diets, nutritional supplements, cannabis, acupuncture, chelation and energy healing. This chapter reviews these in detail. We also describe 3 models by which physicians may frame discussions about alternative therapies: paternalism, autonomy and shared decision making. Finally, we review a program called ALSUntangled which using shared shared decision making to review alternative therapies for ALS. PMID:26515629

Roles for Intestinal Bacteria, Viruses, and Fungi in Pathogenesis of Inflammatory Bowel Diseases and Therapeutic Approaches

PubMed Central

Sartor, R. Balfour; Wu, Gary D.

2017-01-01

Intestinal microbiota are involved in the pathogenesis of Crohn’s disease, ulcerative colitis, and pouchitis. We review the mechanisms by which these gut bacteria, fungi, and viruses mediate mucosal homeostasis, via their composite genes (metagenome) and metabolic products (metabolome). We explain how alterations to their profiles and functions under conditions of dysbiosis contribute to inflammation and effector immune responses that mediate inflammatory bowel diseases (IBD) in humans and enterocolitis in mice. It could be possible to engineer the intestinal environment by modifying the microbiota community structure or function to treat patients with IBD— either with individual agents, via dietary management, or as adjuncts to immunosuppressive drugs. We summarize the latest information on therapeutic use of fecal microbial transplantation and propose improved strategies to selectively normalize the dysbiotic microbiome in personalized approaches to treatment. PMID:27769810

Pharmacophore-based design and discovery of (-)-meptazinol carbamates as dual modulators of cholinesterase and amyloidogenesis.

PubMed

Xie, Qiong; Zheng, Zhaoxi; Shao, Biyun; Fu, Wei; Xia, Zheng; Li, Wei; Sun, Jian; Zheng, Wei; Zhang, Weiwei; Sheng, Wei; Zhang, Qihong; Chen, Hongzhuan; Wang, Hao; Qiu, Zhuibai

2017-12-01

Multifunctional carbamate-type acetylcholinesterase (AChE) inhibitors with anti-amyloidogenic properties like phenserine are potential therapeutic agents for Alzheimer's disease (AD). We reported here the design of new carbamates using pharmacophore model strategy to modulate both cholinesterase and amyloidogenesis. A five-feature pharmacophore model was generated based on 25 carbamate-type training set compounds. (-)-Meptazinol carbamates that superimposed well upon the model were designed and synthesized, which exhibited nanomolar AChE inhibitory potency and good anti-amyloidogenic properties in in vitro test. The phenylcarbamate 43 was highly potent (IC 50 31.6 nM) and slightly selective for AChE, and showed low acute toxicity. In enzyme kinetics assay, 43 exhibited uncompetitive inhibition and reacted by pseudo-irreversible mechanism. 43 also showed amyloid-β (Aβ) lowering effects (51.9% decrease of Aβ 42 ) superior to phenserine (31% decrease of total Aβ) in SH-SY5Y-APP 695 cells at 50 µM. The dual actions of 43 on cholinergic and amyloidogenic pathways indicated potential uses as symptomatic and disease-modifying agents.

Interleukin-10: biology, role in inflammation and autoimmunity.

PubMed

Lalani, I; Bhol, K; Ahmed, A R

1997-12-01

Reading this article will increase the readers' knowledge of the biology of interleukin-10 (IL-10) an important cytokine. The survival of an organism and its host defense mechanisms require, among other processes, a complex but target-oriented interaction and an interdependence between the immune and inflammatory pathways. The biologic role of interleukin-10 in these processes is presented as well as the possible involvement of IL-10 in the pathogenesis of various diseases. The influence of pharmacologic agents on IL-10 production and the possible pharmacologic role of IL-10 itself are discussed. A detailed literature search was conducted. Studies considered relevant and important involving both humans and animals, in all languages were used. Material was taken only from peer reviewed journals. IL-10 is produced by CD4+, Tho, Th1, B lymphocytes, mast cells, eosinophils, monocytes, macrophages and keratinocytes. IL-10 has a diverse array of actions, which differ depending on cell type, nature of stimulus and the cellular microenvironment. Interleukin-10 has an important role in the inflammatory and immune systems. In addition, present studies suggest that IL-10 may well play a pivotal role in the pathogenesis of several diseases. It has the potential for therapeutic use. Most of the data on IL-10 have been obtained from in vitro studies or animal experiments. Studies on humans are few, but rapidly increasing. Interleukin-10 is an important molecule with a central role in maintaining health and in the pathogenesis of disease. Known pharmacologic agents and some under investigation can modify IL-10 production in vivo. Development of agents that can selectively affect a very specific biologic action of IL-10 may provide significant benefit in treating autoimmune and inflammatory diseases.

Adsorption of hexavalent chromium on modified corn stalk using different cross-linking agents

NASA Astrophysics Data System (ADS)

Chen, Suhong; Zhu, Yi; Han, Zhijun; Feng, Gao; Jia, Yuling; Fu, Kaifang; Yue, Qinyan

2017-12-01

In this study, four different types of adsorbents modified from corn stalk were synthesized after the reaction with epichlorohydrin, N,N-dimethylformamide, triethylamine and different cross-linking agents. The surface functional groups and thermal stability of modified corn stalk (MCSs) were characterized using FTIR and TG analysis, respectively. The feasibility of using MCSs to remove Cr(VI) were evaluated. Adsorption isotherms were determined and modeled with Langmuir, Freundlich and Temkin equations. The experimental results showed that MCS modified using diethylenetriamine (DETA) had the best modification effect, and the adsorption capacity of Cr(VI) reached as high as 227.27 mg/g at 323 K. Thermodynamic study showed that the Cr(VI) adsorption onto MCSs was endothermic processes. As a result, MCS by using DETA as cross-linking agent has good potential for the removal of Cr(VI) from aqueous solutions.

Bond Strength of Composite to Dentin using Resin-Modified Glass Ionomers as Bonding Agents

DTIC Science & Technology

2016-03-02

59 MDW/SGVU SUBJECT: Professional Presentation Approval 2 MAR 20 16 l. Your paper, entitl ed Bond Strength of Composite to Dentin using Resin...Modified G lass Ionomers as Bonding Agents presented at Journal of Dental Research with MDWI 41- 108, and has been assigned local fi le #16086. 2...Vandewalle /Civ/SGDTG (59th CSPG/SGVU) DECS I 5-009 PROTOCOL TITLE Bond Strength of Composite to Dentin using Resin-modified Glass lonomers as

A case of methimazole-induced chronic arthritis masquerading as seronegative rheumatoid arthritis.

PubMed

Gruber, Conor N; Finzel, Kathleen; Gruber, Barry L

2014-06-01

We report a 40-year-old woman with onset of oligoarthritis shortly after initiating treatment with methimazole for Graves disease. Over the course of 7 years, her arthritis became progressively severe, leading to a diagnosis of seronegative rheumatoid arthritis. Treatment with disease-modifying antirheumatic agents and surgical intervention was contemplated. Ultrasound and magnetic resonance imaging revealed exuberant synovitis, involving right elbow and knees. Upon withdrawal of methimazole, prompt resolution of all signs and symptoms of arthritis was observed within several weeks. Following a MEDLINE search of available literature concerning antithyroid drug-induced arthritis, it is evident that this case represents the lengthiest duration of inflammatory arthropathy ever described in a patient that nonetheless was rapidly reversible with discontinuation of methimazole.

The management of pain in arthritis and the use of cyclooxygenase-2 inhibitors: new paradigms and insights.

PubMed

Ross, Edgar

2004-12-01

Chronic pain from arthritis has been one of the biggest causes of disability and loss of function in the United States. This is still the case despite many new insights into the pathophysiology of pain, effective treatment approaches, and new safer medications that can be used for long-term use. There are many different types of arthritic problems. New disease- modifying agents that are available for some of these types of arthritic diseases such as rheumatoid arthritis have the potential to have a substantial impact on improvement in the long-term prognosis. Despite this optimistic outlook, pain often is a significant problem and should be treated whenever it becomes a barrier to function.

Macrolides in Chronic Inflammatory Skin Disorders

PubMed Central

Alzolibani, Abdullateef A.; Zedan, Khaled

2012-01-01

Long-term therapy with the macrolide antibiotic erythromycin was shown to alter the clinical course of diffuse panbronchiolitis in the late 1980s. Since that time, macrolides have been found to have a large number of anti-inflammatory properties in addition to being antimicrobials. These observations provided the rationale for many studies performed to assess the usefulness of macrolides in other inflammatory diseases including skin and hair disorders, such as rosacea, psoriasis, pityriasis rosea, alopecia areata, bullous pemphigoid, and pityriasis lichenoides. This paper summarizes a collection of clinical studies and case reports dealing with the potential benefits of macrolides antibiotics in the treatment of selected dermatoses which have primarily been classified as noninfectious and demonstrating their potential for being disease-modifying agents. PMID:22685371

Pharmacological Management of Cardiorenal Syndromes

PubMed Central

House, Andrew A.; Haapio, Mikko; Lassus, Johan; Bellomo, Rinaldo; Ronco, Claudio

2011-01-01

Cardiorenal syndromes are disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other. The pharmacological management of Cardiorenal syndromes may be complicated by unanticipated or unintended effects of agents targeting one organ on the other. Hence, a thorough understanding of the pathophysiology of these disorders is paramount. The treatment of cardiovascular diseases and risk factors may affect renal function and modify the progression of renal injury. Likewise, management of renal disease and associated complications can influence heart function or influence cardiovascular risk. In this paper, an overview of pharmacological management of acute and chronic Cardiorenal Syndromes is presented, and the need for high-quality future studies in this field is highlighted. PMID:21660311

Investigational and experimental drugs for intraocular pressure reduction in ocular hypertension and glaucoma.

PubMed

Lusthaus, Jed Asher; Goldberg, Ivan

2016-10-01

Intraocular pressure (IOP) is the most significant modifiable risk factor to prevent onset or progression of glaucoma. Glaucoma prevalence continues to increase, emphasizing the need for improved ocular hypotensive treatment options. To try to improve on both tolerance and IOP control of currently available therapies, different receptors or mechanisms are being explored to reduce IOP more effectively and to improve tolerance. We review synthetic topical and oral drugs in early development for the management of ocular hypertension and glaucoma. New therapeutic agents for IOP control have been discovered; some appear to be reasonably tolerated. IOP reduction may be limited with some agents, but other benefits although unproven may compensate for this, such as less ocular surface disease, enhanced neuro-protection or increased ocular blood flow. Further product development promises improved treatment options for ocular hypertensives and glaucoma sufferers.

Gold Nanoparticles for Biology and Medicine

PubMed Central

Giljohann, David A.; Seferos, Dwight S.; Daniel, Weston L.; Massich, Matthew D.; Patel, Pinal C.

2014-01-01

Gold colloids have fascinated scientists for over a century and are now heavily utilized in chemistry, biology, engineering, and medicine. Today these materials can be synthesized reproducibly, modified with seemingly limitless chemical functional groups, and, in certain cases, characterized with atomic-level precision. This Review highlights recent advances in the synthesis, bioconjugation, and cellular uses of gold nanoconjugates. There are now many examples of highly sensitive and selective assays based upon gold nanoconjugates. In recent years, focus has turned to therapeutic possibilities for such materials. Structures which behave as gene-regulating agents, drug carriers, imaging agents, and photoresponsive therapeutics have been developed and studied in the context of cells and many debilitating diseases. These structures are not simply chosen as alternatives to molecule-based systems, but rather for their new physical and chemical properties, which confer substantive advantages in cellular and medical applications. PMID:20401880

Beneficial effects of anti-inflammatory therapy in a mouse model of Niemann-Pick disease type C1.

PubMed

Smith, David; Wallom, Kerri-Lee; Williams, Ian M; Jeyakumar, Mylvaganam; Platt, Frances M

2009-11-01

Niemann-Pick disease type C1 (NPC1) is a neurodegenerative lysosomal disorder characterized by sphingolipid and cholesterol storage in the late endocytic system. In common with other neurodegenerative diseases, activation of the innate immune system occurs in the brain resulting in neuro-inflammation. Targeting inflammation in the brain therefore represents a potential clinical intervention strategy that aims to slow the rate of disease progression and improve quality of life. We evaluated non-steroidal anti-inflammatory drugs (NSAIDs) and an anti-oxidant to determine whether these agents are disease modifying in an acute mouse model of NPC1. NSAIDs significantly prolonged the lifespan of NPC1 mice and slowed the onset of clinical signs. However, anti-oxidant therapy was of no significant benefit. Combining NSAID therapy with substrate reduction therapy (SRT) resulted in additive benefit. These data suggest that anti-inflammatory therapy may be a useful adjunctive treatment in the clinical management of NPC1, alone or combined with SRT.

2, 3-dimercaptosuccinic acid-modified iron oxide clusters for magnetic resonance imaging.

PubMed

Xiong, Fei; Yan, Caiyun; Tian, Jilai; Geng, Kunkun; Zhu, Ziyi; Song, Lina; Zhang, Yu; Mulvale, Matthew; Gu, Ning

2014-12-01

Over the last decade, various magnetic nanomaterials have been developed as magnetic resonance imaging (MRI) contrast agents; the greatest challenges encountered for clinical application have been insufficient stability. In this paper, a lyophilization method for 2, 3-dimercaptosuccinic acid-modified iron oxide (γ-Fe2 O3 @DMSA) nanoparticles was developed to simultaneously overcome two disadvantages; these include insufficient stability and low-magnetic response. After lyophilization, the clusters of γ-Fe2 O3 @DMSA with the size of 156.7 ± 15.3 nm were formed, and the stability of the lyophilized powder (γ-Fe2 O3 @DMSA-LP) increased up to over 3 years. It was also found that rehydrated γ-Fe2 O3 @DMSA-LP could be ingested by RAW264.7 cells in very large quantities. Results of pharmacokinetics and biodistribution studies in vivo indicated that γ-Fe2 O3 @DMSA-LP is a promising liver-targeted material. Furthermore, it also exhibited higher MRI efficiency and longer imaging time in the liver than the well-known product Feridex(®) . Moreover, results of vascular irritation and long-term toxicity experiments demonstrated γ-Fe2 O3 @DMSA-LP could be a nontoxic, biocompatible contrast agent in vivo. Therefore, the proposed γ-Fe2 O3 @DMSA-LP can be used as a potential MRI contrast agent in clinic for hepatic diseases. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Glycogen Synthase Kinase-3 Inhibitors as Potent Therapeutic Agents for the Treatment of Parkinson Disease.

PubMed Central

2012-01-01

Parkinson's disease (PD) is a devastating neurodegenerative disorder characterized by degeneration of the nigrostriatal dopaminergic pathway. Because the current therapies only lead to temporary, limited improvement and have severe side effects, new approaches to treat PD need to be developed. To discover new targets for potential therapeutic intervention, a chemical genetic approach involving the use of small molecules as pharmacological tools has been implemented. First, a screening of an in-house chemical library on a well-established cellular model of PD was done followed by a detailed pharmacological analysis of the hits. Here, we report the results found for the small heterocyclic derivative called SC001, which after different enzymatic assays was revealed to be a new glycogen synthase kinase-3 (GSK-3) inhibitor with IC50 = 3.38 ± 0.08 μM. To confirm that GSK-3 could be a good target for PD, the evaluation of a set of structurally diverse GSK-3 inhibitors as neuroprotective agents for PD was performed. Results show that inhibitors of GSK-3 have neuroprotective effects in vitro representing a new pharmacological option for the disease-modifying treatment of PD. Furthermore, we show that SC001 is able to cross the blood–brain barrier, protects dopaminergic neurons, and reduces microglia activation in in vivo models of Parkinson disease, being a good candidate for further drug development. PMID:23421686

Management of disease-modifying treatments in neurological autoimmune diseases of the central nervous system.

PubMed

Salmen, A; Gold, R; Chan, A

2014-05-01

The therapeutic armamentarium for autoimmune diseases of the central nervous system, specifically multiple sclerosis and neuromyelitis optica, is steadily increasing, with a large spectrum of immunomodulatory and immunosuppressive agents targeting different mechanisms of the immune system. However, increasingly efficacious treatment options also entail higher potential for severe adverse drug reactions. Especially in cases failing first-line treatment, thorough evaluation of the risk-benefit profile of treatment alternatives is necessary. This argues for the need of algorithms to identify patients more likely to benefit from a specific treatment. Moreover, paradigms to stratify the risk for severe adverse drug reactions need to be established. In addition to clinical/paraclinical measures, biomarkers may aid in individualized risk-benefit assessment. A recent example is the routine testing for anti-John Cunningham virus antibodies in natalizumab-treated multiple sclerosis patients to assess the risk for the development of progressive multi-focal leucoencephalopathy. Refined algorithms for individualized risk assessment may also facilitate early initiation of induction treatment schemes in patient groups with high disease activity rather than classical escalation concepts. In this review, we will discuss approaches for individiualized risk-benefit assessment both for newly introduced agents as well as medications with established side-effect profiles. In addition to clinical parameters, we will also focus on biomarkers that may assist in patient selection. © 2013 British Society for Immunology.

Advances in the treatment of rheumatoid arthritis: old versus new therapies.

PubMed

Saravanan, Vadivelu; Hamilton, Jennifer

2002-07-01

Rheumatoid arthritis (RA) is a common cause of disability in the western population, with an annual incidence of 0.05% and a prevalence of 1%. Although a small percentage of patients go into natural remission, the untreated disease progresses to cause disability, morbidity and early mortality. Unravelling of the cytokine network in the pathogenesis of RA has led to the development of drugs that target these cytokines and prevent joint damage. Three biological anticytokine agents, etanercept, infliximab and anakinra, are now available for use in RA. More experience will quantify their safety and benefits. The potency of the older disease-modifying antirheumatic drugs (DMARDs), such as methotrexate and sulfasalazine, is also being realised, especially when used early in the disease process and in combination. Leflunomide is a new DMARD with efficacy similar to methotrexate and sulfasalazine. Symptomatic treatment of RA with nonsteroidal anti-inflammatory drugs has also undergone a revolution with the availability of a new class of COX-2-specific inhibitors. These drugs control inflammation and provide pain relief with less GI toxicity. Management of comorbid conditions associated with RA and its treatment (i.e., osteoporosis, cardiovascular and lung disease) has also become a priority for the rheumatologist. It is hoped that more aggressive use of conventional DMARDs and biological agents will result in less disability and a higher proportion of patients achieving remission.

A blood-brain barrier (BBB) disrupter is also a potent α-synuclein (α-syn) aggregation inhibitor: a novel dual mechanism of mannitol for the treatment of Parkinson disease (PD).

PubMed

Shaltiel-Karyo, Ronit; Frenkel-Pinter, Moran; Rockenstein, Edward; Patrick, Christina; Levy-Sakin, Michal; Schiller, Abigail; Egoz-Matia, Nirit; Masliah, Eliezer; Segal, Daniel; Gazit, Ehud

2013-06-14

The development of disease-modifying therapy for Parkinson disease has been a main drug development challenge, including the need to deliver the therapeutic agents to the brain. Here, we examined the ability of mannitol to interfere with the aggregation process of α-synuclein in vitro and in vivo in addition to its blood-brain barrier-disrupting properties. Using in vitro studies, we demonstrated the effect of mannitol on α-synuclein aggregation. Although low concentration of mannitol inhibited the formation of fibrils, high concentration significantly decreased the formation of tetramers and high molecular weight oligomers and shifted the secondary structure of α-synuclein from α-helical to a different structure, suggesting alternative potential pathways for aggregation. When administered to a Parkinson Drosophila model, mannitol dramatically corrected its behavioral defects and reduced the amount of α-synuclein aggregates in the brains of treated flies. In the mThy1-human α-synuclein transgenic mouse model, a decrease in α-synuclein accumulation was detected in several brain regions following treatment, suggesting that mannitol promotes α-synuclein clearance in the cell bodies. It appears that mannitol has a general neuroprotective effect in the transgenic treated mice, which includes the dopaminergic system. We therefore suggest mannitol as a basis for a dual mechanism therapeutic agent for the treatment of Parkinson disease.

A hepcidin lowering agent mobilizes iron for incorporation into red blood cells in an adenine-induced kidney disease model of anemia in rats

PubMed Central

Sun, Chia Chi; Vaja, Valentina; Chen, Shanzhuo; Theurl, Igor; Stepanek, Aaron; Brown, Diane E.; Cappellini, Maria D.; Weiss, Guenter; Hong, Charles C.; Lin, Herbert Y.; Babitt, Jodie L.

2013-01-01

Background Anemia is a common complication of chronic kidney disease (CKD) that negatively impacts the quality of life and is associated with numerous adverse outcomes. Excess levels of the iron regulatory hormone hepcidin are thought to contribute to anemia in CKD patients by decreasing iron availability from the diet and from body stores. Adenine treatment in rats has been proposed as an animal model of anemia of CKD with high hepcidin levels that mirrors the condition in human patients. Methods We developed a modified adenine-induced kidney disease model with a higher survival rate than previously reported models, while maintaining persistent kidney disease and anemia. We then tested whether the small molecule bone morphogenetic protein (BMP) inhibitor LDN-193189, which was previously shown to lower hepcidin levels in rodents, mobilized iron into the plasma and improved iron-restricted erythropoiesis in this model. Results Adenine-treated rats exhibited increased hepatic hepcidin mRNA, decreased serum iron, increased spleen iron content, low hemoglobin (Hb) and inappropriately low erythropoietin (EPO) levels relative to the degree of anemia. LDN-193189 administration to adenine-treated rats lowered hepatic hepcidin mRNA, mobilized stored iron into plasma and increased Hb content of reticulocytes. Conclusions Our data suggest that hepcidin lowering agents may provide a new therapeutic strategy to improve iron availability for erythropoiesis in CKD. PMID:23345622

Spasticity in multiple sclerosis and role of glatiramer acetate treatment

PubMed Central

Meca-Lallana, Jose Eustasio; Hernández-Clares, Rocío; Carreón-Guarnizo, Ester

2015-01-01

Introduction Spasticity is one of the most disabling and difficult-to-treat symptoms shown by patients with multiple sclerosis, who often show a suboptimal and unsatisfactory response to classic treatment and new available nonpharmacological alternatives. Due to the progressive nature of this condition, the early management should be essential to improve long-term outcomes. Methods We performed a narrative literature review of the contribution of spasticity to the burden of multiple sclerosis and the potential role of classic disease-modifying drugs. Results Added to the underlying pathophysiology of spasticity, certain external factors and drugs such as interferon may exacerbate the existing condition, hence their awareness is crucial as part of an effective management of spasticity. Furthermore, the evidence for the effectiveness of glatiramer acetate in preventing spasticity in naïve patients and in those switching from interferon should not be ignored. Conclusions This literature review proposes the examination of spasticity and the influence of classic disease-modifying agents on the level of existing condition among the variables to be considered when deciding on therapy for multiple sclerosis in clinical practice. PMID:26445705

Cannabinoids: novel medicines for the treatment of Huntington's disease.

PubMed

Sagredo, Onintza; Pazos, M Ruth; Valdeolivas, Sara; Fernandez-Ruiz, Javier

2012-04-01

Cannabinoid pharmacology has experienced a notable increase in the last 3 decades which is allowing the development of novel cannabinoid-based medicines for the treatment of different human pathologies, for example, Cesamet® (nabilone) or Marinol® (synthetic Δ9-tetrahydrocannabinol for oral administration) that were approved in 80s for the treatment of nausea and vomiting associated with chemotherapy treatment in cancer patients and in 90s for anorexiacachexia associated with AIDS therapy. Recently, the british company GW Pharmaceuticals plc has developed an oromucosal spray called Sativex®, which is constituted by an equimolecular combination of Δ9-tetrahydrocannabinol- and cannabidiol- enriched botanical extracts. Sativex® has been approved for the treatment of specific symptoms (i.e. spasticity and pain) of multiple sclerosis patients in various countries (i.e. Canada, UK, Spain, New Zealand). However, this cannabis- based medicine has been also proposed to be useful in other neurological disorders given the analgesic, antitumoral, anti-inflammatory, and neuroprotective properties of their components demonstrated in preclinical models. Numerous clinical trials are presently being conducted to confirm this potential in patients. We are particularly interested in the case of Huntington's disease (HD), an autosomal-dominant inherited disorder caused by an excess of CAG repeats in the genomic allele resulting in a polyQ expansion in the encoded protein called huntingtin, and that affects primarily striatal and cortical neurons thus producing motor abnormalities (i.e. chorea) and dementia. Cannabinoids have been studied for alleviation of hyperkinetic symptoms, given their inhibitory effects on movement, and, in particular, as disease-modifying agents due to their anti-inflammatory, neuroprotective and neuroregenerative properties. This potential has been corroborated in different experimental models of HD and using different types of cannabinoid agonists, including the phytocannabinoids present in Sativex®, and we are close to initiate a clinical trial with this cannabis-based medicine to evaluate its capability as a disease-modifying agent in a population of HD patients. The present review will address all preclinical evidence supporting the potential of Sativex® for the treatment of disease progression in HD patients. The article presents some promising patents on the cannabinoids.

Small molecules as therapy for uveitis: a selected perspective of new and developing agents.

PubMed

Pleyer, Uwe; Algharably, Engi Abdel-Hady; Feist, Eugen; Kreutz, Reinhold

2017-09-01

Intraocular inflammation (uveitis) remains a significant burden of legal blindness. Because of its immune mediated and chronic recurrent nature, common therapy includes corticosteroids, disease-modifying anti-rheumatic drugs and more recently biologics as immune modulatory agents. The purpose of this article is to identify the role of new treatment approaches focusing on small molecules as therapeutic option in uveitis. Areas covered: A MEDLINE database search was conducted through February 2017 using the terms 'uveitis' and 'small molecule'. To provide ongoing and future perspectives in treatment options, also clinical trials as registered at ClinicalTrials.gov were included. Both, results from experimental as well as clinical research in this field were included. Since this field is rapidly evolving, a selection of promising agents had to be made. Expert opinion: Small molecules may interfere at different steps of the inflammatory cascade and appear as an interesting option in the treatment algorithm of uveitis. Because of their highly targeted molecular effects and their favorable bioavailability with the potential of topical application small molecules hold great promise. Nevertheless, a careful evaluation of these agents has to be made, since current experience is almost exclusively based on experimental uveitis models and few registered trials.

Identification of O-linked β-d-N-acetylglucosamine-Modified Proteins from Arabidopsis

PubMed Central

Xu, Shou-Ling; Chalkley, Robert J.; Wang, Zhi-Yong; Burlingame, Alma L.

2013-01-01

The posttranslational modification of proteins with O-linked β-d-N-acetylglucosamine (O-GlcNAc) on serine and threonine residues occurs in all animals and plants. This modification is dynamic and ubiquitous, and regulates many cellular processes, including transcription, signaling and cytokinesis and is associated with several diseases. Cycling of O-GlcNAc is tightly regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Plants have two OGTs, SPINDLY (SPY) and SECRET AGENT (SEC); disruption of both causes embryo lethality. Despite O-GlcNAc modification of proteins being discovered more than 20-years ago, identification and mapping of protein GlcNAcylation is still a challenging task. Here we describe the use of lectin affinity chromatography combined with electron transfer dissociation mass spectrometry to enrich and to detect O-GlcNAc modified peptides from Arabidopsis. PMID:22576084

Endophytic bacterial community living in roots of healthy and 'Candidatus Phytoplasma mali'-infected apple (Malus domestica, Borkh.) trees.

PubMed

Bulgari, Daniela; Bozkurt, Adem I; Casati, Paola; Cağlayan, Kadriye; Quaglino, Fabio; Bianco, Piero A

2012-11-01

'Candidatus Phytoplasma mali', the causal agent of apple proliferation (AP) disease, is a quarantine pathogen controlled by chemical treatments against insect vectors and eradication of diseased plants. In accordance with the European Community guidelines, novel strategies should be developed for sustainable management of plant diseases by using resistance inducers (e.g. endophytes). A basic point for the success of this approach is the study of endophytic bacteria associated with plants. In the present work, endophytic bacteria living in healthy and 'Ca. Phytoplasma mali'-infected apple trees were described by cultivation-dependent and independent methods. 16S rDNA sequence analysis showed the presence of the groups Proteobacteria, Acidobacteria, Bacteroidetes, Actinobacteria, Chlamydiae, and Firmicutes. In detail, library analyses underscored 24 and 17 operational taxonomic units (OTUs) in healthy and infected roots, respectively, with a dominance of Betaproteobacteria. Moreover, differences in OTUs number and in CFU/g suggested that phytoplasmas could modify the composition of endophytic bacterial communities associated with infected plants. Intriguingly, the combination of culturing methods and cloning analysis allowed the identification of endophytic bacteria (e.g. Bacillus, Pseudomonas, and Burkholderia) that have been reported as biocontrol agents. Future research will investigate the capability of these bacteria to control 'Ca. Phytoplasma mali' in order to develop sustainable approaches for managing AP.

Guidance on Noncorticosteroid Systemic Immunomodulatory Therapy in Noninfectious Uveitis: Fundamentals Of Care for UveitiS (FOCUS) Initiative.

PubMed

Dick, Andrew D; Rosenbaum, James T; Al-Dhibi, Hassan A; Belfort, Rubens; Brézin, Antoine P; Chee, Soon Phaik; Davis, Janet L; Ramanan, Athimalaipet V; Sonoda, Koh-Hei; Carreño, Ester; Nascimento, Heloisa; Salah, Sawsen; Salek, Sherveen; Siak, Jay; Steeples, Laura

2018-05-01

An international, expert-led consensus initiative to develop systematic, evidence-based recommendations for the treatment of noninfectious uveitis in the era of biologics. The availability of biologic agents for the treatment of human eye disease has altered practice patterns for the management of noninfectious uveitis. Current guidelines are insufficient to assure optimal use of noncorticosteroid systemic immunomodulatory agents. An international expert steering committee comprising 9 uveitis specialists (including both ophthalmologists and rheumatologists) identified clinical questions and, together with 6 bibliographic fellows trained in uveitis, conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol systematic review of the literature (English language studies from January 1996 through June 2016; Medline [OVID], the Central Cochrane library, EMBASE, CINAHL, SCOPUS, BIOSIS, and Web of Science). Publications included randomized controlled trials, prospective and retrospective studies with sufficient follow-up, case series with 15 cases or more, peer-reviewed articles, and hand-searched conference abstracts from key conferences. The proposed statements were circulated among 130 international uveitis experts for review. A total of 44 globally representative group members met in late 2016 to refine these guidelines using a modified Delphi technique and assigned Oxford levels of evidence. In total, 10 questions were addressed resulting in 21 evidence-based guidance statements covering the following topics: when to start noncorticosteroid immunomodulatory therapy, including both biologic and nonbiologic agents; what data to collect before treatment; when to modify or withdraw treatment; how to select agents based on individual efficacy and safety profiles; and evidence in specific uveitic conditions. Shared decision-making, communication among providers and safety monitoring also were addressed as part of the recommendations. Pharmacoeconomic considerations were not addressed. Consensus guidelines were developed based on published literature, expert opinion, and practical experience to bridge the gap between clinical needs and medical evidence to support the treatment of patients with noninfectious uveitis with noncorticosteroid immunomodulatory agents. Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Recent progress on fabrication and drug delivery applications of nanostructured hydroxyapatite.

PubMed

Mondal, Sudip; Dorozhkin, Sergy V; Pal, Umapada

2018-07-01

Through this brief review, we provide a comprehensive historical background of the development of nanostructured hydroxyapatite (nHAp), and its application potentials for controlled drug delivery, drug conjugation, and other biomedical treatments. Aspects associated with efficient utilization of hydroxyapatite (HAp) nanostructures such as their synthesis, interaction with drug molecules, and other concerns, which need to be resolved before they could be used as a potential drug carrier in body system, are discussed. This review focuses on the evolution of perceptions, practices, and accomplishments in providing improved delivery systems for drugs until date. The pioneering developments that have presaged today's fascinating state of the art drug delivery systems based on HAp and HAp-based composite nanostructures are also discussed. Special emphasis has been given to describe the application and effectiveness of modified HAp as drug carrier agent for different diseases such as bone-related disorders, carriers for antibiotics, anti-inflammatory, carcinogenic drugs, medical imaging, and protein delivery agents. As only a very few published works made comprehensive evaluation of HAp nanostructures for drug delivery applications, we try to cover the three major areas: concepts, practices and achievements, and applications, which have been consolidated and patented for their practical usage. The review covers a broad spectrum of nHAp and HAp modified inorganic drug carriers, emphasizing some of their specific aspects those needed to be considered for future drug delivery applications. This article is categorized under: Implantable Materials and Surgical Technologies > Nanomaterials and Implants Therapeutic Approaches and Drug Discovery > Nanomedicine for Respiratory Disease Nanotechnology Approaches to Biology > Cells at the Nanoscale. © 2017 Wiley Periodicals, Inc.

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

PubMed Central

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

42 CFR 73.3 - HHS select agents and toxins.

Code of Federal Regulations, 2010 CFR

2010-10-01

... been genetically modified. (d) HHS select agents or toxins that meet any of the following criteria are... Recombinant Organisms: (1) Nucleic acids that can produce infectious forms of any of the select agent viruses...

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

PubMed

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).

Use magnetic resonance imaging to assess articular cartilage

PubMed Central

Wang, Yuanyuan; Wluka, Anita E.; Jones, Graeme; Ding, Changhai

2012-01-01

Magnetic resonance imaging (MRI) enables a noninvasive, three-dimensional assessment of the entire joint, simultaneously allowing the direct visualization of articular cartilage. Thus, MRI has become the imaging modality of choice in both clinical and research settings of musculoskeletal diseases, particular for osteoarthritis (OA). Although radiography, the current gold standard for the assessment of OA, has had recent significant technical advances, radiographic methods have significant limitations when used to measure disease progression. MRI allows accurate and reliable assessment of articular cartilage which is sensitive to change, providing the opportunity to better examine and understand preclinical and very subtle early abnormalities in articular cartilage, prior to the onset of radiographic disease. MRI enables quantitative (cartilage volume and thickness) and semiquantitative assessment of articular cartilage morphology, and quantitative assessment of cartilage matrix composition. Cartilage volume and defects have demonstrated adequate validity, accuracy, reliability and sensitivity to change. They are correlated to radiographic changes and clinical outcomes such as pain and joint replacement. Measures of cartilage matrix composition show promise as they seem to relate to cartilage morphology and symptoms. MRI-derived cartilage measurements provide a useful tool for exploring the effect of modifiable factors on articular cartilage prior to clinical disease and identifying the potential preventive strategies. MRI represents a useful approach to monitoring the natural history of OA and evaluating the effect of therapeutic agents. MRI assessment of articular cartilage has tremendous potential for large-scale epidemiological studies of OA progression, and for clinical trials of treatment response to disease-modifying OA drugs. PMID:22870497

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

PubMed Central

Gajofatto, Alberto; Benedetti, Maria Donata

2015-01-01

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

Effect of modifying agents on the hydrophobicity and yield of zinc borate synthesized by zinc oxide

NASA Astrophysics Data System (ADS)

Acarali, Nil Baran; Bardakci, Melek; Tugrul, Nurcan; Derun, Emek Moroydor; Piskin, Sabriye

2013-06-01

The aim of this study was to synthesize zinc borate using zinc oxide, reference boric acid, and reference zinc borate (reference ZB) as the seed, and to investigate the effects of modifying agents and reaction parameters on the hydrophobicity and yield, respectively. The reaction parameters include reaction time (1-5 h), reactant ratio (H3BO3/ZnO by mass: 2-5), seed ratio (seed crystal/(H3BO3+ZnO) by mass: 0-2wt%), reaction temperature (50-120°C), cooling temperature (10-80°C), and stirring rate (400-700 r/min); the modifying agents involve propylene glycol (PG, 0-6wt%), kerosene (1wt%-6wt%), and oleic acid (OA, 1wt%-6wt%) with solvents (isopropyl alcohol (IPA), ethanol, and methanol). The results of reaction yield obtained from either magnetically or mechanically stirred systems were compared. Zinc borate produced was characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), and contact angle tests to identify the hydrophobicity. In conclusion, zinc borate is synthesized successfully under the optimized reaction conditions, and the different modifying agents with various solvents affect the hydrophobicity of zinc borate.

Disease-modifying antirheumatic drugs other than methotrexate in rheumatoid arthritis and seronegative arthritis.

PubMed

Nandi, Pradip; Kingsley, Gabrielle H; Scott, David L

2008-05-01

To outline recent research findings with nonmethotrexate disease-modifying antirheumatic drugs in rheumatoid arthritis and seronegative arthritis spanning systematic reviews, randomized controlled trials, observational clinical practice trials and assessments of adverse effects. Systematic reviews show no important differences between methotrexate, leflunomide and sulfasalazine monotherapies; early disease-modifying antirheumatic drug therapy reduces erosive progression. Observational studies show that nonmethotrexate disease-modifying antirheumatic drugs are widely prescribed; their usage has increased in the biologic era. A systemic review also showed patients who failed monotherapy benefited from disease-modifying antirheumatic drug combinations without excess toxicity. Randomized controlled trials of intensive initial disease-modifying antirheumatic drug combinations showed they reduce synovitis and erosive damage, especially when used with steroids. The subsequent sequence of disease-modifying antirheumatic drugs and the value of changing disease-modifying antirheumatic drug monotherapies or stepping-up to combination disease-modifying antirheumatic drugs are, however, unresolved. The adverse risks of nonmethotrexate disease-modifying antirheumatic drugs have been evaluated, including infections and lung disease; patient-related risks seem more important than drug-related risks, though several disease-modifying antirheumatic drugs increase both types of adverse reactions. Two limitations of nonmethotrexate disease-modifying antirheumatic drugs are reduced impact on comorbidities like cardiovascular disease and reduced patient and clinician preferences for these treatments. Nonmethotrexate disease-modifying antirheumatic drugs are effective, relatively well tolerated and widely used. Their role in intensive treatment strategies in early rheumatoid arthritis appears of crucial importance.

Development of oral immunomodulatory agents in the management of multiple sclerosis

PubMed Central

Nicholas, Richard; Giannetti, Paolo; Alsanousi, Ali; Friede, Tim; Muraro, Paolo A

2011-01-01

The emergence of oral disease-modifying therapies in multiple sclerosis (MS) will have a significant impact on the evolving scenario of immunomodulatory treatments in MS where current therapies are all injectable. Reducing relapses in trials translates for individuals with MS into a therapeutic aim of stopping future events. Thus the possible absence of any perceived benefits to the individual together with the long disease course, variable outcome, and a younger age group affected in MS makes side effects the major issue. The use of disease-modifying therapies as a whole needs to be placed in the context of a widening therapeutic indication where the use of these therapies is being justified at an increasingly early stage and in pre-MS syndromes such as clinically isolated and radiologically isolated syndromes where no fixed disability is likely to have accumulated. The five oral therapies discussed (cladribine, fingolimod, laquinimod, BG-12, and teriflunomide) have just completed Phase III studies and some have just been licensed. New oral drugs for MS need to be placed within this evolving marketplace where ease of delivery together with efficacy and side effects needs to be balanced against the known issues but also the known long-term safety of standard injectables. PMID:21625416

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

PubMed Central

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. Thus, the full-length cDNA clone of FMDV can be a useful tool to develop genetically engineered FMDV vaccine candidates to help control porcinophilic FMD epidemics in China. PMID:22591597

Inflammatory bowel disease pathogenesis: where are we?

PubMed

Fiocchi, Claudio

2015-03-01

Inflammatory bowel disease (IBD) is presently one of the most investigated human disorders. Expansion of knowledge of its pathophysiology has helped in developing novel medications to combat gut inflammation with a considerably degree of success. Despite this progress, much more remains to be done in regard to gaining a more profound understanding of IBD pathogenesis, detecting inflammation before it clinically manifests, implementing lifestyle modifications, and developing agents that can modify the natural course of the disease. One of the limitations to achieve these goals is the lack of integration of the major components of IBD pathogenesis, that is the exposome, the genome, the gut microbiome, and the immunome. An "IBD integrome" approach that takes advantage of all functional information derived from the detailed investigation of each single pathogenic component through the use of systems biology may offer the solution to understand IBD and cure it. © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

Coagulation Abnormalities of Sickle Cell Disease: Relationship with Clinical Outcomes and the Effect of Disease Modifying Therapies

PubMed Central

Noubouossie, Denis; Key, Nigel S.; Ataga, Kenneth I.

2015-01-01

Sickle cell disease (SCD) is a hypercoagulable state. Patients exhibit increased platelet activation, high plasma levels of markers of thrombin generation, depletion of natural anticoagulant proteins, abnormal activation of the fibrinolytic system, and increased tissue factor expression, even in the non-crisis “steady state.” Furthermore, SCD is characterized by an increased risk of thrombotic complications. The pathogenesis of coagulation activation in SCD appears to be multi-factorial, with contributions from ischemia-reperfusion injury and inflammation, hemolysis and nitric oxide deficiency, and increased sickle RBC phosphatidylserine expression. Recent studies in animal models suggest that activation of coagulation may contribute to the pathogenesis of SCD, but the data on the contribution of coagulation and platelet activation to SCD-related complications in humans are limited. Clinical trials of new generations of anticoagulants and antiplatelet agents, using a variety of clinical endpoints are warranted. PMID:26776344

The role of chemotherapy in the treatment of malignant astrocytomas.

PubMed

Mathieu, David; Fortin, David

2006-05-01

Malignant astrocytomas are aggressive neoplasms with a dismal prognosis despite optimal treatment. Maximal resective surgery is traditionally complemented by radiation therapy. Chemotherapy is now used on patients as initial therapy when their functional status is congruent with further treatment. The classic agents used are nitrosoureas, but temozolomide has taken the front seat recently, with recent data demonstrating increased survival when this agent is used concurrently with radiation therapy in newly diagnosed glioblastoma patients. A new class of agents, refered to as biological modifiers, are increasingly used in clinical trials in an effort to affect the intrinsic biologic aberrations harboured by tumor cells. These drugs comprise differentiation agents, anti-angiogenic agents, matrix-metalloproteinase inhibitors and signal transduction inhibitors, among others. This article reviews the standard cytotoxic agents that have been used to treat malignant astrocytomas, and the different combination regimens offering promise. In addition, recent advances with biological modifiers are also discussed.

Biological and Clinical Aspects of Lanthanide Coordination Compounds

PubMed Central

Misra, Sudhindra N.; M., Indira Devi; Shukla, Ram S.

2004-01-01

The coordinating chemistry of lanthanides, relevant to the biological, biochemical and medical aspects, makes a significant contribution to understanding the basis of application of lanthanides, particularly in biological and medical systems. The importance of the applications of lanthanides, as an excellent diagnostic and prognostic probe in clinical diagnostics, and an anticancer material, is remarkably increasing. Lanthanide complexes based X-ray contrast imaging and lanthanide chelates based contrast enhancing agents for magnetic resonance imaging (MRI) are being excessively used in radiological analysis in our body systems. The most important property of the chelating agents, in lanthanide chelate complex, is its ability to alter the behaviour of lanthanide ion with which it binds in biological systems, and the chelation markedly modifies the biodistribution and excretion profile of the lanthanide ions. The chelating agents, especially aminopoly carboxylic acids, being hydrophilic, increase the proportion of their complex excreted from complexed lanthanide ion form biological systems. Lanthanide polyamino carboxylate-chelate complexes are used as contrast enhancing agents for Magnetic Resonance Imaging. Conjugation of antibodies and other tissue specific molecules to lanthanide chelates has led to a new type of specific MRI contrast agents and their conjugated MRI contrast agents with improved relaxivity, functioning in the body similar to drugs. Many specific features of contrast agent assisted MRI make it particularly effective for musculoskeletal and cerebrospinal imaging. Lanthanide-chelate contrast agents are effectively used in clinical diagnostic investigations involving cerebrospinal diseases and in evaluation of central nervous system. Chelated lanthanide complexes shift reagent aided 23Na NMR spectroscopic analysis is used in cellular, tissue and whole organ systems. PMID:18365075

DNA Vaccines - A Modern Gimmick or a Boon to Vaccinology?

PubMed

Manickan, Elanchezhiyan; Karem, Kevin L; Rouse, Barry T

2017-01-01

The reports in 1993 that naked DNA encoding viral genes conferred protective immunity came as a surprise to most vaccinologists. This review analyses the expanding number of examples where plasmid DNA induces immune responses. Issues such as the type of immunity induced, mechanisms of immune protection, and how DNA vaccines compare with other approaches are emphasized. Additional issues discussed include the likely means by which DNA vaccines induce CTL, how the potency and type of immunity induced can be modified, and whether DNA vaccines represent a practical means of manipulating unwanted immune response occurring during immunoinflammatory diseases. It seems doubtful if DNA vaccines will replace currently effective vaccines, but they may prove useful for prophylactic use against some agents that at present lack an effective vaccine. DNA vaccines promise to be valuable to manipulate the immune response in situations where responses to agents are inappropriate or ineffective.

A Phase I/II adaptive design for heterogeneous groups with application to a stereotactic body radiation therapy trial.

PubMed

Wages, Nolan A; Read, Paul W; Petroni, Gina R

2015-01-01

Dose-finding studies that aim to evaluate the safety of single agents are becoming less common, and advances in clinical research have complicated the paradigm of dose finding in oncology. A class of more complex problems, such as targeted agents, combination therapies and stratification of patients by clinical or genetic characteristics, has created the need to adapt early-phase trial design to the specific type of drug being investigated and the corresponding endpoints. In this article, we describe the implementation of an adaptive design based on a continual reassessment method for heterogeneous groups, modified to coincide with the objectives of a Phase I/II trial of stereotactic body radiation therapy in patients with painful osseous metastatic disease. Operating characteristics of the Institutional Review Board approved design are demonstrated under various possible true scenarios via simulation studies. Copyright © 2015 John Wiley & Sons, Ltd.

Infectious Agents as Stimuli of Trained Innate Immunity.

PubMed

Rusek, Paulina; Wala, Mateusz; Druszczyńska, Magdalena; Fol, Marek

2018-02-03

The discoveries made over the past few years have modified the current immunological paradigm. It turns out that innate immunity cells can mount some kind of immunological memory, similar to that observed in the acquired immunity and corresponding to the defense mechanisms of lower organisms, which increases their resistance to reinfection. This phenomenon is termed trained innate immunity. It is based on epigenetic changes in innate immune cells (monocytes/macrophages, NK cells) after their stimulation with various infectious or non-infectious agents. Many infectious stimuli, including bacterial or fungal cells and their components (LPS, β-glucan, chitin) as well as viruses or even parasites are considered potent inducers of innate immune memory. Epigenetic cell reprogramming occurring at the heart of the phenomenon may provide a useful basis for designing novel prophylactic and therapeutic strategies to prevent and protect against multiple diseases. In this article, we present the current state of art on trained innate immunity occurring as a result of infectious agent induction. Additionally, we discuss the mechanisms of cell reprogramming and the implications for immune response stimulation/manipulation.

Bacterial-Derived Polymer Poly-y-Glutamic Acid (y-PGA)-Based Micro/Nanoparticles as a Delivery System for Antimicrobials and Other Biomedical Applications.

PubMed

Khalil, Ibrahim R; Burns, Alan T H; Radecka, Iza; Kowalczuk, Marek; Khalaf, Tamara; Adamus, Grazyna; Johnston, Brian; Khechara, Martin P

2017-02-02

In the past decade, poly-γ-glutamic acid (γ-PGA)-based micro/nanoparticles have garnered remarkable attention as antimicrobial agents and for drug delivery, owing to their controlled and sustained-release properties, low toxicity, as well as biocompatibility with tissue and cells. γ-PGA is a naturally occurring biopolymer produced by several gram-positive bacteria that, due to its biodegradable, non-toxic and non-immunogenic properties, has been used successfully in the medical, food and wastewater industries. Moreover, its carboxylic group on the side chains can offer an attachment point to conjugate antimicrobial and various therapeutic agents, or to chemically modify the solubility of the biopolymer. The unique characteristics of γ-PGA have a promising future for medical and pharmaceutical applications. In the present review, the structure, properties and micro/nanoparticle preparation methods of γ-PGA and its derivatives are covered. Also, we have highlighted the impact of micro/nanoencapsulation or immobilisation of antimicrobial agents and various disease-related drugs on biodegradable γ-PGA micro/nanoparticles.

Bacterial-Derived Polymer Poly-γ-Glutamic Acid (γ-PGA)-Based Micro/Nanoparticles as a Delivery System for Antimicrobials and Other Biomedical Applications

PubMed Central

Khalil, Ibrahim R.; Burns, Alan T. H.; Radecka, Iza; Kowalczuk, Marek; Khalaf, Tamara; Adamus, Grazyna; Johnston, Brian; Khechara, Martin P.

2017-01-01

In the past decade, poly-γ-glutamic acid (γ-PGA)-based micro/nanoparticles have garnered remarkable attention as antimicrobial agents and for drug delivery, owing to their controlled and sustained-release properties, low toxicity, as well as biocompatibility with tissue and cells. γ-PGA is a naturally occurring biopolymer produced by several gram-positive bacteria that, due to its biodegradable, non-toxic and non-immunogenic properties, has been used successfully in the medical, food and wastewater industries. Moreover, its carboxylic group on the side chains can offer an attachment point to conjugate antimicrobial and various therapeutic agents, or to chemically modify the solubility of the biopolymer. The unique characteristics of γ-PGA have a promising future for medical and pharmaceutical applications. In the present review, the structure, properties and micro/nanoparticle preparation methods of γ-PGA and its derivatives are covered. Also, we have highlighted the impact of micro/nanoencapsulation or immobilisation of antimicrobial agents and various disease-related drugs on biodegradable γ-PGA micro/nanoparticles. PMID:28157175

Synthesis and Photophysical Properties of Sulfonamidophenyl Porphyrins as Models for Activatable Photosensitizers

PubMed Central

Bhaumik, Jayeeta; Weissleder, Ralph; McCarthy, Jason R.

2009-01-01

The ability to localize agents to specific anatomic sites remains an important aspect in designing more efficient therapeutics. Light-activated therapies, in particular, allow for the focal ablation of target tissues and cells. In order to increase the specificity of these agents, stimuli-activated systems have been developed, which are non-phototoxic in the absence of activation. To this end, we propose a novel paradigm for excited state quenching and activation based upon the direct conjugation of quenching moieties to the porphyrinic macrocycle. Model compounds, based upon meso-(p-aminophenyl)porphyrins were synthesized bearing 1 to 4 sulfonamide-linked 2,4-dinitrobenzene. The singlet oxygen and fluorescence quantum yields of these compounds were obtained and compared, as well as the kinetics of activation with relevant activating agents. In addition, methods were developed to further modify the porphyrin in order to modulate the polarity and effect conjugation to biomolecules or nanoparticulate scaffolds. These systems may prove useful in the treatment of a number of disease states, such as cancer and bacterial infection. PMID:19610602

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

Chen, Zonghai; Amine, Khalil; Belharouak, Ilias

An active material for an electrochemical device wherein a surface of the active material is modified by a surface modification agent, wherein the surface modification agent is an organometallic compound.

Impact of traditional therapies and biologics on cardiovascular diseases in rheumatoid arthritis.

PubMed

Boyer, Jean-Frédéric; Cantagrel, Alain; Constantin, Arnaud

2008-07-01

In chronic inflammatory diseases such as rheumatoid arthritis (RA), systemic inflammation appears as an independent risk factor, contributing to increased cardiovascular mortality. This high cardiovascular mortality reveals the existence of accelerated atherosclerosis, the pathogenesis of which may be associated with traditional risk factors such as smoking, hypertension, dyslipidemia, deterioration of insulin sensitivity, and less traditional risk factors such as hyperhomocysteinemia, inflammatory conditions and endothelial dysfunction. Control of systemic inflammation theoretically provides a means of preventing this higher cardiovascular mortality among RA patients. In this review we address the question of the impact of anti-rheumatic drugs currently used in RA, such as non-steroidal anti-inflammatory drugs (e.g. non-selective or cyclooxygenase-2 selective inhibitors), steroidal anti-inflammatory drugs (glucocorticoids), traditional disease-modifying anti-rheumatic drugs (e.g. methotrexate) or biologics (e.g. anti-tumour necrosis factor alpha anti-tumour necrosis factor alpha) on cardiovascular diseases in RA patients. We also discuss the specific mechanisms involved in the differential cardiovascular effects of these therapeutic agents.

Structure-Based Prediction of Unstable Regions in Proteins: Applications to Protein Misfolding Diseases

NASA Astrophysics Data System (ADS)

Guest, Will; Cashman, Neil; Plotkin, Steven

2009-03-01

Protein misfolding is a necessary step in the pathogenesis of many diseases, including Creutzfeldt-Jakob disease (CJD) and familial amyotrophic lateral sclerosis (fALS). Identifying unstable structural elements in their causative proteins elucidates the early events of misfolding and presents targets for inhibition of the disease process. An algorithm was developed to calculate the Gibbs free energy of unfolding for all sequence-contiguous regions of a protein using three methods to parameterize energy changes: a modified G=o model, changes in solvent-accessible surface area, and solution of the Poisson-Boltzmann equation. The entropic effects of disulfide bonds and post-translational modifications are treated analytically. It incorporates a novel method for finding local dielectric constants inside a protein to accurately handle charge effects. We have predicted the unstable parts of prion protein and superoxide dismutase 1, the proteins involved in CJD and fALS respectively, and have used these regions as epitopes to prepare antibodies that are specific to the misfolded conformation and show promise as therapeutic agents.

Identifying Unstable Regions of Proteins Involved in Misfolding Diseases

NASA Astrophysics Data System (ADS)

Guest, Will; Cashman, Neil; Plotkin, Steven

2009-05-01

Protein misfolding is a necessary step in the pathogenesis of many diseases, including Creutzfeldt-Jakob disease (CJD) and familial amyotrophic lateral sclerosis (fALS). Identifying unstable structural elements in their causative proteins elucidates the early events of misfolding and presents targets for inhibition of the disease process. An algorithm was developed to calculate the Gibbs free energy of unfolding for all sequence-contiguous regions of a protein using three methods to parameterize energy changes: a modified G=o model, changes in solvent-accessible surface area, and all-atoms molecular dynamics. The entropic effects of disulfide bonds and post-translational modifications are treated analytically. It incorporates a novel method for finding local dielectric constants inside a protein to accurately handle charge effects. We have predicted the unstable parts of prion protein and superoxide dismutase 1, the proteins involved in CJD and fALS respectively, and have used these regions as epitopes to prepare antibodies that are specific to the misfolded conformation and show promise as therapeutic agents.

A Review of the Use of Complementary and Alternative Medicines by Children with Inflammatory Bowel Disease

PubMed Central

Day, Andrew S.

2013-01-01

The Inflammatory Bowel Diseases (IBDs) are diagnosed more commonly in children and adolescents. Following diagnosis, the key objectives are to achieve and then maintain remission. Although some therapies are able to effectively modify and modulate inflammatory events, none of the available interventions cure these conditions. Consequently, children and their parents face uncertainty and may look to alternative management options as ways to help their child, which may include various complementary and alternative medicines (CAMs). A number of studies have shown that many children with IBD receive or are given CAM agents. This article reviews the rates and patterns of CAM use in children with IBD, and emphasizes the increasing importance of these aspects of the management of children with IBD. PMID:24400255

[Diagnosis and treatment of pulmonary hypertension].

PubMed

Román, J Sánchez; Hernández, F J García; Palma, M J Castillo; Medina, C Ocaña

2008-03-01

Pulmonary arterial hypertension is an idiopathic process or can be associated with another circumstances (connective tissue diseases, congenital heart disease, portal hypertension, exposure to appetite suppressants or another drugs or infectious agents such as HIV). Most patients are diagnosed as the result of an evaluation of symptoms, whereas others are diagnosed incidentally or during screening of asymptomatic populations at risk. We reviews systematic screening for the approach to diagnosing pulmonary arterial hypertension. A diagnostic algorithm can guide the evaluation but it can be modified according to specific clinical circumstances. The number of therapeutic options has increased.in the last years. We reviews the use of calcium-channel blockers, prostacyclin (and analogues), endothelin-receptor antagonists, and phosphodiesterase-5 inhibitors, and the use of combination therapy, and provides specific recommendations about the actual treatment.

Fiber Surface Modification Technology for Fiber-Optic Localized Surface Plasmon Resonance Biosensors

PubMed Central

Zhang, Qiang; Xue, Chenyang; Yuan, Yanling; Lee, Junyang; Sun, Dong; Xiong, Jijun

2012-01-01

Considerable studies have been performed on the development of optical fiber sensors modified by gold nanoparticles based on the localized surface plasmon resonance (LSPR) technique. The current paper presents a new approach in fiber surface modification technology for biosensors. Star-shaped gold nanoparticles obtained through the seed-mediated solution growth method were found to self-assemble on the surface of tapered optical fibers via amino- and mercapto-silane coupling agents. Transmitted power spectra of 3-aminopropyltrimethoxy silane (APTMS)-modified fiber were obtained, which can verify that the silane coupling agent surface modification method is successful. Transmission spectra are characterized in different concentrations of ethanol and gentian violet solutions to validate the sensitivity of the modified fiber. Assembly using star-shaped gold nanoparticles and amino/mercapto silane coupling agent are analyzed and compared. The transmission spectra of the gold nanoparticles show that the nanoparticles are sensitive to the dielectric properties of the surrounding medium. After the fibers are treated in t-dodecylmercaptan to obtain their transmission spectra, APTMS-modified fiber becomes less sensitive to different media, except that modified by 3-mercaptopropyltrimethoxy silane (MPTMS). Experimental results of the transmission spectra show that the surface modified by the gold nanoparticles using MPTMS is firmer compared to that obtained using APTMS. PMID:22736974

Elevated Steady State WBC and Platelet Counts Are Associated with Frequent Emergency Room Use in Adults with Sickle Cell Anemia

PubMed Central

Danda, Neeraja; Etzion, Zipora

2015-01-01

Introduction Sickle cell anemia has many sequelae that result in emergency department (ED) use, but a minority of patients with sickle cell disease are frequent utilizers and make up the majority of ED visits. If patients who are likely to be frequent ED can be identified in steady state, they can be treated with disease modifying agents in an attempt to reduce ED use frequency. We sought to identify steady state markers for frequent ED use. Methods We identified all patients with SS/Sβ0 seen at our facilities in 2012. Health care utilization over the entire year was calculated and ED visit numbers categorized as either 0–1, 2–5, or 6 or more visits a year. Steady state and acutely active laboratory parameters were collected and analyzed using analysis of variance models and odds ratios. Results 432 adult sickle cell patients were identified, ages 18–87, 54% female, and 38% had been prescribed hydroxyurea. Of the 432 patients,192 had 0–1 visits in the year, 144 had 2–5 visits in the year, and 96 had >6 visits for a total of 2259 visits. Those who had >6 visits accounted for 1750 (77%) of the total visits for the year. When steady state laboratory markers were examined, each additional 50x109/L platelets was associated with 22% greater risk (p < .001); each 1x109/L of WBC was associated with 11% greater risk (p = .003), and each 1g/dL Hb was associated with 23% lower risk (p = .007) of >6 ED visits/year. We did not observe a relationship between baseline HbF, LDH or reticulocyte count with >6 ED visits. Conclusion Patients with elevated white blood cell counts, elevated platelet counts, and low hemoglobin levels exhibited higher risk for frequent ED utilization and could be candidates for early and aggressive therapy with disease modifying agents. PMID:26248283

Articular cartilage tissue engineering: the role of signaling molecules

PubMed Central

Kwon, Heenam; Paschos, Nikolaos K.; Hu, Jerry C.; Athanasiou, Kyriacos

2017-01-01

Effective early disease modifying options for osteoarthritis remain lacking. Tissue engineering approach to generate cartilage in vitro has emerged as a promising option for articular cartilage repair and regeneration. Signaling molecules and matrix modifying agents, derived from knowledge of cartilage development and homeostasis, have been used as biochemical stimuli toward cartilage tissue engineering and have led to improvements in the functionality of engineered cartilage. Clinical translation of neocartilage faces challenges, such as phenotypic instability of the engineered cartilage, poor integration, inflammation, and catabolic factors in the arthritic environment; these can all contribute to failure of implanted neocartilage. A comprehensive understanding of signaling molecules involved in osteoarthritis pathogenesis and their actions on engineered cartilage will be crucial. Thus, while it is important to continue deriving inspiration from cartilage development and homeostasis, it has become increasing necessary to incorporate knowledge from osteoarthritis pathogenesis into cartilage tissue engineering. PMID:26811234

Modification of the mitochondrial sulfonylurea receptor by thiol reagents.

PubMed

Szewczyk, A; Wójcik, G; Lobanov, N A; Nalecz, M J

1999-08-19

The purpose of this study was to investigate the effects exerted by thiol-modifying reagents on themitochondrial sulfonylurea receptor. The thiol-oxidizing agents (timerosal and 5, 5'-dithio-bis(2-nitrobenzoic acid)) were found to produce a large inhibition (70% to 80%) of specific binding of [(3)H]glibenclamide to the beef heart mitochondrial membrane. Similar effects were observed with membrane permeable (N-ethylmaleimide) and non-permeable (mersalyl) thiol modifying agents. Glibenclamide binding was also decreased by oxidizing agents (hydrogen peroxide) but not by reducing agents (reduced gluthatione, dithiothreitol and the 2,3-dihydroxy-1,4-dithiolbutane). The results suggest that intact thiol groups, facing the mitochondrial matrix, are essential for glibenclamide binding to the mitochondrial sulfonylurea receptor. Copyright 1999 Academic Press.

New anabolic therapies in osteoporosis.

PubMed

Rubin, Mishaela R; Bilezikian, John P

2003-03-01

Anabolic agents represent an important new advance in the therapy of osteoporosis. Their potential might be substantially greater than the anti-resorptives. Because the anti-resorptives and anabolic agents work by completely distinct mechanisms of action, it is possible that the combination of agents could be significantly more potent than either agent alone. Recent evidence suggests that a plateau in BMD might occur after prolonged exposure to PTH. Anti-resorptive therapy during or after anabolic therapy might prevent this skeletal adaptation. Protocols to consider anabolic agents as intermittent recycling therapy would be of interest. Of all the anabolics, PTH is the most promising. However, there are unanswered questions about PTH. More studies are needed to document an anabolic effect on cortical bone. More large-scale studies are needed to further determine the reduction in nonvertebral fractures with PTH, especially at the hip. In the future, PTH is likely to be modified for easier and more targeted delivery. Oral or transdermal delivery systems may become available. Recently, Gowen et al have described an oral calcilytic molecule that antagonizes the parathyroid cell calcium receptor, thus stimulating the endogenous release of PTH. This approach could represent a novel endogenous delivery system for intermittent PTH administration. Rising expectations that anabolic therapies for osteoporosis will soon play a major role in treating this disease are likely to fuel further studies and the development of even more novel approaches to therapy.

Biology of IL-5 in health and disease.

PubMed

Lalani, T; Simmons, R K; Ahmed, A R

1999-04-01

Reading this article will increase the readers' knowledge of the biology of interleukin-5 (IL-5), an important cytokine. The immune and inflammatory responses of any organism are the basis of the defense mechanism ensuring its survival. The role of IL-5 in these processes, as well as in the pathogenesis of various diseases has been discussed along with the effects of various pharmacologic agents on the production and function of IL-5. A detailed literature search was performed. Studies considered relevant and important, in all languages, which involved humans and animals were used. Information was obtained only from peer reviewed journals. Interleukin-5 is normally produced by T-cells, mast cells, and eosinophils while Reed Sternberg and Epstein Barr virus (EBV) transformed cells also produce IL-5. Monoclonal antibodies (mAb) to IL-5 are potent inhibitors of IL-5 mediated tissue damage, secondary to eosinophil infiltration. The majority of the studies on IL-5 are preliminary, often the information is obtained from animal studies or in vitro systems and occasionally from pathologic tissue analysis. This along with the absence of confirmatory studies is a limiting factor. Nonetheless, the role of IL-5 in allergic and immunologic disease and asthma may be central to their pathogenesis. Interleukin-5 is an important molecule that is participant to many processes that maintain health and are involved directly or indirectly in the pathogenesis of disease. Some pharmacologic agents can modify IL-5 production in vivo. Development of selective inhibitors of IL-5 may have a potential use for specific therapy of certain autoimmune, inflammatory, and neoplastic diseases.

Management of upper extremity dysfunction in people with Parkinson disease and Huntington disease: facilitating outcomes across the disease lifespan.

PubMed

Quinn, Lori; Busse, Monica; Dal Bello-Haas, Vanina

2013-01-01

Parkinson Disease (PD) and Huntington Disease (HD) are degenerative neurological diseases, which can result in impairments and activity limitations affecting the upper extremities from early in the disease process. The progressive nature of these diseases poses unique challenges for therapists aiming to effectively maximize physical functioning and minimize participation restrictions in these patient groups. Research is underway in both diseases to develop effective disease-modifying agents and pharmacological interventions, as well as mobility-focused rehabilitation protocols. Rehabilitation, and in particular task-specific interventions, has the potential to influence the upper extremity functional abilities of patients with these degenerative conditions. However to date, investigations of interventions specifically addressing upper extremity function have been limited in both PD, and in particular HD. In this paper, we provide an update of the known pathological features of PD and HD as they relate to upper extremity function. We further review the available literature on the use of outcome measures, and the clinical management of upper extremity function in both conditions. Due to the currently limited evidence base in both diseases, we recommend utilization of a clinical management framework specific for degenerative conditions that can serve as a guideline for disease management. Copyright © 2013. Published by Elsevier Inc.

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

PubMed

Roche, Benjamin; Guégan, Jean-François; Bousquet, François

2008-10-15

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. 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. 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.

Preliminary evaluation of antimicrobial activity of some chemicals on in vitro apple shoots infected by 'Candidatus Phytoplasma mali'.

PubMed

Aldaghi, M; Massart, S; Druart, Ph; Bertaccini, A; Jijakli, M H; Lepoivre, P

2008-01-01

Phytoplasmas are associated with several hundred plant diseases worldwide, including numerous ones with important economical impact. Control of epidemic outbreak of phytoplasma diseases can be theoretically carried out by antibiotics. However, they are expensive, not allowed or prohibited in several countries, and even not always efficient. Presently, effective but safe antimicrobial agents are needed to control severe phytoplasma diseases in field. The aim of the present study was to evaluate the susceptibility of 'Candidatus Phytoplasma mali' to several chemical or synthetic antimicrobial agents. We tested nisin, esculetin, pyrithione and chloramphenicol as molecules having different target activities against micro-organisms. Because of their antimicrobial properties against fungi and bacteria, 4 phyto-essential oils (carvacrol, eugenol, terpineol, alpha-pinene) had also been tested. The activity of these molecules was compared with two antibiotics (tetracycline and enrofloxacin) used as control products. All these compounds were tested in in vitro culture of apples (MM106) infected by 'Ca. P. mall'. All compounds were added to the proliferation medium (modified MS) after autoclaving at 3 concentrations (100, 500, 1,000 ppm), except nisin and pyrithione which were tested at 10, 100 and 500 ppm. Phytoplasma infection was quantified in plant materials by real-time PCR before their transfer and after one or two months of culture in the presence of antimicrobial agents. Primary results showed that phytoplasma were not detectable after one and two months in the presence of pyrithione (at 10 and 100 ppm). Moreover, some other products reduced the concentration of phytoplasma after two months. Shoots died or withered on media enriched with essential oils; that made them impossible to assess, especially when they were used at concentration of 500 and 1,000 ppm.

The Impact of Biologics and Tofacitinib on Cardiovascular Risk Factors and Outcomes in Patients with Rheumatic Disease: A Systematic Literature Review.

PubMed

Nurmohamed, Michael; Choy, Ernest; Lula, Sadiq; Kola, Blerina; DeMasi, Ryan; Accossato, Paola

2018-05-01

Rheumatic diseases are autoimmune, inflammatory diseases often associated with cardiovascular (CV) disease, a major cause of mortality in these patients. In recent years, treatment with biologic and targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs), either as monotherapy or in combination with other drugs, have become the standard of treatment. In this systematic literature review, we evaluated the effect of treatment with biologic or tofacitinib on the CV risk and outcomes in these patients. A systematic search was performed in MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews for articles reporting on CV risk and events in patients with rheumatic disease treated with a biologic agent or tofacitinib. Articles identified were subjected to two levels of screening. Articles that passed the first level based on title and abstract were assessed on full-text evaluation. The quality of randomized clinical trials was assessed by Jadad scoring system and the quality of the other studies and abstracts was assessed using the Downs and Black instrument. The data extracted included study design, baseline patient characteristics, and measurements of CV risk and events. Of the 5722 articles identified in the initial search, screening yielded 105 unique publications from 90 unique studies (33 clinical trials, 39 prospective cohort studies, and an additional 18 retrospective studies) that reported CV risk outcomes. A risk of bias analysis for each type of report indicated that they were of good or excellent quality. Importantly, despite some limitations in data reported, there were no indications of significant increase in adverse CV events or risk in response to treatment with the agents evaluated. Treatment with biologic or tofacitinib appears to be well-tolerated with respect to CV outcomes in these patients.

Investigating and managing the rapid emergence of white-nose syndrome, a novel, fatal, infectious disease of hibernating bats

USGS Publications Warehouse

Foley, Janet; Clifford, Deana; Castle, Kevin; Cryan, Paul M.; Ostfeld, Richard S.

2011-01-01

White-nose syndrome (WNS) is a fatal disease of bats that hibernate. The etiologic agent of WNS is the fungus Geomyces destructans, which infects the skin and wing membranes. Over 1 million bats in six species in eastern North America have died from WNS since 2006, and as a result several species of bats may become endangered or extinct. Information is lacking on the pathogenesis of G. destructans and WNS, WNS transmission and maintenance, individual and site factors that contribute to the probability of an outbreak of WNS, and spatial dynamics of WNS spread in North America. We considered how descriptive and analytical epidemiology could be used to fill these information gaps, including a four-step (modified) outbreak investigation, application of a set of criteria (Hill's) for assessing causation, compartment models of disease dynamics, and spatial modeling. We cataloged and critiqued adaptive-management options that have been either previously proposed for WNS or were helpful in addressing other emerging diseases of wild animals. These include an ongoing program of prospective surveillance of bats and hibernacula for WNS, treatment of individual bats, increasing population resistance to WNS (through vaccines, immunomodulators, or other methods), improving probability of survival from starvation and dehydration associated with WNS, modifying hibernacula environments to eliminate G. destructans, culling individuals or populations, controlling anthropogenic spread of WNS, conserving genetic diversity of bats, and educating the public about bats and bat conservation issues associated with WNS.

The effect of salivary pH on diametral tensile strength of resin modified glass ionomer cement coated with coating agent

NASA Astrophysics Data System (ADS)

Ismayanti, D.; Triaminingsih, S.; Eriwati, Y. K.

2017-08-01

The aim of this study was to evaluate the effect of artificial saliva with different acidities on the diametral tensile strength of Resin Modified Glass Ionomer Cement (RMGIC) coated with varnish and nanofilled coating agent. The specimens coated with coating agents were immersed in artificial saliva with pH of 4.5, 5.5, and 7 for 24 hours in an incubatorat 37°C. The diametral tensile strength of the specimens was tested with Universal Testing Machine. There were no significant differences on the diametral tensile strength of all specimens that were put into groups based on the acidity of the saliva and the type of coating agent (p>0.05). Both varnish and nanofilled coating agent stayed on the RMGIC in the acidic condition that simulated the true condition of oral cavity in people with high caries risk for the 24 hours of maturation.

Scopolamine provocation-based pharmacological MRI model for testing procognitive agents.

PubMed

Hegedűs, Nikolett; Laszy, Judit; Gyertyán, István; Kocsis, Pál; Gajári, Dávid; Dávid, Szabolcs; Deli, Levente; Pozsgay, Zsófia; Tihanyi, Károly

2015-04-01

There is a huge unmet need to understand and treat pathological cognitive impairment. The development of disease modifying cognitive enhancers is hindered by the lack of correct pathomechanism and suitable animal models. Most animal models to study cognition and pathology do not fulfil either the predictive validity, face validity or construct validity criteria, and also outcome measures greatly differ from those of human trials. Fortunately, some pharmacological agents such as scopolamine evoke similar effects on cognition and cerebral circulation in rodents and humans and functional MRI enables us to compare cognitive agents directly in different species. In this paper we report the validation of a scopolamine based rodent pharmacological MRI provocation model. The effects of deemed procognitive agents (donepezil, vinpocetine, piracetam, alpha 7 selective cholinergic compounds EVP-6124, PNU-120596) were compared on the blood-oxygen-level dependent responses and also linked to rodent cognitive models. These drugs revealed significant effect on scopolamine induced blood-oxygen-level dependent change except for piracetam. In the water labyrinth test only PNU-120596 did not show a significant effect. This provocational model is suitable for testing procognitive compounds. These functional MR imaging experiments can be paralleled with human studies, which may help reduce the number of false cognitive clinical trials. © The Author(s) 2015.

Pharmacological therapy of spondyloarthritis.

PubMed

Palazzi, Carlo; D'Angelo, Salvatore; Gilio, Michele; Leccese, Pietro; Padula, Angela; Olivieri, Ignazio

2015-01-01

The current pharmacological therapy of spondyloarthritis (SpA) includes several drugs: Non-steroidal anti-inflammatory drugs, corticosteroids, traditional disease-modifying antirheumatic drugs and biologic drugs. A systematic literature search was completed using the largest electronic databases (Medline, Embase and Cochrane), starting from 1995, with the aim to review data on traditional and biologic agents commercialised for SpA treatment. Randomised controlled trials and large observational studies were considered. In addition, studies performed in SpA patients treated with other, still unapproved, drugs (rituximab, anti-IL6 agents, apremilast, IL17 inhibitors and anakinra) were also taken into account. Biologic agents, especially anti-TNF drugs, have resulted in significant progress in improving clinical symptoms and signs, reducing inflammatory features in laboratory tests and imaging findings, and recovering all functional indexes. Anti-TNF drugs have radically changed the evolution of radiographic progression in peripheral joints; the first disappointing data concerning their efficacy on new bone formation of axial SpA has been recently challenged by studies enrolling patients who have been earlier diagnosed and treated. The opportunity to extend the interval of administration or to reduce the doses of anti-TNF agents can favourably influence the costs. Ustekinumab, the first non-anti-TNF biologic drug commercialised for psoriatic arthritis, offers new chances to patients that are unresponsive to anti-TNF.

Prehispanic Functional Foods and Nutraceuticals in the Treatment of Dyslipidemia Associated to Cardiovascular Disease: a Mini-Review.

PubMed

Ríos-Hoyo, Alejandro; Romo-Araiza, Alejandra; Meneses-Mayo, Marcos; Guttiérrez-Salmeán, Gabriela

2017-01-27

Dyslipidemia is an important modifi able risk factor for cardiovascular and metabolic diseases, which are responsible for a large number of mortality and disability cases around the globe. Different strategies have been used within the treatment of dyslipidemia, including lifestyle modifi cations, pharmacologic therapy, as well as functional foods and nutraceuticals. Functional foods have been used worldwide since ancient times, particularly, the prehispanic civilizations utilized several as medicinal foods. In the current pandemic of dyslipidemia as well as the nutritional transition, particularly in Latin America, the use of native functional foods represents an attractive target for the treatment and/ or prevention of these conditions. In this mini-review, evidence regarding different functional foods such as cacao, amaranth, chia, nopal, spirulina, as well as their nutraceutical compounds, including fl avonoids, omega-3 PUFAs, fi ber, prebiotics, lovastatin, c-phycocyanin, among others, and their mechanism of action are presented and discussed. Although such foods certainly are considered as attractive potential agents to target dyslipidemia thus decrease the associated cardiometabolic risk, we conclude that for most of the presented functional foods there is currently not enough evidence to support its recommendation and every-day use.

A Single Dose of Modified Vaccinia Ankara expressing Ebola Virus Like Particles Protects Nonhuman Primates from Lethal Ebola Virus Challenge.

PubMed

Domi, Arban; Feldmann, Friederike; Basu, Rahul; McCurley, Nathanael; Shifflett, Kyle; Emanuel, Jackson; Hellerstein, Michael S; Guirakhoo, Farshad; Orlandi, Chiara; Flinko, Robin; Lewis, George K; Hanley, Patrick W; Feldmann, Heinz; Robinson, Harriet L; Marzi, Andrea

2018-01-16

Ebola virus (EBOV), isolate Makona, was the causative agent of the West African epidemic devastating predominantly Guinea, Liberia and Sierra Leone from 2013-2016. While several experimental vaccine and treatment approaches have been accelerated through human clinical trials, there is still no approved countermeasure available against this disease. Here, we report the construction and preclinical efficacy testing of a novel recombinant modified vaccinia Ankara (MVA)-based vaccine expressing the EBOV-Makona glycoprotein GP and matrix protein VP40 (MVA-EBOV). GP and VP40 form EBOV-like particles and elicit protective immune responses. In this study, we report 100% protection against lethal EBOV infection in guinea pigs after prime/boost vaccination with MVA-EBOV. Furthermore, this MVA-EBOV protected macaques from lethal disease after a single dose or prime/boost vaccination. The vaccine elicited a variety of antibody responses to both antigens, including neutralizing antibodies and antibodies with antibody-dependent cellular cytotoxic activity specific for GP. This is the first report that a replication-deficient MVA vector can confer full protection against lethal EBOV challenge after a single dose vaccination in macaques.

Gray Matter Pathology in MS: Neuroimaging and Clinical Correlations

PubMed Central

Honce, Justin Morris

2013-01-01

It is abundantly clear that there is extensive gray matter pathology occurring in multiple sclerosis. While attention to gray matter pathology was initially limited to studies of autopsy specimens and biopsies, the development of new MRI techniques has allowed assessment of gray matter pathology in vivo. Current MRI techniques allow the direct visualization of gray matter demyelinating lesions, the quantification of diffuse damage to normal appearing gray matter, and the direct measurement of gray matter atrophy. Gray matter demyelination (both focal and diffuse) and gray matter atrophy are found in the very earliest stages of multiple sclerosis and are progressive over time. Accumulation of gray matter damage has substantial impact on the lives of multiple sclerosis patients; a growing body of the literature demonstrates correlations between gray matter pathology and various measures of both clinical disability and cognitive impairment. The effect of disease modifying therapies on the rate accumulation of gray matter pathology in MS has been investigated. This review focuses on the neuroimaging of gray matter pathology in MS, the effect of the accumulation of gray matter pathology on clinical and cognitive disability, and the effect of disease-modifying agents on various measures of gray matter damage. PMID:23878736

Composite materials with improved phyllosilicate dispersion

DOEpatents

Chaiko, David J.

2004-09-14

The present invention provides phyllosilicates edge modified with anionic surfactants, composite materials made from the edge modified phyllosilicates, and methods for making the same. In various embodiments the phyllosilicates are also surface-modified with hydrophilic lipophilic balance (HLB) modifying agents, polymeric hydrotropes, and antioxidants. The invention also provides blends of edge modified phyllosilicates and semicrystalline waxes. The composite materials are made by dispersing the edge modified phyllosilicates with polymers, particularly polyolefins and elastomers.

Prevalence of cardiovascular disease and major risk factors in patients with rheumatoid arthritis: a multinational cross-sectional study.

PubMed

Pappas, Dimitrios A; Nyberg, Fredrik; Kremer, Joel M; Lampl, Kathy; Reed, George W; Horne, Laura; Ho, Meilien; Onofrei, Alina; Malaviya, Anand N; Rillo, Oscar L; Radominski, Sebastiao C; Gal, Janos; Gibofsky, Allan; Popkova, Tatiana V; Laurindo, Leda; Kerzberg, Eduardo M; Zahora, Roman; Pons-Estel, Bernado A; Curtis, Jeffrey R; Furst, Daniel E; Greenberg, Jeffrey D

2018-04-25

To compare the prevalence of cardiovascular disease (CVD) and major CVD risk factors among rheumatoid arthritis (RA) patients enrolled in a large US and multinational registry. We compared CVD and CVD risk factor prevalence from 11 countries enrolled in the CORRONA US and CORRONA International registries; patients from the 10 ex-US participating countries were grouped by region (Eastern Europe, Latin America, and India). Unadjusted summary data were presented for demographics and disease characteristics; comparisons for prevalence of CVD risk factors and CVD were age/gender standardized to the age/gender distribution of the US enrolled patients. Overall, 25,987 patients were included in this analysis. Compared to patients from the ex-US regions, US participants had longer disease duration and lower disease activity, yet were more likely to receive a biologic agent. Additionally, CORRONA US participants had the highest body mass index (BMI). Enrolled patients in India had the lowest BMI, were more rarely smokers, and had a low prevalence of hyperlipidemia, hypertension, and prior CVD compared to the US and other ex-US regions. Participants from Eastern Europe had a higher prevalence of hypertension and hyperlipidemia and highest prevalence of all manifestations of CVD. Differences in the prevalence of both CVD and major CVD risk factors were observed across the four regions investigated. Observed differences may be influenced by variations in both non-modifiable/modifiable characteristics of patient populations, and may contribute to heterogeneity on the observed safety of investigational and approved therapies in studies involving RA patients from different origins.

Endoplasmic Reticulum Ca2+ Handling in Excitable Cells in Health and Disease

PubMed Central

Mattson, Mark P.

2011-01-01

The endoplasmic reticulum (ER) is a morphologically and functionally diverse organelle capable of integrating multiple extracellular and internal signals and generating adaptive cellular responses. It plays fundamental roles in protein synthesis and folding and in cellular responses to metabolic and proteotoxic stress. In addition, the ER stores and releases Ca2+ in sophisticated scenarios that regulate a range of processes in excitable cells throughout the body, including muscle contraction and relaxation, endocrine regulation of metabolism, learning and memory, and cell death. One or more Ca2+ ATPases and two types of ER membrane Ca2+ channels (inositol trisphosphate and ryanodine receptors) are the major proteins involved in ER Ca2+ uptake and release, respectively. There are also direct and indirect interactions of ER Ca2+ stores with plasma membrane and mitochondrial Ca2+-regulating systems. Pharmacological agents that selectively modify ER Ca2+ release or uptake have enabled studies that revealed many different physiological roles for ER Ca2+ signaling. Several inherited diseases are caused by mutations in ER Ca2+-regulating proteins, and perturbed ER Ca2+ homeostasis is implicated in a range of acquired disorders. Preclinical investigations suggest a therapeutic potential for use of agents that target ER Ca2+ handling systems of excitable cells in disorders ranging from cardiac arrhythmias and skeletal muscle myopathies to Alzheimer disease. PMID:21737534

A Blood-Brain Barrier (BBB) Disrupter Is Also a Potent α-Synuclein (α-syn) Aggregation Inhibitor

PubMed Central

Shaltiel-Karyo, Ronit; Frenkel-Pinter, Moran; Rockenstein, Edward; Patrick, Christina; Levy-Sakin, Michal; Schiller, Abigail; Egoz-Matia, Nirit; Masliah, Eliezer; Segal, Daniel; Gazit, Ehud

2013-01-01

The development of disease-modifying therapy for Parkinson disease has been a main drug development challenge, including the need to deliver the therapeutic agents to the brain. Here, we examined the ability of mannitol to interfere with the aggregation process of α-synuclein in vitro and in vivo in addition to its blood-brain barrier-disrupting properties. Using in vitro studies, we demonstrated the effect of mannitol on α-synuclein aggregation. Although low concentration of mannitol inhibited the formation of fibrils, high concentration significantly decreased the formation of tetramers and high molecular weight oligomers and shifted the secondary structure of α-synuclein from α-helical to a different structure, suggesting alternative potential pathways for aggregation. When administered to a Parkinson Drosophila model, mannitol dramatically corrected its behavioral defects and reduced the amount of α-synuclein aggregates in the brains of treated flies. In the mThy1-human α-synuclein transgenic mouse model, a decrease in α-synuclein accumulation was detected in several brain regions following treatment, suggesting that mannitol promotes α-synuclein clearance in the cell bodies. It appears that mannitol has a general neuroprotective effect in the transgenic treated mice, which includes the dopaminergic system. We therefore suggest mannitol as a basis for a dual mechanism therapeutic agent for the treatment of Parkinson disease. PMID:23637226

Pediatric chronic nonbacterial osteomyelitis.

PubMed

Borzutzky, Arturo; Stern, Sara; Reiff, Andreas; Zurakowski, David; Steinberg, Evan A; Dedeoglu, Fatma; Sundel, Robert P

2012-11-01

Little information is available concerning the natural history and optimal treatment of chronic nonbacterial osteomyelitis (CNO). We conducted a retrospective review to assess the clinical characteristics and treatment responses of a large cohort of pediatric CNO patients. Children diagnosed with CNO at 3 tertiary care centers in the United States between 1985 and 2009 were identified. Their charts were reviewed, and clinical, laboratory, histopathologic, and radiologic data were extracted. Seventy children with CNO (67% female patients) were identified. Median age at onset was 9.6 years (range 3-17), and median follow-up was 1.8 years (range 0-13). Half of the patients had comorbid autoimmune diseases, and 49% had a family history of autoimmunity. Patients with comorbid autoimmune diseases had more bone lesions (P < .001), higher erythrocyte sedimentation rate (P < .05), and higher use of second line therapy (P = .02). Treatment response to nonsteroidal antiinflammatory drugs (NSAIDs), sulfasalazine, methotrexate, tumor necrosis factor α inhibitors, and corticosteroids was evaluated. The only significant predictor of a positive treatment response was the agent used (P < .0001). Estimated probability of response was 57% for NSAIDs, 66% for sulfasalazine, 91% for methotrexate, 91% for tumor necrosis factor α inhibitors, and 95% for corticosteroids. In a US cohort of 70 children with CNO, coexisting autoimmunity was a risk factor for multifocal involvement and treatment with immunosuppressive agents. Disease-modifying antirheumatic drugs and biologics were more likely to lead to clinical improvement than NSAIDs.

Nanodrugs to target articular cartilage: An emerging platform for osteoarthritis therapy.

PubMed

Bottini, Massimo; Bhattacharya, Kunal; Fadeel, Bengt; Magrini, Andrea; Bottini, Nunzio; Rosato, Nicola

2016-02-01

Cartilage undergoes drastic structural changes during the development of osteoarthritis and cannot heal itself due to a defective chondrocyte response. Thus, much effort has been invested in the development of disease modifying drugs able to block key mediators within the cartilage matrix and biochemical pathways inside chondrocytes. However, the delivery of therapeutic agents into cartilage is ineffective. This has led to the use of cartilage-targeted nanodrugs to accumulate therapeutic agents into specific cartilage sub-compartments. This review will describe the nanodrugs targeted to specific components of cartilage matrix to generate drug reservoirs within the cartilage. The nanodrugs used as chondrocyte-specific gene delivery systems are also described. Although the use of cartilage-targeted nanodrugs in osteoarthritis is still in its infancy, these studies lay the foundation for the development of novel approaches for preventing the progression of cartilage breakdown and improving the quality of life of patients with osteoarthritis. Osteoarthritis is a degeneration of joint cartilage, which affects a large number of aging people. Current therapy for disease modification is often suboptimal. Recent research in nanomedicine has led to the design and use of nanodrugs with the aim to help reverse the disease process. In this comprehensive review, the authors described and discussed various nanodrugs in the hope that newer drugs could be discovered in the future. Copyright © 2015 Elsevier Inc. All rights reserved.

Multifunctional agents for concurrent imaging and therapy in cardiovascular disease

PubMed Central

McCarthy, Jason R.

2010-01-01

The development of agents for the simultaneous detection and treatment of disease has recently gained significant attention. These multifunctional theranostic agents posses a number of advantages over their monofunctional counterparts, as they potentially allow for the concomitant determination of agent localization, release, and efficacy. Whereas the development of these agents for use in cancers has received the majority of the attention, their use in cardiovascular disease is steadily increasing. As such, this review summarized some of the most poignant recent advances in the development of theranostic agents for the treatment of this class of diseases. PMID:20654664

New pharmacological strategies in rheumatic diseases.

PubMed

Schiotis, R E; Buzoianu, A D; Mureșanu, D F; Suciu, S

2016-01-01

Targeting the pathogenic pathway of chronic inflammation represents an unmet challenge for controlling disease activity, preventing functional disability, and maintaining an adequate quality of life in patients with rheumatic diseases. Abatacept, a novel molecule that inhibits co-stimulation signal, induces an inhibitory effect on the T-cells. This will further interfere with the activity of several cell lines, leading to the normalization of the immune response. In the latest years, abatacept has been extensively investigated in studies of rheumatoid arthritis for which it was recently approved as a second line biologic treatment in Romania. This review presents the clinical efficacy of abatacept in several rheumatic diseases and highlights the safety profile of this biological agent. Abbreviations : ACR = American College of Rheumatology, ADR = Adverse drug reaction, APC = antigen presenting cell, ApS = psoriatic arthritis, CRP = C reactive protein, CTLA-4 = Cytotoxic T-Cell Lymphocyte Antigen-4, DAS = Disease activity score, DMARDs = Disease modifying antirheumatic drugs, EMA = European Medicine Agency, EULAR = European League Against Rheumatism, FDA = Food and Drugs Administration, HBV = Hepatitis B virus, JIA = Juvenile Idiopathic Arthritis, LDA = low disease activity (LDA), MRI = magnetic resonance imaging (MRI), MTX = methotrexate, RA = rheumatoid arthritis, RCT = randomized controlled trial, SS = Sjogren's syndrome, TCR = T cell receptor.

Textural and sensory properties of low fat pork sausages with added hydrated oatmeal and tofu as texture-modifying agents.

PubMed

Yang, Han-Sul; Choi, Sung-Gil; Jeon, Jin-Tae; Park, Gu-Boo; Joo, Seon-Tea

2007-02-01

Low fat sausages were prepared with added hydrated oatmeal or tofu as texture-modifying agents at levels of 10%, 15%, and 25% (w/w), respectively. The effects of the type and level of texture-modifying agents on the physical and sensory properties of low fat sausages were investigated. The water-holding capacity in sausage products increased by increasing the hydrated oatmeal level, but no significant differences was observed by the addition of tofu. The higher level of the agents produced a sausage product with less cooking loss and with a softer texture. The moisture absorption measurements suggest that the decrease in hardness of oatmeal-added sausage products may be due to the higher water-retention properties of oatmeal in response to heat treatment, while that of tofu-added sausage products may be associated with a weaker internal structure of tofu than the pork loin. The sensory evaluations indicated that the greatest overall acceptability in a low fat sausage was attained when the hydrated oatmeal or tofu were at their 15% addition level, respectively.

A modified Galam’s model for word-of-mouth information exchange

NASA Astrophysics Data System (ADS)

Ellero, Andrea; Fasano, Giovanni; Sorato, Annamaria

2009-09-01

In this paper we analyze the stochastic model proposed by Galam in [S. Galam, Modelling rumors: The no plane Pentagon French hoax case, Physica A 320 (2003), 571-580], for information spreading in a ‘word-of-mouth’ process among agents, based on a majority rule. Using the communications rules among agents defined in the above reference, we first perform simulations of the ‘word-of-mouth’ process and compare the results with the theoretical values predicted by Galam’s model. Some dissimilarities arise in particular when a small number of agents is considered. We find motivations for these dissimilarities and suggest some enhancements by introducing a new parameter dependent model. We propose a modified Galam’s scheme which is asymptotically coincident with the original model in the above reference. Furthermore, for relatively small values of the parameter, we provide a numerical experience proving that the modified model often outperforms the original one.

Model-based Utility Functions

NASA Astrophysics Data System (ADS)

Hibbard, Bill

2012-05-01

Orseau and Ring, as well as Dewey, have recently described problems, including self-delusion, with the behavior of agents using various definitions of utility functions. An agent's utility function is defined in terms of the agent's history of interactions with its environment. This paper argues, via two examples, that the behavior problems can be avoided by formulating the utility function in two steps: 1) inferring a model of the environment from interactions, and 2) computing utility as a function of the environment model. Basing a utility function on a model that the agent must learn implies that the utility function must initially be expressed in terms of specifications to be matched to structures in the learned model. These specifications constitute prior assumptions about the environment so this approach will not work with arbitrary environments. But the approach should work for agents designed by humans to act in the physical world. The paper also addresses the issue of self-modifying agents and shows that if provided with the possibility to modify their utility functions agents will not choose to do so, under some usual assumptions.

Fe3O4-based PLGA nanoparticles as MR contrast agents for the detection of thrombosis

PubMed Central

Liu, Jia; Xu, Jie; Zhou, Jun; Zhang, Yu; Guo, Dajing; Wang, Zhigang

2017-01-01

Thrombotic disease is a great threat to human health, and early detection is particularly important. Magnetic resonance (MR) molecular imaging provides noninvasive imaging with the potential for early disease diagnosis. In this study, we developed Fe3O4-based poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) surface-modified with a cyclic Arg-Gly-Asp (cRGD) peptide as an MR contrast agent for the detection of thrombosis. The physical and chemical characteristics, biological toxicity, ability to target thrombi, and biodistribution of the NPs were studied. The Fe3O4-PLGA-cRGD NPs were constructed successfully, and hematologic and pathologic assays indicated no in vivo toxicity of the NPs. In a rat model of FeCl3-induced abdominal aorta thrombosis, the NPs readily and selectively accumulated on the surface of the thrombosis and under vascular endothelial cells ex vivo and in vivo. In the in vivo experiment, the biodistribution of the NPs suggested that the NPs might be internalized by the macrophages of the reticuloendothelial system in the liver and the spleen. The T2 signal decreased at the mural thrombus 10 min after injection and then gradually increased until 50 min. These results suggest that the NPs are suitable for in vivo molecular imaging of thrombosis under high shear stress conditions and represent a very promising MR contrast agent for sensitive and specific detection of thrombosis. PMID:28223802

Postinoculation PMPA Treatment, but Not Preinoculation Immunomodulatory Therapy, Protects against Development of Acute Disease Induced by the Unique Simian Immunodeficiency Virus SIVsmmPBj

PubMed Central

Hodge, Shekema; de Rosayro, Juliette; Glenn, Amanda; Ojukwu, Ifeoma C.; Dewhurst, Stephen; McClure, Harold M.; Bischofberger, Norbert; Anderson, Daniel C.; Klumpp, Sherry A.; Novembre, Francis J.

1999-01-01

The fatal disease induced by SIVsmmPBj4 clinically resembles endotoxic shock, with the development of severe gastrointestinal disease. While the exact mechanism of disease induction has not been fully elucidated, aspects of virus biology suggest that immune activation contributes to pathogenesis. These biological characteristics include induction of peripheral blood mononuclear cell (PBMC) proliferation, upregulation of activation markers and Fas ligand expression, and increased levels of apoptosis. To investigate the role of immune activation and viral replication on disease induction, animals infected with SIVsmmPBj14 were treated with one of two drugs: FK-506, a potent immunosuppressive agent, or PMPA, a potent antiretroviral agent. While PBMC proliferation was blocked in vitro with FK-506, pig-tailed macaques treated preinoculation with FK-506 were not protected from acutely lethal disease. However, these animals did show some evidence of modulation of immune activation, including reduced levels of CD25 antigen and FasL expression, as well as lower tissue viral loads. In contrast, macaques treated postinoculation with PMPA were completely protected from the development of acutely lethal disease. Treatment with PMPA beginning as late as 5 days postinfection was able to prevent the PBj syndrome. Plasma and cellular viral loads in PMPA-treated animals were significantly lower than those in untreated controls. Although PMPA-treated animals showed acute lymphopenia due to SIVsmmPBj14 infection, cell subset levels subsequently recovered and returned to normal. Based upon subsequent CD4+ cell counts, the results suggest that very early treatment following retroviral infection can have a significant effect on modifying the subsequent course of disease. These results also suggest that viral replication is an important factor involved in PBJ-induced disease. These studies reinforce the idea that the SIVsmmPBj model system is useful for therapy and vaccine testing. PMID:10482616

Seaweeds as Preventive Agents for Cardiovascular Diseases: From Nutrients to Functional Foods

PubMed Central

Cardoso, Susana M.; Pereira, Olívia R.; Seca, Ana M. L.; Pinto, Diana C. G. A.; Silva, Artur M. S.

2015-01-01

Being naturally enriched in key nutrients and in various health-promoting compounds, seaweeds represent promising candidates for the design of functional foods. Soluble dietary fibers, peptides, phlorotannins, lipids and minerals are macroalgae’s major compounds that can hold potential in high-value food products derived from macroalgae, including those directed to the cardiovascular-health promotion. This manuscript revises available reported data focusing the role of diet supplementation of macroalgae, or extracts enriched in bioactive compounds from macroalgae origin, in targeting modifiable markers of cardiovascular diseases (CVDs), like dyslipidemia, oxidative stress, vascular inflammation, hypertension, hypercoagulability and activation of the sympathetic and renin-angiotensin systems, among others. At last, the review also describes several products that have been formulated with the use of whole macroalgae or extracts, along with their claimed cardiovascular-associated benefits. PMID:26569268

Rheumatoid Arthritis in Sickle-Cell Population: Pathophysiologic Insights, Clinical Evaluation and Management

PubMed Central

McFarlane, Isabel M; Ozeri, David J; Saperstein, Yair; Alvarez, Milena Rodriguez; Leon, Su Zhaz; Koci, Kristaq; Francis, Sophia; Singh, Soberjot; Salifu, Moro

2018-01-01

The advent of hydroxyurea and advanced medical care, including immunizations has led to improved survival among patients with Sickle Cell Disease (SCD). This prolonged survival however, introduces a chronic inflammatory disorder, Rheumatoid Arthritis (RA), which presents at a relatively older age and is rarely reported among SCD patients. In this review, we highlight the epidemiological association of SCD-RA and discuss the underlying common pathogenetic mechanisms, such as endothelial dysfunction, the role of inflammatory cytokines and oxidative stress. We also point to the difficulties in ascertaining the clinical diagnosis of RA in SCD patients. Finally, we provide rationale for therapeutic options available for RA and the challenges in the management of these patients with agents that are known to increase the risk of infection and immunosuppression such as steroids, disease modifying anti-rheumatic drugs and biologics. PMID:29375934

[Life style: instrument in health promotion programs].

PubMed

Jiménez, D

1993-05-01

Non communicable diseases are increasing in third world countries, including Chile. Life style is one of the principal factors influencing this increase. Therefore programs and health strategies to modify the population life styles are needed. The programs developed to change life styles depend on the medical sociocultural scenery and the concept becomes outstanding when disease prevention is replaced by health promotion. The requirements for the application of the concept of life style in health promotion plans and fostering of healthy life styles are: 1) Training in behavioral epidemiology. 2) Election of a biopsychosocial concept of life style. 3) Identify the predominant scenery and target population. 4) Choose the appropriate educational methodologies to change behaviors. 5) Formalize strategies according to the boundaries where the program is applied. 6) Specify the qualifying requisites of the change agents, health promoters and program operators.

The California Oak Disease and Arthropod (CODA) Database

Treesearch

Tedmund J. Swiecki; Elizabeth A. Bernhardt; Richard A. Arnold

1997-01-01

The California Oak Disease and Arthropod (CODA) host index database is a compilation of information on agents that colonize or feed on oaks in California. Agents in the database include plant-feeding insects and mites, nematodes, microorganisms, viruses, and abiotic disease agents. CODA contains summarized information on hosts, agents, information sources, and the...

A Virtual Laboratory for Digital Signal Processing

ERIC Educational Resources Information Center

Dow, Chyi-Ren; Li, Yi-Hsung; Bai, Jin-Yu

2006-01-01

This work designs and implements a virtual digital signal processing laboratory, VDSPL. VDSPL consists of four parts: mobile agent execution environments, mobile agents, DSP development software, and DSP experimental platforms. The network capability of VDSPL is created by using mobile agent and wrapper techniques without modifying the source code…

9 CFR 121.3 - VS select agents and toxins.

Code of Federal Regulations, 2010 CFR

2010-01-01

... genetically modified. (d) VS select agents or toxins that meet any of the following criteria are excluded from... AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS POSSESSION, USE, AND... recombinant organisms: (1) Nucleic acids that can produce infectious forms of any of the select agent viruses...

75 FR 22189 - Obtaining Information From the Postal Service

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-27

... rules governing (1) the issuance of subpoenas requiring officers, employees, agents, or contractors of... transmitted to third-party agents or contractors. Rule 14 is modified to revise the Postal Service's... officers and employees), to persons or entities currently acting as agents for the Postal Service, or to...

Screening for Natural Chemoprevention Agents that Modify Human Keap1

PubMed Central

Hu, Chenqi; Nikolic, Dejan; Eggler, Aimee L.; Mesecar, Andrew D.; van Breemen, Richard B.

2012-01-01

Upregulation of cytoprotective enzymes by therapeutic agents to prevent damage by reactive oxygen species and xenobiotic electrophiles is a strategy for cancer chemoprevention. The Kelch-like ECH-associated protein 1 (Keap1) and its binding partner, transcription factor NF-E2-related factor-2 (Nrf2), are chemoprevention targets because of their role in regulating the antioxidant response element (ARE) in response to oxidative stress and exposure to electrophiles. Modification of the sensor protein Keap1 by electrophiles such as the isothiocyanate sulforaphane can direct Nrf2 accumulation in the nucleus and subsequent ARE activation. Since our previous matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF MS)-based screening method to discover natural products that modify Keap1 does not detect covalent modification of Keap1 by some highly reversible agents such as sulforaphane, a more sensitive screening assay was developed. In this new assay, electrophiles that have reversibly modified Keap1 can be released, trapped and detected as β-mercaptoethanol adducts by mass spectrometry. Isoliquiritigenin and sulforaphane, known ARE activators that target Keap1, were used to validate the assay. To determine the ability of the assay to identify electrophiles in complex matrixes that modify Keap1, sulforaphane was spiked into a cocoa extract, and LC-MS/MS using high resolution mass spectrometry with accurate mass measurement was used to identify β-mercaptoethanol adducts of sulforaphane that had been released from Keap1. This screening assay permits identification of potential chemoprevention agents in complex natural product mixtures that reversibly modify Keap1 but cannot be detected using MALDI-TOF MS. PMID:22074792

[To Protect Corneal Transparency against Diseases].

PubMed

Usui, Tomohiko

2016-03-01

To protect corneal transparency, we tried to develop a new therapeutic strategy for corneal neovascularization, corneal scar, and TGFBI-related corneal dystrophy using nucleic acid drug. 1. The expression of angiopietin-like protein 2 (Angptl2) markedly increased in the neovascularized corneas compared to the normal cornea, and Angtpl2 was(a potent inducer of inflammatory corneal neovascularization. We have produced a single-stranded proline-modified short hairpin anti-Angptl2 ribonucleric acid interference (RNAi) molecule that is carried in a lipid nanoparticle for topical application. We have found this agent can penetrate all layers of the cornea. Angptl2 mRNA expression and corneal neovascularization were inhibited in a mouse alkari injury model by topical application of this agent. Thus, this modified RNAi agent is a new topical formulation for use against corneal neovascularization and scar. 2. Human umbilical vein endothelial cells (HUVECs) were cultured with human corneal keratocytes under serum-free conditions. We performed microarray gene-expression analysis in the coculture system and selected angiopoietin-like protein 7 (Angptl7). In vivo, intrastromal injections of an anti-Angptl7 RNAi agent into the avascular corneal stroma of mice resulted in the growth of blood vessels. Further, we examined the effects of Angptl7 on corneal nerves using culture rat trigeminal cells and this molecule had neurotrophic property on the cornea. Thus, Angpt17 is a unique molecule, which contain its bilateral character (anti-angiogenic and neurotrophic) in the cornea; an agonistic nucleic acid drug for Angptl7 may be a new therapeutic tool for protecting corneal transparency. 3. We examined local gene editing for TGFBI-related corneal dystrophy using CRISPR-Cas9 mediated homology directed repair (HDR). Cultured corneal keratocytes were obtained from a patient of R124H granular dystrophy. The R124H gene arrangement was corrected by a tranfection of guide RNA and HDR repair template single strand DNA in vitro. Thus, CRISPR-Cas9 medi-ated HDR could be a future radical treatment for TGFBI-related corneal dystrophy.

Anti-thrombogenicity and permeability of polyethersulfone hollow fiber membrane with sulfonated alginate toward blood purification.

PubMed

Salimi, Esmaeil; Ghaee, Azadeh; Ismail, Ahmad Fauzi; Karimi, Majid

2018-04-30

The main aim of this study was to evaluate the suitability of sulfonated alginate as a modifying agent to enhance the hemocompatibility of self-fabricated polyethersulfone (PES) hollow fiber membrane for blood detoxification. Sodium alginate was sulfonated with a degree of 0.6 and immobilized on the membrane via surface amination and using glutaraldehyde as cross-linking agent. Coating layer not only improved the membrane surface hydrophilicity, but also induced -39.2 mV negative charges on the surface. Water permeability of the modified membrane was enhanced from 67 to 95 L/m 2 ·h·bar and flux recovery ratio increased more than 2-fold. Furthermore, the modified membrane presented higher platelet adhesion resistance (reduced by more than 90%) and prolonged coagulation time (35 s for APTT and 14 s for PT) in comparison with the pristine PES hollow fiber membrane, which verified the improved anti-thrombogenicity of the modified membrane. On the other hand, obtained membrane after 3 h coating could remove up-to 60% of the uremic toxins. According to the obtained data, sulfonated alginate can be a promising modifying agent for the future blood-contacting membrane and specially blood purification issues. Copyright © 2018 Elsevier B.V. All rights reserved.

Triple therapy for age-related macular degeneration.

PubMed

Augustin, Albert

2009-06-01

Choroidal neovascularization is a hallmark sign of wet age-related macular degeneration (AMD) but it is not an isolated feature. Several processes are likely to contribute to the fibrotic scarring and vision loss that accompanies progressive disease. In a case series, a triple therapy approach to wet AMD was based on the goals of halting choroidal neovascularization, controlling the inflammatory response, and modifying proliferative factors. To address each of these goals, respectively, patients received photodynamic therapy, bevacizumab, and the steroid dexamethasone. The encouraging rate of response, including significant improvements in visual acuity, is consistent with the combined activities of these agents and provides the basis for more definitive studies.

7 CFR 331.3 - PPQ select agents and toxins.

Code of Federal Regulations, 2012 CFR

2012-01-01

...) Select agents and toxins listed in paragraph (b) of this section that have been genetically modified. (d... variegated chlorosis strain). (c) Genetic elements, recombinant nucleic acids, and recombinant organisms: (1...

42 CFR 73.4 - Overlap select agents and toxins.

Code of Federal Regulations, 2010 CFR

2010-10-01

... genetically modified. (d) Overlap select agents or toxins that meet any of the following criteria are excluded... Equine Encephalitis virus (c) Genetic Elements, Recombinant Nucleic Acids, and Recombinant Organisms: (1...

7 CFR 331.3 - PPQ select agents and toxins.

Code of Federal Regulations, 2010 CFR

2010-01-01

...) Select agents and toxins listed in paragraph (b) of this section that have been genetically modified. (d... variegated chlorosis strain). (c) Genetic elements, recombinant nucleic acids, and recombinant organisms: (1...

Use of Attenuated but Metabolically Competent Salmonella as a Probiotic To Prevent or Treat Salmonella Infection

PubMed Central

Sabag-Daigle, Anice; Blunk, Henry M.; Gonzalez, Juan F.; Steidley, Brandi L.; Boyaka, Prosper N.

2016-01-01

Salmonella enterica is among the most burdensome of foodborne disease agents. There are over 2,600 serovars that cause a range of disease manifestations ranging from enterocolitis to typhoid fever. While there are two vaccines in use in humans to protect against typhoid fever, there are none that prevent enterocolitis. If vaccines preventing enterocolitis were to be developed, they would likely protect against only one or a few serovars. In this report, we tested the hypothesis that probiotic organisms could compete for the preferred nutrient sources of Salmonella and thus prevent or treat infection. To this end, we added the fra locus, which encodes a utilization pathway for the Salmonella-specific nutrient source fructose-asparagine (F-Asn), to the probiotic bacterium Escherichia coli Nissle 1917 (Nissle) to increase its ability to compete with Salmonella in mouse models. We also tested a metabolically competent, but avirulent, Salmonella enterica serovar Typhimurium mutant for its ability to compete with wild-type Salmonella. The modified Nissle strain became more virulent and less able to protect against Salmonella in some instances. On the other hand, the modified Salmonella strain was safe and effective in preventing infection with wild-type Salmonella. While we tested for efficacy only against Salmonella Typhimurium, the modified Salmonella strain may be able to compete metabolically with most, if not all, Salmonella serovars, representing a novel approach to control of this pathogen. PMID:27185789

Potential Linkage Between Cerebrovascular Diseases and Metabolic Syndrome.

PubMed

Jabir, Nasimudeen R; Firoz, Chelapram Kandy; Khan, Mohd Shahnawaz; Zaidi, Syed Kashif; Ashraf, Ghulam Md; Shakil, Shazi; Kamal, Mohammad Amjad; Tabrez, Shams

2017-01-01

Cerebrovascular disease (CD) and metabolic syndrome (MetS) are two devastating health dilemma that continues to be a potential contributor to disability and mortality in human population all across the world. Scientific data clearly shows several mechanistic similarities between these two co-existing and interlinked conditions. The linkage exacerbates ongoing patho-physiological condition towards more lethal events. In view of the presence of modifiable risk factors in both CD and MetS, their management holds potential therapeutic value. Hence, developing common treatment strategies for these diseases could involve common molecular agents. In this communication, we have summarized some of the common pathological conditions viz. abdominal obesity, insulin resistance, dyslipidemia, hypertension, and endothelial dysfunction that further deteriorate existing homeostasis in CD and MetS. Based on our article, it is advocated that substantial improvements in novel multi-targeted drug discovery could provide the effective treatment methods in order to avoid the fatal complications related with CD and MetS. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

[Current treatment of rheumatoid arthritis].

PubMed

Carli, P; Landais, C; Aletti, M; Cournac, J-M; Poisnel, E; Paris, J-F

2009-12-01

Over the past 10 years, the management of rheumatoid arthritis has been revolutionized. Early diagnosis is essential and should allow an early initiation of disease modifying anti-rheumatic drugs (DMARD), if possible within the first 3 three months after disease onset, aiming at disease remission and the best long-term prognosis. Recommendations for the prescription of synthetic and biologic DMARD (mainly anti-TNFalpha agents) are available since September 2007 [6] by HAS in France. The great efficacy of these drugs has been established from many clinical trials including tens of thousands of patients. However, severe adverse side effects may occur (allergy, tuberculosis, opportunistic infections, demyelination) and rheumatologists should remain vigilant. Global care of the patient includes prescription of pharmacologic and non-pharmacologic treatments (education, physical treatment, ergotherapy, psychotherapy, surgery). A good coordination between all specialists is required. Screening and treatment of extra-articular manifestations, prevention of infections, osteoporosis and cardiovascular complications are essential to allow a better long-term prognosis, and reduce disability and mortality of rheumatoid arthritis.

Surfactant-modified zeolite can protect drinking water wells from viruses and bacteria

NASA Astrophysics Data System (ADS)

Schulze-Makuch, Dirk; Pillai, Suresh D.; Guan, Huade; Bowman, Robert; Couroux, Emile; Hielscher, Frank; Totten, James; Espinosa, Isabell Y.; Kretzschmar, Thomas

Septic tanks, sewage effluents, and landfills can release microbial pathogens into groundwater. This problem is amplified in the so-called colonias along the U.S.-Mexico border and other low-income areas around the world that have no public sewage systems. The result is often outbreaks of groundwater-associated disease for which enteric viruses and bacteria, spread via a fecal-oral route, are responsible. However, due to difficulties and limitations in detection and surveillance of disease outbreaks, the causative agents for more than 50% of the outbreaks are unknown, though the clinical features suggest a viral etiology for most of those cases [U.S. Centers for Disease Control and Prevention, 1993]. Enteric pathogens such as E coli 0157:H7, Campylobacter, Enteroviruses, Hepatitis A virus, and caliciviruses have been responsible for groundwater-related microbial infections in humans. Inexpensive solutions to this problem are urgently needed. The recent threat of bio-terrorism and concerns about the safety of drinking water supplies further add to that urgency.

Paratransgenic Control of Vector Borne Diseases

PubMed Central

Hurwitz, Ivy; Fieck, Annabeth; Read, Amber; Hillesland, Heidi; Klein, Nichole; Kang, Angray; Durvasula, Ravi

2011-01-01

Conventional methodologies to control vector borne diseases with chemical pesticides are often associated with environmental toxicity, adverse effects on human health and the emergence of insect resistance. In the paratransgenic strategy, symbiotic or commensal microbes of host insects are transformed to express gene products that interfere with pathogen transmission. These genetically altered microbes are re-introduced back to the insect where expression of the engineered molecules decreases the host's ability to transmit the pathogen. We have successfully utilized this strategy to reduce carriage rates of Trypanosoma cruzi, the causative agent of Chagas disease, in the triatomine bug, Rhodnius prolixus, and are currently developing this methodology to control the transmission of Leishmania donovani by the sand fly Phlebotomus argentipes. Several effector molecules, including antimicrobial peptides and highly specific single chain antibodies, are currently being explored for their anti-parasite activities in these two systems. In preparation for eventual field use, we are actively engaged in risk assessment studies addressing the issue of horizontal gene transfer from the modified bacteria to environmental microbes. PMID:22110385

Generation of improved humanized mouse models for human infectious diseases

PubMed Central

Brehm, Michael A.; Wiles, Michael V.; Greiner, Dale L.; Shultz, Leonard D.

2014-01-01

The study of human-specific infectious agents has been hindered by the lack of optimal small animal models. More recently development of novel strains of immunodeficient mice has begun to provide the opportunity to utilize small animal models for the study of many human-specific infectious agents. The introduction of a targeted mutation in the IL2 receptor common gamma chain gene (IL2rgnull) in mice already deficient in T and B cells led to a breakthrough in the ability to engraft hematopoietic stem cells, as well as functional human lymphoid cells and tissues, effectively creating human immune systems in immunodeficient mice. These humanized mice are becoming increasingly important as pre-clinical models for the study of human immunodeficiency virus-1 (HIV-1) and other human-specific infectious agents. However, there remain a number of opportunities to further improve humanized mouse models for the study of human-specific infectious agents. This is being done by the implementation of innovative technologies, which collectively will accelerate the development of new models of genetically modified mice, including; i) modifications of the host to reduce innate immunity, which impedes human cell engraftment; ii) genetic modification to provide human-specific growth factors and cytokines required for optimal human cell growth and function; iii) and new cell and tissue engraftment protocols. The development of “next generation” humanized mouse models continues to provide exciting opportunities for the establishment of robust small animal models to study the pathogenesis of human-specific infectious agents, as well as for testing the efficacy of therapeutic agents and experimental vaccines. PMID:24607601

7 CFR 58.235 - Modified dry milk products.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 3 2014-01-01 2014-01-01 false Modified dry milk products. 58.235 Section 58.235 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Standards... Materials § 58.235 Modified dry milk products. Dry milk products to which approved neutralizing agents or...

7 CFR 58.235 - Modified dry milk products.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 3 2013-01-01 2013-01-01 false Modified dry milk products. 58.235 Section 58.235 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Standards... Materials § 58.235 Modified dry milk products. Dry milk products to which approved neutralizing agents or...

7 CFR 58.235 - Modified dry milk products.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 3 2012-01-01 2012-01-01 false Modified dry milk products. 58.235 Section 58.235 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Standards... Materials § 58.235 Modified dry milk products. Dry milk products to which approved neutralizing agents or...

7 CFR 58.235 - Modified dry milk products.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 3 2010-01-01 2010-01-01 false Modified dry milk products. 58.235 Section 58.235 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Standards... Materials § 58.235 Modified dry milk products. Dry milk products to which approved neutralizing agents or...

7 CFR 58.235 - Modified dry milk products.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 3 2011-01-01 2011-01-01 false Modified dry milk products. 58.235 Section 58.235 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Standards... Materials § 58.235 Modified dry milk products. Dry milk products to which approved neutralizing agents or...

Systemic delivery of blood-brain barrier-targeted polymeric nanoparticles enhances delivery to brain tissue.

PubMed

Saucier-Sawyer, Jennifer K; Deng, Yang; Seo, Young-Eun; Cheng, Christopher J; Zhang, Junwei; Quijano, Elias; Saltzman, W Mark

2015-01-01

Delivery of therapeutic agents to the central nervous system is a significant challenge, hindering progress in the treatment of diseases such as glioblastoma. Due to the presence of the blood-brain barrier (BBB), therapeutic agents do not readily transverse the brain endothelium to enter the parenchyma. Previous reports suggest that surface modification of polymer nanoparticles (NPs) can improve their ability to cross the BBB, but it is unclear whether the observed enhancements in transport are large enough to enhance therapy. In this study, we synthesized two degradable polymer NP systems surface-modified with ligands previously suggested to improve BBB transport, and tested their ability to cross the BBB after intravenous injection in mice. All the NP preparations were able to cross the BBB, although generally in low amounts (<0.5% of the injected dose), which was consistent with prior reports. One NP produced significantly higher brain uptake (∼0.8% of the injected dose): a block copolymer of polylactic acid and hyperbranched polyglycerol, surface modified with adenosine (PLA-HPG-Ad). PLA-HPG-Ad NPs provided controlled release of camptothecin, killing U87 glioma cells in culture. When administered intravenously in mice with intracranial U87 tumors, they failed to increase survival. These results suggest that enhancing NP transport across the BBB does not necessarily yield proportional pharmacological effects.

Multiple sclerosis therapeutic pipeline: opportunities and challenges.

PubMed

Krieger, Stephen

2011-01-01

The year 2010 marked the beginning of the era of oral medications for the treatment of multiple sclerosis, with the approval of dalfampridine to improve walking and fingolimod as the first oral disease-modifying agent. This review provides an overview of these and other emerging therapies, with an emphasis on the opportunities for new treatment paradigms they have the potential to offer, followed by a discussion of the challenges they will pose in the new era of multiple sclerosis management. Therapeutics in late-stage development for MS include non-selective immunosupressants, targeted immune-modulators, and monoclonal antibodies. Oral agents including cladribine, teriflunomide, laquinimod, and dimethyl fumarate, as well as monoclonal antibodies alemtuzumab, daclizumab, and rituximab are considered. Potential side effects and adverse event monitoring, including opportunistic infections, emergent malignancies, and other systemic consequences of immunosuppression are discussed in a unified section. Challenges of optimally staging, sequencing, and combining treatments in the expanding multiple sclerosis armamentarium are discussed. This review emphasizes the multifactorial decision making that these new therapeutics will warrant in terms of patient selection and personalization/individualization of therapy, and the increasingly interdisciplinary approach that will be necessitated by the new generation of agents. © 2011 Mount Sinai School of Medicine.

Mn(II) based T1 and T2 potential MRI contrast agent appended with tryptamine: Recognition moiety for Aβ-plaques.

PubMed

Rastogi, Neeraj; Tyagi, Nidhi; Singh, Ovender; Hemanth Kumar, B S; Singh, Udai P; Ghosh, Kaushik; Roy, Raja

2017-12-01

We report the synthesis and characterization of manganese(II) complexes having pentadentate ligands L 1 (2,6-bis(1-(2-phenyl-2-(pyridin-2-yl)hydrazono)ethyl)pyridine), L 2 (methyl 2,6-bis((E)-1-(2-phenyl-2-(pyridin-2yl)hydrazono)ethyl)isonicotinate), L 3 (N-(2-(1H-indol-3-yl)ethyl)-2,6-bis((E)-1-(2-phenyl-2-(pyridin2yl)hydrazono)ethyl)isonicotiamide) and their application as dual contrast agents for simultaneous T 1 and T 2 weighted magnetic resonance imaging. Single crystal analysis of all the complexes [Mn II L 1 , Mn II L 2 and Mn II L 3 ] confirm the formation of novel seven-coordinate manganese complexes with an inner sphere water and perchlorate ion. The Magnetic Resonance Imaging (MRI) contrast agent [MnL 2 ] was further modified by incorporating tryptamine as a binding moiety specific to Amyloid Beta-fibrils (Aβ-fibrils) in Alzhiemer's disease (AD) and it's in vitro evaluation for specific binding with Aβ-fibrils indicated as a bio-marker of AD. Copyright © 2017 Elsevier Inc. All rights reserved.

Molecular Targeted Intervention for Pancreatic Cancer

PubMed Central

Mohammed, Altaf; Janakiram, Naveena B.; Pant, Shubham; Rao, Chinthalapally V.

2015-01-01

Pancreatic cancer (PC) remains one of the worst cancers, with almost uniform lethality. PC risk is associated with westernized diet, tobacco, alcohol, obesity, chronic pancreatitis, and family history of pancreatic cancer. New targeted agents and the use of various therapeutic combinations have yet to provide adequate treatments for patients with advanced cancer. To design better preventive and/or treatment strategies against PC, knowledge of PC pathogenesis at the molecular level is vital. With the advent of genetically modified animals, significant advances have been made in understanding the molecular biology and pathogenesis of PC. Currently, several clinical trials and preclinical evaluations are underway to investigate novel agents that target signaling defects in PC. An important consideration in evaluating novel drugs is determining whether an agent can reach the target in concentrations effective to treat the disease. Recently, we have reported evidence for chemoprevention of PC. Here, we provide a comprehensive review of current updates on molecularly targeted interventions, as well as dietary, phytochemical, immunoregulatory, and microenvironment-based approaches for the development of novel therapeutic and preventive regimens. Special attention is given to prevention and treatment in preclinical genetically engineered mouse studies and human clinical studies. PMID:26266422

Processing Diabetes Mellitus Composite Events in MAGPIE.

PubMed

Brugués, Albert; Bromuri, Stefano; Barry, Michael; Del Toro, Óscar Jiménez; Mazurkiewicz, Maciej R; Kardas, Przemyslaw; Pegueroles, Josep; Schumacher, Michael

2016-02-01

The focus of this research is in the definition of programmable expert Personal Health Systems (PHS) to monitor patients affected by chronic diseases using agent oriented programming and mobile computing to represent the interactions happening amongst the components of the system. The paper also discusses issues of knowledge representation within the medical domain when dealing with temporal patterns concerning the physiological values of the patient. In the presented agent based PHS the doctors can personalize for each patient monitoring rules that can be defined in a graphical way. Furthermore, to achieve better scalability, the computations for monitoring the patients are distributed among their devices rather than being performed in a centralized server. The system is evaluated using data of 21 diabetic patients to detect temporal patterns according to a set of monitoring rules defined. The system's scalability is evaluated by comparing it with a centralized approach. The evaluation concerning the detection of temporal patterns highlights the system's ability to monitor chronic patients affected by diabetes. Regarding the scalability, the results show the fact that an approach exploiting the use of mobile computing is more scalable than a centralized approach. Therefore, more likely to satisfy the needs of next generation PHSs. PHSs are becoming an adopted technology to deal with the surge of patients affected by chronic illnesses. This paper discusses architectural choices to make an agent based PHS more scalable by using a distributed mobile computing approach. It also discusses how to model the medical knowledge in the PHS in such a way that it is modifiable at run time. The evaluation highlights the necessity of distributing the reasoning to the mobile part of the system and that modifiable rules are able to deal with the change in lifestyle of the patients affected by chronic illnesses.

Meta-Analysis of Creatine for Neuroprotection Against Parkinson's Disease.

PubMed

Attia; Ahmed, Hussien; Gadelkarim, Mohamed; Morsi, Mahmoud; Awad, Kamal; Elnenny, Mohamed; Ghanem, Esraa; El-Jaafary, Shaimaa; Negida, Ahmed

2017-01-01

Creatine is an antioxidant agent that showed neuroprotective effects in animal models of Parkinson's disease (PD). Creatine was selected by the National Institute of Neurological Disorders and Stroke as a possible disease modifying agent for Parkinson's disease. Therefore, many clinical trials evaluated the efficacy of creatine for patients with PD. The aim of this systematic review and meta-analysis is to synthesize evidence from published randomized controlled trials (RCTs) about the efficacy of Creatine for patients with PD. We followed PRISMA statement guidelines during the preparation of this systematic review and meta-analysis. A computer literature search for PubMed, EBSCO, web of science and Ovid Midline was carried out. We included RCTs comparing creatine with placebo in terms of motor functions and quality of life. Outcomes of total Unified Parkinson's Disease Rating Scale (UPDRS), UPDRS I, UPDRS II, and UPDRS III were pooled as mean difference (MD) between two groups from baseline to the endpoint. Statistical heterogeneity was assessed by visual inspection of the forest plot and measured by chi-square and I square tests. Three RCTs (n=1935) were included in this study. The overall effect did not favor either of the two groups in terms of: UPDRS total score (MD 1.07, 95% CI [3.38 to 1.25], UPDRS III (MD 0.62, 95% CI [2.27 to 1.02]), UPDRS II (MD 0.03, 95% CI [0.81 to 0.86], or UPDRS I (MD 0.03, 95% CI [0.33 to 0.28]). Current evidence does not support the use of creatine for neuroprotection against PD. Future well-designed, randomized controlled trials are needed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The Relationship of Cardiovascular Risk in Rheumatoid Arthritis Comparing TNFα Blockade with Non-Biologic DMARDs

PubMed Central

Solomon, Daniel H.; Curtis, Jeffrey R.; Saag, Kenneth G.; Lii, Joyce; Chen, Lang; Harrold, Leslie R.; Herrinton, Lisa J; Graham, David J; Kowal, Mary K.; Kuriya, Bindee; Liu, Liyan; Griffin, Marie R.; Lewis, James D.; Rassen, Jeremy A.

2015-01-01

Background Elevated TNFα likely contributes to the excess cardiovascular risk observed in rheumatoid arthritis. We compared the cardiovascular risk in rheumatoid arthritis patients starting a TNFα blocking agent versus a non-biologic disease-modifying anti-rheumatic drug (nbDMARD). Methods Subjects with rheumatoid arthritis participating in several different US insurance programs between 1998-2007 who received methotrexate were eligible. Those who added a TNFα blocking agent were compared with subjects who added a nbDMARD in Cox regression models stratified by propensity score decile and adjusted for oral glucocorticoid dosage. We examined the composite cardiovascular endpoint of myocardial infarction, stroke, or coronary re-vascularization after six months. Results We compared 8,656 new users of a nbDMARD with 11,587 new users of a TNFα blocking agent with similar baseline covariates. Incidence rates per 100 person-years for the composite cardiovascular endpoint were 3.05 (95% CI 2.54 – 3.65) for nbDMARDs and 2.52 (95% CI 2.12-2.98) for TNFα blocking agents. The hazard ratio (HR) for the TNFα blocking agent compared with nbDMARD carrying the first exposure forward was 0.80 (95% CI 0.62 - 1.04), while the HR for the as-treated analysis was 0.71 (95% CI 0.52 - 0.97). The potential cardiovascular benefit of TNFα blocking agents was strongest among persons ≥ 65 years of age (HR 0.52, 95% CI 0.34 – 0.77; p for interaction = 0.075). Conclusion Among subjects with rheumatoid arthritis, TNFα blocking agents may be associated with a reduced risk of cardiovascular events compared to a nbDMARD. Randomized controlled clinical trials should be considered to test this hypothesis. PMID:23885678

Pest and Disease Management: Why We Shouldn't Go against the Grain

PubMed Central

Skelsey, Peter; With, Kimberly A.; Garrett, Karen A.

2013-01-01

Given the wide range of scales and mechanisms by which pest or disease agents disperse, it is unclear whether there might exist a general relationship between scale of host heterogeneity and spatial spread that could be exploited by available management options. In this model-based study, we investigate the interaction between host distributions and the spread of pests and diseases using an array of models that encompass the dispersal and spread of a diverse range of economically important species: a major insect pest of coniferous forests in western North America, the mountain pine beetle (Dendroctonus ponderosae); the bacterium Pseudomonas syringae, one of the most-widespread and best-studied bacterial plant pathogens; the mosquito Culex erraticus, an important vector for many human and animal pathogens, including West Nile Virus; and the oomycete Phytophthora infestans, the causal agent of potato late blight. Our model results reveal an interesting general phenomenon: a unimodal (‘humpbacked’) relationship in the magnitude of infestation (an index of dispersal or population spread) with increasing grain size (i.e., the finest scale of patchiness) in the host distribution. Pest and disease management strategies targeting different aspects of host pattern (e.g., abundance, aggregation, isolation, quality) modified the shape of this relationship, but not the general unimodal form. This is a previously unreported effect that provides insight into the spatial scale at which management interventions are most likely to be successful, which, notably, do not always match the scale corresponding to maximum infestation. Our findings could provide a new basis for explaining historical outbreak events, and have implications for biosecurity and public health preparedness. PMID:24098739

Pest and disease management: why we shouldn't go against the grain.

PubMed

Skelsey, Peter; With, Kimberly A; Garrett, Karen A

2013-01-01

Given the wide range of scales and mechanisms by which pest or disease agents disperse, it is unclear whether there might exist a general relationship between scale of host heterogeneity and spatial spread that could be exploited by available management options. In this model-based study, we investigate the interaction between host distributions and the spread of pests and diseases using an array of models that encompass the dispersal and spread of a diverse range of economically important species: a major insect pest of coniferous forests in western North America, the mountain pine beetle (Dendroctonus ponderosae); the bacterium Pseudomonas syringae, one of the most-widespread and best-studied bacterial plant pathogens; the mosquito Culex erraticus, an important vector for many human and animal pathogens, including West Nile Virus; and the oomycete Phytophthora infestans, the causal agent of potato late blight. Our model results reveal an interesting general phenomenon: a unimodal ('humpbacked') relationship in the magnitude of infestation (an index of dispersal or population spread) with increasing grain size (i.e., the finest scale of patchiness) in the host distribution. Pest and disease management strategies targeting different aspects of host pattern (e.g., abundance, aggregation, isolation, quality) modified the shape of this relationship, but not the general unimodal form. This is a previously unreported effect that provides insight into the spatial scale at which management interventions are most likely to be successful, which, notably, do not always match the scale corresponding to maximum infestation. Our findings could provide a new basis for explaining historical outbreak events, and have implications for biosecurity and public health preparedness.

76 FR 4480 - Privacy Act of 1974; Report of Modified or Altered System of Records

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-25

... of Subjects in Agent Orange, Vietnam Experience, and Selected Cancers Studies, HHS/CDC/CCEHIP/ NCEH.../NCEH proposes to alter System of Records, No. 09-20-0162, ``Records of Subjects in Agent Orange... Agent Orange) to possible adverse health consequences. Such possible effects to be evaluated include...

The effect of bleaching agents on the microhardness of dental aesthetic restorative materials.

PubMed

Türker, S B; Biskin, T

2002-07-01

This study investigated the effects of three home bleaching agents on the microhardness of various dental aesthetic restorative materials. The restorative materials were: feldspatic porcelain, microfilled composite resin and light-cured modified glass-ionomer cement and the bleaching agents Nite-White (16% carbamide peroxide), Opalescence (10% carbamide peroxide and carbapol jel) and Rembrandt (10% carbamide peroxide jel). A total of 90 restorative material samples were prepared 1 cm diameter and 6 mm thick and kept in distilled water for 24 h before commencing bleaching which was carried out for 8 h day-1 for 4 weeks. Microhardness measurements were then made using a Tukon tester. Statistically significant differences with respect to unbleached controls were found only for the feldspatic porcelain and microfilled composite resins (P <0.05) for Nite-White and Opalescence. All the bleaching agents decreased the microhardness of the porcelain and increased that of the light cured modified glass-ionomer cement. For the composite resin, whereas Nite-White increased its microhardness, the other bleaching agents decreased it. There were no significant differences between the bleaching agents for any of the restorative materials.

[Association between indoor contamination and respiratory diseases in children living in Temuco and Padre Las Casas, Chile].

PubMed

Rivas R, Edith; Barrios C, Sara; Dorner P, Anita; Osorio S, Ximena

2008-06-01

Indoor air pollution, is the main cause of population exposure to polluting agents. To establish an environmental profile of indoor contamination emission sources in families of children under 5 years that assist to kindergartens in Temuco and Padre Las Casas. To associate respiratory disease episodes in children with indoor contamination. Cross sectional analysis of 355 family groups subjected to questionnaires about indoor contamination and number of respiratory disease episodes. Forty six percent of mothers or caregivers smoked, 37% smoked at home and 93% smoked one to two cigarettes per day. There was a significant association between respiratory diseases in children and drying clothes in the kitchen, using firewood for heating and the presence of humidity in the dwelling. Mothers identified as indoor contaminants the use of braziers in 76% of cases and firewood stoves in 24%. Ninety seven percent considered that these appliances were detrimental for respiratory health. The lack of awareness about indoor contamination among subjects of low socioeconomic status should prompt educational campaigns to modify behaviors in their dwellings.

High quality polyacrylic acid modified multifunction luminescent nanorods for tri-modality bioimaging, in vivo long-lasting tracking and biodistribution

NASA Astrophysics Data System (ADS)

Yi, Zhigao; Lu, Wei; Liu, Hongrong; Zeng, Songjun

2014-12-01

Polyacrylic acid (PAA) modified NaYF4:Gd/Yb/Er upconversion nanorods (denoted as PAA-UCNRs) are demonstrated for tri-modal upconversion (UC) optical, computed X-ray tomography (CT), and magnetic resonance imaging (MRI). The hydrophilic PAA-UCNRs were obtained from hydrophobic oleic acid (OA) capped UCNRs (denoted as OA-UCNRs) using a ligand exchange method. The as-prepared UCNRs with a hexagonal phase structure present high monodispersity. These PAA-UCNRs are successfully used as ideal probes for in vivo UC luminescence bioimaging and synergistic X-ray and UC bioimaging. Moreover, X-ray CT imaging reveals that PAA-UCNRs can act as contrast agents for improved detection of the liver and spleen. In addition, a significant signal enhancement in the liver is observed in in vivo MRI, indicating that PAA-UCNRs are ideal T1-weighted MRI agents. More importantly, in vivo long-term tracking based on these PAA-UCNRs in the live mice and the corresponding ex vivo bioimaging of isolated organs also verify the translocation of PAA-UCNRs from the liver to the spleen, and the observed intense UC signals from the feces reveal the biliary excretion mechanism of these UCNRs. These findings contribute to understanding of the translocation and potential route for excretion of PAA-UCNRs, which can provide an important guide for the diagnosis and detection of diseases based on these UCNRs.Polyacrylic acid (PAA) modified NaYF4:Gd/Yb/Er upconversion nanorods (denoted as PAA-UCNRs) are demonstrated for tri-modal upconversion (UC) optical, computed X-ray tomography (CT), and magnetic resonance imaging (MRI). The hydrophilic PAA-UCNRs were obtained from hydrophobic oleic acid (OA) capped UCNRs (denoted as OA-UCNRs) using a ligand exchange method. The as-prepared UCNRs with a hexagonal phase structure present high monodispersity. These PAA-UCNRs are successfully used as ideal probes for in vivo UC luminescence bioimaging and synergistic X-ray and UC bioimaging. Moreover, X-ray CT imaging reveals that PAA-UCNRs can act as contrast agents for improved detection of the liver and spleen. In addition, a significant signal enhancement in the liver is observed in in vivo MRI, indicating that PAA-UCNRs are ideal T1-weighted MRI agents. More importantly, in vivo long-term tracking based on these PAA-UCNRs in the live mice and the corresponding ex vivo bioimaging of isolated organs also verify the translocation of PAA-UCNRs from the liver to the spleen, and the observed intense UC signals from the feces reveal the biliary excretion mechanism of these UCNRs. These findings contribute to understanding of the translocation and potential route for excretion of PAA-UCNRs, which can provide an important guide for the diagnosis and detection of diseases based on these UCNRs. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr05161k

Preparedness for pandemics: does variation among states affect the nation as a whole?

PubMed

Potter, Margaret A; Brown, Shawn T; Lee, Bruce Y; Grefenstette, John; Keane, Christopher R; Lin, Chyongchiou J; Quinn, Sandra C; Stebbins, Samuel; Sweeney, Patricia M; Burke, Donald S

2012-01-01

Since states' public health systems differ as to pandemic preparedness, this study explored whether such heterogeneity among states could affect the nation's overall influenza rate. The Centers for Disease Control and Prevention produced a uniform set of scores on a 100-point scale from its 2008 national evaluation of state preparedness to distribute materiel from the Strategic National Stockpile (SNS). This study used these SNS scores to represent each state's relative preparedness to distribute influenza vaccine in a timely manner and assumed that "optimal" vaccine distribution would reach at least 35% of the state's population within 4 weeks. The scores were used to determine the timing of vaccine distribution for each state: each 10-point decrement of score below 90 added an additional delay increment to the distribution time. A large-scale agent-based computational model simulated an influenza pandemic in the US population. In this synthetic population each individual or agent had an assigned household, age, workplace or school destination, daily commute, and domestic intercity air travel patterns. Simulations compared influenza case rates both nationally and at the state level under 3 scenarios: no vaccine distribution (baseline), optimal vaccine distribution in all states, and vaccine distribution time modified according to state-specific SNS score. Between optimal and SNS-modified scenarios, attack rates rose not only in low-scoring states but also in high-scoring states, demonstrating an interstate spread of infections. Influenza rates were sensitive to variation of the SNS-modified scenario (delay increments of 1 day versus 5 days), but the interstate effect remained. The effectiveness of a response activity such as vaccine distribution could benefit from national standards and preparedness funding allocated in part to minimize interstate disparities.

7 CFR 331.3 - PPQ select agents and toxins.

Code of Federal Regulations, 2014 CFR

2014-01-01

... (b) of this section that have been genetically modified. (d) Select agents or toxins that meet any of..., and recombinant and/or synthetic organisms: (1) Nucleic acids that can produce infectious forms of any...

7 CFR 331.3 - PPQ select agents and toxins.

Code of Federal Regulations, 2013 CFR

2013-01-01

... (b) of this section that have been genetically modified. (d) Select agents or toxins that meet any of..., and recombinant and/or synthetic organisms: (1) Nucleic acids that can produce infectious forms of any...

Efficacy and safety of down-titration versus continuation strategies of biological disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis with low disease activity or in remission: a systematic review and meta-analysis.

PubMed

Jiang, Mei; Ren, Feifeng; Zheng, Yaning; Yan, Ruyu; Huang, Wenhan; Xia, Ning; Luo, Lei; Zhou, Jun; Tang, Lin

2017-01-01

To evaluate the efficacy and safety of down-titration (dose reduction/tapering) strategies compared with continuation of biological disease-modifying anti-rheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA) who achieved and maintained low disease activity or remission. We searched the following electronic database up to March 2016: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and conference proceedings of the American College of Rheumatology (ACR) and European League against Rheumatism (EULAR). Our meta-analysis included randomized controlled trials (RCTs) of RA patients with low disease activity or in remission that compared down-titration treatment with continuation treatment. Data on flare, defined as a 28-joint Disease Activity Score of ≥3.2, had to have been reported. Outcomes on efficacy or safety were collected. Of 1136 references identified, five RCTs (total, 771 participants) were included. The incidence of disease relapse in the down-titration and continuation groups was similar (risk ratio (RR)=1.14, 95% CI=0.88-1.49). There was no statistical difference in the number of serious adverse events (RR=1.15, 95% CI=0.53-2.49). Withdrawals due to inefficacy or toxicity were similar between groups and no clinically meaningful difference in efficacy outcomes was observed by continuation treatment. Our findings indicated that continuing a standard dose of biological DMARDs in patients with low disease activity conveyed no significant benefit as compared with down-titration therapy, suggesting that a down-titration strategy is as effective as a continuation strategy. Since the number of trials meeting the criteria for this meta-analysis was relatively low, future analyses with additional prospective RCTs are required to compare other biological agents and evaluate the long-term efficacy of these two strategies.

42 CFR 73.13 - Restricted experiments.

Code of Federal Regulations, 2013 CFR

2013-10-01

... acquisition could compromise the control of disease agents in humans, veterinary medicine, or agriculture, or... control of disease agents in humans, veterinary medicine, or agriculture, or recombinant and/or synthetic... trait naturally, if such acquisition could compromise the control of disease agents in humans...

Sphingosine 1-phosphate receptor modulators in multiple sclerosis.

PubMed

Subei, Adnan M; Cohen, Jeffrey A

2015-07-01

Sphingosine 1-phosphate (S1P) receptor modulators possess a unique mechanism of action as disease-modifying therapy for multiple sclerosis (MS). Subtype 1 S1P receptors are expressed on the surfaces of lymphocytes and are important in regulating egression from lymph nodes. The S1P receptor modulators indirectly antagonize the receptor's function and sequester lymphocytes in lymph nodes. Fingolimod was the first S1P agent approved in the USA in 2010 for relapsing MS after two phase III trials (FREEDOMS and TRANSFORMS) demonstrated potent efficacy, and good safety and tolerability. Post-marketing experience, as well as a third phase III trial (FREEDOMS II), also showed favorable results. More selective S1P receptor agents-ponesimod (ACT128800), siponimod (BAF312), ozanimod (RPC1063), ceralifimod (ONO-4641), GSK2018682, and MT-1303-are still in relatively early stages of development, but phase I and II trials showed promising efficacy and safety. However, these observations have yet to be reproduced in phase III clinical trials.

Sphingosine 1-Phosphate Receptor Modulators in Multiple Sclerosis

PubMed Central

Subei, Adnan M.

2015-01-01

Sphingosine 1-phosphate (S1P) receptor modulators possess a unique mechanism of action as disease modifying therapy for multiple sclerosis (MS). Subtype 1 S1P receptors are expressed on the surfaces of lymphocytes and are important in regulating egression from lymph nodes. The S1P receptor modulators indirectly antagonize the receptor’s function and sequester lymphocytes in lymph nodes. Fingolimod was the first S1P agent approved in the United States in 2010 for relapsing MS after two phase 3 trials (FREEDOMS and TRANSFORMS) demonstrated potent efficacy, and good safety and tolerability. Post-marketing experience as well as a third phase 3 trial (FREEDOMS II) also showed favorable results. More selective S1P receptor agents: ponesimod (ACT128800), siponimod (BAF312), ozanimod (RPC1063), ceralifimod (ONO-4641), GSK2018682, and MT-1303 are still in relatively early stages of development, but phase 1 and 2 trials showed promising efficacy and safety. However, these observations have yet to be reproduced in phase 3 clinical trials. PMID:26239599

Plant microRNAs as novel immunomodulatory agents

PubMed Central

Cavalieri, Duccio; Rizzetto, Lisa; Tocci, Noemi; Rivero, Damariz; Asquini, Elisa; Si-Ammour, Azeddine; Bonechi, Elena; Ballerini, Clara; Viola, Roberto

2016-01-01

An increasing body of literature is addressing the immuno-modulating functions of miRNAs which include paracrine signaling via exosome-mediated intercellular miRNA. In view of the recent evidence of intake and bioavailability of dietary miRNAs in humans and animals we explored the immuno-modulating capacity of plant derived miRNAs. Here we show that transfection of synthetic miRNAs or native miRNA-enriched fractions obtained from a wide range of plant species and organs modifies dendritic cells ability to respond to inflammatory agents by limiting T cell proliferation and consequently dampening inflammation. This immuno-modulatory effect appears associated with binding of plant miRNA on TLR3 with ensuing impairment of TRIF signaling. Similarly, in vivo, plant small RNAs reduce the onset of severity of Experimental Autoimmune Encephalomyelities by limiting dendritic cell migration and dampening Th1 and Th17 responses in a Treg-independent manner. Our results indicate a potential for therapeutic use of plant miRNAs in the prevention of chronic-inflammation related diseases. PMID:27167363

Future directions in lipid therapies.

PubMed

Ansell, Benjamin

2002-01-01

Cholesterol management to reduce the burden of cardiovascular disease is a major public health concern. Despite widespread recognition of lipid abnormalities as cardiovascular risk factors, significant cardiovascular event reductions with cholesterol-lowering therapies, and dissemination of treatment guidelines, most high-risk patients are not at target lipid levels. In addition to lifestyle changes, four major drug classes are available to modify lipid levels: fibrates, niacin, resins, and statins. High efficacy and tolerability in clinical trials make statins the most widely prescribed of these agents. Newer, more potent members of this class and novel formulations of niacin and resins may provide more effective therapy for dyslipidemia with fewer side effects. Several agents in development (cholesterol-absorption inhibitors and ACAT inhibitors) exploit mechanisms of action complementary to those of current treatments and combined with statins may produce greater improvements in lipid profiles than are now possible. These innovations should enable a greater number of patients to achieve more aggressive cholesterol goals, thereby reducing the risk of cardiovascular events.

Identification of a Novel Class of Covalent Modifiers of Hemoglobin as Potential Antisickling Agents

PubMed Central

Omar, A. M.; Mahran, M. A.; Ghatge, M. S.; Chowdhury, N.; Bamane, F. H. A.; El-Araby, M. E.; Abdulmalik, O.; Safo, M. K.

2015-01-01

Aromatic aldehydes and ethacrynic acid (ECA) exhibit antipolymerization properties that are beneficial for sickle cell disease therapy. Based on ECA pharmacophore and its atomic interaction with hemoglobin, we designed and synthesized several compounds--designated as KAUS (imidazolylacryloyl derivatives)--that we hypothesized would bind covalently to βCys93 of hemoglobin and inhibit sickling. The compounds surprisingly showed weak allosteric and antisickling properties. X-ray studies of hemoglobin in complex with representative KAUS compounds revealed an unanticipated mode of Michael addition reaction between the β-unsaturated carbon and the N-terminal αVal1 nitrogen at the α-cleft of hemoglobin, with no observable interaction with βCys93. Interestingly, the compounds exhibited almost no reactivity with the free amino acids, L-Val, L-His and L-Lys, however showed some reactivity with both glutathione and L-Cys. Our findings provide a molecular level explanation to the compounds biological activities and an important framework for targeted modifications that would yield novel potent antisickling agents. PMID:25974708

Experimental transmission of the chronic wasting disease agent to swine after oral or intracranial inoculation

USDA-ARS?s Scientific Manuscript database

Chronic wasting disease (CWD) is a naturally occurring, fatal neurodegenerative disease of cervids. The potential for swine to serve as a host for the agent of chronic wasting disease is unknown. The purpose of this study was to investigate the susceptibility of swine to the CWD agent following oral...

When myasthenia gravis is deemed refractory: clinical signposts and treatment strategies

PubMed Central

Mantegazza, Renato; Antozzi, Carlo

2018-01-01

The prognosis for patients with myasthenia gravis (MG) has improved significantly over the past half century, including substantial reductions in mortality and morbidity. However, approximately 10% of patients fails to respond adequately to current therapies and are considered treatment refractory, or treatment intolerant, and up to 80% have disease that fails to achieve complete stable remission. Although patients with autoantibodies to muscle-specific tyrosine kinase (anti-MuSK positive) are more likely to become treatment refractory than those with autoantibodies to the acetylcholine receptor (anti-AChR positive), each of these serotypes is substantially represented in the refractory MG population. Other risk factors for becoming treatment refractory include history of thymoma or thymectomy and female sex. A modified treatment algorithm for MG is proposed: patients who have disease that fails to respond to the stepwise approach to therapy, are treatment intolerant, or who require chronic rescue measures despite ongoing therapy, should be considered treatment refractory and emerging therapies should be considered. Three emerging monoclonal antibody-based therapies are discussed: the anti-B-cell agent rituximab; the terminal complement activation inhibitor eculizumab; and belimumab, which targets B-cell activating factor. Increased understanding of molecular pathophysiology and accurate antibody subtyping in MG should lead to the use of new therapeutic agents and successful management of treatment-refractory patients. PMID:29403543

Clinical trials for neuroprotection in ALS.

PubMed

Siciliano, G; Carlesi, C; Pasquali, L; Piazza, S; Pietracupa, S; Fornai, F; Ruggieri, S; Murri, L

2010-07-01

Owing to uncertainty on the pathogenic mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis (ALS) riluzole remains the only available therapy, with only marginal effects on disease survival. Here we review some of the recent advances in the search for disease-modifying drugs for ALS based on their putative neuroprotective effetcs. A number of more or less established agents have recently been investigated also in ALS for their potential role in neuroprotection and relying on antiglutamatergic, antioxidant or antiapoptotic strategies. Among them Talampanel, beta-lactam antibiotics, Coenzyme Q10, and minocycline have been investigated. Progress has also been made in exploiting growth factors for the treatment of ALS, partly due to advances in developing effective delivery systems to the central nervous system. A number of new therapies have also been identified, including a novel class of compounds, such as heat-shock protein co-inducers, which upregulate cell stress responses, and agents promoting autophagy and mitochondriogenesis, such as lithium and rapamycin. More recently, alterations of mRNA processing were described as a pathogenic mechanism in genetically defined forms of ALS, as those related to TDP-43 and FUS-TLS gene mutations. This knowledge is expected to improve our understanding of the pathogenetic mechanism in ALS and developing more effective therapies.

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

PubMed

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.

Intelligent judgements over health risks in a spatial agent-based model.

PubMed

Abdulkareem, Shaheen A; Augustijn, Ellen-Wien; Mustafa, Yaseen T; Filatova, Tatiana

2018-03-20

Millions of people worldwide are exposed to deadly infectious diseases on a regular basis. Breaking news of the Zika outbreak for instance, made it to the main media titles internationally. Perceiving disease risks motivate people to adapt their behavior toward a safer and more protective lifestyle. Computational science is instrumental in exploring patterns of disease spread emerging from many individual decisions and interactions among agents and their environment by means of agent-based models. Yet, current disease models rarely consider simulating dynamics in risk perception and its impact on the adaptive protective behavior. Social sciences offer insights into individual risk perception and corresponding protective actions, while machine learning provides algorithms and methods to capture these learning processes. This article presents an innovative approach to extend agent-based disease models by capturing behavioral aspects of decision-making in a risky context using machine learning techniques. We illustrate it with a case of cholera in Kumasi, Ghana, accounting for spatial and social risk factors that affect intelligent behavior and corresponding disease incidents. The results of computational experiments comparing intelligent with zero-intelligent representations of agents in a spatial disease agent-based model are discussed. We present a spatial disease agent-based model (ABM) with agents' behavior grounded in Protection Motivation Theory. Spatial and temporal patterns of disease diffusion among zero-intelligent agents are compared to those produced by a population of intelligent agents. Two Bayesian Networks (BNs) designed and coded using R and are further integrated with the NetLogo-based Cholera ABM. The first is a one-tier BN1 (only risk perception), the second is a two-tier BN2 (risk and coping behavior). We run three experiments (zero-intelligent agents, BN1 intelligence and BN2 intelligence) and report the results per experiment in terms of several macro metrics of interest: an epidemic curve, a risk perception curve, and a distribution of different types of coping strategies over time. Our results emphasize the importance of integrating behavioral aspects of decision making under risk into spatial disease ABMs using machine learning algorithms. This is especially relevant when studying cumulative impacts of behavioral changes and possible intervention strategies.

Agent-Based Modeling of Chronic Diseases: A Narrative Review and Future Research Directions

PubMed Central

Lawley, Mark A.; Siscovick, David S.; Zhang, Donglan; Pagán, José A.

2016-01-01

The United States is experiencing an epidemic of chronic disease. As the US population ages, health care providers and policy makers urgently need decision models that provide systematic, credible prediction regarding the prevention and treatment of chronic diseases to improve population health management and medical decision-making. Agent-based modeling is a promising systems science approach that can model complex interactions and processes related to chronic health conditions, such as adaptive behaviors, feedback loops, and contextual effects. This article introduces agent-based modeling by providing a narrative review of agent-based models of chronic disease and identifying the characteristics of various chronic health conditions that must be taken into account to build effective clinical- and policy-relevant models. We also identify barriers to adopting agent-based models to study chronic diseases. Finally, we discuss future research directions of agent-based modeling applied to problems related to specific chronic health conditions. PMID:27236380

Agent-Based Modeling of Chronic Diseases: A Narrative Review and Future Research Directions.

PubMed

Li, Yan; Lawley, Mark A; Siscovick, David S; Zhang, Donglan; Pagán, José A

2016-05-26

The United States is experiencing an epidemic of chronic disease. As the US population ages, health care providers and policy makers urgently need decision models that provide systematic, credible prediction regarding the prevention and treatment of chronic diseases to improve population health management and medical decision-making. Agent-based modeling is a promising systems science approach that can model complex interactions and processes related to chronic health conditions, such as adaptive behaviors, feedback loops, and contextual effects. This article introduces agent-based modeling by providing a narrative review of agent-based models of chronic disease and identifying the characteristics of various chronic health conditions that must be taken into account to build effective clinical- and policy-relevant models. We also identify barriers to adopting agent-based models to study chronic diseases. Finally, we discuss future research directions of agent-based modeling applied to problems related to specific chronic health conditions.

Diagnosis and Management of Behavioral Issues in Frontotemporal Dementia

PubMed Central

Manoochehri, Masood; Huey, Edward D.

2012-01-01

Frontotemporal lobar degeneration (FTLD) is an umbrella term for several different disorders. In behavioral variant frontotemporal dementia (bvFTD), patients show deterioration in cognition and social behavior. New diagnostic criteria proposed by the International Behavioral Variant FTD Consortium provide greater sensitivity in diagnosing bvFTD. Current pharmacological management of symptoms relies on medications borrowed from treating Alzheimer’s Disease (AD) and psychiatric disorders. The evidence for using AD medications such as acetylcholinesterase inhibitors is questionable. Psychiatric medications can be helpful. Trazodone or SSRIs can have some efficacy in reducing disinhibition, repetitive behaviors, sexually inappropriate behaviors, and hyperorality. Small doses of atypical antipsychotics may be helpful in decreasing agitation and verbal outbursts. Non-pharmacological management includes caregiver education and support and behavioral interventions. While symptomatic treatments are likely to remain important behavior management tools, targeting the underlying pathology of bvFTD with disease-modifying agents will hopefully be the future of treatment. PMID:22847063

Biological Control Strategies for Mosquito Vectors of Arboviruses.

PubMed

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.

Natural Products as a Source for Treating Neglected Parasitic Diseases

PubMed Central

Ndjonka, Dieudonné; Rapado, Ludmila Nakamura; Silber, Ariel M.; Liebau, Eva; Wrenger, Carsten

2013-01-01

Infectious diseases caused by parasites are a major threat for the entire mankind, especially in the tropics. More than 1 billion people world-wide are directly exposed to tropical parasites such as the causative agents of trypanosomiasis, leishmaniasis, schistosomiasis, lymphatic filariasis and onchocerciasis, which represent a major health problem, particularly in impecunious areas. Unlike most antibiotics, there is no “general” antiparasitic drug available. Here, the selection of antiparasitic drugs varies between different organisms. Some of the currently available drugs are chemically de novo synthesized, however, the majority of drugs are derived from natural sources such as plants which have subsequently been chemically modified to warrant higher potency against these human pathogens. In this review article we will provide an overview of the current status of plant derived pharmaceuticals and their chemical modifications to target parasite-specific peculiarities in order to interfere with their proliferation in the human host. PMID:23389040

Sugammadex: A Review of Neuromuscular Blockade Reversal.

PubMed

Keating, Gillian M

2016-07-01

Sugammadex (Bridion(®)) is a modified γ-cyclodextrin that reverses the effect of the steroidal nondepolarizing neuromuscular blocking agents rocuronium and vecuronium. Intravenous sugammadex resulted in rapid, predictable recovery from moderate and deep neuromuscular blockade in patients undergoing surgery who received rocuronium or vecuronium. Recovery from moderate neuromuscular blockade was significantly faster with sugammadex 2 mg/kg than with neostigmine, and recovery from deep neuromuscular blockade was significantly faster with sugammadex 4 mg/kg than with neostigmine or spontaneous recovery. In addition, recovery from neuromuscular blockade was significantly faster when sugammadex 16 mg/kg was administered 3 min after rocuronium than when patients spontaneously recovered from succinylcholine. Sugammadex also demonstrated efficacy in various special patient populations, including patients with pulmonary disease, cardiac disease, hepatic dysfunction or myasthenia gravis and morbidly obese patients. Intravenous sugammadex was generally well tolerated. In conclusion, sugammadex is an important option for the rapid reversal of rocuronium- or vecuronium-induced neuromuscular blockade.

The importance of reaching lipid targets: statins and the prevention of atherosclerosis.

PubMed

Schwandt, P

2003-06-01

To help prevent the development of coronary heart disease (CHD), the European and NCEP guidelines have recommended target cholesterol levels for all individuals. Lifestyle changes are advocated for individuals not achieving these targets. Intervention with lipid-modifying agents may be required for patients at high risk of a cardiovascular event and statins are generally recognised as first-line therapy. Unfortunately, large numbers of patients at risk of cardiovascular events are not being treated to the guideline targets. Primary care physicians are in a good position to improve lipid management by assessing risk factors, implementing lipid management strategies, monitoring whether targets are being reached and amending treatment appropriately. Furthermore, by educating and motivating patients,primary care physicians may improve compliance with lifestyle changes and medication. These approaches may help more patients to achieve recommended lipid levels and prevent the development of cardiovascular disease.

Biological Control Strategies for Mosquito Vectors of Arboviruses

PubMed Central

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

2017-01-01

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. PMID:28208639

Clinical trials with rasagiline: evidence for short-term and long-term effects.

PubMed

Siderowf, Andrew; Stern, Matthew

2006-05-23

Rasagiline (N-propargyl-1 (R)-aminoindan) is a selective, potent irreversible inhibitor of MAO-B that possesses neuroprotective and anti-apoptotic properties in a variety of in vitro and in vivo animal models relevant to Parkinson's disease (PD). Several randomized controlled clinical trials have demonstrated the safety and efficacy of rasagiline as monotherapy in PD and as adjunctive therapy for patients receiving levodopa. In addition, the 1-year randomized, delayed-start analysis of the TEMPO study suggests that rasagiline may slow the rate of progression of PD. The randomized delayed-start paradigm has potential to differentiate short-term symptomatic effects from long-term effects of anti-parkinsonian agents. In the future, long-term trials to examine the potential disease-modifying effects of rasagiline, which incorporate biological markers as well as clinical endpoints, may further elucidate the role of rasagiline in the treatment of both early and advanced PD.

Human Papilloma Virus in Oral Squamous Cell Carcinoma - The Enigma Unravelled.

PubMed

Khot, Komal P; Deshmane, Swati; Choudhari, Sheetal

2016-03-01

Squamous cell carcinoma of the head and neck (HNSCC) has long been regarded as a disease entity having a remarkable incidence worldwide and a fairly onerous prognosis; thus encouraging further research on factors that might modify disease outcome. Squamous cell carcinomas encompass at least 90% of all oral malignancies. Several factors like tobacco and tobacco-related products, alcohol, genetic predisposition and hormonal factors are suspected as possible causative factors. Human papilloma virus (HPV), the causal agent of cervical cancer also appears to be involved in the aetiology of oral and oropharyngeal cancer. HPVpositive squamous cell carcinoma (SCC) seems to differ from HPV-negative SCC. Many questions about the natural history of oral HPV infection remain under investigation. The aim of this review is to highlight the current understanding of HPV-associated oral cancer with an emphasis on its prognosis, detection and management.

Managed care aspects of managing multiple sclerosis.

PubMed

Owens, Gary M

2013-11-01

Multiple sclerosis (MS) is a chronic disease of the central nervous system usually diagnosed in the second or third decade of life; MS is more common among women than men by a ratio of 3 to 1. With its relatively early age of onset and symptoms that impair patients' quality of life, MS requires lifelong, dynamic treatment, and places a substantial economic burden on individuals, healthcare systems, and society. The costs associated with providing benefits for MS therapy are growing rapidly and the increasing complexity of the MS market is impacting disease management for payers. Employers are also increasingly aware of the costs associated with MS and are asking health plans to advise on the most appropriate and cost-effective ways to manage both pharmacologic and non-pharmacologic therapies for MS. Health plans, by necessity, must therefore balance appropriate access to treatments for MS with the need to manage rising treatment costs. To meet this goal, payers require population-based solutions, guidelines, and treatment algorithms for the management of MS that can be used in clinical and formulary management decision making in the context of an evolving therapeutic landscape. Further, comparative studies are necessary for payers to determine which agents may work best on a population basis. Due to the current lack of appropriate clinical guidance and insufficient head-to-head data on disease-modifying drugs, strategies for health plans and clinical management have been designed using the best available evidence. Undoubtedly, management of this class will continue to evolve with the launch of newer agents.

Treatment with Biologicals in Rheumatoid Arthritis: An Overview.

PubMed

Rein, Philipp; Mueller, Ruediger B

2017-12-01

Management and therapy of rheumatoid arthritis (RA) has been revolutionized by the development and approval of the first biological disease-modifying antirheumatic drugs (bDMARDs) targeting tumor necrosis factor (TNF) α at the end of the last century. Today, numerous efficacious agents with different modes of action are available and achievement of clinical remission or, at least, low disease activity is the target of therapy. Early therapeutic interventions aiming at a defined goal of therapy (treat to target) are supposed to halt inflammation, improving symptoms and signs, and preserving structural integrity of the joints in RA. Up to now, bDMARDs approved for therapy in RA include agents with five different modes of action: TNF inhibition, T cell co-stimulation blockade, IL-6 receptor inhibition, B cell depletion, and interleukin 1 inhibition. Furthermore, targeted synthetic DMARDs (tsDMARDs) inhibiting Janus kinase (JAK) and biosimilars also are approved for RA. The present review focuses on bDMARDs and tsDMARDS regarding similarities and possible drug-specific advantages in the treatment of RA. Furthermore, compounds not yet approved in RA and biosimilars are discussed. Following the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) recommendations, specific treatment of the disease will be discussed with respect to safety and efficacy. In particular, we discuss the question of favoring specific bDMARDs or tsDMARDs in the two settings of insufficient response to methotrexate and to the first bDMARD, respectively.

Rewriting the epigenetic code for tumor resensitization: a review.

PubMed

Oronsky, Bryan; Oronsky, Neil; Scicinski, Jan; Fanger, Gary; Lybeck, Michelle; Reid, Tony

2014-10-01

In cancer chemotherapy, one axiom, which has practically solidified into dogma, is that acquired resistance to antitumor agents or regimens, nearly inevitable in all patients with metastatic disease, remains unalterable and irreversible, rendering therapeutic rechallenge futile. However, the introduction of epigenetic therapies, including histone deacetylase inhibitors (HDACis) and DNA methyltransferase inhibitors (DNMTIs), provides oncologists, like computer programmers, with new techniques to "overwrite" the modifiable software pattern of gene expression in tumors and challenge the "one and done" treatment prescription. Taking the epigenetic code-as-software analogy a step further, if chemoresistance is the product of multiple nongenetic alterations, which develop and accumulate over time in response to treatment, then the possibility to hack or tweak the operating system and fall back on a "system restore" or "undo" feature, like the arrow icon in the Windows XP toolbar, reconfiguring the tumor to its baseline nonresistant state, holds tremendous promise for turning advanced, metastatic cancer from a fatal disease into a chronic, livable condition. This review aims 1) to explore the potential mechanisms by which a group of small molecule agents including HDACis (entinostat and vorinostat), DNMTIs (decitabine and 5-azacytidine), and redox modulators (RRx-001) may reprogram the tumor microenvironment from a refractory to a nonrefractory state, 2) highlight some recent findings, and 3) discuss whether the current "once burned forever spurned" paradigm in the treatment of metastatic disease should be revised to promote active resensitization attempts with formerly failed chemotherapies.

Peptide-Like Nylon-3 Polymers with Activity against Phylogenetically Diverse, Intrinsically Drug-Resistant Pathogenic Fungi

PubMed Central

Rank, Leslie A.; Walsh, Naomi M.; Lim, Fang Yun

2018-01-01

ABSTRACT Understanding the dimensions of fungal diversity has major implications for the control of diseases in humans, plants, and animals and in the overall health of ecosystems on the planet. One ancient evolutionary strategy organisms use to manage interactions with microbes, including fungi, is to produce host defense peptides (HDPs). HDPs and their synthetic analogs have been subjects of interest as potential therapeutic agents. Due to increases in fungal disease worldwide, there is great interest in developing novel antifungal agents. Here we describe activity of polymeric HDP analogs against fungi from 18 pathogenic genera composed of 41 species and 72 isolates. The synthetic polymers are members of the nylon-3 family (poly-β-amino acid materials). Three different nylon-3 polymers show high efficacy against surprisingly diverse fungi. Across the phylogenetic spectrum (with the exception of Aspergillus species), yeasts, dermatophytes, dimorphic fungi, and molds were all sensitive to the effects of these polymers. Even fungi intrinsically resistant to current antifungal drugs, such as the causative agents of mucormycosis (Rhizopus spp.) and those with acquired resistance to azole drugs, showed nylon-3 polymer sensitivity. In addition, the emerging pathogens Pseudogymnoascus destructans (cause of white nose syndrome in bats) and Candida auris (cause of nosocomial infections of humans) were also sensitive. The three nylon-3 polymers exhibited relatively low toxicity toward mammalian cells. These findings raise the possibility that nylon-3 polymers could be useful against fungi for which there are only limited and/or no antifungal agents available at present. IMPORTANCE Fungi reside in all ecosystems on earth and impart both positive and negative effects on human, plant, and animal health. Fungal disease is on the rise worldwide, and there is a critical need for more effective and less toxic antifungal agents. Nylon-3 polymers are short, sequence random, poly-β-amino acid materials that can be designed to manifest antimicrobial properties. Here, we describe three nylon-3 polymers with potent activity against the most phylogenetically diverse set of fungi evaluated thus far in a single study. In contrast to traditional peptides, nylon-3 polymers are highly stable to proteolytic degradation and can be produced efficiently in large quantities at low cost. The ability to modify nylon-3 polymer composition easily creates an opportunity to tailor efficacy and toxicity, which makes these materials attractive as potential broad-spectrum antifungal therapeutics. PMID:29794056

Gastrointestinal bioavailability of 2.0 nm diameter gold nanoparticles.

PubMed

Smith, Candice A; Simpson, Carrie A; Kim, Ganghyeok; Carter, Carly J; Feldheim, Daniel L

2013-05-28

The use of gold nanoparticles as imaging agents and therapeutic delivery systems is growing rapidly. However, a significant limitation of gold nanoparticles currently is their low absorption efficiencies in the gastrointestinal (GI) tract following oral administration. In an attempt to identify ligands that facilitate gold nanoparticle absorption in the GI tract, we have studied the oral bioavailability of 2.0 nm diameter gold nanoparticles modified with the small molecules p-mercaptobenzoic acid and glutathione, and polyethylene glycols (PEG) of different lengths and charge (neutral and anionic). We show that GI absorption of gold nanoparticles modified with the small molecules tested was undetectable. However, the absorption of PEGs depended upon PEG length, with the shortest PEG studied yielding gold nanoparticle absorptions that are orders-of-magnitude larger than observed previously. As the oral route is the most convenient one for administering drugs and diagnostic reagents, these results suggest that short-chain PEGs may be useful in the design of gold nanoparticles for the diagnosis and treatment of disease.

Recommendations for control of pathogens and infectious diseases in fish research facilities☆

PubMed Central

Kent, Michael L.; Feist, Stephen W.; Harper, Claudia; Hoogstraten-Miller, Shelley; Mac Law, J.; Sánchez-Morgado, José M.; Tanguay, Robert L.; Sanders, George E.; Spitsbergen, Jan M.; Whipps, Christopher M.

2012-01-01

Concerns about infectious diseases in fish used for research have risen along with the dramatic increase in the use of fish as models in biomedical research. In addition to acute diseases causing severe morbidity and mortality, underlying chronic conditions that cause low-grade or subclinical infections may confound research results. Here we present recommendations and strategies to avoid or minimize the impacts of infectious agents in fishes maintained in the research setting. There are distinct differences in strategies for control of pathogens in fish used for research compared to fishes reared as pets or in aquaculture. Also, much can be learned from strategies and protocols for control of diseases in rodents used in research, but there are differences. This is due, in part, the unique aquatic environment that is modified by the source and quality of the water provided and the design of facilities. The process of control of pathogens and infectious diseases in fish research facilities is relatively new, and will be an evolving process over time. Nevertheless, the goal of documenting, detecting, and excluding pathogens in fish is just as important as in mammalian research models. PMID:18755294

Recommendations for control of pathogens and infectious diseases in fish research facilities

USGS Publications Warehouse

Kent, M.L.; Feist, S.W.; Harper, C.; Hoogstraten-Miller, S.; Law, J.M.; Sanchez-Morgado, J. M.; Tanguay, R.L.; Sanders, G.E.; Spitsbergen, J.M.; Whipps, Christopher M.

2009-01-01

Concerns about infectious diseases in fish used for research have risen along with the dramatic increase in the use of fish as models in biomedical research. In addition to acute diseases causing severe morbidity and mortality, underlying chronic conditions that cause low-grade or subclinical infections may confound research results. Here we present recommendations and strategies to avoid or minimize the impacts of infectious agents in fishes maintained in the research setting. There are distinct differences in strategies for control of pathogens in fish used for research compared to fishes reared as pets or in aquaculture. Also, much can be learned from strategies and protocols for control of diseases in rodents used in research, but there are differences. This is due, in part, the unique aquatic environment that is modified by the source and quality of the water provided and the design of facilities. The process of control of pathogens and infectious diseases in fish research facilities is relatively new, and will be an evolving process over time. Nevertheless, the goal of documenting, detecting, and excluding pathogens in fish is just as important as in mammalian research models.

Riboflavin Has Neuroprotective Potential: Focus on Parkinson’s Disease and Migraine

PubMed Central

Marashly, Eyad T.; Bohlega, Saeed A.

2017-01-01

With the huge negative impact of neurological disorders on patient’s life and society resources, the discovery of neuroprotective agents is critical and cost-effective. Neuroprotective agents can prevent and/or modify the course of neurological disorders. Despite being underestimated, riboflavin offers neuroprotective mechanisms. Significant pathogenesis-related mechanisms are shared by, but not restricted to, Parkinson’s disease (PD) and migraine headache. Those pathogenesis-related mechanisms can be tackled through riboflavin proposed neuroprotective mechanisms. In fact, it has been found that riboflavin ameliorates oxidative stress, mitochondrial dysfunction, neuroinflammation, and glutamate excitotoxicity; all of which take part in the pathogenesis of PD, migraine headache, and other neurological disorders. In addition, riboflavin-dependent enzymes have essential roles in pyridoxine activation, tryptophan-kynurenine pathway, and homocysteine metabolism. Indeed, pyridoxal phosphate, the active form of pyridoxine, has been found to have independent neuroprotective potential. Also, the produced kynurenines influence glutamate receptors and its consequent excitotoxicity. In addition, methylenetetrahydrofolate reductase requires riboflavin to ensure normal folate cycle influencing the methylation cycle and consequently homocysteine levels which have its own negative neurovascular consequences if accumulated. In conclusion, riboflavin is a potential neuroprotective agent affecting a wide range of neurological disorders exemplified by PD, a disorder of neurodegeneration, and migraine headache, a disorder of pain. In this article, we will emphasize the role of riboflavin in neuroprotection elaborating on its proposed neuroprotective mechanisms in opposite to the pathogenesis-related mechanisms involved in two common neurological disorders, PD and migraine headache, as well as, we encourage the clinical evaluation of riboflavin in PD and migraine headache patients in the future. PMID:28775706

Agricultural pathogen decontamination technology-reducing the threat of infectious agent spread.

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

Betty, Rita G.; Bieker, Jill Marie; Tucker, Mark David

Outbreaks of infectious agricultural diseases, whether natural occurring or introduced intentionally, could have catastrophic impacts on the U.S. economy. Examples of such agricultural pathogens include foot and mouth disease (FMD), avian influenza (AI), citrus canker, wheat and soy rust, etc. Current approaches to mitigate the spread of agricultural pathogens include quarantine, development of vaccines for animal diseases, and development of pathogen resistant crop strains in the case of plant diseases. None of these approaches is rapid, and none address the potential persistence of the pathogen in the environment, which could lead to further spread of the agent and damage aftermore » quarantine is lifted. Pathogen spread in agricultural environments commonly occurs via transfer on agricultural equipment (transportation trailers, tractors, trucks, combines, etc.), having components made from a broad range of materials (galvanized and painted steel, rubber tires, glass and Plexiglas shields, etc), and under conditions of heavy organic load (mud, soil, feces, litter, etc). A key element of stemming the spread of an outbreak is to ensure complete inactivation of the pathogens in the agricultural environment and on the equipment used in those environments. Through the combination of enhanced agricultural pathogen decontamination chemistry and a validated inactivation verification methodology, important technologies for incorporation as components of a robust response capability will be enabled. Because of the potentially devastating economic impact that could result from the spread of infectious agricultural diseases, the proposed capability components will promote critical infrastructure protection and greater border and food supply security. We investigated and developed agricultural pathogen decontamination technologies to reduce the threat of infectious-agent spread, and thus enhance agricultural biosecurity. Specifically, enhanced detergency versions of the patented Sandia decontamination chemistry were developed and tested against a few surrogate pathogens under conditions of relatively heavy organic load. Tests were conducted on surfaces commonly found in agricultural environments. Wide spectrum decontamination efficacy, low corrosivity, and biodegradability issues were addressed in developing an enhanced detergency formulation. A method for rapid assessment of loss of pathogenic activity (inactivation) was also assessed. This enhanced technology will enable rapid assessment of contamination following an intentional event, and will also be extremely useful in routine assessment of agricultural environments. The primary effort during the second year was progress towards a demonstration of both decontamination and viral inactivation technologies of Foot and Mouth virus (FMDv) using the modified SNL chemistry developed through this project. Lab studies using a surrogate virus (bovine enterovirus) were conducted using DF200, modified DF200 chemistry, and decontaminants currently recommended for use in heavily loaded organic, agricultural environments (VirkonS, 10% bleach, sodium hydroxide and citric acid). Tests using actual FMD virus will be performed at the Department of Homeland Security's Plum Island facilities in the fall of 2005. Success and the insight gained from this project will lead to enhanced response capability, which will benefit agencies such as USDA, DHS, DOD, and the agricultural industry.« less

Role of hormones and neurosteroids in epileptogenesis

PubMed Central

Reddy, Doodipala Samba

2013-01-01

This article describes the emerging evidence of hormonal influence on epileptogenesis, which is a process whereby a brain becomes progressively epileptic due to an initial precipitating event of diverse origin such as brain injury, stroke, infection, or prolonged seizures. The molecular mechanisms underlying the development of epilepsy are poorly understood. Neuroinflammation and neurodegeneration appear to trigger epileptogenesis. There is an intense search for drugs that truly prevent the development of epilepsy in people at risk. Hormones play an important role in children and adults with epilepsy. Corticosteroids, progesterone, estrogens, and neurosteroids have been shown to affect seizure activity in animal models and in clinical studies. However, the impact of hormones on epileptogenesis has not been investigated widely. There is emerging new evidence that progesterone, neurosteroids, and endogenous hormones may play a role in regulating the epileptogenesis. Corticosterone has excitatory effects and triggers epileptogenesis in animal models. Progesterone has disease-modifying activity in epileptogenic models. The antiepileptogenic effect of progesterone has been attributed to its conversion to neurosteroids, which binds to GABA-A receptors and enhances phasic and tonic inhibition in the brain. Neurosteroids are robust anticonvulsants. There is pilot evidence that neurosteroids may have antiepileptogenic properties. Future studies may generate new insight on the disease-modifying potential of hormonal agents and neurosteroids in epileptogenesis. PMID:23914154

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

PubMed Central

Omar, Abdelsattar M.; Mahran, Mona A.; Ghatge, Mohini S.; Bamane, Faida H. A.; Ahmed, Mostafa H.; El-Araby, Moustafa E.; Abdulmalik, Osheiza; Safo, Martin K.

2017-01-01

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. PMID:27529207

The spectrum and clinical impact of epigenetic modifier mutations in myeloma

PubMed Central

Pawlyn, Charlotte; Kaiser, Martin F; Heuck, Christoph; Melchor, Lorenzo; Wardell, Christopher P; Murison, Alex; Chavan, Shweta; Johnson, David C; Begum, Dil; Dahir, Nasrin; Proszek, Paula; Cairns, David A; Boyle, Eileen M; Jones, John R; Cook, Gordon; Drayson, Mark T; Owen, Roger G; Gregory, Walter M; Jackson, Graham H; Barlogie, Bart; Davies, Faith E; Walker, Brian A; Morgan, Gareth J

2016-01-01

Purpose Epigenetic dysregulation is known to be an important contributor to myeloma pathogenesis but, unlike in other B cell malignancies, the full spectrum of somatic mutations in epigenetic modifiers has not been previously reported. We sought to address this using results from whole-exome sequencing in the context of a large prospective clinical trial of newly diagnosed patients and targeted sequencing in a cohort of previously treated patients for comparison. Experimental Design Whole-exome sequencing analysis of 463 presenting myeloma cases entered in the UK NCRI Myeloma XI study and targeted sequencing analysis of 156 previously treated cases from the University of Arkansas for Medical Sciences. We correlated the presence of mutations with clinical outcome from diagnosis and compared the mutations found at diagnosis with later stages of disease. Results In diagnostic myeloma patient samples we identify significant mutations in genes encoding the histone 1 linker protein, previously identified in other B-cell malignancies. Our data suggest an adverse prognostic impact from the presence of lesions in genes encoding DNA methylation modifiers and the histone demethylase KDM6A/UTX. The frequency of mutations in epigenetic modifiers appears to increase following treatment most notably in genes encoding histone methyltransferases and DNA methylation modifiers. Conclusions Numerous mutations identified raise the possibility of targeted treatment strategies for patients either at diagnosis or relapse supporting the use of sequencing-based diagnostics in myeloma to help guide therapy as more epigenetic targeted agents become available. PMID:27235425

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

PubMed

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.

The role of the intestinal microvasculature in inflammatory bowel disease: studies with a modified Caco-2 model including endothelial cells resembling the intestinal barrier in vitro.

PubMed

Kasper, Jennifer Y; Hermanns, Maria Iris; Cavelius, Christian; Kraegeloh, Annette; Jung, Thomas; Danzebrink, Rolf; Unger, Ronald E; Kirkpatrick, Charles James

The microvascular endothelium of the gut barrier plays a crucial role during inflammation in inflammatory bowel disease. We have modified a commonly used intestinal cell model based on the Caco-2 cells by adding microvascular endothelial cells (ISO-HAS-1). Transwell filters were used with intestinal barrier-forming Caco-2 cells on top and the ISO-HAS-1 on the bottom of the filter. The goal was to determine whether this coculture mimics the in vivo situation more closely, and whether the model is suitable to evaluate interactions of, for example, prospective nanosized drug vehicles or contrast agents with this coculture in a physiological and inflamed state as it would occur in inflammatory bowel disease. We monitored the inflammatory responsiveness of the cells (release of IL-8, soluble intercellular adhesion molecule 1, and soluble E-selectin) after exposure to inflammatory stimuli (lipopolysaccharide, TNF-α, INF-γ, IL1-β) and a nanoparticle (Ba/Gd: coprecipitated BaSO 4 and Gd(OH) 3 ), generally used as contrast agents. The barrier integrity of the coculture was evaluated via the determination of transepithelial electrical resistance and the apparent permeability coefficient (P app ) of NaFITC. The behavior of the coculture Caco-1/ISO-HAS-1 was compared to the respective monocultures Caco-2 and ISO-HAS-1. Based on transepithelial electrical resistance, the epithelial barrier integrity of the coculture remained stable during incubation with all stimuli, whereas the P app decreased after exposure to the cytokine mixture (TNF-α, INF-γ, IL1-β, and Ba/Gd). Both the endothelial and epithelial monocultures showed a high inflammatory response in both the upper and lower transwell-compartments. However, in the coculture, inflammatory mediators were only detected on the epithelial side and not on the endothelial side. Thus in the coculture, based on the P app , the epithelial barrier appears to prevent a potential inflammatory overreaction in the underlying endothelial cells. In summary, this coculture model exhibits in vivo-like features, which cannot be observed in conventional monocultures, making the former more suitable to study interactions with external stimuli.

Phosphodiesterase 7 Inhibition Induces Dopaminergic Neurogenesis in Hemiparkinsonian Rats

PubMed Central

Morales-Garcia, Jose A.; Alonso-Gil, Sandra; Gil, Carmen; Martinez, Ana; Santos, Angel

2015-01-01

Parkinson’s disease is characterized by a loss of dopaminergic neurons in a specific brain region, the ventral midbrain. Parkinson’s disease is diagnosed when approximately 50% of the dopaminergic neurons of the substantia nigra pars compacta (SNpc) have degenerated and the others are already affected by the disease. Thus, it is conceivable that all therapeutic strategies, aimed at neuroprotection, start too late. Therefore, an urgent medical need exists to discover new pharmacological targets and novel drugs with disease-modifying properties. In this regard, modulation of endogenous adult neurogenesis toward a dopaminergic phenotype might provide a new strategy to target Parkinson’s disease by partially ameliorating the dopaminergic cell loss that occurs in this disorder. We have previously shown that a phosphodiesterase 7 (PDE7) inhibitor, S14, exerts potent neuroprotective and anti-inflammatory effects in different rodent models of Parkinson’s disease, indicating that this compound could represent a novel therapeutic agent to stop the dopaminergic cell loss that occurs during the progression of the disease. In this report we show that, in addition to its neuroprotective effect, the PDE7 inhibitor S14 is also able to induce endogenous neuroregenerative processes toward a dopaminergic phenotype. We describe a population of actively dividing cells that give rise to new neurons in the SNpc of hemiparkinsonian rats after treatment with S14. In conclusion, our data identify S14 as a novel regulator of dopaminergic neuron generation. Significance Parkinson’s disease is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the ventral midbrain. Currently, no cure and no effective disease-modifying therapy are available for Parkinson’s disease; therefore, an urgent medical need exists to discover new pharmacological targets and novel drugs for the treatment of this disorder. The present study reports that an inhibitor of the enzyme phosphodiesterase 7 (S14) induces proliferation in vitro and in vivo of neural stem cells, promoting its differentiation toward a dopaminergic phenotype and therefore enhancing dopaminergic neuron generation. Because this drug is also able to confer neuroprotection of these cells in animal models of Parkinson’s disease, S14 holds great promise as a therapeutic new strategy for this disorder. PMID:25925836

A few bad apples: a model of disease influenced agent behaviour in a heterogeneous contact environment.

PubMed

Enright, Jessica; Kao, Rowland R

2015-01-01

For diseases that infect humans or livestock, transmission dynamics are at least partially dependent on human activity and therefore human behaviour. However, the impact of human behaviour on disease transmission is relatively understudied, especially in the context of heterogeneous contact structures such as described by a social network. Here, we use a strategic game, coupled with a simple disease model, to investigate how strategic agent choices impact the spread of disease over a contact network. Using beliefs that are based on disease status and that build up over time, agents choose actions that stochastically determine disease spread on the network. An agent's disease status is therefore a function of both his own and his neighbours actions. The effect of disease on agents is modelled by a heterogeneous payoff structure. We find that the combination of network shape and distribution of payoffs has a non-trivial impact on disease prevalence, even if the mean payoff remains the same. An important scenario occurs when a small percentage (called noncooperators) have little incentive to avoid disease. For diseases that are easily acquired when taking a risk, then even when good behavior can lead to disease eradication, a small increase in the percentage of noncooperators (less than 5%) can yield a large (up to 25%) increase in prevalence.

Human pregnancy safety for agents used to treat rheumatoid arthritis: adequacy of available information and strategies for developing post-marketing data

PubMed Central

Chambers, Christina D; Tutuncu, Zuhre N; Johnson, Diana; Jones, Kenneth L

2006-01-01

For female patients with rheumatoid arthritis, the availability of a host of new disease modifying antirheumatic drugs has raised important questions about fetal safety if a woman becomes pregnant while she is being treated. In addition, there is limited safety information regarding many of the older medications commonly used to treat rheumatoid arthritis in women of reproductive age. Current summary pregnancy risk information for selected medications used to treat rheumatoid arthritis is reviewed in the context of the pregnancy label category. In addition, the strengths and weaknesses of post-marketing strategies for developing new pregnancy safety information are described. PMID:16774693

Developing new drugs for ovarian cancer: a challenging task in a changing reality.

PubMed

Canetta, R M; Carter, S K

1984-01-01

Recent therapeutic and technological advances have profoundly modified the parameters of new drug testing in ovarian cancer. The potential of compounds tested today in this disease therefore needs to be assessed according to this changing reality. Previous treatment with or without cisplatin is the criterion we have applied in our review of the single agent clinical data. Results obtained with older compounds have also been, when possible, reassessed in order to facilitate a comparative interpretation of recent trials. A brief overview of the most recently developed laboratory screening models has been conducted in order to stress their close relationship and their crucial role in future new drug development.

Bacterial meningitis - principles of antimicrobial treatment.

PubMed

Jawień, Miroslaw; Garlicki, Aleksander M

2013-01-01

Bacterial meningitis is associated with significant morbidity and mortality despite the availability of effective antimicrobial therapy. The management approach to patients with suspected or proven bacterial meningitis includes emergent cerebrospinal fluid analysis and initiation of appropriate antimicrobial and adjunctive therapies. The choice of empirical antimicrobial therapy is based on the patient's age and underlying disease status; once the infecting pathogen is isolated, antimicrobial therapy can be modified for optimal treatment. Successful treatment of bacterial meningitis requires the knowledge on epidemiology including prevalence of antimicrobial resistant pathogens, pathogenesis of meningitis, pharmacokinetics and pharmacodynamics of antimicrobial agents. The emergence of antibiotic-resistant bacterial strains in recent years has necessitated the development of new strategies for empiric antimicrobial therapy for bacterial meningitis.

Production And Artile Of Iron/Surfactant-Modified Zeolite Pellets To Retain And Destroy Water Pollutants

DOEpatents

BOWMAN, ROBERT S.; [et al

2001-07-17

A method of producing a pollutant adsorption and degradation article, and such article, are provided. At least one adsorbent is mixed with at least one pollutant transforming agent to form a mixture. This mixture is compacted to form a porous, highly permeable article. If necessary, the article can be modified with surfactant either after the compacting step or by adding the surfactant to the mixture prior to the compacting step. In addition, if necessary, a binding agent can be added to the mixture prior to the compacting step.

Vedolizumab as a Treatment for Crohn's Disease and Ulcerative Colitis.

PubMed

Ha, Christina; Kornbluth, Asher

2014-12-01

The management of Crohn's disease and ulcerative colitis has become increasingly complex. With the current utilization of immunosuppressive therapies earlier in the disease course for patients presenting with moderate to severe disease, there is a great need for additional biologic agents targeting inflammatory mediators other than anti-tumor necrosis factor-α (anti-TNF) agents. Although anti-TNF agents have positively impacted the treatment of inflammatory bowel disease, many patients can lose their response or develop intolerance to these agents over time through the formation of antidrug antibodies. Furthermore, a sizeable percentage of patients are primary nonresponders to anti-TNF drugs. Vedolizumab (Entyvio, Takeda Pharmaceuticals), a monoclonal antibody to the α4β7 integrin, inhibits gut lymphocyte trafficking and has been demonstrated to be an effective and safe agent for the treatment of both Crohn's disease and ulcerative colitis. This article reviews the clinical trial evidence and rationale for the use of vedolizumab in moderate to severe Crohn's disease and ulcerative colitis.

Vedolizumab as a Treatment for Crohn’s Disease and Ulcerative Colitis

PubMed Central

Ha, Christina

2014-01-01

The management of Crohn’s disease and ulcerative colitis has become increasingly complex. With the current utilization of immunosuppressive therapies earlier in the disease course for patients presenting with moderate to severe disease, there is a great need for additional biologic agents targeting inflammatory mediators other than anti-tumor necrosis factor-α (anti-TNF) agents. Although anti-TNF agents have positively impacted the treatment of inflammatory bowel disease, many patients can lose their response or develop intolerance to these agents over time through the formation of antidrug antibodies. Furthermore, a sizeable percentage of patients are primary nonresponders to anti-TNF drugs. Vedolizumab (Entyvio, Takeda Pharmaceuticals), a monoclonal antibody to the α4β7 integrin, inhibits gut lymphocyte trafficking and has been demonstrated to be an effective and safe agent for the treatment of both Crohn’s disease and ulcerative colitis. This article reviews the clinical trial evidence and rationale for the use of vedolizumab in moderate to severe Crohn’s disease and ulcerative colitis. PMID:27524947

Recent advances in the management of chronic stable angina II. Anti-ischemic therapy, options for refractory angina, risk factor reduction, and revascularization

PubMed Central

Kones, Richard

2010-01-01

The objectives in treating angina are relief of pain and prevention of disease progression through risk reduction. Mechanisms, indications, clinical forms, doses, and side effects of the traditional antianginal agents – nitrates, β-blockers, and calcium channel blockers – are reviewed. A number of patients have contraindications or remain unrelieved from anginal discomfort with these drugs. Among newer alternatives, ranolazine, recently approved in the United States, indirectly prevents the intracellular calcium overload involved in cardiac ischemia and is a welcome addition to available treatments. None, however, are disease-modifying agents. Two options for refractory angina, enhanced external counterpulsation and spinal cord stimulation (SCS), are presented in detail. They are both well-studied and are effective means of treating at least some patients with this perplexing form of angina. Traditional modifiable risk factors for coronary artery disease (CAD) – smoking, hypertension, dyslipidemia, diabetes, and obesity – account for most of the population-attributable risk. Individual therapy of high-risk patients differs from population-wide efforts to prevent risk factors from appearing or reducing their severity, in order to lower the national burden of disease. Current American College of Cardiology/American Heart Association guidelines to lower risk in patients with chronic angina are reviewed. The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial showed that in patients with stable angina, optimal medical therapy alone and percutaneous coronary intervention (PCI) with medical therapy were equal in preventing myocardial infarction and death. The integration of COURAGE results into current practice is discussed. For patients who are unstable, with very high risk, with left main coronary artery lesions, in whom medical therapy fails, and in those with acute coronary syndromes, PCI is indicated. Asymptomatic patients with CAD and those with stable angina may defer intervention without additional risk to see if they will improve on optimum medical therapy. For many patients, coronary artery bypass surgery offers the best opportunity for relieving angina, reducing the need for additional revascularization procedures and improving survival. Optimal medical therapy, percutaneous coronary intervention, and surgery are not competing therapies, but are complementary and form a continuum, each filling an important evidence-based need in modern comprehensive management. PMID:20859545

Treatment of very early rheumatoid arthritis with symptomatic therapy, disease-modifying antirheumatic drugs, or biologic agents: a cost-effectiveness analysis.

PubMed

Finckh, Axel; Bansback, Nick; Marra, Carlo A; Anis, Aslam H; Michaud, Kaleb; Lubin, Stanley; White, Marc; Sizto, Sonia; Liang, Matthew H

2009-11-03

Long-term control or remission of rheumatoid arthritis (RA) may be possible with very early treatment. However, no optimal first therapeutic strategy has been determined. To assess the potential cost-effectiveness of major therapeutic strategies for very early RA. Decision analytic model with probabilistic sensitivity analyses. Published data, the National Data Bank for Rheumatic Diseases, and actual 2007 hospital costs. U.S. adults with very early RA (symptom duration

Diseases as agents of disturbance in ponderosa pine

Treesearch

Gregory M. Filip

2005-01-01

Several diseases affect the growth and survival of ponderosa pine in the Pacific Northwest and serve as agents of disturbance. Probably the most widespread and damaging class of disease agents is dwarf mistletoe, which causes serious growth loss and mortality of ponderosa pine. Dwarf mistletoes (Arceuthobium spp.) are seed plants that can parasitize...

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

PubMed

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 chosen in the illustration). It would also require additional evaluations to estimate the rate of ADAS-cog change toward the end of the trial. A regulatory claim of disease modification for any compound will likely require additional verification of a drug's effect on a validated biomarker of Alzheimer's pathology. Incorporation of the RSD in AD trials is feasible. With proper trial setup and statistical procedures, this design could support the detection of a disease-modifying effect. In our opinion, a two-phase RSD with a stepwise hypothesis testing procedure could be a reasonable option for future studies.

Synthesis of bio-based nanocomposites for controlled release of antimicrobial agents in food packaging

NASA Astrophysics Data System (ADS)

DeGruson, Min Liu

The utilization of bio-based polymers as packaging materials has attracted great attention in both scientific and industrial areas due to the non-renewable and nondegradable nature of synthetic plastic packaging. Polyhydroxyalkanoate (PHA) is a biobased polymer with excellent film-forming and coating properties, but exhibits brittleness, insufficient gas barrier properties, and poor thermal stability. The overall goal of the project was to develop the polyhydroxyalkanoate-based bio-nanocomposite films modified by antimicrobial agents with improved mechanical and gas barrier properties, along with a controlled release rate of antimicrobial agents for the inhibition of foodborne pathogens and fungi in food. The ability for antimicrobial agents to intercalate into layered double hydroxides depended on the nature of the antimicrobial agents, such as size, spatial structure, and polarity, etc. Benzoate and gallate anions were successfully intercalated into LDH in the present study and different amounts of benzoate anion were loaded into LDH under different reaction conditions. Incorporation of nanoparticles showed no significant effect on mechanical properties of polyhydroxybutyrate (PHB) films, however, significantly increased the tensile strength and elongation at break of polyhydroxybutyrate-co-valerate (PHBV) films. The effects of type and concentration of LDH nanoparticles (unmodified LDH and LDH modified by sodium benzoate and sodium gallate) on structure and properties of PHBV films were then studied. The arrangement of LDH in the bio-nanocomposite matrices ranged from exfoliated to phase-separated depending on the type and concentration of LDH nanoparticles. Intercalated or partially exfoliated structures were obtained using modified LDH, however, only phase-separated structures were formed using unmodified LDH. The mechanical (tensile strength and elongation at break) and thermo-mechanical (storage modulus) properties were significantly improved with low concentrations of nanoparticles incorporated into the polymer. The incorporation of LDH modified by sodium benzoate further improved the mechanical properties in comparison with unmodified LDH, which may be due to the increased compatibility between PHBV and nanoparticles and the larger basal distance between nanolayers after modification. The concentration of benzoate anions in LDH nanoparticles was another factor which affected the properties of PHBV composite films. The PHBV film with 2% modified LDH with 20.9 % w/w of benzoate anions in LDH had the best mechanical and thermomechanical properties. Apparent glass transition temperature increased with the addition of modified LDH but did not change with the addition of unmodified LDH. Moreover, the effect of nanoparticles on thermal properties as well as crystallization of PHBV composites was dependent on the type of nanoparticles. A comparison of mechanical properties and release kinetics of antimicrobial agents directly dispersed in PHBV and modified in LDH and then dispersed in PHBV was made. The results indicated that mechanical properties increased and release rate decreased in the latter case. The release of benzoate and gallate into DI water from PHBV composite films with LDH modified by benzoate and gallate followed pseudo-Fickian behavior fitted with a power law model. The release of benzoate from PHBV composite films with LDH modified by benzoate was also fitted with a Weibull model indicating Fickian behavior in fractal substrate morphologically similar to the percolation cluster. The concentration of modified LDH and the loading of benzoate in modified LDH showed a significant effect on the release kinetics of benzoate. The diffusivities of benzoate at 21 °C ranged from 3.41 to14.97 x 10-16 m 2/s. The slowest release rate was achieved by the PHBV film containing 5 % w/w of modified LDH with medium loading of benzoate (21 % w/w of benzoate) in nanoparticles. The release of gallate from PHBV was much faster than that of benzoate. The effective diffusivity of benzoate increased with increase of temperature and the activation energy Ea for benzoate diffusion was calculated as 66.4 kJ/mol. It will be thus possible to design biodegradable polymeric nanocomposites with a tunable release of active molecules for various applications. (Abstract shortened by UMI.).

A review of the possible mechanisms of action of tocotrienol - a potential antiosteoporotic agent.

PubMed

Chin, Kok-Yong; Mo, Huanbiao; Soelaiman, Ima-Nirwana

2013-12-01

Osteoporosis is posing a tremendous healthcare problem globally. Much effort has been invested in finding novel antiosteoporotic agents to stop the progression of this disease. Tocotrienol, one of the isoforms of vitamin E, is poised as a potential antiosteoporotic agent. Previous studies showed that tocotrienol as a single isomer or as a mixture demonstrated both anabolic and antiresorptive effects in various rodent models of osteoporosis. In vitro experiments further demonstrated that tocotrienol could up-regulate genes related to osteoblastogenesis and modify receptor activator of nuclear factor kappa B signaling against osteoclastogenesis. Additionally, tocotrienol was also shown to be a strong 3- hydroxy-3-methyl-glutaryl-CoA reductase down-regulator with a mechanism different from that of statins. Inhibition of the mevalonate pathway affects both osteoblast and osteoclast formation in favor of the former. Tocopherol, a more commonly used isoform of vitamin E does not possess similar effects. Tocotrienol is also a potent antioxidant. It can scavenge free radicals and prevent oxidative damage on osteoblast thus promoting its survival. It may also up-regulate the antioxidant defense network in osteoclast and indirectly act against free radical signaling essential in osteoclastogenesis. The effects of tocotrienol on Wnt/β-catenin signaling essential in osteoblastogenesis have not been determined. More mechanistic studies need to be conducted to illustrate the antiosteoporotic effects of tocotrienol. Clinical trials are also required to confirm its effects in humans. In conclusion, tocotrienol demonstrates great potential as an antiosteoporotic agent and much research effort should be invested to develop it as an agent to curb osteoporosis.

Co-infection with Helicobacter pylori and Epstein-Barr virus in benign upper digestive diseases: An endoscopic and serologic pilot study.

PubMed

Buzás, György M; Konderák, Judith

2016-06-01

Some gastric cancers are Epstein-Barr virus associated. To assess the prevalence of Helicobacter pylori and viral co-infection in benign upper digestive diseases. One hundred and four outpatients were included in a prospective endoscopic-serologic study. Epstein-Barr virus immunoglobulin G (IgG), immunoglobulin M and viral capsid antigen titres were assayed with an ELISA test. Helicobacter pylori was determined by the modified Giemsa stain and by IgG-chemiluminescence. The overall prevalence of Helicobacter pylori was 56.7%. Duodenal ulcer patients were infected in 72.5 % of the cases, with the prevalence being 33.3% in functional dyspepsia (p = 0.0008) and 25.8% in reflux patients (p = 0.0001). Epstein-Barr virus IgG was detected in 70.1% of the whole group, 75% of duodenal ulcer patients, 51.2% of functional dyspepsia patients (p = 0.04) and 51.6% of the reflux disease cases (p = 0.04). Co-infection with both agents was detected in 60% of duodenal ulcer patients, 18.1% of functional dyspepsia (p = 0.00014) and 12.9% of reflux disease patients (p = 0.00012). Anti-viral IgG titre displayed a 31.7 ± 3.0 cut-off index in duodenal ulcer, 20.5 ± 3.5 in functional dyspepsia (p = 0.01) and 21.4 ± 3.6 in reflux cases (p = 0.03). Both Helicobacter pylori and Epstein-Barr virus, and co-infection with these agents, were significantly more prevalent in duodenal ulcer patients than in dyspeptic/reflux patients.

Epigallocatechin Gallate (EGCG) Inhibits Alpha-Synuclein Aggregation: A Potential Agent for Parkinson's Disease.

PubMed

Xu, Yan; Zhang, Yanyan; Quan, Zhenzhen; Wong, Winnie; Guo, Jianping; Zhang, Rongkai; Yang, Qinghu; Dai, Rongji; McGeer, Patrick L; Qing, Hong

2016-10-01

Protein aggregation is a prominent feature of many neurodegenerative disorders including Parkinson's disease (PD). Aggregation of alpha-synuclein (SNCA) may underlie the pathology of PD. They are the main components of Lewy bodies and dystrophic neurites that are the intraneuronal inclusions characteristic of the disease. We have demonstrated that the polyphenol (-)-epi-gallocatechine gallate (EGCG) inhibited SNCA aggregation, which made it a candidate for therapeutic intervention in PD. Three methods were used: SNCA fibril formation inhibition by EGCG in incubates; inhibition of the SNCA fluorophore A-Syn-HiLyte488 binding to plated SNCA in microwells; and inhibition of the A-Syn-HiLyte488 probe binding to aggregated SNCA in postmortem PD tissue. Recombinant human SNCA was incubated under conditions that result in fibril formation. The aggregation was blocked by 100 nM EGCG in a concentration-dependent manner, as shown by an absence of thioflavin T binding. In the microplate assay system, the ED 50 of EGCG inhibition of A-Syn-HiLyte488 binding to coated SNCA was 250 nM. In the PD tissue based assay, SNCA aggregates were recognized by incubation with 7 nM of A-Syn-HiLyte488. This binding was blocked by EGCG in a concentration dependent manner. The SNCA amino acid sites, which potentially interacted with EGCG, were detected on peptide membranes. It was implicated that EGCG binds to SNCA by instable hydrophobic interactions. In this study, we suggested that EGCG could be a potent remodeling agent of SNCA aggregates and a potential disease modifying drug for the treatment of PD and other α-synucleinopathies.

Borrelia burgdorferi-specific IgA in Lyme Disease.

PubMed

D'Arco, Christina; Dattwyler, Raymond J; Arnaboldi, Paul M

2017-05-01

The laboratory diagnosis of Lyme disease is currently dependent on the detection of IgM and IgG antibodies against Borrelia burgdorferi, the causative agent of the disease. The significance of serum IgA against B. burgdorferi remains unclear. The production of intrathecal IgA has been noted in patients with the late Lyme disease manifestation, neuroborreliosis, but production of antigen-specific IgA during early disease has not been evaluated. In the current study, we assessed serum IgA binding to the B. burgdorferi peptide antigens, C6, the target of the FDA-cleared C6 EIA, and FlaB(211-223)-modVlsE(275-291), a peptide containing a Borrelia flagellin epitope linked to a modified VlsE sequence, in patients with early and late Lyme disease. Specific IgA was detected in 59 of 152 serum samples (38.8%) from early Lyme disease patients. Approximately 50% of early Lyme disease patients who were seropositive for peptide-specific IgM and/or IgG were also seropositive for peptide-specific IgA. In a subpopulation of patients, high peptide-specific IgA could be correlated with disseminated disease, defined as multiple erythema migrans lesions, and neurological disease complications. These results suggest that there may be an association between elevated levels of antigen-specific IgA and particular disease manifestations in some patients with early Lyme disease. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

9 CFR 121.4 - Overlap select agents and toxins.

Code of Federal Regulations, 2010 CFR

2010-01-01

... in paragraph (b) of this section that have been genetically modified. (d) Overlap select agents or... OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS POSSESSION, USE... elements, recombinant nucleic acids, and recombinant organisms: (1) Nucleic acids that can produce...

21 CFR 1271.90 - Are there exceptions from the requirement of determining donor eligibility, and what labeling...

Code of Federal Regulations, 2011 CFR

2011-04-01

... agents and/or (B) Risk factors for or clinical evidence of relevant communicable disease agents or... performed indicate: (i) The presence of relevant communicable disease agents and/or (ii) Risk factors for or... is for autologous use only, “WARNING: Advise recipient of communicable disease risks,” (i) When the...

The kuru infectious agent is a unique geographic isolate distinct from Creutzfeldt–Jakob disease and scrapie agents

PubMed Central

Manuelidis, Laura; Chakrabarty, Trisha; Miyazawa, Kohtaro; Nduom, Nana-Aba; Emmerling, Kaitlin

2009-01-01

Human sporadic Creutzfeldt–Jakob disease (sCJD), endemic sheep scrapie, and epidemic bovine spongiform encephalopathy (BSE) are caused by a related group of infectious agents. The new U.K. BSE agent spread to many species, including humans, and clarifying the origin, specificity, virulence, and diversity of these agents is critical, particularly because infected humans do not develop disease for many years. As with viruses, transmissible spongiform encephalopathy (TSE) agents can adapt to new species and become more virulent yet maintain fundamentally unique and stable identities. To make agent differences manifest, one must keep the host genotype constant. Many TSE agents have revealed their independent identities in normal mice. We transmitted primate kuru, a TSE once epidemic in New Guinea, to mice expressing normal and ≈8-fold higher levels of murine prion protein (PrP). High levels of murine PrP did not prevent infection but instead shortened incubation time, as would be expected for a viral receptor. Sporadic CJD and BSE agents and representative scrapie agents were clearly different from kuru in incubation time, brain neuropathology, and lymphoreticular involvement. Many TSE agents can infect monotypic cultured GT1 cells, and unlike sporadic CJD isolates, kuru rapidly and stably infected these cells. The geographic independence of the kuru agent provides additional reasons to explore causal environmental pathogens in these infectious neurodegenerative diseases. PMID:19633190

Effect of bioadhesion on initial in vitro buoyancy of effervescent floating matrix tablets of ciprofloxacin HCL

PubMed Central

Negi, Jeetendra Singh; Trivedi, Abhinav; Khanduri, Praveen; Negi, Vandana; Kasliwal, Nikhil

2011-01-01

The purpose of this study was to investigate effect of bioadhesion on the initial in vitro buoyancy behaviour of effervescent matrix tablets of ciprofloxacin HCl (CIPRO). Tablets were prepared by direct compression using HPMC K4M and Carbopol 971P as hydrophilic-controlled release polymers, sodium bicarbonate (NaHCO3) as gas-generating agent, polyplasdone XL, Explotab and Ac-Di-Sol as swelling agents. Tablets were evaluated for normal and modified initial in vitro floating behavior, floating duration, swelling behavior and in vitro drug release studies. A modified buoyancy lag time for tablets was determined in order to include the effect of bioadhesion on initial buoyancy. The initial buoyancy was found depended on bioadhesion ability of tablets. The lowest modified buoyancy lag time of 20 seconds was obtained for Formulation F7 having both NaHCO3 and polyplasdone XL. The floating duration was also found dependent on concentration of NaHCO3 and swelling agents. The drug release of F7 was also sustained up to 12-hr duration with anomalous drug transport mechanism. PMID:22171304

Hybrid Modified K-Means with C4.5 for Intrusion Detection Systems in Multiagent Systems

PubMed Central

Laftah Al-Yaseen, Wathiq; Ali Othman, Zulaiha; Ahmad Nazri, Mohd Zakree

2015-01-01

Presently, the processing time and performance of intrusion detection systems are of great importance due to the increased speed of traffic data networks and a growing number of attacks on networks and computers. Several approaches have been proposed to address this issue, including hybridizing with several algorithms. However, this paper aims at proposing a hybrid of modified K-means with C4.5 intrusion detection system in a multiagent system (MAS-IDS). The MAS-IDS consists of three agents, namely, coordinator, analysis, and communication agent. The basic concept underpinning the utilized MAS is dividing the large captured network dataset into a number of subsets and distributing these to a number of agents depending on the data network size and core CPU availability. KDD Cup 1999 dataset is used for evaluation. The proposed hybrid modified K-means with C4.5 classification in MAS is developed in JADE platform. The results show that compared to the current methods, the MAS-IDS reduces the IDS processing time by up to 70%, while improving the detection accuracy. PMID:26161437

Hybrid Modified K-Means with C4.5 for Intrusion Detection Systems in Multiagent Systems.

PubMed

Laftah Al-Yaseen, Wathiq; Ali Othman, Zulaiha; Ahmad Nazri, Mohd Zakree

2015-01-01

Presently, the processing time and performance of intrusion detection systems are of great importance due to the increased speed of traffic data networks and a growing number of attacks on networks and computers. Several approaches have been proposed to address this issue, including hybridizing with several algorithms. However, this paper aims at proposing a hybrid of modified K-means with C4.5 intrusion detection system in a multiagent system (MAS-IDS). The MAS-IDS consists of three agents, namely, coordinator, analysis, and communication agent. The basic concept underpinning the utilized MAS is dividing the large captured network dataset into a number of subsets and distributing these to a number of agents depending on the data network size and core CPU availability. KDD Cup 1999 dataset is used for evaluation. The proposed hybrid modified K-means with C4.5 classification in MAS is developed in JADE platform. The results show that compared to the current methods, the MAS-IDS reduces the IDS processing time by up to 70%, while improving the detection accuracy.

Management of lower-risk myelodysplastic syndromes without del5q: current approach and future trends.

PubMed

Stahl, Maximilian; Zeidan, Amer M

2017-04-01

Myelodysplastic syndromes (MDS) are characterized by progressive bone marrow failure manifesting as blood cytopenia and a variable risk of progression into acute myeloid leukemia. MDS is heterogeneous in biology and clinical behavior. MDS are generally divided into lower-risk (LR) and higher-risk (HR) MDS. Goals of care in HR-MDS focus on changing the natural history of the disease, whereas in LR-MDS symptom control and quality of life are the main goals. Areas covered: We review the epidemiology, tools of risk assessment, and the available therapeutic modalities for LR-MDS. We discuss the use of erythropoiesis stimulating agents (ESAs), immunosuppressive therapy (IST), lenalidomide and the hypomethylating agents (HMAs). We also discuss the predictors of response, combination treatment modalities, and management of iron overload. Lastly, we overview the most promising investigational agents for LR-MDS. Expert commentary: It remains unclear how to best incorporate a wealth of new genetic and epigenetic prognostic markers into risk assessment tools especially for LR-MDS patients. Only a subset of patients respond to current treatment modalities and most responders eventually lose their response. Once standard therapeutic options fail, management becomes more challenging. Combination-based approaches have been largely unsuccessful. Among the most promising investigational are the TPO agonists, TGF- β pathway inhibitors, telomerase inhibitors, and the splicing modifiers.

Manganese-containing Prussian blue nanoparticles for imaging of pediatric brain tumors

PubMed Central

Dumont, Matthieu F; Yadavilli, Sridevi; Sze, Raymond W; Nazarian, Javad; Fernandes, Rohan

2014-01-01

Pediatric brain tumors (PBTs) are a leading cause of death in children. For an improved prognosis in patients with PBTs, there is a critical need to develop molecularly-specific imaging agents to monitor disease progression and response to treatment. In this paper, we describe manganese-containing Prussian blue nanoparticles as agents for molecular magnetic resonance imaging (MRI) and fluorescence-based imaging of PBTs. Our core-shell nanoparticles consist of a core lattice structure that incorporates and retains paramagnetic Mn2+ ions, and generates MRI contrast (both negative and positive). The biofunctionalized shell is comprised of fluorescent avidin, which serves the dual purpose of enabling fluorescence imaging and functioning as a platform for the attachment of biotinylated ligands that target PBTs. The surfaces of our nanoparticles are modified with biotinylated antibodies targeting neuron-glial antigen 2 or biotinylated transferrin. Both neuron-glial antigen 2 and the transferrin receptor are protein markers overexpressed in PBTs. We describe the synthesis, biofunctionalization, and characterization of these multimodal nanoparticles. Further, we demonstrate the MRI and fluorescence imaging capabilities of manganese-containing Prussian blue nanoparticles in vitro. Finally, we demonstrate the potential of these nanoparticles as PBT imaging agents by measuring their organ and brain biodistribution in an orthotopic mouse model of PBTs using ex vivo fluorescence imaging. PMID:24920896

A comparison of DNA extraction procedures for the detection of Mycobacterium ulcerans, the causative agent of Buruli ulcer, in clinical and environmental specimens.

PubMed

Durnez, Lies; Stragier, Pieter; Roebben, Karen; Ablordey, Anthony; Leirs, Herwig; Portaels, Françoise

2009-02-01

Mycobacterium ulcerans is the causative agent of Buruli ulcer, the third most common mycobacterial disease in humans after tuberculosis and leprosy. Although the disease is associated with aquatic ecosystems, cultivation of the bacillus from the environment is difficult to achieve. Therefore, at the moment, research is based on the detection by PCR of the insertion sequence IS2404 present in M. ulcerans and some closely related mycobacteria. In the present study, we compared four DNA extraction methods for detection of M. ulcerans DNA, namely the one tube cell lysis and DNA extraction procedure (OT), the FastPrep procedure (FP), the modified Boom procedure (MB), and the Maxwell 16 Procedure (M16). The methods were performed on serial dilutions of M. ulcerans, followed by PCR analysis with different PCR targets in M. ulcerans to determine the detection limit (DL) of each method. The purity of the extracted DNA and the time and effort needed were compared as well. All methods were performed on environmental specimens and the two best methods (MB and M16) were tested on clinical specimens for detection of M. ulcerans DNA. When comparing the DLs of the DNA extraction methods, the MB and M16 had a significantly lower DL than the OT and FP. For the different PCR targets, IS2404 showed a significantly lower DL than mlsA, MIRU1, MIRU5 and VNTR6. The FP and M16 were considerably faster than the MB and OT, while the purity of the DNA extracted with the MB was significantly higher than the DNA extracted with the other methods. The MB performed best on the environmental and clinical specimens. This comparative study shows that the modified Boom procedure, although lengthy, provides a better method of DNA extraction than the other methods tested for detection and identification of M. ulcerans in both clinical and environmental specimens.

[Application of basic research to development of diagnostics and therapeutic agents against inflammatory diseases].

PubMed

Izuhara, Kenji; Ohta, Shoichiro; Arima, Kazuhiko; Suzuki, Shoichi; Inamitsu, Masako; Yamamoto, Ken-ichi

2013-10-01

Biomarkers are generally important for the treatment of patients from the points of diagnosis of disease, assessment of cure, assessment of prognosis such as metastasis or recurrence, prevention of disease, and prediction of drug efficacy. Currently it is well accepted that allergic diseases such as bronchial asthma and atopic dermatitis are not single diseases, but syndromes encompassing different diseases entities. Therefore, it is important to cluster allergic disease patients to assess prognosis or the choice of therapeutic drugs, and useful biomarkers are required for these purposes. Periostin, an extracellular matrix protein, has recently emerged as a biomarker useful for clustering asthma patients. We further found that periostin plays an important role in allergic inflammation and based on this finding we are now developing therapeutic agents targeting periostin against allergic diseases. Since periostin is involved in the pathogenesis of various inflammatory diseases in addition to allergic diseases, such diagnostics and therapeutic agents can be applied to many inflammatory diseases. In this article, we describe the history of periostin research and our application of basic research to the development of diagnostics and therapeutic agents against inflammatory diseases.

Triumph and tragedy: anemia management in chronic kidney disease.

PubMed

Novak, James E; Szczech, Lynda A

2008-11-01

Recent trial data have resulted in a reevaluation of the management of anemia in chronic kidney disease, including the use of erythropoiesis-stimulating agents, intravenous iron, and novel pharmaceuticals. In this review, we evaluate the latest research on anemia management in chronic kidney disease. Clinical trials of erythropoiesis-stimulating agents indicate that targeting the complete correction of anemia in patients with chronic kidney disease results in a greater risk of morbidity and mortality despite improved hemoglobin and quality of life. Conversely, intravenous iron has been found effective and relatively well tolerated in treating anemia in chronic kidney disease, even in patients with elevated ferritin. New agents to manage anemia, including long-acting erythropoietin derivatives, are also in active development. Erythropoiesis-stimulating agents should be used to target hemoglobin 11-12 g/dl in patients with chronic kidney disease. Intravenous iron may be beneficial for patients with hemoglobin less than 11 g/dl and transferrin saturation less than 25% despite elevated ferritin (500-1200 ng/ml). An upcoming placebo-controlled trial of darbepoetin should help to define the role of erythropoiesis-stimulating agents in chronic kidney disease.

Ex-Ante Economic Impact Assessment of Genetically Modified Banana Resistant to Xanthomonas Wilt in the Great Lakes Region of Africa.

PubMed

Ainembabazi, John Herbert; Tripathi, Leena; Rusike, Joseph; Abdoulaye, Tahirou; Manyong, Victor

2015-01-01

Credible empirical evidence is scanty on the social implications of genetically modified (GM) crops in Africa, especially on vegetatively propagated crops. Little is known about the future success of introducing GM technologies into staple crops such as bananas, which are widely produced and consumed in the Great Lakes Region of Africa (GLA). GM banana has a potential to control the destructive banana Xanthomonas wilt disease. To gain a better understanding of future adoption and consumption of GM banana in the GLA countries which are yet to permit the production of GM crops; specifically, to evaluate the potential economic impacts of GM cultivars resistant to banana Xanthomonas wilt disease. The paper uses data collected from farmers, traders, agricultural extension agents and key informants in the GLA. We analyze the perceptions of the respondents about the adoption and consumption of GM crop. Economic surplus model is used to determine future economic benefits and costs of producing GM banana. On the release of GM banana for commercialization, the expected initial adoption rate ranges from 21 to 70%, while the ceiling adoption rate is up to 100%. Investment in the development of GM banana is economically viable. However, aggregate benefits vary substantially across the target countries ranging from US$ 20 million to 953 million, highest in countries where disease incidence and production losses are high, ranging from 51 to 83% of production. The findings support investment in the development of GM banana resistant to Xanthomonas wilt disease. The main beneficiaries of this technology development are farmers and consumers, although the latter benefit more than the former from reduced prices. Designing a participatory breeding program involving farmers and consumers signifies the successful adoption and consumption of GM banana in the target countries.

Practice, progress and future directions for physical therapies in Huntingtons disease.

PubMed

Busse, Monica; Khalil, Hanan; Brooks, Simon; Quinn, Lori; Rosser, Anne

2012-01-01

Physical therapies and exercise may have potential as a disease modifying agent in Huntington's disease (HD) and in recent years, there have been several small scale feasibility studies that have shown benefit as a result of physical interventions. When evaluating complex physical interventions, a phased approach using mixed methodology designs that report specific intervention components, adherence, acceptability, adverse events and defined intervention protocols is important for replication and planning of future trials and to ensure potential for implementation in clinical practice. A narrative review of the available literature related to physical activity, physical therapy and exercise in people with HD was performed using a population, intervention, comparison and outcome (PICO) approach. Eight studies met specific inclusion criteria and were reviewed in terms of their systematic conduct and reporting standards. All of the studies (n = 8) provided details of intervention including location and duration. The majority of interventions included balance training activities in combination with other complex activities of daily living that required therapist supervision. Two of the interventions were home based, the remainder were facility or hospital based. None of the studies reported adverse events whilst only 3/8 reported adherence rates which were ranging from 60-80%. In general, limited detail was provided on the specific individual components of the interventions. This review of primary publications and conference proceedings, suggests that researchers working in the field need to focus on clearer reporting of intervention protocols so as to generate a clearer understanding of the impact of exercise and physical therapies on the symptoms of HD, as well as any potential synergistic role alongside the impending disease-modifying interventions.

Performance of QuantiFERON®-TB Gold In-Tube assay in children receiving disease modifying anti-rheumatic drugs.

PubMed

Gabriele, Francesca; Trachana, Maria; Simitsopoulou, Maria; Pratsidou-Gertsi, Polixeni; Iosifidis, Elias; Pana, Zoi Dorothea; Roilides, Emmanuel

2017-10-01

To evaluate the performance of the Quantiferon ® -TB Gold In-Tube (QFT-IT) interferon (IFN)-γ assay for the detection of latent tuberculosis infection (LTBI) in children receiving anti-rheumatic treatment in a tertiary referral hospital of Northern Greece. A total of 79 consecutive children receiving anti-rheumatic treatment [of which 18 screened prior to antitumor necrosis factor (TNF)-α treatment] were tested using Mantoux tuberculin skin test (TST) and QFT-IT. Association of both tests with risk factors for latent tuberculosis and Bacillus Calmette-Guerin immunization was determined. Influence of age, TNF-α inhibitors, systemic corticosteroids, conventional disease modifying anti-rheumatic drugs (DMARDs) and total duration of therapy on the QFT-IT mitogen-induced response was evaluated. Agreement between TST and QFT-IT results was moderate (k=0.38). Frequency of QFT-IT indeterminate results was low (2.5%). In patients with risk factors for LTBI, the odds of a positive IFN-γ assay was increased by a factor of 27.6 (P=0.002), whereas there was no positive TST. There was a significant difference in the mitogen-induced IFN-γ secretion among various treatments (P=0.038). TNF-α inhibitors were associated with increased mitogen-induced IFN-γ secretion compared to monotherapy with conventional DMARDs (P=0.008). All children screened prior to anti-TNF-α treatment exhibited a negative QFT-IT and no active TB disease was detected during a 2-year follow-up. QFT-IT may be a more reliable test than TST for detection of LTBI in children with rheumatic diseases receiving anti-rheumatic treatment. Drug regimen might influence the mitogen-induced IFN-γ secretion and the effect of TNF-α inhibitors might vary according to the specific agent administered.

Microbial origins of chronic diseases.

PubMed

Gargano, Lisa M; Hughes, James M

2014-01-01

Chronic diseases such as cardiovascular disease and cancer are among the leading causes of death worldwide and have been on the rise over the past decade. Associations between microbial agents and development of chronic diseases have been made in the past, and new connections are currently being assessed. Investigators are examining the relationship between infectious agents and chronic disease using new technologies with more rigor and specificity. This review examines microbial agents' links to and associations with cardiovascular diseases, cancer, neurodegenerative diseases, renal diseases, psychiatric disorders, and obesity and addresses the important role of the human microbiome in maintenance of health and its potential role in chronic diseases. These associations and relationships will impact future research priorities, surveillance approaches, treatment strategies, and prevention programs for chronic diseases.

9 CFR 121.4 - Overlap select agents and toxins.

Code of Federal Regulations, 2014 CFR

2014-01-01

... this section that have been genetically modified. (d) Overlap select agents or toxins that meet any of... OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS POSSESSION, USE...) Genetic elements, recombinant and/or synthetic nucleic acids, and recombinant and/or synthetic organisms...

9 CFR 121.4 - Overlap select agents and toxins.

Code of Federal Regulations, 2013 CFR

2013-01-01

... this section that have been genetically modified. (d) Overlap select agents or toxins that meet any of... OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS POSSESSION, USE...) Genetic elements, recombinant and/or synthetic nucleic acids, and recombinant and/or synthetic organisms...

Incidence of insects, diseases, and other damaging agents in Oregon forests.

Treesearch

Paul A. Dunham

2008-01-01

This report uses data from a network of forest inventory plots sampled at two points in time, annual aerial insect and disease surveys, and specialized pest damage surveys to quantify the incidence and impact of insects, diseases, and other damaging agents on Oregon's forests. The number and volume of trees damaged or killed by various agents is summarized....

Current Treatments in Familial Dysautonomia

PubMed Central

Palma, Jose-Alberto; Kaufmann, Lucy; Fuente, Cristina; Percival, Leila; Mendoza, Carlos; Kaufmann, Horacio

2014-01-01

Introduction Familial dysautonomia (FD) is a rare hereditary sensory and autonomic neuropathy (type III). The disease is caused by a point mutation in the IKBKAP gene that affects the splicing of the elongator-1 protein (also known as IKAP). Patients have dramatic blood pressure instability due to baroreflex failure, chronic kidney disease, and impaired swallowing leading to recurrent aspiration pneumonia, which results in chronic lung disease. Diminished pain and temperature perception results in neuropathic joints and thermal injuries. Impaired proprioception leads to gait ataxia. Optic neuropathy and corneal opacities lead to progressive visual loss. Areas covered This article reviews current therapeutic strategies for the symptomatic treatment of FD, as well as the potential of new gene modifying agents. Expert opinion Therapeutic focus on FD is centered on reducing the catecholamine surges caused by baroreflex failure. Managing neurogenic dysphagia with effective protection of the airway passages and prompt treatment of aspiration pneumonias is necessary to prevent respiratory failure. Sedative medications should be used cautiously due to risk of respiratory depression. Non-invasive ventilation during sleep effectively manages apneas and prevents hypercapnia. Clinical trials of compounds that increase levels of IKAP (ELP-1) are underway and will determine whether they can reverse or slow disease progression. PMID:25323828

Highlights in BACE1 Inhibitors for Alzheimer's Disease Treatment

NASA Astrophysics Data System (ADS)

Coimbra, Judite R. M.; Marques, Daniela F. F.; Baptista, Salete J.; Pereira, Cláudia M. F.; Moreira, Paula I.; Dinis, Teresa C. P.; Santos, Armanda E.; Salvador, Jorge A. R.

2018-05-01

Alzheimer's Disease (AD) is a severe neurodegenerative disorder and the most common type of dementia in the elderly. The clinical symptoms of AD include a progressive loss of memory and impairment of cognitive functions interfering with daily life activities. The main neuropathological features consist in extracellular Amyloid-β (Aβ) plaque deposition and intracellular Neurofibrillary Tangles (NFTs) of hyperphosphorylated Tau. Understanding the pathophysiological mechanisms that underlie neurodegeneration in AD is essential for rational design of neuroprotective agents able to prevent disease progression. According to the “Amyloid Cascade Hypothesis” the critical molecular event in the pathogenesis of AD is the accumulation of Aβ neurotoxic oligomers. Since the proteolytic processing of Amyloid Precursor Protein (APP) by β-secretase (BACE1) is the rate-limiting step in the production of Aβ, this enzyme is considered a major therapeutic target and BACE1 inhibitors have the potential to be disease-modifying drugs for AD treatment. Therefore, intensive efforts to discover and develop inhibitors that can reach the brain and effectively inhibit BACE1 have been pursued by several groups worldwide. The aim of this review is to highlight the progress in the discovery of potent and selective small BACE1 inhibitors over the past decade.

Disease modifying therapies in type 1 diabetes: where have we been, and where are we going?

PubMed Central

Lord, Sandra

2015-01-01

With more than four decades of clinical research and 25 years of clinical trials, much is known about the natural history of T1D before and after clinical diagnosis. We know that autoimmunity occurs early in life, that islet autoimmunity inevitably leads to clinically overt disease, and that some immune therapies can alter the disease course. In the future, we will likely conduct trials to more deeply explore mechanisms of disease and response to therapy, employ combinations of agents including those aimed at supporting beta cells, consider the use of chronic, intermittent therapy, focus studies on preventing progression from islet autoimmunity, and consider the potential benefits of studying children independently from adults. Much of this work will depend upon clinical trial networks such as Diabetes TrialNet. Such networks not only have the expertise to conduct studies; sharing of data and samples allow for discovery work by multiple investigators laying the groundwork for the future. Working with patients, families, funders and industry, such collaborative networks can accelerate the translation of science to clinical practice to improve the lives of those living with T1D. PMID:25771310

Disease modifying therapies in type 1 diabetes: Where have we been, and where are we going?

PubMed

Lord, Sandra; Greenbaum, Carla J

2015-08-01

With more than four decades of clinical research and 25 years of clinical trials, much is known about the natural history of T1D before and after clinical diagnosis. We know that autoimmunity occurs early in life, that islet autoimmunity inevitably leads to clinically overt disease, and that some immune therapies can alter the disease course. In the future, we will likely conduct trials to more deeply explore mechanisms of disease and response to therapy, employ combinations of agents including those aimed at supporting beta cells, consider the use of chronic, intermittent therapy, focus studies on preventing progression from islet autoimmunity, and consider the potential benefits of studying children independently from adults. Much of this work will depend upon clinical trial networks such as Diabetes TrialNet. Such networks not only have the expertise to conduct studies but their sharing of data and samples also allows for discovery work by multiple investigators, laying the groundwork for the future. Working with patients, families, funders and industry, such collaborative networks can accelerate the translation of science to clinical practice to improve the lives of those living with T1D. Copyright © 2015 Elsevier Ltd. All rights reserved.

Combination therapies - the next logical step for the treatment of synucleinopathies?

PubMed Central

Valera, E.; Masliah, E.

2015-01-01

Currently there are no disease-modifying alternatives for the treatment of most neurodegenerative disorders. The available therapies for diseases such as Parkinson’s disease (PD), PD dementia (PDD), Dementia with Lewy bodies (DLB) and Multiple system atrophy (MSA), in which the protein alpha-synuclein (α-syn) accumulates within neurons and glial cells with toxic consequences, are focused on managing the disease symptoms. However, utilizing strategic drug combinations and/or multi-target drugs might increase the treatment efficiency when compared to monotherapies. Synucleinopathies are complex disorders that progress through several stages, and toxic α-syn aggregates exhibit prion-like behavior spreading from cell to cell. Therefore, it follows that these neurodegenerative disorders might require equally complex therapeutic approaches in order to obtain significant and long-lasting results. Hypothetically, therapies aimed at reducing α-syn accumulation and cell-to-cell transfer, such as immunotherapy against α-syn, could be combined with agents that reduce neuroinflammation with potential synergistic outcomes. Here we review the current evidence supporting this type of approach, suggesting that such rational therapy combinations, together with the use of multi-target drugs, may hold promise as the next logical step for the treatment of synucleinopathies. PMID:26388203

Monitoring the tobacco use epidemic II. The Agent: Current and Emerging Tobacco Products

PubMed Central

Stellman, Steven D.; Djordjevic, Mirjana V.

2009-01-01

Objective This Agent paper summarizes the findings and recommendations of the Agent (product) Working Group of the November, 2002, National Tobacco Monitoring, Research and Evaluation Workshop. Methods The Agent Working Group evaluated the need to develop new surveillance systems for quantifying ingredients and emissions of tobacco and tobacco smoke and to improve methods to assess uptake and metabolism of these constituents taking into account variability in human smoking behavior. Results The toxic properties of numerous tobacco and tobacco smoke constituents are well known, yet systematic monitoring of tobacco products has historically been limited to tar, nicotine, and CO in mainstream cigarette smoke using a machine-smoking protocol that does not reflect human smoking behavior. Toxicity of smokeless tobacco products has not been regularly monitored. Tobacco products are constantly changing and untested products are introduced into the marketplace with great frequency, including potential reduced-exposure products (PREPs). The public health impact of new or modified tobacco products is unknown. Conclusions Systematic surveillance is recommended for mainstream smoke constituents such as polycyclic aromatic hydrocarbons (PAH), tobacco-specific nitrosamines (TSNA), total and free-base nicotine, volatile organic compounds, aromatic amines, and metals; and design attributes including tobacco blend, additives, and filter ventilation. Research on smoking topography is recommended to help define machine-smoking protocols for monitoring emissions reflective of human smoking behavior. Recommendations are made for marketplace product sampling and for population monitoring of smoking topography, emissions of toxic constituents, biomarkers of exposure and, eventually, risk of tobacco-related diseases. PMID:18848577

[Public health pests. Arthropods and rodents as causative disease agents as well as reservoirs and vectors of pathogens].

PubMed

Faulde, M; Freise, J

2014-05-01

Globally, infectious diseases pose the most important cause of death. Among known human pathogenic diseases, approximately 50 % are zoonoses. When considering emerging infectious diseases separately 73 % currently belong to the group of zoonoses. In Central Europe, hard ticks show by far the biggest potential as vectors of agents of human disease. Lyme borreliosis, showing an estimated annual incidence between 60,000 and 214,000 cases is by far the most frequent tick-borne disease in Germany. Continually, formerly unknown disease agents could be discovered in endemic vector species. Additionally, introduction of new arthropod vectors and/or agents of disease occur constantly. Recently, five mosquito species of the genus Aedes have been newly introduced to Europe where they are currently spreading in different regions. Uncommon autochthonous transmission of dengue and chikungunya fever viruses in Southern Europe could be directly linked to these vector species and of these Ae. albopictus and Ae. japonicus are currently reported to occur in Germany. The German Protection against Infection Act only covers the control of public health pests which are either active hematophagous vectors or mechanical transmitters of agents of diseases. Use of officially recommended biocidal products aiming to interrupt transmission cycles of vector-borne diseases, is confined to infested buildings only, including sewage systems in the case of Norway rat control. Outdoor vectors, such as hard ticks and mosquitoes, are currently not taken into consideration. Additionally, adjustments of national public health regulations, detailed arthropod vector and rodent reservoir mapping, including surveillance of vector-borne disease agents, are necessary in order to mitigate future disease risks.

Mitochondrial-targeted DNA delivery using a DF-MITO-Porter, an innovative nano carrier with cytoplasmic and mitochondrial fusogenic envelopes

NASA Astrophysics Data System (ADS)

Yamada, Yuma; Kawamura, Eriko; Harashima, Hideyoshi

2012-08-01

Mitochondrial gene therapy has the potential for curing a variety of diseases that are associated with mitochondrial DNA mutations and/or defects. To achieve this, it will be necessary to deliver therapeutic agents into the mitochondria in diseased cells. A number of mitochondrial drug delivery systems have been reported to date. However, reports of mitochondrial-targeted DNA delivery are limited. To achieve this, the therapeutic agent must be taken up by the cell (1), after which, the multi-processes associated with intracellular trafficking must be sophisticatedly regulated so as to release the agent from the endosome and deliver it to the cytosol (2) and to pass through the mitochondrial membrane (3). We report herein on the mitochondrial delivery of oligo DNA as a model therapeutic using a Dual Function (DF)-MITO-Porter, an innovative nano carrier designed for mitochondrial delivery. The critical structural elements of the DF-MITO-Porter include mitochondria-fusogenic inner envelopes and endosome-fusogenic outer envelopes, modified with octaarginine which greatly assists in cellular uptake. Inside the cell, the carrier passes through the endosomal and mitochondrial membranes via step-wise membrane fusion. When the oligo DNA was packaged in the DF-MITO-Porter, cellular uptake efficiency was strongly enhanced. Intracellular observation using confocal laser scanning microscopy showed that the DF-MITO-Porter was effectively released from endosomes. Moreover, the findings confirmed that the mitochondrial targeting activity of the DF-MITO-Porter was significantly higher than that of a carrier without outer endosome-fusogenic envelopes. These results support the conclusion that mitochondrial-targeted DNA delivery using a DF-MITO-Porter can be achieved when intracellular trafficking is optimally regulated.

Small cell foams and blends and a process for their preparation

DOEpatents

Hedstrand, D.M.; Tomalia, D.A.

1995-02-07

Dense star polymers or dendrimers, modified by capping with a hydrophobic group capable of providing a hydrophobic outer shell, act as molecular nucleating agents. These modified dense star polymers or dendrimers are particularly effective for the production of small cell foams.

Small cell foams and blends and a process for their preparation

DOEpatents

Hedstrand, David M.; Tomalia, Donald A.

1995-01-01

Dense star polymers or dendrimers, modified by capping with a hydrophobic group capable of providing a hydrophobic outer shell, act as molecular nucleating agents. These modified dense star polymers or dendrimers are particularly effective for the production of small cell foams.

Emerging techniques for the discovery and validation of therapeutic targets for skeletal diseases.

PubMed

Cho, Christine H; Nuttall, Mark E

2002-12-01

Advances in genomics and proteomics have revolutionised the drug discovery process and target validation. Identification of novel therapeutic targets for chronic skeletal diseases is an extremely challenging process based on the difficulty of obtaining high-quality human diseased versus normal tissue samples. The quality of tissue and genomic information obtained from the sample is critical to identifying disease-related genes. Using a genomics-based approach, novel genes or genes with similar homology to existing genes can be identified from cDNA libraries generated from normal versus diseased tissue. High-quality cDNA libraries are prepared from uncontaminated homogeneous cell populations harvested from tissue sections of interest. Localised gene expression analysis and confirmation are obtained through in situ hybridisation or immunohistochemical studies. Cells overexpressing the recombinant protein are subsequently designed for primary cell-based high-throughput assays that are capable of screening large compound banks for potential hits. Afterwards, secondary functional assays are used to test promising compounds. The same overexpressing cells are used in the secondary assay to test protein activity and functionality as well as screen for small-molecule agonists or antagonists. Once a hit is generated, a structure-activity relationship of the compound is optimised for better oral bioavailability and pharmacokinetics allowing the compound to progress into development. Parallel efforts from proteomics, as well as genetics/transgenics, bioinformatics and combinatorial chemistry, and improvements in high-throughput automation technologies, allow the drug discovery process to meet the demands of the medicinal market. This review discusses and illustrates how different approaches are incorporated into the discovery and validation of novel targets and, consequently, the development of potentially therapeutic agents in the areas of osteoporosis and osteoarthritis. While current treatments exist in the form of hormone replacement therapy, antiresorptive and anabolic agents for osteoporosis, there are no disease-modifying therapies for the treatment of the most common human joint disease, osteoarthritis. A massive market potential for improved options with better safety and efficacy still remains. Therefore, the application of genomics and proteomics for both diseases should provide much needed novel therapeutic approaches to treating these major world health problems.

KOVATS RETENTION INDICES OF HALOCARBONS ON A HEXAFLUOROPROPYLENE EPOXIDE-MODIFIED GRAPHITIZED CARBON BLACK

EPA Science Inventory

The article gives results of measuring Kovats retention indices of 97 halocarbons related to research on alternative refrigerants, propellants, foaming agents, and blowing agents, on a packed-column stationary phase consisting of a 5% mass coating of a low-molecular-weight polyme...

Thermal Inactivation of Viruses

DTIC Science & Technology

1977-10-01

thermal inactivation . 12 Bibliography 20 Table 3. Thermal inactivation of viruses in foods 25 Bibliography 31 Table 4, Agents modifying...the presence of protective agents that reduce the lethal effect of heat on the viruses at temperatures below 60 C In addition, whtn solid foods...systems but were observed j when animal inoculation was utilized. It is possible that free virus nucl’lc < acid may have been the causative agent in

Lyme Disease Agent in Egypt?

DTIC Science & Technology

1989-02-01

reverse if necessary and identify by block number) CIELD CPzOUP ISUB-GRO0UP Lyme disease; Borrelia spp. ; Treponema pallidumv ARSTRACTPatients...AD-A240 332 CC PUBLICATION REPORT O!t2 TAh 1583 By~ 65189-90 r ! tb ut I ui LYME DISEASE AGENT IN EGYPT? ’’ Ave Richard L. Habarberger’, Niel T...a dilution of Lyme disease agent in Egypt? 1:100 with the prototype strain B-31 ofB. burgdorferi. Results indicated that none of the 16 meningitis or

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

PubMed

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.

Disease-associated prion protein detected in lymphoid tissues from pigs challenged with the agent of chronic wasting disease

USDA-ARS?s Scientific Manuscript database

Aims: Chronic wasting disease (CWD) is a naturally-occurring, fatal neurodegenerative disease of cervids. We previously demonstrated that disease-associated prion protein (PrPSc) can be detected in the brain and retina from pigs challenged intracranially or orally with the CWD agent. In that study,...

Modifiable risk factors in periodontitis: at the intersection of aging and disease.

PubMed

Reynolds, Mark A

2014-02-01

Chronic inflammation is a prominent feature of aging and of common age-related diseases, including atherosclerosis, cancer and periodontitis. This volume examines modifiable risk factors for periodontitis and other chronic inflammatory diseases. Oral bacterial communities and viral infections, particularly with cytomegalovirus and other herpesviruses, elicit distinct immune responses and are central in the initiation of periodontal diseases. Risk of disease is dynamic and changes in response to complex interactions of genetic, environmental and stochastic factors over the lifespan. Many modifiable risk factors, such as smoking and excess caloric intake, contribute to increases in systemic markers of inflammation and can modify gene regulation through a variety of biologic mechanisms (e.g. epigenetic modifications). Periodontitis and other common chronic inflammatory diseases share multiple modifiable risk factors, such as tobacco smoking, psychological stress and depression, alcohol consumption, obesity, diabetes, metabolic syndrome and osteoporosis. Interventions that target modifiable risk factors have the potential to improve risk profiles for periodontitis as well as for other common chronic diseases. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The combined use of aspirin, a statin, and blood pressure-lowering agents (polypill components) in clinical practice in patients with vascular diseases or type 2 diabetes mellitus.

PubMed

Lafeber, Melvin; Grobbee, Diederick E; Spiering, Wilko; van der Graaf, Yolanda; Bots, Michiel L; Visseren, Frank L J

2013-10-01

Based on guidelines, patients with established cardiovascular disease are likely to already receive a combination of aspirin, a statin, and blood pressure (BP)-lowering agents. Combining these pharmacological agents into a cardiovascular polypill could be considered in these patients to reduce prescription gaps and non-adherence. We aimed to assess the prevalence of the combined use of aspirin, statin, and BP-lowering agents in patients with established cardiovascular diseases or type 2 diabetes mellitus (DM2) in the period 1996-2009. In total, 5702 patients with coronary artery disease (CAD), cerebrovascular disease (CVD), peripheral arterial occlusive disease (PAOD), abdominal aortic aneurysm (AAA) or, DM2 were included in the period 1996-2009. The overall use of combination therapy with aspirin, statin, and ≥ 1 BP-lowering agent increased substantially from 9% in 1996 to 66% in 2009 and ≥ 2 BP-lowering agents increased from 1% to 47%. In 2009, combination therapy with ≥ 1 BP-lowering agent was used by 83% of those with CAD, 48% of those with CVD, 43% of those with PAOD, 36% of the patients with AAA, and 19% of the patients with DM2. In most patient groups, obesity, metabolic syndrome, hypertension concomitant CAD, CVD, or DM2 were related to the use of combination therapy in models adjusted for age and gender. A high proportion of patients with established cardiovascular diseases already uses a combination of pharmacological agents. Introduction of a polypill in high-risk patients might be feasible to reduce prescription gaps and increase adherence to indicated therapy.

Does the buck stop with the bugs?: an overview of microbial dysbiosis in rheumatoid arthritis.

PubMed

Sandhya, Pulukool; Danda, Debashish; Sharma, Disha; Scaria, Vinod

2016-01-01

The human body is an environmental niche which is home to diverse co-habiting microbes collectively referred as the human microbiome. Recent years have seen the in-depth characterization of the human microbiome and associations with diseases. Linking of the composition or number of the human microbiota with diseases and traits date back to the original work of Elie Metchnikoff. Recent advances in genomic technologies have opened up finer details and dynamics of this new science with higher precision. Microbe-rheumatoid arthritis connection, largely related to the gut and oral microbiomes, has showed up as a result - apart from several other earlier, well-studied candidate autoimmune diseases. Although evidence favouring roles of specific microbial species, including Porphyromonas, Prevotella and Leptotricha, has become clearer, mechanistic insights still continue to be enigmatic. Manipulating the microbes by traditional dietary modifications, probiotics, and antibiotics and by currently employed disease-modifying agents seems to modulate the disease process and its progression. In the present review, we appraise the existing information as well as the gaps in knowledge in this challenging field. We also discuss the future directions for potential clinical applications, including prevention and management of rheumatoid arthritis using microbial modifications. © 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

Application of nanotechnologies for improved immune response against infectious diseases in the developing world

PubMed Central

Look, Michael; Bandyopadhyay, Arunima; Blum, Jeremy S.; Fahmy, Tarek M.

2010-01-01

There is an urgent need for new strategies to combat infectious diseases in developing countries. Many pathogens have evolved to elude immunity and this has limited the utility of current therapies. Additionally, the emergence of co-infections and drug resistant pathogens has increased the need for advanced therapeutic and diagnostic strategies. These challenges can be addressed with therapies that boost the quality and magnitude of an immune response in a predictable, designable fashion that can be applied for wide-spread use. Here, we discuss how biomaterials and specifically nanoscale delivery vehicles can be used to modify and improve the immune system response against infectious diseases. Immunotherapy of infectious disease is the enhancement or modulation of the immune system response to more effectively prevent or clear pathogen infection. Nanoscale vehicles are particularly adept at facilitating immunotherapeutic approaches because they can be engineered to have different physical properties, encapsulated agents, and surface ligands. Additionally, nanoscaled point-of-care diagnostics offer new alternatives for portable and sensitive health monitoring that can guide the use of nanoscale immunotherapies. By exploiting the unique tunability of nanoscale biomaterials to activate, shape, and detect immune system effector function, it may be possible in the near future to generate practical strategies for the prevention and treatment of infectious diseases in the developing world. PMID:19922750

The relationship between intestinal parasites and some immune-mediated intestinal conditions

PubMed Central

Mohammadi, Rasoul; Hosseini-Safa, Ahmad; Ehsani Ardakani, Mohammad Javad; Rostami-Nejad, Mohammad

2015-01-01

Over the last decades, the incidence of infestation by minor parasites has decreased in developed countries. Infectious agents can also suppress autoimmune and allergic disorders. Some investigations show that various protozoa and helminthes are connected with the main immune-mediated intestinal conditions including celiac disease (CD), inflammatory bowel diseases (IBD) and irritable bowel syndrome (IBS). Celiac disease is a digestive and autoimmune disorder that can damage the small intestine and characterized by a multitude gastrointestinal (GI) and extra GI symptoms. IBD (including ulcerative colitis and Crohn’s disease) is a group of inflammatory conditions of the small intestine and colon. The etiology of IBD is unknown, but it may be related to instability in the intestinal microflora that leading to an immoderate inflammatory response to commensal microbiota. Irritable bowel syndrome (IBS) is a common, long-term condition of the digestive system. Bloating, diarrhoea and/or constipation are nonspecific symptoms of IBS. Various studies have shown that some intestinal parasites can effect on immune system of infected hosts and in some cases, they are able to modify and change the host’s immune responses, particularly in autoimmune disorders like celiac disease and IBD. The main objective of this review is to investigate the relationship between intestinal parasites and different inflammatory bowel disorders. PMID:25926937

Multiple Ligands Targeting Cholinesterases and β-Amyloid: Synthesis, Biological Evaluation of Heterodimeric Compounds with Benzylamine Pharmacophore.

PubMed

Szałaj, Natalia; Bajda, Marek; Dudek, Katarzyna; Brus, Boris; Gobec, Stanislav; Malawska, Barbara

2015-08-01

Alzheimer's disease (AD) is a fatal and complex neurodegenerative disorder for which effective treatment remains the unmet challenge. Using donepezil as a starting point, we aimed to develop novel potential anti-AD agents with a multidirectional biological profile. We designed the target compounds as dual binding site acetylcholinesterase inhibitors, where the N-benzylamine pharmacophore is responsible for interactions with the catalytic anionic site of the enzyme. The heteroaromatic fragment responsible for interactions with the peripheral anionic site was modified and three different heterocycles were introduced: isoindoline, isoindolin-1-one, and saccharine. Based on the results of the pharmacological evaluation, we identified compound 8b with a saccharine moiety as the most potent and selective human acetylcholinesterase inhibitor (IC50  = 33 nM) and beta amyloid aggregation inhibitor. It acts as a non-competitive acetylcholinesterase inhibitor and is able to cross the blood-brain barrier in vitro. We believe that compound 8b represents an important lead compound for further development as potential anti-AD agent. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Pharmacotherapy and motor recovery after stroke.

PubMed

Viale, Luciano; Catoira, Natalia Paola; Di Girolamo, Guillermo; González, Claudio Daniel

2018-01-01

Stroke is one of the most prevalent neurological diseases worldwide, especially among the elderly population. There are various mechanisms that enhance motor recovery after a stroke. In clinical practice, we have the opportunity to enhance plasticity by designing specific rehabilitation programs. Areas covered: There are a variety of drugs commonly administered to people after the acute phase of a stroke. These drugs may modify motor performance. Herein reviewed is the evidence concerning motor enhancement or decline in stroke patients, produced by drugs commonly used in rehabilitation settings. An extensive review of animal and human studies is performed. Expert commentary: Many of the clinical trials carried out were underpowered. Modest evidence supports the claim that there are agents that can affect motor rehabilitation after a stroke. Amphetamine-like agents, serotonin reuptake inhibitors, and levodopa might improve motor outcomes, while antipsychotics, some antiepileptic drugs, and GABAmimetic drugs could impair the recovery process. To draw definite recommendations, more comprehensive knowledge about the efficacy, long-term effects, and safety of these drugs is required. There are also other interesting molecules that open a promising field for basic and clinical research, in the search for new therapeutic options.

Magnetoferritin nanoparticles for targeting and visualizing tumour tissues

NASA Astrophysics Data System (ADS)

Fan, Kelong; Cao, Changqian; Pan, Yongxin; Lu, Di; Yang, Dongling; Feng, Jing; Song, Lina; Liang, Minmin; Yan, Xiyun

2012-07-01

Engineered nanoparticles have been used to provide diagnostic, therapeutic and prognostic information about the status of disease. Nanoparticles developed for these purposes are typically modified with targeting ligands (such as antibodies, peptides or small molecules) or contrast agents using complicated processes and expensive reagents. Moreover, this approach can lead to an excess of ligands on the nanoparticle surface, and this causes non-specific binding and aggregation of nanoparticles, which decreases detection sensitivity. Here, we show that magnetoferritin nanoparticles (M-HFn) can be used to target and visualize tumour tissues without the use of any targeting ligands or contrast agents. Iron oxide nanoparticles are encapsulated inside a recombinant human heavy-chain ferritin (HFn) protein shell, which binds to tumour cells that overexpress transferrin receptor 1 (TfR1). The iron oxide core catalyses the oxidation of peroxidase substrates in the presence of hydrogen peroxide to produce a colour reaction that is used to visualize tumour tissues. We examined 474 clinical specimens from patients with nine types of cancer and verified that these nanoparticles can distinguish cancerous cells from normal cells with a sensitivity of 98% and specificity of 95%.

Multiple sclerosis - New treatment modalities

PubMed Central

Totaro, Rocco; Di Carmine, Caterina; Marini, Carmine; Carolei, Antonio

2015-01-01

Ever since the introduction of the first disease modifying therapies, the concept of multiple sclerosis treatment algorithms developed ceaselessly. The increasing number of available drugs is paralleled by impelling issue of ensuring the most appropriate treatment to the right patient at the right time. The purpose of this review is to describe novel agents recently approved for multiple sclerosis treatment, namely teriflunomide, alemtuzumab and dimethylfumarate, focusing on mechanism of action, efficacy data in experimental setting, safety and tolerability. The place in therapy of newer treatment implies careful balancing of risk-benefit profile as well as accurate patient selection. Hence the widening of therapeutic arsenal provides greater opportunity for personalized therapy but also entails a complex trade-off between efficacy, tolerability, safety and eventually patient preference. PMID:26831413

Infectious Disease risks associated with exposure to stressful environments

NASA Technical Reports Server (NTRS)

Meehan, Ichard T.; Smith, Morey; Sams, Clarence

1993-01-01

Multiple environmental factors asociated with space flight can increase the risk of infectious illness among crewmembers thereby adversely affecting crew health and mission success. Host defences can be impaired by multiple physiological and psychological stressors including: sleep deprivation, disrupted circadian rhythms, separation from family, perceived danger, radiation exposure, and possibly also by the direct and indirect effects of microgravity. Relevant human immunological data from isolated or stressful environments including spaceflight will be reviewed. Long-duration missions should include reliable hardware which supports sophisticated immunodiagnostic capabilities. Future advances in immunology and molecular biology will continue to provide therapeutic agents and biologic response modifiers which should effectively and selectively restore immune function which has been depressed by exposure to environmental stressors.

Nanoimages show disruption of tubulin polymerization by chlorpyrifos oxon: Implications for neurotoxicity

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

Grigoryan, Hasmik; Lockridge, Oksana

2009-10-15

Organophosphorus agents cause cognitive deficits and depression in some people. We hypothesize that the mechanism by which organophosphorus agents cause these disorders is by modification of proteins in the brain. One such protein could be tubulin. Tubulin polymerizes to make the microtubules that transport cell components to nerve axons. The goal of the present work was to measure the effect of the organophosphorus agent chlorpyrifos oxon on tubulin polymerization. An additional goal was to identify the amino acids covalently modified by chlorpyrifos oxon in microtubule polymers and to compare them to the amino acids modified in unpolymerized tubulin dimers. Purifiedmore » bovine tubulin (0.1 mM) was treated with 0.005-0.1 mM chlorpyrifos oxon for 30 min at room temperature and then polymerized by addition of 1 mM GTP to generate microtubules. Microtubules were visualized by atomic force microscopy. Chlorpyrifos oxon-modified residues were identified by tandem ion trap electrospray ionization and matrix-assisted laser desorption/ionization mass spectrometry of tryptic peptides. Nanoimaging showed that low concentrations (0.005 and 0.01 mM) of chlorpyrifos oxon yielded short, thin microtubules. A concentration of 0.025 mM stimulated polymerization, while high concentrations (0.05 and 0.1 mM) caused aggregation. Of the 17 tyrosines covalently modified by chlorpyrifos oxon in unpolymerized tubulin dimers, only 2 tyrosines were labeled in polymerized microtubules. The two labeled tyrosines in polymerized tubulin were Tyr 103 in EDAANNY*R of alpha tubulin, and Tyr 281 in GSQQY*R of beta tubulin. In conclusion, chlorpyrifos oxon binding to tubulin disrupts tubulin polymerization. These results may lead to an understanding of the neurotoxicity of organophosphorus agents.« less

Nanoimages show disruption of tubulin polymerization by chlorpyrifos oxon; implications for neurotoxicity

PubMed Central

Grigoryan, Hasmik; Lockridge, Oksana

2009-01-01

Organophosphorus agents cause cognitive deficits and depression in some people. We hypothesize that the mechanism by which organophosphorus agents cause these disorders is by modification of proteins in the brain. One such protein could be tubulin. Tubulin polymerizes to make the microtubules that transport cell components to nerve axons. The goal of the present work was to measure the effect of the organophosphorus agent chlorpyrifos oxon on tubulin polymerization. An additional goal was to identify the amino acids covalently modified by chlorpyrifos oxon in microtubule polymers and to compare them to the amino acids modified in unpolymerized tubulin dimers. Purified bovine tubulin (0.1 mM) was treated with 0.005-0.1 mM chlorpyrifos oxon for 30 min at room temperature and then polymerized by addition of 1 mM GTP to generate microtubules. Microtubules were visualized by atomic force microscopy. Chlorpyrifos oxon-modified residues were identified by tandem ion trap electrospray ionization and matrix-assisted laser desorption/ionization mass spectrometry of tryptic peptides. Nanoimaging showed that low concentrations (0.005 and 0.01 mM) of chlorpyrifos oxon yielded short, thin microtubules. A concentration of 0.025 mM stimulated polymerization, while high concentrations (0.05 and 0.1 mM) caused aggregation. Of the 17 tyrosines covalently modified by chlorpyrifos oxon in unpolymerized tubulin dimers, only 2 tyrosines were labeled in polymerized microtubules. The two labeled tyrosines in polymerized tubulin were Tyr 103 in EDAANNY*R of alpha tubulin, and Tyr 281 in GSQQY*R of beta tubulin. In conclusion, chlorpyrifos oxon binding to tubulin disrupts tubulin polymerization. These results may lead to an understanding of the neurotoxicity of organophosphorus agents. PMID:19631231

TNF-alpha antagonist induced lupus on three different agents.

PubMed

Mudduluru, Bindu Madhavi; Shah, Shalin; Shamah, Steven; Swaminath, Arun

2017-03-01

Tumor necrosis factor alpha (TNF alpha) antagonists are biologic agents used in the management of inflammatory conditions such as rheumatoid arthritis, seronegative spondyloarthropathies and inflammatory bowel disease. These agents have been recently shown to cause a syndrome called anti-TNF induced lupus (ATIL), a rare condition which has similar clinical manifestations to idiopathic systemic lupus erythematosus (SLE). Given that extra-intestinal manifestations of inflammatory bowel disease include arthritis, it can be difficult to separate arthritis due to underlying disease from drug-induced arthritis. We present a case of a 28-year-old female with Crohn's disease, who developed disabling arthritis as a clinical manifestation of ATIL following treatment with three anti-TNF agents, namely infliximab, adalimumab and certolizumab.

Non-Clostridium perfringens infectious agents producing necrotic enteritis-like lesions in poultry.

PubMed

Uzal, F A; Sentíes-Cué, C G; Rimoldi, G; Shivaprasad, H L

2016-06-01

Necrotic enteritis (NE) produced by Clostridium perfringens is amongst the most prevalent enteric diseases of chickens and turkeys. However, several other bacterial, parasitic and viral agents can cause clinical signs, gross and microscopic lesions in poultry very similar to those of NE and the diseases produced by those agents need to be differentiated from NE. The main differential diagnoses for C. perfringens NE include bacterial (Clostridium colinum, Clostridium sordellii, Clostridium difficile, Pasteurella multocida, Brachyspira spp.), parasitic (Eimeria spp., Histomonas meleagridis) and viral (Duck Herpesvirus type 1, Avian Paramyxovirus type 1) diseases. Confirmation of the diagnosis of these diseases requires identification of the aetiological agents by morphological, cultural and/or molecular methods.

Synthesis and biological evaluation of sialyl-oligonucleotide conjugates targeting leukocyte B trans-membranal receptor CD22 as delivery agents for nucleic acid drugs.

PubMed

St-Pierre, Gabrielle; Pal, Sudip; Østergaard, Michael E; Zhou, Tianyuan; Yu, Jinghua; Tanowitz, Michael; Seth, Punit P; Hanessian, Stephen

2016-06-01

Antisense oligonucleotides (ASOs) modified with ligands which target cell surface receptors have the potential to significantly improve potency in the target tissue. This has recently been demonstrated using triantennary N-acetyl d-galactosamine conjugated ASOs. CD22 is a cell surface receptor expressed exclusively on B cells thus presenting an attractive target for B cell specific delivery of drugs. Herein, we reported the synthesis of monovalent and trivalent ASO conjugates with biphenylcarbonyl (BPC) modified sialic acids and their study as ASO delivery agents into B cells. CD22 positive cells exhibited reduced potency when treated with ligand modified ASOs and mechanistic examination suggested reduced uptake into cells potentially as a result of sequestration of ASO by other cell-surface proteins. Copyright © 2016 Elsevier Ltd. All rights reserved.

[The future of inflammatory bowel disease from the perspective of Digestive Disease Week 2012].

PubMed

Gomollón, Fernando

2012-09-01

The new information presented in Digestive Disease Week has allowed us to speculate on the future of inflammatory bowel disease. Manipulation of diet and the microbioma will probably play an increasingly important role in the treatment of this disease and, in the long term, in its prevention. Biological agents will probably be used earlier and more widely; new information on levels of biological agents, mucosal healing and new comparative studies will also allow these agents to be used in a more precise and personalized way. In addition to infliximab, adalimumab, natalizumab and certolizumab, other biological agents will be employed; among the first of these to be used will be ustekinumab, golimumab and vedolizumab. In the near future, biological agents will be used as frequently in ulcerative colitis as in Crohn's disease. New healthcare models will be developed that will progressively include greater participation among patients and nurses. The ability to predict new diagnostic and prognostic models will allow decisions to be more individualized. Copyright © 2012 Elsevier España, S.L. All rights reserved.

Evaluation of disease modifying activity of Coriandrum sativum in experimental models

PubMed Central

Nair, Vinod; Singh, Surender; Gupta, Y.K.

2012-01-01

Background & objectives: Coriandrum sativum (CS), has been widely used in traditional systems of medicine for treatment of rheumatoid arthritis. However, the mechanism of action for its antiarthritic effects is not clearly known. Therefore, the present study was carried out to evaluate the antiarthritic activity of CS in rats in two experimental models. Methods: The antiarthritic activity of CS seed hydroalcoholic extract (CSHE) was evaluated in adult Wistar rats by using two experimental models, viz. formaldehyde and Complete Freund's adjuvant (CFA) induced arthritis. The expression of pro-inflammatory cytokines (predominantly contributed by macrophages) was also evaluated. TNF-α level was estimated in serum by ELISA method. TNF-R1, IL-1 β and IL-6 expression in the synovium was analysed by immunohistochemistry. Results: CSHE produced a dose dependent inhibition of joint swelling as compared to control animals in both, formaldehyde and CFA induced arthritis. Although there was a dose dependent increase in serum TNF-α levels in the CSHE treated groups as compared to control, the synovial expression of macrophage derived pro-inflammatory cytokines/cytokine receptor was found to be lower in the CSHE treated groups as compared to control. Interpretation & conclusions: Our results demonstrate that the antiarthritic activity of CSHE may be attributed to the modulation of pro-inflammatory cytokines in the synovium. In further studies CSHE could be explored to be developed as a disease modifying agent in the treatment of RA. PMID:22446868

BIOSENSOR FOR DIRECT DETERMINATION OF ORGANOPHOSPHATE NERVE AGENTS. 1. POTENTIOMETRIC ENZYME ELECTRODE. (R823663)

EPA Science Inventory

A potentiometric enzyme electrode for the direct measurement of organophosphate (OP)
nerve agents was developed. The basic element of this enzyme electrode was a pH electrode
modified with an immobilized organophosphorus hydrolase (OPH) layer formed by cross-linking
OPH ...

75 FR 10539 - Self-Regulatory Organizations; The Depository Trust Company; Notice of Filing and Immediate...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-08

... SECURITIES AND EXCHANGE COMMISSION [Release No. 34-61620; File No. SR-DTC-2010-04] Self-Regulatory... Change To Modify Its Registered Transfer Agent Notification Methods for Assumption or Termination of... transfer agent notification methods for assumption or termination of services. II. Self-Regulatory...

Performance of waste-paper/PETG wood–plastic composites

NASA Astrophysics Data System (ADS)

Huang, Lijie; An, Shuxiang; Li, Chunying; Huang, Chongxing; Wang, Shuangfei; Zhang, Xiaoxiao; Xu, Mingzi; Chen, Jie; Zhou, Lei

2018-05-01

Wood-plastic composites were prepared from polyethylene terephthalate- 1,4-cyclohexanedimethanol ester (PETG) and waste-paper fiber that was unmodified, modified with alkyl-ketene-dimer (AKD), and modified with a silane-coupling agent. The mechanical properties, water absorption properties, surface structure, and thermal properties of the three prepared materials were compared. The results showed that the optimum amount of waste-paper powder is 10 wt%, while that of the waste-paper particles is 60-80 mesh. The use of AKD and coupling agent KH550 can reduce the water absorption of the composite; however, the reductive effect of the coupling agent is better, in that it is reduced by 0.3%. Modification using a 1-wt% KH550 coupling agent can effectively increase the tensile strength of a composite from 31.36 to 41.67 MPa (increase of 32.8%), while the bending strength increased from 86.47 to 98.31 MPa (increase of 13.7%). This also enhances the thermal stability of the composites. With the addition of the coupling agent, the composite material maintains good mechanical properties even after being immersed in water; this can enable the safe use of these composite materials in outdoor environments.

Emerging infectious diseases at the beginning of the 21st century.

PubMed

Lashley, Felissa R

2006-01-31

The emergence and re-emergence of infectious diseases involves many interrelated factors. Global interconnectedness continues to increase with international travel and trade; economic, political, and cultural interactions; and human-to-human and animal-to-human interactions. These interactions include the accidental and deliberate sharing of microbial agents and antimicrobial resistance and allow the emergence of new and unrecognized microbial disease agents. As the 21st century begins, already new agents have been identified, and new outbreaks have occurred. Solutions to limiting the spread of emerging infectious diseases will require cooperative efforts among many disciplines and entities worldwide. This article defines emerging infectious diseases, summarizes historical background, and discusses factors that contribute to emergence. Seven agents that have made a significant appearance, particularly in the 21st century, are reviewed, including: Ebola and Marburg hemorrhagic fevers, human monkeypox, bovine spongiform encephalopathy, severe acute respiratory syndrome (SARS), West Nile virus, and avian influenza. The article provides for each agent a brief historical background, case descriptions, and health care implications.

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

PubMed

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.

Critical review of the current recommendations for the treatment of systemic inflammatory rheumatic diseases during pregnancy and lactation.

PubMed

Levy, Roger A; de Jesús, Guilherme R; de Jesús, Nilson R; Klumb, Evandro M

2016-10-01

The crucial issue for a better pregnancy outcome in women with autoimmune rheumatic diseases is appropriate planning, with counseling of the ideal timing and treatment adaptation. Drugs used to treat rheumatic diseases may interfere with fertility or increase the risk of miscarriages and congenital abnormalities. MTX use post-conception is clearly linked to abortions as well as major birth defects, so it should be stopped 3months before conception. Leflunomide causes abnormalities in animals even in low doses. Although in humans, it does not seem to be as harmful as MTX, when pregnancy is detected in a patient on leflunomide, cholestyramine is given for washout. Sulfasalazine can be used safely and is an option for those patients who were on MTX or leflunomide. Azathioprine is generally the immunosuppressive of choice in many high-risk pregnancy centers because of the safety profile and its steroid-sparing property. Cyclosporine and tacrolimus can also be used as steroid-sparing agents, but experience is smaller. Although prednisone and prednisolone are inactivated in the placenta, we try to limit the dose to the minimal effective one, to prevent side effects. Antimalarials have been broadly studied and are safe during pregnancy and breastfeeding. Among biologic disease modifying anti-rheumatic agents (bDMARD), the anti-TNFs that have been used for longer are the ones with greater experience. The large monoclonal antibodies do not cross the placenta in the first trimester, and after conception, the decision to continue medication should be taken individually. The experience is larger in women with inflammatory bowel diseases, where anti-TNF is generally maintained at least until 30weeks to reduce fetal exposure. Live vaccines should not be administrated to the infant in the first 6months of life. Pregnancy data for rituximab, abatacept, anakinra, tocilizumab, ustekinumab, belimumab, and tofacitinib are limited and their use in pregnancy cannot currently be recommended. Copyright © 2016 Elsevier B.V. All rights reserved.

Peptide-Like Nylon-3 Polymers with Activity against Phylogenetically Diverse, Intrinsically Drug-Resistant Pathogenic Fungi.

PubMed

Rank, Leslie A; Walsh, Naomi M; Lim, Fang Yun; Gellman, Samuel H; Keller, Nancy P; Hull, Christina M

2018-01-01

Understanding the dimensions of fungal diversity has major implications for the control of diseases in humans, plants, and animals and in the overall health of ecosystems on the planet. One ancient evolutionary strategy organisms use to manage interactions with microbes, including fungi, is to produce host defense peptides (HDPs). HDPs and their synthetic analogs have been subjects of interest as potential therapeutic agents. Due to increases in fungal disease worldwide, there is great interest in developing novel antifungal agents. Here we describe activity of polymeric HDP analogs against fungi from 18 pathogenic genera composed of 41 species and 72 isolates. The synthetic polymers are members of the nylon-3 family (poly-β-amino acid materials). Three different nylon-3 polymers show high efficacy against surprisingly diverse fungi. Across the phylogenetic spectrum (with the exception of Aspergillus species), yeasts, dermatophytes, dimorphic fungi, and molds were all sensitive to the effects of these polymers. Even fungi intrinsically resistant to current antifungal drugs, such as the causative agents of mucormycosis ( Rhizopus spp.) and those with acquired resistance to azole drugs, showed nylon-3 polymer sensitivity. In addition, the emerging pathogens Pseudogymnoascus destructans (cause of white nose syndrome in bats) and Candida auris (cause of nosocomial infections of humans) were also sensitive. The three nylon-3 polymers exhibited relatively low toxicity toward mammalian cells. These findings raise the possibility that nylon-3 polymers could be useful against fungi for which there are only limited and/or no antifungal agents available at present. IMPORTANCE Fungi reside in all ecosystems on earth and impart both positive and negative effects on human, plant, and animal health. Fungal disease is on the rise worldwide, and there is a critical need for more effective and less toxic antifungal agents. Nylon-3 polymers are short, sequence random, poly-β-amino acid materials that can be designed to manifest antimicrobial properties. Here, we describe three nylon-3 polymers with potent activity against the most phylogenetically diverse set of fungi evaluated thus far in a single study. In contrast to traditional peptides, nylon-3 polymers are highly stable to proteolytic degradation and can be produced efficiently in large quantities at low cost. The ability to modify nylon-3 polymer composition easily creates an opportunity to tailor efficacy and toxicity, which makes these materials attractive as potential broad-spectrum antifungal therapeutics. Copyright © 2018 Rank et al.

The development and validation of EpiComet-Chip, a modified high-throughput comet assay for the assessment of DNA methylation status.

PubMed

Townsend, Todd A; Parrish, Marcus C; Engelward, Bevin P; Manjanatha, Mugimane G

2017-08-01

DNA damage and alterations in global DNA methylation status are associated with multiple human diseases and are frequently correlated with clinically relevant information. Therefore, assessing DNA damage and epigenetic modifications, including DNA methylation, is critical for predicting human exposure risk of pharmacological and biological agents. We previously developed a higher-throughput platform for the single cell gel electrophoresis (comet) assay, CometChip, to assess DNA damage and genotoxic potential. Here, we utilized the methylation-dependent endonuclease, McrBC, to develop a modified alkaline comet assay, "EpiComet," which allows single platform evaluation of genotoxicity and global DNA methylation [5-methylcytosine (5-mC)] status of single-cell populations under user-defined conditions. Further, we leveraged the CometChip platform to create an EpiComet-Chip system capable of performing quantification across simultaneous exposure protocols to enable unprecedented speed and simplicity. This system detected global methylation alterations in response to exposures which included chemotherapeutic and environmental agents. Using EpiComet-Chip on 63 matched samples, we correctly identified single-sample hypermethylation (≥1.5-fold) at 87% (20/23), hypomethylation (≥1.25-fold) at 100% (9/9), with a 4% (2/54) false-negative rate (FNR), and 10% (4/40) false-positive rate (FPR). Using a more stringent threshold to define hypermethylation (≥1.75-fold) allowed us to correctly identify 94% of hypermethylation (17/18), but increased our FPR to 16% (7/45). The successful application of this novel technology will aid hazard identification and risk characterization of FDA-regulated products, while providing utility for investigating epigenetic modes of action of agents in target organs, as the assay is amenable to cultured cells or nucleated cells from any tissue. Environ. Mol. Mutagen. 58:508-521, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Enhanced Detection of Vibrio Cholerae in Oyster Homogenate Based on Centrifugal Removal of Inhibitory Agents

NASA Technical Reports Server (NTRS)

Alexander, Donita; DePaola, Angelo; Young, Ronald B.

1998-01-01

The disease cholera, caused by Vibrio cholerae, has been associated with consumption of contaminated seafood, including raw oysters. Detection of V. cholerae in foods typically involves blending the oysters, diluting the homogenate in alkaline peptone water (APW), overnight enrichment, and isolation on selective agar. Unfortunately, the oyster homogenate must be diluted to large volumes because lower dilutions inhibit the growth of V. cholerae. The goals of this study were to develop an alternative to large dilutions and to evaluate the basis for the inhibition observed in lower dilutions of oyster homogenates. Centrifugation of oyster homogenates at 10,000 x g for 15 min, followed by enrichment of the resulting pellet in APW, was found to eliminate the inhibition of V. cholerae growth. Inhibition appears not to be due to competing microflora but to a component(s) released when V. cholerae grows in the presence of oyster homogenate. The inhibitory component(s) kills the V. cholerae after the cell concentration reaches > 10(exp 8) cells/mL, rather than initially preventing their growth. The pH also declines from 8.0 to 5.5 during this period; however, the pH decline by itself appears not to cause V. cholerae death. Seven strains of V. cholerae (01 and non-01) and two strains of V. vulnificus were susceptible to the inhibitory agent(s). However, other Vibrio and non-Vibrio species tested were not inhibited by the oyster homogenates. Based on digestion of oyster homogenates with pronase, trypsin and lipase, the inhibitory reaction involves a protein(s). In a preliminary trial with oyster homogenate seeded with 1 cfu/g of V. cholerae, the modified centrifugation technique detected a slightly higher percentage of samples at a 1:10 dilution than the standard FDA Bacteriological Analytical Method (BAM) detected in uncentrifuged oyster homogenate at a 1:100 dilution. V. cholerae in seeded samples could also be detected more frequently by the modified centrifugation method than by PCR at a 1:10 dilution.

Modified carbohydrate-chitosan compounds, methods of making the same and methods of using the same

DOEpatents

Venditti, Richard A; Pawlak, Joel J; Salam, Abdus; El-Tahlawy, Khaled Fathy

2015-03-10

Compositions of matter are provided that include chitosan and a modified carbohydrate. The modified carbohydrate includes a carbohydrate component and a cross linking agent. The modified carbohydrate has increased carboxyl content as compared to an unmodified counterpart carbohydrate. A carboxyl group of the modified carbohydrate is covalently bonded with an amino group of chitosan. The compositions of matter provided herein may include cross linked starch citrate-chitosan and cross linked hemicellulose citrate-chitosan, including foams thereof. These compositions yield excellent absorbency and metal chelation properties. Methods of making cross linked modified carbohydrate-chitosan compounds are also provided.

Small cell foams containing a modified dense star polymer or dendrimer as a nucleating agent

DOEpatents

Hedstrand, David M.; Tomalia, Donald A.

1995-01-01

A small cell foam having a modified dense star polymer or dendrimer is described. This modified dense star polymer or dendrimer has a highly branched interior of one monomeric composition and an exterior structure of a different monomeric composition capable of providing a hydrophobic outer shell and a particle diameter of from about 5 to about 1,000 nm with a matrix polymer.

Small cell foams containing a modified dense star polymer or dendrimer as a nucleating agent

DOEpatents

Hedstrand, D.M.; Tomalia, D.A.

1995-02-28

A small cell foam having a modified dense star polymer or dendrimer is described. This modified dense star polymer or dendrimer has a highly branched interior of one monomeric composition and an exterior structure of a different monomeric composition capable of providing a hydrophobic outer shell and a particle diameter of from about 5 to about 1,000 nm with a matrix polymer.

Observations on Mildew Susceptibility of Painted Surfaces in Tropical Chamber Exposure

DTIC Science & Technology

1983-12-01

resins of iron oxide, red iron urea formaldehyde or oxide. blends of urea / melamine + modifiers, stabili- zers, wetting and sus- pension agents. MIL-E...type, modified or chromate yellow, molyb- with not less than 20% date orange, carbazole di- butylated melamine oxazine violet, yellow formaldehyde ...com- Pure short oil length Enamel, Modified Alkyd posed of cobalt, zinc, phthalic alkyd resin Camouflage, Lusterless and chromium oxides, and/ baking

Effects of different surface modifying agents on the cytotoxic and antimicrobial properties of ZnO nanoparticles.

PubMed

Esparza-González, S C; Sánchez-Valdés, S; Ramírez-Barrón, S N; Loera-Arias, M J; Bernal, J; Meléndez-Ortiz, H Iván; Betancourt-Galindo, R

2016-12-01

Zinc oxide (ZnO) nanoparticles (NPs) have received considerable attention in the medical field because of their antibacterial properties, primarily for killing and reducing the activity of numerous microorganisms. The purpose of this study was to determine whether surface-modified ZnO NPs exhibit different properties compared with unmodified ZnO. The antimicrobial and cytotoxic properties of modified ZnO NPs as well as their effects on inflammatory cytokine production were evaluated. ZnO NPs were prepared using a wet chemical method. Then, the surfaces of these NPs were modified using 3-aminopropyltriethoxysilane (APTES) and dimethyl sulfoxide (DMSO) as modifying agents via a chemical hydrolysis method. According to infrared spectroscopy analysis (FTIR), the structure of the ZnO remained unchanged after modification. Antibacterial assays demonstrated that APTES modification is more effective at inducing an antimicrobial effect against Gram-negative bacteria than against Gram-positive bacteria. Cytotoxicity studies showed that cell viability was dose-dependent; moreover, pristine and APTES-modified ZnO exhibited low cytotoxicity, whereas DMSO-modified ZnO exhibited toxicity even at a low NP concentration. An investigation of inflammatory cytokine production demonstrated that the extent of stimulation was related to the ZnO NP concentration but not to the surface modification, except for IFN-γ and IL-10, which were not detected even at high NP concentrations. Copyright © 2016 Elsevier B.V. All rights reserved.

Pharmacotherapy of Scleritis: Current Paradigms and Future Directions

PubMed Central

Beardsley, Robert M.; Suhler, Eric B.; Rosenbaum, James T.; Lin, Phoebe

2013-01-01

Introduction Scleritis is an inflammatory condition affecting the eye wall that may be associated with a number of systemic inflammatory diseases. Because scleritis can be refractory to standard treatment, knowledge of the body of available and emerging therapies is paramount and is reviewed here. Areas Covered This review focuses on both traditional and emerging therapies for non-infectious scleritis. We will cover the mechanisms of action and potential adverse effects of each of the treatment modalities. Additionally, a summary of the significant MEDLINE indexed literature under the subject heading “scleritis,” “treatment,” “immunomodulator” will be provided on each therapy, including commentary on appropriate use and relative contraindications. Lastly, novel treatments and potential drug candidates that are currently being evaluated in clinical trials with therapeutic potential will also be reviewed. Expert Opinion While oral non-steroidal anti-inflammatory drugs (NSAIDs) and oral corticosteroids are widely used, effective, first-line agents for inflammatory scleritis, refractory cases require anti-metabolites, T cell inhibitors, or biologic response modifiers. In particular, there is emerging evidence for the use of targeted biologic response modifiers, and potentially, for local drug delivery. PMID:23425055

Tempol effect on epithelial-mesenchymal transition induced by hyperglycemia

PubMed Central

Jafari, Mohammad; Dadras, Farahnaz; Ghadimipour, Hamid Reza; Seif Rabiei, Mohamad Ali; Khoshjou, Farhad

2017-01-01

Background One of common mechanisms in pathophysiology of chronic kidney diseases is epithelial-mesenchymal transition (EMT). On the other hand oxidative stress has been known to participate in kidney damage of diabetic nephropathy (DN). Objectives We studied if tempol, a well-known antioxidant agent, can ameliorate EMT in DN induced in male rats. Materials and Methods Twenty-seven male rats were equally divided in to 4 groups. Group I (control or C), group II (diabetic or D), group III (T) rats which was given tempol (100 mg/kg/day) by gavages for 28 days and group IV (D&T) was diabetic rats that also received same dose of tempol. After treatment, their kidneys were studied by immunohistochemicalstaining. Results Pathological changes in the kidney were detected concurrently with increasing kidney weight and urinary albumin excretion. In addition, EMT indices, i.e. decline of E-cadherin and increase of α SMA staining were significantly emerged in the renal tubular cells of diabetic group and were partially modified in diabetic group which were simultaneously treated by tempol. Conclusions Tempol can modify, but not significantly, EMT induced by DN. PMID:28042546

Incidence of hypophosphatemia in advanced cancer patients: a recent report from a single institution.

PubMed

Yoshida, Taichi; Taguchi, Daiki; Fukuda, Koji; Shimazu, Kazuhiro; Inoue, Masahiro; Murata, Katsunori; Shibata, Hiroyuki

2017-04-01

Recent approval of molecular-targeted agents has contributed to improving the therapeutic outcomes of advanced cancer patients. However, they result in unusual adverse events that rarely occur with cytotoxic agents, such as hypertension, hypomagnesemia, and an acne-like rash. Although hypophosphatemia can be induced by various agents, some kinds of molecular-targeted agents are known to induce it. In addition, cancer survivors may be at a risk of hypophosphatemia. One hundred and seventy patients, who visited the Department of Clinical Oncology at Akita University from 1 April 2014 to 31 August 2016 were enrolled in this study after providing informed consent. Serum inorganic phosphorus levels were examined along with other routine clinical examinations. Correlation between the serum inorganic phosphorus level and other clinical data were also analyzed. Grade ≥2 severe hypophosphatemia (<2.5 mg/dL of phosphorus) was detected in 49.4% of patients, and grade ≥3 (<2.0 mg/dL of phosphorus) was observed in 22.9% patients. These results indicated that the presence of bone metastasis (p < 0.001), history of bone-modifying agents (p < 0.001) and molecular-targeted drugs (p = 0.001), and time from the date of the first visit to the date of minimum serum phosphorus level (p < 0.001) might correlate with hypophosphatemia. Multivariate logistic regression analysis showed that disease duration might be a risk factor (p = 0.0466). As hypophosphatemia can be induced by various factors in advanced cancer patients, the serum phosphorus level of cancer patients at risk should be cautiously examined.

Virus-Based Nanoparticles as Versatile Nanomachines

PubMed Central

Koudelka, Kristopher J.; Pitek, Andrzej S.; Manchester, Marianne; Steinmetz, Nicole F.

2016-01-01

Nanoscale engineering is revolutionizing the way we prevent, detect, and treat diseases. Viruses have played a special role in these developments because they can function as prefabricated nanoscaffolds that have unique properties and are easily modified. The interiors of virus particles can encapsulate and protect sensitive compounds, while the exteriors can be altered to display large and small molecules in precisely defined arrays. These properties of viruses, along with their innate biocompatibility, have led to their development as actively targeted drug delivery systems that expand on and improve current pharmaceutical options. Viruses are naturally immunogenic, and antigens displayed on their surface have been used to create vaccines against pathogens and to break self-tolerance to initiate an immune response to dysfunctional proteins. Densely and specifically aligned imaging agents on viruses have allowed for high-resolution and noninvasive visualization tools to detect and treat diseases earlier than previously possible. These and future applications of viruses have created an exciting new field within the disciplines of both nanotechnology and medicine. PMID:26958921

Safety of treatment options for spondyloarthritis: a narrative review.

PubMed

D'Angelo, Salvatore; Carriero, Antonio; Gilio, Michele; Ursini, Francesco; Leccese, Pietro; Palazzi, Carlo

2018-05-01

Spondyloarthritis (SpA) are chronic inflammatory diseases with overlapping pathogenic mechanisms and clinical features. Treatment armamentarium against SpA includes non-steroidal anti-inflammatory drugs, glucocorticoids, conventional disease-modifying antirheumatic drugs (DMARDs, including sulfasalazine, methotrexate, leflunomide, cyclosporine), targeted synthetic DMARDs (apremilast) and biological DMARDs (TNF inhibitors, anti-IL 12/23 and anti-IL-17 agents). Areas covered: A narrative review of published literature on safety profile of available SpA treatment options was performed. Readers will be provided with a comprehensive overview on frequent and rare adverse events associated with each drug listed in current SpA treatment recommendations. Expert opinion: The overall safety profile of such molecules is good and serious adverse events are rare but need to be promptly recognized and treated. However, the monitoring of adverse events is a major challenge for clinicians because it is not adequately addressed by current treatment recommendations. A tailored treatment is crucial and rheumatologists must accurately select patients in order to identify those more susceptible to develop adverse events.

Reconfigurable acquisition system with integrated optics for a portable flow cytometer

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

Kirleis, Matthew A., E-mail: matthew.kirleis@nrl.navy.mil; Mathews, Scott A.; Verbarg, Jasenka

2013-11-15

Portable and inexpensive scientific instruments that are capable of performing point of care diagnostics are needed for applications such as disease detection and diagnosis in resource-poor settings, for water quality and food supply monitoring, and for biosurveillance activities in autonomous vehicles. In this paper, we describe the development of a compact flow cytometer built from three separate, customizable, and interchangeable modules. The instrument as configured in this work is being developed specifically for the detection of selected Centers for Disease Control (CDC) category B biothreat agents through a bead-based assay: E. coli O157:H7, Salmonella, Listeria, and Shigella. It has two-colormore » excitation, three-color fluorescence and light scattering detection, embedded electronics, and capillary based flow. However, these attributes can be easily modified for other applications such as cluster of differentiation 4 (CD4) counting. Proof of concept is demonstrated through a 6-plex bead assay with the results compared to a commercially available benchtop-sized instrument.« less

Reciprocal interactions between bile acids and gut microbiota in human liver diseases.

PubMed

Ikegami, Tadashi; Honda, Akira

2018-01-01

The gut microbiota (GM) play a central role in their host's metabolism of bile acids (BAs) by regulating deconjugation, dehydroxylation, dehydrogenation, and epimerization reactions to generate unconjugated free BAs and secondary BAs. These BAs generated by the GM are potent signaling molecules that interact with BA receptors, such as the farnesoid X receptor and Takeda G-protein-coupled receptor 5. Each BA has a differential affinity to these receptors; therefore, alterations in BA composition by GM could modify the intensity of receptor signaling. Bile acids also act as antimicrobial agents by damaging bacterial membranes and as detergents by altering intracellular macromolecular structures. Therefore, BAs and the GM reciprocally control each other's compositions. In this review, we discuss the latest findings on the mutual effects of BAs and GM on each other; we also describe their roles in the pathophysiology of liver disease progression and potential therapeutic applications of targeting this cross-talk. © 2017 The Japan Society of Hepatology.

Reconfigurable acquisition system with integrated optics for a portable flow cytometer.

PubMed

Kirleis, Matthew A; Mathews, Scott A; Verbarg, Jasenka; Erickson, Jeffrey S; Piqué, Alberto

2013-11-01

Portable and inexpensive scientific instruments that are capable of performing point of care diagnostics are needed for applications such as disease detection and diagnosis in resource-poor settings, for water quality and food supply monitoring, and for biosurveillance activities in autonomous vehicles. In this paper, we describe the development of a compact flow cytometer built from three separate, customizable, and interchangeable modules. The instrument as configured in this work is being developed specifically for the detection of selected Centers for Disease Control (CDC) category B biothreat agents through a bead-based assay: E. coli O157:H7, Salmonella, Listeria, and Shigella. It has two-color excitation, three-color fluorescence and light scattering detection, embedded electronics, and capillary based flow. However, these attributes can be easily modified for other applications such as cluster of differentiation 4 (CD4) counting. Proof of concept is demonstrated through a 6-plex bead assay with the results compared to a commercially available benchtop-sized instrument.

Targeting brain metastases in ALK-rearranged non-small-cell lung cancer.

PubMed

Zhang, Isabella; Zaorsky, Nicholas G; Palmer, Joshua D; Mehra, Ranee; Lu, Bo

2015-10-01

The incidence of brain metastases has increased as a result of improved systemic control and advances in imaging. However, development of novel therapeutics with CNS activity has not advanced at the same rate. Research on molecular markers has revealed many potential targets for antineoplastic agents, and a particularly important aberration is translocation in the ALK gene, identified in non-small-cell lung cancer (NSCLC). ALK inhibitors have shown systemic efficacy against ALK-rearranged NSCLC in many clinical trials, but the effectiveness of crizotinib in CNS disease is limited by poor blood-brain barrier penetration and acquired drug resistance. In this Review, we discuss potential pathways to target ALK-rearranged brain metastases, including next generation ALK inhibitors with greater CNS penetration and mechanisms to overcome resistance. Other important mechanisms to control CNS disease include targeting pathways downstream of ALK phosphorylation, increasing the permeability of the blood-brain barrier, modifying the tumour microenvironment, and adding concurrent radiotherapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

Reconfigurable acquisition system with integrated optics for a portable flow cytometer

NASA Astrophysics Data System (ADS)

Kirleis, Matthew A.; Mathews, Scott A.; Verbarg, Jasenka; Erickson, Jeffrey S.; Piqué, Alberto

2013-11-01

Portable and inexpensive scientific instruments that are capable of performing point of care diagnostics are needed for applications such as disease detection and diagnosis in resource-poor settings, for water quality and food supply monitoring, and for biosurveillance activities in autonomous vehicles. In this paper, we describe the development of a compact flow cytometer built from three separate, customizable, and interchangeable modules. The instrument as configured in this work is being developed specifically for the detection of selected Centers for Disease Control (CDC) category B biothreat agents through a bead-based assay: E. coli O157:H7, Salmonella, Listeria, and Shigella. It has two-color excitation, three-color fluorescence and light scattering detection, embedded electronics, and capillary based flow. However, these attributes can be easily modified for other applications such as cluster of differentiation 4 (CD4) counting. Proof of concept is demonstrated through a 6-plex bead assay with the results compared to a commercially available benchtop-sized instrument.

Synonymous codon changes in the oncogenes of the cottontail rabbit papillomavirus lead to increased oncogenicity and immunogenicity of the virus

PubMed Central

Cladel, Nancy M.; Budgeon, Lynn R.; Hu, Jiafen; Balogh, Karla K.; Christensen, Neil D.

2013-01-01

Papillomaviruses use rare codons with respect to the host. The reasons for this are incompletely understood but among the hypotheses is the concept that rare codons result in low protein production and this allows the virus to escape immune surveillance. We changed rare codons in the oncogenes E6 and E7 of the cottontail rabbit papillomavirus to make them more mammalian-like and tested the mutant genomes in our in vivo animal model. While the amino acid sequences of the proteins remained unchanged, the oncogenic potential of some of the altered genomes increased dramatically. In addition, increased immunogenicity, as measured by spontaneous regression, was observed as the numbers of codon changes increased. This work suggests that codon usage may modify protein production in ways that influence disease outcome and that evaluation of synonymous codons should be included in the analysis of genetic variants of infectious agents and their association with disease. PMID:23433866

Medical Management of Crohn Disease

PubMed Central

Scott, Frank I.; Osterman, Mark T.

2013-01-01

Crohn disease (CD) is one of the major subtypes of inflammatory bowel disease and can occur in any segment of the alimentary tract. There have been significant advances in the medical therapy of CD over the past several decades. For mild CD, the oral corticosteroid derivative budesonide has demonstrated superior efficacy compared with traditional therapies such as 5-aminosalicylic acid, and can be used concurrently with these agents. For the management of moderate to severe disease, the immunomodulators azathioprine, 6-mercaptopurine, and methotrexate, as well as the antitumor necrosis factor-alpha (TNF-α) agents infliximab, adalimumab, and certolizumab pegol, have become the mainstay of therapy, with growing interest in combining these agents for maximal effect. Immunomodulators and anti-TNF-α agents have also demonstrated benefit in fistulizing CD. There has been growing evidence suggesting that both of these agents, along with the antibiotics metronidazole and ornidazole, are also effective in preventing postoperative recurrence of CD. PMID:24436652

Corundum ceramic materials modified with silica nanopowders: structure and mechanical properties

NASA Astrophysics Data System (ADS)

Kostytsyn, M. A.; Muratov, D. S.; Lysov, D. V.; Chuprunov, K. O.; Yudin, A. G.; Leybo, D. V.

2016-01-01

Filtering elements are often used in the metallurgy of rare earth metals. Corundum ceramic is one of the most suitable materials for this purpose. The process of formation and the properties of nanomodified ceramic materials, which are proposed as filtering materials with tunable effective porosity, are described. A silica nanopowder is used as a porosity-increasing agent. Vortex layer apparatus is used for mixing of precursor materials. The obtained results show that nanomodification with the vortex layer apparatus using 0.04 wt. % silica nanopowder as a modifying agent leads to an increase in the compression strength of corundum ceramic by the factor of 1.5.

Three-body-wear resistance of the experimental composites containing filler treated with hydrophobic silane coupling agents.

PubMed

Nihei, Tomotaro; Dabanoglu, Alp; Teranaka, Toshio; Kurata, Shigeaki; Ohashi, Katsura; Kondo, Yukishige; Yoshino, Norio; Hickel, Reinhard; Kunzelmann, Karl-Heinz

2008-06-01

This paper evaluated the wear resistance of resin composite materials with fillers which were modified with a novel hydrophobic silane coupling agent. The novel silane coupling agent containing hydrophobic phenyl group 3-(3-methoxy-4-methacryloyloxyphenyl)propyltrimethoxysilane (p-MBS) was synthesized. The experimental light-cure hybrid composites containing 85wt% of filler modified with this silane were formulated. Twelve specimens were prepared for the three-body-wear test with the ACTA machine and the collected data were analyzed statistically using a one-way ANOVA and Tukey's multiple comparison test as the post hoc test. The wear of the composites containing fillers treated with p-MBS was significantly lower compared with the composite materials containing fillers pretreated with 3-methacryloyloxypropyltrimethoxysilane or the commercially composites (AP-X and ELS extra low shrinkage) after a wear test for 200,000 cycles (p<0.05). It is suggested that the resin composites containing fillers modified with the novel hydrophobic silane has high wear resistant, because of the coupling layers treated with this silane had an excellent affinity with the base resin and formed a highly hydrophobic layer on the filler surface.

Multifunctional PEG modified DOX loaded mesoporous silica nanoparticle@CuS nanohybrids as photo-thermal agent and thermal-triggered drug release vehicle for hepatocellular carcinoma treatment

NASA Astrophysics Data System (ADS)

Wu, Lingjie; Wu, Ming; Zeng, Yongyi; Zhang, Da; Zheng, Aixian; Liu, Xiaolong; Liu, Jingfeng

2015-01-01

The combination of a multi-therapeutic mode with a controlled fashion is a key improvement in nanomedicine. Here, we synthesized polyethylene glycol (PEG)-modified doxorubicin (DOX)-loaded mesoporous silica nanoparticle (MSN) @CuS nanohybrids as efficient drug delivery carriers, combined with photothermal therapy and chemotherapy to enhance the therapeutic efficacy on hepatocellular carcinoma (HCC). The physical properties of the nanohybrids were characterized by transmission electron microscopy (TEM), N2 adsorption and desorption experiments and by the Vis-NIR absorption spectra. The results showed that the doxorubicin could be stored in the inner pores of mesoporous silica nanoparticles; the CuS nanoparticles, which are coated on the surface of a mesoporous silica nanoparticle, could serve as efficient photothermal therapy (PTT) agents; the loaded drug release could be easily triggered by NIR irradiation. The combination of the PTT treatment with controlled chemotherapy could further enhance the cancer ablation ability compared to any of the single approaches alone. Hence, the reported PEG-modified DOX-loaded mesoporous silica nanoparticle@CuS nanohybrids might be very promising therapeutic agents for HCC treatment.

Jack of All Trades: Pleiotropy and the application of Chemically Modified Tetracycline -3 in Sepsis and the Acute Respiratory Distress Syndrome (ARDS)

PubMed Central

Roy, Shreyas K.; Kendrick, Daniel; Sadowitz, Benjamin D.; Gatto, Louis; Snyder, Kathleen; Satalin, Joshua M.; Golub, Lorne M.; Nieman, Gary

2011-01-01

Sepsis is a disease process that has humbled the medical profession for centuries with its resistance to therapy, relentless mortality, and pathophysiologic complexity. Despite 30 years of aggressive, concerted, well-resourced efforts the biomedical community has been unable to reduce the mortality of sepsis from 30%, nor the mortality of septic shock from greater than 50%. In the last decade only one new drug for sepsis has been brought to the market, drotrecogin alfa-activated (Xigris™), and the success of this drug has been limited by patient safety issues. Clearly a new agent is desperately needed. The advent of recombinant human immune modulators held promise but the outcomes of clinical trials using biologics that target single immune mediators have been disappointing. The complex pathophysiology of the systemic inflammatory response syndrome (SIRS) is self-amplifying and redundant at multiple levels. In this review we argue that perhaps pharmacologic therapy for sepsis will only be successful if it addresses this pathophysiologic complexity; the drug would have to be pleiotropic, working on many components of the inflammatory cascade at once. In this context, therapy that targets any single inflammatory mediator will not adequately address the complexity of SIRS. We propose that Chemically Modified Tetracycline-3, CMT-3 (or COL-3), a non-antimicrobial modified tetracycline with pleiotropic anti-inflammatory properties, is an excellent agent for the management of sepsis and its associated complication of the Acute Respiratory Distress Syndrome (ARDS). The purpose of this review is threefold: 1) to examine the shortcomings of current approaches to treatment of sepsis and ARDS in light of their pathophysiology, 2) to explore the application of COL-3 in ARDS and sepsis, and finally 3) to elucidate the mechanisms of COL-3 that may have potential therapeutic benefit in ARDS and sepsis. PMID:21767646

Gaucher disease: clinical profile and therapeutic developments.

PubMed

Cox, Timothy M

2010-12-06

Gaucher disease is a rare inborn error of glycosphingolipid metabolism due to deficiency of lysosomal acid β-glucocerebrosidase; the condition has totemic significance for the development of orphan drugs. A designer therapy, which harnesses the mannose receptor to complement the functional defect in macrophages, ameliorates the principal clinical manifestations in hematopoietic bone marrow and viscera. While several aspects of Gaucher disease (particularly those affecting the skeleton and brain) are refractory to treatment, enzyme (replacement) therapy has become a pharmaceutical blockbuster. Human β-glucocerebrosidase was originally obtained from placenta and the Genzyme Corporation (Allston, MA) subsequently developed a recombinant product. After purification, the enzyme is modified to reveal terminal mannose residues which facilitate selective uptake of the protein, imiglucerase (Cerezyme(®)), in macrophage-rich tissues. The unprecedented success of Cerezyme has attracted fierce competition: two biosimilar agents, velaglucerase-alfa, VPRIV(®) (Shire Human Genetic Therapies, Dublin, Ireland) and taliglucerase-alfa (Protalix, Carmiel, Israel), are now approved or in late-phase clinical development as potential 'niche busters'. Oral treatments have advantages over biological agents for disorders requiring lifelong therapy and additional stratagems which utilize small, orally active molecules have been introduced; these include two chemically distinct compounds which inhibit uridine diphosphate glucose: N-acylsphingosine glucosyltransferase, the first step in the biosynthesis of glucosylceramide - a key molecular target in Gaucher disease and other glycosphingolipidoses. Academic and commercial enterprises in biotechnology have combined strategically to expand the therapeutic repertoire in Gaucher disease. The innovative potential of orphan drug legislation has been realized - with prodigious rewards for companies embracing its humanitarian precepts. In the era before enzyme therapy, bone marrow transplantation was shown to correct systemic disease in Gaucher patients by supplying a source of competent donor macrophages. As a radical advance on cell- or protein-replacement techniques, contemporary methods for transferring genes to autologous hematopoietic stem cells, and to the brain, merit further exploration. At present, the inflated pharmaceutical niche of Gaucher disease appears to be resilient, but if the remaining unmet needs of patients are to be convincingly addressed and commercial development sustained, courageous scientific investment and clinical experimentation will be needed.

Gaucher disease: clinical profile and therapeutic developments

PubMed Central

Cox, Timothy M

2010-01-01

Gaucher disease is a rare inborn error of glycosphingolipid metabolism due to deficiency of lysosomal acid β-glucocerebrosidase; the condition has totemic significance for the development of orphan drugs. A designer therapy, which harnesses the mannose receptor to complement the functional defect in macrophages, ameliorates the principal clinical manifestations in hematopoietic bone marrow and viscera. While several aspects of Gaucher disease (particularly those affecting the skeleton and brain) are refractory to treatment, enzyme (replacement) therapy has become a pharmaceutical blockbuster. Human β-glucocerebrosidase was originally obtained from placenta and the Genzyme Corporation (Allston, MA) subsequently developed a recombinant product. After purification, the enzyme is modified to reveal terminal mannose residues which facilitate selective uptake of the protein, imiglucerase (Cerezyme®), in macrophage-rich tissues. The unprecedented success of Cerezyme has attracted fierce competition: two biosimilar agents, velaglucerase-alfa, VPRIV® (Shire Human Genetic Therapies, Dublin, Ireland) and taliglucerase-alfa (Protalix, Carmiel, Israel), are now approved or in late-phase clinical development as potential ‘niche busters’. Oral treatments have advantages over biological agents for disorders requiring lifelong therapy and additional stratagems which utilize small, orally active molecules have been introduced; these include two chemically distinct compounds which inhibit uridine diphosphate glucose: N-acylsphingosine glucosyltransferase, the first step in the biosynthesis of glucosylceramide – a key molecular target in Gaucher disease and other glycosphingolipidoses. Academic and commercial enterprises in biotechnology have combined strategically to expand the therapeutic repertoire in Gaucher disease. The innovative potential of orphan drug legislation has been realized – with prodigious rewards for companies embracing its humanitarian precepts. In the era before enzyme therapy, bone marrow transplantation was shown to correct systemic disease in Gaucher patients by supplying a source of competent donor macrophages. As a radical advance on cell- or protein-replacement techniques, contemporary methods for transferring genes to autologous hematopoietic stem cells, and to the brain, merit further exploration. At present, the inflated pharmaceutical niche of Gaucher disease appears to be resilient, but if the remaining unmet needs of patients are to be convincingly addressed and commercial development sustained, courageous scientific investment and clinical experimentation will be needed. PMID:21209725

Modified silicas with different structure of grafted methylphenylsiloxane layer

NASA Astrophysics Data System (ADS)

Bolbukh, Yuliia; Terpiłowski, Konrad; Kozakevych, Roman; Sternik, Dariusz; Deryło-Marczewska, Anna; Tertykh, Valentin

2016-06-01

The method of a chemical assembly of the surface polymeric layer with high contents of the modifying agent was developed. Powders of nanodispersed silica with chemisorbed polymethylphenylsiloxane (PMPS) were synthesized by solvent-free chemical assembly technique with a dimethyl carbonate (DMC) as scission agent. Samples were characterized using FTIR spectroscopy, transmission electron microscopy (TEM), atomic force microscopy (AFM), and elemental analysis (CHN analysis). Coating microstructure, morphology, and hydrophilic-hydrophobic properties of nanoparticles were estimated. The results indicate a significant effect of the PMPS/DMC ratio at each modification stage on hydrophobic properties of modified silicas. Modification with a similar composition of the PMPS/DMC mixture, even with different polymer amount at each stage, provides the worst hydrophobicity. Results suggest that the highest hydrophobicity (contact angle θ = 135°-140°) is achieved in the case when silica modified with the PMPS/DMC mixture using multistage approach that providing a formation of the monomolecular layer of polysiloxane at the first modification step. The characteristics of surface structure were interpreted in terms of density of polymer-silica bonds at the interfaces that, usually, are reduced for modified surfaces, in a coupling with conformation model that accented the shape of chains (arch- and console-like) adsorbed on solid surfaces.

Poisoning of a Silica-Supported Cobalt Catalyst due to Presence of Sulfur Impurities in Syngas during Fischer–Tropsch Synthesis: Effects of Chelating Agent

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

Bambal, Ashish S.; Guggilla, Vidya S.; Kugler, Edwin L.

2014-04-09

The effects of sulfur impurities on the performance of cobalt-based Fischer–Tropsch catalysts are evaluated under industrially relevant operating conditions of temperature, pressure, and impurity levels. Chelating agents (CAs) were used to modify the SiO 2 support, and the performances of the CA-modified catalysts are compared with conventional Co/SiO 2 catalysts. For both the Co/SiO 2 and CA-modified catalysts, the presence of sulfur in the inlet syngas results in a notable drop in the CO conversion, an undesired shift in the hydrocarbon selectivity toward short-chain hydrocarbons, more olefins in the products, and lower product yields. In the post-poisoning stage, i.e., aftermore » termination of sulfur introduction in the inlet syngas, the CA-modified catalysts recover activity and selectivity (to some extent at least), whereas such trends are not observed for the base-case, i.e., unmodified Co/SiO 2 catalyst. Finally, the improved performance of the CA-modified catalysts in the presence of sulfur is attributed to higher densities of active sites.« less

Sugar-Coated PPE's, Novel Nanomaterial's and Sensing Modules for Disease and Bioterrorism Related Threats

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

Bunz, Uwe

2003-11-21

The detection and sensing of biological warfare agents (ricin, anthrax toxin), of disease agents (cholera, botulinum, and tetnus toxins, influenza virus, etc.) and of biologically active species important for national security and disease control.

HOW to Identify and Control Noninfectious Diseases of Trees

Treesearch

USDA Forest Service Northern Area State & Private Forestry

Noninfectious tree diseases are those caused by nonliving agents. This type of disease is not transmitted from one plant to another. Extremes in temperature and water supply are the most common causes of this type of disease. Other causes are chemical substances in the soil, water, and air; transplant shock; and mechanical injuries. These nonliving disease agents are a...

Unresolved issues in theories of autoimmune disease using myocarditis as a framework

PubMed Central

Root-Bernstein, Robert; Fairweather, DeLisa

2014-01-01

Many theories of autoimmune disease have been proposed since the discovery that the immune system can attack the body. These theories include the hidden or cryptic antigen theory, modified antigen theory, T cell bypass, T cell-B cell mismatch, epitope spread or drift, the bystander effect, molecular mimicry, anti-idiotype theory, antigenic complementarity, and dual-affinity T cell receptors. We critically review these theories and relevant mathematical models as they apply to autoimmune myocarditis. All theories share the common assumption that autoimmune diseases are triggered by environmental factors such as infections or chemical exposure. Most, but not all, theories and mathematical models are unifactorial assuming single-agent causation of disease. Experimental and clinical evidence and mathematical models exist to support some aspects of most theories, but evidence/models that support one theory almost invariably supports other theories as well. More importantly, every theory (and every model) lacks the ability to account for some key autoimmune disease phenomena such as the fundamental roles of innate immunity, sex differences in disease susceptibility, the necessity for adjuvants in experimental animal models, and the often paradoxical effect of exposure timing and dose on disease induction. We argue that a more comprehensive and integrated theory of autoimmunity associated with new mathematical models is needed and suggest specific experimental and clinical tests for each major theory that might help to clarify how they relate to clinical disease and reveal how theories are related. PMID:25484004

Unresolved issues in theories of autoimmune disease using myocarditis as a framework.

PubMed

Root-Bernstein, Robert; Fairweather, DeLisa

2015-06-21

Many theories of autoimmune disease have been proposed since the discovery that the immune system can attack the body. These theories include the hidden or cryptic antigen theory, modified antigen theory, T cell bypass, T cell-B cell mismatch, epitope spread or drift, the bystander effect, molecular mimicry, anti-idiotype theory, antigenic complementarity, and dual-affinity T cell receptors. We critically review these theories and relevant mathematical models as they apply to autoimmune myocarditis. All theories share the common assumption that autoimmune diseases are triggered by environmental factors such as infections or chemical exposure. Most, but not all, theories and mathematical models are unifactorial assuming single-agent causation of disease. Experimental and clinical evidence and mathematical models exist to support some aspects of most theories, but evidence/models that support one theory almost invariably supports other theories as well. More importantly, every theory (and every model) lacks the ability to account for some key autoimmune disease phenomena such as the fundamental roles of innate immunity, sex differences in disease susceptibility, the necessity for adjuvants in experimental animal models, and the often paradoxical effect of exposure timing and dose on disease induction. We argue that a more comprehensive and integrated theory of autoimmunity associated with new mathematical models is needed and suggest specific experimental and clinical tests for each major theory that might help to clarify how they relate to clinical disease and reveal how theories are related. Copyright © 2014 Elsevier Ltd. All rights reserved.

Zoonotic risks from small ruminants.

PubMed

Ganter, M

2015-12-14

Zoonoses are infections that spread naturally between species (sometimes by a vector) from animals to other animal species or to humans or from humans to animals. Most of the zoonoses diagnosed in sheep and goats are transmitted by close contact of man with these animals and are, more often, occupational diseases that principally affect breeders, veterinarians and/or slaughterhouse workers. Some other diseases have an airborne transmission and affect the population in the vicinity of sheep/goat farms. Due to the fact that small ruminants are almost the only remaining animals which are migrating in industrialised countries, there is a severe risk for transmitting the diseases. Some other zoonotic diseases are foodborne diseases, which are mainly transmitted from animals to humans and to other animal species by contaminated food and water. Within the last decade central Europe was threatened by some new infections, e.g., bluetongue disease and schmallenberg disease, which although not of zoonotic interest, are caused by pathogens transmitted by vectors. Causal agents of both diseases have found highly effective indigenous vectors. In the future, climate change may possibly modify conditions for the vectors and influence their distribution and competence. By this, other vector-borne zoonotic infections may propagate into former disease free countries. Changes in human behaviour in consummation and processing of food, in animal housing and management may also influence future risks for zoonosis. Monitoring, prevention and control measures are proposed to limit further epidemics and to enable the containment of outbreaks. Measures depend mainly on the damage evoked or anticipated by the disease, the local situation, and the epidemiology of the zoonoses, the presence of the infective agent in wild and other animals, as well as the resistance of the causal microorganisms in the environment and the possibility to breed sheep and goats which are resistant to specific infections. In this review, the clinical signs in animals and humans of the main sheep and goat zoonoses, as well as the transmission route and the control measures are reported. Brucellosis, chlamydophilosis, Q fever, Orf, Rift valley fever and Bovine Spongiform Encephalopathy are described in greater detail, in order to determine factors that contribute to the choice of the control strategies. Copyright © 2015 Elsevier B.V. All rights reserved.

21 CFR 178.3130 - Antistatic and/or anti-fogging agents in food-packaging materials.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Antistatic and/or anti-fogging agents in food..., fresh fruits, and fresh vegetables. Alpha-(Carboxymethyl)-omega-(tetradecyloxy)polyoxyethylene) For use... at levels not to exceed 3.0 percent by weight of polystyrene or rubber-modified polystyrene complying...

21 CFR 178.3130 - Antistatic and/or anti-fogging agents in food-packaging materials.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Antistatic and/or anti-fogging agents in food..., fresh fruits, and fresh vegetables. Alpha-(Carboxymethyl)-omega-(tetradecyloxy)polyoxyethylene) For use... at levels not to exceed 3.0 percent by weight of polystyrene or rubber-modified polystyrene complying...

COMPARISON OF RAPID METHODS TO EVALUATE CHLORINE INACTIVATION OF THE BIOLOGICAL AGENT E. COLI 0157:H7

EPA Science Inventory

Rapid viability tests of the Catagory B agent Escherichia coli O157:H7 were evaluated after disinfection with chlorine. The metabolic activity dyes ChemChrome V6, a modified fluorescein diacetate (FDA) and 5-cyano-2,3-ditolyl tetrazolium chloride (CTC) were compared to standard ...

Construction of multi-agent mobile robots control system in the problem of persecution with using a modified reinforcement learning method based on neural networks

NASA Astrophysics Data System (ADS)

Patkin, M. L.; Rogachev, G. N.

2018-02-01

A method for constructing a multi-agent control system for mobile robots based on training with reinforcement using deep neural networks is considered. Synthesis of the management system is proposed to be carried out with reinforcement training and the modified Actor-Critic method, in which the Actor module is divided into Action Actor and Communication Actor in order to simultaneously manage mobile robots and communicate with partners. Communication is carried out by sending partners at each step a vector of real numbers that are added to the observation vector and affect the behaviour. Functions of Actors and Critic are approximated by deep neural networks. The Critics value function is trained by using the TD-error method and the Actor’s function by using DDPG. The Communication Actor’s neural network is trained through gradients received from partner agents. An environment in which a cooperative multi-agent interaction is present was developed, computer simulation of the application of this method in the control problem of two robots pursuing two goals was carried out.

Modifying the risk of atypical antipsychotics in the treatment of juvenile-onset schizophrenia.

PubMed

Townsend, Lisa; Findling, Robert L

2010-02-01

This review summarizes the evidence for use of typical and atypical antipsychotic medications for the treatment of juvenile-onset schizophrenia. We highlight the risks and benefits of antipsychotic agents for youth with this disorder, paying special attention to weight gain and metabolic effects, an area of specific concern within child and adolescent psychiatry. We describe the seriousness of juvenile-onset schizophrenia and its impact on long-term functioning, noting that pharmacological treatment remains the standard of care for this disorder. We focus on weight gain and metabolic effects associated with atypical agents and review strategies to modify risks associated with these agents. We summarize strategies for attenuating the risk of weight gain for youth on atypical antipsychotics, including what is known about nutritional counseling and exercise programs as well as pharmacotherapy with adjunctive weight loss agents. Given the negative consequences associated with untreated schizophrenia, it appears that the most effective way to improve the risk:benefit ratio in the treatment of adolescents with schizophrenia is to reduce the risks associated with pharmacological treatment.

Effect of the ultrasound-Fenton oxidation process with the addition of a chelating agent on the removal of petroleum-based contaminants from soil.

PubMed

Li, Ying; Li, Fangmin; Li, Fanxiu; Yuan, Fuqian; Wei, Pingfang

2015-12-01

The effects of ultrasonic irradiation, the chelating agent modified Fenton reaction, and a combination of ultrasound and the Fenton method in removing petroleum contaminants from a soil were studied. The results showed that the contaminant removal rate of the Fenton treatment combined with an oxalic acid chelating agent was 55.6% higher than that without a chelating agent. The average removal rate of the contaminants using the ultrasound-Fenton treatment was 59.0% higher than that without ultrasonic treatment. A combination of ultrasound and an Fe(2+)/Fe(3+)-oxalate complex-modified Fenton reagent resulted in significantly higher removal rates of n-alkanes (C(n)H(2n+2), n < 28), isoprenoid hydrocarbons, aromatic hydrocarbons, and saturated polycyclic terpenes compared with the ultrasound treatment alone or the Fenton method. The Fenton reaction and the ultrasound-Fenton treatment can unselectively remove multiple components of residual hydrocarbons and a number of benzene rings in polycyclic aromatic hydrocarbons. The chemistry of the heterocyclic compounds and the position and number of substituents can affect the degradation process.

Balancing stealth and echogenic properties in an ultrasound contrast agent with drug delivery potential.

PubMed

Jablonowski, Lauren J; Alfego, David; Andorko, James I; Eisenbrey, John R; Teraphongphom, Nutte; Wheatley, Margaret A

2016-10-01

Contrast agents are currently being modified to combine diagnostic and therapeutic capabilities. For ultrasound (US) imaging with polymeric contrast agents, it is necessary to modify the shell to create "stealth" microbubbles but without these modifications sacrificing the agent's ability to interact with the focused US beam. We hypothesize that addition of the classic immune shielding molecule polyethylene glycol (PEG) to a polylactide (PLA) microbubble shell will affect the acoustic and physical properties of the resulting agents. In an effort to determine the best formulation to achieve a balance between stealth and acoustic activity, we compared two PEGylation techniques; addition of increasing amounts of PEG-PLA copolymer and employing incorporation of a PEG lipid (LipidPEG) into the shell. Loss of acoustic enhancement occurred in a dose-dependent manner for both types of PEGylated agents (loss of signal occurred at >5 wt% PEG-PLA and >1 wt% LipidPEG), while immune activation was also reduced in a dose-dependent manner for the PEG-PLA agents. This study shows that the balance between acoustic behavior and improved immune avoidance was scalable and successful to different degrees with both PEGylation methods, and was best achieved using for PEG-PLA at 5 wt% and for LipidPEG at 1 wt%. Studies are ongoing to evaluate the best method for the targeting and drug delivery capabilities of these agents for applications in cancer treatment. This study represents the basis for understanding the consequences of making modifications to the native polymeric shell. Copyright © 2016 Elsevier Ltd. All rights reserved.

Predicting the characteristics of the aetiological agent for Kawasaki disease from other paediatric infectious diseases in Japan.

PubMed

Nagao, Y; Urabe, C; Nakamura, H; Hatano, N

2016-02-01

Although Kawasaki disease (KD), which was first reported in the 1960s, is assumed to be infectious, its aetiological agent(s) remains unknown. We compared the geographical distribution of the force of infection and the super-annual periodicity of KD and seven other paediatric infectious diseases in Japan. The geographical distribution of the force of infection, which was estimated as the inverse of the mean patient age, was similar in KD and other paediatric viral infections. This similarity was due to the fact that the force of infection was determined largely by the total fertility rate. This finding suggests that KD shares a transmission route, i.e. sibling-to-sibling infection, with other paediatric infections. The super-annual periodicity, which is positively associated with the sum of an infectious disease's incubation period and infectious period, was much longer for KD and exanthema subitum than other paediatric infectious diseases. The virus for exanthema subitum is known to persist across the host's lifespan, which suggests that the aetiological agent for KD may also be capable of persistent infection. Taken together, these findings suggest that the aetiological agent for KD is transmitted through close contact and persists asymptomatically in most hosts.

Agent Orange exposure and prevalence of self-reported diseases in Korean Vietnam veterans.

PubMed

Yi, Sang-Wook; Ohrr, Heechoul; Hong, Jae-Seok; Yi, Jee-Jeon

2013-09-01

The aim of this study was to evaluate the association between Agent Orange exposure and self-reported diseases in Korean Vietnam veterans. A postal survey of 114 562 Vietnam veterans was conducted. The perceived exposure to Agent Orange was assessed by a 6-item questionnaire. Two proximity-based Agent Orange exposure indices were constructed using division/brigade-level and battalion/company-level unit information. Adjusted odds ratios (ORs) for age and other confounders were calculated using a logistic regression model. The prevalence of all self-reported diseases showed monotonically increasing trends as the levels of perceived self-reported exposure increased. The ORs for colon cancer (OR, 1.13), leukemia (OR, 1.56), hypertension (OR, 1.03), peripheral vasculopathy (OR, 1.07), enterocolitis (OR, 1.07), peripheral neuropathy (OR, 1.07), multiple nerve palsy (OR, 1.14), multiple sclerosis (OR, 1.24), skin diseases (OR, 1.05), psychotic diseases (OR, 1.07) and lipidemia (OR, 1.05) were significantly elevated for the high exposure group in the division/brigade-level proximity-based exposure analysis, compared to the low exposure group. The ORs for cerebral infarction (OR, 1.08), chronic bronchitis (OR, 1.05), multiple nerve palsy (OR, 1.07), multiple sclerosis (OR, 1.16), skin diseases (OR, 1.05), and lipidemia (OR, 1.05) were significantly elevated for the high exposure group in the battalion/company-level analysis. Korean Vietnam veterans with high exposure to Agent Orange experienced a higher prevalence of several self-reported chronic diseases compared to those with low exposure by proximity-based exposure assessment. The strong positive associations between perceived self-reported exposure and all self-reported diseases should be evaluated with discretion because the likelihood of reporting diseases was directly related to the perceived intensity of Agent Orange exposure.

Alternative Causes of Wide-Spread, Low Concentration Perchlorate Impacts to Groundwater

DTIC Science & Technology

2005-05-05

to as water gels, contain AN in aqueous solution. To aid water resistance and handling, they are thickened and gelled with a gum , such as guar gum ...enamels Curing/Drying Agent Photography Flash powder / oxidizing agent Oxygen generators Burn Rate Modifier Road flares Oxidizing agent...fuse, stars, black powder , a launch tube, main fuse and a lift charge, as shown in Figure 3-1. The break or breaks house the stars in cardboard

Pre-Clinical Testing of Real-Time PCR Assays for Diarrheal Disease Agents of Genera Escherichia and Shigella

DTIC Science & Technology

2014-05-16

FOR DIARRHEAL DISEASE AGENTS OF GENERA ESCHERICHIA AND SHIGELLA May 16, 2014 Reporting Period: October 1, 2010 to September 30, 2013...10-2010 - 30-09-2013 PRE-CLINICAL TESTING OF REAL-TIME PCR ASSAYS FOR DIARRHEAL DISEASE AGENTS OF GENERA ESCHERICHIA AND SHIGELLA ...Texas (MOA 2007 - 2013. Agreement No.: DODI 4000.19; AFI 25-201). Pre-clinical test results qualify ETEC and Shigella real-time PCR assays as lead

Advances in the treatment of cutaneous lupus erythematosus.

PubMed

Kuhn, A; Landmann, A; Wenzel, J

2016-07-01

Lupus erythematosus (LE) is a multifactorial autoimmune disease with clinical manifestations of differing severity which may present with skin manifestations as primary sign of the disease (cutaneous lupus erythematosus, CLE) or as part of a disease spectrum (systemic lupus erythematosus, SLE). To date, no drugs are approved specifically for the treatment of CLE and only single agents have been applied in randomized controlled trials. Therefore, topical and systemic agents are used "off-label", primarily based on open-label studies, case series, retrospective analyses, and expert opinions. In contrast, several agents, such as hydroxychloroquine, chloroquine, cyclophosphamide, azathioprine, and belimumab, are approved for the treatment of SLE. Recent approaches in the understanding of the molecular pathogenesis of LE enabled the development of further new agents, which target molecules such as interleukin 6 (IL-6) and interferon (IFN). Only single trials, however, applied these new agents in patients with cutaneous involvement of the disease and/or included endpoints which evaluated the efficacy of these agents on skin manifestations. This article provides an updated review on new and recent approaches in the treatment of CLE. © The Author(s) 2016.

Environmental isolation of black yeast-like fungi involved in human infection

PubMed Central

Vicente, V.A.; Attili-Angelis, D.; Pie, M.R.; Queiroz-Telles, F.; Cruz, L.M.; Najafzadeh, M.J.; de Hoog, G.S.; Zhao, J.; Pizzirani-Kleiner, A.

2008-01-01

The present study focuses on potential agents of chromoblastomycosis and other endemic diseases in the state of Paraná, Southern Brazil. Using a highly selective protocol for chaetothyrialean black yeasts and relatives, environmental samples from the living area of symptomatic patients were analysed. Additional strains were isolated from creosote-treated wood and hydrocarbon-polluted environments, as such polluted sites have been supposed to enhance black yeast prevalence. Isolates showed morphologies compatible with the traditional etiological agents of chromoblastomycosis, e.g. Fonsecaea pedrosoi and Phialophora verrucosa, and of agents of subcutaneous or systemic infections like Cladophialophora bantiana and Exophiala jeanselmei. Some agents of mild disease were indeed encountered. However, molecular analysis proved that most environmental strains differed from known etiologic agents of pronounced disease syndromes: they belonged to the same order, but mostly were undescribed species. Agents of chromoblastomycosis and systemic disease thus far are prevalent on the human host. The hydrocarbon-polluted environments yielded yet another spectrum of chaetothyrialean fungi. These observations are of great relevance because they allow us to distinguish between categories of opportunists, indicating possible differences in pathogenicity and virulence. PMID:19287536

Synthesis and Biological Evaluation of Water-soluble Progesterone-Conjugated Probes for Magnetic Resonance Imaging of Hormone Related Cancers

PubMed Central

Sukerkar, Preeti A.; MacRenaris, Keith W.; Townsend, Taryn R.; Ahmed, Roshan A.; Burdette, Joanna E.; Meade, Thomas J.

2011-01-01

Progesterone receptor (PR) is strongly associated with disease prognosis and therapeutic efficacy in hormone related diseases such as endometriosis and breast, ovarian, and uterine cancers. Receptor status is currently determined by immunohistochemistry assays. However, noninvasive PR imaging agents could improve disease detection and help elucidate pathological molecular pathways, leading to new therapies and animal disease models. A series of water-soluble PR-targeted magnetic resonance imaging (MRI) probes were synthesized using Cu(I)-catalyzed click chemistry and evaluated in vitro and in vivo. These agents demonstrated activation of PR in vitro and preferential accumulation in PR(+) compared to PR(−) human breast cancer cells with low toxicity. In xenograft tumor models, the agents demonstrated enhanced signal intensity in PR(+) tumors compared to PR(−) tumors. The results suggest that these agents may be promising MRI probes for PR(+) diseases. PMID:21972997

Psychopharmacological neuroprotection in neurodegenerative disease: assessing the preclinical data.

PubMed

Lauterbach, Edward C; Victoroff, Jeff; Coburn, Kerry L; Shillcutt, Samuel D; Doonan, Suzanne M; Mendez, Mario F

2010-01-01

This manuscript reviews the preclinical in vitro, ex vivo, and nonhuman in vivo effects of psychopharmacological agents in clinical use on cell physiology with a view toward identifying agents with neuroprotective properties in neurodegenerative disease. These agents are routinely used in the symptomatic treatment of neurodegenerative disease. Each agent is reviewed in terms of its effects on pathogenic proteins, proteasomal function, mitochondrial viability, mitochondrial function and metabolism, mitochondrial permeability transition pore development, cellular viability, and apoptosis. Effects on the metabolism of the neurodegenerative disease pathogenic proteins alpha-synuclein, beta-amyloid, and tau, including tau phosphorylation, are particularly addressed, with application to Alzheimer's and Parkinson's diseases. Limitations of the current data are detailed and predictive criteria for translational clinical neuroprotection are proposed and discussed. Drugs that warrant further study for neuroprotection in neurodegenerative disease include pramipexole, thioridazine, risperidone, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, fluoxetine, buspirone, clonazepam, diphenhydramine, and melatonin. Those with multiple neuroprotective mechanisms include pramipexole, thioridazine, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, clonazepam, and melatonin. Those best viewed circumspectly in neurodegenerative disease until clinical disease course outcomes data become available, include several antipsychotics, lithium, oxcarbazepine, valproate, several tricyclic antidepressants, certain SSRIs, diazepam, and possibly diphenhydramine. A search for clinical studies of neuroprotection revealed only a single study demonstrating putatively positive results for ropinirole. An agenda for research on potentially neuroprotective agent is provided.

Richard Bradley: a unified, living agent theory of the cause of infectious diseases of plants, animals, and humans in the first decades of the 18th century.

PubMed

Santer, Melvin

2009-01-01

During the years 1714 to 1721, Richard Bradley, who was later to become the first Professor of Botany at Cambridge University, proposed a unified, unique, living agent theory of the cause of infectious diseases of plants and animals and the plague of humans. Bradley's agents included microscopic organisms, revealed by the studies of Robert Hooke and Antony van Leeuwenhoek. His theory derived from his experimental studies of plants and their diseases and from microscopic observation of animalcules in different naturally occurring and artificial environments. He concluded that there was a microscopic world of "insects" that lived and reproduced under the appropriate conditions, and that infectious diseases of plants were caused by such "insects." Since there are structural and functional similarities between plants and animals, Bradley concluded that microscopic organisms caused human and animal infectious diseases as well. However, his living agent cause of infectious diseases was not accepted by the contemporary scientific society.

Targeted Delivery of Hyaluronan-Immobilized Magnetic Ceramic Nanocrystals.

PubMed

Wu, Hsi-Chin; Wang, Tzu-Wei; Hsieh, Shun-Yu; Sun, Jui-Sheng; Kang, Pei-Leun

2016-01-01

Effective cancer therapy relies on delivering the therapeutic agent precisely to the target site to improve the treatment outcome and to minimize side effects. Although surgery, chemotherapy, and radiotherapy are the standard methods commonly used in clinics, hyperthermia has been developed as a new and promising strategy for cancer therapy. In this study, magnetic bioceramic hydroxyapatite (mHAP) nanocrystals have been developed as heat mediator for intracellular hyperthermia. Hyaluronic acid (HA) modified mHAP nanocrystals are synthesized by a wet chemical precipitation process to achieve active targeting. The results demonstrate that the HA targeting moiety conjugated by a poly(ethylene glycol) (PEG) spacer arm is successfully immobilized on the surface of mHAP. The HA-modified mHAP possesses relatively good biocompatibility, an adequate biodegradation rate and superparamagnetic properties. The HA-modified mHAP could be localized and internalized into HA receptor-overexpressed malignant cells (e.g., MDA-MB-231 cell) and used as the heat generating agent for intracellular hyperthermia. The results from this study indicate that biocompatible HA-modified mHAP shows promise as a novel heat mediator and a specific targeting nanoagent for intracellular hyperthermia cancer therapy.

Epidemiology and detection as options for control of viral and parasitic foodborne disease.

PubMed Central

Jaykus, L. A.

1997-01-01

Human enteric viruses and protozoal parasites are important causes of emerging food and waterborne disease. Epidemiologic investigation and detection of the agents in clinical, food, and water specimens, which are traditionally used to establish the cause of disease outbreaks, are either cumbersome, expensive, and frequently unavailable or unattempted for the important food and waterborne enteric viruses and protozoa. However, the recent introduction of regulatory testing mandates, alternative testing strategies, and increased epidemiologic surveillance for food and waterborne disease should significantly improve the ability to detect and control these agents. We discuss new methods of investigating foodborne viral and parasitic disease and the future of these methods in recognizing, identifying, and controlling disease agents. PMID:9366607

Risk of Lymphoma in Patients With Inflammatory Bowel Disease Treated With Anti-Tumor Necrosis Factor Alpha Agents: A Systematic Review and Meta-analysis.

PubMed

Yang, Chen; Huang, Junlin; Huang, Xiaowen; Huang, Shaozhuo; Cheng, Jiaxin; Liao, Weixin; Chen, Xuewen; Wang, Xueyi; Dai, Shixue

2018-05-12

The association between anti-tumor necrosis factor alpha agents and the risk of lymphoma in patients with inflammatory bowel disease has already been sufficiently reported. However, the results of these studies are inconsistent. Hence, this analysis was conducted to investigate whether anti-tumor necrosis factor alpha agents can increase the risk of lymphoma in inflammatory bowel disease patients. MEDLINE, EMBASE and the Cochrane Library were searched to identify relevant studies which evaluated the risk of lymphoma in inflammatory bowel disease patients treated with anti-tumor necrosis factor alpha agents. A random-effects meta-analysis was performed to calculate the pooled incidence rate ratios as well as risk ratios. Twelve studies comprising 285811 participants were included. The result showed that there was no significantly increased risk of lymphoma between anti-tumor necrosis factor alpha agents exposed and anti-tumor necrosis factor alpha agents unexposed groups (random effects: incidence rate ratio [IRR], 1.43 95%CI, 0.91-2.25, p= 0.116; random effects: risk ratio [RR], 0.83 95%CI, 0.47-1.48, p=0.534). However, monotherapy of anti-tumor necrosis factor alpha agents (random effects: IRR=1.65, 95%CI, 1.16-2.35; p=0.006; random effects: RR=1.00, 95%CI, 0.39-2.59; p=0.996) or combination therapy (random effects: IRR=3.36, 95%CI, 2.23-5.05; p< 0.001; random effects: RR=1.90, 95%CI, 0.66-5.44; p=0.233) can significantly increase the risk of lymphoma. Exposition of anti-tumor necrosis factor alpha agents in patients with inflammatory bowel disease is not associated with a higher risk of lymphoma. Combination therapy and anti-tumor necrosis factor alpha agents monotherapy can significantly increase the risk of lymphoma in patients with inflammatory bowel disease.

Protective agents used as additives in University of Wisconsin solution to promote protection against ischaemia-reperfusion injury in rat lung.

PubMed

Chiang, C H; Wu, K; Yu, C P; Perng, W C; Yan, H C; Wu, C P; Chang, D M; Hsu, K

1998-09-01

1. An intervention to reduce ischaemia-reperfusion lung injury will be an important advance in transplant medicine. Although the mechanisms associated with producing ischaemia-reperfusion endothelial injury have not been completely elucidated, many of the injury mediators have been studied in detail. While no single pharmacological therapy is likely to be totally effective in eliminating this complex injury, we have developed a mixture of agents that are known to block pathways involved in producing ischaemia-reperfusion-associated lung vascular injury.2. The present study modified University of Wisconsin solution (UW) by adding one of the protective agents prostaglandin E1 (PGE1), dexamethasone (Dex) or dibutyryl cAMP (Bt2-cAMP), or a combination of these, to the perfusate of rat lungs exposed to 4 h of cold ischaemia followed by 1 h of reperfusion. Nine modified UW solutions were studied: (1) UW+Dex, (2) UW+PGE1, (3) UW+Bt2-cAMP, (4) UW+Dexx3, (5) UW+PGE1x3, (6) UW+Bt2-cAMPx3, (7) UW+Dex+PGE1, (8) UW+Dex+Bt2-cAMP, (9) UW+PGE1+Bt2-cAMP. These solutions were utilized in individual experiments to assess haemodynamic changes, lung weight gain, the capillary filtration coefficient (Kfc) and pathology in all lungs.3. The results indicate that lung weight gain and Kfc values were significantly lower than with UW alone in groups 1, 2 and 3, which contained only one additional protective agent. In groups 4, 5 and 6, which contain three times the concentration of each protective agent, both Kfc and lung weight gain were similar to those measured in groups 1, 2 and 3, i.e. lungs were protected but the protection was not dose dependent. In groups 7, 8 and 9, which contained two protective agents, lung weight gain and Kfc were greatly reduced compared with UW alone. Histopathological studies showed similar decreases in the injury profiles of lungs.4. Although UW contains several antioxidant protective agents such as allopurinol and glutathione, it did not provide effective protection in our ischaemia-reperfusion lung injury model. UW modified with an additive of PGE1, Dex or Bt2-cAMP attenuated ischaemia-reperfusion injury. Furthermore, UW containing two of these protective agents augmented the protection. Among the modified solutions, it appears that UW+PGE1+Bt2-cAMP protects the lungs to a greater extent than all other solutions used in our study. We suggest that preservation solutions containing PGE1-Bt2-cAMP will provide additional protective effects to organs stored for transplantation.

Basic problems of serological laboratory diagnosis.

PubMed

Fierz, Walter

2004-01-01

Serological laboratory diagnosis of infectious diseases is inflicted with several kinds of basic problems. One difficulty relates to the fact that the serological diagnosis of infectious diseases is double indirect: The first indirect aim in diagnosing an infectious disease is to identify the microbial agent that caused the disease. The second indirect aim is to identify this infectious agent by measuring the patient's immune response to the potential agent. Thus, the serological test is neither measuring directly disease nor the cause of the disease, but the patient's immune system. The latter poses another type of problem, because each person's immune system is unique. The immune response to an infectious agent is usually of polyclonal nature, and the exact physicochemical properties of antibodies are unique for each clone of antibody. The clonal makeup and composition and, therefore, the way an individual's immune system sees an infectious agent, depends not only on the genetic background of the person but also on the individual experience from former encounters with various infectious agents. In consequence, the reaction of a patient's serum in an analytical system is not precisely predictable. Also, the antigenic makeup of an infectious agent is not always foreseeable. Antigenic variations leading to different serotypes is a quite common phenomenon. Altogether, these biological problems lead to complexities in selecting the appropriate tests and strategies for testing, in interpreting the results, and in standardizing serological test systems. For that reason, a close collaboration of the laboratory with the clinic is mandatory to avoid erroneous conclusions from serological test results, which might lead to wrong decisions in patient care.

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

PubMed Central

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

2014-01-01

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

Study design of PANGAEA 2.0, a non-interventional study on RRMS patients to be switched to fingolimod.

PubMed

Ziemssen, Tjalf; Kern, Raimar; Cornelissen, Christian

2016-08-08

The therapeutic options for patients with Multiple Sclerosis (MS) have steadily increased due to the approval of new substances that now supplement traditional first-line agents, demanding a paradigm shift in the assessment of disease activity and treatment response in clinical routine. Here, we report the study design of PANGAEA 2.0 (Post-Authorization Non-interventional GermAn treatment benefit study of GilEnyA in MS patients), a non-interventional study in patients with relapsing-remitting MS (RRMS) identify patients with disease activity and monitor their disease course after treatment switch to fingolimod (Gilenya®), an oral medication approved for patients with highly active RRMS. In the first phase of the PANGAEA 2.0 study the disease activity status of patients receiving a disease-modifying therapy (DMT) is evaluated in order to identify patients at risk of disease progression. This evaluation is based on outcome parameters for both clinical disease activity and magnetic resonance imaging (MRI), and subclinical measures, describing disease activity from the physician's and the patient's perspective. In the second phase of the study, 1500 RRMS patients identified as being non-responders and switched to fingolimod (oral, 0.5 mg/daily) are followed-up for 3 years. Data on relapse activity, disability progression, MRI lesions, and brain volume loss will be assessed in accordance to 'no evidence of disease activity-4' (NEDA-4). The modified Rio score, currently validated for the evaluation of treatment response to interferons, will be used to evaluate the treatment response to fingolimod. The MS management software MSDS3D will guide physicians through the complex processes of diagnosis and treatment. A sub-study further analyzes the benefits of a standardized quantitative evaluation of routine MRI scans by a central reading facility. PANGAEA 2.0 is being conducted between June 2015 and December 2019 in 350 neurological practices and centers in Germany, including 100 centers participating in the sub-study. PANGAEA 2.0 will not only evaluate the long-term benefit of a treatment change to fingolimod but also the applicability of new concepts of data acquisition, assessment of MS disease activity and evaluation of treatment response for the in clinical routine. BfArM6532; Trial Registration Date: 20/05/2015.

Pulmonary aspergillosis after treatment with infliximab in Still's disease and a literature review of Still's disease and pulmonary aspergillosis.

PubMed

Şeyhoğlu, Emrah; Erden, Abdülsamet; Kılıç, Levent; Karadağ, Ömer; Akdağlı, Sevtap Arıkan; Akdoğan, Ali; Kalyoncu, Umut

2018-03-01

The use of anti-tumor necrosis factor alpha (anti-TNF-α) agents has increased during the past decade in rheumatology practice. Opportunistic infections have been reported with anti-TNF-α agents in clinical trials and post-marketing usage. Aspergillus infection is a rare opportunistic infection that is associated with immunosuppression, and there are reported cases of pulmonary aspergillosis in various rheumatic diseases treated with anti-TNF-α agents. Here, we present the first case of pulmonary aspergillosis associated with infliximab treatment in a patient with Still's disease.

Pulmonary aspergillosis after treatment with infliximab in Still’s disease and a literature review of Still’s disease and pulmonary aspergillosis

PubMed Central

Erden, Abdülsamet; Kılıç, Levent; Karadağ, Ömer; Akdağlı, Sevtap Arıkan; Akdoğan, Ali; Kalyoncu, Umut

2018-01-01

The use of anti-tumor necrosis factor alpha (anti-TNF-α) agents has increased during the past decade in rheumatology practice. Opportunistic infections have been reported with anti-TNF-α agents in clinical trials and post-marketing usage. Aspergillus infection is a rare opportunistic infection that is associated with immunosuppression, and there are reported cases of pulmonary aspergillosis in various rheumatic diseases treated with anti-TNF-α agents. Here, we present the first case of pulmonary aspergillosis associated with infliximab treatment in a patient with Still’s disease. PMID:29657880

Synthesis of a fluorine-free polymeric water-repellent agent for creation of superhydrophobic fabrics

NASA Astrophysics Data System (ADS)

Shen, Keke; Yu, Miao; Li, Qianqian; Sun, Wei; Zhang, Xiting; Quan, Miao; Liu, Zhengtang; Shi, Suqing; Gong, Yongkuan

2017-12-01

A non-fluorinated polymeric alkylsilane, poly(isobutyl methacrylate-co-3-methacryloxypropyltrimethoxysilane) (PIT), is designed and synthesized to replace the commercial long-chain perfluoroalkylsilane (FAS) water-repellent agent. The superhydrophobic polyester fabrics are prepared by anchoring sol-gel derived silica nanoparticles onto alkali-treated polyester fabric surfaces and subsequently hydrophobilizing with PIT, using FAS as control. The surface chemical composition, surface morphology, wetting behavior and durability of the modified polyester fabrics are characterized by scanning electron microscopy (SEM), X-ray photoelectron spectrophotometer (XPS) and video-based contact angle goniometer, respectively. The results show that a porous silica layer could be successfully fabricated onto the surface of polyester fabric through base-catalyzed sol-gel process with tetraethoxysilane (TEOS) as precursor, incorporating additional nanostructured roughness essential for superhydrophobicity. At the same time, such a silica primer layer could provide both secondary reactive moieties (-Si - OH) for the subsequent surface hydrophobization and acceptable adhesion at the silica-polyester fabric interface. When silica modified polyester fabric (SiO2@ fabric) is hydrophobized by PIT solution (10 mg/mL), excellent water-repellency could be obtained. The water contact angle is up to 154° and the sliding angle is about 5°. Compared with small molecule water-repellent agent FAS, PIT modified SiO2@ fabric exhibits greatly improved solvent resistance under ultra-sonication, abrasion and simulated laundering durability. The anti-stain property of PIT-modified SiO2@ fabric is also evaluated by using different aqueous colored solutions.

Feasibility of Cancer Immunotherapy with WT1 Peptide Vaccination for Solid and Hematological Malignancies in Children.

PubMed

Sawada, Akihisa; Inoue, Masami; Kondo, Osamu; Yamada-Nakata, Kayo; Ishihara, Takashi; Kuwae, Yuko; Nishikawa, Masanori; Ammori, Yasuhiro; Tsuboi, Akihiro; Oji, Yusuke; Koyama-Sato, Maho; Oka, Yoshihiro; Yasui, Masahiro; Sugiyama, Haruo; Kawa, Keisei

2016-02-01

Advances in cancer immunotherapy in the pediatric field are needed in order to improve the prognosis of children with malignancies. We conducted a prospective phase I/II study of WT1 peptide vaccination for children with relapsed or refractory malignancies. The main eligibility criteria were affected tissues or leukemic cells expressing the WT1 gene, and patients (and donors for allogeneic hematopoietic stem cell transplantation) having HLA-A*24:02. Vaccination using the WT1 peptide (CYTWNQMNL), which was modified for higher affinity to this HLA-type molecule with the adjuvant Montanide ISA51, was performed weekly 12 times. Twenty-six patients were enrolled and 13 (50.0%) completed the vaccination 12 times. Evidence for the induction of WT1-specific cytotoxic T-lymphocyte (CTL) responses without severe systemic side effects was obtained. Two out of 12 patients with bulky disease exhibited a transient clinical effect (one mixed response and one stable disease), three out of six patients with minimal residual disease achieved transient molecular remission, and five out of eight patients without a detectable level of the molecular marker, but with a high risk of relapse, had the best outcome of long-term continuous complete remission. WT1 vaccination is a safe immunotherapy and induced WT1-specific CTL responses in children; however, as a single agent, vaccination only provided patients in remission, but with a high risk of relapse, with "long-term benefits" in the context of its use for relapse prevention. WT1 peptide-based treatments in combination with other modalities, such as anti-tumor drugs or immunomodulating agents, need to be planned. © 2015 Wiley Periodicals, Inc.

Critical analysis of economic tools and economic measurement applied to rheumatoid arthritis.

PubMed

Her, Minyoung; Kavanaugh, Arthur

2012-01-01

Rheumatoid arthritis (RA) is chronic, progressive systemic inflammatory disease that if uncontrolled may lead to significant joint damage, dysfunction, work disability and other sequelae that result in large economic losses. A rich literature estimating the economic burden of RA, has been intensified recently, driven by costly biologic agents that have had a notable effect improving the outcomes of patients with RA. In order to optimally assess the value of therapies, it is best to take a comprehensive approach, considering all related costs of illness. This includes direct costs (e.g. the costs of the medications themselves and the monitoring required), indirect costs (e.g. loss of productivity, such as employment due to uncontrolled disease) and intangible cost (e.g. effects on pain and quality of life). Indirect costs constitute a substantial part of total cost in the patient with RA. In order to help assess the impact of RA on productivity, various tools for measuring productive loss like absenteeism and presenteeism have been introduced. No single tool reflects the entire spectrum of the productive loss clearly, as other factors such as use of a human capital approach or friction cost approach affect the valuation of productive loss monetarily. Although favourable outcomes are achieved with the use of biologic agents, their higher acquisition costs, as compared to traditional disease-modifying anti-rheumatic drugs (DMARDs) remain a barrier to their use. Assessments of the cost effectiveness of novel therapies are critically important, but published results have been contradictory, in some measure due to the heterogeneity of instruments utilised. While the various instruments appear to be valid and reliable, correlations between instruments has been modest, driven by factors such as differences in recall times, attribution and other confounders.

Direct covalent modification as a strategy to inhibit nuclear factor-kappa B.

PubMed

Pande, Vineet; Sousa, Sérgio F; Ramos, Maria João

2009-01-01

Nuclear Factor-KkappaB (NF-kappaB) is a transcription factor whose inappropriate activation may result in the development of a number of diseases including cancer, inflammation, neurodegeneration and AIDS. Recent studies on NF-kappaB mediated pathologies, made therapeutic interventions leading to its inhibition an emerging theme in pharmaceutical research. NF-kappaB resides in the cytoplasm and is activated by several time-dependent factors, leading to proteasome-dependent degradation of its inhibitory protein (IkappaB), resulting in free NF-kappaB (p50 and p65 subunits, involved in disease states), which binds to target DNA sites, further resulting in enhanced transcription of several disease associated proteins. The complex pathway of NF-kappaB, finally leading to its DNA binding, has attracted several approaches interfering with this pathway. One such approach is that of a direct covalent modification of NF-kappaB. In this article, we present a critical review on the pharmacological agents that have been studied as inhibitors of NF-kappaB by covalently modifying redox-regulated cysteine residues in its subunits, ultimately resulting in the inhibition of kappaB DNA recognition and binding. Beginning with a general overview of NF-kappaB pathway and several possibilities of chemical interventions, the significance of redox-regulation in NF-kappaB activation and DNA binding is presented. Further, protein S-thiolation, S-nitrosylation and irreversible covalent modification are described as regular biochemical events in the cell, having provided a guideline for the development of NF-kappaB inhibitors discussed further. Although just a handful of inhibitors, with most of them being alkylating agents have been studied in the present context, this approach presents potential for the development of a new class of NF-kappaB-inhibitors.

Online Bahavior Aquisition of an Agent based on Coaching as Learning Assistance

NASA Astrophysics Data System (ADS)

Hirokawa, Masakazu; Suzuki, Kenji

This paper describes a novel methodology, namely ``Coaching'', which allows humans to give a subjective evaluation to an agent in an iterative manner. This is an interactive learning method to improve the reinforcement learning by modifying a reward function dynamically according to given evaluations by a trainer and the learning situation of the agent. We demonstrate that the agent can learn different reward functions by given instructions such as ``good or bad'' by human's observation, and can also obtain a set of behavior based on the learnt reward functions through several experiments.

21 CFR 1271.75 - How do I screen a donor?

Code of Federal Regulations, 2011 CFR

2011-04-01

...) Risk factors for, and clinical evidence of, relevant communicable disease agents and diseases... risk factors for and clinical evidence of relevant cell-associated communicable disease agents and... having either of the following: (1) A risk factor for or clinical evidence of any of the relevant...

A Functional Iron Oxide Nanoparticles Modified with PLA-PEG-DG as Tumor-Targeted MRI Contrast Agent.

PubMed

Xiong, Fei; Hu, Ke; Yu, Haoli; Zhou, Lijun; Song, Lina; Zhang, Yu; Shan, Xiuhong; Liu, Jianping; Gu, Ning

2017-08-01

Tumor targeting could greatly promote the performance of magnetic nanomaterials as MRI (Magnetic Resonance Imaging) agent for tumor diagnosis. Herein, we reported a novel magnetic nanoparticle modified with PLA (poly lactic acid)-PEG (polyethylene glycol)-DG (D-glucosamine) as Tumor-targeted MRI Contrast Agent. In this work, we took use of the D-glucose passive targeting on tumor cells, combining it on PLA-PEG through amide reaction, and then wrapped the PLA-PEG-DG up to the Fe 3 O 4 @OA NPs. The stability and anti phagocytosis of Fe 3 O 4 @OA@PLA-PEG-DG was tested in vitro; the MRI efficiency and toxicity was also detected in vivo. These functional magnetic nanoparticles demonstrated good biocompatibility and stability both in vitro and in vivo. Cell experiments showed that Fe 3 O 4 @OA@PLA-PEG-DG nanoparticles exist good anti phagocytosis and high targetability. In vivo MRI images showed that the contrast effect of Fe 3 O 4 @OA@PLA-PEG-DG nanoparticles prevailed over the commercial non tumor-targeting magnetic nanomaterials MRI agent at a relatively low dose. The DG can validly enhance the tumor-targetting effect of Fe 3 O 4 @OA@PLA-PEG nanoparticle. Maybe MRI agents with DG can hold promise as tumor-targetting development in the future.

Nanoparticles as potential new generation broad spectrum antimicrobial agents.

PubMed

Yah, Clarence S; Simate, Geoffrey S

2015-09-02

The rapid emergence of antimicrobial resistant strains to conventional antimicrobial agents has complicated and prolonged infection treatment and increased mortality risk globally. Furthermore, some of the conventional antimicrobial agents are unable to cross certain cell membranes thus, restricting treatment of intracellular pathogens. Therefore, the disease-causing-organisms tend to persist in these cells. However, the emergence of nanoparticle (NP) technology has come with the promising broad spectrum NP-antimicrobial agents due to their vast physiochemical and functionalization properties. In fact, NP-antimicrobial agents are able to unlock the restrictions experienced by conventional antimicrobial agents. This review discusses the status quo of NP-antimicrobial agents as potent broad spectrum antimicrobial agents, sterilization and wound healing agents, and sustained inhibitors of intracellular pathogens. Indeed, the perspective of developing potent NP-antimicrobial agents that carry multiple-functionality will revolutionize clinical medicine and play a significant role in alleviating disease burden.

Update on genetics and pathogenesis of autoinflammatory diseases: the last 2 years.

PubMed

Aksentijevich, Ivona

2015-07-01

Autoinflammatory diseases are a genetically heterogeneous group of rheumatologic diseases that are driven by abnormal activation of the innate immune system. Patients present with recurrent episodes of systemic inflammation and a spectrum of organ-specific comorbidities. These diseases are mediated by the overproduction of various inflammatory cytokines, such as IL-1, IL-18, IL-6, TNFα, and type I interferon. Treatments with biologic agents that inhibit these cytokines have been very efficient in most patients. During the past 2 years, remarkable progress has been made in the identification of disease-associated genes owing mostly to new technologies. Next generation sequencing technologies (NGS) have become instrumental in finding single-gene defects in undiagnosed patients with early onset symptoms. NGS has advanced the field of autoinflammation by identifying disease-causing genes that point to pathways not known to regulate cytokine signaling or inflammation. They include a protein that has a role in differentiation of myeloid cells, a ubiquitously expressed enzyme that catalyzes the addition of the CCA terminus to the 3-prime end of tRNA precursors, and an enzyme that catalyzes the oxidation of a broad range of substrates. Lastly, newly described mutations have informed a whole new dimension on genotype-phenotype relationships. Mutations in the same gene can give rise to a range of phenotypes with a common inflammatory component. This suggests greater than anticipated contributions by modifying alleles and environmental factors to disease expressivity.

HFE gene variants affect iron in the brain.

PubMed

Nandar, Wint; Connor, James R

2011-04-01

Iron accumulation in the brain and increased oxidative stress are consistent observations in many neurodegenerative diseases. Thus, we have begun examination into gene mutations or allelic variants that could be associated with loss of iron homeostasis. One of the mechanisms leading to iron overload is a mutation in the HFE gene, which is involved in iron metabolism. The 2 most common HFE gene variants are C282Y (1.9%) and H63D (8.9%). The C282Y HFE variant is more commonly associated with hereditary hemochromatosis, which is an autosomal recessive disorder, characterized by iron overload in a number of systemic organs. The H63D HFE variant appears less frequently associated with hemochromatosis, but its role in the neurodegenerative diseases has received more attention. At the cellular level, the HFE mutant protein resulting from the H63D HFE gene variant is associated with iron dyshomeostasis, increased oxidative stress, glutamate release, tau phosphorylation, and alteration in inflammatory response, each of which is under investigation as a contributing factor to neurodegenerative diseases. Therefore, the HFE gene variants are proposed to be genetic modifiers or a risk factor for neurodegenerative diseases by establishing an enabling milieu for pathogenic agents. This review will discuss the current knowledge of the association of the HFE gene variants with neurodegenerative diseases: amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and ischemic stroke. Importantly, the data herein also begin to dispel the long-held view that the brain is protected from iron accumulation associated with the HFE mutations.

Rationally Designed Peptidomimetic Modulators of Aβ Toxicity in Alzheimer's Disease

NASA Astrophysics Data System (ADS)

Rajasekhar, K.; Suresh, S. N.; Manjithaya, Ravi; Govindaraju, T.

2015-01-01

Alzheimer's disease is one of the devastating illnesses mankind is facing in the 21st century. The main pathogenic event in Alzheimer's disease is believed to be the aggregation of the β-amyloid (Aβ) peptides into toxic aggregates. Molecules that interfere with this process may act as therapeutic agents for the treatment of the disease. Use of recognition unit based peptidomimetics as inhibitors are a promising approach, as they exhibit greater protease stability compared to natural peptides. Here, we present peptidomimetic inhibitors of Aβ aggregation designed based on the KLVFF (P1) sequence that is known to bind Aβ aggregates. We improved inhibition efficiency of P1 by introducing multiple hydrogen bond donor-acceptor moieties (thymine/barbiturate) at the N-terminal (P2 and P3), and blood serum stability by modifying the backbone by incorporating sarcosine (N-methylglycine) units at alternate positions (P4 and P5). The peptidomimetics showed moderate to good activity in both inhibition and dissolution of Aβ aggregates as depicted by thioflavin assay, circular dichroism (CD) measurements and microscopy (TEM). The activity of P4 and P5 were studied in a yeast cell model showing Aβ toxicity. P4 and P5 could rescue yeast cells from Aβ toxicity and Aβ aggregates were cleared by the process of autophagy.

Drug delivery strategies for Alzheimer's disease treatment.

PubMed

Di Stefano, Antonio; Iannitelli, Antonio; Laserra, Sara; Sozio, Piera

2011-05-01

Current Alzheimer's disease (AD) therapy is based on the administration of the drugs donepezil, galantamine, rivastigmine and memantine. Until disease-modifying therapies become available, further research is needed to develop new drug delivery strategies to ensure ease of administration and treatment persistence. In addition to the conventional oral formulations, a variety of drug delivery strategies applied to the treatment of AD are reviewed in this paper, with a focus on strategies leading to simplified dosage regimens and to providing new pharmacological tools. Alternatives include extended release, orally disintegrating or sublingual formulations, intranasal or short- and long-acting intramuscular or transdermal forms, and nanotechnology-based delivery systems. The advent of new research on molecular mechanisms of AD pathogenesis has outlined new strategies for therapeutic intervention; these include the stimulation of α-secretase cleavage, the inhibition of γ-secretase activity, the use of non-steroidal anti-inflammatory drugs, neuroprotection based on antioxidant therapy, the use of estrogens, NO synthetase inhibitors, and natural agents such as polyphenols. Unfortunately, these compounds might not help patients with end stage AD, but might hopefully slow or stop the disease process in its early stage. Nanotechnologies may prove to be a promising contribution in future AD drug delivery strategies, in particular drug carrier nano- or microsystems, which can limit the side effects of anti-Alzheimer drugs.

POEMS SYNDROME: an Update

PubMed Central

Nozza, Andrea

2017-01-01

POEMS syndrome is a rare, chronic and disabling condition. The causes of this condition remain unknown; however, chronic overproduction of proinflammatory cytokines appears to be a major contributor. Early diagnosis is essential to start treatment before the clinical state of the patient becomes compromised. A complete evaluation of the disease at its onset is critical to the treatment decision. In localized disease, curative doses of radiation (50 Gy) is the recommended therapy. On the other hand, patients with disseminated disease should be given systemic therapy. Treatment-related morbidity can be minimized by an efficient induction therapy that modifies the cytokine status, improving clinical condition and control disease severity before mobilization and transplantation. Patients not suitable for hematopoietic stem cell transplantation (HSCT) are usually treated with alkylator-based therapy. Novel agents may also offer benefits to patients with a poor performance status or renal dysfunction, and induce transplantation eligibility. Given the biological characteristics of POEMS, immunomodulatory effects and the absence of neurotoxicity, lenalidomide appears to be an effective therapy for the treatment of POEMS, both as short induction therapy before PBSCT and in non-transplant eligible patients, as it showed high response rate and durable responses. At present, however, guidelines for the diagnosis and treatment of POEMS are not available and appear advocated. PMID:28894560

Smallpox: the basics.

PubMed

Slifka, Mark K; Hanifin, Jon M

2004-07-01

Variola major is the causative agent of smallpox, a severe disease that was arguably one of the most serious human pathogens in recorded history. Humans are the only known reservoir of variola major; no known animal or insect reservoirs have been identified. Thus, after eradication of smallpox through a global immunization effort, this incredibly lethal scourge was eliminated from all corners of the globe. Despite the total eradication of naturally occurring smallpox, there are still stockpiles of smallpox virus maintained in the United States and the former Soviet Union. Unfortunately, it is impossible to know if all smallpox stocks have been accounted for or whether unknown or unreported stocks of smallpox may still exist. In the age of genetic engineering, these viruses could theoretically be modified to increase their virulence to the levels associated with smallpox itself.

Update on anti-tumor necrosis factor agents and other new drugs for inflammatory bowel disease.

PubMed

Cohen, Benjamin L; Sachar, David B

2017-06-19

The treatment of inflammatory bowel disease (IBD)-ulcerative colitis (UC) and Crohn's disease (CD)-has evolved beyond surgery with the introduction of biologic agents, primarily antibodies against mediators of inflammation and cell attraction. Anti-tumor necrosis factor (TNF) agents have been the first line treatment for moderate to severe ulcerative colitis and Crohn's disease for more than 15 years. During that time much has been learnt about how best to use these agents. This review will assess the evidence on how to optimize the use of anti-TNF agents; when and how to start treatment; how to monitor treatment and when to de-escalate it; and the potential adverse effects of these drugs. New and emerging treatments such as anti-attractants, anti-interleukins, and Janus kinase (JAK) inhibitors will also be discussed. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Tick-Borne Zoonoses in the United States: Persistent and Emerging Threats to Human Health

PubMed Central

Eisen, Rebecca J.; Kugeler, Kiersten J.; Eisen, Lars; Beard, Charles B.; Paddock, Christopher D.

2017-01-01

In the United States, ticks transmit the greatest diversity of arthropod-borne pathogens and are responsible for the most cases of all vector-borne diseases. In recent decades, the number of reported cases of notifiable tick-borne diseases has steadily increased, geographic distributions of many ticks and tick-borne diseases have expanded, and new tick-borne disease agents have been recognized. In this review, we (1) describe the known disease agents associated with the most commonly human-biting ixodid ticks, (2) review the natural histories of these ticks and their associated pathogens, (3) highlight spatial and temporal changes in vector tick distributions and tick-borne disease occurrence in recent decades, and (4) identify knowledge gaps and barriers to more effective prevention of tick-borne diseases. We describe 12 major tick-borne diseases caused by 15 distinct disease agents that are transmitted by the 8 most commonly human-biting ixodid ticks in the United States. Notably, 40% of these pathogens were described within the last two decades. Our assessment highlights the importance of animal studies to elucidate how tick-borne pathogens are maintained in nature, as well as advances in molecular detection of pathogens which has led to the discovery of several new tick-borne disease agents. PMID:28369515

Simple Fabrication of Gd(III)-DTPA-Nanodiamond Particles by Chemical Modification for Use as Magnetic Resonance Imaging (MRI) Contrast Agent

NASA Astrophysics Data System (ADS)

Nakamura, Takako; Ohana, Tsuguyori; Yabuno, Hajime; Kasai, Rumiko; Suzuki, Tetsuya; Hasebe, Terumitsu

2013-01-01

We have developed a simple and useful process for fabricating nanodiamond (ND) particles modified with an organogadolinium moiety by chemical modification for their use as a magnetic resonance imaging (MRI) contrast agent. The introduction of the organogadolinium moiety on the surface of the ND particles was performed by the condensation of ND and diethylenetriaminepentaacetic acid (DTPA) followed by treatment with GdCl3. The modified surfaces were evaluated by X-ray photoelectron spectroscopy, diffuse reflectance Fourier transform infrared spectroscopy, mass spectroscopy, and inductively coupled plasma atomic emission spectroscopy analyses. MRI experiments on the Gd-DTPA-ND particles indicated their high signal intensity on T1-weighted images.

Membrane separation of hydrocarbons

DOEpatents

Chang, Y. Alice; Kulkarni, Sudhir S.; Funk, Edward W.

1986-01-01

Mixtures of heavy oils and light hydrocarbons may be separated by passing the mixture through a polymeric membrane. The membrane which is utilized to effect the separation comprises a polymer which is capable of maintaining its integrity in the presence of hydrocarbon compounds and which has been modified by being subjected to the action of a sulfonating agent. Sulfonating agents which may be employed will include fuming sulfuric acid, chlorosulfonic acid, sulfur trioxide, etc., the surface or bulk modified polymer will contain a degree of sulfonation ranging from about 15 to about 50%. The separation process is effected at temperatures ranging from about ambient to about 100.degree. C. and pressures ranging from about 50 to about 1000 psig.

Facilitation of the flexor reflex in the cat by intrathecal injection of catecholamines

PubMed Central

Dhawan, B. N.; Sharma, J. N.

1970-01-01

1. Effects of some α- and β-adrenoceptor stimulants and antagonists were investigated on flexor reflex (FR) in chloralosed cats. 2. Noradrenaline (NA) produced facilitation of FR which was dose-dependent and reproducible and was blocked by α-adrenoceptor blocking agents. 3. Strychnine also produced facilitation of FR but the response was unaffected by α-adrenoceptor blocking agents. 4. Metaraminol and α-methyl-noradrenaline had little effect on FR but blocked the NA response. 5. β-adrenoceptor stimulants and antagonists had neither any effect on FR nor modified the NA response. 6. Vasopressin and histamine also failed to modify FR. 7. Possibility of α-adrenoceptors in the neurones integrating FR is suggested. PMID:4395376

Hydrophilic modification of polyethersulfone and its membrane characteristics

NASA Astrophysics Data System (ADS)

Liu, Haiju; Huangfu, Feng-yun; Bai, Yundong; Kong, Yuanyuan

2010-07-01

In order to enhance the hydrophilicity of PES, A series of sulfonated polyethersulfone (SPES) were readily prepared via a reaction of sulphonation which used chlorosulfonic as sulfonating agent and concentrated sulfuric acid as solvent. Sulfonation was confirmed by Fourier transform infrared spectroscopy and Thermo gravimetric analyzer. We studied forming film characteristic of SPES by phase diagram. The sulfonated PES materials were then utilized as a hydrophilic modifier for fabrication of SPES membranes. The solvent was NMP and PEG-6000 was pore-forming agent. The characteristics of membranes were studied. It was found that the surface hydrophilicity of the modified PES membranes was remarkably enhanced by contact angle. Water flux was obvious increased and antifouling performance was also improved.

Addenda to Allied Medical Publication 8, NATO Planning Guide for the Estimation of Chemical, Biological, Radiological, and Nuclear (CBRN) Casualties (AMedP-8(C)) to Consider the Impact of Medical Treatment on Casualty Estimation

DTIC Science & Technology

2013-05-01

122 I. Q Fever Model Parameters (Section C131) ....................................................128 1...needed to incorporate human response models for five biological agents not originally considered in AMedP-8(C): brucellosis, glanders, Q fever ...0103.1b should be modified to read: b. Biological agents include the causative agents of anthrax, brucellosis, glanders, Q fever , tularemia

Synthesis of mutual azo prodrugs of anti-inflammatory agents and peptides facilitated by α-aminoisobutyric acid.

PubMed

Kennedy, David A; Vembu, Nagarajan; Fronczek, Frank R; Devocelle, Marc

2011-12-02

Reported is the synthesis of azo mutual prodrugs of the nonsteroidal anti-inflammatory agents (NSAIDs) 4-aminophenylacetic acid (4-APAA) or 5-aminosalicylic acid (5-ASA) with peptides, including an antibiotic peptide temporin analogue modified at the amino terminal by an α-aminoisobutyric acid (Aib) residue. These prodrugs are designed for colonic delivery of two agents to treat infection and inflammation by the bacterial pathogen Clostridium difficile . © 2011 American Chemical Society

Morphological and Molecular Identification of the Causal Agent of Anthracnose Disease of Avocado in Kenya

PubMed Central

Monda, E.; Cheruiyot, R. C.; Mbaka, J.; Alakonya, A.

2018-01-01

Anthracnose disease of avocado contributes to a huge loss of avocado fruits due to postharvest rot in Kenya. The causal agent of this disease has not been clear but presumed to be Colletotrichum gloeosporioides as reported in other regions where avocado is grown. The fungus mainly infects fruits causing symptoms such as small blackish spots, “pepper spots,” and black spots with raised margin which coalesce as infection progresses. Due to economic losses associated with the disease and emerging information of other species of fungi as causal agents of the disease, this study was aimed at identifying causal agent(s) of the disease. A total of 80 fungal isolates were collected from diseased avocado fruits in Murang'a County, the main avocado growing region in Kenya. Forty-six isolates were morphologically identified as Colletotrichum spp. based on their cultural characteristics, mainly whitish, greyish, and creamish colour and cottony/velvety mycelia on the top side of the culture and greyish cream with concentric zonation on the reverse side. Their spores were straight with rounded end and nonseptate. Thirty-four isolates were identified as Pestalotiopsis spp. based on their cultural characteristics: whitish grey mycelium with black fruiting structure on the upper side and greyish black one on the lower side and septate spores with 3-4 septa and 2 or 3 appendages at one end. Further molecular studies using ITS indicated Colletotrichum gloeosporioides, Colletotrichum boninense, and Pestalotiopsis microspora as the causal agents of anthracnose disease in avocado. However, with this being the first report, there is a need to conduct further studies to establish whether there is coinfection or any interaction thereof. PMID:29681943

Morphological and Molecular Identification of the Causal Agent of Anthracnose Disease of Avocado in Kenya.

PubMed

Kimaru, S K; Monda, E; Cheruiyot, R C; Mbaka, J; Alakonya, A

2018-01-01

Anthracnose disease of avocado contributes to a huge loss of avocado fruits due to postharvest rot in Kenya. The causal agent of this disease has not been clear but presumed to be Colletotrichum gloeosporioides as reported in other regions where avocado is grown. The fungus mainly infects fruits causing symptoms such as small blackish spots, "pepper spots," and black spots with raised margin which coalesce as infection progresses. Due to economic losses associated with the disease and emerging information of other species of fungi as causal agents of the disease, this study was aimed at identifying causal agent(s) of the disease. A total of 80 fungal isolates were collected from diseased avocado fruits in Murang'a County, the main avocado growing region in Kenya. Forty-six isolates were morphologically identified as Colletotrichum spp. based on their cultural characteristics, mainly whitish, greyish, and creamish colour and cottony/velvety mycelia on the top side of the culture and greyish cream with concentric zonation on the reverse side. Their spores were straight with rounded end and nonseptate. Thirty-four isolates were identified as Pestalotiopsis spp. based on their cultural characteristics: whitish grey mycelium with black fruiting structure on the upper side and greyish black one on the lower side and septate spores with 3-4 septa and 2 or 3 appendages at one end. Further molecular studies using ITS indicated Colletotrichum gloeosporioides , Colletotrichum boninense , and Pestalotiopsis microspora as the causal agents of anthracnose disease in avocado. However, with this being the first report, there is a need to conduct further studies to establish whether there is coinfection or any interaction thereof.

Indian Herbal Medicines: Possible Potent Therapeutic Agents for Rheumatoid Arthritis

PubMed Central

Rathore, Brijesh; Ali Mahdi, Abbas; Nath Paul, Bhola; Narayan Saxena, Prabhu; Kumar Das, Siddharth

2007-01-01

Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology and is mainly characterized by the progressive erosion of cartilage leading to chronic polyarthritis and joint distortion. Although the exact pathogenesis of the disease has yet not been elucidated, however, studies suggest that cellular proliferation of synoviocytes result in pannus formation which damages the cartilage and bone. Recent reports also support the role of free radicals in its pathogenesis. Apart from the conventional treatment strategies using nonsteroidal anti-inflammatory drugs, disease modifying antirheumatic drugs and glucocorticoids, newer and safer drugs are continuously being searched, as long term usage of these drugs have resulted in adverse effects. Alternative medicine provides another approach for treatment of RA and currently a number of medicinal plants are under scientific evaluation to develop a novel drug. There is a dire need to investigate the complete therapeutic potential and adverse effects, if any, of these herbals for providing newer and safer treatment options with minimum side effects. In this review we have tried to explore various Indian ancient Ayurvedic, Unani and Tibbi, as also some Chinese and Korean, herbals for their potential to treat RA. PMID:18392103

Alzheimer disease therapy--moving from amyloid-β to tau.

PubMed

Giacobini, Ezio; Gold, Gabriel

2013-12-01

Disease-modifying treatments for Alzheimer disease (AD) have focused mainly on reducing levels of amyloid-β (Aβ) in the brain. Some compounds have achieved this goal, but none has produced clinically meaningful results. Several methodological issues relating to clinical trials of these agents might explain this failure; an additional consideration is that the amyloid cascade hypothesis--which places amyloid plaques at the heart of AD pathogenesis--does not fully integrate a large body of data relevant to the emergence of clinical AD. Importantly, amyloid deposition is not strongly correlated with cognition in multivariate analyses, unlike hyperphosphorylated tau, neurofibrillary tangles, and synaptic and neuronal loss, which are closely associated with memory deficits. Targeting tau pathology, therefore, might be more clinically effective than Aβ-directed therapies. Furthermore, numerous immunization studies in animal models indicate that reduction of intracellular levels of tau and phosphorylated tau is possible, and is associated with improved cognitive performance. Several tau-related vaccines are in advanced preclinical stages and will soon enter clinical trials. In this article, we present a critical analysis of the failure of Aβ-directed therapies, discuss limitations of the amyloid cascade hypothesis, and suggest the potential value of tau-targeted therapy for AD.

The Evolution of Poxvirus Vaccines

PubMed Central

Sánchez-Sampedro, Lucas; Perdiguero, Beatriz; Mejías-Pérez, Ernesto; García-Arriaza, Juan; Di Pilato, Mauro; Esteban, Mariano

2015-01-01

After Edward Jenner established human vaccination over 200 years ago, attenuated poxviruses became key players to contain the deadliest virus of its own family: Variola virus (VARV), the causative agent of smallpox. Cowpox virus (CPXV) and horsepox virus (HSPV) were extensively used to this end, passaged in cattle and humans until the appearance of vaccinia virus (VACV), which was used in the final campaigns aimed to eradicate the disease, an endeavor that was accomplished by the World Health Organization (WHO) in 1980. Ever since, naturally evolved strains used for vaccination were introduced into research laboratories where VACV and other poxviruses with improved safety profiles were generated. Recombinant DNA technology along with the DNA genome features of this virus family allowed the generation of vaccines against heterologous diseases, and the specific insertion and deletion of poxvirus genes generated an even broader spectrum of modified viruses with new properties that increase their immunogenicity and safety profile as vaccine vectors. In this review, we highlight the evolution of poxvirus vaccines, from first generation to the current status, pointing out how different vaccines have emerged and approaches that are being followed up in the development of more rational vaccines against a wide range of diseases. PMID:25853483

Ionotropic Glutamate Receptors & CNS Disorders

PubMed Central

Bowie, Derek

2008-01-01

Disorders of the central nervous system (CNS) are complex disease states that represent a major challenge for modern medicine. Although etiology is often unknown, it is established that multiple factors such as defects in genetics and/or epigenetics, the environment as well as imbalance in neurotransmitter receptor systems are all at play in determining an individual’s susceptibility to disease. Gene therapy is currently not available and therefore, most conditions are treated with pharmacological agents that modify neurotransmitter receptor signaling. Here, I provide a review of ionotropic glutamate receptors (iGluRs) and the roles they fulfill in numerous CNS disorders. Specifically, I argue that our understanding of iGluRs has reached a critical turning point to permit, for the first time, a comprehensive re-evaluation of their role in the cause of disease. I illustrate this by highlighting how defects in AMPA receptor trafficking are important to Fragile X mental retardation and ectopic expression of kainate (KA) receptor synapses contributes to the pathology of temporal lobe epilepsy. Finally, I discuss how parallel advances in studies of other neurotransmitter systems may allow pharmacologists to work towards a cure for many CNS disorders rather than developing drugs to treat their symptoms. PMID:18537642

The evolution of poxvirus vaccines.

PubMed

Sánchez-Sampedro, Lucas; Perdiguero, Beatriz; Mejías-Pérez, Ernesto; García-Arriaza, Juan; Di Pilato, Mauro; Esteban, Mariano

2015-04-07

After Edward Jenner established human vaccination over 200 years ago, attenuated poxviruses became key players to contain the deadliest virus of its own family: Variola virus (VARV), the causative agent of smallpox. Cowpox virus (CPXV) and horsepox virus (HSPV) were extensively used to this end, passaged in cattle and humans until the appearance of vaccinia virus (VACV), which was used in the final campaigns aimed to eradicate the disease, an endeavor that was accomplished by the World Health Organization (WHO) in 1980. Ever since, naturally evolved strains used for vaccination were introduced into research laboratories where VACV and other poxviruses with improved safety profiles were generated. Recombinant DNA technology along with the DNA genome features of this virus family allowed the generation of vaccines against heterologous diseases, and the specific insertion and deletion of poxvirus genes generated an even broader spectrum of modified viruses with new properties that increase their immunogenicity and safety profile as vaccine vectors. In this review, we highlight the evolution of poxvirus vaccines, from first generation to the current status, pointing out how different vaccines have emerged and approaches that are being followed up in the development of more rational vaccines against a wide range of diseases.

Ocular Behçet disease: current therapeutic approaches.

PubMed

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.

Genetic resistance to smallpox: lessons from mousepox.

PubMed

Karupiah, Gunasegaran; Panchanathan, Vijay; Sakala, Isaac G; Chaudhri, Geeta

2007-01-01

There is increased interest in understanding protective immunity to smallpox for two principal reasons. First, it is the only disease that has been successfully eradicated using a live virus vaccine and, second, there exists a potential threat of intentional or unintentional release of variola virus, the causative agent of smallpox. Although mortality rates associated with smallpox were as high as 40%, a significant subset of those infected recovered. The basis of susceptibility or resistance, and the immune parameters associated with recovery, are still unknown. Animal models of poxvirus infections are being employed to understand what constitutes an effective host response. Ectromelia virus is closely related to variola virus and it causes a disease similar to smallpox in mice. This model is well established, resistant and susceptible strains of mice are defined and four genetic loci associated with resistance have been identified. Susceptibility to infec tion and disease severity is also influenced by virus immune evasion strategies. The outcome of infection is clearly dictated by several factors including host and viral genes, both of which influence the immune response. Here we present data on one virus-encoded immune modifier and its effect on the functions of two host genetic loci associ ated with resistance.

75 FR 54496 - Diseases Associated With Exposure to Certain Herbicide Agents (Hairy Cell Leukemia and Other...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-08

... Certain Herbicide Agents (Hairy Cell Leukemia and Other Chronic B-Cell Leukemias, Parkinson's Disease and..., VA published in the Federal Register (75 FR 53202), an amendment to 38 CFR 3.309 to add hairy cell leukemia and other chronic B-cell leukemias, Parkinson's disease and ischemic heart disease to the list of...

Protection against Shiga-Toxigenic Escherichia coli by Non-Genetically Modified Organism Receptor Mimic Bacterial Ghosts.

PubMed

Paton, Adrienne W; Chen, Austen Y; Wang, Hui; McAllister, Lauren J; Höggerl, Florian; Mayr, Ulrike Beate; Shewell, Lucy K; Jennings, Michael P; Morona, Renato; Lubitz, Werner; Paton, James C

2015-09-01

Shiga-toxigenic Escherichia coli (STEC) causes severe gastrointestinal infections in humans that may lead to life-threatening systemic sequelae, such as the hemolytic uremic syndrome (HUS). Rapid diagnosis of STEC infection early in the course of disease opens a window of opportunity for therapeutic intervention, for example, by administration of agents that neutralize Shiga toxin (Stx) in the gut lumen. We previously developed a recombinant bacterium that expresses a mimic of the Stx receptor globotriaosyl ceramide (Gb3) on its surface through modification of the lipopolysaccharide (A. W. Paton, R. Morona, and J. C. Paton, Nat Med 6:265-270, 2000, http://dx.doi.org/10.1038/73111). This construct was highly efficacious in vivo, protecting mice from otherwise fatal STEC disease, but the fact that it is a genetically modified organism (GMO) has been a barrier to clinical development. In the present study, we have overcome this issue by development of Gb3 receptor mimic bacterial ghosts (BGs) that are not classified as GMOs. Gb3-BGs neutralized Stx1 and Stx2 in vitro with high efficiency, whereas alternative Gb3-expressing non-GMO subbacterial particles (minicells and outer membrane blebs) were ineffective. Gb3-BGs were highly efficacious in a murine model of STEC disease. All mice (10/10) treated with Gb3-BGs survived challenge with a highly virulent O113:H21 STEC strain and showed no pathological signs of renal injury. In contrast, 6/10 mice treated with control BGs succumbed to STEC challenge, and survivors exhibited significant weight loss, neutrophilia, and histopathological evidence of renal damage. Thus, Gb3-BGs offer a non-GMO approach to treatment of STEC infection in humans, particularly in an outbreak setting. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Protection against Shiga-Toxigenic Escherichia coli by Non-Genetically Modified Organism Receptor Mimic Bacterial Ghosts

PubMed Central

Paton, Adrienne W.; Chen, Austen Y.; Wang, Hui; McAllister, Lauren J.; Höggerl, Florian; Mayr, Ulrike Beate; Shewell, Lucy K.; Jennings, Michael P.; Morona, Renato; Lubitz, Werner

2015-01-01

Shiga-toxigenic Escherichia coli (STEC) causes severe gastrointestinal infections in humans that may lead to life-threatening systemic sequelae, such as the hemolytic uremic syndrome (HUS). Rapid diagnosis of STEC infection early in the course of disease opens a window of opportunity for therapeutic intervention, for example, by administration of agents that neutralize Shiga toxin (Stx) in the gut lumen. We previously developed a recombinant bacterium that expresses a mimic of the Stx receptor globotriaosyl ceramide (Gb3) on its surface through modification of the lipopolysaccharide (A. W. Paton, R. Morona, and J. C. Paton, Nat Med 6:265–270, 2000, http://dx.doi.org/10.1038/73111). This construct was highly efficacious in vivo, protecting mice from otherwise fatal STEC disease, but the fact that it is a genetically modified organism (GMO) has been a barrier to clinical development. In the present study, we have overcome this issue by development of Gb3 receptor mimic bacterial ghosts (BGs) that are not classified as GMOs. Gb3-BGs neutralized Stx1 and Stx2 in vitro with high efficiency, whereas alternative Gb3-expressing non-GMO subbacterial particles (minicells and outer membrane blebs) were ineffective. Gb3-BGs were highly efficacious in a murine model of STEC disease. All mice (10/10) treated with Gb3-BGs survived challenge with a highly virulent O113:H21 STEC strain and showed no pathological signs of renal injury. In contrast, 6/10 mice treated with control BGs succumbed to STEC challenge, and survivors exhibited significant weight loss, neutrophilia, and histopathological evidence of renal damage. Thus, Gb3-BGs offer a non-GMO approach to treatment of STEC infection in humans, particularly in an outbreak setting. PMID:26099582

Nuclear PTEN localization contributes to DNA damage repair in Endometrial cancer and could have a diagnostic benefit for therapeutic management of the disease.

PubMed

Mukherjee, Ananda; Patterson, Amanda L; George, Jitu W; Carpenter, Tyler J; Madaj, Zachary B; Hostetter, Galen; Risinger, John I; Teixeira, Jose M

2018-06-13

Endometrial adenocarcinoma (EndoCA) is the most common gynecological cancer type in the US, and its incidence is increasing. The majority of patients are disease-free after surgical resection of stage I tumors, which is often followed by radiation therapy, but most patients with advanced disease recur and have a poor prognosis, largely because the tumors become refractory to cytotoxic chemotherapies. PTEN, a commonly mutated tumor suppressor in EndoCAs, is well known for its ability to inhibit the AKT/mTOR signaling pathway. Nuclear functions for PTEN have been proposed as well, but whether those affect EndoCA development, progression, or outcomes is not well understood. Using immunohistochemistry, nuclear PTEN expression was observed in approximately half of EndoCA patient tumors, independent of grade and cytoplasmic PTEN expression. Higher levels of the DNA damage response (DDR) marker, yH2AX, were observed by immunohistochemistry and immunofluorescence in human EndoCA tumor sections that were PTEN-negative, in murine EndoCA tissues that were genetically modified to be PTEN-null, and in Ishikawa EndoCA cells, which do not express endogenous PTEN. Over-expression of exogenous PTEN-WT or PTEN-NLS, a modified PTEN with an added nuclear localization signal, significantly improved both DDR and G2/M transition in Ishikawa cells treated with a DNA damaging agent. Whereas PARP inhibition with Olaparib was not as effective in Ishikawa cells expressing native or PTEN-NLS, inhibition with Talazoparib was not affected by PTEN overexpression. These results suggest that nuclear PTEN subcellular localization in human EndoCA could be diagnostic when considering DDR therapeutic intervention. Copyright ©2018, American Association for Cancer Research.

The role of adalimumab in rheumatic and autoimmune disorders: comparison with other biologic agents

PubMed Central

Reimold, Andreas M

2012-01-01

Adalimumab (ADA) is a biologic medication that dampens inflammatory pathways by binding to the cytokine tumor necrosis factor alpha. The US Food and Drug Administration has approved ADA as a medication for use in rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, psoriasis, and juvenile idiopathic arthritis. This year marks 10 years of clinical experience with ADA. Long-term extension studies of some of the initial clinical trials, as well as data from large patient registries, are demonstrating ongoing benefit for responders. Potential side effects such as increased risk of infection, lymphoma, congestive heart failure, and demyelination continue to be examined, as the available data are not unanimous in showing an increase in incidence. In balancing both the advantages and the disadvantages of using ADA, the drug’s overall effectiveness and its availability for use in patients with hepatic or renal comorbidities are weighed against the high cost. ADA is expected to have a leading role in the treatment of rheumatoid arthritis and other inflammatory conditions for years to come. Future studies will need to address the optimal sequence of disease-modifying antirheumatic drugs and biologics to use, combinations of disease-modifying antirheumatic drugs and biologics, and head-to-head comparisons of biologics in clinical trials. For those who go into clinical remission on an anti-tumor necrosis factor medication, unanswered questions remain about identifying the patients who can maintain the remission off all drugs, or at least off injected medication. Given the cost of biologic drugs, even studies that increase the interval between drug doses in well-controlled patients could provide financial benefits. PMID:27790010